Clinical Handbook of Psychotropic Drugs

Ric M. Procyshyn

Kalyna Z. Bezchlibnyk-Butler J. Joel Jeffries

(Editors)

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

HOW TO USE THIS BOOK

The Clinical Handbook of Psychotropic Drugs uses color coding and icons for intuitive navigation:

– Bluesectionscontaingeneralinformationondrugs/treatmentsandtheir

availability.

– Greensectionscoverdrugactionanddosing.

– Redsectionsoutlinewarningsandprecautions.

– Orangesectionsdetailpatient-relatedinformation,suchasconsiderationsfor

special populations, nursing and patient advice.

This page provides a summary of the colors and icons used.

At the end of each chapter, additional useful sources of information are listed as

Further Reading

Classi cation, De nition

Product Availability

Indications

General Comments

Pharmacology / Mechanisms of Action

Pharmacology

Pharmacological & Psychiatric E ects

Dosing

Pharmacokinetics

Onset and Duration of Action

Adverse E ects

Contraindications

Discontinuation Syndrome

Precautions

Toxicity

Food Interactions

Drug Interactions

Lab Tests / Monitoring

Pediatric Considerations

Geriatric Considerations

Use in Pregnancy

Medicolegal Issues

Nursing Implications, Treatment

Warnings and Precautions

General Information / Availability

Patient-Related Issues

Switching, Augmentation Strategies Patient Instructions

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Clinical Handbook of Psychotropic Drugs

Ric M. Procyshyn, BScPharm, MSc, PharmD, PhD(A, B) (Principal Editor) Kalyna Z. Bezchlibnyk-Butler, BScPhm, FCSHP (Co-Editor)

J. Joel Je ries, MB, FRCPC, DFCPA(C) (Co-Editor)

The Editors wish to acknowledge contributions from the following chapter co-editors:

Ana Aleksic, MScPharm(A) (Antipsychotic-Induced Extrapyramidal Side E ects and Their Management)

Alasdair Barr, PhD(D) (Drugs of Abuse)

Agnieszka K. Biala, MPharm, PhD(E) (Sex-Drive Depressants)

Andrius Baskys, MD, PhD(F) (Drugs for Treatment of Dementia, Pharmacogenomic Information for Common Psychotropic Drugs) Sue Corrigan, BScPharm, ACPR, PharmD(G) (Antipsychotics)

Robert Dickey, MD, FRCPC(C) (Sex-Drive Depressants)

Lynda Eccott, BSc, MScPharm(H) (Natural Health Products)

Dean Elbe, BScPharm, PharmD, BCPP(I) (Drugs for ADHD)

Katelyn Halpape, BSP, ACPR, PharmD, BCPP(J) (Mood Stabilizers)

Gary Hasey, MD, FRCPC, MSc(K) (Repetitive Transcranial Magnetic Stimulation)

Steven Kary, BSP, ACPR(L) (Mood Stabilizers)

David D. Kim, MSc(D) (Antidepressants, Drugs of Abuse)

Barry A. Martin, MD, FRCPC(C) (Electroconvulsive Therapy)

Melanie McLeod, BSP, ACPR, PharmD, BCPP(M) (Mood Stabilizers)

Reza Ra zadeh, BScPharm, RPh, ACPR, BCPP(G) (Antipsychotics, Treatment of Substance Use Disorders)

Christian G. Schütz, MD, PhD, MPH, FRCPC(N) (Treatment of Substance Use Disorders)

Jacky T. P. Siu, BScPharm, ACPR, PharmD(G) (Anxiolytics, Hypnotics/Sedatives)

Fidel Vila-Rodriguez, MD, FRCPC, FAPA(A) (Electroconvulsive Therapy)

Vivian Yih, BScPharm, PharmD(O) (Antidepressants)

Bree Zehm, PharmD(P) (Antidepressants)

Tony Zhou, PharmD(H) (Drug Interactions)

(A) Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada; (B) British Columbia Mental Health & Addictions Research Institute, Vancouver, BC, Canada; (C) Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, ON, Canada; (D) Department of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia, Vancouver, BC, Canada; (E) Department of Pediatrics, Canadian Pharmacogenomics Network for Drug Safety, University of British Columbia, Vancouver, BC, Canada; (F) Riverside Psychiatric Medical Group Memory Disorders Program, Riverside, CA, USA; (G) Lower Mainland Pharmacy Services and Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada; (H) Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada; (I) Children’s & Women’s Mental Health Programs, BC Mental Health and Substance Use Services/BC Children’s Hospital, Vancouver, BC, Canada; (J) College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada; (K) Departments of Psychiatry and Behavioural Neurosciences, Biomedical, Electrical and Computer Engineering, McMaster University, Hamilton, ON, Canada; (L) Saskatoon Cancer Centre, Saskatoon, SK, Canada; (M) Department of Psychiatry, Saskatchewan Health Authority, Regina, SK, Canada;

(N) Institute of Mental Health, Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada, and Burnaby Center for Mental Health & Addiction, Burnaby, BC, Canada; (O) Fraser Health Authority Mental Health and Substance Use Tertiary Older Adult Program, Vancouver, BC, Canada; (P) Department of Pharmacy, Island Health, Victoria, BC, Canada

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Library of Congress Cataloging in Publication information for the print version of this book is available via the Library of Congress Marc Database under the LC Control Number 2019936599

Canadian Cataloging-in-Publication Data

Main entry under title:

Clinical handbook of psychotropic drugs

21st rev. ed.

Includes bibliographical references and index

ISBN 978-0-88937-474-4

1. Psychotropic drugs – Handbooks, manuals, etc. I. Bezchlibnyk-Butler, Kalyna Z., 1947–.

C93-094102-0

The e-book, including all its individual chapters, is protected under international copyright law. The unauthorized use or distribution of copyrighted or proprietary content is illegal and could subject the purchaser to substantial damages. The user agrees to recognize and uphold the copyright.

License Agreement

The purchaser is granted a single, nontransferable license for the personal use of the e-book and all related les.

Making copies or printouts and storing a backup copy of the e-book on another device is permitted for private, personal use only.

Other than as stated in this License Agreement, you may not copy, print, modify, remove, delete, augment, add to, publish, transmit, sell, resell, create derivative works from, or in any way exploit any of the e-book’s content, in whole or in part, and you may not aid or permit others to do so. You shall not: (1) rent, assign, timeshare, distribute, or transfer all or part of the e-book or any rights granted by this License Agreement to any other person; (2) duplicate the e-book, except for reasonable backup copies; (3) remove any proprietary or copyright notices, digital watermarks, labels, or other marks from the e-book or its contents; (4) transfer or sublicense title to the

e-book to any other party.

These conditions are also applicable to any audio or other les belonging to the e-book. Should the print edition of this book include electronic supplementary material then all this material (e.g., audio, video, pdf les) is also available in the e-book edition.

The authors and publisher have made every e ort to ensure that drug selections and dosages suggested in this text are in accord with current recommendations and practice at the time of publication. However, due to changing government regulations, continuing research, and changing information concerning drug therapy and reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage, or for added precautions. The authors and publisher disclaim any responsibility for any consequences which may follow from the use of information presented in this book.

Format: PDF

ISBN 978-0-88937-561-1 (print), 978-1-61676-561-3 (pdf) https://dx.doi.org/10.1027/00561-000

II. Je ries, J. Joel, 1939–. RM315.C55 2015

http://www.hogrefe.com

PUBLISHING OFFICES

USA: Hogrefe Publishing Corporation, 7 Bul nch Place, Suite 202, Boston, MA 02114

Phone (866) 823-4726, Fax (617) 354-6875; E-mail customerservice@hogrefe.com EUROPE: Hogrefe Publishing GmbH, Merkelstr. 3, 37085 Göttingen, Germany

Phone +49 551 99950-0, Fax +49 551 99950-111; E-mail publishing@hogrefe.com

SALES & DISTRIBUTION

USA: Hogrefe Publishing, Customer Services Department,

30 Amberwood Parkway, Ashland, OH 44805

Phone (800) 228-3749, Fax (419) 281-6883; E-mail customerservice@hogrefe.com UK: Hogrefe Publishing, c/o Marston Book Services Ltd.,

160 Eastern Ave., Milton Park, Abingdon, OX14 4SB, UK

Phone +44 1235 465577, Fax +44 1235 465556; E-mail direct.orders@marston.co.uk EUROPE: Hogrefe Publishing, Merkelstr. 3, 37085 Göttingen, Germany

Phone +49 551 99950-0, Fax +49 551 99950-111; E-mail publishing@hogrefe.com

OTHER OFFICES

CANADA: Hogrefe Publishing, 660 Eglinton Ave. East, Suite 119-514,

Toronto, Ontario, M4G 2K2

SWITZERLAND: Hogrefe Publishing, Länggass-Strasse 76, CH-3000 Bern 9

Hogrefe Publishing

Incorporated and registered in the Commonwealth of Massachusetts, USA, and in Göttingen, Lower Saxony, Germany

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

INTRODUCTION

The Clinical Handbook of Psychotropic Drugs is a user-friendly and practical resource guide for health care practitioners working in any setting where psychotropic drugs are utilized. Its content is derived from various forms of published literature (including randomized controlled trials, scienti c data such as pharmacokinetic trials, cohort trials, case series, and case reports) as well as from leading clinical experts. The handbook is continually updated as the scienti c literature evolves, so we can provide current evidence-based and clinically relevant information to optimize patient care. New sections, periodically added, re ect changes in therapy and in current practice.

For this 23rd edition, we have again revised and updated the book throughout and included a number of new treatments and formulations. We have added sections on the NMDA receptor antagonist antidepressant esketamine as well as the 5-HT2A inverse agonist antipsychotic pimavanserin. The antipsychotics augmentation strategies have been comprehensively revised. The treatment options for extrapyramidal side e ects have been expanded, as have the pharmacogenomics-based dosage adjustment recommendations and guidelines. And the developments don’t stop there. A potential breakthrough treatment has been given the go-ahead: Brexanolone IV injection was approved by the FDA for treatment of postpartum depression on March 19, 2019, and expected to become available in the US by late June 2019. Little information is available on this thus far but we will keep a close eye on this as well as all other developments in psychopharmacology to bring further updates to users of the Clinical Handbook.

As in previous editions, charts and tables of comparisons are employed to enable the reader to have quick access to informa- tion.

Both American and Canadian trade names are used in the text. Though plasma levels are given in SI units, conversion rates to Imperial US units are available in the text.

Given that changes may occur in a medication’s indications, and di erences are seen among countries, speci c “indications” listed in this text as “approved” should be viewed in conjunction with product monographs approved in your jurisdiction of interest.

Dose comparisons and plasma levels are based on scienti c data. However, it is important to note that some patients will respond to doses outside the reported ranges. Age, sex, and the medical condition of the patient must always be taken into consideration when prescribing any psychotropic agent.

Patient Information Sheets for most drug categories are provided as printable pdf les to facilitate education/counselling of patients receiving these medications. For details, please see p. 440.

For those who like the convenience of electronic resources, the Clinical Handbook of Psychotropic Drugs is also available as an online version that provides even quicker access to all the information in the handbook, with some added extras: (1) An auto- completion powered search function, (2) browse features for generic names, trade names, indications, and interacting agents, (3) column-selector enhancement of comparison charts (dosages, side e ects, pharmacokinetics, interactions, etc.) that allows you to choose which information is displayed, and (4) hundreds of additional references. Further details on this can be found at https://chpd.hogrefe.com/

On behalf of the editors, I would like to express my abundant gratitude to each of the contributors. The Clinical Handbook of Psychotropic Drugs would not be possible if it were not for their collective expertise, investment of time, and commitment to patient care. Over the years, many readers have asked challenging questions and provided useful feedback regarding the content and format of the handbook. This input is critical to keeping this handbook current, accurate, and relevant. Please feel free to e-mail me at the address below with your comments and questions.

E-mail: rprocyshyn@bcmhs.bc.ca

Ric M. Procyshyn

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

http://www.hogrefe.com

Clinical Handbook of Psychotropic Drugs Online

The Clinical Handbook of Psychotropic Drugs Online is

the full-text online version of the popular Clinical Handbook of Psychotropic Drugs. It retains all the practical features for which the Clinical Handbook is renowned and makes the information even more easily accessible.

As in the print edition, instantly recognizable icons and color coding allow you to nd at a glance the information you seek. But the CHPD Online version offers much more. Unique features that allow even quicker access to the wealth of information include:

• Auto-completion powered search function

• Browse features for Generic Names, Trade Names, Indications, and Interacting Agents

• Column-selector enhancement of comparison charts that allows you to choose which information is displayed

• Hundreds of additional references

• Literature hot links for quick access to further reading

Access to the Clinical Handbook of Psychotropic Drugs ONLINE is available by subscription.

For details see https://chpd.hogrefe.com

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Antidepressants 2 Selective Serotonin Reuptake Inhibitors (SSRI) 3

Norepinephrine Dopamine Reuptake Inhibitor (NDRI) 17 Serotonin Norepinephrine Reuptake Inhibitors (SNRI) 23 Serotonin-2 Antagonists/Reuptake Inhibitors (SARI) 31 Serotonin-1A Partial Agonist/Serotonin Reuptake

Inhibitor (SPARI) 37 Serotonin Modulator and Stimulator (SMS) 41 Noradrenergic/Speci c Serotonergic Antidepressants

(NaSSA) 46 Nonselective Cyclic Antidepressants 50 Monoamine Oxidase Inhibitors 60 Reversible Inhibitor of MAO-A (RIMA) 60 Irreversible Monoamine Oxidase (A&B) Inhibitors (MAOIs) 64 Irreversible MAO-B Inhibitor 70 NMDA Receptor Antagonist 73 E ects of Antidepressants on Neurotransmitters/

Receptors 77 Pharmacological E ects of Antidepressants on

Neurotransmitters/Receptors 78 Frequency of Adverse Reactions to Antidepressants at

Therapeutic Doses 79 Antidepressant Doses and Pharmacokinetics 82 Switching Antidepressants 85 Antidepressant Augmentation Strategies 87

Electroconvulsive Therapy (ECT) 93 Bright Light Therapy (BLT) 100 Repetitive Transcranial Magnetic Stimulation (rTMS) 104

Antipsychotics 109 First-Generation Antipsychotics/FGAs 115

Second-Generation Antipsychotics/SGAs 132 Third-Generation Antipsychotics/TGAs 161 5-HT2A Inverse Agonist Antipsychotic 174 E ects of Antipsychotics on Neurotransmitters/Receptors 176 Pharmacological E ects of Antipsychotics on

Neurotransmitters/Receptor Subtypes 177 Relative Tolerability Pro les of Antipsychotics 178 Frequency (%) of Adverse Reactions to Antipsychotics

at Therapeutic Doses 180 Antipsychotic Doses and Pharmacokinetics (Oral and

Short-Acting Injections) 182 Comparison of Long-Acting IM Antipsychotics 191 Switching Antipsychotics 197 Antipsychotic Augmentation Strategies 198

Nicotine/Tobacco 363 203 Treatment of Substance Use Disorders 367

Benzodiazepines 222

TABLE OF CONTENTS

Extrapyramidal Adverse E ects of Antipsychotics Treatment Options for Extrapyramidal Side E ects E ects on Extrapyramidal Symptoms

Comparison of Agents for Treating Acute

Extrapyramidal Side E ects and Tardive Dyskinesia Doses and Pharmacokinetics of Agents for Treating

Extrapyramidal Side E ects and Tardive Dyskinesia

Anxiolytic (Antianxiety) Agents

208 Acamprosate 369

214 Disul ram 371 Naltrexone 373 Buprenorphine 377

215 Methadone 380 Pharmacotherapy for Nicotine/Tobacco Use Disorder 385

217 Comparison of Treatments for Nicotine/Tobacco Use

221 Disorder 387

Comparison of the Benzodiazepines Buspirone

Hypnotics/Sedatives

L-Tryptophan

Comparison of Hypnotics/Sedatives

Mood Stabilizers

229 Unapproved Treatments of Psychiatric Disorders 391 234 Adrenergic Agents 392

Anti-in ammatory Agents 395 238 Dopaminergic Agents 398 244 GABA Agents/Anticonvulsants 400 246 Hormones 402 NMDA Agents 406 253 5-HT3 Antagonists 409 253 Miscellaneous 409

Lithium

Anticonvulsants 262 Comparison of Anticonvulsants 279 Frequency of Adverse Reactions to Mood Stabilizers

at Therapeutic Doses 287

Drugs for ADHD 289 Psychostimulants 289

Natural Health Products 412 Ginkgo Biloba 412 Kava Kava 414 Melatonin 415 Omega-3 Polyunsaturated Fatty Acids 416 S-Adenosyl-L-Methionine (SAMe) 419

Atomoxetine

Comparison of Drugs for ADHD

α2 agonists

Augmentation Strategies in ADHD 311

Drugs for Treatment of Dementia 314 Cholinesterase Inhibitors 314

Memantine 320 Comparison of Drugs for Treatment of Dementia 323

299 St. John’s Wort 420 302 Valerian 421 307 Vitamins 423

Sex-Drive Depressants

Comparison of Sex-Drive Depressants

Genotype E ects on Pharmacokinetic Properties

of Psychotropic Drugs 426

Pharmacogenomics-Based Dose Adjustment Recommendations and Guidelines 427

Drugs of Abuse 335 Alcohol 337

Stimulants 341 Hallucinogens 346 Opioids 354

Glossary 435 Drug Use in Pregnancy and E ects on Breast Milk 439

Patient Information Sheets 440 Appendix: Neuroscience-Based Nomenclature (NbN) 441

Index of Drugs 445

328 Genotype E ects on Pharmacokinetic Properties

331 of Psychotropic Drugs 432

Antipsychotic-Induced Extrapyramidal Side E ects

and Their Management 203

Inhalants/Aerosols

Gamma-hydroxybutyrate (GHB)/Sodium Oxybate 360 Flunitrazepam (Rohypnol) 362

359

Pharmacogenomic Information for Common

Psychotropic Drugs 425

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Classi cation

Pharmacological Class

ANTIDEPRESSANTS

• Antidepressantscanbeclassi edasfollows:

Examples

Page

Citalopram, escitalopram, uoxetine, uvoxamine, paroxetine, sertraline Bupropion

Seep.3 See p. 17

Desvenlafaxine, duloxetine, levomilnacipran, venlafaxine Nefazodone, trazodone

Vilazodone

See p. 23 See p. 31 See p. 37

Vortioxetine

Mirtazapine

Amitriptyline, desipramine, imipramine, maprotiline, nortriptyline

See p. 41 See p. 46 See p. 50

Moclobemide

Phenelzine, tranylcypromine

See p. 60 See p. 64

Selegiline

See p. 70

Esketamine

See p. 73

Brexanolone

Cyclic Antidepressants (*)

Selective Serotonin Reuptake Inhibitors (SSRI)

Norepinephrine Dopamine Reuptake Inhibitor (NDRI)

Selective Serotonin-Norepinephrine Reuptake Inhibitor (SNRI) Serotonin-2 Antagonists/Serotonin Reuptake Inhibitors (SARI) Serotonin-1A Partial Agonist/Serotonin Reuptake Inhibitor (SPARI) Serotonin Modulator and Stimulator (SMS)

Noradrenergic/Speci c Serotonergic Agent (NaSSA)

Nonselective Cyclic Agents (Mixed Reuptake Inhibitor/Receptor Blockers)

Monoamine Oxidase Inhibitors

Reversible MAO-A Inhibitor (RIMA) Irreversible MAO (A&B) Inhibitors (MAOIs) Irreversible MAO-B Inhibitor

NMDA Receptor Antagonist GABAA Receptor Modulator(**)

(*) Cyclic antidepressants are currently classi ed according to their effect on brain neurotransmitters. These neurotransmitter effects determine the antidepressants’ spectrum of activity and adverse effects (see table p. 77),

this chapter. Brexanolone IV injection (trade name: Zulresso) was approved by the FDA for the treatment of postpartum depression (PPD) on March 19, 2019, and expected to become available in the US in late June 2019. It is the rst and thus far only medication speci cally approved for this indication. Findings from three multicenter trials showed it to rapidly reduce symptoms in moderate–severe PPD.

(**) Not dealt with speci cally in

General Comments

• Antidepressantsareassociatedwithasmall(2–3%)riskofhostilityorsuicidalideationandassociatedbehaviorsinchildren,adolescents,andyoung adults (aged up to 24 years). Risk for suicide should be closely assessed and monitored during the initial weeks of antidepressant therapy

• Inpatientspresentingwithdepressionandahighriskofsuicide,treatmentselectionshouldconsidersafetyinoverdose(i.e.,considerusingnewer antidepressant agents rather than nonselective cyclic and MAOI antidepressants). Prescription quantities should be consistent with safe patient care

• Some antidepressants are associated with restlessness or psychomotor agitation prior to seeing any change in core symptoms of depression. On average, all antidepressants are equally e cacious at reducing symptoms of depression though some randomized double-blind, controlled trials and systematic reviews suggest otherwise. Overall e ects of antidepressants are modest when the e ects of publication bias are considered.

Compared to placebo, the e ect size of antidepressant treatment is reported as 0.31

• Results from the most comprehensive network meta-analysis and systematic review of adult major depression trials to date suggest that, al-

though there were very few overall di erences amongst the 21 antidepressants reviewed, escitalopram, sertraline, paroxetine, mirtazapine, and agomelatine had a relatively higher response rate and lower dropout rate.[1] However, the authors make it clear that there are important limitations to these results – they may only help inform as to initial treatment choice, they do not re ect longer term tolerability or bene t with respect to functionality, and they do not account for individual factors which are typically used to help guide treatment selection in clinical practice

• Prophylaxis of depression is most e ective if the therapeutic dose is maintained; continued therapy with all classes of antidepressants has been shown to signi cantly reduce risk of relapse

• Di erent antidepressant classes may be combined in patients with a partial response or in refractory cases; however, combinations should be assessed for potential interactions such as serotonin syndrome; additional monitoring should be implemented when necessary

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Therapeutic Effects

Product Availability∗

• Tolerance (tachyphylaxis or “poop-out” syndrome) has been reported in 10–20% of patients on antidepressants, despite adherence to therapy. Possible explanations include adaptations in the CNS, increased disease severity or pathogenesis, loss of placebo e ect, unrecognized rapid-cycling, incorrect diagnosis, comorbid substance use, anxiety disorders, ADHD or eating disorders [Management: check compliance; adjust dosage; switch to an alternate antidepressant (p. 85) or utilize augmentation strategies (p. 87)]

• Elevation of mood, improved appetite and sleep patterns, increased physical activity, improved clarity of thinking, better memory; decreased feelings of guilt, worthlessness, helplessness, inadequacy, decrease in delusional preoccupation and ambivalence

Selective Serotonin Reuptake Inhibitors (SSRI)

Generic Name

Chemical Class

Trade Name(A)

Dosage Forms and Strengths

Citalopram

Phthalane derivative

Celexa

Tablets/capsules: 10 mg, 20 mg, 30 mg(C), 40 mg Oral solution(B) : 10 mg/5 mL

Escitalopram

Phthalane derivative

Cipralex(C), Lexapro(B) Cipralex Meltz(C)

Tablets/capsules: 5 mg(B), 10 mg, 20 mg Oral solution: 5 mg/5 mL(B) Orodispersible tablets: 10 mg, 20 mg

Fluoxetine

Bicyclic

Prozac, Sarafem(B) Prozac Weekly(B)

Capsules: 10 mg, 20 mg, 40 mg(B) Tablets(B): 10 mg, 15 mg, 20 mg, 60 mg Oral solution: 20 mg/5 mL Delayed-release pellets 90 mg(B)

Fluoxetine/olanzapine

Bicyclic

Symbyax

Capsules(B): Fluoxetine 25mg with 3 mg, 6 mg or 12 mg olanzapine; uoxetine 50 mg with 6 mg or 12 mg olanzapine

Fluvoxamine(D)

Monocyclic

Luvox Luvox CR

Tablets: 25 mg(B), 50 mg, 100 mg Extended-release capsules(B): 100mg, 150mg

Paroxetine hydrochloride

Phenylpiperidine

Paxil Paxil CR

Tablets: 10 mg, 20 mg, 30 mg, 40 mg

Oral suspension(B) : 10 mg/5 mL

Controlled-release tablets: 12.5 mg, 25 mg, 37.5 mg(B)

Paroxetine mesylate(B)

Phenylpiperidine

Pexeva

Tablets(B): 10 mg, 20 mg, 30 mg, 40 mg

Brisdelle

Capsules(B) : 7.5 mg

Sertraline

Tetrahydronaphthylmethylamine

Zoloft

Capsules/tablets: 25 mg, 50 mg, 100 mg, 150mg(B), 200mg(B) Oral solution: 20 mg/mL(B)

∗ Refer to Health Canada’s Drug Product Database or the FDA’s Drugs@FDA for the most current availability information (A) Generic preparations may be available, in the USA

(B) Not marketed in Canada,

(D) Not approved for depression

Indications‡

( approved)

Major depressive disorder (MDD)

MDD, recurrent: Prophylaxis

Bulimia nervosa ( uoxetine and sertraline)

‡ Indications listed here do not necessarily apply to all SSRIs or all countries. Please refer to a country’s regulatory database (e.g., US Food and Drug Administration, Health Canada Drug Product Database) for the most current availability information and indications

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 3 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

General Comments

Selective Serotonin Reuptake Inhibitors (SSRI) (cont.)

Obsessive-compulsive disorder (OCD) ( uvoxamine, uoxetine, paroxetine, escitalopram, and sertraline) Panic disorder with or without agoraphobia (paroxetine, sertraline, uoxetine)

Social anxiety disorder (paroxetine, sertraline)

Posttraumatic stress disorder (PTSD) (paroxetine, sertraline)

Premenstrual dysphoric disorder (paroxetine, sertraline)

Generalized anxiety disorder (GAD) (escitalopram, paroxetine)

Depressive episodes associated with bipolar I disorder and treatment-resistant depression ( uoxetine/olanzapine combination – Symbyax) Moderate-to-severe vasomotor symptoms of menopause (low-dose paroxetine mesylate (LDPM); the only SSRI approved speci cally for this indica- tion in the US)

• Dysthymia

• Depression,atypical

• MDDinpatientswithcomorbidmedicaldisorder(i.e.,poststrokedepressionandcrying,myocardialinfarction)orpsychiatricillness

• Preventionofpeginterferon-α2a-associateddepressioninhepatitisCinfectedindividualswithoutpreviouspsychiatricillness

• Binge-eatingdisorder:Double-blindstudiessuggeste cacyof uvoxamineandcitalopram

• Dementiaandborderlinepersonalitydisorder:Treatmentofself-injuriousbehavior,aggression,impulsivebehavior,andbehaviordisturbances

• Smokingcessationandwithdrawalfromdrugs,includingalcohol–variableresponsereported

• Chronicfatiguesyndrome:Openlabeltrialshaveshown70%e ectivenessbutrandomizedcontrolledtrialshavenotreplicatedthis

• Bodydysmorphicdisorder(BDD)–recommendedasa rst-linemedicationforBDD,includingdelusionalBDD.Relativelyhighdosesmaybeneeded

and at least 12 weeks duration may be necessary to determine e cacy

• Postpartumdepression–areviewofrandomizedtrialsfailedtoshowasuperiorityofSSRIsoverothertreatments

• Pervasive developmental disorder (autism) in adults ( uoxetine)[2] – limited evidence of e cacy

• Pain management (e.g., diabetic neuropathy, arthritis), phantom limb pain ( uoxetine, sertraline), Raynaud’s phenomenon ( uoxetine), brositis,

and bromyalgia ( uoxetine) – data con icting as to e cacy

• Trichotillomania,excoriationdisorder( uoxetine)

• Prematureejaculation

• Enuresis,functional–datacontradictoryastoe cacy;casereportsofbedwettinginchildrentreatedwithSSRIs

• Schizophrenia,negativesymptoms( uoxetine)[3]

• Tardivedyskinesia:Casereportssuggest uvoxaminemaybehelpfulduetoitspotentsigma-1receptoragonistactivity[4]

• Malignancy,cholestasisorchronickidneydisease-relatedpruritusunresponsivetostandardtreatment(paroxetine,sertraline)

• SSRIs have been associated with increased suicidal ideation, hostility, and psychomotor agitation in clinical trials involving children, adolescents, and young adults (up to 24 years old). This e ect was not seen in those aged 24–65 and SSRIs were preventative for these concerns in those over the age of 65. Monitor all patients for worsening of depression and suicidal thinking

• IntheSTAR*Dtrial,patientswithnonpsychoticmajordepressivedisorderreceived1–4successiveacutetreatmentswiththeinitialtreatmentbeing citalopram. Approximately 30% of these patients reached remission after 10 weeks of therapy (average dose = 42 mg) and 50% had a response

• Exact mechanism of antidepressant action unknown; SSRIs, through inhibition of serotonin reuptake, increase concentrations of serotonin in the synapse, which causes downregulation of post-synaptic receptors (e.g., 5-HT2A). Some SSRIs can also a ect other neurotransmitters, e.g., some SSRIs also inhibit the reuptake of norepinephrine (i.e., uoxetine, paroxetine), while others inhibit the reuptake of dopamine (i.e., sertraline)

• Seep.82

• SSRIs are thought to have a at dose-response curve (i.e., most patients respond to the initial or even low doses, such as 5–10 mg of uoxetine).

Not recommended to increase dose until steady state has been reached rst (4 weeks for uoxetine and 1–2 weeks for other drugs). However, a study published in 2016 contradicts such ndings – shows that a higher dose for MDD is associated with a slightly increased likelihood of response, although this is at the cost of reduced tolerability

Pharmacology

Dosing

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Pharmacokinetics

Onset & Duration of Action

Adverse Effects

• Patientsmaintainedon uoxetine20mg/daymaybechangedtoProzacWeekly90mg/week,starting7daysafterthelast20mg/daydose

• Dosageshouldbedecreased(by50%)inpatientswithsigni canthepaticimpairment,asplasmalevelscanincreaseupto3-fold

• In kidney impairment, sertraline levels may increase by 50%; use 50% of the standard dose of paroxetine if CrCl is 10–50 mL/min, and 25% of the

standard dose if CrCl is less than 10mL/min

• HigherdosesmayberequiredinthetreatmentofOCD,eatingdisorders,andPTSD

• Lowerstartingdosemaybee ectiveforpanicdisorderandshouldbeconsidered,aspatientsaremoresensitivetostimulatinge ects

• Dosing interval of every 2 to 7 days has been used with uoxetine in prophylaxis of depression; once weekly dosing used in the maintenance

treatment of panic disorder

• Intermittentdosing(duringlutealphaseofmenstrualcycle)founde ectiveforthetreatmentofpremenstrualdysphoricdisorder

• Dosageoflow-doseparoxetinemesylateforvasomotorsymptomsassociatedwithmenopauseis7.5mgdailygivenatbedtime

• Seep.82

• SSRIsareabsorbedrelativelyslowlybutcompletely(timetopeakplasmaconcentrationis3–8h);undergolittle rst-passe ect

• Highly bound to plasma protein ( uoxetine, paroxetine, and sertraline) and will displace other drugs from protein binding although this is rarely

clinically signi cant (see Interactions, p. 11)

• Metabolizedprimarilybytheliver;allSSRIsa ectCYP450metabolizingenzyme(least:citalopramandescitalopram)andwilla ectthemetabolism

of other drugs metabolized by this system (see Interactions, p. 11). Fluoxetine and paroxetine have been shown to decrease their own metabolism

over time. Clearance of all SSRIs reduced in patients with liver cirrhosis

• Peakplasmalevelofsertralineis30%higherwhendrugtakenwithfood,as rst-passmetabolismisreduced

• Fluoxetine as well as its active metabolite, nor uoxetine, have the longest half-lives (up to 70 h and 330 h, respectively); this has implications for

reaching steady-state drug levels as well as for drug withdrawal and drug interactions

• Controlled-releaseparoxetineisenteric-coatedandformulatedforcontrolleddissolution;suggestedtobebettertoleratedthantheregular-release

preparations in regards to GI e ects, especially at start of therapy

• Once weekly dose of delayed-release uoxetine 90 mg results in similar mean steady-state plasma concentration of uoxetine and nor uoxetine,

achieved with a daily dose of 10–20 mg; peak to trough di erences vary (rates of nausea appear to be similar)

• SSRIs are long-acting drugs and can be given in a single daily dose, usually in the morning; of the SSRIs, uvoxamine and paroxetine have the highest incidence of sedation and can be prescribed at night if necessary

• Therapeutic e ect typically seen after 28 days (though some patients may respond sooner); most patients with depression respond to the initial (low) dose; increasing the dose too rapidly due to absence of therapeutic e ect or adverse e ects can result in higher doses than necessary being used and higher rate of adverse e ects

• Tolerancetoe ectsseeninsomepatientsaftermonthsoftreatment(“poop-outsyndrome”ortachyphylaxis)(seep.3)

• The pharmacological and side e ect pro le of SSRIs is related to their in vivo a nity for and activity on neurotransmitters/receptors (see Table p. 77)

• Forincidenceofadversee ectsattherapeuticdosesseechart(p.79)

• Incidencemaybegreaterinearlydaysoftreatment;patientsadapttomanysidee ectsovertime

• Ruleoutwithdrawalsymptomsofpreviousantidepressant–canbemisattributedtosidee ectsofcurrentdrug

• Headachecommon,worseningofmigraines[Management:acetaminophenprn]

• Seizuresreported,primarilyinpatientswithunderlyingseizuredisorder(risk0.04–0.3%);doserelated

• Bothactivationandsedationcanoccurearlyintreatment

• Activation, excitement, impulse dyscontrol, anxiety, agitation, and restlessness; more frequent at higher doses [may respond to lorazepam]; psy-

chosis or panic reactions may occur; isolated reports of antidepressants causing motor activation, aggression, depersonalization, suicidal urges, and

potential to harm others. CAUTION in children and adolescents (see p. 9)

• Insomnia:DecreasedREMsleep,prolongedsleeponsetlatency,reducedsleepe cacy,andincreasedawakeningswithallSSRIs;increaseddreaming,

nightmares, sexual dreams and obsessions reported with uoxetine [may respond to clonazepam or cyproheptadine 2–4 mg]; case reports of somnambulism with paroxetine

CNS Effects

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 5 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Selective Serotonin Reuptake Inhibitors (SSRI) (cont.)

• Drowsiness – more common with uvoxamine and sertraline; prescribe bulk of dose at bedtime; sedation with uoxetine may be related to high concentration of metabolite nor uoxetine

• Precipitationofhypomaniaormania(between10%and25%ofpatientswithahistoryofbipolardisorders–lessfrequentifpatientreceivingmood stabilizers); increased risk in patients with comorbid substance abuse

• Lethargy, apathy or amotivational syndrome (asthenia) reported – may be dose related and is reversible; more likely with SSRIs than SNRIs [prescribe bulk of dose at bedtime; amantadine (100–200 mg/day), bupropion, buspirone, moda nil (100–400 mg/day), or psychostimulant (e.g., methylphenidate 5–20 mg bid) or consider alternate agent]

• Casereportsofcognitiveimpairment,decreasedattention,andshort-termmemoryimpairment[earlydatasuggestdonepezil2.5–10mg/daymay be of bene t]

• Casereportsofvisualhallucinationswith uoxetine, uvoxamine,paroxetine,andsertraline

• Finetremor[mayrespondtodosereductionortopropranolol]

• Akathisia[mayrespondtodosereduction,topropranololortoabenzodiazepine]

• Dystonia,dyskinesia,parkinsonismortics;morelikelyinolderpatients

• IncreasedextrapyramidalsymptomsreportedinpatientswithParkinson’sdisease

• Mayinduceorworsenextrapyramidale ectswhengivenwithantipsychotics(seeInteractionsp.13)

• Casereportsoftardivedyskinesiafollowingchronic uoxetine,sertraline,andparoxetineuse;morelikelyinolderpatients

• Tinnitus

• Myoclonus(e.g.,periodiclegmovementsduringsleep);mayincreasespasticity;recurrenceofrestlesslegssyndrome

• Myoclonicticsmaybeseeninthefaceandshoulders

• Dysphasia,stuttering

• Impairedbalancereported,especiallyintheelderly

• Nocturnal bruxism reported – may result in morning headache or lead to damage to teeth or bridgework [may respond to buspirone up to

50 mg/day]

• Paresthesias;maybecausedbypyridoxinede ciency[Management:Pyridoxine50–150mg/day];“electric-shock-like”sensations

• Jointpain

• Cerebrovasculardiseaseandcasereportsofstroke(highdosesofhigh-a nitySSRIsmayincreaseriskofbleedingorvasospasmduetoantiplatelet

e ect or serotonergic overstimulation)

• Casereportsofurinaryretention,urgency,incontinenceorcystitis

• Casereportofacuteangleclosurewithparoxetineinpatientwithnarrow-angleglaucoma(paroxetinehasthemostanticholinergicactivityofthe

SSRIs)

• Citalopramandescitalopramcausedose-dependentQTintervalprolongation.Citalopramnotrecommendedtobeprescribedatdosesgreaterthan 40 mg/day, and 20 mg/day in patients above age 60 (65 in Canada), in individuals with liver impairment, or if combined with CYP2C19 inhibitors. Similarly, the dose of escitalopram should be limited to 20 mg/day in individuals with liver impairment and to 10 mg/day if combined with CYP2C19 inhibitors. Citalopram use is discouraged in patients with congenital long QT syndrome. Patients with congestive heart failure, bradyarrhythmias, or predisposition to hypokalemia or hypomagnesemia because of concomitant illness or drugs are at higher risk of developing torsades de pointes

• In certain selected circumstances, a decision to exceed these dosing recommendations may occur; if so, consider the following recommendations: con rm there is no personal or family history of premature sudden cardiac death, QTc prolongation or structural and ischemic heart disease; a risk-bene t discussion should occur before commencing; review concomitant medications to ensure others may not contribute to QTc prolongation risk; and nally, perform an ECG prior to increasing dose and repeat ECG following dose increase when steady state has been reached – reconsider this dosing if absolute QTc more than 500 ms or change in QTc of more than 60 ms

• Slowingofsinusnodereportedwith uoxetine;cautioninsinusnodediseaseandinpatientswithseriousleftventricularimpairment;casereports of QT prolongation with uoxetine (two mechanisms proposed: Direct blockade of the hERG potassium ion channels and disruption of hERG protein expression on the cell membrane)

• Rarereportsoftachycardia,palpitations,hypertension,andatrial brillation

Anticholinergic Effects

Cardiovascular Effects

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

• Bradycardia

• Dizziness

• Maycausecoronaryvasoconstriction;cautioninpatientswithangina/ischemicheartdisease

• IncreasedLDLcholesterollevelsreportedwithparoxetineandsertraline

• In a meta-analysis of SSRIs in patients with depression and coronary heart disease, SSRIs were found to decrease depressive symptoms with no

signi cant di erence in mortality or readmission rates

• Bleeding disorders including petechiae, purpura (1% risk with uoxetine); thrombocytopenia with uoxetine; bruising, nosebleeds, and bleeding after surgery reported with all SSRI drugs; increased bleeding attributed to inhibition of serotonin uptake by platelets; increased GI bleed attributed to increase in gastric acid secretion; risk increased in older individuals, those with a history of GI bleed or in combination with drugs such as NSAIDs, ASA, anticoagulants or antiplatelet drugs (see Interactions p. 10–15); GI bleed risk decreased with use of proton pump inhibitors

• In surgical patients, a small evidence base suggests SSRI use is associated with bleeding and adverse outcomes. In coronary bypass surgery, SSRI use has been associated with increased bleeding risk. Similar ndings have been seen in orthopedic surgical procedures. Receiving SSRIs in the perioperative period is associated with higher odds for bleeding. Note: there are no high-quality prospective studies examining the risk–bene t pro le for cessation of SSRIs and risk of surgical bleeding

• Rareblooddyscrasiasincludingneutropeniaandaplasticanemia

• Can induce SIADH with hyponatremia; can result in nausea, fatigue, headache, cognitive impairment, confusion, and seizures; risk increases with age (up to 32% incidence), female sex, low body weight, smoking and concomitant diuretic use

• Monitoring of serum sodium is suggested in the elderly, those with a history of hyponatremia or on other agents associated with hyponatremia, such as diuretics, or with comorbid conditions associated with hyponatremia, such as heart failure

• Elevated prolactin – risk increased in females (up to 22% reported in women on uoxetine); cases of galactorrhea reported; breast enlargement; case of gynecomastia in a male on paroxetine – not related to dose

• Case reports of blood glucose increases in patients taking paroxetine and other antidepressants associated with weight gain. Preliminary data suggest use of SSRIs was associated with lower insulin secretion in nondiabetic patients and an increased risk of insulin dependence in older adults with type 2 diabetes

• Onemeta-analysisfoundthatweightlossoccurredwithacutetreatmentwithmostoftheSSRIsbutthiswasnotsustainedwithchronictreatment. Weight gain reported: Up to 18% of individuals gain more than 7% of body weight with chronic use – reported more frequently in females (more common with paroxetine)[5]

• A result of inhibition of 5-HT reuptake (activation of 5-HT3 receptors)

• Nausea; vomiting – generally decreases over time due to gradual desensitization of 5-HT3 receptors [may respond to taking drug with meals or

switching to the delayed/controlled-release preparation; cyproheptadine 2 mg or lactobacillus acidophilus (e.g., yogurt)]

• Diarrhea,bloating–usuallytransientanddose-related;maybemorefrequentwith uoxetine90mggivenweekly

• Anorexia and weight loss frequently reported during early treatment – more pronounced in overweight patients and those with carbohydrate

cravings

• Weightgainreported,particularlywithparoxetine

• 2–4timeshigherriskofupperGIbleedingwithSSRIs,especiallyifcombinedwithNSAIDs(riskincreased12-fold)orASA

• Casereportsofstomatitiswith uoxetine;glossodynia(burningmouthsyndrome)reportedduringtreatmentwith uoxetine,sertraline

• A result of increased serotonergic transmission by way of the 5-HT2A receptor which results in reduced dopaminergic transmission, acetylcholine (ACh) blockade, and reduced nitric oxide levels – appears to be dose-related; risk increased with age and concomitant drug use

• All three phases of the sexual cycle may be a ected: Reduced interest and desire for sex; erectile dysfunction in men and diminished arousal in women; and di culty in attaining orgasm in both sexes; reducing the dose is helpful in some (but not all) cases

• ParoxetinemaybemorelikelythanotherSSRIstocausesexualdysfunction(upto75%ofpatients)

• The phosphodiesterase inhibitors such as sildena l have been shown by double-blind randomized placebo-controlled trials to be e ective in

overcoming erectile dysfunction and orgasmic problems induced by SSRIs in men, and in reducing adverse sexual e ects including reversal of

anorgasmia in women, with similar adverse events to the general population

• Decreased libido, impotence, ejaculatory disturbances occur relatively frequently [Management: Sildena l (25–100 mg prn), amantadine (100–

400 mg prn), bethanechol (10 mg tid or 10–50 mg prn), cyproheptadine (4–16 mg prn – sedation and/or loss of antidepressant response reported occasionally), neostigmine (7.5–15 mg prn), yohimbine (5.4–16.2 mg prn or 5.4 mg tid – may cause anxiety/agitation), buspirone (15–60 mg od

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 7 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Hematologic Effects

Endocrine & Metabolic Effects

GI Effects

Urogenital & Sexual Effects

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Hypersensitivity Reactions

Other Adverse Effects

Discontinuation Syndrome

Selective Serotonin Reuptake Inhibitors (SSRI) (cont.)

or prn), bupropion (75–300 mg/day – results contradictory), or “drug holidays” (i.e., skip dose for 24 h prior to sexual activity; not e ective with

uoxetine]

• Anorgasmiaordelayedorgasm[Management:Amantadine(100–400mgprn);cyproheptadine(4–16mgprn–sedationand/orlossofantidepres- sant response reported occasionally), buspirone (15–60 mg od or prn), bupropion (75–300 mg od – results contradictory); mirtazapine (15–45 mg od), yohimbine (5.4–10.8 mg od or prn – may cause anxiety/agitation); methylphenidate (5–40 mg od), dextroamphetamine (5–40 mg od), ginseng, sildena l (25–150 mg prn)]

• Spontaneousorgasmwithyawning

• Casesofpriapisminbothmalesandfemalesreportedwithcitalopram, uoxetine,paroxetine,andsertraline

• Rare

• Rash(upto1%incidence),urticaria,psoriasis,pruritus,edema,photoallergy/photosensitivity(cross-sensitivitybetweenSSRIshasbeensuggested);

rare cases of Stevens-Johnson syndrome

• Serumsickness,toxicepidermalnecrolysis( uvoxamine)

• Increasedhepaticenzymelevels,bilirubinemia,jaundice,hepatitis

• Rarereportsofhypersensitivitypneumonitis

• Casereportsofalopecia

• Rhinitiscommon

• CasereportsofexacerbationofRaynaud’ssyndrome

• Sporadiccasesofeosinophilicpneumonia,idiopathicpulmonary brosis,granulomatouslungdisease,anddi usealveolardamage

• Severalcasesofdecreasedthyroidindicesreportedwithsertraline

• Nocturia(inupto16%ofpatients)

• Osteoporosis:RateofbonelosshigherinSSRIusers;increasedriskoffracturesinwomenandolderadults[6]

• Thereisagrowingbodyofevidencetosuggestanincreased,dose-dependentriskoffracturesamongpatientstakingSSRIs.WhenprescribingSSRIs,

the increased risk of fractures must be considered, including risk of falls and potential fracture risk

• Amongst all SSRIs, sweating is most likely with paroxetine (a result of NE-reuptake inhibition) [Management: Daily showering, talcum powder; in

severe cases: Drysol solution, oxybutynin up to 5 mg bid, clonidine 0.1 mg bid, guanfacine 2 mg at bedtime, benztropine 0.5 mg at bedtime; drug may need to be changed]

• Abrupt discontinuation of high doses may cause a syndrome consisting of somatic symptoms: Dizziness (exacerbated by movement), lethargy, nausea, vomiting, diarrhea, headache, fever, sweating, chills, malaise, incoordination, insomnia, vivid dreams; neurological symptoms: Myalgia, paresthesias; “electric-shock-like” sensations, dyskinesias, visual discoordination; psychological symptoms: Anxiety, agitation, crying, irritability, confusion, slowed thinking, disorientation; rarely aggression, impulsivity, hypomania, and depersonalization; cases of mania reported following antidepressant taper, despite adequate concomitant mood-stabilizing treatment

• Mostlikelytooccurwithin1–7daysafterashorthalf-lifedrugstoppedordosedrasticallyreduced,andtypicallydisappearswithin3weeks

• Incidence (of 2–78%) is related to half-life of antidepressant – reported most frequently with paroxetine, least with uoxetine; attributed to rapid decrease in 5-HT availability. With paroxetine, discontinuation symptoms may also be due to its ability to inhibit its own metabolism, causing a

rapid decline in plasma levels if it is stopped rapidly

☞ THEREFORE THESE MEDICATIONS SHOULD BE WITHDRAWN GRADUALLY AFTER PROLONGED USE. Taper antidepressant no more rapidly than by 25% per week (or nearest dose possible) and monitor for recurrence of depressive symptoms (except for uoxetine, which can be tapered more rapidly due to its prolonged half-life)

• Re-institutedrugandtapermoreslowly

• Reportthatgingercanmitigatenauseaanddisequilibriume ects;substitutionwithonedoseof uoxetine(10–20mg)alsorecommendedtohelp

in the withdrawal process; if the switch is successful, uoxetine can usually be stopped after several weeks of treatment without discontinuation symptoms returning

Management

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Precautions

• Monitor all patients for worsening depression and suicidal thinking especially at start of therapy or following an increase or decrease in dose; see comments under Pediatric Considerations, p. 9

• Mayimpairthementalandphysicalabilitytoperformhazardoustasks(e.g.,drivingacaroroperatingmachinery)

• Mayinducemanicreactionsinupto20%ofpatientswithbipolardisorder–reportedmorefrequentlywith uoxetine;becauseofriskofincreased

cycling, bipolar disorder is a relative contraindication unless a mood stabilizer is added

☞ Use of SSRIs with other serotonergic agents may result in a hypermetabolic serotonin syndrome – usually occurs within 24 hours of medication

initiation (but can occur within minutes to hours), overdose or change in dose. Symptoms include: Nausea, diarrhea, chills, sweating, dizziness, el- evated temperature, elevated blood pressure, palpitations, increased muscle tone with twitching, tremor, myoclonic jerks, hyperre exia, unsteady gait, restlessness, agitation, excitation, disorientation, confusion and delirium; may progress to rhabdomyolysis, coma, and death (see Interactions) [Management: Stop medication and administer supportive care, cyproheptadine 4–16 mg may reduce duration of symptoms]. Residual symptoms such as muscle aches may last for up to 8 weeks in SSRIs with long half-lives

• Fluoxetine, uvoxamine,andparoxetinea ectCYP450andwillinhibitthemetabolism(andelevatethelevels)ofdrugsmetabolizedbythissystem; sertraline will inhibit metabolism in higher doses (over 100 mg/day) (see Interactions, pp. 11–17)

• CombinationofSSRIswithothercyclicantidepressantscanleadtoincreasedplasmalevelofotherantidepressants.Combinationtherapyhasbeen used in the treatment of resistant patients. Caution when switching from uoxetine to another antidepressant (see Interactions). Caution when switching from one SSRI to another

• Treatment with medications that inhibit the serotonin transporter may be associated with abnormal bleeding, particularly when combined with NSAIDs, acetylsalicylic acid, or other medications that a ect coagulation

• SSRIs generally have a low probability of causing dose-related toxicity; symptoms include: Nausea, vomiting, tremor, myoclonus, irritability (one fatality reported with dose of 6000 mg of uoxetine; seizure reported in adolescent after ingestion of 1880 mg)

• RapidonsetofseizureswithQTcintervalprolongationiscommonwithcitalopram;citalopramandescitalopramaremorelikelytocausecardiotox- icity than other SSRIs. Cardiac arrest and torsades de pointes have been reported with citalopram although toxicity has occurred in adults ingesting as little as 100–190 mg

• Altered mental state, QT prolongation, bradyarrhythmias, syncope, and seizures reported following an overdose of citalopram; fatal outcome in 6 patients with citalopram 840–3920 mg (some had also taken other sedative drugs or alcohol); fatalities reported with overdoses of citalopram and moclobemide when co-prescribed

• Caseofserotoninsyndromereportedafteroverdoseof8gofsertraline

• Treatment:Symptomaticandsupportive

• Citalopram and escitalopram overdose – asymptomatic patients should have continuous ECG monitoring and monitoring of vital signs for 6 h;

symptomatic patients until resolution of symptoms

• FordetailedinformationontheuseofSSRIsinthispopulation,pleaseseetheClinicalHandbookofPsychotropicDrugsforChildrenandAdolescents[7]

• NoSSRIsareapprovedforuseinpediatricdepressioninCanada

• Fluoxetineisapprovedforuseinchildrenandadolescentswithdepression(age8–17)orOCD(age7–17)intheUSA

• Fluvoxamine and sertraline approved for the treatment of OCD (in children and adolescents over 7 years and over 6 years of age, respectively) (USA)

• E cacy for major depressive disorder (MDD) in children and adolescents NOT demonstrated in controlled trials with sertraline, paroxetine, and

citalopram; no data with uvoxamine and escitalopram

• CAUTION: Suicidal ideation and attempts (NOT completed suicides) are increased by antidepressants in people under the age of 24 (compared to

placebo)

• SSRIs have been used in the treatment of depression, dysthymia, social phobia, anxiety, panic disorder, bulimia, OCD, autism, selective mutism,

Tourette’s syndrome, and ADHD; preliminary data suggest e cacy in some children with pervasive developmental disorders (autism) and selective

mutism

• Childrenaremorepronetobehavioraladversee ectsincluding:Agitation,restlessness(32–46%),activation,hypomania(upto13%),insomnia(up

to 21%), irritability, and social disinhibition (up to 25%)

Toxicity

Management

Pediatric Considerations

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 9 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Geriatric Considerations

Selective Serotonin Reuptake Inhibitors (SSRI) (cont.)

• SSRIsareused(o -label)inthetreatmentofbehavioralandpsychologicalsymptomsofdementia[8,9]

• SSRIsgenerallyhavealowriskofCNS,anticholinergic,andcardiovasculare ects

• Initiateatalowerdoseandincreasemoreslowly;higherdosesof uoxetinehavebeenassociatedwithdelirium

• Elderly patients may take longer to respond and may need trials of at least 12 weeks before treatment response noted; data contradictory as to

e cacy in older patients

• Half-life of paroxetine increased by 170% and mean plasma level increased 4-fold in the elderly; clearance of sertraline decreased; citalopram

plasma level and TV increased; Cmax, AUC, and TV of escitalopram increased by 35%, 50%, and 50%, respectively

• Limitdoseofcitalopramandescitalopramtoamaximumof20mg/dayand10mg/day,respectively,duetoriskofQTprolongation

• Monitorfordrug-druginteractions

• Improvementaswellasworseningincognitivefunctioninginelderlydepressedpatientshasbeennoted

• Impairedbalanceandfallsreported;tendtooccurearlyintreatmentandaremorelikelywithhigherdoses[10];SSRIsincreasefractureriskbycausing

a reduction in bone mineral density – a reduction of 3.9% of the bone mineral density at the hip and 5.9% at the lumbar spine was found in older

men

• Bothweightgainandweightlossreported;monitorforexcessiveweightlossindebilitatedpatients

• Neurologicalsidee ectsmorelikely

• Extrapyramidal e ects including dyskinesias and parkinsonism reported; they are not dose related and can develop with short-term or long-term

use

• Monitor serum electrolytes (sodium and urea nitrogen levels); hyponatremia reported with all SSRIs (e.g., in 12% of elderly on paroxetine) usually

within 2 weeks of drug initiation; can present with confusion, somnolence, fatigue, delirium, hallucinations, urinary incontinence, hypotension, and vomiting

• Teratogenicity–moststudieshavenotfoundSSRIsasaclasstobemajorteratogens

• Cardiacdefects–con ictingevidenceregardingantenatalexposuretoSSRIs;instudies ndinganincreasedrisk,theabsoluteriskislow

• Reports of an increase in premature births and poor neonatal adaptation when drug taken in the third trimester. Inadequate evidence speci cally

linking maternal antidepressant use and preeclampsia or gestational hypertension; existence of additional risk that is independent of depression and severity thereof remains unknown, although analyses of preeclampsia in depression or anxiety (untreated) show similar odds ratios to those found in maternal SSRI exposure analyses

• Neonatal abstinence syndrome (NAS), which includes poor neonatal adaption and neonatal withdrawal, is the most commonly reported adverse neonatal outcome associated with early-life SSRI exposure, occurs in approximately 30% of exposed infants. Symptoms peak within 2–4 days after birth, then typically dissipate within a few weeks

• Neonates exposed to SSRIs (especially paroxetine) in the third trimester (after 20th week) have developed complications upon delivery including: Jitteriness, restlessness, irritability, tremors, feeding di culties, changes in muscle tone, respiratory distress, persistent pulmonary hypertension, temperature instability, seizures (with uoxetine these are related to blood level of uoxetine and nor uoxetine)[11]

• FDA has reviewed the additional data and has concluded that, given the con icting results from di erent studies, it is premature to reach any conclusion about a possible link between SSRI use in pregnancy and pulmonary hypertension

• Higherplasmalevelsofparoxetinereportedininfantswhosemothersalsoreceivedclonazepam

• Itshouldbenotedthatsomeofthepotentialoutcomesascribedtoantidepressantexposurearealsoseenwithmaternalstresswhichcomplicates

the ability to determine the e ect of illness versus those of the medication on outcomes

• Risk of autism spectrum disorder in children of mothers exposed to SSRIs during pregnancy – several analyses suggest an increased risk; it should

be noted that maternal psychiatric illness is considered a strong confounder but whether this and other possible confounders entirely account for the risk is unclear; underlying biological plausibility of SSRI exposure and such developmental disorders also requires further exploration. Maternal exposure to SSRIs is associated with an increased risk of postpartum hemorrhage

Use in Pregnancy♢

♢ See p. 439 for further information on drug use in pregnancy and e ects on breast milk

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Breast Milk

Nursing Implications

• Withthepossibleexceptionofparoxetine,availableevidenceisn’tadequatetodiscernspeci crisksamongstthedi erentSSRIs;prenatalexposure to escitalopram and uvoxamine have been far less studied than other SSRIs

• Although all SSRIs may be secreted in breast milk, concentrations are generally low and overall infant exposure relatively limited so SSRIs are all considered compatible; however, when initiating treatment during breastfeeding, sertraline and paroxetine are considered preferred agents as they have the most research combined with low to undetectable levels; uoxetine is well researched but exhibits the highest breast milk concentrations and its long half-life increases risk of accumulation in the infant, making it less advisable in this scenario

• Mothers who are already stabilized on an SSRI at delivery should not be discouraged from breastfeeding, nor is there any evidence that would advise switching agents in the context of stable illness

• Psychotherapyandeducationarealsoimportantinthetreatmentofdepression

• Monitortherapybywatchingforadversee ectsandmoodandactivitylevelchanges,includingworseningofsuicidalthoughts,especiallyatstart

of therapy or following an increase or decrease in dose

• Be aware that the medication reduces the degree of depression and may increase psychomotor activity; this may create concern about suicidal

behavior

• Watchforincreasedbruising,nosebleeds,orevidenceofGIbleed,especiallyinpatientsalsotakingASAorNSAIDs,steroidsoranticoagulants

• Excessiveingestionofca einatedfoods,drugsorbeveragesmayincreaseanxietyandagitationandconfusethediagnosis

• Extended/controlled-release uvoxamine,paroxetineand uoxetineproducts,anddelayed-release uoxetinetabletsshouldnotbebroken,crushed

or chewed but swallowed whole, with water

• Sertralineshouldbegivenwithfood(increasespeakplasmalevel);foodreducesincidenceofnauseawithallSSRIs

• Ingestionofgrapefruitjuicewhiletaking uvoxamineandsertralinemayincreasetheplasmalevelofthesedrugs

• SSRIsshouldnotbestoppedsuddenlyduetoriskofprecipitatingwithdrawalreactions

• FordetailedpatientinstructionsonSSRIantidepressants,seethePatientInformationSheet(detailsp.440)

• Clinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterforthesecondagent

Patient Instructions

Drug Interactions

Class of Drug

Example

Interaction Effects

α2-adrenergic agonist

Tizanidine

Increased AUC of tizanidine (14- to 103-fold), increased Cmax (5- to 32-fold), and half-life (3-fold) with uvoxamine due to inhibition of metabolism via CYP1A2

Analgesic

Acetylsalicylic acid (see NSAID p. 16)

Increased risk of upper GI bleed from 3.6-fold with SSRI alone to 5-fold in combination

Anorexiant

Phentermine Sibutramine

Case reports of mania and psychosis in combination

Reports of serotonin syndrome (see p. 9) Case report of hypomania with citalopram

Antiarrhythmic

Flecainide, mexiletine, propafenone Lidocaine, quinidine

Increased plasma level of antiarrhythmic with uoxetine and paroxetine due to inhibited metabolism via CYP2D6

Increased plasma level of antiarrhythmic possible with uoxetine, uvoxamine, sertraline, and paroxetine due to inhibited metabolism via CYP3A4

Antibiotic

Clarithromycin Erythromycin

Linezolid

Case of delirium with uoxetine; case of serotonin syndrome with citalopram

Increased plasma level of citalopram due to inhibited metabolism via CYP3A4 is possible – this can lead to QTc interval prolongation with citalopram and escitalopram; case of serotonin syndrome with sertraline in a 12-year-old

Monitor for increased serotonergic effects due to linezolid’s weak MAO inhibition

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 11 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Selective Serotonin Reuptake Inhibitors (SSRI) (cont.)

Class of Drug

Example

Interaction Effects

Anticoagulant

Apixaban, dabigatran, rivaroxaban Warfarin

Increased risk of bleeding possible due to decreased platelet aggregation secondary to depletion of serotonin in platelets

Increased risk of bleeding; increased prothrombin ratio or INR response due to decreased platelet aggregation secondary to depletion of

serotonin in platelets

65% increase in plasma level of warfarin with uvoxamine due to accumulation of R-warfarin through inhibited metabolism (via CYP1A2 and 3A4) and decreased clearance of S-isomer (via CYP2C9)

Anticonvulsant

Barbiturates

Carbamazepine, phenobarbital, phenytoin

Divalproex, Valproate, valproic acid

Barbiturate metabolism inhibited by uoxetine; reduced plasma level of SSRIs due to enzyme induction by barbiturate Decreased plasma level of SSRIs; half-life of paroxetine decreased by 28%

Increased plasma level of carbamazepine or phenytoin due to inhibition of metabolism with uoxetine and uvoxamine; elevated phenytoin level with sertraline and paroxetine

Increased nausea with uvoxamine and carbamazepine

Increased plasma level of valproate (up to 50%) with uoxetine

Valproate may increase plasma level of uoxetine

Topiramate

Two case reports of angle-closure glaucoma in females on combination

Antidepressant

NDRI

SNRI

SARI

NaSSA

Nonselective cyclic

Bupropion

Duloxetine Venlafaxine Nefazodone, trazodone

Mirtazapine

Amitriptyline, desipramine, imipramine

Clomipramine

Additive antidepressant effect in refractory patients. Bupropion may reverse SSRI-induced sexual dysfunction. Case of hypersexual behavior in combination with uoxetine

Reports of unsteadiness and ataxia in elderly subjects in combination with paroxetine

Cases of anxiety, panic, delirium, tremor, myoclonus, and seizure reported with uoxetine due to inhibited metabolism of bupropion and/or uoxetine (via CYP3A4 and 2D6), competition for protein binding, and additive pharmacological effects

Increased plasma level of duloxetine due to inhibition of metabolism via CYP1A2 by uvoxamine; reported to reduce duloxetine plasma clearance by 77% in one study; avoid combination

Reports that combination with SSRIs that inhibit CYP2D6 (e.g., paroxetine, uoxetine) can result in increased levels of venlafaxine, with possible increase in blood pressure, anticholinergic effects, and serotonergic effects

Additive antidepressant effect

Elevated plasma level of SARI; increased serotonergic effects

Increased level of mCPP metabolite of trazodone and nefazodone with paroxetine (via inhibition of CYP2D6), resulting in increased anxiogenic potential

Combination reported to alleviate insomnia with low mirtazapine doses (less than 30 mg) and augment antidepressant response May mitigate SSRI-induced sexual dysfunction and “poop-out” syndrome

Increased serotonergic effects possible

Increased sedation and weight gain reported with combination

Increased mirtazapine level (up to 4-fold) reported in combination with uvoxamine due to inhibited metabolism

Elevated plasma level of cyclic antidepressant with uoxetine, uvoxamine, and paroxetine due to inhibition of oxidative metabolism; can occur with higher doses of sertraline

Increased desipramine level (by 50%) with citalopram and escitalopram

Additive antidepressant effect in treatment-resistant patients

Increased serotonergic effects

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Example

Interaction Effects

Moclobemide

Phenelzine, tranylcypromine

Combined therapy may have additive antidepressant effect in treatment-resistant patients; use caution and monitor for serotonergic effects; case reports of serotonin syndrome, especially with citalopram and escitalopram

Hypermetabolic syndrome (serotonin syndrome – see p. 9) and death reported with combined use. Suggest waiting 5 weeks when switching from uoxetine to MAOI and vice versa. Increased plasma level of tranylcypromine (by 15%) reported with paroxetine

Dolasetron, granisetron, ondansetron

Alosetron

Reports of serotonin syndrome with paroxetine and sertraline

One case study suggests SSRIs may reduce the antiemetic effectiveness of 5-HT3 antagonists due to the accumulation of serotonin from SSRIs overcoming the blockade by 5-HT3 antagonists

DO NOT USE with uvoxamine as plasma level of alosetron increased 6-fold and half-life increased 3-fold due to inhibited metabolism via CYP1A2

Fluconazole, ketoconazole Terbina ne

Decreased Cmax of ketoconazole by 21% with citalopram

2 cases of life-threatening serotonin syndrome reported with citalopram

Increased paroxetine exposure (AUC by 2.5-fold, Cmax by 86%, half-life by 48%) via CYP2D6 inhibition by terbina ne

Diphenhydramine

Increased plasma levels of uoxetine and paroxetine possible due to inhibited metabolism via CYP2D6 Additive CNS effects

Benztropine Procyclidine

Increased plasma level of benztropine with paroxetine; case report of delirium associated with paroxetine combination Increased plasma level of procyclidine with paroxetine (by 40%)

Clopidogrel

Increased risk of bleeding by (54%)

General

Chlorpromazine, uphenazine, haloperidol, perphenazine

Pimozide

Thioridazine Asenapine Clozapine

May worsen extrapyramidal effects and akathisia, especially if antidepressant added early in the course of antipsychotic therapy

May be useful for negative symptoms of schizophrenia

Increased plasma level of antipsychotic due to inhibition of metabolism via CYP1A2 (potent – uvoxamine), 2D6 (potent – uoxetine and paroxetine), and/or 3A4 ( uvoxamine). Monitor for increased antipsychotic adverse effects (e.g., sedation, orthostatic hypotension, EPS) when starting and antipsychotic ef cacy when stopping SSRI. Adjust antipsychotic dose as needed. Alternatively, consider using an SSRI with no or weak effects on CYPs such as citalopram, escitalopram, and sertraline (at doses of 100 mg/day or less) or use an SSRI that does not affect the speci c CYP enzyme which metabolizes the speci c antipsychotic

Haloperidol levels: 20–35% higher with uoxetine; 23–60% higher with uvoxamine; 28% higher with sertraline Perphenazine peak levels 2- to 13-fold higher with paroxetine

Case report of QT prolongation and patient collapsing with concurrent chlorpromazine and uoxetine

Increased EPS and akathisia

Pimozide levels: 151% higher AUC and 62% higher peak level with paroxetine; 40% higher AUC and peak level with sertraline. Case reports of bradycardia with concurrent use of pimozide and uoxetine

Pimozide level also increased when combined with citalopram, escitalopram or uvoxamine, increasing risk of QTc prolongation – DO NOT COMBINE

3-fold increase in thioridazine levels with uvoxamine

DO NOT COMBINE uvoxamine, uoxetine, sertraline or paroxetine with thioridazine due to risk of cardiac conduction disturbances Asenapine’s Cmax (+13%) and AUC (+29%) increased by uvoxamine. Asenapine (a weak inhibitor of CYP2D6) increases paroxetine exposure by ~2-fold. Reduce paroxetine dose by 50% if asenapine added

Clozapine levels: With uoxetine, 41–76% higher clozapine levels plus 38–45% higher norclozapine levels; one fatality reported; case report of acute myocarditis after addition of clozapine to uoxetine and lithium. With uvoxamine, 3–11-fold higher levels. With

paroxetine, no change to 41% increase in clozapine plus 45% increase in norclozapine. With sertraline, 41–76% clozapine increase plus 45% norclozapine increase; one fatal arrhythmia reported but causality unclear

Class of Drug

RIMA

Irreversible MAOI Antiemetic (5-HT3 antagonist)

Antifungal

Antihistamine Antiparkinsonian

Antiplatelet Antipsychotic

First generation

Second generation

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 13 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Selective Serotonin Reuptake Inhibitors (SSRI) (cont.)

Class of Drug

Example

Interaction Effects

Third generation

Iloperidone Olanzapine

Paliperidone, risperidone, ziprasidone

Aripiprazole

Iloperidone’s AUC increased by ~1.6- to 3-fold in the presence of uoxetine or paroxetine. Reduce iloperidone dose by 50% if uoxetine or paroxetine added

Olanzapine levels: With uoxetine, 16% increase in peak concentration; not clinically signi cant. In the USA, olanzapine/ uoxetine available as a combination product. With uvoxamine, 2.3- to 4-fold increase in olanzapine levels; consider use of an SSRI with less effect on CYP1A2 or use lower olanzapine doses and monitor for adverse effects (e.g., EPS, hypersalivation)

Case reports of dose-related mania when risperidone or ziprasidone added to SSRI

Risperidone levels: With uoxetine, 2.5- to 8-fold increased levels and case report of TD. With paroxetine, 3- to 9-fold higher levels and cases of serotonin syndrome; consider using an alternative SSRI. Case reports of serotonin syndrome and/or NMS with uvoxamine and trazodone plus sertraline

Case report of serotonin syndrome with ziprasidone and citalopram

CAUTION with paliperidone and ziprasidone; possible additive prolongation of QT interval and associated life-threatening cardiac arrhythmias. Factors that further increase the risk include anorexia, bradycardia, hypokalemia, and hypomagnesemia

44% increase in aripiprazole plasma level possible by uoxetine or paroxetine, due to inhibited metabolism via CYP2D6. Reduce aripiprazole dose by 50%. No signi cant pharmacokinetic changes to escitalopram, uoxetine, paroxetine, or sertraline. Case report of NMS with uoxetine 20 mg/day and aripiprazole 30 mg/day. Case report of urinary obstruction with citalopram 10 mg/day and aripiprazole 20 mg/day; unknown if due to citalopram alone. Case reports of severe akathisia, acute dystonia, and myxedema coma with sertraline 200 mg/day and aripiprazole 10, 15, and 20 mg/day, respectively. Consider using an SSRI with no or weak effects on CYPs, such as citalopram and escitalopram

Antiretroviral

Non-nucleoside reverse transcriptase inhibitor (NNRTI)

Efavirenz Nevirapine

Decreased plasma level of sertraline (39% decrease in AUC) via CYP3A4 induction; one case report of serotonin syndrome after initiation of efavirenz while taking uoxetine

One study suggests nevirapine may decrease uoxetine plasma levels, and uvoxamine may increase nevirapine plasma levels

Protease inhibitor

Darunavir/ritonavir Fosamprenavir/ritonavir Ritonavir

Decreased plasma level of paroxetine (39% decrease in AUC) and sertraline (49% decrease in AUC) Decreased plasma level of paroxetine (54% decrease in AUC)

Increased plasma level of sertraline due to competition for metabolism; moderate increase in level of uoxetine and paroxetine. Serotonin syndrome reported in combination with high dose of uoxetine

Cardiac and neurological side effects reported with uoxetine due to elevated ritonavir level (19% increase in AUC)

Antitubercular

Rifampin

Case reports of SSRI withdrawal symptoms and decreased therapeutic ef cacy of sertraline and citalopram due to CYP3A4 induction by rifampin

Anxiolytic

Benzodiazepine

Buspirone

Alprazolam, bromazepam, diazepam

Increased plasma level of benzodiazepine metabolized by CYP3A4; alprazolam (by 100% with uvoxamine and 46% with uoxetine), bromazepam, triazolam, midazolam, and diazepam; small (13%) decrease in clearance of diazepam reported with sertraline Increased sedation, psychomotor and memory impairment

Combination may increase risk of falls in the elderly

Anxiolytic effects of buspirone may be antagonized

Increased plasma level of buspirone (3-fold increase in AUC) with uvoxamine Case report of possible serotonin syndrome with uoxetine

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Example

Metoprolol, propranolol

Pindolol

Nifedipine, verapamil

Diltiazem

Digoxin

Alcohol, antihistamines Chloral hydrate

Prednisone

Dihydroergotamine

Ergotamine

Cimetidine

LSD

Ramelteon Zolpidem

Cyclosporine

Class of Drug Interaction Effects

β-blocker

Caffeine

Calcium channel blocker Cannabis/marijuana

Cardiac glycoside CNS depressant

Corticosteroid Cyclobenzaprine DDAVP

Ergot alkaloid

Ginkgo biloba Grapefruit juice H2 antagonist Hallucinogen

Hypnotic/sedative

Immunosuppressant Insulin

Kava kava

Licorice

Lithium

L-Tryptophan

Decreased heart rate and syncope (additive effect) reported

Increased side effects, lethargy, and bradycardia with uoxetine, uvoxamine, and paroxetine due to decreased metabolism of the β-blocker via CYP2D6 (5-fold increase in propranolol level reported with uvoxamine)

Increased metoprolol level with citalopram (by 100%) and with escitalopram (by 50%)

Increased concentration of serotonin at postsynaptic sites; faster onset of therapeutic response

Increased half-life of pindolol (by 28%) with uoxetine; increased plasma level with paroxetine due to inhibited metabolism via CYP2D6 Increased caffeine levels with uvoxamine due to inhibited metabolism via CYP1A2; half-life increased from 5 to 31 h

Increased jitteriness and insomnia

Increased side effects (headache, ushing, edema) due to inhibited clearance of calcium channel blocker via CYP3A4 with uoxetine, uvoxamine, sertraline, and paroxetine

Case report of mania in combination with uoxetine possibly due to additive serotonin reuptake inhibition from the THC component of cannabis; caution with concurrent use due to risk of additive CNS effects

Bradycardia in combination with uvoxamine

Decreased level (AUC) of digoxin (by 18%) reported with paroxetine

Potentiation of CNS effects; low risk

Rate of uvoxamine absorption increased by ethanol

Increased sedation and side effects with uoxetine due to inhibited metabolism of chloral hydrate

Increased risk of GI bleed

Increased side effects of cyclobenzaprine with uoxetine due to inhibited metabolism; observe for QT prolongation

Water intoxication and hyponatremia in rare cases

Increased serotonergic effects with intravenous use – AVOID. Oral, rectal, and subcutaneous routes can be used, with monitoring Elevated ergotamine levels possible due to inhibited metabolism via CYP3A4 with uoxetine and uvoxamine

Possible increased risk of petechiae and bleeding due to combined anti-hemostatic effects

Decreased metabolism via CYP3A4 of uvoxamine and sertraline resulting in increased plasma levels

Inhibited metabolism and increased plasma level of sertraline (by 25%), paroxetine (by 50%), citalopram, and escitalopram

Recurrence or worsening of ashbacks reported with uoxetine, sertraline, and paroxetine; con icting studies suggest SSRIs may be associated with either an increase or decrease in subjective response to LSD

DO NOT COMBINE with uvoxamine; increased Cmax (70-fold) and AUC (190-fold) of ramelteon due to inhibited metabolism via CYP1A2 Case reports of hallucinations and delirium when combined with sertraline, uoxetine, and paroxetine

Administration of sertraline resulted in faster onset of action and increase in peak plasma concentration of zolpidem

Decreased clearance of cyclosporine with sertraline due to competition for metabolism via CYP3A4

Increased insulin sensitivity reported

Case report of lethargic state with paroxetine

Increased serotonergic effects possible via MAO inhibition by licorice constituents

Increased serotonergic effects

Changes in lithium level and clearance reported

Caution with uoxetine and uvoxamine; neurotoxicity and seizures reported

Increased tremor and nausea reported with sertraline and paroxetine

Additive antidepressant effect in treatment-resistant patients

May result in central and peripheral toxicity, hypermetabolic syndrome (serotonin syndrome – see p. 9)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 15 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Selective Serotonin Reuptake Inhibitors (SSRI) (cont.)

Example

Interaction Effects

Selegiline (L-deprenyl)

Case reports of serotonin syndrome (see p. 3), hypertension, and mania when combined with uoxetine

Increased levels of melatonin with uvoxamine due to inhibited metabolism via CYP1A2 or 2C9 (12-fold increase in plasma melatonin levels reported); endogenous melatonin secretion increased

Enhanced serotonergic effects through inhibition of MAO-A and B by methylene blue. Risk for serotonin syndrome (see Precautions)

Report of increased extrapyramidal effects with uoxetine, uvoxamine, paroxetine, and sertraline potentially via additive D2 receptor antagonism by metoclopramide and inhibition of dopamine neurotransmission by SSRIs; case reports of serotonin syndrome with sertraline and uoxetine potentially via the 5-HT3 receptor blocking effect of metoclopramide

Increased risk of upper GI bleed with combined use (risk increased 12-fold) CAUTION

Codeine, oxycodone, hydrocodone Dextromethorphan

Decreased analgesic effect with uoxetine and paroxetine due to inhibited metabolism to active moiety – morphine, oxymorphone, and hydromorphone, respectively (interaction may be bene cial in the treatment of dependence by decreasing morphine and analog formation and opiate reinforcing properties)

Visual hallucinations reported with uoxetine; uoxetine and paroxetine may inhibit metabolism via CYP2D6; monitor for increased serotonergic effects

Methadone Morphine

Elevated plasma level of methadone (by 10–100%) reported with uvoxamine

Con icting studies show uoxetine antagonized and augmented analgesia from morphine

Pentazocine Tramadol[12]

Report of excitatory toxicity (serotonergic) with uoxetine and pentazocine Increased risk of seizures and serotonin syndrome

Possible decreased analgesic effect with SSRIs that inhibit CYP2D6 ( uoxetine, paroxetine) due to decreased conversion to the active M1 metabolite

Sildena l

Possible enhanced hypotension due to inhibited metabolism of sildena l via CYP3A4 with uoxetine and uvoxamine

The conversion of proguanil to its active metabolite, cycloquanil, is markedly inhibited by uvoxamine (via CYP2C19 inhibition) in patients who have normal CYP2C19 activity

Omeprazole

Increased plasma level of citalopram due to inhibited metabolism via CYP2C19

Atomoxetine

Increased plasma level and half-life of atomoxetine due to inhibited metabolism via CYP2D6 ( uoxetine, paroxetine)

Increased metabolism of uvoxamine (by 25%) via CYP1A2

Lovastatin, simvastatin Pravastatin

Increased plasma level of statin with uoxetine, uvoxamine, sertraline, and paroxetine due to inhibited metabolism via CYP3A4 Synergistic effect on increasing blood glucose (paroxetine)

May augment serotonergic effects – several reports of serotonin syndrome (see p. 9)

Amphetamine, methylphenidate

Potentiated effect in depression, dysthymia, and OCD, in patients with comorbid ADHD; may improve response in treatment-refractory paraphilias and paraphilia-related disorders

Plasma level of antidepressant may be increased

Glyburide, tolbutamide

Increased hypoglycemia reported in diabetics

Increased plasma level of tolbutamide due to reduced clearance (up to 16%) with sertraline

Inhibitors of CYP2D6 (paroxetine, uoxetine) appear to reduce the conversion of tamoxifen to its active metabolite (endoxifen) and may decrease the therapeutic ef cacy of this drug

Class of Drug

MAO-B inhibitor Melatonin

Methylene blue Metoclopramide

NSAID

Opioids and related drugs

Phosphodiesterase type 5 (PDE5) inhibitor

Proguanil

Proton pump inhibitor

Selective norepinephrine reuptake inhibitor

Smoking (tobacco)

Statin

St. John’s Wort Stimulant

Sulfonylurea Tamoxifen

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Class of Drug

Example

Interaction Effects

Theophylline

Increased plasma level of theophylline with uvoxamine due to decreased metabolism via CYP1A2

Thyroid drug

Triiodothyronine (T3-liothyronine)

Antidepressant effect potentiated

Elevated serum thyrotropin (and reduced free thyroxine concentration) reported with sertraline; however, a newer study reports no clinically signi cant changes in thyroid function with uoxetine or sertraline

Tolterodine

Decreased oral clearance of tolterodine (by up to 93%) with uoxetine (a CYP2D6 inhibitor) – interaction not considered clinically signi cant unless patient is also taking a CYP3A4 inhibitor

Triptan

Rizatriptan, sumatriptan

Inadequate data available to determine the risk of serotonin syndrome with the addition of a triptan to SSRIs. However, given the seriousness of serotonin syndrome, caution is warranted

Norepinephrine Dopamine Reuptake Inhibitor (NDRI)

Product Availability∗

Generic Name

Chemical Class

Trade Name(A)

Dosage Forms and Strengths

Bupropion

Monocyclic (aminoketone)

Aplenzin(B)

Extended-release tablets(B): 174 mg, 348 mg, 522 mg

Wellbutrin(B) Wellbutrin SR, Zyban(D) Wellbutrin XL, For vo(B)

Tablets(B) : 75 mg, 100 mg

Sustained-release tablets(C): 100 mg, 150 mg, 200 mg(B) Extended-release tablets: 150 mg, 300 mg, 450 mg(B)

∗ Refer to Health Canada’s Drug Product Database or the FDA’s Drugs@FDA for the most current availability information (A) Generic preparations may be available, cessation (as 150 mg)

(B) Not marketed in Canada,

(D) Marketed as aid in smoking

Indications‡

( approved)

Major depressive disorder (MDD) Seasonal a ective disorder (SAD) Smoking cessation

• Dysthymiaandchronicfatiguesyndrome–e cacyreported

• MDD,recurrent:Prophylaxis

• Bipolardisorder:Depressedphase(usewithanantimanicagent)

• Socialphobia–casereportsofe cacy

• ADHD–controlledstudiessuggestbene tinadultsandchildren;primarilyinindividualswithsimpleADHDorwithcomorbiddepression,cigarette

smoking or active substance use disorder

• Sexual dysfunction (e.g., reduced sexual desire, anorgasmia, erectile problems) induced by SSRIs and SNRI: Mitigating e ect (sustained-release

preparations may be less e ective than regular-release products)

• Neuropathicpain–randomizedcontrolstudiessuggestbene t

• Trichotillomania–casereportsofbene t

• Addictive disorders (e.g., cocaine, alcohol[13] , marijuana)

• Internetgamingdisorder

• Weightlossinpatientstakingnaltrexone

‡ Indications listed here do not necessarily apply to all NDRIs or all countries. Please refer to a country’s regulatory database (e.g., US Food and Drug Administration, Health Canada Drug Product Database) for the most current availability information and indications

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 17 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

General Comments

Norepinephrine Dopamine Reuptake Inhibitor (NDRI) (cont.)

• Mayhavealowerswitchrate(tohypomaniaormania)thanotherantidepressants,althougharecentmeta-analysisfoundasimilarphaseshifting rate

• May enhance energy and motivation early in treatment due to e ects on norepinephrine and dopamine; reported to improve neurocognitive function in patients with depression

• ComparedtoIR,SRpreparationappearstobebettertoleratedandisassociatedwithadecreasedriskofseizuresandlowerriskofsexualdysfunction

• Monitorpatientsforworseningofdepressionandsuicidalthinking

• Monitorpatientstakingbupropionforsmokingcessationasseriousneuropsychiatriceventshaveoccurredinthispopulation

• Superiortoplaceboforsmokingcessationat3monthsand12months.Abstinenceratesat12months:Bupropion19%(vs.9%onplacebo)

• Leastlikelyofallantidepressantstoimpairsexualfunctioning

• Casereportsofrecreationalabusewithbupropionviaoral,intranasal,andintravenousadministration

• Inhibitsthereuptakeofprimarilynorepinephrine(anddopaminetoalesserextent)intopresynapticneurons

• Its major metabolite (hydroxybupropion), which in humans is present at blood levels 10- to 20-fold higher than bupropion, blocks only nore-

pinephrine reuptake

• Seep.82

• Regularimmediate-releasebupropionandSRpreparationshouldbeprescribedindivideddoses(preferably8hormoreapart),withamaximumof

150 mg per IR dose and 200 mg per SR dose; XL preparation formulated for once daily dosing

• Initiatedosesfordepressionat100–150mgdaily.Dosemaybeincreasedto300mg/dayinpatientswhodonotrespondto150mg/day;iftolerated,

may be further titrated as necessary to a maximum of 200 mg bid for SR and 450 mg XL for major depressive disorder (doses beyond 300 mg/day

not studied in seasonal a ective disorder)

• For vo XL for treatment of depression may only be used after initial titration with other bupropion products; patients receiving 300 mg daily of

bupropion HCL (as immediate-release, SR or XL) for at least 2 weeks and requiring a dose increase, or patients already taking 450 mg daily of

bupropion HCL may switch to For vo XL 450 mg daily

• Aplenzin (bupropion hydrobromide): Initial dosing of 174 mg daily and may increase on day 4 (for treatment of depression) or on day 7 (for

treatment of SAD) to 348 mg daily; maximum dose is 522 mg daily; Bupropion HCL (as immediate-release, SR or XL): 150 mg, 300 mg, 450 mg

is equivalent to 174 mg, 348 mg, 522 mg bupropion hydrobromide, respectively

• Forsmokingcessation:Initialdosingof150mgdailyfor3days,then150mgtwicedaily.Treatmentshouldcontinuefor1weekbeforetargetquit

date and continue for 7-12 weeks

• InadultswithADHD,beginat150mg/dayandtitratedosegraduallytoamaximumof450mg/dayindivideddoses;upto4weeksmayberequired

for maximum drug e ect

• Inrenalimpairment,reducedoseandfrequencyandmonitorforadversee ectssuchasinsomnia,drymouth,orseizuresthatcouldindicatehigher

than normal levels; For vo XL not recommended in renal impairment

• Inmildtomoderatehepaticimpairment(Child-PughGradeAorB),initiatetreatmentatthelowestrecommendeddose.Usewithextremecaution

in patients with severe hepatic impairment. For vo XL not recommended

• Rapid absorption with peak concentration occurring within 2 h after administration of immediate-release tablets, 3 h after administration of sustained-release tablets, 5 h after administration of extended-release tablets; peak plasma concentration of sustained-release preparation is 50– 85% that of the immediate-release tablets after single dosing, and 25% after chronic dosing

• Proteinbinding80–85%

• Metabolizedpredominantlybytheliver,primarilyviaCYP2B6andtoalesserextentbyotherisoenzymes–6metabolites;3areactive

• BupropionandhydroxybupropioninhibitCYP2D6isoenzyme

• Elimination half-life: 11–14 h; with chronic dosing: 21 h (mean); increased half-life of bupropion and its metabolites and decreased clearance

Pharmacology

Dosing

Pharmacokinetics

reported in the elderly

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Onset & Duration of Action

• Therapeutice ecttypicallyseenafter28days(thoughe ectsmaybesoonerinsomepatients)

• Seechartonp.79forincidenceofadversee ects

• Aresultofe ectsondopamineandnorepinephrine

• Insomnia;vividdreamsandnightmaresreported;decreasedREMlatencyandincreasedREMsleep

• Agitation,anxiety,irritability,dysphoria,aggression,hostility,depersonalization,coupledwithurgesofself-harmorharmtoothers

• Traditionally,precipitationofhypomaniaormaniafelttobelesslikelythanwithothercyclicantidepressants

• Canexacerbatepsychoticsymptoms

• VeryhighdosescanresultinCNStoxicityincludingdelirium,confusion,impairedconcentration,hallucinations,delusions,EPS,andseizures

• ReportedtoexacerbatesymptomsofOCD

• Short-termmemorylossreported

• RiskofseizureswithSRformulationatdosesof100–300mg/day=0.1%andatdosesof400mg/day=0.4%.Withimmediate-releaseformulation,

seizure incidence of 0.4% with dosing of 300-450 mg/day, risk increases almost tenfold with dosing of 450-600 mg/day; in clinical trials for XL formulation, overall seizure incidence was 0.1% – in those treated with 450 mg, incidence with higher dose was 0.39%; however, seizures have been observed across all doses and formulations in the post-marketing setting

• Disturbanceingait, netremor,myoclonus

• Reversibledyskinesiareported;mayaggravateneuroleptic-inducedtardivedyskinesia

• Headache,arthralgia(4%),neuralgias(5%),myalgia[Management:Analgesicsprn]

• Tinnitusreported

• Noappreciablea nityforcholinergicreceptors

• Occurrarely

• Mydriasis

• Drymouth

• Constipation

• Modest sustained increases in blood pressure reported in adults and children (more likely in patients with pre-existing hypertension and in those receiving nicotine replacement therapy) – caution in patients with ischemic heart disease

• Orthostatichypotension,dizzinessoccursoccasionally,especiallywhenbupropionaddedtoSSRI–cautionintheelderly

• Palpitations

• Caseoftransientischemicattacksreported

• Rarecasesofmyocarditis,myocardialinfarction,andcardiacdeath

• Menstrualirregularitiesreported(upto9%risk)

• Casesofhypoglycemia,hyperglycemia,SIADH

• Urticarialorpruriticrasheshavebeenreported;rarecasesoferythemamultiformeandStevens-Johnsonsyndrome

• Anaphylactoidreactionswithpruritus,urticaria,angioedema,anddyspnea(upto0.3%)

• Delayed hypersensitivity reactions with arthralgia, myalgia, fever, and rash. The symptoms may resemble serum sickness. Post-marketing reports

of hypersensitivity reactions in those who consumed alcohol

• Urinaryfrequency

• Nausea,anorexia,andweightlosswithacuteandlong-termtreatment

• Rarelyfebrileneutropenia

• Alopecia

• Casereportofrhabdomyolysisinapatientwithhepaticdysfunction

• Casereportsofliverfailure

• Sweating(alsoduetoNE-reuptakeinhibition)

• Rarecasesofstuttering

Adverse Effects

CNS Effects

Anticholinergic Effects

Cardiovascular Effects

Endocrine & Metabolic Effects

Other Adverse Effects

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 19 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Norepinephrine Dopamine Reuptake Inhibitor (NDRI) (cont.)

Discontinuation Syndrome

Precautions

• Abrupt discontinuation may cause a syndrome consisting of dizziness, lethargy, nausea, vomiting, diarrhea, headache, fever, sweating, chills, malaise, incoordination, insomnia, vivid dreams, myalgia, paresthesias, dyskinesias, “electric-shock-like” sensations, visual discoordination, anxiety, irritability, confusion, slowed thinking, disorientation; rarely aggression, impulsivity, hypomania, and depersonalization

• Caseofmaniareported2weeksafterabruptdiscontinuationofbupropion300mg/daytakenfor5weekstoaidinsmokingcessation

• Rarecasesofacutedystoniafollowingabruptdiscontinuation

• Mostlikelytooccurwithin1–7daysafterdrugstoppedordosedrasticallyreduced,andtypicallydisappearswithin3weeks

• Monitorallpatientsforworseningdepressionandsuicidalthoughts,especiallyatthestartoftherapyandfollowinganincreaseordecreaseindose

• Maylowertheseizurethreshold;thereforeadministercautiouslytopatientswithorganicbraindiseaseandwhencombiningwithotherdrugsthat may lower the seizure threshold; contraindicated in patients with a history of or current seizure disorder. To minimize seizures with regular-release bupropion, do not exceed a dose increase of 100 mg in a 3-day period. No single dose should exceed 150 mg for the immediate-release or the

sustained-release preparation

• Contraindicated in patients with a history of anorexia or bulimia, undergoing alcohol or benzodiazepine withdrawal or with other conditions

predisposing to seizures

• Usewithcaution(i.e.,uselowerdoseandmonitorregularly)inpatientswithhepaticimpairment

• Zyban,marketedforsmokingcessation,containsbupropion–DONOTCOMBINEwithotherbupropionproducts

• Cautioninpatientswithnarrow-angleglaucoma

• Commonly causes agitation, drowsiness, seizures (delayed in onset 18 h), and sinus tachycardia; rarely causes hypotension, bradycardia, serious cardiac dysrhythmia, hyperre exia, elevated transaminases

• HighriskofQTcintervalprolongationfollowingoverdose

• Rarereportsofdeathfollowingmassiveoverdose,precededbyuncontrolledseizures,bradycardia,cardiacfailure,andcardiacarrest

• Singledoseofactivatedcharcoalifpatientpresentswithin1hofingestion

• Supportivetreatment

• MonitorECGandvitalsignsfor18haswellasEEG

• Benzodiazepinesare rst-linetherapyforseizures

• For detailed information on the use of bupropion in this population, please see the Clinical Handbook of Psychotropic Drugs for Children and Adolescents[7]

• Noapprovedindicationsinchildrenandadolescents

• InADHD,controlledstudiessuggestbene tinchildren,primarilyinindividualswithsimpleADHDorwithcomorbiddepression

• MayexacerbateticsinpatientswithADHDandevoketicsinpatientswithTourette’ssyndrome

• Dosageinchildren:Initiateat1mg/kg/day(individeddoses)andincreasegraduallytoamaximumof6mg/kg/day(individeddoses)

• Rashreportedinupto17%ofyouths

• Theelderlyareatriskforaccumulationofbupropionanditsmetabolitesduetodecreasedclearance

• Initiateatthelowestrecommendeddose

• Orthostatichypotensionordizzinessreported;maypredisposetofalls

• Extrapyramidale ectshavebeenreported;theyarenotdoserelatedandcandevelopwithshort-termorlong-termuse

• Priortoprescribingbupropion,screenforfactorsthatmaypredisposeanelderlypatienttoseizures

Toxicity

Management

Pediatric Considerations

Geriatric Considerations

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Use in Pregnancy♢

• Noharmtofetusreportedinanimalstudies;noteratogenice ectsreportedinhumansfollowinguseofbupropioninthe rsttrimester

• Higher umbilical cord concentration of metabolites suggest a higher fetal exposure vs. parent drug – consequences of exposure yet to be deter-

mined

• Small prospective pharmacokinetic study concluded that, although maternal exposure of bupropion may be slightly reduced over the course of

pregnancy, exposure to the pharmacologically active metabolite appears similar to non-pregnant state

• Bupropionandmetabolitesaresecretedinbreastmilk;infantcanreceiveupto2.7%ofmaternaldose

• Seizuresandsleepdisturbancesreportedinbreastfedinfantsfollowingbupropionexposureviabreastmilk

• Infantsofmothersusingpsychotropicmedicationsshouldbemonitoreddailyforchangesinsleep,feedingpatterns,andbehavioraswellasinfant

growth and neurodevelopment

• Ifapatientisbreastfeedingandrequirestheadditionofanantidepressant,otheragentsmaybepreferableas rst-lineoptions;however,maternal

use of bupropion is not considered a reason to discontinue breastfeeding

• Risk of seizures increases if any single dose exceeds 150 mg (immediate-release or sustained-release) or if total daily dose exceeds 300 mg; doses above 150 mg daily should be given in divided doses, preferably 8 h or more apart

• Crushing or chewing the sustained or extended-release preparation destroys the slow-release activity of the product; cutting or splitting the SR preparation in half will increase the rate of drug release in the rst 15 min. If the tablet is split, the unused half should be discarded unless used within 24 h

• Donotcrush,splitorchewFor votablets

• Canbeadministeredwithorwithoutfood

• Bupropiondegradesrapidlyonexposuretomoisture,thereforetabletsshouldnotbestoredinanareaofhighhumidity

• Monitor therapy by watching for adverse e ects and mood and activity level changes including worsening depression and suicidal thoughts,

especially at the start of therapy or following an increase or decrease in dose

• Ifthepatienthasdi cultysleeping,ensurethatthelastdoseofbupropionisnolaterthan1500h

• EnsurethepatientisnotcurrentlybeingtreatedforsmokingcessationwithZyban(alsocontainsbupropion)

• Fordetailedpatientinstructionsonbupropion,seethePatientInformationSheet(detailsonp.440)

• Clinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterforthesecondagent

Breast Milk

Nursing Implications

Patient Instructions

Drug Interactions

Class of Drug

Example

Interaction Effects

Alcohol

Post-marketing reports of adverse neuropsychiatric events/reduced alcohol tolerance and hypersensitivity reactions. Avoid alcohol while taking bupropion

Antiparkinsonian

Amantadine, L-dopa

Caution with concurrent use with amantadine or L-dopa; increased side effects, including excitement, restlessness, and tremor due to increased dopamine availability

Case reports of neurotoxicity in elderly patients; delirium

Antiarrhythmic (Type 1c)

Flecainide, propafenone

Increased plasma level of antiarrhythmic due to inhibited metabolism via CYP2D6

Antibiotic

Cipro oxacin, linezolid

Seizure threshold may be reduced

Case report of severe intraoperative hypertension in combination with linezolid via MAO inhibition

Anticholinergic

Orphenadrine

Altered levels of either drug due to competition for metabolism via CYP2B6

Anticonvulsant

Carbamazepine, phenobarbital, phenytoin

Decreased plasma level of bupropion and increased level of its metabolite hydroxybupropion due to increased metabolism by the anticonvulsant

Valproate

Increased level of hydroxybupropion due to inhibited metabolism; level of bupropion not affected

♢ See p. 439 for further information on drug use in pregnancy and e ects on breast milk

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 21 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Example

Fluoxetine Venlafaxine

Vortioxetine Desipramine, imipramine, nortriptyline

Phenelzine

Chloroquine, me oquine

Clopidogrel

Chlorpromazine Thioridazine

Risperidone

Efavirenz, nevirapine Efavirenz, nel navir, ritonavir

Rifampin

Metoprolol

Diazepam

Estrogen/progesterone

Zolpidem

Class of Drug

Antidepressant

SSRI

SNRI

SMS

Nonselective cyclic

Irreversible MAOI

Antimalarial Antiplatelet

Antipsychotic

First generation

Second generation

Antiretroviral

Non-nucleoside reverse transcriptase inhibitor (NNRTI)

Protease inhibitor

Antitubercular β-blocker Benzodiazepine

Corticosteroid (systemic) Ginkgo biloba

Hormone

Hypnotic/sedative Methylene blue

Norepinephrine Dopamine Reuptake Inhibitor (NDRI) (cont.)

Interaction Effects

Case of delirium, anxiety, panic, and myoclonus with uoxetine due to inhibited metabolism of bupropion and/or uoxetine (via CYP2D6), competition for protein binding, and additive pharmacological effects

Additive antidepressant effect in treatment-refractory patients; bupropion may mitigate SSRI-induced sexual dysfunction

3-fold increase in venlafaxine level due to inhibited metabolism via CYP2D6, and reduction of level of OD-metabolite Potentiation of noradrenergic effects

May increase vortioxetine levels signi cantly. Recommend reducing dose by 50% when combining

Elevated imipramine level (by 57%) and nortriptyline level (by 200%) with combination; desipramine peak plasma level and half-life

increased 2-fold due to decreased metabolism (via CYP2D6) Seizure threshold may be reduced

DO NOT COMBINE – dopamine metabolism inhibited Washout of 14 days recommended between drugs

Seizure threshold may be reduced

May inhibit CYP2B6-catalysed bupropion hydroxylation; increased plasma bupropion concentration and reduced hydroxybupropion concentration. May affect ef cacy of bupropion and increase risk of seizures

Seizure threshold may be reduced

Increased plasma level of thioridazine due to decreased metabolism via CYP2D6; increased risk of thioridazine-related ventricular arrhythmias and sudden death. DO NOT COMBINE. Washout of 14 days recommended between drugs

Inhibits CYP2D6, leading to decreased metabolism of antipsychotic and/or bupropion – risk of delirium

Decreased AUC of bupropion by 55% via CYP2B6 induction of efavirenz and nevirapine; an increase in bupropion dose may be required, but do not exceed maximum daily bupropion dose

Increased plasma level of bupropion due to decreased metabolism via CYP2B6; risk of seizure

Decreased bupropion AUC by 67% reported via CYP2B6 induction; potential reduced ef cacy of bupropion Increased plasma level of β-blocker possible due to inhibited metabolism via CYP2D6

Bupropion may antagonize the functional impairment and drowsiness associated with diazepam; bupropion is contraindicated during abrupt withdrawal of benzodiazepines due to an additive decrease in seizure threshold

Seizure threshold may be reduced

Decreased metabolism (hydroxylation) of bupropion via CYP2B6; interaction with combined oral contraceptive is unlikely to be clinically signi cant

Case reports of visual hallucinations with combination

Due to risk of hypertensive reaction through inhibition of MAO by methylene blue, the concurrent use of IV methylene blue and bupropion is contraindicated

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Class of Drug

Example

Interaction Effects

Nicotine transdermal

Combination reported to promote higher rates of smoking cessation than either drug alone Increased risk of hypertension with combination

Nitrogen mustard analog

Cyclophosphamide, ifosfamide

Altered levels of either drug due to competition for metabolism via CYP2B6

Opioid

Tramadol

Increased risk of seizures

Possible decreased analgesic effect due to decreased conversion to the active M1 metabolite

Selective norepinephrine reuptake inhibitor

Atomoxetine

Increased plasma level and half-life of atomoxetine due to inhibited metabolism via CYP2D6 5-fold increase in atomoxetine exposure

St. John’s Wort

Case report of orofacial dystonia due to additive effect on serotonin reuptake

Sympathomimetic

Methylphenidate Pseudoephedrine

Case reports of grand mal seizures and myocardial infarction associated with concurrent use with methylphenidate

Report of manic-like reaction with pseudoephedrine Seizure threshold may be reduced

Tamoxifen

Combination appears to reduce the conversion of tamoxifen to its active metabolite (endoxifen) and may decrease the therapeutic ef cacy of this drug

Theophylline

Seizure threshold may be reduced

Serotonin Norepinephrine Reuptake Inhibitors (SNRI)

Product Availability∗

Generic Name

Chemical Class

Trade Name(A)

Dosage Forms and Strengths

Desvenlafaxine

Bicyclic (phenethylamine)

Khedezla(B), Pristiq

Extended-release tablets: 25 mg(B), 50 mg, 100 mg

Duloxetine

Bicyclic (phenethylamine)

Cymbalta, Irenka(B)

Capsules, delayed-release pellets: 20 mg(B) , 30 mg, 40 mg(B) ,60 mg

Levomilnacipran

Bicyclic (phenethylamine)

Fetzima

Fetzima Titration

Extended-release capsules: 20 mg, 40 mg, 80 mg, 120 mg Extended-release capsules (28 pack): 20 mg, 40 mg

Venlafaxine

Bicyclic (phenethylamine)

Effexor Effexor XR

Tablets(B): 25 mg, 37.5 mg, 50 mg, 75 mg, 100 mg

Extended-release tablets(B): 37.5 mg, 75 mg, 150 mg, 225 mg Extended-release capsules: 37.5 mg, 75 mg, 150 mg

∗ Refer to Health Canada’s Drug Product Database or the FDA’s Drugs@FDA for the most current availability information. (A) Generic preparations may be available,

(B) Not marketed in Canada

Indications‡

( approved)

Major depressive disorder (MDD) – all

Generalized anxiety disorder (GAD) (venlafaxine and duloxetine)

Social anxiety disorder (venlafaxine)

Panic disorder with or without agoraphobia (venlafaxine)

Pain due to diabetic peripheral neuropathy (duloxetine)

Pain due to bromyalgia (duloxetine)

Chronic musculoskeletal pain: low back pain and pain due to osteoarthritis of the knee (duloxetine)

‡ Indications listed here do not necessarily apply to all SNRIs or all countries. Please refer to a country’s regulatory database (e.g., US Food and Drug Administration, Health Canada Drug Product Database) for the most current availability information and indications

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 23 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

General Comments

Serotonin Norepinephrine Reuptake Inhibitors (SNRI) (cont.)

• Bipolardisorder:Depressedphase(venlafaxine)

• Treatment-resistantdepression,dysthymia,postpartumdepression,andmelancholicdepression

• OCD–higherdosesofvenlafaxine

• PTSD(venlafaxine,duloxetine)

• Premenstrualdysphoricdisorder(smallstudiesshowedbene twithvenlafaxine)

• ADHDinchildrenandadults–potentialforbene twithvenlafaxineandduloxetine(evidenceisweakfortheseindications)

• Hot ashesinmenopausalwomen–double-blindstudieshaveshownreductionbyvenlafaxine(forwomenwithnaturalorsurgicalmenopauseas

well as a history of breast cancer), desvenlafaxine (natural or surgical menopause), and open label study by duloxetine (for those with concurrent

depression)

• Migraineandtensionheadaches(limiteddatafromsmalltrialsforvenlafaxine)

• Urinaryincontinence,stressinduced(duloxetine)

• Vasomotor symptoms (moderate to severe) and neuropathic pain – desvenlafaxine has shown e ect but for the latter possibly at doses higher

than for depression

• Bingeeating(duloxetine)–preliminarydata

• SNRIs are associated with increased suicidal ideation, hostility, and psychomotor agitation in clinical trials involving children and adolescents. Monitor all patients for worsening depression and suicidal thinking

• Meta-analysis of trials with venlafaxine versus SSRI for depression showed superiority in achieving remission and response but with higher rates of discontinuation due to adverse e ects. Results not reproduced in other meta-analyses[14]

• Desvenlafaxine is the major active metabolite of venlafaxine and does not undergo metabolism via CYP2D6. This may result in a reduced risk of drug interactions

• Levomilnacipranisthemoreactiveenantiomerofmilnacipran,anSNRIapprovedforthetreatmentof bromyalgia(USA)butnocurrentstudiesthat directly compare it to other antidepressant agents. Recent systematic review and network meta-analysis do not indicate any signi cant di erences in bene ts from levomilnacipran compared to other second-generation antidepressant agents

• Potent uptake inhibitors of serotonin and norepinephrine; venlafaxine inhibits NE reuptake at doses above 150 mg, while duloxetine has equal a nity to both NE and serotonin transporter “reuptake” proteins; inhibition of dopamine reuptake occurs at high doses

• Levomilnacipranhasapproximately2-foldgreaterpotencyforinhibitionofnorepinephrinerelativetoserotoninreuptake.Comparedwithdesven- lafaxine, duloxetine, and venlafaxine, levomilnacipran has more than 10-fold higher selectivity for norepinephrine relative to serotonin reuptake inhibition

• Note: higher selectivity for norepinephrine occurs at lowest e ective dose; as dose is titrated upwards, levomilnacipran has equipotent e ects on 5HT and NE transporters and no e ects on dopamine transporters

• Seep.83

• Desvenlafaxine:Initiatedrugat50mgoncedaily–usualmaintenancedose;dosemaybeincreasedto100mg/dayifneeded.Inpatientswithrenal

insu ciency (CrCl 30–50 mL/min), use maximum of 50 mg/day; if less than 30 mL/min, use 50 mg every other day. A meta-analysis[15] of registration

trials showed no increased e cacy with doses greater than 50 mg/day; however, adverse e ects and discontinuations increase with dose

• Duloxetine: Initiate drug at 30–60 mg daily; 30 mg daily may be considered to improve tolerability (e.g. lower incidence of nausea), with a target dose of 60 mg daily within 1–2 weeks. Although 120 mg is e ective, there is no evidence that it confers additional bene t. AVOID in severe renal insu ciency as AUC increased 100% and metabolites increase up to 9-fold; in hepatic disorders, AUC increased 5-fold and half-life increased 3-fold

• Levomilnacipran: Initiate drug at 20 mg once daily for 2 days, increase to 40 mg once daily, may then be increased in increments of 40 mg at intervals of 2 or more days; maintenance: 40–120 mg once daily; maximum: 120 mg/day. In patients with renal insu ciency (CrCl 30–59 mL/min), use maximum of 80 mg/day; if CrCl 15–29 mL/min, use maximum of 40 mg/day. Use not recommended in end-stage renal disease (ESRD). No

adjustments necessary for any hepatic impairment or in the elderly

Pharmacology

Dosing

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Pharmacokinetics

Onset & Duration of Action

• Venlafaxine:Initiatedrugat37.5–75mg(oncedailyforXRpreparation,twicedailyforregularpreparation)andincreaseafter1weekinincrements no greater than 75 mg q 4 days, up to 225 mg/day for moderately depressed patients. There is very limited experience at higher doses (375 mg/day) in severely depressed inpatients. Decrease dose by 50% in hepatic disease and by 25–50% in renal disease. For panic disorder, start at 37.5 mg/day. For social anxiety disorder, there is no evidence that doses above 75 mg/day confer any additional bene t

• Seep.83

• Desvenlafaxine:WellabsorbedfromGItract;foodhasnoe ectonabsorption;peakplasmaconcentrationreachedinabout7.5handmeanhalf-life

is about 11 h. Metabolized primarily in the liver by UGT conjugation and, to a lesser extent, by CYP3A4; potentially lower risk for signi cant drug

interactions. Steady state achieved in 4 days

• Duloxetine:Canbegivenwithorwithoutmeals,althoughfooddelaysTmaxby6–10h.Bioavailabilityisreducedbyabout30%insmokers.Duloxetine

is metabolized by CYP1A2 and 2D6 and is an inhibitor of CYP2D6; potential risk for drug interactions and susceptibility to genetic polymorphism;

elimination half-life increased from 12 h (mean) to 47.8 h (mean) in patients with liver impairment

• Levomilnacipran: Can be given with or without food; bioavailability is 92%. Peak plasma concentration Cmax is reached in 6–8 h and mean half-life

is about 12 h. Metabolized in the liver primarily by CYP3A4, therefore if utilized with strong CYP3A4 inhibitor recommendations to not exceed 80 mg/day; with minor contributions by CYP2C8, CYP2C19, CYP2D6 to inactive metabolites. Levomilnacipran and its metabolites are eliminated primarily by renal excretion. Approximately 58% of dose is excreted in urine as unchanged levomilnacipran. N-desethyl levomilnacipran is the major metabolite excreted in urine and accounts for approximately 18% of the dose. The metabolites are inactive. Displays linear pharmacoki- netics over the therapeutic dosage range (and up to 300 mg). No clinically relevant e ects of gender, age, bodyweight or hepatic impairment on pharmacokinetics

• Venlafaxine:WellabsorbedfromGItract,foodhasnoe ectonabsorption;absorptionofXRformulationisslow(15±6h);peakplasmalevel(Cmax) reached by parent drug in 1–3 h and by active metabolite (O-desmethylvenlafaxine, ODV) in 2–6 h; with XR formulation, Cmax reached by parent drug in 6 h and metabolite in 8.8 h (mean). Elimination half-life of oral tablet: Parent = 3–7 h and metabolite = 9–13 h; XR elimination half-life is dependent on absorption half-life (15 h mean). Steady state of parent and metabolite reached in about 3 days. Parent drug metabolized by CYP2D6 and is also a weak inhibitor of this enzyme; ODV metabolite is metabolized by CYP3A3/4; potential risk for drug interactions and susceptibility to genetic polymorphism

• Therapeutice ectonemotional/psychologicalsymptomscantakeupto28daysorlonger(thoughsomepatientsmayrespondsooner)butphysical symptoms may respond sooner (within 1-2 weeks)

• Generallydose-related;seechartp.79forincidenceofadversee ects

• Bothsedationandinsomniareported;prolongedsleeponsetlatency,disruptionofsleepcycle,decreasedREMsleep,increasedawakenings,reduced sleep e ciency, vivid nightmares

• Headachecommon

• Nervousness,agitation,hostility,suicidalurges

• Asthenia,fatigue,di cultyconcentrating,decreasedmemory–morelikelywithhigherdosesofvenlafaxine

• Risk of hypomania/mania estimated to be 0.5% with venlafaxine, 0.1% with desvenlafaxine in Phase 2 and 3 studies, 0.1% with duloxetine in

placebo-controlled trials; caution in bipolar patients with comorbid substance abuse

• 10–30% of patients on venlafaxine who improve initially can have breakthrough depression after several months (“poop-out syndrome”) – an

increase in dosage or augmentation therapy may be of bene t

• Seizuresreportedrarely(lessthan2%)withvenlafaxine,desvenlafaxine,levomilnacipran;doserelated

• Casereportsofrestlesslegsyndrome,periodiclimbmovement,andmyoclonuswithvenlafaxine

• Extrapyramidalsymptomsreportedwithduloxetineandlevomilnacipran[16]

Adverse Effects

CNS Effects

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 25 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Serotonin Norepinephrine Reuptake Inhibitors (SNRI) (cont.)

• Drymouthcommon

• Urinary retention; cases of urinary frequency and incontinence in females on venlafaxine as well as reports of both retention and hesitancy with

duloxetine; dose-related side e ect of levomilnacipran, with case reports indicating successful treatment with tamsulosin

• Constipation

• Mydriasis; cases of elevated ocular pressure in patients with narrow-angle glaucoma (duloxetine and levomilnacipran contraindicated for those

with uncontrolled narrow angle glaucoma)

• Increased blood pressure: Venlafaxine/desvenlafaxine: Modest, sustained increase in blood pressure can occur, usually within 2 months of dose stabilization; seen in over 3% of individuals on less than 100 mg/day of venlafaxine and up to 13% of individuals on doses above 300 mg/day of immediate-release drug, and 3–4% with sustained-release product. Duloxetine is associated with case reports of increase in blood pressure and, rarely, hypertensive crisis.

• Levomilnacipran:Asexpectedfortheclass,someindividualsexperiencedincreasesinheartrateandbloodpressure

• Tachycardia;increaseby4beats/min–morelikelyintheelderly

• Dizzinessandorthostatichypotensioncommon

• QTcprolongation:Venlafaxineattherapeuticdosesmaynothaveanyclinicallysigni cantconcernbutcanoccurinsituationsofoverdoseandwhen

used in the elderly; desvenlafaxine and levomilnacipran do not seem to have any clinically relevant impact but data for both are limited; duloxetine has no e ect on QTc interval

• Noweightgainreported

• MinorchangesinbloodglucoseandcholesterolareinfrequentlynotedwithallSNRIs

• IncidenceofhyponatremiainsomestudiesfoundtobecomparabletoSSRIs,higherriskintheelderlyandwithconcurrentuseofdiuretics

• Nauseaandvomitingoccurfrequentlyatstartoftherapyandtendstodecreaseafter1–2weeks;lessfrequentwithXRformulationofvenlafaxine but higher rates than with SSRIs and duloxetine; 22–43% incidence with duloxetine – most common side e ect; 17% incidence with levomilnacipran – most common side e ect

• Casereportofglossodynia(burningmouthsyndrome)inafemaleonvenlafaxine

• Sexualsidee ectsreportedinclude:Decreasedlibido,delayedorgasm/ejaculation,anorgasmia,noejaculation,anderectiledysfunction(seeSSRIs p. 7 for suggested treatments)

• Riskincreasedwithincreasingage,useofhigherdoses,andconcomitantmedication

• No large studies comparing venlafaxine to SSRIs but one small study found that rates of sexual dysfunction for venlafaxine were between those

for moclobemide and the SSRIs paroxetine and sertraline

• Duloxetineappearstohavesigni cantlyfewersexualdysfunctione ectsthantheSSRIs

• Levomilnacipran may cause dose-related erectile dysfunction, ejaculatory disorder, and testicular pain; spontaneous reports of sexual dysfunction

were greater than with placebo

• Sweating(inmorethan10%)

• Riskofbonefractures:Cautionintheelderlyandthosewithlowbonedensity

• Hepatotoxicity–duloxetineandvenlafaxine:Casesofhepatitisaccompaniedbyabdominalpain,hepatomegaly,andserumtransaminaseconcen-

trations more than 20 times the upper limit of normal, with or without jaundice, have been reported during postmarketing surveillance. Elevation in serum transaminase concentrations has in some cases required the discontinuation of duloxetine. Laboratory ndings suggestive of severe hepatic injury with evidence of cholestasis were reported in 3 patients who received duloxetine in clinical studies. Case reports of elevated hepatic enzyme levels, hepatitis, bilirubinemia, and jaundice with venlafaxine. Case reports of life-threatening toxicity requiring transplantation reported for both

• Epistaxis,bruisingandabnormalbleedingwithvenlafaxine

• Venlafaxine:Casereportsofbreastengorgementandpain,SIADHwithhyponatremia,Stevens-Johnsonsyndrome.Myoclonicjerksoccurfrequently

• Duloxetine:Severeskinreactions,includingerythemamultiformeandStevens-Johnsonsyndrome,canoccur

Anticholinergic Effects

Cardiovascular Effects

Endocrine & Metabolic Effects

GI Effects

Urogenital & Sexual Effects

Other Adverse Effects

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Discontinuation Syndrome

• Abrupt discontinuation may cause a syndrome consisting of dizziness, lethargy, nausea, vomiting, diarrhea, headache, fever, sweating, chills, malaise, incoordination, insomnia, vivid dreams, myalgia, paresthesias, dyskinesias, “electric-shock-like” sensations, tinnitus, visual discoordination, anxiety, irritability, confusion, slowed thinking, disorientation; rarely aggression, impulsivity, hypomania, and depersonalization

• Mostlikelytooccurwithin1–7daysafterdrugstoppedordosedrasticallyreduced,andtypicallydisappearswithin3weeks

• Cases of inter-dose withdrawal reported with regular-release tablet; withdrawal reactions also reported with XR product; withdrawal from ven-

lafaxine can be problematic, with symptom severity occasionally preventing cessation of the medication even when a prolonged taper is used

• Caseofmaniareportedfollowingvenlafaxinetaper,despiteadequateconcomitantmoodstabilizingtreatment

• Althoughlevomilnacipranstudiesreportedcomparableratesofdiscontinuationsymptomsbetweenactivetreatmentandplacebo,gradualtitration

still recommended

☞ THEREFORETHESEMEDICATIONSSHOULDBEWITHDRAWNGRADUALLY(OVERSEVERALWEEKS)AFTERPROLONGEDUSE

• Suggestedtotaperslowlyovera2-weekperiod(somesuggestover6weeks)

• Substitutingonedoseof uoxetine(10or20mg)neartheendofthetapermayhelpinthewithdrawalprocess

• Towithdrawdesvenlafaxine,increasethedosingintervalbygivingiteveryotherday,thenincreasethisintervalgradually

• Monitorallpatientsforworseningdepressionandsuicidalthoughts,especiallyatstartoftherapyandfollowinganincreaseordecreaseindose

• AVOIDduloxetineinpatientswithsevererenalinsu ciency(CrCllessthan30mL/min)

• AVOID duloxetine in patients with underlying liver disease; DO NOT USE in patients with substantial alcohol use, chronic liver disease or hepatic

insu ciency

• AVOIDlevomilnacipraninend-stagerenaldisease

• Donotuseinpatientswithuncontrolledhypertension,asSNRIscancausemodest,sustainedincreasesinbloodpressure[bloodpressuremonito-

ring recommended for all patients]

• MayinducemanicreactioninpatientswithBD

• Serotoninsyndromemayoccur,particularlywhenusedwithotheragentsthata ecttheserotoninsystem

• Treatment with medications that inhibit the serotonin transporter may be associated with abnormal bleeding, particularly when combined with

NSAIDs, acetylsalicylic acid, or other medications that a ect coagulation

• FatalityratessecondarytooverdoseweresecondtothatofTCA

• Symptoms of toxicity include vomiting, excess adrenergic stimulation, mydriasis, tachycardia, hypotension, arrhythmias, increase in QTc interval,

bowel dysmotility, decreased level of consciousness, seizures – increased risk of fatal outcomes following overdose

• Delayedonsetrhabdomyolysis

• Fatal outcomes have been reported for acute overdoses, primarily with mixed overdoses, but also with duloxetine alone, at doses as low as

1000 mg. Signs and symptoms of overdose (duloxetine alone or with mixed drugs) included somnolence, serotonin syndrome, seizures, vomiting,

and tachycardia

• There is limited clinical experience with desvenlafaxine overdosage in humans. No cases of fatal acute overdose reported in premarketing clinical

trials. The most common symptoms associated with desvenlafaxine overdose are headache, vomiting, agitation, dizziness, nausea, constipation, diarrhea, dry mouth, paresthesia, and tachycardia. Desvenlafaxine is the major active metabolite of venlafaxine. Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI antidepressant products, but lower than that of tricyclic antidepressants

• Epidemiological studies have shown that venlafaxine-treated patients have a higher burden of suicide risk than SSRI patients; high risk of QTc prolongation in overdose

• Cardiactoxicityandserotoninsyndromereportedinawomanwhoingested3goflevomilnacipran

• FordetailedinformationontheuseofSNRIsinthispopulation,pleaseseetheClinicalHandbookofPsychotropicDrugsforChildrenandAdolescents[7]

• CAUTION: No approved indications in children and adolescents; recommend against using venlafaxine in pediatric patients due to lack of e cacy

and concerns about increased hostility and suicidal ideation (rate 2% vs. placebo 1%)

Management

Precautions

Toxicity

Pediatric Considerations

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 27 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Serotonin Norepinephrine Reuptake Inhibitors (SNRI) (cont.)

• Dosage adjustments in healthy elderly patients are not usually required; 14% increase in metabolite level and 24% increase in half-life reported with venlafaxine

• Canincreaseheartrateinfrailelderly,relatedtoitsnoradrenergicactivity;increasedcardiovascularandcerebrovascularadversee ectsreported

• Hyponatremiareportedinolderaldults

• Clearanceofdesvenlafaxinedecreasedintheelderly;higherincidenceoforthostatichypotension

• MonitorforSIADH

• Extrapyramidale ectshavebeenreportedwithduloxetine;theyarenotdoserelatedandcandevelopwithshort-termorlong-termuse

• Fourlevomilnacipranstudiesincludedpatientsolderthan65years

• Duloxetine and venlafaxine have been associated with increased risk of postpartum hemorrhage; venlafaxine has also been associated with an increased risk of hypertension during pregnancy

• Noteratogenice ectsreportedinhumanswithvenlafaxine;theremaybeatrendtowardhigherratesofspontaneousabortion;useofduloxetine during pregnancy is associated with an increased risk of spontaneous abortion; one study suggests an absolute risk of 18%, and another suggested a trebled relative risk

• Neonatesexposedtovenlafaxineanddesvenlafaxineinthirdtrimesterhavedevelopedcomplicationsupondeliveryincludingrespiratorydistress, temperature instability, feeding di culties, agitation, irritability, changes in muscle tone, and seizures

• No developmental toxicity or other signs of toxicity were observed in an infant exposed to duloxetine during the second half of gestation and during breast-feeding in the rst 32 days after birth[17]

• Therearenoadequatewell-controlledstudiesoflevomilnacipraninpregnantwomen

• ThetotaldoseofvenlafaxineanditsODVmetaboliteingestedbyabreastfedinfantcanbeashighas9.2%ofthematernaldose

• Anexclusivelybreastfedinfantwouldreceiveanestimated5.7–7.4%ofthematernalweight-adjusteddoseofdesvenlafaxine

• Infantexposuretoduloxetineinbreastmilkislessthan1%ofthematernalweight-adjusteddose,implyingthatawomanreceivingduloxetinecan

probably safely breast feed her infant

• Thee ectoflevomilnacipranonlactationandnursinginhumansisunknown

• Agradualtitrationofdosageatstartoftherapywillminimizenausea

• Psychotherapyandeducationarealsoimportantinthetreatmentofdepression

• Monitortherapybywatchingforadversee ectsaswellasmoodandactivitylevelchangesincludingworseningofsuicidalthoughts,especiallyat

start of therapy or following an increase or decrease in dose; keep physician informed

• Beawarethatthemedicationmayincreasepsychomotoractivity;thismaycreateconcernaboutsuicidalbehavior

• Excessiveingestionofca einatedfoods,drugsorbeveragesmayincreaseanxietyandagitationandconfusethediagnosis

• InstructpatientnottocheworcrushthevenlafaxineXRtablets,theextended-releasedesvenlafaxinetablets,theextended-releaselevomilnacipran

capsules, or the delayed-release duloxetine capsules, but to swallow these sustained-release products whole. Venlafaxine XR capsules may be opened and the contents sprinkled onto applesauce. This drug/food mixture should be swallowed immediately without chewing and followed with a glass of water

• Ifadoseismissed,donotattempttomakeitup;continuewithregulardailyschedule(divideddoses)

• SNRIsshouldnotbestoppedsuddenlyduetoriskofprecipitatingawithdrawalreaction;desvenlafaxinecanbewithdrawnbygraduallyincreasing

the dosing interval

• Patientstakingdesvenlafaxinemayseean“empty”tabletintheirstoolsincetheouterinerttabletdoesnotdissolve

• Fordetailedpatientinstructionsonvenlafaxine,seethePatientInformationSheet(detailsp.440) ♢ See p. 439 for further information on drug use in pregnancy and e ects on breast milk

Geriatric Considerations

Use in Pregnancy♢

Breast Milk

Nursing Implications

Patient Instructions

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Drug Interactions

• Clinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterforthesecondagent

Example

Clonidine

Acetylsalicylic acid (see NSAID)

Flecainide, propafenone

Quinidine

Cipro oxacin, enoxacin Clarithromycin, telithromycin

Linezolid

Antiparkinsonian agents, antipsychotics, etc.

Apixaban, dabigatran, rivaroxaban, warfarin

Stiripentol

Paroxetine, uoxetine Fluvoxamine Bupropion

Nefazodone Trazodone

Mirtazapine Imipramine Desipramine

Trimipramine Moclobemide

Phenelzine

Fluconazole, itraconazole, ketoconazole

Diphenhydramine

Class of Drug Interaction Effects

Alcohol

α2 agonist Analgesic Antiarrhythmic

Antibiotic

Anticholinergic

Anticoagulant

Anticonvulsant Antidepressant

SSRI

NDRI

SARI

NaSSA Nonselective cyclic

RIMA

Irreversible MAOI

Antifungal

Antihistamine Antihypertensive

Increased risk of psychomotor impairment and hepatotoxicity

Inhibition of antihypertensive effect of clonidine

Increased risk of upper GI bleeding with combined use

Increased plasma level of venlafaxine and duloxetine due to inhibited metabolism via CYP2D6 Duloxetine may increase plasma levels of propafenone

Increased plasma level of duloxetine due to inhibited metabolism

Increased plasma level of duloxetine due to inhibition of metabolism via CYP1A2

Increased plasma level of levomilnacipran due to inhibited methabolism vial CYP3A4. Do not exceed a maximum of 80 mg/day Due to linezolid’s weak MAOI activity, monitor for increased serotonergic and noradrenergic effects

Increased anticholinergic effects

Increased risk of bleeding possible due to decreased platelet aggregation secondary to depletion of serotonin in platelets Strong CYP3A4 inhibitors may increase levomilnacipran concentrations signi cantly. Do not exceed a maximum of 80 mg/day

Reports that combination with SSRIs that inhibit CYP2D6 can result in increased levels of venlafaxine and duloxetine, with possible increases in blood pressure, anticholinergic effects, and serotonergic effects

6-fold increase in AUC, 2.5-fold increase in Cmax, and 3-fold increase in half-life of duloxetine due to inhibited metabolism via CYP1A2 (AVOID concomitant use)

3-fold increase in venlafaxine plasma level due to inhibited metabolism via CYP2D6 and reduction in level of ODV metabolite Potentiation of noradrenergic effects

Bupropion may mitigate SNRI-induced sexual side effects

May increase plasma level of levomilnacipran through inhibition of CYP3A4

Case report of serotonin syndrome with venlafaxine

Cmax and AUC of imipramine increased by 40% with venlafaxine

Desipramine (metabolite) clearance reduced by 20% with venlafaxine; desipramine level increased 3-fold with duloxetine

Increased levels of cyclic antidepressants metabolized by CYP2D6 possible with duloxetine

Case report of seizure in combination with venlafaxine – postulated to be a result of inhibited metabolism via CYP2D6

Enhanced effects of norepinephrine and serotonin; CAUTION – no data on safety with combined use

AVOID; possible hypertensive crisis and serotonergic reaction

Strong CYP3A4 inhibitors may increase levomilnacipran concentrations signi cantly. Do not exceed a maximum of 80 mg/day Moderate CYP3A4 inhibitors may increase levomilnacipran levels

Decreased metabolism of venlafaxine via CYP2D6

Case reports of hypertension with use of SNRIs for patients previously well controlled with antihypertensives; reduction in SNRI dose or stopping SNRIs altogether may be required

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 29 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Example

Clopidogrel

General

Haloperidol Thioridazine

Clozapine

Risperidone Aripiprazole

Delavirdine, efavirenz

Indinavir Ritonavir

Propranolol

Nicardipine Verapamil

Cimetidine

Zolpidem

Selegiline (L-deprenyl)

Meperidine Tramadol

Class of Drug

Antiplatelet Antipsychotic

First generation

Second generation

Third generation

Antiretroviral

Non-nucleoside reverse transcriptase inhibitor (NNRTI)

Protease inhibitor

β-blocker

Calcium channel blocker

Diuretic

H2 antagonist

Hypnotic/sedative Lithium

Licorice Lomitapide L-tryptophan

MAO-B inhibitor Methylene blue Metoclopramide NSAID

Opioid

Serotonin Norepinephrine Reuptake Inhibitors (SNRI) (cont.)

Interaction Effects

Increased risk of upper GI bleeding with combined use

Increased levels of antipsychotics metabolized by CYP2D6 possible with duloxetine

Increased Cmax and AUC of haloperidol with venlafaxine; no change in half-life

Increased plasma level of venlafaxine and decreased concentration of ODV metabolite

Increased plasma levels of thioridazine and other phenothiazines possible with duloxetine due to inhibition of CYP2D6 – AVOID duloxetine and CAUTION with other SNRIs due to possible additive prolongation of QTc interval

Increased levels of both clozapine and venlafaxine possible due to competitive inhibition of CYP2D6 and/or CYP3A4. A study with venlafaxine doses of 150 mg/day or less suggests no clinically signi cant interaction. Case report of NMS/serotonin syndrome Increased AUC of risperidone by 32% and decreased renal clearance by 20% with venlafaxine

Case report of parkinsonism with venlafaxine 225 mg/day and aripiprazole 15 mg/day

Strong CYP3A4 inhibitors (cobicistat, delavirdine) may increase levomilnacipran concentrations signi cantly. Do not exceed a maximum of 80 mg/day

Moderate CYP3A4 inhibitors (efavirenz) may increase levomilnacipran levels

Both increases (by 13%) and decreases (by 60%) in total concentration (AUC) of indinavir reported with venlafaxine

Ritonavir moderately decreases clearance of venlafaxine

Increased plasma level of venlafaxine due to competition for metabolism via CYP2D6

Strong CYP3A4 inhibitors may increase levomilnacipran concentrations signi cantly. Do not exceed a maximum of 80 mg/day Moderate CYP3A4 inhibitors may increase levomilnacipran levels

Concurrent use of diuretics may increase risk of developing hyponatremia

Increased plasma level of venlafaxine due to decreased clearance (by 43%); peak concentration increased by 60%

Increased plasma level of duloxetine due to inhibited metabolism

Case report of delirium and hallucinations with venlafaxine

Case report of serotonin syndrome with venlafaxine (see p. 9)

Increased serotonergic effects possible

Moderate CYP3A4 inhibitors may increase levomilnacipran levels

Additive effects with duloxetine in treatment-resistant patients

May potentiate the risk of serotonin syndrome. Monitor for increased serotonergic effects

Case reports of serotonergic reaction with venlafaxine

Enhanced serotonergic effects through inhibition of MAO-A and B by methylene blue. Risk for serotonin syndrome (see Precautions) Case report of extrapyramidal and serotonergic effects with venlafaxine

Increased risk of upper GI bleed with combined use. CAUTION

Increased risk of serotonin syndrome

Increased risk of seizures and serotonin syndrome

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Class of Drug

Example

Interaction Effects

St. John’s Wort

May augment serotonergic effects – increased risk of serotonin syndrome

Stimulant

Dextroamphetamine Methylphenidate

Case report of serotonin syndrome with venlafaxine Potentiated effect in the treatment of depression and ADHD

Tolterodine

Cmax and half-life of tolterodine increased; no effect on active metabolites

Triptan

Rizatriptan, Sumatriptan

Inadequate data available to determine the risk of serotonin syndrome with the addition of a triptan to SNRIs. However, given the seriousness of serotonin syndrome, caution is warranted

Serotonin-2 Antagonists/Reuptake Inhibitors (SARI)

Product Availability∗

∗ Refer to Health Canada’s Drug Product Database or the FDA’s Drugs@FDA for the most current availability information. (A) Generic preparations may be available,

(B) Not marketed in Canada,

Generic Name

Chemical Class

Trade Name(A)

Dosage Forms and Strengths

Nefazodone(B)

Phenylpiperidine

Serzone

Tablets: 50 mg, 100 mg, 150 mg, 200 mg, 250mg

Trazodone

Triazolopyridine

Desyrel Oleptro(C)

Tablets: 50 mg, 75 mg(C), 100 mg, 150 mg, 300 mg(B) Extended-release caplets: 150 mg, 300 mg

Indications‡

( approved)

Major depressive disorder (MDD)

• Secondarydepressioninothermentalillnesses(e.g.,schizophrenia,dementia)

• MDD,recurrent:Prophylaxis

• Agoraphobiaassociatedwithpanicdisorder

• Dysthymia

• Socialphobia

• Posttraumaticstressdisorder(PTSD)

• Insomnia

• Impotence,erectiledysfunction(trazodone),anorgasmia(nefazodone)

• Fibromyalgia,inopen-labelstudies–monitorfortachycardia

• Diabeticneuropathy

• Antipsychotic-inducedakathisia

• Bulimia

• Benzodiazepineabuse

• Schizophrenia:Negativesymptoms(trazodone)

• Behavioralandpsychologicalsymptomsofdementia(BPSD)

General Comments

• NefazodonewaswithdrawninCanadainNovember2003duetoriskofhepatotoxicity

• Trazodoneincreasesslow-wave(stage3–4)sleep

• Monitorallpatientsforworseningdepressionand/orsuicidalthoughts

‡ Indications listed here do not necessarily apply to all SARIs or all countries. Please refer to a country’s regulatory database (e.g., US Food and Drug Administration, Health Canada Drug Product Database) for the most current availability information and indications

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 31 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Pharmacology

Dosing

Serotonin-2 Antagonists/Reuptake Inhibitors (SARI) (cont.)

• Exact mechanism of action unknown; equilibrate the e ects of biogenic amines through various mechanisms; cause downregulation of β-adrenergic receptors

• Trazodone[18]: Potent antagonist of the 5-HT2A receptor as well as a dose-dependent blockade of serotonin transporter; also blocks 5-HT2C, α1, and H1 receptors

• Nefazodone: Inhibits neuronal reuptake of serotonin and norepinephrine; also blocks 5-HT2A/C receptors and α1 receptors; has no signi cant a nity for α2, β-adrenergic, 5-HT1A, cholinergic, dopaminergic, or benzodiazepine receptors

• Seep.83

• Initiatedrugatalowdoseandincreasedoseevery3–5daystoamaximumtolerateddosebasedonsidee ects;thereisawidevariationindosage

requirements; prophylaxis is most e ective if therapeutic dose is maintained

• Trazodonedosesof25–100mgatbedtimeusedinchronicsleepdisorders

• For treatment of depression with trazodone regular-release formulation: start with 150-200 mg/day in 2 or 3 divided doses; usual maximum is

300 mg/day in divided doses

• Dosesoftrazodoneupto400mgand,rarely,600mghavebeenusedinhospitalizedpatients

• Trazodone should be taken on an empty stomach when used for sedation, as food delays absorption, but otherwise should be taken after a light

meal or snack to reduce side e ects

• XR formulation (Oleptro) dosing: 150–375 mg daily, should be given on an empty stomach in the late evening, caplets can be halved along score

line but should not be crushed or chewed

• Seep.83

• CompletelyabsorbedfromtheGItract;foodsigni cantlydelays(from1toseveralh)anddecreasespeakplasmae ectofregular-releasetrazodone;

peak plasma level of XR formulation not a ected by food

• Nefazodonebioavailabilityonly20%duetohigh rst-passmetabolism;canbegivenwithoutregardtomeals

• Highly bound to plasma protein (trazodone 85–95%; nefazodone more than 99%)

• Metabolizedprimarilybytheliver;half-lifeofnefazodoneisdosedependent,varyingfrom2hat100mg/dayto4–5hat600mg/day;half-lifeand

AUC of nefazodone and hydroxy metabolite doubled in patients with severe liver impairment

• Trazodone metabolized by CYP3A4 to active metabolite m-chlorophenylpiperazine (mCPP); elimination half-life 4–9 h in adults and 11.6 h (mean)

in the elderly; steady state reached in about 3 days

• NefazodoneisapotentinhibitorofCYP3A4andmaydecreasethemetabolismofdrugsmetabolizedbythisisoenzyme(seeInteractionspp.35–37)

• Regularingestionofgrapefruitjuicewhileonnefazodonemaya ecttheantidepressantplasmalevel(seeInteractionsp.37)

• Therapeutice ectistypicallyseenafter28days(thoughsomepatientsmayrespondsooner)

• Sedativee ectsareseenwithinafewhoursoforaladministration;decreasedsleepdisturbancereportedafterafewdays

• The pharmacological and side e ect pro le of SARI antidepressants is dependent on their a nity for and activity on neurotransmitters/receptors (see table p. 77)

• Seechartp.79forincidenceofadversee ectsattherapeuticdoses;incidenceofadversee ectsmaybegreaterinearlydaysoftreatment;patients adapt to many side e ects over time

• A result of antagonism at histamine H1 receptors and α1 adrenoreceptors

• Occurfrequently

• Drowsiness(mostcommonadversee ect;reportedin20–50%)[Management:Prescribebulkofdoseatbedtime]

• Weakness,lethargy,fatigue

• Conversely,excitement,agitation,andrestlessnesshaveoccurred

Pharmacokinetics

Onset & Duration of Action

Adverse Effects

CNS Effects

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

• Confusion,disturbedconcentration,anddisorientation

• NefazodoneincreasesREMsleepandsleepquality

• Improved psychomotor and complex memory performance reported with nefazodone after single doses; dose-related impairment noted after

repeated doses

• Precipitationofhypomaniaormania,increasedriskinbipolarpatientswithcomorbidsubstanceabuse

• Psychosis,panicreactions,anxietyoreuphoriamayoccur

• Finetremor

• Akathisia(rare–checkserumironforde ciency)

• Seizurescanoccurrarelyfollowingabruptdrugincreaseorafterdrugwithdrawal;riskincreaseswithhighplasmalevels

• Myoclonus;includesmusclejerksoflowerextremities,jaw,andarms,andnocturnalmyoclonus–maybesevereinupto9%ofpatients[Ifsevere,

clonazepam, valproate or carbamazepine may be of bene t]

• Dysphasia,stuttering

• Disturbanceingait,parkinsonism,dystonia

• Headache;worseningofmigrainereportedwithtrazodoneandnefazodone

• Aresultofantagonismatmuscarinicreceptors

• Includedryeyes,blurredvision,constipation,drymouth[seep.53fortreatmentsuggestions]

• A result of antagonism at α1 adrenoreceptors, muscarinic, 5-HT2A/C, and H1 receptors, and inhibition of sodium fast channels

• Morecommonintheelderly

• Riskincreaseswithhighplasmalevels

• Bradycardiaseenwithnefazodone

• Dizziness(10–30%),orthostatichypotension,andsyncope

• Trazodonecanexacerbateischemicattacks;arrhythmiasreported(withdosesabove200mg/day)includingtorsadesdepointes

• Cases of prolonged conduction time with trazodone and nefazodone (by inhibiting hERG potassium ion channels); contraindicated in heart block

or post-myocardial infarction

• Decreasesinbloodsugarlevelsreported(nefazodone)

• CaninduceSIADHwithhyponatremia;riskincreasedwithage

• Weightgainreportedwithtrazodone;rarewithnefazodone

• A result of inhibition of 5-HT uptake and M1 receptor antagonism

• Peculiartaste,“blacktongue,”glossitis

• Nausea

• ReportsofupperGIbleeding

• A result of altered dopamine (D2) activity, 5-HT2A blockade, inhibition of 5-HT reuptake, α1 blockade, and M1 blockade

• Occurrarely

• Testicularswelling,painfulejaculation,retrogradeejaculation,increasedlibido;spontaneousorgasmwithyawning(trazodone)

• Priapism with trazodone and nefazodone due to prominent α1 blockade in the absence of anticholinergic activity

• Rare

• Rash,urticaria,pruritus,edema,blooddyscrasias

• Jaundice, hepatitis, hepatic necrosis and hepatic failure reported with therapeutic doses of nefazodone (laboratory evidence includes: Increased levels of ALT, AST, GGT, and bilirubin and increased prothrombin time) – cases of liver failure and death reported. Recommend baseline and periodic liver function tests with nefazodone. Monitor for signs of hepatotoxicity

• Casesofpalinopsiawithbothtrazodoneandnefazodoneandscotomawithnefazodone–maybedoserelated

• Rarereportsofalopeciawithnefazodone

• Casereportsofburningsensationsinvariouspartsofthebodywithnefazodone

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 33 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Anticholinergic Effects

Cardiovascular Effects

Endocrine & Metabolic Effects

GI Effects

Urogenital & Sexual Effects

Hypersensitivity Reactions

Other Adverse Effects

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Discontinuation Syndrome

Precautions

Serotonin-2 Antagonists/Reuptake Inhibitors (SARI) (cont.)

• Mostlikelytooccurwithin1–7daysafterdrugstoppedordosedrasticallyreduced,andtypicallydisappearswithin3weeks

• Paradoxicalmoodchangesreportedonabruptwithdrawal,includinghypomaniaormania

☞ THEREFORETHESEMEDICATIONSSHOULDBEWITHDRAWNGRADUALLYAFTERPROLONGEDUSE

• Reinstitutethedrugatalowerdoseandtapergraduallyoverseveraldays

• Trazodone is a substrate for CYP3A4 and its metabolism can be inhibited by CYP3A4 inhibitors; nefazodone is a potent inhibitor of CYP3A4 (see Interactions pp. 35–37)

• UsecautionincombinationwithdrugsthatprolongtheQTinterval

• Priapismhasoccurredwithtrazodonerequiringsurgicalinterventioninonethirdofcases

• Maybearrhythmogenicinpatientswithahistoryofcardiacdisease

• Use nefazodone cautiously in patients in whom excess anticholinergic activity could be harmful (e.g., prostatic hypertrophy, urinary retention,

narrow-angle glaucoma)

• Use nefazodone with caution in patients with respiratory di culties, since antidepressants with anticholinergic properties can dry up bronchial

secretions and make breathing more di cult

• May lower the seizure threshold; therefore, administer cautiously to patients with a history of convulsive disorders, organic brain disease or

a predisposition to convulsions (e.g., alcohol withdrawal)

• May impair the mental and physical ability to perform hazardous tasks (e.g., driving a car or operating machinery); will potentiate the e ects of

alcohol

• Mayinducemanicreactionsinpatientswithbipolardisorderandrarelyinunipolardepression;becauseofriskofincreasedcycling,bipolardisorder

is a relative contraindication

• Use caution in prescribing nefazodone for patients with a history of alcoholism or liver disorder. Monitor liver function tests at baseline and

periodically during treatment, and at rst symptom or clinical sign of liver dysfunction

• CombinationwithSSRIscanleadtoincreasedplasmaleveloftrazodone.Combinationtherapyhasbeenusedinthetreatmentofresistantpatients;

use caution and monitor for serotonin syndrome

• Usecautionwhenswitchingfromtrazodoneto uoxetineandviceversa(seeInteractionspp.35–37,andSwitchingAntidepressantsp.85)

• Treatment with medications that inhibit the serotonin transporter may be associated with abnormal bleeding, particularly when combined with

NSAIDs, acetylsalicylic acid or other medications that a ect coagulation

• Acute poisoning results in drowsiness, ataxia, nausea, vomiting; deep coma as well as arrhythmias (including torsades de pointes) and AV block reported; no seizures reported

• For detailed information on the use of trazodone in this population, please see the Clinical Handbook of Psychotropic Drugs for Children and Adolescents[7]

• Noapprovedindicationsinchildrenandadolescents

• Trazodone used in acute and chronic treatment of insomnia and night terrors, and in MDD and behavior disturbances in children (agitation,

aggression)

• Startdrugatalowdose(10–25mg)andincreasegraduallyby10–25mgevery5daystoamaximumtolerateddosebasedonsidee ects

Management

Toxicity

Pediatric Considerations

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Geriatric Considerations

• Trazodoneisused(o -label)inthetreatmentofbehavioralandpsychologicalsymptomsofdementiaandforinsomnia

• Initiatedoselowerandmoreslowlythaninyoungerpatients;elderlypatientsmaytakelongertorespondandmayrequiretrialsofupto12weeks

before response is noted

• AUCincreasedintheelderly;highestinelderlyfemales

• MonitorforexcessiveCNSandanticholinergice ects

• Caution when combining with other drugs with CNS and anticholinergic properties; additive e ects can result in confusion, disorientation, and

delirium; the elderly are sensitive to anticholinergic e ects

• Cautionregardingcardiovascularsidee ects:Orthostatichypotension(canleadtofalls).Canpotentiatee ectsofantihypertensivedrugs

• Cognitiveimpairmentcanoccur

• Trazodoneinhighdoseswasfoundtobeteratogenicandtoxictothefetusinsomeanimalspecies;trazodoneandnefazodonefoundnottoincrease rates of malformations in humans above the baseline of 1–3%

• Ifpossible,avoidduring rsttrimester

• SARIantidepressantsaresecretedintobreastmilk

• TheAmericanAcademyofPediatricsclassi esSARIantidepressantsasdrugs“whosee ectsonnursinginfantsareunknownbutmaybeofconcern”

• Psychotherapyandeducationarealsoimportantinthetreatmentofdepression

• Monitortherapybywatchingforadversesidee ectsandmoodandactivitylevelchanges,includingworseningofsuicidalthoughts;keepphysician

informed

• Be aware that as the medication reduces the degree of depression it may increase psychomotor activity; this may create concern about suicidal

behavior

• Expectalagtimeofupto28daysbeforeantidepressante ectswillbenoticed

• Reassure patient that drowsiness and dizziness usually subside after rst few weeks; if dizzy, patient should get up from lying or sitting position

slowly, and dangle legs over edge of bed before getting up

• Instructpatienttoavoidingestionofgrapefruitjuice,asthebloodleveloftrazodoneandnefazodonemayincrease

• Excessiveuseofca einatedfoods,drugsorbeveragesmayincreaseanxietyandagitationandconfusethediagnosis

• Thesedrugsshouldnotbestoppedsuddenlyduetoriskofprecipitatingwithdrawalreactions

• Becausethesedrugscancausedrowsiness,cautionpatientthatactivitiesrequiringmentalalertnessshouldnotbeperformeduntilresponsetothe

drug has been determined

• Withnefazodone,monitorforsignsofhepatatoxicity,includingnausea,vomiting,fatigue,pruritus,jaundice,anddarkurine

• Trazodone should be taken on an empty stomach when used for sedation, as food delays absorption, but otherwise should be taken after a light

meal or snack to reduce side e ects

• Ingestionofgrapefruitjuicewhiletakingnefazodoneshouldbeavoidedasthebloodleveloftheantidepressantmayincrease

• FordetailedpatientinstructionsonSARIantidepressants,seethePatientInformationSheet(detailsp.440)

• Clinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterforthesecondagent

Use in Pregnancy♢

Nursing Implications

Breast Milk

Patient Instructions

Drug Interactions

♢ See p. 439 for further information on drug use in pregnancy and e ects on breast milk

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 35 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Serotonin-2 Antagonists/Reuptake Inhibitors (SARI) (cont.) Class of Drug Interaction Effects

Example

Linezolid

Macrolide (clarithromycin, erythromycin)

Antihistamines, antiparkinsonian agents

Apixaban, dabigatran, rivaroxaban, warfarin

Barbiturates, carbamazepine, phenytoin

Carbamazepine, phenytoin

Fluoxetine, uvoxamine, paroxetine, sertraline

Venlafaxine

Levomilnacipran Moclobemide

Phenelzine, tranylcypromine

Ketoconazole

Acetazolamide, thiazide diuretics Clonidine

Guanethidine, methyldopa

Chlorpromazine, haloperidol, perphenazine

Pimozide

Clozapine, olanzapine, quetiapine, risperidone

Lurasidone

Alcohol Antibiotic

Anticholinergic Anticoagulant Anticonvulsant

Antidepressant

SSRI

SNRI

RIMA

Irreversible MAOI

Antifungal Antihypertensive

Antipsychotic

First generation Second generation

Short-term or acute use reduces rst-pass metabolism of antidepressant and increases its plasma level; chronic use induces metabolizing enzymes and decreases its plasma level

Monitor for increased serotonergic effects due to weak MAOI activity of linezolid

Increased plasma level and decreased clearance of trazodone reported via potent CYP3A4 inhibition by clarithromycin; reduction in trazodone dose may be necessary when used concurrently with macrolides

Increased anticholinergic effect; may increase risk of hyperthermia, confusion, urinary retention, etc.

Increased risk of bleeding possible due to decreased platelet aggregation secondary to depletion of serotonin in platelets

Decreased plasma level of trazodone and its mCPP metabolite (by 76% and 60%, respectively, with carbamazepine) and of nefazodone, due to enzyme induction via CYP3A4

Increased plasma level of carbamazepine or phenytoin, possibly due to competitive inhibition of metabolism via CYP3A4 with trazodone Increased plasma level of carbamazepine with nefazodone due to inhibited metabolism via CYP3A4

Elevated SSRI plasma level (due to inhibition of oxidative metabolism); monitor plasma level and for signs of toxicity Nefazodone metabolite (mCPP) level increased 4-fold with uoxetine; case report of serotonin syndrome with combination Combined use may increase risk of serotonin syndrome

Nefazodone may increase plasma level of levomilnacipran through inhibition of CYP3A4

Monitor for serotonergic effects

Low doses of trazodone (25–50 mg) used to treat antidepressant-induced insomnia

Monitor for serotonergic effects

Increased plasma level of trazodone due to inhibited metabolism via CYP3A4

Hypotension augmented

Additive hypotension and sedation

Decreased antihypertensive effect due to inhibition of α-adrenergic receptors

Potential for additive adverse effects (e.g., sedation, orthostatic hypotension)

Elevated pimozide levels and cardiac arrhythmias may occur with combination

Increased plasma levels of clozapine (case report) and quetiapine (in vitro data), possibly due to inhibited metabolism via CYP3A4 and

associated adverse effects (e.g., dizziness, hypotension)

Case report of NMS with nefazodone and olanzapine

Case report of serotonin syndrome with trazodone, sertraline, and risperidone Contraindicated with concomitant use of potent CYP3A4 inhibitors such as nefazodone

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Example

Interaction Effects

Delavirdine

Potential increased concentration of trazodone via CYP3A4 inhibition; monitor for increased adverse effects

Indinavir, ritonavir

Increased plasma levels of trazodone and nefazodone due to decreased metabolism (with ritonavir, trazodone clearance decreased 52%)

Alprazolam, triazolam Buspirone

Increased plasma levels of alprazolam (by 200%) and triazolam (by 500%), due to inhibited metabolism via CYP3A4 by nefazodone Concomitant use increases the risk of serotonin syndrome

Amlodipine

Elevated amlodipine level due to inhibited metabolism via CYP3A4 with nefazodone

Digoxin

Increased digoxin plasma level, with possible toxicity

Increased sedation and side effects of chloral hydrate due to inhibited metabolism with uoxetine and uvoxamine

Alcohol, antihistamines, benzodiazepines, hypnotics

Increased sedation, CNS depression

Decreased absorption of antidepressant, if given together

Case report of coma with trazodone (postulated to be due to excess stimulation of GABA receptors)

Decreased metabolism of trazodone and nefazodone via CYP3A4

Additive antidepressant effect; monitor for serotonergic effects

Selegiline (L-deprenyl)

Reports of serotonergic reactions

Enhanced serotonergic effects through inhibition of MAO-A and B by methylene blue. Risk for serotonin syndrome (see Precautions)

Tramadol

Increased risk of seizures and serotonin syndrome

Sildena l

Possible enhanced hypotension due to inhibited metabolism of sildena l via CYP3A4 with nefazodone

Atorvastatin, pravastatin, simvastatin

Inhibited metabolism of statins by nefazodone (via CYP3A4); increased plasma level and adverse effects – myositis and rhabdomyolysis reported

May augment serotonergic effects – case reports of serotonergic reactions

Tolbutamide

Increased hypoglycemia

Class of Drug

Antiretroviral

Non-nucleoside reverse transcriptase inhibitor (NNRTI) Protease inhibitor

Anxiolytic

Calcium channel blocker Cardiac glycoside Chloral hydrate

CNS depressant

Cholestyramine

Ginkgo biloba

Grapefruit juice

L-Tryptophan

MAO-B inhibitor

Methylene blue

Opioid

Phosphodiesterase type 5 (PDE5) inhibitor

Statins

St. John’s Wort Sulfonylurea

Serotonin-1A Partial Agonist/Serotonin Reuptake Inhibitor (SPARI) Product Availability∗

∗ Refer to Health Canada’s Drug Product Database or the FDA’s Drugs@FDA for the most current availability information

Generic Name

Chemical Class

Trade Name

Dosage Forms and Strengths

Vilazodone

Indolalkylamine

Viibryd

Tablets: 10 mg, 20 mg, 40 mg

Indications‡

( approved)

Major depressive disorder (MDD) Generalized anxiety disorder (GAD)

‡ Indications listed here do not necessarily apply to all countries. Please refer to a country’s regulatory database (e.g., US Food and Drug Administration, Health Canada Drug Product Database) for the most current availability information and indications

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 37 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Serotonin-1A Partial Agonist/Serotonin Reuptake Inhibitor (SPARI) (cont.)

General Comments

• Anewclassofantidepressants(SPARI)incorporatingtwomechanismsofactionbutitsclinicalpro leremainssimilartoSARIsandSSRIs.Itremains unclear whether vilazodone has any e cacy advantages compared to other serotonergic antidepressant agents as there are no published head- to-head trials. In a double-blind study, nonresponders to citalopram 20 mg/day showed improvement if the dose was increased to 40 mg/day or switched to vilazodone

• Thee cacyofvilazodone(overplacebo)wasestablishedinfour8-to10-week,randomized,double-blind,controlledtrialsinadultpatientswitha diagnosis of MDD; 41–58% of patients on vilazodone had a response compared to 31–47% of patients who received placebo

• The e cacy of vilazodone (over placebo) for generalized anxiety disorder was studied in two 10-week, randomized, double-blind, controlled trials in adults; 46–55% of patients on vilazodone had a response compared to 42–48% of patients who received placebo

• Dual 5-HT1A receptor partial agonist and 5-HT reuptake inhibitor. Vilazodone has greater a nity for the 5-HT1A receptor (IC50 = 0.2nM) compared to serotonin itself; its a nity for the 5-HT reuptake pump (IC50 = 0.5nM) is comparatively lower

• 5-HT1A agonism produces a more rapid desensitization of presynaptic 5-HT1A autoreceptors

• Seep.83

• Initialdoseof10mgoncedailywithfoodfor7days,followedby20mgoncedailyforanadditional7days,andthenincreaseto40mgoncedaily;

slower dose titration helps to minimize GI side e ects

• Somepatientswereunabletoreach40mginclinicaltrialsduetolackoftolerability

• Nodosageadjustmentrequiredinrenalinsu ciencyormoderateliverimpairment

• Givewithfoodasabsorptiondecreasedbyupto50%infastingstate

• Seep.83

• Thepharmacokineticsofvilazodone(5–80mg)aredoseproportional.Vilazodoneconcentrationspeakatamedianof4–5h(Tmax)afteradministra-

tion and decline with a terminal half-life of approximately 25 h

• The bioavailability is 72% with food. Administration with food (high-fat or light meal) increases oral bioavailability (Cmax increased by approximately

147–160%, and AUC increased by approximately 64–85%)

• Distribution:Vilazodoneiswidelydistributedandapproximately96–99%proteinbound

• Metabolism and elimination: Elimination of vilazodone is primarily by hepatic metabolism through CYP and non-CYP pathways (possibly by car-

boxylesterase), with only 1% of the dose recovered in urine and 2% of the dose recovered in feces as unchanged vilazodone. CYP3A4 is primarily responsible for its metabolism, with minor contributions from CYP2C19 and CYP2D6. It has no active metabolites

• Seechartp.79forincidenceofadversee ectsattherapeuticdoses

• Headachewasacommonsidee ect(over10%)butthiswasnodi erenttoplaceboorcitalopram

• In pooled analysis of pivotal trials, dizziness was also a common side e ect (16.5% vs. 3.3% placebo), as were insomnia (11.1% vs. 5.4%), fatigue

(8.7% vs. 3%), and lethargy (6.8% vs. 0.5%)

• Restlessnessandabnormaldreams,nightmaresreportedininitialtrials

• E ects on sleep were speci cally investigated in a randomized crossover study with 10 healthy young men (20 mg single dose); slow-wave sleep

increased in the rst and third one-third of the night, whereas wakefulness was enhanced in the second and third one-third of the night; rapid eye movement almost totally disappeared in patients receiving vilazodone

• A thorough ECG study in healthy volunteers found that vilazodone had no clinically signi cant e ect on heart rate, PR interval, or corrected QT interval, indicating a low potential for it to induce cardiac arrhythmias

Pharmacology

Dosing

Pharmacokinetics

Adverse Effects

CNS Effects

Cardiovascular Effects

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Endocrine & Metabolic Effects

GI Effects

Urogenital & Sexual Effects

Other Adverse Effects

Discontinuation Syndrome

Precautions

• Nostatisticallysigni cantweightgaininthetwopivotaltrials;meanweightincreaseinthelong-termstudywas1.7kg

• Increasedappetitereported,butincidencewaslowandnotsigni cantlydi erenttoplacebo

• InoneGADtrial,ahigherpercentageofvilazodone-treatedpatientscomparedtoplacebo-treatedpatientsshiftedfromnormalbaselinevaluesto

high values at the end of treatment for total cholesterol (18% vs. 11%), glucose (10% vs. 4%), and triglycerides (19% vs. 12 %)

• Diarrhea(>25%)andnausea(>20%)werethemostcommonsidee ects

• Vomiting,dyspepsia,abdominalpain,drymouth,and atulencealsoreported

• Spontaneously-reported sexual side e ects were generally more frequent with vilazodone than placebo in 8- or 10-week trials, decreased libido being most common (4% vs. less than 1 % in men and 2% vs. less than 1% in women for vilazodone 40 mg once daily); in open-label treatment with vilazodone for 1 year, the most frequent sexual function-related adverse e ects were decreased libido (4.2%), erectile dysfunction (4.2%), delayed ejaculation (3.1%), and abnormal orgasm (2.3%)

• In 3 trials prospectively evaluating sexual dysfunction using validated scales, over half of the participants had baseline sexual dysfunction; scores for those whose MADRS score was reduced by ≥ 50% improved in all treatment groups with a small numerical (but not statistically signi cant) di erence between vilazodone (20 mg/40 mg) and placebo relative to citalopram 40 mg

• Hyperhidrosis,nightsweats,blurredvision,arthralgia,tremor,drymouth,anddryeyes

• Mostlikelytooccurwithin1–7daysafterdrugstoppedordosedrasticallyreduced,andtypicallydisappearswithin3weeks

• Paradoxicalmoodchangesreportedonabruptwithdrawal,includinghypomaniaormania

☞ THEREFORETHISMEDICATIONSHOULDBEWITHDRAWNGRADUALLYAFTERPROLONGEDUSE

• Reinstitutethedrugatalowerdoseandtapergraduallyoverseveraldays

• Strong CYP3A4 inhibitors can result in elevated plasma levels of vilazodone, recommended dose reduction to 20 mg/day; alternatively, potent inducers of CYP3A4 can lower plasma levels of the drug and decrease its e ectiveness

• Black-boxwarningregardingincreasedriskofsuicidalthinkingandbehaviorinchildren,adolescents,andyoungadultstakingantidepressantsfor MDD and other psychiatric disorders

• Similartootherantidepressants,vilazodonelabelingcarrieswarningsaboutserotoninsyndrome,seizures,abnormalbleeding,activationofmania/ hypomania (reported in 0.1% of patients in clinical trials), and hyponatremia

• Regularingestionofgrapefruitjuicewhileonvilazodonemayincreasetheantidepressantplasmalevel

• If urgent treatment with linezolid or IV methylene blue is required in a patient already receiving vilazodone and potential bene ts outweigh

potential risks, discontinue vilazodone promptly and administer linezolid or IV methylene blue. Monitor for serotonin syndrome for 2 weeks or until 24 h after the last dose of linezolid or IV methylene blue, whichever comes rst. May resume vilazodone 24 h after the last dose of linezolid or IV methylene blue

• Dosetaperingisrecommendedwhenthedrugisdiscontinued

• Mayimpairplateletaggregation,resultinginincreasedriskofbleedingevents,particularlyifusedconcomitantlywithacetylsalicylicacid,NSAIDs,

warfarin, or other anticoagulants

• Thereislimitedclinicalexperienceregardinghumanoverdose;4patientsand1patient’schildexperiencedanoverdoseandallrecovered

• Casereportofa23-month-old,11kgchildingesting60mgvilazodone(unwitnessed)whodevelopedrecurrentseizureactivityalongwithlethargy, fever, and hyperre exia; managed with supportive care, benzodiazepines, and phenobarbital – patient recovered 24 h following ingestion. No serum

analysis was performed to con rm exposure or establish pharmacokinetic parameters

• The adverse reactions associated with overdose at doses of 200–280mg as observed in clinical trials included serotonin syndrome, lethargy,

restlessness, hallucinations, and disorientation

Management

Toxicity

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 39 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Serotonin-1A Partial Agonist/Serotonin Reuptake Inhibitor (SPARI) (cont.)

Pediatric Considerations

Geriatric Considerations Use in Pregnancy♢

Nursing Implications

• For detailed information on the use of vilazodone in this population, please see the Clinical Handbook of Psychotropic Drugs for Children and Adolescents[7]

• Noapprovedindicationsinchildrenandadolescents

• Thesafetyande cacyofvilazodoneinchildrenandadolescentshasnotbeenadequatelystudied

• No dosage adjustments recommended on the basis of age, renal or mild liver impairment although there is no published data evaluating use in geriatric depression

• GADtrialsincludedpatientsupto70yearsofage

• Therearenoadequate,well-controlledstudiesofvilazodoneinpregnantwomenandnohumandataregardingvilazodoneconcentrationsinbreast milk

• One published case report of vilazodone used in pregnancy: 32-year-old woman unexpectedly became pregnant while on 40 mg/day, continued medication and gave birth to a healthy child. The child experienced transient neonatal jaundice but none of the irritability or feeding or respiratory di culties reported with other serotonergic antidepressants

• Nohumandataregardingvilazodoneconcentrationsinbreastmilk

• Psychotherapyandeducationarealsoimportantinthetreatmentofdepression

• MUSTgivewithamealforfullabsorption

• Instructpatienttoavoidingestionofgrapefruitjuice,asotherwisethebloodlevelofvilazodonemayincrease

• Avoidexcessiveuseofca einatedfoods,drugs,orbeveragesasthesemayincreaseanxietyandagitationthatcanoccurduringinitialtitration

• Monitortherapybywatchingforadversesidee ectsandmoodandactivitylevelchanges,includingworseningofsuicidalthoughts;keepphysician

informed

• Be aware that as the medication reduces the degree of depression it may increase psychomotor activity; this may create concern about suicidal

behavior

• Expectalagtimeofupto28daysbeforeantidepressante ectswillbenoticed,signi cantimprovementmaynotbeseenbefore6weeks

• Reassure patient that most early side e ects usually subside after the rst few weeks; if dizzy, patient should get up from lying or sitting position

slowly and dangle legs over edge of bed before getting up

• Shouldnotbestoppedsuddenlyduetoriskofprecipitatingwithdrawalreactions

• Vilazodone may cause drowsiness; caution patient that activities requiring mental alertness should not be performed until response to the drug

has been determined

• Fordetailedpatientinstructionsonvilazodone,seethePatientInformationSheet(detailsp.440)

• Clinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterforthesecondagent

Breast Milk

Patient Instructions

Drug Interactions

♢ See p. 439 for further information on drug use in pregnancy and e ects on breast milk

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Example

Interaction Effects

Clarithromycin, erythromycin Linezolid

Increased plasma level of vilazodone due to inhibition of metabolism via CYP3A4; reduce dose to maximum of 20 mg May enhance serotonergic effect. May increase risk for serotonin syndrome (see Precautions)

Apixaban, dabigatran, rivaroxaban, warfarin

Increased risk of bleeding possible due to decreased platelet aggregation secondary to depletion of serotonin in platelets

Moclobemide, phenelzine, tranylcypromine

Risk of serotonin syndrome. Contraindicated if used concurrently or within 14 days of stopping

Metoclopramide

May enhance serotonergic effect. May increase risk for serotonin syndrome

Ketoconazole

Increased plasma level of vilazodone due to inhibition of metabolism via CYP3A4; reduce dose to maximum of 20 mg

Pimozide

May enhance antipsychotic side effects due to inhibition of metabolism via CYP3A4

Ritonavir

Increased plasma level of vilazodone due to inhibition of metabolism via CYP3A4; reduce dose to maximum of 20 mg

Buspirone

May enhance serotonergic effect. May increase risk for serotonin syndrome

Verapamil

Increased plasma level of vilazodone due to inhibition of metabolism via CYP3A4; reduce dose to maximum of 20 mg

Digoxin

Cmax of digoxin increased signi cantly when co-administered with vilazodone, monitoring of digoxin plasma concentrations and possible digoxin dosage reduction may be required

Carbamazepine, cimetidine, phenytoin, rifampin

May induce the metabolism of vilazodone due to induction of metabolism via CYP3A4

Hydrochlorothiazide

May increase risk for hyponatremia

Increased plasma level of vilazodone possible due to inhibition of metabolism via CYP3A4

Alfalfa, anise, ginger, glucosamine, omega-3 fatty acids

Enhanced antiplatelet properties that can result in increased risk of bleeding events

Enhanced serotonergic effects through inhibition of MAO-A and B by methylene blue. Risk for serotonin syndrome (see Precautions)

Acetylsalicylic acid, ibuprofen, naproxen

May impair platelet aggregation, resulting in increased risk of bleeding events

Meperidine Tramadol

May enhance serotonergic effect. May increase risk for serotonin syndrome May also increase risk of seizure

Methylphenidate

May enhance serotonergic effects. May increase risk for serotonin syndrome

Class of Drug

Antibiotic

Anticoagulant

Antidepressant

MAOI

Antiemetic Antifungal Antipsychotic Antiretroviral

Protease inhibitor Anxiolytic

Calcium channel blocker Cardiac glycoside

CYP450 inducers

Diuretic

Grapefruit juice

Herbal preparation/supplement

Methylene blue NSAID

Opioid Stimulant

Product Availability∗

Serotonin Modulator and Stimulator (SMS)

Generic Name

Chemical Class

Trade Name

Dosage Forms and Strengths

Vortioxetine

Bisarylsulfanyl amine

Brintellix(B), Trintellix(C)

Tablets: 5 mg, 10 mg, 15 mg, 20 mg

∗ Refer to Health Canada’s Drug Product Database or the FDA’s Drugs@FDA for the most current availability information (B) Not marketed in Canada, (C) Not marketed in the USA

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 41 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Indications‡

( approved)

General Comments

Serotonin Modulator and Stimulator (SMS) (cont.)

Major depressive disorder (MDD)

• Generalizedanxietydisorder(GAD)

• Structurallyrelatedtobuspirone,citalopram,andondansetron,eachofwhichsharessomemechanismsofactionwithvortioxetine

• Non-US-basedtrialsdemonstratede cacyforMDDatlowerdoses(5mg)comparedtoUStrials

• Severalpublishedhead-to-headtrialswithotherclassesofantidepressantsdemonstratevariablebene t

• Post-hoc analyses of short-term trials to assess safety of vortioxetine in later life depression (de ned as 55 years or older with a majority having

stable chronic physical diseases for these analyses) suggest no di erences in this population

• Criteriaforallcurrentlypublishedvortioxetinetrialsmorerestrictivethanfortrialsofearlierantidepressantdrugs,includingepisodedurationand

symptom severity; this may better assure internal validity but possibly at the cost of generalizability of results in routine clinical practice

• Bene cial cognitive e ects were initially demonstrated as a secondary outcome in the late-life depression trial; e ects con rmed in a short-term prospective, active comparator (duloxetine) trial with non-elderly patients where cognitive e ect was the primary outcome. This was determined to be a direct e ect of treatment not simply an epiphenomenon of symptomatic improvement. Improvements in functionality, anxiety and quality

of life seem to be more substantial in GAD subpopulations who are working or pursuing education

• Aswiththeotherantidepressants,vortioxetinecarriesthewarningregardingclinicalworsening,suicidality,andunusualchangesinbehavior

• The mechanism of action of vortioxetine is thought to be related to its direct modulation of serotonergic receptor activity and inhibition of the serotonin (5-HT) transporter

• BasedonPETdata,themean5-HTtransporteroccupancyintheraphenucleiwasapproximately50%at5mg/day,65%at10mg/day,andincreased to above 80% at 20 mg/day

• Nonclinical data indicate that vortioxetine inhibits the serotonin transporter protein (Ki = 1.6) and, in decreasing order of a nity, acts as a 5-HT3 antagonist (Ki = 3.7), 5-HT1A receptor agonist (Ki = 15), 5-HT7 antagonist (Ki = 19), 5-HT1B receptor partial agonist (Ki = 33), and 5-HT1D receptor antagonist (Ki = 54). Based on rat studies only – clinical correlation is not yet clear – this leads to modulation of serotonin, norepinephrine, dopamine, acetylcholine, GABA, glutamate, and histamine in the medial prefrontal cortex and ventral hippocampus

• Oftenreferredtoasamultimodalantidepressantbecauseithaspartialagonistandantagoniste ects,plusinhibitsserotoninreuptake

• 5-HT1A agonism produces a more rapid desensitization of presynaptic 5-HT1A autoreceptors

• 5-HT3 a nity for vortioxetine is greater than that of mirtazapine (Ki = 7–8) and olanzapine (Ki = 6) but it is lacking in H1 a nity, which may explain

the signi cant rates of nausea despite strong 5-HT3 antagonist activity

• Serotonergic modulation of glutamate neurotransmission via 5-HT1A, 5-HT1B, 5-HT3, and 5-HT7 receptors has been postulated as a potential mech-

anism of action for relief of depression-related cognitive dysfunction

• Seep.83

• Initial dose of 10 mg once daily without regard to meals; increase to 20 mg once daily after one week as tolerated because higher doses demon-

strated better treatment e ects in trials conducted in the USA; consider 5 mg once daily for patients who do not tolerate higher doses. Maintenance:

5-20 mg once daily. The maximum recommended dose is 10 mg/day in known CYP2D6 poor metabolizers

• Nodoseadjustmentnecessaryonthebasisofage,renalfunctionormild–moderaterenalimpairment

• NotrecommendedwithChild-PughclassCbecauseithasnotbeenstudiedinpatientswiththisdegreeofliverdysfunction

• Vortioxetine can be discontinued abruptly. However, it is recommended that doses of 15 mg/day or 20 mg/day be reduced to 10 mg/day for one

week prior to full discontinuation, if possible

Pharmacology

Dosing

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Pharmacokinetics

• Seep.83

• Displayslinearpharmacokinetics(upto60mgaftermultipledoses);bioavailability(75%)isNOTa ectedbyfood

• Vortioxetineconcentrationspeakin7–11h(Tmax).Widelydistributedandabout98%proteinbound

• Eliminationhalf-lifeis57–66h.Eliminationisviahepaticmetabolism,primarilythroughoxidation(CYP2D6isthemajorisoenzymeresponsiblefor

metabolism) with subsequent glucuronic acid conjugation. The major metabolite has no clinical activity and a minor metabolite has the capacity

to inhibit the serotonin transport protein, but it has limited ability to penetrate blood/brain barrier

• Vortioxetine or its metabolites have not shown any potential for clinically meaningful CYP450 inhibition or induction. It is also not considered a

good P-glycoprotein substrate, nor does it have any P-glycoprotein inhibitory e ects

• Steadystatelevelsoccurinabout14days

• Excretionviaurine(59%)andfeces(26%).Negligibleamountsoftheunchangeddrugremainintheurine

• Seechartp.79forincidenceofadversee ectsattherapeuticdoses

• Fatigue,sedationorsomnolencepossiblebutnotcommon

• During short-term clinical trials in patients with no history of seizure disorders, seizures were reported in less than 0.1% of patients receiving

vortioxetine

• Headachescommoninmaintenancetrials

• One industry-sponsored RCT suggests vortioxetine (at 10 mg/day over a 15-day period) has no signi cant impact on cognitive and psychomotor

performance in the context of driving

• Althoughsymptomsofmania/hypomaniawereseeninlessthan0.1%ofpatientstreatedwithvortioxetineinpre-marketingtrials,cautionisstill

warranted in using vortioxetine in patients with a personal or family history of bipolar disorder, mania or hypomanic symptoms

• Nosigni cante ectsonbloodpressure,heartrate,andECGparameterswereseeninpremarketingtrialsatdosesupto40mg/day

• No signi cant e ect on body weight as measured by the mean change from baseline (5.8% of patients in one long-term trial reported a mean weight increase of 1 kg)

• Nauseawasthemostcommonadversee ect(20.9–30.2%);generallydoserelated(seemstoplateauat15mg)andusuallytransient,withamedian duration of 10–16 days

• Diarrheacommon,alsodrymouth,constipation,vomiting,abdominaldiscomfort,dyspepsia,and atulence

• Liver test abnormalities in a small proportion of patients (less than 1%) on long-term vorioxetine therapy, but elevations are usually mild, asymp-

tomatic, and transient, reversing even with continuation of medication. No instances of acute liver injury with jaundice attributable to vortioxetine reported, but the total experience with its use has been limited

• Based on registration trials, there was a low incidence of orgasmic dysfunction in men and women treated with lower doses of vortioxetine (5– 10 mg/day), but this potential advantage was lost with 20 mg/day dose

• When trials used ASEX to evaluate sexual dysfunction in patients without baseline sexual dysfunction, rates were higher: Incidence of treatment- related sexual dysfunction (TRSD) across the dosing range was 22–34% for women and 16–29% for men

• Arandomized,double-blindtrialofvortioxetinevs.escitalopramfoundthatvortioxetinesuggestsalowerpropensityforsexualsidee ectsrelative to SSRIs

• Rashandurticariareportedinfrequently

• Rarepost-marketingreportsofangioedemaandallergicdermatitis

• Generalizedpruritis,hyperhidrosis,nasopharyngitis,andarthralgiarelativelycommon

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 43 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Adverse Effects

CNS Effects

Cardiovascular Effects

Endocrine & Metabolic Effects

GI Effects

Urogenital & Sexual Effects

Hypersentsitivity Reactions

Other Adverse Effects

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Discontinuation Syndrome

Precautions

Serotonin Modulator and Stimulator (SMS) (cont.)

• Inclinicaltrials,vortioxetinedosesof10mg,15mg,and20mgdailywereabruptlydiscontinued,withnon-signi cantdi erencesintheDiscontin- uation–Emergent Signs and Symptoms checklist total scores vs. placebo (likely explained by long serum half-life)

• However, because of individual variation and sensitivity, some may still experience withdrawal symptoms. Most likely to occur within rst weeks after drug stopped or dose drastically reduced, and typically disappear within 1 week

☞ THEREFORETHISMEDICATIONSHOULDBEWITHDRAWNGRADUALLYAFTERPROLONGEDUSE

• Reinstitutethedrugatalowerdoseandtapermoregradually

• Strong CYP2D6 inhibitors can result in elevated plasma levels of vortioxetine. Vortioxetine should be reduced by 50% in the presence of strong inhibitors such as bupropion

• Although CYP3A4 is not a primary metabolic pathway, the product label recommends increasing the dose of vortioxetine when a strong CYP3A4 inducer such as carbamazepine, phenytoin or rifampin is co-administered for more than 14 days. The maximum recommended dose should not exceed 3 times the original dose

• Contraindicated in patients taking MAOIs or in patients who have taken MAOIs within the preceding 14 days. Using MAOIs within 21 days of stopping treatment with vortioxetine is also contraindicated

• As with other serotonergic antidepressants, serotonin syndrome may occur with vortioxetine, both when taken alone and especially when co- administered with other serotonergic agents. If such symptoms occur, discontinue the medications and initiate supportive treatment. If concomi- tant use of vortioxetine with other serotonergic drugs is clinically warranted (note that linezolid or intravenous methylene blue use is speci cally mentioned as a contraindication), patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases

• Aswithotherantidepressants,vortioxetineshouldbeintroducedcautiouslyinpatientswhohaveahistoryofseizuresorinpatientswithunstable epilepsy

• Treatment with medications that inhibit the serotonin transporter may be associated with abnormal bleeding, particularly when combined with NSAIDs, acetylsalicylic acid or other medications that a ect coagulation

• Ingestion of vortioxetine in the dose range of 40–75 mg has caused an aggravation of the following adverse reactions: nausea, postural dizzi- ness, diarrhea, abdominal discomfort, generalized pruritus, somnolence, and ushing. Management of overdose should consist of treating clinical symptoms and relevant monitoring

• Nodosageadjustmentsrecommendedonthebasisofage,renalormildhepaticimpairment

• Elderlypatients,especiallythosetakingdiuretics,areathigherriskofdevelopinghyponatremia

• Adverseeventswereobservedinanimalreproductionstudies.Non-teratogenice ectsinthenewbornfollowingserotonergicexposurelateinthe third trimester include respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding di culty, vomiting, hypoglycemia, hypo- or hypertonia, hyper-re exia, jitteriness, irritability, constant crying, and tremor. In the majority of instances, such complications began immediately or soon (less than 24 h) after delivery. Symptoms may be due to the toxicity of serotonergic antidepressants or a discontinuation syndrome – although no speci c reports of such exist to date related speci cally to vortioxetine exposure, it may be a possibility

• Epidemiological data suggest that the use of SSRIs in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension (PPHN) in the newborn. Although no studies have investigated the association of PPHN with vortioxetine treatment, this potential risk cannot be ruled out, taking into account the related mechanism of action (increase in serotonin concentrations)

Management

Toxicity

Geriatric Considerations Use in Pregnancy♢

♢ See p. 439 for further information on drug use in pregnancy and e ects on breast milk

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Breast Milk

Nursing Implications

• No evidence in humans at this time. Available data in animals have shown excretion of vortioxetine and metabolites in milk. It is expected that vortioxetine is excreted into human milk. A risk to the nursing child cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from vortioxetine, taking into account the bene t of breastfeeding for the child and the bene t of therapy for the woman

• Psychotherapyandeducationarealsoimportantinthetreatmentofdepression

• Monitortherapybywatchingforadversesidee ectsandmoodandactivitylevelchanges,includingworseningofsuicidalthoughts;keepphysician

informed

• Be aware that as the medication reduces the degree of depression it may increase psychomotor activity; this may create concern about suicidal

behavior

• Expectalagtimeofupto28daysbeforeantidepressante ectsarenoticed

• Reassure patient that most early side e ects usually subside after the rst few weeks; if dizzy, patient should get up from lying or sitting position

slowly and dangle legs over edge of bed before getting up

• Excessiveuseofca einatedfoods,drugs,orbeveragesmayincreaseanxietyandagitationandconfusethediagnosis

• Shouldnotbestoppedsuddenlyduetoriskofprecipitatingwithdrawalreactions

• Fordetailedpatientinstructionsonvortioxetine,seethePatientInformationSheet(detailsp.440)

• Clinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterforthesecondagent

Patient Instructions

Drug Interactions

Class of Drug

Example

Interaction Effects

Analgesic

Acetylsalicylic acid, NSAIDs

Increased risk of abnormal bleeding

Antibiotic

Linezolid

May enhance serotonergic effect. May increase risk for serotonin syndrome (see Precautions)

Anticoagulant

Apixaban, dabigatran, rivaroxaban, warfarin

Increased risk of bleeding possible due to decreased platelet aggregation secondary to depletion of serotonin in platelets

Antidepressant

SSRI NDRI

Fluoxetine, paroxetine Bupropion

May increase vortioxetine levels signi cantly. Recommend reducing dose by 50% when combining with these signi cant CYP2D6 inhibitors May increase vortioxetine levels signi cantly. Recommend reducing dose by 50% when combining

Antifungal

Fluconazole, ketoconazole

Moderate to strong CYP2C9/2C19/3A4 inhibitors can increase AUC and Cmax of vortioxetine only modestly (15–46%), therefore no dosage adjustment is recommended but monitoring may be warranted

CYP450 inducers

Carbamazepine, phenytoin, rifampin

May reduce vortioxeine levels due to CYP3A4 induction

Broad CYP inducer rifampin decreased the exposure of vortioxetine by 72%

CYP450 inhibitor

Protease inhibitors, quinidine

Strong CYP2D6 inhibitors can increase vortioxetine levels signi cantly. Recommend reducing vortioxetine dose by 50% when combining

Desmopressin

Increased risk of hyponatremia if combined with vortioxetine, particularly in the elderly

Diuretic

Hydrochlorothiazide

Increased risk of hyponatremia if combined with vortioxetine, particularly in the elderly

Methylene blue

Enhanced serotonergic effects through inhibition of MAO-A and B by methylene blue. Risk for serotonin syndrome (see Precautions)

Opioid

Meperidine

Increased risk of serotonin syndrome

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 45 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Noradrenergic/Speci c Serotonergic Antidepressants (NaSSA)

Product Availability∗

∗ Refer to Health Canada’s Drug Product Database or the FDA’s Drugs@FDA for the most current availability information. (A) Generic preparation may be available, (B) Not marketed in Canada, (C) Not marketed in the USA

Generic Name

Chemical Class

Trade Name(A)

Dosage Forms and Strengths

Mirtazapine

Tetracyclic agent

Remeron

Tablets: 7.5 mg(B), 15 mg, 30 mg, 45 mg

Remeron RD(C), Remeron SolTab(B)

Oral disintegrating tablets: 15 mg, 30 mg, 45 mg

Indications‡

( approved)

Major depressive disorder (MDD) (with or without comorbid anxiety)

• Sexualdysfunction,SSRI-induced,and“poop-out”syndrome(seep.3):Maybemitigatedbymirtazapine

• Panic disorder, generalized anxiety disorder, social anxiety disorder, somatoform disorder, OCD[19], PTSD, dysthymia, and premenstrual dysphoric

disorder – preliminary reports of e cacy[20]

• Pervasive developmental disorders (autism) – open-label study suggests improvement in symptoms of aggression, self-injury, irritability, hyperac-

tivity, anxiety, depression, and insomnia

• Schizophreniaandpsychoticdepression–mirtazapinemaybene tnegativesymptoms

• Akathisia–double-blindstudyshowedimprovementwithadditionoflow-dose(15mg)mirtazapine

• Chronicpain(e.g.,tensionheadache, bromyalgia);e ectsizecomparedtoplaceboinrecent bromyalgia(withoutcomorbiddepression)trialwas

similar to placebo-controlled trials with duloxetine and pregabalin

• Alcoholwithdrawal–hasbeenfoundhelpful;mayhelpmaintainabstinence

• Substance use: Methamphetamine – addition of mirtazapine to substance use counseling decreased methamphetamine use among active users

and was associated with decreases in sexual risk despite low to moderate medication adherence

• Nausea/vomiting in a variety of clinical scenarios including cyclical vomiting syndrome; longer half-life and decreased cost relative to traditional

5-HT3 antagonists but formal comparative trials are lacking

• HeadachesandnauseainducedbyECT–caseseriessuggestsbene t

• Appetitestimulation

• Functional dyspepsia (FD) – short-term evidence (pilot trial) suggests that, of the various symptoms encountered in FD, issues with early satiety

may respond best to mirtazapine

• Insomnia–althoughbothsleeplatencyandsleepquantitymaybeimproved,additionalpromotionofslow-wavesleepmaybene tsleepquality

• Malignancy-relatedpruritusunresponsivetostandardtreatment

• Reduces sleep latency and prolongs sleep duration due to H1 and 5-HT2A/C blockade – may be helpful in treating depression with prominent insomnia or agitation

• Hasmildanxiolytice ectsatlowerdoses

• A Cochrane review found mirtazapine was more e ective at 2 weeks and at the end of acute-phase treatment than SSRIs and venlafaxine and

was more likely to cause weight gain or increased appetite and somnolence than SSRIs but less likely to cause nausea or vomiting and sexual

dysfunction

• Monitorallpatientsforworseningdepressionandsuicidalthinking

• Presynaptic α2-adrenergic antagonist e ects, which result in increased release of norepinephrine and serotonin. It is also a potent antagonist of 5-HT2A, 5-HT2C, 5-HT3, and H1 receptors and a moderate peripheral α1-adrenergic and muscarinic antagonist; it does not inhibit the reuptake of norepinephrine or serotonin

General Comments

Pharmacology

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Dosing

• Seep.83

• Initiateat15mgdailyforaminimumofoneweekbeforeconsideringfurtherdoseincreasessincemirtazapinehasahalf-lifeof20–40h;patients

who do not respond may bene t from increases up to 45 mg daily for depression

• Lowerdosagerangesuggestedifspeci callytargetingsleep(7.5–15mg)

• Thedoseisbestadministeredintheeveningpriortosleep

• Bioavailabilityisapproximately50%duetogutwallandhepatic rst-passmetabolism;foodslightlydecreasesabsorptionrate

• RemeronSolTabsdissolveonthetonguewithin30seconds;canbeswallowedwithorwithoutwater,chewed,orallowedtodissolve

• Peakplasmalevelachievedin2h

• Proteinbindingof85%

• Femalesandtheelderlyshowhigherplasmaconcentrationsthanmalesandyoungadults

• ExtensivelymetabolizedviaCYP1A2,2D6,and3A4;desmethylmetabolitehassomeclinicalactivity

• Half-life20–40h–signi cantlylongerinfemalesthaninmales

• Hepaticclearancedecreasedby40%inpatientswithcirrhosis

• Clearancereducedby30–50%inpatientswithrenalimpairment

• Therapeutice ectistypicallyseenafter28days(thoughsomee ectsmaybeseensooner),especiallyonsymptomsrelatedtosleepandappetite

• Meta-analysisofdouble-blindtrialsinpatientswithdepressionsuggestsanearlieronsetofe cacywithmirtazapinethanwithSSRIsalthoughno

di erence in number of responders at study end[19]

• Seep.80

• Somnolence,hyperphagia,andweightgainarethemostcommonlyreportedsidee ects[20]

• Fatigue, sedation in over 30% of patients; less sedation at doses above 15 mg due to increased e ect on α2 receptors and increased release of NE

• Showntoimpairdrivingperformanceanddecreasedpsychomotorfunctioningduringtheacutetreatmentphasealthoughaprospectiverandom-

ized study in depressed patients using a simulator showed a signi cant improvement in performance and decrease in crash rates

• Insomnia, agitation, hostility, depersonalization, restlessness, and nervousness reported occasionally, coupled with urges of self-harm or harm to

others

• Increases slow-wave sleep and decreases stage 1 sleep. Reported to shorten sleep onset latency, improve sleep e ciency and increase total sleep

time; vivid dreams reported; case reports of REM sleep behavior disorder with hallucinations and confusion; case report of somnambulism on dose

increase

• Casereportofpanicattackduringdoseescalation

• Rarelydelirium,hallucinations,psychosis

• Seizures(veryrare–0.04%)

• Drymouthfrequent;thirst,constipation[fortreatmentsuggestionsseeNonselectiveCyclicAntidepressants,p.53]

• Blurredvision,andurinaryretentionreportedrarely

• Hypotension,hypertension,vertigo,tachycardia,andpalpitationsreportedrarely

• Edema1–2%

• RiskofQTcprolongationandtorsadesdepointes

• Carbohydratecraving,increasedappetiteandleptinconcentrations,andweightgain(ofover4kg)reportedinover16%ofpatients(duetopotent antihistaminic properties); occur primarily in the rst 4 weeks of treatment and may be dose related – may be of bene t in depressed patients with marked anorexia. Weight gain may appear more slowly in elderly patients, especially octogenarians, relative to younger individuals

• MaybelesslikelythanSSRIstocausehyponatremia

• Increases in plasma cholesterol, to over 20% above the upper limit of normal, seen in 15% of patients; increases in nonfasting triglyceride levels

(7%)

• Rarereportsofbittertaste,dyspepsia,nausea,vomiting,anddiarrhea

• Decreasedappetiteandweightlossoccasionallyreported

Pharmacokinetics

Onset & Duration of Action

Adverse Effects

CNS Effects

Anticholinergic Effects

Cardiovascular Effects

Endocrine & Metabolic Effects

GI Effects

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 47 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Noradrenergic/Speci c Serotonergic Antidepressants (NaSSA) (cont.)

Other Adverse Effects

Discontinuation Syndrome

Precautions

• Sexualdysfunctionoccursoccasionally;riskincreasedwithage,useofhigherdoses,andconcomitantmedication

• Casereportsoferoticdream-relatedejaculationinelderlypatients

• Rates of sexual dysfunction in a naturalistic study were citalopram 60%, venlafaxine 54.5%, paroxetine 54.2%, uoxetine 46.2%, and mirtazapine

18.2%

• Increasedsweating

• Rarereportsoftremor,hot ashes

• TransientelevationofALTreportedinabout2%ofpatients;casesofhepatitis

• Febrile neutropenia (1.5% risk) and agranulocytosis (0.1%) reported; monitor WBC if patient develops signs of infection [some recommend doing

baseline and annual CBC]

• Casesofjointpainorworseningofarthritisreported

• Myalgiaand u-likesymptomsin2–5%ofpatients

• Caseofpalinopsiareported

• Casesofpancreatitisandofgall-bladderdisorder

• Casesofrhabdomyolysisreportedwithmirtazapineusedalone,incombinationwithrisperidone,andinoverdose

• Reportsofvenousthromboembolismincludingdeepveinthrombosis

• Mostlikelytooccurwithin1–7daysafterdrugstoppedordosedrasticallyreduced,andtypicallydisappearswithin3weeks

• Casereportofhypomania,akathisia,andpanicattack

☞ THEREFORETHISMEDICATIONSHOULDBEWITHDRAWNGRADUALLYAFTERPROLONGEDUSE

• Reinstitutedrugatalowerdoseandtapergraduallyoverseveraldays

• Monitorallpatientsforworseningdepressionandsuicidalthoughts,especiallyatstartoftherapyorfollowinganincreaseordecreaseindose;see Pediatric Considerations (p. 48)

• CasesofQTprolongationandtorsadesdepointes;cautioninpatientswithriskfactorssuchasknowncardiovasculardisease,familyhistoryofQT prolongation, and concomitant use of QT-prolonging medications

• Cautioninpatientswithcompromisedliverfunctionorrenalimpairment

• MonitorWBCifpatientdevelopssignsofinfection;alowWBCrequiresdiscontinuationoftherapy

• MayinducemanicreactionsinpatientswithBDandrarelyinunipolardepression

• Treatment with medications that inhibit the serotonin transporter may be associated with abnormal bleeding, particularly when combined with

NSAIDs, acetylsalicylic acid or other medications that a ect coagulation

• Lowliabilityfortoxicityinoverdoseiftakenalone;depressionofCNSwithdisorientationandprolongationofsedation,withtachycardiaandmild hyper or hypotension

• CasesofQTprolongationandtorsadesdepointes

• Post-marketingcasereportsoffatalities;noneduringclinicaltrialsexceptinmixedoverdose

• For detailed information on the use of mirtazapine in this population, please see the Clinical Handbook of Psychotropic Drugs for Children and Adolescents[7]

• No approved indications in children and adolescents. There are limited well-conducted randomized controlled trials of mirtazapine in pediatric patients for any indication

• CAUTION:Episodesofself-harmandpotentialsuicidalbehaviorsreportedwithcertainserotonergicantidepressantsinpatientsunderage18

Management

Toxicity

Pediatric Considerations

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Geriatric Considerations

Use in Pregnancy♢

• Clearancereducedinelderlymalesbyupto40%,andinelderlyfemalesbyupto10%

• Dosing:Startat7.5mgatbedtimeandincreaseto15mgafter1–2weeks,dependingonresponseandsidee ects;monitorforsedation,hypoten-

sion, and anticholinergic e ects

• Usedtocounteractorstabilizeweightlossinpatientswithdementia

• Hyponatremiareportedinolderadults

• Limiteddatasuggestsnomajorteratogenice ectsinhumans

• Although some evidence suggests higher rate of spontaneous abortions, preterm births, and low birthweight, no correction has been made for

depressive symptoms, a known risk factor

• Nolong-termoutcomedataorevidenceavailableonneonatalabstinencesyndrome

• Mirtazapineanditsmetabolitearesecretedintobreastmilkinlowconcentrations(e.g.,undetectablylowto2.86%ofthematernalweight-adjusted dose)

• Verylimitedinformationregardingoutcomes–noapparentshort-termadversee ectsbutsmallsamplesize(lessthan50publishedcases)makes overall safety index unknown

• Ifapatientisbreastfeedingandrequirestheadditionofanantidepressant,otheragentsmaybepreferableas rst-lineoptions;however,maternal use of mirtazapine is not considered a reason to discontinue breastfeeding

• Psychotherapyandeducationarealsoimportantinthetreatmentofdepression

• Monitortherapybywatchingforadversee ectsandmoodandactivitylevelchanges,includingworseningofsuicidalthoughts

• Signs and symptoms of infections (e.g., sore throat, fever, mouth sores, elevated temperature) should be reported to the physician as soon as

possible

• Because mirtazapine can cause drowsiness, caution patient not to perform activities requiring mental alertness until response to this drug has

been determined

• Mirtazapineshouldnotbestoppedsuddenlyduetoriskofprecipitatingawithdrawalreaction

• Fordetailedpatientinstructionsonmirtazapine,seethePatientInformationSheet(detailsonp.440)

• Clinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterforthesecondagent

Breast Milk

Nursing Implications

Patient Instructions

Drug Interactions

Class of Drug

Example

Interaction Effects

Antibiotic

Linezolid

Monitor for increased serotonergic and noradrenergic effects due to linezolid’s weak MAO inhibition

Anticoagulant

Warfarin

May increase INR; monitor

Anticonvulsant

Carbamazepine, phenytoin

Decreased plasma level of mirtazapine by 60% with carbamazepine and 46% with phenytoin due to induction of metabolism via CYP3A4

Antidepressant

SSRI

SNRI

Fluoxetine, sertraline Fluvoxamine Venlafaxine

Combination reported to alleviate insomnia and augment antidepressant response; may have activating effects May mitigate SSRI-induced sexual dysfunction and “poop-out” syndrome

Increased serotonergic effects possible; case reports of increased mirtazapine concentrations (3–4 fold) Increased sedation and weight gain reported with combination

Increased plasma level of mirtazapine (3- to 4-fold) due to inhibited metabolism Case report of serotonin syndrome (see p. 9)

♢ See p. 439 for further information on drug use in pregnancy and e ects on breast milk

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 49 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Noradrenergic/Speci c Serotonergic Antidepressants (NaSSA) (cont.)

Class of Drug

Example

Interaction Effects

Irreversible MAOI Irreversible MAO-B inhibitor

Phenelzine, tranylcypromine Rasagiline, selegiline

Possible serotonergic reaction; DO NOT COMBINE Possible serotonergic reaction

Antiemetic (5-HT3 antagonist)

Dolasetron, granisetron, ondansetron

Case reports of serotonin syndrome

Antifungal

Ketoconazole

Increased peak plasma levels of mirtazapine (by about 40%)

Antihypertensive

Clonidine, guanabenz, guanfacine

Antihypertensive effect may be antagonized by mirtazapine

Antiplatelet

Clopidogrel

Increased risk of bleeding possible

Antipsychotic

Olanzapine

Case report of status epilepticus with mirtazapine and olanzapine; and of serotonin syndrome with mirtazapine, tramadol, and olanzapine

Potential for additive metabolic adverse effects (e.g., increased cholesterol, sedation) and increased appetite

CNS depressant

Alcohol, benzodiazepines, opioid analgesics etc.

Impaired cognition and motor performance

H2 antagonist

Cimetidine

Increased serum levels of mirtazapine (by 61%), dose adjustments of mirtazapine may be required

Methylene blue

Enhanced serotonergic effects through inhibition of MAO-A and B by methylene blue. Risk for serotonin syndrome (see Precautions)

Opioid

Tramadol

Case of lethargy, hypotension, and hypoxia in elderly patient Increased risk of seizures and serotonin syndrome

Stimulant

Dextroamphetamine, methylphenidate, phentermine

May increase agitation and risk of mania, especially in patients with bipolar disorder

Tobacco (smoking)

Signi cantly decreased levels of mirtazapine

Nonselective Cyclic Antidepressants

Product Availability∗

Generic Name

Chemical Class

Trade Name(A)

Dosage Forms and Strengths

Amitriptyline(E)

Tricyclic antidepressant (TCA)

Elavil, Levate(C)

Tablets: 10 mg, 25 mg, 50 mg, 75 mg, 100 mg(B), 150 mg(B)

Amoxapine(B)

Dibenzoxazepine

Asendin

Tablets: 25 mg, 50 mg, 100 mg, 150 mg

Clomipramine(D)

TCA

Anafranil

Tablets(C): 10 mg, 25 mg, 50 mg Capsules(B): 25 mg, 50 mg, 75 mg

Desipramine

TCA

Norpramin

Tablets: 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg(B)

Doxepin

TCA

Adapin(B), Sinequan

Capsules: 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg Oral solution(B) : 10 mg/mL

Silenor(B) Zonalon

Tablets: 3 mg, 6 mg 5% topical cream

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Generic Name

Chemical Class

Trade Name(A)

Dosage Forms and Strengths

Imipramine HCl

TCA

Tofranil

Tablets: 10 mg, 12.5 mg(C), 25 mg, 50 mg, 75 mg(C)

Imipramine pamoate

TCA

Tofranil PM(B), Impril(C)

Capsules(B): 75 mg, 100 mg, 125 mg, 150 mg

Maprotiline

Tetracyclic

Ludiomil

Tablets: 10 mg, 25 mg, 50 mg, 75 mg

Nortriptyline

TCA

Aventyl(C)

Capsules: 10 mg, 25 mg, 50 mg(B), 75 mg(B)

Protriptyline(B)

TCA

Vivactil

Tablets: 5 mg, 10 mg

Trimipramine

TCA

Surmontil

Tablets(C): 12.5 mg, 25 mg, 50 mg, 75 mg, 100 mg Capsules: 25 mg(B) , 50 mg(B) , 75 mg(C) , 100 mg(B)

∗ Refer to Health Canada’s Drug Product Database or the FDA’s Drugs@FDA for the most current availability information. (A) Generic preparations may be available, in the USA, (E) Available in combination with perphenazine and also in combination with chlordiazepoxide in the USA

(B) Not marketed in Canada,

(D) Not approved for depression

Indications‡

( approved)

Major depressive disorder (MDD): Acute treatment and maintenance

Secondary depression in other mental illnesses (e.g., schizophrenia, dementia)

Bipolar disorder: Depressed phase

Obsessive-compulsive disorder (OCD) (clomipramine)

Childhood enuresis (imipramine)

Depression and/or anxiety associated with alcoholism or organic disease (doxepin)

Psychoneuroses with MDD (doxepin)

Insomnia (doxepin marketed in US as low dose, i.e., 3 and 6 mg at bedtime, for di culty with sleep maintenance)

General Comments

• Panicdisorder(imipramine,clomipramine)

• Agoraphobiaassociatedwithpanicdisorder

• Dysthymia–e cacyreported(imipramine,desipramine)

• Depression,poststroke(nortriptyline)

• Posttraumaticstressdisorder(PTSD)–e cacyagainstintrusivesymptomsreported

• Generalizedanxietydisorder(GAD)(imipramine)

• Temporomandibularjointdisorders

• Attention-de cit/hyperactivitydisorder(ADHD)notresponsivetootheragents(desipramine,nortriptyline)

• Premenstrualdysphoricdisorder(clomipramine,nortriptyline)

• Prematureejaculation(clomipramine)

• Sialorrheainducedbyclozapine(amitriptyline)

• Pain management, including migraine headache, diabetic neuropathy, postherpetic neuralgia, irritable bowel syndrome, chronic oral-facial pain,

and adjuvant analgesic; may help with sleep problems associated with bromyalgia and other pain syndromes (i.e., amitriptyline)

• Smokingcessation(nortriptyline),aloneorincombinationwithnicotinepatch.Nortriptyline(25–75mg/day)appearsase ectiveasbupropionfor

smoking cessation and has been recommended as second-line therapy for treating smoking dependence

• Chronicidiopathicurticaria(doxepin)

• Overactivebladder(imipramine,doxepin)

• Behavioralandpsychologicalsymptomsofdementia(BPSD)

• Antidepressantsareassociatedwithasmall(2–3%)riskofhostilityorsuicidalideationandassociatedbehaviorsinchildren,adolescents,andyoung adults (aged up to 24 years). Risk for suicide should be assessed and closely monitored during the initial weeks of antidepressant therapy

‡ Indications listed here do not necessarily apply to all nonselective cyclic antidepressants or all countries. Please refer to a country’s regulatory database (e.g., US Food and Drug Administration, Health Canada Drug Product Database) for the most current availability information and indications

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 51 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Pharmacology

Dosing

Nonselective Cyclic Antidepressants (cont.)

• Prior to using, consider a thorough cardiac evaluation that can include: known/existing heart disease (e.g., congenital or acquired prolonged QT syndrome), family history of heart disease (sudden death, cardiac dysrhythmias, cardiac conduction disturbances); baseline ECG for patients over 40 years old

• Thepresenceofhallucinationsordelusionsisanegativepredictorofresponsetotricyclicantidepressants(TCAs)

• MenmayrespondbettertoTCAsandlesswelltoSSRIsthanwomen

• Studiessuggestimprovedoutcomesinpanicdisorderwithcombinationofimipramineandpsychotherapy

• Exactmechanismofactionunknown

• TCAs equilibrate the e ects of biogenic amines through various mechanisms (i.e., reuptake blockade, downregulation of β-adrenergic receptors);

tertiary amine agents (amitriptyline, clomipramine, doxepine, imipramine, trimipramine) have greater a nity for serotonin blockade; secondary

amine agents (desipramine, nortriptyline, protriptyline) have greater a nity for norepinephrine blockade

• TCAsmayfacilitatemanagementofenuresis;anticholinergice ectsinhibiturinationandCNSstimulationencourageseasierarousalwhenstimu-

lated by a full bladder

• Theanalgesice ectsobservedwithTCAsmaybeduetosodiumchannelblockade

• Low-dose doxepin’s histamine (H1) blockade enables its use as a sedative and in urticaria (a nity for H1 receptor greater than that of diphenhy-

dramine)

• Thereiswidevariationindosagerequirementsbetweenindividuals;dosageshouldbeindividualized

• Monitoringserumdruglevelsmaysupportdosageadjustment(mostevidencefornortriptyline)

• Initiate at a low dose and increase dosage every 3–5 days to a maximum tolerated dose based on side e ects. TCAs demonstrate a clear dose-

response relationship

• Once steady state is achieved, medications can be provided as a single bedtime dose; this facilitates compliance, helps with sleep, and reduces

daytime sedation. Exception: protriptyline, which is usually given in the morning

• Dosagescanbedividedortheentiredosegiveninthemorningifthepatientdevelopsnightmaresorexperiencesinsomniaorstimulation

• Adolescentandgeriatricpatientsgenerallyrequirelowerdoses

• Prophylaxisismoste ectiveifthetherapeuticdoseismaintained

• Hepaticdisease:CAUTIONmayrequirealowerdosage

• Renaldisease:CAUTIONmayrequirealowerdosage

• Seep.83

• CompletelyabsorbedfromtheGItract

• Largepercentagemetabolizedby rst-passe ect

• Highlylipophilic;primarilyconcentratedinmyocardialandcerebraltissue

• Highlyboundtoplasmaandtissueproteins

• Metabolizedbytheliver;poormetabolizers(e.g.,CYP2D6)mayexperienceanupto8-foldincreaseinplasmaconcentrations,resultinginincreased

adverse e ects (e.g., cardiac toxicity, etc.)

• MostTCAsdemonstratelinearpharmacokinetics(exceptdesipramine),achangeindoseresultsinaproportionalchangeintheplasmaconcentra-

tion

• Pharmacokinetics may vary between males and females; data suggest that plasma levels of TCAs may decrease in female patients prior to mens-

truation

• Primaryrouteofeliminationisurinaryexcretion

• Eliminationhalf-life:seep.83;steadystatereachedinabout5half-livesor5days

• ConcurrentingestionofTCAswithhigh- berfoodsorlaxatives(e.g.,bran,psyllium)canresultindecreasedabsorptionoftheantidepressant

Pharmacokinetics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Onset & Duration of Action

• TCAsandrelateddrugsarelongactingandcanbeprovidedasasingledailydose

• Onsetofantidepressante ecttypicallyoccursafter28daysalthoughsomepatientsmayrespondsooner,analgesice ectscantakeupto3weeks

• Sedativee ectsoccurwithinafewhoursoforaladministration;sleepdisturbanceisreducedafterafewdays

• Patientsmayreportalossofantidepressantresponseor“poop-outsyndrome”[Management:Checkcompliance;optimizedose,plasmalevelsmay

be helpful; consider switching antidepressants or augmenting therapy]

• Thepharmacologicalandsidee ectpro leofTCAsisdependentontheira nityforandactivityonneurotransmitters/receptors(seetablep.77)

• Seechartp.79fortheincidenceofcommonadversee ectsattherapeuticdoses

• Adversee ectsmaybemoreproblematicearlyintreatment;patientsmayadapttosidee ectsovertime,e.g.,anticholinergice ects,hypotension,

sedation, etc. [Management: Initiate at low doses, gradually increase dose]

• Occur due to antagonism at histamine H1 receptors and α1 adrenoreceptors

• CNSandneuromusculare ectsoccurfrequently

• Drowsiness is the most common adverse e ect; weakness, lethargy, and fatigue also occur. Conversely, excitement, agitation, restlessness, and

insomnia have been reported

• Secondary amines reduce sleep e ciency and increase wake time after sleep onset; tertiary amines improve sleep continuity; decrease REM sleep

(exception: trimipramine); vivid dreaming or nightmares can occur, especially if all the medication is given at bedtime

• Confusion,disturbedconcentration,delusions,disorientation,andhallucinationscanoccur;morecommoningeriatricpatients

• Precipitation of hypomania or mania (patients with a history of bipolar disorder – less frequent in patients on a mood stabilizer) and episode

acceleration (occurs in up to 67% of patients)

• Anxiety,euphoria,panicreactions,andhostilitymayoccur

• Finetremor;dosedependent;observedinyoungandoldpatients

• Disturbanceingait,parkinsonism,anddystonia;geriatricpatientsaremorelikelytoexperienceparkinsonismathighdoses

• Akathisiacanoccurfollowingabruptdrugwithdrawal;reportedwithamoxapine,imipramine,anddesipramine

• Paresthesias,numbingandtingling;approximaterisk4%

• Myoclonus, including muscle jerks of lower extremities, jaw, and arms, and nocturnal myoclonus; more likely with serotonergic agents; severe

symptoms occur in up to 9% of patients [Management: If severe, clonazepam, valproate or carbamazepine may be of bene t]

• Dysphasia,stuttering

• Tardivedyskinesia;reportedwithamoxapinebutalsoseenwithotherantidepressantsonrareoccasions

• Tinnitus–morelikelywithserotonergicagents

• Seizures;seePrecautionsp.55;canoccurfollowinganabruptincreaseinthedrugdosageorafterdrugwithdrawal;riskbothdoseandconcentration

dependent

• Occurduetoantagonismatmuscarinicreceptors(ACh)

• Mostcommonsidee ectsassociatedwithTCAs:increasedfrequencynotedinelderlypatients

• Dry mucous membranes predispose patient to monilial infections and dental caries [Management: Review oral hygiene, sugar-free gum or candy,

oral lubricants (e.g., MoiStir, OraCare D), pilocarpine tablets or mouthwash (tablets 10–15 mg/day, mouthwash 4% solution 4–12 drops in water

swished in mouth and spat out), bethanechol]

• Blurredvision,increasedintraocularpressure

• Dryeyes;maybeaproblemintheelderlyorthosewearingcontactlenses[Management:Patientswhowearcontactlensesshouldusetheirusual

wetting solutions or comfort drops, others may use arti cial tears]

• TCAscaninduceorexacerbateexistinghiatushernia;TCAsshouldbediscontinuedifesophagealre uxdevelops

• Constipation; frequent side e ect in children on therapy for enuresis [Management: Increase dietary bulk and uid intake, fecal softener, bulk-

forming laxative ]

• Urinaryretention,delayedmicturition[Management:Bethanechol10–30mgtid]

• Confusion,disorientation,delirium,delusions,andhallucinations(morecommonintheelderly,especiallywithhigherdoses)

• Hyperthermia;increasedriskwhencombinedwithotheragentswithanticholinergicactivityorthosethata ectthermoregulation

• Occur due to antagonism at α1 adrenoreceptors, muscarinic, 5-HT2, and H1 receptors and inhibition of sodium fast channels

• Riskincreaseswithhighplasmalevels

Adverse Effects

CNS Effects

Anticholinergic Effects

Cardiovascular Effects

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 53 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Endocrine & Metabolic Effects

GI Effects

Urogenital & Sexual Effects

Hypersensitivity Reactions

Other Adverse Effects

Discontinuation Syndrome

Nonselective Cyclic Antidepressants (cont.)

• Orthostatichypotensioncommon;additionalriskfactorsincludepre-exisitingposturalhypotensionandconcurrentuseofantihypertensivemedi- cations [Management: Sodium chloride tablets, ca eine, udrocortisone (0.1–0.2 mg/day), midodrine (2.5–10 mg tid), support stockings]

• Hypertensive episodes reported in patient on TCAs receiving surgery [Management: Whenever possible, discontinue TCAs several days prior to surgery]

• Prolonged conduction time by delaying the inward sodium current into cardiomyocytes, slowing cardiac depolarization and lengthening the QTc interval; see Precautions p. 55; risk factors for ventricular arrhythmias can include combination with other antidepressant medications, underlying bundle branch block, preexisting conduction delays, higher doses of TCA, baseline QTc interval of ≥ 450 ms

• QTcprolongation;nortriptylineattherapeuticdosesdoesnota ectQTcinterval

• Tachycardia;maybemorepronouncedinyoungerpatients

• Syncope,thrombosis,thrombophlebitis,stroke,andcongestiveheartfailurehavebeenreportedonoccasion

• Bothincreasedanddecreasedbloodsugarlevelsreported

• Weightgainreportedinupto30%ofpatientswithchronicuse;averagegainofupto7kg;weightgainislinearovertimeandoftenaccompanied

by a craving for sweets [Management: Nutritional counseling, exercise, dose reduction, consider switching antidepressants] • Menstrualirregularities,amenorrhea,andgalactorrheainfemales,breastenlargementinmales

• CaninduceSIADHwithhyponatremia;riskincreaseswithage

• Occurduetoinhibitionof5-HTuptakeandAChantagonism • Anorexia,nausea,vomiting,diarrhea,andabdominalcramps • Increasedpancreaticenzymes

• Constipation(seeAnticholinergicE ects,p.53)

• Peculiartaste,“blacktongue,”glossitis

• Occur due to altered dopamine activity, 5-HT2A blockade, inhibition of 5-HT reuptake, α1 blockade, and ACh blockade

• Decreasedlibido,impotence[Management:Amantadine(100–400mgprn),bethanechol(10mgtidor10–25mgprn),neostigmine(7.5–15mgprn),

cyproheptadine (4–16 mg prn), yohimbine (5.4–16.2 mg prn)]

• Anorgasmia or marked delay in up to 90% of clomipramine-treated patients[21] [Management: Amantadine (100–400 mg prn), cyproheptadine (4–

16 mg prn), yohimbine (5.4–10.8 mg od or prn), ginseng, ginkgo biloba (180–900 mg)]

• Testicular swelling, painful ejaculation, retrograde ejaculation, increased libido, and priapism; spontaneous orgasm with yawning reported with

clomipramine

• Rare

• Drugfever,edema,erythema,petechiae,pruritus,rash,andurticaria

• Photosensitivity,skinhyperpigmentation;13casereportswithimipramine[22],alsoreportedwithdesipramine • Rarelyagranulocytosis,eosinophilia,leukopenia,purpura,andthromobocytopenia

• Asymptomaticincreasesinaminotransferaselevels

• Jaundice,hepatitis;reversibleondiscontinuationofTCA[Management:MonitorLFTs,discontinueiflevelscontinuetoincrease]

• Excessive sweating [Management: Daily showering, talcum powder; in severe cases: Drysol solution, terazosin 1–10 mg daily, oxybutynin up to

5 mg bid, clonidine 0.1 mg bid; consider switching antidepressant] • RarereportsofalopeciawithTCAs

☞ THESE MEDICATIONS SHOULD BE WITHDRAWN GRADUALLY AFTER PROLONGED USE

• Mostfrequentwithclomipramine;likelyduetocholinergicandadrenergicrebound

• Abrupt withdrawal from high doses may cause a “ u-like” syndrome consisting of fever, fatigue, sweating, coryza, malaise, myalgia, headache.

Anxiety, agitation, hypomania or mania, insomnia, vivid dreams, as well as dizziness, nausea, vomiting; akathisia and dyskinesia also reported • Symptomsaremostlikelytooccur24–48hafterwithdrawal,oralargedosagedecrease

• Paradoxicalmoodchangesreportedonabruptwithdrawal,includinghypomaniaormania

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Management

Precautions

• Re-institutedrug,consideraslightlylowerdose,andgraduallytaperthedoseoverseveraldays

• Alternatively,cantreatspeci cwithdrawalsymptoms:

– Cholinergicrebound(e.g.,nausea,vomiting,sweating)–ginger,benztropine0.5–4mgprn,atropine1–4mgtidtoqid

– Anxiety,agitation,insomnia–benzodiazepine(e.g.,lorazepam0.5–2mgprn)

– Neurologicalsymptoms:Akathisia(propranolol10–20mgtidtoqid),dyskinesia(clonazepam0.5–2mgprn),dystonia(benztropine0.5–4mgprn)

• TCAshavealowtherapeuticmargin(lethaldoseisabout3timesthemaximumtherapeuticdose);monitorduringinitiationoftherapyandduring dose increases. Prescribe limited quantities

• Contraindicated

– intheacuterecoveryphasefollowingamyocardialinfarctionandinheartblock;cautioninpatientswithpre-existingcardiovasculardisease – ifhypersensitivetotricyclics

– within14daysofstoppingaMAOI

• Maylowertheseizurethreshold;administercautiouslytopatientswithahistoryofconvulsivedisorders,organicbraindiseaseorapredisposition to convulsions (e.g., alcohol withdrawal), patients with eating disorder

• Patients with existing cardiovascular disease may be sensitive to the cardiac adverse e ects associated with TCAs; particularly those who have an eating disorder, are underweight, malnourished, or elderly

• Patientsinwhomexcessanticholinergicactivitycouldbeharmful(e.g.,increasedintraocularpressure,narrow-angleglaucoma,prostatichypertro- phy, urinary retention), reduced GI motility, paralytic ileus

• Patientswithrespiratorydi cultiesasanticholinergicpropertiescandryupbronchialsecretions,makingbreathingmoredi cult

• Mayinducemanicreactionsinupto50%ofpatientswithbipolardisorder;riskofincreasedcycling,bipolardisorderisarelativecontraindication;

screen for bipolar depression before the initiation of therapy

• May impair the mental and physical ability to perform hazardous tasks (e.g., driving a car or operating machinery); will potentiate the e ects of

alcohol

• Combining TCAs with SSRIs can result in increased plasma level of the TCA. Combination therapy has been used in the treatment of resistant

patients; see Drug Interactions

• CombiningserotonergicTCAswithSSRIscancauseaserotoninsyndrome(seep.9)

• Symptoms of toxicity are extensions of the common adverse e ects; anticholinergic e ects, CNS stimulation followed by CNS depression, my- oclonus, hallucinations, respiratory depression, and seizures (can develop rapidly after overdose)

• SymptomsofCNSstimulationincludeagitation,confusion,delirium,irritability,hallucinations,andhyperpyrexia

• Increasedriskofseizuresinchildren

• CNSdepressionfollowsstimulationandmaypresentwithcoma,depressedlevelofconsciousness,cyanosis,drowsiness,hypotension,hypothermia,

and respiratory depression

• Cardiac irregularities are extremely dangerous and common; duration of QRS complex on the electrocardiogram (ECG) re ects the severity of the

overdose; a QRS equaling or exceeding 0.12 sec should be considered a danger sign (normal 0.08–0.11 sec)

• Patientswithcardiacdisease,eatingdisordersorrenaldisease,aswellastheelderlyandchildrenaremoresusceptibletoTCAcardiotoxicity

• Acid-baseimbalancescanoccur

• Hospitalize;monitorandprovidesupportivetreatment

• Activatedcharcoal(25-100gifpatientpresentswithinanhourofingestion);forceddiuresisanddialysisareoflittlebene t

• DONOTGIVEIPECACduetopossibilityofrapidneurologicaldeteriorationandhighincidenceofseizures

• Seizures:Recommendbenzodiazepines,diazepamIVisthedrugofchoice.Caution–CNSandrespiratorydepressionmayoccur

• Fordetailedinformationontheuseofnonselectivecyclicantidepressantsinthispopulation,pleaseseetheClinicalHandbookofPsychotropicDrugs for Children and Adolescents[7]

• Antidepressants are suggested for management of enuresis, insomnia and parasomnias, ADHD, MDD, obsessional disorder, panic disorder, school phobia, separation anxiety disorder, bulimia, and Tourette’s syndrome (clomipramine)

Toxicity

Management

Pediatric Considerations

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 55 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Geriatric Considerations

Use in Pregnancy♢

Nonselective Cyclic Antidepressants (cont.)

• Priortotreatment,considerabaselineECG.AsteadystateserumlevelandECGshouldbeobtainedwhenane ectivedailydoseisreached.Follow- up ECGs should be obtained at any dose change. Plasma levels should be obtained every few months

• TheU.S.FDAde nesthefollowingECGandexaminationvaluesasunsafeinchildrentreatedwithtricyclics:(a)PRinterval>200ms,(b)QRSinterval > 30% above a baseline (or > 120 ms), (c) BP > 140 mmHg systolic or 90 mmHg diastolic, (d) Heart rate > 130 beats/min at rest

• Suddendeathhasbeenreportedrarelywithdesipramine,despitetherapeuticplasmalevels;plasmalevelsmaybehigherby42%inchildrenthan adults, at the same dose

• StartTCAsatalowdose(10–25mg)andincreasegraduallyby10–25mgevery4–5daystoamaximumdoseof3–5mg/kg

• Safetyande cacyofTCAsinelderlypatientshasnotbeensystematicallystudied

• MonitorforexcessiveCNSandanticholinergice ects;selectanantidepressantleastlikelytocausethesee ects(e.g.,nortriptyline,desipramine)

• Caution when combining with other medications with CNS and anticholinergic properties; additive e ects can result in confusion, disorientation,

and delirium; the elderly are sensitive to anticholinergic e ects

• Cognitiveimpairmentcanoccur,includingdecreasedwordrecallandfacialrecognition

• Cautionregardingcardiovascularsidee ects:Orthostatichypotension(canleadtofalls),tachycardia,andconductionslowing

• Initiate at low doses and increase the dosage more slowly than in younger patients; elderly patients may take longer to respond and may require

trials of up to 12 weeks before response is noted

• Clomipramine,nortriptyline,andpossiblyotherscrosstheplacenta

• FetalmalformationsanddevelopmentaldelayhavebeenreportedinchildrenofmotherswhoreceivedTCAsduringpregnancy

• CNSe ects,urinaryretention,andwithdrawalsymptomshavealsobeenreported

• AvoidTCAsduring rsttrimesterifpossible

• Thedosagerequiredtoachievetherapeuticplasmalevelsmayincreaseduringthethirdtrimester

• TheAmericanAcademyofPediatricsclassi esantidepressantsasdrugs“whosee ectsonnursinginfantsareunknownbutmaybeofconcern”

• TCAsaresecretedintobreastmilk;estimatesindicatethatthebabywillreceiveupto4%ofthemother’sdose

• Thehalf-lifeofantidepressantsintheneonateisincreased3-to4-fold

• Reports indicate that the doxepin metabolite concentration reaches similar plasma levels in mothers and infants; one case report of respiratory

depression; doxepin is contraindicated in breastfeeding

• Recommendtoeitherdiscontinuemedicationorbottlefeed

• Be aware that although antidepressants reduce symptoms of depression they may increase psychomotor activity, thus increasing concern about suicidal behavior

• Monitortherapybyobservingforchangesinmoodandactivityandtheemergenceofadversesidee ects;keepphysicianinformed

• Expecta28-daylagtimebeforeantidepressante ectsarenoticed

• PsychotherapyandeducationareimportantinthetreatmentofMDD

• Antidepressantscancausesedation,cautionpatientnottoperformactivitiesrequiringalertnessuntilresponsetothedrughasbeendetermined

• Reassurepatientthatdrowsinessanddizzinessusuallysubsideafterthe rstfewweeks;ifdizzy,patientshouldgetupfromlyingorsittingposition

slowly, and dangle legs over edge of bed before getting up

• Excessiveuseofca einatedfoods,drugsorbeveragesmayincreaseanxietyandagitation,confusingthediagnosis

• Arti cialtearsmaybeusefulforpatientswhocomplainofdryeyes;suggestusingwettingsolutionsforthosewearingcontactlenses

• Expectadrymouth;suggestrinsingthemouthfrequentlywithwaterandusingsourorsugarlesshardcandyorgum

• Checkforconstipation;recommendincreasing uidanddietary berintakebutavoidingestinghigh- berfoodsorlaxatives(e.g.,bran)concurrently

with medication, as this may interfere with absorption, reducing antidepressant levels

• Checkforurinaryretention;ifrequired,thephysicianmayorderbethanecholorallyorbysubcutaneousinjection

• Cautionpatienttoavoidsuddenlystoppingtheantidepressantduetoriskofprecipitatingawithdrawalreaction

Breast Milk

Nursing Implications

♢ See p. 439 for further information on drug use in pregnancy and e ects on breast milk

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

• Fordetailedpatientinstructionsoncyclicantidepressants,seethePatientInformationSheet(detailsp.440) • Clinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterforthesecondagent

Patient Instructions

Drug Interactions

Example

Interaction Effects

Enalapril

Increased plasma level of clomipramine due to decreased metabolism

Short-term or acute use reduces rst-pass metabolism of TCAs, increasing plasma levels; chronic use induces metabolizing enzymes, decreasing plasma levels

Additive effects on sedation and CNS depression

En urane

Report of seizures with amitriptyline

Procainamide, propafenone, quinidine

Increased plasma level due to CYP2D6 inhibition; risk for increased side effects)

Azithromycin, clarithromycin, erythromycin

Additive QTc prolongation, arrhythmia

Cipro oxacin, o oxacin Linezolid

Decreased clearance due to CYP1A2 inhibition; risk of increased side effects

Monitor for increased serotonergic and noradrenergic effects due to linezolid’s weak MAO inhibition

Antihistamines, antiparkinsonian agents, antipsychotics

Increased anticholinergic effect; may increase risk of hyperthermia, confusion, urinary retention, etc.

Apixaban, dabigatran, rivaroxaban, warfarin

Increased risk of bleeding possible due to decreased platelet aggregation secondary to depletion of serotonin in platelets

Barbiturates, carbamazepine, phenytoin Divalproex, valproate, valproic acid

Decreased plasma level of TCAs due to enzyme induction; increased levels of carbamazepine Increased plasma level of TCAs

Phenobarbital

Increased plasma level of phenobarbital with clomipramine

Fluoxetine, uvoxamine, paroxetine, sertraline (less likely with citalopram or escitalopram)

Bupropion

Venlafaxine

Isocarboxazid, phenelzine, tranylcypromine

Elevated TCA plasma level (due to inhibition of oxidative metabolism); monitor plasma level and for signs of toxicity, also for additive QTc prolongation effects

Elevated imipramine level (by 57%), desipramine level (by 82%), and nortriptyline level (by 200%) with combination

Cases of serotonin syndrome, increased antimuscarinic adverse effects (dry mouth, urinary retention, constipation), movement disorders, and seizures reported with concurrent use of venlafaxine and tricyclic antidepressants

If used together, do not add TCAs to MAOI: Start TCAs rst or simultaneously with MAOI; for patients already on MAOI, discontinue MAOI 10–14 days before starting combination therapy

Combined TCA and MAOI therapy has additive antidepressant effects in treatment-resistant patients

Serotonin syndrome and deaths have been reported

Fluconazole, itraconazole, ketoconazole, miconazole

Terbina ne

Increased plasma level of antidepressant due to inhibited metabolism (89% with amitriptyline; 70% with nortriptyline); 20% increase with imipramine and no increase with desipramine

Prolonged increase in plasma level of amitriptyline and its metabolite nortriptyline, due to inhibited metabolism via CYP2D6

Diphenhydramine

Increased plasma level of antidepressants metabolized via CYP2D6 is possible (e.g., amitriptyline, desipramine, clomipramine, imipramine) due to inhibited metabolism

Additive CNS and anticholinergic effects

Class of Drug

ACE inhibitor Alcohol

Anesthetic Antiarrhythmic Antibiotic

Anticholinergic Anticoagulant Anticonvulsant

Antidepressant

SSRI

NDRI NDRI

Irreversible MAOI

Antifungal Antihistamine

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 57 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Nonselective Cyclic Antidepressants (cont.)

Class of Drug Interaction Effects

Example

Acetazolamide, thiazide diuretics

Clonidine, guanethidine, methyldopa, reserpine

Labetalol

Chlorpromazine, uphenazine, haloperidol, perphenazine, pimozide, thioridazine

Clozapine

Stribild (elevitegravir + cobicistat + emtricitabine + tenofovir) Ritonavir

Alprazolam Buspirone Triazolam

Diltiazem, verapamil

Nifedipine

Alcohol, antihistamines, benzodiazepineshypnotics

Cimetidine

Estrogen/progesterone oral contraceptive

Antihypertensive

Antipsychotic

First generation

Second generation

Antiretroviral

Combination Protease inhibitor

Anxiolytic

Calcium channel blocker Cannabis/marijuana CNS depressant

Cholestyramine Evening primrose oil Grapefruit juice

H2 antagonist

Hormone

Insulin Lithium

Hypotension augmented

Decreased antihypertensive effect due to inhibition of α-adrenergic receptors Abrupt discontinuation of clonidine may precipitate hypertensive crisis Increased plasma level of imipramine (by 54%) and desipramine

Haloperidol and phenothiazines may increase the plasma level of TCAs. TCAs may increase the plasma level of chlorpromazine. Clinical signi cance unknown

DO NOT COMBINE pimozide or thioridazine with TCAs; NOT recommended with phenothiazines or zuclopenthixol. CAUTION with all other FGAs. Possible additive prolongation of QT interval and associated life-threatening cardiac arrhythmias

Additive sedation, hypotension, and anticholinergic effects

Possible serotonin syndrome reported in a patient taking clomipramine following the withdrawal of clozapine

Increased plasma level of desipramine (AUC by 65%, Cmax by 24%) via CYP2D6 inhibition

Dose-dependent increase in plasma levels of tricyclic antidepressant due to decreased metabolism (AUC of desipramine increased by 145% and peak plasma level increased by 22% with ritonavir 500 mg bid, while ritonavir 100 mg bid has no signi cant effects on desipramine pharmacokinetics)

Increased plasma levels of desipramine and imipramine with alprazolam (by 20% and 31%, respectively)

Concomitant use of serotonergic agents (clomipramine, amitriptyline) increases the risk of serotonin syndrome

Desipramine and triazolam: Report of hypothermia (neither drug causes this effect alone); triazolam potentiates anorexic effect of desipramine

Increased imipramine plasma level (by 30% and 15%, respectively); increased level of trimipramine

May antagonize the ef cacy of antidepressant drugs

Case reports of tachycardia, lightheadedness, confusion, mood lability, and delirium with nortriptyline and desipramine; may evoke cardiac complications in youth

Increased sedation, CNS depression

Decreased absorption of antidepressant due to binding by cholestyramine, if given together

May lower the seizure threshold

Decreased conversion of clomipramine to metabolite due to inhibition of CYP3A4

Increased plasma level of antidepressant; for desipramine, inhibition of hydroxylation only occurs in patients who are rapid metabolizers

Increased plasma level of antidepressant due to decreased metabolism

Reduced clearance of combined oral contraceptive possible with amitriptyline due to inhibited metabolism Decreased insulin sensitivity reported with amitriptyline

May increase risk of neurotoxicity

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Example

Interaction Effects

May potentiate the risk of serotonin syndrome. Monitor for increased serotonergic effects

Selegiline (L-deprenyl)

Reports of serotonergic reactions

Baclofen

Warning of tricyclic antidepressants potentiating the effects of baclofen, resulting in pronounced muscular hypotonia; case report of a patient taking baclofen being unable to walk after taking nortriptyline and imipramine (reversed after discontinuing tricyclics)

Codeine Methadone

Marked inhibition of conversion of codeine to morphine (active moiety) with amitriptyline, clomipramine, desipramine, imipramine, and nortriptyline

Increased plasma level of desipramine (by about 108%)

Morphine Tramadol

Enhanced analgesic effect

Increased risk of seizures and serotonin syndrome

Increased metabolism of clomipramine (may be due to induction of CYP3A4) and additive anticholinergic effects

Omeprazole

Increased plasma level of antidepressant due to inhibited metabolism

Decreased plasma level of antidepressant due to increased metabolism

Methylphenidate

Plasma level of antidepressant may be increased

Used together to augment antidepressant effect and response to symptoms of ADHD Cardiovascular effects increased with combination, in children – monitor

Case reports of neurotoxic effects with imipramine, considered rare – monitor Decreased seizure threshold

Elevated heart rate and diastolic pressure (by 20–30%); increased risk of arrhythmia

Decreased amitriptyline concentration Additive serotonergic effects

Tolbutamide

Increased hypoglycemia

Epinephrine, norepinephrine (levarterenol), phenylephrine

Isoproterenol

Enhanced pressor response from 2- to 8-fold; bene t may outweigh risks in anaphylaxis

Avoid concurrent use of parenteral epinephrine, norepinephrine, phenylephrine, or other direct-acting sympathomimetic amines due to increased risk of hypertension and cardiac arrhythmias

May increase likelihood of arrhythmias

Decreased plasma level of doxepin (by 25%) due to induced metabolism via CYP3A4

Sumatriptan, zolmitriptan

Possible serotonergic reaction when combined with antidepressants with serotonergic activity (e.g., clomipramine)

Case report of visual hallucinations in combination with desipramine

In one study, 5 of 8 patients on imipramine experienced anterograde amnesia

Class of Drug

L-Tryptophan MAO-B inhibitor Muscle relaxant

Opioid

Oxybutynin

Proton pump inhibitor Rifampin

Stimulant

St. John’s Wort

Sulfonylurea Sympathomimetic

Tamoxifen Triptan Zolpidem

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 59 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

General Comments

Monoamine Oxidase Inhibitors

• Monoamineoxidaseinhibitorsareclassi edasfollows:

Chemical Class

Agent

Page

Reversible Inhibitor of MAO-A (RIMA)

Moclobemide

See p. 60

Irreversible MAO (A&B) Inhibitors (MAOIs)

Isocarboxazid(B) Phenelzine Tranylcypromine

See p. 64 See p. 64 See p. 64

Irreversible MAO-B Inhibitor

Selegiline (L-deprenyl)(B)

See p. 70

(B) NotmarketedinCanada

Product Availability∗

∗ Refer to Health Canada’s Drug Product Database or the FDA’s Drugs@FDA for the most current availability information. (A) Generic preparations may be available,

Reversible Inhibitor of MAO-A (RIMA)

Generic Name

Chemical Class

Trade Name(A)

Dosage Forms and Strengths

Moclobemide(C)

Reversible Inhibitor of MAO-A (RIMA)

Manerix

Tablets: 100 mg, 150 mg, 300 mg

Indications‡

( approved)

General Comments

Major depressive disorder (MDD)

Dysthymia, chronic

• Seasonala ectivedisorder(SAD),chronicfatiguesyndrome,andobsessive-compulsivedisorder(OCD)–weakevidencesuggestse cacy

• Borderlinepersonalitydisorder–suggestedtomodulateimpulsivity/aggressionanda ectiveinstability

• Socialanxietydisorder

• IncreasesREMsleep

• Short-actingreversibleinhibitoroftheenzymeMAO-A;inhibitsthemetabolismofserotonin,norepinephrine,anddopamine

• Chronicdosingover400mgdailywillinhibit20–30%ofMAO-Binplatelets

• Inhibitionreverseswithin24h

• CombiningmoclobemidewithTCAsorlithiummayincreaseantidepressante ect

Pharmacology

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Dosing

• Startingdose:300mgdailyindivideddoses;furtherdoseincreasesshouldwaitatleast1week;bioavailabilityincreasesoverthe rstweek.Usual dose range: 300–600 mg daily; some patients respond to 150 mg daily, but most require doses above 450 mg/day

• Moclobemideshouldbetakenaftermealstominimizetyramine-relatede ects(e.g.,headache)

• Preliminarydatasuggeststhatoncedailydosingisase ectiveasdivideddosing

• Dosingisnota ectedbyage

• Hepaticdisease:Decreasesclearance[Management:Decreasedosebyonethirdtoonehalfinpatientswithseverehepaticimpairment]

• Renaldisease:Usewithcaution,doesnota ectdosing

• Seep.84

• Rapidlyabsorbedfromthegutwithahigh rst-passe ect;absorptionincreasesfrom50%with rstdosetoapproximately90%after2weeks

• Relativelylipophilic,buthighlywatersolubleatlowpH

• Lowplasma-proteinbinding,approximately50%,primarilyalbumin

• Peake ectoccursbetween0.7and1.1hintheabsenceandpresenceoffood,respectively

• Plasmalevelsincreaseinproportiontodose;blockadeofMAO-Acorrelateswithplasmaconcentrations

• Extensivelymetabolizedbyoxidation;partialmetabolismprimarilyviaCYP2C19and2D6

• Clearancedecreasesasdosageincreasesbecauseofauto-inhibitionormetabolite-inducedinhibition

• Eliminationhalf-life1–3h;4.6hintheelderly

• Therapeutice ectsaretypicallyobservedby28days

• Seetablep.81

• Mostcommon:Insomnia,sedation,agitation,nervousness,anxiety,headache,anddizziness

• Dose-relatedstimulante ectsincluderestlessness,anxiety,agitation,andaggression

• Tremor

• Hypomaniareported,especiallyinpatientswithbipolardisorder

• Drymouth,blurredvision

• Tachycardia,hypotension

• Reportsofgalactorrheainfemales

• Bothweightlossandweightgain

• Constipation,nausea,vomiting,diarrhea,abdominalpain

• Lowincidenceofsexualdysfunction;24%comparedto62%forSSRIs[21]

• Casereportofmoclobemidediscontinuationsyndromepresentingwithin uenza-likesymptoms(muscularcramps,shivering,neckpain,headache, nausea, hot ush without fever)

• Patientsprescribeddosesabove600mg/dayshouldminimizeconsumptionoftyramine-richfoods

• Hypertensivepatientsshouldavoidingestinglargequantitiesoftyramine-richfoods

• Hypertensivereactionsmayoccurinpatientswiththyrotoxicosisorpheochromocytoma

• Use caution when combining with serotonergic drugs as serotonin syndrome has been reported (see p. 9) with CNS irritability, increased muscle

tone, myoclonus, diaphoresis, and elevated temperature (see Interactions, p. 62)

• Reducedosebyonethirdtoonehalfinpatientswithsevereliverimpairment

Pharmacokinetics

Onset & Duration of Action

Adverse Effects

CNS Effects

Anticholinergic Effects

Cardiovascular Effects

Endocrine & Metabolic Effects

GI Effects

Urogenital & Sexual Effects

Discontinuation Syndrome Precautions

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 61 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Toxicity

Pediatric Considerations Geriatric Considerations

Nursing Implications

Reversible Inhibitor of MAO-A (RIMA) (cont.)

• Symptoms of toxicity are the same as side e ects but intensi ed: drowsiness, disorientation, stupor, hypotension, tachycardia, hyperre exia, grimacing, sweating, agitation, and hallucinations; serotonin syndrome has been reported, convulsions

• Fatalitieshaveoccurredwhencombinedwithcitalopramorclomipramineinoverdose

• Gastriclavage,emesis,activatedcharcoalmaybeofbene t

• Monitorvitalfunctions,supportivetreatment

• For detailed information on the use of moclobemide in this population, please see the Clinical Handbook of Psychotropic Drugs for Children and

Adolescents[7]

• Dosingisnota ectedbyageorrenalfunction

• Improvementincognitivefunctioninginelderlydepressedpatientshasbeennoted

• Dataonsafetyinpregnancyislacking

• Animalstudieshavenotshownanyparticularadversee ectsonreproduction

• Moclobemideissecretedintobreastmilkatabout1%ofmaternaldose

• Monitorforsignsofsuicidalideation

• Monitorbloodpressure

• Warn patient not to self-medicate with over-the-counter drugs or herbal preparations; consult physician or pharmacist to prevent drug-drug

interactions

• It is not necessary to maintain a special diet when moclobemide is prescribed in low to moderate doses; excessive amounts of foods with high

tyramine content can lead to headache

• Patientsshouldbeinstructedtorecognizesignsofhypertensivecrisis(e.g.,headache,necksti ness,palpitations,etc.)

• Administermoclobemideafterfoodtominimizesidee ects;avoidbigmealsaftertakingmoclobemide

• Ifpatienthasdi cultysleeping,ensurethatthelastdoseofmoclobemideisnolaterthan1700h

• Fordetailedpatientinstructionsonmoclobemide,seethePatientInformationSheet(detailsp.440)

• Noparticularprecautionsarerequired;avoidexcessiveconsumptionoftyramine-containingfoodtominimizetheriskofhypertension

• Clinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterforthesecondagent

Management

Use in Pregnancy♢

Breast Milk

Patient Instructions

Food Interactions

Drug Interactions

♢ See p. 439 for further information on drug use in pregnancy and e ects on breast milk

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Example

Linezolid

Antiparkinsonian drugs

Citalopram, escitalopram, uoxetine, uvoxamine

Bupropion

Venlafaxine

Nefazodone

Desipramine, nortriptyline

Clomipramine

General

Buspirone

Cimetidine

Selegiline (L-deprenyl)

Dextromethorphan, meperidine, pentazocine

Tramadol

Atomoxetine

Amphetamine, methylphenidate

Indirect-acting: Amphetamine, ephedrine, L-dopa, methylphenidate, etc. Direct-acting: Epinephrine, salbutamol, etc.

Rizatriptan

Sumatriptan, zolmitriptan

Class of Drug Interaction Effects

Anesthetic, general Antibiotic Anticholinergic Antidepressant

SSRI

NDRI

SNRI

SARI

Nonselective cyclic

MAOI

Antipsychotic

Anxiolytic

H2 antagonist L-Tryptophan

MAO-B inhibitor Methylene blue

Opioids and related drugs

Selective norepinephrine reuptake inhibitor

Stimulant

St. John’s Wort

Sympathomimetic

Triptan

Stop antidepressant two days prior

MAOIs increase the adverse effects of linezolid; AVOID concomitant use

Enhanced anticholinergic adverse effects

MAOIs may enhance the adverse effects of other antidepressants

Use cautiously and monitor for serotonergic adverse effects (e.g., serotonin syndrome), especially with citalopram and escitalopram Higher incidence of insomnia may occur; increased headache reported with uvoxamine

Fluoxetine and uvoxamine can inhibit the metabolism of moclobemide

Enhanced neurotoxic effects; MAOIs may increase the antihypertensive effects of bupropion; AVOID

Enhanced effects of serotonin and/or norepinephrine; no data on safety with combination; AVOID

Potentiation of weight gain, hypotension, and anticholinergic effects; use cautiously and monitor for serotonergic adverse effects (e.g., serotonin syndrome)

Enhanced serotonergic effects; AVOID

Concurrent use contraindicated

May enhance dopamine blockade; antipsychotic agents may enhance serotonergic effects resulting in serotonin syndrome

Additive hypotension, particularly with low-potency FGAs such as chlorpromazine

Buspirone may increase the adverse effects of MAOIs (e.g., increased blood pressure); AVOID

MAOIs may potentiate the activity of buspirone via inhibition of serotonin metabolism; serotonergic reaction possible

May decrease metabolism of moclobemide; plasma level may double

May enhance adverse effects of moclobemide. Serotonin syndrome possible; AVOID

CAUTION with combination; dietary restrictions recommended as both A + B MAO enzymes will be inhibited

Enhanced serotonergic effects through inhibition of MAO-A and B by methylene blue. Risk for serotonin syndrome (see Precautions) MAOIs will enhance the serotonergic effects; may cause serotonin syndrome; increased restlessness; death reported with meperidine – AVOID COMBINATION

Vertigo, tremor, nausea, and vomiting reported; increased risk of serotonin syndrome; AVOID COMBINATION

May enhance neuroexcitatory effects, increasing the risk of seizures and serotonin syndrome

MAOIs may enhance the neurotoxic effects of atomoxetine; AVOID

MAOIs enhance the antihypertensive effects; AVOID

May augment serotonergic effects and cause serotonin syndrome. AVOID combination

Increased blood pressure and enhanced effects if used over prolonged periods or at high doses; AVOID

Decreased metabolism of rizatriptan; AUC and peak plasma level increased by 119% and 41%, respectively, and AUC of metabolite increased by 400%

Possible increased serotonergic effects

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 63 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Irreversible Monoamine Oxidase (A&B) Inhibitors (MAOIs)

Product Availability∗

∗ Refer to Health Canada’s Drug Product Database or the FDA’s Drugs@FDA for the most current availability information. (A) Generic preparations may be available, (B) Not marketed in Canada

Generic Name

Chemical Class

Trade Name(A)

Dosage Forms and Strengths

Isocarboxazid(B)

Hydrazine derivative

Marplan

Tablets: 10 mg

Phenelzine

Hydrazine derivative

Nardil

Tablets: 15 mg

Tranylcypromine

Non-hydrazine derivative

Parnate

Tablets: 10 mg

Indications‡

( approved)

Depression, atypical

Major depressive disorder (MDD) unresponsive to other antidepressants (phenelzine, tranylcypromine)

• Bipolardepression,atypical(anergic)

• Phobia:Phobicanxietystatesorsocialphobia

• Panicdisorder:Prophylaxis

• Obsessive-compulsivedisorder(OCD)

• MDDinpatientswithborderlinepersonalitydisorder

• Dysthymia,chronic

• Posttraumaticstressdisorder(PTSD)–e cacyreported

• Schizophrenia,chronic:Mayimprovenegativesymptoms

• Herpes:Possibleantiherpetice ect

• Abilityofpatienttoadheretodietaryanddrugrestrictionsshouldbeassessedbeforeprescribing

• Use with caution in elderly, debilitated patients and those with hypertension, cardiovascular or cerebrovascular disease due to increased risk for

hypertensive crisis or hyperthermia

• MonitorBPandheartrate

• PremenopausalwomenmayrespondbettertoMAOIsthantoTCAs

• Nonselectively inhibit MAO-A and B enzymes; involved in oxidative deamination of serotonin, norepinephrine, and dopamine; down-regulate β adrenoceptors

• Inhibitionisirreversibleandlastsabout10days

• Seep.84

• Bidormorefrequentdosingrequiredduetoshorthalf-life(seeindividualagents);givedosesinthemorningandmid-daytoavoidoverstimulation

and insomnia; sedation can occur occasionally

• Delayintherapeuticresponse;allowsu cienttimebetweendoseincreases(e.g.,1–2weeks)

• Gradualdoseincreasesarerecommendedindebilitated,emaciatedorgeriatricpatients

• Hepaticdisease:AVOID

• Renaldisease:CAUTION,mayhavetodecreasethedose

General Comments

Pharmacology

Dosing

‡ Indications listed here do not necessarily apply to all MAOIs or all countries. Please refer to a country’s regulatory database (e.g., US Food and Drug Administration, Health Canada Drug Product Database) for the most current availability information and indications

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Pharmacokinetics

Onset & Duration of Action

• Seep.84

• RapidlyabsorbedfromtheGItract,metabolizedbytheliverandexcretedalmostentirelyintheurine

• Peakplasmaleveloftranylcypromineoccursin1–2h,ofphenelzineinupto1handcorrelateswithelevationsinsupinebloodpressure,orthostatic

drop in systolic blood pressure, and rise in pulse rate. Blood pressure elevation correlates with dose

• Irreversible MAOIs can impair their own metabolism with long-term use, resulting in nonlinear pharmacokinetics and the potential for drug

accumulation

• Theenergizinge ectoftenobservedwithinafewdays

• Mayrequireupto2weekstoreachmaximumMAOinhibition

• DurationofMAOinhibitioncanbeupto2weeksafterdiscontinuationofphenelzine;10daysfortranylcypromine

• Tolerancetoantipanice ectsreported

• Seep.81

• Most common e ects; dizziness, drowsiness (phenelzine most sedating), fatigue, headache (without increased blood pressure), hyperre exia, and sleep disturbance that can occur early on [Management: slowing dosage titration, divided dosing, bedtime dosing]

• Othersymptomsincludeakinesia,confusion,disorientation,euphoria,memoryloss,andnystagmus

• Stimulante ectsincludeagitation,anxiety,hyperexitability,manicsymptoms,precipitationofpsychosis,andrestlessness(maybemoreprevalent

with higher doses of tranylcypromine)

• Hypomania and mania: reported in patients with bipolar disorder (risk up to 35%; lower risk with concomitant use of a mood stabilizer); in MDD,

risk about 4%

• Increased sleep onset latency and reduced sleep e ciency; REM sleep decreased and may be eliminated at start of therapy, rebound REM of up to

250% above baseline reported on drug withdrawal

• Paresthesias or “electric-shock-like” sensations and carpal tunnel syndrome (numbness) reported; may be due to vitamin B6 de ciency [Manage-

ment: Pyridoxine 50–150 mg/day]

• Myoclonicmovements(especiallyduringsleep,10–15%),musclecramps,tension,tremorandtwitching,anddose-relatedakathisia[Management:

Cyproheptadine may be helpful for cramps or jerks; clonazepam or valproate for nocturnal myoclonus]

• Constipationcommon[Management:Increasebulkand uidintake,fecalsoftener,bulk-forminglaxative]

• Drymouth

• Urinaryretention

• Dizziness, weakness, orthostatic hypotension (can be early or late e ect); usually temporary but if symptoms persist the drug may need to be discontinued [Management: slower dosage titration, divided dosing, increased uid intake, udrocortisone 0.1–0.2 mg/day]

• Occasionally,hypertensivepatientsmayexperienceariseinbloodpressure(prevalencemaybehigherwithtranylcypromine)

• Edemainlowerextremities(morecommonwithtranylcypromine)[Management:Restrictsodium;supporthose;amiloride5–10mg/dayuptobid,

monitor frequently for hypotension]

• Normocytic,normochromicanemia,agranulocytosis,andneutropeniareported

• Casereportsofthrombocytopenia

• HyponatremiaandSIADHreported

• Increasedappetiteandweightgain

• Hypoglycemiareported

• Mostcommonareanorexia,nausea,andvomiting

Adverse Effects

CNS Effects

Anticholinergic Effects

Cardiovascular Effects

Hematologic Effects

Endocrine & Metabolic Effects

GI Effects

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 65 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Urogenital & Sexual Effects

Other Adverse Effects

Hypertensive Crisis

Irreversible Monoamine Oxidase (A&B) Inhibitors (MAOIs) (cont.)

• Urinaryfrequency,incontinence,andretentionreported

• Decreasedlibido,impotence,anorgasmia,andejaculationdi culties[Management:SeeSSRIsp.7]

• Maydiminishspermcount

• Rarelypriapism

• Themostcommonadversee ectiselevatedtransaminaselevels;rarereportsoflivertoxicity

• Rarereportsofhairlosswithtranylcypromine

• CanoccurwithirreversibleMAOIsduetoingestionofincompatiblefoods(containingsubstantiallevelsoftyramine)ordrugs(seelistspp.67–68)

• Notrelatedtodrugdosage

• Otherriskfactorscaninclude:elderly,debilitatedpatients,pre-existinghypertension,cardiovascularorcerebrovasculardisease

• Occipital headache, neck sti ness or soreness, nausea, vomiting, sweating (sometimes with fever and sometimes with cold, clammy skin), dilated pupils and photophobia, sudden nose bleed, tachycardia, bradycardia, and constricting chest pain

• Headacheisusuallythe rstsymptom

• Warnpatientstodiscontinuethemedicationimmediatelyiftheyexperienceanyoftheabovesymptoms

• Withholdmedicationandnotifyphysicianimmediately

• Monitorbloodpressureandclinicalstatus

• Monitorvitalsigns,ECG

• Sublingualcaptopril25mgmaydecreasebloodpressure(occasionallydrastically–monitor)

• Phentolamineisanalternativeparenteraltreatment

• Patientshouldstandandwalk,ratherthanliedown,duringahypertensivereaction;BPwilldropsomewhat

• Canoccur1–4daysafterabruptwithdrawalofmedications

• Reportsofmuscleweakness,agitation,vividnightmares,headache,palpitations,nausea,sweating,irritability,andmyoclonicjerking;acuteorganic

psychosis with hallucinations also reported

• REMrebound(upto250%abovebaseline)

• Importanttomaintaindietaryanddrugrestrictionsforatleast10daysafterstoppingMAOI

• Monitorforworseningofdepressionorsuicidalideation,especiallyduringinitiationoftherapyorwithdosechanges

• CONTRAINDICATEDinpatientswithahistoryofliverdiseaseorabnormalliverfunctiontests

• Shouldnotbeadministeredtopatientswithcerebrovasculardisease,cardiovasculardisease,orahistoryofhypertension

• Usewithcautioninpatientswithhyperthyroidism,Parkinsoniansyndrome,impairedrenalfunctionorahistoryofseizures

• Shouldnotbeusedaloneinpatientswithmarkedpsychomotoragitation

• Need 10–14 days washout before an incompatible drug or food is given; hypertensive crisis can occur if given concurrently with certain drugs or

foods (see lists pp. 67–68)

• WhenchangingfromoneMAOItoanother,ortoaTCA,allowaminimumof10medication-freedays

• Discontinue at least 7–14 days before elective surgery (tranylcypromine: 7 days; phenelzine, isocarboxazid: 10 days); may want to discontinue use

prior to ECT

• Usecautionwhencombiningwithserotonergicdrugs;serotoninsyndromehasbeenreported(seep.9)

• Symptomssameassidee ectsbutintensi ed

• Severecasesprogresstoextremedizzinessandshockduetoe ectsoncardiacconduction

• Overdose, whether accidental or intentional, can be fatal; patient may appear symptom-free up to 6 h, then progress to restlessness-coma-death;

Signs and Symptoms

Management

Discontinuation Syndrome

Precautions

Toxicity

close medical supervision is indicated for 48 h following an overdose

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Pediatric Considerations Geriatric Considerations

Use in Pregnancy♢

Nursing Implications

• Ideally should not be used in this patient population. For detailed information on the use of MAOIs in this population, please see the Clinical Handbook of Psychotropic Drugs for Children and Adolescents[7]

• SuggestedthatMAOIsmayhaveparticulare cacyintheelderly,asmonoamineoxidaseactivityinthebrainincreaseswithage

• Theelderlyarealsomoresusceptibletoadversee ectsassociatedwithMAOIuseandthesee ectsareassociatedwithanincreasedmortality

• Initiateatlowdosesandmonitor

• Orthostatichypotensionmaybeproblematic,usedivideddoses[Management:Supportstockings,sodiumchloridetablets, udrocortisone]

• Experienceistoolimitedtoadequatelyassessrisk;increasedincidenceofmalformationsassociatedwithusein rsttrimester

• Limiteddataontranylcypromine,phenelzine,orisocarboxazid;molecularweightislowenoughtoexpectexcretionintobreastmilk

• Usewithcautioninnursingwomen

• AdvisepatienttoinformphysiciansanddentiststhattheyaretakingaMAOI

• Educatepatientregardingwhichfoodsanddrugstoavoid;adietsheetshouldbeprovidedforeachpatient

• Warn patient to avoid self-medicating with over-the-counter drugs or herbal preparations; always consult a physician or pharmacist to prevent

drug-drug interactions

• MonitorBPandheartrateandreportincreasestophysicianimmediately

• Advise patient to immediately report severe headache, neck sti ness, palpitations or other atypical or unusual symptoms not previously experi-

enced

• Theincidenceoforthostatichypotensionishigh,especiallyintheelderlyandatthestartoftreatment[Management:Advisepatienttogetupand

out of bed slowly]

• Ifpatienthasdi cultysleeping,ensurethatthelastdoseofMAOIistakennolaterthan1500h

• FordetailedpatientinstructionsonMAOIs,seethePatientInformationSheet(detailsonp.440)

There are many serious food and drug interactions that can precipitate a hypertensive crisis; maintain dietary and drug restrictions for at least 10 days

after stopping MAOI

☞ MAKE SURE ALL FOOD IS FRESH, STORED PROPERLY, AND EATEN SOON AFTER BEING PURCHASED – refrigerated products will show an increase in tyramine content after several days

• Neverconsumefoodthatisfermentedorpossibly“o ” • Avoidrestaurantsauces,gravy,andsoup

Foods to avoid (high tyramine content):

• Allmaturedoragedcheeses(e.g.,cheddar,brie,blue,Stilton,Roquefort,camembert) • Broadbeanpods(e.g.,Fava)–containdopamine

• Concentratedyeastextracts(e.g.,Marmite)

• Driedsalted sh,pickledherring

• Packetsoup,especiallymiso

• Sauerkraut

• Aged/smokedmeats(especiallysalami,mortadella,pastrami,summersausage),sausage,otherunrefrigeratedfermentedmeats,gamemeatthat

has been hung, liver

• Soysauceorsoybeancondiments,tofu

• Tap(draft)beer,alcohol-freebeer

• Improperlystoredorspoiledmeats,poultryor sh

Breast Milk

Patient Instructions

Food Interactions

♢ See p. 439 for further information on drug use in pregnancy and e ects on breast milk

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 67 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Drug Interactions

Irreversible Monoamine Oxidase (A&B) Inhibitors (MAOIs) (cont.)

SAFE to use in moderate amounts but only if fresh:

• Cottagecheese,creamcheese,farmer’scheese,processedcheese,CheezWhiz,ricotta,Havarti,Boursin,briewithoutrind,gorgonzola • Liver(aslongasitisfresh),freshorprocessedmeats,poultryor sh(e.g.,hotdogs,bologna)

• Spirits(inmoderation)

• Sourcream

• Soymilk

• Saladdressings

• Worcestershiresauce

• Yeast-leavenedbread

Reactions have been reported with the following (moderate tyramine content) – use moderately with caution: • Smoked sh,caviar,snails,tinned sh,shrimppaste

• Yogurt

• Meattenderizers

• Homemaderedwine,Chianti,canned/bottledbeer,sherry,champagne

• Cheeses(e.g.,Parmesan,muenster,Swiss,gruyere,mozzarella,feta)

• Pepperoni

• Overripefruit:bananas,avocados,raspberries,plums,tomatoes,canned gsorraisins,orangepulp

• Meatextract(e.g.,Bovril,Oxo)

• Asianfoods

• Spinach,eggplant

Over-the-counter drugs – DO NOT USE without prior consultation with doctor or pharmacist:

• Coldremedies,decongestants(includingnasalspraysanddrops),someantihistaminesandcoughmedicines • Opioidpainkillers(e.g.,productscontainingcodeine)

• Allstimulantsincludingpep-pills(Wake-ups,Nodoz)

• Allappetitesuppressants

• Anti-asthmadrugs(PrimatineP)

• Sleepaidsandsedatives(Sominex,Nytol)

• Yeast,dietarysupplements(e.g.,Ultrafast,Optifast)

• Clinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterforthesecondagent

Class of Drug

Example

Interaction Effects

Anesthetic, general

MAOIs may exaggerate the hypotension and CNS effects of anesthetics; discontinue 10 days prior to elective surgery

Antibiotic

Linezolid

Monitor for increased serotonergic and noradrenergic effects due to linezolid’s weak MAO inhibition

Anticholinergic

Antihistamines, antiparkinsonian agents

Severe reactions reported, including prolonging and intensifying some anticholinergic effects Increased atropine-like effects

Anticonvulsant

Carbamazepine

Possible decrease in metabolism and increased plasma level of carbamazepine with phenelzine

Antidepressant

SSRI NDRI

Citalopram, uoxetine, uvoxamine, paroxetine, sertraline

Bupropion

Serotonin syndrome and death reported with serotonergic antidepressants; AVOID; do not use within 5 weeks of uoxetine and 2 weeks of other SSRIs

MAOIs enhance toxic effects of bupropion; AVOID

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Example

Venlafaxine Trazodone

Mirtazapine

Amitriptyline, desipramine

Clomipramine

α-blockers, β-blockers, ACE-inhibitors

Guanethidine

General Quetiapine

Ziprasidone

Buspirone

Alcohol, barbiturates, sedatives

Selegiline (L-deprenyl)

Succinylcholine

Dextromethorphan Dextromethorphan, diphenoxylate, meperidine, tramadol

Tramadol

MDA, MDMA (“Ecstasy”)

Class of Drug Interaction Effects

SNRI SARI

NaSSA Nonselective cyclic

Antihypertensive Antipsychotic

Second generation

Anxiolytic Atropine Bromocriptine CNS depressant Diuretic Ginseng Insulin

L-Dopa

Licorice

Lithium

L-Tryptophan

MAO-B inhibitor Methylene blue

Muscle relaxant

Nicotine

Opioids and related drugs

Reserpine Stimulants

St. John’s Wort

Metabolism of serotonin and norepinephrine inhibited; AVOID

Low doses of trazodone (25–50 mg) used to treat antidepressant-induced insomnia

Monitor for serotonergic adverse effects

Possible serotonergic reaction; AVOID

If used together, do not add cyclic antidepressant to MAOI. Start cyclic antidepressant rst or simultaneously with MAOI. For patients already on MAOI, discontinue the MAOI for 10–14 days before starting combination therapy

Combined cyclic and MAOI therapy has increased antidepressant effects and will potentiate weight gain, hypotension, and anticholinergic effects

Serotonin syndrome and deaths have been reported

Serotonin syndrome (see p. 9) reported; AVOID

MAOIs should not be administered with hypotensive agents as marked hypotension may occur

Severe pressor response can occur due to catecholamine release; AVOID

Additive hypotension and anticholinergic effects

Case report of serotonin syndrome with quetiapine and phenelzine

Case report of serotonin syndrome with tranylcypromine

Several cases of increased blood pressure reported; AVOID; discontinue MAOIs at least 10 days before initiation of buspirone Prolonged action of atropine

Increased serotonergic effects

May enhance CNS depression

MAOIs should not be administered with hypotensive agents as marked hypotension may occur

May cause headache, tremulousness or hypomania; case report of irritability and visual hallucinations with combination

Enhanced hypoglycemic response through stimulation of insulin secretion and inhibition of gluconeogenesis

Increase in storage and release of dopamine and/or norepinephrine

Headache, hyperexcitability, hypertension, and related symptoms reported

Increased serotonergic effects possible

Increased serotonergic effects

Reports of serotonin syndrome (see p. 9) with hyperre exia, tremor, myoclonic jerks, and ocular oscillations; AVOID

Increased serotonergic effects

Enhanced serotonergic effects through inhibition of MAO-A and B by methylene blue. Risk for serotonin syndrome (see Precautions) Phenelzine may prolong muscle relaxation by inhibiting metabolism

Low doses of tranylcypromine reported to inhibit nicotine metabolism by competitive inhibition via CYP2A6

Reports of bizarre behavior and psychosis. Case reports of serotonin syndrome; AVOID

Excitation, sweating, and hypotension reported; may lead to development of encephalopathy, convulsions, coma, respiratory depression, and serotonin syndrome. If an opioid is required, meperidine should not be used; institute other opioids cautiously Increased risk of seizures and serotonin syndrome

Central excitatory syndrome and hypertension reported due to central and peripheral release of catecholamines

Case reports of serotonin syndrome (see p. 9) and hypertensive crisis

Increased serotonergic effects possible

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 69 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Irreversible Monoamine Oxidase (A&B) Inhibitors (MAOIs) (cont.)

Class of Drug

Example

Interaction Effects

Sulfonylurea

Tolbutamide

Enhanced hypoglycemic response

Sympathomimetic

Indirect-acting: Amphetamine, dopamine, ephedrine, methylphenidate, pseudoephedrine, tyramine Direct-acting: Epinephrine, isoproterenol, norepinephrine (levarterenol), salbutamol

Release of large amounts of norepinephrine with hypertensive reaction; AVOID No interaction

Phenylephrine

Increased pressor response

Tetrabenazine

Central excitatory syndrome and hypertension reported due to central and peripheral release of catecholamines

Triptan

Rizatriptan, sumatriptan, zolmitriptan

Serotonin syndrome (see p. 9); AVOID; recommended that 2 weeks elapse after discontinuing an irreversible MAOI before using sumatriptan

Irreversible MAO-B Inhibitor

Product Availability∗

Generic Name

Chemical Class

Trade Name

Dosage Forms and Strengths

Selegiline (L-deprenyl)

Levo-acetylenic derivative of phenethylamine

EMSAM(B) Zelapar(B)

Transdermalpatch:20mg/20cm2,30mg/30cm2,40mg/40cm2 thatdeliveronaverage6mg/24h, 9 mg/24 h, 12 mg/24 h, respectively

Orally disintegrating tablet: 1.25 mg

∗ Refer to Health Canada’s Drug Product Database or the FDA’s Drugs@FDA for the most current availability information. (B) Not marketed in Canada

Indications‡

( approved)

General Comments

Major depressive disorder (MDD) in adults (US only)

• Cocaineuse:Selegilinemayreducephysiologicalandsubjectivee ects

• OralformulationapprovedinlowdosesforthetreatmentofParkinson’sdisease;higherdosesrequiredfortreatmentofMDD

• Transdermal patches contain 1 mg of selegiline per cm2 and deliver approximately 0.3 mg of selegiline per cm2 over 24 h

• Dietaryrestrictionsarenotrequiredatlowestdoses;usecautionathigherdosesasselegilinelosesitsselectivityforMAO-Binhibition

• Mayproducefalse-positivedrugscreen(L-amphetaminemetabolites)

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Pharmacology

Dosing

• Transdermal selegiline provides sustained plasma concentrations of the parent compound, increasing the amount of drug delivered to the brain and decreasing metabolite production

• Atlowdoses,selegilineirreversiblyinhibitsMAO-B,whichisinvolvedinoxidativedeaminationofdopamineinthebrainandalsoinhibitstheuptake of dopamine

• At higher doses, selegiline inhibits both MAO-A and B, which are involved in the catabolism of norepinephrine, dopamine, and serotonin. In vivo animal models using the transdermal patch suggest that both MAO-A and MAO-B inhibition is required for antidepressant e ects

• ThetransdermalformulationallowsfortargetedinhibitionofcentralnervoussystemMAO-AandMAO-Bwithminimale ectsonMAO-AintheGI (gut wall) and hepatic systems, avoiding rst-pass e ect, reducing the risk of interactions with tyramine-rich foods

• Inducesantioxidantenzymesanddecreasestheformationofoxygenradicals;itinterfereswithearlyapoptoticsignalingeventsinducedbyvarious kinds of insults in cell cultures, protecting cells from apoptotic death

• Seep.84

• EMSAMshouldbeappliedtodry,intactskinontheuppertorso(belowtheneckandabovethewaist),upperthighortheoutersurfaceoftheupper

arm once every 24 h. Avoid using the same site on consecutive days

• The6mg/24hpatchistherecommendedstartingandtargetdose.Ifdoseincreasesareindicatedforindividualpatients,theyshouldoccurindose

increments of 3 mg/24 h (up to a maximum dose of 12 mg/24 h) at intervals of no less than 2 weeks

• Noadjustmentindosagenecessaryinmoderatehepaticorrenalinsu ciency

• Seep.84

• Onaverage,25–30%oftheselegilinecontentissystemicallydeliveredover24h(range∼10–40%)followingdermalapplication

• Absorptionofselegilineissimilarwhentransdermalselegilineisappliedtotheuppertorsoorupperthigh;thedrugisnotmetabolizedinhuman

skin

• Transdermal selegiline bypasses the GI tract, thus avoids inhibiting MAO-A in the GI tract; patient sensitivity to dietary tyramine is more than 20

times less than with oral tranylcypromine, the e ect of avoiding excessive amounts of tyramine entering the bloodstream

• Transdermaldosingavoidsextensive rst-passmetabolism,resultinginsubstantiallyhigherselegilineexposureandlowerexposuretometabolites

compared to oral dosing

• Selegilineisapproximately90%boundtoplasmaprotein

• Steady-stateselegilineplasmaconcentrationsareachievedwithin5daysofdailydosing

• ExtensivelymetabolizedbyCYP450enzymesincludingCYP2B6,CYP2C9,andCYP3A4/5andCYP2A6

• SelegilineisinitiallymetabolizedviaN-dealkylationorN-depropargylationtoformN-desmethylselegilineorR(–)-methamphetamine,respectively.

Both of these metabolites can be further metabolized to R(–)-amphetamine

• Selegiline and N-desmethylselegiline produce a concentration-dependent inhibition of CYP2D6 at 10–250μM and CYP3A4/5 at 25–250μM;

CYP2C19 and CYP2B6 were also inhibited at concentrations ≥ 100μM. All inhibitory e ects of selegiline and N-desmethylselegiline occurred at

concentrations that were several orders of magnitude higher than clinical concentrations

• Mean half-lives of selegiline and its three metabolites, R( )-N-desmethylselegiline, R( )-amphetamine, and R( )-methamphetamine, range from

18 to 25h

• Therapeutic e ects are typically seen within 28 days; a lack of an antidepressant response within 6–8 weeks may require a dosage increase or

selegiline may not work at all

• Seep.81

• Insomniaiscommon[Management:Takethepatcho beforebedtime]

• Dermatologicalreactionsarecommonatthesiteofapplication;usuallyerythema(24%)[Management:Rotateapplicationsites]

• Diarrhea,pharyngitis,dizziness,lightheadedness,headache(18%);hypotension(10%);drymouth

• Increasedbloodpressureatdosesabove6mg/24hpossible

• Increasedanxiety,agitation,irritability,increaseinsuicidalthoughts;activationofmania/hypomania(0.4%)

• Weightlossofmorethan5%ofbodyweight(5%incidence)

Pharmacokinetics

Onset & Duration of Action

Adverse Effects

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 71 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Contraindications

Precautions

Toxicity

Irreversible MAO-B Inhibitor (cont.)

• Simultaneousadministrationofdrugswithserotonergicproperties(seeInteractions,p.73)

• Combination with sympathomimetic amines, amphetamines, cold products, and weight-reducing preparations that contain vasoconstrictors or

local vasoconstrictors (i.e., cocaine or local anesthesia containing sympathomimetic vasoconstrictors)

• Carbamazepine,oxcarbazepine(seeInteractions,p.73)

• Both adults and children with depression (whether under treatment or not) may experience worsening of their MDD, unusual changes in their behavior, and/or the emergence of suicidal ideation and behavior (see Nursing Implications p. 72 for monitoring)

• Althoughdietaryrestrictionsarenotrequiredforthe6mg/24hdose,higherdosescannegatedrugselectivityandapressorresponsecanoccuron exposure to tyramine-rich foods. Patients should observe dietary and drug restrictions for doses over 6 mg (as per irreversible MAO inhibitors p. 67)

• A 14-day washout is required between termination of selegiline and initiating an antidepressant with serotonergic activity; prevents serotonin

syndrome (see Interactions p. 16 and Switching Antidepressants pp. 85–87)

• Patientsshouldbecarefullyevaluatedforahistoryofdrugabuse;patientsshouldbecloselyobservedforsignsoftransdermalselegilinemisuseor

abuse (e.g., development of tolerance, increases in dose, or drug-seeking behavior)

• Noinformationavailableonoverdosebyselegilinepatches.OverdosewithMAOIagentsistypicallyassociatedwithCNSandcardiovasculartoxicity

• Delaysofupto12hbetweeningestionofdrugandappearanceofsymptomsmayoccur;peake ectsmaynotbeobservedfor24–48h

• DeathhasbeenreportedfollowingoverdosagewithMAOIagents;hospitalizationandclosemonitoringduringthisperiodareessential

• Symptomaticandsupportive

• Notrecommended

• Recommendeddoseforelderlypatientsis6mg/24h

• ObservecloselyfororthostaticBPchangesduringtreatment

• Patientsaged50andolderappeartobeathigherriskforrash(4.4%vs.0%placebo)thanyoungerpatients

• Verylimitedhumandata,avoidwhenpossible

• Itisnotknownwhetherselegilinehydrochlorideisexcretedinhumanmilkbutlowmolecularweightsuggeststhatitwillbe.Signi cantneurotox-

icity observed in animals

• Dietaryrestrictionsarenotnecessaryatadoseof6mg/24h;however,patientsshouldbeinformedaboutthesignsandsymptomsassociatedwith MAOI-induced hypertensive crisis and urged to seek immediate medical attention if these symptoms occur

• FollowMAOIdietaryrestrictionsfordosesover6mg/24h

• Patientsshouldbeadvisedtoimmediatelyreportsevereheadache,necksti ness,palpitationsorotheratypicalorunusualsymptomsnotpreviously

experienced

• Advise patient to avoid exposing the application site of patches to external sources of direct heat, such as heating pads or electric blankets, heat

lamps, saunas, hot tubs, heated water beds, and prolonged direct sunlight, as this may result in an increase in the amount of selegiline absorbed

from the patch, producing elevated serum levels

• Theoretically, there is a 3-day reservoir of drug in each patch; discard patches in a manner that prevents accidental application or ingestion by

Management

Pediatric Considerations

Geriatric Considerations

Use in Pregnancy♢

Breast Milk

Nursing Implications

children, pets, etc.

♢ See p. 439 for further information on drug use in pregnancy and e ects on breast milk

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Instructions

Drug Interactions

• All patients being treated with antidepressants should be observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of therapy or following an increase or decrease in dose

• Fordetailedpatientinstructionontransdermalselegiline,seethePatientInformationSheet(detailsp.440)

• Clinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterforthesecondagent

Class of Drug

Example

Interaction Effects

Antibiotic

Linezolid

Monitor for increased serotonergic and noradrenergic effects due to linezolid’s weak MAO inhibition

Anticonvulsant

Carbamazepine, oxcarbazepine

Increased level of selegiline and its metabolite (2-fold)

Antidepressant

SSRI, SNRI, SARI, NaSSA, tricyclic, RIMA, MAOI

Increased serotonergic effects with possibility of serotonin syndrome

Anxiolytic

Buspirone

Several cases of elevated blood pressure have been reported

Opioid

Meperidine Tramadol

Stupor, muscular rigidity, severe agitation, and elevated temperature reported in some patients receiving the combination of selegiline and meperidine

Increased risk of seizures and serotonin syndrome

St. John’s Wort

Increased serotonergic effects with possibility of serotonin syndrome

Sympathomimetic

Amphetamines, dextromethorphan, ephedrine, phenylephrine, phenylpropanolamine, pseudoephedrine

Risk of hypertensive crisis

NMDA Receptor Antagonist

Product Availability∗

Generic Name

Chemical Class

Trade Name

Dosage Forms and Strengths

Esketamine

NMDA receptor antagonist

Spravato(B)

Nasal spray: 28 mg of esketamine per device

Each spray device delivers two sprays containing a total of 28 mg

∗ Refer to Health Canada’s Drug Product Database or the FDA’s Drugs@FDA for the most current availability information (B) Not marketed in Canada,

Indications‡

( approved)

Treatment-resistant depression (in conjunction with an oral antidepressant)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 73 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

General Comments

NMDA Receptor Antagonist (cont.)

• Must be administered under the direct supervision of a healthcare provider. A treatment session consists of nasal administration of esketamine and post-administration observation under supervision for at least 2 h

• Because of the risk of serious adverse outcomes resulting from sedation and dissociation caused by esketamine administration, and the potential for abuse and misuse of the drug, it is only available through a restricted distribution system, under a Risk Evaluation and Mitigation Strategy (REMS)

• Monitorallpatientsforworseningdepressionandsuicidalthinking

• Esketamine, the S-enantiomer of racemic ketamine, is a non-selective, non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor

• Themechanismbywhichesketamineexertsitsantidepressante ectisunknown

• Themajorcirculatingmetaboliteofesketamine(noresketamine)demonstratedactivityatthesamereceptorwithlowera nity

• Seep.84

• Dosageadjustmentsshouldbemadebasedone cacyandtolerability

• Evidenceoftherapeuticbene tshouldbeevaluatedattheendoftheinductionphasetodetermineneedforcontinuedtreatment

• Inductionphase(weeks1–4,administertwiceperweek):Day1startingdose56mg;subsequentdoses56mgor84mg

• Maintenancephase(weeks5–8,administeronceweekly):56mgor84mg

• Maintenancephase(week9andafter,administerevery2weeksoronceweekly):56mgor84mg.Dosingfrequencyshouldbeindividualizedtothe

least frequent dosing to maintain remission/response

• Esketamine is for nasal use only. The nasal spray device delivers a total of 28 mg of esketamine. To prevent loss of medication, do not prime the

device before use. Use 2 devices (for a 56 mg dose) or 3 devices (for an 84 mg dose), with a 5-minute rest between use of each device

• Ifapatientmissestreatmentsessionsandthereisworseningofdepressionsymptoms,considerreturningtothepatient’spreviousdosingschedule

• Themeanabsolutebioavailabilityisapproximately48%followingnasalsprayadministration

• Timetoreachmaximumesketamineplasmaconcentrationis20–40minafterthelastnasalsprayofatreatmentsession

• Cmax (inter-subject variability) ranges from 27% to 66%; Cmax (intra-subject variability) is approximately 15%

• AUC(inter-subjectvariability)rangesfrom18%to45%;AUC(intra-subjectvariability)isapproximately10%

• Meansteady-statevolumeofdistributionis709L

• Proteinbindingisapproximately43–45%

• Brain-to-plasmaratioofnoresketamineis4–6timeslowerthanthatofesketamine

• Half-liferangesfrom7to12h

• AUCandhalf-lifehigherinpatientswithmoderatehepticimpairment

• Clearanceisapproximately89L/hfollowingIVadministration

• PrimarilymetabolizedtonoresketamineviaCYP2B6andCYP3A4andtoalesserextentviaCYP2C9andCYP2C19

• NoresketamineismetabolizedviaCYP-dependentpathwaysandcertainsubsequentmetabolitesundergoglucuronidation

• In a 4-week study comparing esketamine (plus oral antidepressant) vs. intranasal placebo (plus oral antidepressant), most of the esketamine treatment di erence compared to placebo was observed at 24 h

• Patients in stable remission who continued treatment with esketamine (plus oral antidepressant) experienced a statistically signi cantly longer time to relapse of depressive symptoms than did patients on intranasal placebo (plus oral antidepressant)

Pharmacology

Dosing

Pharmacokinetics

Onset & Duration of Action

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Adverse Effects

• Seechartp.81forincidenceofadversee ectsattherapeuticdoses

• Dissociation,dizziness,nausea,sedation,vertigo,hypoesthesia,anxiety,lethargy,bloodpressureincrease,vomiting,andfeelingdrunkarethemost

commonly reported side e ects (incidence ≥ 5% and at least twice that of placebo plus oral antidepressant)

• Sedationin49–61%ofpatients

• Dissociativeorperceptualchanges(includingdistortionoftime/spaceandillusions),derealization,anddepersonalizationin61–75%ofpatients

• Anxiety13%inpatientstreatedwithesketamine(plusoralantidepressant)vs.6%inplacebo(plusoralantidepressant)

• Dizziness 29%, lethargy 11%, and feeling drunk 5% in patients treated with esketamine (plus an oral antidepressant) vs. 8%, 5%, and 0.5%,

respectively, with placebo (plus oral antidepressant)

• Hypoesthesia18%inpatientstreatedwithesketamine(plusoralantidepressant)vs.2%withplacebo(plusoralantidepressant)

• Twoplacebo-controlledstudiesfoundcomparabledrivingperformancebetweenpatientstreatedwithesketamine(84mg)andplaceboat6hand

18 h post dose (except two esketamine-treated patients who discontinued the driving test at 8 h post dose due to esketamine-related adverse

reactions)

• Mayimpairshort-termcognitiveperformance(noe ectoncognitiveperformanceinaone-yearopen-labelsafetystudy,butunknownbeyondone

year)

• Notsigni cant

• Increaseof40mmHginsystolicbloodpressure(BP)and/or25mmHgindiastolicBPin8–17%ofesketamine-treatedpatientsvs.1–3%ofplacebo- treated patients in the rst 1.5 h during the rst 4 weeks of treatment

• Notsigni cant

• Nausea28%inpatientstreatedwithesketamine(plusoralantidepressant)vs.9%withplacebo(plusoralantidepressant)

• Vomiting9%inpatientstreatedwithesketamine(plusoralantidepressant)vs.2%withplacebo(plusoralantidepressant)

• Vertigo23%inpatientstreatedwithesketamine(plusoralantidepressant)vs.3%withplacebo(plusoralantidepressant)

• Higher rate of lower urinary tract symptoms (pollakiuria, dysuria, micturition urgency, nocturia, and cystitis) in esketamine-treated patients than

with placebo

• Nodiscontinuationsyndromenotedupto4weeksafteresketaminecessation

• Withdrawal symptoms have been reported after discontinuation of frequently used (more than weekly) large doses of ketamine for long periods

of time. Such withdrawal symptoms are likely to occur if esketamine were similarly abused. Symptoms may include craving, fatigue, poor appetite,

and anxiety

☞ THEREFORETHISMEDICATIONSHOULDBEWITHDRAWNGRADUALLYAFTERPROLONGEDUSE

• Contraindicatedinpatientswith:Aneurysmalvasculardiseaseorarteriovenousmalformation,historyofintracerebralhemorrhage,orhypersensi-

tivity to esketamine, ketamine, or any of the excipients

• Assessbloodpressurepriortodosing.IfbaselineBPiselevated(e.g.,>140mmHgsystolic,>90mmHgdiastolic),considertherisksofshort-term increases in BP and bene t of esketamine. Do not administer esketamine if an increase in BP or intracranial pressure poses a serious risk. After dosing, reassess BP at approximately 40 min (corresponds to Cmax) and subsequently as clinically warranted

• MonitorforsedationduringconcomitanttreatmentwithesketamineandCNSdepressants

• Due to risks of sedation and dissociation, patient must be monitored for at least 2 h after each treatment session, followed by an assessment to

determine when the patient is considered clinically stable and ready to leave the healthcare setting

• Assess each patient’s risk for abuse or misuse prior to prescribing esketamine and monitor for the development of these behaviors or conditions,

including drug-seeking behavior, while on therapy

• Monitor all patients for worsening depression and suicidal thoughts, especially during the initial few months of drug therapy and at times of

dosage changes

CNS Effects

Anticholinergic Effects

Cardiovascular Effects

Endocrine & Metabolic Effects

GI Effects

Other Adverse Effects

Discontinuation Syndrome

Contraindications Precautions

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 75 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Pediatric Considerations Geriatric Considerations

Use in Pregnancy♢

Nursing Implications

NMDA Receptor Antagonist (cont.)

• Esketamineisnotapprovedforuseinpediatricpatients

• Thesafetyande ectivenessofesketamineinpediatricpatientshavenotbeenestablished

• Mean esketamine Cmax and AUC higher in elderly patients

• E cacy was assessed in a 4-week RCT comparing esketamine (plus an oral antidepressant) to intranasal placebo (plus an oral antidepressant) in

patients 65 years of age and older. Esketamine was initiated at 28 mg twice weekly and titrated to 56 mg or 84 mg administered twice-weekly. At the end of the 4 weeks, there was no statistically signi cant di erence between the groups on the primary e cacy endpoint of change from baseline to week 4 using MADRS

• Notrecommendedduringpregnancy

• Embryo-fetaltoxicity;maycausefetalharm

• Insu cientdatatodrawconclusionsaboutriskofmajorbirthdefects,miscarriage,oradversematernalorfetaloutcomes

• If a woman becomes pregnant while being treated with esketamine, treatment should be discontinued and the patient counseled about the

potential risk to the fetus

• Esketamineispresentinhumanmilk

• Potentialforneurotoxicityinbreastfedinfants

• Esketamineisfornasaluseonly

• Priortoesketamineadministration,instructpatientsnottoengageinpotentiallyhazardousactivities,suchasdrivingamotorvehicleoroperating

machinery, until the next day after a restful sleep

• Advisepregnantwomenofthepotentialriskoffetalharm

• Topreventlossofmedication,donotprimethedevicebeforeuse

• Ifmorethanonespraydeviceisused,allowa5-minuterestperiodbetweenuseofdevices

• Assessbloodpressurepriortoand40min(Cmax)afteresketamineadministration

• Monitorforurinarytractandbladdersymptomsduringthecourseofesketaminetreatment

• Psychotherapyandeducationarealsoimportantinthetreatmentofdepression

• Monitortherapybywatchingforadversesidee ectsandmoodandactivitylevelchanges,includingworseningofsuicidalthoughts

• Fordetailedpatientinstructionsonescetamine,seethePatientInformationSheet(detailsp.440)

• Clinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterforthesecondagent

Breast Milk

Patient Instructions

Drug Interactions

Class of Drug

Example

Interaction Effects

Antidepressant

Irreversible MAOI

Phenelzine, tranylcypromine

May increase blood pressure

CNS depressant

Alcohol, benzodiazepines, opioids

May increase sedation

Psychostimulant

Amphetamines, armoda nil, methyphenidate, moda nil

May increase blood pressure

♢ See p. 439 for further information on drug use in pregnancy and e ects on breast milk

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

E ects of Antidepressants on Neurotransmitters/Receptors∗

SSRI

NDRI

SNRI

SARI

SPARI

Citalopram

Escitalo- pram

Fluoxetine

Fluvoxa- mine

Paroxetine

Sertraline

Bupropion

Venlafax- ine(*)

Duloxetine

Levomil- nacipran

Trazodone

Nefazo- done

Vilazodone

NE reuptake block

+++

++++

+++

–

+++

5-HT reuptake block

++++

+++++

–

+++

++++

+++

+++++

DA reuptake block

–

+++

–

+++

5-HT1A blockade

–

+++

++++(**)

5-HT2A blockade

–

+++

M1(ACh) blockade

–

H1 blockade

–

α1 blockade

–

+++

α2 blockade

–

D2 blockade

–

Selectivity

NE < 5-HT

NE > 5-HT

NE < 5-HT

NE > 5-HT

NE < 5-HT

(*) Desvenlafaxine has similar effects on neurotransmitters as venlafaxine (**) Vilazodone is a partial agonist at the 5-HT1A receptor,

SMS

NaSSA

Nonselective Cyclics

NMDA Receptor Antagonist

Vortioxe- tine

Mirtaza- pine

Amitripty- line

Clomipra- mine

Desipra- mine

Doxepin

Imipra- mine

Nortripty- line

Protripty- line

Trimipra- mine

Amoxa- pine

Maproti- line

Esketamine

NE reuptake block

+++

+++++

+++

++++

+++++

++++

–

5-HT reuptake block

++++

–

+++

++++

+++

–

DA reuptake block

–

5-HT1A blockade

+++(***)

+++

–

5-HT2A blockade

–

+++

+++++

–

M1(ACh) blockade

–

+++

–

H1 blockade

–

++++

+++

+++++

+++

+++++

+++

++++

–

α1 blockade

–

+++

–

α2 blockade

–

+++

–

D2 blockade

–

Selectivity

NE < 5-HT

NE = 5-HT

NE > 5-HT

NE < 5-HT

NE > 5-HT

n/a

(***) Vortioxetineisanagonistatthe5-HT1Areceptor

Key: Ki (nM) > 10,000 = –; 1000–10,000 = +; 100–1000 = ++; 10–100 = +++; 1–10 = ++++; 0.1–1 = +++++; ? = unknown

See also the National Institute of Mental Health’s Psychoactive Drugs Screening Program. Available at http://pdsp.med.unc.edu

∗ The ratio of Ki values (inhibition constant) between various neurotransmitters/receptors determines the pharmacological pro le for any one drug

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 77 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Pharmacological E ects of Antidepressants on Neurotransmitters/Receptors

• Antidepressante ect

• Sidee ects:Tremors,tachycardia,hypertension,sweating,insomnia,erectileandejaculationproblems

• Potentiationofpressore ectsofNE(e.g.,sympathomimeticamines)

• Interactionwithguanethidine(blockadeofantihypertensivee ect)

• Antidepressant,anti-anxiety,anti-panic,anti-obsessionale ect

• Canincreaseordecreaseanxiety,dependingondose

• Sidee ects:Dyspepsia,nausea,headache,nervousness,akathisia,extrapyramidale ects,anorexia,sexualsidee ects

• Potentiation of drugs with serotonergic properties (e.g., L-tryptophan); caution regarding serotonin syndrome

• Antidepressant,antiparkinsoniane ect;mayenhancemotivationandcognitionandmitigateagainstprolactinelevation

• Sidee ects:Psychomotoractivation,aggravationofpsychosis

• Antidepressant,anxiolytic,andantiaggressiveaction

• Anxiolytic,antidepressant,antipsychotic,andantimigrainee ect,improvedsleep

• Sidee ects:Hypotension,ejaculatoryproblems,sedation

• Anxiolytic,antidepressant,postulatedtobeassociatedwithprocognitivee ects

• Sidee ects:Increasedappetite,weightgain

• Secondmostpotentactionofcyclicantidepressants

• Side e ects: Dry mouth, blurred vision, constipation, urinary retention, sinus tachycardia, QRS changes, memory disturbances, sedation,

exacerbation/attack of narrow-angle glaucoma

• Potentiationofe ectsofdrugswithanticholinergicproperties

• Sidee ects:Sedation,posturalhypotension,weightgain

• Potentiationofe ectsofotherCNSdrugs

• Sidee ects:Posturalhypotension,dizziness,re extachycardia,sedation

• Potentiation of antihypertensives acting via α1 blockade (e.g., prazosin, doxazosin, labetalol)

• CNSarousal;possibledecreaseindepressivesymptoms

• Sidee ect:Sexualdysfunction,priapism

• Antagonism of antihypertensives acting as α2 agonists (e.g., clonidine)

• Antipsychotice ect

• Sidee ects:Extrapyramidal(e.g.,tremor,rigidity),endocrinechanges,sexualdysfunction(males)

NE Reuptake Blockade

5-HT Reuptake Blockade

DA Reuptake Blockade

5-HT1A Agonism

5-HT2A Blockade

5-HT2C Blockade

M1 (ACh) Blockade

H1 Blockade

α1 Blockade

α2 Blockade

D2 Blockade

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Frequency of Adverse Reactions to Antidepressants at Therapeutic Doses

> 2%

SSRI

> 2%

NDRI

< 2%

SNRI

Citalo- pram

Escitalo- pram

Fluoxe- tine

Fluvox- amine

Paroxe- tine

Sertraline

Bupro- pion

Venla- faxine

Desvenla- faxine

Duloxe- tine

Levomil- nacipran

> 2%(d)

Trazodone

> 10% > 10% > 2%

> 2% > 10% < 2%

> 10% > 10%(a) > 2%

> 10% > 10% > 10%

> 10% > 10% > 2%

> 10% > 10% > 10%

> 2% > 10% > 10%(b)

> 10% > 10%(a) > 10%(b)

> 10% > 10% > 3%

> 10% > 10% > 2%

–

> 5% –

> 30%

> 2% –(b)

< 2% > 10%

< 2% < 2%

> 10% > 10%

> 2% > 10%

< 2% > 10%

> 2% > 10%

< 2% > 3%

–

> 10%

–

> 10%

< 2% > 2%

> 10%

> 2%

> 10%

> 2%

> 10%

–

> 10%

> 10% > 2%

> 10% < 2%

> 10% > 2%

> 10% > 10%

> 10% > 2%

> 10% > 3%

> 10% > 2%

> 5% < 2%

> 10% > 2%(c)

> 2% > 10%

> 2% > 2%

> 10% > 10%

> 2% > 2%

> 10% > 10%

< 10% < 10%

> 2% –

> 2%

–

> 2%

< 2%

> 2%

< 2%

> 2% > 2%

< 2% < 2%

< 2% > 10%

> 2%(e) > 10%

> 2% > 10%

< 2% > 10%

> 2% > 2%

> 2%

< 2% > 2%

< 2% < 2%

> 2%(e) > 2%

> 2% > 2%(h)

> 10% < 2%(h)

> 2% < 2%(h)

> 10% > 2%(h)

> 2%(f) > 2%

> 10%(f) > 2%(i)

> 10%(f) > 3%

> 10%(f) > 2%

> 10% > 2%

> 10%(g) > 2%

< 2% < 2%

< 2% < 2%(k)

< 2% < 2%

< 2%(i) < 2%

> 30%

< 2% < 2%

– –

< 2% < 2%

> 2% > 2%(l)

> 10%

> 30%

> 10%

> 30%

> 10%

> 30%

> 10%

> 20%

> 10%

< 2%

> 2%

< 2%

> 2%

< 2%

> 2%

< 2%

> 2%

< 2%

> 2%(m)

> 10%(m)

≥ 2%(m)

< 2%(m)

> 2%(m)

> 2%

–

> 2%

> 30%

> 10%

> 30%(n)

> 30%

> 30%(n)

2%(n) (o)

> 30%(n)

> 3%

> 30%

< 10%

< 2%(n)

< 2%

< 2%(p)

< 2%

< 1%

< 2%

Reaction

CNS Effects

Drowsiness, sedation Insomnia

Excitement, hypomania* Disorientation/confusion Headache

Asthenia, fatigue

Anticholinergic Effects

Dry mouth

Blurred vision Constipation Sweating

Delayed micturition** Extrapyramidal Effects Unspeci ed

Tremor

Cardiovascular Effects

Orthostatic hypotension/dizziness Tachycardia, palpitations

ECG changes***

Cardiac arrhythmia

GI distress

Dermatitis, rash

Weight gain (over 6 kg) # Sexual disturbances

Seizures ##

Nefazo- done

> 30% > 2% >2% > 10% > 30% > 10%

> 10% > 10% > 10% >2% <2%

<2% <2%

> 10% < 2%(h) <2% <2% > 10% <2% >2% >2%

<2%

SARI

***

– None reported in literature perused,

# With chronic treatment, ## In nonepileptic patients; risk increased with elevated plasma levels (a) Especially if given in the evening, (b) Less likely to precipitate mania,

More likely in bipolar patients,

Primarily in the elderly,

ECG abnormalities usually without cardiac injury,

(c)

node and atrial dysrhythmia, (l) Patients with pre-existing cardiac disease have a 10% incidence of premature ventricular contractions, (m) Weight loss reported initially, (n) Priapism reported, (o) Improved sexual functioning, doses used above 450 mg/day of bupropion or in patients with bulimia

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 79 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Found to lower intraocular pressure,

reported (rarely), (f) Hypertension reported; may be more common in patients with pre-existing hypertension, (g) Less frequent if drugs given after meals, (h) Decreased heart rate reported, (i) Increased risk with higher doses,

Tardive dyskinesia (k) Slowing of sinus (p) Higher incidence if

(d)

(e)

Dose-related

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Frequency of Adverse Reactions to Antidepressants at Therapeutic Doses (cont.)

Nonselective Cyclics

SPARI

SMS

NaSSA

Vilazo- done

Vortioxe- tine

Mirtaza- pine

Amitrip- tyline

Clomip- ramine

Desip- ramine

Doxepin

Imip- ramine

Nortrip- tyline

Protrip- tyline

Trimip- ramine

Amoxa- pine

< 2% < 2%

< 2% –

> 30%(q) > 2%

> 30% > 2%

> 2% > 10%

> 2% > 2%

> 30% > 2%

> 10% > 10%

> 2% < 2%

< 2% > 10%

> 30% > 2%(r)

> 10% > 10%

< 2% < 2% < 2%

< 0.1% –

> 5%

> 2% > 2% > 2%

< 2% > 10% > 2%

< 2% > 2% > 2%

> 2% –

< 2%

< 2% < 2% < 2%

> 10% > 2% > 10%

> 2% > 10% < 2%

> 10% –

–

< 2% > 10% > 2%

> 2% > 2% > 2%

< 2%

> 2%

> 10%

> 2%

> 10%

> 2%

< 2%

> 5%

> 30%

> 10%

> 30%

> 10%

> 30%

< 2% < 2% < 2%

–

> 5% > 5%

> 10% > 10% > 2%

> 10% > 10% > 10%

> 2% > 2% > 2%

> 10% > 10% > 2%

> 10% > 10% > 10%

> 2% > 10% < 2%

> 10% > 10% > 10%

> 2% > 10% > 2%

> 2% > 30% > 2%

> 2%

< 2%

> 2%

–

< 2%

> 10%

< 2%

> 10%

< 2%

–

> 2%

> 2%(e)

< 2%(e)

< 2%

> 2%(e)

< 2%

–

< 2%

> 2%(e)

< 2%

–

> 2%

> 10%

> 2%

> 10%

> 2%

> 10%

> 2%

< 2% < 2%

< 10% –

> 2% > 2%

> 10% > 10%

> 2% > 10%

> 10% > 2%

> 30% > 10%

> 2% > 2%

> 10% > 2%

> 10% > 10%

< 2% < 2%

– –

< 2% < 2%

> 2%

> 10%(s) > 2%

> 10%

> 2%(s) > 2%

> 10%(s) > 2%

> 10%

> 2%(s) > 2%

> 10%(s) > 2%

< 2%(s) < 2%

> 2%

> 30%

> 2%

< 2%

–

< 2%

> 2%

< 2%

> 2%

< 2%

> 2%

< 2%

> 2%

< 2%

> 10%

< 2%

–

> 30%

> 10%

> 2%

> 10%

> 2%

< 2%

> 10%

< 2%

> 20%

> 2%

> 30%

> 2%

> 30%

< 2%

> 2%

< 2%

–

< 2%

< 2%(t)

< 2%

< 2%(t)

Reaction

CNS Effects

Drowsiness, sedation Insomnia

Excitement, hypomania* Disorientation/confusion Headache

Asthenia, fatigue

Anticholinergic Effects

Dry mouth

Blurred vision Constipation Sweating

Delayed micturition** Extrapyramidal Effects Unspeci ed

Tremor

Cardiovascular Effects

Orthostatic hypotension/dizziness Tachycardia, palpitations

ECG changes***

Cardiac arrhythmia

GI distress

Dermatitis, rash Weight gain (over 6 kg) Sexual disturbances Seizures ##

Mapro- tiline

> 10% <2% >2% >2% <2% >2%

> 30% > 10% > 10% >2%

>2% > 10%

>2% >2% < 2%(s) <2% >2% > 10% > 10% <2% < 2%(t)

Higher incidence if dose above 250 mg

More likely in bipolar patients, daily clomipramine, 225 mg daily maprotiline, or 300 mg daily amoxapine

***

– None reported in literature perused,

## In nonepileptic patients (e) Tardive dyskinesia reported (rarely), (q) Sedation decreased at higher doses (above 15 mg), (r) No effect on REM sleep, (s)

Primarily in the elderly,

ECG abnormalities usually without cardiac injury,

(t)

Conduction delays: Increased PR, QRS or QTc interval,

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

MAOI

Isocarboxazid

Phenelzine

Tranylcypromine

Moclobemide

Selegiline Transdermal

> 2% > 2%(a) > 2%

> 10% > 10%(a) > 10%

> 2% > 10%(a) > 10%

< 2% > 10% > 2%

> 2% > 10%

> 2% > 2%

> 2% > 10%

< 2% > 10%

> 2%

< 2%

> 10% > 2%

> 30% > 10%

> 10% > 2%

> 10% > 10%

> 2% < 2%

> 10% –

> 2% > 2%

> 2%

< 2%

> 2% > 10%

> 10% > 10%

< 2% > 2%

< 2% < 2%

> 10% –

> 10% > 10%(h)

> 10% > 2%

> 2%(g) < 2%

> 2% > 2%

< 2%(u) < 2%

> 2% > 2%

< 2% < 2%

> 10%

> 2%

> 10%

> 2%

< 2%

> 2%

> 10%(w)

> 2%

> 10%

> 2%

< 2%

> 2%(m)

> 2%

> 30%(n)

> 2%(n)

> 2%

< 2%

–

< 2%

–(x)

< 2%

–

Reaction

CNS Effects

Drowsiness, sedation Insomnia

Excitement, hypomania* Disorientation/confusion Headache

Asthenia, fatigue

Anticholinergic Effects

Dry mouth

Blurred vision Constipation Sweating

Delayed micturition** Extrapyramidal Effects Unspeci ed

Tremor

Cardiovascular Effects

Orthostatic hypotension/dizziness Tachycardia

ECG changes***

Cardiac arrhythmia

GI distress (nausea) Dermatitis, rash Weight gain (over 6 kg) Sexual disturbances Seizures ##

NMDA Receptor Antagonist Esketamine

> 10% >2% >2% > 10% > 10% >2%

>2% – >2% <2% >2%

– >2%

– >2% –

–

> 10% –

–

At site of patch application,

***

– None reported in literature perused,

## In nonepileptic patients (a) Especially if given in the evening, (g) Hypertension reported, (h) Decreased heart rate reported, (m) Weight loss reported,

have anticonvulsant activity

More likely in bipolar patients,

Primarily in the elderly,

ECG abnormalities usually without cardiac injury,

(n)

(u)

(x) May

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 81 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Priapism reported,

Shortened QTc interval,

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Antidepressant Doses and Pharmacokinetics

Drug

Therapeutic Dose Range (mg)

Comparable Dose (mg)

Suggested Plasma Level (nmol/L)

Bio- availability (%)

Protein Binding (%)

Peak Plasma Level (h) (Tmax)

Elimination Half-life (h) (T1/2)

Metabolizing Enzymes* (CYP450; other)

Enzyme Inhibition** (CYP450; other)

SSRIs

Citalopram (Celexa) Escitalopram (Lexapro, Cipralex) Fluoxetine (Prozac)

Fluoxetine delayed release (Prozac Weekly)

Fluvoxamine (Luvox) Paroxetine (Paxil) Paroxetine CR (Paxil CR) Sertraline (Zoloft)

10–40 10–20 10–80(e)

90 mg/week 50–300(e) 10–60(e) 12.5–75 50–200(e)

10 5 10

10 35 10 12.5 25

80 80 72–85

72–85 60 >90 >90 70

80 56 94

94 77–80 95

4–5 (metabolite = 14)

6–8 (immediate release)

6–8 (absorption delayed 1–2 h)

1.5–8

5.2 (immediate release)

Cmax = 6–10 (CR) 6

23–45(b) 27–32(b) (d)

24–144 (parent)(b) 200–330 (metabolite) 24–144 (parent)(b) 200–330 (metabolite) 9–28(b)

3–65(b) (d)

15–20

22–36 (parent) (b) (d)

62–104 (metabolite)

2D6(c)(m), 2C19(m), 3A4(m) 2D6(m), 3A4(m), 2C19(m)

1A2(w), 2B6(w), 2D6(c) (p),

3A4(w), 2C9(p), 2C19(p), 2E1

1A2(w), 2B6(w), 2D6(c) (m),

3A4(w), 2C9(p), 2C19(p), 2E1

1A2(w), 2D6

2D6(p); P-gp 2D6(p); P-gp

2B6, 2D6, 3A4(p), 2C9, 2C19(m); UGT2B7

2D6(w), 2C9(w),

2C19(w)

2D6(w), 2C9(w),

2C19(w)

1A2(m), 2B6(w), 2D6(p), 3A4(c) (w),

2C9(w), 2C19(m); P-gp 1A2(m), 2B6(w),

2D6(p), 3A4(c) (w), 2C9(w), 2C19(m); P-gp 1A2(p), 2B6(w), 2D6(m), 3A4(w), 2C9(m), 2C19(p); P-gp 1A2(w), 2B6(p), 2D6(p), 3A4(w), 2C9(w), 2C19(m); P-gp 1A2(w), 2B6(p), 2D6(p), 3A4(w), 2C9(w), 2C19(m); P-gp 1A2(w), 2B6(m),

2D6(w), 3A4(w), 2C9(w), 2C19(p); P-gp

NDRI

Bupropion (Wellbutrin)

Bupropion SR (Wellbutrin SR, Zyban)

Bupropion ER (For vo XL – only used after initial titration with other bupropion HCL products) Bupropion ER (Aplenzin)

225–450(f) 150–300(f)

450 174–522

100(f) 150(f)

450 150–450

75–350(a)

>90

80–85

1.6 (immediate release)

3 (bupropion) 6 (metabolite) (SR)

5 (fasting); delayed in fed state

10–14 (parent)(b)

20–27 (metabolites)

1A2(w), 2B6(p), 2D6(c), 3A4(w), 2C9(w), 2E1(m)

2D6(w)

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Therapeutic Dose Range (mg)

Comparable Dose (mg)

Suggested Plasma Level (nmol/L)

Bio- availability (%)

Protein Binding (%)

Peak Plasma Level (h) (Tmax)

Elimination Half-life (h) (T1/2)

Metabolizing Enzymes* (CYP450; other)

Enzyme Inhibition** (CYP450; other)

75–375

2 (immediate release) XR=5.5

3–7 (parent)(b) (d) 9–13 (metabolite) 9–12 (absorption half-life)

2D6(p), 3A4(c) (w), 2C9, 2C19

2D6(w), 3A4(w)

50–100 60–120 20–120

40 ? ?

– n/a

80 70 92

30 >95 22

7.5 6 6–8

11(d) 8–19(b) (d)

UGT(p), 3A4 1A2, 2D6

2C8, 2C19, 3A4

2D6 2D6(m)

100–600

150–600

130

100

70–90

15–23

2–5(h) (parent) 3–18 (metabolites)

4–9

2D6(c), 3A4(p)

1A2(w), 2D6(w), 3A4(p); P-gp (acute dosing); inducer of P-gp

2D6(w); inducer of P-gp

10–40

n/a

72 with food (50 fasting)

96–99

4–5

~25

1A2(w), 2D6(w), 3A4(p)

2C8(w), 2D6(w)

5–20

n/a

7–11

2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4/5

–

15–60

12.5

20–40(b) (d)

1A2(p), 2D6(c) (p), 3A4(p), 2C9

–

75–300

250–825(a) (g)

43–48

92–96

2–8

10–46(b)

1A2(w), 2B6(w), 2D6(m), 3A4(p), 2C9(w), 2C19(p) 1A2(w), 2D6, 3A4(w), 2C9(w), 2C19(w); P-gp

1A2, 2D6(m), 3A4, 2C9(w), 2C19(m), 2E1; P-gp; UGT

75–300 75–300

30 50

300–1000 400–1000(g)

98 73–92

2–6 2–6

17–37(b) 12–76(b)

1A2, 2D6(p)

1A2, 2D6(p), 3A4, 2C9(w), 2C19(p)

2D6(m); UGT

2D6(m), 2C19(w), 2E1; P-gp

Drug

SNRI

Venlafaxine (Effexor) Venlafaxine XR (Effexor XR)

Desvenlafaxine (Pristiq) Duloxetine (Cymbalta) Levomilnacipran (Fetzima)

SARI

Nefazodone (Serzone)

Trazodone (Desyrel)

SPARI

Vilazodone (Viibryd)

SMS

Vortioxetine (Brintellix)

NaSSA

Mirtazapine (Remeron)

NONSELECTIVE CYCLIC AGENTS – Tricyclic

Amitriptyline (Elavil)

Clomipramine (Anafranil) Desipramine (Norpramin)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 83 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Antidepressant Doses and Pharmacokinetics (cont.)

Therapeutic Dose Range (mg)

Comparable Dose (mg)

Suggested Plasma Level (nmol/L)

Bio- availability (%)

Protein Binding (%)

Peak Plasma Level (h) (Tmax)

Elimination Half-life (h) (T1/2)

Metabolizing Enzymes* (CYP450; other)

Enzyme Inhibition** (CYP450; other)

75–300

40–200

20–60 75–300

35 25

15 50

500–950(a)

500–800(a)

150–500(g)

350–700 500–800

89 89–92

90–96 95

89 89–92

90–96 95

2–6

2–6 2–6

12 2–6

8–36(b)

4–34(b)

13–88(b)

54–124(b) 7–30(b)

1A2(w), 2B6(w), 2D6(p), 3A4(m), 2C9(w), 2C19(m); UGT1A3; UGT1A4 2D6(p), 3A4(m), 2C9(w), 2C19(m); UGT1A4

1A2, 2D6(m), 3A4(m), 2C19; P-gp

2D6, 2C9, 2C19

–

1A2, 2D6(m), 2C19(m), 2E1; P-gp; UGT1A3 2D6, 2C19(w), 2E1

2D6; P-gp

100–600

100

46–82

1–2

8–14(b)

–

2D6

100–225

200–950(a)

66–100

9–16

27–58(b)

1A2, 2D6(p)

2D6; P-gp

300–600

150

–

50–90 (after 2 weeks)

1–3(b)

2C19 (p)

1A2(m), 2D6(m), 2C9, 2C19(m)

30–50 45–90 20–60

10 15 10

– – –

? ? ?

2.5 1.5–4 2.4(b)

– 2E1 –

– –

1A2(w) ,2A6(p) , 2D6(w), 2C9(w), 2C19(w), 3A4(w), 2E1(m)

6mg/24hto 12 mg/24 h

–

10–40

18–25

2A6, 2B6, 2C9, 3A4/5

2B6, 2D6, 3A4/5

56–84

n/a

43–45

.33–.66

7–12

2B6, 2C9, 2C19, 3A4

–

Drug

Doxepin (Sinequan, Triadapin)

Imipramine (Tofranil) Nortriptyline (Aventyl, Pamelor)

Protriptyline (Vivactil)

Trimipramine (Surmontil)

Dibenzoxazepine

Amoxapine (Asendin)

Tetracyclic

Maprotiline (Ludiomil)

RIMA

Moclobemide (Manerix)

MAOI (irreversible)

Isocarboxazid (Marplan) Phenelzine (Nardil) Tranylcypromine (Parnate)

MAO-B Inhibitor

Selegiline Transdermal

NMDA Receptor Antagonist

Esketamine (Spravato)

* CYP450 isoenzymes involved in drug metabolism,

and its metabolites, (b) Increased in liver disorders – consider dose adjustment, (c) Speci c to metabolite, (d) Increased in moderate to severe renal impairment – consider dose adjustment, (e) SSRIs have a at dose response curve. For depression most patients respond to the initial (low) dose. Higher doses are used in the treatment of OCD, (f) Give in divided doses (maximum of 150 mg per dose), (g) Established ranges for ef cacy in major depressive disorder, (h) Dose-dependent, (m) Moderate activity,

(p) Potent activity, Weak activity

P-gp = P-glycoprotein [a transporter of hydrophobic substances in or out of speci c body organs (e.g., block absorption in the gut)]; UGT = uridine diphosphate glucuronosyl transferase [involved in Phase II reactions (conjugation)]

** CYP450 isoenzymes inhibited by the drug; magnitude may be in uenced by drug dose and plasma concentration, and by genotype and basal metabolic capacity of each patient,

(a) Includes sum of drug

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Antidepressant Nonresponse

Factors Complicating Response

Switching Antidepressants

• Ascertainthatdiagnosisiscorrectandthatpatientiscompliantwiththerapy

• Ensure dosage prescribed is therapeutic; measure plasma level; ensure there has been an adequate trial period, i.e., up to 6 weeks at a reasonable

dose

• Regular, systematic assessment of the patient’s response to drug therapy, with the use of measurement tools for symptoms, adverse e ects, and

patient adherence is useful to guide future clinical decisions[23]

• Concurrentmedicalorpsychiatricillness,e.g.,hypothyroidism,OCD

• Personality disorders lead to poor outcome; however, depression may evoke personality problems that may disappear when the depression is

alleviated

• Drugabusemaymakemanagementdi cult(e.g.,cocaine);seeCANMATrecommendations

• Psychosocialfactorsmaya ectresponse

• Lowfolatelevelsassociatedwithlackofremission,responseandrelapse

• Concurrentprescriptiondrugsmayinterferewithe cacy(e.g.,calciumchannelblockers)

• Metabolicinducers(e.g.,carbamazepine)orinhibitors(e.g.,erythromycin)willa ectplasmalevelofantidepressant

• SwitchingfromoneSSRItoanothercanenhanceresponseinpreviouslynonresponsivepatients

• 20–25%remissionratewhenswitchingfromSSRItoanotherclassofantidepressantoradi erentSSRIafterfailureof rstSSRI(STAR*Dstudies)

• Switchingbetweentricyclicagentsisofquestionablebene t

• Onestudyfoundsigni cantlyhigherresponserateswhenswitchingfromimipraminetosertralinethanviceversaandbettertolerability[24]

• Two studies have demonstrated that switching imipramine nonresponders to phenelzine was superior to switching phenelzine nonresponders to

imipramine

• UsecautionwhenswitchingtoorfromirreversibleMAOIs(seeSwitchingAntidepressantspp.85–87)

• Minimizespolypharmacy

• Decreasedriskofdruginteractions

• Secondagentmaybebettertolerated

• Improvedcompliance

• Lesscostly

• Lossofpartiale cacyof rstagent

• Timerequiredtotaper rstagentorneedforawashout(riskofrelapse)

• Delayedonsetofaction

Advantages of Switching

Disadvantages of Switching

Switching Strategies

Switching from

Switching to

Switching Method(a)

SSRI (not uoxetine)

→ → →

SSRI (including uoxetine) NDRI, SPARI, clomipramine SNRI

Direct switch, OR taper, stop, and switch Taper, stop, and switch

Taper, stop, and switch, OR cross-taper

→ →

SARI, SMS, NaSSA, nonselective cyclics (not clomipramine) RIMA, Irrev. MAOI, MAO-B

Cross-taper

Taper, stop, washout (1 week), and switch

Fluoxetine

→

SSRI, NDRI, SPARI, SMS, nonselective cyclics (not clomipramine)

Taper, stop, washout (4–7 days), and switch

→

SNRI

Taper, stop, and switch

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 85 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Switching Antidepressants (cont.)

Switching from Switching Method(a)

Switching to

→ →

SARI NaSSA

→ → →

Clomipramine RIMA

Irrev. MAOI, MAO-B

→ →

SSRI (including uoxetine), SNRI, SARI, SPARI, SMS, NaSSA, nonselective cyclics (including clomipramine) RIMA, Irrev. MAOI, MAO-B

→

SSRI (not uoxetine), SARI, SMS, NaSSA, nonselective cyclics (not clomipramine)

→ → →

Fluoxetine, SPARI

NDRI, SNRI, clomipramine RIMA, Irrev. MAOI, MAO-B

→

SSRI (including uoxetine), NDRI, SNRI, SPARI, SMS, NaSSA, nonselective cyclics (including clomipramine)

→

RIMA, Irrev. MAOI, MAO-B

→ →

SSRI (including uoxetine), NDRI, SNRI, clomipramine SARI, SMS, NaSSA

→ →

Nonselective cyclics (not clomipramine) RIMA, Irrev. MAOI, MAO-B

→

SSRI (not uoxetine)

→ → →

Fluoxetine, NDRI, clomipramine

SNRI, SARI, SPARI, NaSSA, nonselective cyclics (not clomipramine) RIMA, Irrev. MAOI, MAO-B

→ → →

SSRI (including uoxetine), SNRI, SPARI, nonselective cyclics (including clomipramine) NDRI

SARI, SMS

→ →

RIMA

Irrev. MAOI, MAO-B

→

SSRI (including uoxetine), NDRI, SNRI, SARI, SPARI, SMS, nonselective cyclics (including clomipramine)

→ → →

NaSSA

RIMA

Irrev. MAOI, MAO-B

→ → →

SSRI (not uoxetine), SNRI, SPARI, SMS Fluoxetine

NDRI, SARI, NaSSA, nonselective cyclics

→ →

RIMA

Irrev. MAOIs, MAO-B

Cross-taper Taper, stop, Taper, stop, Taper, stop, Taper, stop, Taper, stop Taper, stop,

washout (4–7 days), and switch OR cross-taper washout (2 weeks), and switch

washout (5 weeks), and switch

washout (5–6 weeks), and switch

NDRI

and switch washout (1

and switch, and switch washout (1

washout (1 and switch

and switch washout (2 and switch

and switch

washout (3 and switch and switch

washout (1 washout (2

and switch washout (1 washout (2

SNRI Cross-taper Taper, stop Taper, stop,

Taper, stop, SARI Cross-taper Taper, stop,

week), and switch OR cross-taper week), and switch week), and switch

OR cross-taper weeks), and switch

OR cross-taper week), and switch

weeks), and switch

OR cross-taper week), and switch weeks), and switch

SPARI(b)

SMS

NaSSA

Nonselective cyclic

Clomipramine(c)

Taper, stop Cross-taper Taper, stop, Taper, stop, Taper, stop, Taper, stop Cross-taper Taper, stop, Taper, stop, Taper, stop Cross-taper Taper, stop, Taper, stop, Cross-taper Taper, stop, Taper, stop, Taper, stop, Taper, stop Taper, stop, Cross-taper Taper, stop, Taper, stop,

and switch

washout (2–3 weeks), and switch

washout (1 week), and switch washout (3 weeks), and switch

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Switching from

Switching to

Switching Method(a)

RIMA

→ →

SSRI (including uoxetine), NDRI, SNRI, SARI, SMS, NaSSA, nonselective cyclics (including clomipramine), Irrev. MAOI, MAO-B

SPARI

Taper, stop, washout (1 day), and switch Taper, stop, washout (2 weeks), and switch

Irreversible MAOI(d)

→ →

SSRI (including uoxetine), NDRI, SNRI, SARI, SPARI, SMS, NaSSA, nonselective cyclics (not clomipramine or imipramine), irrev. MAOI, MAO-B

Clomipramine, imipramine

Taper, stop, washout (2 weeks), and switch Taper, stop, washout (3 weeks), and switch

MAO-B

→ →

SSRI (including uoxetine), NDRI, SNRI, SARI, SPARI, SMS, NaSSA, nonselective cyclics (not clomipramine or imipramine), irrev. MAOI, MAO-B

Clomipramine, imipramine

Taper, stop, washout (2 weeks), and switch Taper, stop, washout (3 weeks), and switch

(a) SwitchingMethod:

Direct Switch: Stop the rst antidepressant and start the new antidepressant the following day. Recommended if rst antidepressant therapy duration is less than 6 weeks (interactions less likely) and/or switching to an antidepressant with similar mode of action (ameliorates withdrawal effects)

Taper, stop and switch: Gradually taper the rst antidepressant and start the new antidepressant immediately after discontinuation. Recommended if rst antidepressant therapy duration is more than 6 weeks

Taper, stop, washout, and switch: Gradually taper the rst antidepressant and start the new antidepressant after a washout period

Cross-taper: Gradually taper down the rst antidepressant and slowly simultaneously introduce and increase the dose of the new antidepressant

Speed of tapering and cross-taper is most commonly 1–2 weeks or longer and should be judged by monitoring tolerability of the individual patient, (b) Vilazodone is both an SSRI and a partial agonist of the 5-hydroxytryptamine 1A receptors. Caution is advised when switching to and from vilazodone due to limited relevant information from studies, (c) Clomipramine should not be co-administered with SSRIs, venlafaxine or duloxetine (except under specialist use) and cross-tapering is not recommended, (d) Should not be commenced before all other antidepressants have been trialed due to risk of hypertensive crisis and serotonin syndrome. Allow washout period and monitor patients individually

Antidepressant Augmentation Strategies

Largest evidence base for antidepressant nonresponders with MDD is the use of adjunctive atypical antipsychotics with at least 15 randomized double- blind studies to date[24]

Augmentation Strategies

• • • •

• •

MAOI + Cyclic ☞ •

Mayhaverapidonsetofresponse Responsegreaterthan50%withmostcombinations Noneedtotaper rstagentorhaveawashout Avoidsriskofwithdrawale ectsfrom rstdrug

Increasedpotentialforsidee ects

Increasedriskofdruginteractions

Increasedcost Decreasedcompliancepossibleduetoneedtotakeanincreasednumberoftablets/capsules

Combiningantidepressantswhicha ectdi erentneurotransmittersystemsmayproduceabetterantidepressantresponsethaneitherdrugalone; consider potential drug-drug interactions (pharmacokinetic and pharmacodynamic) TheCO-MEDstudydemonstratedthat,inseverelydepressedindividuals,combinationtherapieswerenomoree ectivethanSSRImonotherapy[25]

DO NOT COMBINE AN IRREVERSIBLE MAOI WITH THE FOLLOWING: SSRI, SNRI, NDRI, SARI, RIMA, NaSSA, vilazodone or vortioxetine

Sixopenseriescasesreportresponseratesof54–100%

Advantages of Augmentation

Disadvantages of Augmentation

Antidepressant Combinations

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 87 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

SSRI + Cyclic

RIMA + Cyclic

RIMA + SSRI

NDRI + SSRI NDRI + SNRI

NaSSA + SSRI

SARI + SSRI

SNRI + Cyclic

Antidepressant Augmentation Strategies (cont.)

• Combination therapy should be started together, or MAOI can be added to the cyclic drug. Use caution with serotonergic agents (see Drug Inter- actions p. 69)

• Require6weeksatadequatedoses

• Combination of an SSRI and a noradrenergic cyclic drug (e.g., desipramine ) reported to cause greater downregulation of β-adrenergic receptors, a more rapid response, and higher remission rates

• Upto50%ofpatientsmayrespondtocombinationofSSRIandnoradrenergicTCA(e.g.,desipramine,nortriptyline) • UselowerdosesofTCAandmonitorTCAlevelstopreventtoxicity(seeDrugInteractions,p.12)

• Up to 57% response rate in open trials

• Monitorforserotonergicadversee ects

• Up to 67% of refractory patients may respond to combination • Monitorforserotonergicadversee ects

• STAR*D studies: 30% remission rate when bupropion was added to citalopram after failure of SSRI

• Up to 85% of partial responders reported to have clinically signi cant bene t from the combination in open trials and case series; adverse e ects (e.g., tremor, panic attacks, increased seizure risk) may limit dosage (see Drug Interactions p. 22)

• Bupropionmayimprovesleepe cacy,energy,fatigue,andexecutivefunctions,andmitigateSNRI-orSSRI-inducedsexualdysfunction

• Response reported in 64% of refractory patients after mirtazapine 15–30 mg was added to SSRI in an open trial

• Combination treatment of paroxetine and mirtazapine produced signi cant faster response and a larger proportion of therapeutic responses and

remissions than either drug alone[26]

• Reportedtoalleviateinsomnia;mayhaveanactivatinge ect;weightgainandsedationalsoreported

• Nefazodone (100–200 mg bid) used to augment antidepressant response and alleviate SSRI-induced sexual dysfunction

• Upto55%responsereportedwhennefazodone(100–200mgbid)usedtoaugmentSSRIsinpatientswithtreatment-refractorydepression • Low-dosetrazodone(25–50mg)usedtoalleviateinsomnia

• Monitorforserotonergice ects;combinationmayincreaseanxietyandirritability

• 64% of patients achieved full clinical remission

• Augmentationreportedtobene tpatientswithrefractorydepressionorOCD(casereports)

• MonitorTCAlevelsduetoincreasedmetabolismwithcarbamazepine;withSSRI,monitorcarbamazepinelevel(seeInteractionsp.12)

• Thereisnosigni cantcorrelationbetweenanticonvulsantplasmalevelandclinicalimprovement

• Lamotrigine – 2 small double-blind randomized placebo-controlled studies failed to nd superiority to placebo in antidepressant nonresponders

with MDD

• 5-HT2c blockade suggested to increase NE and dopamine and acetylcholine levels in the prefrontal cortex; blockade of 5-HT2A and 5-HT2C receptors may improve the e cacy and side e ect pro le of SSRIs and enhance sleep; reported to improve cognition in MDD

• Lowdosesofrisperidone(0.5–2mg/day),olanzapine(2.5–10mg/day),quetiapine,orziprasidonecanaugmentSSRIsinpatientswithMDDorOCD; reported to decrease anxiety, irritability, and insomnia, improve cognition and remission rates

• Fluoxetine/olanzapinecombination(Symbyax)approvedintheUSAfortreatmentofbipolardepressionandtreatment-resistantdepression(unre- sponsive to 2 trials of di erent antidepressants)

• Meta-analysisof10trialsinvolvingolanzapine,quetiapine,andrisperidoneshowedthemtobemoree ectivethanadjunctiveplacebo,withpooled remission rates of 47% vs. 22%, but 3-fold higher discontinuation rates due to adverse events[24]. Since this meta-analysis, 2 trials demonstrated superior e cacy for quetiapine augmentation

• Consideradditiveadversee ectswithdrugcombination,includingCNSandEPS

Anticonvulsants

(e.g., Carbamazepine)

Antipsychotics, Second-Generation (SGAs)

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

• Aripiprazole (2 mg/day) as an augmenting agent for patients with inadequate response demonstrated marginal e cacy with the nonsigni cant, pooled weighted di erence from placebo in response rates of 5.6%[27]

• Aripiprazoleapprovedforadjunctivetreatmentofdepressioninpatientswhoobtaininadequatebene tfrom rst-lineantidepressantsasaresult of two RCTs at an average dose of 10 mg/day

• 3trialswitharipiprazoledemonstratedslightlyhigherremissionratesandin2008itwasapprovedbytheFDAasadjunctivetherapytoantidepres- sants for patients with antidepressant-resistant MDD

• Brexpiprazole approved for adjunctive treatment of depression in patients who obtain inadequate response to prior antidepressant therapy as a result of two RCTs

• Recommended starting dose for brexpiprazole as adjunctive treatment is 0.5 mg or 1 mg once daily. Titrate to 1 mg once daily, then up to the target dose of 2 mg once daily. Dose increases should occur at weekly intervals based on the patient’s clinical response and tolerability. Maximum recommended daily dose is 3 mg

• E ectobservedwithin2–4weeks

• Remissionrate=30%whenaddedtocitalopraminpeoplewhofailedSSRIinSTAR*Dtrial

• 43–100%ofdepressedpatientsreportedtorespondtocombinationwithantidepressantinopen-labeltrials–datacontradictorywithdouble-blind

studies

• MaytreatpersistentanxietyandhelpalleviateSSRI-inducedsexualdysfunction

• Monitorforadversee ectsduetoserotonergicexcess

• Usualdose:15–60mg/day

• Seep.93

• Maybeusedwithantidepressantforacutetreatment;maintenancetherapywithanantidepressantorlithiummayberequired

• HigherfolatelevelsinpatientstakingSSRIsandTCAspredictabetterresponse,butthetrendisstrongerwithSSRIs[28]

• Augmentationof20mg uoxetinewith500microgramsoffolateresultedin55%greaterlikelihoodofachievingHAM-Dlessthan9inwomen;not

signi cant in men

• Meta-analysisofcontrolledstudiessuggeststhatlithiumaugmentationofconventionalantidepressantsise ectiveintreatment-resistantdepres- sion; up to 60% of patients may respond to combined treatment (lower response rates reported with SSRIs); response may occur within 48 h, but usually within 3 weeks. May be less e ective in the elderly

• Unclearifthereisacorrelationbetweenlithiumlevelandclinicalimprovementwhenusedasaugmentationtherapy;however,plasmalevelabove 0.4 mmol/L is suggested for e cacy; usual dose: 600–900 mg/day

• Responsemorelikelyinprobablebipolarpatients(witha rst-degreerelativewithBDorwithahistoryofhypomania)

• Disadvantagesoflithiumaugmentationincluderiskofcardiotoxicity,nephrotoxicity,thyrotoxicity,andweightgainaswellasneedformonitoring

of blood levels

• Seep.398

• Placebo-controlled and open label studies suggest moda nil can decrease daytime sleepiness and fatigue in patients with MDD and improve

response and quality of life in patients treated with SSRI antidepressants

• Moda nilinducesCYP3A4andmaydecreasetheplasmalevelofdrugsmetabolizedbythisisoenzyme(e.g.,citalopram).Invitrostudiessuggestit

also inhibits CYP2C19 and 2C9, and can increase the plasma level of drugs metabolized by this isoenzyme (e.g., uoxetine, moclobemide)

• Randomizeddouble-blindplacebo-controlledstudiessupporttheuseofadjunctiveomega-3fattyacids(EPAandDHA)forpatientswithMDDwho do not experience su cient symptoms improvement following antidepressant therapy (see pp. 416–419)

• Relativelywelltoleratedandacceptedbypatients

• Con ictingresultswithdosing–onestudyfound2g/dayofethyl-EPAtobesuperiortoplaceboasadjunctivetherapy,asecondfound1gbutnot

2 g or 4 g to be superior to placebo, while a third found 660 mg/day of EPA-DHA mix to be superior to placebo

• Blocks β-adrenoreceptors and serotonin (5-HT1A and 5-HT1B/1D) autoreceptors and increases serotonin concentration at postsynaptic sites (see p. 392)

• Data contradictory, most recent data does not support using pindolol as an adjuntive agent. Some controlled studies show mixed results with regard to a more rapid antidepressant response when pindolol used in combination with antidepressants

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 89 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics, Third-Generation (TGAs)

Buspirone

Electroconvulsive Treatment

Folate

Lithium

Moda nil

Omega-3 Fatty Acids

Pindolol

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Psychostimulants

Repetitive Transcranial Magnetic Stimulation

Testosterone

Thyroid Hormone (T3)(T4)

Tryptophan

Further Reading

Antidepressant Augmentation Strategies (cont.)

• Monitorbloodpressureandheartrate;cautioninpatientswithasthmaorcardiacconductionproblems.Sidee ectsreportedwiththiscombination include somnolence, nausea, postural hypotension, sweating, and dry mouth[24]

• Methylphenidate(10–40mg)ord-amphetamine(5–30mg)usedasaugmentationtherapywithcyclicagents,SSRIs,SNRIorirreversibleMAOIs

• Rapidsymptomresolutionreportedinupto78%ofpatientsinopentrials;responsewassustained(notoleranceobserved)

• Improveresidualsymptomsofsleepiness,fatigue,andexecutivedysfunctioninMDD

• Caution:Observeforactivationandbloodpressurechanges

• Irritability,anxietyandparanoiareported–usecautioninpatientswhoareanxiousoragitated

• Seep.104

• Double-blindstudyreportsthatcombinedtreatmentusinglow-frequencyrTMSfor10sessions,withanantidepressant,wassuperiortoanantide-

pressant alone in patients with partially responsive depression

• Greaterresolutionofdepressivesymptomsreportedamonghypogonadalmenwithrefractorydepression.Sidee ectsincluderiskoferythrocytosis and irritability

• Dosage:25–50micrograms/dayofliothyronine(syntheticversionofT3)or150–500micrograms/dayoflevothyroxine(syntheticversionofT4)–if ine ective, discontinue after 3 weeks; T3 considered to be more e ective than T4 (T3 augmentation may be more e ective in women than in men) (see p. 393)

• Mixedresultsreported–maybemoree ectiveincombinationwithTCAsthanwithSSRIs

• Seep.244

• Usualdose:1.5–12g/day

• Datasuggestse cacywhencombinedwithTCAs,SSRIs,orMAOIs;monitorforincreasedserotonergice ects

References

1 Cipriani A, Furukawa TA, Salanti G, et al. Comparative ef cacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: A systematic review and network meta-analysis. Lancet. 2018;391(10128):1357–1366. doi:10.1016/S0140-6736(17)32802-7

2 Hollander E, Soorya L, Chaplin W, et al. A double-blind placebo-controlled trial of uoxetine for repetitive behaviors and global severity in adult autism spectrum disorders. Am J Psychiatry 2012;169(3):292–299. doi:10.1176/appi.ajp.2011.10050764

3 Singh, SP, Singh V, Kar N, et al. Ef cacy of antidepressants in treating the negative symptoms of chronic schizophrenia: Meta-analysis. Br J Psychiatry. 2010;197(3):174–179. doi:10.1192/ bjp.bp.109.067710

4 Albayrak Y, Hashimoto, K. Bene cial effects of the sigma-1 agonist uvoxamine for tardive dyskinesia in patients with postpsychotic depressive disorder of schizophrenia: Report of 5 cases. Prim Care Companion CNS Disord. 2012;14(6):PCC.12br01401. doi:10.4088/PCC.12br01401

5 Serretti A, Mandelli L. Antidepressants and body weight: A comprehensive review and meta-analysis. J Clin Psychiatry. 2010;71(10):1259–1272. doi:10.4088/JCP.09r05346blu

6 Tsapakis EM, Gamie Z, Tran GT, et al. The adverse skeletal effects of selective serotonin reuptake inhibitors. Eur Psychiatry. 2012;27(3):156–169. doi:10.1016/j.eurpsy.2010.10.006

7 Elbe D, Black TR, McGrane IR, et al. Clinical handbook of psychotropic drugs for children and adolescents. (4th ed.). Boston, MA: Hogrefe Publishing, 2019.

8 Seitz DP, Adunuri N, Gill SS, et al. Antidepressants for agitation and psychosis in dementia. Cochrane Database Syst Rev. 2011;2:CD008191. doi:10.1002/14651858.CD008191.pub2

9 Henry G, Williamson D, Tampi RR. Ef cacy and tolerability of antidepressants in the treatment of behavioral and psychological symptoms of dementia, a literature review of evidence.

Am J Alzheimers Dis Other Demen. 2011;26(3):169–183. doi:10.1177/1533317511402051

10 Sterke CS, Ziere G, van Beeck EF, et al. Dose-response relationship between selective serotonin re-uptake inhibitors and injurious falls: A study in nursing home residents with dementia.

Br J Clin Pharmacol. 2012;73(5):812–820. doi:10.1111/j.1365-2125.2011.04124.x

11 Koren G, Nordeng H. SSRIs and persistent pulmonary hypertension of the newborn. BMJ. 2011;343:d7642. doi:10.1136/bmj.d7642

12 Wedge, MK. The truth behind tramadol and antidepressants: An interaction of concern? Can Pharm J. 2009;142(2):71–73.

13 Karam-Hage M, Strobbe S, Robinson JD, et al. Bupropion-SR for smoking cessation in early recovery from alcohol dependence: A placebo-controlled, double-blind pilot study. Am J Drug

Alcohol Abuse. 2011;37(6):487–490. doi:10.3109/00952990.2011.598591

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

14 de Silva VA, Hanwella R. Ef cacy and tolerability of venlafaxine versus speci c serotonin reuptake inhibitors in treatment of major depressive disorder: A meta-analysis of published studies. Int Clin Psychopharmacol. 2012;27(1):8–16. doi:10.1097/YIC.0b013e32834ce13f

15 Thase ME, Kornstein SG, Germain JM, et al. An integrated analysis of the ef cacy of desvenlafaxine compared with placebo in patients with major depressive disorder. CNS Spectr. 2009;14(3):144–154.

16 Madhusoodanan S, Alexeenko L, Sanders R, et al. Extrapyramidal symptoms associated with antidepressants – a review of the literature and an analysis of spontaneous reports. Ann Clin Psychiatry. 2010; 22(3):148–156.

17 Briggs GG, Ambrose PJ, Ilett KF, et al. Use of duloxetine in pregnancy and lactation. Ann Pharmacother. 2009;43(11):1898–1902. doi:10.1345/aph.1M317

18 Stahl S. Mechanism of action of trazodone: A multifunctional drug. CNS Spectr. 2009;14(10):536–546.

19 Croom KF, Perry CM, Plosker GL. Mirtazapine: A review of its use in major depression and other psychiatric disorders. CNS Drugs. 2009;23(5):427–452.

doi:10.2165/00023210-200923050-00006

20 Benjamin S, Doraiswamy PM. Review of the use of mirtazapine in the treatment of depression. Expert Opin Pharmacother. 2011;12(10):1623–1632. doi:10.1517/14656566.2011.585459

21 Schweitzer I, Maguire K, Ng C. Sexual side-effects of contemporary antidepressants: A review. Aust N Z J Psychiatry. 2009;43(9):795–808. doi:10.1080/00048670903107575

22 D’Agostino ML, Risser J, Robinson-Bostom L. Imipramine-induced hyperpigmentation: A case report and review of the literature. J Cutan Pathol. 2009;36(7):799–803. doi:10.1111/j.

1600-0560.2008.01121.x

23 Tackling partial response to depression treatment. Prim Care Companion J Clin Psychiatry. 2009;11(4):155–162. doi:10.4088/PCC.8133ah3c

24 Papakostas, GI. Managing partial response or nonresponse: Switching, augmentation, and combination strategies for major depressive disorder. J Clin Psychiatry. 2009;70(Suppl. 6):

16–25.

25 Friedman ES, Davis LL, Zisook S et al. Baseline depression severity as a predictor of single and combination antidepressant treatment outcome: Results from the CO-MED trial. Eur

Neuropsychopharmacol. 2012;22(3):183–199. doi:10.1016/j.euroneuro.2011.07.010

26 Blier P, Gobbi G, Turcotte JE, et al. Mirtazapine and paroxetine in major depression: A comparison of monotherapy versus their combination from treatment intiation. Eur Neuropsy-

chopharmacol. 2009;19(7):457–465. doi:10.1016/j.euroneuro.2009.01.015

27 Fava M, Mischoulon D, Iosifescu D, et al. A double-blind, placebo-controlled study of aripiprazole adjunctive to antidepressant therapy among depressed outpatients with inadequate

response to prior antidepressant therapy (ADAPT-A Study). Psychother Psychosom. 2012;81(2):87–97. doi:10.1159/000332050

28 Fava M. Mischoulon D. Folate in depression: Ef cacy, safety, differences in formulations, and clinical issues. J Clin Psychiatry. 2009;70(Suppl. 5):12–17. doi:10.4088/JCP.8157su1c.03

Additional Suggested Reading

• AmericanPsychiatricAssociation.Practiceguidelineforthetreatmentofpatientswithobsessive-compulsivedisorder.Arlington,VA:AmericanPsychiatricAssociation,2007.Retrieved from http://www.psychiatryonline.com/pracGuide/pracGuideTopic_10.aspx

• AmericanPsychiatricAssociation.Practiceguidelineforthetreatmentofpatientswithpanicdisorder(2nded).Arlington,VA:AmericanPsychiatricAssociation,2009.Retrievedfrom http://www.psychiatryonline.com/pracGuide/pracGuideTopic_9.aspx

• CanusoCM,SinghJB,FedgchinM,etal.Ef cacyandsafetyofintranasalesketaminefortherapidreductionofsymptomsofdepressionandsuicidalityinpatientsatimminentriskfor suicide: Results of a double-blind, randomized, placebo-controlled study. Am J Psychiatry. 2018;175(7):620–630. doi:10.1176/appi.ajp.2018.17060720

• CitromeL.Levomilnacipranformajordepressivedisorder:Asystematicreviewoftheef cacyandsafetypro leforthisnewlyapprovedantidepressant–whatisthenumberneededto treat, number needed to harm and likelihood to be helped or harmed? Int J Clin Pract. 2013;67(11):1089–1104. doi:10.1111/ijcp.12298

• CitromeL.Vortioxetineformajordepressivedisorder:Asystematicreviewoftheef cacyandsafetypro leforthisnewlyapprovedantidepressant–whatisthenumberneededto treat, number needed to harm and likelihood to be helped or harmed? Int J Clin Pract. 2014;68(1):60–82. doi:10.1111/ijcp.12350

• CohenLJ,SclarDA,CulpepperL,etal.Afreshlookatmonoamineoxidaseinhibitorsfordepression.JClinPsychiatry.2012;73(Suppl.1):1–45.doi:10.4088/JCP.11096su1c.07

• ConnollyKR,ThaseME.Ifat rstyoudon’tsucceed:Areviewoftheevidenceforantidepressantaugmentation,combinationandswitchingstrategies.Drugs.2011;71(1):43–64.doi:

10.2165/11587620-000000000-00000

• CouplandC,HillT,MorrissR,etal.Antidepressantuseandriskofsuicideandattemptedsuicideorselfharminpeopleaged20to64:Cohortstudyusingaprimarycaredatabase.BMJ.

2015;350:h517. doi:10.1136/bmj.h517

• DalyEJ,SinghJB,FedgchinM,etal.Ef cacyandsafetyofintranasalesketamineadjunctivetooralantidepressanttherapyintreatment-resistantdepression:Arandomizedclinicaltrial.

JAMA Psychiatry. 2018;75(2):139–148. doi:10.1001/jamapsychiatry.2017.3739

• DavidsonJR.MajordepressivedisordertreatmentguidelinesinAmericaandEurope.JClinPsychiatry.2010;71(Suppl.E1):e04.doi:10.4088/JCP.9058se1c.04gry

• HairP,CameronF,Garnock-JonesKP.Levomilnacipranextendedrelease:Firstglobalapproval.Drugs.2013;73(14):1639–1645.doi:10.1007/s40265-013-0116-1

• Jonkman K, Duma A, Olofsen E, et al. Pharmacokinetics and bioavailability of inhaled esketamine in healthy volunteers. Anesthesiology. 2017;127(4):675–683. doi:10.1097/ALN.

0000000000001798

• KatonaCL,KatonaCP.Newgenerationmulti-modalantidepressants:Focusonvortioxetineformajordepressivedisorder.NeuropsychiatrDisTreat.2014;10:349–354.doi:10.2147/NDT.

S39544

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 91 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antidepressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Antidepressants (cont.)

• KennedySH,LamRW,McIntyreRS,etal.CanadianNetworkforMoodandAnxietyTreatments(CANMAT)2016clinicalguidelinesforthemanagementofadultswithmajordepressive disorder: Section 3. Pharmacological treatments. Can J Psychiatry. 2016;61(9):540–560. doi:10.1177/0706743716659417

• Mago R, Forero G, Greenberg WM, et al. Safety and tolerability of levomilnacipran ER in major depressive disorder: Results from an open-label, 48-week extension study. Clin Drug Investig. 2013;33(10):761–771. doi:10.1007/s40261-013-0126-5 Erratum in: Clin Drug Investig. 2013 Nov;33(11):861. doi:10.1007/s40261-013-0133-6

• MagoR,MahajanR,ThaseME.Levomilnacipran:Anewlyapproveddrugfortreatmentofmajordepressivedisorder.ExpertRevClinPharmacol.2014;7(2):137–145.doi:10.1586/17512433. 2014.889563

• MalmH.Prenatalexposuretoselectiveserotoninreuptakeinhibitorsandinfantoutcome.TherDrugMonit.2012;34(6):607–614.doi:10.1097/FTD.0b013e31826d07ea

• MoleroP,Ramos-QuirogaJA,Martin-SantosR,etal.Antidepressantef cacyandtolerabilityofketamineandesketamine:Acriticalreview.CNSDrugs.2018;32(5):411–420.doi:10.1007/

s40263-018-0519-3

• National Institute for Health and Care Excellence. Depression: The treatment and management of depression in adults [Clinical Guideline 90]. London: NICE; 2010. Retrieved from

http://guidance.nice.org.uk/CG90/Guidance

• NulmanI,KorenG,RovetJ,etal.Neurodevelopmentofchildrenfollowingprenatalexposuretovenlafaxine,selectiveserotoninreuptakeinhibitors,oruntreatedmaternaldepression.

Am J Psychiatry. 2012;169(11):1165–1174. doi:10.1176/appi.ajp.2012.11111721

• QaseemA,SnowV,DenbergTD,etal.Usingsecondgenerationantidepressantstotreatdepressivedisorders:AclinicalpracticeguidelinefromtheAmericanCollegeofPhysicians.Ann

Intern Med. 2008;149(10):725–733. doi:10.7326/0003-4819-149-10-200811180-00007

• RayS,StoweZ.Theuseofantidepressantmedicationinpregnancy.BestPractResClinObstetGynaecol.2014;28(1):71–83.doi:10.1016/j.bpobgyn.2013.09.005

• RickelsK,AthanasiouM,RobinsonDS,etal.Evidenceforef cacyandtolerabilityofvilazodoneinthetreatmentofmajordepressivedisorder:Arandomized,double-blind,placebo-

controlled trial. J Clin Psychiatry. 2009;70(3): 326–333. doi:10.4088/JCP.08m04637

• ShiovitzT,GreenbergWM,ChenC,etal.Arandomized,double-blind,placebo-controlledtrialoftheef cacyandsafetyoflevomilnacipranER40–120mg/dayforpreventionofrelapse

in patients with major depressive disorder. Innov Clin Neurosci. 2014;11(1–2):10–22. Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3960779/

• vandeLooAJAE,BervoetsAC,MoorenL,etal.Theeffectsofintranasalesketamine(84mg)andoralmirtazapine(30mg)onon-roaddrivingperformance:Adouble-blind,placebo-

controlled study. Psychopharmacology (Berl). 2017;234(21):3175–3183. doi:10.1007/s00213-017-4706-6

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

De nition

Indications

ELECTROCONVULSIVE THERAPY (ECT)

• Noninvasive convulsive neurostimulation treatment whose therapeutic mechanism is mediated by a tonic-clonic generalized seizure induced by means of a brief current applied under anesthesia, for the treatment of indicated psychiatric and neurological disorders (note: Magnetic seizure therapy (MST) is a noninvasive convulsive therapy under investigation as an alternative means of seizure induction – electromagnetic induction)

• Nottobeconfusedwiththeadministrationofsub-convulsiveelectricstimuli,referredtoascranialelectrostimulationorelectrosleeptherapy;nor transcranial direct current stimulation (tDCS); nor the administration of aversive electric stimuli as a behavior modi cation protocol; nor repetitive transcranial magnetic stimulation (rTMS).

• Major depressive disorder (MDD); especially when associated with high suicide risk (rapid reduction in suicidal drive after 6–8 treatments), ina- nition/dehydration, severe agitation, depressive stupor, catatonia, delusions, nonresponse to one or more adequate trials of antidepressants or intolerance of therapeutic dosages[1, 2]

• MDD, recurrent: Prophylaxis or attenuation; i.e., “maintenance” ECT after response to an acute/index course of ECT, if previous antidepressants have not prevented recurrence[3]

• MDD:Preventionofrelapse,i.e.,“continuation”ECTforupto6monthsafterresponsetoanacute/indexcourseofECT,ifpreviousantidepressants have not prevented rapid relapse; may provide better outcome than antidepressants alone following an acute/index course; ECT equivalent to most e ective pharmacotherapy (nortriptyline or venlafaxine plus lithium) in preventing early relapse[4]

• Depression,atypical–arandomizedtrialfoundthatpatientswithatypicaldepressionwere2.6timesmorelikelytohaveremissionwithECTthan those with other types of depression

• Bipolardisorder:Manicphase;adjuncttomoodstabilizersandantipsychoticsforseveremania(manic“delirium”)andrapid-cyclingillness

• Mania,dysphoric(“mixedbipolar”)ordepressedphase

• Bipolardisorder:Prophylaxisofdepressedandmanicphasesifmoodstabilizershavebeenine ective

• Postpartum psychosis: treatment of choice for some patients; secondary line of treatment after nonresponse to antidepressants and/or antipsy-

chotics[5]

• Schizophrenia: especially with concurrent catatonic and/or a ective symptoms; adjunct to adequate dosage of antipsychotics for nonresponsive

“positive” symptoms; after failed clozapine trial[6]

• Schizoa ectivedisorder, rst-episodepsychosis:afternonresponsetooneormoreadequatedrugtrials

• Catatonia:MostdramaticimprovementwithECTregardlessofunderlyingcondition[7].Shouldbeusediftreatmentwithbenzodiazapinesdoesnot

elicit response or as rst-line treatment. When catatonia is improved, ECT can be continued to treat underlying psychiatric disorder

• Parkinson’s disease (“on-o ” phenomenon), neuroleptic malignant syndrome, malignant catatonia, status epilepticus, tardive dyskinesia, and

a ective/psychotic disorders associated with mental retardation – reports of e ectiveness

• Obsessive-compulsivedisorder(OCD),refractory–e cacyreportedthoughtherearenorandomizedtrials

• PTSD studied: Open trial suggests ECT may improve the core symptoms of treatment-refractory PTSD, independently of improvement in depres-

sion[8]. Study results require replication and validation prior to using ECT for PTSD. Positive results reported in patients with comorbid MDD and

PTSD

• Somaticsymptomsandrelateddisorders(SSDs):CasereportssuggestECTcouldbeincludedforrefractorySSD

• Consider ECT early in the treatment algorithm, in the presence of very severe illness (do not regard as treatment of last resort); may be rst-line treatment for very severe depression or mania, active suicidality, psychotic depression in older adults (95% e cacy rates), or catatonic states[7]; however, very chronic episodes may reduce e ectiveness

• High-dose,right-sidedunilateralECTisconsideredtobeequivalentine cacytomoderate-dosagebilateralECTandsuggestedtohaveadvantages with respect to cognitive adverse e ects, though reviews of studies still suggest right-sided unilateral ECT is somewhat less e cacious at improving depressive symptoms than bilateral ECT and there are small di erences in cognition at 6 months post ECT[2, 9]

• Concomitanttreatmentwithanantidepressantcanenhancethee cacyofECT,butmayhavevariablee ectsoncognition[10]

General Comments

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 93 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

ECT/BLT/rTMS

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Therapeutic Effects

Mechanism of Action

Electroconvulsive Therapy (ECT) (cont.)

• Concomitant treatment with antipsychotic may result in faster and more pronounced symptom improvement but may cause more memory im- pairment – evidence is limited [7]

• Assessanddocumentpatient’scapacitytoconsenttotreatment;answerpatient’squestionsaboutECT;obtainsignedandwitnessedconsentform (valid consent requires full disclosure to the patient of the nature of the procedure, all material risks and expected bene t of ECT and those of alternative available treatments, and the prognosis if no treatment is given); if patient incapable, obtain written consent from eligible substitute decision maker

• ECTremainsthemoste ectivetreatmentfordepressionwithoverallresponseratesof80%,and60%remissionrates.“Melancholic”and“psychotic” presentations respond best[11]

• Vegetativesymptomsofdepression,suchasinsomniaandfatigue,andcatatonicsymptomsmayrespondinitially;cognitivesymptomsmayimprove with resolution of emotional symptoms, such as impaired self-esteem, helplessness, hopelessness, suicidal and delusional ideation

• Manicsymptomswhichrespondincludeagitation,euphoria,motoroveractivity,andthoughtdisorder

• Inpsychosis,“positive”symptomssuchashallucinationsanddelusionsmayrespondbetterthan“negative”symptoms(e.g.,anhedonia)

• Triggeringcontrolledseizuresisassociatedwithanarrayofneurophysiologicalchanges.Thevarietyofneurophysiologicale ectsmayberelatedto the fact that ECT is e ective in treating diverse neuropsychiatric conditions

• A ects almost all neurotransmitters implicated in the pathogenesis of the mental disorders (norepinephrine, serotonin, acetylcholine, dopamine, GABA); dopamine potentiation may be especially relevant[12]; imaging studies have shown changes in brain volumes following response to ECT

• Neurophysiological e ects include increased permeability of the blood-brain barrier, suppression of regional cerebral blood ow and neu- rometabolic activity; “anticonvulsant” e ects may be related to outcome (inhibitory neurotransmitters are increased by ECT)

• A ectsneuroendocrinesubstances(CRF,ACTH,TRH,prolactin,vasopressin,metenkephalins,β-endorphins)

• SuppressionofREMsleepabnormalities[12]

• COMThigh/highgenotypemaybeassociatedwithbetterresponse

• InECT,doseismeasuredinmillicoulombs(mC),whichisanabsolutemeasureofelectronsdelivered.Doseisassociatedtotheextentandintensity of the electric eld elicited in the brain

• Othervariablesthatin uencethedistributionandintensityoftheelectric eldelicitedareelectrodeplacementorresistance

• Aminimumof15secondsofseizureisconsiderednecessary,shorterdurationisconsideredan“aborted”seizureandanindicationtore-stimulate. Barely supra-threshold seizures may be prolonged and are not associated with better outcome; augmenting agents (e.g., ca eine) are seldom used

• Minimum stimulus energy/charge necessary to induce a convulsion is the “threshold stimulus”; a multiple of this “threshold” stimulus is recom- mended for e ective treatment (most accurate estimate of “threshold” is by “titration” dosing technique); the threshold may be altered in patients

who consume alcohol regularly or who are on medications that increase seizure threshold (e.g., benzodiazepines, anticonvulsants)

• Bilateral stimulus electrode placement (1.5 times “threshold” stimulus energy/charge) has been found more e ective than unilateral placement; “high-energy” bilateral (2.5 times “threshold stimulus”) may be e ective for nonresponse to 1.5 times “threshold” bilateral treatment. No substan-

tive di erence in overall outcome or cognitive side e ects between bitemporal and bifrontal placement[9]

• Unilateralelectrodeplacementcanbease ectiveasbitemporalformanypatientsbut,whenused,thestimulusenergy/chargeshouldbesubstan-

tially greater than the “threshold” stimulus (i.e., 4–6 times “threshold”); if no response after 6–8 treatments, recommend switch to bilateral

• Ultrabriefstimuluspulsewidthmaybee ectivewithreducedcognitivesidee ects;e cacyofultrabriefstimulushasbeenshownonlyinunilateral

placement; generally lower seizure “threshold” on titration but may require more treatments[13]

• Gender, age, and electrode placement a ect seizure threshold: Males have higher thresholds than females, thresholds increase with age and are

greater with bilateral than unilateral ECT

• Bifrontalplacementmayhaveadvantagesinselectedindications(e.g.,psychosis)

• AnindexcourseofECTfordepressioninvolves10–12treatments;onsetoftherapeutice ectmaybeevidentwithin1–3treatmentsinsomecases. Index courses for schizophrenia tend to be more prolonged (15–20 treatments). If there is no bene t after 12-15 treatments, it is unlikely that ECT will be e ective

Dosage

Onset & Duration of Action

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Procedure

• Relapse rate following discontinuation is high (30–70%) within 1 year, partly dependent on degree of medication resistance pre-ECT; prophylactic antidepressants should be administered in almost all cases; “continuation” ECT for up to 6 months (once per week for rst 4–8 weeks, then one treatment every 2 weeks, then one treatment every 4 weeks) if antidepressant prophylaxis of rapid relapse is ine ective; lithium plus antidepressant may be the most e ective medications to decrease relapse of major depression following ECT

• Administer3timesperweekonalternatedays,particularlyformostseverecases.Twiceaweekhasbeenassociatedwithsimilaroutcomesatthe end of index course; twice-a-week treatments are also associated with less risk of cognitive side e ects. Outpatient ECT is mostly delivered twice a week

• ECT must always be administered (“modi ed”) under general anesthesia with partial neuromuscular blockade; “unmodi ed” ECT still used in developing countries with limited resources/personnel

• Induce light “sleep” anesthesia with methohexital; little clinical advantage seen with newer agents such as propofol (more expensive and almost always results in much briefer convulsions; may also raise the seizure threshold; reserve for patients with post-treatment delirium or severe nausea unresponsive to antinauseants, or very prolonged seizures)[14]; also consider propofol if patient is slow to recover from anesthesia[15]; if no seizures are elicited at maximum device output, etomidate or combination of methohexital/ketamine, methohexital/remifentanil may be used[16]

• Induce neuromuscular blockade with succinylcholine or a short-acting non-depolarizing agent. Post-ECT myalgia may be due to insu cient relax- ation or fasciculations (attenuate the latter if necessary with adjunctive non-depolarizing muscle relaxant – e.g., rocuronium – which necessitates a higher dosage of succinylcholine); if a reduction in the duration of neuromuscular blockade is necessary, a reversal agent can be used; rocuronium is indicated if there is cholinesterase de ciency or post-polio syndrome

• Pretreatwithatropineorglycopyrrolateifexcessoralsecretionsand/orsigni cantbradycardiaanticipated(i.e.,during“threshold”titration,patient on a β-blocker); post-treat with atropine if bradycardia develops. It has also been used to reduce the parasympathetic e ects of subconvulsive stimulation(s) (i.e., when more than one stimulation is required to elicit a seizure)

• Pretreatanyconcurrentphysicalillnesswhichmaycomplicateanesthesia(i.e.,usingantihypertensives,gastricacid/motilitysuppressants,hypoglycemics); special circumstances require anesthesia and/or internal medicine consultation

• If possible, discontinue or reduce dosage of all psychotropics with anticonvulsant properties (i.e., benzodiazepines, carbamazepine, valproate) during the course of treatment; use of anticonvulsant medication during a course of ECT has been associated with shorter seizure duration and higher dose required if benzodiazepines cannot be discontinued, drugs with shorter half-life are recommended (lorazepam); pre-treat with umazenil if necessary to reverse benzodiazepines (i.e., high dosage/dependent patient)

• ConsiderdiscontinuationoflithiumorreducedoseduringcourseofECTduetoincreasedriskofpost-ECTdelirium

• Continueallotherpsychotropics,exceptMAOIs(seeContraindicationsp.96),whenclinicallynecessary

• Outpatienttreatmentcanbeadministeredifwarrantedbytheclinicalcircumstances,ifthereisnomedical/anesthesiacontraindication,andifthe

patient can comply with the pre- and posttreatment procedural requirements

• MemorylossoccurstosomedegreeduringmostcoursesofECT[17]

– Signi cant,patchyamnesiafortheperiodduringwhichECTisadministered;recallofperiodaroundtimeofECTadministrationisusuallyvague

– Retrogradeepisodicamnesiaforsomeeventsuptoanumberofmonthspre-ECT;maybepermanent;uncommonly,longerperiodsofretrograde

amnesia

– Patchyanterogradeamnesiafor3–6monthspost-ECT

– Patients may rarely complain of permanent anterograde memory impairment; unknown if this is a residual e ect of the ECT or an e ect of

residual symptoms of the illness for which ECT was prescribed

– A number of pharmacological agents (i.e., liothyronine, cholinesterase inhibitors, thiamine), behavioral strategies (cognitive remediation), and

treatment parameters (i.e., ultra-brief stimulus pulse width, right unilateral or more focal electrode placement) may attenuate some of the

cognitive e ects[18, 19, 20]

• Mortalityrate2deathsper100,000treatments;higherriskinthosewithconcurrentcardiovasculardisease.Mostrecentevidencefoundnodeaths

over a course of 10 years in VA system and almost 80,000 treatments[21]

• Post-treatmentdeliriumuncommon;usuallyofshortduration

– Reportedinelderlypatients;whenmorethanoneelectricstimulusisusedtoinduceaconvulsion;afterprolongedseizures – Duetoconcurrentdrugtoxicity(e.g.,lithiumcarbonate,clozapine–seeDrugInteractionsp.98)

– Mayoccurwithtoorapidpre-ECTdiscontinuationofsomeantidepressants

– Ifoccurs,considerpropofolanesthesiaforsubsequenttreatments

Adverse Effects

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 95 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

ECT/BLT/rTMS

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Precautions

Electroconvulsive Therapy (ECT) (cont.)

• Tachycardiaandhypertensionmaybepronounced;durationseveralminutesposttreatment;preventwithβ-blockerifnecessary

• Bradycardia(tothepointofasystole)andhypotensionmaybepronounced,particularlyifstimulusissubconvulsive

– Increasedriskifpatientonaβ-blocker

– Attenuatedbythesubsequentconvulsion,atropine,andmedicationwithanticholinergice ect

• Prolonged seizures and status epilepticus rare; monitor treatment with EEG until convulsion ends; seizures should be terminated after 3 min

duration (with anesthetic dosage of the induction agent, repeated if necessary, or with a benzodiazepine – IV diazepam more rapidly e ective

than lorazepam)

• LimitedevidencethatetomidatemayinduceseizuresduringECT;highestriskinpatientswithahistoryofepilepsyorcerebralcorticallesions

• Spontaneousseizures

– Recentevidencesuggestspatientsunderage40whoreceiveECTmightbeatslightlyincreasedriskofdevelopingspontaneousseizurespost-ECT, but patients older than 60 years may be at decreased risk of seizures after ECT

• Headacheandmusclepaincommonbutnotusuallysevere

– Trypre-treatmentisometricexercisestopreventmusclepain

– Pretreatwithrocuroniumbromide(approximately3mg)forseveremusclepain

• Temporomandibularjointpain;maybereducedwithbifrontalelectrodeplacement(comparedtostandardbitemporalplacement)

– All patients should have a bite block inserted in their mouth during the electric stimulus and seizure to minimize jaw pain and prevent dental

injury, even if edentulous

• Temporarymenstrualirregularity;possiblyduetoincreasedprolactin(transient)

• Transientpost-ictalparalysis(Todd’sparalysis)

• Obtainpretreatmentanesthesiaand/orinternalmedicineconsultationforallpatientswithsigni cantpreexistingcardiovasculardisease,potential gastro-esophageal re ux, compromised airway, and other circumstances which may complicate the procedure (i.e., personal or family history of signi cant adverse e ects, or delay in recovery from general anesthesia); treat as indicated

• MonitorbyECG,pulseoximetry,andbloodpressure,before,during,andafterECT;EEGduringtreatment

• Patients with insulin-dependent diabetes mellitus may have a reduced need for insulin after ECT, as ECT reduces blood glucose levels for several

hours (may be related to pretreatment fasting)

• 10–30%ofbipolardepressedpatientscanswitchtohypomaniaormaniafollowingECT;importanttocontinueantimanicmedicationifnotunduly

a ecting the treatment procedure (i.e., increased seizure threshold)

• Modifyelectrodeplacementinpatientswithmetallicface/skullimplantsorintracranialobjects[22]

• ECTsafelyusedwithclozapinefortreatment-refractoryschizophrenia.Maybeassociatedwithprolongedseizuresorspontaneoustardiveseizure

Note: all contraindications should be regarded in the context of, and relative to, the risks of withholding ECT • Rheumatoidarthritiscomplicatedbyerosionoftheodontoidprocess

• Recentmyocardialinfarction,suggestedwaitisapproximately8weeks

• Increasedintracranialpressure

• Recentintracerebralhemorrhage/unstableaneurysm,recentischemicstroke,suggestedwaitaftereventisapproximately8weeks

• Extremelylooseteethwhichmaybeaspiratedifdislodged

• Threatenedretinaldetachment

• ConcurrentadministrationofanirreversibleMAOI,whichmayinteractwithanestheticagents(althoughmostreportshaveimplicatedmeperidine

as the interacting drug). Severe impairment in cardiac output and hypotension during ECT may require resuscitation with a pressor agent; the choice may be limited in the presence of an irreversible MAOI. The literature therefore recommends that MAOIs be discontinued 14 days prior to elective anesthesia; if there are compelling reasons to continue the MAOI, or start ECT prior to this waiting period, obtain anesthesia consultation. The potential for a hypertensive response is much less in the presence of a selective, reversible MAOI (RIMA) such that their concurrent administration is acceptable

Contraindications

• Concurrentdrugtoxicity

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Lab Tests/Monitoring

• Fullneuropsychologicalassessmentmaybeneededifthereisevidenceofsigni cantcognitiveimpairment;reassessiftreatment-emergentlossis unduly severe. Otherwise, screening tools such as Montreal Cognitive Assessment of Mini Mental Status Examination before and after the course of ECT are su cient

• Physicalexamination

• Hb,WBC,anddi erentialforallpatientsoverage60andwhenclinicallyindicated

• Electrolytes and creatinine for all patients on any diuretic, on lithium or with insulin-dependent diabetes, and as clinically indicated, including

patients with a history or risk of water intoxication

• ECGforallpatientsoverage45,thosebeingtreatedforhypertension,orwithahistoryofcardiacdiseaseandasclinicallyindicated

• Spinalx-raysforthosepatientswithahistoryofcompressionfractureorotherinjury,signi cantbackpain,andasclinicallyindicated;cervicalspine

x-rays for all patients with rheumatoid arthritis

• SicklecellscreeningofallblackpatientsofAfricandescent

• Fastingbloodglucoseondayofeachtreatmentforpatientswithdiabetesmellitusortakingantidiabeticmedication

• Prothrombintimeandpartialthromboplastintimeforallpatientsonanticoagulants

• SerumlithiumbeforeandperiodicallyduringcourseofECT

• FordetailedinformationontheuseofECTinthispopulation,pleaseseetheClinicalHandbookofPsychotropicDrugsforChildrenandAdolescents[23]

• ECT may be used in most severe forms of psychosis, catatonia, or a ective disorder with suicide risk in adolescence/childhood if medications are

ine ective

• Shouldneverbeprescribedwithoutconsultationbyaspecialistinchildandadolescentpsychiatryandaneurostimulationspecialist

• ECTprocedureinpediatricpopulationisverysimilartoadult.Anestheticmedicationsneedtobeadjustedtoweight.Thereisscarcityofdatausing

any electrode placement other than bitemporal. Dose required to elicit seizures is signi cantly lower in this population as seizure threshold is lower than in adults

• Nospeci crisks,bene tsorcontraindicationsattributabletoage

• Concurrentearlydementiaisnotacontraindication;ECTmaybeadministeredforanyconcurrentdiagnosticindication

• Evidence from randomized controlled trials is sparse; suggestions that response to ECT is at least equal to that in younger depressed patients.

Evidence on use of ECT in the elderly suggests it is safe and e ective at reducing symptoms of depression

• Lowerspeedofrecoveryafter rstandthirdtreatmentmaypredictworseoutcome

• ECT may be used in all trimesters if a severe condition requires it; rates of fetal and maternal complications are not trivial; obtain obstetrical consultation, shared care is preferred

• Potentialriskofadversee ects(tobothmotherandchild)shouldbeweighedagainstthebene ts

• Shouldbeadministeredbyahighlyskilledspecialistteam

• Fetalmonitoringrecommended

• Precaution:Increasedriskofgastro-esophagealre ux;tiltpositionisrecommended,especiallyinlasttrimester

• PatientsmustbekeptNPO(especiallyforsolidfood)forapproximately8hbeforetreatment;continuousobservationofpotentiallynon-compliant patients may be required

• Denturesmustberemovedbeforetreatment

• Observeandmonitorvitalsignsuntilpatientisrecovered,oriented,andalertbeforedischargefromrecoveryroom;patientshouldbeadvisednotto

operate a motor vehicle or potentially dangerous equipment/machinery/tools until the day after each treatment. Outpatients should be escorted

home after treatment

• Whenpossible,avoidprnbenzodiazepinesandlimittheuseofsedativesandhypnoticsthenightpriortoandthemorningoftreatment

• Lithium and anticonvulsants may be held the night prior to ECT as a way to decrease the risk of delirium (lithium) or increase seizure threshold

(anticonvulsants)

• FordetailedpatientinstructionsonECT,seethePatientInformationSheet(detailsp.440)

Pediatric Considerations

Geriatric Considerations

Use in Pregnancy

Nursing Implications

Patient Instructions

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 97 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

ECT/BLT/rTMS

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Drug Interactions

Class of Drug

Anesthetic Anticonvulsant

Antidepressant

SSRI NDRI SARI

Nonselective cyclic Irreversible MAOI

Antihypertensive Antipsychotic

Benzodiazepine Caffeine

Hypnotic/sedative Lithium

L -Tryptophan Theophylline

Electroconvulsive Therapy (ECT) (cont.)

• Clinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterfortheinteractant

Example

Interaction Effects

Propofol Thiopental

Decreased seizure duration compared with methohexital (may be very substantial); may increase seizure threshold Increased time to recovery compared with propofol

Carbamazepine, valproate Gabapentin, lamotrigine ,topiramate

Increased seizure threshold with potential adverse effects of subconvulsive stimuli; it is possible to override the anticonvulsant effect with a modest increase in energy/charge of electric stimulus; carbamazepine interferes with muscle relaxants; valproate may prolong effects of thiopental

May have less of an effect on seizure threshold and duration

Fluoxetine Bupropion Trazodone

Nortriptyline

Potential risk of serotonin syndrome with SSRIs; otherwise considered safe

Reported change to mania in two patients with recurrent depression, concomitant ECT and bupropion – limited evidence

Lower seizure threshold and prolonged seizures reported; clinical signi cance unknown. Rare case reports of cardiovascular complications in patients with and without cardiac disease – more likely to occur at high dosages (i.e., more than 300 mg/day) Lowers seizure threshold; may increase the risk of cardiac arrhythmias (especially in the elderly and those with cardiovascular disease) In combination with sympathomimetic drugs, can cause hypertensive crisis

Phenelzine

Possible need for a pressor agent for resuscitation requires that this combination be avoided, if possible

β-blockers (e.g., propranolol)

May potentiate bradycardia and hypotension with subconvulsive stimuli Confusion reported with combined use

Clozapine

Increased seizure duration reported in 16.6% of patients; spontaneous (tardive) seizures reported following ECT

Delirium reported with concurrent or shortly following clozapine treatment; however, there are many case reports of uncomplicated concurrent use, even with very high dosages. May be associated with increased tachycardia

Risperidone

Minimal risk of convulsions compared to other antipsychotics; EEG abnormalities may occur

Diazepam, lorazepam

Increased seizure threshold with potential adverse effects of subconvulsive stimuli or abbreviated seizure

Increased seizure duration

Reports of hypertension, tachycardia, and cardiac dysrhythmia

Zopiclone

May reduce seizure duration (used the night before ECT)

Lithium toxicity may occur, perhaps due to an increased permeability of the blood-brain barrier or release of lithium from cells by ECT resulting in systemic toxicity; prolongs seizure duration and succinylcholine action duration; may lower seizure threshold; decrease or discontinue lithium and monitor patient. Concurrent administration not contraindicated if lithium level within the therapeutic range. Suggest hold dose night prior to ECT

Ventricular tachycardia reported with the combination of lithium and duloxetine

Increased seizure duration

Increased seizure duration, status epilepticus. Concurrent administration not contraindicated if serum level within the therapeutic range

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Further Reading

References

1 2 3

4 5 6

7 8

9 10

11 12 13

14 15

16 17 18 19

20 21

22 23

Fink M, Kellner CH, McDall WV. The role of ECT in suicide prevention. J ECT. 2014;30(1):5–9. doi:10.1097/YCT.0b013e3182a6ad0d

Fink M. What was learned: Studies by the consortium for research in ECT (CORE) 1997–2011. Acta Psychiatr Scand. 2014;129(6):417–426. doi:10.1111/acps.12251

Rabheru K. Maintenance electroconvulsive therapy (M-ECT) after acute response: Examining the evidence for who, what, when, and how? J ECT 2012;28(1):39–47. doi:10.1097/YCT. 0b013e3182455758

Prudic J, Haskett RF, McCall WV, et al. Pharmacological strategies in the prevention of relapse after electroconvulsive therapy. J ECT. 2013;29(1):3–12. doi:10.1097/YCT.0b013e31826ea8c4 Focht A, Kellner CH. Electroconvulsive therapy (ECT) in the treatment of postpartum psychosis. J ECT. 2012;28(1):31–33. doi:10.1097/YCT.0b013e3182315aa8

Petrides G, Malur C, Braga RJ, et al. Electroconvulsive therapy augmentation in clozapine-resistant schizophrenia: A prospective, randomized study. Am J Psychiatry. 2015;172(1):52–58. doi:10.1176/appi.ajp.2014.13060787

Sienaert P. What we have learned about electroconvulsive therapy and its relevance for the practising psychiatrist. Can J Psychiatry. 2011;56(1):5–12. doi:10.1177/070674371105600103 Margoob MA, Ali Z, Andrade C. Ef cacy of ECT in chronic, severe, antidepressant- and CBT-refractory PTSD: An open, prospective study. Brain Stimul. 2010;3(1):28–35. doi:10.1016/j.brs. 2009.04.005

Kellner CH, Tobias KG, Wiegand J. Electrode placement in electroconvulsive therapy (ECT): A review of the literature. J ECT 2010;26(3):175–180. doi:10.1097/YCT.0b013e3181e48154

Sackeim HA, Dillingham EM, Prudic J, et al. Effect of concomitant pharmacotherapy on electroconvulsive therapy outcomes: Short-term ef cacy and adverse effects. Arch Gen Psychiatry. 2009;66(7):729–737. doi:10.1001/archgenpsychiatry.2009.75

Rasmussen KG. Electroconvulsive therapy and melancholia: Review of the literature and suggestions for further study. J ECT. 2011;27(4):315–322. doi:10.1097/YCT.0b013e31820a9482 McCall WV, Andrade C, Sienaert P. Searching for the mechanism(s) of ECT’s therapeutic effect. J ECT. 2014;30(2):87–89. doi:10.1097/YCT.0000000000000121

Sackeim HA, Prudic J, Nobler MS, et al. Effects of pulse width and electrode placement on the ef cacy and cognitive effects of electroconvulsive therapy. Brain Stimulat. 2008;1(2):78–83. doi:10.1016/j.brs.2008.03.001

Vaidya PV, Anderson EL, Bobb A, et al. A within-subject comparison of propofol and methohexital anesthesia for electroconvulsive therapy. J ECT 2012;28(1):14–19. doi:10.1097/YCT. 0b013e31823a4220

Lihua P, Su M, Ke W, et al. Different regimens of intravenous sedatives or hypnotics for electroconvulsive therapy (ECT) in adult patients with depression. Cochrane Database Syst Rev. 2014;4:CD009763. doi:10.1002/14651858.CD009763.pub2

Chen ST. Remifentanil: A review of its use in electroconvulsive therapy. J ECT 2011;27(4):323–327. doi:10.1097/YCT.0b013e31821072d2

Ingram A, Saling MM, Schweitzer I. Cognitive side effects of brief pulse electroconvulsive therapy: A review. J ECT 2008;24(1):3–9. doi:10.1097/YCT.0b013e31815ef24a

Merk W, Kucia K. Combined use of ECT and psychotropic drugs. Psychiatr Pol. 2015;49(6):1241–1253. doi:10.12740/PP/37462

Pigot M, Andrade C, Loo C. Pharmacological attenuation of electroconvulsive therapy-induced cognitive de cits: Theoretical background and clinical ndings. J ECT 2008;24(1):57–67. doi:10.1097/YCT.0b013e3181616c14

Prudic J. Strategies to minimize cognitive side effects with ECT: Aspects of ECT technique. J ECT 2008;24(1):46-51. doi:10.1097/YCT.0b013e31815ef238

Watts B V, Groft A, Bagian JP, et al. An examination of mortality and other adverse events related to electroconvulsive therapy using a national adverse event report system. J ECT. 2011;27(2):105–108. doi:10.1097/YCT.0b013e3181f6d17f

Vila-Rodriguez F, McGirr A, Tham J, et al. Electroconvulsive therapy in patients with deep brain stimulators. J ECT. 2014;30(3):e16–e18. doi:10.1097/YCT.0000000000000074

Elbe D, Black TR, McGrane IR, et al. Clinical handbook of psychotropic drugs for children and adolescents. (4th ed.). Boston, MA: Hogrefe Publishing, 2019.

Additional Suggested Reading

• AmanullahS,DelvaN,McRaeH,etal.Electroconvulsivetherapyinpatientswithskulldefectsormetallicimplants:Areviewoftheliteratureandcasereport.PrimCareCompanionCNS Disord. 2012;14(2):[no pagination]. doi:10.4088/PCC.11r01228

• FinkM.Electroconvulsivetherapy:Aguideforprofessionalsandtheirpatients(2nded.)NewYork,NY:OxfordUniversityPress,2009.

• KennedySH,MilevR,GiacobbeP,etal.CanadianNetworkforMoodandAnxietyTreatments(CANMAT)clinicalguidelinesforthemanagementofmajordepressivedisorderinadults.

IV. Neurostimulation therapies. J Affect Disord. 2009;117(Suppl. 1):S44–53. doi:10.1016/j.jad.2009.06.043

• MathesonSL,GreenMJ,LooC,etal.Qualityassessmentandcomparisonofevidenceforelectroconvulsivetherapyandrepetitivetranscranialmagneticstimulationforschizophrenia:

A systematic meta-review. Schizophr Res. 2010;118(1-3):201–210. doi:10.1016/j.schres.2010.01.002

• PeterchevAV,RosaMA,DengZDetal.Electroconvulsivetherapystimulusparameters:Rethinkingdosage.JECT.2010;26(3):159–174.doi:10.1097/YCT.0b013e3181e48165

• Semkovska M, McLoughlin DM. Objective cognitive performance associated with electroconvulsive therapy for depression: A systematic review and meta-analysis. Biol Psychiatry.

2010;68(6):568–577. doi:10.1016/j.biopsych.2010.06.009

• TrevinoK,McClintockSM,HusainMM.Areviewofcontinuationelectroconvulsivetherapy:application,safety,andef cacy.JECT.2010;26(3):186–195.doi:10.1097/YCT.0b013e3181efa1b2

• VersianiJ,CheniauxE,Landeira-FernandezJ.Ef cacyandsafetyofelectroconvulsivetherapyinthetreatmentofbipolardisorder:Asystematicreview.JECT2011;27(2):153-164.doi:

10.1097/YCT.0b013e3181e6332e

• Wilkins KM, Ostroff R, Tampi RR. Ef cacy of electroconvulsive therapy in the treatment of nondepressed psychiatric illness in elderly patients: A review of the literature. J Geriatr

Psychiatry Neurol. 2008;21(1):3–11. doi:10.1177/0891988707311027

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 99 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

ECT/BLT/rTMS

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

De nition

Indications

( approved)

BRIGHT LIGHT THERAPY (BLT)

• Regular daily exposure to ultraviolet- ltered visible light. For standard light boxes, this involves at least 5000 lux-hours (units of illumination per unit time) per day

Seasonal a ective disorder (SAD)[1]

• Circadianrhythmsleepdisorders(e.g.,jet-lag,shift-work)

• Insomnia: A systematic review and meta-analysis reported that light therapy was found e ective in the treatment of sleep problems in general

(g = 0.39), and for circadian rhythm sleep disorders (g = 0.41), insomnia (g = 0.47), and sleep problems related to Alzheimer’s disease/dementia

(g = 0.30) speci cally

• E cacyoflighttherapyforantepartumorpostpartumdepressionreportedinafewpublishedstudiesthathaveproducedmixedresults

• Nonseasonal depression: Randomized double-blind placebo-controlled studies showed that BLT, both as monotherapy and as adjunctive therapy,

was e cacious and well tolerated in the treatment of adults with nonseasonal unipolar and bipolar depression; combination treatment had the

most consistent e ects[2]. BLT was more e ective than placebo (sham treatment) in drug-resistant depression

• Bipolar depression – BLT shown to be e ective as adjunctive therapy in double-blind studies.[3, 4] Response reported within 48 h in conjunction with sleep deprivation and consecutive sleep phase advance; patients treated with bright white light experienced a signi cantly higher remission rate.

Caution suggested regarding possible risk for mood shift

• Parkinson’s disease: Several studies have demonstrated a positive e ect of BLT on sleep and mood; suggested to decrease daytime drowsiness[5];

variable e ects seen on motor function

• ADHD: Preliminary data suggest that morning BLT in combination with melatonin in the afternoon/evening e ective in sleep-onset insomnia

(delayed phase sleep disorder) in adolescents and adults. Pilot study in adults showed that BLT signi cantly advanced the phase of dim light melatonin onset and mid sleep time, which was correlated with decreased ADHD rating scale scores and hyperactive-impulsive sub scores; total sleep time, sleep e ciency, wake after sleep onset, or percent wake during sleep interval did not improve[6]

• Borderline personality disorder: Open trials suggest improvement in sleep and daytime alertness with morning BLT, alone or in combination with an antidepressant[7]

• Dementia:EarlydatasuggestpossibleroleofBLTintreatingsleepdisordersinpatientswithmildtomoderateAlzheimer’sdementia

• Eatingdisorders:Areviewofpublishedliterature(casestudies,openandDBtrials)suggeststhatBLTmaypotentiallybee ectiveatimprovingboth

disordered eating behavior and mood acutely, although timing of symptom response and duration of treatment e ects remain unknown

• Fibromyalgia:Apilotstudydemonstratedthatmorninglighttreatmentimprovedfunctionandpainsensitivityin10femalepatientswith bromyal-

gia

• Acceptablelightboxesmust lteroutpotentiallyharmfulultravioletrays

• The wavelength of visible light used is not of great importance; the most consistent wavelength-speci c e ects have been found with short-

wavelength light of 480 nm (blue light)[8]

• The magnitude of response increases with increased duration of exposure in a nonlinear fashion, as the majority of phase shift occurs at the

beginning of the exposure[9]

• Because they are used closer to the eyes, light visors produce much lower levels of light than do standard light boxes (which produce 2500–

10,000 lux). Brightness appears to be less important for visors than for light boxes

• Seasonal a ective disorder: Hypersomnia appears to be most consistently associated with a good response to BLT; hyperphagia (especially carbo-

hydrate craving) and a less severe symptom pro le at baseline also predict response

• Thee cacyofBLTisdependentonthetime-of-dayofthecircadiancyclethatthelightisadministered–seeDosing[10]

• Standardantidepressantsmayenhancethee ectsofBLT

• Eyesandretinas,nottheskin,mediatethetherapeutice ectoflight.Notwithstanding,patientsdonotneedtoglancedirectlyatthelightsource to experience a therapeutic e ect

General Comments

Therapeutic Effects

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Dosage

• Thespeci cmechanismofBLTremainsunknown.Whilelightsuppressesmelatonin,thismaynotbetheprimarymechanismofaction.Modulation of serotonin and autonomic function have also been proposed[8]

• Light induces gene expression in the adrenal gland via the suprachiasmatic nucleus (SCN)-sympathetic nervous system. This gene expression accompanies the surge of plasma and brain corticosterone levels without accompanying activation of the hypothalamo-adenohypophysial axis; SCN activation is closely linked to the circadian clock. The magnitude of corticosterone response is dose-dependently correlated with the light intensity[8]

• Theabilityoflighttophase-advancecircadianrhythmsmaybeimportantinsomepatients;manipulationofthecircadiantimingsystemviabright light (also sleep deprivation or pharmacological therapy) has been shown to alleviate depressive symptoms and suggests that circadian dysfunction may play a role in the pathophysiology of depression[11]

• Exposure to light in the late evening/early night causes phase delays, suppresses melatonin, and increases alertness; brief exposure may be more e cient than longer exposure[9]

• BLTusuallyworkswithinseveraldays;ondiscontinuation,bene tsarelostafterseveraldays

• Thestandard“dose”oflightis5000lux-hoursperday.Themostpopularmethodtoachievethisisexposurefor30minperdayusinga10,000-lux light unit

• One study suggests that 60min of intermittent light (20ms light ashes) may be more e ective at eliciting circadian rhythm changes than continuous light exposure

• SuggestedguidelinesfortimeofBLTforcircadianrhythmsleepdisorders[10]:

– Advancedsleep-phasesyndrome(earlysleep-waketimes):BLTbeforebedtimeanddimlightafterwaketime

– Delayedsleep-phasesyndrome(latesleep-waketimes,sleep-onsetinsomnia):BLTinthemorningafterawakeninganddimlightpriortobedtime – Shiftworkdisorder(insomniaduringdaytimesleep,drowsiness/fatiguewhenawake):BLTintheevening/night,dimlightafterwork,andstrict

adherence to regular sleep-wake times

– Jet lag (eastward; sleep-onset insomnia, daytime drowsiness/fatigue): BLT in the morning after wake time (home time) and dim light prior to

bedtime

– Jetlag(westward;earlymorningawakening,daytimedrowsiness/fatigue):BLTbeforebedtime(hometime)anddimlightafterwaketime – Non-24-hoursleep-wakedisorder(nopatterntosleep-waketimes):BLTinthemorningafterwaketimeifsleepepisodeoccursatnight

• Nonseasonaldepression:AugmentationwithBLTadministeredatmidday(e.g.,between12:00p.m.and2:30p.m.)maybemoste cacious

• SAD: Several randomized trials indicate that BLT is more bene cial if administered early in the morning rather than later in the morning or in the

evening

• Cumulative exposure to light therapy over 6 years has shown no ocular damage. Notwithstanding, overuse of light may cause a decrease in sensitivity to light[12]

• Nausea,headache,nervousness/jitteriness,andirritabilitycanoccur

• Casereportsofsuicidalideation/attemptswithindaysofstartingtreatment

• Eyestrain,blurredvision;eyeirritation(itching,stinging)–graduallydisappearswithtime(mayneedtositfurtherfromthelightsourceorinitiate

exposure gradually)

• Skinirritation–rare

• Hypomaniacanoccur,particularlyiflightisoverusedorinpatientswithbipolardisorder

• ParanoiddelusionsreportedinpatientswithAlzheimer’sdisease;casereportofinducedpsychoticepisodein38-year-oldfemale

• Rarely,menstrualdisturbances

• Patientswithunidenti edretinalconditionsmaybeatrisk;consultanophthalmologistforsuchcases,ifneeded

• Patientswithglaucoma,cataracts,retinaldetachmentorretinopathy

• Lighttherapyiscontraindicatedinpatientstakingphotosensitizingmedications

• Earlydatasuggestsbene tofBLTasmonotherapy,andalsoasadd-ontherapy,inadolescentswithnon-seasonaldepression

Adverse Effects

Precautions Contraindications

Pediatric Considerations

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 101 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

ECT/BLT/rTMS

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Geriatric Considerations

Use in Pregnancy Patient Instructions

Drug Interactions

Bright Light Therapy (BLT) (cont.)

• Used,togetherwithCBT,inadolescentswithdelayedsleepphasedisorder

• Randomizedcontrolledstudyofadolescentswithdelayedsleep-phasedisordershowedthatBLTplusmelatoninimprovedsleeponsetandduration,

and had continued bene t after 3 months

• UseofBLTinthemorninghadpositiveoutcomesinelderlypatientswithsleepdisturbancesandnon-seasonalmooddisorders

• LongersleeptimesreportedwhenBLTwasusedaspartofamulticomponentdeliriummanagementprogram[13]

• Dementia:Thoughseveralreportssuggestthattailoredlightinterventionimprovesmeasuresofsleep,depression,andagitationinindividualswith

Alzheimer’s disease and related dementia, an updated Cochrane review found no e ect of light therapy on cognitive function, sleep, challenging behavior (e.g., agitation), or psychiatric symptoms associated with dementia. Reduction in the development of activities of daily living (ADL) limitations was reported in one study, at three of ve time points

• Open studies, case reports, and randomized studies suggest BLT is well tolerated during pregnancy and no adverse e ects on the fetus have been reported

• FordetailedpatientinstructionsonBrightLightTherapy,seethePatientInformationSheet(detailsp.440)

• Prior to initiating BLT, consult with your physician and/or pharmacist to determine whether any drugs you are taking (including over-the-counter

and herbal preparations) may interact with the therapy

• Itisnotnecessarytoglancedirectlyatthelightsource

• Clinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterfortheinteractant

Class of Drug

Example

Interaction Effects

Acne preparation

Benzoyl peroxide, retinoids (e.g., isotretinoin)

May cause photosensitivity reaction

Antibiotic

Doxycycline, tetracycline

May cause photosensitivity reaction

Antidepressant

SSRI /SNRI MAOIs

Citalopram, uoxetine, paroxetine, sertraline, venlafaxine, etc. Tranylcypromine

May augment the effects of bright light therapy

Rarely used in SAD. May augment the effect of bright light therapy Standard MAOI precautions needed

Antipsychotic

Chlorpromazine

May cause photosensitivity reaction

Diuretic

Hydrochlorothiazide

May cause photosensitivity reaction

Hypoglycemic

Chlorpropamide

May cause photosensitivity reaction

L-Tryptophan

May augment the effects of bright light therapy

St. John’s Wort

May cause photosensitivity reaction

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Further Reading

References

1 Nussbaumer B, Kaminski-Hartenthaler A, Forneris CA,et al. Light therapy for preventing seasonal affective disorder. Cochrane Database Syst Rev. 2015;11:CD011269. doi:10.1002/14651858. CD011269.pub2

2 Lam RW, Levitt RJ, Levitan RD, et al. Ef cacy of bright light treatment, uoxetine, and the combination in patients with nonseasonal major depressive disorder: A randomized clinical trial. JAMA Psychiatry. 2016;73(1):56–63. doi:10.1001/jamapsychiatry.2015.2235

3 Yorguner Kupeli N, Bulut NS, Carkaxhiu Bulut G, et al. Ef cacy of bright light therapy in bipolar depression. Psychiatry Res. 2018;260:432–438. doi:10.1016/j.psychres.2017.12.020

4 Zhou TH, Dang WM, Ma YT, et al. Clinical ef cacy, onset time and safety of bright light therapy in acute bipolar depression as an adjunctive therapy: A randomized controlled trial. J Affect

Disord. 2018;227:90–96. doi:10.1016/j.jad.2017.09.038

5 Videnovic A, Klerman EB, Wang W, et al. Timed light therapy for sleep and daytime sleepiness associated with Parkinson disease: A randomized clinical trial. JAMA Neurol. 2017;74(4):411–

418. doi:10.1001/jamaneurol.2016.5192

6 Fargason RE, Fobian AD, Hablitz LM,et al. Correcting delayed circadian phase with bright light therapy predicts improvement in ADHD symptoms: A pilot study. J Psychiatr Res.

2017;91:105–110. doi:10.1016/j.jpsychires.2017.03.004

7 Bromundt V, Wirz-Justice A, Kyburz S, et al. Circadian sleep-wake cycles, well-being, and light therapy in borderline personality disorder. J Pers Disord. 2013;27(5):680–696. doi:10.1002/

14651858.CD003946.pub3

8 Oldham MA, Ciraulo DA. Bright light therapy for depression: A review of its effects on chronobiology and the autonomic nervous system. Chronobiol Int. 2014;31(3):305–319. doi:

10.3109/07420528.2013.833935

9 Chang AM, Santhi N, St Hilaire M, et al. Human responses to bright light of different durations. J Physiol. 2012;590:3103–3112. doi:10.1113/jphysiol.2011.226555

10 Gooley JJ. Treatment of circadian rhythm sleep disorders with light. Ann Acad Med Singapore. 2008;37(8):669–676. Retrieved from http://www.annals.edu.sg/pdf/37VolNo8Aug2008/

V37N8p669.pdf

11 Mendlewicz J. Disruption of the circadian timing systems: Molecular mechanisms in mood disorders. CNS Drugs. 2009;23(Suppl. 2):15–26. doi:10.2165/11318630-000000000-00000.

12 Gagné AM, Gagné P, Hébert M. Impact of light therapy on rod and cone functions in healthy subjects. Psychiatry Res. 2007;151(3):259–263. doi:10.1016/j.psychres.2006.09.004

13 Chong MS, Tan KT, Tay L, et al. Bright light therapy as part of a multicomponent management program improves sleep and functional outcomes in delirious older hospitalized adults.

Clin Interv Aging. 2013;8:565–572. doi:10.2147/CIA.S44926

Additional Suggested Reading

• Al-KarawiD,JubairL.Brightlighttherapyfornonseasonaldepression:Meta-analysisofclinicaltrials.JAffectDisord.2016;198:64–71.doi:10.1016/j.jad.2016.03.016

• BotanovY,IlardiSS.Theacutesideeffectsofbrightlighttherapy:Aplacebo-controlledinvestigation.PLoSOne.2013;8(9):e75893.doi:10.1371/journal.pone.0075893

• Gradisar M, Dohnt H, Gardner G, et al. A randomized controlled trial of cognitive-behavior therapy plus bright light therapy for adolescent delayed sleep phase disorder. Sleep.

2011;34(12):1671–1680. doi:10.5665/sleep.1432

• KooijJJ,BijlengaD.Thecircadianrhythminadultattention-de cit/hyperactivitydisorder:Currentstateofaffairs.ExpertRevNeurother.2013;13(10):1107–1116.doi:10.1586/14737175.

2013.836301

• Münch M, Bromundt V. Light and chronobiology: Implications for health and disease. Dialogues Clin Neurosci. 2012;14(4):448–453. Retrieved from http://www.dialogues-cns.com/

publication/light-and-chronobiology-implications-for-health-and-disease/

• PendersTM,StanciuCN,SchoemannAM,etal.Brightlighttherapyasaugmentationofpharmacotherapyfortreatmentofdepression:Asystematicreviewandmeta-analysis.PrimCare

Companion CNS Disord. 2016;18(5). doi:10.4088/PCC.15r01906

• RuttenS,VriendC,vandenHeuvelOA,etal.BrightlighttherapyinParkinson’sdisease:Anoverviewofthebackgroundandevidence.ParkinsonsDis.2012;2012:767105.doi:10.1155/

2012/767105

• SchwartzRS,OldsJ.Thepsychiatryoflight.HarvRevPsychiatry.2015;23(3):188–194.doi:10.1097/HRP.0000000000000078

• van Maanen A, Meijer AM, van der Heijden KB, et al. The effects of light therapy on sleep problems: A systematic review and meta-analysis. Sleep Med Rev. 2016;29:52–62. doi:

10.1016/j.smrv.2015.08.009

• Wirz-Justice A, Bader A, Frisch U, et al. A randomized, double-blind, placebo-controlled study of light therapy for antepartum depression. J Clin Psychiatry. 2011;72(7):986–993. doi:

10.4088/JCP.10m06188blu

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 103 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

ECT/BLT/rTMS

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION (rTMS)

De nition

• Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive procedure that employs high-powered time-varying magnetic elds to alter cortical neuronal activity. rTMS has been approved for the treatment of depression in most industrialized countries, including the USA, Canada, Great Britain and other European countries, Australia, Mexico, and Israel. Many double-blind, sham (i.e., simulated rTMS) controlled studies and several meta-analyses con rm the antidepressant e cacy of rTMS. However, uncertainties related to the optimal treatment parameters such as treatment site, pulse frequency, and number of treatments are still being researched. Hence, this technology is still regarded as being under development

• A pharmaco–economic analysis suggests that, after two previous failed antidepressant drug trials, rTMS may be more cost e ective and lead to greater improvement of quality-adjusted life years (QALY) than a third antidepressant drug. Another analysis suggests that ECT is even more cost e ective than rTMS though the reverse was observed in a 2nd analysis

Medication-resistant major depressive disorder (MDD): Left high-frequency, right low-frequency, or bilateral (left high- plus right low-frequency) rTMS are applied over the dorsolateral prefrontal cortex to treat MDD. Sham-controlled studies and meta-analysis suggest rTMS can hasten the response to antidepressants

• Maintenancetreatmentafterremissionofdepression[2]

• Schizophrenia: Left low-frequency temporoparietal rTMS in combination with antipsychotics may reduce auditory hallucinations; e ects on other

positive symptoms not established. Inconsistent results reported on e cacy for negative symptoms of schizophrenia

• Mania: Open trial reports antimanic e ects following high-frequency rTMS of the right prefrontal cortex (controlled trials show contradictory

results). Case reports suggest that rTMS may precipitate mild hypomania in bipolar patients

• Obsessive compulsive disorder: Newer studies suggest low-frequency rTMS over the supplementary motor cortex may relieve some symptoms of

OCD

• PTSD:Casereportsanddouble-blindstudiessuggestpositiveresponsetobothhigh-andlow-frequencyrTMSandRCTsuggestpretreatmentwith

rTMS may facilitate cognitive processing therapy for PTSD[3]

• Autism spectrum disorders: In a sham-controlled trial in 28 subjects with high-functioning autism or Asperger’s, “social relating” impairment and

socially-related anxiety were signi cantly reduced by bilateral rTMS

• Neurologicaldisease:PatientswithmigraineanddepressionmayexperienceimprovementofbothwithrTMS.Post-strokedepressionmayrespond

well to rTMS.[4] Early data suggest that rTMS may improve depressed mood and possibly slow disease progress in patients with Parkinson’s disease. There is early evidence that rTMS to the right hemisphere may improve verbal functioning in patients with aphasia and may reduce postconcussive symptoms after mild traumatic brain injury

• Response to rTMS varies depending on individual patient pathophysiology, stimulus frequency and intensity, coil orientation, and brain region treated

• Noninvasiveoutpatienttreatmentthatdoesnotrequireanesthesiaorsedation

• Labor-intensiveprocedure,astreatmentisadministeredover30–45min,5days/week,forupto30sessionspercourseoftreatment

• The neuronal depolarization and other changes in brain activity can be detected by electroencephalography and positron emission tomography

(PET) imaging

• Most meta-analyses of rTMS in mood disorders report modest but statistically signi cant antidepressant e ects after 2 weeks of daily treatment

of high-frequency repetitive left dorsolateral prefrontal cortex stimulation; randomized controlled studies suggest that longer courses of higher-

intensity threshold, and greater number of pulses/day may be more e ective than 2 weeks of daily rTMS

• DepressivesymptomsmaycontinuetodecreasefollowingcessationofacourseofrTMStreatment

• InthetreatmentofMDD,sham-controlledstudiesreportedresponseratesof18-58%andremissionratesof10–40%

• OnestudysuggeststhatrTMSmaypositivelya ectthepersonalitydimensionofneuroticism

• CognitivefunctioningmayimproveindepressedpatientstreatedwithrTMS

Indications

( approved)

General Comments

Therapeutic Effect

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Mechanism of Action

• ThereisevidencethatrTMSmayimprovemigraineheadache

• rTMS may be an alternative to ECT for some patients with MDD. Although early open-label trials suggest that ECT and rTMS are equivalent,

larger open-label trials, meta-analysis, and clinical experience indicate that rTMS is less e cacious than ECT, particularly in psychotically depressed

individuals[5]

• ClinicalgainsreportedtolastatleastaslongasthoseobtainedfollowingECT

• Continuation or “maintenance” – an open-label study suggests that single maintenance rTMS to the left prefrontal cortex, o ered once weekly or

at greater intervals, may prevent relapse in those successfully treated with either an acute course of rTMS or ECT

• Robustantidepressante ectsreportedwithcombinedECTandrTMS,withfewercognitiveadversee ectsthanwithECTalone

• Comparative study of rTMS and uoxetine 20 mg/day showed similar response in depression in patients with Parkinson’s disease, with additional

improvement in motor function and cognition with rTMS

• Magnetic seizure therapy (MST), where very high-energy rTMS is employed to induce a seizure, has been used to treat severe depression in open-

label trials. In one study, 5 of 13 patients responded to MST. No evidence of any impairment of orientation, memory, or other elements of cognition

was observed

• In a meta-analysis of 36 RCTs, antidepressant e ect size was greater with rTMS treatment courses of 4 weeks compared to shorter ones, and

greatest when the number of magnetic pulses delivered was 1200–1500 compared to higher or lower pulse numbers[6]

• “Accelerated”rTMSwith2–3sessionsdeliveredeachdaymayleadtoslightlyfasterrecoverycomparedtostandardoncedailyrTMSsessions[7]

• rTMSmayhaveananti-suicidee ectthatisindependentoftheantidepressante ect[8,9]

• Preliminarystudiessuggestthatpre-treatmentEEGmaybeusedtopredictresponsetorTMS

• ThetherapeuticmechanismofactionofrTMSisunknown

• The magnetic eld penetrates the skull to enter brain tissue where, through the principle of Faraday induction, a secondary electrical current is

generated in those cortical neurons lying beneath the coil. These neurons demonstrate either increased or decreased excitability, depending upon whether the magnetic pulses are delivered at high or low frequency. Excitability changes may be mediated through a direct e ect of rTMS on inhibitory cortical interneurons. Changes in neuronal activity at remote sites may occur through transynaptic mechanisms. The procedure is only mildly uncomfortable and no anesthetic is required.

• Studies suggest that rTMS may downregulate α-adrenergic receptors, increase dopamine and serotonin levels in the striatum, frontal cortex, and hippocampus; increased prefrontal cortex metabolism and blood ow has been noted in patients responding to high-frequency rTMS. Glutamate levels may increase in brain regions below the coil

• Low- and high-frequency rTMS may exert opposite neurophysiological e ects. High-frequency pulses (more than 1 pulse/s) may increase cortical excitability while low-frequency pulses (1 pulse/s or less) may reduce cortical excitability by increasing cortical inhibition. These e ects have been likened to the processes of “kindling” and “quenching” described in animals

• The e ects of rTMS appear to depend on the side of the brain treated (e.g., depression may respond to either high-frequency rTMS to the left dorsolateral prefrontal cortex (DLPFC) or to low-frequency rTMS to the right DLPFC); however, one study demonstrated that bilateral low-frequency rTMS may be an e ective antidepressant. High-frequency rTMS to the right DLPFC may lessen mania while the same frequency to the left DLPFC may make it worse. PTSD symptoms are reported to respond more robustly to right high-frequency rTMS in some studies

• Doseisdeterminedbythestimulusintensitysetting(typically90–120%oftheintensityrequiredtoelicitamuscletwitchbyactivatingthemotor cortex), and total number of stimuli administered (120–3000 pulses) over a single treatment session. When used to treat depression, rTMS is usually administered daily for 20–30 days. The duration of each treatment is dependent on frequency of pulses (1–20 Hz) but typically lasts about 30 min. Shorter protocols have been employed

• ThetaburstrTMS(TBS)involvesveryhigh-frequencystimulationadministeredoverasfewas3min,eithercontinuouslyorintermittently.TBSwould signi cantly reduce the duration of an rTMS treatment, thereby increasing the number treatable by a single operator in a day.[10] One RCT of true TBS (either intermittent, continuous or both) vs. sham reported a signi cant antidepressant e ect for true TBS, with greater e cacy when intermittent or bilateral protocols were used.[11] Although a small RCT showed no di erence between true continuous TBS and sham TBS[12], a much larger RCT demonstrated that intermittent theta burst rTMS done over 3 min is as e ective as 10 Hz standard rTMS given over 37.5 minutes[13]

• An8.5minprotocolusinglow-frequencyrTMSwasshowntobeane ectiveantidepressantinalargemulticentercontrolledtrial

Dosing

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 105 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

ECT/BLT/rTMS

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Procedure

Repetitive Transcranial Magnetic Stimulation (rTMS) (cont.)

• Awirecoil(encasedininsulatedplastic)isheldovertheskullandaverypowerfulelectricalcurrentispulsedthroughthecoiltogenerateatransient magnetic eld of up to 2 Tesla in intensity. The patient is awake and alert throughout and may resume normal activity, including operating a motor vehicle, immediately after the rTMS session

• Thepsychologicale ects,includingthoseuponmood,dependonthepulsefrequencyandtheregionofthebraintreated.Moodandanxietyseem to be most in uenced when rTMS is administered over the DLPFC. Pilot studies suggest that the antidepressant e ect is greater with more lateral coil placement over the DLPFC

• Studies have demonstrated that the standard coil positioning technique using the motor cortex as a reference site is quite inaccurate and will result in signi cant di erences in the brain areas stimulated from day to day and from one expert operator to another. Neuronavigation systems that could improve this, however, are expensive, technically complicated, and require a pretreatment MRI. A spandex swim hat marked with cranial bony landmarks (nasion, inion, and external auditory meati) can be used to record treatment site during the rst session to assist with consistent coil placement over future sessions

• Ameta-analysisofbilateralvs.unilateralrTMSsuggestsnoadvantageforbilateraltreatment

• Usuallyverywelltolerated;aminorityofpatientsfeelpainatthesiteofstimulation

• Discomfortinscalpbecauseofmuscularcontraction

• Headaches, usually with motor or premotor stimulation, have commonly been reported in rTMS studies; muscle tension headache can continue

beyond treatment [analgesics are of bene t]. Headache is less common as the course of rTMS proceeds and most patients no longer experience

headache after the rst 3–4 treatments have been completed

• SomecasesofnauseaandtremorafterrTMShavebeenreportedbutthisisuncommon

• Transientincreaseinauditorythresholds[foamearplugsduringtreatmentminimizeoreliminatethisproblem]

• Reportsofmildneckpain,eyepain,toothache,likelyduetostimulationofcranialnerves,andmuscletwitches

• Case reports of seizures with use of high-frequency rTMS, or in patients on concurrent seizure-lowering medication. Other sham-controlled trials

report decreased seizure frequency in epileptics treated with low-frequency rTMS

• CasereportsofswitchestomaniainpatientswithbipolarIandbipolarIIdisorderswhentreatedwithhigh-frequencyrTMSoftheleftDLPFC;one

case report with high-frequency treatment of the right DLPFC

• Caseofpsychoticsymptomsinpatientafter3sessions

• Veryrarelytransientdysphasiamayoccurduringstimulation(ifcoilplacementisclosetoBroca’sareaintheinferiorfrontalcortex)

• Minimalde citsinshort-termmemoryreportedfollowingtreatment;somestudiesreportenhancedcognitivefunctioning

• Metallic implants in the head, cardiac pacemaker, personal history of seizures or history of seizures in rst-degree relative. Drugs that lower the seizure threshold (e.g., bupropion) could theoretically increase the likelihood of rTMS-induced seizure

• rTMShasbeenusedinchildrenandadolescentsforvariousdiagnosesincludingADHD,withandwithoutTourette’s,anddepression

• A review study examining noninvasive brain stimulation techniques including rTMS in over 500 children and adolescents concluded that rTMS is

safe

• Onestudyreportsresponsein5of7youthswithdepressiontreatedwithrTMStotheleftDLPFC

• Anopen-labeltrialin8medication-resistantadolescentsshowedimprovementofdepressionafter6–8weeksoflefthigh-frequencyrTMS

• Nosigni cantadversecognitivee ectsorseizuresreported

• A meta-analysis of studies of rTMS in depression in the elderly showed contradictory results; the authors stated, however, that published data suggest e cacy for this treatment. Poor response possibly related to low-intensity pulses, number of stimulations, number of sessions, as well as patient-related factors

• rTMS is considered to be safe and does not produce signi cant cognitive de cits, even among patients with clinical evidence of cerebrovascular disease. Improved cognitive functioning noted in some elderly subjects with cognitive impairment treated with rTMS[8]

Adverse Effects

Contraindications

Pediatric Considerations

Geriatric Considerations

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Use in Pregnancy

• rTMSappliedtotherightDLPFChasbeenshowntoimprovemotorperformanceinpatientswithParkinson’sDisease

• Earlydatasuggestsresponseinlate-onsetvasculardepression

• Two case reports of successful treatment of females with depression; one in the second trimester, and the second through all 3 trimesters. No adverse e ects were reported in mothers or infants (one of the babies was followed for 22 months)

• AcasecontrolstudyofinfantsofdepressedmotherseitheruntreatedduringpregnancyortreatedwithrTMSshowednoabnormalitiesofcognitive functioning or motor development. Though the rTMS-treated mothers felt language development was delayed, this was similar to delays previously noted in children of mothers treated with SSRIs during pregnancy

• FordetailedpatientinstructionsonrTMS,seethePatientInformationSheet(detailsp.440)

• Clinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterfortheinteractant

Patient Instructions

Drug Interactions

Class of Drug

Example

Interaction Effects

Anticonvulsant

Clonazepam, valproate Gabapentin

May theoretically reduce the ef cacy of high-frequency rTMS; however, this has not been well studied One report suggests gabapentin may prolong duration of the antidepressant effect of rTMS

Antidepressant

Bupropion, TCAs

Drugs that lower the seizure threshold may increase the risk of seizure during high-frequency rTMS

rTMS has been used successfully combined with various antidepressants including SSRIs, MAOIs, and amitriptyline

Antipsychotic

Haloperidol, clozapine

Drugs that lower the seizure threshold may increase the risk of seizure during high-frequency rTMS

In one reported case, a person seized during high-frequency rTMS after taking amitriptyline in combination with haloperidol; other studies have combined low frequency rTMS with various antipsychotics without adverse effects

Further Reading

References

1 Nguyen KH, Gordon LG. Cost-effectiveness of repetitive transcranial magnetic stimulation versus antidepressant therapy for treatment-resistant depression. Value Health. 2015;18(5):597– 604. doi:10.1016/j.jval.2015.04.004

2 Haesebaert F, Moirand R, Schott-Pethelaz AM, et al. Usefulness of repetitive transcranial magnetic stimulation as a maintenance treatment in patients with major depression. World J Biol Psychiatry. 2018;19(1):74–78. doi:10.1080/15622975.2016.1255353

3 Kozel FA, Motes MA, Didehbani N, et al. Repetitive TMS to augment cognitive processing therapy in combat veterans of recent con icts with PTSD: A randomized clinical trial. J Affect Disord. 2018;229:506–514. doi:10.1016/j.jad.2017.12.046

4 Shen X, Liu M, Cheng Y, et al. Repetitive transcranial magnetic stimulation for the treatment of post-stroke depression: A systematic review and meta-analysis of randomized controlled clinical trials. J Affect Disord. 2017;211:65–74. doi:10.1016/j.jad.2016.12.058

5 Berlim MT, Van den Eynde F, Daskalakis ZJ. Ef cacy and acceptability of high frequency repetitive transcranial magnetic stimulation (rTMS) versus electroconvulsive therapy (ECT) for major depression: A systematic review and meta-analysis of randomized trials. Depress Anxiety. 2013;30(7):614–623. doi:10.1002/da.22060

6 Teng S, Guo Z, Peng H, et al. High-frequency repetitive transcranial magnetic stimulation over the left DLPFC for major depression: Session-dependent ef cacy: A meta-analysis. Eur Psychiatry. 2017;41:75–84. doi:10.1016/j.eurpsy.2016.11.002

7 Fitzgerald PB, Hoy KE, Elliot D, et al. Accelerated repetitive transcranial magnetic stimulation in the treatment of depression. Neuropsychopharmacology. 2018;43(7):1565–1572. doi: 10.1038/s41386-018-0009-9

8 Cheng CPW, Wong CSM, Lee KK, et al. Effects of repetitive transcranial magnetic stimulation on improvement of cognition in elderly patients with cognitive impairment: A systematic review and meta-analysis. Int J Geriatr Psychiatry. 2018;33(1):e1–e13. doi:10.1002/gps.4726

9 Weissman CR, Blumberger DM, Brown PE, et al. Bilateral repetitive transcranial magnetic stimulation decreases suicidal ideation in depression. J Clin Psychiatry. 2018;79(3). doi:10.4088/ JCP.17m11692

10 Bakker N, Shahab S, Giacobbe P, et al. rTMS of the dorsomedial prefrontal cortex for major depression: Safety, tolerability, effectiveness, and outcome predictors for 10 Hz versus intermittent theta-burst stimulation. Brain Stimul. 2015;8(2):208–215. doi:10.1016/j.brs.2014.11.002

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 107 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

ECT/BLT/rTMS

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Repetitive Transcranial Magnetic Stimulation (rTMS) (cont.)

11 12 13 14

Li CT, Chen MH, Juan CH, et al. Ef cacy of prefrontal theta-burst stimulation in refractory depression: A randomized sham-controlled study. Brain. 2014;137(Pt 7):2088–2098. doi:10.1093/ brain/awu109

Chistyakov AV, Kreinin B, Marmor S, et al. Preliminary assessment of the therapeutic ef cacy of continuous theta-burst magnetic stimulation (cTBS) in major depression: A double-blind sham-controlled study. J Affect Disord. 2015;170:225–229. doi:10.1016/j.jad.2014.08.035

Blumberger DM, Vila-Rodriguez F, Thorpe KE, et al. Effectiveness of theta-burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): A randomized non-inferiority trial. Lancet. 2018;391(10131):1683–1692. doi:10.1016/S0140-6736(18)30295-2

Chen JJ, Liu Z, Zhu D, et al. Bilateral vs. unilateral repetitive transcranial magnetic stimulation in treating major depression: A meta-analysis of randomized controlled trials. Psychiatry Res. 2014;219(1):51–57. doi:10.1016/j.psychres.2014.05.010

Additional Suggested Reading

• Berlim MT, McGirr A, Beaulieu MM, et al. Are neuroticism and extraversion associated with the antidepressant effects of repetitive transcranial magnetic stimulation (rTMS)? An exploratory 4-week trial. Neurosci Lett. 2013;534:306–310. doi:10.1016/j.neulet.2012.12.029

• ConnollyKR,HelmerA,CristanchoMA,etal.Effectivenessoftranscranialmagneticstimulationinclinicalpracticepost-FDAapprovalintheUnitedStates:Resultsobservedwiththe rst 100 consecutive cases of depression at an academic medical center. J Clin Psychiatry. 2012;73(4):e567–573. doi:10.4088/JCP.11m07413

• CristanchoMA,HelmerA,ConnollyR,etal.Transcranialmagneticstimulationmaintenanceasasubstituteformaintenanceelectroconvulsivetherapy:Acaseseries.JECT.2013;29(2):106– 108. doi:10.1097/YCT.0b013e31827a70ba

• D’AgatiD,BlochY,LevkovitzY,etal.rTMSforadolescents:Safetyandef cacyconsiderations.PsychiatryRes.2010;177(3):280–285.doi:10.1016/j.psychres.2010.03.004

• EnticottPG,FitzgibbonBM,KennedyHA,etal.Adouble-blind,randomizedtrialofdeeprepetitivetranscranialmagneticstimulation(rTMS)forautismspectrumdisorder.BrainStimul.

2014;7(2):206–211. doi:10.1016/j.brs.2013.10.004

• GallettaEE,RaoPR,BarrettAM.Transcranialmagneticstimulation(TMS):Potentialprogressforlanguageimprovementinaphasia.TopStrokeRehabil.2011;18(2):87–91.doi:10.1310/

tsr1802- 87

• GaynesBN,LloydSW,LuxL,etal.Repetitivetranscranialmagneticstimulationfortreatment-resistantdepression:Asystematicreviewandmeta-analysis.JClinPsychiatry.2014;75(5):477–

489. doi:10.4088/JCP.13r08815

• JanicakPG,O’ReardonJP,SampsonSM,etal.Transcranialmagneticstimulationinthetreatmentofmajordepressivedisorder:Acomprehensivesummaryofsafetyexperiencefrom

acute exposure, extended exposure, and during reintroduction treatment. J Clin Psychiatry 2008; 69(2):222–232.

• LeggettLE,SorilLJ,CowardS,etal.Repetitivetranscranialmagneticstimulationfortreatment-resistantdepressioninadultandyouthpopulations:Asystematicliteraturereviewand

meta-analysis. Prim Care Companion CNS Disord. 2015;17(6). doi:10.4088/PCC.15r01807

• MayerG,AviramS,WalterG,etal.(2012).Long-termfollow-upofadolescentswithresistantdepressiontreatedwithrepetitivetranscranialmagneticstimulation.JECT;28(2):84–86.

doi:10.1097/YCT.0b013e318238f01a

• MilevRV,GiacobbeP,KennedySH,etal.CanadianNetworkforMoodandAnxietyTreatments(CANMAT)2016clinicalguidelinesforthemanagementofadultswithmajordepressive

disorder: Section 4. Neurostimulation treatments. Can J Psychiatry. 2016;61(9):561–575. doi:10.1177/0706743716660033

• NauczycielC,HellierP,MorandiX,etal.Assessmentofstandardcoilpositioningintranscranialmagneticstimulationindepression.PsychiatryRes.2011;186(2–3):232–238.doi:10.1016/

j.psychres.2010.06.012

• SlotemaCW,BlomJD,HoekHW,etal.:Shouldweexpandthetoolboxofpsychiatrictreatmentmethodstoincluderepetitivetranscranialmagneticstimulation(rTMS)?Ameta-analysis

of the ef cacy of rTMS in psychiatric disorders. J Clin Psychiatry. 2010;71(7):873-884. doi:10.4088/JCP.08m04872gre

• Wall CA, Croarkin PA, Sim LA, et al. Adjunctive use of repetitive transcranial magnetic stimulation in depressed adolescents: A prospective, open pilot study. J Clin Psychiatry.

2011;72(9):1263–1269. doi:10.4088/JCP.11m07003

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Classi cation∗

Chemical Class

First-Generation Antipsychotics (FGAs) (*) Butyrophenone

Dibenzoxazepine Diphenylbutylpiperidine Phenothiazines

– aliphatic

– piperazine

– piperidine Thioxanthenes

ANTIPSYCHOTICS

• Antipsychoticscanbeclassi edasfollows:

Agent

Page

Haloperidol

See p. 115

Loxapine Pimozide

Example: Chlorpromazine Example: Perphenazine Example: Periciazine(C) Example: Thiothixene

Iloperidone(B), paliperidone, risperidone Lurasidone

See p. 132

Ziprasidone Clozapine Asenapine

Quetiapine Olanzapine

Aripiprazole, Cariprazine(B) Brexpiprazole

See p. 161

Pimavanserin

See p. 174

Second-Generation Antipsychotics (SGAs) (**) Benzisoxazole

Benzisothiazol

Benzothiazolylpiperazine Dibenzodiazepine

Dibenzo-oxepino pyrrole Dibenzothiazepine Thienobenzodiazepine

Third-Generation Antipsychotics (TGAs)

Phenylpiperazine

N-arylpiperazine

5-HT2A Inverse Agonist Antipsychotic

(*) Formerlycalledtypicalandconventional,

(**) Formerly called atypical, which describes antipsychotics that have a decreased incidence of EPS at therapeutic doses; the boundaries, however, between typical and atypical antipsychotics are not de nitive. Atypical antipsychotics (1) may have low af nity

for D2 receptors and are readily displaced by endogenous dopamine in striatum (e.g., clozapine, quetiapine); (2) may have high D2 blockade and high muscarinic blockade-anticholinergic activity; (3) block both D2 and 5-HT2 receptors (e.g., risperidone, clozapine, olanzapine, quetiapine); (4) may have high D4 blockade (e.g., clozapine, olanzapine, loxapine); (5) may lack a sustained increased prolactin response (e.g., clozapine, quetiapine, olanzapine); (6) show mesolimbic selectivity (e.g., olanzapine , clozapine, quetiapine),

(B) Not marketed in Canada. May be available through Health Canada’s Special Access Programme, (C) Not marketed in the USA

General Comments

• Antipsychotics are indicated in the treatment of a number of disorders, most notably schizophrenia and other related psychotic disorders and bipolar disorder. See the indications sections for SGAs (p. 133), TGAs (p. 161), and FGAs (p. 116) for detailed listings

• Despitethecategorizationof rst,second,orthirdgeneration,theseclassesareheterogeneousanddi erencesexistinthepharmacology,adverse e ect pro les, and cost of the agents within them. These di erences often help guide individualized treatment decisions. Non-industry-sponsored, randomized clinical trials comparing the e ectiveness of a number of SGAs along with one FGA (i.e., perphenazine) suggest that some FGAs may be considered as appropriate rst-line therapeutic alternatives. This has been re ected in a number of treatment guidelines that suggest selection of an antipsychotic agent should be tailored to best meet an individual’s speci c needs. Generally speaking, FGAs, especially high-potency agents,

∗ This classi cation system is under review.

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 109 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Pharmacology

Adverse Effects

Lab Tests/Monitoring

Antipsychotics (cont.)

are associated with a higher incidence of extrapyramidal side e ects (EPS) and tardive dyskinesia (TD). Haloperidol, in particular, appears to be associated with more EPS, even when lower doses are used. SGAs are less likely to result in EPS and TD but many are associated with a higher burden of metabolic adverse e ects, most notably clozapine and olanzapine

• Allclasseshavedemonstratede cacyinthetreatmentofpositivesymptomsofpsychosis(e.g.,hallucinations,delusions,hostility,andaggression) and relapse prevention

• No antipsychotic has demonstrated clinically signi cant e cacy to decrease primary negative symptoms of psychosis (i.e., a ective attening, alogia, amotivation, social withdrawal)

• See p. 134, p. 162, and p. 117 for speci c pharmacological statements relating to SGAs, TGAs, and FGAs, respectively, and the related charts listing e ects on neurotransmitters/receptors (p. 176 and p. 177)

• When individualizing therapy, the greater variation in adverse e ect pro les observed among agents may play a more signi cant role in the selection of an antipsychotic than the smaller di erences demonstrated in e cacy pro les

• Seedetaileddiscussionofadversee ectsassociatedwithSGAs(pp.137–144),TGAs(p.165),FGAs(pp.118–122)andrelatedcharts(pp.180–180)

• Monitoringfrequenciesproposedbelowareguidelinesonlyandshouldnotreplacegoodclinicaljudgment

Type

Details

Frequency

Initial history

Complete medical, substance use, smoking, and family history (including history of CVD, dyslipidemias, dementia, lung disease speci cally for loxapine inhaler, and glucose dysregulation/diabetes in rst-degree relatives)

Baseline

Physical assessment

Physical exam

Waist circumference, weight, and BMI

Blood pressure and pulse Temperature

Baseline and annually

Baseline and routinely thereafter (e.g., monthly for rst 3 months, then every 3 months thereafter while on a stable antipsychotic dose)

Baseline and regularly thereafter (e.g., at 1 week, 1 month, 3 months, and every 6 months thereafter). More frequent assessments may be necessary during dosage titration with asenapine, chlorpromazine, clozapine, quetiapine, risperidone, thioridazine, and ziprasidone

When clinically indicated

Clinical assessment

Hyperprolactinemia

EPS, TD, and other abnormal involuntary movements

Diabetes

Sexual dysfunction Sleep/sedation Anticholinergic effects

Screen for symptoms (e.g., decreased libido, erectile or ejaculatory dysfunction, menstrual changes, galactorrhea) at baseline and routinely thereafter (e.g., 1 month, 3 months, 6 months, and 12 months, then annually thereafter)

Screen at baseline and routinely thereafter (e.g., at 2 weeks, monthly for 3 months, then every 6 months thereafter)

Screen for symptoms (e.g., polydipsia, polyuria, polyphagia with weight loss, etc.) at baseline and routinely thereafter (e.g., baseline, at 6 months, 12 months, then annually thereafter)

Screen at baseline and routinely (e.g., at 3 months, 6 months, and every 6 months thereafter)

Assess at baseline and routinely (e.g., at 2 weeks, 1 month, 2 months, 6 months, as clinically indicated thereafter)

Screen for symptoms (e.g., confusion, constipation, dry eyes/mouth, blurred vision, urinary retention) at baseline and routinely as indicated (e.g., at 2 weeks, 1 month, 2 months, and as clinically indicated thereafter)

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Type

Details

Frequency

Laboratory and other assessments

ECG

At baseline, along with serum potassium and magnesium levels in individuals with cardiac risk factors (e.g., heart disease

– especially heart failure, recent MI, or preexisting conduction abnormalities; syncope; family history of early (before age 40) sudden cardiac death; or long QT syndrome) is recommended prior to prescribing antipsychotics with more de nite associations/higher degrees of prolongation (e.g., chlorpromazine, haloperidol, pimozide)

EEG

Fasting blood glucose

If seizures or myoclonus occur

At baseline and routinely (e.g., at 6 months, 12 months, then annually thereafter). More frequent assessments may be

required in patients with obesity, a family history of diabetes, or those who gain more than 5% of their body weight while on medication or experience a rapid increase in waist circumference

A1c

Fasting lipid pro le Complete blood count

If impaired fasting glucose or diabetes present

At baseline and routinely (e.g., at 3 months, 12 months, and annually thereafter)

At baseline and as clinically indicated. Note: Speci c hematological monitoring requirements exist for clozapine (see p. 146)

Liver function tests Prolactin level

At baseline and at 1 month, then as clinically indicated thereafter

As clinically indicated (e.g., signs of hyperprolactinemia on clinical assessment)

Pediatric Considerations Geriatric Considerations

• For detailed information on the use of antipsychotics in this population, please see the Clinical Handbook of Psychotropic Drugs for Children and Adolescents[1]

• Pharmacokineticandpharmacodynamicalterationsassociatedwithaging(decreasedcardiacoutput,renalandhepaticblood ow,GFR,leanbody mass, and hepatic metabolism – e.g., CYP3A4, etc.) may contribute to a marked sensitivity to the e ects of antipsychotics

• Higher incidence of comorbid medical conditions often translates into use of multiple medications, thereby increasing the potential for adverse drug reactions, drug-drug interactions, and adherence issues

• Age-relatedsensoryde citsandcognitiveimpairmentmayadverselyimpactadherence

• Asageneralrule,startwithlowerdoses(e.g.,1/4–1/2usualstartingdose,anddividedoseswherepossible)andtitrategradually.Assesstolerability

following each dosage increase[2]

• Frequentlyreportedadversee ectsofantipsychoticmedicationsintheelderlyincludeneurologicale ects,orthostatichypotension,sedation,and

anticholinergic e ects[2]

• NeurologicalE ects

– The elderly are more sensitive to extrapyramidal reactions (e.g., akathisia, pseudoparkinsonism), which can be persistent and create di culties in moving, eating, and sleeping and contribute to falls. These e ects are typically dose related and are more common with high-potency FGAs. Exercise caution if opting to treat by adding anticholinergic agents or benzodiazepines, as these agents may exacerbate other conditions (e.g., constipation, memory impairment, falls, etc.) or precipitate a delirium

– Considercomorbidmedicalconditionswhenchoosingantipsychotic(e.g.,Parkinson’sdisease,Lewy-bodydementia)

– TheriskofTDincreaseswithprolongeduseandishigherwithFGAs

• OrthostaticHypotension

– As most antipsychotics can cause orthostatic hypotension, use caution during dosage titration and when other hypotensive agents are pre- scribed – may result in falls and hip fracture. May be more common with asenapine, clozapine, quetiapine, and risperidone

• Sedation

– Tendstolastlongerintheelderlyandcanimpairarousallevelsduringtheday.Mayleadtoconfusion,disorientation,delirium,andincreaserisk

of falls. Typically a dose related e ect; more common with low-potency FGAs, asenapine, clozapine, olanzapine, and quetiapine. Caution when

combining with other CNS depressants. If drug is prescribed in the morning or during the day, suggest moving it to evening or bedtime

• Activation

– Ifactivationorrestlessnessoccurs,evaluatefordrug-inducedakathisia

– Ifpatienthasproblemssleeping,considermovingthedosetoearlierintheday

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 111 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Nursing Implications

Antipsychotics (cont.)

• AnticholinergicE ects

– The elderly are more sensitive to anticholinergic e ects; can result in physical as well as mental adverse e ects (e.g., tachycardia, constipation,

dry mouth and eyes, blurry vision, di culty urinating, impairment in concentration and memory, delirium, worsening dementia, etc.). Most

common with low-potency FGAs, clozapine, and olanzapine

• CognitiveE ects

– DatacontradictoryastocognitivedeclinesecondarytouseofantipsychoticsforbehaviordisturbancesinpatientswithAlzheimer’sdisease

• UseinDementia

– Individualswithdementiaoftendevelopneuropsychiatricsymptomssuchasagitation,aggression,andpsychosis(e.g.,delusions,hallucinations)

over the course of illness. Many of these are challenging to control via nonpharmacological interventions and may result in the prescription of antipsychotic medication. SGAs and TGAs are preferred in this population (vs. FGAs), primarily as a consequence of their perceived improved tolerability (i.e., fewer EPS & other movement disorders)

– A number of clinical trials evaluating these agents in the treatment of agitation and/or psychosis in dementia suggest modest clinical bene t, potentially negated in some cases by side e ect burden

– In 2005, both the FDA and Health Canada issued advisories concerning a small but signi cant increase in overall mortality in elderly patients with dementia receiving treatment with SGAs and aripiprazole. “Black box” warnings describing this risk were added to the labeling of these agents. The warnings were based primarily on the results of a meta-analysis of 15 smaller studies comparing various SGAs and aripiprazole vs. placebo in elderly patients with dementia. The increased risk reached statistical signi cance only when the results were pooled in the meta- analysis, potentially due to the low event rate and small sample sizes in the individual trials. The increased risk was evident early on, as the studies involved patients treated over the course of 8–12 weeks. The number needed to harm was reported as 100 or 1 death per 100 patients treated with SGAs over 10–12 weeks. Deaths were primarily from cardiac-related events and pneumonias

– SubsequentstudieshavesuggestedasimilarriskwithFGAs.In2008,theFDAreleasedasimilarwarningforconventionalorFGAs,inadditionto warnings for paliperidone

– Itiscurrentlyunknownifthisriskextendsbeyondtheearlytreatmentperiod.Conversely,thebene tsoflong-termtreatmentwithantipsychotics in this population are also uncertain

– Considerindividual’srisk-bene tratiowhenprescribingtheseagentsinpatientswithdementia.Ithasbeensuggestedtolimitusetosituations in which there is signi cant risk of harm to self or others, when hallucinations or delusions are problematic, or when symptoms are causing signi cant distress despite attempts to treat precipitating factors (e.g., infection, sleep deprivation, anticholinergic e ects of medications) or implementation of alternative treatments, including nonpharmacological measures. Reassess the need for continued treatment regularly

– Strategiesfortheuseofantipsychoticsinpatientswithdementiaincludeslowdosagetitration,usingtheloweste ectivedose,avoidingagents with anticholinergic properties, avoiding using solely for indications of insomnia, depression, nonspeci c agitation, and anxiety[3]

• Nurses may assist in baseline and routine assessment of mental status (to identify target symptoms & their subsequent response to drug ther- apy), physiological parameters (including weight, waist circumference, BP, heart rate, temperature, presence of abnormal movements), as well as documentation of any comorbidities, concomitant medications, and issues around medication adherence

• Excessiveuseofca eine(e.g.,colas,co ee,tea,chocolate)mayworsenanxietyandagitationandcounteractthebene ciale ectsofantipsychotics

• Adversee ectsfromtherapyareacommonlycitedreasonfornonadherence

• Earlyonset(morecommonduringthe rst3monthsoftherapy)adversee ectsinclude:

– Anticholinergice ects–drymouth,dryeyes,blurryvision,constipation,urinaryretention,confusion/delirium

• Frequentsipsofwater,chewingicechipsorsugarlessgum,orarti cialsalivaproductsmayrelievedrymouth.Arti cialtearsmayrelievedry

eyes. Blurred vision is usually transient; only near vision a ected; if severe, pilocarpine eye drops may be prescribed

• Anticholinergicsreduceperistalsisanddecreaseintestinalsecretions,leadingtoconstipation;increasing uidsandbulk(e.g.,bran,salads),as well as fruit in the diet is bene cial; increasing exercise may help; if necessary, bulk laxatives (e.g., psyllium or polycarbophil) or lactulose for

chronic constipation

• Monitorpatient’sintakeandoutput;urinaryretentioncanoccur,especiallyintheelderlyand/orindividualswithBPH;bethanechol(Urecholine)

can reverse this

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

– Extrapyramidalsidee ects

• Early-onsetextrapyramidalsidee ects(EPS)(e.g.,acutedystonias,akathisia,andpseudoparkinsonism);acutedystoniastypicallyoccurwithin

the rst few days and akathisia and pseudoparkinsonism within the rst 6 weeks of treatment. These adverse e ects are more commonly noted with FGAs, although they may occur with SGAs (most notably risperidone) and TGAs (e.g., aripiprazole). Anticholinergic agents (e.g., benztropine, procyclidine) may be used to prevent and/or treat some of these conditions (see p. 205 for details on treatment)

• TheuseofprophylacticanticholinergicmedicationstopreventEPSiscontroversialastheseagentscanworsenanticholinergicadversee ects, including delirium. Young males on high-potency FGAs and individuals with a prior history of EPS may be at a higher risk for developing EPS and as such may be suitable candidates for prophylaxis. If an anticholinergic agent is prescribed to treat EPS, the need for its continued use should be reassessed periodically

• Hold dose and notify physician if patient develops acute dystonia, severe persistent extrapyramidal reactions (longer than a few hours), or has symptoms of jaundice or blood dyscrasias (e.g., fever, sore throat, infection, cellulitis, weakness)

• Beawarethatakathisiacanbemisdiagnosedasanxietyorpsychoticagitationandtheincorrecttreatmentprescribed – Posturalhypotension,dizziness,andre extachycardia

• Sittingonthesideofthebedforafewminutesbeforerisingorrisingslowlyfromaseatedpositionmayhelpreducefalls

• Hypotensionmaybecompoundedbyconcomitantadministrationofantihypertensives – Somnolence,sedation

• Cautionpatientnottoperformactivitiesrequiringalertnessuntilresponsetothedrughasbeendetermined

• Ifdrugisprescribedinthemorningorduringtheday,suggestmovingittoeveningorbedtime – Activation

• Ifdrugissuspectedofcausingactivationorrestlessnessorifpatienthasproblemssleeping,evaluatefordrug-inducedakathisia;movingthe dose to earlier in the day may be helpful

– Weightgain

• Weight gain may occur in patients receiving antipsychotics (especially SGAs); proper diet, exercise, and avoidance of calorie-laden beverages

is important; monitor weight, waist circumference, and BMI during course of treatment

• Late-onsetadversee ectsinclude:

– Metabolice ects–dyslipidemias,glucoseintolerance,type2diabetes,weightgain

• Baselineandperiodicevaluationofweight,waistcircumference,BP,andfastingbloodglucoseandlipidpro lesrecommended – Menstrualabnormalities,sexualdysfunction

• Amenorrhea,sexualdysfunctionincludinganorgasmiareported – Tardivemovementdisorders

• RiskofdevelopingTDbelievedtoincreasewithdurationoftreatmentandtotaldose

• Usetheloweste ectivedosefortheshortestpossibledurationtominimizeriskofdevelopment • Thereisnoe ectivetreatment;considerdiscontinuingantipsychoticwerefeasible

• Othersigni cantadversee ects(maynotbetimedependent)include: – Agranulocytosis/leukopenia/neutropenia

• Patientswithlowneutrophilcountsshouldbemonitoredcloselyforfeverandothersignsofinfectionandtreatedaccordingly

• DiscontinueantipsychoticuseifANCcountslessthan1.5ô109/l – DiabeticKetoacidosis

• Hasbeennotedtooccurinindividualstreatedwithantipsychoticsdespitenohistoryofhyperglycemia

• Signs/symptoms may include hypotension, tachycardia, fruity odor on breath, lethargy, shortness of breath, nausea, vomiting, abdominal

pain, polyuria, polydipsia

– Neurolepticmalignantsyndrome(NMS)

• Patientsshouldavoiddehydrationandexposuretoextremeheatandhumidityasantipsychoticsa ectthebody’sabilitytoregulatetemper- ature

• SignsofNMSmayincludeautonomicinstability,hyperpyrexia,alteredmentalstatus,rigidity,elevatedcreatinephosphokinase,elevatedwhite blood cell count, and potentially renal failure

• Antipsychoticshouldbediscontinuedimmediatelyandsupportivemeasuresimplemented

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 113 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Patient Instructions

Antipsychotics (cont.)

– Seizures(typicallydoserelated)

• Useantipsychoticswithcautioninpatientswithseizuredisorder,especiallyifpoorlycontrolled

– QTcprolongation/arrhythmia

• Monitor patients for symptoms that may be associated with QT prolongation (e.g., dizziness, fainting spells, palpitation, nausea, and vomit-

ing). Symptomatic patients will require an ECG

• Fordetailedpatientinstructionsonantipsychotics,seethePatientInformationSheets(detailsonp.440)

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

First-Generation Antipsychotics/FGAs

Product Availability∗ Generic Name

Chlorpromazine Flupenthixol (Flupentixol)(C) Fluphenazine

Haloperidol

Loxapine

Methotrimeprazine (Levomepromazine)(C) Periciazine(C)

Perphenazine

Pimozide Thioridazine(B) , (D) Thiothixene Tri uoperazine Zuclopenthixol(C)

∗ Refer to Health Canada’s Drug Product Database or the FDA’s Drugs@FDA for the most current availability information (A) Generic preparations may be available, refractory schizophrenia in adults

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 115 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

(B) Not marketed in Canada,

(D) Restricted to treatment-

Chemical Class

Trade Name(A)

Dosage Forms and Strengths

Aliphatic phenothiazine

Largactil(C), Thorazine(B)

Tablets: 10 mg(B), 25 mg, 50 mg, 100 mg, 200 mg(B) Short-acting injection: 25 mg/mL, 27.9 mg/mL(C)

Thioxanthene

Fluanxol(C) Fluanxol Depot(C)

Tablets(C):0.5mg,3mg

Long-acting injection ( upenthixol decanoate depot)(C) : 20 mg/mL, 100 mg/mL

Piperazine phenothiazine

Moditen(C), Prolixin(B)

Modecate(C), Prolixin decanoate(B)

Tablets: 1 mg, 2 mg(C) , 2.5 mg(B) , 5 mg, 10 mg(B)

Oral elixir(B) : 2.5 mg/5 mL

Oral liquid concentrate(B) : 5 mg/mL

Short-acting injection(B) : 2.5 mg/mL

Long-acting injection ( uphenazine decanoate depot): 25 mg/mL(B) , 100 mg/mL(C)

Butyrophenone

Haldol

Haldol Decanoate

Tablets:0.5mg,1mg,2mg,5mg,10mg,20mg

Oral solution: 2 mg/mL

Short-acting injection (haloperidol lactate): 5 mg/mL

Long-acting injection (haloperidol decanoate depot): 50 mg/mL, 100 mg/mL

Dibenzoxazepine

Loxapac(C), Loxitane(B)

Tablets(C): 2.5 mg, 5 mg, 10 mg, 25 mg, 50 mg Capsules(B): 5 mg, 10 mg, 25 mg, 50 mg Short-acting injection(C) : 50 mg/mL

Adasuve(B)

Inhalation powder: 10 mg in a single-use inhaler

Aliphatic phenothiazine

Nozinan(C)

Tablets(C): 2 mg, 5 mg, 25 mg, 50 mg Short-acting injection(C) : 25 mg/mL

Piperidine phenothiazine

Neuleptil(C)

Capsules(C): 5 mg, 10 mg, 20 mg Oral drops(C) : 10 mg/mL

Piperazine phenothiazine

Trilafon Etrafon(B)

Tablets:2mg,4mg,8mg,16mg

Tablets (perphenazine/amitriptyline): 2 mg/10 mg, 2 mg/24 mg, 4 mg/10 mg, 4 mg/25 mg, 4 mg/50 mg

Diphenylbutylpiperidine

Orap

Tablets: 1 mg(B), 2 mg, 4 mg(C)

Piperidine phenothiazine

Mellaril(B)

Tablets: 10 mg, 25 mg, 50 mg, 100 mg

Thioxanthene

Navane(B)

Capsules: 1 mg, 2 mg, 5 mg, 10 mg

Piperazine phenothiazine

Stelazine

Tablets: 1 mg, 2 mg, 5 mg, 10 mg, 20 mg(C)

Thioxanthene

Clopixol(C)

Clopixol Acuphase(C) Clopixol Depot(C)

Tablets(C) : 10 mg, 25 mg

Short-acting injection (zuclopenthixol acetate depot)(C) : 50 mg/mL Long-acting injection (zuclopenthixol decanoate depot)(C) : 200 mg/mL

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Indicationsa ‡

( approved)

First-Generation Antipsychotics/FGAs (cont.)

Schizophrenia (chlorpromazine, uphenazine, uphenazine decanoate, haloperidol, haloperidol decanoate, loxapine, perphenazine, thiothixene, tri uoperazine – Canada and USA; methotrimeprazine, thioproperazine, zuclopenthixol – Canada)

Chronic schizophrenia ( upentixol, pimozide – Canada, in individuals whose main manifestations do not include excitement, agitation or hyperac- tivity; pipotiazine palmitate – Canada, in individuals who are non-agitated)

Acute agitation associated with schizophrenia (loxapine inhalation powder – USA)

Rapid control of acute manifestations of schizophrenia and acute psychotic episodes (haloperidol, zuclopenthixol acetate – Canada)

Refractory schizophrenia (thioridazine – USA)

Schizophrenia in patients with depressive symptoms (perphenazine + amitriptyline – USA)

Psychotic disorders (chlorpromazine, uphenazine, haloperidol – Canada and USA; methotrimeprazine, perphenazine, tri uoperazine, thiothixene – Canada)

Adjunctive therapy in psychotic patients for control of residual prevailing hostility, impulsiveness, and aggressiveness (periciazine – Canada)

• Psychoticdepression(loxapineismetabolizedtotheantidepressantamoxapine)

• Delusionaldisorder

Manic phase of bipolar disorder/manic syndromes (chlorpromazine – Canada and USA; thioproperazine, tri uoperazine – Canada) Manic states: Rapid control of acute manifestations (haloperidol short-acting injection – Canada)

Acute agitation associated with bipolar 1 disorder (loxapine inhalation powder – USA)

Psychosis associated with manic-depressive syndromes (haloperidol, methotrimeprazine – Canada)

Chronic brain syndrome and mental retardation: Management of aggressive and agitated behavior (haloperidol – Canada)

Senile psychoses (methotrimeprazine – Canada). In severe dementia, for the short-term symptomatic management of inappropriate behavior due to aggression and/or psychosis. The risks and bene ts in this population should be considered

Delirium (chlorpromazine, haloperidol)

Generalized anxiety disorder (GAD): Short-term management (tri uoperazine – USA)

Depression/depressed mood with anxiety in association with chronic physical disease or with moderate to severe anxiety and/or agitation (perphenazine + amitriptyline – USA)

Conditions associated with anxiety and tension, such as autonomic disturbances, personality disturbances, emotional troubles secondary to such physical conditions as resistant pruritus (methotrimeprazine, tri uoperazine – Canada)

Restlessness and apprehension before surgery (chlorpromazine – Canada and USA)

• Dyskinesias:Managementofvarioustypes,includingSydenham’schorea(haloperidol,risperidone)

ADHD: Short-term treatment of hyperactive children who exhibit excessive motor activity that is manifested as impulsive behavior, di culty sustaining attention, aggression, mood lability, and/or poor frustration tolerance (chlorpromazine, haloperidol – USA)

Severe behavioral problems in children marked by combativeness and/or explosive hyperexcitable behavior that is not accounted for by immediate provocation with failure to respond to non-antipsychotic medication or psychotherapy (chlorpromazine, haloperidol – USA)

Tourette’s syndrome: Symptomatic control of tics and vocal utterances in adults and children (haloperidol – Canada and USA; pimozide – USA, in

those who have failed standard treatment and daily life is severely compromised by motor and phonic tics)

• Trichotillomania

Schizophrenia and Psychotic Disorders

Bipolar Disorder

Acute Agitation, Delirium, and Dementia

Anxiety Disorders

Movement Disorders

Mental Health – Other

a Adult population unless otherwise stated ‡ Indications listed here do not necessarily apply to all FGAs or all countries. Please refer to a country’s regulatory database (e.g., US Federeal Drug Administration, Health Canada Drug Product Database) for the most current availability information and indications

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Other

General Comments

Analgesia in pain due to cancer, zona (herpes zoster/shingles), trigeminal neuralgia, and neurocostal neuralgia, and in phantom limb pains and muscular discomforts (methotrimeprazine – Canada)

Potentiator of anesthetics; in general anesthesia, can be used as both a pre- and post-sedative and analgesic (methotrimeprazine – Canada) Intractable hiccups (chlorpromazine, haloperidol – USA)

Nausea and vomiting: Prevention and/or treatment (chlorpromazine, perphenazine – Canada and USA; methotrimeprazine, tri uoperazine – Canada; haloperidol – USA)

Nausea, vomiting, and restlessness/anxiety associated with attacks of acute intermittent porphyria: Management (chlorpromazine – USA) Tetanus: Treatment adjunct (chlorpromazine – USA)

• Low-potencyFGAsaremorelikelytobeassociatedwithanticholinergice ects(e.g.,constipation,drymouth/eyes,blurredvision,urinaryretention, confusion/delirium), antihistaminic e ects (e.g., sedation, weight gain), and anti-adrenergic e ects (e.g., orthostatic hypotension, dizziness, and re ex tachycardia). Signi cant metabolic e ects appear to be less of a concern in comparison to some of the SGAs, although weight gain may occur, especially with the low-potency FGAs. Conduction abnormalities are a signi cant concern with some FGAs, notably pimozide and thioridazine

• All rst-generation (previously called typical or conventional) antipsychotics antagonize postsynaptic D2 receptors as their main pharmacological activity. They may be further subclassi ed as low (e.g., chlorpromazine), moderate (e.g., perphenazine, loxapine, zuclopenthixol), or high (e.g., haloperidol) potency agents according to their a nity for the D2 receptor

• Antagonism of D2 receptors in the various dopaminergic pathways is thought responsible for the e cacy and also for some of the adverse e ects associated with these agents. D2 antagonism in the mesolimbic pathway relieves positive symptoms of psychosis; D2 antagonism in the mesocor- tical pathway may worsen negative symptoms, mood, and cognition; D2 antagonism in the nigrostriatal pathway may result in EPS (early onset) and TD (late onset); D2 antagonism in the tuberoinfundibular tract may lead to hyperprolactinemia

• FGAs also have varying abilities to antagonize three other main receptors – α1-adrenergic, H1, and M1 receptors. Generally, their a nities for these three receptors are the inverse of their a nities for the D2 receptor

• For dosing of individual oral and short-acting agents for schizophrenia and psychosis, see table pp. 182–184. For long-acting agents, see table pp. 191

• Foradministrationdetails,pleaseseeNursingImplicationspp.125–125

• Current opinion suggests use of lower doses (i.e., haloperidol 2–10 mg daily, or equivalent); clinical e cacy of FGAs is correlated with D2 binding

above 60%, while hyperprolactinemia and EPS are associated with D2 occupancies of 50–75% and 78%, respectively (see p. 118 and p. 120); outcome

studies show that most patients respond similarly to low doses as to high doses, with decreased adverse e ects

• Patientswithacutesymptomsmayrequireslightlyhigherdosesthanchronicpatients;manicpatientsmayneedevenhigherdoses;maintenance

doses for bipolar patients tend to be about half those used in schizophrenia

• Lowerdosesareusedin rst-episodepatients,children,theelderly,andthosewithcompromisedliverand/orrenalfunction

• Seetablespp.182–184andpp.191forkineticsofindividualagents

• Hepaticprimaryrouteofmetabolism:Chlorpromazine,haloperidol,loxapine,methotrimeprazine,perphenazine,pimozide,tri uoperazine

• Renalprimaryrouteofexcretion:Chlorpromazine,pimozide,tri uoperazine

• Peakplasmalevelsoforaldosesgenerallyreached1–4hafteradministration

• Highlyboundtoplasmaproteins

• Mostphenothiazinesandthioxantheneshaveactivemetabolites

• Metabolizedextensivelybytheliver;speci cagentsinhibitCYP450metabolizingenzymes(seepp.182–184)

• Peakplasmalevelsafterinhalation(loxapine)achievedwithin2min

• Metabolizedbytheliver,withasimilarhalf-lifetooraladminstration

• Generallypeakplasmalevelreachedsoonerthanwithoralpreparation

• Bioavailabilityusuallygreaterthanwithoraldrug(loxapineexcepted);dosageshouldbeadjustedaccordingly

• LoxapinesingleIMdosesproducelowerconcentrationsofactivemetabolitefor rst12–16hthanoraltherapydoes–thismayresultinadi erent

balance between D2 and 5-HT2 blockade

Pharmacology

Dosing

Pharmacokinetics

Oral

Inhalation

Short-acting IM

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 117 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Long-acting IM

Adverse Effects

First-Generation Antipsychotics/FGAs (cont.)

• ZuclopenthixolAcuphase:intermediate-actingdepotinjection(seep.184)withapeakplasmalevelof24–48handeliminationhalf-life=48–72h

• Seechartpp.191

• Bioavailability is greater than with oral agents (by a factor of at least 2); eliminates bioavailability problems related to absorption and rst-pass

metabolism and maintains stable plasma concentrations

• Presenceof“free” uphenazineinmulti-dosevialsof uphenazinedecanoateisresponsibleforhighpeakplasmalevelseenwithin24hofinjection

• Seechartspp.180–180andpp.192forincidenceofadversee ects

• High-potency agents typically cause more D2-related adverse e ects (EPS and hyperprolactinemia), low-potency agents cause more α1, H1, and

M1-related adverse e ects (e.g., postural hypotension, sedation, anticholinergic e ects), and moderate-potency agents fall somewhere in the middle

• Some adverse e ects may be preventable by employing simple strategies (e.g., slow upwards titration or dosing schedule manipulation – e.g.,

dosing a sedating drug at bedtime or dividing up the daily dose to minimize adverse e ects related to higher peak levels)

• Manyadversee ectsmaybetransientinnatureandrequirenointerventionotherthanreassuranceandfollow-uptoensuretheyresolve

• Confusion, disturbed concentration, disorientation (more common with high doses or in the elderly). Concomitant anticholinergic agents may exacerbate

• Extrapyramidal – acute onset: A result of antagonism at dopamine D2 receptors (extrapyramidal reactions correlated with D2 binding greater than 80%)

– Includes acute dystonias, akathisia, pseudoparkinsonism, Pisa syndrome, rabbit syndrome – see p. 205 for onset, symptoms, and treatment options and pp. 203–220 for detailed treatment options

– Morecommonwithhigh-potencyFGAsvs.moderate-tolow-potencyagents,alsomorecommonwithFGAsvs.SGAs/TGAs–seepp.205–207to compare incidence of EPS associated with these agents

– Mostcommonlyoccurwithinthe rstdaystoweeksoftreatmentandaredoserelated

• Extrapyramidal–lateonsetortardivemovementdisorders

– Include tardive akathisia, tardive dyskinesia, and tardive dystonia – see p. 207 for onset, symptoms, and therapeutic management options. Valbenazine and deutetrabenazine are approved in the USA for treatment of tardive dyskinesia. They are VMAT2 inhibitors (vesicular monoamine transporter 2 inhibitors) and act to decrease dopamine release[4]

– Lateonsetmovementdisordersusuallydevelopaftermonthsoryearsoftreatment

– Maybeirreversiblesopreventioniskey–uselowestdosesforshortestpossibletimeperiodandassessforsignsofmovementdisordersregularly.

Symptoms are not alleviated and may be exacerbated by antiparkinsonian medications – AnnualriskofTDwithFGAsestimatedtobe4–5%withacumulativeriskofupto50%

• Neurolepticmalignantsyndrome(NMS)–raredisordercharacterizedbyautonomicdysfunction(e.g.,tachycardiaandhypertension),hyperthermia, altered consciousness, and muscle rigidity with an increase in creatine kinase and myoglobinuria. Can occur with any class of antipsychotic agent, at any dose, and at any time (although usually occurs early in the course of treatment). Risk factors may include dehydration, young age, male sex, organic brain syndromes, exhaustion, agitation, and rapid or parenteral antipsychotic administration

• Sedation – common, especially with low-potency agents, following treatment initiation, and with dosage increases. Usually transient, but some individuals may complain of persistent e ects. [Management: Prescribe majority of daily dose at bedtime; minimize use of concomitant CNS depressants, if possible]

• Seizures – all FGAs may lower seizure threshold, resulting in seizures ranging from myoclonus to grand mal type. At usual dosage ranges, seizure rates are less than 1% for FGAs. Risk greater with low-potency agents and is dose related. May occur if dose increased rapidly or may also be secondary to hyponatremia associated with SIADH. Use with caution in patients with a history of seizures

• Seerelativetolerabilitypro lestablep.178foracomparisonofthelikelihoodofanticholinergice ectsamongantipsychotics

• Morecommonwithlow-potencyFGAs

• Manyoftheseadversee ectsareoftendoserelatedandmayalsoresolveovertimewithouttreatment.Treatmentoptionsmayincludereducingthe

dose of the FGA or switching to another antipsychotic with less potential to cause anticholinergic e ects or employing a speci c drug or non-drug strategy to treat the adverse e ect (see below for suggestions)

CNS Effects

Anticholinergic Effects

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

• Blurredvision,dryeyes[Management:Useadequatelightingwhenreading;pilocarpine0.5%eyedrops]

• Constipation [Management/prevention: Increase dietary ber and uid intake, increase exercise, or use a stool softener (e.g., docusate) or bulk

laxative (e.g., psyllium)]

• Delirium–characterizedbyagitation,confusion,disorientation,visualhallucinations,tachycardia,etc.Mayresultwithuseofhighdosesorcombi-

nation anticholinergic medication. Drugs with high anticholinergic activity have also been associated with slowed cognition and selective impair-

ments of memory and recall

• Dryeyes(Management:Arti cialtears,wettingsolutions)

• Dry mouth/mucous membranes – if severe or persistent, may predispose patient to candida infection [Management: Sugar-free gum and candy,

oral lubricants (e.g., MoiStir, OraCare D), pilocarpine mouth wash – see p. 53]

• Urinaryretention–maybemoreproblematicforolderpatients,especiallymaleswithbenignprostatichypertrophy[Management:Bethanechol]

• ArrhythmiasandECGchanges(seep.139):

– Thioridazine has the most compelling evidence regarding QTc prolongation, with numerous reports of torsades de pointes and sudden car-

diac death. There also appears to be an association for pimozide at higher doses. There have also been reports of torsades de pointes with chlorpromazine, droperidol and haloperidol. All the aforementioned agents are rated as “Risk of TdP – QT prolongation and clear association of risk of TdP even when used as directed” by Credible Meds Wordlwide[5]

– Seerelativetolerabilitypro lestablep.178foracomparisonofthelikelihoodofQTprolongationamongantipsychotics

– The presence of other known risk factors for QT prolongation should be assessed and, to the extent possible, controlled (e.g., electrolyte im- balances corrected, interacting drugs or use of concomitant drugs that prolong QT avoided) before consideration is given to the initiation of treatment with a FGA. The e ectiveness of baseline and follow-up ECGs as a monitoring tool has not been proven and may not be of value given the inherent variability within the QT interval (approximately 100 msec), though it has been recommended by some. See p. 139 for more

information on QT/TdP

– Tachycardia may occur as a compensatory mechanism to orthostatic hypotension caused by α1-adrenergic antagonism. Tachycardia due to

anticholinergic e ects in the absence of above conditions, may be treated with a low-dose peripherally-acting β-blocker

• Death/dementia – FGAs are associated with an increased risk of mortality in elderly patients treated for dementia-related psychosis with these

agents, see p. 112

• Dyslipidemia(seep.140

• Orthostatic hypotension/compensatory tachycardia/dizziness/syncope – may occur as a result of α1-adrenergic antagonism. More likely to occur

with low-potency FGAs. DO NOT USE EPINEPHRINE, as it may further lower the blood pressure (see Drug Interactions p. 131). Elderly patients are susceptible to this adverse e ect and syncopal episodes may result in falls and fractures. [Management: Rise slowly, divide the daily dose, consider a switch to another agent, increase uid and salt intake, use support hose; treatment with uid-retaining corticosteroid – udrocortisone]

• Venous thrombosis – low-potency agents may be a risk factor for venous thrombosis in predisposed individuals, case reports of deep vein throm- bosis in patients on chlorpromazine – usually occurs in rst 3 months of therapy

• Cardiovascular disease (CVD) is the leading cause of death in individuals with schizophrenia. There may be a number of contributing factors to CVD in this population, including smoking, sedentary lifestyles, poverty, poor nutrition, reduced access to health care, and a number of metabolic abnormalities including weight gain, dyslipidemias, glucose intolerance, and hypertension. Please see p. 140 for more details on these endocrine and metabolic e ects and their role in CVD

• Antidiuretichormonedysfunction:

– Disturbancesinantidiuretichormonefunction:PIP(polydipsia,intermittenthyponatremia,andpsychosissyndrome);prevalenceinschizophre-

nia estimated at 6–20%, can range from mild cognitive de cits to seizures, coma, and death; increased risk in the elderly, smokers, and alcoholics. Monitor sodium levels in chronically treated patients to help identify risk for seizures [Management: Fluid restriction, demeclocycline up to 1200 mg/day, captopril 12.5 mg/day, propranolol 30–120 mg/day; replace electrolytes]

• Dyslipidemia:

– Seep.110forsuggestedmonitoringguidelines

– The comparative metabolic risks associated with various FGAs are less well studied, but in general these agents are associated with a lower

metabolic risk (weight gain, glucose dysregulation, and lipid abnormalities) vs. many SGAs. In general, low-potency FGAs > moderate-potency FGAs > high-potency FGAs with repect to metabolic risk liability

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 119 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Cardiovascular Effects

Endocrine & Metabolic Effects

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

First-Generation Antipsychotics/FGAs (cont.)

– Treatmentoptionsmayincludelifestyleanddietarymodi cations;switchingtoanotherantipsychoticassociatedwithalowerpotentialforlipid dysregulation; adding cholesterol-lowering medication (e.g., statins, brates, salmon oil, etc.)

• Glucoseintolerance,insulinresistance,hyperglycemia,type2diabetes,diabeticketoacidosis:

– Schizophrenia is a risk factor for the development of type 2 diabetes. Certain antipsychotic medications have also been associated with an

increased risk for glucose intolerance/diabetes. While the risk appears highest with SGAs (most notably clozapine and olanzapine), there are also reports in the literature of glycosuria, glucose intolerance, hyperglycemia, and diabetes mellitus occurring in association with FGAs. Within FGAs, the risk may be greater with low-potency agents or phenothiazines

– Seep.110forsuggestedmonitoringguidelines

– Treatment options may include lifestyle and dietary modi cations; switching to another antipsychotic associated with a lower potential for

glucose dysregulation; adding hypoglycemic agent • Hyperprolactinemia:

– Prolactin level may be elevated up to 10-fold from baseline. Develops over rst week of treatment and usually remains throughout treatment course

– Clinicalconsequencesofelevatedprolactinlevelsmayincludeshort-termriskssuchasgalactorrhea,gynecomastia,menstrualirregularities,and sexual dysfunction, and potential long-term risks such as osteoporosis (as a result of decreased bone density secondary to chronic hypogo- nadism), pituitary tumors, and breast cancer (data con icting)

– E ectsinwomen:Breastengorgementandlactation(maybemorecommoninwomenwhohavepreviouslybeenpregnant),amenorrhea(with risk of infertility), menstrual irregularities, changes in libido, hirsutism (due to increased testosterone). Bone mineral density loss may be more intense in females than males and may vary by ethnic group; extent of loss may correlate with duration of hyperprolactinemia. Recommended women with hyperprolactinemia or amenorrhea for more than 12 months have a bone mineral density evaluation

– E ectsinmen:Gynecomastia,rarelygalactorrhea,decreasedlibido,anderectileorejaculatorydysfunction

– Seerelativetolerabilitypro lestablep.178foracomparisonofthelikelihoodofhyperprolactinemiaamongantipsychotics

– Seep.110forsuggestedmonitoringguidelines

– Treatmentoptions:Assumingdiscontinuationofantipsychotictherapyisnotanoption,thepreferredtreatmentistoswitchtoanotherantipsy-

chotic agent with a reduced risk of hyperprolactinemia – weighing the potential risk for relapse associated with this action. Other treatment options may include lowering the dose or adding a medication to treat the condition. Use of a dopamine agonist such as bromocriptine (1.25– 2.5 mg bid) or cabergoline (0.25–2 mg/week) may be considered but has the potential to exacerbate the underlying illness. Use of a D2 partial agonist such as aripiprazole (5 mg/day) has also been used to treat antipsychotic-associated hyperprolactinemia

• Metabolicsyndrome:

– Seep.141fordetails

– LittleisknownabouttherelativerisksofFGAswithrespecttocausingorcontributingtometabolicsyndrome,asheightenedawarenessofthe

relationship between antipsychotics and this condition arose primarily during the reign of SGAs. Since weight gain, dyslipidemias, and glycemic abnormalities have been noted to occur with FGAs (though typically at a much lower rate than with many of the SGAs), it is likely that metabolic syndrome may occur especially with low-potency FGAs, albeit less commonly vs. the majority of SGAs

• Weightgain:

– Reportedinupto40%ofpatientsreceivingtreatmentwithFGAs.Morelikelytooccurearlyintreatment(e.g.,within rst6months)andtherisk

appears greater with low-potency FGAs[2]

– Seerelativetolerabilitypro lestablep.178foracomparisonofthelikelihoodofweightgainamongantipsychotics

– Themechanismbywhichantipsychoticsmayin uenceweightgainisunknown(maybearesultofmultiplesystemsincluding5-HT1B-,5-HT2C-,

α1-, and H1-blockade, prolactinemia, gonadal and adrenal steroid imbalance, and increase in circulating leptin; may also be due to sedation and

inactivity, carbohydrate craving, and excessive intake of high-calorie beverages to alleviate drug-induced thirst and dry mouth)

– Weight gain may contribute to or have deleterious e ects on a number of conditions, including dyslipidemia, glucose dysregulation and type 2

diabetes, hypertension, coronary artery disease, stroke, osteoarthritis, sleep apnea, and self-image

– Seep.110forsuggestedmonitoringguidelinesandp.142fortreatmentoptions

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

• Anorexia,dyspepsia

• Constipation–seeAnticholinergicE ectsp.138

• Dysphagia – (di culty swallowing) and aspiration have been reported with antipsychotic use. Use all agents cautiously in individuals at risk for

developing aspiration pneumonia (e.g., advanced Alzheimer’s disease)

• Drymouth–seeAnticholinergicE ectsp.138

• Pancreatitis–rarereportsofpancreatitiswithhaloperidol

• Peculiartaste,glossitis

• Sialorrhea,di cultyswallowing,gagging[seep.142foradditionalinformationonmanagement

• Vomitingcommonafterprolongedtreatment,especiallyinsmokers

• Sexual e ects may result from altered dopaminergic (including hyperprolactinemia – main cause of sexual dysfunction in women), serotonergic, ACh, α1, or H1 activity

• Anestimated25–60%ofpatientsonFGAsreportsexualdysfunction

• Treatment options may include: 1) dosage reduction, 2) waiting 1–3 months to see if tolerance develops, 3) switching antipsychotics, or 4) adding

a medication to treat the problem (see below for treatment suggestions regarding speci c types of dysfunction; evidence for their use is based

primarily on open-label studies and case reports)

• Anorgasmia [Management: Bethanechol (10mg tid or 10–25mg prn before intercourse), neostigmine (7.5–15mg prn), cyproheptadine (4–

16 mg/day), amantadine (100–300 mg/day)]

• Ejaculation dysfunction (incl. inhibition of ejaculation, abnormal ejaculation, retrograde ejaculation – especially thioridazine) – reported to be

the most common sexual disturbance associated with FGAs [Management suggestions: For retrograde ejaculation – imipramine (25–50 mg at

bedtime), yohimbine (5.4 mg 1–3 ô daily, 1–4 h prior to intercourse), or cyproheptadine (4–16 mg/day)]

• Erectile dysfunction, impotence – ED is reported to occur in 23–54% of males on FGAs [Management suggestions: Bethanechol (10mg tid or

10–50mg prn before intercourse), yohimbine (5.4mg 1–3ô daily, 1–4h prior to intercourse), sildena l (25–100mg prn), amantadine (100–

300 mg/day)]

• Libido–decreasedlibido[Management:Neostigmine(7.5–15mgprn)orcyproheptadine(4–16mgprn30minbeforeintercourse)]

• Priapism – rare case reports of priapism occurring in patients on FGAs (i.e., chlorpromazine, uphenazine, perphenazine, prochlorperazine, thiori-

dazine, thiothixene, and tri uoperazine). Antagonism of α-adrenergic receptors is believed to play a role in this e ect

• Urinaryretention–seeAnticholinergicE ectsp.138

• Blurredvision/dryeyes–seeAnticholingericE ectsp.138

• Cataracts/lens changes: Association reported between phenothiazine use and cataract formation. Though eye examination (e.g., slit lamp exam)

has been recommended at baseline and 6-month intervals thereafter, this recommendation is controversial

• Lenticularpigmentation

– Relatedtolong-termuseofantipsychotics(primarilychlorpromazine) – Presentsasglare,halosaroundlightsorhazyvision

– Granulardepositsineye

– Visionisusuallynotimpaired;maybereversibleifdrugstopped

– Oftenpresentinpatientswithantipsychotic-inducedskinpigmentationorphotosensitivityreactions

• Pigmentaryretinopathy(retinitispigmentosa)

– Primarilyassociatedwithchronicuse/higherdosesofthelow-potencyFGAsthioridazineorchlorpromazine[annualophthalmologicalexamina- tion recommended]

– RecommendedtoNOTexceedamaximumdoseof800mgperdayofthioridazine

– Reducedvisualacuity(mayoccasionallyreverseifdrugstopped) – Blindnesscanoccur

• Withchronicuse,chlorpromazinecancausepigmentationoftheendotheliumandDescemet’smembraneofthecornea;itmaycauseaslate-bluish discoloration of the conjunctiva, sclera, and eyelids – may not be reversible when drug stopped

• Blooddyscrasias,includingthosea ectingerythropoesis,granulopoesis,andthrombopoesis,havebeenreportedwithmostantipsychotics

• The development of any blood abnormalities in individuals on antipsychotics, especially other than clozapine, should undergo rigorous medical

assessment to determine the underlying cause

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 121 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

GI Effects

Urogenital & Sexual Effects

Ocular Effects

Hematological Effects

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Hepatic Effects

Hypersensitivity Reactions

Temperature Regulation

Other Adverse Effects

Discontinuation Syndrome

First-Generation Antipsychotics/FGAs (cont.)

• Aplastic anemia – reported primarily with chlorpromazine and tri uoperazine. Also noted to have occurred in patients treated with uphenazine, upenthixol, haloperidol, perphenazine, and thioridazine

• Eosinophilia–nottypicallyofclinicalsigni canceunlesssevere.Reportedwithchlorpromazineandtri uoperazine

• Leukopenia [de ned as WBC <4ô109/l] and neutropenia/agranulocytosis [neutropenia (de ned as ANC < 1.5ô109/L) may be subclassi ed as mild (ANC = 1–1.5 ô 109 /L), moderate (ANC = 0.5–1 ô 109 /L) or severe (also termed agranulocytosis – de ned as ANC < 0.5 ô 109 /L or sometimes

as ANC < 0.2 ô 109/L)].

– Mild neutropenia may be transient (returning to normal without a change in medication/dose), or progressive (continuing to drop, leading to

agranulocytosis)

– Reportedincidenceofsevereneutropeniain1studywas0.02%withphenothiazinesand0.003%withbutyrophenones

• Thrombocytopenia – reported with a number of FGAs, including chlorpromazine, prochlorperazine, and thioridazine. In most cases withdrawal of the medication was reported to result in normalization of platelet counts

• Cholestaticjaundice

– Occursinlessthan0.1%ofpatientswithin rst4weeksoftreatment,withmostantipsychotics – Notedtooccurin0.1–0.5%ofpatientstakingchlorpromazine

• Transientasymptomatictransaminaseelevations(ALT2–3timestheupperlimitofnormal)reportedwithhaloperidol(upto16%ofpatients)

• Usuallyappearwithinthe rstfewmonthsoftherapy(butmayoccurafterthedrugisdiscontinued)

• Photosensitivity and photoallergy reactions including sunburn-like erythematous eruptions that may be accompanied by blistering. Occurs

most commonly with low-potency phenothiazines. Patients should be advised to avoid excess exposure to sunlight and wear appropriate

clothing/sunscreen

• Loxapineinhalationpowderhasbeenassociatedwithbronchospasmwhichhasthepotentialtoleadtorespiratorydistressandrespiratoryarrest.

This product is only available through a restricted program in the USA – Adasuve Risk Evaluation and Mitigation Strategy (REMS) – in which the health care facility must have immediate access to advanced airway management personnel and equipment. This product is contraindicated in patients with asthma, COPD or other respiratory disease associated with bronchospasm or in patients with a known hypersensitivity to loxapine or amoxapine

• Hypersensitivereactionsatinjectionsite(especiallyhaloperidoldecanoate100mg/mL);indurationsreportedwithhigherdoses(seep.192)

• Casesofsystemiclupuserythematosusreportedwithchlorpromazine

• Altered ability of body to regulate response to changes in temperature and humidity; may become hyperthermic or hypothermic in temperature extremes due to inhibition of the hypothalamic control area. Patients should be advised to avoid temperature extremes, dress appropriately, and maintain adequate hydration

• Low-potencyantipsychoticsassociatedwithincreasedriskoffatalpulmonaryembolism(highestriskwiththioridazine)

• Abruptdiscontinuationofanantipsychoticoccursprimarilyinsituationsinvolvingasudden/severeadversereactiontothedrug(e.g.,hepaticfailure with chlorpromazine) or when patients become nonadherent by stopping their antipsychotic medication abruptly

• Abruptdiscontinuation(orinsomecaseslargedosereductions)ofanantipsychoticmaybeassociatedwithanumberofwithdrawalordiscontinu- ation e ects (see below). Prolonged antagonism of (dopaminergic, muscarinic, histaminic, adrenergic) receptors by the antipsychotic, resulting in a compensatory up-regulation, which then produces a rebound-type reaction when the antagonist is removed and the supersensitized receptors are exposed, has been proposed as a pharmacological explanation for these e ects:

1. Discontinuation syndromes – typically characterized by development of a number of symptoms including nausea, vomiting, diarrhea, diaphore- sis, cold sweats, muscles aches and pains, insomnia, anxiety, and confusion. Many are believed to be the result of cholinergic rebound. Usually appear within days of discontinuation [Management: Mild cases may only require comfort and reassurance; for more severe symptoms consider restarting the antipsychotic followed by slow taper if possible; or, if rebound cholinergic e ects present, consider adding an anticholinergic agent short term]

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Precautions

2. Psychosis – exacerbation or precipitation of psychosis including a severe, rapid onset or supersensitivity psychosis, most notable with clozapine and possibly quetiapine vs. FGAs. Most likely to occur within the rst 2–3 weeks post discontinuation or sooner [Management: Restart antipsy- chotic]

3. Movement disorders – withdrawal dyskinesias noted to appear, usually around 2–4 weeks post abrupt withdrawal [Management: Restart antipsychotic and taper slowly]. Rebound dystonia, parkinsonism, and akathisia also reported to occur, usually within days to the rst week post discontinuation [Management: Restart antipsychotic and taper or treat with appropriate anti-EPS medication]

• Abruptcessationofalong-actingordepotantipsychoticisoflessconcernasplasmaconcentrationsdeclineslowly(i.e.,drugtapersitself)

• Clinicians should be cognizant of the potential for withdrawal e ects to occur from a discontinued agent when switching to a new antipsychotic,

in order to avoid misinterpreting them as adverse e ects of the new agent and subsequently discontinuing it unnecessarily

☞ AFTER PROLONGED USE, THESE MEDICATIONS SHOULD BE WITHDRAWN GRADUALLY WHERE POSSIBLE. If switching to another antipsychotic, see

pp. 197–198 for speci c recommendations

• Hypotension occurs most frequently with parenteral use, especially with high doses; the patient should be in supine position during short-acting IM administration and remain supine or seated for at least 30 min; measure BP before and following each IM dose

• IMinjectionsshouldbeadministeredslowly

• Use with caution in the elderly, in the presence of cardiovascular disease, chronic respiratory disorder, hypoglycemia or convulsive disorders (see

Use in Dementia p. 112)

• Should be used very cautiously/avoided in patients with narrow-angle glaucoma, BPH, decreased gastrointestinal motility, urinary retention,

prolactin-dependent tumors or Parkinson’s disease

• Priortoprescribingthioridazineorpimozide,abaselineECGandserumpotassiumshouldbedoneandmonitoredperiodicallyduringthecourseof

therapy. DO NOT USE these drugs in patients with QTc interval over 450 msec or with signi cant risk factors for QTc prolongation/development of

torsades de pointes (see p. 139)

• MonitorifQTintervalexceeds420msanddiscontinuedrugif500msexceeded;donotexceed800mgthioridazineor20mgpimozidedaily

• Allergiccross-reactivity(rash)betweenchlorpromazineandclozapinereported

• Inthemajorityofcases,overdoseisassociatedwithalowmortalityandmorbidityrateasFGAshaveahightherapeuticindex

• Symptoms may include nausea and vomiting, confusion, hallucinations, agitation, drowsiness progressing to coma, hypotension, respiratory de-

pression, electrolyte imbalances, ECG changes and arrhythmias, and/or EPS

• Seep.146forfurtherdetailsonantipsychotictoxicityandmanagement

• General:

– For each individual, consider the risks of not treating/undertreating (e.g., illness relapse, self-harm, poor adherence with prenatal care, poor

nutrition, exposure to additional medication or herbal remedies, increased alcohol, tobacco or recreational drug use, de cits in mother-infant

bonding) vs. the risks of continuing or starting an antipsychotic

– Pregnancy-relatedchanges(i.e.,increasedbodyweight,bloodvolume,andbodyfat,altereddrugmetabolism,andincreaseddrugexcretion)may

require the use of higher drug doses to maintain e cacy. Postpartum dose tapering may be needed as liver metabolism and uid volumes return

to baseline levels. Monitor for FGA adverse e ects and reduce dose as needed

– AvailabledatasuggestsmostFGAsdonotincreasetheriskofteratogenice ectsinhumans.However,humandataforsomeFGAsislimited

– Early data suggests in utero exposure to FGAs may decrease infant birth weight, increase the risk of small size for gestational age, and slightly

increase the risk of preterm birth. However, data is con icting and complicated by di erences in study design, study population (e.g., use of

concurrent medications, psychiatric diagnosis), and the inherent di culties in studying medication use during pregnancy

– Consider the potential e ects on delivery (e.g., maternal hypotension with chlorpromazine) and for withdrawal e ects in the newborn if used during the third trimester. There are case reports of fetal and neonatal toxicity including NMS, dyskinesia, EPS (manifested by heightened muscle tone and increased rooting and tendon re exes persisting for several months), neonatal jaundice, and postnatal intestinal obstruction. In 2011, the US FDA and Health Canada asked manufacturers to update their prescribing information to warn clinicians and patients that third- trimester use of antipsychotics is associated with risk of EPS and withdrawal symptoms in newborns. Symptoms in the neonate may include:

Toxicity

Use in Pregnancy♢

Management

♢ See p. 439 for further information on drug use in pregnancy and e ects on breast milk

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 123 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

First-Generation Antipsychotics/FGAs (cont.)

Feeding disorder, hypertonia, hypotonia, tremor, respiratory distress, and agitation. Signs related to atropinic properties of phenothiazines such

as meconium ileus, delayed meconium passage, abdominal bloating, tachycardia, and feeding disorders in neonates can occur

– Useofthelong-actinginjectionformneardeliverylikelytoprolonganywithdrawale ectsintheneonate

– If an antipsychotic will be used during pregnancy, consider patient enrollment or registration in any relevant studies or pregnancy exposure

registries (e.g., in Canada: Motherisk list of current studies http://www.motherisk.org/prof/currentStudies.jsp; in the USA: FDA list of pregnancy

registries http://www.fda.gov/scienceresearch/specialtopics/womenshealthresearch/ucm134848.htm)

– Avoid, if possible, FGAs that have no or very limited human pregnancy data (e.g., upenthixol, loxapine, periciazine, pimozide, pipotiazine,

thiothixene, and zuclopenthixol). FGAs with a larger reproductive safety pro le include chlorpromazine, uphenazine, haloperidol, perphenazine,

and thioridazine

– High-potency FGAs (e.g., haloperidol) may yield the best therapeutic bene t with the least anticholinergic and sedative e ects, however, com-

parative safety with other FGAs in pregnancy is unavailable

• Chlorpromazine was initially used for nausea and vomiting during pregnancy. This data suggests chlorpromazine is safe if used in low doses during pregnancy. However, when given near term, particularly in doses of 500 mg or greater, chlorpromazine may cause an increased incidence of respiratory distress in the neonate and has been implicated in producing lethargy and EPS in the neonate

• Flupenthixol:Limitedhumandata.Norelevantanimaldata

• Fluphenazine: Limited human data. Human data suggest risk in 3rd trimester. Case reports of withdrawal e ects (e.g., EPS, irribtability) that

developed up to 6 weeks post delivery with in utero exposure to the long-acting injection form

• Haloperidol: Limited human data. Animal data suggest moderate risk. Although the rates of major malformations in humans do not appear to

be greater than baseline there have been cases of limb defects after rst-trimester (time of greatest risk for malformations) exposure in hu- mans to haloperidol. If haloperidol is required during pregnancy, ultrasound with particular attention to limb formation should be considered in rst-trimester exposures. Two case reports of neonate tardive dyskinesia. Case report of NMS with third-trimester exposure to haloperidol and risperidone

• Loxapine: Manufacturer reports outcomes from only 3 pregnancies with loxapine exposure – one child born with achondroplasia, one child born with multiple unspeci ed malformations, and one child with tremors at 15 weeks of age

• Methotrimeprazine:Limitedhumandata;probablycompatible.Norelevantanimaldata.Initiallyusedinobstetricanalgesia

• Perphenazine: Limited human data. Sporadic cases of both fetal malformations and gestational metabolic complications also emerged from a

recent retrospective study investigating the use of perphenazine during pregnancy

• Periciazine:Nopublishedhumandata.Norelevantanimaldata

• Pimozide:Limitedhumandata(fewerthan5casereports).Animaldatasuggestlowrisk

• Thioridazine:Limitedhumandata.Norelevantanimaldata

• Thiothixene:Limitedhumandata.Noteratogenice ectsseeninanimals

• Tri uoperazine: Limited human data. Animal data suggest low risk. Studies indicate no causal relationship between tri uoperazine exposure and

congenital malformations

• Zuclopenthixol:Publishedhumandata(fewerthan10casereports).Notteratogenicinanimals

• Foreachindividual,considerthebene tsofbreastfeedingvs.therisksofinfantdrugexposureviabreastmilkandpossiblee ectsonmilkproduction

• Antipsychotics, like most medications, pass into breast milk, however, antipsychotic amounts found are generally low. Antipsychotics have been

detected in breast milk in concentrations of 0.1–11%. Long-term e ects on the infant are largely unknown

• Ifusedwhilebreastfeeding,useloweste ectivedoseandmonitorinfant’sprogress

• Very limited data. Single or small numbers of case reports have found no short-term adverse e ects of breastfed infants exposed to upenthixol,

perphenazine or zuclopenthixol. One report of drowsiness and lethargy with chlorpromazine.[6] Cases of a decline in mental and psychomotor development at age 12–18 months with higher dose haloperidol (20–40 mg/day) and chlorpromazine (200–600 mg/day). Long-term e ects on neurodevelopment are largely unknown. A 5-year follow-up study of 7 breastfed infants exposed to chlorpromazine found no developmental de cits[6]

• Phenothiazinesgivendirectlytoinfantsandchildrenforsedationorcoughandcoldsymptomshavebeenassociatedwithapneaandsuddeninfant death syndrome (SIDS); however, phenothiazine exposure via breast milk is signi cantly lower

Breast Milk

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

• Hale’s lactation risk category = L3 (give only if the potential bene t outweighs the potential risk to the infant): chlorpromazine, uphenazine, haloperidol, perphenazine, tri uoperazine, zuclopenthixol; risk category = L4 (no information available): loxapine, pimozide, thioridazine, thiothix- ene

• A review categorized chlorpromazine, haloperidol, and zuclopenthixol as possible for breastfeeding under medical supervision and categorized uphenazine, upenthixol, perphenazine, pimozide, tri uoperazine, and thiothixene as currently cannot be recommended for breastfeeding[7]

• RefertotheDrugsandLactationDatabase(LactMed)website(http://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm)formoreinformation

• Seepp.112–114

• AVOIDgrapefruitjuicewithpimozide(SeeDrugInteractionsp.130)

• Oral solutions should be diluted just prior to administration to improve palatability. Not compatible with all beverages. Dilute uphenazine and

perphenazine solution with water, 7-Up, milk, V-8, or pineapple, apricot, prune, orange or tomato juice. Dilute haloperidol oral liquid with water or

an acidic beverage such as juice; DO NOT mix with tea or co ee. Dilute loxapine with orange or grapefruit juice

• Someliquidssuchaschlorpromazineandmethotrimeprazinehavelocalanesthetice ectsandshouldbewelldilutedtopreventchoking

• Ifpatientissuspectedofnotswallowingtabletmedication,liquidmedicationcanbegiven

• AVOIDskincontactwithliquidformsof uphenazineasitmayresultincontactdermatitis

• Loxapineoralinhalationisgivenviaasingle-useinhaler.Onceactivated,theinhalershouldbeusedwithin15min.Anindicatorlightontheinhaler

device will turn o once the full dose is delivered. It may take several breaths to deliver the full dose. Patient should hold their breath for as long as possible (up to 10 sec) after inhaling the dose. Can only be given in enrolled healthcare facilities with immediate, on-site resources to manage bronchospasm and/or respiratory distress

• Watch for orthostatic hypotension, especially with parenteral administration of chlorpromazine or methotrimeprazine; keep patient supine or seated for 30 min afterwards; monitor BP before and after each injection

• Give IM into upper outer quadrant of buttocks or in the deltoid (deltoid o ers faster absorption as it has better blood perfusion); alternate sites, charting (L) or (R); massage slowly after, to prevent sterile abscess formation; tell patient injection may sting

• Prevent contact dermatitis by keeping drug solution o patient’s skin and clothing and injector’s hands, AVOID contact with uphenazine, in particular

• Donotletdrugstandinsyringeforlongerthan15minasplasticmayadsorbdrug

• IfirritationatthechlorpromazineIMinjectionsiteoccurs,dilutedrugwith0.9%sodiumchlorideinjectionor2%procaineHCl

• HaloperidollactatecanbeadministeredIMinthesamesyringeaslorazepam

• Storage:Roomtemperatureandprotectedfromlight(chlorpromazineHCl, uphenazineHCl,haloperidollactate,loxapineHCl,methotrimeprazine

HCl)

• Recommendedtoestablishtolerabilitywithanoralformpriortoinitializingalong-actingIMdosageform

• Short-actingpreparationsmayberequiredforsupplementationwhiledosagetitrationistakingplace

• Useaneedleofatleast21gauge;givedeepIMintolargemuscle(e.g.,buttock,usingZ-trackmethod);rotatesitesandspecifyincharting

• Aswithalloilyinjections,itisimportanttoensure,byaspirationbeforeinjection,thatinadvertentintravascularinjectiondoesnotoccur

• Donotletdrugstandinsyringeforlongerthan15minasplasticmayadsorbdrug

• DONOTmassageinjectionsite

• SCadministrationcanbeusedfor uphenazinedecanoate

• AVOIDskincontactwithliquidformsof uphenazineasitmayresultincontactdermatitis

• Storage:Roomtemperatureandprotectedfromlight–haloperidoldecanoate, upenthixoldecanoate, uphenazinedecanoate

• Someshort-actinginjectionformulationscanbeadministeredintravenously.Long-actingformulationsCANNOTbeadministeredviathisroute.

• IVadministrationgenerallyoccursintheintensivecareorsurgicalsetting

• HaloperidollactateandchlorpromazinecanbegivenviadirectIVinjectionorIVinfusion

• HaloperidoladministeredIVisassociatedwithhigherratesofsuddendeath,torsadesdepointes,andQTprolongation

• Methotrimeprazine injection diluted with 5% dextrose can be given as a slow infusion (20–40 drops per min) to potentiate anesthetics during surgery

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 125 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Nursing Implications

Oral

Short-acting IM

Long-acting IM

Intravenous

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Drug Interactions

First-Generation Antipsychotics/FGAs (cont.)

• Clinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterforthesecondagent

Class of Drug

Example

Interaction Effects

Acetylcholinesterase inhibitor (central)

General

Donepezil, galantamine, rivastigmine

Increase in mortality in elderly patients with dementia taking antipsychotics irrespective of acetylcholinesterase inhibitor use. Deaths were related to cardiac disease and cancer

grimacing) in elderly patients within a few days of starting an antipsychotic (risperidone or haloperidol) and an acetylcholinesterase inhibitor (donepezil). Symptoms resolved after discontinuing the antipsychotic agent, the acetylcholinesterase inhibitor, or both

Adsorbent

Activated charcoal, attapulgite (kaolin-pectin), cholestyramine

Oral absorption decreased signi cantly when used simultaneously; give at least 1 h before or 2 h after the antipsychotic

α1-adrenergic blocker

Doxazosin, prazosin, terazosin

Additive hypotension, particularly with low-potency FGAs like chlorpromazine. Antipsychotics generally cause hypotension via α1 blockade

Anesthetic

En urane

Additive hypotension, particularly with low-potency FGAs such as chlorpromazine

Amylinomimetic

Pramlintide

Pramlintide slows the rate of gastric emptying. Antipsychotics with signi cant anticholinergic effects can further reduce GI motility. Use drugs with minimal anticholinergic effects at the lowest effective dose. See frequency of adverse effects table p. 180

Antiarrhythmic

General

Amiodarone, quinidine

DO NOT COMBINE with chlorpromazine, uphenazine, pimozide or thioridazine. NOT recommended with phenothiazines or zuclopenthixol. CAUTION with all other FGAs. Possible additive prolongation of QTc interval and associated life-threatening cardiac arrhythmias. Factors that further increase the risk include uncompensated heart failure, recent acute MI, eating disorders (e.g., anorexia), bradycardia, electrolyte imbalances (e.g., hypokalemia, hypomagnesemia), and a family history of sudden death. Also see FGA Cardiovascular Effects p. 119

With quinidine, increased peak plasma level and AUC of haloperidol by ∼2-fold due to inhibited metabolism via CYP2D6 and/or displacement from tissue binding

With amiodarone and quinidine likely to increase chlorpromazine, uphenazine, pimozide, and thioridazine levels via inhibition of CYP2D6; further increasing risk of QT prolongation

Antibiotic

Macrolide

Clarithromycin, erythromycin, telithromycin

DO NOT COMBINE with pimozide or thioridazine. NOT recommended with phenothiazines or zuclopenthixol. CAUTION with all other FGAs. Possible additive prolongation of QTc interval and associated life-threatening cardiac arrhythmias. Factors that further increase the risk include anorexia, bradycardia, hypokalemia, and hypomagnesemia. Also see Cardiovascular Effects p. 119

With clarithromycin, decreased clearance of pimozide by 46% due to inhibition of metabolism via CYP3A4. Two reports of deaths occurring within days of adding clarithromycin to pimozide. Azithromycin (which does not inhibit CYP3A4) may have a lower risk when used with pimozide, although all macrolides including azithromycin are speci cally listed as contraindicated in the US pimozide product monograph Clarithromycin may decrease clearance of chlorpromazine and haloperidol. Similar interaction with erythromycin and telithromycin likely. Increased antipsychotic adverse effects including prolonged QT interval possible

Quinolone

Cipro oxacin, levo oxacin, moxi oxacin

CAUTION. Potential to exacerbate psychiatric conditions as quinolone-induced psychosis has been reported

With cipro oxacin, may increase plasma level of tri uoperazine due to inhibition of metabolism via CYP1A2. Clinical signi cance unknown

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Example

Interaction Effects

Antidepressants, antihistamines, antiparkinsonian drugs

Increases the risk of anticholinergic adverse effects (e.g., dry mouth, urinary retention, inhibition of sweating, blurred vision, constipation, paralytic ileus, confusion, toxic psychosis)

Warfarin

Decreased INR possible with chlorpromazine or haloperidol

General Carbamazepine

Lamotrigine

All FGAs may lower seizure threshold. At usual dosage ranges, seizure rates are less than 1%. Risk greater with low-potency FGAs and is dose related

Decreased antipsychotic plasma levels via potent induction of CYP3A4, CYP1A2, CYP2D6, and/or possibly UGT1A4. Note it may take

2–4 weeks to reach maximum induction and an equivalent period to return to baseline after discontinuation of an inducer

With haloperidol, decreased plasma levels of carbamazepine (40%). Con icting reports on haloperidol levels likely a result of a dose-dependent interaction (i.e., the interaction is more signi cant with increasing carbamazepine doses). Carbamazepine 100 mg daily reduced haloperidol levels by 15% while carbamazepine 600 mg daily reduced haloperidol levels by 75%. Adjust dose as needed

Likely to decrease levels of chlorpromazine, uphenazine, upenthixol, thiothixene, and zuclopenthixol

With loxapine, increased plasma levels of carbamazepine epoxide metabolite

Chlorpromazine may inhibit metabolism of lamotrigine, resulting in increased lamotrigine levels. Clinical signi cance unknown

Phenobarbital, phenytoin

Valproate (divalproex, valproic acid)

Decreased plasma level of antipsychotic due to potent induction of metabolism; for phenytoin via CYP2C9 and CYP3A4; for phenobarbital primarily via CYP1A2, CYP2C9, and CYP3A4

With phenytoin, reduced levels of chlorpromazine, haloperidol, and thioridazine reported. With phenobarbital, reduced levels of chlorpromazine (by 25%) and haloperidol reported. Limited data available; interactions with other FGAs probable. Adjust antipsychotic dose as needed

Loxapine decreased phenytoin levels in one case report

Chlorpromazine inhibits the metabolism of valproate, resulting in increased valproate levels. Clinical signi cance unknown

General

Citalopram, escitalopram, uoxetine, uvoxamine, paroxetine, sertraline

DO NOT COMBINE with pimozide or thioridazine and CAUTION with all other FGAs applies to the majority of antidepressants, due to possible additive prolongation of QT interval and associated life-threatening cardiac arrhythmias. Factors that further increase the risk include anorexia, bradycardia, hypokalemia, and hypomagnesemia. Also see Cardiovascular Effects p. 119 and Antipsychotic Augmentation Strategies p. 198

Case report of QT prolongation and patient collapsing with concurrent chlorpromazine and uoxetine

Case report of galactorrhea and amenorrhea with loxapine and uvoxamine possibly via additive increase in prolactin levels

Increased EPS and akathisia

Increased plasma level of antipsychotic due to inhibition of metabolism of CYP1A2 (potent – uvoxamine), 2D6 (potent – uoxetine and paroxetine), and/or 3A4 ( uvoxamine). Adjust antipsychotic dose as needed

DO NOT COMBINE with pimozide or thioridazine; CAUTION with all other FGAs due to additive prolongation of QTc interval. A single dose of pimozide added to citalopram did not alter the kinetics of pimozide, but did cause a prolongation of QTc by ∼10 ms

Pimozide levels: With paroxetine, 151% higher AUC and 62% higher peak level. With sertraline, 40% higher AUC and peak level. Case reports of bradycardia with concurrent use of pimozide and uoxetine

Haloperidol levels: With uoxetine, 20–35% higher levels. With uvoxamine, 23–60% higher. With sertraline, 28% higher

Desvenlafaxine, duloxetine, venlafaxine

Phenothiazine levels: With uvoxamine, thioridazine levels 3-fold higher. With paroxetine, perphenazine peak levels 2- to 13-fold higher DO NOT COMBINE with pimozide or thioridazine; CAUTION with all other FGAs; due to additive prolongation of QTc interval. Increased

plasma levels of thioridazine and other phenothiazines possible due to inhibition of CYP2D6 by duloxetine

Venlafaxine increased AUC (70%) and peak plasma level (88%) of haloperidol; case report of urinary retention developing when venlafaxine was added to haloperidol

Class of Drug

Anticholinergic

Anticoagulant Anticonvulsant

Antidepressant

SSRI

SNRI

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 127 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

First-Generation Antipsychotics/FGAs (cont.)

Example

Interaction Effects

Nefazodone

Trazodone

Vortioxetine

Amitriptyline, clomipramine, maprotiline, trimipramine

Tranylcypromine, moclobemide

DO NOT COMBINE with pimozide or thioridazine; CAUTION with all other FGAs; due to additive prolongation of QTc interval. Increased plasma levels of pimozide possible due to inhibition of CYP3A4 by nefazodone

Increased AUC (36%) and peak plasma level (13%) of haloperidol. Clinical signi cance likely minor

Case reports of hypotension in combination with chlorpromazine or tri uoperazine, and fatal hepatic necrosis via additive hepatotoxicity of trazodone and phenothiazines

Serotonin modulators may enhance the dopamine blockade of antipsychotics and increase the risk of side effects

Additive sedation, hypotension, and anticholinergic effects

Haloperidol and phenothiazines may increase the plasma level of cyclic antidepressants (TCAs). TCAs may increase the plasma level of chlorpromazine. Clinical signi cance unknown

Additive hypotension, particularly with low-potency FGAs such as chlorpromazine

Fluconazole, itraconazole, ketoconazole, voriconazole

Increased plasma levels of antipsychotics due to inhibition of metabolism via CYP3A4 and possibly P-glycoprotein. Increased plasma level of haloperidol (by 30% with itraconazole)

Losartan, metoprolol, ramipril

β-blocker

Calcium channel blocker Clonidine

Diuretic

Additive hypotensive effect particularly with low-potency FGAs such as chlorpromazine. Antipsychotics generally cause hypotension via α1 blockade (see receptor table p. 176 and frequency of adverse effects table p. 180). Start with a lower dose of antipsychotic, titrate slowly, and monitor for orthostatic hypotension

See Class of Drug “β-blocker” p. 129

See Class of Drug “Calcium channel blocker” p. 130

Clonidine lowers blood pressure by having agonist effects on presynaptic α2-adrenergic receptors. FGAs that are potent α2-adrenergic receptor antagonists can block clonidine’s antihypertensive effects (see receptor table p. 176); additive hypotensive effects also possible See Class of Drug “Diuretic” p. 130

Levodopa, pramipexole, ropinirole

Potential for reduced antiparkinson ef ciency. Antipsychotics reduce dopamine while antiparkinson agents increase dopamine in the CNS

General

Increased risk of adverse effects (e.g., EPS, elevated prolactin levels, sedation, hypotension, anticholinergic effects), increased cost, and potential for decreased adherence with use of multiple antipsychotic agents

CAUTION – possible additive prolongation of QTc interval and associated life-threatening cardiac arrhythmias. DO NOT COMBINE with

pimozide or thioridazine. Factors that further increase the risk include anorexia, bradycardia, hypokalemia, and hypomagnesemia. Also see Cardiovascular Effects p. 119

Haloperidol + aripiprazole Haloperidol + SGAs

Phenothiazines (e.g., chlorpromazine, thioridazine) + SGAs

See TGA Drug Interactions, p. 172 See SGA Drug Interactions, p. 156

Possible additive QT prolongation (see above). DO NOT COMBINE with asenapine, iloperidone, paliperidone or ziprasidone. See SGA Drug Interactions, p. 156 for further information

Class of Drug

SARI

SMS Cyclic

Irrev. MAOI, RIMA

Antifungal

Antihypertensive

Antiparkinsonian Antipsychotic combination

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Example

Interaction Effects

Pimozide + SGAs Thioridazine + SGAs

Possible additive QT prolongation (see above). DO NOT COMBINE with asenapine, iloperidone, paliperidone or ziprasidone

Possible additive QT prolongation (see above). DO NOT COMBINE with asenapine, iloperidone, paliperidone or ziprasidone. See SGA Drug Interactions, p. 156 for further information

Pimozide, thioridazine + FGAs

DO NOT COMBINE. Possible additive QT prolongation (see above)

Delavirdine, efavirenz, etravirine, nevirapine

Atazanavir, boceprevir, darunavir, fosamprenavir, indinavir, lopinavir, nel navir, ritonavir, saquinavir, simeprevir telaprevir, tipranavir

CAUTION. Possible interactions as NNRTIs inhibit and induce CYP enzymes (e.g., delavirdine is a strong inhibitor of 2D6, nevirapine weakly inhibits 2D6. Efavirenz and etravirine induce 3A4 moderately, nevirapine weakly induces it)

Delavirdine may increase levels of perphenazine, chlorpromazine, and zuclopenthixol due to CYP2D6 inhibition

Efavirenz and etravirine may decrease levels of haloperidol and pimozide due to CYP3A4 induction

CAUTION. Complex interactions likely as various protease inhibitors potently inhibit as well as induce a variety of CYP enzymes (e.g., on CYP3A4, ritonavir is a potent inhibitor; atazanavir, boceprevir, darunavir, saquinavir, and telaprevir are strong inhibitiors; indinavir and fosamprenavir are mild to moderate inhibitors; tipranavir is an inducer. Low boosting doses of ritonavir have little effect on CYP2D6 but higher doses cause inhibition)

AVOID with pimozide and thioridazine. Increased plasma levels of pimozide/thioridazine possible due to inhibition of metabolism via CYP3A4 or CYP2D6, respectively, which increases the risk of cardiotoxicity (QT prolongation, cardiac arrest)

Increased levels of FGAs metabolized by CYP3A4 (i.e., haloperidol, loxapine, phenothiazines, upenthixol, and zuclopenthixol) possible. Higher doses of ritonavir may cause a signi cant increase even for FGAs that are weak substrates of CYP3A4 and/or are metabolized by CYP2D6 (e.g., potentially increased chlorpromazine levels with higher doses of ritonavir, but unlikely with lower boosting doses of ritonavir). With unboosted tipranavir, levels of the FGAs may be decreased. Clinical signi cance unknown. Adjust antipsychotic dose as needed

Isoniazid

Rifabutin, rifampin, rifapentine

Limited data suggests some may experience increased plasma levels of haloperidol. Adjust antipsychotic dose as needed

Decreased plasma levels of haloperidol (by 30–70%) due to induction via CYP3A4 and/or P-glycoprotein with rifampin and accompanying increase in psychiatric symptoms. Adjust antipsychotic dose as needed

Buspirone, clonazepam, diazepam, lorazepam

Synergistic effect with antipsychotics; used to calm agitated patients

Potential for additive CNS adverse effects (e.g., dizziness, sedation, confusion, respiratory depression) and hypotension

May increase extrapyramidal reactions

Con icting information with respect to effects on haloperidol levels from no change to increased levels (by 19%). Likely not clinically signi cant

Haloperidol lactate can be administered IM in the same syringe as lorazepam

Atropine, hyoscyamine, scopolamine

Additive anticholinergic effects (e.g., dry mouth, urinary retention, inhibition of sweating, blurred vision, constipation, paralytic ileus, confusion, toxic psychosis)

Pindolol Propranolol

Also see Class of Drug “Antihypertensive” p. 128

DO NOT COMBINE with thioridazine. Increased plasma level of thioridazine due to inhibition of metabolism via CYP2D6, thus increasing

the risk of cardiotoxicity (QT prolongation, cardiac arrest) and pindolol levels may be increased. Pindolol may increase plasma levels of other phenothiazines

DO NOT COMBINE with thioridazine. Increased plasma level of thioridazine (3- to 5-fold) due to inhibition of metabolism via CYP2D6, thus increasing the risk of cardiotoxicity (QT prolongation, cardiac arrest)

Increased plasma level of both chlorpromazine (5-fold) and propranolol (decreased clearance by 25–32%). Case report of delirium and seizures. With haloperidol, case report of a severe hypotensive reaction

Class of Drug

Antiretroviral

Non-nucleoside reverse transcriptase inhibitor (NNRTI)

Protease inhibitor

Antitubercular drug Anxiolytic

Azapirone, benzodiazepines

Belladonna alkaloid β-blocker

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 129 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

First-Generation Antipsychotics/FGAs (cont.)

Example

Interaction Effects

Two case reports of severe EPS following a period of heavy betel nut consumption in those who were maintained on a depot FGA ( uphenazine decanoate and upenthixol, respectively). Symptoms occurred within 2 weeks and resolved 4–7 days after stopping Betel nut. Betel nut’s potent cholinergic effects potentially counteracted procyclidine, the anticholinergic agent both patients were taking to control EPS

Diltiazem, verapamil

Also see Class of Drug “Antihypertensive” p. 128

DO NOT COMBINE with pimozide or thioridazine. Increased risk of cardiotoxicity (QT prolongation, cardiac arrest) due to possible additive calcium-channel blocking effects and increased plasma levels of pimozide due to inhibition of metabolism via CYP3A4

Coffee, tea, cola, energy drinks, guarana or mate-containing products

Increased akathisia/agitation/insomnia

Haloperidol oral liquid is incompatible with tea or coffee (see Nursing Implications, p. 125)

Drugs with anticholinergic and α1-adrenergic properties (e.g., chlorpromazine) can cause marked hypotension and increased disorientation

Alcohol, antihistamines, hypnotics, opioids

CAUTION. Increased CNS effects (e.g., sedation, fatigue, impaired cognition). Additive orthostatic hypotension Alcohol may worsen EPS

Furosemide, hydrochlorothiazide

Also see Class of Drug “Antihypertensive” p. 128 above

CAUTION with all FGAs. Diuretics can cause electrolyte disturbances resulting in additive QTc interval prolongation and risk of associated life-threatening cardiac arrhythmias. Monitor for dehydration, hypokalemia, and hypomagnesemia. Also see Cardiovascular Effects, p. 119

CAUTION. Case reports of disul ram-induced psychosis possibly due to blockade of dopamine β-hydroxylase, however, no increased psychotic features seen in small studies of participants with psychotic disorders

Case report of decreased plasma level of perphenazine, increased level of its metabolite, and clinical decline; potentially due to inhibition of CYP2E1

AVOID with pimozide. Increased plasma level of pimozide possible due to inhibition of metabolism via CYP3A4, which increases the risk cardiotoxicity (QT prolongation, cardiac arrest)

Haloperidol levels not affected by consumption of grapefruit juice 600 mL/day for 7 days

Cimetidine

Both elevated and decreased chlorpromazine plasma levels have been reported. Chlorpromazine absorption may be decreased at higher doses of cimetidine, possibly due to increased gastric pH. Chlorpromazine metabolism may be decreased by inhibition of CYP2D6. Case reports of excessive sedation with the addition of cimetidine to chlorpromazine. May interact with other phenothiazines

Oral contraceptive

Estrogen potentiates hyperprolactinemic effect of antipsychotics

Case report of increased plasma level of chlorpromazine (6-fold) and development of severe tremor and dyskinesias after the addition of an oral contraceptive (ethinyl estradiol [50 micrograms]/norgestrel [0.5 mg]). Mechanism unknown; ethinyl estradiol is known to be an inhibitor of CYP1A2 and CYP2C19 and substrate of CYP3A4

Case report of atrial utter and hypoxia after administration of IM haloperidol and lorazepam for severe aggression; suggested due to kava inhibition of CYP2D6

CAUTION with all FGAs. Avoid toxic lithium plasma levels when used concurrently with pimozide or thioridazine, since both pimozide/thioridazine and toxic lithium levels are associated with QT prolongation

Although numerous studies indicate lithium and FGAs can be safely used together, there are rare cases of severe neurotoxicity (e.g., delirium, dyskinesias, seizures, encephalopathic syndrome, NMS) and EPS with concurrent lithium and haloperidol and other FGAs (i.e., loxapine, thiothixene or phenothiazines). Factors that may increase the risk of developing neurotoxicity are the presence of acute mania, pre-existing brain damage, infection, fever, dehydration, a history of EPS, and high doses of one or both agents

Decreased plasma levels of chlorpromazine (by 40%) and both increased and decreased lithium levels reported

Class of Drug

Betel (areca) nut

Calcium channel blocker Caffeine

Cannabis/marijuana CNS depressant

Diuretic Disul ram

Grapefruit juice H2 antagonist Hormone

Kava kava Lithium

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Class of Drug

Example

Interaction Effects

Opioid

Codeine Methadone

Tramadol

CAUTION. Additive CNS effects. See Class of Drug “CNS depressant” p. 130

Inhibition of conversion of codeine to its active metabolite, morphine, with haloperidol and phenothiazines. Monitor for ef cacy of pain control. Switch to an analgesic which doesn’t require CYP2D6 conversion if needed

DO NOT COMBINE with pimozide or thioridazine. NOT recommended with phenothiazines or zuclopenthixol.

CAUTION with all other FGAs. Possible additive prolongation of QT interval and associated life-threatening cardiac arrhythmias. Factors that further increase the risk include anorexia, bradycardia, hypokalemia, and hypomagnesemia. Also see Cardiovascular Effects p. 119 CAUTION. Tramadol lowers the seizure threshold; potential additive lowering of seizure threshold with FGAs

Prokinetic agent/Antiemetic

Metoclopramide

CAUTION. Metoclopramide is a potent central dopamine receptor antagonist that can cause EPS, hyperprolactinemia, and rarely NMS. Concurrent use with a FGA may increase the risk of these adverse effects

QT-prolonging agent

Antiarrhythmics (e.g., amiodarone, sotalol), antimalarials (e.g., chloroquine, me oquine), antiprotozoals (e.g., pentamidine), arsenic trioxide, contrast agents (e.g., gadobutrol), dolasetron, droperidol, methadone, pazopanib, ranolazine, tacrolimus

DO NOT COMBINE with pimozide or thioridazine. NOT recommended with phenothiazines or zuclopenthixol. CAUTION with all other FGAs. Possible additive prolongation of QT interval and associated life-threatening cardiac arrhythmias. A study suggests ziprasidone causes less QT prolongation than thioridazine but about twice that of quetiapine, risperidone, haloperidol, and olanzapine. Factors that further increase the risk include anorexia, bradycardia, hypokalemia, and hypomagnesemia. Also see Cardiovascular Effects, p. 119

Smoking (tobacco)

Smoking induces CYP1A2; polycyclic aromatic hydrocarbons in tobacco smoke are believed to be responsible for this induction, not nicotine Decreased plasma levels of chlorpromazine (by 24%), uphenazine (by 51%), and thioridazine (by 46%) and increased clearance of haloperidol (by 44–61%), perphenazine (by 33%), and thiothixene (by 36%) due to the induction of CYP1A2. Similar interaction with other phenothiazines possible. Case report of marked worsening of adverse effects and increased chlorpromazine plasma levels after abrupt smoking cessation. Discuss with patient the effects of and assess on a regular basis any changes in smoking behavior

Stimulant

Amphetamine, methylphenidate

Antipsychotic agents may impair the stimulatory effect of amphetamines

Case reports of worsening of tardive movement disorder and prolongation or exacerbation of withdrawal dyskinesia following

antipsychotic discontinuation Concurrent use not recommended

Sympathomimetic

Cocaine

Epinephrine/adrenaline, dopamine

Increased risk of EPS (especially dystonia) with concurrent use, possibly via dopamine depletion from chronic use of cocaine AVOID using for the treatment of FGA-induced hypotension. May result in paradoxical fall in blood pressure as antipsychotics block

peripheral α1-adrenergic receptors, thus inhibiting α1-vasoconstricting effects of epinephrine and leaving β-vasodilator effects relatively unopposed

Norepinephrine and phenylephrine are safe substitutes for severe hypotension unresponsive to uids

Zileuton

AVOID with pimozide. Zileuton is an inhibitor of CYP3A4 and may increase pimozide levels, increasing the risk of QTc interval prolongation and associated life-threatening cardiac arrhythmias. Factors which further increase the risk include anorexia, bradycardia, hypokalemia, and hypomagnesemia. Also see Cardiovascular Effects p. 119

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 131 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Second-Generation Antipsychotics/SGAs

Product Availability∗

Generic Name

Asenapine Clozapine

Iloperidone(B) Lurasidone Olanzapine

Paliperidone

Quetiapine Risperidone

Ziprasidone

∗ Refer to Health Canada’s Drug Product Database or the FDA’s Drugs@FDA for the most current availability information. (A) Generic preparations may be available,

(B) Not marketed in Canada,

Chemical Class

Trade Name(A)

Dosage Forms and Strengths

Dibenzo-oxepino pyrrole

Saphris

Sublingual tablets: 5mg, 10mg

Dibenzodiazepine

Clozaril FazaClo ODT(B) Versacolz(B)

Tablets: 12.5 mg(B), 25 mg, 50 mg, 100 mg, 200 mg(B)

Oral disintegrating tablets(B): 12.5 mg, 25 mg, 100 mg, 150 mg, 200 mg Oral suspension: 50 mg/mL

Benzisoxazole

Fanapt

Tablets:1mg,2mg,4mg,6mg,8mg,10mg,12mg

Benzisothiazol

Latuda

Tablets: 20 mg, 40 mg, 60 mg, 80 mg, 120 mg

Thienobenzodiazepine

Zyprexa

Zyprexa Zydis

Zyprexa IntraMuscular Zyprexa Relprevv(B) Symbyax(B)

Tablets: 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg

Oral disintegrating tablets: 5 mg, 10 mg, 15 mg, 20 mg

Short-acting injection (olanzapine tartrate): 10 mg/vial

Long-acting injection (olanzapine pamoate)(B) : 210 mg/vial, 300 mg/vial, 405 mg/vial

Capsules ( uoxetine/olanzapine)(B): 25 mg/3 mg, 25 mg/6 mg, 25 mg/12 mg, 50 mg/6 mg, 50 mg/12 mg

Benzisoxazole

Invega

Invega Sustenna

Invega Trinza

Extended-release tablets: 1.5 mg(B), 3 mg, 6 mg, 9 mg

Long-acting 1-monthly IM (paliperidone palmitate) (PP1M): US labeling indicates the amount of paliperidone palmitate

– 39 mg/0.25 mL, 78 mg/0.5 mL, 117 mg/0.75 mL, 156 mg/mL, 234 mg/1.5 mL; Canadian labeling indicates only the amount of paliperidone (not the palmitate base) – 50 mg/0.5 mL, 75 mg/0.75 mL, 100 mg/mL,150 mg/1.5 mL Long-acting 3-monthly IM (paliperidone palmitate) (PP3M): US labeling indicates the amount of paliperidone palmitate

– 273 mg/0.875 mL, 410 mg/1.315 mL, 546 mg/1.75 mL, 819 mg/2.625mL; Canadian labeling indicates only the amount of paliperidone (not the palmitate base) – 175 mg/0.875 mL, 263 mg/1.315 mL, 350 mg/1.75 mL, 525 mg/2.625 mL

Dibenzothiazepine

Seroquel Seroquel XR

Tablets: 25 mg, 50 mg(B), 100 mg, 150 mg, 200 mg, 300 mg, 400 mg(B) Extended-release tablets: 50 mg, 150 mg, 200 mg, 300 mg, 400 mg

Benzisoxazole

Risperdal

Risperdal M-tab Risperdal Consta

Tablets:0.25mg,0.5mg,1mg,2mg,3mg,4mg

Oral solution: 1 mg/mL

Oral disintegrating tablets: 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg

Long-acting injection: 12.5 mg/vial, 25 mg/vial, 37.5 mg/vial, 50 mg/vial

Benzothiazolylpiperazine

Geodon(B), Zeldox(C)

Capsules (ziprasidone HCl): 20 mg, 40 mg, 60 mg, 80 mg Short-acting injection (ziprasidone mesylate)(B) : 20 mg/mL

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Indicationsa ‡

( approved)

Schizophrenia & Psychotic Disorders

Schizophrenia-related psychotic disorders Schizoaffective disorder

Other psychotic disorders

Manic episodes

Mixed episodes Depressive episodes Maintenance treatment Other bipolar

Schizophrenia

Treatment (asenapine, lurasidone, olanzapine, paliperidone, paliperidone long-acting 1-monthly (PP1M) injection, quetiapine, quetiapine XR, risperidone, risperidone long-acting injection, ziprasidone – Canada and USA; paliperidone long-acting 3-monthly (PP3M) injection after stabilized on PP1M injection – Canada and USA; iloperidone, olanzapine long-acting injection – USA)

Acute agitation (olanzapine short-acting IM – Canada and USA; ziprasidone short-acting IM – USA)

Treatment resistant (clozapine – Canada and USA)

Reduction of recurrent suicidal behavior in those at chronic risk (clozapine – USA)

Treatment (paliperidone, olanzapine, risperidone long-acting injection, ziprasidone – Canada) Acute agitation (olanzapine short-acting IM – Canada)

Monotherapy treatment (paliperidone – USA; PP1M injection – Canada and USA)

Adjunctive therapy to mood stabilizers and/or antidepressants (paliperidone, PP1M injection – USA) Risk reduction of recurrent suicidal behavior in those at chronic risk (clozapine – USA)

• Psychosis/hallucinations associated with Parkinson’s disease treatment (most evidence for clozapine)

• Drug-induced(e.g.,amphetamines)psychosistreatment

• Monotherapyandco-therapywithanantidepressantforpsychoticsymptomsassociatedwithPTSD(mostevidenceforrisperidone) • Delusionalinfestation/parasitosistreatment(anecdotalreports–olanzapine,risperidone)

• Postpartumpsychosis

Acute monotherapy treatment (asenapine, olanzapine, quetiapine, quetiapine XR, risperidone, ziprasidone – Canada and USA)

Acute adjunctive therapy (e.g., with lithium or divalproex/valproate) (asenapine, olanzapine – Canada and USA; quetiapine, quetiapine XR, risperi- done – USA)

Acute agitation (olanzapine short-acting IM – Canada and USA)

Acute monotherapy treatment (asenapine, olanzapine, ziprasidone – Canada and USA; quetiapine, risperidone – USA

Acute adjunctive therapy (e.g., with lithium or divalproex/valproate) (asenapine, olanzapine – Canada and USA; quetiapine XR, risperidone – USA)

Acute monotherapy treatment (lurasidone, quetiapine, quetiapine XR – Canada and USA; uoxetine/olanzapine combination – USA) Acute adjunctive therapy (e.g., with lithium or divalproex/valproate) (lurasidone – Canada and USA)

Monotherapy treatment (olanzapine – Canada, risperidone long-acting injection – Canada and USA)

Adjunctive therapy to lithium or divalproex/valproate (quetiapine, quetiapine XR, risperidone long-acting injection, ziprasidone – USA)

• Refractory and rapid-cycling bipolar disorder • Treatmentofdelirium

In severe dementia, for the short-term symptomatic management of inappropriate behavior due to aggression and/or psychosis. The risks and

bene ts in this population should be considered (risperidone – Canada; other agents not approved but some evidence for use)

• Management of Lewy-body dementia: Psychosis (olanzapine: Small RCT; quetiapine: Case series); inappropriate sexual behavior; reducing visual

hallucinations refractory to donezepil without worsening motor e ects (quetiapine: Case reports)

Bipolar Disorder

Delirium

Dementia

a Adult population unless otherwise stated ‡ Indications listed here do not necessarily apply to all SGAs or all countries. Please refer to a country’s regulatory database (e.g., US Food and Drug Administration, Health Canada Drug Product Database) for the most current availability information and indications

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 133 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Depression

Movement Disorders

Other

General Comments

Second-Generation Antipsychotics/SGAs (cont.)

Treatment-resistant major depressive disorder (quetiapine XR – Canada; uoxetine/olanzapine combination – USA)

Adjunctive therapy to antidepressants (quetiapine XR – USA)

• Adjuncttherapyformajordepressivedisorder(olanzapine,risperidone,ziprasidone)

• Monotherapyformajordepressivedisorder(olanzapine)

• Monotherapyforcombineddepressionandanxiety(caseseries:Low-dosequetiapine,low-doserisperidone)

• Levodopa-induceddyskinesias(clozapine)

• Tardivedyskinesia;improvedsymptoms(clozapine,olanzapine,quetiapine,risperidone)

• Movementdisorders;decreasedmotorsymptomsindisorderssuchastremor,dyskinesiaandbradykinesiaofParkinson’sdisease,essentialtremor,

akinetic disorders, Huntington’s chorea, blepharospasm, and Meige syndrome

• Addictivebehaviors(e.g.,smoking,alcoholism,drugabuse)indualdiagnosisindividuals(clozapine,olanzapine,quetiapine,risperidone)

• Anorexianervosa(olanzapine,quetiapine,risperidone;alldatacomesfrompoor-qualityclinicaltrials)

• Generalizedanxietydisorder(quetiapine–limitedevidence)

• Borderlinepersonalitydisorder(olanzapine,quetiapine,risperidone;earlydata)

• Insomniarefractorytootherhypnotics/sedatives(quetiapine,olanzapine;limiteddata)

• Deliriuminhospitalizedpatients(limiteddatawitholanzapine,quetiapine,andrisperidone)

• Nausearelatedtoadvancedcancerandassociatedpain(olanzapine,risperidone;earlydata)

• Obsessive-compulsive disorder (OCD): Augmentation in treatment-resistant OCD (olanzapine, quetiapine, paliperidone: Case report, risperidone,

ziprasidone); occasional reports of worsening of OCD symptoms, usually in individuals with primary psychotic disorders

• Pervasivedevelopmentaldisorders(clozapine,olanzapine,quetiapine,risperidone,ziprasidone)

• Posttraumatic stress disorder: Treatment-resistant PTSD; some improvement in ashbacks, hyperarousal, and intrusive symptoms (olanzapine,

risperidone)

• Ticdisorders,Tourette’ssyndrome,andtrichotillomania(olanzapine,quetiapine,risperidone,ziprasidone)

• Clozapinehasconsistentlydemonstratedsuperiorityoverotherantipsychoticagentsandisthedrugofchoicefortreatment-resistantschizophrenia

• Versusthehigh-potencyFGAhaloperidol,SGAsaregenerallyassociatedwithalowerincidenceofEPSandtardivedyskinesia.OftheSGAs,risperi-

done appears to have the highest frequency of EPS

• Unwanted metabolic e ects of SGAs may include weight gain, dyslipidemias, glucose intolerance, and diabetes. The risk appears greatest with

olanzapine and clozapine and lowest with ziprasidone, lurasidone, and asenapine. Individuals may also meet the criteria for metabolic syndrome

• Seep.110andthechartslistinge ectsonneurotransmitters/receptors(p.176andp.177)

• SGAs (and the TGA, aripiprazole) are frequently referred to as “atypical” agents because of a lower incidence of EPS vs. FGAs. Although several

mechanisms have been postulated to account for these di erences, none are without confounding factors:

– Unlike FGAs, most SGAs have greater a nity for 5-HT2A vs. D2 receptors. (Note: Amisulpride, not currently available in Canada or the USA,

does not share this feature). Antagonism of 5-HT2A receptors in dopaminergic pathways outside the limbic system is believed to enhance dopaminergic transmission, thereby reducing EPS and hyperprolactinemia and potentially improving (or not exacerbating) negative, cognitive, and mood symptoms

– Regionally selective binding to the D2 receptor in mesolimbic/cortical areas has also been proposed to account for the atypical features of SGAs

– Variation in receptor speci city – e.g., the relative lower a nity of SGAs for the D2 receptor appears to be determined at least in part by their faster rate of dissociation (i.e., unbinding) from the D2 receptor (speed is determined by the fat solubility of the antipsychotic). Rapid dissociation from the D2 receptor (aka “Fast-o D2 theory”), allowing the receptor to periodically accommodate endogenous dopamine, has also been postulated as an explanation for why “atypical” agents may be less likely to cause EPS. However, some SGAs (e.g., asenapine, olanzapine,

risperidone, ziprasidone) appear to dissociate more slowly from the D2 receptor

Pharmacology

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Dosing

• For dosing of individual oral and short-acting agents for schizophrenia and psychosis, see table pp. 185–188. For long-acting agents, see table pp. 192–192

• Foradministrationdetails,pleaseseetheimplicationsfornursingsectionpp.149–149

• Ingeneral,lowerdosesarerecommendedintheelderly,children,andpatientswithcompromisedliverorrenalfunction

• Lowerdosesshowntobee ectiveasaugmentationtherapyofacutemania

• Initialdosesshouldbelower,andtitrationslowerinpatientspronetohypotensionorwithmentalretardation

• Dose titration recommended to minimize orthostatic hypotension: Clozapine (also minimizes sedation, and seizures); iloperidone, quetiapine,

risperidone

• Prescribing restrictions apply for clozapine – dependent on results of WBC and granulocyte/neutrophil counts (see p. 146 for details): Weekly for

26 weeks, then every 2nd week for 26 weeks, monthly thereafter

• Bipolar:

– Acutemanicepisodes(monotherapy):Asenapine–10mgtwicedaily;olanzapineoral–10–15mgoncedaily;quetiapine–startwith50mgtwice daily, increase by 100–200 mg/day as needed to a target range of 600–800 mg/day; quetiapine XR – start with 300 mg once daily, increase to a target range of 400–800 mg/day as needed; risperidone oral – start with 2–3 mg once daily, increase or decrease by 1 mg/day as needed, to a maximum of 6 mg/day; ziprasidone – day 1 = 40 mg twice daily with a meal, day 2 = 60–80 mg twice daily

– Acutemanicepisodes(adjunctivetherapy):Asenapine–5mgtwicedaily;olanzapineoral–10mgoncedaily;quetiapineXR–startwith300mg once daily, increase to a target range of 400–800 mg/day as needed; risperidone oral – start with 2–3 mg once daily, increase or decrease by 1 mg/day as needed, to a maximum of 6 mg/day

– Depressiveepisodes:Olanzapineoralincombinationwith uoxetine–startwith5mg/day,titrateupto12.5mg/dayifneeded;quetiapine–start with 50 mg once daily at bedtime, increase by 50–100 mg/day as needed to a target dose of 300 mg/day; quetiapine XR – start with 50 mg once daily, increase by 50–100 mg to a target dose of 300 mg/day by day 4

– Maintenance: Asenapine – 5–10 mg twice daily; olanzapine oral – 5–20 mg/day; quetiapine – 200–400 mg twice daily; quetiapine XR – 400– 800 mg/day; risperidone Consta – 25 mg IM every 2 weeks, if needed increase no sooner than in 4 weeks to a maximum of 50 mg IM every 2 weeks as monotherapy or adjunctive therapy; ziprasidone – 40–80 mg twice daily with food as adjunctive therapy

• Depression: Olanzapine oral in combination with uoxetine – start with 5 mg/day, titrate up to 20 mg/day if needed; quetiapine XR – start with 50 mg once daily at bedtime, increase by 50 mg/day as needed to a target dose of 150 mg/day

• Dementia (behavioral disturbances in severe dementia): Risperidone oral – start with 0.25 mg daily, increase by 0.25 mg, if needed, no sooner than every 7 days to an optimal dose of 0.5 mg twice daily or a maximum dose of 1 mg twice daily

• Mild impairment (i.e., CrCl 50–79 mL/min): Clozapine (starting dose should be 12.5 mg once daily); paliperidone oral (starting dose = 3 mg once daily, maximum dose = 6 mg once daily); paliperidone palmitate 1-monthly IM (Canadian product – day 1 = 100 mg IM, day 8 = 75 mg IM, fol- lowed by 50 mg IM q monthly; US product – day 1 = 156 mg IM, day 8 = 117 mg IM, followed by 78 mg IM q monthly); paliperidone palmitate 3-monthly IM (adjust dose and stabilize patient using paliperidone 1-monthly injectable, then transition to an equivalent long-acting 3-monthly dose); risperidone Consta (caution, start with 12.5–25 mg IM q 2 weeks)

• Moderate to severe impairment (i.e., CrCl 10–49mL/min): Lurasidone (starting dose = 20mg/day, titrate to a maximum dose of 80mg/day); paliperidone oral (starting dose = 1.5mg once daily, maximum dose = 3mg once daily); paliperidone palmitate 1- and 3- monthly IM not recommended; risperidone oral (if CrCl less than 30 mL/min, starting and consecutive doses should be halved with slow titration and BID dosing to a maximum of 1.5 mg BID)

• Severeimpairment:Clozapinecontraindicated

• No dose adjustment required: Asenapine, iloperidone, olanzapine (however, suggested to start with a lower dose and use a slower titration),

quetiapine (however, information with the XR form is limited), ziprasidone (however, ziprasidone short-acting IM contains cyclodextrin, which is renally cleared; caution advised)

• Contraindicated:Clozapine(inactiveliverdiseaseassociatedwithnausea,anorexiaorjaundice,progressiveliverdiseaseorhepaticfailure)

• Not recommended: Asenapine (in severe impairment – Child-Pugh Classi cation C); iloperidone (primarily hepatic metabolism; not studied in

hepatic impairment)

• Caution: Clozapine (can be given to those with pre-existing, stable liver disorders, however, regular monitoring for signs and symptoms of liver

dysfunction required); quetiapine (moderate to severe impairment)

Renal Impairment

Hepatic Impairment

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 135 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Second-Generation Antipsychotics/SGAs (cont.)

• Reducedose:Lurasidone(startingdose=20mg/day,maximumdoseinmoderateimpairment[ChildPughScore=7–9]is80mg/dayandinsevere impairment [Child Pugh Score = 10–15] is 40 mg/day); quetiapine (in mild impairment, start with 25 mg/day, increase by 25–50 mg/day as needed); quetiapine XR (in mild impairment, start with 50 mg/day, increase by 50 mg/day as needed) risperidone oral (starting and consecutive dosing should be halved; dose titration slower and use BID dosing); risperidone Consta (caution, start with 12.5 mg or 25 mg IM q 2 weeks); ziprasidone (in Child-Pugh Class A and B, start with a lower dose and use a slower titration)

• Nodoseadjustmentrequiredinmildtomoderateimpairment(i.e.,Child-PughClassi cationAandB):Asenapine,olanzapine(however,suggested to start with a lower dose and use a slower titration), paliperidone oral, paliperidone palmitate IM

• Seetablespp.185–188andp.195forkineticsofindividualagents

• Hepaticprimaryrouteofmetabolism(i.e.,≥50%):Asenapine,clozapine,iloperidone,lurasidone,olanzapine,quetiapine,risperidone,ziprasidone

• Hepatic impairment: Asenapine’s exposure ∼7 times higher in severe impairment; quetiapine’s AUC and Cmax increased by 40%, clearance reduced

by 25%, and half-life increased to prolonged by 45% in mild impairment; lurasidone’s AUC increased 1.5, 1.7, and 3-fold in mild, moderate, and severe impairment, respectively, with Cmax 1.3-fold higher in all levels of impairment; risperidone’s free fraction in the plasma increased by ∼35%; ziprasidone’s AUC increased by 19% and 34%, respectively, in mild to moderate impairment – half-life prolonged by ∼2.3 h

• Renalprimaryrouteofexcretion(i.e.,≥50%)[11]:Asenapine,clozapine,iloperidone,olanzapine,paliperidone,quetiapine,risperidone

• Renal impairment: Lurasidone’s Cmax increased by 40%, 92%, and 54%, and AUC increased by 53%, 91%, and 2-fold in mild, moderate, and severe impairment, respectively; paliperidone’s clearance 32%, 64%, and 71% lower and half-life increased to 24 h, 40 h, and 51 h in mild, moderate, and severe impairment, respectively; risperidone’s and metabolite’s Cmax and AUC increased by ∼40% and 160%, respectively – half-life prolonged and

clearance reduced by 60%

• Once-dailydosingisappropriateformostdrugsbecauseoflongeliminationhalf-life;recommendedthatdosesofclozapineabove200–300mgbe divided due to seizure risk; manufacturer recommends quetiapine (immediate release) and ziprasidone be given twice daily (due to short half-life)

• Lurasidone’s Cmax and AUC increased 3- and 2-fold, respectively, when given with food. These increases were independent of meal size (i.e., 350– 1000 calories) and meal fat content

• QuetiapineXRdosedoncedailyatsteadystatehascomparablebioavailability,Cmax,andAUCtoanequivalenttotaldailydoseofquetiapineregular release tablets administered bid

• Quetiapine XR can be taken with or without food. When given with a high-fat meal (∼800–1000 calories), it had increases in Cmax (44–52%) and AUC (20–22%). In comparison, a light meal (∼300 calories) had no e ect. Suggest taking consistently with respect to food

• The following agents can be taken with or without meals: Clozapine, iloperidone, olanzapine, paliperidone, risperidone (tablets, M-tabs, and solution)

• Ziprasidone’s bioavailability increased 2-fold with food. The calorie count, not the fat content, of food in uences ziprasidone’s bioavailability. Optimal bioavailability when given with a meal of at least 500 calories

• Ziprasidone suspension yields a lower Cmax (∼10–17%) and AUC (4–13%) than ziprasidone capsules. Not clinically signi cant

• Asenapine sublingual tablets’ absolute bioavailability is 35%, however, this is greatly reduced when swallowed (less than 2% with an oral tablet formulation) due to extensive rst-pass metabolism

• Asenapine, when administered with water or food, results in reduced drug exposure. Reduced exposure following water administration at 2 min (19% decrease) and 5 min (10% decrease); food consumption immediately prior to or following asenapine decreases exposure by 20% and 4 h after asenapine decreases exposure by ∼10%

• Supralingualpreparations(orallydisintegratingtablets)ofolanzapine(Zydis)andrisperidone(M-Tab)dissolveinsalivawithin15sec(canbeswal- lowed with or without liquid) – bioequivalent to oral tablet

• Olanzapine short-acting IM Cmax occurs in 15–45 min (compared to 5–8 h with oral form) and is 4–5 times higher than for the same oral dose. Half-life for IM and oral forms is similar

• Ziprasidoneshort-actingIMpeakplasmalevelreachedwithin60minandisdoserelated

Pharmacokinetics

Oral

Disintegrating and Sublingual Tablets

Short-acting IM

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Long-acting IM

Adverse Effects

• Seetablep.195

• Long-actingantipsychoticsprovideimprovedbioavailabilityandmoreconsistentbloodlevelswithoutthepeaksandtroughsobservedwithshort-

acting oral therapy

• Treatment with olanzapine pamoate IM for ∼3 months may be required to re-establish steady-state levels when switching from oral olanzapine.

Olanzapine plasma concentrations during the rst injection interval may be lower than those maintained by a corresponding oral dose. Steady- state olanzapine plasma concentrations for doses of 150–405 mg q 2–4 weeks are within the range of steady-state concentrations achieved with oral doses of 5–20 mg olanzapine once daily

• Following a single IM dose of paliperidone palmitate 1-monthly IM, plasma concentrations gradually rise to reach maximum at a median Tmax of 13 days. Release of the drug starts as early as day 1 and lasts for as long as 126 days. The median apparent half-life after a single dose increased over the dose range of 39–234 mg of paliperidone palmitate 1-monthly IM (i.e., 25–150 mg of paliperidone) to 25–49 days

• Paliperidone palmitate 1-monthly IM’s Cmax is 28% higher where administered into the deltoid vs. gluteal muscle (deltoid o ers faster absorption as it has better blood perfusion). Two initial deltoid injections on day 1 and day 8 help attain therapeutic concentrations rapidly without the need for oral supplementation

• Following a single IM dose of paliperidone palmitate 3-monthly IM, plasma concentrations gradually rise to reach a maximum at a median Tmax of 30–33 days. Release of the drug starts as early as day 1 and lasts for as long as 18 months. The median apparent half-life after a single dose increased over the dose range of 273–819mg (175–525mg of paliperidone), ranging from 84–95 days following deltoid injections and 118– 139 days following gluteal injections

• Paliperidone palmitate 3-monthly IM’s Cmax is 11–12% higher where administered into the deltoid vs. gluteal muscle (deltoid o ers faster absorp- tion as it has better blood perfusion)

• Immediatelyafterinjectionoftherisperidonelong-actingformulation,anegligibleamountofrisperidoneisreleased(lessthan1%,mostlyfromthe surface of the microspheres). Over several weeks, the microspheres are gradually hydrolyzed and release a steady amount of risperidone, producing therapeutic levels within 3–4 weeks for most patients. Oral antipsychotic supplementation should be given during the rst 3 weeks to maintain therapeutic levels until risperidone long-acting injection reaches therapeutic plasma concentration. When administered q 2 weeks, steady-state plasma concentrations are reached after the 4th injection and maintained for 4–6 weeks after the last injection. Complete elimination occurs approximately 7–8 weeks after the last injection

• Seechartonp.181forincidenceofadversee ects

• WhilearelativelowerincidenceofEPSmaymakethemmoretolerabletopatients,metabolice ectsmaybeacontributingfactortothesigni cant

degree of premature cardiovascular mortality noted among individuals with schizophrenia

• Someadversee ectsmaybepreventablebyemployingsimplestrategies(e.g.,slowupwardstitration,dosingschedulemanipulation–e.g.,dosing

a sedating drug at bedtime or dividing up the daily dose to minimize adverse e ects related to higher peak levels)

• Certainadversee ectsmaybemorecommonand/orproblematicinfemales(e.g.,weightgain,metabolicsyndrome,hyperprolactinemia)

• Activation, insomnia, disturbed sleep, nightmares, vivid dreams – activation reported with lower doses of ziprasidone, may subside with dosage increase. Although complaints of sedation are more common with most SGAs, insomnia has been reported with many agents including asenapine, clozapine (may be more common following withdrawal), olanzapine, paliperidone, risperidone, and ziprasidone. Disturbed sleep, nightmares, or vivid dreams occasionally reported for some of these agents (clozapine, olanzapine, quetiapine, risperidone)

• Confusion, disturbed concentration, disorientation (more common with high doses or in the elderly); toxic delirium reported with clozapine. Concomitant anticholinergic agents may exacerbate. Post-injection delirium sedation syndrome (PDSS) with olanzapine pamoate injection – see post-injection delirium sedation syndrome below

• EPS – acute onset: A result of antagonism at dopamine D2 receptors in the nigrostriatal tract (extrapyramidal reactions correlate with D2 binding above 80%).

– Generally speaking, extrapyramidal reactions are less common with SGAs vs. FGAs but may still occur (see p. 180 to compare incidence of EPS associated with these agents). See the relative tolerability pro les table p. 178 for a comparison of the likelihood of EPS among antipsychotics

– Dose-relatedakathisia,dystonia,andparkinsonismcommonlyreportedwithlurasidone

– Asenapinealsoassociatedwithdose-relatedakathisiaandparkinsonism

• EPS–lateonsetortardivemovementdisorders(TD)

– Includestardiveakathisia,tardivedyskinesia,andtardivedystonia(seep.207foronset,symptoms,andtherapeuticmanagementoptions) – Lateonsetmovementdisordersusuallydevelopaftermonthsoryearsoftreatment

CNS Effects

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 137 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Second-Generation Antipsychotics/SGAs (cont.)

– Maybeirreversible,sopreventioniskey–uselowestpossibledosesandassessforsignsofmovementdisordersregularly.Dyskineticsymptoms are not alleviated and may be exacerbated by antiparkinsonian medications

– AnnualriskofTDwithFGAsestimatedtobe4–5%,withacumulativeriskofupto50%.RiskofTDlowerwithSGAandTGAsantipsychotics

– ClozapinehaslowestTDriskanditsusehasbeenassociatedwithasigni cantreductioninexistingTD(especiallytardivedystonia),oftenwithin

1–4 weeks (sometimes up to 12 weeks)

• Sedation,somnolence,andfatigue–common,especiallyfollowingtreatmentinitiationanddosageincrease.Usuallytransient,butsomeindividuals

may complain of persistent e ects. See the relative tolerability pro les table p. 178 for a comparison of the likelihood of sedating e ects among

antipsychotics [Management: Evening/bedtime administration; lower dose, if feasible; minimize use of concomitant CNS depressants, if possible]

• Headache–reportedwithclozapine,olanzapine,paliperidone,quetiapine,risperidone,andasenapineatanincidenceof5–15%

• Neurolepticmalignantsyndrome(NMS)–raredisordercharacterizedbyautonomicdysfunction(e.g.,tachycardiaandhypertension),hyperthermia,

altered consciousness, and muscle rigidity with an increase in creatine kinase (CK) and myoglobinuria. Fatalities from NMS are rare if syndrome identi ed early

– Can occur with any class of antipsychotic agent, at any dose, and at any time (although usually occurs early in the course of treatment). Risk factors may include dehydration, young age, male sex, organic brain syndromes, exhaustion, agitation, and rapid or parenteral antipsychotic administration

– Potentially fatal unless recognized early and medication stopped. Supportive therapy (e.g., maintain hydration, correct electrolyte imbalances, control fever) must be instituted as soon as possible. Additional treatment with dopamine agonists such as amantadine and bromocriptine may be helpful (controversial – may reduce muscle rigidity without an e ect on overall outcome); ECT has also been used successfully to improve symptoms. Treatment with an antipsychotic agent may recommence several weeks post recovery

• Paresthesias – or “burning sensations” reported with risperidone. Oral parathesia/hypesthesia reported to occur in about 5% of patients treated with asenapine. The e ect occurs immediately following sublingual administration, is 15–25 mm in diameter, and lasts approximately 10-30 min

• Post-injection delirium sedation syndrome (PDSS) – associated with olanzapine pamoate long-acting injection. CNS symptoms may include seda- tion (ranging from mild sedation to coma), delirium, dizziness, weakness, dysarthria, and seizures. Injection must be administered in a facility with access to emergency services. Patients should be assessed every 30 min for 3 h post each injection for signs of post-injection syndrome

• Seizures – all antipsychotics may lower seizure threshold, resulting in seizures ranging from myoclonus to grand mal type. May occur if dose increased rapidly or may also be secondary to hyponatremia associated with SIADH. See the relative tolerability pro les table p. 178 for a comparison of the likelihood of seizures among antipsychotics

• Stroke – higher incidence of transient ischemic attacks and stroke reported in placebo-controlled trials of elderly patients with dementia treated with risperidone, olanzapine or aripiprazole. The relationship, if any, between antipsychotic medication and these events is uncertain

• Seetherelativetolerabilitypro lestablep.178foracomparisonofthelikelihoodofanticholinergice ectsamongantipsychotics

• Manyoftheseadversee ectsareoftendoserelatedandmayresolveovertimewithouttreatment

• Blurredvision[Management:Useadequatelightingwhenreading;pilocarpine0.5%eyedrops]

• Constipation – [Management/prevention: Increase dietary ber and uid intake, increase exercise or use a fecal softener (e.g., docusate) or bulk

laxative (e.g., psyllium, polycarbophil)] occasionally associated with olanzapine and quetiapine. Clozapine has been associated with varying degrees

of impairment of peristalsis ranging from constipation to intestinal obstruction, fecal impaction, and paralytic ileus (potentially fatal if undetected)

• Delirium – characterized by agitation, confusion, disorientation, visual hallucinations, tachycardia, etc. May result with use of high doses or com- bination anticholinergic medication. Drugs with high anticholinergic activity have also been associated with impaired cognition and selective

impairments of learning and memory[2]

• Dryeyes[Management:Arti cialtears,wettingsolutions]

• Dry mouth/mucous membranes – if severe or persistent, may predispose patient to candida infection [Management: Sugar-free gum and candy

oral lubricants (e.g., MoiStir, OraCare D), pilocarpine mouth wash – see p. 53]

• Urinaryretention–maybemoreproblematicforolderpatients,especiallymaleswithbenignprostatichypertrophy[Management:bethanechol]

Anticholinergic Effects

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

• CVD is the leading cause of death in individuals with schizophrenia, with an estimated 2/3 dying from coronary heart disease. There may be a number of contributing factors to CVD in this population, including smoking, sedentary lifestyles, poverty, poor nutrition, reduced access to health care, and a number of interrelated metabolic abnormalities including obesity, dyslipidemias, glucose intolerance, insulin resistance and diabetes, and hypertension. Please see p. 140 for more details on these endocrine and metabolic e ects and their role in CVD

• ArrhythmiasandECGchanges:

– Bradycardia reported with IM olanzapine, often accompanied by decreased resting BP or an orthostatic drop. Caution in patients who have

received other medications associated with hypotensive or bradycardic e ects

– ECGchanges(e.g.,T-waveinversion,STsegmentdepression,QTclengthening–mayincreaseriskofarrhythmias)reportedwithmanyantipsychotic

medications, the clinical signi cance of which is unclear for many. A QTc of more than 500 msec or an increase from baseline of more than 60 msec is associated with an increased risk for torsades de pointes (TdP), ventricular brillation, and sudden cardiac death. Prominent risk factors for QTc prolongation include congenital long QT syndrome, elderly age, female sex, heart failure, myocardial infarction (MI), and concomitant use of medications that prolong the QT interval or inhibit the metabolism of a drug known to prolong QT (see Drug Interactions pp. 151–160). Other risk factors may include altered nutritional status (e.g., eating disorders, alcoholism), bradycardia, cerebrovascular disease, diabetes, electrolyte imbalances (e.g., hypokalemia, hypomagnesemia, hypocalcemia), hypertension, hypothyroidism, and obesity. The presence of risk factors for QT prolongation should be controlled (e.g., electrolyte imbalances corrected, interacting drugs or use of concomitant drugs that prolong QT avoided), where possible, before initiation of treatment with a SGA. A list of drugs associated with QT prolongation and ranking with respect to risk for causing TdP can be found at https://www.crediblemeds.org

– In2006,HealthCanadaadoptednewguidelinesregardingQT/QTc,includingtherequirementtosubmitathoroughQT/QTcstudy.Thismayhave translated into more stringent warnings and precautions appearing in the product monographs for antipsychotics approved since this time:

• ZiprasidoneiscontraindicatedinpatientswithrecentMI,uncompensatedheartfailure,andaknownhistoryofQTprolongation.Theproduct monograph also includes warnings against using it in combination with drugs known to prolong QT, as well as recommendations regarding its use in patients with stable heart disease, at risk of signi cant electrolyte disturbances or who develop cardiac symptoms while taking the drug

• TherearewarningsadvisingcautioususeofantipsychoticsinpatientswithknownCVDandreportsofarrhythmiasandsuddencardiacdeath

– Seetherelativetolerabilitypro lestablep.178foracomparisonofthelikelihoodofQTcprolongationamongantipsychotics

– CautionisadvisedwhendirectlycomparingapproximateQTcprolongationtimesamongthevariousagentsasdi erencesexistwithrespectto

various methods used to calculate the QTc as well as the characteristics of the study population (e.g., concomitant medications, comorbidities,

antipsychotic dosage, etc.)

– Credible Meds Worldwide[5] categorizes risk of developing TdP as follows:

• Risk of TdP (QT prolongation and clear association of risk of TdP even when used as directed): chlorpromazine, haloperidol, pimozide, thiori- dazine

• PossibleRiskofTdP(cancauseQTprologationbutinsu cientevidenceofassociatedriskofTdPwhenusedasdirected):aripiprazole,asenap- ine, clozapine, upenthixol, iloperidone, paliperidone, perphenazine, risperidone, zuclopenthixol

• ConditionalriskofTdP(associatedwithariskofTdPbutonlyundercertainconditions–e.g.,excessivedose,hypokalemia,congenitallongQT syndrome, drug-drug interaction): amisulpride, olanzapine, quetiapine, ziprasidone

– Tachycardia reported with clozapine, iloperidone, olanzapine, quetiapine, risperidone, paliperidone, and ziprasidone. Tachycardia may occur as a compensatory mechanism to orthostatic hypotension caused by α1-adrenergic antagonism. On the other hand, persistent sinus tachycardia results from antagonism of presynaptic α2 receptors as well as antagonism of M2 receptors located on the sinoatrial node. Persistent tachycardia at rest accompanied by other signs of heart failure requires cardiology consultation

– Collapse/respiratory/cardiacarrestreportedwithclozapinealoneandincombinationwithbenzodiazepinesandotherpsychotropics

• Cardiomyopathy, pericarditis, myocardial e usion, heart failure, myocardial infarction, mitral valve insu ciency, and myocarditis reported with clozapine. Deaths have been reported. Drug should be promptly discontinued and not rechallenged. Rare reports of arrhythmias and myocardial

infarction with olanzapine

– Theincidenceofclozapine-inducedmyocarditisisestimatedtobe3%.Theriskofmyocarditisappearsgreatestinthe rst3–4weeksoftherapy.

DO NOT USE in patients with severe cardiac disease. The clinical presentation of myocarditis may be nonspeci c. Investigate patients who develop persistent tachycardia at rest and/or fatigue, u-like symptoms, hypotension, and unexplained fever. Patients with myocarditis may also have new onset symptoms of respiratory, gastrointestinal or urinary tract infections. Some will also exhibit symptoms of heart failure (e.g., chest pain, shortness of breath, edema or arrhythmia). A new monitoring protocol based on an analysis of 75 cases of clozapine-related myocarditis

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 139 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Cardiovascular Effects

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Second-Generation Antipsychotics/SGAs (cont.)

suggested fever and elevations in C-reactive protein and Troponin may be early indicators and therefore diagnostically useful; recommended regular monitoring of vital signs at least every second day and weekly monitoring of C-reactive protein and Troponin during the rst month of clozapine initiation[13]

– Clozapine-inducedcardiomyopathycanpresentmuchlaterduringclozapinetherapy,withmostcasesoccurringbetween6–9monthsoftherapy but some reported as late as 4 years. Patients with a signi cant history of heart disease or abnormal cardiac ndings on physical exam should be assessed by a physician or cardiologist before starting clozapine therapy. Clinical presentation of cardiomyopathy includes shortness of breath, orthopnea palpitations, cough, fatigue, edema, and chest pain. Patients should be assessed for the presence of these signs and symptoms regularly (e.g., four times per year). Patients with new symptoms consistent with heart failure should receive an ECG, chest x-ray and, where possible, an echocardiogram. There may be a role for routine monitoring of serum B-type brain natriuretic (BNP) or echocardiograms serially for patients on long-term clozapine therapy although this has not been evaluated with controlled studies

• Increasedriskofmortalityindementiapatients(seep.112)

• Dyslipidemia(seep.140)

• Orthostatichypotension/compensatorytachycardia/dizziness/syncope–mayoccurasaresultofα1-adrenergicantagonism.Seetherelativetoler-

ability pro les table p. 178 for a comparison of the likelihood of orthostatic e ects among antipsychotics. Individuals receiving treatment with agents associated with a higher incidence of postural hypotension should be advised to rise slowly for the rst few weeks of treatment and following dosage increases to minimise risk of falls. DO NOT USE EPINEPHRINE, as it may further lower the blood pressure (see Drug Interactions, p. 160). Risperidone, quetiapine, clozapine, and iloperidone dosing increases should be gradual to minimize hypotension as well as sinus and re ex tachycardia – may result in falls in the elderly. [Management: Rise slowly, divide the daily dose, increase uid and salt intake, use support hose; treatment with uid-retaining corticosteroid – udrocortisone]

• Thromboembolism–casereportsofpulmonaryand/orvenousthromboembolismwithasenapine,clozapine,lurasidone,olanzapine,andquetiapine

• Antidiuretichormonedysfunction:

– Disturbancesinantidiuretichormonefunction:PIP(polydipsia,intermittenthyponatremia,andpsychosissyndrome);prevalenceinschizophre-

nia estimated at 6–20% – can range from mild cognitive de cits to seizures, coma, and death; increased risk in the elderly, smokers, and alcoholics. Monitor sodium levels in chronically treated patients (especially with clozapine) to help identify patients at risk for seizure [Management: Fluid restriction, demeclocycline up to 1200 mg/day (note: Not currently available in Canada), captopril 12.5 mg/day, propranolol 30–120 mg/day; correct any electrolyte imbalances]

• Metabolic abnormalities associated with SGAs include dyslipidemia, glucose intolerance/diabetes, metabolic syndrome, and weight gain. A 2010 head-to-head meta-analysis suggested clozapine and olanzapine are associated with the highest overall metabolic liability (most elevation in weight, cholesterol, and glucose). Quetiapine and risperidone had more of an intermediate risk (except for cholesterol, for which quetiapine had a greater risk than risperidone). Ziprasidone and the TGA, aripiprazole, had the lowest risk. The SGAs lurasidone and ziprasidone appear to have the lowest overall metabolic risk potential but it is di cult to rank these agents according to their propensity to cause metabolic e ects for a number of reasons (e.g., lack of comparative RCTs assessing metabolic abnormalities as primary outcome, di erences in how metabolic e ects are de ned and measured, di erences in trial duration, etc.)

• Dyslipidemia:

– Lipid abnormalities (increases in fasting total cholesterol, LDL cholesterol, and triglycerides) have been associated with SGAs. Overall the risk

appears greatest with clozapine and olanzapine; moderate with quetiapine; lower with risperidone, paliperidone, and ziprasidone. A 2012 systematic review and meta-analysis of asenapine, iloperidone, lurasidone, and paliperidone reported that these agents did not appear to have a clinically signi cant e ect on cholesterol. No longer term trials were available for iloperidone and lurasidone

– This risk appears to be associated with, but not dependent on, weight gain. Weight gain and obesity, dietary changes, glucose intolerance, and insulin resistance have all been proposed as possible causes/contributors to lipid dysregulation

– See p. 110 for suggested monitoring guidelines. The 2012 Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dys- lipidemia and prevention of cardiovascular disease may be accessed online at http://www.onlinecjc.ca/article/S0828-282X%2812%2901510-3/ fulltext[14]

– Treatmentoptionsmayincludelifestyleanddietarymodi cations;switchingtoanotherantipsychoticassociatedwithalowerpotentialforlipid dysregulation; adding cholersterol-lowering medication (e.g., statins, brates, salmon oil, etc.)

Endocrine & Metabolic Effects

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

• Glucoseintolerance/insulinresistance/hyperglycemia/type2diabetesmellitus(DM):

– Treatment with SGAs has been associated with an increased risk for insulin resistance, hyperglycemia, and type 2 diabetes (new onset, exacer-

bation of existing DM, ketoacidosis)

– Overall the risk of developing disturbances in glucose metabolism appear greatest with clozapine and olanzapine; moderate with quetiapine;

lowest with risperidone and ziprasidone. A 2012 meta-analysis reported no clinically signi cant increases in glucose levels seen in short- (under 12 weeks) or long-term (more than 12 weeks) trials of asenapine and paliperidone; no clinically signi cant increases in glucose reported in short-term trials of iloperidone or lurasidone (long-term trials not available)

– Treatment options may include lifestyle and dietary modi cations; switching to another antipsychotic associated with a lower potential for glucose dysregulation; adding a hypoglycemic agent such as metformin

– Diabeticketoacidosisanddiabetichyperosmolarcomaareveryrareadversee ectsofantipsychotics,buthavebeenreportedwithclozapine • Hyperprolactinemia:

– Prolactinlevelmaybeelevated–increasesoccurseveralhoursafterdosingandnormalizeby12–24hwithclozapine,olanzapine,quetiapine,and ziprasidone; elevation persists during chronic administration with risperidone (incidence greater than 30% – less with long-acting IM risperidone) and paliperidone; increased plasma prolactin level related to dose of olanzapine (higher if more than 20 mg/day). Prolactin elevation has been reported to occur in individuals receiving iloperidone in short-term clinical trials. Chronic elevation of prolactin levels reported with asenapine. Dose-dependent increases in serum prolactin concentrations reported with lurasidone but no reports of associated adverse e ects

– Seetherelativetolerabilitypro lestablep.178foracomparisonofthehyperprolactinemiae ectsamongantipsychotics

nadism), pituitary tumors, and breast cancer (data con icting)

– E ects in women: Breast engorgement and lactation (may be more common in women who have previously been pregnant), amenorrhea

(with risk of infertility), menstrual irregularities, changes in libido, hirsutism (due to increased testosterone), and possibly osteoporosis (due to decreased estrogen). Recommended that women with hyperprolactinemia or amenorrhea for more than 12 months have a bone mineral density evaluation

– E ectsinmen:Gynecomastia,rarelygalactorrhea,decreasedlibido,anderectileorejaculatorydysfunction

– Monitoring/investigation: Recent guidelines suggest routine assessments for the presence of symptoms associated with prolactin elevation. In

the event of a positive nding, a prolactin level should be ordered and an attempt made to rule out nonpharmacologic causes. The fasting morning serum prolactin level is recommended as it is least variable and best correlated with disease states. In cases where an antipsychotic medication is strongly suspected as the cause, discontinuing the suspected agent (or switching to another antipsychotic agent with less poten- tial for prolactin elevation) for a short period of time (e.g., 3–4 days) if clinically feasible and follow-up monitoring to determine if prolactin levels have fallen may be a simple means to con rm suspicions and avoid MRI or CT of the hypothalamic/pituitary region

– Treatmentoptions:Assumingdiscontinuationofantipsychotictherapyisnotanoption,thepreferredtreatmentistoswitchtoanotherantipsy- chotic agent with a reduced risk of hyperprolactinemia – weighing the potential risk for relapse associated with this action. Other treatment options may include lowering the dose or adding a medication to treat the condition. Use of a dopamine agonist such as bromocriptine (1.25– 2.5 mg bid) or cabergoline (0.25–2 mg/week) may be considered but has the potential to exacerbate the underlying illness. In female patients with hyperprolactinemia induced by risperidone, use of adjunctive low-dose aripiprazole 3–6 mg/day has been shown to reduce prolactin levels

• Metabolicsyndrome:

– Metabolic syndrome is an interrelated cluster of CVD risk factors that include abdominal obesity, dyslipidemia, hypertension, and impaired

glucose tolerance. Using the International Diabetes Federation (IDF) criteria, individuals must have central obesity, which is de ned according to ethnicity (e.g., for Europoids a waist circumference of 94 cm or more in males and 80 cm or more in females is required), in addition to at least 2 of the following characteristics:

1. Triglycerides: > 1.7 mmol/L (150 mg/dl)

2. HDL cholesterol: Men < 1.03 mmol/L (40 mg/dl)/Women < 1.3 mmol/L (50 mg/dl) 3. Blood pressure: ≥ 130/> 85 mmHg (or treatment for hypertension)

4. Fasting glucose: > 5.6 mmol/L (100 mg/dl)

– Shown to be an important risk factor in the development of type 2 diabetes and CVD. Individuals with metabolic syndrome are 5 times more likely to develop type 2 diabetes and 2–3 times more likely to experience heart attack or stroke

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 141 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Second-Generation Antipsychotics/SGAs (cont.)

– Theriskofdevelopingmetabolicsyndromeappearstobegreaterwithclozapineandolanzapine,followedbyrisperidone,asenapine,iloperidone, and quetiapine. Ziprasidone and lurasidone appear to have a lower risk

• Thyroid hormone e ects – dose-dependent decrease in total T4 and free T4 concentrations reported with quetiapine; clinical signi cance unknown

• Weightgain:

– Approximately50%ofpatientsgainanaverageof20%oftheirweight(primarilyadiposetissue)

– Twometa-analysesin2013and2017whichincludedindirectanddirectcomparisonsofantipsychoticssuggestedthatclozapine,olanzapine,and

iloperidone have the highest amount of weight gain; quetiapine, risperidone, paliperdone, and asenapine intermediate amounts; and lurasidone

and ziprasidone the lowest amounts (comparable to placebo rates)

– There may be temporal di erences in the weight gain that occurs with antipsychotic therapy: A rapid initial gain in the rst three months of

treatment (phase 1); a continued steady gain over the following year (phase 2); and nally a stable weight plateau with ongoing therapy (phase

– Only olanzapine and clozapine appear to have a dose-related correlation with weight gain, the other SGAs are lacking studies looking at this

correlation

– Risk factors for antipsychotic-induced weight gain appear to be baseline lower BMI of the patient, younger age, being treatment naïve with

antipsychotics, higher parental BMI, and non-smoking status

– The mechanism by which antipsychotics may in uence weight gain is unknown (may be a result of multiple systems including 5-HT1B, 5-HT2C,

α1, and H1 blockade, prolactinemia, gonadal and adrenal steroid imbalance, and increase in circulating leptin; may also be due to sedation and

inactivity, carbohydrate craving, and excessive intake of high-calorie beverages to alleviate drug-induced thirst and dry mouth)

– Seetherelativetolerabilitypro lestablep.178foracomparisonofthelikelihoodofweightgainamongantipsychotics

– Treatmentoptions:Sinceitisoftenchallengingtoloseweight,preventativestrategiesthatfocusonhealthylifestyles(e.g.,dietandexercise)are

recommended. May not be dose dependent, so the e cacy of dosage reduction strategies is uncertain. Treatment options may include healthy lifestyle strategies; switching from an antipsychotic with higher weight gain liability to one of lower liability (may result in signi cant reductions in body weight); or use of medications to promote weight loss. Treatment with the following agents has been tried with varying degrees of success based on case reports and randomized controlled trials: Amantadine (100–300mg/day), bromocriptine (2.5mg/day), famotidine (40mg/day), topiramate (up to 200mg/day), nizatidine (300mg bid), orlistat (120mg tid), and metformin (850–1000mg bid). The bulk of evidence is for metformin and topiramate with studies typically reporting a gradual loss of weight up to 5–10 kg over 12–16 weeks

• Constipation – see Anticholinergic E ects p. 138. Clozapine and olanzapine have high a nity for M1 receptors; quetiapine has moderate a nity, the remaining SGAs are categorized as low to negligible a nity for these receptors

• Dysphagia (di culty swallowing) and aspiration have been reported with antipsychotic use. Use all agents cautiously in individuals at risk for developing aspiration pneumonia (e.g., advanced Alzheimer’s disease)

• Drymouth–seeAnticholinergicE ects,p.138

• GIobstructions–donotadministerpaliperidonetopatientswithpre-existingsevereGInarrowing(e.g.,esophagealmotilitydisorders,smallbowel

in ammatory disease, short gut syndrome, etc.) due to its OROS formulation. Clozapine associated with varying degrees of impaired intestinal peri- stalsis, including bowel obstruction, ischemia, perforation, and aspiration; 102 cases of suspected life-threatening hypomotility disorder reviewed, resulting in mortality rate of 27.5% and considerable morbidity, largely due to bowel resection – see Anticholinergic E ects p. 138

• Oralhypoesthesia–decreasedoralsensitivityreportedwithasenapine

• Parotitisreportedwithclozapine

• Re uxesophagitis(approximately11%incidencereportedwithclozapine)

• Sialorrhea (most commonly associated with clozapine), with di culty swallowing/gagging that is most profound during sleep; dose related –

may lead to aspiration pneumonia. May be due to stimulation of M4 muscarinic or α2 receptors in salivary glands. [Management: Chew sugar- less gum, cover pillow with towels, reduce dose. Preliminary evidence suggests bene t with: Amitriptyline (25–100 mg), benztropine (1–4 mg) or trihexyphenidyl (5–15 mg per day) – caution: Additive anticholinergic e ects; pirenzepine (25–100 mg), clonidine (0.05–0.4 mg once daily orally or transdermal patch 0.1–0.2 mg applied weekly) – caution: Additive hypotension; terazosin (2 mg daily), scopolamine patch (1.5 mg/2.5 cm2 patch applied every 72 h), atropine “eye” drops (1 drop sublingually 1–2 times a day), tropicamide “eye” drops (1–2 drops bilaterally sublingually once daily; case reports), ipratropium nasal (given as 2 sprays under the tongue tid)]

GI Effects

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

• Sexual e ects may result from altered dopamine (D2), serotonergic, ACh, α1 or H1 activity; hyperprolactinemia is the main cause of sexual dysfunc- tion in women

• Treatment options may include: 1) dosage reduction, 2) waiting 1–3 months to see if tolerance develops, 3) switching antipsychotics or 4) adding a medication to treat the problem. (See below for treatment suggestions regarding speci c types of dysfunction; evidence for their use based primarily on open-label studies and case reports)

• Treatmentoptionswithlowerratesofsexualdysfunctionreportedincludequetiapine,ziprasidone,andaripiprazole

• Anorgasmia [Management: Bethanechol (10mg tid or 10–25mg prn before intercourse), neostigmine (7.5–15mg prn), cyproheptadine (4–

16 mg/day), amantadine (100–300 mg/day)]

• Ejaculation dysfunction (including inhibition of ejaculation, abnormal ejaculation, retrograde ejaculation – especially risperidone) [Manage-

ment suggestions for retrograde ejaculation: Imipramine (25–50 mg at bedtime), yohimbine (5.4 mg 1–3 ô daily, 1–4 h prior to intercourse) or

cyproheptadine (4–16 mg/day)]

• Erectile dysfunction (ED), impotence. The incidence with SGAs is unclear but appears to be lower than with the FGAs (especially with agents other

than risperidone) [Management suggestions: Bethanechol (10 mg tid or 10–50 mg prn before intercourse), yohimbine (5.4 mg 1–3 ô daily, 1–4 h

prior to intercourse), sildena l (25–100 mg prn), amantadine (100–300 mg/day)]

• Libido–decreasedlibido[Management:Neostigmine(7.5–15mgprn)orcyproheptadine(4–16mgprn)30minbeforeintercourse]

• Priapism – has been reported in patients on most SGAs, including newer SGAs such as iloperidone. Antagonism of α1-adrenergic receptors is

believed to play a role. See p. 176 for information on which agents have more α1 -antagonistic e ects

• Renaldysfunction–rarereportsofinterstitialnephritisandacuterenalfailurewithclozapine

• Urinaryincontinence(over owincontinence)/enuresis(nocturnalenuresis)reportedwithclozapine(upto42%);casereportswitholanzapineand

risperidone. Appears to be more frequent with clozapine but the relative risks of the various SGAs for causing this e ect are unknown. [Management strategies: Dosage reduction; limiting uid intake in the evening, especially ca eine-containing beverages or alcohol; voiding directly before bed; and setting an alarm to wake up and void during the night. Case reports of successful treatment with a wide array of pharmacological treatments including amitriptyline 25 mg/day, aripiprazole 10–15 mg/day, or ephedrine 25–150 mg/day, oxybutynin 5–15 mg/day, pseudoephedrine 60 mg, trihexyphenidyl 5–6 mg/day or tolterodine 1–4 mg/day; verapamil 80 mg/day]

• Urinaryretention–seeAnticholinergicE ectsp.138

• Blurredvision/dryeyes:seeAnticholingericE ectsp.138

• Esotropia:Casereportofesotropia(formofstrabismus)witholanzapine

• Intraoperative oppy iris syndrome (IFIS) – a complication during eye surgery (cataract removal) characterized by a accid iris and progressive

intraoperative pupil constriction that may result in damage to the eye has been associated with the use of risperidone

• Blooddyscrasias,includingthosea ectingerythropoesis,granulopoesis,andthrombopoesis,havebeenreportedwithmostantipsychotics

• Clinically signi cant hematological abnormalities with antipsychotics are, with the exception of clozapine, rare. Accordingly, the development of any blood abnormalities in individuals on antipsychotic medication, especially other than clozapine, should undergo rigorous medical assessment

to determine the underlying cause

• Aplasticanemia–reportedwithrisperidoneandclozapine

• Anemia–reportedwithasenapine,clozapine,iloperidone,lurasidone,andziprasidone

• Eosinophilia – not typically of clinical signi cance unless severe. Transient elevations in eosinophil counts without clinical sequelae reported with

olanzapine, quetiapine, and ziprasidone. Eosinophilia reported with clozapine frequently between weeks 3 and 5 of treatment; higher incidence in

females. Neutropenia can occur concurrently. In most case reports, withdrawal of the drug resulted in normalization of the hematological pro le

• Leukopenia[de nedasWBC<4ô109/l]andneutropenia/agranulocytosis[neutropenia(de nedasANC<1.5ô109/L)maybesubclassi edas mild (ANC = 1–1.5 ô 109 /L), moderate (ANC = 0.5–1 ô 109 /L) or severe (also termed agranulocytosis – de ned as ANC < 0.5 ô 109 /L or sometimes

as ANC < 0.2 ô 109/L)]

– Transientneutropeniaoccurringonlyinthemorning(withanafternoonANCcountreturningtonormal)hasbeenreportedwithclozapine

– Recurrenceofpreviousclozapine-inducedneutropeniareportedafterolanzapinestarted

– Agranulocytosiscanoccurwithallantipsychoticsbutisgenerallyrare(incidencelessthan0.1%)exceptwithclozapine(occursinapproximately

1% of patients; 0.38% risk with monitoring). The rate of occurrence is highest in the rst 26 weeks of clozapine therapy. Fatalities typically resulting from infections due to compromised immune status have been reported. Patients treated with clozapine must consent to routine hematological monitoring (see p. 146 for guidelines). Risk factors include older age, female gender, and certain ethnic groups (i.e., Ashkenazi

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 143 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Urogenital & Sexual Effects

Ocular Effects

Hematological Effects

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Hepatic Effects

Hypersensitivity Reactions

Temperature Regulation

Discontinuation Syndrome

Second-Generation Antipsychotics/SGAs (cont.)

Jews). Do not use clozapine in patients with myeloproliferative disorders, granulocytopenia or WBC count < 3.5 ô 109 /L and/or ANC < 2 ô 109 /l. Monitor for, and advise patients to immediately report, any signs of infection or u-like symptoms (e.g., fever, sore throat, chills, malaise, etc.). Individuals on clozapine may develop transient, benign fever, especially during the rst few weeks of treatment. Fever due to underlying blood dyscrasia/infection, neuroleptic malignant syndrome or myocarditis must be ruled out. Avoid concomitant use of other medications associated with blood dyscrasias (see Drug Interactions pp. 151–160)

• Leukocytosis–41%riskoftransientleukocytosisreportedwithclozapine.Leukocytosisalsoreportedwithziprasidone

• Pancytopenia–casereportwithquetiapine,hematologicalpro lenormalizedwithin7daysofdiscontinuingdrug

• Thrombocytopenia–plateletabnormalitiesreportedinfrequently.Casereportsofthrombocytopeniawithasenapine,clozapine,olanzapine,queti-

apine, risperidone, and ziprasidone

• Thrombocytosis–casereportswithclozapine.Inmostcases,withdrawalofthemedicationresultedinnormalizationofplateletcounts

• Acuteliverfailure–2013HealthCanadaAdvisoryregarding3reportsofliverfailureinfemales(aged58–77years)associatedwithquetiapineuse. The duration of quetiapine exposure in these cases was relatively short (9 days – 6 weeks) and although not all the cases included information about dosing, those that did involved low doses (25–100 mg/day) of quetiapine. Two of the three cases had fatal oucomes

• Cholestaticjaundice(reversibleifdrugstopped).Occursinlessthan0.1%ofpatientsonantipsychoticswithin rst4weeksoftreatment.Reported with clozapine, olanzapine, and ziprasidone

• Hepatomegaly/steatohepatitis – case reports of nonalcoholic steatohepatitis (i.e., fatty liver with in ammation, necrosis, and hepatomegaly, with mild to moderate increase in ALT/SGPT and/or AST/SGOT) reported with olanzapine and risperidone; risk factors include weight gain, hyperlipidemia, type 2 diabetes mellitus, and polypharmacy – usually benign but can progress to cirrhosis. Hepatomegaly and fatty liver deposits also reported with ziprasidone

• Pancreatitis – reports of pancreatitis with risperidone, olanzapine, quetiapine, and clozapine; generally occurred within rst 6 months of therapy (possibly associated with hyperglycemia or hypertriglyceridemia); hyperamylasemia reported with risperidone

• Transaminaseelevations–elevationsinALT,ASTand/orgamma-GThavebeenreportedtypicallywithinthe rst2–6weeksoftreatment.Upto40% of clozapine patients experience alanine transaminase levels above 2 times the upper limit of normal. May be asymptomatic and transient in nature with rare/very rare reports of hepatitis/hepatic failure. Increases in levels beyond 3 times the normal upper limit usually warrant discontinuation; icteric hepatitis observed in only 0.06% of clozapine patients

• Seep.135fordosinginhepaticimpairment

• Usuallyappearwithinthe rstfewmonthsoftherapy(butmayoccurafterthedrugisdiscontinued)

• Photosensitivityandphotoallergyreactionsincludingsunburn-likeerythematouseruptionswhichmaybeaccompaniedbyblistering

• Skin reactions, rashes, and, rarely, abnormal skin pigmentation (risperidone); rash (5%) and urticaria reported with ziprasidone, potentially dose

related, improved with antihistamine/steroid administration and/or discontinuation of ziprasidone in most cases

• Rarely, asthma, laryngeal, angioneurotic or peripheral edema, and anaphylactic reactions occur. Serious allergic reactions (Type 1 hypersensitivity) have been reported in patients treated with asenapine. Patients should be informed and advised to seek emergency medical treatment if they

develop signs and symptoms of a serious reaction (swelling of face, tongue, or throat, di culty breathing, feeling lightheaded or faint, itching)

• Altered ability of body to regulate response to changes in temperature and humidity; may become hyperthermic or hypothermic; more likely in temperature extremes due to inhibition of the hypothalamic control area. Patients should be counseled to avoid becoming overheated or dehydrated, and to avoid prolonged exposure to freezing temperatures

• Transienttemperatureelevationcanoccurwithclozapineinupto55%ofpatients,usuallywithinthe rst3weeksoftreatmentandlastingseveral days; not correlated with dose; older individuals at higher risk; may be accompanied by respiratory and gastrointestinal symptoms, mild creatine kinase elevation, and an elevation in WBC

• Abruptdiscontinuationofanantipsychoticoccursprimarilyinsituationsinvolvingasudden/severeadversereactiontothedrug(e.g.,agranulocy- tosis with clozapine) or when patients become nonadherent by stopping their antipsychotic medication abruptly

• Abrupt discontinuation (or in some cases large dosage reduction) of an antipsychotic may be associated with a number of withdrawal or discon- tinuation e ects (see below). Prolonged antagonism of (dopaminergic, muscarinic, histaminic, adrenergic) receptors by the antipsychotic, resulting

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Precautions

in a compensatory up-regulation which then produces a rebound-type reaction when the antagonist is removed and the supersensitized receptors are exposed, has been proposed as a pharmacological explanation for these e ects

1. Discontinuation syndromes – typically characterized by development of a number of symptoms including nausea, vomiting, diarrhea, diaphore-

sis, cold sweats, muscles aches and pains, insomnia, anxiety, and confusion. Many are believed to be the result of cholinergic rebound. Usually appear within days of discontinuation [Management: Mild cases may only require comfort and reassurance; for more severe symptoms, consider restarting the antipsychotic, followed by slow taper if possible; or, if rebound cholinergic e ects present, consider adding an anticholinergic agent short term]

2. Psychosis – exacerbation or precipitation of psychosis including a severe, rapid onset or supersensitivity psychosis, most notable with clozapine and quetiapine. Most likely to occur within the rst 2–3 weeks of discontinuation or sooner [Management: Restart antipsychotic]

3. Movement disorders – withdrawal dyskinesias noted to appear usually around 2–4 weeks post abrupt withdrawal [Management: Restart antipsychotic and taper slowly] Rebound dystonia, parkinsonism, and akathisia also reported to occur, usually within days to the rst week post discontinuation [Management: Restart antipsychotic and taper or treat with appropriate anti-EPS medication]

• Abruptcessationofalong-actingordepotantipsychoticisoflessconcern,asplasmaconcentrationsdeclineslowly

• Clinicians should be cognizant of the potential for withdrawal e ects to occur from a discontinued agent when switching to a new antipsychotic

in order to avoid misinterpreting them as adverse e ects of the new agent and subsequently discontinuing it unnecessarily

• If planning to discontinue clozapine, a gradual dose reduction over 1–2 weeks is recommended. However, if a patient’s medical condition requires abrupt discontinuation (e.g., severe leukopenia, cardiovascular toxicity), observe for recurrence of psychotic symptoms and symptoms related to

cholinergic rebound such as headache, diaphoresis, nausea, vomiting, and diarrhea

☞ AFTER PROLONGED USE, THESE MEDICATIONS SHOULD BE WITHDRAWN GRADUALLY where possible. If switching to another antipsychotic, see

pp. 197–198 for speci c recommendations. Readers may nd the website http://switchrx.ca helpful

• UseofSGAsinelderlypatientswithdementiaisassociatedwithincreasedriskofdeath,stroke,andTIA(seeGeriaticConsiderationsp.111)

• Dysphagia and aspiration have been associated with use of antipsychotic medications. These agents should be used cautiously in patients at risk

for aspiration pneumonia (e.g., advanced Alzheimer’s disease)

• Assess patients routinely for presence of signi cant risk factors for cardiovascular disease, including a family history of premature CVD, smoking,

hypertension, dyslipidemias, diabetes, and metabolic syndrome. See pp. 110 and 146 for suggested monitoring guidelines. Control risk factors and

consider SGAs with lower metabolic liabilities where possible

• SGAs may lower the seizure threshold (especially clozapine at doses exceeding 600 mg per day); use with caution in individuals with a history of

seizures or with cormorbidities or concomitant medications that may also increase vulnerability to seizure development

• Agents with higher a nities for the antagonizing M1 receptor (e.g., clozapine, olanzapine, quetiapine) should be used very cautiously in patients

with narrow-angle glaucoma or prostatic hypertrophy or in other conditions that may be exacerbated by anticholinergic actions

• Patientsathighriskofsuicideshouldbefollowedclosely.Considerclozapine

• Evaluate clinical status and vital signs prior to IM olanzapine administration and monitor for oversedation and cardiorespiratory depression. DO

NOT ADMINISTER within one hour of an IM benzodiazepine (see Interactions p. 157)

• Rapideliminationofclozapineandquetiapinefromplasmaandbrainfollowingabruptdiscontinuationmayresultinearlyandsevererelapse

• Allergiccross-reactivity(rash)betweenchlorpromazineandclozapinereported

• Quetiapineimmediatereleasecanbeusedasastreetdrugforitssedativeandanxiolytice ects–called“quell”or“babyheroin”

• Mayoccurasaconsequenceofanacuteingestion,intentionaloraccidental,orwithchronicuse.Ingeneral,signsandsymptomsoftoxicitypresent as exaggerations of known adverse e ects within a few hours post ingestion

• Serioustoxicityprimarilyinvolvesthecardiovascularandcentralnervoussystems

• Antipsychotics with a high a nity for muscarinic receptor blockade may produce potent anticholinergic e ects such as tachycardia, urinary re-

tention, dry mouth (may see hypersalivation with clozapine), decreased/absent sweating (may cause mild temperature elevations), agitation, and

delirium

• Impairedconsciousness(rangingfromsomnolencetocoma),tachycardia,andhypotensionarecommon

• ECGmanifestationsincludeprolongationoftheQRScomplexandQTinterval

• Dystonicreactionsandotherextrapyramidaladversee ectsaswellasneurolepticmalignantsyndrome(NMS)mayalsooccur

• Convulsionsoccurlate,exceptwithclozapine;symptomsmaypersistasdrugeliminationmaybeprolongedfollowingintoxication

Toxicity

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 145 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Management

Lab Tests/Monitoring

Second-Generation Antipsychotics/SGAs (cont.)

• Anypatientexperiencingsignsorsymptomsotherthanmilddrowsinessshouldbetransportedtoanemergencydepartment.Localpoisoncontrol centers should be contacted

• Gastriclavageand/oractivatedcharcoalmaybeconsiderediflessthan1hhaselapsedsinceingestionandairwaysarenotcompromised.Syrupof ipecac should not be administered due to concerns of additive sedation and potential for aspiration pneumonia. Hemoperfusion/hemodialysis not recommended due to large volumes of distribution and high plasma protein binding pro les of antipsychotics

• No speci c antidotes; provide supportive treatment for symptomatic patients – establish/maintain airway, ensure adequate oxygenation/ ventilation. Monitor vital signs and ECG for at least 6 h and admit the patient for at least 24 h if signi cant intoxication apparent. Agents with extended-release technologies such as paliperidone may require longer supervision/monitoring

• HypotensionandcirculatorycollapsetreatedwithIV uids(0.9%NaClsolution).Intravenousvasopressorsmaybeconsideredifthereisnoresponse to uids (caution – use of epinephrine or dopamine or other sympathomimetics with β-agonist activity may worsen hypotension in the presence of antipsychotic-induced α1 blockade; see Drug Interactions pp. 151–160; norepinephrine or phenylephrine are preferred)

• Sodiumbicarbonate(1-2meq/kg)shouldbeconsideredforventriculardysrhythmiasorQRSprolongationabove0.12sec

• QT prolongation should be monitored and hypokalemia or hypomagnesemia corrected. TdP is treated with IV magnesium sulfate. Avoid co-admi-

nistration of drugs that produce additive QT prolongation (see Drug Interactions pp. 151–160)

• Seizuresmaynotrequiretreatmentifshort-lived.Multipleorrefractoryseizuresmaybetreatedwithlorazepamordiazepam

• Acutedystoniasmaybetreatedwithbenztropine(2mgIVorIM)

• NMS treatment may include oxygenation/ventilation, correction of hyperthermia with cooling blankets, ice-water bath, etc., and correction of

hypotension (see above)

• Seep.110forsuggestedmonitoringguidelines

• Clozapine:Thresholdplasmalevelsuggestedforresponsetoclozapine(intherangeof350–550ng/mLor1050–1650nmol/L)

• On initiation and with dose increases, monitor: Clozapine (for hypotension, sedation, and seizures); iloperidone, risperidone (for orthostatic

hypotension)

• Olanzapine:Thresholdplasmalevelmaybeimportantforresponsetoolanzapineinacutelyillpatientswithschizophrenia(9ng/mLor27nmol/L)

• Olanzapine injection: Recommend clinical status and vital signs be evaluated prior to and as clinically indicated post olanzapine IM (short-acting

or long-acting) administration; monitor for orthostatic hypotension, oversedation, delirium, and cardiorespiratory depression. Olanzapine IM long-

acting: Observe for at least 3 h and instruct patient not to drive or operate heavy machinery for remainder of the day

• Quetiapine:Mayresultinfalse-positivemethadoneurinedrugscreen.Consultyourlab

• Ziprasidone: Patients at risk of signi cant electrolyte disturbances should have baseline serum potassium and magnesium measurements. Low

serum potassium and magnesium should be replaced before proceeding with treatment. Patients who are started on diuretics during ziprasidone

therapy need periodic monitoring of serum potassium and magnesium

☞ Clozapinemonitoring:

– SummaryofWBCmonitoringrequirementsinCanadaandtheUSA

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Hematological Parameters

Monitoring and Treatment Implications

USA and Canada

WBC≥3500/mm3 (3.5×109/L)and/orANC≥2000/mm3 (2.0×109/L)

Continue clozapine and appropriate frequency of monitoring (weekly for 6 months, then every 2 weeks for 6 months, then q 4 weeks thereafter)

USA only

3000/mm3 ≤ WBC < 3500/mm3, 1500/mm3 ≤ ANC < 2000/mm3, and/or

Single drop or cumulative drop within 3 weeks of WBC ≥ 3000/mm3 or ANC ≥ 1500/mm3

Continue clozapine

Monitor twice weekly until WBC > 3500/mm3 and ANC > 2000/mm3 , then return to prior frequency

2000/mm3 ≤ WBC < 3000/mm3 and/or 1000/mm3 ≤ ANC < 1500/mm3

Hold clozapine

Monitor daily until WBC > 3000/mm3 and ANC > 1500/mm3 , then twice weekly until WBC > 3500/mm3 and ANC > 2000/mm3 May rechallenge at this point and monitor weekly for 1 year

WBC < 2000/mm3 and /or ANC < 1000/mm3

Discontinue treatment and do not rechallenge

Monitor until normal and for at least 4 weeks from day of discontinuation

Canada only

2.0×109/L≤WBC<3.5×109/L,or1.5×109/L≤ANC<2.0×109/l,or

Single fall or sum of falls in WBC of ≥ 3.0 × 109 /L measured in the last 4 weeks and reaching a value of<4.0×109/L,or

Single fall or sum of falls in ANC of ≥ 1.5 × 109 /L measured in the last 4 weeks and reaching a value of<2.5×109/L,or

Flu-like complaints, fever, or other symptoms suggestive of infection

Continue clozapine Monitor twice weekly

WBC<2.0×109/LorANC<1.5×109/L

Hold clozapine and con rm laboratory results within 24 h Stop clozapine if con rmed and do not rechallenge

(Modi ed from: Gardner DM, Teehan MD. Antipsychotics and their side effects. Cambridg, UK/New York: Cambridge University Press, 2010, p. 14. Reproduced by permission.)

Use in Pregnancy♢

• General:

– For each individual, consider the risks of not treating/undertreating (e.g., illness relapse, self-harm, poor adherence with prenatal care, poor

nutrition, exposure to additional medication or herbal remedies, increased alcohol, tobacco or recreational drug use, de cits in mother-infant

bonding) vs. the risks of continuing or starting an antipsychotic

– Pregnancy-relatedchanges(i.e.,increasedbodyweight,bloodvolume,andbodyfat,altereddrugmetabolismandincreaseddrugexcretion)may

require the use of higher drug doses to maintain e cacy. Postpartum dose tapering may be needed, as liver metabolism and uid volumes

return to baseline levels. Monitor for SGA adverse e ects and reduce dose as needed

– Data suggest most SGAs do not signi cantly increase the risk of teratogenic e ects in humans, however, some data suggest otherwise (e.g.,

major malformations 5.1% in SGA cohort vs. 2.5% in comparison cohort found in one study). Animal data suggest there may be at least a moderate risk with some agents but animal reproduction studies are not always predictive of human response. The greatest risk of fetal malformations is associated with use during the rst trimester

– Theremaybeincreasedweightgainandriskofgestationaldiabetes(irrespectiveoftheamountofweightgain)inpregnantwomentakingSGAs (particularly clozapine and olanzapine and possibly quetiapine) during gestation

– In2011,theUSFDAandHealthCanadaaskedmanufacturerstoupdatetheirprescribinginformationtowarncliniciansandpatientsthatthird trimester use of antipsychotics is associated with risk of EPS and withdrawal symptoms in newborns. Symptoms in the neonate may include: Feeding disorder, hypertonia, hypotonia, tremor, respiratory distress, and agitation

– If an antipsychotic will be used during pregnancy, consider patient enrollment or registration in any relevant studies or pregnancy exposure registries (e.g., in Canada: Motherisk list of current studies http://www.motherisk.org/prof/currentStudies.jsp; in the USA: FDA list of pregnancy registries http://www.fda.gov/scienceresearch/specialtopics/womenshealthresearch/ucm134848.htm)

• Asenapine:Nopublishedhumandata.Animaldatasuggestpotentialforfetalrisk(i.e.,deathanddecreasedweight)

• Clozapine: Limited human data. Animal data suggest low risk. Possible increased incidence of maternal excessive weight gain and gestational diabetes. A case report suggests the concentration of clozapine in fetus plasma can exceed (by 2-fold) that in the mother and potential adverse

♢ See p. 439 for further information on drug use in pregnancy and e ects on breast milk

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 147 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Second-Generation Antipsychotics/SGAs (cont.)

e ects have had reported (i.e., oppy infant syndrome, neonatal seizures, and rare cases of congenital malformations). Monitor WBC of newborn infants if mother on clozapine. One case report of delayed peristalsis in a newborn. One case report of delayed speech acquisition after in utero and breast milk exposure to clozapine

• Iloperidone:Nopublishedhumandata.Animaldatasuggestmoderaterisk(i.e.,deathanddecreasedweight)

• Lurasidone: No human data. Potential risk in third trimester due to antipsychotics potential to cause EPS and withdrawal symptoms in newborn.

No adverse developmental or teratogenic e ects seen in animals

• Olanzapine: Human data suggest there is low risk from in utero exposure, however, there is a potential for excessive weight gain and gestational

diabetes. A preliminary study found olanzapine use associated with infants who were large for gestational age, however, there is con icting data. Another preliminary study found ∼72% (CI 47–98%) of human maternal olanzapine levels in umbilical cord blood, however, there was considerable variability in the range (7–167%). In clinical trials, 7 pregnancies occurred, which resulted in 2 normal births, 1 neonatal death due to cardiovascular defect, 3 therapeutic abortions, and 1 spontanous abortion

• Paliperidone:Nopublishedhumandata.Animaldatasuggestlowrisk.Aspaliperidoneistheactivemetaboliteofrisperidone,alsoconsultrisperi- done information

• Quetiapine: Limited human data. Animal data suggest risk (i.e., delays in skeletal development seen in rats and rabbits using doses slightly below and above the corresponding maximum human dose). However, no pattern of issues in humans seen to date with at least 65 cases of no major malformations with quetiapine exposure. Potential for excessive weight gain and gestational diabetes. A preliminary study found ∼24% (CI 19– 30%; range 9–47%) of human maternal quetiapine levels in umbilical cord blood

• Risperidone: Limited human data. Reversible EPS (e.g., tremor, jitteriness, irritability) seen in neonates with third trimester risperidone exposure. Four retrospective reports of poorly de ned developmental syndromes reported, however, relationship to risperidone use unclear. Case report of maternal NMS with third-trimester exposure to haloperidol and risperidone. Case report of maternal tardive dyskinesia with rst trimester exposure to low-dose, short-term risperidone. A preliminary study found ∼49% (CI 14–85%) of human maternal risperidone levels in umbilical cord blood, however, there was considerable variability in the range (17–105%)

• Ziprasidone:Limitedhumandata.Animaldatasuggestrisk,includingpossibleteratogenice ectsatdosessimilartohumantherapeuticdoses.One case report of ziprasidone use throughout pregnancy (in combination with citalopram) reports no adverse e ects to mother or infant at 6-month follow-up, while another report describes malformations of the face and extremities in an infant

• For each individual, consider the bene ts of breastfeeding (e.g., clinical and psychosocial advantages for mother and infant, cost savings) vs. the risks of infant drug exposure via breast milk and possible e ects on milk production

• Antipsychotics, like most medications, pass into breast milk, however, antipsychotic amounts found are generally low. Long-term e ects on neu- rodevelopment are largely unknown

• Ifusedwhilebreastfeeding,useloweste ectivedoseandmonitorinfant’sprogress

• Asenapine:Hale’slactationriskcategory=L3(giveonlyifthepotentialbene toutweighsthepotentialrisktotheinfant).Nohumandataavailable

• Clozapine:Hale’slactationriskcategory=L3(giveonlyifthepotentialbene toutweighsthepotentialrisktotheinfant).Experienceinbreastfeed-

ing is limited to a few case reports. In one case report, clozapine concentrations in breast milk exceeded that in the mother’s plasma. Case reports of exposed infants developing agranulocytosis, and lethargy. One case report describes delay in speech developmental milestones in a child who was exposed to clozapine via breastfeeding for one year. If the mother does breastfeed, recommend monitoring for excessive sedation and regular monitoring of infant’s WBC

• Iloperidone:Hale’slactationriskcategory=L3(giveonlyifthepotentialbene toutweighsthepotentialrisktotheinfant).Nohumandataavailable

• Lurasidone:Hale’slactationriskcategory=L3(giveonlyifthepotentialbene toutweighsthepotentialrisktotheinfant).Nohumandataavailable

• Reports suggest low levels of olanzapine (0–4% of mother’s plasma level), quetiapine (0.09–6%), risperidone/paliperidone (0.84-4.7%), and

ziprasidone (1.2% – from a single case report) pass into breast milk

• Olanzapine: Hale’s lactation risk category = L2 (risk likely remote). Categorized as acceptable for breastfeeding. Experience limited to case reports

(more than 100) and a prospective observational study involving 22 mothers who took olanzapine while breastfeeding. Case reports of breastfed infants developing diarrhea, sedation, lethargy, sleep disorder, shaking, jaundice, and temporary motor development delay, however, many also had in utero exposure and/or exposure to other psychotropic medications. Rate of adverse e ects suggested to be 16%, with somnolence (4%), irritability (2%), tremor (2%), and insomnia (2%) being the most common

Breast Milk

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

• Paliperidone: Hale’s lactation risk category = L3 (give only if the potential bene t outweighs the potential risk to the infant). No case reports speci cally with paliperidone, however, risperidone data indicate that concentrations of paliperidone (9-hydroxyrisperidone) in breast milk are low

• Quetiapine: Hale’s lactation risk category = L2 (risk likely remote). Categorized as acceptable for breastfeeding. Experience limited to fewer than 20 case reports. Case reports of breastfed infants developing excessive drowsiness and mild neurodevelopmental delay (infants also exposed to

paroxetine and neither quetiapine nor paroxetine was detectable in the breast milk)

• Risperidone:Hale’slactationriskcategory=L3(giveonlyifthepotentialbene toutweighsthepotentialrisktotheinfant).Categorizedaspossible

for breastfeeding under medical supervison. Experience limited to fewer than 10 case reports. No adverse e ects reported

• Ziprasidone:Hale’slactationriskcategory=L2(risklikelyremote).However,experienceinbreastfedinfantslimitedtoasinglecasereportinwhich

no negative outcomes were seen

• RefertotheDrugsandLactationDatabase(LactMed)website(http://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm)formoreinformation

• Seepp.112–114

• Withorwithoutfood?

– Clozapine,iloperidone,olanzapine,paliperidone,andrisperidone(tablets,M-tabs,andsolution)maybetakenwithorwithoutmeals

– Asenapineshouldbetakenwithoutfoodordrinkforatleast10minpostdose

– Lurasidoneshouldbetakenwithfood(atleast350calories)

– Quetiapine can be taken with or without food, however, high-fat meals (∼800–1000 calories) increase quetiapine exposure, which may be

clinically relevant for some patients. Suggest taking consistently with respect to food, particularly for once daily dosing

– Ziprasidonemustbetakenwithfood,ideallywithamealofatleast500calories[12].Foodincreasesziprasidone’sbioavailability2-fold

• Compatibilitywithbeverages

– CAUTION:Grapefruitjuicemayincreasethelevelsofclozapine,iloperidone,quetiapine,andziprasidone(seeDrugInteractionsp.158)

– Risperidonesolutioniscompatiblewithwater,co ee,orangejuice,andlow-fatmilk.ItisNOTcompatiblewithcolaortea

– OlanzapineZydisiscompatiblewithwater,milk,co ee,orangejuice,andapplejuice.Themixtureshouldbeconsumedpromptlyaftermixing

• Oralformulationconsiderations–sublingual,oraldisintegratingtablets,extendedrelease,suspensions

– Asenapine sublingual tablets dissolve in saliva within seconds when placed under the tongue. DO NOT swallow tablets as absorption is signif-

icantly reduced. DO NOT push tablet through foil backing as this could damage tablet. Use dry hands to remove tablet and immediately place

tablet under the tongue

– Oral disintegrating tablets (ODT) (clozapine ODT, risperidone M-tabs, and olanzapine Zydis) disintegrate rapidly in saliva and can be taken with

or without liquid. These products are not absorbed sublingually but swallowed, then absorbed enterally. Because they start to disintegrate upon

contact with moisture, ODT tablets should be handled carefully with dry hands (direct contact with hands should be avoided as much as possible)

– IfhalftabletsofolanzapineZydisarerequired,breaktabletcarefullyandwashhandsaftertheprocedure.Avoidexposuretopowderasdermati- tis, eye irritation, and hypersensitivity reactions reported. Store broken tablet in tight, light-resistant container (tablet discolors) and use within

7 days

– Asenapine,paliperidone,quetiapineXR,andrisperidoneM-tabsmustnotbechewed,dividedorcrushed

– Paliperidoneissuppliedinanon-absorbableshellthatmayappearinthestoolandisnotacauseforconcern

– Useliquid(risperidone,ziprasidone),oraldisintegratingtablets(clozapineODT,olanzapine,risperidone)orasenapinesublingualtabletsifpatient

has di culty swallowing or is suspected of nonadherence. However, more challenging individuals can cheek disintegrating tablets. Time to

dissolution may vary by product and also by patient (e.g., dry mouth may impede dissolution times)

– Ziprasidonesuspension–shakewellpriortouse

– Storage:Roomtemperature,protectedfromlightandmoisture–clozapineODT,olanzapineZydis,risperidonesolutionandM-tabs,ziprasidone

suspension

• Olanzapine

– OlanzapineIMisreconstitutedusingtheprovided2.1mLofsterilewaterforinjectiontoyieldaclear,yellow5mg/mLsolution.Usewithin1hof

mixing. Inject slowly, deep into the muscle mass

– ConcomitantadministrationofolanzapineIMandparenteralbenzodiazepineisNOTRECOMMENDED(seeDrugInteractionsp.157)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 149 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Nursing Implications

Oral

Short-acting IM

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Second-Generation Antipsychotics/SGAs (cont.)

– Prior to olanzapine IM administration, evaluation of vital signs is recommended. Post-injection monitor for hypotension, oversedation, and cardiorespiratory depression

– Storage:Roomtemperature(pre-mixingandreconstitutedstableforamaximumof1h)

• Ziprasidone

– Ziprasidoneshort-actingIMisreconstitutedintoasuspensionusingtheprovided1.2mLofsterilewaterforinjection.Shakevialvigorouslyuntil all of the drug is dissolved. Following reconstitution, any unused portion should be discarded after 24 h, since no preservative or bacteriostatic agent is present in this product

– Storage:Roomtemperature(protectfromlight;pre-mixingandreconstitutedstableforamaximumof24h)

• Itisrecommendedtoestablishtolerabilitywithanoralformpriortoinitializingalong-actingIMdosageform

• Rotateadministrationsites.Documentinchartingthemuscleandlocation(e.g.,leftorright)ofeachinjection

• Storage:Roomtemperature–olanzapinepamoate(pre-mixingandreconstitutedstableforamaximumof24h),paliperidonepalmitate,risperidone

(pre-mixing stable for a maximum of 7 days and reconstituted stable for a maximum of 6 h); refrigerate – risperidone (pre-mixing)

• OlanzapinepamoateIM

– Can cause a post-injection sedation (including coma)/delirium syndrome. Administer where emergency services are readily accessible. Observe for at least 3 h. Instruct patient not to drive or operate heavy machinery for remainder of the day. Risk less than 0.1% at each injection

– Wear gloves when reconstituting to prevent skin irritation. Reconstitute with supplied diluent. Inject slowly, deep into the gluteal muscle. Use 1.5-inch 19-gauge needle provided for non-obese patients. In the obese, may use 2-inch 19-gauge or larger needle. To prevent clogging, a 19-gauge or larger needle must be used. If not administered immediately, use within 24 h and shake vigorously to resuspend prior to adminis- tration. After insertion of the needle into the muscle, aspirate for several seconds to ensure that no blood appears. If any blood is drawn into the syringe, discard the syringe and the dose and begin with a new kit

• Theinjectionshouldbeperformedwithsteady,continuouspressure

• DONOTmassageinjectionsite

• Paliperidonepalmitate1-and3-monthlyIM

– Paliperidone palmitate 1-monthly IM is a suspension in a pre lled syringe. Shake the syringe vigorously for a minimum of 10 sec to ensure a homogeneous suspension

– Paliperidone palmitate 1-monthly initial dose (day 1) and second dose (day 8) should be administered intramuscularly into the deltoid muscle. These two initial injections help attain therapeutic concentrations rapidly without the need for oral supplementation. Further doses can be administered into the deltoid or upper outer quadrant of the gluteal muscle. (See Pharmacokinetics, p. 137). Inject slowly, deep into the muscle. Alternate injections between arms or buttocks and specify in charting. For the deltoid injection, use 1.5-inch 22-gauge needle for patients ≥ 90 kg (≥ 200 lb) or 1-inch 23-gauge for patients less than 90 kg (less than 200 lb). For the gluteal injection, use 1.5-inch 22-gauge needle regardless of patient weight. Needles are provided in the kit

– Paliperidone palmitate 3-monthly IM is a suspension in a pre lled syringe. With the syringe tip pointed upwards, shake the syringe vigorously for a minimum of 15 sec to ensure a homogenous suspension. Ensure the dose is administered within 5 min or the syringe must be shaken again for 15 sec (note it takes longer to redisperse this suspension compared to the paliperidone 1-monthly injection syringes). The suspension should appear uniform and milky white in color

– Paliperidone palmitate 3-monthly IM may be administered into the deltoid or gluteal muscle. Needle selection is based on patient weight. For deltoid injection, use 1.5-inch 22-gauge needle for patients ≥ 90 kg (≥ 200 lb) or 1-inch 22-gauge for patients less than 90 kg (200 lb). For gluteal injection, use 1.5-inch 22-gauge needle regardless of patient weight. Needles are provided in the kit

• RisperidoneConsta

– RisperidoneConstaisapowderforreconstitution;dosepackshouldbeallowedtocometoroomtemperaturebeforereconstitutionandinjection.

Reconstitute with diluent provided. Should be used as soon as possible – shelf life is 6 h; some clinicians recommend a test oral dose of 1– 2 mg/day for 2 days if the patient has never taken risperidone

• Only use needles supplied with the kit as use of a higher gauge may impede the passage of microspheres. Needle detachments have been reported; to prevent, follow the accompanying instructions and recheck the syringe-needle attachment prior to injection[16]

Long-acting IM

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Drug Interactions

• Shake the preparation vigorously for at least 10 sec within 2 min before administering; give deep IM into deltoid (1-inch needle) or gluteal (2-inch needle) muscle; alternate injections between arms or buttocks and specify in charting

• DONOTmassageinjectionsite

• Clinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterforthesecondagent

Class of Drug

Example

Interaction Effects

Acetylcholinesterase inhibitor (central)

General

Donepezil, galantamine, rivastigmine

Increase in mortality in elderly patients with dementia taking antipsychotics irrespective of acetylcholinesterase inhibitor use. Deaths largely either cardiovascular or infectious in nature

May enhance neurotoxicity of antipsychotics, presumably due to a relative acetylcholine/dopamine imbalance (i.e., increased acetylcholine in the presence of dopamine receptor blockade) in the CNS. Case reports of severe EPS (e.g., generalized rigidity, shuf ing gait, facial grimacing) in elderly patients within a few days of starting an antipsychotic (risperidone or haloperidol) and an acetylcholinesterase

inhibitor (donepezil). Symptoms resolved after discontinuing the antipsychotic, the acetylcholinesterase inhibitor or both. Case reports of NMS with concurrent use of olanzapine and an acetylcholinesterase inhibitor (donepezil and rivastigmine).

Adsorbent

Activated charcoal, attapulgite (kaolin-pectin), cholestyramine

Gastrointestinal absorption decreased signi cantly when used simultaneously; give at least 1 h before or 2 h after the antipsychotic. Charcoal (1 g) reduced the Cmax and AUC of olanzapine by 50–60%

α1-adrenergic receptor blocker

Doxazosin, prazosin, terazosin

Additive hypotensive effect possible. Antipsychotics generally cause hypotension via α1 blockade (see Effects of Antipsychotics on Receptors table p. 176)

Amylinomimetic

Pramlintide

Pramlintide slows the rate of gastric emptying. Antipsychotics with signi cant anticholinergic effects can further reduce GI motility

Antiarrhythmic

General

Amiodarone, quinidine

Possible additive prolongation of QT interval and associated life-threatening cardiac arrhythmias. DO NOT COMBINE with asenapine, iloperidone, paliperidone or ziprasidone. CAUTION with all other SGAs. Also see Cardiovascular Effects of SGAs section p. 139

CYP2D6 is inhibited by amiodarone and potently by quinidine. With amiodarone and quinidine, increased plasma levels of asenapine, clozapine (case report with amiodarone), iloperidone, and risperidone likely

Antibiotic

Quinolone

Cipro oxacin, levo oxacin, moxi oxacin, nor oxacin

DO NOT COMBINE with asenapine, iloperidone, paliperidone or ziprasidone. CAUTION with all other SGAs. Possible additive prolongation of QT interval and associated life-threatening cardiac arrhythmias. Also see Cardiovascular Effects of SGAs section p. 139

CAUTION. Potential to exacerbate psychiatric conditions, as quinolone-induced psychosis has been reported

Cipro oxacin and nor oxacin inhibit CYP1A2. With cipro oxacin, increased clozapine and norclozapine levels (by 29–100%; case report of a 5-fold increase); increased olanzapine level (by more than 2-fold in a case report). Increased levels of asenapine likely. Case report of

sudden-onset dystonia in a patient taking asenapine and cipro oxacin. Nor oxacin likely to cause similar SGA level increases. Adjust antipsychotic dose as needed

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 151 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Second-Generation Antipsychotics/SGAs (cont.)

Example

Interaction Effects

Clarithromycin, erythromycin, telithromycin

Tetracycline

CYP3A4 is inhibited potently by clarithromycin and telithromycin, and moderately by erythromycin. With erythromycin, decreased clearance of quetiapine (by 52%) and with clarithromycin, a case report of ∼7-fold increase in quetiapine levels. Consider reducing quetiapine dose by 50% with concurrent use of strong CYP3A4 inhibitors and by 25% with moderate CYP3A4 inhibitors. Although a pharmacokinetic study suggests no signi cant interaction between erythromycin and clozapine, there are case reports of increased clozapine levels (by ∼2- to 3-fold) and associated symptoms (e.g., disorientation, seizures, neutropenia, somnolence, slurred speech). Reduce iloperidone dose by 50% with concurrent use of strong CYP3A4 inhibitors. Lurasidone should NOT be used concurrently with strong CYP3A4 inhibitors and reduce its dose by 50% in the presence of moderate CYP3A4 inhibitors. Ziprasidone levels increased by ∼40% in the presence of strong CYP3A4 inhibitors

Adjust antipsychotic dose as needed

Case report of increased motor and vocal tics when tetracycline added to risperidone and sertraline; mechanism unknown

Antidepressants, antihistamines, antiparkinsonian drugs

Increased risk of anticholinergic adverse effects (e.g., dry mouth, urinary retention, inhibition of sweating, blurred vision, constipation, paralytic ileus, confusion, toxic psychosis)

Warfarin

Two case reports of increased INR with the addition of quetiapine to warfarin

General Carbamazepine

All SGAs may lower seizure threshold. May occur if dose is increased rapidly or may also be secondary to hyponatremia. Potential additive risk for hyponatremia as both SGAs and carbamazepine/oxcarbazepine can cause low sodium levels. Risk of seizures is greatest with clozapine and is dose related: 1% (doses below 300 mg), 2.7% (300–599 mg), and 4.4% (above 600 mg)

Decreased antipsychotic plasma levels via potent induction of CYP3A4, CYP1A2, CYP2D6 and/or possibly UGT1A4. Note it may take

2–4 weeks to reach maximum induction and an equivalent period to return to baseline after discontinuation of an inducer. Adjust antipsychotic dose as needed

Clozapine levels reduced by 50%. AVOID due to potential additive risk for agranulocytosis. Case report of fatal pancytopenia

Olanzapine levels reduced by 36–71%.

Paliperidone’s Cmax level reduced by 37% with 400 mg/day of carbamazepine

Quetiapine levels reduced by up to 80% with other reports of undetectable levels. Two case reports of 3- to 4-fold increase in the ratio of carbamazepine epoxide/carbamazepine resulting in ataxia and agitation in one case. AVOID combination if possible

Risperidone and 9-hydroxyrisperidone levels reduced by 50%. Risperidone causes a modest, clinically insigni cant increase in carbamazepine level

Lamotrigine

Ziprasidone AUC reduced by 36% with 400 mg/day of carbamazepine. Higher carbamazepine doses may have a greater effect

Lamotrigine is a weak UGT inducer. A signi cant reduction (58%) of quetiapine levels suggested by one study, however, a larger study found

a clinically insigni cant (17%) reduction. Studies suggest low dose lamotrigine (≤ 200 mg/day) does not signi cantly affect the levels of clozapine, olanzapine or risperidone. However, case reports of clinically signi cant increased levels of clozapine and risperidone and a study found an increase in olanzapine levels (35%) in smokers taking lamotrigine. Mechanism unknown. With concurrent clozapine, monitor CBC as both drugs can depress bone marrow function. Case report of fatal agranulocytosis within 6 weeks of starting concurrent quetiapine, lamotrigine, mirtazapine, and venlafaxine. Monitor for reduced antipsychotic ef cacy as well as antipsychotic toxicity (e.g., sedation, dizziness), particularly with higher doses of lamotrigine

Class of Drug

Macrolide

Tetracycline

Anticholinergic

Anticoagulant Anticonvulsant

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Class of Drug

Example

Interaction Effects

Oxcarbazepine Phenobarbital, phenytoin

Topiramate

Valproate (divalproex, valproic acid)

Oxcarbazepine is a weak CYP3A4 inducer and does not appear to signi cantly affect the levels of clozapine, olanzapine, quetiapine or risperidone, however, consider the potential for additive bone marrow suppression with clozapine and possibility of more signi cant SGA level reductions with high doses of oxcarbazepine (≥ 1500 mg/day)

Decreased level of SGA due to potent induction of metabolism; for phenytoin via CYP2C9 and CYP3A4; for phenobarbital primarily via CYP1A2, CYP2C9, and CYP3A4. Note it may take 2–4 weeks to reach maximum induction and an equivalent period to return to baseline after discontinuation of an inducer. Adjust antipsychotic dose as needed

Iloperidone level likely to decrease by 2-fold based on interaction with potent inducers. Iloperidone dose may need to be increased by 50% Lurasidone levels decreased by 5-fold in the presence of other potent CYP3A4 inducers (i.e., rifampin). Recommended to avoid lurasidone with concurrent potent CYP3A4 inducers

Paliperidone, risperidone, and ziprasidone levels reduced by other potent CYP3A4 inducers (i.e., carbamazepine); similar interaction anticipated

With phenytoin, clozapine level decreased by 65–85%, which resulted in re-emergence of psychotic symptoms and a case report of phenytoin intoxication after IV phenytoin loading possibly due to clozapine inhibition of CYP2C9. Quetiapine level decreased by 80% With phenobarbital, clozapine level decreased by 35%

Olanzapine level signi cantly reduced by other potent CYP1A2 inducers (i.e., carbamazepine); similar interactions anticipated Topiramate is a weak CYP3A4 inducer and CYP2C19 inhibitor. Modest reduction of risperidone’s Cmax (by 23–29%) with no effect on 9-hydroxyrisperidone. Likely not clinically signi cant. One study found no signi cant changes to the levels of clozapine, norclozapine, olanzapine, risperidone, 9-hydryoxyrisperidone or quetiapine. The effects of higher doses of topiramate (more than 400 mg/day) are unknown

Valproate inhibits CYP2C9 and UGT and weakly inhibits CYP1A2, CYP2D6, and CYP2E1. Adjust antipsychotic dose as needed

Asenapine: Product monograph states no dose adjustment required based on a single dose of asenapine and 9 days of valproate

Clozapine: Con icting information. Both increased and decreased clozapine levels reported. Possibly a clinically signi cant reduction in clozapine levels in smokers. Case reports of hepatic encephalopathy, onset of seizures in nonepileptic patients, and delirium. Reports suggest a greater risk of agranulocytosis with concurrent valproate and clozapine than with either alone. Concurrent valproate with rapid clozapine dose titration may increase risk of myocarditis

Olanzapine: Most studies found no clinically signi cant change in the levels of either medication. However, reduced olanzapine levels found in one study (by ∼20%) and seen in case reports (by ∼50%). Incidence of hepatic enzyme elevations may increase the risk of hepatic adverse effects

Paliperidone: Cmax of a single dose of paliperidone increased by 50% with no effect on valproate level. Consider reduction of paliperidone dose

Quetiapine: Case reports of adverse effects possibly due to increased quetiapine levels. Case report of severe cervical dystonia with the addition of valproic acid. Case report of drug-induced parkinsonism and cognitive decline with concurrent use of quetiapine (800 mg/day) and valproic acid (1500 mg/day). Two case reports of delirium in patients with mild renal impairment after the addition of valproate to quetiapine. A case report of severe hypertriglyceridemia in the absence of weight gain with the addition of valproate to quetiapine that resolved on valproate discontinuation. Cases of hyperannomemia induced by interaction with valproate and quetiapine reported. Four case reports of neutropenia with concurrent quetiapine and valproate, with one also having thrombocytopenia. Monitor CBC at baseline, in

1–2 weeks, and after any dose increases

Risperidone: No effect on risperidone levels with a modest (20%) increase in valproate levels. A case report of elevated and another of

reduced valproate levels. Two case reports of generalized edema. Case report of neutropenia resolving after valproic acid stopped. Two cases in children of hyperammonemia, and one case of catatonia with the addition of valproic acid to risperidone and sertraline. Monitoring of serum ammonia levels may be warranted if new or increased manic behavior occurs

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 153 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Second-Generation Antipsychotics/SGAs (cont.)

Example

Interaction Effects

General

Citalopram, escitalopram,

uoxetine, uvoxamine, paroxetine, sertraline

Case reports of serotonin syndrome with concurrent use of antidepressants that increase serotonin and SGAs

CAUTION with paliperidone and ziprasidone; possible additive prolongation of QT interval and associated life-threatening cardiac arrhythmias

Increased plasma level of antipsychotic possible due to inhibition of CYP1A2 (potent – uvoxamine), 2D6 (potent – uoxetine and paroxetine) and/or 3A4 ( uvoxamine). Adjust antipsychotic dose as needed

Asenapine’s Cmax (+ 13%) and AUC (+ 29%) increased by uvoxamine based on an asenapine single-dose study. Asenapine (a weak inhibitor of CYP2D6) increased exposure to a single dose of paroxetine by ∼2-fold

Clozapine levels: With citalopram, no change to increased. With uoxetine, 41–76% higher levels plus 38–45% higher norclozapine levels; one fatality reported; case report of acute myocarditis after addition of clozapine to uoxetine and lithium. With uvoxamine, 3–11-fold higher levels. With paroxetine, no change to 41% increase plus 45% norclozapine increase. With sertraline, 41-76% increase plus 45% norclozapine increase; one fatal arrhythmia reported but causality unclear

Iloperidone’s AUC increased by ∼1.6- to 3-fold in the presence of uoxetine or paroxetine. Reduce iloperidone dose by 50% if uoxetine or paroxetine added

Olanzapine levels: With uoxetine, 16% increase in Cmax; not clinically signi cant. With uvoxamine, 2.3- to 4-fold increase in olanzapine levels. Case reports of fatal hyponatremia, marked hyperglycemia, and acute pancreatitis with long-term use of paroxetine + uphenazine + haloperidol + olanzapine

Quetiapine levels: With uvoxamine, may be increased by up to 159%. Case reports of NMS/serotonin syndrome with quetiapine and SSRIs (i.e., citalopram, uvoxamine). Monitor for symptoms (e.g., fever, myoclonus, and tremor)

Risperidone levels: With uoxetine, 2.5- to 8-fold increased levels and case report of tardive dyskinesia. With paroxetine, 3- to 9-fold higher levels and cases of serotonin syndrome. Case reports of serotonin syndrome and/or NMS with uvoxamine and trazodone + sertraline Case of gynecomastia and galactorrhea without elevated prolactin level in a male taking risperidone and uvoxamine

Ziprasidone: Case report of serotonin syndrome with ziprasidone and citalopram

Bupropion Venlafaxine

Nefazodone, trazodone

Vortioxetine Mirtazapine

Risperidone: Potential for additive seizure risk due to increased plasma levels of risperidone due to competitive inhibition of CYP2D6 Clozapine: Increased levels of both clozapine and venlafaxine possible due to competitive inhibition of CYP2D6 and/or CYP3A4. A study with

venlafaxine doses of 150 mg/day or less suggests no clinically signi cant interaction. Case report of NMS/serotonin syndrome

Quetiapine: Case report of fatal agranulocytosis within 6 weeks of starting concurrent quetiapine, lamotrigine, mirtazapine, and venlafaxine Potential for additive adverse effects (e.g., sedation, orthostatic hypotension). Nefazodone is a potent CYP3A4 inhibitor

Increased plasma levels of clozapine (case report) and quetiapine (in vitro data) possibly due to inhibited metabolism via CYP3A4 and associated adverse effects (e.g., dizziness, hypotension)

Lurasidone is contraindicated with concomitant use of potent CYP3A4 inhibitors

Case report of NMS with nefazodone and olanzapine. Case report of serotonin syndrome with trazodone, sertraline, and risperidone Serotonin modulators may enhance the dopamine blockade of antipsychotics and increase the risk of side effects. Antipsychotics may enhance the serotonergic effects of serotonin modulators and increase the risk of serotonin syndrome

Potential for additive metabolic adverse effects (e.g., increased cholesterol, weight), and increased appetite and sedation. Case report of status epilepticus with mirtazapine and olanzapine. Case report of serotonin syndrome with mirtazapine, tramadol, and olanzapine and

another within 7 weeks of adding quetiapine and mirtazapine to venlafaxine and donepezil. Case report of fatal agranulocytosis within 6 weeks of starting concurrent quetiapine, lamotrigine, mirtazapine, and venlafaxine

Class of Drug

Antidepressant

SSRI

NDRI SNRI

SARI

SMS NaSSA

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Example

Interaction Effects

Amitriptyline, clomipramine, maprotiline, trimipramine

Additive sedation, hypotension, and anticholinergic effects. Potential for additive seizure risk

DO NOT COMBINE with asenapine, iloperidone, paliperidone or ziprasidone. CAUTION with all other SGAs. Possible additive prolongation of QT interval and associated life-threatening cardiac arrhythmias

Potential for increased SGA levels as CYP2D6 is moderately inhibited by amitriptyline, clomipramine, desipramine, and imipramine

Moclobemide, phenelzine, tranylcypromine

Asenapine: Imipramine caused modest (17%) increase in Cmax of a single dose of asenapine. No adjustment of asenapine dose required Clozapine: Case report of serotonin syndrome after withdrawal of clozapine in a patient taking clomipramine. Case report of 2-fold increase

in nortriptyline levels after the addition of clozapine. Patient developed delirium, which was preceded by extreme fatigue and slurred speech. Case report of increased clomipramine levels and myoclonic jerks followed by seizures, possibly due to competitive inhibition for CYP1A2 and/or CYP2D6

Olanzapine: Case report of NMS/serotonin syndrome with clomipramine. Suggest using lowest doses possible if olanzapine and clomipramine used concurrently

Quetiapine: Case report of 17-fold increase in quetiapine levels with concurrent doxepin and pantoprazole; mechanism unknown Risperidone: Case reports of increased maprotiline levels (40–60%) and anticholinergic effects with risperidone, possibly due to competitive inhibition of CYP2D6

Additive hypotension

Case report of serotonin syndrome with quetiapine and phenelzine and another with ziprasidone and tranylcypromine

Loperamide

Case report of fatal gastroenteritis with clozapine. Potentially anticholinergic effects of clozapine added to antimotility effects of loperamide lead to toxic megacolon

Fluconazole, itraconazole, ketoconazole, voriconazole

Terbina ne

Ketoconazole and itraconazole are potent, while uconazole and voriconazole are moderate CYP34A inhibitors. Increased iloperidone (level by 57% with ketoconazole), lurasidone (Cmax 6- to 9-fold and AUC 9-fold), 9-hydroxyrisperidone (level by 70% in a study of risperidone with itraconazole), quetiapine (Cmax by 335% with ketoconazole), risperidone (level by ∼80% with itraconazole), and ziprasidone (AUC and Cmax by 35–40% with ketoconazole). Adjust antipsychotic dose as needed. Recommended to AVOID concurrent use of lurasidone and ketoconazole or itraconazole

CAUTION – possible additive prolongation of QT interval and associated life-threatening cardiac arrhythmias with antipsychotics

Increased plasma levels of iloperidone and risperidone possible due to inhibited metabolism via CYP2D6. Any interaction will be prolonged (up to 3 months) due to terbina ne’s long half-life (200–400 h)

Diphenhydramine, hydroxyzine

See Class of Drug “Anticholinergic” above (p. 152) and “CNS depressant” below (p. 157)

Additive hypotensive effect possible. Antipsychotics generally cause hypotension via α1 blockade (see receptor table p. 176 and frequency of adverse effects table pp. 180–181). Start with a lower dose of antipsychotic, titrate slowly, and monitor for orthostatic hypotension

Calcium channel blockers Clonidine

Also see Class of Drug “calcium channel blocker” p. 157

SGAs that are potent α2-adrenergic receptor antagonists may block clonidine’s antihypertensive effects via α2-adrenergic receptor agonism (see receptor table p. 176). Additive hypotensive effects also possible

Diuretic Lisinopril

Also see Class of Drug “diuretic” p. 157

Case report of signi cantly increased plasma levels of clozapine and norclozapine. Case report of pancreatitis 3 months after lisinopril added to olanzapine

Levodopa, pramipexole, ropinirole

Potential for reduced antiparkinson ef ciency. Antipsychotics reduce dopaminergic activity while antiparkinson agents increase dopamine in the CNS. If a SGA is necessary, consider using clozapine or quetiapine, which have been reported to be less likely to cause worsening control of movement disorders than other antipsychotics

General

Increased risk of adverse effects (e.g., EPS elevated prolactin levels, sedation hypotension, and anticholinergic effects), increased cost, and potential for decreased adherence with use of multiple antipsychotic agents

Class of Drug

Cyclic

Irreversible MAOI, RIMA

Antidiarrheal Antifungal

Antihistamine Antihypertensive

Antiparkinsonian agent Antipsychotic combination

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 155 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Second-Generation Antipsychotics/SGAs (cont.)

Class of Drug

Example

Interaction Effects

Aripiprazole + SGAs Clozapine + olanzapine

Clozapine + quetiapine Clozapine + risperidone

Haloperidol + SGAs

Phenothiazines (e.g., chlorpromazine) + SGAs

Pimozide + SGAs

See p. 172 in TGA interaction section

Case reports of NMS. Potential for additive metabolic effects and weight gain

Case report of delayed recovery of clozapine-induced agranulocytosis when given olanzapine

Clozapine increased serum concentration of quetiapine by 82% (unknown mechanism but suggested to be clinically signi cant); consider starting at a lower than usual dose of quetiapine

Isolated case reports suggest increased clozapine and risperidone levels with concurrent use. However, kinetic studies found no effects on levels. Discrepancy potentially due to genetic variability in metabolism. Chronic concurrent administration may increase risperidone levels. Most common adverse effects with concurrent use are EPS (e.g., akathisia), higher fasting glucose, sedation, hyperprolactinemia and hypersalivation. Case reports of NMS

With clozapine, a case of signi cantly elevated haloperidol decanoate levels and cases of NMS; including one after a single IM dose of haloperidol following abrupt clozapine discontinuation, another after abrupt discontinuation of both medications

With olanzapine, a case of extreme parkinsonism potentially due to competitive inhibition of CYP2D6 and/or additive adverse effects

Case report of fatal hyponatremia, marked hyperglycemia, and acute pancreatitis with long-term use of paroxetine + uphenazine + haloperidol + olanzapine

Possible additive QT prolongation (see Cardiovascular Effects p. 139). DO NOT COMBINE with asenapine, iloperidone, paliperidone or ziprasidone

Case reports of NMS including with olanzapine + uphenazine; olanzapine + chlorpromazine; after several years of olanzapine + clozapine + uphenazine. Case report of fatal hyponatremia, marked hyperglycemia, and acute pancreatitis with long-term use of paroxetine + uphenazine + haloperidol + olanzapine

Possible additive QT prolongation (see above). DO NOT COMBINE with asenapine, iloperidone, paliperidone or ziprasidone

Thioridazine + SGAs

Quetiapine + ziprasidone

Possible additive QT prolongation (see above). DO NOT COMBINE with asenapine, iloperidone, paliperidone or ziprasidone

Increased clearance (i.e., decreased plasma levels) of quetiapine (by 65%). Increased plasma levels of risperidone (by ∼5-fold) with reduced

9-hydroxyrisperidone levels due to inhibition of metabolism via CYP2D6. Increased levels of other SGAs (e.g., iloperidone, clozapine) possible. Increased SGA levels have the potential to further increase the risk of QT prolongation

Case report of increased QTc prolongation with cardiac arrhythmia, possibly due to increased plasma level of either drug as a result of competitive inhibition via CYP3A4

Antiretroviral

Non-nucleoside reverse transcriptase inhibitor (NNRTI)

Protease inhibitor

Delavirdine, efavirenz, etravirine, nevirapine

Atazanavir, boceprevir, darunavir, fosamprenavir, indinavir, lopinavir, nel navir, ritonavir, saquinavir, simeprevir, telaprevir, tipranavir

Delavirdine may increase levels of risperidone and iloperidone due to CYP2D6 inhibition

Efavirenz and etravirine may decrease levels of quetiapine and lurasidone due to CYP3A4 induction

CAUTION. Complex interactions likely as various protease inhibitors (PI) potently inhibit as well as induce a variety of CYP enzymes (e.g., on CYP3A4, ritonavir is a potent inhibitor; atazanavir, boceprevir, darunavir, saquinavir, and telaprevir are strong inhibitiors; fosamprenavir and indinavir are mild to moderate inhibitors; tipranavir is an inducer. Low boosting doses of ritonavir have little effect on CYP2D6 but higher doses cause inhibition)

Increased plasma level of clozapine possible due to inhibition of CYP3A4, however, ritonavir may also decrease levels via induction of CYP1A2. Net effect of ritonavir dif cult to predict.[18] AVOID if possible due to potential for clozapine toxicity and additive effects on cardiac conduction. Consider monitoring clozapine levels if used concurrently

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Class of Drug

Example

Interaction Effects

Antitubercular drug

Rifabutin, rifampin, rifapentine

Decreased clozapine (plasma levels by 6-fold), lurasidone (Cmax by 86% and AUC by 80%), risperidone (Cmax by up to 50%), and 9-hydroxyrisperidone (i.e., paliperidone; Cmax by 46%) due to induction via CYP3A4, CYP2C and/or P-glycoprotein with rifampin. Coadministration of lurasidone and rifampin NOT recommended. Reduced levels of iloperidone and quetiapine likely

Anxiolytic

Benzodiazepines

Clonazepam, diazepam, urazepam, lorazepam, midazolam

Buspirone

Synergistic effect with antipsychotics; used to calm agitated patients

Potential for additive CNS adverse effects (e.g., dizziness, sedation, confusion, respiratory depression) and hypotension

Increased incidence of dizziness, hypotension, sedation, excessive salivation, and ataxia when combined with clozapine; cases of ECG changes, delirium, cardiovascular or respiratory arrest and deaths reported – more likely to occur early in treatment when clozapine added to benzodiazepine regimen

Lurasidone (120 mg/day) slightly increased levels of midazolam (Cmax by 21% and AUC by 44%). May not be clinically signi cant Concomitant administration of short-acting IM olanzapine and parenteral benzodiazepine and/or other drugs with CNS depressant activity has been associated with serious adverse events (e.g., hypotension, bradycardia, respiratory or CNS depression), including fatalities; thus it is NOT RECOMMENDED

Case report of GI bleeding and hyperglycemia with clozapine

Aprepitant

Case report of 11-fold increase in quetiapine levels with accompanying somnolence. Quetiapine dose reduced by 50% with subsequent aprepitant courses and somnolence did not occur

Belladonna alkaloid

Atropine, hyoscyamine, scopolamine

Additive anticholinergic effects (e.g., dry mouth, urinary retention, inhibition of sweating, blurred vision, constipation, paralytic ileus, confusion, toxic psychosis). The elderly are particularly vulnerable to these effects. See frequency of adverse reactions table p. 181 Caution is advised

Calcium channel blocker

Diltiazem, verapamil

Increased lurasidone (Cmax 2.1-fold and AUC 2.2-fold) with diltiazem. If coadministered, maximum dose of lurasidone should be 40 mg/day Increased risperidone (Cmax 1.8-fold), and 9-hydroxyrisperidone (i.e., paliperidone; slight increase) with verapamil. Interactions likely due to diltiazem’s/verapamil’s ability to inhibit metabolism via CYP3A4 and/or to increase intestinal absorption via inhibition of P-glycoprotein. Increased quetiapine possible

Caffeine

Coffee, tea, cola, energy drinks, guarana or mate containing products

Increased akathisia/agitation/insomnia

Increased plasma levels of clozapine due to competition for metabolism via CYP1A2. Clozapine and norclozapine levels decreased by a mean of 47% and 31% following a 5-day caffeine-free period

More likely to be clinically relevant in those who are nonsmokers or consuming more than 400 mg of caffeine/day (e.g., more than 4 cups of caffeinated coffee/day). Variations in caffeine intake should be considered when clozapine concentrations uctuate

Risperidone solution is incompatible with cola or tea, but it is compatible with coffee

CNS depressant

Alcohol, antihistamines, hypnotics, opioids

CAUTION. Increased CNS effects (e.g., sedation, fatigue, impaired cognition) and orthostatic hypotension. Alcohol may worsen EPS. Monitor for adverse effects when starting a SGA or increasing the dose; recommended to avoid alcohol during these times

Disul ram

CAUTION. Case reports of disul ram-induced psychosis, possibly due to blockade of dopamine β-hydroxylase, however, no increased psychotic features seen in small studies of participants with psychotic disorders. Decreased metabolism and increased plasma level of clozapine possible due to inhibition of CYP2E1

Diuretic

General Furosemide

CAUTION. Diuretics can cause electrolyte disturbances resulting in additive QT interval prolongation and risk of associated life-threatening cardiac arrhythmias. Monitor for dehydration, hypokalemia, and hypomagnesemia. Also see Cardiovascular Effects p. 139

In risperidone placebo-controlled trials in elderly patients with dementia, a higher incidence of mortality was observed in patients treated with furosemide plus risperidone (7.3%) when compared to patients treated with risperidone alone (3.1%), furosemide alone (4.1%) or

placebo without furosemide (2.9%). The increase in mortality with furosemide plus risperidone was observed in two of four clinical trials. No pathophysiological mechanism has been identi ed to explain this nding and no consistent pattern for cause of death observed

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 157 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Second-Generation Antipsychotics/SGAs (cont.)

Class of Drug

Example

Interaction Effects

Ginkgo biloba

Case report of priapism with recent addition of ginkgo to long-standing risperidone. Mechanism unclear; potentially due to additive vessel-dilating properties. In theory, reduction of clozapine levels may occur via induction of CYP2E1

Glucocorticoid

Betamethasone, hydrocortisone, prednisone

CAUTION. Potential to exacerbate psychiatric conditions as glucocorticoid-induced psychiatric disorders such as psychosis can occur. Glucocorticoids can induce metabolism via CYP3A4. Higher doses of antipsychotics metabolized via CYP3A4 (e.g., clozapine, iloperidone, lurasidone, quetiapine or ziprasidone) may be needed

Grapefruit

CAUTION. Increased plasma level of clozapine, iloperidone, lurasidone, quetiapine, and ziprasidone possible due to inhibition of metabolism via intestinal CYP3A4 and possibly inhibition of intestinal transporters such as P-glycoprotein. Grapefruit’s inhibitory effects may be prolonged (i.e., 24–48 h). Data with clozapine suggests 500 mL or less of grapefruit juice daily may not result in clinical changes

Pertinent to avoid or minimize grapefruit and grapefruit juice until more information is available

H2 antagonist

Cimetidine

Nizatidine Ranitidine

Increased plasma levels of clozapine (case reports), possibly due to inhibited metabolism via CYP1A2, 2D6, and/or 3A4. Effect on quetiapine and ziprasidone not clinically signi cant. Increased bioavailability of risperidone (by 64%), however, no effect on AUC, therefore unlikely to be clinically signi cant

Case report of higher doses (600 mg/day) of nizatidine in combination with quetiapine and paroxetine resulting in akathisia, bradykinesia, mild rigidity, and bilateral tremor in upper extremities

Increased bioavailability of risperidone (26%) and AUC of risperidone plus 9-hydroxyrisperidone (20%). Not clinically signi cant

Hormone

Oral contraceptive, ethinyl estradiol

Estrogen potentiates hyperprolactinemic effect of antipsychotics

Ethinyl estradiol is an inhibitor of CYP1A2 and CYP2C19 and substrate of CYP3A4, which are the main enzymes that metabolize clozapine. Case report of ∼2-fold increase in clozapine levels and marked drowsiness, anergy, and dizziness with the addition of an ethinyl estradiol-containing oral contraceptive (OC). Another report of increased plasma level of clozapine with an OC (ethinyl estradiol

[35 micrograms]/norethindrone [0.5 mg]). Case report of seizures with addition of lithium 900 mg/day to clozapine 300–600 mg/day and an OC (ethinyl estradiol [35 micrograms]/norethindrone [0.5/0.75/1 mg])

Lithium

CAUTION. Monitor plasma levels of lithium closely when it is used concurrently with SGAs, since both SGAs (in particular ziprasidone) and high lithium levels are associated with QT prolongation. Also see Cardiovascular Effects p. 139

Although studies indicate lithium and SGAs can be safely used together, there are cases of severe adverse effects. Factors that may increase the risk of developing neurotoxicity are the presence of acute mania, pre-existing brain damage, infection, fever, dehydration, a history of EPS, and high doses of one or both agents

With clozapine: Asterixis (+ zuclopenthixol), diabetic ketoacidosis (no history of hyperglycemia and no signs of lithium toxicity), acute myocarditis (+ uoxetine), rhabdomyolysis, and seizures (one case also taking an oral contraceptive and exhibiting mild jerking of the arms 2 days prior to the seizure)

With olanzapine: Encephalopathy, NMS, nonketotic hyperosmolar syndrome (+ valproic acid), priapism, and somnambulism (+ valproic acid) With quetiapine: Delirium and tonic-clonic seizure

With risperidone: Diabetic ketoacidosis + NMS + MI, encepatholopathy, EPS (acute rabbit syndrome), NMS, and priapism

Potential for additive adverse effects (e.g., weight gain)

Monitor patients closely, especially during the rst 3 weeks and after dose increases. In particular, monitor for EPS, NMS, and hyperglycemia. Monitor lithium levels, however, note that in the case reports of severe adverse effects listed above, lithium levels were within therapeutic range

Case reports of adding lithium in those who developed neutropenia with clozapine or olanzapine. Lithium resulted in normalization of WBC (via its ability to induce leukocytosis) and permitted continued use of clozapine or olanzapine

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Class of Drug

Example

Interaction Effects

Opioid

General Methadone

Tramadol

CAUTION. Additive CNS effects

DO NOT COMBINE with asenapine, iloperidone, paliperidone or ziprasidone. CAUTION with all other SGAs. Possible additive prolongation of

QT interval and associated life-threatening cardiac arrhythmias. Also see Cardiovascular Effects p. 139

Quetiapine modestly increased methadone levels (7–30%), possibly via inhibition of CYP2D6 and/or P-glycoprotein; this may be clinically signi cant for some patients. Quetiapine may result in a false-positive methadone urine drug screen.

CAUTION. Tramadol lowers the seizure threshold; potential additive lowering of seizure threshold with SGAs (in particular clozapine); case report of a fatal seizure in a complicated patient who was taking tramadol and clozapine. Tramadol blocks reuptake of serotonin; potential additive increase in serotonin with SGAs, which could result in serotonin syndrome; case report with mirtazapine, tramadol, and olanzapine

Prokinetic agent/antiemetic

Metoclopramide

CAUTION. Metoclopramide is a potent central dopamine receptor antagonist that can cause EPS, hyperprolactinemia, and rarely NMS. Concurrent use with a SGA may increase the risk of these adverse effects. Case report of Pisa syndrome after addition of metoclopramide to clozapine

Proton pump inhibitor

Esomeprazole, omeprazole

Case reports of decreased plasma level of clozapine (by ∼40%) likely due to induction of metabolism via CYP1A2 and/or CYP3A4 with omeprazole. Similar interaction likely with the S-isomer of omeprazole (i.e., esomeprazole). Increase clozapine dose as needed or use an alternative proton pump inhibitor. The interaction may be more clinically relevant in nonsmokers. Decreased levels of asenapine and olanzapine possible

QT-prolonging agent

DO NOT COMBINE with asenapine, iloperidone, paliperidone or ziprasidone. CAUTION with all other SGAs. Possible additive prolongation of QT interval and associated life-threatening cardiac arrhythmias

Smoking (tobacco)

Smoking induces CYP1A2; polycyclic aromatic hydrocarbons in tobacco smoke are believed to be responsible for this induction, not nicotine. Decreased plasma level of clozapine/norclozapine and olanzapine due to induction of metabolism via CYP1A2. Dosage modi cations not routinely recommended, however, some patients, in particular males who are heavy smokers, may require higher doses of clozapine for ef cacy. Caution when patient stops smoking as level of antipsychotic will increase; case reports suggest after smoking cessation symptoms from increased antipsychotic levels emerge after 4–10 days with olanzapine and 2–4 weeks with clozapine. Case reports of serious clozapine toxicity and EPS with olanzapine following smoking cessation; serum clozapine increases of 72–261% reported. Smoking induces olanzapine clearance by ∼55%.

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 159 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Second-Generation Antipsychotics/SGAs (cont.)

Class of Drug

Example

Interaction Effects

Statin

Lovastatin Simvastatin

Case report of prolonged QTc interval with quetiapine, possibly due to competitive inhibition of CYP3A4

Case report of rhabdomyolysis with quetiapine, however, an interaction between simvastatin and clarithromycin may have been the cause

Three case reports of rhabdomyolysis with simvastatin plus risperidone; possibly due to competitive inhibition of CYP3A4; in one case, cyclosporine may also have contributed to the event

Stimulant

Amphetamine, methylphenidate

Armoda nil

Antipsychotic agents may impair the stimulatory effect of amphetamines. Concurrent use not recommended

Case reports of acute EPS, agitation, irritability, worsening of tardive movement disorder, and prolongation or exacerbation of withdrawal dyskinesia following the abrupt discontinuation of risperidone with the concurrent start of methylphenidate

Case reports of rebound dystonia when a stimulant medication was withdrawn from patients taking risperidone. These reactions may be due to supersensitivity of dopamine receptors

Two case reports of priapism with concurrent use of stimulants and SGAs (quetiapine, olanzapine) Decreased Cmax and AUC of quetiapine by 45% and 42% respectively

Moda nil

CAUTION. Potential to exacerbate psychosis. Case report of re-emergence of psychotic symptoms after the addition of moda nil to clozapine

Case report of an almost 2-fold increase in clozapine levels and related toxicity (dizziness, gait disturbance, tachycardia, and hypoxia). Moda nil may inhibit clozapine metabolism via inhibition of CYP2C19

St. John’s Wort

Potential for additive increase in serotonin resulting in serotonin syndrome

St. John’s Wort induces P-glycoprotein, CYP1A2; to a lesser extend CYP3A4 and possibly CYP2C19. Decreased plasma levels of SGAs (in particular asenapine, clozapine, quetiapine, risperidone, and olanzapine) reported (mechanism unclear)

Sympathomimetic

Epinephrine/adrenaline, dopamine

Cocaine

AVOID using for the treatment of SGA-induced hypotension. May result in paradoxical fall in blood pressure, as antipsychotics block peripheral α1-adrenergic receptors, thus inhibiting α-vasoconstricting effects of epinephrine and leaving β-vasodilator effects relatively unopposed

Case reports of EPS, particularly dystonia, with concurrent use of ziprasidone and risperidone, possibly via dopamine depletion from chronic use of cocaine; case report of clozapine causing a dose-dependent increase in plasma concentration of intranasal cocaine dose, though the positive effects of cocaine were reduced

Case reports of severe hypotension in those with quetiapine overdose who were given IV epinephrine. Substitution with norepinephrine resolved the problem. Case report of severe hypotension with olanzapine and venlafaxine overdose unresponsive to IV dopamine but responsive to norepinephrine

Norepinephrine and phenylephrine are safe substitutes for severe hypotension unresponsive to uids

Bene ts may outweigh risk in anaphylaxis

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Third-Generation Antipsychotics/TGAs

Product Availability∗

Generic Name

Chemical Class

Trade Name

Dosage Forms and Strengths

Aripiprazole

Phenylpiperazine

Abilify

Abilify Discmelt(B)

Tablets:2mg,5mg,10mg,15mg,20mg,30mg Oral solution(B) : 1 mg/mL

Short-acting injection(B) : 9.75 mg/1.3 mL (7.5 mg/mL) Oral disintegrating tablets: 10 mg, 15 mg

Abilify Maintena Aristada(B) Aristada Initio(B)

Long-acting injection: 300 mg/vial, 400 mg/vial

Prolonged-release injectable suspension in pre- lled syringe: 441 mg/1.6 mL, 662 mg/2.4 mL, 882 mg/3.2 mL Extended-release injectable suspension in single-dose pre- lled syringe: 675 mg/2.4 mL

Brexpiprazole

N-arylpiperazine

Rexulti

Tablets: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg,

Cariprazine

Phenylpiperazine

Vraylar(B)

Capsules: 1.5 mg, 3 mg, 4.5 mg, 6 mg

∗ Refer to Health Canada’s Drug Product Database or the FDA’s Drugs@FDA for the most current availability information (B) Not marketed in Canada Indicationsa ‡

( approved)

Schizophrenia:

– Treatment in adults (aripiprazole, aripiprazole long-acting injection, aripiprazole prolonged-release injectable, brexpiprazole – Canada and USA;

cariprazine – USA) and adolescents (aged 15–17 years: aripiprazole – Canada; 13–17 years: aripiprazole – USA) – Agitationassociatedwithschizophrenia(aripiprazoleshort-actinginjection–USA)

• Schizoa ective disorder (subpopulation in RCTs[21] )

Bipolar I disorder:

– Acute manic/mixed episodes (aripiprazole as monotherapy or as adjunctive therapy with lithium or valproate in adults – Canada and USA;

cariprazine as monotherapy – USA)

– Maintenance treatment (aripiprazole, aripiprazole long-acting injection as adjunctive therapy with lithium or valproate – Canada and USA;

aripiprazole, aripiprazole long-acting injection as monotherapy – USA)

– Agitationassociatedwithmanic/mixedepisodes(aripiprazoleshort-actinginjection–USA)

Adjunctive treatment to antidepressants (aripiprazole – Canada and USA; brexpiprazole – USA)

• Addiction:Alcohol,amphetamines,cocaine(aripiprazole–limitedstudies,somesuggestalackofe cacyandpotentialforincreaseddrugabuse)

• Anxietydisorders(aripiprazole–small,openstudiesinavarietyofanxietydisorderssuggestingbene t)

• Borderlinepersonalitydisorder(aripiprazole–small,short-termRCT)

• Delirium(aripiprazole–smallopenorcohortstudies)

• Dementia-related psychosis or agitation (aripiprazole – meta-analysis: small but statistically signi cant e ect). Product monographs highlight safety concerns in the elderly with dementia

Schizophrenia & Psychotic Disorders

Bipolar Disorder

Depression

Other

a Adult population unless otherwise stated ‡ Indications listed here do not necessarily apply to all countries. Please refer to a country’s regulatory database (e.g., US Food and Drug Administration, Health Canada Drug Product Database) for the most current availability information and indications

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 161 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

General Comments

Third-Generation Antipsychotics/TGAs (cont.)

• Parkinson’s disease: Dyskinesia due to levodopa (aripiprazole – small open-label study using very low doses); psychosis (aripiprazole – open study with mixed results)

• Tourette’ssyndromeandticdisorders(aripiprazole–smallstudiessuggestingbene t)

• TGAs may be classi ed as atypical antipsychotics and are sometimes referred to as second-generation antipsychotics although they have distinct pharmacological pro les (see below)

• TGAshavecomparablee cacytootherantipsychoticagentsinthetreatmentofpositivesymptoms

• TGAsareassociatedwithaloweroverallriskof:

– Metabolic adverse e ects (such as weight gain, dyslipidemias, and glucose intolerance/diabetes mellitus) vs. many SGAs – monitoring for such e ects is still advised

– EPS(mostnotably,akathisiahasbeenreported)

– Hyperprolactinemia

– Sedation

– Anticholinergice ects

• Mostnotableadversee ectsofTGAs:

– Maycausedizzinessand/ororthostatichypotensionduringinitiationordosageincrease – Insomnia

– Activation/akathisia

• TGAs have long half-lives which may result in delayed-onset adverse events (see Pharmacokinetics pp. 164 and 189). They require dosage adjust- ment with potent inhibitors of CYP2D6 and/or 3A4 (see Dosing with concomitant medications pp. 163 and Drug Interactions pp. 170–173

• TGAs act as partial agonists with high a nity at pre- and post-synaptic D2 receptors and serotonin (5-HT1A) receptors, and as antagonists at 5-HT2A receptors

• Aripiprazoleexhibitshigha nityfordopamineD2andD3,serotonin5-HT1A,and5-HT2Areceptorsandmoderatea nityfordopamineD4,serotonin 5-HT2C and 5-HT7, α1, and histamine H1 receptors as well as for the serotonin reuptake site. It has no appreciable a nity for cholinergic muscarinic receptors

• Brexpiprazole acts as a partial agonist at the 5HT1A, D2 (high a nity), and D3 (high a nity) receptors and as an antagonist at 5-HT2A, 5-HT2B, 5-HT7, α1A, α1B, α1D, and α2C receptors. It also exhibits a nity for histamine H1 and muscarinic M1 receptors

• Cariprazine acts as a partial agonist at dopamine D2 and D3 receptors with high binding a nity and at serotonin 5-HT1A receptors. It acts as an antagonist at 5-HT2A (moderate a nity) and 5-HT2B (high a nity) receptors as well as binding to histamine H1 receptors. It shows lower binding a nity to the serotonin 5HT2C and α1A-adrenergic receptors and has no appreciable a nity for cholinergic muscarinic receptors

• As a partial dopamine agonist, the intensity of interaction with the dopamine receptor is less than that of endogenous dopamine (intrinsic activity = 100%). Accordingly, the net e ect of dopamine partial agonism depends on whether a hypo- or hyperdopaminergic state exits. In areas of hypodopaminergic activity, partial D2 agonism results in an increase in overall dopaminergic function (postulated as an explanation for bene t in negative symptoms and a ective symptoms, and less EPS). Conversely, in areas of hyperdopaminergic activity, partial D2 agonism results in a net decrease in dopaminergic function (postulated as explanation for improvement of positive symptoms)

• Seetablep.188formoreinformationondosingforschizophreniaandpsychosis

• Activation,agitation,akathisiaand/orinsomniamayoccuroninitiationofTGAs.Somepractitionersrecommenddosinginthemorningandstarting

with a lower dose than is recommended by the monograph

• Schizophrenia:

– Aripiprazole: Begin at 10 or 15 mg orally once daily. If needed, increase at intervals of 2 weeks or greater, up to 30 mg/day. Doses greater than

10–15 mg/day not shown to have greater e cacy

– Brexpiprazole: Begin at 1 mg orally once daily. If needed, titrate to 2 mg once daily on day 5 of therapy through day 7, then to 4 mg on day 8

Pharmacology

Dosing

based on patient’s clinical response and tolerability. Recommended target dose is 2–4 mg once daily

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

– Cariprazine: Begin at 1.5mg orally daily. Can be increased to 3mg on day 2. Depending on clinical response and tolerability, further dose adjustments can be made in 1.5 mg or 3 mg increments. Recommended dose range is 1.5–6 mg once daily

– Aripiprazolelong-actinginjection(AbilifyMaintena):Forpatientsnaïvetoaripiprazole,establishtolerabilitywithoralaripiprazolepriortoinitiat- ing treatment. Starting dose is 400 mg every 4 weeks with concurrent use of oral aripiprazole 10–20 mg daily for the rst 14 days. Maintenance dose is 400 mg every 4 weeks. If adverse e ects occur, dose may be reduced to 300 mg every 4 weeks. Dosing interval should be no shorter than 26 days. If the 2nd or 3rd dose is missed and time since last injection is more than 5 weeks, or if the 4th or subsequent doses are missed and time since last injection is more than 6 weeks, restart concurrent oral aripiprazole for 14 days

– Aripiprazolelauroxil(Aristada):Forpatientsnaïvetoaripiprazole,establishtolerabilitywithoralaripiprazolepriortoinitiatingtreatment.Starting dose can be 441 mg, 662 mg or 882 mg administered monthly, 882 mg dose every 6 weeks, or 1064 mg dose every 2 months. There are two ways to initiate treatment with aripiprazole lauroxil (Aristada):

• Option1:Administeroneinjectionof675mgofAristadaInitio(ineitherthedeltoidorglutealmuscle)andone30mgdoseoforalaripiprazole in conjunction with the rst aripiprazole lauroxil (Aristada) injection. The rst aripiprazole lauroxil (Aristada) injection may be administered on the same day as Aristada Initio or up to 10 days thereafter. Avoid injecting both Aristarda Initio and aripiprazole lauroxil (Aristada) concomitantly into the same deltoid or gluteal muscle

• Option2:Administer21consecutivedaysoforalaripiprazoleinconjunctionwiththe rstaripiprazolelauroxil(Aristada)injection

Dose adjustments are required for 1) known CYP2D6 poor metabolizers and 2) patients taking CYP2D6 inhibitors, CYP3A4 inhibitors or CYP3A4 inducers for more than 2 weeks

• BipolarI:

– Aripirazole:Startingdoseis15mg(monotherapy)or10–15mg(adjunctivewithlithiumorvalproate)orallyoncedaily;targetdoseis15mgorally

once daily; range is 10–30 mg/day

– Aripirazolelong-actinginjection(AbilifyMaintena):Seedosingforschizophrenia

– Cariprazine:Startingdoseforacutemanicormixedepisodesis1.5mgorallyoncedaily.Canbeincreasedto3mgonday2.Dependingonclinical

response and tolerability, further dose adjustments can be made in 1.5 mg or 3 mg increments. Recommended dose range is 3–6 mg once daily • Majordepression(adjunctivetreatment):

– Aripiprazole:Beginat2or5mgorallyoncedaily.Ifneeded,increasebyupto5mgatintervalsofoneweekorgreater.Usualtreatmentrangeis 2–15 mg/day

– Brexpiprazole: Begin at 0.5 or 1 mg orally once daily. Further dose increases should be done at weekly intervals based on clinical response and tolerability, up to the target dose of 2 mg orally once daily

• Agitation(schizophreniaorbipolarmania/mixedepisode):

– Aripiprazole short-acting IM injection: Usual dose is 9.75 mg IM as a single dose; range is 5.25–15 mg IM; maximum total daily dose is 30 mg.

Wait at least 2 h between doses as shorter intervals have not been studied

– Aripiprazoleoralsolutioncanbesubstitutedfortabletsonamg-per-mgbasisuptothe25mgdoselevel.Patientsreceiving30mgtabletsshould

receive 25 mg of the solution as plasma levels achieved with solution are slightly higher than with the tablet formulation • DoseadjustmentNOTrequiredinsmokersortheelderly

• Concomitantmedications:

– StronginhibitorsofCYP2D6(e.g.,paroxetine)

• Reducedoseofshort-actingaripiprazoleformulationstoonehalf(50%)

• If taking a strong inhibitor for more than 14 days, reduce aripiprazole long-acting injection from 400 mg to 300 mg every 4 weeks, or from

300 mg to 200 mg every 4 weeks

• Reducedoseofbrexpiprazoletohalftheusualdose(50%)

– StronginhibitorsofCYP3A4(e.g.,clarithromycin)

• Reducedoseofshort-actingaripiprazoleformulationstoonehalf(50%)

• If taking a strong inhibitor for more than 14 days, reduce aripiprazole long-acting injection from 400 mg to 300 mg every 4 weeks, or from

300 mg to 200 mg every 4 weeks

• Reducedoseofbrexpiprazoletohalftheusualdose(50%)

• Reduce current dose of cariprazine by 50%. For patients taking 4.5 mg daily, reduce dose to 1.5 mg or 3 mg daily. For patients taking 1.5 mg

daily, adjust dose to every other day. Cariprazine dose may need to be increased if CYP3A4 inhibitor is withdrawn – StronginhibitorsofCYP2D6andCYP3A4

• Reducedoseofshort-actingaripiprazoleformulationstoonequarter(25%)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 163 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Third-Generation Antipsychotics/TGAs (cont.)

• If taking strong inhibitors for more than 14 days, reduce aripiprazole long-acting injection from 400 mg to 200 mg every 4 weeks, or from 300 mg to 160 mg every 4 weeks

• Reducedoseofbrexpiprazoletoonequarteroftheusualdose(25%) – StronginducersofCYP3A4(e.g.,carbamazepine)

• Doublethedoseofshort-actingaripiprazoleformulations

• Iftakingastronginducerformorethan14days,avoiduseofaripiprazolelong-actinginjection • Doubletheusualdoseofbrexpiprazoleover1–2weeks

• Concomitantuseofcariprazinenotrecommended

– Increasethedoseappropriatelyifastronginhibitorisstopped

– Decreasethedoseappropriatelyifastronginducerisstopped • Pharmacogenetics:

– CYP poor metabolizers may be at increased risk of adverse drug events at usual doses and lower starting doses or avoidance of speci c agents may be recommended. CYP intermediate metabolizers have some degree of metabolic activity and have often not been described as “clinically important” with regard to drug dosing adjustments. CYP ultra-rapid metabolizers may be at increased risk of therapeutic failure when certain agents are used; avoiding agents that are substrates for certain CYP isoenzymes or using therapeutic drug monitoring is usually warranted. See https://www.pharmgkb.org for updated clinical guidelines and dosing recommendations when utilizing pharmacogenetic testing

– Foradministrationdetails,pleaseseeNursingImplicationsp.169

• Aripiprazole:Nodosageadjustmentrequired(however,basedonasmall,single-dosestudy)

• Brexpiprazole: If CrCl less than 60 mL/min, administer maximum dose of 2 mg once daily for major depressive disorder; maximum dose of 3 mg

once daily for schizophrenia

• Cariprazine:IfCrCllessthan30mL/min,useisnotrecommended(hasnotbeenstudied),nodosageadjustmentnecessaryifCrCl≥30mL/min

• Aripiprazole:Nodosageadjustmentrequired(however,basedonasmall,single-dosestudy)

• Brexpiprazole: In moderate to severe impairment (Child-Pugh class B or C), administer maximum dose of 2 mg once daily for major depressive

disorder; maximum dose of 3 mg once daily for schizophrenia; no dose adjustment necessary for mild impairment

• Cariprazine: In moderate to severe impairment (Child-Pugh class of B or C) use is not recommended; no dose adjustment necessary for mild

impairment

• Alsoseetablep.188

• AllTGAscanbetakenwithorwithoutfood

• Oral:

– Bioavailability of aripiprazole tablet is 87%. At equivalent doses, peak plasma concentrations from the oral solution are higher (by ~22%) than from the tablet formulation

– Timetopeakplasmaconcentration(Tmax)is3–5hwhentakenonanemptystomach,andupto6hiftakenwithahigh-fatmeal

– Bioavailabilityofbrexpiprazoleis95%.Aftersingledoseadministrationofbrexpiprazoletablets,peakplasmaconcentrationsoccurredwithin4h

– Bioavailability of cariprazine is high and after single dose administration of cariprazine, peak plasma concentrations occurred in approximately

3–6 h

• Aripiprazoledisintegratingtablet:

– Bioequivalenttooraltablet.Dissolvesinsalivawithin15sec.Recommendedtobetakenwithoutliquid,butcanbegivenwithliquidifneeded

• Aripiprazoleshort-actingIMinjection:

– Bioavailabilityis100%

– Time to peak plasma concentration Tmax is 1–3 h

• Aripiprazolelong-actingIMinjection:

Renal Impairment

Hepatic Impairment

Pharmacokinetics

Absorption

– Time to peak plasma concentration Tmax is 5–6 days

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Distribution

Metabolism and Elimination

Adverse Effects

• Proteinbindingofarripiprazoleanddehydro-aripiprazole(major,activemetabolite)ismorethan99%(primarilytoalbumin).Volumeofdistribution at steady state is high (404 L or 4.9 L/kg), indicating extensive extravascular distribution

• Brexpiprazole is highly protein bound in plasma (over 99%) to serum albumin and α1-acid glycoprotein, and its protein binding is not a ected by renal or hepatic impairment. Volume of distribution following intravenous administration is high (1.56 ± 0.42 L/kg), indicating extravascular distribution

• Cariprazineanditsmajoractivemetabolitesarehighlybound(91–97%)toplasmaproteins

• Aripiprazole:

– Metabolismofaripiprazoleishepatic,primarilyviatheP450isozymesCYP2D6(dehydrogenation,hydroxylation)andCYP3A4(dehydrogenation,

hydroxylation, N-dealkylation)

– Dehydro-aripiprazole is the major metabolite of aripiprazole. It is active, represents 40% of parent drug exposure in plasma, and has similar

a nity for D2 receptors

– Mean half-lives are about 75 h and 94 h for aripiprazole and dehydro-aripiprazole, respectively. Steady-state concentrations for oral doses are

attained within 14 days for both active moieties while they take 3–4 months to reach with aripiprazole long-acting injections

– Half-lifeandaripiprazoleexposurearein uencedbycapacitytometabolizeCYP2D6substrates.Ariprazoleexposureincreasesbyabout80%and dehydro-aripiprazole exposure decreases by about 30% in poor CYP2D6 metabolizers. In extensive CYP2D6 metabolizers, aripiprazole’s half-life = 75 h vs. poor metabolizers = 146 h. Steady-state concentrations may take 28 days to be attained in poor metabolizers. The majority of the population are extensive CYP2D6 metabolizers. Approximately 8% of Caucasians, 3–8% of Black/African Americans, 3–6% of Hispanics, 0–4% of

Native Americans, and 0.3–1% East Asians are poor CYP2D6 metabolizers

– Excretion of an oral dose is via feces (55%, with about 18% as unchanged aripiprazole) and urine (25%, with less than 1% as unchanged

aripiprazole)

• Brexpiprazole:

– Metabolismofbrexpiprazoleishepatic,primarilyviaCYP2D6andCYP3A4

– Itsmajormetaboliteisnotconsideredtocontributetothetherapeutice ectsofbrexpiprazole

– CYP2D6poormetabolizershavehigherbrexpiprazoleconcentrationsthannormalmetabolizersofCYP2D6.Approximately8%ofCaucasiansand

3–8% of Black/African Americans cannot metabolize CYP2D6 substrates and are classi ed as poor metabolizers

• Cariprazine:

– Extensively metabolized by CYP3A4 and, to a lesser extent, by CYP2D6 to two major active metabolites: desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR). DCAR is further metabolized into DDCAR by CYP3A4 and CYP2D6. DDCAR is then metabolized by CYP3A4 to a hydroxylated metabolite

– DCARandDDCARarepharmacologicallyequipotenttocariprazine

– Half-lives based on time to reach steady state, estimated from the mean concentration-time curves, are 2–4 days for cariprazine and approxi-

mately 1–3 weeks for DDCAR

– CYP2D6poormetabolizerstatusdoesnothaveclinicallyrelevante ectonpharmacokineticsofcariprazine,DCAR,orDDCAR

• SeeGeneralComments(p.162)andp.181foraquicksummary

• Adverse events may rst appear several weeks after the initiation of TGA treatment, probably because plasma levels of TGAs and their major

metabolites accumulate over time. As a result, the incidence of adverse reactions in short-term trials may not re ect the rates after longer-term

exposure

• A2013studyofthelong-termsafetyandtolerabilityofaripiprazolelong-actinginjectionreportedatolerabilitypro lecomparabletooralaripipra-

zole. Treatment-emergent adverse e ects occurring at rate of 5% or more were anxiety, akathisia, headache, nausea, and weight gain

• Mostcommonadversereactions(over5%andatleasttwicetherateofplacebo)forbrexpiprazoleintwopooled6-weeks,placebo-controlled,MDD trials (dose range 1–4 mg once daily) were akathisia and weight gain; however, incidence of these adverse events was lower (less than 5%) in two

short-term (up to 6 weeks) schizophrenia trials

• Basedonfourplacebo-controlled,6-weekschizophreniatrialswithcariprazinedosesrangingfrom1.5mgto12mgoncedaily,themostcommon

adverse e ects (over 5% and at least twice the rate of placebo) were EPS and akathisia. The pooled data from three short-term cariprazine trials with dose range of 3–12 mg once daily in bipolar mania (duration of 3 weeks) suggested the most common adverse e ects (over 5% and at least twice the rate of placebo) are EPS, akathisia, dyspepsia, vomiting, somnolence, and restlessness

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 165 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Third-Generation Antipsychotics/TGAs (cont.)

• Aripiprazolecommonlyreportedadversee ectsinclude:Headache(morethan20%),agitation(morethan15%),anxiety(morethan25%),insomnia (more than 15%), nervousness, lightheadedness, and dizziness (more than 10%), somnolence (more than 10%), and asthenia. Many of these develop during the rst week of treatment and resolve over time. A lower starting dose of 2–5 mg once daily may minimize many of these adverse e ects

• Basedonpooleddatafromshort-termtrials,brexpiprazoleandcariprazineseemtocauselessagitation,insomnia,andsedation(lessthan10%)

• EPS–acuteonset

– Aripiprazole has a favorable EPS pro le, though dystonia, akathisia reported; tremor (mostly described as mild intensity, limited duration) re- ported (more than 2%); case report of exacerbation of Parkinson’s disease and 2 case reports of rabbit syndrome

– Based on pooled data from short-term trials, brexpiprazole appears to cause less akathisia (less than 10%) compared to aripiprazole and cariprazine (more than 10%)

• EPS–lateonsetortardivemovementdisorders(TD):RiskofTDappearshighestamongtheelderly,especiallyelderlywomen,butitisnotpossible to predict which patients are likely to develop the syndrome. Whether TGA drug products di er in their potential to cause TD is unknown. Case reports of tardive movement disorders associated with aripiprazole in literature

• Neurolepticmalignantsyndromehasbeenreportedinpatientstreatedwitharipiprazole.AlsorhabdomyolysisintheabsenceofadiagnosisofNMS

• SeizureincidenceinpatientsreceivingTGAsisreportedtobelessthan2%–usecautiouslyinindividualswithahistoryofseizures,poorlycontrolled

seizures, or medications and/or conditions known to lower the seizure threshold

• ArrhythmiasandECGchanges

– ECG changes (e.g., T-wave inversion, ST segment depression, QTc lengthening – may increase risk of arrhythmias) reported with many antipsy-

chotic medications, the clinical signi cance of which is unclear for many. See p. 139

– One published case report associated aripiprazole with the development of torsades de pointes (TdP). CredibleMeds risk category rated as

“possible risk of TdP” – (see p. 139 for more information)

• Cardiomyopathy – 1 case report noting eosinophilic myocarditis and elevated levels of aripiprazole found on autopsy of a 36-year-old male with

schizophrenia

• Dyslipidemias–seeEndocrine&MetabolicE ects

• Orthostatichypotension/compensatorytachycardia/dizziness/syncope–antagonismofα1-adrenergicreceptorsmayresultinorthostatichypoten-

sion, dizziness, and re ex tachycardia. Incidence appears low with TGAs

• Antidiuretichormonedysfunction–afewcasesofhyponatremia/SIADHdocumentingresolutionwithin7–10daysofaripiprazolediscontinuation have been reported

• Dyslipidemias–riskappearslowwithTGAs;monitoringstillsuggested–seep.110forsuggestedmonitoringguidelines

– Inlong-term,open-labelschizophreniastudies,shiftsinnormalbaselinefastingtriglyceridewereobservedin13%ofpatientsonbrexpiprazole

(to triglyceride level of less than 500 mg/dL); less than 1% patients had increase in triglyceride resulting in level of more than 500 mg/dL

• Glucosedysregulation,ketoacidosis,type2diabetesmellitus;riskappearslowwithTGAs;casereportsofhyperglycemiaandofdiabeticketoacidosis

in patients treated with aripiprazole, so monitoring still suggested – see p. 110 for suggested monitoring guidelines

• Hyperprolactinemia – partial D2 agonists appear to have minimal e ect on prolactin and, in some cases, a drop in prolactin levels has been reported. However, a few cases of galactorrhea have been reported; assess for signs and symptoms routinely. For more information on hyperprolactinemia

symptoms, monitoring, and treatment options see p. 141

• Seerelativetolerabilitypro lestablep.178foracomparisonofthelikelihoodofweightgainamongantipsychotics

• Constipation incidence reported to be more than 10% in aripiprazole-treated patients. Based on pooled short-term data, incidence seems to be lower in brexpiprazole-treated patients (2–3%). 6% incidence reported in cariprazine-treated patients in short-term trials

• Dysphagiaandaspirationreportedwithantipsychoticuse;usecautiouslyinindividualsatriskfordevelopingaspirationpneumonia(e.g.,advanced Alzheimer’s disease)

• Nauseaandvomitingreportedinmorethan10%ofpatientsreceivingaripiprazole,generallyseenatstartoftherapy;appearstodissipateoverthe rst week. Based on pooled data from short-term trials, incidence of nausea and vomiting seems to be lower with brexpiprazole (less than 10%). Incidence of nausea with cariprazine appears to be higher (more than 10%)

CNS Effects

Cardiovascular Effects

Endocrine & Metabolic Effects

GI Effects

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Urogenital and Sexual Effects

Hematological Effects

Hepatic Effects

Hypersensitivity Reactions

Other Adverse Effects

Discontinuation Syndrome

• Priapism–casereportofrecurrentpriapismstarting6hafterthe rstdoseofaripiprazole

• Based on their pharmacological pro le (D2 partial agonist in tuberoinfundibular tract translating into less hyperprolactinemia and low a nity for

cholinergic receptors), it seems unlikely that these agents would cause sexual dysfunction

• The 2009 PORT treatment recommendations for schizophrenia rank the relative risk for prolactin elevation and sexual side e ects with antipsy-

chotics as follows: Risperidone = paliperidone > FGA medications > olanzapine > ziprasidone > quetiapine = clozapine > aripiprazole

• Leukopenia and neutropenia reported during treatment with antipsychotics, including TGAs. A few case reports suggest a possible association of aripiprazole and the development of leukopenia and/or neutropenia, and thrombocytopenia

• StopTGAtreatmentifneutrophilcountdropsbelow1.0ô109/L(1000/mm3)

• Elevationsinliverfunctiontests(ALT,AST,BUN)reportedinfrequently

• Rareoccurrencesofallergicreaction(anaphylacticreaction,angioedema,laryngospasm,pruritus/urticaria,ororopharyngealspasm)reported

• Acneiformeruption–casereportofacneiformeruptionswhichresolvedupondiscontinuationofaripiprazole

• Raynaud’sphenomenon,epistaxis,gingivalbleeding(rare)witharipiprazole

• Hiccups

• Blurredvision(2.5%)

• Rhinitisandpharyngitis

• Withdrawalsymptomsreportedsimilartothoseseenwithotherclassesofantipsychotics.However,duetothelongeliminationhalf-livesofTGAs, these medications may self-taper with few withdrawal symptoms if promptly discontinued. See Discontinuation Syndrome p. 144 for a general discussion.

• Sincearipiprazoleandcariprazinehaveminimala nityforcholinergicmuscarinicreceptors,anabruptswitchfromanagentwithhigha nityfor these receptors to aripiprazole could result in symptoms of cholinergic rebound upon withdrawal of the initial antipsychotic

• Utilizing the delayed withdrawal method when switching from an SGA/FGA to a TGA may be advisable. Theoretically, an abrupt switch from a D2 antagonist to a D2 partial agonist (aripiprazole, brexpiprazole, and cariprazine) could result in a temporary surge of dopaminergic activity as a result of unmasking upregulated D2 receptors. In the mesolimbic tract, this could translate into a temporary exacerbation of positive symptoms. The same actions in the nigrostriatal tract could result in the onset of withdrawal dyskinesias. It may be advisable to use the delayed withdrawal method when switching to aripiprazole to minimize the occurrence of these e ects

• Readersmay ndthewebsitehttp://switchrx.cahelpfulformanagingantipsychoticswitching

• Cautioninpatientswithknowncardiovasculardisease,cerebrovasculardisease,seizuredisordersorconditionsthatpredisposepatientstohypoten- sion or aspiration pneumonia

• Increased risk of suicidal thinking in children, adolescents, and young adults; occurrence of pathological gambling or other impulsive activities (aripiprazole – possibly others), neuroleptic malignant syndrome, tardive dyskinesia, cognitive and motor impairment, risk of falling, metabolic changes, leukopenia, neutropenia, and agranulocytosis

• Aripiprazole:

– A retrospective study of 286 cases of isolated aripiprazole exposures found 55% of patients reported symptoms – somnolence (56%), sinus

tachycardia (20%), nausea/vomiting (18%), dystonia (13%), tremor (6%), agitation, dizziness (2%), paresthesias, headache (1%)[22] – A2009reviewofatypicalantipsychoticoverdosessuggestedcardiovasculartoxicitywitharipiprazoleingestionwasminimal[23]

– Acuteingestionsofupto1080mgaripiprazolereportedwithnofatalities

• Thereislimitedclinicaltrialexperiencewithbrexpiprazoleandcariprazineoverdose

• No speci c antidote is available. Close medical supervision, monitoring of vital signs and functions including cardiac function, and supportive therapy to maintain airways and oxygenation and manage symptoms is required. Early administration of charcoal may help in partially preventing absorption of aripiprazole or brexpiprazole. Hemodialysis is not deemed likely to be of bene t due to aripiprazole’s or brexpiprazole’s high plasma protein binding

• Nospeci cantidotesforcariprazineareknown.Inmanagingoverdose,providesupportivecare,includingclosemedicalsupervisionandmonitoring, and consider the possibility of multiple drug involvement. Consult a Certi ed Poison Control Center for up-to-date guidance and advice

Precautions

Toxicity

Management

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 167 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Lab Tests/Monitoring

Use in Pregnancy♢

Third-Generation Antipsychotics/TGAs (cont.)

• TherapeuticrangenotestablishedforTGAs

• Onestudysuggestsbeste cacyforschizophreniawithserumaripiprazolelevelsbetween150and300ng/mLandminimaladversee ectswhen

levels are between 110 and 249ng/mL. A target plasma level range between 150 and 210ng/mL has also been proposed. Therapeutic drug monitoring suggested to be of limited value other than assessing adherence, optimizing e cacy

• Aripiprazole:

– Pregnancy alters the pharmacokinetic pro le of aripiprazole, a 52% decrease of serum aripiprazole concentrations was observed in the third

trimester. Pregnancy induces CYP2D6 and 3A4 enzymes, therefore TGAs, which are substrates for these metabolic pathways, may have reduced

concentrations in late pregnancy. Consider therapeutic drug monitoring if indicated

– Aripiprazoleisconsideredadrugwith“Limitedhumandata–Animaldatasuggestrisk”

– Chemical properties (e.g., small molecular weight) and measurement of umbilical cord blood levels of aripiprazole and dehydro-aripiprazole at

delivery in case reports indicate aripiprazole and dehydro-aripiprazole both cross the human placenta

– Noteratogenicityordevelopmentaltoxicitywereseenineightcases.Fiveoftheminvolvedexposureatsomepointduringthe rsttrimester,the

trimester most sensitive to structural malformations. There was increased risk of malformations, in particular cardiovascular defects, in a cohort

study of SGAs where 60 of 561 patients were taking aripiprazole at some time during pregnancy

– Thefollowingadverseeventshavebeenreportedwiththird-trimesterexposuretoaripiprazole:Fetaldistress(i.e.,tachycardia)duringlaborwith

subsequent failure to establish lactation, mild respiratory distress 10 min post-delivery, and no spontaneous breath with poor muscle tone just

after birth requiring short-term (1 min) resuscitation

• Brexpiprazole:

– Adequate and well-controlled studies with brexpiprazole have not been conducted in pregnant women to inform drug-associated risks. In animal reproduction studies, no teratogenicity was observed with oral administration of brexpiprazole to pregnant rats and rabbits during organogenesis at doses up to 73 and 146 times, respectively, of the maximum recommended human dose (MRHD) of 4 mg/day on a mg/m2 basis. However, when brexpiprazole was administered to pregnant rats during the period of organogenesis through lactation, the number of perinatal deaths of pups was increased at 73 times the MRHD. The background risk of major birth defects and miscarriage for the indicated population(s) is unknown

• Cariprazine:

– There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to cariprazine during pregnancy. For more infor-

mation, contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-

and-researchprograms/pregnancyregistry/

– Noavailabledataoncariprazineuseinpregnantwomentoinformanydrug-associatedrisksforbirthdefectsormiscarriage

– Based on animal data, cariprazine may cause fetal harm. Administration of cariprazine to rats during the period of organogenesis caused

malformations, lower pup survival, and developmental delays at drug exposures less than the human exposure at the maximum recommended

human dose (MRHD) of 6 mg/day

• If an antipsychotic will be used during pregnancy, consider patient enrollment or registration in any relevant studies or pregnancy exposure

registries (e.g., in Canada: Motherisk list of current studies http://www.motherisk.org/prof/currentStudies.jsp; in the USA: FDA list of pregnancy registries http://www.fda.gov/scienceresearch/specialtopics/womenshealthresearch/ucm134848.htm)

• Aripiprazole:

– Casereportsindicatearipiprazolelikelytransferstobreastmilkwiththerelativeinfantdoseestimatedtobelessthan0.7%to8.3% – Possibilityofsomnolenceinbreastfedinfants

– Hale’slactationriskcategory=L3(giveonlyifthepotentialbene toutweighsthepotentialrisktotheinfant)

• Brexpiprazole: Lactation studies have not been conducted to assess the presence of brexpiprazole in human milk, the e ects of the drug on the breastfed infant, or the e ects on milk production

Breast Milk

♢ See p. 439 for further information on drug use in pregnancy and e ects on breast milk

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Nursing Implications

• Cariprazine:Lactationstudieshavenotbeenconductedtoassessthepresenceofcariprazineinhumanmilk,thee ectsofthedrugonthebreastfed infant, or the e ects on milk production

• The development and health bene ts of breastfeeding should be considered along with the mother’s clinical need for TGAs and any potential adverse e ects on the breastfed infant from the medication or from the underlying maternal condition. Refer to the Drugs and Lactation Database (LactMed) website (http://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm) for more information

• Seep.112

• TGAscanbetakenwithorwithoutfood

• AVOIDgrapefruitjuice(seeDrugInteractionsp.172)

• Aripiprazoledisintegratingtabletsdissolverapidlyinsaliva;recommendedtobetakenWITHOUTliquid,butifneededcanbetakenwithliquid

• Aripiprazoledisintegratingtabletsbreakeasily.DoNOTpushthetabletthroughthefoilbackingasthiscoulddamagethetablet.Usedryhandsto

remove the tablet and immediately place tablet on the tongue

• Aripiprazoleoralsolutioncanbeusedforupto6monthsafteropening,butnotbeyondtheexpirationdateonthebottle.Storeatroomtemperature

• EachmLoforalsolutioncontains400mgofsucroseand200mgoffructose

• Availableasaready-to-usesolutionof9.75mg/1.3mLinasingle-dosevialforIMadministrationonly.Discardanyunusedportionofthevial

• Injectslowly,deepintothemusclemass

• Waitatleast2hbetweendoses

• AbilifyMaintena:

– Resconstitutepowderwithprovideddiluent.Shakevialvigorouslyfor30secuntilthesuspensionappearsuniform

– Canstorethereconstitutedmixtureinthevialatroomtemperatureforupto4h.Reshakevialvigorouslyforatleast60secbeforeuse – Injectslowly,deepintothedeltoidorglutealmuscle

– Fordeltoidadministration:Use23gauge,1-inchneedlefornon-obesepatientsand22gauge,1.5inchneedleforobesepatients

– Forglutealadministration:Use22gauge,1.5-inchneedlefornon-obesepatientsand21gauge,2-inchneedleforobesepatients

– DoNOTmassagetheinjectionsite

– Rotatesites

• Aristada:

– Suppliedasinjectablesuspensioninpre- lledsyringe

– Canbestoredatroomtemperature(20–25degreesCelsius)

– Tapsyringeatleast10timestodislodgeanymaterialwhichmayhavesettled

– Shakesyringevigorouslyforaminimumof30sectoensureauniformsuspension.Ifsyringeisnotusedwith15min,shakeagainfor30sec

– The 441 mg (1.6 mL) strength kit contains a 1-inch 21 gauge, a 1.5-inch 20 gauge, and a 2-inch 20 gauge needle. Can be given in deltoid or

gluteal muscle

– The662mg(2.4mL),882mg(3.2mL),and1064mg(3.9mL)strengthkitscontaina1.5-inch20gaugeanda2-inch20gaugeneedle.Forgluteal

administration only

– DoNOTmassagetheinjectionsite – Rotatesites

• AristadaInitio:

– Suppliedasinjectablesuspensioninpre- lledsyringe

– Canbestoredatroomtemperature(20–25degreesCelsius)

– Tapsyringeatleast10timestodislodgeanymaterialwhichmayhavesettled

– Shakesyringevigorouslyforaminimumof30sectoensureauniformsuspension.Ifsyringeisnotusedwith15min,shakeagainfor30sec

– The 675 mg (2.4 mL) kit contains a 1-inch 21 gauge, a 1.5-inch 20 gauge, and a 2-inch 20 gauge needle. Can be given in deltoid (using a 1-inch

21 gauge or a 1.5-inch 20 gauge needle) or gluteal (using a 1.5-inch 20 gauge or a 2-inch 20 gauge needle – DoNOTmassagetheinjectionsite

Oral

Aripiprazole Short-Acting IM Injection

Aripiprazole Long-Acting IM Injection

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 169 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Drug Interactions

Third-Generation Antipsychotics/TGAs (cont.)

• Clinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterforthesecondagent

Class of Drug

Example

Interaction Effects

Acetylcholinesterase inhibitor (central)

General

Donepezil, galantamine, rivastigmine

Increase in mortality in elderly patients with dementia taking antipsychotics irrespective of acetylchoinesterase inhibitor use. Deaths largely either cardiovascular or infectious in nature. Also see p. 112

May enhance neurotoxicity of antipsychotics, presumably due to a relative acetylcholine/dopamine imbalance (i.e., increased acetylcholine in the presence of dopamine receptor blockade) in the CNS

Antiarrhythmic

General Quinidine

Amiodarone

Possible additive prolongation of QT interval and associated life-threatening cardiac arrhythmias. However, aripiprazole, brexpiprazole, and cariprazine appear to have a low potential to prolong the QT interval compared to other antipsychotics. Also see TGA Cardiovascular Effects p. 166

Quinidine is a potent CYP2D6 inhibitor resulting in an increased AUC of aripiprazole by 107–112% (i.e., doubled). AUC of active metabolite decreased by 32–35%. Due to aripiprazole’s long half-life, interaction effects may be delayed for up to 10–14 days. Brexpiprazole AUC was approximately 2-fold higher with concurrent use of quinidine (brexpiprazole’s major metabolite is inactive). Cariprazine does not get metabolized extensively by CYP2D6, consequently the interaction with quinidine might not be clinically signi cant

Amiodarone is a CYP2D6 inhibitor. Increased plasma level of aripiprazole and brexpiprazole possible

Antibiotic

Clarithromycin, erythromycin, telithromycin

CYP3A4 is inhibited potently by clarithromycin and telithromycin, and moderately by erythromycin. Increased plasma level of aripiprazole, brexpiprazole, and cariprazine likely to occur. Effects may be delayed due to the their long half-life

Anticonvulsant

General

Carbamazepine, oxcarbazepine

Clobazam Lamotrigine

Phenobarbital, phenytoin Valproate (divalproex, valproic acid)

As with other antipsychotics, aripiprazole, brexpiprazole, and cariprazine may lower seizure threshold. Monitor for increased seizure frequency and increase anticonvulsant medication as needed. See also Antipsychotic Augmentation Strategies p. 198

CYP3A4 is induced potently by carbamazepine and weakly by oxcarbazepine

Carbamazepine reduces Cmax and AUC of aripiprazole and its active metabolite by about 70% with concurrent use and one week after discontinuing carbamazepine. Brexpiprazole prescribing information recommends increase in dose when used concomitantly with strong CYP3A4 inducer. Cariprazine prescribing information recommends concomitant use to be avoided

Note it may take 2–4 weeks to reach maximum induction and an equivalent period to return to baseline after discontinuation of an inducer. Oxcarbazepine at higher dose (i.e., ≥ 1500 mg/day) may result in a clinically relevant induction of aripiprazole

Clobazam may cause potent CYP2D6 inhibition and weak CYP3A4 induction

No clinically signi cant pharmacokinetic changes. Case reports of adverse effects with concurrent use: Three cases of Stevens-Johnson syndrome within 2–4 weeks after adding lamotrigine to aripiprazole; one case of disabling intention tremor

2 months after the addition of aripiprazole to lamotrigine which resolved on lamotrigine discontinuation; one case of false-positive diagnosis of pheochromocytoma

Phenobarbital and phenytoin are potent CYP3A4 inducers. Degree of induction likely similar to the interaction between aripiprazole, brexpiprazole, and cariprazine and carbamazepine

Case report of leucopenia and thrombocytopenia with addition of aripiprazole (10 mg/day) to phenytoin (300 mg/day)

Mild reductions of aripiprazole’s Cmax and AUC (by up to 25%). Not clinically signi cant. No dose adjustment required. Approved for

concurrent use in the management of bipolar disorder. Adverse effects reported with concurrent use include: More frequent – akathisia, increased triglyceride levels, tiredness, tremor, weight gain; serious – one case of severe abdominal pain

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Class of Drug

Example

Interaction Effects

Antidepressant

SSRI

NDRI

SNRI

General

Citalopram, escitalopram, sertraline

Fluoxetine, paroxetine

Fluvoxamine Bupropion

Duloxetine

Venlafaxine

Increased rates of akathisia and fatigue with concurrent antidepressant use

Serotonin syndrome theoretically possible with antidepressants that increase serotonin (e.g., SNRIs, SSRIs)

No clinically signi cant pharmacokinetic changes to escitalopram, sertraline or aripiprazole. Adverse effect case reports with citalopram and aripiprazole include one of urinary obstruction and one of EPS. Adverse effect case reports with sertraline (at

200 mg/day) and aripiprazole include one each of severe akathisia, acute dystonia, and myxedema coma

Fluoxetine and paroxetine are signi cant CYP2D6 inhibitors. Increased aripiprazole levels (30–70%) reported. Effects may be delayed due to the antipsychotic’s long half-life. Small changes in uoxetine (18% increase), nor uoxetine (36% increase), and paroxetine (27% decrease) levels reported. Case reports with uoxetine and aripiprazole of: NMS 2 weeks after starting the combination; leucopenia that resolved on aripiprazole discontinuation and reoccurred on rechallenge

Secondary to strong inhibition of CYP2D6, dosage decrease has been recommended for brexpiprazole

Fluvoxamine is a weak CYP2D6 and CYP3A4 inhibitor. Clearance of aripiprazole may be reduced by 40%. Clinical signi cance unknown

CAUTION. Potential for additive risk of seizures. No published reports of seizures with concurrent use, however, data limited to six patients. Bupropion is an inhibitor of CYP2D6, which could increase aripiprazole and brexpiprazole levels. No published reports of aripiprazole levels with concurrent bupropion. In the six cases of concurrent use, akathisia and/or insomnia occurred in at least three

Duloxetine is a moderate CYP2D6 inhibitor, however, a study found no signi cant change in aripiprazole levels. Case report of high aripiprazole levels, confusion, and loss of coordination in a patient taking high-dose aripiprazole (50 mg/day) with darunavir and ritonavir (modest CYP2D6 and potent CYP3A4 inhibitors) and duloxetine. Case report of hypertensive crisis within 2 weeks of adding aripiprazole to duloxetine; blood pressure decreased on aripiprazole dose reduction

No clinically signi cant pharmacokinetic changes. Case report of hypertensive crisis with confusion and agitation 2 days after

adding apiprazole to venlafaxine which resolved on aripiprazole discontinuation. Two case report of parkinsonism with concurrent use of venlafaxine and aripiprazole

Antifungal

Fluconazole, itraconazole, ketoconazole, voriconazole

Terbina ne

Ketoconazole and itraconazole are potent, while uconazole and voriconazole are moderate CYP3A4 inhibitors. AUC of aripiprazole and metabolite increased by 63% and 77% with ketoconazole and 48% and 39% with itraconazole, respectively

AUC of brexpiprazole approximately 2-fold higher with concurrent administration of ketoconazole. Refer to dosing recommendations for concurrent administration of strong CYP3A4 inhibitors

AUC of cariprazine on average 4-fold higher with concurrent administration of ketoconazole. Refer to dosing recommendations for concurrent administration of strong CYP3A4 inhibitors

Increased plasma level of aripiprazole and brexpiprazole possible due to inhibited metabolism via CYP2D6. Any interaction will be prolonged (up to 3 months) due to terbina ne’s long half-life (200–400 h)

Antihistamine

Trimeprazine (aka alimemazine)

Increased serum level of aripiprazole (by 56%) but not of dehydro-aripiprazole found in a pharmacokinetic study. Mechanism and clinical signi cance unknown

Antiparkinsonian agent

Levodopa, pramipexole, ropinirole

Worsening of motor symptoms reported in some patients with Parkinson’s disease. Antipsychotics reduce dopaminergic activity while antiparkinson agents increase dopamine in the CNS. If an antipsychotic is necessary, consider using clozapine or quetiapine, which have been reported to be less likely to cause worsening control of movement disorders than other antipsychotics. Note: A pilot study of very low-dose aripiprazole (0.625 mg/day) found improvement in levodopa-induced dyskinesias. Case report of hypoglycemia 10 days after adding aripipirazole to levodopa

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 171 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Third-Generation Antipsychotics/TGAs (cont.)

Example

Interaction Effects

General Clozapine Haloperidol

Olanzapine

Quetiapine Paliperidone, risperidone Ziprasidone

When combining antipsychotics, consider the risks (e.g., additive adverse effects, cost, increased pill burden) vs. potential and evidence for ef cacy

Preliminary data on adding aripiprazole to clozapine to improve ef cacy and/or mitigate adverse effects of clozapine (e.g., weight gain, enuresis)

Resolution of haloperidol-induced hyperprolactinemia with addition of aripiprazole (15–30 mg/day) in a small RCT. No signi cant change in serum haloperidol levels. Case report of asymptomatic QTc prolongation (by 75 ms) when haloperidol (5 mg/day) added to aripiprazole (30 mg/day)

Case report of NMS with the addition of aripiprazole (10 mg/day) to olanzapine (10 mg/day). Case reports of worsening hallucinations, paranoia, and delusions with addition of aripiprazole (10–30 mg/day)

Case report of worsening irritation, grandiosity, and hallucinations with the addition of aripiprazole (15–30 mg/day) to quetiapine (800 mg/day)

Preliminary data on adding aripiprazole to resolve risperidone- or paliperidone-induced hyperprolactinemia. Case report of improvement in tardive dyskinesia with addition of aripiprazole (15 mg/day)

Case report of worsening psychosis with addition of aripiprazole (30 mg/day)

Atazanavir, boceprevir, darunavir, fosamprenavir, indinavir, lopinavir, nel navir, ritonavir, saquinavir, simeprevir telaprevir, tipranavir

CAUTION. Complex interactions likely as various protease inhibitors potently inhibit as well as induce a variety of CYP enzymes (e.g., on CYP3A4 ritonavir is a potent inhibitor; atazanavir, boceprevir, darunavir, saquinavir, and telaprevir are strong inhibitiors; indinavir and fosamprenavir are mild to moderate inhibitors; tipranavir is an inducer. Low boosting doses of ritonavir have little effect on CYP2D6 but higher doses cause inhibition)

Increased levels of TGAs possible with enzyme-inhibiting protease inhibitors (e.g., ritonavir, indinavir). Decreased levels possible with unboosted tipranavir

Case report of high aripiprazole levels, confusion, and loss of coordination in a patient taking high-dose aripiprazole (50 mg/day) with darunavir and ritonavir (modest CYP2D6 and potent CYP3A4 inhibitors) and duloxetine

Rifampin

Decreased brexipiprazole AUC (70%) and Cmax (20%) via CYP3A4 induction

Lorazepam

Increased incidence of sedation and orthostatic hypotension

Metoprolol, propranolol

Increased serum levels of aripiprazole and dehydro-aripiprazole found in one study, possibly due to inhibition of metabolism via CYP2D6

Metoprolol may increase serum levels of brexpiprazole

Ranolazine

CAUTION. In theory, increased plasma level of aripiprazole and brexpiprazole possible due to inhibited metabolism via CYP2D6

General (e. g., alcohol, hypnotics, opioids)

Alcohol

CAUTION. Potentiation of CNS effects (e.g., sedation, hypotension, respiratory depression) May worsen EPS

Betamethasone, methylprednisolone, hydrocortisone, prednisone

CAUTION. Potential to exacerbate psychiatric conditions, as glucocorticoid-induced psychiatric disorders such as psychosis can occur Glucocorticoids can induce metabolism via CYP3A4. In theory, higher TGA doses may be needed

Grapefruit juice is a moderate CYP3A4 inhibitor. In theory, increased plasma level of TGAs possible

Class of Drug

Antipsychotic combination

Antiretroviral

Protease inhibitor

Antitubercular Benzodiazepine β-blocker

Cardiac

CNS depressant

Glucocorticoid Grapefruit

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Class of Drug

Example

Interaction Effects

H2 antagonist

Famotidine Cimetidine

Decreased rate (Cmax) by 37% and 21%, and extent of absorption (AUC) by 13% and 15% of aripiprazole and its active metabolite, respectively. Of low clinical signi cance; no dose adjustment required

Cimetidine is a moderate CYP2D6 and CYP3A4 inhibitor. In theory, increased plasma level of TGAs possible

Lithium

Increased rates of akathisia and tremor generally occur within 6 weeks and resolve with continued use. Adverse effect case reports with concurrent use include one each of NMS, Pisa syndrome, and tardive dyskinesia

Metoclopramide

CAUTION. Metoclopramide is a potent central dopamine receptor antagonist that can cause EPS, hyperprolactinemia, and rarely NMS. Concurrent use with an antipsychotic may increase the risk of these adverse effects

Opioid

Methadone

Methadone is a moderate CYP2D6 inhibitor and weak CYP3A4 inhibitor. Potential for increased aripiprazole and brexpiprazole levels

Stimulant

Amphetamine, methylphenidate

CAUTION. Potential to exacerbate psychiatric conditions as stimulant-induced psychosis can occur

Antipsychotics can counteract many signs of stimulant toxicity (e.g., anxiety, aggression, visual or auditory hallucinations,

psychosis), may impair the stimulatory effect of amphetamines, and have additive adverse effects (e.g., insomnia, restlessness, tremor)

Case report of acute dystonia on abrupt discontinuation of methylphenidate. Case report of acute dystonia with recreational amphetamine use

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 173 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

5-HT2A Inverse Agonist Antipsychotic

Product Availability∗

∗ Refer to Health Canada’s Drug Product Database or the FDA’s Drugs@FDA for the most current availability information (B) Not marketed in Canada

Generic Name

Chemical Class

Trade Name

Dosage Forms and Strengths

Pimavanserin

Not part of a class

Nuplazid(B)

Tablets: 17 mg

Indicationsa ‡

( approved)

General Comments

Parkinson’s disease: For the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis

• Pimavanserin is the rst and only medication approved by the FDA for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis

• The mechanism of action of pimavanserin in the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis is un- known. However, the drug’s e ect could be mediated through a combination of inverse agonist and antagonist activity at serotonin 5-HT2A recep- tors and to a lesser extent at serotonin 5-HT2C receptors

• In vitro, pimavanserin acts as an inverse agonist and antagonist at serotonin 5-HT2A receptors with high binding a nity (Ki value 0.087 nM) and at serotonin 5-HT2C receptors with lower binding a nity (Ki value 0.44 nM). Pimavanserin shows low binding to sigma 1 receptors (Ki value 120 nM) and has no appreciable a nity (Ki value < 300nM), to serotonin 5-HT2B, dopaminergic (including D2), muscarinic, histaminergic, or adrenergic receptors, or to calcium channels

• Recommendeddoseis34mg,takenorallyastwo17mgtabletsoncedaily,withouttitration

• Concomitantmedications:

– StronginhibitorsofCYP3A4(e.g.,ketoconazole):Reducepimavanserindosebyone-half

– StronginducersofCYP3A4(e.g.,carbamazepine):Anincreaseinpimavanserindosemaybeneeded

• Nodosageadjustmentneededinpatientswithmild–moderaterenalimpairment.Usenotrecommendedinpatientswithsevererenalimpairment

• Notrecommendedinpatientswithhepaticimpairment

• Alsoseetablep.189

• Ingestionofahigh-fatmealhadnosigni cante ectonrate(Cmax)andextent(AUC)ofexposure

• Tmax:6h(range4–24h)

• Approximately95%proteinbound

• Half-life:57h(activemetabolite:200h)

• Volumeofdistribution:2173(307)L

• PredominantlymetabolizedbyCYP3A4andCYP3A5,toalesserextentbyCYP2J2,CYP2D6,andvariousotherCYPandFMOenzymes

• Approximately0.55%eliminatedasunchangeddruginurineand1.53%eliminatedinfecesafter10days

Pharmacology

Dosing

Renal Impairment

Hepatic Impairment

Pharmacokinetics

a Adult population unless otherwise stated ‡ Indications listed here do not necessarily apply to all hypnotics/sedatives or all countries. Please refer to a country’s regulatory database (e.g., US Food and Drug Administration, Health Canada Drug Product Database) for the most current availability information and indications

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Adverse Effects

Cardiovascular Effects

Discontinuation Syndrome

Precautions

Toxicity

Lab Tests/Monitoring

Use in Pregnancy♢

Breast Milk

Nursing Implications

Drug Interactions

• Most common adverse reactions (≥ 2% for pimavanserin and greater than placebo): Peripheral edema (7% vs. 2%), nausea (7% vs. 4%), confusion state (6% vs. 3%), hallucination (5% vs. 3%), constipation (4% vs. 3%), and gait disturbance (2% vs. 1%)

• PimavanserinprolongstheQTinterval.AvoidinpatientswithknownQTprolongationorincombinationwithotherdrugsknowntoprolongQTin- terval including Class 1A antiarrhythmics (e.g., procainamide, quinidine) or Class 3 antiarrhythmics (e.g., amiodarone, sotalol), certain antipsychotic medications (e.g., chlorpromazine, ziprasidone), and certain antibiotics (e.g., gati oxacin, moxi oxacine)

• Avoid in patients with a history of cardiac arrhythmias, as well as other circumstances that may increase the risk of the occurrence of torsades de pointes and/or sudden death, including symptomatic bradycardia, hypokalemia, or hypomagnesemia, and the presence of congenital prolongation of the QT interval

• Noinformationavailable

• Antipsychoticdrugsincreasetheall-causeriskofdeathinelderlypatientswithdementia-relatedpsychosis

• Noinformationavailable

• Therapeuticrangenotestablishedforpimavanserin

• No data on pimavanserin use in pregnant women that would allow assessment of the drug-associated risk of major congenital malformations or miscarriage

• Noinformationregardingthepresenceofpimavanserininhumanmilk,e ectsonthebreastfedinfant,ore ectsonmilkproduction

• Thedevelopmentalandhealthbene tsofbreastfeedingshouldbeconsideredalongwiththemother’sclinicalneedforpimavanserin

• Seep.112

• Takenoncedailywithorwithoutfood

• CAUTION:Grapefruitjuicemayincreasethelevelofpimavanserin

• Advise patient to inform their healthcare providers if there are any changes to their current prescription or over-the-counter medications, since

there is a potential for drug interactions

• Clinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterforthesecondagent

Class of Drug

Example

Interaction Effects

CYP3A4 inducer

Carbamazepine, phenytoin, rifampin, St. John’s Wort

May reduce pimavanserin exposure, resulting in a potential decrease in ef cacy

CYP3A4 inhibitor

Clarithromycin, indinavir, itraconazole, ketoconazole

Increased pimavanserin exposure

QT interval prolonging agents

Class 1 A antiarrhythmics (disopyramide, procainamide, quinidine), class 3 antiarrhythmics (amiodarone, sotalol), antipsychotics (chlorpromazine, ziprasidone), antibiotics (gati oxacin, moxi oxacin)

Concomitant use of drug that prolongs QT interval may add to QT effects of pimavanserin and increase risk of cardiac arrhythmia

♢ See p. 439 for further information on drug use in pregnancy and e ects on breast milk

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 175 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

E ects of Antipsychotics on Neurotransmitters/Receptors∗

FGAs

Chlorprom- azine

Flu- penthixol

Fluphen- azine

Haloperi- dol

Loxapine

Methotri- meprazine

Periciazine

Perphen- azine

Pimozide

Thiori- dazine

Thiothix- ene

Tri uo- perazine

Zuclo- penthixol

D2 blockade

++++

+++++

++++

+++

++++

+++++

++++

+++++

++++

+++++

H1 blockade

+++

+++++

++++

+++

M1 blockade

+++

++++

M3 blockade

+++

α1 blockade

++++

+++

++++

+++

++++

α2 blockade

5-HT1A blockade

5-HT2A blockade

++++

+++

++++

+++

++++

+++

++++

5-HT2C blockade

+++

5-HT7 blockade

+++

++++

+++

+++++

+++

SGAs

TGAs

Asenapine

Clozapine

Iloperidone

Lurasidone

Olanzapine

Paliperidone

Quetiapine

Risperidone

Ziprasidone

Aripiprazole

Brexpi- prazole

Cariprazine

D2 blockade

++++

+++

++++

+++

++++

+++++(a)

H1 blockade

++++

+++

M1 blockade

+++(a)

++++

M3 blockade

+++

α1 blockade

++++

+++

++++

+++

++++

+++

α2 blockade

++++

+++

5-HT1A blockade

++++

++(a)

++++(a)

++(a)

+++(a)

++++(a)

+++++(a)

++++(a)

5-HT2A blockade

+++++

+++

+++++

++++

+++++

+++

+++++

++++

+++++

+++

5-HT2C blockade

+++++

+++

++++

+++

5-HT7 blockade

+++++

+++

+++++

+++

++++

(a) Partialagonist

Key: Ki (nM) > 10,000 = –; 1000–10,000 = +; 100–1000 = ++; 10–100 = +++; 1–10 = ++++; 0.1–1 = +++++; ? = unknown

See p. 177 for Pharmacological Effects on Neurotransmitters.

Adapted from: [24, 25, 26]. See also the National Institute of Mental Health’s Psychoactive Drug Screening Program. Available at http://pdsp.med.unc.edu

∗ The ratio of Ki values (inhibition constant) between various neurotransmitters/receptors determines the pharmacological pro le for any one drug

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Pharmacological E ects of Antipsychotics on Neurotransmitters/Receptor Subtypes

H1 M1

M3 α1 α2

5-HT1A 5-HT2A 5-HT2C

5-HT7

• Antagonism of postsynaptic D2 receptors:

– In mesolimbic tract – reduction in positive symptoms (note: TGAs are partial agonists at D2 receptors, partial agonism of this receptor may also

reduce positive symptoms; partial agonist behaves like an antagonist in cases where a hyperdopaminergic state exists)

– Innigrostriataltract–EPS(e.g.,dystonias,pseudoparkinsonism,akathisia,tardivemovementdisorders,etc.)

– Intuberoinfundibulartract–prolactinelevation(e.g.,galactorrhea,sexualdysfunction,etc.)

– Inmesocorticaltract–mayexacerbatenegativesymptoms

• Antagonism of H1 receptors:

– Anti-emetice ect,anxiolytice ects

– Sedation,drowsiness,appetiteincrease,weightgain

• Antagonism of M1 receptors:

– Mitigationofextrapyramidaladversee ects

– Drymouth,dryeyes,blurredvision,constipation,urinaryretention,sinustachycardia,QRSchanges,confusion,worseningcognition,delirium – Potentiationofe ectsofdrugswithanticholinergicproperties

• Antagonism of M3 receptors:

– Betacellfailure,reducedinsulinrelease,glucoseintolerance,type2diabetesmellitus

• Antagonism of α1 adrenergic receptors:

– Posturalhypotension,dizziness,re extachycardia,sedation

• Antagonism of α2 -adrenergic receptors:

– Mayimprovecognitivede citsandhaveantidepressantactivity

– Antagonismofpresynapticα2-adrenergicreceptorsenhancesserotonergicandnoradrenergictransmission

• Antagonism/partial agonism of 5-HT1A serotonergic receptors:

– Postulatedtobeassociatedwithprocognitive,anxiolytic,andantidepressante ects

• Antagonism of 5-HT2A serotonergic receptors:

– Sedation,prodopaminergicactionsmayameliorateEPS,andpostulatedtoimprove(notworsen)negative,cognitive,andmoodsymptoms

• Antagonism of 5-HT2C serotonergic receptors:

– Increasedappetite,weightgain

– Postulatedtobeassociatedwithprocognitiveandantidepressante ects

• Antagonism of 5-HT7 serotonergic receptors:

– Postulatedtobeassociatedwithprocognitive,anxiolytic,andantidepressante ects

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 177 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Relative Tolerability Pro les of Antipsychotics

Adverse Effect

Higher Likelihood

Moderate Likelihood

Lower Likelihood

Sedation

LP-FGAs Clozapine Olanzapine Quetiapine

MP-FGAs Asenapine Brexpiprazole Cariprazine Risperidone Ziprasidone

HP-FGAs Aripiprazole Iloperidone Lurasidone Paliperidone

EPS

HP-FGAs

MP-FGAs Asenapine Cariprazine Lurasidone Paliperidone Risperidone Ziprasidone

LP-FGAs Aripiprazole Brexpiprazole Clozapine Iloperidone Olanzapine Quetiapine

Tardive dyskinesia

FGAs

TGAs Asenapine Iloperidone Lurasidone Olanzapine Paliperidone Quetiapine Risperidone Ziprasidone

Clozapine

Seizures

HP-FGAs Clozapine

LP-FGAs

TGAs Asenapine Iloperidone Lurasidone Olanzapine Paliperidone Quetiapine Risperidone Ziprasidone

Hyperprolactinemia

HP-FGAs Paliperidone Risperidone

MP-FGAs Asenapine Iloperidone Olanzapine Ziprasidone

LP-FGAs TGAs Clozapine Quetiapine

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Adverse Effect

Higher Likelihood

Moderate Likelihood

Lower Likelihood

Anticholinergic effects

LP-FGAs Clozapine Olanzapine

MP-FGAs Quetiapine

HP-FGAs TGAs Asenapine Iloperidone Lurasidone Paliperidone Risperidone Ziprasidone

Orthostatic hypotension/ re ex tachycardia

LP-FGAs Clozapine

MP-FGAs Asenapine Iloperidone Paliperidone Quetiapine Risperidone Ziprasidone

HP-FGAs TGAs Lurasidone Olanzapine

Weight gain (and possibly other metabolic effects)

Clozapine Iloperidone Olanzapine

LP-FGAs MP-FGAs Quetiapine

HP-FGAs TGAs Asenapine Lurasidone Paliperidone Risperidone Ziprasidone

QT prolongation

(Credible Meds Worldwide rating)

Known risk of TdP: Chlorpromazine Haloperidol Pimozide Thioridazine

Possible risk of TdP: Aripiprazole Asenapine Clozapine Flupenthixol Iloperidone Paliperidone Perphenazine Risperidone Zuclopenthixol

Conditional risk of TdP: Amisulpride Olanzapine Quetiapine Ziprasidone

HP-FGAs = high-potency FGAs, LP-FGAs = low-potency FGAs, MP-FGAs = medium-potency FGAs, TdP = torsades de pointes (see p. 139 for de nitions of Credible Meds Worldwide risk categories for TdP)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 179 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Frequency (%) of Adverse Reactions to Antipsychotics at Therapeutic Doses

FIRST-GENERATION AGENTS

Chlor- promazine

Flu- penthixol

Fluphen- azine

Haloperi- dol

Loxapine

Methotri- meprazine

Periciazine

Perphena- zine

Pimozide

Thiorida- zine

Thiothix- ene

Tri uoper- azine

>30 <2

>2 <2

>2 >2

> 2(a) >10

>30 <2

>10 >10

>10 >2

>30 <2

>10 >10

>2 >2

>10 >2 >2

>30 >30 >10

> 30(b) >30 > 30(b)

>30 >30 >10

>10 >2 <2

>2 >2 <2

>10 >10 >10

>30 >10 >2

>2 >2 <2

>30 >30 >2

>30 >30 >10

>30

>10

>30

>10

>30

> 30(a)

>10

> 30(e) > 2(e)

>2 >2 >2 <2

>10

<2 > 2(e)

>10 >10 <2 –

> 30(a) (d)

>10 >10 >2

>10 >10 <2 >2

>10 >10 >2 <2

>2 >2

> 2(f) > 2(f)

>30 <2 > 30(e) > 10(e)

>2 >2 <2 <2

>10 <2 <2 >2

> 30(g) >30 >30 >30 >30

> 30(g) – >10 >10

> 30(g) >10 >30 >10

> 30(g) <2 >10 >10 >2

>2 >2

< 2(h) > 2(i)

>10

> 2(g) >30

>10 > 2(i)

> 10(g) >10

>10 > 2(i)

> 10(g) >10 >10

>10 > 2(i)

>30 <2

> 2(h)

>2 ?

> 30(g)

>30

>30 > 2(i)

>30

> 2(g) <2

>10 > 2(i)

> 30(g) >10 >10 >2

>2 >2

<2 <2

<2 –

<2 <2

>2 >2

>2 –

<2 <2

<2 –

>2 >10

<2 <2

<2 < 2(a)

<2 <2 <2

>10 >10 > 30(e)

<2 >2 –

<2 <2 –

<2 <2 <2

<2 >2 –

>10 >2 <2

>2 >2 –

<2 <2 –

– >2 –

> 10(e) >10 >2

<2 <2 >2

<2 <2 –

Reaction

CNS Effects

Zuclo- penthixol

Drowsiness, sedation

Insomnia, agitation

Extrapyramidal Effects

Parkinsonism >30 Akathisia >10

>30 >10

> 10(b) > 10(c)

>2 <2

> 30(g) –

>10 > 2(i)

<2 – <2 <2

Photosensitivity <2 Rashes <2 Pigmentation*** <2

Dystonic reactions

Anticholinergic Effects

Cardiovascular Effects

Orthostatic hypotension

Tachycardia >2

ECG abnormalities*

QTc prolongation

(> 450 ms)

Endocrine Effects

Sexual dysfunction**

Galactorrhea

Weight gain

Hyperglycemia

Hyperlipidemia

Ocular Effects ***

Lenticular pigmentation

Pigmentary retinopathy

Blood dyscrasias

Hepatic disorder

Seizures# <2 Skin Reactions

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

SECOND-GENERATION AGENTS

Asenapine

Clozapine

Iloperi- done

Lurasidone

Olanza- pine

Paliperi- done

Quetia- pine

Risperi- done

Ziprasi- done

Aripipra- zole

Brexpipra- zole

>10 >10

>30 >2

>10 >10

>10 >2

>30 >10

>2 >10

>30 >10

> 10(d) >10

>10 >30

>10 >10

>2 >2

? ? ?

>2 >10 <2

<2 >2 <2

>2 >10 >2

>2 >10 <2

>2 >2 <2

> 10(k)

> 10(k) < 2(k)

>2 >2 >2

>2 >10 <2

>2 >2 <2

> 30(c)

>10

>30

>10

>10 <2 ?

> 10–30(d)

> 10(d)

> 30(e) < 2(e)

>10 >10 <2 <2

>2 <2 –

>2 > 10(l) <2 <2

>2 >2 <2 >2

>10 >10 <2 <2

> 10(d) <2 >2 <2

>10 <2

> 2(e) < 2(e)

>2 >2 <2 –

>2 <2 <2 –

? >10 >10 >10

< 2(g)

<2 >30 >30 >30

>2 <2 >10 ?

<2 <2 <2 <2 <2

> 30(g) >2 >30 >30 >30

<2 <2 >10 ?

> 30(g) – >10 >30 >10

> 30(g) >10 >10 >10 >10

< 2(g)

>2 >2 >2 <2

< 2(g) <2

> 2(h)

<2 <2

< 2(g) <2

> 2(h)

<2 <2

? ?

– –

? ?

– –

? –

<2 –

– –

<2 >2 <2

< 2(m)

>2 > 2(n)

? <2 <2

<2 <2

<2 >2 <2

? <2

– >2 <2

<2 <2 <2

<2 –

–

<2 <2 <2

? ? ?

>2 >2 –

? ? ?

– <2 –

? ? ?

– <2 –

>2 <2 <2

– >2 –

<2 >2 –

<2 <2 –

Reaction

CNS Effects

THIRD-GENERATION AGENTS Caripra-

zine

Drowsiness, sedation

Insomnia, agitation

Extrapyramidal Effects

Parkinsonism >2 Akathisia >2

Dystonic reactions

>2 >2

<2 <2

>2 <2

–

< 2(g)

Anticholinergic Effects

Cardiovascular Effects

Orthostatic hypotension

Tachycardia <2

ECG abnormalities*

QTc prolongation (> 450 ms)

Endocrine Effects

Sexual dysfunction**

Galactorrhea <2

< 2(h)

–

– <2 <2

–

Weight gain

Hyperglycemia <2 Hyperlipidemia <2 Ocular Effects***

Lenticular pigmentation

Pigmentary retinopathy

Blood dyscrasias

Hepatic disorder

Seizures# <2 Skin Reactions

Photosensitivity <2 Rashes <2

Pigmentation***

Data are pooled from separate studies and are not necessarily comparable; the gures in the table cannot be used to predict the incidence of side effects in the course of usual medical practice, where patient characteristics and other factors differ from those in the clinical trials.

– = None reported in literature perused

* ECG abnormalities usually without cardiac injury including ST segment depression, attened T waves, and increased U wave amplitude, ** Includes impotence, inhibition of ejaculation, anorgasmia, *** Usually seen after prolonged use, # In nonepileptic patients

(a) More frequent with rapid dose increase, (b) Lower incidence with depot preparation, (c) Sialorrhea reported, (d) May be higher at start of therapy or with rapid dose increase, (e) Higher doses pose greater risk, (f) Pimozide above 20 mg daily poses greater risk, (g) Priapism reported, (h) Weight loss reported, (i) Reported to occur, but no de nitive data published as to incidence, (k) Increased risk with oral doses above 10 mg daily, (l) Bradycardia frequent with IM olanzapine; often accompanied by hypotension, (m) Risk < 2% with strict monitoring (legal requirement in North America), (n) Risk increased with doses above 300 mg

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 181 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Antipsychotic Doses and Pharmacokinetics (Oral and Short-Acting Injections)

FIRST-GENERATION AGENTS (FGAs)

Drug

CPE (mg)

OLE in Schizo- phrenia (mg)

Monograph Doses for Psychosis

Bio- availability

Protein Binding

Peak Plasma Level (h) (Tmax)

Elimination Half-Life (h)

Metabolizing Enzymes(1) / Transporters (CYP450; other)

Enzyme Inhi- bition(2) / Transporters (CYP450; other)

% D2 Receptor Occupancy(3) (dose & plasma level)

% 5-HT2A Occu- pancy (dose)

Chlorpromazine

(Largactil(C) , Thorazine(B) )

100

600

Oral: Start: 25–75 mg daily in 2–4 divided doses; increase by 20–50 mg twice weekly. Recommended maximum: 1 g/day. Give od or bid for maintenance with larger dose at at bedtime

Short-acting IM: Start: 25 mg followed by 25–50 mg in 1 h if needed, then q 3–12 h prn. Can increase over several days. Recommended maximum: 400 mg q 4–6 h

Oral: 25–65%

95–99%

(to albumin)

Oral: 0.51

Oral: 16–30

1A2(w) , 2D6(p) , 3A4(w) ; UGT1A4

1A2, 2D6(p), 3A4(w) , 2C9(w), 2C19, 2E1; P-gp

78–80% (100–200 mg; 10 nmol/L)

Flupenthixol(C) (Fluanxol)

2–5

Oral: Start: 1 mg tid; increase by 1 mg q 2–3 days if needed. Usual =

3–6 mg/day in divided doses; up to 12 mg/day used in some patients

30–70%

99%

3–8

26–36

2D6(w)

70–74% (5–10 mg; 2–5 nmol/L)

Fluphenazine HCL

(Moditen(C), Prolixin(B))

Oral: Start: 2.5–10 mg daily in divided doses q 6–8 h.

Maintenance: 1–5 mg/day. Doses greater than 20 mg = use with caution

Short-acting IM or SC: Start: 1.25 mg; range 2.5–10 mg daily divided q

6–8 h. Doses greater than 10 mg = use with caution

1–50%

90–99%

Oral: 0.5

Short- acting IM: 1.5–2

Oral: 13–58

Short-acting IM: 13–58

1A2, 2D6; P-gp

1A2, 2D6(p), 3A4(w), 2E1 2C8/9; P-gp

Haloperidol

(Haldol)

Oral: Start: 1.5–3 mg divided bid or tid (elderly 0.25–1 mg od or divided bid) Maintenance: 4–12 mg divided od–tid

Usual maximum = 20 mg/day 85–100 mg daily used rarely

40–80%

92% (to α1 -AGP)

0.5–3

12–36

1A2(w) , 2D6(w) , 3A4(p)

2D6, 3A4; P-gp(w)

75–89%

(4–6 mg; 6–13 nmol/L)

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

FIRST-GENERATION AGENTS (FGAs)

Drug

CPE (mg)

OLE in Schizo- phrenia (mg)

Monograph Doses for Psychosis

Bio- availability

Protein Binding

Peak Plasma Level (h) (Tmax)

Elimination Half-Life (h)

Metabolizing Enzymes(1) / Transporters (CYP450; other)

Enzyme Inhi- bition(2) / Transporters (CYP450; other)

% D2 Receptor Occupancy(3) (dose & plasma level)

% 5-HT2A Occu- pancy (dose)

Haloperidol lactate

Short-acting IM: 2–5 mg (0.5–1 mg in the elderly) q 4–8 h prn; may repeat q 1 h if required

Maximum: 20 mg/day (elderly

∼5 mg/day)

Short- acting IM (lactate): 10–20 min

Loxapine

(Adasuve(B) , Loxapac(C), Loxitane(B))

Oral: Start: 10 mg bid (up to

50 mg/day if needed)

Usual = 60–100 mg/day divided bid–qid

Usual maintenance: 20-60 mg/day Maximum = 250 mg/day

Oral inhalation: 10 mg via single-use inhaler

Maximum = 10 mg/day

33%

97%

Oral = 1–2 Oral inhalation =2min

Oral = 3 (range 1–14); 5–19 (metabolites)

1A2, 2D6, 3A4; UGT1A4

P-gp

60–80% (15–30 mg)

58–75% (10–

30 mg) 75–90% metabo- lite

(> 30 mg)

Loxapine hydrochloride

Short-acting IM: 12.5–50 mg q 4–6 h prn or longer

Short- acting IM = 2–5

Short-acting IM = 12 h (range 8–23); 8–30 (metabolites)

Methotrimeprazine/ Levomepromazine(C) (Nozinan)

300; Rarely used

Oral (for severe psychosis): Start: 50–200 mg daily divided into 2 or 3 doses. Caution if starting with

100 mg or greater/day. Increase up to 1gormoreadayifneeded Short-acting IM: 75–100 mg daily given as 3 or 4 deep IM injections

Oral: 21–50%

Oral: 1–3

Short- acting IM: 30–90 min

Oral: 16–78

1A2, 2D6, 3A2; P-gp

2D6(p) ; P-gp

Periciazine(C) (Neuleptil)

15–24

50; Not used

Oral: 5–20 mg AM + 10–40 mg PM Maintenance: 2.5–15 mg AM + 5–30 mg PM

∼12

2D6, 3A4

P-gp

Perphenazine

(Trilafon)

Oral: Start: 8–16 mg bid to qid. Recommended maximum:

64 mg/day

25%

91–92%

1–4

9–21

1A2, 2D6(p), 3A4, 2C9, 2C19

1A2(w) , 2D6(p), 3A4, 2C9, 2C19; P-gp

79% (4–8 mg)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 183 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Antipsychotic Doses and Pharmacokinetics (Oral and Short-Acting Injections) (cont.)

FIRST-GENERATION AGENTS (FGAs)

Drug

CPE (mg)

OLE in Schizo- phrenia (mg)

Monograph Doses for Psychosis

Bio- availability

Protein Binding

Peak Plasma Level (h) (Tmax)

Elimination Half-Life (h)

Metabolizing Enzymes(1) / Transporters (CYP450; other)

Enzyme Inhi- bition(2) / Transporters (CYP450; other)

% D2 Receptor Occupancy(3) (dose & plasma level)

% 5-HT2A Occu- pancy (dose)

Pimozide

(Orap)

Oral: Start: 2–4 mg once daily; increase by 2–4 mg q week; average dose: 6 mg/day (usual range

2–12 mg/day)

Doses above 20 mg/day not recommended(x)

15–50%

97%

6–8 (range 4–12)

29–55(y)

1A2(w) , 3A4(p)

2D6(p), 3A4; P-gp(p)

77–79% (4–8 mg)

Thioridazine(B) , (x) (Mellaril)

100

500; Not recom- mended

Oral: 150–400 mg daily in outpatients with severe symptoms given in 2–4 divided doses; 200–800 mg daily in hospitalized patients;

Recommended maximum:

800 mg/day

10–60%

97–99%

1–4

9–30

1A2(w) , 2D6(w) , 2C19(w)

1A2, 2D6(p), 2C8/9, 2E1; P-gp; Inducer of 3A4

74–81% (100–400 mg; 620–

900 nmol/L)

Thiothixene(B) (Navane)

Oral: Start: 2 mg tid – 5 mg bid. Usual = 15–30 mg od; > 60 mg/day rarely increases response

50%

90–99%

1–3

1A2(p)

2D6(w)

Tri uoperazine

(Stelazine)

Oral: Start: 2–5 mg bid or tid. Usual = 15–20 mg/day. A few may need

40 mg/day or more. 80 mg/day or more rarely necessary

95–99%

2–4

7–18

1A2; P-gp; UGT1A4

P-gp

75–80% (5–10 mg)

Zuclopenthixol(C) (Clopixol)

Oral: Start: 10–50 mg/day divided bid tid; increase by 10–20 mg q 2 3 days; usual daily dose:

20–60 mg; doses above 100 mg/day not recommended

44%

98%

2–4

12–28

2D6(p)

2D6

> 70%

Zuclopenthixol acetate(C)

(Clopixol acuphase)

30 mg q2–

3 days

Usual dose: 50–150 mg IM and repeated q 2–3 days prn to a maximum cumulative dose of

400 mg and maximum of 4 injections (a 2nd injection may need to be given 1–2 days later in some patients)

–

98%

24–48

48–72

2D6(p)

2D6

> 70%

(1) CYP450 isoenzymes involved in drug metabolism, (2) CYP450 isoenzymes inhibited by drug, (3) D2 receptor occupancy correlates better to plasma level than to dose, and appears to relate to clinical ef cacy in controlling positive symptoms of schizophrenia as well as risk of extrapyramidal adverse effects (if > 80%)

(B) Not marketed in Canada, (C) Not marketed in the USA

(p) Potent activity, Weak activity, (x) Monitor cardiac function, (y) Half-life longer (mean 66–111 h) in children and adults with Tourette’s syndrome

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

SECOND-GENERATION AGENTS (SGAs)

Drug

CPE (mg)

OLE in Schizo- phrenia (mg)

Monograph Doses for Psychosis (for doses for other indications and in renal impairment, see pp. 135–135)

Bioavaila- bility

Protein Binding

Peak Plasma Level (h) (Tmax)

Elimination Half-Life (h)

Metabolizing Enzymes(1) / Transporters (CYP450; other)

Enzyme Inhi- bition(2) / Transporters (CYP450; other)

% D2 Receptor Occupancy(3) (dose & plasma level)

% 5-HT2A Occu- pancy (dose)

Asenapine

(Saphris)

Oral: 5 mg sublingually bid – starting and target dose Maximum: 10 mg bid

35% (<2%if swallowed; reduced if food/drink taken within 10 min)

95% (including albumin and α1 -AGP)

0.5–1

1A2(p), 2D6(w), 3A4(w) ; UGT1A4(p)

2D6(w)

79% (4.8 mg sublingual)

Clozapine

(Clozaril, FazaClo ODT(B) )

400

Oral: 12.5 mg once or twice daily to start; increase gradually by 25–50 mg/day increments up to 300–450 mg/day in divided doses(F) by the end of 2 weeks; subsequent increases ≤ once or twice/week in increments ≤100 mg/day

Usual range: 300–600 mg/day Maximum: 900 mg/day(G) Prescribing restrictions: see p. 134

90–95% (40–60% after 1st pass metabolism)

95–97% (to α1 -AGP)

1–6 (mean 2.5)

6–33 (mean 12; parent)

11–105 (active metabolite) Caution in the elderly

Reduced in smokers (20–40% shorter)

1A2(p), 2D6(w), 3A4(m), 2C9(w), 2C19(m), 2E1(w); FMO; UGT1A4; P-gp(w)

1A2(w) , 2D6(w), 3A4, 2C9(w), 2C19, 2E1(w)

38–68% (300–900 mg; 600–2500 nmol/L)(G)

85–94% (> 125 mg)

Iloperidone

(Fanapt)(B)

Oral: 1 mg bid to start and increase daily by 2–4 mg over

7 days to a target dose of 6–12 mg bid

Maximum: 24 mg/day

96%

∼95%

2–4

18(K)–33(D) (parent) 26(K)–37(D) and 23(K)–31(D) (active metabolites)

2D6(p), 3A4(p) (Reduce dose by 50% in poor metabolizers of 2D6. Dose changes required with concurrent use of drugs that affect 2D6 and/or 3A4)

–

Lurasidone

(Latuda(B) )

100

Oral: 40 mg once daily to start Maximum: 160 mg once daily

9 19%

>99.8% (to albumin and α1 -AGP)

1 3

18 37 (parent) 7.5 10 (active metabolite)

3A4(p) (Avoid concomitant use with strong CYP3A4 inhibitors or inducers)

–

63 79% (40 80 mg)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 185 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Antipsychotic Doses and Pharmacokinetics (Oral and Short-Acting Injections) (cont.)

SECOND-GENERATION AGENTS (SGAs)

Drug

CPE (mg)

OLE in Schizo- phrenia (mg)

Monograph Doses for Psychosis (for doses for other indications and in renal impairment, see pp. 135–135)

Bioavaila- bility

Protein Binding

Peak Plasma Level (h) (Tmax)

Elimination Half-Life (h)

Metabolizing Enzymes(1) / Transporters (CYP450; other)

Enzyme Inhi- bition(2) / Transporters (CYP450; other)

% D2 Receptor Occupancy(3) (dose & plasma level)

% 5-HT2A Occu- pancy (dose)

Olanzapine

(Zyprexa, Zyprexa Zydis)

(Zyprexa IntraMuscular)

Oral: 5–10 mg once daily to start, with a target of 10 mg/day within several days

Further dose increases of

≤ 5 mg/day at intervals of ≥1week

Maximum: 20 mg/day (higher doses, e.g., 40 mg/day, have safety but not ef cacy data)

Short-acting IM: 10 mg to start (2.5–5 mg in the elderly)

If needed, give 2nd dose of

5–10 mg 2 h after 1st; if 3rd dose needed, give ≥ 4 h after 2nd dose Maximum: 30 mg/day (high rate of orthostatic hypotension) with no more than 3 injections in 24 h

Oral: 57–80%

93% (to albumin and α1 -AGP)

Oral: 5–8

Short- acting IM: 15– 45 min (Cmax 4 5 fold > same oral dose)

21–54 (30 mean) No change in hepatic disease (only based on single-dose study) or renal disease. Prolonged in the elderly (1.5 times longer) and females (30% longer – clinical signi cance unclear)

Reduced in smokers (40% shorter)

1A2(p), 2D6(w); FMO; UGT1A4(p)

1A2(w) , 2D6(w) , 3A4(w) , 2C9(w) , 2C19(w)

55–80% (5–20 mg; 59– 187 nmol/L) 83–88% (30–40 mg)

80–90% (5–20 mg)

Paliperidone (active metabolite of risperidone) (Invega)

1.5

Oral: 6 mg once daily (preferably in AM)

If needed, increase by 3 mg q 4–5 days to a maximum of

12 mg/day

28%

74% (to albumin and α1 -AGP)

In mild, moderate, and severe renal impairment: 24, 40, and 51, respectively

2D6(w), 3A4(w), P-gp (Minimally metabolized, < 7%)

P-gp(w) (at high doses in vitro)

66% (6 mg) 70 80% predicted for 4.5 9 mg

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

SECOND-GENERATION AGENTS (SGAs)

Drug

CPE (mg)

OLE in Schizo- phrenia (mg)

Monograph Doses for Psychosis (for doses for other indications and in renal impairment, see pp. 135–135)

Bioavaila- bility

Protein Binding

Peak Plasma Level (h) (Tmax)

Elimination Half-Life (h)

Metabolizing Enzymes(1) / Transporters (CYP450; other)

Enzyme Inhi- bition(2) / Transporters (CYP450; other)

% D2 Receptor Occupancy(3) (dose & plasma level)

% 5-HT2A Occu- pancy (dose)

Quetiapine

(Seroquel)

(Seroquel XR)

750

Oral: 25 mg bid to start; increase by 25–50 mg bid per day, as tolerated, to a target dose of 300–400 mg/day (given bid or tid) within 4–7 days. Further increases ≥ 2 days.

Usual daily dose:

300–600 mg/day, in divided doses

Maximum(H) : 800 mg/day

Oral (XR): 300 mg once daily in the evening to start, increase by up to 300 mg/day Maintenance: 400–800 mg/day Maximum: 800 mg/day

∼73% (relative bioavailabil- ity; absolute unknown)

83%

Oral: 0.5–3

Oral (XR): ∼6

∼6–7 (parent) ∼12 (active metabolite) Prolonged in hepatic disease (45% longer; based on a low-, single-dose study in those with mild disease), renal disease (25% longer; based on a low-, single-dose study in those with severe disease), and the elderly (30–50% longer)

3A4(p), 2D6(w); P-gp

1A2(w) , 2D6(w) , 3A4(w) , 2C9(w) , 2C19(w)

20–44% (300–700 mg) 13–41% (150–750 mg)

21–80% (150– 600 mg) 38–74% (150– 750 mg)

Risperidone

(Risperdal, Risperdal M-tab)

6.0

Oral: 1–2 mg once to twice daily and increase by 0.5–2 mg q

1–7 days

Usual daily dose: 4–6 mg Doses above 10 mg/day do not usually produce further improvement

Maximum: 16 mg/day with a maximum of 8 mg/dose

70%

88–90% (parent; to albumin and α1 -AGP) 77% (active metabolite) Reduced in hepatic disease

1–1.5

(parent) 3(K) –17(D)

(active metabo- lite)

3(K)–20(D) (parent) 21(K)–30(D) (active metabolite) Increased by ∼60% in moderate to severe renal disease

2D6(p), 3A4(m), P-gp

2D6, 3A4(w)

60–75% (2–4 mg) 63–85% (2–6 mg; 36–252 nmol/L)

60–90% (1–4 mg)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 187 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Antipsychotic Doses and Pharmacokinetics (Oral and Short-Acting Injections) (cont.)

SECOND-GENERATION AGENTS (SGAs)

Drug

CPE (mg)

OLE in Schizo- phrenia (mg)

Monograph Doses for Psychosis (for doses for other indications and in renal impairment, see pp. 135–135)

Bioavaila- bility

Protein Binding

Peak Plasma Level (h) (Tmax)

Elimination Half-Life (h)

Metabolizing Enzymes(1) / Transporters (CYP450; other)

Enzyme Inhi- bition(2) / Transporters (CYP450; other)

% D2 Receptor Occupancy(3) (dose & plasma level)

% 5-HT2A Occu- pancy (dose)

Ziprasidone

(Geodon(B) , Zeldox(C) )

160

Oral: 20–40 mg bid to start. If needed, increase ≥ q 2 days. Doses > 80 mg bid generally not recommended. Short-term ef cacy data for 100 mg bid but limited safety data

Oral: 30% (60% with food)

> 99% (to albumin and α1 -AGP)

Oral: 6–8 (Cmax in- creased 32–72% in mild renal impair- ment)

Oral: 4–10

dose- dependent (6.6 mean)

No change in the elderly or renal disease

Prolonged in hepatic disease (mean in hepatic disease = 7.1 vs. 4.8 in control group)

3A4(m), 1A2(w), 2D6, 3C18/19; Aldehyde oxydase(w)

2D6(w) , 3A4(w)

45–75% (40–80 mg)

80–90% (40–

80 mg)

Ziprasidone mesylate(B)

Short-acting IM: 10 mg q 2 h or 20mgq4htoamaximumof 40mg/24hforupto3days

Short- acting IM: 100%

Short- acting IM:

∼60 min

Short-acting IM: 2–5 h

(Caution in renal disease due to excipient

– cyclodextrin)

(B) Not marketed in Canada, (C) Not marketed in the USA, (D) Poor metabolizers of CYP2D6, (F) Three times daily dosing can also be used for titration to minimize adverse effects (e.g., hypotension, sedation, and seizure). Dose can be divided unevenly such that a larger dose is given at bedtime. Maintenance doses ≤ 200 mg/day can be given as a single dose at bedtime (G) Occasionally higher doses (i.e., 950–1400 mg/day) may be required to reach therapeutic levels, in particular in males who are heavy smokers. In such cases, monitor clozapine levels and for any signs/symptoms of toxicity[19, 20] , (H) Maximum dose suggested by manufacturer. Anecdotal and preliminary data with doses > 800 mg/day, including one case report using 2400 mg/day. However, further study of ef cacy and safety required[27] , (K) Extensive metabolizers of CYP2D6

(m) Moderate activity, (p) Potent activity, Weak activity

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

THIRD-GENERATION AGENTS (TGAs)

Drug

CPE (mg)

OLE in Schizo- phrenia (mg)

Monograph Doses for Psychosis

Bio- availability

Protein Binding

Peak Plasma Level (h) (Tmax)

Elimination Half-Life (h)

Metabolizing Enzymes(1) / Transporters (CYP450; other)

Enzyme Inhibition(2) / Transporters (CYP450; other)

%D2 Receptor Occupancy(3) (dose & plasma level)

% 5-HT2A Occupancy (dose)

Aripiprazole

(Abilify)

7.5

Oral: Start and target dose: 10 or 15 mg once daily. If needed, increase q 2 weeks (up to

30 mg/day).

However, greater ef cacy has not been demonstrated at doses

> 10 mg/day

Anecdotal evidence suggests dosing in the morning and using lower starting doses to minimize activation effects

Short-acting IM: Usual: 9.75 mg Range: 5.25–15 mg as a single dose

Maximum: 30 mg/day with at least 2 h between doses

87% (tablet; slightly higher with oral solution form)

Short- acting IM: 100%

> 99% (primarily to albumin)

Oral: 3–5

Short- acting IM: 1–3

75 146(D) (active metabolite = 94) No change in renal or hepatic impairment or in elderly

2D6(p), 3A4(p) (Reduce dose by 50% in poor metabolizers of 2D6. Dose changes required with concurrent use of drugs that affect 2D6 and/or 3A4)

–

40–95% (0.5–30 mg)

54 60% (10 30 mg)

Brexpiprazole

(Rexulti)

1 mg once daily on days 1–4. Titrate to 2 mg once daily on days 5–7,thento4mgonday8 depending on response and tolerability. Recommended target dose is 2–4 mg once daily

95%

> 99%

(major metabolite = 86)

2D6(p), 3A4(p) (Reduce dose by 50% in poor metabolizers of 2D6. Dose changes required with concurrent use of drugs that affect 2D6 and/or 3A4)

–

Cariprazine(B) (Vraylar)

Starting dose is 1.5 mg; can be increased to 3 mg on day 2. Depending on response and tolerability, further dose adjustments can be made in 1.5 or 3 mg increments. Recommended dose range is 1.5–6 mg once daily

High

19–97%

3–6

2–5 days

(2–3 weeks for active metabolite)

3A4(p), 2D6(w) (Reduce dose by 50% in patients initiating a strong CYP3A4 inhibitor)

–

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 189 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Antipsychotic Doses and Pharmacokinetics (Oral and Short-Acting Injections) (cont.)

5-HT2A INVERSE AGONIST

Drug

CPE (mg)

OLE in Schizo- phrenia (mg)

Monograph Doses for Psychosis

Bioavailability

Protein Binding

Peak Plasma Level (h) (Tmax)

Elimination Half-Life (h)

Metabolizing Enzymes(1) / Transporters (CYP450; other)

Enzyme Inhi- bition(2) / Transporters (CYP450; other)

% D2 Receptor Occupancy (dose & plasma level)

% 5-HT2A Occu- pancy (dose)

Pimavanserin

(Nuplazid)

–

34 mg, taken orally as two 17 mg tablets once daily, without titration

N/A. High-fat meal had no signi cant effect on Cmax and AUC

~95%

6 (range 4–24)

57 (active metabolite = 200)

3A4, 3A5

–

No appreciable af nity for D2 receptors

–

(1) CYP450 isoenzymes involved in drug metabolism, (2) CYP450 isoenzymes inhibited by drug

NOTES:

• Comparabledosesareonlyapproximations.Generallydosesusedarehigherintheacutestageoftheillnessthaninmaintenance.Eachpatient’smedicationdosagemustbeindividualized

• Plasmalevelsareavailableforsomeantipsychoticsbuttheirclinicalusefulnessislimited

• ForCYPactivitydata,see:[28,29,30];productmonographsasofMay2017;[Note:dataregardingCYP450pro lesmaynotbeconsistentamongreferences]

• Abbreviations:α1-AGP=α1-acidglycoprotein;bid=twicedaily;CPE=chlorpromazineequivalents[theapproximatedoseofcomparatorantipsychoticthatwouldbeequivalenttooralchlorpromazine100mgwithrespecttoD2receptoraf nity];FMO= avin

monooxygenase enzyme involved in N-oxidation reactions; od = once daily; OLE = olanzapine equivalents [the approximate oral dose of comparator antipsychotic (mg/day) that would be equivalent to oral olanzapine 20 mg/day with respect to clinical ef cacy – based on expert consensus opinion[31, 32]]; P-gp = P-glycoprotein [a transporter of hydrophobic substances in or out of speci c body organs (e.g., block absorption in the gut)]; qid = four times daily; tid = three times daily; UGT = uridine diphosphate glucuronosyl transferase [involved in Phase II reactions (conjugation)]

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Comparison of Long-Acting IM Antipsychotics

FIRST-GENERATION AGENTS (FGAs)

Flupenthixol decanoate(C) (Fluanxol)

Fluphenazine decanoate (Modecate, Prolixin)

Haloperidol decanoate (Haldol LA)

Zuclopenthixol decanoate(C) (Clopixol Depot)

Thioxanthene

Piperazine phenothiazine

Butyrophenone

Thioxanthene

Esteri ed with decanoic acid (a 10-carbon chain fatty acid) and dissolved in vegetable oil; must be hydrolyzed to free upenthixol; metabolites inactive

Esteri ed with decanoic acid and dissolved in sesame oil; must be hydrolyzed to free uphenazine

Esteri ed with decanoic acid and dissolved in sesame oil; must be hydrolyzed to free haloperidol

Esteri ed with decanoic acid in coconut oil; must be hydrolyzed to free zuclopenthixol

20 mg/mL (2%) 100 mg/mL (10%)

25 mg/mL 100 mg/mL(C)

50 mg/mL 100 mg/mL

200 mg/mL

Gluteal muscle Deep IM injection

Gluteal muscle (IM) Deltoid muscle (SC)

SC or deep IM injection

Gluteal muscle Deep IM injection

1 week

None to 4 weeks

2 weeks

Long-acting IM naive: Test dose of 5–20 mg; assess over next 5–10 days Non-naive: 20–40 mg

Increase in increments not exceeding 20 mg

Continue oral for rst week in a diminishing dose

IM or SC: 2.5–12.5 mg

50 mg[33] or 10–20 times previous oral dose (10–15 times if elderly, debilitated or on stable oral doses of ≤ 10 mg/d) to a max. of 100 mg[34]

Continue oral in a diminshing dose if starting with a low IM dose

100–200 mg

Supplemental oral in diminishing dosage may be needed for the rst 2 weeks

20–80 mg

12.5–50 mg

50–200 mg or 10–15 times previous oral dose[34]

150–300 mg

Doses above 80 mg generally unnecessary

Doses above 50 mg generally unnecessary; doses up to 100 mg q

2 weeks have been used in some cases[33]

450 mg/month

400mgq2weeks

2–4 weeks

2–5 weeks[33]

4 weeks

2–4 weeks

16–40 mg q 2 weeks

10–25 mg q 2 weeks

40–100 mg q 4 weeks

80–200 mg q 2 weeks

40mgq2weeks

25mgq2weeks

150mgq4weeks

200mgq2weeks

3–7 days[33]

8 days (after single injection), 17 days (multiple dosing)

2 months[33]

First peak in 8–10 h (due to presence of hydrolyzed “free” uphenazine); level drops, then peaks again in 8–12 days

6.8–9.6 days (single injection), up to 14.3 days (multiple dosing)

2 months[33]

3–9 days

18–21 days 2–3 months[33]

3–7 days

19 days

2 months[33]

Chemical class Form

Strength supplied Administration

Overlap with oral formulation Starting dose

Usual dose range Maximum dose (D)

Usual duration of action CPE

OLE

Pharmacokinetics

Time to peak plasma level(G)

Elimination half-life(H) Time to steady state

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 191 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Comparison of Long-Acting IM Antipsychotics (cont.)

FIRST-GENERATION AGENTS (FGAs)

Flupenthixol decanoate(C) (Fluanxol)

Fluphenazine decanoate (Modecate, Prolixin)

Haloperidol decanoate (Haldol LA)

Zuclopenthixol decanoate(C) (Clopixol Depot)

Adverse effects: Generally similar to oral drugs in same class

Flupenthixol (see p. 180)

Fluphenazine (see p. 180)

Haloperidol (see p. 180)

Zuclopenthixol (see p. 180)

CNS

Both sedating and alerting effects reported; may have energizing effects at low doses

Both drowsiness and insomnia reported

Both drowsiness and insomnia reported (less frequent than with oral zuclopenthixol)

Extrapyramidal

Frequent; more frequent with rst few injections, diminish thereafter

Less frequent than with oral preparation. Tend to occur in the rst few days after an injection. Increased frequency of dystonia noted with use of “older” multipunctured multidose vials due to presence of “free” uphenazine

Frequent, however, reported less often than with oral haloperidol

Reported in 5–15% of patients

Skin and local reactions

Indurations rarely seen (at high doses) Photosensitivity and hyperpigmentation very rare; dermatological reactions seen Pain at injection site

One case of induration seen at a high dose; dermatological reactions have been reported

Pain at injection site

Local dermatological reactions; In ammation and nodules at injection site (may be more common with

100 mg/mL preparation or with higher volumes); less common if deltoid used One case of photosensitization reported; “tracking” reported

Pain at injection site can continue for

2 days after administration

No indurations but local dermatological reactions reported

Pain at injection site

Laboratory changes

Rarely leukopenia, eosinophilia

Dose-dependent rise in prolactin[33]; one case of jaundice reported; rarely agranulocytosis; ECG changes seen in some patients

Dose-dependent rise in prolactin[33]; rarely jaundice, leukopenia, agranulocytosis

Transient changes in liver function seen Rarely neutropenia, agranulocytosis

(C) = Not marketed in the USA, (D) Typical maximal doses based on product monographs. Some clinicians may use higher doses if they are effective with minimal adverse effects, (G) Important as indicator when maximum adverse effects will occur, (H) Useful for determining dosing interval; steady state will be reached in approximately 5 half-lives

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

SECOND-GENERATION AGENTS (SGAs)*

THIRD-GENERATION AGENTS (TGAs)

Olanzapine pamoate(B) (Zyprexa Relprevv)

Paliperidone palmitate 1-monthly (Invega Sustenna)

Paliperidone palmitate 3-monthly (Invega Trinza)

Risperidone (Risperdal Consta)

Aripiprazole (Abilify Maintena)

Aripiprazole lauroxil (Aristada(B) )

Chemical class

Thieobenzodiazepine

Benzisoxazole

Phenylpiperazine

Form

Yellow solid of olanzapine pamoate monohydrate crystals forming a yellow, opaque suspension on reconstitution with provided aqueous diluent

White to off-white sterile, aqueous, extended-release suspension in pre lled syringes

White to off-white, free- owing powder with risperidone encapsulated in a polymer as extended-release microspheres. Must be reconstituted with provided aqueous base just prior to use

White to off-white lyophilized powder forming an opaque, milky-white suspension on reconstitution with provided sterile water for injection

White to off-white sterile aqueous extended-release suspension in pre lled syringe, supplied as a kit with safety needles

Strength supplied

210 mg/vial, 300 mg/vial, 405 mg/vial

Strengths vary in different countries, e.g., US labeling indicates the amount of paliperone palmitate:

39 mg/0.25 mL,

78 mg/0.5 mL,

117 mg/0.75 mL, 156 mg/mL, 234 mg/1.5 mL

Canadian labeling indicates only the amount of paliperidone (not the palmitate base):

50 mg/0.5 mL,

75 mg/0.75 mL, 100 mg/mL, 150 mg/1.5 mL

Strengths vary in different countries, e.g., US labeling indicates amount of paliperone palmitate: 273 mg/0.875 mL, 410 mg/1.315 mL,

546 mg/1.75 mL,

819 mg/2.625 mL

Canadian labeling indicates only the amount of paliperidone (not the palmitate base): 175 mg/0.875 mL,

263 mg/1.315 mL,

350 mg/1.75 mL,

525 mg/2.625 mL

12.5 mg/vial, 25 mg/vial, 37.5 mg/vial, 50 mg/vial

300 mg/vial, 400 mg/vial

441 mg, 662 mg, 882 mg, 1064 mg pre lled syringe

Administration

Gluteal muscle Deep IM injection

Deltoid muscle for days 1 and 8. Deltoid or gluteal muscle thereafter

Deep IM injection

Deltoid or gluteal muscle Single, deep IM injection (not divided)

Deltoid or gluteal muscle

Deep IM injection

Deltoid or gluteal muscle

Deep IM injection

Deltoid (441 mg dose only) or gluteal muscle (all strengths)

Deep IM injection

Overlap with oral formulation

None

3 weeks

2 weeks

3 weeks

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 193 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Comparison of Long-Acting IM Antipsychotics (cont.)

SECOND-GENERATION AGENTS (SGAs)*

THIRD-GENERATION AGENTS (TGAs)

Olanzapine pamoate(B) (Zyprexa Relprevv)

Paliperidone palmitate 1-monthly (Invega Sustenna)

Paliperidone palmitate 3-monthly (Invega Trinza)

Risperidone (Risperdal Consta)

Aripiprazole (Abilify Maintena)

Aripiprazole lauroxil (Aristada(B) )

Starting dose(A)

For 1st 8 weeks: If previously on 10 mg/day oral = 210 mg IM/q 2 weeks or 405 mg/q 4 weeks; 15–20 mg/day oral = 300 mg/q 2 weeks. In patients who are debilitated or prone to hypotension, start with 150 mg IM/q

4 weeks

Day1:234mgIMof paliperidone palmitate

(150 mg of paliperidone) Day8:156mgIMof paliperidone palmitate

(100 mg of paliperidone)

For dosing in renal or hepatic impairment see SGA Dosing section p. 135

Only to be used after treatment with paliperidone 1-monthly IM has been established as an adequate treatment for at least 4 months

Initiate paliperidone 3-monthly IM when the next paliperidone 1-monthly IM dose is due (+/- 7days), using a 3.5-fold higher dose than that of the previous 1-monthly formulation injection

25mgIMq2weeks Continue oral risperidone for the rst 3 weeks

For dosing in renal or hepatic impairment see SGA Dosing section p. 135

400mgIMq

4 weeks

Continue oral aripiprazole (10–20 mg) for the rst 14 days

Depending on patient’s needs. Can be initiated at 441mg,662mgor882mg IMq4weeks,882mgIMq 6weeksor1064mgIMq 2 months. (Continue oral aripiprazole for the rst

21 days OR administer one injection of 675 mg Aristada Initio and one

30 mg dose of oral aripiprazole in conjunction with the rst dose of Aristada (see Dosing

p. 163))

Usual dose range(A)

After 1st 8 weeks: If previously on 10 mg/day oral = 150 mg IM/q 2 weeks or 300 mg/q 4 weeks;

15 mg/day oral = 210 mg/q 2 weeks or 405 mg/q

4 weeks; 20 mg/day oral = 300 mg/q 2 weeks

117 mg IM paliperidone palmitate (75 mg paliperidone) q 4 weeks Dose can be higher or lower within the recommended range of 78–234 mg of paliperidone palmitate (50–150 mg paliperidone) based on individual patient tolerability and/or ef cacy

273–819 mg paliperidone palmitate (175–525 mg paliperidone) q 3 months. Dose can be adjusted within the range every 3 months based on tolerability and/or ef cacy

25–50 mg q 2 weeks

400mgIMq

4 weeks. If adverse effects, can reduce to300mgq

4 weeks. Interval should be no shorter than

26 days and no longer than 5 weeks for the 2nd and 3rd dose or 6 weeks for the 4th and subsequent doses. Dose varies if known CYP2D6 poor metabolizer or if taking strong 2D6 or 3A4 inhibitors

– see monograph

441mgIMq4weekto 1064 mg q 2 months. Dose varies if known CYP2D6 poor metabolizer or if taking strong 2D6 or 3A4 inhibitors (see Dosing

p. 163)

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

SECOND-GENERATION AGENTS (SGAs)*

THIRD-GENERATION AGENTS (TGAs)

Olanzapine pamoate(B) (Zyprexa Relprevv)

Paliperidone palmitate 1-monthly (Invega Sustenna)

Paliperidone palmitate 3-monthly (Invega Trinza)

Risperidone (Risperdal Consta)

Aripiprazole (Abilify Maintena)

Aripiprazole lauroxil (Aristada(B) )

Maximum dose(A),(D)

300mgIMq2weeks/ 405mgIMq4weeks

234 mg IM of paliperidone palmitate (150 mg paliperidone) q 4 weeks

819 mg paliperidone palmitate (525 mg paliperidone) q

3 months

50 mg q 2 weeks(E)

400mgIMq 4 weeks

1064 mg q 2 months

Usual duration of action

2–4 weeks

4 weeks

3 months

2 weeks

4 weeks

441 mg, 662 mg: 4 weeks 882 mg: 4–6 weeks

1064 mg: 2 months

CPE

25mgq2weeks

OLE

50mgq2weeks

Pharmacokinetics

Time to peak plasma level(G)

Elimination half-life(H)

Time to steady state

2–4 days[35, 33]

∼30 days

2–3 months[33]

13 days

25–49 days

Increased in renal disease

2–3 months

Median: 30–33 days

Median: 84–95 days following deltoid injection, 118–139 days following gluteal injection

30 days[36]

3–6 days Elimination complete by

7–8 weeks Increased in hepatic or renal disease

2 months

Following multiple injections: 4 days (deltoid), 7 days (gluteal)

30 days (300 mg), 47 days (400 mg)

3–4 months

Not in monograph. Reaches systemic circulation after 5–6 days

53.9–57.2 days

4 months

Adverse effects(I): Generally similar to oral drugs in same class

Olanzapine (see p. 181)

Paliperidone (see p. 181)

As per paliperidone 1-monthly IM, except where noted

Risperidone (see p. 181)

Aripiprazole (see p. 165)

CNS

Post-injection delirium sedation syndrome (PDSS). Administer when ER services readily accessible. Observe for at least 3 h. Instruct not to drive/operate heavy machinery for remainder of the day. Risk < 0.1% at each injection

Headache ≤ 18%, sedation ≤ 13%

Insomnia, headache ≤ 15%; anxiety ≤ 8%; drowsiness ≤7%

Adverse effects increase with dose over50mgq

2 weeks Drowsiness 3–6%, anxiety 25%, insomnia 23%, headache 13%, depression 16%

Sedation (IM: 2.4%, oral: 1.1%, placebo: 0.7%)

Headache (IM: 3–4%, placebo: 3%) Insomnia (IM:2–4%, placebo: 2%)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 195 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Comparison of Long-Acting IM Antipsychotics (cont.)

SECOND-GENERATION AGENTS (SGAs)*

THIRD-GENERATION AGENTS (TGAs)

Olanzapine pamoate(B) (Zyprexa Relprevv)

Paliperidone palmitate 1-monthly (Invega Sustenna)

Paliperidone palmitate 3-monthly (Invega Trinza)

Risperidone (Risperdal Consta)

Aripiprazole (Abilify Maintena)

Aripiprazole lauroxil (Aristada(B) )

Extrapyramidal

Akathisia (100 mg IM: 11%, 50 mg IM: 5%, placebo: 5%); parkinsonism (100 mg IM: 18%, 50 mg IM: 9%, placebo: 7%)

Akathisia 4%; parkinsonism 6%

Akathisia (50 mg IM: 9%, 25 mg IM: 2%, placebo: 4%); parkinsonism

(50 mg IM: 10%, 25 mg IM: 4%, placebo: 3%)

Akathisia (IM: 8.2%, oral: 6.8%, placebo: 6%); parkinsonism (IM: 6.9%, oral: 4.1%, placebo: 3%)

Akathisia (IM: 11%, placebo: 4%); parkinsonism (IM: 5–7% placebo: 4%)

Skin and local reactions

At injection site: Pain, induration or site mass ≤ 3.6%

At injection site: Pain, redness, swelling or induration ≤ 10% (more common with 1st injection; reduced incidence with subsequent injections)

At injection site: Pain, redness, and swelling 2%

At injection site: Pain, redness, swelling or induration (more than 10%) [ensure solution is at room temperature and inject into alternate buttocks]

At injection site: Pain (5%), redness, swelling, induration of mild to moderate severity (decreased frequency and intensity with subsequent injections)

At injection site: Pain (IM: 3–4%, placebo: 2%); redness, swelling, induration: 1% (decreased frequency and intensity with subsequent injections)

Other

Orthostatic hypotension 0.1%; weight gain ≤ 7% (mean gain = 11.2 kg after at least 24 weeks)

Orthostatic hypotension <2%

Weight gain 9%; headache 9%

Hypotension < 2%

* See the relevant sections in Second-Generation Antipsychotics/SGAs (pp. 132 146) for further information (A) For schizophrenia and related psychotic disorders. See Dosing section p. 135 for dosing in renal and hepatic impairment, (B) Not marketed in Canada, (D) Typical maximal doses based on product monographs. Some clinicians may use higher doses if they are effective with minimal adverse effects, (E) Maximum dose suggested by manufacturer. Increase in adverse effects without any increase in ef cacy reported with 75 mg q 2 weeks, (G) Important as indicator when maximum adverse effects will occur, (H) Useful for determining dosing interval; steady state will be reached in approximately 5 half-lives, (I) Incidences are not from head to head trials of agents thus incidences may not be comparable

Abbreviations: CNS = central nervous system; q X weeks = every X weeks

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Switching Antipsychotics

• 1.Aswitchmaybeconsideredincasesofnonresponse,partialorlessthanoptimalresponse,orrelapsedespiteadherence.Motivatingfactorsmay include:

– Persistentpositivesymptoms(consideraFGAoraSGA;switchingtoclozapinemayo eradditionalresponseinuptoafurther50%ofpatients) – Persistentnegativesymptoms(consideralternateSGA,loweringdose,oraTGA)

– Persistentcognitiveora ectivesymptoms(considerSGA)

– Persistentsuicidalideationorbehaviors(considerclozapine)

– Arequestforchangefrompatientorfamilymember

– Achangeinpatient’smedicalorpsychiatricconditionwarrantingachangeintreatment

• 2.Torelieveordecreaseabothersomeadversee ect(e.g.,sexualdysfunction,sedation,EPS)oronethatmaybeassociatedwithshort-orlong-term

morbidity (e.g., TD, metabolic e ects). These are often major contributors to nonadherence and eventual treatment failure

• Acombinationof1.and2.

• Rea rmdiagnosisandrationaleforswitchingmakessense

• Addressanyconfoundingorcomplicatingfactors.Forexample:

– Attempt to rule out partial adherence or nonadherence. If present, identify and address barriers to adherence if possible (e.g., some adverse e ects may be resolved by lowering the dose, changing the administration schedule or waiting for tolerance to develop)

– Ensure adequate trial period was employed – adequate dose for adequate duration [at least 4–6 weeks at maximally tolerated dose (longer for clozapine)]

– Determineifanydruginteractionsmaybeimpactingone cacyoradversee ects

– Determineifsubstanceabuseorpsychosocialstressorsmaybeconfoundingresponse

– Givethoughtfulconsiderationtotheprosandconsofmakingachange

– Establish a thorough plan including how to make the switch and what to expect. How long will it take to work? What unwanted e ects might

occur and how to monitor for them

– Con rmthepatientisagreeabletothechangeanddiscusstheswitchingplanwiththem

• Potentialproblemsthatmaybeanticipatedduringaswitchare:

– Withdrawale ectsrelatedtodiscontinuationoftheinitialantipsychotic – Adversee ectsthatresultfromtheadditionofanewagent

• These, coupled with a time lag to response, may discourage the patient and negatively impact on adherence unless the patient is educated as to what to expect

• Abrupt withdrawal of a medication that strongly antagonizes one or more receptors results in the exposure of sensitized receptors, leaving them potentially vulnerable to excessive stimulation. This may result in:

– Dopaminergic rebound – if a high D2 a nity medication (e.g., risperidone) is abrupty replaced with a low D2 a nity medication or a rapid on/o fast-dissociating antipsychotic (e.g., quetiapine) or a partial D2 agonist (e.g., aripiprazole), dopaminergic rebound may result. In the mesolimbic tract, this could lead to supersensitivity psychosis; in the nigrostriatal tract, treatment-emergent EPS and TD may materialize

– Cholinergic rebound – if a high-a nity cholinergic antagonist (e.g., olanzapine) is abruptly replaced by an antipsychotic with little a nity for blocking cholinergic receptors, cholinergic rebound may ensue, causing the patient to complain of u-like symptoms such as nausea, vomiting, diarrhea, diaphoresis, and insomnia

– Histaminic rebound – abrupt replacement of a high-a nity histamine antagonist (e.g., clozapine) with a low-a nity agent (e.g., aripiprazole) may see improvement in several metabolic parameters such as weight gain, glucose intolerance, and dyslipidemias. Sedation may also improve, but some individuals may experience distressing rebound insomnia which may be interpreted as a sign of relapse

– Serotonergic rebound – it has been suggested that abrupt discontinuation of a high-a nity serotonin 5-HT2A antagonist may result in serotonin syndrome (agitation, diaphoresis, fever, tremor, confusion, etc.) or NMS-like symptoms

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 197 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Switching Antipsychotics

Reasons for Considering a Switch

When Switching Therapies

Withdrawal Effects

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Switching Methods

Augmentation Strategies

Switching Antipsychotics (cont.)

– In the absence of any strong scienti c evidence, empirical recommendations favor a slow cross-taper method to minimize rebound and the addition/continuation of adjunctive treatments (e.g., anticholinergics for cholinergic rebound or benzodiazepines for insomnia) when necessary

• Fouroptions(noclearevidencetosupportonemethodoveranother) 1. Washout/start:

– Withdraw the rst drug gradually and begin the second drug following a suitable washout period. May minimize withdrawal-emergent reactions. Not clinically practical when patient is symptomatic. May increase the risk of relapse

2. Stop/start:

– Abruptly discontinue the rst drug, then start the second drug at its usual initial dose; increase the dose to a therapeutic range accordingly.

This technique is often used when the patient has a signi cant/serious adverse reaction to the initial drug (e.g., agranulocytosis, NMS,

ketoacidosis). Potential drawbacks include an increased risk of relapse and withdrawal-emergent reactions 3. Cross-taper:

– Taper the dose of the rst medication while simultaneously increasing the dose of the second drug. Commonly used when stable patients are experiencing bothersome adverse e ects and require a medication change. Consider using at least 2 weeks for tapering down or titrating up antipsychotics that have higher likelihood of sedation or anticholinergic e ects (see table Relative Tolerability Pro les of Antipsychotics p. 178) to allow for patient tolerability and to minimize potential for withdrawal-emergent e ects. Generally the most well accepted or preferred strategy, thought to minimize the potential for withdrawal-emergent e ects and relapse. Drawbacks of this strategy include an increased risk of relapse should the patient spend time with subtherapeutic doses of both antipsychotics, an increased risk of polypharmacy should the patient improve during the switch and the practitioner become reluctant to make further changes, and an increased risk of additive or synergistic e ects from both drugs

4. Delayed withdrawal:

– Establishing the patient on a therapeutic dose of the second drug before reducing the existing medication. The strategy may be preferred in

situations for which relapse is a signi cant concern. There is an increased risk for polypharmacy with this method if the changeover is not

completed. There is also an increased risk of additive or synergistic e ects from both drugs during the procedure

• Rateofswitching/cross-taperingshouldbeslowintheelderlyandinyoungpatients

Antipsychotic Augmentation Strategies

• The addition of another pharmacological agent or treatment to an antipsychotic in an attempt to augment or improve the response to the initial antipsychotic

• The ultimate goal is to combine di erent mechanisms of action to create a synergistic e ect that will enhance e cacy while minimizing the potential for increased adverse e ects and drug interactions

• Most of the literature on augmentation strategies evaluates augmentation of clozapine therapy, the assumption being that monotherapy with clozapine would often be attempted rst before less well-studied alternatives such as augmentation strategies with other antipsychotics would be employed. There are still circumstances in which augmentation of other antipsychotics may be considered before a clozapine trial. In many of these cases, the target symptom is something other than residual psychotic symptoms – e.g., benzodiazepines for agitation and hostility, antidepressants for depressive symptomatology, mood stabilizers for a ective lability

• An estimated one third of individuals with schizophrenia do not achieve an adequate response to antipsychotic treatment. The superiority of clozapine in treatment-resistant schizophrenia (commonly de ned as inadequate response to sequential trials of two or more antipsychotics) is well established. Estimates of improvement when switched to clozapine vary from 30% to 60%. A number of strategies have been proposed to augment clozapine in treatment-resistant schizophrenia. There is currently insu cient evidence (small number of studies; study design issues – few RCTs, small sample sizes, industry sponsors; con icting outcomes; etc.) to endorse any of these

• Beforeconcludingthatatrialofclozapinemonotherapyhasbeenunsuccessful,thefollowingissuggested

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Anticonvulsants

Lamotrigine

– Anadequatetrialhasbeenemployedforatleast3months(trialsofupto6monthsareoftensuggested)

– Ruleoutnonadherence(includingpartialadherence)toclozapine

– Ruleoutsubstanceabuseasacontributingfactor

– Ruleoutpresenceofanuntreateddepression

– Rule out inadequate dosing (Note: On average, smokers require a 50% greater dose to achieve the same clozapine plasma level as nonsmokers – see also p. 159 for interactions of smoking with SGAs)

– Considerobtainingaclozapineplasmaleveltocon rmadherence/adequatedosing

• Should a decision to employ an augmentation strategy be made, a detailed plan should be documented that clearly states the agent to be used,

the planned dosage strategy, the target symptoms to be evaluated, and the anticipated time to see e ect/trial period (e.g., 3–4 months), and how and when to monitor for e cacy and safety. The plan should also include a strategy for discontinuing the augmenting agent should it prove to be ine ective. An adequate trial period of at least 10 weeks has been suggested when augmenting clozapine with a second antipsychotic

• Anoverviewofaugmentationstrategiesispresentedbelow

• Inadditiontotheinformationprovidedbelow,refertothecorrespondingdruginteractionsection

• A meta-analysis of ve RCTs reported modest bene t in 20–30% of clozapine-resistant patients following augmentation with lamotrigine versus placebo

• AreviewfromtheCochraneCollaborationconcludedthattherewasevidenceofamarginalbene ciale ectonsomepsychoticsymptomswiththe addition of lamotrigine, but that the current evidence was not su cient to recommend the routine addition of lamotrigine in treatment-resistant schizophrenia

• Lamotrigineaugmentstheanti-aggressione ectsofclozapine,particularlyverbalaggression

• Caution – one case report of a tripling in the clozapine level with the addition of lamotrigine, the mechanism of this potential drug interaction is

unknown

• Caution–bothlamotrigineandclozapinehavethepotentialtodepressbonemarrowfunction

• May be of bene t for schizoa ective patients (rather than with schizophrenia), with improvements in negative and cognitive symptoms • Hasbeenusedforclozapine-rechallengeinpatientswithpreviousclozapine-inducedneutropenia

• Tremors,involuntarymovements,andseizures,reversibleleukocytosisandrhabdomyolysisreportedwhencombinedwithclozapine

• A meta-analysis of RCTs of topiramate augmentation with antipsychotics vs. placebo/ongoing antipsychotic treatment found adjunctive topiramate to be an e ective and safe treatment choice for symptomatic improvement and weight reduction

• Augmentingwithtopiramatemaycausememoryimpairmentandde citsincognitiveprocessing • Augmentingwithtopiramatewillo setsomeoftheweightgainresultingfromclozapine

• There is con icting evidence regarding the use of valproic acid as augmentation agent. Case reports suggest bene t in refractory patients on clozapine. A meta-analysis of ve randomized controlled trials examining valproate as an add-on to various antipsychotics did not report bene cial results

• Reduceshostilityandanxiety

• Caution – there are con icting reports that valproic acid may increase serum clozapine levels and worsen the severity of weight gain (see Drug

Interactions p. 153)

• Clozapinehasanti-serotonergice ectsthatmaybeassociatedwiththedevelopmentofobsessive-compulsivesymptoms.SSRIscouldalleviatethis to some extent

• Fluvoxamine inhibits CYP1A2, thereby increasing the clozapine/norclozapine ratio. Reduction of norclozapine levels results in improved metabolic pro le

• Citalopram may be the antidepressant of choice to treat depressive symptoms in clozapine-treated patients due to its limited e ect on serum clozapine levels

• Amitriptyline reported to reduce clozapine-associated sialorrhea, possibly by antagonizing M4 receptors • Mirtazapinemayimproveavolitionandanhedonia

Lithium Topiramate

Valproic acid

Antidepressants

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 199 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Antipsychotics

Amisulpride

Aripiprazole

Antipsychotic Augmentation Strategies (cont.)

• Augmentation of clozapine with a number of antipsychotics (amisulpride, aripiprazole, haloperidol, quetiapine, risperidone, and ziprasidone) has been studied. There is currently insu cient evidence to conclude superior e cacy of combination therapy over monotherapy

• Open retrospective study showed bene cial e ects in ameliorating positive and negative symptoms. Allowed for a 24% reduction in clozapine dose and thus a better side e ect pro le

• Comparisonstudy:Clozapineaugmentedwithamisulpridewassuperiortoclozapineaugmentedwithquetiapineat8weeksusingBPRS • Anotherstudyshowedimprovementinglobalpsychopathologywithdosesupto600mgamilsupride

• Mayreduceclozapine-inducedhypersalivation

• Has resulted in improvements in waist circumference, BMI, body weight, and serum lipids • Overalle ectonpsychoticsymptomsappearsmixed

• A24-weekstudyshowedsigni cantimprovementsinpositivesymptoms

• Mayhelpimprovenegativesymptoms

• Ofbene tinacuteschizophreniawhenarapidreductioninsymptomsisdesired,especiallyifcatatoniaora ectivesymptomsarepresent

• Maybemoree ectiveinschizoa ectivedisorderthanincatatonicorhebephenicschizophrenia

• Somereportssuggestsuperioritywithbilateraltreatment;usually12–20treatmentsrequiredforschizophrenia

• In a systematic review and meta-analysis (4 open label trial (n = 32) and 1 RCT (n = 39)), the data suggests that ECT may be an e ective and safe

clozapine augmenation strategy for treatment-resistant schizophrenia. A higher number of ECT treatments may be required than is standard for

other clinical indications

• Bene tsmaynotbesustainedupondiscontinuationofECTandtherisk-to-bene tratioofmaintenanceECTinthispopulationisunknown • Predominantsidee ectsincludenausea,tachycardia,hypertension,memoryproblems,andconfusion

• Suggestedtoexertaugmentinge ectbyinhibitingphospholipase-A2,anenzymefoundtobeoveractiveinpatientswithschizophrenia(seep.417) • Two small studies evaluating the bene t of 3g/day E-EPA on individuals with schizophrenia/schizoa ective disorder with residual symptoms

despite antipsychotic treatment yielded mixed results

• Mayhaveabene ciale ectonelevatedtriglyceridelevels(dosesgreaterthan2g/day) • Thepurityandconsistencyamongproductsmaynotbereliable

• Asmallplacebo-controlledstudyreportedimprovementinnegativesymptomsonlywiththeadditionofanextractofginkgobilobatoclozapinein individuals with treatment-refractory schizophrenia

• Purityandconsistencyamongginkgoproductsmaynotbereliable

• A small RCT reported bene t in positive and negative symptoms when memantine 20 mg/day (a nonselective NMDA receptor antagonist) was added to clozapine in patients with refractory schizophrenia

• InanRCTcrossoverstudyinpatientswithclozapine-treatedrefractoryschizophrenia,memantineadditionsigni cantlyimprovedverbalandvisual memory and negative symptoms without serious adverse e ects; results were sustained in an open-label 1-year extension study

• Mixed results in males and females in restoring cognition or reducing symptom serverity; bene ts may be related to patient’s age, dosage, and duration of treatment

• Showntohavebene ciale ectsonattention/processingspeedandmemoryforbothmenandwomen

• Double-blind placebo-controlled studies report contradictory results with raloxifene (120 mg/day) augmentation of antipsychotics in postmeno-

pausal women: Negative results seen in severely decompensated patients with schizophrenia, positive results reported in refractory schizophrenia • Consideration:Smallincreaseintheriskofvenousthromboembolismandendometrialcancer

• A review of the literature nds evidence that repetitive transcranial magnetic stimulation can have bene t in relieving positive and negative symptoms of schizophrenia, particularly auditory hallucinations

Electroconvulsive Therapy (ECT)

Ethyl Eicosapentaenoic Acid (E-EPA) or Omega-3 Fatty Acids

Ginkgo Biloba

Memantine

Raloxifene

Repetitive Transcranial Magnetic Stimulation (rTMS)

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Selegiline

Stimulants

Further Reading

• A case report and a number of small open-label trials reported improvement in negative symptoms of schizophrenia following the augmentation of antipsychotic therapy with selegiline

• These ndings were not supported by two controlled trials that showed either no bene t or bene t that was not deemed clinically signi cant. Currently low-dose selegiline cannot be recommended as augmentation treatment for negative symptoms

• E.g.,dextroamphetamine,methylphenidate

• Transientimprovementinnegativesymptomsandcognitivefunctionreported

• Exacerbationofpositivesymptomscanoccur

References

1 Elbe D, Black TR, McGrane IR, et al. Clinical handbook of psychotropic drugs for children and adolescents. (4th ed.). Boston, MA: Hogrefe Publishing, 2019.

2 AmericanPsychiatricAssociation.Practiceguidelineforthetreatmentofpatientswithschizophrenia.(2nded.).Retrievedfromhttps://psychiatryonline.org/pb/assets/raw/sitewide/

practice_guidelines/guidelines/schizophrenia.pdf

3 Kalapatapu RK, Schimming C. Update on neuropsychiatric symptoms of dementia: Antipsychotic use. Geriatrics. 2009:64(5):10–18.

4 Sarva H, Henchcliffe C. Valbenazine as the rst and only approved treatment for adults with tardive dyskinesia. Expert Rev Clin Pharmacol. 2018;11(3):209–217. doi:10.1080/17512433.

2018.1429264

5 Credible Meds Worldwide. https://www.crediblemeds.org

6 LactMed, National Library of Medicine. Chlorpromazine. Retrieved from http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT.

7 Klinger G, Stahl B, Fusar-Poli P, et al. Antipsychotic drugs and breastfeeding. Pediatr Endocrinol Rev. 2013;10(3):308–317.

8 Azorin JM, Bowden CL, Garay RP, et al. Possible new ways in the pharmacological treatment of bipolar disorder and comorbid alcoholism. Neuropsychiatr Dis Treat. 2010;6:37–46.

doi:10.2147/NDT.S6741

9 Angelucci F, Ricci V, Martinotti G, et al. Paliperidone for treatment of obsessive compulsive resistant symptoms in schizophrenia: A case report. Prog Neuropsychopharmacol Biol

Psychiatry. 2009;33(7):1277–1278. doi:10.1016/j.pnpbp.2009.06.014

10 Aman MG, McDougle CJ, Scahill L, et al. Medication and parent training in children with pervasive developmental disorders and serious behavior problems: Results from a randomized

clinical trial. J Am Acad Child Adolesc Psychiatry. 2009;48(12):1143–1154. doi:10.1097/CHI.0b013e3181bfd669

11 Sheehan JJ, Sliwa JK, Amatniek JC, et al. Atypical antipsychotic metabolism and excretion. Curr Drug Metab. 2010;11(6):516–525. doi:10.2174/138920010791636202#sthash.ou4XZBI4.

dpuf

12 Lincoln J, Stewart ME, Preskorn SH. How sequential studies inform drug development: evaluating the effect of food intake on optimal bioavailability of ziprasidone. J Psychiatr Pract.

2010;16(2):103–114. doi:10.1097/01.pra.0000369971.64908.dc

13 Ronaldson KJ, Fitzgerald PB, Taylor AJ, et al. A new monitoring protocol for clozapine-induced myocarditis based on an analysis of 75 cases and 94 controls. Aust N Z J Psychiatry.

2011;45(6):458–465. doi:10.3109/00048674.2011.572852

14 Genest J, McPherson R, Frohlich J, et al. 2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular

disease in the adult – 2009 recommendations. Can J Cardiol. 2009;25(10):567–579.

15 Babu GN, Desai G, Tippeswamy H, et al. Birth weight and use of olanzapine in pregnancy: A prospective comparative study. J Clin Psychopharmacol. 2010;30(3):331–332. doi:10.1097/

JCP.0b013e3181db8734

16 Health Canada. Risperdal Consta (risperidone powder for injectable prolonged-release suspension) – Needle detachments associated with the needle assembly used for gluteal injection

[April 7, 2010]. Retrieved from http://hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2010/risperdal_consta_hpc-cps-eng.php

17 Lexi-Interact online. Interaction monograph antipsychotics/acetylcholinesterase inhibitors (central).

18 Drug interaction guide. Immunode ciency Clinic, Toronto General Hospital. Retrieved from http://app.hivclinic.ca/

19 Ng W, Uchida H, Ismail Z, et al. Clozapine exposure and the impact of smoking and gender: A population pharmacokinetic study. Ther Drug Monit. 2009;31(3):360–366. doi:10.1097/

FTD.0b013e31819c7037

20 Maccall C, Billcliff N, Igbrude W, et al. Clozapine: More than 900 mg/day may be needed. J Psychopharmacol. 2009;23(2):206–210. doi:10.1177/0269881108089819

21 Glick ID, Mankoski R, Eudicone JM, et al. The ef cacy, safety, and tolerability of aripiprazole for the treatment of schizoaffective disorder: Results from a pooled analysis of a sub- population of subjects from two randomized, double-blind, placebo-controlled, pivotal trials. J Affect Disord. 2009;115(1–2):18–26. doi:10.1016/j.jad.2008.12.017

22 Young MC, Shah N, Cantrell FL, et al. Risk assessment of isolated aripiprazole exposures and toxicities: A retrospective study. Clin Toxicol (Phila). 2009;47(6):580–583. doi:10.1080/ 15563650902980027

23 Tan HH, Hoppe J, Heard K. A systematic review of cardiovascular effects after atypical antipsychotic medication overdose. Am J Emerg Med. 2009;27(5):607–616. doi:10.1016/j.ajem. 2008.04.020

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 201 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Antipsychotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Antipsychotics (cont.)

24 Brunton LL, Lazo JS, Parker K. Goodman & Gillman’s The pharmacological basis of therapeutics (11th ed.) New York, NY: McGraw-Hill, 2006.

25 Buckley PF. Receptor-binding pro les of antipsychotics: Clinical strategies when switching between agents. J Clin Psychiatry. 2007;68(Suppl. 6):5–9.

26 Horacek J, Bubenikova-Valesova V, Kopecek M. Mechanism of action of atypical antipsychotic drugs and the neurobiology of schizophrenia. CNS Drugs 2006;20(5):389–409. doi:

10.2165/00023210-200620050-00004

27 Khazaal Y, Chatton A, Khan R, et al. Quetiapine dosage across diagnostic categories. Psychiatr Q. 2009;80(1):17-22. doi:10.1007/s11126-008-9090-2

28 Flockhart DA. Drug interactions: Cytochrome P450 drug interaction table. Indiana University School of Medicine. Retrieved from http://medicine.iupui.edu/clinpharm/ddis/

29 Oesterheld JR, Osser DN. P450 Drug Interactions. Retrieved from http://www.mhc.com/Cytochromes

30 http://www.atforum.com/SiteRoot/pages/addiction_resources/P450%20Drug%20Interactions.PDF, http://mhc.daytondcs.com:8080/ddi46/resources/PgpTable.html, http://mhc.

daytondcs.com:8080/ddi46/resources/UGTTable.html, http://www.psychresidentonline.com/CYP450%20drug%20interactions.htm

31 Gardner DM, Murphy AL, O’Donnell H, et al. International consensus study of antipsychotic dosing. Am J Psychiatry. 2010;167(6):686-693. doi:10.1176/appi.ajp.2009.09060802

32 Leucht S, Samara M, Heres S, et al. Dose equivalents for second-generation antipsychotics: The minimum effective dose method. Schizophr Bull. 2014;40(2):314–326. doi:10.1093/

schbul/sbu001

33 Taylor D. Psychopharmacology and adverse effects of antipsychotic long-acting injections: A review. Br J Psychiatry Suppl. 2009;52:S13–S19. doi:10.1192/bjp.195.52.s13

34 Haldol decanoate product monograph. Raitan, NJ: Ortho-McNeil Pharmaceutical Inc., June 2009.

35 Citrome L. Olanzapine pamoate: A stick in time? A review of the ef cacy and safety pro le of a new depot formulation of a second-generation antipsychotic. Int J Clin Pract.

2009;63(1):140–150. doi:10.1111/j.1742-1241.2008.01900.x

36 Thyssen A, Rusch S, Herben V, et al. Risperidone long-acting injection: Pharmacokinetics following administration in deltoid versus gluteal muscle in schizophrenic patients. J Clin

Pharmacol. 2010;50(9):1011–1021. doi:10.1177/0091270009355156

Additional Suggested Reading

• BuckleyPF.Treatingmovementdisordersandakathisiaassideeffectsofantipsychoticpharmacotherapy.JClinPsychiatry.2008;69(5):e14.

• EinarsonA,BoskovicR.Useandsafetyofantipsychoticdrugsduringpregnancy.JPsychiatrPract.2009;15(3):183–192.doi:10.1097/01.pra.0000351878.45260.94

• GentileS.Antipsychotictherapyduringearlyandlatepregnancy.Asystematicreview.SchizophrBull.2010;36(3):518–544.doi:10.1093/schbul/sbn107

• GreenblattHK,GreenblattDJ.Useofantipsychoticsforthetreatmentofbehavioralsymptomsofdementia.JClinPharmacol.2016;56(9):1048–1057.doi:10.1002/jcph.731

• LeeLH,ChoiC,CollierAC,etal.Thepharmacokineticsofsecond-generationlong-actinginjectableantipsychotics:Limitationsofmonographvalues.CNSDrugs.2015;29(12):975–983.

doi:10.1007/s40263-015-0295-2

• LindenmayerJP,KaurA.Antipsychoticmanagementofschizoaffectivedisorder:Areview.Drugs.2016;76(5):589–604.doi:10.1007/s40265-016-0551-x

• MarinoJ,CaballeroJ.Iloperidoneforthetreatmentofschizophrenia.AnnPharmacother.2010;44(5):863–870.doi:10.1345/aph.1M603

• RemingtonG,FoussiasG,FervahaG,etal.Treatingnegativesymptomsinschizophrenia:Anupdate.CurrTreatOptionsPsychiatry.2016;3(2):133–150.doi:10.1007/s40501-016-0075-8

• Shahid M, Walker GB, Zorn SH, et al. Asenapine: A novel psychopharmacologic agent with a unique human receptor signature. J Psychopharmacol. 2009;23(1):65-73.doi:10.1177/

0269881107082944

• VentriglioA,GentileA,StellaE,etal.Metabolicissuesinpatientsaffectedbyschizophrenia:Clinicalcharacteristicsandmedicalmanagement.FrontNeurosci.2015;9:297.doi:10.3389/

fnins.2015.00297

• YinJ,CollierAC,BarrAM,etal.Paliperidonepalmitatelong-actinginjectablegivenintramuscularlyinthedeltoidversustheglutealmuscle:Aretheytherapeuticallyequivalent?JClin

Psychopharmacol. 2015;35(4):447–449. doi:10.1097/JCP.0000000000000361

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

ANTIPSYCHOTIC-INDUCED EXTRAPYRAMIDAL SIDE EFFECTS AND THEIR MANAGEMENT

Extrapyramidal Adverse E ects of Antipsychotics

Acute Extrapyramidal Effects

Tardive Syndromes

Onset

Acute or insidious (up to 30 days)

• After months or years of treatment, especially if drug dose is decreased or discontinued • Tends to persist for years or decades

Proposed mechanism

Most EPS symptoms are due to dopamine (D2) blockade (if > 80%)

• Precise pathophysiology remains unclear

• Upregulation and supersensitivity of postsynaptic dopamine receptors induced by long-term blockade

• Neurotoxic effects of free radicals produced by the metabolism of excessive compensatory dopamine release, coupled with impairment of the antioxidant

system

• Glutamate-associated excitotoxicity

• GABA dysfunction in the globus pallidus/substantia nigra

• Multiple genetic associations related to schizophrenia, the dopamine system, metabolism of antipsychotics and free radicals (Nur77 deletion, ICOMT, DRD2,

CYP1A2, IP5K2A gene polymorphisms)

• Cholinergic de ciency

Treatment

• Respond to antiparkinsonian drugs

•Seep.203

• Akathisia may be

mediated by different mechanisms and is therefore more responsive to other treatments (e.g., benzodiazepines, β-blockers – see p. 214)

• Valbenazine and deutetrabenazine are FDA-approved drugs for treating tardive dyskinesia (TD). No other agents or strategies have proven ef cacy in the treatment of tardive syndromes

• Valbenazine (prodrug of the (+)-a isomer of tetrabenazine): Reported to improve TD in a randomized double-blind placebo-controlled 6-week Phase III trial of 234 patients (following a Phase II trial). During the study extension, valbenazine maintained ef cacy and safety for up to 46 weeks; adverse effects similar to tetrabenazine

• Deutetrabenazine is a derivative of tetrabenazine (deuterated formulation). Deutetrabenazine improved TD in two phase III 12-week randomized, double-blind placebo-controlled studies. In the rst study of 117 patients with moderate to severe TD, deutetrabenazine reduced abnormal movements (measured with AIMS). The second study of 298 patients with TD demonstrated the ef cacy, safety, and tolerability of deutetrabenazine 24 mg/day and 36 mg/day

• Consider the severity of TD, the degree of distress, and potential risks and bene ts of any treatment strategy before taking action

• Early recognition and discontinuation of the offending antipsychotic have been recommended as a means to improve the chance of remission, but

discontinuation of antipsychotic treatment is not often feasible

• Dosage reduction or use of lowest effective dose have also been suggested, but the success of dosage reduction or cessation has not been proven and must

be weighed against the risk of relapse[1]

• Slow taper recommended to avoid worsening of TD or chorea-like withdrawal-emergent syndrome. Switching to an atypical antipsychotic, such as clozapine or

quetiapine, has also been recommended. However, high doses of atypical antipsychotics may cause TD and should not be used for long-term treatment of TD

• Restarting or increasing the dose of the causative antipsychotic should be avoided and reserved only for the most severe cases that require immediate control

of involuntary movements

• The tendency for antipsychotic discontinuation to worsen TD and for antipsychotic dosage increase to suppress TD in the short term, as well as the

waxing/waning nature of TD over time may bias placebo-controlled studies examining the effectiveness of antipsychotics in treating TD in favor of the

antipsychotic and make interpretation of the results dif cult

• Anticholinergic agents: No bene t and may worsen tardive dyskinesias – taper and discontinuation recommended. May bene t tardive dystonia

• Other experimental therapies/potential interventions (Note: large-scale clinical trials are required to con rm results) include:

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 203 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Extrapyramidal

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Extrapyramidal Adverse E ects of Antipsychotics (cont.)

Acute Extrapyramidal Effects

Tardive Syndromes

Benzodiazepines (indirect GABA agonist): Limited evidence – small bene t reported in 1 study. Small double-blind RCT reported bene t with clonazepam β-blockers: Used in tardive akathisia – insuf cient evidence regarding ef cacy. Low doses of propranolol suggested to have an antidyskinesia effect – very limited evidence from case reports

Botulinum toxin: Limited studies with con icting results – botulinum toxin has been shown to bene t patients with cervical dystonia, involuntary tongue protrusion in case reports; a small, single-blind study failed to show bene t in orofacial TD

Branched-chain amino acids: Limited evidence demonstrating potential bene t in children and adolescents and in men. One double-blind, placebo-controlled 3-week study with 18 patients showed bene t

Calcium channel blockers: Currently no evidence to support routine use. Diltiazem – moderate evidence against

Clonidine: Insuf cient evidence – few studies, small number of patients, poor methodology

Deep brain stimulation (DBS): Insuf cient evidence – bene ts reported in tardive dystonia

Dopamine-depleting medications: Tetrabenazine: A number of small trials with design issues suggesting potential bene t. Duration of treatment and

dose-dependent serious adverse effects are concerns. TD relapse in most patients once drug is withdrawn. Reserpine: insuf cient evidence, central and peripheral adverse effects. Amantadine: two small double-blind trials showed symptom improvement – weak evidence

Essential Fatty Acids (omega-3): Experimental – bene t reported in animal studies. No bene t reported in recent placebo-controlled double-blind trial with 77 patients

Fluvoxamine: Five case reports of bene t at doses of 100–200 mg/day; uvoxamine is a potent sigma-1 receptor agonist

Ginkgo biloba (antioxidant): Double-blind study of 157 patients showed bene t with a standardized extract of G. biloba leaves (EGb-761) vs. placebo over 12 weeks Levetiracetam (reduces neurotransmitter release): A number of studies reporting bene t. Most were small size, open-label design, and of short duration. One small RCT reporting bene t vs. placebo

Melatonin (hormone with antioxidant effects, role in circadian rhythms): Two small placebo-controlled, double-blind studies showed signi cant improvement in a few patients with doses of 10 and 20 mg/day

Piracetam (nootropic, structural similarity to GABA): Weak evidence – initially effective in study 30 years ago. Recent randomized DBPC study (n = 40) reported symptom improvement

Pyridoxine: Low-quality evidence – may have bene t; a small (n = 15) DBPC crossover study reported bene t with vitamin B6. A more recent larger (n = 50) 26-week randomized DBPC reported ef cacy with 1200 mg/day

Resveratrol (antioxidant found in grapes, cranberries): Experimental – reported to have protective effect when co-administered with antipsychotic agent in animal models

Vitamin E: Most studied antioxidant for improving TD; 40 trials conducted over the past 30 years – evidence is limited and contradictory. May protect against further deterioration or reduce the risk of development. Patients with TD for less than 5 years might respond better

Zolpidem: Limited evidence from case reports

Zonisamide (antiepileptic – enhances GABA): Small open-label study reporting signi cant improvement in AIMS score in some patients

Miscellaneous (baclofen, sodium valproate, ECT, estrogen, insulin, tryptophan): No strong evidence to support use. GABA agonists (baclofen, sodium valproate) associated with adverse effects which likely outweigh any possible bene ts

See p. 207 for additional information on potential treatments

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

A: Dystonicreactions:uncoordinatedspasticmovementsofmusclegroups(e.g.,trunk,tongue,face)

B: Akathisia:restlessness,pacing(mayresultininsomnia)

C: Bradykinesia:decreasedmuscularmovements

Rigidity: coarse muscular movement; loss of facial expression

D: Tremors: nemovement(shaking)oftheextremities(“pill-rolling”)

Rabbit syndrome: involuntary movements around the lips

Pisa syndrome: can either be acute or tardive in nature (rare; occurs more commonly in people with brain damage/abnormality)

E: Tardivesyndromes:Symptomsofmovementdisordersthatstartabout3months(orlater)aftertherapyisinitiated

Type

Physical (Motor) Symptoms

Psychological Symptoms

Onset

Proposed Risk Factors

Clinical Course

Treatment Options

Differential Diagnosis

Acute dystonias

Torsions and spasms of muscle groups; mostly affects muscles of the head and neck; muscle spasms, e.g., oculogyric crisis, trismus, laryngospasm, torti/retro/antero- collis tortipelvis, opisthotonus, blepharospasm

Anxiety, fear, panic Dysphoria Repetitive meaningless thoughts

Acute (usually within 24–48 h after the rst dose); 90% occur within rst week of treatment

Young males, children Antipsychotic naive

High potency FGAs; low risk with SGAs and TGAs

Rapid dose increase Moderate to high doses Lack of prophylactic antiparkinsonian medication

Previous dystonic reaction Hypocalcemia, hyperthyroidism, hypoparathyroidism Dehydration

Recent cocaine use

Family history of dystonia

Acute, painful, spasmodic; oculogyria may be recurrent

Acute laryngeal/ pharyngeal dystonia may be potentially life threatening

IM benztropine (1st line), IM diphenhydramine, sublingual lorazepam

To prevent recurrence: prophylactic antiparkin-

sonian agents

Reduce dose or change antipsychotic

Seizures

Catatonia

Hysteria Malingering Hypocalcemia Primary genetic disorders Neurodegenerative disorders

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 205 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Extrapyramidal

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Extrapyramidal Adverse E ects of Antipsychotics (cont.)

Type

Physical (Motor) Symptoms

Psychological Symptoms

Onset

Proposed Risk Factors

Clinical Course

Treatment Options

Differential Diagnosis

Acute akathisia

Motor restlessness, dgeting, pacing, rocking, swinging of leg, trunk rocking forward and backward, repeatedly crossing and uncrossing legs, inability to lie still, shifting from foot to foot Respiratory symptoms: Dyspnea or breathing discomfort

Restlessness, intense urge to move, irritability, agitation, violent outbursts, dysphoria,

feeling “wound-up” or “antsy” or like “having a motor running inside”; sensation of skin crawling

Mental unease

Acute to insidious (within hours to days); 90% occur within rst

6 weeks of treatment; sometimes only with higher doses

Elderly female, young adults High caffeine intake High-potency FGAs; lower risk with SGAs and TGAs Genetic predisposition Anxiety

Diagnosis of mood disorder Microcytic anemia

Low serum ferritin Concurrent use of SSRI

May continue through entire treatment Increases risk of tardive dyskinesia Suggested that it may contribute to suicide and/or violence

Antiparkinsonian drugs not very effective

Diazepam, clonazepam, lorazepam or β-blockers (e.g., propranolol 10–20 mg bid, mirtazapine 15 mg hs)

Reduce dose or change antipsychotic

Psychotic agitation/ decompensation Severe agitation Anxiety Drug-intoxication Drug-seeking behavior/ withdrawal

Excess caffeine intake Restless leg syndrome

Acute pseudo- parkinsonism

Tremor: “pill-rolling”-type tremor (4–8 cycles per second; greater at rest and bilateral)

Rigidity: cogwheel rigidity Bradykinesia: mask-like facial expression, diminished or absent arm swing, shuf ing gait, stooped posture, slowness of movement

Slowed thinking Fatigue, anergia Cognitive impairment Depression

Acute to insidious (within 30 days); 90% occur within rst 6 weeks of treatment

Elderly female

High potency FGAs; low risk with SGAs and TGAs Increased dose

Adding second antipsychotic Discontinuation of anticholinergics

Concurrent neurological disorder

HIV infection

Family history of Parkinson’s disease

May continue through entire treatment (especially in the elderly)

Reduce dose or change antipsychotic Antiparkinsonian drug

Negative symptoms of schizophrenia Idiopathic Parkinson’s disease Depression Essential tremor Vascular Parkinsonism

Pisa syndrome

Leaning to one side

Can be acute or tardive

Elderly patients Compromised brain function, dementia

Often ignored by patients

Antiparkinsonian drug (higher doses)

Rabbit syndrome

Fine tremor of lower lip

After months of therapy

Elderly patients

Antiparkinsonian drug

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Type

Physical (Motor) Symptoms

Psychological Symptoms

Onset

Proposed Risk Factors

Clinical Course

Treatment Options

Differential Diagnosis

Tardive dyskinesia

Involuntary abnormal movements of face (e.g., tics, frowning, grimacing), lips (pursing, puckering, smacking), jaw (chewing, clenching), tongue (“ y-catcher,” rolling, dysarthria), eyelids (blinking, blepharospasm), limbs (tapping, piano-playing ngers or toes), trunk (rocking, twisting), neck (nodding), respiratory (dyspnea, gasping, sighing, grunting, forceful breathing)

Often coexists with parkinsonism and akathisia. Abnormal movements disappear during sleep

Cognitive impairment, distress (talking, swallowing, eating) and embarrassment

After 3 or more months of therapy in adults and earlier in the elderly

Common early sign is rapid icking movement of the tongue (“ y-catcher tongue”)

Age over 40, female, history of severe EPS early in treatment, chronic use of antipsychotics (FGAs more than SGAs/TGAs) or metoclopramide, chronic use of high doses of dopamine agonists in the treatment of Parkinson’s disease, presence of a mood component, history of diabetes, cognitive impairment, alcohol and drug abuse, organic brain damage

Persistent

– discontinuation of antipsychotic early increases chance of remission Spontaneous remission in 14–24% after 5 years

Valbenazine 40 mg/day initial dose, increase to recommended dose of

80 mg/day after one week Deutetrabenazine 12 mg/day (6 mg bid) initial dose, increase at weekly intervals in increments of 6 mg/day; not to exceed 48 mg/day (24 mg bid). Dose should not exceed 36 mg/day (18 mg bid) in patients who are either poor CYP2D6 metabolizers or concomitantly taking strong CYP2D6 inhibitors

Other treatment suggestions without proven ef cacy include:

Switch to a SGA or TGA

Pyridoxine 300–400 mg/day Clonazepam 0.5–6 mg/day Tetrabenazine 50–150 mg/day Branched-chain amino acids (Tarvil, 222 mg/kg tid)

Vitamin E 1200–1600 units/day Levetiracetam 1000-3000 mg Ginkgo biloba extract (EGb 761, 120–240 mg/day)

Spontaneous or withdrawal dyskinesia Stereotypic behavior Tourette’s syndrome Huntington’s

chorea or other neurological conditions Movement disorder secondary to co-prescribed drug Systemic lupus erythematosus and other neuroimmune diseases

Tardive dystonia

Sustained muscle contractions of face, jaw, tongue, eyes, neck, limbs, back, or trunk (craniocervical area involved most frequently), e.g., blepharospasm, laryngeal dystonia, dysarthria, retro exed hands

After months or years of therapy

Young male

Genetic predisposition (?) Neurological disorder, mental retardation Coexisting tardive dyskinesia

Akathisia

Persistent; discontinuation of antipsychotic early increases chance of remission

Switch to a SGA (clozapine?) or TGA Suggestions for treatment include: Tetrabenazine 50–150 mg/day; higher doses of anticholinergics (e.g., trihexyphenidyl 40 mg/ day); Botulinum toxin 25–50 mg/site (multiple sites used)

Myoclonus

Motor tics Idiopathic dystonia Meige syndrome

Tardive akathisia

Persistent symptoms of akathisia following dose decrease or withdrawal of antipsychotic

As for akathisia, but subjective sense of restlessness may be less intense

After months of therapy; after drug withdrawal

As for akathisia Coexisting tardive dyskinesia, dystonia, and iron de ciency

Persistent, discontinuation of antipsychotic early increases chance of remission. Fluctuating course

Potential treatments (insuf cient evidence for ef cacy) include switch to a SGA (clozapine?) or TGA

Suggested treatments include: anticholinergics

Benzodiazepines;

β-blockers;

Propranolol

As for akathisia

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 207 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Extrapyramidal

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Treatment Options for Extrapyramidal Side E ects

Product Availability∗ Generic Name

Amantadine Benztropine

Biperiden(B) Clonazepam Cyproheptadine

Deutetrabenazine Diazepam

Diphenhydramine

Ethopropazine(C) Lorazepam

Orphenadrine

Procyclidine(C) Propranolol

Chemical Class

Trade Name(A)

Dosage Forms and Strengths

Dopamine agonist

Symmetrel

Capsules/Tablets(B):100mg Syrup: 50 mg/5 mL

Anticholinergic

Cogentin

Tablets: 0.5 mg(B), 1 mg, 2 mg Injection: 1 mg/mL

Anticholinergic

Akineton(B)

Tablets(B):2mg

Benzodiazepine

Rivotril(C), Klonopin(B)

Tablets: 0.5 mg, 1 mg, 2 mg

Antihistamine

Periactin

Tablets: 4 mg Syrup: 2 mg/5 mL

Vesicular monoamine transporter 2 (VMAT2) inhibitor

Austedo

Tablets(B): 6 mg, 9 mg, 12 mg

Benzodiazepine

Diastat

Diazemuls(C) Diazepam Intensol(B) Valium

Rectal gel: 5 mg/mL

Emulsion injection (IM/IV)(C) : 5 mg/mL Oral solution concentrate(B) : 5 mg/mL Tablets: 2 mg, 5 mg, 10 mg

Injection: 5 mg/mL Oral solution: 1 mg/mL

Antihistamine

Benadryl

Caplets/Capsules/Liquigels/Tablets: 25 mg, 50 mg Oral liquid: 6.25 mg/5 mL(C) , 12.5 mg/5 mL Injection: 50 mg/mL

Anticholinergic

Parsitan(C)

Tablets(C):50mg

Benzodiazepine

Ativan

Lorazepam Intensol(B)

Tablets: 0.5 mg, 1 mg, 2 mg

Sublingual tablets(C): 0.5 mg, 1 mg, 2 mg Injection: 2 mg/mL(B) , 4 mg/mL Solution(B) : 2 mg/mL

Skeletal muscle relaxant

Orfenace(C), Orphenadrine citrate

Extended-release tablets: 100 mg Injection(B) : 30 mg/mL

Anticholinergic

Kemadrin(C)

Tablets(C) : 2.5 mg, 5 mg

β-blocker

Hemangeol Hemangiol(C) Inderal(B)

Oral solution(B) : 4.28 mg/mL (propranolol hydrochloride) Oral solution: 3.75 mg/mL (propranolol base)

Tablets: 10 mg, 20 mg, 40 mg, 60 mg, 80 mg

Inderal LA InnoPran XL(B)

Sustained-release capsules: 60 mg, 80 mg, 120 mg, 160 mg Extended-release capsules: 80 mg, 120 mg

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Generic Name

Chemical Class

Trade Name(A)

Dosage Forms and Strengths

Trihexyphenidyl

Anticholinergic

Artane

Tablets: 2 mg, 5 mg Elixir(B) : 2 mg/5 mL

Valbenazine

Vesicular monoamine transporter 2 (VMAT2) inhibitor

Ingrezza

Capsules(B) : 40 mg, 80 mg

Indications‡

( approved)

General Comments

Indications related to EPS (see p. 214 for comparison of drugs):

Tardive dyskinesia (valbenazine – USA; deutetrabenazine, also indicated for the treatment of chorea associated with Huntington’s disease – USA) Pseudoparkinsonian e ects (tremor, rigidity, shu ing) (benztropine, trihexyphenidyl – Canada and USA; ethopropazine – Canada; amantadine, biperiden, diphenhydramine injection – USA)

Drug-induced extrapyramidal reactions (benztropine, trihexyphenidyl – Canada and USA; ethopropazine – Canada; amantadine, biperiden – USA) Musculoskeletal conditions (acute, painful) (orphenadrine – Canada and USA)

Tremor (essential) (propranolol – USA)

• Individualpatientsmayrespondbetter,ortolerateonedrugoveranother

• Becauseoftheacuteonsetanddistressingnatureofacutedystonicreactions,IMbenztropineistypicallythepreferredtreatmentandusuallybrings

relief within 15 min

• Anticholinergicsincludingbenztropinemaybepreferredfordystonias,parkinsonism(especiallyrigidity);benzodiazepinesmostusefulforakathisia;

and propranolol most useful for akathisia and tremor

• Valbenazine and deutetrabenazine are the only proven treatments for tardive dyskinesia. For other tardive movement disorders, prevention (use

antipsychotics at the lowest e ective dose and only when necessary) and frequent assessment/early detection are important

• Controversy exists whether antiparkinsonian agents should be given prophylactically to patients at risk of developing EPS with FGAs, or whether they should only be started when EPS develop. The decision to initiate preventative agents should be made on an individual basis with consideration given to a number of factors including patient preference, history of EPS, potential of the particular antipsychotic to induce EPS, presence of

comorbidities or concomitant medications, which may be exacerbated by anticholinergic e ects

• Thereisawidevariance(e.g.,2–50%)inthereportedincidenceofdrug-inducedparkinsoniane ects.Ratesarehigherintheelderlyandinfemales

and are dose related

• Considerdosagereductionordiscontinuationoftheo endingantipsychoticagent(ifappropriate)orswitchingtoanewergenerationantipsychotic

as potential treatment options

• Centrally-active anticholinergic drugs cross the blood-brain barrier, block excitatory muscarinic pathways in the basal ganglia, and restore the dopamine/acetylcholine balance disrupted by antipsychotic drugs, thus treating EPS

• Five subtypes of muscarinic receptors have been determined; the M1 and M2 subtypes are the best characterized; the M1 subtype is found centrally and peripherally, whereas the M2 subtype is located in the heart

• Agents in order from highest to lowest a nity for the M1 receptor as follows: Benztropine (0.2 nM), biperiden (0.48 nM), trihexyphenidyl (1.6 nM), procyclidine (4.6 nM) [values in parentheses are Ki values as determined using cloned human receptors][2]

• Agents in order from highest to lowest a nity for the M2 receptor as follows: Benztropine (1.4 nM), biperiden (6.3 nM), trihexyphenidyl (7 nM), procyclidine (25 nM) [values in parentheses are Ki values as determined using cloned human receptors][2]

• Anticholinergic drugs also block presynaptic reuptake of dopamine (primarily benztropine), norepinephrine (primarily diphenhydramine), and serotonin (diphenhydramine, weakly)

• Valbenazine and deutetrabenazine block presynaptic monoamine uptake through reversible inhibition of the vesicular monoamine transporter 2 (VMAT2)

• Amantadine and ethopropazine have moderate NMDA (n-methyl-D-aspartate) receptor blocking properties; amantadine may exert its activity by increasing dopamine at the receptor (facilitates presynaptic release and inhibits reuptake)

Pharmacology

‡ Indications listed here do not necessarily apply to all agents for treating extrapyramidal side e ects or all countries. Please refer to a country’s regulatory database (e.g., US Food and Drug Administration, Health Canada Drug Product Database) for the most current availability information and indications

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 209 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Extrapyramidal

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Dosing

Treatment Options for Extrapyramidal Side E ects (cont.)

• Seechartpp.217–220

• Dosageincreasesmustbebalancedagainsttheriskofevokinganticholinergicadversee ects

• Dosageshouldbeadjustedforpatientswithmoderate–severehepaticimpairment(reducevalbenazineto40mg/day)

• ConsiderdosagereductioninCYP2D6poormetabolizersorwhengivenincombinationwithpotentCYP2D6and/orCYP3A4inhibitors(valbenazine)

or CYP2D6 inhibitors (deuterabenazine)

• Plasmalevelmonitoringisnotcurrentlyadvocated

• CNS e ects: Seen primarily in the elderly and at high doses; include cognitive impairment (including decreased memory and distractibility), som- nolence, confusion, disorientation, delirium, hallucinations, restlessness, stimulation, weakness, headache

• Excessuse/abuseofthesedrugsmayleadtoananticholinergic(toxic)psychosiswithsymptomsofdisorientation,confusion,euphoria(seeToxicity p. 210), in addition to physical signs such as dry mouth, blurred vision, dilated pupils, dry ushed skin

• Dopamine-agonistactivityofamantadinecanoccasionallycauseworseningofpsychoticsymptoms,nightmares,insomnia,andmooddisturbances

• Tetrabenazine may cause neuroleptic malignant syndrome (NMS) due to reduced dopaminergic transmission. Patients on deutetrabenazine or

valbenazine should be closely observed for any signs of NMS

• DeutetrabenazinemayincreasedepressioninpatientswithTD;itcanalsoincreasedepressionandsuicidalityinpatientswithHuntington’sdisease

• Relatedtoanticholinergicpotency(i.e.,M1antagonism):Benztropine>biperiden>trihexyphenidyl>procyclidine>orphenadrine>diphenhydramine

• Common:Drymouth,blurredvision,decreasedbronchialsecretions,constipation,dryeyes, ushedskin

• Occasional:Delayedmicturition,urinaryretention,sexualdysfunction

• Excessdosescansuppresssweating,resultinginhyperthermia

• Palpitations,tachycardia;highdosescancausearrhythmias

• QTprolongation(valbenazineanddeutetrabenazineathigherconcentrations)

• Nausea,vomiting,gastroesophagealre uxdisease,paralyticileus

• Use cautiously in patients with conditions in which excess anticholinergic activity could be harmful (e.g., benign prostatic hypertrophy, urinary retention, narrow-angle glaucoma, myasthenia gravis, GI obstruction, arrhythmias)

• AvoidvalbenazineanddeutetrabenazineinpatientswithcongenitallongQTsyndromeorinpatientswitharrhythmiasassociatedwithaprolonged QT interval

• Maydecreasesweating;educateandmonitorpatientsonthesemedicationsinhotweathertopreventhyperthermia

• Monitor breathing patterns in patients with respiratory di culties since antiparkinsonian medications can dry bronchial secretions and make

breathing di cult

• Caution when using amantadine in patients with peripheral edema or history of congestive heart failure (there are patients who developed

congestive heart failure while receiving amantadine); the clearance of amantadine is signi cantly reduced in adult patients with renal insu ciency

• If withdrawn abruptly, anticholinergic drugs may cause a cholinergic rebound: Symptoms include restlessness, anxiety, dyskinesia, dysphoria,

sweating, and diarrhea

• Euphorigenicandhallucinogenicpropertiesmayleadtoabuseofanticholinergicagents

• UseofanticholinergicagentsinpatientswithexistingTDcanexacerbatethemovementdisorderandmayunmasklatentTD

• MonitorpatientsondeutetrabenazineorvalbenazineforsignsofNMS

• Canoccurfollowingexcessivedoses,withcombinationtherapy,intheelderly,poormetabolizers,hepaticimpairment,orwithdrugabuse

Adverse Effects

of Anticholinergics

CNS

Peripheral

Cardiovascular Effects

GI Effects

Precautions

Toxicity

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Management

Pediatric Considerations

Geriatric Considerations

Use in Pregnancy♢

Nursing Implications

• Symptomsofanticholinergictoxicityinclude:

– Blindasabat(mydriasis,blurredvision)

– Dryasabone(dryskinandmucousmembranes,nosweating,urinaryretention)

– Hotasahare(hyperthermia)

– Madasahatter(confusion,delirium,hallucinations)

– Redasabeet( ushedskin)

– Sinustachycardia,hypertension,decreasedbowelsounds,muscletwitching,seizures,andcomamayalsooccur

• Generalguidelines:

– Absorptionmaybedelayedbecauseofthepharmacologicale ectsofanticholinergicsongastrointestinalmotility.E ectsofbenztropineintoxi-

cation can persist for 2–3 days

– Maintainanopenairwayandassistventilationifrequired;cardiacandpulseoximetrymonitoring

– Decontamination with single-dose activated charcoal may be administered under appropriate conditions – delayed gut emptying and reduced

peristalsis caused by anticholinergics may permit use of activated charcoal even when patients present hours post ingestion. Hemodialysis,

hemoperfusion, and peritoneal dialysis are not e ective in removing these agents

– Following GI decontamination, many cases can be managed well with supportive care – e.g., control agitation (benzodiazepines); fever ( uids,

antipyretics, active cooling measures); seizures (benzodiazepines); urinary retention (bladder catheterization), manage cardiac conduction dis- turbances

• For detailed information on the use of antiparkinsonian agents in this population, please see the Clinical Handbook of Psychotropic Drugs for Children and Adolescents[3]

• Doses up to 80 mg trihexyphenidyl have been employed in the treatment of hereditary dystonias in children; these were well tolerated with few side e ects

• Theelderlyareverysensitivetoanticholinergicdrugs.Monitorforconstipation,urinaryretentionaswellasincreasedconfusion,memoryloss,and disorientation. Avoid drugs with potent central or peripheral anticholinergic activity

• Cautionwhenusingtwoormoredrugswithanticholinergicproperties

• CautionwithVMAT2inhibitors,startlowandgoslow

• Greatestriskofmalformationduring rsttrimesteruse

• Considerpotentialforwithdrawalorothere ects(e.g.,metabolism)innewbornande ectsondeliveryduringthirdtrimester

• Limitedhumandatawithmanyoftheseagents

• Seechartpp.215–216

• Thesedrugsshouldbegivenonlytorelieveextrapyramidalsidee ectsofantipsychotics;excessuseorabusecanprecipitateatoxicpsychosis

• Someadversee ectsofthesedrugs(i.e.,anticholinergic)areadditivetothoseofantipsychotics;observepatientforsignsofsidee ectsortoxicity

• Monitor patient’s intake and output. Urinary retention can occur, especially in the elderly; bethanechol (Urecholine) can be used to reverse this

e ect

• Tohelppreventgastricirritation,administerdrugaftermeals

• Relieve dry mouth by giving patient cool drinks, ice chips, sugarless chewing gum, or hard, sour candy. Suggest frequent rinsing of the mouth,

and teeth should be brushed regularly. Patients should avoid calorie-laden beverages and sweet candy as they increase the likelihood of dental caries and promote weight gain. Formerly well- tting dentures may cause rubbing and/or ulceration of the gums. Products that promote or replace salivation (e.g., MoiStir, Saliment) may be of bene t

• Blurring of near vision is due to paresis of the ciliary muscle. This can be helped by wearing suitable glasses, reading by a bright light or, if severe, by the use of pilocarpine eye drops 0.5%

Breast Milk

♢ See p. 439 for further information on drug use in pregnancy and e ects on breast milk

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 211 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Extrapyramidal

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Patient Instructions

Drug Interactions

Treatment Options for Extrapyramidal Side E ects (cont.)

• Dry eyes may be of particular di culty to the elderly or those wearing contact lenses. Arti cial tears or contact lens wetting solutions may be of bene t in dealing with this problem

• Anticholinergics reduce peristalsis and decrease intestinal secretions, leading to constipation. Increasing uids and bulk (e.g., bran, salads) as well as fruit in the diet is bene cial. If necessary, bulk laxatives (e.g., Metamucil, Prodiem) can be used; lactulose may be used for chronic constipation

• Warnthepatientnottodriveacaroroperatemachineryuntilresponsetothedrughasbeendetermined

• Appropriatepatienteducationregardingmedicationandsidee ectsisnecessarypriortodischarge

• For detailed patient instructions on antiparkinsonian agents for treating extrapyramidal side e ects, see the Patient Information Sheet (details p. 440)

• Onlyclinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterforthesecondagent

• Fordruginteractionsassociatedwithbenzodiazepines,pleaseseep.227

Class of Drug

Example

Interaction Effects

Adsorbent

Activated charcoal, antacids, cholestyramine, kaolin-pectin (attapulgite)

Oral absorption decreased when used simultaneously

Antiarrhythmic

Quinidine

Valbenazine: Increased exposure to valbenazine’s active metabolite due to CYP2D6 inhibition; may increase risk of adverse reactions

Antibiotic

Clarithromycin

Increased exposure to valbenazine due to strong CYP3A4 inhibition; may increase risk of adverse reactions

Co-trimoxazole (trimethoprim /sulfamethoxazole)

Amantadine: Competition for renal clearance resulting in elevated plasma level of amantadine

Anticholinergic

Antidepressants, antihistamines, FGAs (low potency)

Anticholinergic agents: Increased atropine-like effects causing dry mouth, blurred vision, constipation, etc. May produce inhibition of sweating and may lead to paralytic ileus

High doses can bring on a toxic psychosis

Anticonvulsant

Carbamazepine, phenytoin Topiramate

Valbenazine: Decreased exposure to valbenazine and its active metabolite due to CYP3A4 induction; may reduce ef cacy

Anticholinergic agents: May potentiate the risk of oligohidrosis and hyperthermia, particularly in pediatric patients

Antidepressant

SSRI

NDRI MAOI

Fluoxetine, paroxetine

Bupropion

Isocarboxazid, phenelzine, selegiline

Valbenazine and deutetrabenazine: Increased exposure to the active metabolites of valbenazine and tetrabenazine due to CYP2D6 inhibition; may increase risk of adverse reactions

Cyproheptadine: Case reports of reversal of antidepressant and antibulimic effects of uoxetine and paroxetine Procyclidine: Increased plasma level of procyclidine (by 40%) with paroxetine

Amantadine: Case reports of neurotoxicity in elderly patients

Valbenazine and deutetrabenazine: Bupropion may increase active metabolites of valbenazine and deutetrabenazine at higher doses via moderate CYP2D6 inhibition

Deutetrabenazine: Contraindicated. Stop MAOI and wait at least 14 days before starting deutetrabenazine Valbenazine: May increase monoamine neurotransmitters in synapses, cause serotonin syndrome or reduce therapeutic effect of valbenazine

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Example

Interaction Effects

Itraconazole, ketoconazole

Valbenazine: Increased exposure to valbenazine due to strong CYP3A4 inhibition; may increase risk of adverse reactions

Hydrochlorothiazide, triamterene Reserpine

Reduced renal clearance of amantadine resulting in drug accumulation and possible toxicity

Deutetrabenazine: Contraindicated. Stop reserpine and wait at least 20 days before starting deutetrabenazine to reduce the risk of overdosage

Aripiprazole, chlorpromazine, clozapine, upenthixol, haloperidol, olanzapine, tri uoperazine

Thioridazine

Anticholinergic agents: May aggravate tardive dyskinesia or unmask latent TD

Additive anticholinergic effects may occur, resulting in paralytic ileus, hyperthermia, heat stroke, and anticholinergic intoxication syndrome

Propranolol: May signi cantly increase thioridazine levels or cause arrhythmias

Potential for additive hypotensive effects

Deutetrabenazine: Increased risk of parkinsonism, NMS, and akathisia

Rifampin

Valbenazine: Decreased exposure to valbenazine and its active metabolite due to CYP3A4 induction; may reduce ef cacy

May offset bene cial effects by increasing tremor and akathisia

Digoxin

Anticholinergic agents: May increase bioavailability of digoxin tablets (not capsules or liquids) due to decreased gastric motility or inhibition of intestinal P-glycoprotein (valbenazine)

Propranolol: May increase risk of bradycardia

Donepezil, rivastigmine

Benztropine, diphenhydramine: Antagonism of effects

Hawthorn, kava kava, Siberian ginseng, valerian Henbane

St. John’s Wort

Diphenhydramine: May increase effects of diphenhydramine. May enhance CNS depression Diphenhydramine: Increased anticholinergic effects with combination

Valbenazine: Decreased exposure to valbenazine and its active metabolite due to CYP3A4 induction; may reduce ef cacy

Codeine, methadone, tramadol Methadone, tramadol

Anticholinergic agents: Additive CNS effects including cognitive and psychomotor impairment

Diphenhydramine: May interfere with analgesic effect of codeine due to reduced conversion of codeine to morphine via CYP2D6 inhibition

Diphenydramine: Additive respiratory depressant effects

Potassium chloride, potassium citrate

Anticholinergic agents: May potentiate the risk of upper GI injury of oral solid formulations of potassium salts, possibly due to increased GI transit time secondary to reduction of stomach and intestinal mobility

Deutetrabenazine, tetrabenazine, valbenazine

Concomittant use of two VMAT2 inhibitors is not recommended. Deutetrabenazine concomittant use with tetrabenazine or valbenazine is contraindicated. Deutetrabenazine can be initiated the following day after stopping tetrabenazine

Class of Drug

Antifungal Antihypertensive

Antipsychotic

Antitubercular

Caffeine

Cardiac glycoside

Cholinesterase inhibitor Herbal preparation

Opioid

Potassium supplement VMAT2 inhibitor

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 213 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Extrapyramidal

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

E ects on Extrapyramidal Symptoms

Agent

Tremor

Rigidity

Dystonia

Akinesia

Akathisia

Amantadine

(Symmetrel)

+++

Benztropine

(Cogentin)

+++

Biperiden

(Akineton)

+++

β-blockers

(e.g., propranolol, nadolol)

–

+++

Clonazepam

(Rivotril, Klonopin)

–

+++

Cyproheptadine

(Periactin)

–

+++

Diazepam

(Valium)

+++

Diphenhydramine

(Benadryl)

–

+++

Ethopropazine

(Parsitan)

+++

Lorazepam

(Ativan)

+++

–

+++

Orphenadrine

(Nor ex)

–

Procyclidine

(Kemadrin)

Trihexyphenidyl

(Artane)

+++

Based on literature and clinical observations: – effect not established, + some effect (20% response), ++ moderate effect (20–50% response), +++ good effect (over 50% response)

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Comparison of Agents for Treating Acute Extrapyramidal Side E ects and Tardive Dyskinesia

Agent

Therapeutic Effects

Adverse Effects

Pregnancy

Breast Milk

Amantadine

(Symmetrel)

An NMDA-receptor antagonist. Pro-dopaminergic. Is not anticholinergic. Not recommended for acute dystonias – no injectable dosage form

May improve akathisia (less effective than β-blockers and benzodiazepines), akinesia, rigidity, parkinsonism; may enhance the effects of other antiparkinsonian agents Tolerance to xed dose may develop after 1–8 weeks. Long-term ef cacy not established May be useful in levodopa-induced movement disorder

1–10%: Anorexia, nausea, orthostatic hypotension, peripheral edema, agitation, anxiety, ataxia, confusion, dizziness, fatigue, insomnia, hallucinations, livido reticularis (mottled skin discoloration). Many are dose related and disappear on drug withdrawal

< 1%: NMS, seizures, coma, increased LFTs, respiratory failure, suicidal ideation

The elderly and those with diminished renal function may be more vulnerable to CNS effects

Less anticholinergic than other agents

Withdrawal syndrome reported – taper dose upon discontinuation

Limited human data. Teratogenic and embryotoxic in rats but not in rabbits. In humans, possible association with cardiovascular and limb reduction defects in rst trimester exposure, but the number of exposures is too small to draw a conclusion. Avoid in rst trimester if possible

Excreted into breast milk in small amounts; should be used with caution because of potential adverse effects in nursing infants such as vomiting, skin rash, and urinary retention. As it can reduce prolactin levels, milk production may be reduced

Benztropine

(Cogentin)

Bene cial effect on rigidity

Relieves sialorrhea and drooling

Powerful muscle relaxant; sedative action Cumulative and long-acting; once-daily dosing can be used (preferably in the morning)

IM/IV: Dramatic effect on dystonic symptoms – drug of choice for acute dystonic reactions Does not relieve tardive dyskinesia – use not recommended

Dry mouth, dry eyes, blurred vision, urinary retention, constipation, nausea, GERD, paralytic ileus, tachycardia, decreased cognition, hallucinations, delirium, convulsions, heat stroke, hyperthermia Increased intraocular pressure

Toxic psychosis when abused or overused

The elderly may be more susceptible to anticholinergic (bladder, bowel, CNS) effects – avoid use were possible

Also see p. 210

Limited human data. Probably compatible. Possible association with cardiovascular defects in rst trimester exposure; reported small left colon syndrome in newborns exposed to the drug in utero at term, manifested as decreased intestinal motility, vomiting, abdominal distention, and inability to pass meconium

No human data. Unknown excretion into breast milk. As it can reduce prolactin levels, milk production may be reduced

Biperiden

(Akineton)

Has effect against rigidity and akinesia

Has higher af nity for muscarinic receptors in the CNS and may be less likely to cause peripheral anticholinergic effects

Also see p. 210

Limited data. Human data suggest risk in third trimester (GI toxicity in newborn)

No human data. Unknown excretion into breast milk. As it can reduce prolactin levels, milk production may be reduced

Clonazepam

(Rivotril, Klonopin)

Useful for akathisia

Drowsiness, lethargy, disinhibition (see p. 225)

Crosses the placenta. Potential for increased risk of congenital anomalies with rst trimester use, however, con icting data. Potential for newborn withdrawal symptoms and oppy baby syndrome if used close to delivery

Excreted into breast milk. Potential to cause sedation, feeding dif culties, and weight loss in infant

Cyproheptadine

(Periactin)

Moderate effect on akathisia

Sedative and anticholinergic effects

Has been used to increase appetite

May help ameliorate drug-induced sexual dysfunction

Drowsiness, weight gain, anticholinergic effects (dry eyes, confusion, constipation, urinary retention, etc.) Use with caution in: the elderly, CVD, increased intraocular pressure, asthma, GI obstructions, urinary retention, thyroid dysfunction

May potentiate the effects of other CNS depressants

Limited data. Possible association with hypospadias and oral clefts in rst trimester exposure. Possible association with preterm delivery

Limited data. As it can reduce prolactin levels, milk production may be reduced. Potential for irritability and drowsiness in the infant

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 215 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Extrapyramidal

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Comparison of Agents for Treating Acute Extrapyramidal Side E ects and Tardive Dyskinesia (cont.)

Agent

Therapeutic Effects

Adverse Effects

Pregnancy

Breast Milk

Deutetrabenazine

(Austedo)

Improves symptoms of tardive dyskinesia Long-term ef cacy not established

>3% nasopharyngitis and insomnia

2% depression and akathisia

QT prolongation at higher concentrations

Binds to melanin-containing tissues and may cause long-term ophthalmic complications

Limited data

No human data

Diazepam

(Valium, etc.)

Bene cial effect on akathisia and acute dystonia

Muscle relaxant

Drowsiness, lethargy, disinhibition (see p. 225)

Excreted into breast milk. Potential to cause sedation, feeding dif culties, and weight loss in infant. Potential for prolonged effects due to diazepam’s long half-life. Short-acting agents (e.g., lorazepam) are preferred

Diphenhydramine

(Benadryl)

Has effect on tremor and akathisia

Sedative effect may bene t tension and excitation; may enhance the effects of other antiparkinsonian agents

Some effect on rigidity

Somnolence, confusion, and dizziness, especially in the elderly; delirium reported

Use with caution in: the elderly, CVD, increased intraocular pressure, asthma, GI obstructions, urinary retention, thyroid dysfunction

May potentiate the effects of other CNS depressants

Compatible. Use near delivery can cause neonatal withdrawal effects

Excreted into breast milk. Limited data but probably compatible. High doses or chronic use may reduce prolactin levels and milk production. Potential for irritability and drowsiness in the infant

Ethopropazine

(Parsitan, Parsidol)

Has effect against rigidity; improves posture, gait, and speech

Speci c for tremor

Mild anticholinergic activity. See benztropine for general adverse effects pro le and conditions to avoid use in

Also see p. 210

No human or animal data

No human data. Unknown excretion into breast milk. As it can reduce prolactin levels, milk production may be reduced

Lorazepam

(Ativan)

Bene cial effect on akathisia

Excellent for acute dyskinesia (sublingual works quickest)

Drowsiness, lethargy, disinhibition (see p. 225)

Excreted into breast milk. Potential to cause sedation, feeding dif culties, and weight loss in infant

Orphenadrine

(Nor ex)

Modest effect on sialorrhea, Parkinson’s disease (tremor, rigidity, bradykinesia) Bene cial effects tend to wear off in 2–6 months

See benztropine for general anticholinergic adverse effects pro le and conditions to avoid use in

Has some euphorogenic properties

Limited data

No human data. Unknown excretion into breast milk. May reduce prolactin levels and milk production. Potential for irritability and drowsiness in the infant

Procyclidine

(Kemadrin)

Questionable effect on tremor

Useful agent to use in combination when muscle rigidity is severe

See benztropine for general adverse effects pro le and conditions to avoid use in

Also see p. 210

No human or animal data

No human data. Unknown excretion into breast milk. As it can reduce prolactin levels, milk production may be reduced

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Agent

Therapeutic Effects

Adverse Effects

Pregnancy

Breast Milk

Propranolol

(Inderal)

Very useful for akathisia and tremor

Monitor pulse and blood pressure; do not stop high dose abruptly due to rebound tachycardia

Potential for growth restriction and reduced placental weight with use in second and third trimesters. Potential for β-blockade in newborn if used near delivery. Monitor for bradycardia, respiratory depression, and hypoglycemia

Excreted into breast milk. Compatible with breastfeeding. Monitor for symptoms of β-blockade

Trihexyphenidyl

(Artane)

Mild to moderate effect against rigidity and spasm (occasionally dramatic results)

Tremor alleviated to a lesser degree; as a result of relaxing muscle spasm, more tremor activity may be noted

Stimulating – can be used during the day for sluggish, lethargic, and akinetic patients

See benztropine for general adverse effects pro le and conditions to avoid use in

Also see p. 210

Limited data

No human data. Unknown excretion into breast milk. May reduce prolactin levels and milk production

Valbenazine

(Ingrezza)

Improves symptoms of tardive dyskinesia Long-term ef cacy established (up to

48 weeks)

>10% somnolence, fatigue, sedation 2.7–5.4% anticholinergic adverse effects (see benztropine), balance disorders, akathisia

< 2.7% vomiting, nausea, arthralgia

QT prolongation at higher concentrations

Limited data

No human data. Animal studies suggest excreation into milk. Women should wait at least 5 days after nal dose before breastfeeding

Doses and Pharmacokinetics of Agents for Treating Extrapyramidal Side E ects and Tardive Dyskinesia

Agent

Dose in Adults

Onset of Action

Time to Peak Plasma Level (Tmax)

Bioavailability

Protein Binding

Elimination Half-life (T1/2)

Excretion

Metabolizing Enzymes (CYP450 and/or UGT*

Enzyme Inhibition (CYP450)**

Amantadine

(Symmetrel)

Oral: 100 mg bid, may increase to 300 mg/day in divided doses

CrCl 30–50 mL/min: 100 mg od

CrCl 15–29 mL/min: 100 mg q 48 h CrCl <15 mL/min: 200 mg q 7 days Hepatic impairment: no dosage adjustment suggested – use caution Cocaine withdrawal: 100 mg bid to tid

Within 48h

2–4 h

86–90%

67% (normal renal function); 59% (hemodialy- sis)

9–31 h (normal renal function); 20–41 h (healthy, elderly); 7–10 days (end-stage renal disease)

Urine (80–90% unchanged by glomerular ltration and tubular secretion)

Minimal metabolism. 80–90% excreted unchanged by glomerular ltration and tubular secretion

–

Benztropine

(Cogentin)

Oral: 1–2 mg od–tid up to 4 mg bid if needed

Acute dystonia: IM/IV: 1–2 mg; may repeat in 30 min

Hepatic and renal impairment: no dosage adjustment suggested – use caution

Oral: 1–2 h IM/IV: few minutes

29%

95%

1–2 h

Urine

2D6(m)

–

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 217 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Extrapyramidal

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Doses and Pharmacokinetics of Agents for Treating Extrapyramidal Side E ects and Tardive Dyskinesia (cont.)

Agent

Dose in Adults

Onset of Action

Time to Peak Plasma Level (Tmax)

Bioavailability

Protein Binding

Elimination Half-life (T1/2)

Excretion

Metabolizing Enzymes (CYP450 and/or UGT*

Enzyme Inhibition (CYP450)**

Biperiden

(Akineton)

Oral: 2 mg od–tid

Hepatic and renal impairment: no dosage adjustment available – use caution

Oral: 10–30 min IM/IV: few minutes

1.5 h

87%

60%

18–24 h

Primarily urine

Clonazepam

(Rivotril, Klonopin)

Oral: 0.5–6 mg/day in divided doses Hepatic and renal impairment: no dosage adjustment suggested, metabolites may accumulate – use caution

15–30 min

1–4 h

90%

86%

17–60 h

Urine (< 2% as unchanged drug)

3A4 (p)

–

Cyproheptadine

(Periactin)

Initial: 4 mg tid

up to 32 mg/day

Hepatic and renal impairment: no dosage adjustment suggested – use caution

6–9 h metabolites: 16h

96–99%

1–4 h

Urine (~ 40%, primarily as metabolites); feces (2–20%)

UGT1A

Deutetrabenazine

(Austedo)

Recommended dose: 12–48 mg/day Hepatic impairment: contraindicated Geriatric use: caution, consider dose reduction

CYP2D6 poor metabolizers: do not exceed 36 mg/day

3–4 h

82–85% Metabolites: 59–68%

9–12 h

75–86% urine (< 10% of dose as active metabolites) 8–11% feces

2D6 (p), 1A2, 3A4/5(m)

Diazepam

(Valium, etc.)

Oral:upto5mgqid

IV: 10 mg for acute dystonia by slow direct IV push (rate of 5 mg (1 mL)/min) Renal impairment: No dosage adjustment recommended; decrease dose if prescribed for extended periods as metabolite accumulates

Hepatic impairment: Caution in moderate impairment – reducing dose by 50% recommended, contraindicated in severe impairment

Oral: rapid

(15 min or less) IV: imme- diate

Oral:

15 min–2 h

93%

98%

20–50 h; 50–100 h for active major metabolite (desmethyl- diazepam); increased half-life in the elderly and those with severe hepatic disorders

Urine (very little as unchanged drug)

2C19(p), 3A4(p), 1A2(m), 2B6(m), 2C9(m)

2C19(w) , 3A4(w) UGT

Diphenhydramine

(Benadryl)

IM/IV: 50 mg for dystonia, may repeat in 20–30 min

Oral: 25–50 mg tid–qid

Renal impairment: No adjustment Hepatic impairment: no dosage adjustment suggested – use caution

IM/IV: 15–

20 min Oral: 1–3 h

Oral: ~2 h

40–70%

78%

7–12 h (adults); 9–18 h (elderly)

Urine (as metabolites and unchanged drug)

2D6(p), 1A2(m), 2C9(m), 2C19(m); UGT1A3

2D6

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Agent

Dose in Adults

Onset of Action

Time to Peak Plasma Level (Tmax)

Bioavailability

Protein Binding

Elimination Half-life (T1/2)

Excretion

Metabolizing Enzymes (CYP450 and/or UGT*

Enzyme Inhibition (CYP450)**

Ethopropazine

(Parsitan, Parsidol)

Starting oral dose: 100–500 mg/day as bid–tid

Hepatic and renal impairment: no dosage adjustment available – use caution

Poor?

93%

1–2 h

Lorazepam

(Ativan)

Oral:Upto2mgqid

Sublingual: 1–2 mg up to tid

IM: 1–2 mg for dystonia

Renal impairment: No adjustment Hepatic impairment: mild to moderate – no adjustment; severe impairment

– use caution

Oral: 15–30 min

Oral: 2 h Sublingual: 1 h IM:<3h

90%

88–92%; free fraction may be sig- ni cantly higher in the elderly

10–20 h; 32–70 h (end-stage renal disease)

Urine(88% as inactive metabolites); feces (7%)

UGT2B7, UGT2B15

–

Orphenadrine

(Orfenace)

Oral: 100 mg bid

Renal dosing: No adjustment Hepatic dosing not de ned

20 min

2–4 h

20%

14–16 h

Primarily urine (8% as unchanged drug)

Metabolized extensively but not adequately characterized

Procyclidine

(Kemadrin)

Starting oral dose: 2.5 mg bid–tid; increase by 2.5 mg/day if required Maximum 30 mg/day

Hepatic and renal impairment: no dosage adjustment suggested – use caution

45–60 min

75%

100%

12h

Minimal unchanged drug in urine

2D6 (?)

Propranolol

(Inderal)

Oral: Akathisia: 30–120 mg/day as bid–tid

Essential tremor: 40 mg bid to start (maintenance: 120–320 mg/day

Hepatic and renal impairment: no dosage adjustment suggested – use caution

1–2 h

1–4 h (immediate release); 6–14 h (sustained release)

25% (high rst-pass metabolism); protein-rich foods increase bioavailability by 50%

90%

3–6 h (immediate release); 8–10 h (sustained release)

Metabolites are excreted primarily in urine (96–100%)

< 1% excreted in urine as unchanged drug

1A2(p), 2D6(p), 2C19(m), 3A4(m)

1A2(w) , 2D6(w)

Trihexyphenidyl

(Artane)

Oral: 1 mg/day; increase prn

5–15 mg/day as tid–qid

Hepatic and renal impairment: no dosage adjustment suggested – use caution

1–1.5 h

100%

3.3–4.1 h

Urine and bile

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 219 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Extrapyramidal

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Doses and Pharmacokinetics of Agents for Treating Extrapyramidal Side E ects and Tardive Dyskinesia (cont.)

Agent

Dose in Adults

Onset of Action

Time to Peak Plasma Level (Tmax)

Bioavailability

Protein Binding

Elimination Half-life (T1/2)

Excretion

Metabolizing Enzymes (CYP450 and/or UGT*

Enzyme Inhibition (CYP450)**

Valbenazine

(Ingrezza)

Oral: 40–80 mg/day

Recommended dose: 80 mg

Hepatic impairment: 40 mg

Renal impairment: no dose adjustment Concomitant strong CYP3A4 inducers: Not recommended

Concomitant strong CYP3A4 inhibitors: Reduce dose to 40 mg/day

Concomitant strong CYP2D6 inhibitors or known CYP2D6 poor metabolizers: Consider reducing dose

<30min

30 min–1 h

49%

> 99% Metabolite tetra- benazine: ~64%

15–22 h

60% urine

30% feces

(< 2% overall as unchanged valbenazine or tetrabenazine)

3A4/5 (p), 2D6(m)

–

* Cytochrome P450 isoenzymes involved in Phase I metabolism (data not consistent among references), UGT: UDP-glucuronosyltransferase is the most important Phase II (conjugative) enzyme ** CYP450 isoenzymes inhibited by drug, (m) Minor route of metabolism (p) Primary route of metabolism Weak inhibitor/inducer of CYP450

Further Reading

References

1 Soares-Weiser K, Rathbone J. Neuroleptic reduction and/or cessation and neuroleptics as speci c treatments for tardive dyskinesia. Cochrane Database Syst Rev. 2006;1:CD000459. doi:10.1002/14651858.CD000459.pub2

2 Bolden C, Cusack B, Richelson E. Antagonism by antimuscarinic and neuroleptic compounds at the ve cloned human muscarinic cholinergic receptors expressed in Chinese hamster ovary cells. J Pharmacol Exp Ther. 1992;260(2):576–580.

3 Elbe D, Black TR, McGrane IR, et al. Clinical handbook of psychotropic drugs for children and adolescents. (4th ed.). Boston, MA: Hogrefe Publishing, 2019.

Additional Suggested Reading

• CaroffSN,HurfordI,LybrandJ,etal.Movementdisordersinducedbyantipsychoticdrugs:ImplicationsoftheCATIEschizophreniatrial.NeurolClin.2011;29(1):127–148.doi:10.1016/j.ncl. 2010.10.002

• HaddadPM,DasA,KeyhaniS,etal.Antipsychoticdrugsandextrapyramidalsideeffectsin rstepisodepsychosis:Asystematicreviewofhead-headcomparisons.JPsychopharmacol. 2012;26(5 Suppl):15–26. doi:10.1177/0269881111424929

• Kane JM, Fleischhacker WW, Hansen L, et al. Akathisia: An updated review focusing on second-generation antipsychotics. J Clin Psychiatry. 2009;70(5):627–643. doi:10.4088/JCP. 08r04210

• P450DrugInteractionTable,IndianaUniversitySchoolofMedicine,DivisionofClinicalPharmacology.Retrievedfromhttp://medicine.iupui.edu/clinpharm/ddis/table.asp

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Classi cation

ANXIOLYTIC (ANTIANXIETY) AGENTS

• Anxiolyticagentscanbeclassi edasfollows:

Chemical Class

Agent

Page

Antidepressants

Selective serotonin reuptake inhibitors (SSRI) Serotonin norepinephrine reuptake inhibitors (SNRI)

Examples: Escitalopram, paroxetine, sertraline Example: Venlafaxine

Seep.3 See p. 23

Tricyclic Antidepressants (TCA)

Noradrenergic/speci c serotonergic antidepressants (NaSSA) Monoamine oxidase inhibitors (MAOI)

Example: Clomipramine Example: Mirtazapine Example: Phenelzine

See p. 50 See p. 46 See p. 64

Anticonvulsants GABA analogs Phenyltriazine

Examples: Gabapentin, pregabalin Example: Lamotrigine

See p. 263 and p. 401 See p. 263

Azaspirone

Example: Buspirone

See p. 234

Benzodiazepines

Examples: Alprazolam, diazepam, lorazepam

See p. 222 below

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 221 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Anxiolytics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Benzodiazepines

Product Availability∗ Generic Name

Alprazolam

Bromazepam(C) Chlordiazepoxide Clonazepam

Clorazepate Diazepam

Estazolam(B) Flurazepam Lorazepam

Nitrazepam(C) Oxazepam

Temazepam Triazolam

Chemical Class

Trade Name(A)

Dosage Forms and Strengths

Benzodiazepine

Xanax

Xanax TS(C) Xanax XR(B)

Tablets: 0.25 mg, 0.5 mg, 1 mg, 2 mg

Oral concentrate: 1 mg/mL(B)

Triscored tablets (TS): 2 mg

Extended-release tablets: 0.5 mg, 1 mg, 2 mg, 3 mg

Niravam(B)

Oral disintegrating tablet: 0.25 mg, 0.5 mg, 1 mg, 2 mg

Lectopam

Tablets: 1.5 mg, 3 mg, 6 mg

Librium

Capsules: 5 mg, 10 mg, 25 mg

Rivotril(C), Klonopin(B)

Tablets: 0.25 mg(C), 0.5 mg, 1 mg, 2 mg

Rapidly disintegrating tablets(B): 0.125 mg, 0.25 mg, 0.5 mg, 1 mg, 2 mg

Tranxene

Tablets(B): 3.75 mg, 7.5 mg, 15 mg Capsules(C): 3.75 mg, 7.5 mg, 15 mg

Valium

Diazepam Intensol(B) Diastat, Diastat Acudial(B)

Tablets: 2 mg, 5 mg, 10 mg Oral solution: 1mg/ ml Injection: 5 mg/mL

Oral concentrate(B) : 5 mg/mL Rectal gel: 5 mg/mL

ProSom

Tablets: 1 mg, 2 mg

Dalmane

Capsules: 15 mg, 30 mg

Ativan

Tablets: 0.5 mg, 1 mg, 2 mg

Sublingual tablets(C): 0.5 mg, 1 mg, 2 mg Injection: 2 mg/mL, 4 mg/mL

Lorazepam Intensol(B)

Oral concentrate(B) : 2 mg/mL

Mogadon

Tablets: 5 mg, 10 mg

Serax

Tablets(C): 10 mg, 15 mg, 30 mg Capsules(B): 10 mg, 15 mg, 30 mg

Restoril

Capsules: 7.5 mg(B) , 15 mg, 22.5 mg(B) , 30 mg

Halcion

Tablets: 0.125 mg(B) , 0.25 mg

∗ Refer to Health Canada’s Drug Product Database or the FDA’s Drugs@FDA for the most current availability information (A) Generic preparations may be available,

(B) Not marketed in Canada,

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Approved Indications‡

( approved)

Short-acting Intermediate

Long-acting

(A) Acute use only, (B) Not marketed in Canada,

Other Indications

• Akathisiasecondarytoantipsychoticagents

• Abnormal movements associated with tardive dyskinesia (clonazepam)

• Sedationinsevereagitation

• Mania:Oftenusedshort-termwithantipsychoticsorlithiumtocontrolagitation

• Socialphobia(alprazolam,clonazepam,diazepam,lorazepam)

• Catatonia(parenteralandsublinguallorazepam,diazepam,clonazepam)

• Myoclonus,restlesslegssyndrome,Tourette’ssyndrome(clonazepam)

• Acutedystonia(sublingualorintramuscularlorazepam)

• Alcoholwithdrawal,Deliriumtremens(chlordiazepoxide,diazepam),lorazepam,oxazepam

• Deliriuminolderpersonscausedbywithdrawalfromalcohol/sedative–hypnotics(benzodiazepinesasmonotherapy) • Neuralgicpain(clonazepam)

• Premenstrualdysphoricdisorder(alprazolam)

• Statusepilepticus(lorazepam)

• The potency of a benzodiazepine is the a nity of the parent drug, or its active metabolite(s), for “benzodiazepine”-GABAA receptors in vivo. Potency does not necessarily correlate with onset of action

• Benzodiazepinesaresuggestedtorelievebehavioralandsomaticmanifestationsofanxiety,buthavelittlee ectonpsychicorcognitivesymptoms (e.g., worry, anger, interpersonal sensitivity, and obsessions); may be most helpful during the beginning phase of treatment; not recommended long-term

• A multimodal treatment approach, including medication, psychosocial therapy, and environmental interventions has shown to confer greater improvement in symptoms as compared to medication use alone

Anxiety Disorders

Panic Disorder

Insomnia

Perioperative Sedation

Seizure Disorders

Skeletal Muscle Spasticity

Alcohol Withdrawal

Alprazolam Triazolam

Bromazepam(C)

Estazolam(B) Lorazepam Oxazepam

Temazepam

Chlordiazepoxide Clonazepam

Clorazepate Diazepam Flurazepam

Nitrazepam(C)

General Comments

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 223 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Anxiolytics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Pharmacology

Dosing

Benzodiazepines (cont.)

• Benzodiazepines are positive allosteric modulators of the GABAA-chloride receptor complex. Binding of benzodiazepines to the “benzodiazepine”- GABAA receptor complex increases the frequency of opening of the chloride channels, facilitating inhibition of neuronal ring at the level of the limbic system, the brain stem reticular formation, and the cortex. Intensity of action depends on degree of receptor occupancy

• Benzodiazepines bind nonselectively to various subtypes of “benzodiazepine”-GABAA receptor complexes. GABAA receptor subtypes containing an α1 subunit are associated with sedation, ataxia, and amnesia; GABAA receptor subtypes containing α2 and/or α3 subunits generally have greater anxiolytic activity

• Asthedoseofabenzodiazepineisincreased(i.e.,increasedreceptoroccupancy),theanxiolytice ectsarenoticed rst,followedbyanticonvulsant e ects, a reduction in muscle tone, and nally sedation and hypnosis

• In addition to its activity at the “benzodiazepine”-GABAA receptor complex, clonazepam decreases the utilization of serotonin by neurons

• Seepp.229–233forindividualagents

• Although the majority of indications for benzodiazepines are for short-term (less than 2 months) treatment, many patients are prescribed these

agents for extended periods of time (more than 3 months). Clinicians should discuss the risks and bene ts of long-term use with patients at the

beginning of therapy

• FollowingIVadministrationofdiazepam,localpainandthrombophlebitismayoccurduetoprecipitationofthedrug,orduetoanirritante ectof

propylene glycol (a saline ush following the diazepam reduces the incidence)

• IM use is discouraged with diazepam as absorption is slow, erratic, and possibly incomplete; local pain often occurs. Lorazepam IM is adequately

absorbed (though absorption can also be erratic by this method)

• When switching from immediate-release (divided dose) to XR (single dose), alprazolam 0.5 mg tid = alprazolam XR 1.5 mg daily. Alprazolam XR is

administered once daily, preferably in the morning; should not be chewed, crushed, or broken. Dosage titration recommended of no more than 1 mg/day every 3–4 days. Slower absorption rate results in a relatively constant concentration that is maintained for 5–11 h after dosing. Dose reductions should be in decrements of 0.5 mg every 3 days, or slower. A high-fat meal given up to 2 h before dosing with alprazolam XR can increase the mean Cmax by about 25%, however, the extent of exposure (AUC) and elimination half-life (T1/2) are not a ected by eating

• Seepp.229–233forindividualagents

• Markedinterindividualvariation(upto10-fold)isfoundinallpharmacokineticparameters.Age,liverdisease,physicaldisorders,aswellasconcur-

rent use of other drugs may in uence parameters by changing the volume of distribution, metabolism, and elimination half-life of these drugs

• Well absorbed from GI tract after oral administration; food can delay the rate but not the extent of absorption; onset of action is determined by

rate of absorption and lipid solubility

• Lipid solubility positively correlates with enhancing benzodiazepines’ (a) a nity for peripheral adipose tissue, resulting in redistribution from

the vascular compartment (this increases volume of distribution), and (b) passage across the blood/brain barrier, facilitating its CNS activity.

Benzodiazepines have a high volume of distribution (i.e., the tissue drug concentration is much higher than the blood drug concentration)

• Elimination half-life is a contributor to, but not the sole determinant of, duration of action. The duration of action is dependent on the size of the dose, the rate of absorption, the rate and extent of drug distribution, and the rate of elimination. A benzodiazepine with a long half-life (e.g., diazepam) may have a short duration of action if the dose is small or if it undergoes rapid and extensive distribution. Conversely, a short half-life

benzodiazepine (e.g., lorazepam) may have a long duration of action if the dose is large or if the drug has signi cant peripheral distribution

• Di erences in pharmacokinetics between the various benzodiazepines have been presumed to indicate clinical di erences as well – this is not necessarily so. However, present rationale for selection of a benzodiazepine remains the di erence in pharmacokinetic pro le. Generally, short- acting agents can be used as hypnotics and for acute problems relating to anxiety, while long-acting agents can be used for chronic conditions

where a continuous drug e ect is needed

• The longer the half-life of a benzodiazepine, the greater the likelihood that the compound will have an adverse e ect on daytime functioning

(e.g., hangover e ect). Conversely, shorter half-life benzodiazepines are more often associated with (a) interdose withdrawal, (b) rebound anxiety between doses, and (c) anterograde amnesia

Pharmacokinetics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Adverse Effects

CNS Effects

Other Adverse Effects

Discontinuation Syndrome

• ThemajorpathwayofmetabolismisPhaseI(i.e.,hepaticmicrosomaloxidationanddemethylation).PhaseIImetabolism(i.e.,conjugation)produces more polar (water-soluble) by-products, allowing for easier renal excretion. Phase I metabolism (e.g., oxidation) can be compromised by disease states (e.g., hepatic cirrhosis), age or drugs that inhibit various CYP450 isozymes. Drugs that only undergo Phase II metabolism (i.e., conjugation) are not a ected to the same degree (e.g., lorazepam, oxazepam, temazepam)

• Renal impairment may increase the free unbound plasma concentration of benzodiazepine and reduce its clearance. Reduce dose by 25–50% in patients with CrCl less than 10 mL/min

• Mostcommonareextensionsofthegeneralizedsedativee ect(e.g.,fatigue,drowsiness);alprazolamXRmayprolongdaytimesedation

• Impairedmentalspeed,centralcognitiveprocessingability,memory,andperformance.Associatedwithincreasedriskofmotorvehicleaccidents

• Tolerancetoacuteshort-termmemoryimpairmentmaynotdevelopwithtime

• Anterogradeamnesia(morelikelywithhigh-potencyagentsorhigherdoses);sexualdysmnesia(e.g.,IVdiazepam)

• Chronic use: May impair several neurocognitive domains (e.g., speed of learning, visuospatial ability, speed of processing, verbal memory, motor

control/performance and nonverbal memory)

• Paradoxical irritability, impulsivity, and agitation (increased risk in the young, the elderly, individuals with learning disabilities, and people with a

neurological disorder)

• Confusionanddisorientation–primarilyintheelderly.Periodsofblackoutsoramnesiahavebeenreported

• Treatment-emergentdepression

• Excessivedosescanresultinrespiratorydepressionandapnea

• Dysarthria,muscleweakness,incoordination,ataxia,nystagmus

• Headache

• Sexualdysfunctionincludingdecreasedlibido,erectiledysfunction,anorgasmia,ejaculatorydisturbance,andgynecomastia

• Dizziness(upto12%withhigherdosesofclonazepam)

• Fallsandrelatedinjuries

• Rarereportsofpurpuraandthrombocytopeniawithdiazepam

• Few documented allergies to benzodiazepines; rarely reported skin reactions include rashes, xed drug eruption, photosensitivity reactions, pig- mentation, alopecia, bullous reactions, exfoliative dermatitis, vasculitis, and erythema nodosum

• Benzodiazepinespresentdi erentrisksofphysiologicaldependenceattherapeuticdoses,dependingontheindividualaswellasthedrug’spotency and its elimination half-life. Up to 30% of patients suggested to experience withdrawal after 8 weeks of benzodiazepine treatment

• Discontinuationofabenzodiazepinecanproduce:

– Withdrawal: Occurs 1–2 days (with short-acting agent) to 5–10 days (with long-acting agent) following drug discontinuation. Common symp-

toms include insomnia, agitation, anxiety, perceptual changes, dysphoria, headache, muscle aches, twitches, tremors, loss of appetite, diaphore- sis, tachycardia, and GI distress. Catatonia and depression have also been reported. Severe reactions can occur such as grand mal or petit mal seizures, delirium, depersonalization, psychotic states, and coma

– Rebound:Occurshourstodaysafterdrugdiscontinuation;symptoms(ofanxiety)aresimilarbutmoreintensethanthosereportedoriginally

– Relapse:Occursweekstomonthsafterdrugdiscontinuation;symptomsaresimilartooriginalsymptomsofanxiety,andgetprogressivelyworse

until treated

• Pseudo-withdrawal is a psychological withdrawal as a result of the patient’s apprehension about discontinuing the drug – consists of anxiety

symptoms unaccompanied by true withdrawal symptoms; this may be dealt with by slow withdrawal and reassurance

• Towithdrawapatientfromabenzodiazepine,anequivalentdoseofdiazepamcanbesubstituted(seepp.229–233).Ifinsomniaisamajorproblem, then most of the diazepam should be given at bedtime. Withdrawal schedules will be dependent on patient history and psychological issues regarding benzodiazepine use

– Aconservativeschedulewouldbetoreducethecurrentdoseofdiazepamby10–20%every1–2weeksdependingonpatient’ssymptoms

☞ The withdrawal schedule for alprazolam should be no faster than 0.25 mg every week; quicker withdrawal may result in delirium and seizures

☞ The above withdrawal schedule is only intended as a general guide. The rate of tapering should never be rigid but exible, depending on the

patient’s individual symptoms

Management

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 225 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Anxiolytics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Precautions

Benzodiazepines (cont.)

• Concomitantuseofbenzodiazepineswithopioidsmayresultinprofoundrespiratorydepression,coma,anddeath.Considerotheralternatives

• Donotuseinpatientswithsleepapnea

• Administerwithcautiontoelderlyordebilitatedpatients,thosewithliverdisease,orthosewithchronicobstructivepulmonarydisease

• Administerwithcautiontothoseperforminghazardoustasksrequiringmentalalertnessorphysicalcoordination.Higherriskofinjuryandmotor

vehicle accidents has been reported with benzodiazepine use

• Benzodiazepinesmaydiminishthetherapeutice cacyofelectroconvulsivetherapy(ECT)byraisingtheseizurethreshold

• Anxiolyticslowerthetolerancetoalcohol,andhighdosesmayproducementalconfusionsimilartoalcoholintoxication

• Cancausephysicalandpsychologicaldependence,tolerance,andwithdrawalsymptoms–correlatestodoseanddurationofuse

• Benzodiazepinesareatriskofbeingabusedbysusceptibleindividuals,thesepreferagentswithrapidpeakdruge ects(e.g.,diazepam,lorazepam,

alprazolam)

• Rarely,ifever,fatalwhentakenalone;maybelethalwhentakenincombinationwithotherdrugs,suchasalcohol,opioids,andbarbiturates

• Symptomsofoverdoseincludehypotension,respiratorydepression,andcoma

• Flumazenil injection (benzodiazepine antagonist) reverses the hypnotic-sedative e ects of benzodiazepines. Repeated doses may be required due

to umazenil’s short duration of action (T1/2 : 40–80 min)

• For detailed information on the use of anxiolytics in this population, please see the Clinical Handbook of Psychotropic Drugs for Children and Adolescents[1]

• Probableindicationsforanxiolyticsincludeseizuredisorder,GAD,adjustmentdisorder,insomnia,nightterrors,andsomnambulism

• High-potencybenzodiazepines(clonazepam)usefulforpanicdisorder/agoraphobia,socialphobia,andseparationanxietydisorder

• Benzodiazepinesaremetabolizedfasterinchildrenthaninadults;mayrequiresmalldivideddosestomaintainbloodlevel

• Adverse e ects include sedation, cognitive and motor e ects; disinhibition with irritability and agitation reported in up to 30% of children –

primarily in younger impulsive patients with mental retardation

• Caution when using drugs that are metabolized via Phase I pathways including oxidation (all but lorazepam, oxazepam, and temazepam) as they can accumulate in the elderly or in persons with liver disease

• CautionwhencombiningwithotherdrugsthathaveCNSe ects;excessivesedationcancauseconfusion,disorientation

• TheelderlyaremorevulnerabletoadverseCNSe ects,speci callywithregardtobalance,gait,memory,cognition,behavior–long-termuseshould

be discouraged

• Dataindicatesthatbenzodiazepineuseincreasesincoordinationandriskoffalls3-fold,leadingtofractures;observationaldatasuggestanassoci-

ation with increased dementia risk but causation is not yet proven

• Benzodiazepinesandmetabolitesfreelycrosstheplacentaandaccumulateinfetalcirculation

• Benzodiazepines in general are associated with increased risk of congenital anomalies if used in the rst trimester and with neonatal withdrawal

if used in chronic doses throughout pregnancy

• UseofabenzodiazepineinthelastweeksofpregnancymaycauseneonatalCNSdepression,poorfeeding,hypothermia, accidity,andrespiratory

depression

• Benzodiazepines are excreted into breast milk in levels su cient to produce e ects in the newborn, including sedation, poor feeding, weight loss, lethargy, and poor temperature regulation (e.g., infant can receive up to 13% of maternal dose of diazepam and 7% of lorazepam dose)

• Metabolismofbenzodiazepinesininfantsisslower,especiallyduringthe rst6weeks;long-actingagentscanaccumulate

• Forbreastfeedingwomenwhorequirebenzodiazepines,chooseashort-actingagentwithnoactivemetabolite(e.g.,lorazepam).Monitornewborn

Toxicity

Management

Pediatric Considerations

Geriatric Considerations

Use in Pregnancy♢

Breast Milk

for poor feeding and sedation

♢ See p. 439 for further information on drug use in pregnancy and e ects on breast milk

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Nursing Implications

• Assesstheanxietylevelofpatientsonthesedrugstodetermineifanxietycontrolhasbeenaccomplishedandifoversedationhasoccurred

• Thedoseshouldbemaintainedasprescribed;cautionpatientnottoincreaseordecreasethedosewithoutconsultingtheirphysician

• Informpatientsthatactivitiesrequiringmentalalertnessshouldnotbeperformedaftertakingmedication;advisethepatienttoreportanymemory

lapses or amnesia to their physician immediately

• CautionpatientsnottouseotherCNSdepressantdrugs,includingover-the-counterdrugs(e.g.,antihistaminesoralcohol),withoutconsultingtheir

physician

• Excessiveconsumptionofca einatedbeveragescancounteractthee ectsofanxiolytics

• Toleranceandmisusecanoccur;cautionpatientthatwithdrawalsymptomscanoccurwithabruptdiscontinuationafterprolongeduse

• Inform patients that introducing grapefruit and pomegranate juice into their diet while on some benzodiazepines (i.e., alprazolam, clonazepam,

diazepam, estazolam, and triazolam) can result in increased blood levels, resulting in more pronounced e ects (including side e ects)

• Antacids delay the rate of absorption of benzodiazepines from the intestine. Separate the administration of antacids and benzodiazepines to

prevent this interaction

• AlprazolamXRshouldbeadministeredataconsistenttimeoncedaily(preferablyinthemorning);ahigh-fatmealpriortodrugadministrationcan

a ect the plasma level of this drug. Alprazolam XR should not be broken, crushed, or chewed, but should be swallowed whole

• Fordetailedpatientinstructionsonanxiolyticdrugs,seethePatientInformationSheet(detailsp.440)

• Manyinteractions;onlyclinicallysigni cantonesarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterforthesecondagent

Patient Instructions

Drug Interactions

Class of Drug

Example

Interaction Effects

Anesthetics

Ketamine

Prolonged recovery with diazepam due to decreased metabolism

Benzodiazepines may reduce the antidepressant effects of ketamine in the treatment of depression. Possible attenuation of ketamine response from concurrent use of benzodiazepines also suggested; may be due to 1) the nonspeci c central depressant effect of benzodiazepines, mediated through γ-aminobutyric acid (GABA), or 2) benzodiazepine-induced suppression of ketamine-related activation of dopamine neurons in the nucleus accumbens and striatum

Antibiotic

Clarithromycin, erythromycin, troleandomycin Chloramphenicol Quinolones: Cipro oxacin

Decreased metabolism and increased plasma levels of benzodiazepines metabolized by CYP3A4, including triazolam (by 52%), alprazolam (by 60%), estazolam, and diazepam; no interaction with azithromycin

Decreased metabolism of benzodiazepines that are metabolized via CYP2C19 and 3A4

Decreased metabolism of diazepam via inhibition of CYP1A2 and 3A4

Quinupristin/dalfopristin

Decreased metabolism of diazepam via inhibition of CYP3A4

Anticonvulsant

Barbiturates, carbamazepine Phenytoin

Valproate

Increased metabolism and decreased plasma level of benzodiazepines metabolized by CYP3A4 and 2C19, including alprazolam (more than 50%), clonazepam (19–37%), and diazepam; additive CNS effects

Both increases and decreases in phenytoin plasma levels reported. The exact mechanism of the interaction is unknown

Increased phenytoin level and toxicity reported with diazepam, chlordiazepoxide, and clonazepam

Increased metabolism and decreased plasma level of benzodiazepines metabolized by CYP3A4

Displacement by diazepam from protein binding, resulting in increased plasma level Decreased metabolism and increased pharmacological effects of clonazepam and lorazepam

Antidepressant

Cyclic

Desipramine, imipramine

Increased plasma levels of desipramine and imipramine with alprazolam (by 20% and 31%, respectively) Desipramine and triazolam: Report of hypothermia (neither drug causes this effect alone)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 227 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Anxiolytics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Benzodiazepines (cont.)

Example

Interaction Effects

Fluoxetine, uvoxamine, sertraline Nefazodone

Decreased metabolism and increased plasma level of benzodiazepines metabolized by CYP3A4, including alprazolam (increased by 100% with uvoxamine and 46% with uoxetine) and diazepam (13% with sertraline )

Increased plasma levels of alprazolam (by 200%) and triazolam (by 500%) due to inhibited metabolism via CYP3A4

Fluconazole, itraconazole, ketoconazole

Decreased metabolism and increased half-life of chlordiazepoxide; decreased metabolism of triazolam (6-7 fold); reduce dose by 50–75%; AUC of alprazolam increased up to 4 fold

Clozapine Olanzapine

Marked sedation, increased salivation, hypotension (collapse), delirium, and respiratory depression/arrest reported; more likely to occur early in treatment when clozapine is added to benzodiazepine regimen

Synergistic increase in somnolence when lorazepam given with IM olanzapine. AVOID IM olanzapine with benzodiazepines as this combination can potentiate hypotension, bradycardia, and respiratory or CNS depression

Stribild (Elvitegravir + cobicistat + emtricitabine + tenofovir)

Indinavir, ritonavir

Decreased metabolism of benzodiazepines that are metabolized by oxidation (CYP3A4)

Use with midazolam is contraindicated. Potentially increased midazolam effects (e.g., prolonged sedation, altered mental status, respiratory depression)

Increased plasma level of benzodiazepines that are metabolized by oxidation via CYP3A4 (e.g., alprazolam, triazolam)

Isoniazid

Decreased metabolism of benzodiazepines that are metabolized by oxidation (CYP3A4) (triazolam clearance decreased by 75%)

Buspirone Rifampin

Prior treatment with benzodiazepines for generalized anxiety disorder (GAD) may reduce response to buspirone

Increased metabolism of benzodiazepines that are metabolized by oxidation (e.g., diazepam by 300% and estazolam); rifampin is a pan-inducer of CYP isoenzymes

Propranolol

Increased half-life and decreased clearance of diazepam and bromazepam (no interaction with alprazolam, lorazepam or oxazepam)

May counteract sedation and anxiolytic effects and increase insomnia

Diltiazem

Decreased metabolism and increased plasma level of drugs metabolized by CYP3A4 (e.g., triazolam by 100%)

Alcohol

Antihistamines, barbiturates

Alprazolam reported to increase aggression in moderate alcohol drinkers

Brain concentrations of various benzodiazepines altered by ethanol: Triazolam and estazolam concentrations decreased, diazepam concentration increased, no change with chlordiazepoxide

Increased CNS depression; with high doses coma and respiratory depression can occur

Barbiturates are pan-inducers of CYP isoenzymes and thus may induce the metabolism of benzodiazepines

Digoxin

Alprazolam may increase serum levels of digoxin; mechanism unknown but may be related to reduced protein binding

Decreased plasma clearance of chlordiazepoxide (by 54%) and diazepam (by 41%); no effect reported for oxazepam

Increased absorption (bioavailability) of diazepam and triazolam due to inhibition of CYP3A4 in the gut by grapefruit juice Decreased metabolism of alprazolam, diazepam, and triazolam via inhibition of CYP3A4, resulting in increased peak concentration; clinical relevance not established based on limited case studies

Cimetidine

Decreased metabolism of benzodiazepines that are metabolized by oxidation via CYP1A2, 2C19, 2D6, and/or 3A4; (no effect with ranitidine, famotidine or nizatidine); peak plasma concentration of alprazolam increased by 86%

Estrogen, oral contraceptives

Decreased metabolism of benzodiazepines that are metabolized by oxidation (e.g., diazepam, chlordiazepoxide, nitrazepam); increased half-life of alprazolam by 29%

Clearance of combined oral contraceptives may be reduced with diazepam due to inhibited metabolism

Class of Drug

SSRI SARI

Antifungal Antipsychotic

Antiretroviral

Combination

Protease inhibitor

Antitubercular Anxiolytic

β-blocker

Caffeine

Calcium channel blocker CNS depressant

Cardiac glycoside Disul ram Grapefruit juice

H2 antagonist Hormone

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Class of Drug

Example

Interaction Effects

Kava kava

May potentiate CNS effects, causing increased side effects and toxicity

Lithium

Increased incidence of sexual dysfunction (up to 49%) when combined with benzodiazepines

L -dopa

Benzodiazepines can reduce the ef cacy of L-dopa secondary to the GABA agonist effect

Opioid

Increased risk of severe side effects such as respiratory depression, coma, or death when combined with benzodiazepines

Pomegranate juice

Increased absorption (bioavailability) of diazepam and triazolam due to inhibition of CYP3A4 in the gut by pomegranate juice Decreased metabolism of alprazolam, diazepam, and triazolam via inhibition of CYP3A4, resulting in increased peak concentrations

Probenecid

Decreased clearance of lorazepam (by 50%)

Propoxyphene

Increased half-life of alprazolam (by 58%) due to inhibited hydroxylation

Proton pump inhibitor

Omeprazole

Increased ataxia and sedation due to decreased metabolism of benzodiazepines metabolized by oxidation (no effect with lansoprazole)

St. John’s Wort

Decreased AUC of alprazolam (by 40%) and half-life (by 24%) due to induced metabolism via CYP3A4

Comparison of the Benzodiazepines

Drug

Compara- tive Dose*

Time to

Peak Plasma Level PO (Tmax)

Lipid Solubility**

Onset of Action

Protein Binding (PB) Volume of Distribution (Vd)

Elimination Half-life (Parent and

Active Metabolite)

Metabolic Pathway Active Metabolite(s)

Dosage for Approved Indications

Alprazolam

0.25 mg Potency: High

Oral tablet = 1–2 h Disintegrating tablet = 1.5–2 h XR=5–11h(a high-fat meal increases Cmax by 25% and decreases Tmax by about 30%) Asians reported to reach higher Cmax

Moderate

15–

30 min

PB: 80%

Rapidly and completely absorbed; absorption rate for XR preparation differs signi cantly depending on time of day administered Vd: 0.9–1.2 L/kg

Parent: 12–15 h Half-life increased in obese patients, in hepatic insuf ciency, and in Asians; clearance in the elderly only 50–80% that of young adults Smokers: Plasma level decreased in smokers by up to 50%; half-life reduced; clearance increased by 24%

Oxidation (CYP3A4) Active metabolites: Yes

Anxiety:

Immediate release: Effective doses are 0.5–4 mg/day in divided doses; the manufacturer recommends starting at 0.25–0.5 mg tid; titrate dose upward in increments ≤

1 mg/day; usual maximum: 4 mg/day (however, doses as high as 10 mg/day have been used

Extended release: 0.5–1 mg daily; dose may be increased every 3–4 days in increments ≤ 1 mg/day

(range:3–6 mg/day)

Renal impairment: No dosage adjustment listed in product monograph but renal impairment does increase unbound alprazolam

Hepatic impairment: Advanced hepatic disease: start

0.25 mg po bid-tid, 0.5 mg ER po daily; titrate gradually

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 229 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Anxiolytics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Comparison of the Benzodiazepines (cont.)

Drug

Compara- tive Dose*

Time to

Peak Plasma Level PO (Tmax)

Lipid Solubility**

Onset of Action

Protein Binding (PB) Volume of Distribution (Vd)

Elimination Half-life (Parent and

Active Metabolite)

Metabolic Pathway Active Metabolite(s)

Dosage for Approved Indications

Brom- azepam(C)

2.5–3 mg Potency: High

1–4 h

Elderly: 2–12 h; increase in Cmax

Low

15–

30 min

PB: 70%

Vd: 0.9 L/kg

Parent: 8–30 h Metabolite: 8–30 h Elderly: Half-life increased

Conjugation (glucoronidation) Active metabolites: Yes

Anxiety:

Initial: 6–18 mg/day in divided doses

Maintenance: 6–30 mg/day

Renal impairment: No dosage adjustment necessary; however, since active metabolites may accumulate, dosage should be reduced during long-term administration

Hepatic impairment: Contraindicated in severe hepatic impairment

Chlor- diazepoxide

12.5 mg Potency: Low (Parent compound less potent than metabo- lites)

0.5–4 h

Moderate

15–

30 min

PB: 90–98% Vd: 3.3 L/kg

Parent: 5–30 h Metabolite: 24–96 h Half-life increased (2–3 fold) in patients with cirrhosis

Oxidation (CYP1A2) Active metabolite(s): Yes

Metabolites accumulate on chronic dosing

Anxiety:

5–25 mg tid-qid

Alcohol withdrawal:

50–100 mg to start, dose may be repeated in 2–4h as necessary to a maximum of 300 mg/24 h

Renal impairment: Decrease dose by 50% in patients with CrCl less than 10 mL/min

Hepatic impairment: caution advised Elderly: decrease dose by 50%

Clonazepam

0.25 mg Potency: High

1–2 h Quickly and completely absorbed

Low

15–

30 min

PB: 86%

Vd: 1.5–4.4 L/kg

Parent: 18–50 h

Oxidation (CYP3A4); reduction

Active metabolite(s): No

Panic disorder:

0.25 mg bid; increase in increments of 0.125–0.25 mg bid every 3 days; target dose: 1 mg/day (maximum: 4 mg/day) Seizure disorders:

Initial dose not to exceed 1.5 mg given in 3 divided doses; may increase by 0.5–1 mg every third day until seizures are controlled or adverse effects seen (maximum: 20 mg/day) Renal impairment: No dosage adjustment necessary Hepatic impairment: Contraindicated in patients with signi cant impairment

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Drug

Compara- tive Dose*

Time to

Peak Plasma Level PO (Tmax)

Lipid Solubility**

Onset of Action

Protein Binding (PB) Volume of Distribution (Vd)

Elimination Half-life (Parent and

Active Metabolite)

Metabolic Pathway Active Metabolite(s)

Dosage for Approved Indications

Clorazepate

7.5mg

0.5–2 h

Hydrolyzed in the stomach to active metabolite (parent com-

pound inactive); rate of hydrolysis depends on gastric acidity, therefore absorption is unreliable (one study disputes this)

High

15 min or less

PB: 80–95% Vd: 1.0–1.8 L/kg

Metabolite: 50–100 h

Oxidation

Active metabolite(s): Yes

Metabolite accumulates on chronic dosing

Anxiety:

15–60 mg/day in divided doses; maintenance: 7.5 mg tid (could be switched to 22.5 mg/day as single dose once patient is stabilized)

Seizure disorders (adjunct for partial seizures):

7.5 mg tid; increase by no more than 7.5 mg/week (maximum: 90 mg/day)

Alcohol withdrawal:

30–90 mg in divided doses

Renal impairment: No dosage adjustment necessary Hepatic impairment: No information

Diazepam

5mg Potency: Medium

0.5–2 h

High

15 min or less; rapid onset of action followed by redis- tribution into adipose tissue; IM drug errati- cally absorbed

PB: 98%; less in the elderly, therefore attains higher serum levels; increased free (unbound) diazepam

Vd: 1 L/kg

Parent: 20–80 h Metabolite:

50–100 h

Males have a shorter half-life and higher clearance rate than females; half-life increased (2–-3 fold) in patients with cirrhosis; smoking associated with higher diazepam clearance, especially in the young

Oxidation (CYP1A2, 2C9, 2C19, 3A4) Active metabolite(s): Yes

Accumulation with chronic dosing

Anxiety:

2–10 mg bid-qid (oral); 2–10 mg, may repeat in 3–4 h if needed (IV/IM)

Seizure disorders (adjunct):

2–10 mg bid-qid

Skeletal muscle relaxant:

2–10 mg tid-qid

Muscle spasm (IM/IV): 5–10 mg initially, then 3–10 mg in 3–4 h if needed. Larger doses may be required if associated with tetanus

Alcohol withdrawal:

Oral: 10 mg tid-qid rst 24 h, then 5 mg tid-qid as needed IV: 10 mg initially, then 5–10 mg in 3–4 h if needed (IM/IV) Renal impairment: No dosage adjustment necessary Hepatic impairment: Caution advised in patients with mild–moderate impairment. Contraindicated in patients with severe impairment

Estazolam(B)

0.5–1 mg Potency: High

Low

30– 60 min

PB: 93%

Vd: 0.64 L/kg

Parent: 10–24 h

Oxidation (CYP3A4) Active metabolite(s): No

Metabolism impaired in the elderly and in hepatic disease

Insomnia:

1 mg at bedtime. Some patients may require 2 mg. Start at doses of 0.5 mg in debilitated or small elderly patients Renal impairment: No dosage adjustment necessary Hepatic impairment: Caution advised

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 231 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Anxiolytics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Comparison of the Benzodiazepines (cont.)

Drug

Compara- tive Dose*

Time to

Peak Plasma Level PO (Tmax)

Lipid Solubility**

Onset of Action

Protein Binding (PB) Volume of Distribution (Vd)

Elimination Half-life (Parent and

Active Metabolite)

Metabolic Pathway Active Metabolite(s)

Dosage for Approved Indications

Flurazepam

7.5–15 mg Potency: Low

0.5–1 h

High

15 min or less

PB: 97%

Vd: 3.4 L/kg

Parent: Not signi cant Metabolite: 40–100 h

Oxidation (CYP2C9 and 3A4)

Active metabolite(s): Yes

Rapidly metabolized to active metabolite; elderly males accumulate metabolite more than young males on chronic dosing

Insomnia:

15–30 mg at bedtime

Renal impairment: No dosage adjustment necessary Hepatic impairment: Caution advised

Lorazepam

0.5–1 mg Potency: High

Oral: 2–4 h IM: 45–75 min IV: 5–10 min SL:1h

Well absorbed sublingually

Moderate

15–

30 min

PB: 88–93% Vd: 1.3 L/kg

Parent: 10–20 h; longer elimination half-life in women; half-life and Vd doubled in patients with cirrhosis

Conjugation (glucuronidation) Active metabolite(s): No

Reduced clearance (by 22%) in the elderly (one study)

Anxiety:

1–10 mg/day in 2–3 divided doses; usual dose:

2–6 mg/day in divided doses; largest dose at bedtime Perioperative sedation:

IM 0.05 mg/kg at least 2 h before surgery (maximum:

4 mg)

IV: 0.044 mg/kg 15–20 min before surgery (usual dose:

2 mg)

Seizure disorders (status epilepticus):

4 mg/dose slow IV (maximum rate: 2 mg/min); may repeat in 10–15 min; usual maximum dose: 8 mg Insomnia caused by anxiety or transient situational stress: 2–4 mg at bedtime

Renal impairment: No dosage adjustment necessary if given orally. If given IV, there is an increased risk of propylene/polyethylene glycol toxicity with frequent or high doses

Hepatic impairment: Caution in hepatic insuf ciency

Nitrazepam(C)

5mg Potency: Medium

2–3 h

Low

30– 60 min

PB: 85%

Vd: 2.4 L/kg

Parent: 24–29 h

Reduction (CYP2E1) Active metabolite(s): No

Excreted as amino and acetamide analogs; metabolism impaired in the elderly; accumulates with chronic use

Insomnia:

5–10 mg at bedtime

Renal impairment: Avoid in patients with severe renal failure

Hepatic impairment: No information

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Drug

Compara- tive Dose*

Time to

Peak Plasma Level PO (Tmax)

Lipid Solubility**

Onset of Action

Protein Binding (PB) Volume of Distribution (Vd)

Elimination Half-life (Parent and

Active Metabolite)

Metabolic Pathway Active Metabolite(s)

Dosage for Approved Indications

Oxazepam

10 mg Potency: Low

2–4 h

Low

30– 60 min

PB: 86–99% Vd: 0.6 L/kg

Parent: 5–20 h; longer half-life in women;

prolonged half-life in renal impairment

Conjugation (glucuronidation) Active metabolite(s): No

Anxiety:

10–30 mg tid-qid

Insomnia:

15–30 mg 60 min before bedtime

Alcohol withdrawal:

15–30 mg tid-qid

Renal impairment: No dosage adjustment necessary Hepatic impairment: No information

Temazepam

10 mg Potency: Low

2–3 h

Variable rate of absorption depending on formulation

Moderate

30– 60 min

PB: 96% Vd: 1.4 L/kg

Parent: 10–20 h; longer elimination half-life in women

Conjugation (glucuronidation) Active metabolite(s): None

5% excreted as oxazepam in urine; plasma concentration too low to detect

Insomnia:

7.5–30 mg at bedtime

Renal impairment: No dosage adjustment necessary Hepatic impairment: No information

Triazolam

0.25 mg Potency: High

1–2 h

Well absorbed sublingually

Moderate

15–

30 min

PB: 89–94%

Vd: 0.8–1.8 L/kg

Parent: 1.5–5 h

Oxidation: (CYP3A4) Active metabolite(s): None

Clearance in the elderly only 50–80% that of young adults

Insomnia:

0.125–0.25 mg at bedtime

Renal impairment: No dosage adjustment necessary Hepatic impairment: Start at 0.125 mg qhs

* Based on Dr. Heather Ashton’s “benzodiazepine equivalency table”, see https://www.benzo.org.uk/bzequiv.htm, ** Lipid solubility positively correlates with enhancing benzodiazepines’ (1) af nity for peripheral adipose tissue, resulting in redistribution from the vascular compartment (this increases volume of distribution), and (2) passage across the blood/brain barrier, facilitating their CNS activity. The higher the lipid solubility the more rapid the onset of activity and the greater the risk of memory impairment.

(B) Not marketed in Canada, (C) Not marketed in the USA

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 233 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Anxiolytics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Buspirone

Product Availability∗

∗ Refer to Health Canada’s Drug Product Database or the FDA’s Drugs@FDA for the most current availability information (A) Generic preparations may be available, (B) Not marketed in Canada

Generic Name

Chemical Class

Trade Name(A)

Dosage Forms and Strengths

Buspirone

Azaspirone

Buspar

Tablets: 5 mg(B) , 7.5 mg(B) , 10 mg, 15 mg(B) , 30 mg(B)

Indications‡

( approved)

General Comments

Generalized anxiety disorder (GAD): Short-term symptomatic relief of excessive anxiety

As an alternative to benzodiazepines in situations where sedation or psychomotor impairment may be dangerous

• Obsessive-compulsivedisorder(OCD);mayreducesymptomsofanxiety

• Depression toaugmente ectofantidepressants

• Socialphobia–contradictoryevidenceastoe cacy;maybeusefulasanaugmentingagentinpartialresponderstoSSRIs

• Premenstrualsyndrome–mayhelpreducepremenstrualirritability

• Agitation,aggression/antisocialbehavior

• BruxismcausedbySSRI/SNRIantidepressants–maybeusefulinalleviation(casereports)

• Buspironeisaselectiveanxiolyticoftheazaspironeclass;unlikethebenzodiazepines,ithasnoanticonvulsantormuscle-relaxantproperties

• Tolerancetoe ectsofbuspironehasnotbeenreported

• Lackofe ectonrespirationmaymakeitusefulinpatientswithpulmonarydiseaseorsleepapnea;mayactuallystimulaterespiration

• Minimale ectoncognition,memoryordrivingperformance

• Mayhaveapreferentiale ectforsymptomsofanxiety,irritability,andaggression,withlittlee ectonbehavioralmanifestations

• Eight 3-way (buspirone, diazepam, placebo) controlled trials have been conducted evaluating buspirone as an anxiolytic agent. Buspirone was

signi cantly better than placebo in 4 trials, not better than placebo in the other trials

• Unlike the benzodiazepines, buspirone does not bind to the “benzodiazepine”-GABAA receptor complex

• Buspirone pharmacology is not fully understood; it has a nity for central D2 receptors (antagonist and agonist) and 5-HT1A receptors (partial

agonist)

• Buspironedoesnotblocktransportersofmonoamines

• Buspirone’smajormetabolite(1-(2-pyrimidinyl)-piperazine)isanα2-adrenergicreceptorantagonist,thusenhancingnorepinephrinerelease

• Initialdose:5mgbid-tid;maybeincreasedinincrementsof5mg/dayevery2–3daystoamaximumof60mg/day

• Usualtherapeuticdoseformostpatientsis20–30mg/day(10–15mgbid)

• Dosesupto90mg/dayhavebeenusedinpatientswithmajordepressivedisorderandsigni cantassociatedanxietysymptoms

• Slowonsetofaction,maytakeaslongas2–4weeksforanxiolytice ecttooccur

☞ Note ectiveonaprnbasis

• Absorptionisvirtuallycomplete; rst-passe ectreducesbioavailabilitytoabout4%

• Food may reduce rate of absorption (95%), decrease extent of rst-pass e ect, and therefore increase oral bioavailability; Cmax increased up to 116%

(n=8)

• Highlyboundtoplasmaproteins(86%)

• Tmax:0.7–1.5h

Pharmacology

Dosing

Pharmacokinetics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Adverse Effects

Discontinuation Syndrome Precautions

Toxicity

Pediatric Considerations

Geriatric Considerations

Nursing Implications

Patient Instructions

• Eliminationhalf-life:2–3h.ParentdrugmetabolizedbyCYP3A4;metabolite(1-(2-pyrimidinyl)piperazine)isactiveandmetabolizedby2D6

• Clearancereducedinrenalandhepaticimpairment

• Causeslittlesedation;doesnotimpairpsychomotororcognitivefunctions

• Headache(upto6%),dizziness(upto12%),lightheadedness(3%),nervousness(5%),excitement(2%),fatigue,paresthesia,numbness,andGIupset

seen in less than 10% of patients

• Buspironebindstocentraldopaminereceptors,potentiallyincreasingtheriskofdystonia,pseudoparkinsonism,andakathisia(notsubstantiatedby

trials); however, a syndrome of restlessness appearing shortly after initiation of treatment has been reported, this could be the result of buspirone’s

dopaminergic and/or noradrenergic activity

• Hasbeenreportedtoprecipitatehypomaniaormania(primarilyintheelderly);highdosesmayworsenpsychosis

• Dose-dependentincreaseinprolactinandgrowthhormonelevelsreported

• Withdrawale ectshavenotbeenreported

• Hasnocross-tolerancewithbenzodiazepinesandwillnotalleviatebenzodiazepinewithdrawal;whenswitching,taperbenzodiazepinedosewhile adding buspirone to the regimen

• Buspirone does not have anticonvulsant activity and has not been evaluated in patients with a history of seizures; not recommended for patients with seizures

• Excessive doses produce extension of pharmacological e ects including dizziness, nausea, and vomiting; monitor respiration, blood pressure, and pulse, and give symptomatic and supportive therapy

• For detailed information on the use of buspirone in this population, please see the Clinical Handbook of Psychotropic Drugs for Children and Adolescents[1]

• BuspironeusedinADHD,aggression,autism,andtoaugmentSSRIsinobsessive-compulsivedisorder(10–30mg/day)

• Dizziness,behavioractivation,euphoria,increasedaggression,andpsychosisreported

• Buspironeisnotknowntocausesedation,cognitiveimpairment,disinhibitionormotorimpairmentintheelderly

• Dosageshouldbedecreasedinpatientswithreducedhepaticorrenalfunction

• Nofetaladversee ectsreportedinanimalstudies;inadequatehumandata,safetyinpregnancyhasnotyetbeendetermined

• In animals, buspirone is excreted into milk; unknown excretion into human milk; unknown e ects on nursing infants. Consider alternative anti-

anxiety agent

• Thee ectofbuspironeisgradual;improvementmaybeseen7–10days(butmaytakeaslongas2–4weeks)afterstartingtherapy

• When switching from a benzodiazepine to buspirone, it is important to gradually taper the benzodiazepine to avoid precipitating a withdrawal

reaction

• Buspironeshouldbetakenconsistently,notonanasneededbasis

• Fordetailedpatientinstructionsonbuspirone,seethePatientInformationSheet(detailsonp.440)

Use in Pregnancy♢

Breast Milk

♢ See p. 439 for further information on drug use in pregnancy and e ects on breast milk

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 235 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Anxiolytics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Drug Interactions

Class of Drug

Antibiotic Antidepressant

SSRI

SARI

TCA

Irreversible MAOI

Antifungal Antipsychotic Antiretroviral

Protease inhibitor

Antitubercular drug Benzodiazepine Calcium channel blocker Grapefruit juice

Immunosuppressant St. John’s Wort

Further Reading

Buspirone (cont.)

• Clinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterforthesecondagent

Example

Interaction Effect

Clarithromycin, erythromycin Linezolid

Increased plasma level of buspirone (5-fold increase in Cmax) due to inhibited metabolism via CYP3A4 Linezolid reversibly inhibits MAO and can potentially lead to ampli cation of serotonergic effects of buspirone

Fluoxetine, uvoxamine

Concomitant use of serotonergic agents increases the risk of serotonin syndrome Increased plasma level of buspirone (3-fold increase in AUC) with uvoxamine

Case reports of serotonin syndrome, euphoria, seizures or dystonia with combination

Trazodone

Amitriptyline, clomipramine Phenelzine, tranylcypromine

Concomitant use of serotonergic agents increases the risk of serotonin syndrome Concomitant use of serotonergic agents increases the risk of serotonin syndrome

MAOIs may potentiate the activity of serotonergic agents like buspirone via inhibition of serotonin metabolism. The result is an increased risk of serotonin syndrome

MAOIs combined with buspirone can increase blood pressure

Itraconazole, ketoconazole

Increased plasma level and/or effect of buspirone, due to inhibited metabolism via CYP3A4

Haloperidol

Increased plasma level of haloperidol (by 26%) perhaps due to competitive metabolism via CYP3A4

Indinavir, ritonavir

Increased plasma level of buspirone due to CYP3A4 inhibition

Rifampin

Decreased peak plasma concentration and half-life of buspirone due to induced metabolism via CYP3A4

Diazepam

Prior treatment with benzodiazepines for generalized anxiety disorder (GAD) may reduce response to buspirone

Diltiazem, verapamil

Increased peak plasma level of buspirone (3.4- and 4-fold increase in Cmax, respectively) due to inhibited metabolism via CYP3A4

Increased peak plasma level of buspirone (up to 15-fold), AUC (up to 20-fold), and half-life (1.5-fold) due to inhibited metabolism via CYP3A4

Cyclosporine A

Increased serum level of cyclosporine A with possible renal adverse effects

Concomitant use of serotonergic agents increases the risk of serotonin syndrome Decreased level of buspirone due induction of CYP3A4

References

1 Elbe D, Black TR, McGrane IR, et al. Clinical handbook of psychotropic drugs for children and adolescents. (4th ed.). Boston, MA: Hogrefe Publishing, 2019.

Additional Suggested Reading

• AllgulanderC.Novelapproachestotreatmentofgeneralizedanxietydisorder.CurrOpinPsychiatry.2010;23(1):37–42.doi:10.1097/YCO.0b013e328333d574

• BaldwinDS,AndersonIM,NuttDJ,etal.Evidence-basedpharmacologicaltreatmentofanxietydisorders,post-traumaticstressdisorderandobsessive-compulsivedisorder:Arevision

of the 2005 guidelines from the British Association for Psychopharmacology. J Psychopharmacol. 2014;28(5):403–439. doi:10.1177/0269881114525674

• BaldwinDS,AitchisonK,BatesonA,etal.Benzodiazepines:Risksandbene ts.Areconsideration.JPsychopharmacol.2013;27(11):967–971.doi:10.1177/0269881113503509

• CanadianAgencyforDrugsandTechnologiesinHealth.Discontinuationstrategiesforpatientswithlong-termbenzodiazepineuse:Areviewofclinicalevidenceandguidelines.[Rapid

Response Report: Summary with critical appraisal; July 29, 2015]. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK310990/

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

• Canadian Agency for Drugs and Technologies in Health. Use of antipsychotics and/or benzodiazepines as rapid tranquilization in in-patients of mental facilities and emergency departments: A review of the clinical effectiveness and guidelines. [Rapid Response Report: Summary with critical appraisal; October 29, 2015]. Retrieved from http://www.ncbi.nlm. nih.gov/books/NBK350030/

• CanadianAgencyforDrugsandTechnologiesinHealth.Treatmentofolderadultswithinsomnia,agitation,ordeliriumwithbenzodiazepines:Areviewoftheclinicaleffectivenessand guidelines [Rapid Response Report: Summary with critical appraisal; January 14, 2016]. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK343886/

• CorradoPE,GottliebH,RodriguezRV.Doeslong-termuseofbenzodiazepinesresultinde citsincognition?Acriticalreview.DrugBene tsTrends.2007;19(3):116–120.

• Chen SJ, Yeh CM, Chao TF, et al. The use of benzodiazepine receptor agonists and risk of respiratory failure in patients with chronic obstructive pulmonary disease: A nationwide

population-based case-control study. Sleep. 2015;38(7):1045–1050. doi:10.5665/sleep.4808

• DaillyE,BourinM.Theuseofbenzodiazepinesintheagedpatient:Clinicalandpharmacologicalconsiderations.PakJPharmSci.2008;21(2):144–150.

• DonoghueJ,LaderM.Usageofbenzodiazepines:Areview.IntJPsychiatryClinPract.2010;14(2):78–87.doi:10.3109/13651500903447810

• FortinguerraF,ClavennaA,BonatiM.Psychotropicdruguseduringbreastfeeding:Areviewoftheevidence.Pediatrics.2009;124(4):e547-e556.doi:10.1542/peds.2009-0326

• HogeEA,IvkovicA,FricchioneGL.Generalizedanxietydisorder:Diagnosisandtreatment.BMJ.2012;345:e7500.doi:10.1136/bmj.e7500

• HoodSD.Latestguidelinesforthemanagementoftheanxietydisorders-areportfromTheInternationalAnxietyDisordersSocietyConference,Melbourne2014.AustralasPsychiatry.

2015;23(4):388–391. doi:10.1177/1039856215588209

• MurphyY,WilsonE,GoldnerEM,etal.Benzodiazepineuse,misuse,andharmatthepopulationlevelinCanada:Acomprehensivenarrativereviewofdataanddevelopmentssince1995.

Clin Drug Investig. 2016;36(7):519–530. doi:10.1007/s40261-016-0397-8

• ParienteA,deGageSB,MooreN,etal.Thebenzodiazepine-dementiadisorderslink:Currentstateofknowledge.CNSdrugs.2016;30(1):1–7.doi:10.1007/s40263-015-0305-4

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 237 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Anxiolytics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

HYPNOTICS/SEDATIVES

Product Availability∗ Generic Name

Chloral hydrate(C) Diphenhydramine

Doxepin Doxylamine Eszopiclone(B) , (D) Hydroxyzine

L-Tryptophan(C)

Mirtazapine Pentobarbital** Promethazine

Ramelteon(B) Secobarbital** (B) Suvorexant(B) Tasimelteon(B) Zaleplon(B) Zolpidem

Chemical Class

Trade Name(A)

Dosage Forms and Strengths

Benzodiazepines

See pp. 222–229

Chloral derivative

Oral solution: 100 mg/mL

Antihistamine

Benadryl, Compoz(B), Insomnal, Nytol, Simply Sleep, Sominex, Unisom

Tablets: 12.5 mg, 25 mg, 50 mg Caplets: 25 mg, 50 mg Capsules: 25 mg, 50 mg Chewable tablets: 25 mg

Oral solution: 6.25 mg/5 mL(C) , 12.5 mg/5 mL Injection: 50 mg/mL

Antidepressant

Silenor, Sinequan

See pp. 50–59

Antihistamine

Unisom(B)

Tablets: 25 mg

Cyclopyrrolone

Lunesta

Tablets: 1 mg, 2 mg, 3 mg

Antihistamine

Atarax(C), Vistaril(B)

Tablets(B): 10 mg, 25 mg, 50 mg Capsules(C): 10 mg, 25 mg, 50 mg Oral syrup: 10 mg/5 mL

Injection: 25 mg/mL(B) , 50 mg/mL

Tryptophan (see pp. 244–246)

Tryptan

Capsules: 500 mg

Tablets: 250 mg, 500 mg, 750 mg, 1 g

Antidepressant

Remeron

See pp. 46–50

Barbiturate

Nembutal

Injection: 50 mg/mL(B)

Antihistamine

Phenergan

Tablets:12.5mg(B),25mg(B),50mg

Oral Solution: 6.25 mg/5 mL(B) , 10 mg/5 mL(C) Suppositories(B) : 12.5 mg, 25 mg

Injection: 25 mg/mL, 50 mg/mL(B)

Selective melatonin agonist

Rozerem

Tablets: 8 mg

Barbiturate

Seconal

Capsules: 50 mg, 100 mg

Orexin receptor antagonist

Belsomra

Tablets: 5 mg, 10 mg, 15 mg, 20 mg

Selective melatonin agonist

Hetlioz

Capsules: 20 mg

Pyrazolopyrimidine

Sonata

Capsules: 5 mg, 10 mg

Imidazopyridine derivative

Ambien Ambien CR

Tablets: 5 mg, 10 mg

Extended-release tablets(B) : 6.25 mg, 12.5 mg

Intermezzo(B), Edluar(B), Sublinox (C) Zolpimist(B)

Sublingual tablets: 1.75 mg(B) , 3.5 mg(B) , 5 mg(C) , 10 mg(C) Metered oral spray(B) : 5 mg/spray

Cyclopyrrolone

Imovane

Tablets: 5 mg, 7.5 mg

Zopiclone(C)

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

∗ Refer to Health Canada’s Drug Product Database or the FDA’s Drugs@FDA for the most current availability information. (A) Generic preparations may be available, (B) Not marketed in Canada, (C) Not marketed in the USA, (D) S-isomer of zopiclone ** These drugs are not recommended for use as hypnotics/sedatives because they are habit forming, causing physical dependence and relatively more adverse effects than other options. Furthermore, they can have severe withdrawal symptoms; tolerance develops quickly, requiring increased dosage; they have a low margin of safety (therapeutic dose close to toxic dose); they are involved in many drug interactions (induce metabolizing enzymes); they can evoke behavioral complications in children and depression in adults

Indications‡

( approved)

General Comments

Nocturnal sedation; short-term management of insomnia Preoperative/procedural sedation

Chronic insomnia management (ramelteon, eszopiclone – USA) Non-24-hour sleep-wake disorders (tasimelteon – USA)

• Priortotreatmentofinsomnia,determineifsleepdisturbanceissecondaryto:

– Psychiatricdisorder(e.g.,depression,mania,anxiety,psychosis,Alzheimer’sdisease,ADHD)

– Medicaldisorder(e.g.,thyroid,pepticulcer,pain)

– Drug-induced(e.g.,theophylline,sympathomimetics,someantidepressants,decongestants,diuretics,etc.)

– Breathingdisordersduringsleep(e.g.,sleepapnea,sleep-relatedasthma,hypoventilation)

– Lifestyle(e.g.,shiftwork,poorsleephygiene)

– Excessiveuse/abuseofpsychoactivedrugs(e.g.,ca eine,alcohol,cocaine,amphetamines)

– Othersleepdisorders(e.g.,periodiclimbmovementdisorder,restlesslegssyndrome,circadianrhythmdisorders,narcolepsy)

• Treattheunderlyingcausewheneverpossible(e.g.,precipitatingfactors,perpetuatingfactors)

• Psychological therapies are as e cacious as pharmacological therapies for primary insomnia, and they provide more durable response. Non-

pharmacological methods (e.g., cognitive-behavioral therapy, relaxation therapies) should be tried prior to, or concurrently with, pharmacological

therapy – see nursing section p. 241

• The goals of pharmacologic therapy are (a) prevent the progression from transient to chronic insomnia, (b) reverse sleep disruption to prevent

deterioration of daytime performance, (c) resolve or mitigate underlying conditions that may be contributing to insomnia, promote a sound and satisfying sleep (sleep initiation, quality, quantity, and continuity), (d) prevent dependence on drug therapy, and (e) reinstate a normal sleep pattern without the need for medication

• Useofhypnoticsisonlyrecommendedforlimitedtimeperiods;long-term,continuoustreatmentisnotrecommended(thoughmayberequiredin cases of severe, chronic insomnia)

• Eszopiclone,zaleplon,zolpidem,andzopiclonearefrequentlyreferredtoasz-drugs

• Sedatingantihistaminesantagonizehistamine(subtype1)receptorsinthebrainanddisruptcorticalneurotransmissionassociatedwiththearousal action of histamine

• Benzodiazepines bind nonselectively to various subtypes of “benzodiazepine”-GABAA-chloride ionotropic receptors in the brain; GABAA receptor subtypes containing an α1 subunit are associated with sedation, ataxia, and amnesia; GABAA receptor subtypes containing α2 and/or α3 subunits generally have greater anxiolytic activity

• Zolpidem, zopiclone, eszopiclone, and zaleplon bind selectively to GABAA receptor subtypes containing α1 subunits (not α2 or α3) and thus do not have anxiolytic properties like benzodiazepines

• Ramelteon has high binding a nity for MT1 and MT2 melatonin receptors (in the suprachiasmatic nucleus) and enhances the e ect of endogenous melatonin; it has no anxiolytic or muscle relaxant properties, and has no tolerance or abuse potential. It has not been shown to cause signi cant respiratory depression

• Tasimelteon is an agonist for MT1 and MT2 melatonin receptors (greater a nity for MT2 receptor than MT1 receptor). MT2 melatonin receptor is thought to preferentially in uence regulation of circadian rhythms

• SuvorexantisadualorexinreceptorantagonistthatblocksbothOX1RandOX2R.ItblocksbindingoforexinAandB,whichareneuropeptidesthat promote wakefulness

• Seepp.246–249forindividualagents

• Dosageshouldbeadjustedintheelderlyandinpatientswithhepaticimpairment

Pharmacology

Dosing

‡ Indications listed here do not necessarily apply to all hypnotics/sedatives or all countries. Please refer to a country’s regulatory database (e.g., US Food and Drug Administration, Health Canada Drug Product Database) for the most current availability information and indications

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 239 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Hypnotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Pharmacokinetics

Onset & Duration of Action

Adverse Effects

Hypnotics/Sedatives (cont.)

• Seepp.246–249

• Zaleplon: Absorption and peak plasma level may decrease with high-fat meal (Cmax and Tmax decreased by 35%). In one study, Japanese patients

showed increased Cmax and AUC by 37% and 64%, respectively; di erences in body weight or hepatic enzyme activity may explain this di erence

• Zolpidem:Cmax,Tmax,andAUCincreasedby50%,32%,and64%,respectively,intheelderly(over70years)comparedtoyoungadults(20–40years) following a single 20 mg dose. The CR preparation is formulated with an immediate-release layer and a slow-release layer; Cmax occurs later and is higher than with regular-release product. Women attain signi cantly higher serum zolpidem concentrations than men. Due to high protein

binding, patients with low serum albumin attain higher levels of free zolpidem

• Zopiclone:Half-lifecandoubleintheelderlyandpatientswithhepaticimpairment

• Eszopiclone: Tmax delayed after high-fat meal; increased AUC by 41% and TV to 9 h in the elderly; AUC increased 2-fold in moderate to severe liver

impairment

• Ramelteon: High inter-patient variability in Cmax and AUC; high-fat meal delays Tmax and increases AUC by 31%. Drug exposure increased 4-fold in

mild hepatic impairment; 4 active metabolites; 84% of metabolites are eliminated in urine

• Tasimelteon: High-fat meal delays Tmax by 1.75 h and decreases Cmax by 44%. Smokers have 40% decrease in tasimelteon exposure

• Suvorexant: Food delays Tmax by approximately 90 min

• Seepp.246–249

• Seechartpp.249–251

• Daytime sedation and impairment: Dependent on drug dosage, half-life, and patient tolerance; higher rates of motor vehicle accidents have been

reported

• Anterogradeamnesiaisdependentondrug,potency,anddose

• Reboundinsomniaisdependentondrug,dose,half-life,anddurationofuse

• Highdosemayresultinrespiratorydepressionandreducebloodpressure

• Ramelteon has been associated with an e ect on reproductive hormones (decreased testosterone and increased prolactin) in adults; long-term

e ects unknown

• Priapism reported with hydroxyzine (rare) – the metabolite of hydroxyzine (norchlorcyclizine) has structural and conformational similarities to

trazodone’s metabolite (m-chlorophenylpiperazine) and may suggest common underlying pharmacologic mechanism

• Nightmaresreportedwithzaleplon

• Canoccurwithchronicuseofallhypnotics(exceptions:L-tryptophan,ramelteon,suvorexant,andtasimelteon)

• Discontinuationofhypnoticscanproduce:

– Withdrawal:Occurswithin1–2days(withshort-actingagents)to3–7days(withlong-actingagents)followingdiscontinuationofregularuseof most hypnotics (for more than 2 weeks); suggested to occur less frequently with zopiclone and zolpidem. Common symptoms include insomnia, agitation, dizziness, nausea/vomiting, anxiety, perceptual disturbances (e.g., photophobia), malaise, and anorexia. Abrupt withdrawal of high doses may result in twitching, hyperthermia, tremors, seizures and/or psychosis, and possibly death

– Rebound:Occurshourstodaysafterdrugwithdrawal;describedasworseningofinsomniabeyondpretreatmentlevels,nightmares(duetoREM rebound). More likely to occur with short-acting agents

– Relapse:Recurrenceoftheinsomnia,topretreatmentlevels,whenthehypnoticisdiscontinued

• Withdrawal of a hypnotic (after chronic use) should be tailored to each patient; consider switching medications (if on a short-acting agent) to a comparable dose of a long-acting agent and gradually tapering the dose over several weeks. For benzodiazepines examples, see p. 225

• Concomitantcognitive-behavioraltherapymaybehelpfulinfacilitatingtaperanddiscontinuationofahypnotic

Discontinuation Syndrome

Management

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Precautions

• Abrupt withdrawal of hypnotics (excluding L-tryptophan, ramelteon, suvorexant, and tasimelteon) may produce a signi cant discontinuation syndrome. See preceding section for symptoms and consequences of abrupt discontinuation

• Cautionregardingdruginteractions

• Concomitant use of CNS depressants (e.g., zolpidem, zopiclone) with opioids may result in profound respiratory depression, coma, and death.

Consider other alternatives. Limit dosages and durations to the minimum if required

• Long-term use (for years) of hypnotics occurs as patients report unsuccessful e orts to decrease use (due to withdrawal e ects); can result in

memory impairment or falls/fractures (in the elderly)

• Recreational abuse can occur; avoid use in individuals with high risk of substance misuse (no abuse potential reported with L-tryptophan,

ramelteon, and tasimelteon)

• Abusemayresultincloudingofconsciousnessandvisualhallucinations

• Useinindividualswithsleepapneaiscontraindicated

• Zolpidem reported to cause incidents of sleepwalking, driving while “asleep,” and food binging while “asleep.” Due to reports of next-day impair-

ment, zolpidem maximum dose has been reduced based on gender. See pp. 249 for dosing information

• Symptomsofoverdoseincludevaryingdegreesofdrowsiness,mentalconfusion,andlethargy;inmoreseriouscases,symptomsmayincludeataxia,

hypotonia, hypotension, respiratory depression, rarely coma, and very rarely death

• Symptomaticandsupportivetreatmentalongwithimmediategastriclavagewhereappropriate.Intravenous uidsasneeded

• As in all cases of drug overdose, respiration, pulse, blood pressure, and other appropriate vital signs should be monitored and general supportive

measures employed

• For detailed information on the use of hypnotics in this population, please see the Clinical Handbook of Psychotropic Drugs for Children and Adolescents[1]

• Antihistamines:ParadoxicalCNSexcitationcanoccur

• Loweste ectivedoseshouldbeutilizedintheelderlyfortheleastamountoftime

• Cautionwhenusingdrugsthathavelonghalf-livesandareextensivelymetabolizedviaPhaseIpathways(oxidation,reduction,hydrolysis)asthey

can accumulate in the elderly or in persons with liver disease

• CautionwhencombinedwithotherdrugsthathaveCNSproperties;additivee ectscanincreaseriskofconfusion,disorientation,anddelirium

• Antihistaminehypnotics,includingdiphenhydramine,arenotrecommendedintheelderlybecauseofanticholinergicaswellasCNSproperties(see

table pp. 250)

• Anterogradeamnesiareportedwithhigherdoses

• Ramelteon: AUC and Cmax increased 97% and 86%, respectively, and half-life increased in elderly subjects

• Eszopiclone,zolpidem,andzopiclonelevelsareincreasedintheelderly(seepharmacokineticssectionpp.240–240)

• Observational studies have found a link between use of z-drugs and increased risk of dementia. Causation has not been proven but the elderly

should limit use of z-drugs to short duration

• Theelderlyhaveapproximately2-foldincreasedtasimelteonexposurecomparedtonon-elderlyadults

• Seepp.249–251forindividualagents.Forbenzodiazepines,seep.226

• TheAmericanAcademyofPediatricsconsidersmanyhypnotics/sedativescompatiblewithbreastfeeding–seetablepp.249–251

• Assesspersonalsleephabitsandunderlyingfactorsthatmaybecontributingtoinsomnia(e.g.,medicaldisorders,use/abuseofpsychoactivedrugs, lifestyle, etc.)

• Provideallpatientswithgeneralsleephygienetipssuchasavoidingdaytimenapsandavoidingca eine6hbeforebedtime

• Suggest non-pharmacological methods of treating insomnia (e.g., cognitive-behavioral therapy, relaxation techniques, regular sleep/wake cycle

Toxicity

Management

Pediatric Considerations Geriatric Considerations

Use in Pregnancy♢

Breast Milk

Nursing Implications

7 days/week, sleep restriction)

♢ See p. 439 for further information on drug use in pregnancy and e ects on breast milk

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 241 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Hypnotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Hypnotics/Sedatives (cont.)

• Assesswhethermedications/substances(e.g.,nicotine,stimulants,alcohol)maybecontributingtoinsomnia

• Counselpatientregardingchronicuseofhypnotics,riskofdependence,andpotentialforcognitivesidee ects

• Patientsonramelteonshouldavoidtakingthedrugwithorimmediatelyafterahigh-fatmealbecausefatincreasesthedrug’sabsorptionfromthe

intestine

• Foodsigni cantlydelaysthepeakplasmalevelofsuvorexant,tasimelteon,andzolpidem

• Abruptwithdrawalafterchronicuseofmosthypnoticsmayresultinseriousadverseeventsandreboundsymptoms(seeDiscontinuationSyndrome,

p. 240); drugs should be tapered over time

• PatientstakingzolpidemCRorramelteonshouldnotsplit,crushorchewthetablet

• Fordetailedpatientinstructionsonhypnotics/sedatives,seethePatientInformationSheet(detailsp.440)

• Onlyclinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterforthesecondagent

Patient Instructions

Drug Interactions

Class of Drug

Example

Interaction Effects

Antibiotic

Cipro oxacin Clarithromycin, doxycycline

Ramelteon: Increased plasma level of ramelteon, possibly due to inhibited metabolism via CYP1A2

Eszopiclone, zaleplon, zolpidem, and zopiclone: Increased plasma level of hypnotic due to inhibited metabolism via CYP3A4 Suvorexant: Increased plasma level due to inhibited metabolism via CYP3A4. Avoid combination

Anticoagulant

Warfarin

Chloral hydrate will displace drugs from plasma proteins and temporarily enhance hypoprothrombinemic response; increased or decreased PT ratio or INR response

Anticonvulsant

Carbamazepine, phenytoin

Eszopiclone, suvorexant, zolpidem, zopiclone: Decreased plasma level due to induced metabolism via CYP3A4

Antidepressant

SSRI

SSRI/NDRI

SNRI Tricyclics

Fluoxetine, uvoxamine Fluvoxamine

Fluoxetine, paroxetine, sertraline, bupropion

Venlafaxine

Desipramine

Chloral hydrate: Increased sedation and side effects of chloral hydrate due to inhibited metabolism

Ramelteon: DO NOT COMBINE; increased Cmax (70-fold) and AUC (190-fold) of ramelteon due to inhibited metabolism via CYP1A2 Tasimelteon: Increased Cmax (2-fold) and AUC (7-fold)

Zolpidem: Case reports of hallucinations and delirium with sertraline, uoxetine, paroxetine, and bupropion

Diphenhydramine: Decreased metabolism of venlafaxine via CYP2D6

Diphenhydramine: May increase plasma level of antidepressants metabolized primarily by CYP2D6 due to inhibited metabolism

Antifungal

Itraconazole, ketoconazole

Fluconazole

Eszopiclone: Increased Cmax (1.4-fold) and T1⁄2 (1.3-fold) of eszopiclone with ketoconazole due to decreased metabolism via CYP3A4 Ramelteon: Increased Cmax (36%) and AUC (84%) due to inhibited metabolism by ketoconazole via CYP3A4

Suvorexant: Increased AUC (approximately two-fold) due to inhibition via CYP3A4

Tasimelteon: Increased tasimelteon AUC by approximately 50%

Zaleplon: Increased plasma level of zaleplon due to decreased metabolism via CYP 3A4

Zolpidem: Decreased clearance of zolpidem (by 41%); half-life increased (by 26%) with ketoconazole Zopiclone: Increased AUC and elimination half-life of zopiclone due to inhibited metabolism via CYP3A4 Ramelteon: Increased AUC and Cmax of ramelteon by 150% due to inhibited metabolism via CYP2C9

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Example

Interaction Effects

Aripiprazole, chlorpromazine, uphenazine, perphenazine, quetiapine, risperidone, thiothixene

Diphenhydramine: May increase plasma level of antipsychotic metabolized via CYP2D6 due to inhibited metabolism Additive CNS depression and psychomotor impairment

Stribild (Elvitegravir + cobicistat + emtricitabine + tenofovir) Atazanavir, darunavir,

indinavir,lopinavir, ritonavir, saquinavir

Ramelteon: Cobicistat may increase ramelteon concentrations. Use with caution and monitor for toxicity

Zolpidem: A 50% zolpidem dose reduction may be warranted when used with potent CYP3A4 inhibitors such as cobicistat Eszopiclone, suvorexant, zolpidem, zopiclone: Increased plasma level of hypnotic due to inhibited metabolism via CYP3A4 Ramelteon: Ritonavir may decrease ramelteon plasma level via CYP1A2, 2C9 induction. Use with caution and monitor for ef cacy

Rifampin

Eszopiclone: Decreased AUC of eszopiclone due to induced metabolism via CYP3A4

Ramelteon: Decreased Cmax and AUC of ramelteon (by 40–90%) due to induced metabolism

Suvorexant: Decreased AUC (by 88%) due to induced metabolism via CYP3A4

Tasimelteon: Decreased plasma concentration of tasimelteon (by 90%) via CYP2C9 and CYP3A4

Zaleplon: Decreased AUC of zaleplon (by 80%) due to induced metabolism via CYP3A4

Zolpidem: Decreased peak plasma level of zolpidem (by 60%) and decreased elimination half-life (by 36%) due to induced metabolism via CYP2C9, CYP2C19, CYP2D6, and CYP3A4

Zopiclone: Decreased AUC of zopiclone (by 80%) due to induced metabolism via CYP3A4

General

Additive CNS effects and psychomotor impairment

Lorazepam

Eszopiclone: Cmax of both drugs increased by 22%

Barbiturates are potent inducers of several CYP450 enzymes (see p. 246). Since these agents are rarely utilized as hypnotic agents, many important drug interactions have not been included in this handbook. Please refer to a drug interaction text for a list of drugs interacting with barbiturates

Metoprolol

Diphenhydramine: Decreased clearance of metoprolol (2-fold) due to inhibited metabolism via CYP2D6

Tea, coffee, colas, “energy drinks”

May counteract sedation and increase insomnia

Alcohol

Increased CNS depression and psychomotor impairment; in “high” doses coma and respiratory depression can occur Chloral hydrate: Disul ram-like reaction may occur

Dextroamphetamine, methylphenidate

May counteract sedation and increase insomnia

Zaleplon and zolpidem: Antagonism of hypnotic effects

Eszopiclone, suvorexant, zaleplon, zolpidem, zopiclone: Increased plasma level of hypnotic due to inhibited metabolism via CYP3A4 in gut wall; may result in increased bioavailability

Cimetidine

Diphenhydramine: Increased AUC and half-life, and decreased clearance

Eszopiclone, zopiclone: Increased plasma level of hypnotic due to inhibited metabolism via CYP3A4

Zaleplon: Increased peak plasma level and AUC of zaleplon by 85% due to inhibited metabolism via CYP3A4 and aldehyde oxidase

General Codeine

Increased risk of serious side effects, including slowed or dif cult breathing and death, when used with other CNS depressants Diphenhydramine: Inhibited conversion of codeine to its active moiety morphine, via CYP2D6, resulting in decreased analgesic ef cacy

Methadone

Diphenhydramine: Increased plasma levels of methadone, possibly due to inhibited metabolism via CYP2D6

Eszopiclone, suvorexant, zolpidem, zopiclone: May reduce plasma level of hypnotic due to induced metabolism via CYP3A4

Class of Drug

Antipsychotic Antiretroviral

Combination Protease inhibitor

Antitubercular drug

Anxiolytic Barbiturates

β-blocker Caffeine

CNS depressant

CNS stimulant

Flumazenil Grapefruit juice

H2 antagonist Opioid

St. John’s Wort

For drugs interacting with benzodiazepines see pp. 227–229; for L-tryptophan also see p. 245

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 243 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Hypnotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

L-Tryptophan

Product Availability∗

∗ Refer to Health Canada’s Drug Product Database or the FDA’s Drugs@FDA for the most current availability information. (A) Generic preparations may be available, (C) Not marketed in the USA

Generic Name

Chemical Class

Trade Name(A)

Dosage Forms and Strengths

L-Tryptophan(C)

Tryptophan

Tryptan

Tablets: 250 mg, 500 mg, 750 mg, 1 g

Indications‡

( approved)

Bipolar mania or depression: An adjunctive e ect of L-tryptophan given in combination with lithium has been observed in some cases for whom lithium alone or in combination with antipsychotics or tricyclics has shown little or no e ect. Clinical observations suggest the possibility that the combination of lithium and L-tryptophan may reduce the need for higher, more toxic doses of lithium necessary to control acute mania Depressive disorders (including bipolar depression): Adjunct to antidepressants

• Sedative:Reducessleeplatencywithoutdistortingusualstagesofsleep

• Premenstrualdysphoricdisorder–placebo-controlledtrialreportsbene t

• Anessentialaminoacidthatactsasabiochemicalprecursorforthesynthesisofserotoninviatryptophanhydroxylase

• Serotonin,inturn,canbeconvertedtomelatoninviaN-acetyltransferaseand5-hydroxyindole-O-methyltransferase

• Tryptophanalsoservesasaprecursorforniacinviakynurenineandquinolinicacid

• Asanadjunctinthemanagementofa ectivedisorders:3–12g/day,givenin3–4equallydivideddoses

• Lowerdosesreportedtobee ectiveincombinationwithotherantidepressants

• Somepatientsmaynottolerate12g/daybutmightstillbene tfromdosesreducedto8g/day

• Sedation:1–5gatbedtime

• Half-life=1.5–2.5h

• Highlyboundtoplasmaprotein(80–90%)

• Thereisnocorrelationbetweendoseandplasmalevel

• Majorrouteoftryptophanmetabolismisviahepatictryptophanpyrrolase,anenzymethathasbeenshowntobeinduciblebypre-treatmentwith

L-tryptophan in animals

• Clearanceoftryptophanisdecreasedathighdoses;maybeduetosaturablesystemicclearanceorsaturable rst-passclearancebytheliver

• Drowsiness

• Headache

• Euphoria,disinhibitionofmoodandsexualbehaviorreported

• Tremor

• Constipation

• Drymouth

• Dizziness

Pharmacology

Dosing

Pharmacokinetics

Adverse Effects

CNS Effects

Anticholinergic Effects

Cardiovascular Effects

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

GI Effects

Precautions

Contraindications

Pediatric Considerations

Nursing Implications

Patient Instructions

Drug Interactions

• GIupset

• Anorexia

• Protein-reduceddietscancauseanaminoacidimbalancewhenusingL-tryptophan

• Whenusedwithlithium,thedoseoflithiumshouldbedecreased(iflevelhigh)andplasmalevelsmonitoredfortoxicity

• Photo-oxidation of L-tryptophan and some of its metabolites such as kynurenine may increase susceptibility to cataract formation, particularly if

exposed to ultraviolet light

• Cautioninpatientswithafamilyhistoryofdiabetesasdiabetogenice ectreported

• Irritationofurinarybladder(cystitis)

• Diabetes

• Achlorhydriaormalabsorption

• Highdosescausevomitingand“serotonin”overdriveincludingshivering,diaphoresis,hypomania,andataxia

• Symptomaticandsupportivetreatment;thesesymptomsdisappearsoonaftercessationoftryptophan

• Nodataonuseinchildren

• Contraindicated.L-tryptophansupplementationmaynegativelya ectfetalbreathingmovements,whichcanbeasignoffetaldistress

• AccumulationofL-tryptophanmetabolites(e.g.,xanthurenicacid,kynurenine)duetoinhibitedmetabolismhasbeenassociatedwithpregnancy

• L-tryptophansupplementation(upto4g/day)doesnotappeartoe ecttotalendogenouslevelsinbreastmilk

• Givedrugwithmealsorsnackstoreducenausea

• Protein-reduceddietsmaya ectthee cacyofL-tryptophan

• Whenusedwithlithium,monitorforsignsoflithiumtoxicityincludingnausea,vomiting,tremor,ataxia,andconfusion;dermatologicalsidee ects

may be exacerbated

• FordetailedpatientinstructionsonL-tryptophan,seethePatientInformationSheet(detailsp.440)

• Clinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterforthesecondagent

Toxicity

Management

Use in Pregnancy♢

Breast Milk

Class of Drug

Example

Interaction Effects

Anorexiant

Sibutramine

May potentiate the risk of serotonin syndrome. Monitor for increased serotonergic effects

Antibiotic

Linezolid

Monitor for increased serotonergic effects due to linezolid’s weak MAO inhibition

Antidepressant

SSRI, SNRI, NaSSA, Tricyclic, RIMA, MAOI – Irreversible

Amitriptyline, duloxetine, uvoxamine, moclobemide, tranylcypromine

May potentiate the risk of serotonin syndrome. Monitor for increased serotonergic effects

♢ See p. 439 for further information on drug use in pregnancy and e ects on breast milk

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 245 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Hypnotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

L-Tryptophan (cont.)

Class of Drug

Example

Interaction Effects

Hormone

Estradiol, diethylstilboestrol, oral contraceptives

Increased levels of metabolites (xanthurenic acid, kynurenine), possibly due to inhibited metabolism

Lithium

May potentiate the effect of lithium in treatment of patients with bipolar and schizoaffective disorder; mechanism unclear Increased lithium level and possible toxicity resulting in twitching, agitation (serotonin syndrome)

Opioid

Tramadol

May potentiate the risk of serotonin syndrome. Monitor for increased serotonergic effects

St. John’s Wort

May potentiate the risk of serotonin syndrome. Monitor for increased serotonergic effects

Comparison of Hypnotics/Sedatives

Usual Oral Dose in Adults

Onset of Action

Time to Peak Plasma Level (Tmax)

Bio- availability

Protein Binding (PB) Volume of dis- tribution (Vd)

Elimination Half-life (T1/2)

Tolerance

Metabolizing Enzymes (CYP450)*

CYP450 Effect**

Indications

Chloral hydrate

(Aquachloral(B) )

0.5–1 g

Renal impairment: Contraindicated Hepatic impairment: Contraindicated

15–30 min

> 95% (active metabolite trichloro- ethanol)

PB: 70–80% (trichloro- ethanol)

94% (trichloro- acetic acid metabolite) Vd: 0.61 L/kg

4–12 h (tri- chloroethanol) 100 h (trichloroacetic acid metabolite)

Loses effect after 2 weeks

2E1

Nocturnal and preoperative sedation, procedural sedation, alcohol withdrawal

Diphenhydramine

(Benadryl, Compoz(B), Nytol, Simply Sleep, Sominex, Unisom)

12.5–50 mg (as sleep aid) Renal impairment: No dosage adjustment necessary Hepatic impairment: No information

60–80 min

2–4 h

40–60%

PB: 98–99% Vd:

13–20 L/kg

2–10 h (13.5h in the elderly)

Antihistamines lose hypnotic ef cacy with time

3A4, 2D6(D)

Inhibitor of 2D6

Sedation, insomnia, motion sickness, allergic reactions

Doxylamine(C) (Unisom)

25 mg (as sleep aid)

Renal impairment: Decrease dose by 50% in patients with CrCl less than 10 mL/min— Hepatic impairment: Caution advised

1–2 h

2–4 h

25%

PB: ?

Vd: 2.5 L/kg

10–12 h (15.5h in the elderly)

–

Insomnia, allergic rhinitis, common cold – symptom control

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Usual Oral Dose in Adults

Onset of Action

Time to Peak Plasma Level (Tmax)

Bio- availability

Protein Binding (PB) Volume of dis- tribution (Vd)

Elimination Half-life (T1/2)

Tolerance

Metabolizing Enzymes (CYP450)*

CYP450 Effect**

Indications

Eszopiclone(B) (Lunesta)

1–3 mg

(1–2 mg in the elderly)

Renal impairment: No dosage adjustment necessary Hepatic impairment: If severe, start at 1 mg qhs, max.

2 mg/day

0.5–1 h

(2 h after high-fat meal)

80%

PB: 52–59% Vd: 1.4 L/kg

6h(9hinthe elderly)

No tolerance reported after 12 months

3A4, 2E1

–

Insomnia

Hydroxyzine

(Atarax, Vistaril)

50–100 mg qid (anxiety) 50–100 mg (preoperative sedation)

Renal impairment: Decrease dose by 50% in patients with CrCl less than 50 mL/min Hepatic impairment: No information

15–30 min

80%

PB: 93% Vd: 16 L/kg

3–7 h (shorter in children)

–

Inhibitor of 2D6 (weak)

Anxiety disorder, preoperative sedation, antipruritic

L-Tryptophan(C) (Trofan, Tryptan)

1–5 g

Renal impairment: No information

Hepatic impairment: No information

1–2 h

30 min

47–84%

PB: 80–90% Vd:

0.5–0.7 L/kg

1.5–2.5 h

No tolerance reported

Insomnia, adjunct in management of mood disorders

Pentobarbital

(Nembutal)

100 mg

(150–200 mg

IM for preoperative sedation) Renal impairment: Reduce start dose, amount not de ned Hepatic impairment: Reduce start dose, amount not de ned

1 min

15 min

70–90%

PB: 35–55% Vd: 1 L/kg

35–50 h

Loses effect after 2 weeks

Inducer of 2A6, 2B6, 2C9, 3A4

Preoperative sedation for anxiety and tension, anesthesia, refractory status epilepticus

Promethazine

(Phenergan)

25–50 mg (preoperative sedation)

12.5–25 mg every 4 h prn (nausea/vomiting)

15–60 min

2–3 h

Low (?)

PB: 76–93% Vd: 1970 L

5–14 h

2D6

Preoperative or obstetric sedation, preven- tion/control of nausea and vomiting associated with anesthesia and surgery, prophylactic treatment of motion sickness

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 247 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Hypnotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Comparison of Hypnotics/Sedatives (cont.)

Usual Oral Dose in Adults

Onset of Action

Time to Peak Plasma Level (Tmax)

Bio- availability

Protein Binding (PB) Volume of dis- tribution (Vd)

Elimination Half-life (T1/2)

Tolerance

Metabolizing Enzymes (CYP450)*

CYP450 Effect**

Indications

Ramelteon

(Rozerem(B) )

8mg

Renal impairment: No dosage adjustment necessary

Hepatic impairment: Caution in mild–moderate impairment. Contraindicated if severe

30 min

0.5–1.5 h (fasting); 2.6hinthe elderly; food delays

Tmax by 45 min

Absolute bioavailabil- ity 2% due to extensive rst-pass metabolism

PB: 82%

Vd: 1.05 L/kg

1–2.6 h

(M-II metabolite = 2–5 h)

No tolerance reported

1A2(D), 2C9, 3A4

–

Insomnia

Secobarbital

(Seconal)

100 mg (200–300 mg for preoperative sedation)

Renal impairment: Decrease start dose, amount not de ned Hepatic impairment: Decrease start dose, amount not de ned. Contraindicated in patients with signi cant impairment

15 min

2–4 h

90%

PB: 30–45% Vd: 1.5 L/kg

15–40 h

Loses effect after 2 weeks

–

Inducer of 2A6, 2B6, 2C9, 3A4

Preanesthetic agent, dental procedures, short-term insomnia

Suvorexant

(Belsomra(B) )

10–20 mg

Renal impairment: No dosage adjustment necessary

Hepatic impairment: No dosage adjustment in mild–moderate impairment. No data for severe impairment

30 min

2 h (food delays Tmax by 90 min)

82%

> 99%

Approximately 12h

No tolerance reported

2C19, 3A4(D)

–

Insomnia

Tasimelteon

(Hetlioz(B) )

20 mg

Renal impairment: No dosage adjustment necessary

Hepatic impairment: No dosage adjustment in mild–moderate impairment. Contraindicated if severe

Weeks to months due to action on circadian rhythm

0.5–3 h

38%

PB: 90% Vd:

56–126 L/kg

1.3h (Metabolites = 1.3–3.7 h)

No tolerance reported

1A2, 3A4

–

Non-24-hour sleep-wake disorder

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Usual Oral Dose in Adults

Onset of Action

Time to Peak Plasma Level (Tmax)

Bio- availability

Protein Binding (PB) Volume of dis- tribution (Vd)

Elimination Half-life (T1/2)

Tolerance

Metabolizing Enzymes (CYP450)*

CYP450 Effect**

Indications

Zaleplon

(Sonata)

5–10 mg

(5 mg in the elderly)

Renal impairment: No dosage adjustment necessary for mild–moderate impairment. No data for severe impairment Hepatic impairment: In mild–moderate impairment,

5 mg qhs. Avoid in severe impairment

15–30 min

0.9–1.5 h (delayed up to3hafter high-fat meal)

30%

PB: 60% Vd: 1.4 L/kg

0.9–1.1 h

No tolerance up to

12 months reported

3A4, aldehyde oxidase(D)

Insomnia – useful for nocturnal awakenings due to fast onset and short duration of action

Zolpidem

(Ambien, Ambien CR)(E)

5 mg (female), 5–10 mg (male) (5 mg in the elderly) Extended-release: 6.25 mg (female), 6.25–12.5 mg (male) Sublingual tab for middle-of-night awakening: 1.75 mg (female), 3.5 mg (male) Renal impairment: No dosage adjustment necessary

Mild hepatic impairment: 5 mg Severe hepatic impairment: Avoid use

15–30 min

1.6h;2.2h with food CR:1.5h;4h with food

SL: 0.5–3 h (delayed 28% with food) Spray: 0.9 h (mean; delayed with food)

70%

PB: 93%

Vd: 0.54 L/kg

1.5–4.5 h

CR: 2.8 h

SL: 1.57–6.73 h (5 mg), 1.75–3.77 h

(10 mg)

Spray: 1.7–5 h (5 mg), 1.7–8.4 h

(10 mg) (Increased signi cantly in the elderly and in hepatic impairment)

No tolerance after 50 weeks reported

1A2, 2C9, 2C19, 2D6, 3A4(D)

Insomnia (dif culty of sleep onset and/or maintenance)

Zopiclone(C) (Imovane)

5–7.5 mg (initial dose of 3.75 mg in the elderly)

Renal impairment: Start treatment with 3.75 mg; maximum: 5 mg

Hepatic impairment: Caution in mild–moderate impairment. Recommended dose is 3.75 mg; maximum: 5 mg. Contraindicated in severe impairment

30 min

<2h

> 75% (increased in the elderly to 94%)

PB: 45%

Vd: 0.54 L/kg

3.8–6.5 h (5–10 h in the elderly)

No tolerance up to 4 weeks reported

2C8, 3A4(D)

Insomnia

* Cytochrome P-450 isoenzymes involved in drug metabolism, ** Effect of drug on cytochrome enzymes, (B) Not marketed in Canada, (C) Not marketed in the USA, (D) Primary route of metabolism, (E) Sublingual and oral dissolving tablets have been formulated in two strengths and may have a faster onset of action

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 249 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Hypnotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Comparison of Hypnotics/Sedatives (cont.)

Effect on Sleep Architecture

Main Side Effects

Precautions

Pregnancy/Lactation ♢

Antihistamine

(Diphenhydramine, doxylamine, hydroxyzine)

Decreased sleep onset latency

Residual daytime sedation, incoordination; anticholinergic effects at high doses (dry mouth, blurred vision, confusion, delirium, urinary retention, etc.); elderly patients more prone to CNS effects including inattention, disorganized speech, behavior disturbance, altered consciousness

GI disturbances; paradoxical CNS excitation can occur; tolerance to effects occurs within days or weeks

Elderly patients more susceptible to adverse effects including increased sedation, cognitive impairment, and increased risk of falls

May precipitate seizures in patients with focal lesions Diphenhydramine and hydroxyzine are inhibitors of CYP2D6 and may interact with a number of drugs (see pp. 242–243)

Diphenhydramine:

Fetal risk: Considered safe for use in pregnancy Breastfeeding: Excreted into milk; limited human data; manufacturer states use contraindicated in nursing mother because of increased sensitivity in newborn Hydroxyzine:

Fetal risk: One study reports increased risk of congenital malformations but risk not seen in other studies; consider alternative antihistamine Breastfeeding: Unknown effects on nursing infants Doxylamine:

Approved for use in pregnancy-associated nausea and vomiting; excretion in breast milk unknown

Barbiturate

(Pentobarbital, Secobarbital)

Suppresses REM sleep and delta sleep; REM rebound on withdrawal

Confusion, hangover, drowsiness, lethargy, nightmares, excitement if given to patients in severe pain, bradycardia, hypotension, syncope

Can cause severe depression (risk of suicide)

Skin rash (1–3%), nausea, vomiting Weight gain

AVOID barbiturates in: Severe hepatic impairment, porphyria, uncontrolled pain (delirium may result) pulmonary insuf ciency, confused and restless elderly patients

Watch for CNS depression, hypotension, paradoxical stimulatory response (agitation and hyperactivity), and respiratory depression

Risk of tolerance; high potential for abuse and dependence

Fetal risk: Limited human data but barbiturates cross the placenta; an increase in congenital defects and hemorrhagic disease of newborns reported; withdrawal symptoms seen in neonate Breastfeeding: Excreted in breast milk; not recommended

Chloral hydrate

Decreases sleep onset latency and nighttime awakenings with minimal effects on REM sleep

Nausea, vomiting, unpleasant taste, atulence, hangover, ataxia, nightmares, skin rash

Does not accumulate with chronic use; will displace other highly protein-bound drugs from plasma proteins

CAUTION in hepatic and renal impairment, gastritis, peptic ulcer, and cardiac distress

Doses above 2 g can impair respiration and decrease blood pressure

Tolerance can occur with chronic use; withdrawal reactions reported

Fetal risk: Limited human data to assess risk Breastfeeding: Excreted into human breast milk; use by nursing mothers causes neonatal sedation. Considered compatible with breastfeeding by American Academy of Pediatrics

Eszopiclone

Decreased sleep onset latency, decreased nighttime awakenings, increased total sleep time

> 10%: Unpleasant taste, headache

> 5–10%: Dry mouth, dyspepsia, dizziness, somnolence, respiratory infection

Withdrawal effects have been reported including rebound insomnia

Memory impairment reported in the morning, often only in the rst week of treatment

High doses (> 6 mg) can produce amnesia, euphoria, and hallucinations

Caution in respiratory impairment, liver dysfunction, depression, elderly patients, and in combination with CYP3A4 inhibitors

Fetal risk: No evidence of teratogenicity in animal models (high dose). No adequate or well-controlled studies in pregnant women. Consider alternative agent Breastfeeding: Excretion in breast likely given pharmacokinetic parameters; effects on nursing infant unknown but potential for sedation

L-Tryptophan

Decreased REM latency and REM sleep; increased non-REM and total sleep time

GI upset, nausea, vomiting, dry mouth, dizziness, drowsiness, and headache

In combination with other serotonergic drugs can cause twitching or jerking, (i.e., serotonin syndrome) Eosinophilic myalgia reported with certain preparations made from impure raw material Chronic use associated with niacin and pyridoxine de ciency

Fetal risk: Inadequate human studies

Breastfeeding: Unknown excretion into human breast milk; no problems documented in humans

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Effect on Sleep Architecture

Main Side Effects

Precautions

Pregnancy/Lactation ♢

Ramelteon

Decreased sleep onset latency; no effect on night waking; small decreases in stages 3 and 4

Drowsiness, dizziness, fatigue, headache, nausea No behavioral impairment reported

Case reports of decreased testosterone and increased prolactin levels; not known what effect chronic or even chronic intermittent use may have on the reproductive axis

AUC and Tmax increased 4-fold in mild hepatic impairment

Fetal risk: Animal data suggest low risk. No controlled data in human pregnancy

Breastfeeding: Excretion into breast milk likely given drug properties. No human data available

Suvorexant

Decreased sleep onset latency; small reduction in REM latency. Study suggests sleep architecture appears to be preserved

Somnolence, fatigue, headache, abnormal dreams, muscle weakness, dry mouth

Higher doses (above 20 mg) may increase risk of impaired motor coordination, sleep paralysis, hallucinations, and daytime somnolence

Fetal risk: Animal data suggest low risk. No controlled studies in pregnant women

Breastfeeding: Excretion into breast milk unknown; no human data

Tasimelteon

Entrains circadian rhythm in totally blind patients; increases night-time sleep duration; reduces daytime sleep

Headache, nightmares or abnormal dreams, increased serum ALT

Potential to impair performance of activities requiring mental alertness

Fetal risk: Animal data suggest low risk; no controlled data in human pregnancy

Breastfeeding: Excretion into breast milk unknown; no human data

Zaleplon

Sleep onset latency and short-wave sleep decreased

> 10%: Headache

1–10%: Dizziness, somnolence, amnesia, malaise, pruritus, dysmenorrhea, nausea, paresthesia, tremor < 1%: Alopecia, ALT & AST increased, anemia, angina, ataxia, bundle branch block, palpitation

Case reports: Anaphylaxis, angioedema, complex sleep-related behavior (sleep-driving, cooking or eating food, making phone calls)

Due to rapid onset of action, should be taken immediately before bedtime

Dependence, withdrawal, and rebound insomnia reported after prolonged use

Moderate abuse potential

Caution in liver dysfunction: 4-fold increase in Cmax and 7-fold increase in AUC

Fetal risk: Animal data suggest low risk. Human studies did not identify increased risk of malformations. Consider risk and bene t before use. Restrict use to occasional and short term Breastfeeding: Excreted into breast milk; no data on breastfed infants; possibly compatible

Zolpidem

Decreased sleep onset latency and increased total sleep time

Time spent in REM sleep decreased with higher doses No effect on stages 3 and 4

> 10%: Drowsiness, dizziness, somnolence

1–10%: Abnormal dreams, anxiety, apathy, amnesia, ataxia, attention disturbance, disinhibition, euphoria, constipation, diarrhea

< 1%: Agitation, anorexia, bronchitis, diaphoresis, hepatic function abnormalities, postural hypotension Case reports: Anaphylaxis, angioedema, complex sleep-related behavior (sleep-driving, cooking or eating food, making phone calls)

Residual sedation upon awakening reported, especially with CR preparation

CAUTION in liver dysfunction, respiratory impairment; elderly patients more prone to impaired motor and/or cognitive performance

Due to higher exposure in females and reports of daytime impairment, maximum dose for females has been lowered

Habituation reported

Possible increase in epilepsy risk with typical or supratherapeutic doses

Fetal risk: Studies indicate increased risk for pre-term infant, low birth weight, small gestational age infant, and cesarean birth

Breastfeeding: Excreted into breast milk; can cause sedation, lethargy, and changes in feeding habits in exposed infants; considered compatible with breastfeeding by American Academy of Pediatrics

Zopiclone

Little effect on slow-wave sleep

REM delayed but duration the same; stage 1 shortened; stage 2 increased

Somnolence, dizziness, confusion, anterograde amnesia or memory impairment, agitation, nightmares, bitter taste, dry mouth, bad breath, dyspepsia, palpitations, tremor, rash, chills, sweating Severe drowsiness, confusion, and incoordination are signs of drug intolerance or excessive dosage

Rarely hallucinations and behavioral disturbances

CAUTION. May lead to abuse, physical and psychological dependence, and withdrawal symptoms; rebound insomnia reported. Elderly patients more prone to adverse effects

Caution in liver dysfunction: Tmax and half-life increased

Not recommended in children

Fetal risk: No increase of congential malformations when used in 1st trimester. If used in 3rd trimester, monitor newborn for side effects

Breastfeeding: Excreted into breast milk in small amounts. Monitor infant for side effects

♢ See p. 439 for further information on drug use in pregnancy and effects on breast milk

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 251 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Hypnotics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Hypnotics/Sedatives (cont.)

Further Reading

References

1 Elbe D, Black TR, McGrane IR, et al. Clinical handbook of psychotropic drugs for children and adolescents. (4th ed.). Boston, MA: Hogrefe Publishing, 2019.

Additional Suggested Reading

• BuysseDJ.Insomnia.JAMA.2013;309(7):706–716.doi:10.1001/jama.2013.193

• InagakiT,MiyaokaT,TsujiS,etal.Adversereactionstozolpidem:Casereportsandareviewoftheliterature.PrimCareCompanionJClinPsychiatry.2010;12(6):e1–e8.doi:10.4088/PCC.

09r00849bro

• MorinAK,JarvisCI,LynchAM.Therapeuticoptionsforsleep-maintenanceandsleep-onsetinsomnia.Pharmacotherapy.2007;27(1):89–110.doi:10.1592/phco.27.1.89

• ParienteA,deGageSB,MooreN,etal.Thebenzodiazepine-dementiadisorderslink:Currentstateofknowledge.CNSdrugs.2016;30(1):1–7.doi:10.1007/s40263-015-0305-4

• PillaiV,RothT,RoehrsT,etal.Effectivenessofbenzodiazepinereceptoragonistsinthetreatmentofinsomnia:Anexaminationofresponseandremissionrates.Sleep.2017;40(2):zsw044.

doi:10.1093/sleep/zsw044

• QaseemA,KansagaraD,ForcieaMA,etal.Managementofchronicinsomniadisorderinadults:AclinicalpracticeguidelinesfromtheAmericanCollegeofPhysicians.AnnInternMed.

2016;165(2):125–133. doi:10.7326/M15-2175

• Riemann D, Perlis ML. The treatments of chronic insomnia: A review of benzodiazepine receptor agonists and psychological and behavioral therapies. Sleep Med Rev. 2009;13(3):

205–214. doi:10.1016/j.smrv.2008.06.001

• RoehrsTA,RandallS,HarrisE,etal.Twelvemonthsofnightlyzolpidemdoesnotleadtoreboundinsomniaorwithdrawalsymptoms:Aprospectiveplacebo-controlledstudy.JPsy-

chopharmacol. 2012;26(8):1088–1095. doi:10.1177/0269881111424455

• SateiaMJ,BuysseDJ,KrystalAD,etal.Clinicalpracticeguidelineforthepharmacologictreatmentofchronicinsomniainadults:AnAmericanAcademyofSleepMedicineclinicalpractice

guideline. J Clin Sleep Med. 2017;13(2):307–349. doi:10.5664/jcsm.6470

• Sivertsen B, Omvik S, Pallesen S, et al. Cognitive behavioural therapy vs. zopiclone for treatment of chronic primary insomnia in older adults: A randomized controlled trial. JAMA.

2006;295(24):2851–2858. doi:10.1001/jama.295.24.2851

• VermeerenA,CoenenAM.Effectsoftheuseofhypnoticsoncognition.ProgBrainRes.2011;190:89–103.doi:10.1016/B978-0-444-53817-8.00005-0

• WillemsIA,GorgelsWJ,OudeVoshaarRC,etal.Tolerancetobenzodiazepinesamonglong-termusersinprimarycare.FamPract.2013;30(4):404–410.doi:10.1093/fampra/cmt010

• WilsonSJ,NuttDJ,ArgyropoulosSV,etal.BritishAssociationforPsychopharmacologyconsensusstatementofevidence-basedtreatmentofinsomnia,parasomniasandcircadianrhythm

disorders. J Psychopharmacol. 2010;24(11):1577–1601. doi:10.1177/0269881110379307

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

MOOD STABILIZERS

Classi cation

• Moodstabilizerscanbeclassi edasfollows:

Chemical Class

Agent

Page

Lithium

Example: Lithium carbonate

See p. 253

Anticonvulsant

Carbamazepine, gabapentin, lamotrigine, oxcarbazepine, topiramate, valproate

See p. 262

Antipsychotics Second-generation

Asenapine, brexpiprazole, cariprazine, clozapine, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone

See p. 132

Third-generation

Aripiprazole

See p. 161

Antipsychotic/antidepressant combination

Olanzapine/ uoxetine(B) (Symbyax)

Seep.3

(B) Not marketed in Canada

Product Availability∗

Lithium

Generic Name

Chemical Class

Trade Name(A)

Dosage Forms and Strengths

Lithium carbonate

Lithium salt

Lithane(C), Carbolith(C)

Capsules: 150 mg, 300 mg, 600 mg Tablets: 300 mg(B)

Lithobid(B), Lithmax(C)

Extended-release tablets: 300 mg, 450 mg(B)

Lithium citrate

Oral solution: 8 mEq/5 mL (each 5 mL equivalent to 300 mg lithium carbonate)

∗ Refer to Health Canada’s Drug Product Database or the FDA’s Drugs@FDA for the most current availability information. (A) Generic preparations may be available,

(B) Not marketed in Canada,

Indications‡

( approved)

Bipolar disorder (BD) I and II: Long-term maintenance or prophylaxis

Acute mania, mixed states

• Maniaanddepression:Preventionordiminutionoftheintensityofsubsequentepisodes.Decreasesrelapse(vs.placebo)[OR0.66,95%CI0.52–0.85]

• BD:Reductionofsuicidalbehavior/riskandappearstoreducesuiciderates(0.2%vs.2.6%withplacebo)

• BD: Relapse prevention – in a comparative real-world e ectiveness study, lithium use for bipolar patients was associated with the lowest risk of

all-cause rehospitalization (HR, 0.71 [0.95% CI. 0.66-0.76])

• Depression:Augmentstheactionofantidepressantsinrefractorydepression

• Chronic aggression/antisocial behavior/impulsivity across a broad range of diagnoses; may be useful in patients with an a ective component to

symptoms

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 253 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Mood Stabilizers

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

General Comments

Lithium (cont.)

• Pathologicalgambling–double-blindandopenstudiessuggestthatlithiummayreducegamblingbehavioranda ectiveinstability

• Prophylacticmanagementofchronicclusterheadaches

• Neuroprotection–evidencetosuggestaneuroprotectivee ectonthecentralnervoussystem

• “Classic” mania – responds best (up to 80%). Other possible predictors of response include: Family history of lithium response in rst-degree relatives, few prior episodes of mania or depression, complete recovery between episodes, and no neurological impairment

• Severemania–considered rst-linetherapy(incombinationwithanantipsychotic)

• Rapid cycling – as e ective in reducing clinical symptoms as in non-rapid cycling persons but less likely to prevent recurrences; recent reviews of

mood stabilizers suggest that no mood stabilizer is superior to lithium in preventing recurrences[2]. Since lithium-induced hypothyroidism may

contribute to some rapid cycling, it is important to regularly assess thyroid function

• Depression – may be more e ective in preventing manic/hypomanic or mixed episodes than depressive episodes, especially if mania precedes

depression

• Augmentation–suggestedtobemoree ectiveinaugmentingantidepressantsinbipolarthaninunipolardepression

• Riskofdeathfromsuicideshowntobelowerwithlithiumthanwithvalproate

• Exact mechanism of action unknown; postulated that lithium may stabilize catecholamine receptors, alter calcium-mediated intracellular func- tions, and increase GABA activity. Lithium modulates intracellular signaling through actions on second messenger systems that include: (1) inhibi- tion of inositol monophosphatase that alters neurotransmission via the phosphatidyl inositol system, (2) reduction of protein kinase C activity that a ects genomic expression associated with neurotransmission, and (3) activation of the signaling cascade utilized by endogenous growth factors. Collectively, these mechanisms are thought to reduce the responsiveness of neurons to stimuli from muscarinic, cholinergic, and α-adrenergic neurotransmitters

• Researchdatasuggestthatchroniclithiumuseexertsabene ciale ectonneurotrophins

• Lithiumandvalproicacidin uencecircadianrhythmsinwaysthatmaypromotemoodstability

• Doseisusuallyguidedbyplasmalevel(seepharmacokinetics);increaseslowlytominimizesidee ects.Predictivedosingmethodsshowinconsis- tent or poor results

• Healthyadults:

– Acutetreatmentofmania:900–2100mg/day(0.8–1.2mmol/L)inthreedivideddoses

– Maintenance:900mg/daywitharangeof600–1800mg(0.6–1.0mmol/L)individeddoses.Oncestabilized,canbegivenoncedaily

• Elderly patients: Starting dose should not exceed 300 mg/day. Usual dose range 300–1200 mg/day. The lithium dose found to achieve a given concentration between the ages of 49 and 95 decreased threefold in one study and was related to the decline in estimated glomerular ltration rate. See Geriatric Considerations p. 258

• Renaldisease:IfCrClis10–50mL/min,use50–75%ofthestandarddose;ifCrClislessthan10mL/min,use25–50%ofthestandarddose.Patients undergoing dialysis should take their dose AFTER each dialysis treatment

• Acutemania:Patientsappeartohaveanincreasedtolerancetolithium;controlofmaniamayrequirelithiumlevelof0.9–1.4mmol/L

• Relapseprevention:Concentrationsbelow0.6mmol/Lhavebeenshownincontrolledtrialstobelesse ectiveinpreventingrelapse[3]

• Lithiumhasalowtherapeuticindexandanarrowtherapeuticrange;e ectiveserumlevelsareclosetotoxicconcentrations

• Oncepatientisstabilized,once-dailydosingispreferable(ifpatientcantoleratethis),usuallygivenatnightforimprovedcomplianceand,although

the evidence is con icting, some trials have shown a decrease in urine volume and less renal toxicity; no trials of once daily dosing showed a

reduction in e cacy and once daily dosing was generally well tolerated

• Patientssensitivetosidee ectsthatarerelatedtohighpeakplasmalevels,e.g.,tremor,urinaryfrequency,andGIe ects(i.e.,nausea),mayrespond

to slow-release preparations. Alternatively, continued splitting of the dose may be required to decrease adverse e ects related to peak serum levels

• Missed doses or drug interactions may reduce the lithium level and precipitate relapse; the majority of drug interactions, however, precipitate

toxicity

Pharmacology

Dosing

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Pharmacokinetics

Onset & Duration of Action

Adverse Effects

• LithiumiscompletelyabsorbedfromtheGItract

• Peakplasmalevel:1–2h(slow-releasepreparation=4–5h)

• Half-life:8–35h;half-lifeincreaseswithdurationoftherapy(e.g.,upto58hafter1year’stherapy)

• Excreted primarily (95%) by the kidney; therefore, adequate renal function is essential in order to avoid lithium accumulation and intoxication

(see Dosing, above); clearance is signi cantly correlated with total body weight. 80% of ltered lithium is reabsorbed in the proximal convoluted

tubules; therefore, clearance approximates 20% of GFR or 20–40 mL/min

• Lithiumissecretedinsaliva,reachingconcentrations3timesthatseeninplasma–salivacompositionisaltered(seeGIE ectsbelow)

• SR forms produce lower Cmax but similar AUC

• Steady state concentrations are reached in 4 days, with the onset of antimanic e ect usually occurring in 5-7 days. Full therapeutic e ect may require 10–21 days, therefore acute mania symptoms are often treated with an antipsychotic in conjunction with lithium (or monotherapy, and lithium may subsequently be added)

• Seetablep.287

• Generalweakness(upto33%),fatigue,dysphoria,andrestlessnessareusuallytransientandmaycoincidewithpeaksinlithiumconcentration

• Driving:Notgenerallyconsideredsedatingwhenusedasasingleagent,butreactiontimemaybeimpaired

• Drowsiness,tiredness

• Dizzinessandvertigo[Management:Administerwithfood,useslow-releasepreparationtoavoidpeaklithiumlevels,orreduceorsplitdosage]

• Cognition: A 2009 meta-analysis of cognitive performance found a small but signi cant impairment in immediate verbal learning, memory, and

creativity. Delayed verbal memory, visual memory, attention, executive function, and processing speed were not signi cantly a ected. Psychomotor

performance was substantially impaired in patients on longer-term lithium (46.8 +/- 42.7 months)

• Neuromuscular:Incoordination,muscleweakness, netremor/shakiness

• Tremor–incidencereportedtobeabout27%(rangeof4–65%inindividualstudies).Tremorisgenerallysymmetric,relatedtodoseandbloodlevel,

and non-progressive. Usually limited to hands or upper limbs, worsening with ne motor activities (e.g., writing). The tremor is at a higher frequency than with antipsychotics[4] (8–13 Hz vs. 4–7 Hz). A coarse or severe tremor may be a sign of lithium toxicity. Tremor is more frequent in combination with an antidepressant or antipsychotic, valproic acid, or carbamazepine, with excessive ca eine use, or alcoholism. Frequency of tremor decreases with time [Management: Reduce dose, eliminate dietary ca eine (caution, this can elevate lithium level); β-blocker (e.g., propranolol or atenolol) may be of bene t]

• Cogwheelrigidityandchoreoathetosisreported

• Chronictreatmentcana ecttheperipheralnervoussysteminvolvingmotorandsensoryfunction

• Seizuresrare,willalsooccurwithseveretoxicity

• Headaches;rarely,papilledema/elevatedintracranialpressure(pseudotumorcerebri)reported

• Slurredspeech,ataxia–evaluateforlithiumtoxicity

• Bradycardia

• ECG changes: 20–30% benign T-wave changes ( attening or inversion) and QRS widening at therapeutic doses; use lithium cautiously in patients

with pre-existing cardiac disease; arrhythmias and sinus node dysfunction occur less frequently (sinus node dysfunction reported with lithium- carbamazepine combination, with high plasma levels of lithium, in the elderly, and in patients taking other drugs that may a ect conduction); may unmask Brugada syndrome and should not be used in patients with this syndrome (a cardiac conduction disorder that has led to sudden cardiac death). [Assess patient who has syncopal episode]

• Long-term e ects: Clinical hypothyroidism occurs in up to 34% of patients, often within the rst year – risk greater in women over age 40 and possibly in rapid cyclers – may be more common in regions of high dietary iodine (monitor TSH level – may require levothyroxine therapy). Subclinical hypothyroidism (high TSH and normal free T4) found in 25% of patients on lithium. Rare cases of hyperthyroidism reported

• Goiter(notnecessarilyassociatedwithhypothyroidism)–maybemorecommoninregionsofiodinede ciency

• Hyperparathyroidismwithhypercalcemiareportedin10–40%ofpatientsonmaintenancetherapy;maypredisposetodecreasedbonedensityorto cardiac conduction disturbances; case reports of parathyroid adenoma and hyperplasia. Clinical manifestations of hypercalcaemia may necessitate

lithium withdrawal

CNS Effects

Cardiovascular Effects

Endocrine & Metabolic Effects

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 255 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Mood Stabilizers

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Lithium (cont.)

• Hypermagnesaemiaalsoassociatedwithlithiumtherapy,occurringinupto30%ofcasesinoneseries

• Reportsofirregularorprolongedmenstrualcyclesinupto15%offemales

• Weightgain–upto60%incidence(25%ofpatientsgainexcessiveweightofmorethan4kg);mayberelatedtoincreasedappetite, uidretention,

altered carbohydrate and fat metabolism or to hypothyroidism [Management: Reduce caloric intake]. Mean gain is 7.5 kg (range 3–28 kg) on lithium

alone (may be higher with drug combinations) and may be related to dose

• Abnormalsugarandinsulinmetabolismappeartorelatelesscloselytolithiumconcentrationsthantobeingoverweight,whichmaybeinducedby

lithium. In controlled studies, lithium did not in uence glucose tolerance[4]

• Usuallycoincidewithpeaksinlithiumconcentrationandareprobablyduetorapidabsorptionofthelithiumion;mostdisappearafterafewweeks; if they occur late in therapy, evaluate for lithium toxicity

• Nausea–upto50%incidence,abdominalpain[Management:Administerwithfoodoruseslow-releasepreparationorlithiumcitrateliquid]

• Vomiting; higher incidence with increased plasma level [Management: Use multiple daily dosing, change to a slow-release preparation or lower

dose]

• Diarrhea, loose stools – up to 20% incidence. Slow-release preparation may worsen this side e ect in some patients [Management: If on a slow-

release product, change to a regular lithium preparation; fewer problems noted with lithium citrate preparations; if all else fails and cannot decrease

the lithium dose, loperamide prn]

• Metallictaste:Compositionofsalivaaltered(ionsandproteins)

• Excessivethirst(upto36%incidence),drymouth,mucosalulceration(rare),hypersalivationoccasionallyreported

• Polyuria and polydipsia – up to 60% risk (dose related); monitor for uid and electrolyte imbalance – usually reversible if lithium stopped (after medium-term treatment, i.e., up to 6 years, but often irreversible after 15 years); several cases of persistent diabetes insipidus reported up to 57 months after lithium stopped [potassium-sparing diuretic (amiloride 10–20 mg/day) or DDAVP tablets 0.2 mg may be useful]; sustained-release preparations may cause less impairment of urine concentrating function, as may single daily dosing

• Onestudyfoundpolyuriastronglyassociatedwithconcomitantserotonergicantidepressants

• ReducedGFRreportedwithchronictreatment,especiallyinpatientswhohavehadoneormoreepisodesoflithiumintoxication

• Histological changes include: (a) interstitial brosis, tubular atrophy, and glomerulosclerosis, seen in 26% of patients after treatment beyond

2 years – primarily those with impaired urine concentrating ability; (b) distal tubular dilatation and macrocyst formation

• Rarecasesofnephroticsyndromewithproteinuria,glycosuriaandoliguria,edema,andhypoalbuminemia

• 5%ofpatientsaged40–69havestage4kidneydisease

• Renalfailuremaystillprogressafterdiscontinuationoflithiumandmaydependonseverityofrenaldisease

• Retrospective cohort study found a hazard ratio of 2.5 for renal failure in bipolar patients who had ever used lithium. Absolute risk was age

dependent, with patients over 50 at higher risk

• Dryskincommon

• Skinrash,pruritus,exacerbationornewonsetofpsoriasis.Incidenceofexacerbationhasrangedwidely(3.4–45%).A2012meta-analysissuggested

there was no signi cant di erence in prevalence of skin disorders in patients on lithium[5]

• Acne

• Drynessandthinningofhair(possiblyrelatedtohypothyroidism);alopeciareportedin12–19%ofchroniclithiumusers

• Folliculitis

• Casereportsofnailpigmentation

• Blurredvisionmayberelatedtopeakplasmalevels;reductioninretinallightsensitivity,nystagmus(canalsobeasignoftoxicity)

• Changesinsexualfunction–upto10%risk;includesdecreasedlibido,erectiledysfunction,priapism,anddecreasedspermmotility;sorenessand

ulceration of genitalia (rare)

• Edema,swellingofextremities–evaluateforsodiumretention[usediureticswithcaution–seeDrugInteractionsp.261–spironolactonemaybe

preferred]

• Anemia,leukocytosis1.5timesnormal(common),leukopenia,albuminuria;rarelyaplasticanemia,agranulocytosis,thrombocytopenia,occasional

GI Effects

Renal Effects

Dermatological Effects

Other Adverse Effects

eosinophilia and thrombocytosis

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Discontinuation Syndrome

Precautions

Contraindications

Toxicity

• Rarelyanxiety,instability,andemotionallabilityreportedfollowingabruptwithdrawal

• Rapid discontinuation (over 1–14 days) led to a more rapid (5-fold) recurrence risk of mania or bipolar depression than did a more gradual discon-

tinuation over 2–4 weeks

• Isolatedcaseofhyperthyroidismdevelopingaftercessationorreductionoflithiumtherapy

• Goodkidneyfunction,consistentsaltand uidintakeareessential

• Excessive loss of sodium (due to vomiting, diarrhea, heavy sweating, use of diuretics, etc.) causes increased lithium retention, possibly leading to

toxicity; lower doses of lithium are necessary if patient is on a salt-restricted diet (which includes most low-calorie diets)

• Usecautiouslyandinreduceddosageintheelderlyastheabilitytoexcretelithiumdecreaseswithage(seeGeriatricConsiderationsp.258)

• ECT – concurrent ECT may increase the possibility of developing cerebral toxicity from lithium – early case reports included cognitive disturbance,

prolonged apnea, and prolonged seizures. More recent case reports and series of e ective combined use reported. Average time to post-ECT recovery

was directly correlated with serum lithium level. See also ECT chapter pp. 93–98

• Donotrapidlyincreaselithiumandantipsychoticdosageatthesametime,duetoriskofneurotoxicity

• Braindamage

• Renaldisease–especiallyiflowsodiumdietrequired;absolutecontraindicationinsevereinsu ciency • Severecardiovasculardisease

• Severedebilitationordehydration

• Threetypesoftoxicity:

– Acuteoverdose(someonenottakinglithiumonachronicbasis):

• 10–20%ofcases

• MainlyCNS(confusion,tremor,dysarthria,ataxia,nystagmus)withfasciculations, brillations,myoclonia,andpolyneuropathyseenoccasion-

ally; GI symptoms – frequent nausea, vomiting, and diarrhea; renal symptoms of polyuria, polydipsia or nephrogenic diabetes insipidus and

cardiovascular signs of arrhythmia, Brugada syndrome, low blood pressure, and rarely shock may occur

• Usuallycarrieslessriskandpatientsusuallyshowonlymildsymptomsindependentoflithiumconcentration,possiblyduetodelaybetween

ingestion and clinical signs

– Acute on chronic overdose (someone taking lithium on a chronic basis): Largest group, more likely to develop clinical toxicity as brain concen-

tration has already reached equilibrium with their plasma concentration. Even moderately high serum concentrations may be associated with

severe symptoms. Elimination half-life of lithium may be prolonged

– Chronic poisoning: Can occur at any time during lithium therapy. Contributing factors include change in daily dose, chronic excessive dosing,

changes in sodium or water status, renal disease, drug interactions, infection, and surgery. This type of poisoning demonstrates closest correla-

tion between clinical signs, lithium concentration, and prognosis

• Sustained-releasepreparations:Delayedonsetoftoxicity,mayresultinsevereorprolongedsymptoms.Repeateddeterminationsofserumlithium

levels should be performed due to sustained absorption

• Persistentsequelae,usuallyrenalorCNSlesions,canresultfromepisodesoflithiumtoxicity

• Atlithiumlevelsof1.5–2mmol/L;occasionallyoccurswithlevelsinthenormalrange

• Developsgraduallyoverseveraldays

• Adversee ectssuchasataxia,coarsetremor,confusion,diarrhea,drowsiness,fasciculation,andslurredspeechmayoccur

• Stop lithium or hold dose until serum level normalizes

• Atlithiumlevelsinexcessof2mmol/L

• Acute lithium toxicity can present as acute delirium with disorientation, uctuating levels of consciousness, hallucinations, and extrapyramidal

symptoms; may manifest as a catatonic stupor

• Severepoisoningmayresultincomawithhyperre exia,muscletremor,hyperextensionofthelimbs,pulseirregularities,hypertensionorhypoten-

sion, ECG changes (T wave depression or inversion), peripheral circulatory failure, neuroleptic malignant syndrome, and epileptic seizures; acute tubular necrosis (renal failure) can occur

Mild Toxicity

Management

Moderate/Severe Toxicity

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 257 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Mood Stabilizers

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Management

Lab Tests/Monitoring

Lithium (cont.)

• Insomepatients,lithiumtoxicitycausespersistentneurological(cerebellarandbasalganglia)dysfunction

• Attoxiclevels,lithiummayinhibititsownexcretion,ascanrenaldysfunction,sodiumdepletionaswellascertaindrugs(e.g.,NSAIDs)

• Note:Thediscrepancybetweenhighserumlevelsandadvancedsymptomsoftoxicityre ectsdelayeddistributionofdrugintosusceptibletissues

(see types of toxicity above); accumulation in the CNS explains persistent symptoms despite falling serum levels • Deathshavebeenreported;whenserumlithiumlevelexceeds4mmol/Ltheprognosisispoor

• Symptomatic: Reduce absorption (i.e., vomiting, gastric lavage if appropriate, restore uid and electrolyte balance, correct sodium depletion, and remove drug from the body)

• Bloodlithiumconcentrationmaybereducedbyforcedalkalinediuresisorbyprolongedperitonealdialysiswhichclears15mL/minorhemodialysis which clears 50 mL/min and should be considered in severe cases. Severity of symptoms in additions to serum lithium concentrations should be taken into account when determining whether to use hemodialysis. May require repeating due to rebound increase in serum levels 6–12 h later

• ConvulsionsmaybecontrolledbyIVbenzodiazepines

• Atbeginningoftreatment:Personalandfamilymedicalhistory,includingthyroidfunction,previousheartdisease,renaldisease,co-medications • Labsatinitiation:

1. Fasting blood glucose

2. CBC and di erential

3. TSH, T4

4. BUN, creatinine, electrolytes (sodium) 5. Calcium

6. Urinalysis

7. ECG for patients over 40 or with a history of cardiac problems 8. Lithium level at every admission and as below

9. Weight/BMI

10. Pregnancy test, if appropriate; ensure adequate contraception in place for women of child-bearing age

• On an outpatient basis, repeat tests: (1) and (2) if clinically indicated; (3) and (4) at 3 months, then every 6–12 months in stable patients; (5) at 6 months and annually, and consider parathormone to identify or rule out hyperparathyroidism; (6), (7), and (9) as clinically indicated

• Plasmalevelmonitoring:Measure rstplasmalevel5daysafterstartingtherapy(sooneriftoxicityissuspected).Measureonceweeklyforthe rst 2 weeks until levels stable, thereafter at clinical discretion – at least q 3–6 months, whenever a new drug is prescribed or if the dose is increased, at emergence of adverse e ects or toxicity symptoms, more frequently in the elderly or those with unstable renal function or physical illness

• BloodlevelsshouldbemeasuredatTROUGH,i.e.,9–13hafterlastdose.Notethata.m.troughlevelswillbehigherifmovingfrombidortiddosing to once daily at bedtime if serum levels are taken the following morning

• Inonestudy,serumlevelswere17%higherwhenmovingfromBIDdosingtoHSwhenserumlevelsweretaken12hlater.Symptomsofmoderate toxicity are not always evident, so regular lithium levels are important for detection. In one study, 6.8% of patients had levels greater than 1.5 mmol/L, with only 28% showing toxic symptoms

• For detailed information on the use of lithium in this population, please see the Clinical Handbook of Psychotropic Drugs for Children and Adoles- cents[6]

• Lithium has been used successfully in children with chronic aggressive conduct disorders, in bipolar disorder, in periodic mood and behavior disorders, and in pervasive developmental disorder (autism)

• Half-lifeshorterandclearancefasterthaninadults

• Good kidney function, adequate salt and uid intake are essential; ability to excrete lithium decreases with age, resulting in a longer elimination half-life

Pediatric Considerations

Geriatric Considerations

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Use in Pregnancy♢

• Starttherapyatlowerdoses(i.e.,300mgonceortwicedaily)andmonitorserumlevel

• Dose required to achieve same serum levels estimated to decrease by 35–50% between ages 40 and 65 years, and up to threefold from age 40 to

95 due to decline in renal function

• Lowerendoftherapeuticrange(i.e.,0.5–0.8mmol/L)recommendedfortheelderly

• Theelderlyhavelowervolumeofdistributionsecondarytoincreasedbodyfatanddecreasedtotalbodywater

• Incidence of adverse e ects may be greater and occur at lower plasma levels, including tremor, GI disturbances, polyuria, ataxia, myoclonus, and

EPS

• Elderlypatientsmaybemoreatriskforhypercalcemiaandhyperparathyroidism

• Elderlypatientsareatincreasedriskforhyponatremiaafteranacuteillnessorif uidintakeisrestricted

• Elderlypatientsareathigherriskforneurotoxicityandcognitiveimpairment,evenattherapeuticplasmalevels

• Slow-releasepreparationmaydecreasesidee ectsthatoccurasaresultofpeakplasmalevels

• If possible, lithium should be avoided during pregnancy, especially during the period of organogenesis ( rst trimester). Overall risk of fetal mal- formations is 4–12%; cardiovascular malformations risk ratio is 1.2–7.7 – level A evidence (e.g., tricuspid valve malformations; 0.05–0.1% risk of Ebstein’s anomaly) – fetal echocardiography may be considered if exposure in rst trimester (level C evidence) and high-resolution ultrasound at 16–18 weeks gestation

• Ifnecessary,uselithiumatthelowestpossibledivideddailydosetoavoidpeakconcentrationsandsupplementwithfolicacid5mgdaily

• Discontinuation of lithium therapy during pregnancy is associated with an increase in bipolar recurrences. Gradual cessation over 2–4 weeks is

advised whenever the risk is considered acceptable

• A statistically signi cant association noted between higher doses of lithium in the rst trimester and premature deliveries; a higher rate of

macrosomia reported in these premature infants

• Monitordruglevelsduringpregnancy:Uptomonthlyduringpregnancyanduptoweeklyorbiweeklyinthelastmonthofpregnancy

• Lithium clearance increased by 30–50% in the third trimester because of increases in plasma volume and greater glomerular ltration rate; rate

returns to pre-pregnancy levels after delivery; dose should be decreased, or drug discontinued, 2–3 days prior to delivery

• Use of lithium near term may produce severe toxicity in the newborn, which is usually reversible, including nontoxic goiter, atrial utter, T-wave inversion, nephrogenic diabetes insipidus, oppy baby syndrome, cyanosis, and seizures; can be minimized by withholding maternal lithium 2–

3 days before delivery

• Postpartumperiodisassociatedwithade niteincreaseintherecurrenceofbipolardisorderbyafactorof3–8times.Restartlithiumimmediately

after birth

• Observeinfantforlithiumtoxicityfor rst10daysoflife

• Present in breast milk at a concentration of 30–80% of mother’s serum (infant’s serum concentration is approximately 10–50% of the mother’s serum concentration). Reported symptoms in infant include lethargy, hypothermia, hypotonia, involuntary movements, dehydration, hypothy- roidism, cyanosis, heart murmur, and T-wave changes

• Infants have decreased renal clearance (in general, so may retain lithium in their bodies); the American Academy of Pediatrics recommends that lithium should be given to nursing mothers only if bene ts outweigh risks, and with caution

• Ifbreastfeedingisundertaken,themothershouldbeeducatedaboutsignsandsymptomsoflithiumtoxicityandriskofinfantdehydration;monitor infant lithium levels and consider periodic thyroid evaluation

• Accurateobservationandassessmentofpatient’sbehaviorbeforeandafterlithiumtherapyisinitiatedisimportant

• Bealertfor,observe,andreportanysignsofsidee ectsorsymptomsoftoxicity;ifsignsorsuspicionsoflithiumtoxicityoccur(seep.257),withhold

the next dose and call doctor immediately

• Advisepatienttomaintainconsistentsaltintakeandcheck uidintakeandoutput;adjust uidandsaltingestiontocompensateifexcessiveloss

occurs through vomiting or diarrhea

• Expectnausea,thirst,frequenturination,andgeneralizeddiscomfortduringthe rstfewdays;therapeutice ectsoccurgraduallyandmaytakeup

to 3 weeks

• LithiummaybegivenwithmealstoavoidGIdisturbances

• Ca eineintakeshouldnotbedramaticallyalteredwhiletakinglithium

Breast Milk

Nursing Implications

♢ See p. 439 for further information on drug use in pregnancy and e ects on breast milk

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 259 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Mood Stabilizers

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Lithium (cont.)

• Withholdmorningdoseoflithiumuntilaftertheblooddrawonmorningswhenbloodisdrawnforalithiumlevel

• Thepatientandfamilyshouldbeeducatedregardingthedrug’se ectsandtoxicitiesandpreventionofsame

• Slow-releasepreparationsshouldnotbebrokenorcrushed.Thetherapeuticbene tofintactslow-releasepreparationsisreductionofsidee ects

such as tremor and gastrointestinal symptoms that occur as a result of high peak plasma levels (i.e., 1–2 h post dose)

• Becauselithiummaycausedrowsiness,cautionpatienttoavoidactivitiesrequiringalertnessuntilresponsetodrughasbeendetermined

• Fordetailedpatientinstructionsonlithium,seethePatientInformationSheet(detailsonp.440)

• Clinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterforthesecondagent

Patient Instructions

Drug Interactions

Example

Interaction Effects

Increased tremor/shakiness with chronic alcohol use

Amphetamine, dextroamphetamine

Lithium may diminish the stimulatory effect of amphetamines

Captopril, enalapril, fosinopril, lisinopril, quinapril, ramipril, trandolopril

Increased lithium toxicity – although mechanism not clearly established, it may involve angiotensin II and decreased aldosterone levels, resulting in sodium depletion; average increase in lithium level of 36% reported, with a signi cant delay in the manifestation of toxicity (3–5 weeks after introduction of ACE inhibitor); avoid combination, if possible

Candesartan, losartan, valsartan

Reports of lithium toxicity (timing ranged from 11 days to 5 weeks after starting an ARB), possibly due to reduced renal elimination of lithium; caution advised

Doxycycline, metronidazole, moxi oxacin sulfamethoxazole- trimethoprim, tetracycline

Case reports of increased lithium effect and toxicity due to decreased renal clearance of lithium. Monitor lithium level, electrolytes, and creatinine if combination used

Carbamazepine, fosphenytoin, phenytoin Topiramate

Increased neurotoxicity of both drugs at therapeutic doses May increase the serum concentration of lithium

Valproate

Valproate may aggravate action tremor

Citalopram, escitalopram, uoxetine, uvoxamine, paroxetine, sertraline

Elevated lithium serum level with possible neurotoxicity; serotonin syndrome (see p. 9) reported

Desvenlafaxine, duloxetine, levomilnacipran, venlafaxine Moclobemide, tricyclic antidepressants

Phenelzine, tranylcypromine

Elevated lithium serum level with possible neurotoxicity; serotonin syndrome (see p. 9) reported May increase lithium tremor, neurotoxicity

Avoid due to risk of malignant hyperthermia

5-HT3 antagonists: dolasetron, granisetron, ondansetron Metoclopramide

May enhance the serotonergic effect of lithium; may result in serotonin syndrome

Lithium may enhance the adverse/toxic effect of metoclopramide. This may manifest as symptoms consistent with serotonin syndrome or neuroleptic malignant syndrome

Acetazolamide

Increased renal excretion of lithium, decreasing its effect

Methyldopa

Increased lithium effects and toxicity due to decreased renal clearance of lithium

Class of Drug

Alcohol Amphetamine

Angiotensin-converting enzyme (ACE) inhibitor

Angiotensin II receptor blocker (ARB)

Antibiotic

Anticonvulsant Antidepressant

SSRI

SNRI

Cyclic, RIMA Irreversible MAOI

Antiemetic Antihypertensive

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Example

General Chlorpromazine Clozapine

Haloperidol, perphenazine, phenothiazines Risperidone

Zidovudine

Bisoprolol, carvediolol, metoprolol, oxprenolol, propranolol

Clonazepam

Diltiazem, verapamil (nondihydropyridines)

Acetazolamide Amiloride Eplenerone Furosemide

Mannitol

Spironolactone, triamterene Thiazides

Agrimony, dandelion, horsetail, juniper, licorice, uva ursi Cola nut, guarana, maté

Calcitonin

Sargramostim

Calcium, potassium iodate, potassium iodide

Metaxalone

Celecoxib, diclofenac, ibuprofen, indomethacin, ketorolac, mefenamic acid, naproxen,

sulindac (no interaction with ASA or acetaminophen)

Class of Drug Interaction Effects

Antipsychotic

Antiviral agent β-blocker

Benzodiazepine Caffeine

Calcium channel blocker

Desmopressin (DDAVP) Diuretic

See Antipsychotics chapter for further information

Lithium may decrease the serum concentration of chlorpromazine

Possible increased risk of agranulocytosis with clozapine; case reports of seizures and diabetic ketoacidosis reported with combination

Increased neurotoxicity possible at therapeutic doses; may increase EPS; cases of NMS reported

Case report of severe neurotoxicity

Reversal of zidovudine-induced neutropenia

Bene cial effect in treatment of lithium tremor; propranolol lowers glomerular ltration rate and has been associated with a 19% reduction in lithium clearance

Increased incidence of sexual dysfunction (up to 49%) reported with the combination

Increased renal excretion of lithium, resulting in decreased plasma level

May increase lithium tremor

Increased neurotoxicity of both drugs; increased bradycardia and cardiotoxicity with verapamil due to combined calcium blockade. Does not appear to involve dihydropyridine class (e.g., nifedipine, felodipine) Lithium may diminish the therapeutic effectiveness of desmopressin

May decrease serum concentration of lithium

May be used to treat polyuria

May increase serum concentration of lithium

Isolated reports of lithium toxicity with enhanced risk in older populations and those with comorbid medical conditions or sodium-restricted diets

Increased renal excretion of lithium, decreasing its effect

Monitor for increased effect of lithium

Increased lithium effects and toxicity due to decreased renal clearance of lithium; combination should be avoided in patients already stabilized on lithium, but if thiazide diuretics must be added, a 25–50% decrease in lithium dose and obtaining plasma concentrations once a new steady-state concentration has been achieved (e.g., approximately 1 week after initiation of thiazide) is recommended

Elevated lithium level possible due to decreased renal clearance

Increased excretion and decreased lithium level possible due to high content of caffeine in herbal preparations May decrease lithium concentration

May increase the myeloproliferative adverse effects of lithium

May act synergistically to produce hypothyroidism. AVOID

Case series of 3 acutely manic patients developing lithium toxicity when lactulose added for hyperammonia or constipation, possibly due to volume depletion

Increased plasma level and ef cacy and/or toxicity of lithium

May enhance the serotonergic effect of lithium; may result in serotonin syndrome

Increased lithium level and possible toxicity due to decreased renal clearance of lithium (up to 133% increase reported with celecoxib, up to 300% with mefenamic acid); serum creatinine increased in several reports. Use caution and monitor lithium level every 4–5 days until stable

261

Herbal diuretic

Hormone Immunostimulator Iodide salt Lactulose

L -Tryptophan Methylene blue Muscle relaxant NSAID

Mood Stabilizers

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Lithium (cont.)

Class of Drug

Example

Interaction Effects

Neuromuscular blocker

Pancuronium, succinylcholine

Potentiation of muscle relaxation

Opioid

Fentanyl, meperidine, methadone Tramadol

May enhance serotonergic effect of lithium; may result in serotonin syndrome

Lithium may enhance the adverse/toxic effect of tramadol- the risk of seizures may be increased. Tramadol may enhance the serotonergic effect of lithium; may result in serotonin syndrome

Peripheral nerve blocker

Lidocaine with epinephrine

Cases of extremely prolonged anesthesia

Psyllium

Metamucil, Prodiem

Decreased lithium level if drugs taken at the same time. Increased water drawn into the colon by the bulk laxatives would increase the amount of ionized lithium, which would remain unabsorbed

Retinoid

Isotretinoin

One case report suggested adding isotretinoin to lithium carbonate caused mild lithium toxicity. Isotretinoin may be prescribed for lithium-induced acne, but there is strong evidence that demonstrates an association of isotretinoin to depression, probable clinical exacerbation of bipolar mood disorder, and possible links to psychosis

Sodium salt

Increased intake results in decreased lithium plasma level; decreased intake causes increased lithium plasma level

Stimulant

Methylphenidate

May enhance the adverse/toxic effect of lithium. Speci cally, risk of serotonin syndrome or serotonin toxicity may be increased

Theophylline

Aminophylline, oxtriphylline, theophylline

Enhanced renal lithium clearance and reduced plasma level (by approx. 20%) May increase lithium tremor

Urinary alkalizer

Potassium citrate, sodium bicarbonate

Enhanced renal lithium clearance and reduced plasma level

Anticonvulsants

Product Availability∗

Generic Name

Chemical Class

Trade Name(A)

Dosage Forms and Strengths

Carbamazepine

Second-generation anticonvulsant

Epitol(B), Tegretol

Teril(B), Tegretol (liquid) Tegretol CR

Tablets: 100 mg(B) , 200 mg, 300 mg(B) , 400 mg(B) Chewable tablets: 100 mg, 200 mg

Oral suspension: 100 mg/5 mL Controlled-release tablets(C) : 200 mg, 400 mg

Carbatrol(B), Equetro(B) Tegretol XR(B)

Extended-release capsules: 100 mg, 200 mg, 300 mg Extended-release tablets: 100 mg, 200 mg, 400 mg

Divalproex sodium

Second-generation anticonvulsant

Depakote(B)

Depakote ER(B) Epival ECT(C)

Delayed-release tablets: 125 mg, 250 mg, 500 mg Delayed-release pellets: 125 mg

Extended-release tablets: 250 mg, 500 mg Enteric-coated tablets: 125 mg, 250 mg, 500 mg

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Chemical Class

Trade Name(A)

Dosage Forms and Strengths

Third-generation anticonvulsant

Neurontin

Capsules: 100 mg, 300 mg, 400 mg, 800 mg(B) Tablets: 600 mg, 800 mg

Oral solution(B) : 250 mg/5 mL

Gralise(B)

Fanatrex FusePaq(B)

Tablets: 300 mg, 600 mg Oral suspension: 25 mg/mL

Third-generation anticonvulsant

Horizant(B)

Extended-release tablets: 300 mg, 600 mg

Third-generation anticonvulsant

Lamictal

Tablets: 25 mg, 100 mg, 150 mg, 200 mg(B)

Lamictal CD(B) Lamictal ODT(B) Lamictal XR(B)

Chewable tablets: 2 mg, 5 mg, 25 mg(B)

Oral disintegrating tablets: 25 mg, 50 mg, 100 mg, 200 mg Extended-release tablets: 25 mg, 50 mg, 100 mg, 200 mg, 250 mg, 300 mg

Third-generation anticonvulsant

Trileptal Oxtellar XR(B)

Tablets: 150 mg, 300 mg, 600 mg

Oral suspension: 300 mg/5 mL

Extended-release tablets: 150 mg, 300 mg, 600 mg

Third-generation anticonvulsant

Topamax

Trokendi XR(B) Qudexy XR(B)

Tablets: 25 mg, 50 mg(B), 100 mg, 200 mg

Sprinkle capsules: 15 mg, 25 mg

Extended-release capsules(B): 25 mg, 50 mg, 100 mg, 200 mg Delayed-release capsules(B): 25 mg, 50 mg, 100 mg, 150 mg, 200 mg

Second-generation anticonvulsant

Depacon(B)

Injection: 100 mg/mL

Second-generation anticonvulsant

Depakene

Capsules: 250 mg

Enteric-coated capsules: 500 mg(C) Oral syrup: 250 mg/5 mL

Generic Name

Gabapentin(D)

Gabapentin enacarbil Lamotrigine

Oxcarbazepine Topiramate(D)

Valproate sodium Valproic acid

∗ Refer to Health Canada’s Drug Product Database or the FDA’s Drugs@FDA for the most current availability information. (A) Generic preparations may be available, (B) Not marketed in Canada, (C) Not marketed in the USA, (D) There is no reliable evidence favoring the use of gabapentin or topiramate either in acute mood episodes or to prevent relapse. They have been included here as they are anticonvulsants with some psychotherapeutic effect

Indications‡

( approved)

SECOND-GENERATION AGENTS

THIRD-GENERATION AGENTS

Carbamazepine

Valproate

Gabapentin

Lamotrigine

Oxcarbazepine

Topiramate

Acute mania

+ (second-line agent as combination therapy)

+ ( rst-line agent as mono- or combination therapy; also effective in case series of corticosteroid-induced mania)

not recommended

+/– (third-line agent as combination therapy)

not recommended

Acute bipolar I depression

+ (third-line agent)

+ (second-line agent)

–

+ ( rst-line agent)

‡ Indications listed here do not necessarily apply to all anticonvulsants or all countries. Please refer to a country’s regulatory database (e.g., US Food and Drug Administration, Health Canada Drug Product Database) for the most current availability information and indications

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 263 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Mood Stabilizers

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Anticonvulsants (cont.)

SECOND-GENERATION AGENTS

THIRD-GENERATION AGENTS

Carbamazepine

Valproate

Gabapentin

Lamotrigine

Oxcarbazepine

Topiramate

Maintenance of bipolar I disorder

+ (second-line agent)

+ ( rst-line agent)

+ (third-line adjunctive agent)

+ ( rst-line agent; limited ef cacy in preventing mania)

+/–

Acute bipolar II depression

+ (second-line agent)

Maintenance of bipolar II disorder

+ (third-line agent)

+ ( rst-line agent

Rapid-cycling bipolar disorder

+/–

?/–

– (bipolar I) + (bipolar II)

–

?/–

Mixed states

not recommended

+ (adjunctive drug)

–

Anticonvulsant

Partial and generalized tonic-clonic seizures. Not effective for absence, myoclonic or atonic seizures

Sole or adjunctive agent in simple or complex absence and generalized seizures

Adjunctive in refractory epilepsy. Not effective for absence seizures

Partial seizures (adjunctive), absence seizures (monotherapy), generalized tonic-clonic seizures (monotherapy) Adjunctive for seizures associated with Lennox-Gastaut

Mono- or adjunctive therapy in partial seizures

Mono- or adjunctive therapy in epilepsy

Paroxysmal pain syndromes

Trigeminal neuralgia; glossopharyngeal neuralgia in some patients

? Fibromyalgia

+ (diabetic neuropathy, postherpetic neuralgia)

Postherpetic neuralgia

+ (neuropathic pain) ? Fibromyalgia

+/– (central pain); Cochrane review: ineffective in neuropathic pain and bromyalgia

+/– (neuropathic pain, trigeminal neuralgia)

– (neuropathic pain); Cochrane review: no separation from placebo

Migraine headaches

(prophylaxis)

+/?

+ (Basilar migraine)

–

(prophylaxis)

+ (post-ECT treatment headaches)

Behavior disturbances

Explosive disorder, conduct disorder, mental retardation, brain damage

Dementia

+ (alone or in combination with lithium, antipsychotics or β-blockers)

+/–

–

+ (small case series)

+/? preliminary

–

+/?

?/–

Panic disorder

+ (fourth-line agent)

+ (case report)

– (may be associated with development of panic attacks)

Social phobia, generalized anxiety disorder (GAD)

–

+/– (open trials)

+ (social phobia)

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

SECOND-GENERATION AGENTS

THIRD-GENERATION AGENTS

Carbamazepine

Valproate

Gabapentin

Lamotrigine

Oxcarbazepine

Topiramate

Feeding and eating disorders

+/– bulimia nervosa

+ binge eating disorder

+/– bulimia nervosa and binge-eating disorder

Posttraumatic stress disorder (PTSD)

+ (open trials)

+/– (systematic review, open trials)

+ (adjunctive drug – preliminary data)

+ (case reports)

+/–

Obsessive-compulsive disorder (OCD)

+/– (adjunctive drug – preliminary data)

+/– (adjunctive drug, case reports)

+ (adjunctive to SSRIs – preliminary data)/–

+/– (case report – adjunctive to SSRI in treatment-resistant OCD)

+ (case report

– adjunctive drug)

+/– (trial in treatment-resistant OCD) + (trial as adjunct in bipolar)

+ (pathological gambling)

Core symptoms of borderline personality disorder

+ (preliminary data)

–

+ (preliminary data)

Paranoid ideation, hallucinations, and negative symptoms of schizophrenia

+/– (adjunctive drug)

+ (adjunctive drug)

–

+/– (adjunctive drug – bene t on positive symptoms)

+ (preliminary data

– alone or as adjunctive drug)

+ (adjunctive drug)/?

Movement disorders

Dystonic disorder in children

? Restless legs syndrome

–

+/? essential tremor;

+ restless legs syndrome

–

+ essential tremor (case report)

+ Restless legs syndrome (case reports)

+ Essential tremor

Drug dependence

Aid in alcohol or sedative/hypnotic withdrawal; may play a role in cocaine dependence (– systematic review)

Aid in alcohol withdrawal (open trials)

Adjunct in opioid, alcohol, or cannabis withdrawal. Studies have found gabapentin abuse associated with opioid addiction

Aid in alcohol withdrawal (open trials)

–

Treatment of alcohol dependence Promotes smoking cessation in

alcohol- dependent smokers

Increases cocaine-free days

Not ef cacious for increasing cocaine abstinence in methadone patients

+ = positive data; – = negative data; ? = no data available or data of poor quality to guide therapy

Dosing

• Seetablep.280forspeci cagents

• Carbamazepineandvalproate:Plasmalevelmonitoring(measuredattrough)canhelpguidedosing

• Lamotrigine:Slowerdosagetitrationasperproductmonographisstronglyrecommendedtodecreaseriskofrash

• Gabapentin: Dosing in renal dysfunction: If CrCl 30–59 mL/min, give drug bid to a maximum dose of 1400 mg/day. If CrCl 15–29 mL/min, give

drug once daily to a maximum dose of 700 mg/day. If CrCl is less than 15 mL/min, give drug to a maximum of 300 mg once daily; reduce dose

proportionally with decreasing CrCl

• Reduceddosagesrecommendedintheelderlyandinhepaticorrenaldisorders

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 265 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Mood Stabilizers

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Pharmacokinetics

Carbamazepine

Valproate

Gabapentin

Lamotrigine

Oxcarbazepine

Topiramate

Adverse Effects

Anticonvulsants (cont.)

• Seetablep.281forspeci cagents

• Inducesitsownmetabolism.Single-dosestudiesshowhalf-liferangesof30–40hthatdecreaseto20hafter3weeks.Duringchronicmonotherapy, half-life is 12 h, and during concurrent therapy with enzyme inducers may decrease to 8 h

• The10,11-epoxidemetaboliteofcarbamazepinecanreachupto50%oftheplasmaconcentrationoftheparentdrug;itispharmacologicallyactive and associated with neurological side e ects

• Pharmacokinetics show signi cant variation with changes in body weight. Valproate exhibits concentration-dependent protein binding, therefore at high doses and plasma concentrations a larger proportion may exist in unbound (free) form; the free fraction of drug increases from 10% at a concentration of 40 micrograms/mL to 18.5% at a concentration of 130 micrograms/mL. Elderly, patients with low albumin levels, or those on other highly protein-bound drugs will exhibit a higher free fraction of valproate and may exhibit signs of toxicity within the therapeutic serum level range

• Asbindingsitesbecomesaturatedandthefreefractionincreases,valproateclearancealsoincreases,reducingtotalserumconcentrationssuchthat at higher dosing non-linear changes in serum concentrations occur

• Absorption of divalproex tablets may be delayed such that levels taken in the morning after evening doses may more closely approximate a peak concentration; switching from divalproex tablets to a liquid for compliance purposes may actually show a decline in serum levels

• Gabapentinshowsdose-dependentbioavailabilityasaresultofasaturabletransportmechanism(betterbioavailabilitywithmorefrequentdosing; plasma level is proportional to the dose). Elimination is almost entirely by the kidneys, and reduced in renal dysfunction (see Dosing p. 280)

• Large individual variation seen in plasma lamotrigine concentration in renal impairment; half-life is also prolonged in hepatic dysfunction. Age, gender, and smoking do not a ect pharmacokinetics

• Iscompletelyabsorbedandextensivelymetabolizedtoitspharmacologicallyactive10-monohydroxymetabolite

• Completelyabsorbed.Proteinbindingisinverselyrelatedtoplasmaconcentrations

• Seetablepp.282–285forspeci cagents

• Manysidee ectscanbeminimizedwithslowerdosagetitration

• Common(forallanticonvulsants):

– GI complaints, e.g., nausea [Management: Take with food, change to an enteric-coated preparation, use ranitidine 150 mg/day or famotidine 20 mg/day]

– Dose-related lethargy, sedation, behavior changes/deterioration, reversible dementia/encephalopathy; cognitive e ects are more prominent on drug initiation and are minimized with slow dosage increases

– Tremor: Dose related; tends to be rhythmic, rapid, symmetrical, and most prominent in upper extremities [reduce dose if possible; responds to propranolol]

– Ataxia

– Weight:Changesinappetite,weightgain(excepttopiramateandlamotrigine)–morecommoninfemales;maybeassociatedwithfeaturesof

insulin resistance, hyperlipidemia, impaired glucose tolerance, and hyperinsulinemia. Weight increases with duration of treatment. Obesity may

increase risk of hyperandrogenism in females [Management: metformin 500 mg tid]

– Menstrual disturbances (except gabapentin and topiramate), including: Prolonged cycles, oligomenorrhea, amenorrhea, polycystic ovaries, ele-

vated testosterone – rates may be higher in females who begin taking valproate before age 20. Clinical features of polycystic ovary syndrome include hirsutism, alopecia, acne, menstrual irregularities, and obesity; lab indices show increased total and free testosterone, decreased FSH, increased serum prolactin and LH, and LH/FSH ratio greater than 2, incidence most common with valproate

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Discontinuation Syndrome

Precautions

• Occasional(forallanticonvulsants): – Dysarthria,incoordination

– Diplopia,nystagmus

• Rare: Anticonvulsant hypersensitivity syndrome with fever, rash, and internal organ involvement; cross-sensitivity reported between carba- mazepine, oxcarbazepine, phenytoin, barbiturates, and lamotrigine

• Noevidenceofpsychologicalorphysicaldependencetoanticonvulsants(exceptforgabapentin)

• Myoclonicjerkshavebeenreportedfollowingthetaperingofcarbamazepineorvalproate

• Caseofanhedonia,tremor,tachycardia,andhyperhydrosisreportedfollowingrapiddiscontinuationoflamotrigine

• Abruptdiscontinuation(especiallyinpatientswithaseizuredisorder)mayprovokereboundseizures–tapereveninabsenceofseizurehistory

• Rarereportsofpsychiatricsymptomsonwithdrawal,includingpsychosis(exacerbationofschizophrenia)

• Monitoring:Priortotreatment,laboratoryinvestigationsshouldbeperformed(seep.270)

• Contraception:Ensureadequatecontraceptioninplaceforwomenofchild-bearingage(seeUseinPregnancyp.285)

• Suicidal behavior or ideation: According to the FDA (February 2008), patients receiving antiepileptic drugs have a slightly increased risk of suicidal

behavior or ideation (0.43%) compared to patients receiving placebo (0.22%). The increased risk was observed as early as one week and continued through 24 weeks. Patients who were treated for epilepsy, psychiatric disorders, and other conditions were all at increased risk for suicidality but the relative risk for suicidality was higher in the patients with epilepsy than in those with psychiatric or other conditions

• Tolerancetoe ectshasbeenreported;e cacynotimprovedwithdoseincrease

• CarbamazepineinducesthemetabolismofdrugsmetabolizedbytheCYP450system(includingmetabolismofitself)(seepp.273–275).Monitoring

of clinical status and dosage adjustment of contraceptives (both oral and patches), in particular, may be required

• Duetoanticholinergicaction,givecautiouslytopatientswithincreasedintraocularpressureorurinaryretention

• PatientsofAsianancestry(particularlyHanChinese)andwithapositivetestforHLA-B*1502,andpatientswithHLA-A*3101(particularlyJapanese

and Northern European) are at increased risk of serious skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis). Avoid use if patient

tests positive

• Potentiallyfatalbloodcellabnormalitieshavebeenreported.Milddegreeofbloodcellsuppressioncanoccur;stoptherapyifWBClevelsdropbelow 3,000 white cells/mm3 ; erythrocytes less than 4 ô 106 /mm3 ; platelets less than 100,000/mm3

• Hepatocellularandcholestaticjaundiceaswellashepatitisreported

• Hypersensitivity syndrome with fever, skin eruptions, and internal organ involvement occurs rarely, cross-sensitivity with other aromatic anticon-

vulsants suggested; discontinue carbamazepine at rst sign of drug-induced rash

• Hyponatremia(SIADH)occursin10–15%ofpatients;elderlypatientsatslightlyincreasedrisk

• Use cautiously in patients with history of coronary artery disease, organic heart disease, or congestive heart failure; may suppress ventricular

automaticity

• Donotadministercarbamazepinesuspensiontogetherwithanyotherliquidpreparationasformationofaninsolubleprecipitatecanoccur

• Hepatictoxicity–mayshownorelationtohepaticenzymelevels.Monitorliverfunctionpriortoandatregularintervalsafterinitiationoftherapy. In high-risk patients, monitor serum brinogen and albumin for decreases in concentration, and ammonia for increases secondary to decrease in carnitine levels. Stop drug if hepatic transaminase 2–3 times the upper limit of normal

• Pancreatitis – cases of life-threatening pancreatitis at start of therapy or following years of use. In patients with severe abdominal pain, lethargy, and weight loss, rule out pancreatitis – do serum amylase level

• Thrombocytopenia – platelet counts and bleeding time determinations are recommended prior to therapy and at periodic intervals; withdraw if hemorrhage, bruising, or coagulation disorder is detected

• Hyperammonemia and/or encephalopathy, sometimes fatal, have been reported following initiation of valproic acid therapy and may be present with normal transaminase levels. One study found hyperammonemia encephalopathy in 2.52% of patients treated with valproate over 5 years. Ammonia levels should be measured in patients who develop unexplained lethargy and vomiting or changes in mental status, or in patients who present with hypothermia. Increased risk with higher dose and concomitant phenytoin, phenobarbital, topiramate or carbamazepine use

• Drugreactionwitheosinophiliaandsystemicsymptoms(DRESS)/multiorganhypersensitivityreportedinafewcases.Monitorforsignsandsymp- toms and discontinue if con rmed

Carbamazepine

Valproate

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 267 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Mood Stabilizers

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Anticonvulsants (cont.)

• Diabeticpatientsonvalproicacidmayshowfalse-positiveketoneresults

• Polycystic ovary syndrome: Due to risk, consider monitoring for bioavailable androgens (free testosterone) as well as prolactin, LH, and TSH in

females with menstrual irregularities, obesity, hirsutism, alopecia, and evidence of anovulation

• In patients with decreased or altered protein binding it may be more useful to monitor unbound (free) valproate concentrations rather than total

concentrations

• ValproatewillinhibitthemetabolismofanumberofdrugsmetabolizedbycytochromeP-450(seeinteractionslistedpp.275–277)

• Drug reaction with eosinophilia and systemic symptoms (DRESS)/multi-organ hypersensitivity reported, including fatal cases; evaluate early signs/symptoms and discontinue gabapentin if con rmed

• Riskofpsychomotorimpairment.Advisepatientstoavoidactivitiesthatrequirementalalertnessandphysicalcoordinationuntilcognitivee ects assessed

• Casereportsofmyoclonusinpatientwithrenalfailure

• Severe, potentially life-threatening rashes, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported – higher incidence in children, rapid dosage titration, and in combination with valproate. Most occur within rst 8 weeks of starting lamotrigine. Patient should be educated to immediately report to the physician any rash or systemic symptoms (fever, malaise, pharyngitis, u-like symptoms), sores or blisters on soles, palms or mucus membranes. Do not rechallenge

• Iflamotriginewithheldforlongerthan5half-lives,considerrestartingaccordingtoinitialdosingrecommendationstodecreaseriskofdermatologic reactions

• UsecautiouslyinpatientswithrenaldysfunctionandinpatientswithGradeA,B,orChepaticimpairmentaseliminationhalf-lifeoflamotrigineis increased

• DuetopotentialofPRintervalprolongation,lamotrigineshouldbeusedcautiouslyinpatientswithconductionabnormalities

• FDA warning (August 2010) of aseptic meningitis – more than 40 cases reported; patients should be advised to immediately report symptoms of

headache, fever, sti neck, nausea, vomiting, rash, and sensitivity to light

• Monitorsodiumlevelswithchronicuseduetoriskofhyponatremia–particularlyin rst3months

• Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in both

children and adults; multi-organ hypersensitivity reactions have occurred in close temporal association (median time to detection 13 days, range:

4–60) to the initiation of therapy in adult and pediatric patients

• 25–30% of patients who exhibited hypersensitivity reactions to carbamazepine may also have these reactions with oxcarbazepine. Patients of

Asian ancestry (particularly Han Chinese) and with a positive test for HLA-B*1502 are at increased risk of serious skin reactions (Stevens-Johnson

syndrome and toxic epidermal necrolysis). Avoid use if patient tests positive

• Rarereportsofagranulocytosis,aplasticanemia,andpancytopenia

• Topiramate alone or in combination with valproate can cause hyperammonemia with or without encephalopathy – monitor for acute alterations in level of consciousness with fatigue and/or vomiting; if suspected, order ammonia level

• Hypothermia(bodycoretemperaturebelow35°C(95°F))reportedwithconcurrentvalproateuse

• Decreasedsweating(oligohidrosis)andhyperthermiareported

• Riskofrenalstone(calciumphosphate)formationinmalesonchronictherapy–ensureadequate uidintakeandavoidexcessiveantaciduseand

carbonic anhydrase inhibitors

• Acute myopia secondary to angle closure glaucoma reported; ophthalmological consult recommended for patients who complain of acute visual

problems and/or painful/red eyes

• Decrease in sodium bicarbonate (up to 30% incidence); symptoms include fatigue, anorexia, hyperventilation, cardiac arrhythmia, and stupor.

Chronic metabolic acidosis may increase risk for nephrolithiasis or nephrocalcinosis and may result in osteomalacia and/or osteoporosis with an

increase in risk of fractures [reduce dose or taper and discontinue drug]

• Cognitivesidee ectsarerelatedtodose

• Usecautiouslyinpatientswithhepaticimpairmentduetoreducedclearance

Gabapentin

Lamotrigine

Oxcarbazepine

Topiramate

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Contraindications

Toxicity

• Patientswithahistoryofhepaticorcardiovasculardiseaseorwithablooddyscrasia(gabapentinexcluded)

• Hypersensitivitytoanytricycliccompound(carbamazepine),anddemonstratedhypersensitivitytoanyoftheotheragents

• Patientsprescribedclozapineduetoincreasedriskofagranulocytosis(carbamazepine)

• Patientswithhistoryofbone-marrowdepression(carbamazepine)

• Conjunctionwithitraconazoleandvoriconazoleorcombinedusewithmonoamineoxidaseinhibitor(carbamazepine)

• Patientswithknownporphyria(valproate)

• Usuallyoccurswithplasmalevelsabove50mmol/L;childrenmaybeatriskfortoxicityatlowerserumconcentrationsduetoincreasedproduction of toxic epoxide metabolite. Measurement of epoxide level may be bene cial in patients who develop clinical signs of carbamazepine toxicity at therapeutic concentrations of the parent drug (however, many labs are unable to measure epoxide level)

• Maximum plasma concentration may be delayed for up to 70 h after an overdose; onset of symptoms begin 1–3 h after ingestion of extended- release preparation

• Signs:

– Dizziness,bloodpressurechanges,sinustachycardia,ECGchanges

– Drowsiness,stupor,agitation,disorientation,seizures,andcoma

– Nausea,vomiting,decreasedintestinalmotility,urinaryretention

– Tremor,involuntarymovements,opisthotonos,abnormalre exes,myoclonus,ataxia – Mydriasis,nystagmus

– Flushing,respiratorydepression,cyanosis

• Noknownantidote,treatsymptomatically

• Maximumplasmaconcentrationmaynotoccurforupto18hfollowinganoverdose,andserumhalf-lifemaybeprolonged

• OnsetofCNSdepressionmayberapid(within3h);enteric-coatedpreparationsmaydelayonsetofsymptoms

• Signs/symptoms:Severedizziness,hypotension,supraventriculartachycardia,bradycardia;severedrowsiness;trembling;irregular,sloworshallow

breathing, apnea, and coma; loss of tendon re exes, generalized myoclonus, seizures; cerebral edema – evident 2–3 days after overdose and may

last up to 15 days; hematological changes, electrolyte, and metabolic abnormalities; optic nerve damage reported

• Overdosecanresultinheartblock,coma,ordeath;naloxonemayreversetheCNSdepressante ects,andmayalsoreverseanti-epileptice ects

• Supportive treatment [L-carnitine supplementation 100mg/kg/day (maximum 6g) followed by 15mg/kg every 4h until clinical improvement

recommended for patients with CNS depression, evidence of hepatic dysfunction, and hyperammonemia]. Hemodialysis may result in signi cant removal of drug during acute overdose as unbound valproic acid concentration is high

• Signsandsymptoms:Doublevision,slurredspeech,drowsiness,lethargyanddiarrhea–allpatientsrecovered

• Gabapentincanberemovedbyhemodialysis

• Overdosecanresultinataxia,nystagmus,delirium,seizures,intraventricularconductiondelay,andcoma.Fatalitiesreported

• Noknownantidote–treatsymptomatically

• Nodeathsreportedfollowingoverdoseofupto24,000mg;noknownantidote–treatsymptomatically

• Removalofthedrugbygastriclavageand/orinactivationbyadministeringactivatedcharcoalshouldbeconsidered

• Emesisandgastriclavagerecommended;topiramatecanberemovedbyhemodialysis

• Treatsymptomatically

• Overdosecanresultinseveremetabolicacidosis

Carbamazepine

Valproate

Gabapentin

Lamotrigine

Oxcarbazepine

Topiramate

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 269 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Mood Stabilizers

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Anticonvulsants (cont.)

Lab Tests/Monitoring

Carbamazepine

Valproate

Gabapentin

Lamotrigine

Oxcarbazepine

Topiramate

Work-up

(1) CBC including platelets and differential

(2) Serum electrolytes, urea, creatinine

(3) Liver function

(4) ECG (in patients over age 45 or with a cardiac history)

(5) HLA-B*1502/HLA-A*3101 typing in patients with high-risk ancestry

(6) Pregnancy test if appropriate

(1) CBC including platelets and differential

(2) Liver function

(3) Total and HDL cholesterol and triglycerides

(4) Body weight/BMI

(5) Menstrual history

(6) Bone density

(7) Pregnancy test if appropriate

BUN and serum creatinine

No special baseline monitoring required other than standard work-up

Serum electrolytes Serum creatinine (dose needs to be adjusted with CrCl less than

30 mL/min)

Baseline serum bicarbonate, BUN, and serum creatinine

Follow-up

Repeat CBC, LFT, electrolytes, urea, creatinine monthly for 3 months, as clinically indicated or annually

Bone density if risk factors for osteopenia are present

Repeat (1) and (2) monthly for

2 months, then 2–3 times a year (4) and (5) Q3 months for rst year, then annually

Ammonia level in event of lethargy, mental status changes (6) if risk factors for osteopenia are present

Renal function if suspect toxicity

None required; monitor for rash during titration

Sodium levels periodically and when patient has symptoms of hyponatremia

Periodic serum bicarbonate (to rule out metabolic acidosis) Renal function if suspect toxicity; ammonia levels in unexplained lethargy, vomiting or change in mental state

Plasma level monitoring

Levels for seizure disorders (17–51 μmol/L) are generally used as target range in bipolar disorder not established. Levels are suggested during initiation phase to establish non-toxic and reference levels for the individual patient. Carbamazepine induces its own hepatic metabolism; therefore, levels 4 weeks apart are suggested, after which dose adjustment may be required. Levels also suggested 5 days after change in dose or addition/deletion of possible interacting agent (see Drug Interactions pp. 273–275) or as clinically indicated. It may be necessary to check serum levels of other drugs if carbamazepine is added to the regime

Two levels to establish therapeutic dose (at least

3–5 days after start of therapy) and 5 days after change in dose or addition/deletion of interacting drug (see Drug Interactions pp. 275–277 and Precautions p. 267) or as clinically indicated

Response in mania seen with trough between 350 and

875 μmol/L. Toxicity may occur at levels above 700 μmol/L

None required

None required although may be indicated if interacting drugs present

None required

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Pediatric Considerations

Carbamazepine

Valproate

Gabapentin

Lamotrigine

Oxcarbazepine

Topiramate

Geriatric Considerations

• For detailed information on the use of anticonvulsants in this population, please see the Clinical Handbook of Psychotropic Drugs for Children and Adolescents[6]

• Usedinepisodicdyscontrolandassaultivebehaviordisorder

• Childrenmaybeatriskformajortoxicitiesatlowerserumconcentrationsduetoincreasedproductionoftoxicmetabolite;casereportsofbehavior

disturbances, mania, and worsening of tics

• Commonsidee ectsinclude:Unsteadiness,dizziness,diplopia,drowsiness,nausea,andvomiting

• E cacy reported in treatment of bipolar disorder, acute mania, migraine prophylaxis as well as temper/aggressive outbursts in adolescents and young adults

• Childrenages3–10takingotheranticonvulsantsareathighriskfordevelopinghepatotoxicity

• Use in female children and adolescents may result in increased risk of hyperandrogenism, and polycystic ovary syndrome, delayed or prolonged

puberty; excessive weight gain, hyperinsulinemia, and dyslipidemia; decreased bone mineral density reported (in up to 14%) – may conduce to osteoporosis

• Incidenceofsidee ectsinchildrenreportedtobesimilartothatinadults.Casereportsofbehavioralproblemsincludinghyperactivity,aggression, and irritability

• Hasbeenusedinadolescentsasadd-ontherapyinrefractorybipolardepression.Commonsidee ectsincludedheadache,tremor,somnolence,and dizziness

• Riskofsevere,life-threateningrashincreasedinchildren

• Usedinchildrenandadolescentsassoleoradd-ontherapyforpartialseizures

• Usedasadd-ontherapyinseizuredisordersandprophylaxisofmigraineheadaches

• Sidee ectsincludesedation,cognitiveandbehavioralproblems,andweightloss

• Dose-relatedhyperammonemiareported

• Oligohidrosis(decreasedsweating),anhidrosis,andhyperthermiareported–mostcasereportsinchildren

• Persistenttreatment-emergentdecreasesinserumbicarbonateandmetabolicacidosis

• Dosingshouldbeinstitutedmoregraduallyintheelderlyandthosewithliverimpairment

• Maycauseconfusion,cognitiveimpairment,ataxia(mayleadtofalls)

• Dementia:Meta-analysisand3RCTssupportthee cacyofcarbamazepineinmanagingaggressionandhostilityinpatientswithdementia;meta-

analysis and 5 RCTs do not strongly support the use of valproate. Open trials and case series suggest gabapentin, topiramate, and lamotrigine may

show bene t; oxcarbazepine ine ective. Caution advised due to adverse e ects and potential for drug interactions

• CautionwhencombiningwithotherdrugswithCNSoranticholinergicproperties;additivee ectscanresultinconfusion,disorientation,delirium

• Hip fractures: Continuous anticonvulsant use in elderly women is associated with increased rates of bone loss at the calcaneus and hip. Subse-

quently, increases risk of hip fracture by 29% over 5 years among women aged 65 and older

• Renaldisease:ReducedoseofgabapentinifCrCllessthan60mL/minandofoxcarbazepineifCrCllessthan30mL/min

• Valproate: Due to reduced protein binding and hepatic oxidation, the elderly may have a higher proportion of unbound (free) valproate and a

reduced clearance, resulting in elevated levels of unbound valproate (within therapeutic plasma levels of total drug); case report of acute parkin-

sonism with valproate in an elderly patient with dementia. Increased risk of thrombocytopenia

• Valproate: Similar tolerability and e cacy compared to lithium in treatment of mania in elderly patients while maintaining a mean daily dose of

1200 mg and serum concentration of 513 μmol/L

• Carbamazepine:Elderlypatientswithpre-existingcardiacdiseaseshouldhaveathoroughcardiacevaluationpriortouse

• Carbamazepine/oxcarbazepine: Higher risk of hyponatremia with carbamazepine and oxcarbazepine and increased risk of SIADH with carba-

mazepine

• Lamotrigine:Plasmalevelincreasedinelderlypatients

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 271 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Mood Stabilizers

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Nursing Implications

Anticonvulsants (cont.)

• Monitor patients starting drug treatment for behavioral changes that could indicate emergence or worsening of depression, or suicidal thoughts or behaviors

• Watchoutforsignsoffever,sorethroat,andbruisingorbleeding

• Close clinical and laboratory supervision should be maintained (see Adverse E ects pp. 282–285 and Monitoring p. 270) throughout treatment to

detect signs of possible blood dyscrasias or liver involvement

• Arash,especiallywithcarbamazepineorlamotrigine,maysignalincipientblooddyscrasia;advisethephysician

• Anorexia,nausea,vomiting,edema,malaise,andlethargymaysignifyhepatictoxicity

• Sincedrowsinesscanoccur,patientsshouldexercisecautionwhenperformingtasksthatrequirealertness;willenhancethee ectsofalcoholand

other CNS drugs

• Monitorpatient’sheight,weight,andBMI

• Intheelderly,monitorforataxia,confusion,andcognitiveimpairment

• Advisepatienttostoremedicationawayfromheatandhumidityasthedrugmaylosepotency

• Enteric-coated or controlled-release tablets should not be broken or crushed but should be swallowed whole; chewing capsules can cause local

irritation in the mouth and throat; extended-release capsules can be opened and sprinkled on food

• Carbamazepine:

– Checkforurinaryretentionandconstipation;increase uidstolessenconstipation

– Liquidcarbamazepineshouldnotbemixedortakenatthesametimeasanyotherliquidmedication – Grapefruitandgrapefruitjuiceshouldbeavoidedasitcanelevatethebloodlevelofcarbamazepine – Arashmaysignalincipientblooddyscrasia;advisethephysicianimmediately

• Valproicacid:

– Liquidvalproateshouldnotbeadministeredwithcarbonatedbeveragesasmouthirritationcanoccur

– Infemales(particularlyonvalproate),obtainbaselinebodyweight/BMIandmeasureperiodically,monitorformenstrualdisturbances,hirsutism,

obesity, alopecia, and infertility – two or more of these symptoms may be associated with polycystic ovary syndrome

– Totreatoccasionalpain,avoiduseofacetylsalicylicacid(ASAoraspirin)asitcana ectthebloodlevelofvalproate–acetaminophenoribuprofen

(and related drugs) are safer alternatives

• Lamotrigine:Arash,maysignalincipientblooddyscrasia;advisethephysicianimmediately

• Oxcarbazepine:

– Monitorforsymptomsofhyponatremia–i.e.,nausea,malaise,headache,lethargy,confusion

– Feverorrashmaybeasignofseriousskinreactionororganinvolvement

• Topiramate:

– Patients should drink plenty of uids and avoid the regular use of antacids (e.g., Tums, Maalox, Rolaids, etc.) to reduce risk of renal stone formation

– Patientsshouldreporteyepainorcontinuedvisualdisturbancestothephysician

• FordetailedpatientinstructionsonAnticonvulsantMoodStabilizers,seethePatientInformationSheet(detailsp.440)

• Clinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterforthesecondagent

Patient Instructions

Drug Interactions

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

DRUGS INTERACTING WITH CARBAMAZEPINE

Class of Drug Interaction Effects

Example

Danazol

Halothane

Iso urane, sevo urane

Disopyramide Quinidine

Clarithromycin, erythromycin Doxycycline (no interaction with other tetracyclines)

Metronidazole

Quinupristin/dalfopristin

Apixaban, dabigatran, edoxaban Rivaroxaban

Warfarin

Clobazam, clonazepam, eslicarbazepine, ethosuximide, oxcarbazepine, tiagabine, topiramate, zonisamide

Felbamate

Lamotrigine

Phenobarbital, phenytoin, primidone

Topiramate

Valproate, valproic acid

Fluoxetine, uvoxamine Citalopram, sertraline Nefazodone

Trazodone

Vilazodone

Amitriptyline, doxepin, imipramine, nortriptyline Desipramine

Phenelzine

Androgen Anesthetic

Antiarrhythmic Antibiotic

Anticoagulant

Anticonvulsant

Plasma levels of carbamazepine increased by 50–100%; half-life is doubled and clearance reduced by half Enzyme induction may result in hepatocellular damage

Enzyme induction may result in renal damage

Increased metabolism and decreased plasma level of disopyramide

Increased metabolism and decreased plasma levels of quinidine

Increased plasma levels of carbamazepine due to reduced clearance (by 5–41%)

Decreased serum level and half-life of doxycycline due to enhanced metabolism (alternatively, tetracycline can be used or doxycycline can be dosed q 12 h)

Increased plasma level of carbamazepine due to inhibited metabolism

Increased plasma level of carbamazepine due to inhibited metabolism via CYP3A4

Increased metabolism of anticoagulant; combined use with carbamazepine not recommended Case report of pulmonary embolism suspected due to increased clearance of rivaroxaban

Enhanced metabolism of anticoagulant and impaired hypoprothombinemic response; decreased PT ratio or INR response. Average warfarin dose increased by 49% in one study

Clearance of the anticonvulsants is increased by carbamazepine, with possible decrease in ef cacy (40% decrease in concentration of topiramate and of oxcarbazepine metabolite)

Decreased carbamazepine level by 50%, but increased level of epoxide metabolite

Decreased felbamate level

Increased plasma level of epoxide metabolite of carbamazepine (by 10–45%), with resultant increased side effects Increased metabolism of lamotrigine; half-life and plasma level decreased by 30–50%

Decreased carbamazepine level due to increased metabolism via CYP3A4, but ratio of epoxide metabolite increased Altered plasma level of co-prescribed anticonvulsant

Increased plasma level of carbamazepine by 20%

Increased plasma level of epoxide metabolite of carbamazepine; may result in toxicity even at therapeutic carbamazepine concentrations

Effects on carbamazepine levels are variable and inconsistent

Decreased valproate level due to increased clearance and displacement from protein binding

Increased plasma level of carbamazepine and its active metabolite with uoxetine; increased nausea with uvoxamine Decreased plasma level of sertraline or citalopram due to enzyme induction via CYP3A4 (case report)

Increased plasma level of carbamazepine with nefazodone due to decreased metabolism via CYP3A4

Decreased plasma level of trazodone

Up to 50% decreased plasma level of vilazodone

Decreased plasma level of antidepressant (by up to 46%) due to enzyme induction

Carbamazepine induces the production of hydroxymetabolites of desipramine which have been reported to cause ECG changes. Medically ill patients on a combination of a TCA and carbamazepine should have post-treatment ECGs Possible decrease in metabolism and increased plasma level of carbamazepine

Antidepressant

SSRI

SARI

SPARI

Cyclic (nonselective)

MAOI

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 273 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Mood Stabilizers

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Anticonvulsants (cont.)

Class of Drug Interaction Effects

Example

Caspofungin

Fluconazole, itraconazole, ketoconazole Fluconazole, ketoconazole

Cisplatin

Cyclophosphamide, ge tinib, imatinib, irinotecan, lapatinib, temsirolimus

Doxorubicin

Acetazolamide

General

Aripiprazole, upenthixol, haloperidol, olanzapine, phenothiazines, quetiapine, risperidone, thiothixene, ziprasidone, zuclopenthixol

Clozapine Haloperidol, loxapine

General

Dolutegravir, elvitegravir, raltegravir

Delavirdine, efavirenz, etravirine, nevirapine, rilpivirine

Atazanavir, darunavir, indinavir, lopinavir, nel navir, ritonavir, saquinavir

Isoniazid

Elbasvir, glevaprevir, grazoprevir, ledipasvir, pibrentasvir, sofosbuvir, velpatasvir, voxilaprevir Rifampin

Alprazolam, clonazepam

Propranolol

Diltiazem, verapamil (no interaction with nifedipine)

Dexamethasone, prednisolone

Hydrochlorothiazide

Antifungal

Antineoplastic

Antihypertensive Antipsychotic

Decreased plasma level of antifungal. Consider using increased caspofungin dose Decreased plasma levels of antifungals

Increased plasma level of carbamazepine with ketoconazole (by 29%) due to inhibited metabolism via CYP3A4; clearance decreased by 50% with uconazole

Decreased carbamazepine concentrations due to enzyme induction

Decreased antineoplastic levels; avoid concurrent use when possible

Decreased cisplatin and doxorubicin concentrations due to enzyme induction

Increased plasma level of carbamazepine, due to inhibited metabolism

See Antipsychotics chapter for further information

Decreased plasma level of antipsychotic (64% with aripiprazole, up to 100% with haloperidol, 44% with olanzapine, 45-65% with paliperidone depending on carbamazepine dose, 70% with risperidone, 35% with ziprasidone). Quetiapine may also increase levels of the epoxide metabolite; olanzapine may increase carbamazepine levels

Increased akathisia

Increased neurotoxicity of both antipsychotic and carbamazepine at therapeutic doses

Avoid combination due to possible potentiation of bone marrow suppression

Decreased plasma level of clozapine by up to 63%

Increased plasma level of carbamazepine and metabolite

Decreased concentrations of antiretroviral regimens containing cobicistat (atazanavir/cobicistat, darunavir/cobicstat, elvitegravir/cobicistat); avoid combination

Decreased antiviral concentrations due to increased metabolism; use with caution

Decreased antiviral concentration and potential loss of virologic response; avoid combination

Decreased protease inhibitor concentrations due to increased metabolism; avoid combination

Increased plasma level of carbamazepine due to inhibited metabolism via CYP3A4, potentially resulting in toxicity Increased plasma level of carbamazepine; clearance reduced by up to 45%

Decreased plasma levels and ef cacy of direct-acting antivirals due to enzyme induction via CYP3A4; avoid combination

Decreased plasma level of carbamazepine

Decreased plasma level of alprazolam (more than 50%) and clonazepam (19–37%) due to enzyme induction Decreased plasma level of β-blocker due to enzyme induction

Increased plasma levels of carbamazepine due to decreased metabolism (total carbamazepine increased 46%, free carbamazepine increased 33%)

Decreased plasma level of corticosteroid due to enzyme induction

Concurrent use may increase antidiuretic effect, resulting in decreased sodium concentration with resultant seizures Concomitant use has been associated with hyponatremia, particularly in the elderly

Antiretroviral

Integrase inhibitor Non-nucleoside reverse transcriptase inhibitor (NNRTI) Protease inhibitor

Antitubercular drug Antiviral (direct acting)

Benzodiazepine β-blocker

Calcium channel blocker

Corticosteroids Desmopressin (DDAVP) Diuretic

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Example

Interaction Effects

Decreased plasma level of folic acid

Decreased metabolism of carbamazepine resulting in increased plasma level (by up to 40%)

Cimetidine

Transient increase in carbamazepine levels and possible toxicity due to inhibited metabolism (no interaction with ranitidine, famotidine, and nizatidine)

Oral contraceptive Medroxyprogesterone acetate injection

Increased metabolism of oral contraceptive and increased binding of progestin and ethinyl estradiol to sex hormone binding globulin, may result in decreased contraceptive ef cacy

Concomitant administration is expected to decrease medroxyprogesterone concentrations

Cyclosporine, sirolimus, tacrolimus

Decreased plasma level and ef cacy of immunosuppressants due to CYP3A4 induction

Decreased elimination and increased half-life of carbamazepine

Decreased plasma level of carbamazepine and its metabolite

Increased neurotoxicity of both drugs; sinus node dysfunction reported with combination

Decreased plasma level of moda nil due to enhanced metabolism

Pancuronium

Decreased duration of action and ef cacy of muscle relaxant

Diclofenac, ibuprofen

Increased plasma level of carbamazepine due to decreased metabolism

Buprenorphine, hydrocodone, methadone, tramadol

Decreased effect of methadone (up to 60%) due to enhanced metabolism; buprenorphine, hydrocodone, and tramadol are metabolized by CYP3A4 and concomitant use is expected to decrease ef cacy

Omeprazole

Increased carbamazepine levels

Increased plasma level of carbamazepine (by 37%) and AUC (by 51%) due to inhibited metabolism

Methylphenidate

Decreased plasma level of methylphenidate and its metabolite

Decreased carbamazepine plasma levels

Decreased theophylline level due to enzyme induction by carbamazepine; decreased carbamazepine level by up to 50%

Decreased plasma level of thyroid hormone due to enzyme induction

Class of Drug

Folic acid Grapefruit juice H2 antagonist

Hormone

Immunosuppressant In uenza vaccine Isotretinoin

Lithium

Moda nil

Muscle relaxant (non-depolarizing) NSAID

Opioid

Proton pump inhibitor Quinine

Stimulant

St. John’s Wort Theophylline

Thyroid hormone

DRUGS INTERACTING WITH VALPROATE

Class of Drug

Example

Interaction Effects

Alcohol

Increased sedation, disorientation

Anesthetic

Propofol

Valproate reduces dose required to induce anesthesia for ECT

Antibiotic

Carbapenems Erythromycin Rifampin

Signi cantly decreased valproate plasma concentrations

Increased valproate plasma level due to decreased metabolism; may also occur with clarithromycin May reduce valproate levels by up to 40%

Anticoagulant

Warfarin

Inhibition of secondary phase of platelet aggregation by valproate, thus affecting coagulation; increased PT ratio or INR response

Displacement of protein binding of warfarin (free fraction increased by 33%)

Anticonvulsant

Carbamazepine

Decreased valproate levels due to increased clearance and displacement from protein binding Effects on carbamazepine levels are inconsistent

Ethosuximide Felbamate

Increased half-life of ethosuximide (by 25%)

Increased plasma level of valproate (by 31–51%) due to decreased metabolism

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 275 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Mood Stabilizers

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Anticonvulsants (cont.)

Class of Drug Interaction Effects

Example

Lamotrigine

Phenobarbital, primidone Phenytoin

Topiramate

Fluoxetine

Venlafaxine

Amitriptyline, doxepin, nortriptyline

Guanfacine

Clozapine

Haloperidol Olanzapine

Phenothiazines

Risperidone

Zidovudine

Ritonavir

Ritonavir and/or nevirapine

Isoniazid Rifampin

Acyclovir

Chlordiazepoxide, clonazepam, lorazepam

Clonazepam Diazepam

Antidepressant

SSRI

SNRI

Cyclic (nonselective)

Antihypertensive Antipsychotic

Increased lamotrigine plasma level (by up to 200%), half-life (by up to 50%), and decreased clearance (by up to 60%) Both decreases and increases in plasma level of valproate reported. This combination may be dangerous due to high incidence of Stevens-Johnson syndrome and toxic epidermal necrolysis

Increased level of anticonvulsant (by 30–50%) due to decreased metabolism caused by valproate. Increased clearance of valproate. Additive CNS depression with concomitant administration (possibly severe)

Enhanced anticonvulsant effect due to displacement from protein binding (free fraction increased by 60%) and inhibited clearance (by 25%); toxicity can occur at therapeutic levels

Possible decrease in valproate level

Case reports of delirium and elevated ammonia levels; topiramate increases risk of valproate encephalopathy

Increased plasma level of valproate (up to 50%) Signi cantly increased levels of O-desmethlyvenlafaxine

Increased plasma level and adverse effects of antidepressant – consider therapeutic drug monitoring and monitor for adverse effects of increased antidepressant levels

Increased level of valproate due to inhibited metabolism; monitor for potential CNS side effects

Both increased and decreased clozapine levels reported; changes in clozapine/norclozapine ratio

Case report of hepatic encephalopathy

Valproate may increase risk of clozapine myocarditis

Increased plasma level of haloperidol (by an average of 32%)

Combination associated with high incidence of weight gain

Signi cantly lower levels of olanzapine in combination with valproic acid

Increased neurotoxicity, sedation, and extrapyramidal side effects due to decreased clearance of valproate (by 14%) Case report of encephalopathy with initiation of risperidone

Increased level of zidovudine (by 38%) due to decreased clearance

Severe anemia reported with combination secondary to zidovudine; use combination with caution and monitor for zidovudine toxicity

Decreased level of valproate due to increased metabolism; use with caution

Case of hepatotoxicity with antiretroviral regimen containing ritonavir, saquinavir, stavudine, and nevirapine Increased plasma level of valproate due to inhibited metabolism

Increased clearance of valproate (by 40%)

Decreased level of valproate

Decreased metabolism and increased pharmacological effects of benzodiazepines resulting in increased sedation, disorientation (lorazepam clearance reduced by 41%)

Concomitant use may induce absence status in patients with a history of absence type seizures

Increased plasma level of diazepam due to displacement from protein binding (free fraction increased by 90%)

Antiretroviral

Nucleoside reverse transcriptase inhibitor (NRTI)

Protease inhibitor

Antitubercular drug

Antiviral agent Anxiolytic

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Class of Drug

Example

Interaction Effects

H2 antagonist

Cimetidine

Decreased metabolism and increased half-life of valproate

Hypnotic

Zolpidem

Case of somnambulism with combination

Lithium

Valproate may aggravate action tremor

Salicylate

Acetylsalicylic acid, bismuth subsalicylate

Displacement of valproate from protein binding and decreased clearance, leading to increased level of free drug (4-fold), with possible toxicity

Sulfonylurea

Tolbutamide

Increase in free fraction of tolbutamide from 20 to 50% due to displacement from protein binding

Thiopental

Displacement of thiopental from protein binding, resulting in an increased hypnotic/anesthetic effect

DRUGS INTERACTING WITH GABAPENTIN

Class of Drug

Example

Interaction Effects

Alcohol

Increased sedation, disorientation

Antacid

Al/Mg-containing antacids

Co-administration reduces gabapentin bioavailability by up to 24%. Administer gabapentin at least 2 h after antacid

Opioid

General

Hydrocodone Morphine

Increased sedation, disorientation

Increased risk of opioid-related deaths due to additive respiratory depression and increased gabapentin concentrations (opioids slow GI transit time and gabapentin is absorbed in the upper small intestine, resulting in increased gabapentin bioavailability); monitor for CNS depression

Decreased concentration of hydrocodone reported

Increased gabapentin concentrations; gabapentin has been shown to enhance the acute analgesic effects of morphine

DRUGS INTERACTING WITH LAMOTRIGINE

Class of Drug

Example

Interaction Effects

Alcohol

Increased sedation, disorientation

Analgesic

Acetaminophen

AUC of lamotrigine decreased by 20% when co-administered with 4 g of acetaminophen daily, due to induction of glucuronidation pathways

Antiarrhythmic

Procainamide

Increased procainamide concentrations

Anticonvulsant

Carbamazepine, phenobarbital, phenytoin, primidone

Topiramate Valproate

Plasma level and half-life of lamotrigine decreased due to increased metabolism (clearance increased 30–50% with carbamazepine; by 125% with phenytoin)

Increased plasma level of epoxide metabolite of carbamazepine by 10–45% with resultant increased side effects Decreased plasma level of lamotrigine

Increased plasma level of lamotrigine (by up to 200%) and half-life (by up to 50%), and decreased clearance (by up to 60%), leading to an increased risk of lamotrigine toxicity and life-threatening rashes; both decreases and increases in valproate levels reported

Increased risk of life-threatening rash with combination (Stevens-Johnson syndrome and toxic epidermal necrolysis)

Antidepressant

SSRI

Escitalopram Sertraline

Case reports of myoclonus

Case reports of increased plasma level of lamotrigine resulting in toxicity

Antipsychotic

Olanzapine

AUC of lamotrigine decreased by 24%

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 277 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Mood Stabilizers

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Anticonvulsants (cont.)

Class of Drug

Example

Interaction Effects

Antiretroviral

Non-nucleoside reverse transcriptase inhibitor (NNRTI) Protease inhibitor

Efavirenz, etravirine, nevirapine Atazanavir, lopinavir, ritonavir

Decreased lamotrigine concentrations due to increased metabolism; use with caution

Decreased plasma level of lamotrigine (by 50%) due to increased metabolism; use ritonavir-boosted regimens with caution

Antitubercular

Rifampin

Decreased lamotrigine levels and half-life

Herbal preparation

Ginseng

Case report of drug reaction with eosinophilia and systemic symptoms (DRESS)

Hormone

Oral contraceptive

Decreased plasma level of lamotrigine (by 27–64%)

Reports of breakthrough bleeding and unexpected pregnancies

Opioid

General

Increased sedation, disorientation

DRUGS INTERACTING WITH OXCARBAZEPINE

Class of Drug

Example

Interaction Effects

Alcohol

Increased sedation, disorientation

Anticonvulsant

Carbamazepine, phenobarbital, phenytoin, valproate

Decreased plasma levels of oxcarbazepine MHD metabolite by 40% (carbamazepine); 30% (phenytoin); 25% (phenobarbital); 18% (valproate)

Increased level of phenytoin (by 40%) and phenobarbital (by 14%) due to inhibited metabolism via CYP2C19

Antidepressant

Citalopram Sertraline

May increase risk of QTc prolongation

Case report of fatal serotonin syndrome in elderly patient when oxcarbazepine added, thought to be mediated through CYP2C19

Antiretroviral

General

Decreased concentrations of antiretroviral regimens containing cobicistat (atazanavir/cobicistat, darunavir/cobicstat, elvitegravir/cobicistat); avoid combination

Integrase inhibitor Non-nucleoside reverse transcriptase inhibitor (NNRTI) Protease inhibitor

Dolutegravir, elvitegravir, raltegravir

Delavirdine, efavirenz, etravirine, nevirapine, rilpivirine

Atazanavir, darunavir, indinavir, lopinavir, nel navir, ritonavir, saquinavir

Decreased antiviral concentrations due to increased metabolism; use with caution Decreased antiviral concentration and potential loss of virologic response; avoid combination

Decreased protease inhibitor concentrations due to increased metabolism; avoid combination

Antiviral (direct acting)

Elbasvir, glevaprevir, grazoprevir, ledipasvir, pibrentasvir, sofosbuvir, velpatasvir, voxilaprevir

Decreased plasma levels and ef cacy of direct-acting antivirals due to enzyme induction via CYP3A4; avoid combination

Calcium channel blocker

Felodipine

AUC of felodipine lowered by 28% – similar effect anticipated with other dihydropyridine calcium channel blockers

Verapamil

Reduced oxcarbazepine MHD metabolite plasma level (by about 20%) – mechanism unknown

Diuretic

Furosemide

Increased risk of hyponatremia with oxcarbazepine

Hormone

Oral contraceptives

Increased metabolism of ethinyl estradiol and levonorgestrel through induction of CYP3A4

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

DRUGS INTERACTING WITH TOPIRAMATE

Class of Drug

Example

Interaction Effects

Alcohol

Increased sedation, disorientation

Antacid

Excessive use may increase renal stone (calcium phosphate) formation

Anticonvulsant

Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone

Lamotrigine

Valproate

Decreased plasma levels of topiramate reported; by 40% with carbamazepine and 48% with phenytoin Increased plasma level of carbamazepine (by 20%) and of phenytoin

Decreased plasma level of lamotrigine

Case reports of delirium and elevated ammonia levels; decreased clearance of topiramate by 25%

Biguanide

Metformin

May increase risk of lactic acidosis as topiramate may decrease sodium bicarbonate levels

Carbonic anhydrase inhibitor

Acetazolamide, zonisamide

Excessive use may increase renal stone (calcium phosphate) formation and/or hyperthermia

Cardiac glycoside

Digoxin

Decreased levels of digoxin by 12%

Diuretic

Furosemide, hydrochlorothiazide

Increased risk for hypokalemia

Hormone

Oral contraceptive

Possibly decreased levels of estrogen, resulting in decreased ef cacy of oral contraceptive

Comparison of Anticonvulsants

Carbamazepine

Gabapentin

Lamotrigine

Oxcarbazepine

Topiramate

Valproate

General Comments

Positive predictors of re- sponse include: Non-classic or secondary mania, early age at onset, negative family history of mood dis- order, and patients with neurological abnormalities Less response noted in pa- tients with severe mania, dysphoric mania, and rapid cycling disorder

Not effective as a mood stabilizer

Not recommended for monotherapy in any phase of bipolar disorder

More effective in bipolar depression; suggested to have antidepressant properties

First-line agent for treatment of bipolar depression, acute and maintenance (limited ef cacy in preventing mania): Does not induce switches to hypomania or mania

Prophylaxis of rapid cycling and bipolar II disorder

Pharmacological activ- ity is exerted primarily through the 10-mono hy- droxy metabolite (MHD) of oxcarbazepine

Lower potential for se- rious adverse effects

and drug interactions compared to carba- mazepine. Third-line option in bipolar disorder as monotherapy for acute mania and as adjunctive therapy in maintenance Positive effects on verbal and visual memory, visu- ospatial function, naming ability, and frontal execu- tive function in patients with epilepsy

Not recommended as monotherapy in any phase of bipolar disorder but may be useful as adjunctive ther- apy in maintenance

Positive predictors of response include: Pure mania, mixed or dysphoric mania, and patients with secondary or rapid cycling disorder Recommended if multiple prior episodes, predominant irritable or dysphoric mood, co- morbid substance abuse, or head trauma Good response in adolescents

Less response noted in patients with comorbid personality disorder, severe mania, and those previously treated with antidepressants or stimulants

May be more effective in treating and prevent- ing manic and mixed episodes

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 279 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Mood Stabilizers

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Comparison of Anticonvulsants (cont.)

Carbamazepine

Gabapentin

Lamotrigine

Oxcarbazepine

Topiramate

Valproate

Pharmacology

Anticonvulsant, anti-kin- dling, and GABA-ergic activity

Blocks voltage-dependent sodium channels

May also act on other ion channels for calcium and potassium

Anticonvulsant, anti-kindling, and GABA-ergic activity Blocks voltage- dependent sodium channels and calcium channels

Inhibits excita- tory amino acids (glutamate)

Anticonvulsant and GABA-ergic activity Blocks voltage- dependent sodium channels and calcium channels

Inhibits excitatory amino acids (glutamate)

MHD metabolite has anti- convulsant, anti-kindling, and GABA-ergic activity Blocks voltage-dependent sodium channels and calcium channels

Anticonvulsant, anti- kindling, and GABA-ergic activity

Inhibits excitatory amino acids (glutamate)

Inhibits carbonic anhydrase and blocks voltage-depen- dent sodium channels and calcium channels

Anticonvulsant, anti-kindling, and GABA-ergic activity

Indirectly blunts excitatory activity of glutamin- ergic system

Blocks calcium channels

Indirectly blocks voltage-dependent sodium channels

Increases serotonergic function

Dosing

Renal impairment

Begin at 200 mg daily

and increase by 100 mg twice weekly, until either side effects limit dose, or therapeutic plasma level reached (auto-induction of metabolism complete by week 5 of stable dosing) Extended release: Begin at 200 mg bid and increase by200mgdailyuptoa maximum of 1600 mg/day (capsules can be opened and sprinkled on food) Dose range: 300–

1600 mg/day in single

or divided dose

No change

Begin at 300– 400 mg/day and increase by 300– 400mgaday

Usual dose: 900– 1800 mg/day Anxiety and neuro- pathic pain: Up to 3600 mg/day

Dose range: 900– 3600 mg/day given as tid dosing (divide dosing TID due to saturable absorption) Decrease dose if CrCl less than 60 mL/min (see Precautions,

p. 268)

Rapid titration asso- ciated with serious rash. Intial dose based on concomitant drugs prescribed; follow titra- tion set out in product monograph Antidepressant dose: 200 mg/day

Dose range: 100– 500 mg/day given in single or divided dose

Reduced clearance; half- life prolonged 63% in renal failure

Begin at 150–300 mg/ day and increase by 150mgq2weeks When switching from carbamazepine, the equivalent dose is 50% higher

Dose range: 600– 1200 mg/day (divided doses)

Decrease dose by 50% if CrCl less than 30 mL/min. Start at 300mg and in- crease slowly

Begin at 25–50 mg/day and increase by 25–50 mg every 4–7 days up to 500 mg/day (a low initial dose and grad- ual increases minimize cognitive and behavioral side effects)

Acute dose range: 200– 600 mg/day Maintenance range: 50– 400 mg/day

Moderate: Clearance re- duced by 42%

Severe: Clearance reduced by 54%

If CrCl less than

70 mL/min/1.73 m2 : Admin- ister 50% dose and titrate more slowly

Begin at 250 mg bid and increase dose grad- ually, until either side effects limit dose, or therapeutic plasma level reached

Once daily dosing has been used

Loading dose strategy:

Oral: Give stat dose of 20 mg/kg, then 12 h later initiate bid dosing at 10 mg/kg bid

IV: 1200–1800 mg/day over 3 days

ER: Only available in the USA, usually given once daily. Conversion from regular formula- tions may require 8–20% increase in total daily dose to maintain similar serum concentrations

Dose range: 750–3000 mg/day in single or divided dose

Maximum: 60 mg/kg/day

Decreased protein binding may double val- proate level in renal impairment

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Carbamazepine

Gabapentin

Lamotrigine

Oxcarbazepine

Topiramate

Valproate

Hepatic impairment

Reduced clearance – plasma concentrations increased by approximately 30%

Do not use in active liver disease

Not hepatically metabolized

Reduce initial and main- tenance doses by 25% in mild to moderate im- pairment and 50–75% in severe impairment

No dose adjustments required in mild to moderate impairment

Reduced clearance – plasma concentrations increased by approximately 30%; initiate same dose and titrate ac- cording to clinical outcome

See hepatic adverse effects (p. 283) and Precau- tions (p. 267)

Hepatic disease is also associated with de- creased albumin concentrations and 2- to 2.6-fold increase in unbound fraction. Free concentrations of valproate may be elevated while total concentrations appear normal. Use is contraindicated in severe impairment

Recommended plasma level

17–54 μmol/L

(4–12 micrograms/mL)

2–20mg/L reported for epilepsy (relation- ship between clinical ef cacy and plasma concentration not clearly established)

2.5–15mg/L reported for epilepsy (relation- ship between clinical ef cacy and plasma con- centration not clearly established)

15–35 micrograms/mL (MHD metabolite)

5–20mg/L reported for epilepsy[7] (relationship between clinical ef cacy and plasma concentration not clearly established)

350–800 μmol/L (50–115 micrograms/mL). The higher end of the dosing range is recom- mended for acute mania

Pharmacokinetics

Bioavailability Peak plasma level

Protein binding Half-life

Metabolizing enzymes

Metabolism effects

75–85% 1–6 h

75–90%

15–35 h (acute use); 10–20 h (chronic use) – stimulates own metabolism

CYP1A2, 3A4(m), 2C8, 2C9; P-gp

Inducer of CYP1A2(p), 3A4(p), 2C8(p), 2C9(p), 2C19(p), 2B6(p), 3A4(p) and UGT1A4

Induces own metabolism (auto-induction)

Inducer of P-gp

Approx. 60% (dose dependent; higher with qid dosing) 2–3 h

Minimal 5–7 h

Not metabolized – eliminated by renal excretion

–

100%

1–5 h (rate may be reduced by food)

55%

33 h mean (acute use) 26 h mean (chronic use)

Metabolized primar- ily by glucuronic acid conjugation; also by UGT1A4, 2B7

–

> 95%

1–3 h (parent)

4–12 h (active MHD metabolite) and 2–4 h at steady state

40% (MHD)

Parent: 1–5 h

MHD metabolite: 7–20 h

Rapidly metabolized by cytosolic enzymes to active metabolite MHD

Moderate inducer of CYP3A4

Inhibitor of CYP2C19(w) and UGT1A4 (does not induce own metabolism)

80%

2–4 h (delayed by food)

15–41% 19–23 h

P-gp; 70% eliminated unchanged in urine

Weak inhibitor of CYP2C19; weak inducer of 3A4

78–90%

Oral valproic acid: 1–4 h (may be delayed by food)

Divalproex and extended-release: 3–8 h

60–95% (concentration dependent); increased by low-fat diets. Decreased in elderly, or hep- atic or renal impairment

5–20 h

CYP2C9; UGT1A6, 1A9, 2B7

Inhibitor of CYP2D6(w), 2C9, 2C19; UGT2B7(p), 2B15, 3A4(w)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 281 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Mood Stabilizers

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Comparison of Anticonvulsants (cont.)

Carbamazepine

Gabapentin

Lamotrigine

Oxcarbazepine

Topiramate

Valproate

Adverse Effects

CNS

Anticholinergic

Gastrointestinal

Cardiovascular

Sedation (11%), cognitive blunting, confusion (higher doses)

Agitation, restlessness, irri- tability, insomnia

May exacerbate schizophre- nia on withdrawal

Headache

Tremors, ataxia (up to 50%), paresthesias (3%), acute dystonic reactions, chronic dyskinesias

Blurred vision (6%), mydriasis, cycloplegia, oph- thalmoplegia, dry mouth, slurred speech Constipation

Nausea (4%)

Dry mouth

Dizziness

Vasculitis

Cardiac conduction disor- ders – rare

Sedation (19%), fa- tigue (11%), abnormal thinking, amnesia

Nervousness, anxiety, hostility

Rare switches to hypo- mania/mania

Cases of depression

Tremors (7%), ataxia (13%), incoordination, dysarthria, myalgia Case report of acute dystonia; asterixis Dry mouth or throat (2%)

Constipation

Nausea (4%), diarrhea (6%), dyspepsia (2%)

Dizziness (17%), hypotension Occasionally hyper- tension

Peripheral edema

Sedation (> 10%), asthenia, cognitive blunting, “spaced-out” feeling

Agitation, activation, irritability, insomnia Switches to hypomania/

mania

Headache (> 25%) Tremors, ataxia (22%), incoordination (14%), myalgia, arthralgia Case report of dystonia

Blurred vision Constipation

Dry mouth (> 5%)

Nausea (19%), vomiting (9%), diarrhea (6%) Rarely esophagitis

Breathlessness, dizzi- ness (38%) Conduction changes (prolongation of PR interval)

Sedation (19%), lethargy

Headache (31%) Ataxia (> 25%), gait disturbances, tremor

Blurred vision

Nausea (22%), vomiting (15%)

Dizziness (28%), periph- eral edema, hypotension

Sedation (6–15%), lethargy, fatigue (8–15%)

De cits in word nding, concentration, and memory (dose dependent, 1–11%) Anxiety, agitation, insomnia Increased panic attacks, worsening of depression or psychosis

Headache

Tremors, ataxia; paresthe- sias (19–51%)

Blurred vision, sweating Acute angle closure reported (glaucoma)

Nausea (4–13%), anorexia (4–15%)

Change in taste of carbon- ated beverages

Dizziness common

Sedation (> 10%), lethargy, behavior changes/deterioration, cognitive blunting, encephalopathy

Hyperactivity, aggression

Case of delirium (following loading-dose strat- egy)

Rare cases of psychosis

Headache (3%)

Tremors (10% adults; 15% children – tend to

be rhythmic, rapid, symmetrical, and most prominent in the upper extremities), ataxia, dysarthria, incoordination

Association between prior use and dementia

Nausea common, vomiting

Rarely dizziness

Vasculitis

Case report of hyperkalemia

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Carbamazepine

Gabapentin

Lamotrigine

Oxcarbazepine

Topiramate

Valproate

Dermatological

Hematologic

Hepatic

Rash (10–15%) – severe der- matological reactions may signify impending blood dyscrasias

Hair loss (6%) Photosensitivity reactions Rarely: Fixed drug erup- tions, lichenoid-like reactions, bullous reac- tions, exfoliative dermatitis Hypersensitivity syndrome – rare; with fever, skin eruptions, and internal organ involvement

Transitory leukopenia (10%), persistent leukope- nia (2%)

Rarely, eosinophilia, aplastic anemia, throm- bocytopenia, purpura, and agranulocytosis

Transient enzyme elevation (5–15%) – increased GGT due to hepatic enzyme in- duction common but not often clinically relevant – evaluate for hepatotoxicity if elevation > 3 times nor- mal

Rarely, hepatocellular and cholestatic jaundice, gran- ulomatous hepatitis, and severe hepatic necrosis

Pruritus (1%), rash (1%)

Leukopenia (1%), pur- pura

Case reports of abnor- mal liver function

Rash (up to 10%); in 2–3% require drug discontinuation – risk of severe rash increased with rapid dose titra- tion, in children, and in combination with val- proate

Stevens-Johnson syn- drome in 1–2% of children and 0.1% of adults (usually within rst 8 weeks of therapy) Rarely, erythema multi- forme, hypersensitivity syndrome Photosensitivity reac- tions

Neutropenia

Rarely, hematemesis, hemolytic anemia, thrombocytopenia, pancytopenia, aplastic anemia

Rare

Rash less common than with carbamazepine; 25– 30% of patients are cross- sensitive Stevens-Johnson syn- drome and toxic epidermal necrolysis reported in adults and children

Rare

Case report of increasing LFT in patient with ele- vated levels at baseline

Rash

Purpura

Cases of severe liver damage

Rash

Hair loss (up to 12% – higher incidence with higher doses); changes in texture or color of hair

Case reports of nail pigmentation

Rare cases of Stevens-Johnson syndrome (in- creased risk in combination with lamotrigine), toxic epidermal necrolysis, lupus, erythema multiforme, or skin pigmentation

Reversible thrombocytopenia – may be related to high plasma levels; rare episodes of bleeding Macrocytic anemia, coagulopathies

Case of pancytopenia (following loading-dose strategy)

Asymptomatic hepatic transaminase elevation (44%)

Cases of severe liver toxicity (all patients were also taking lamotrigine)

Steatosis or nonalcoholic fatty liver disease (a symptom of insulin resistance)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 283 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Mood Stabilizers

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Comparison of Anticonvulsants (cont.)

Carbamazepine

Gabapentin

Lamotrigine

Oxcarbazepine

Topiramate

Valproate

Endocrine

Hyponatremia

Menstrual disturbances in females (up to 45%) Decreased libido in males Elevation of total choles- terol (primarily HDL)

Can lower thyroxine levels and TSH response to TRH Polycystic ovaries reported in up to 22% of females; Hyperandrogenism in up to 17%

Weight gain – may be inde- pendent of or secondary to peripheral edema/SIADH Occasional weight loss Hyponatremia and water intoxication (4–12%), more common in the elderly and with higher plasma levels

Weight gain common with higher doses

Menstrual disturbances, dysmenorrhea, vaginitis No weight gain

Decreased T4 levels re- ported with normal T3 and TSH

Hyponatremia (29%), higher risk in the elderly, with diuretics, and with other anti-epileptic drug use

Decreased sweating, hy- perthermia resulting in hospitalization and some deaths; more common in children – caution with anticholinergic agents and carbonic anhydrase inhibitors

Anorexia; weight loss (4–13%)

Hyponatremia (up to 25%)

Menstrual disturbances (up to 60%) including prolonged cycles, oligomenorrhea, amenor- rhea, polycystic ovaries (up to 67%) – higher incidence in obese women

In females: Hyperandrogenism (increased testosterone in 33%), android obesity (in up to 53%), hirsutism, hyperinsulinemia Decreased levels of HDL, low HDL/cholesterol ratio, increased triglyceride levels

Weight gain (59%) – mean gain of up to 21 kg reported; more common in females and with high plasma levels; may be associated with fea- tures of insulin resistance

Weight loss (5%)

Ocular

Diplopia (16%), nystagmus (up to 50%), visual halluci- nations, lens abnormalities 2 cases of pigmentary retinopathy

Diplopia (6%), nystag- mus (8%), amblyopia (4%)

Diplopia (28%) nystag- mus, amblyopia

Diplopia (12%), nystag- mus

Diplopia, nystagmus, visual eld defects

Cases of acute myopia and secondary angle closure glaucoma

In patients under 50, 5-fold increased risk of angle closure glaucoma among current users of topiramate (RR = 1.23 [95% CI, 1.09– 1.40]); new users (RR = 1.54 [95% CI, 1.09–2.17])

Diplopia, nystagmus, asterixis (spots before the eyes)

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Carbamazepine

Gabapentin

Lamotrigine

Oxcarbazepine

Topiramate

Valproate

Osteoporosis

Other

Can decrease vitamin D levels by increasing its metabolism, resulting in increased bone resorption, osteomalacia, osteoporo- sis, and fractures [bone density evaluation, sup- plement with calcium and vitamin D]

Rarely: Acute renal failure, pancreatitis, splenomegaly, lymphadenopathy, systemic lupus erythemato- sus, and serum sickness

Rhinitis (4%), pharyn- gitis (3%)

Rhinitis, pharyngitis, u-like syndrome (7%) Rarely: Apnea, pancre- atitis

Con icting reports on effects on bone mineral density

Upper respiratory tract infection (10%)

Osteomalacia and/or osteo- porosis

Nephrolithiasis (renal stone formation) in up to 1.5% with chronic use

Decrease in sodium bicar- bonate (in up to 30% of pa- tients) usually mild but can be signi cant – see Precau- tions p. 268

Metabolic acidosis (may increase risk for nephroli- thiasis or nephrocalcinosis Epistaxis Hyperammonemia and en- cephalopathy – rare reports Upper respiratory tract in- fection (13-26%)

Increased bone resorption with osteoporosis, osteopenia [bone density evaluation, supple- ment with calcium and vitamin D]

Rarely osteomalacia

Gingival hyperplasia

Carnitine de ciency

Rarely: Cholecystitis, pancreatitis and serum sickness

Elevated ammonia levels common in valproate- treated patients, with risk of hyperammonemia encephalopathy. Consider in patients showing signs of lethargy, mental status changes

Use in Pregnancy♢

Avoid in rst trimester (level A evidence)[8]. If necessary, use lowest amount possible in divided doses. Monitor drug levels throughout pregnancy, maternal α fetoprotein around week 16, and do fetal ultrasound around week 20

Concentration of drug in cord blood equals that in maternal serum

Caution: Overall incidence of major malformations is 5.7%, with lower birth rates reported

Crosses placenta Fetotoxicity reported in animal studies; risk to humans is currently unknown

Crosses placenta; levels comparable to those

in maternal plasma; considered a potential maintenance therapy option for pregnant women with mood disorders (level B evidence)[8]

3.2% risk of malforma- tions in rst trimester; risk noted to increase to 5.4% when total daily dose > 200 mg

Crosses placenta; terato- genic effects reported in animals; likely to cause teratogenic ef- fects in humans (folic acid supplementation recommended)

Data on a limited number of pregnancies report cleft palate and other malformations. Case report of renal and car- diac malformations with hyponatremia and with- drawal symptoms at birth

Fetotoxicity reported in ani- mal studies and evidence of increased risk of oral clefts NA Antiepileptic Drug Pregnancy Registry data suggests topiramate monotherapy in rst trimester is associated with a 1.4% prevalence of oral clefts compared to 0.38– 0.55% for infants exposed to other antiepileptic drugs

AVOID, especially in rst trimester (level A evidence)[8]

Incidence of malformations is 11.1% – related to dose and drug plasma level. Fetal serum con- centrations are 1.4 times that of the mother; half-life prolonged in infant

If absolutely necessary, limit use to less than 1000 mg/day in 3 or more divided doses. Monitor plasma levels throughout pregnancy, maternal α fetoprotein around week 16, and do fetal ultrasound around week 20

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 285 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Mood Stabilizers

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Comparison of Anticonvulsants (cont.)

Carbamazepine

Gabapentin

Lamotrigine

Oxcarbazepine

Topiramate

Valproate

Breast Milk

Risk of spina bi da up to 1%, congenital heart de- fects 2.9%

One prospective study reported craniofacial de- fects in 11%, ngernail hyperplasia in 26%, and developmental delays in 20% of children exposed prenatally

May cause vitamin K de- ciency during latter half of gestation, resulting in bleeding [vitamin K and folic acid supplementation recommended]

Clearance increased 2-fold during pregnancy; dose may need to be increased by 100%

American Academy of Pediatrics considers car- bamazepine compatible with breastfeeding

Breast milk contains 7–95% of maternal drug concen- tration; infant serum level is 6–65% of mother’s Educate mother about signs and symptoms of hepatic dysfunction and CNS effects of drug in the infant

Monitor liver enzymes and CBC of infant and mother No long-term cognitive or behavioral effects reported in infant

Gabapentin is ex- creted in breast milk. No long-term cog- nitive or behavioral effects reported in infant but data is limited

Increased risk of cleft lip and/or cleft palate when used in rst trimester (2–5%) Decreases fetal fo-

late levels [folic acid supplementation rec- ommended] Lamotrigine metabolism appears to be induced during preg- nancy (decreased levels) and plasma levels in- crease rapidly after delivery

Excreted in breast milk; the milk/plasma ratio is about 0.6

Infant serum levels are up to 50% of those of mother

Effect on infant un- known but may be

of concern – monitor serum levels in infant and for sedation and rash; consider risk of life-threatening rash in infant. . Breast feeding not recommended

May cause vitamin K de- ciency during latter half of gestation, resulting in bleeding [vitamin K and folic acid supplementa- tion recommended]

Oxcarbazepine and active metabolite are excreted into breast milk at levels up to 50% of those in ma- ternal plasma

Effects on infant un- known

Monitor for poor suck- ling, vomiting, and sedation. Breast feeding not recommended

Hypospadias in male infants [folic acid supplementation recommended] and anoma- lies involving various body systems

Breastfeeding is not recom- mended due to possible psychomotor slowing

and somnolence in infant; monitor infant for signs of toxicity including changes in alertness, behavior, and feeding habits

Risk of spina bi da 1–2%, neural tube defects up to 5%, neurological dysfunction and de- velopmental de cits seen in up to 71% (FDA warning of lower cognitive test scores in children June 2011); musculoskeletal, cardio- vascular, pulmonary, craniofacial, genital, and skin defects also reported

May cause vitamin K de ciency during lat-

ter half of gestation, resulting in bleeding [vitamin K and folic acid supplementation rec- ommended]

Infants may be at higher risk for hypoglycemia Total plasma valproate concentration de- creased during pregnancy as a result of increased volume of distribution and clearance; plasma protein binding decreased

American Academy of Pediatrics considers val- proate compatible with breastfeeding

Infant plasma level of valproate is up to 40% of that of mother; half-life in infants is signi – cantly longer than in adults

Educate mother about the signs and symptoms of hepatic dysfunction and those of hematolog- ical abnormalities in the infant

Monitor liver enzymes and CBC of infant and mother

No long-term cognitive or behavioral effects reported in infant

(m) moderate, (p) potent, weak; ♢ See p. 439 for further information on drug use in pregnancy and effects on breast milk

P-gp = P-glycoprotein [a transporter of hydrophobic substances across extra- and intra-cellular membranes that include the intestinal lumen and the blood-brain barrier]; UGT = uridine diphosphate glucuronosyl transferase [involved in Phase II reactions (conjugation)]

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Frequency of Adverse Reactions to Mood Stabilizers at Therapeutic Doses

Lithium

Carbamazepine

Gabapentin

Lamotrigine

Oxcarbazepine

Topiramate

< 2%(a) > 2% > 10% > 30%(a) < 2%

> 10% > 2% > 2% > 10% < 2%

> 10% > 10% > 2% > 2% > 2%

> 10% > 30% > 2% > 10% > 2%

> 10% > 10% > 2% > 10% > 2%

> 10%(b) > 10% > 2%(b) > 10% > 10%

< 2%(a)

> 10%

> 2%

–

< 2%(a) > 30%(a) –

–

> 10% > 10% > 30% > 2% > 10%

> 30% > 10% > 2% < 2% > 10%

> 2% > 2% > 10% > 2% > 10%

> 10% > 2% > 10% > 2% > 10%

> 10%(b) > 2%(b) > 2% > 10% > 2%

> 2%(a)

> 2%

> 10%

> 2%

> 10%

> 2%

< 2%

> 2%

–

> 30% > 10%(a) > 30% < 2%

> 10% > 2% > 2% < 2%

> 10% > 2% < 2% > 2%

> 10% > 2% > 2% < 2%

> 10% > 10% > 30% > 2%

> 2% > 2% –

> 10%(b)

> 10% > 10% –

> 30% > 30%

> 2% > 30% > 10% < 2% > 2%

–

> 2% –

< 1% –

< 2% < 2% ?

< 2%

> 10% > 30% > 30% < 2% –

< 2% –

–

> 10%(d)

> 10%(e)

> 2%

< 2%

> 2%

< 2%

–

> 2%

–

< 2% > 10% –

> 10% < 2% > 2%

< 2% –

< 2%

< 2% < 2% –

< 2% < 2% > 30%(b)

< 2% –

–

> 10%

< 2%

> 30%(b)

–

Reaction

CNS

Drowsiness, sedation

Headache

Cognitive blunting, memory impairment Weakness, fatigue

Insomnia, agitation

Neurological

Incoordination

Dizziness

Ataxia

Tremor

Paresthesias

Diplopia

Anticholinergic

Blurred vision

Cardiovascular

ECG changes(c)

Gastrointestinal

Nausea, vomiting

Diarrhea

Weight gain

Weight loss

Endocrine

Hair loss, thinning

Menstrual disturbances

Polycystic ovary syndrome Hypothyroidism

Polyuria, polydipsia

Skin reactions, Rash

Sexual dysfunction

Blood dyscrasias

Transient leukopenia

Leukocytosis

Thrombocytopenia

Hepatic

Transient enzyme elevation(f)

Valproate

> 10% >2% <2% > 10% >2%

<2% > 10% > 10% >2% <2% >2%

<2% –

>2% –

> 10%(b) <2%

<2% ? >2% –

– <2% <2%

<2% –

–

<2%

(a) Higher incidence and more pronounced symptoms with higher serum lithium concentration; may indicate early toxicity – monitor level

attened T waves, and increased U wave amplitude; (d) Worsening of psoriasis reported; (e) May be rst sign of impending blood dyscrasia; (f) Evaluate for hepatotoxicity if elevation more than 3 times normal

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 287 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

(b) Greater with higher doses;

Mood Stabilizers

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Mood Stabilizers (cont.)

Further Reading

References

1 Wingo AP, Wingo TS, Harvey PD, et al. Effects of lithium on cognitive performance: A meta-analysis. J Clin Psychiatry. 2009;70(11):1588–1597. doi:10.4088/JCP.08r04972

2 Grandjean EM, Aubry JM. Lithium: Updated human knowledge using an evidence-based approach. Part I: Clinical ef cacy in bipolar disorder. CNS Drugs. 2009;23(3):225–240. doi:10.2165/

00023210-200923030-00004

3 Grandjean EM, Aubry JM. Lithium: Updated human knowledge using an evidence-based approach. Part II: Clinical pharmacology and therapeutic monitoring. CNS Drugs. 2009;23(4):331–

349. doi:10.2165/00023210-200923040-00005

4 Grandjean EM, Aubry JM. Lithium: Updated human knowledge using an evidence-based approach. Part III: Clinical safety. CNS Drugs. 2009;23(5):397–418.

doi:10.2165/00023210-200923050-00004.

5 McKnight RF, Adida M, Budge, K, et al. Lithium toxicity pro le: A systematic review and meta-analysis. Lancet. 2012; 379(9817):721–728. doi:10.1016/S0140-6736(11)61516-X

6 Elbe D, Black TR, McGrane IR, et al. Clinical handbook of psychotropic drugs for children and adolescents. (4th ed.). Boston, MA: Hogrefe Publishing, 2019.

7 Patsalos PN, Berry DJ, Bourgeois BF, et al. Antiepileptic drugs – best practice guidelines for therapeutic drug monitoring: A position paper by the subcommission on therapeutic drug

monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia. 2008;49(7):1239–1276. doi:10.1111/j.1528-1167.2008.01561.x

8 ACOG Committee on Practice Bulletins – Obstetrics. ACOG Practice Bulletin: Clinical management guidelines for obstetrician-gynecologists number 92, April 2008 (replaces practice

bulletin number 87, November 2007). Use of psychiatric medications during pregnancy and lactation. Obstet Gynecol 2008;111(4):1001–1020. doi:10.1097/AOG.0b013e31816fd910

Additional Suggested Reading

• BauerMS,MillerCJ,LiM,etal.Apopulation-basedstudyofthecomparativeeffectivenessofsecond-generationantipsychoticsvsolderantimanicagentsinbipolardisorder.Bipolar Disord. 2016;18(6):481–489. doi:10.1111/bdi.12425

• BerlinRK,ButlerPM,PerloffMD.Gabapentintherapyinpsychiatricdisorders:Asystematicreview.PrimCareCompanionCNSDisord.2015;17(5).doi:10.4088/PCC.15r01821

• BowdenCL,MintzJ,TohenM.Multi-stateoutcomeanalysisoftreatments(MOAT):Applicationofanewapproachtoevaluateoutcomesinlongitudinalstudiesofbipolardisorder.Mol

Psychiatry. 2016; 21(2):237–242. doi:10.1038/mp.2015.21

• CohenLS.Treatmentofbipolardisorderduringpregnancy.JClinPsychiatry.2007;68(Suppl.9):4–9.

• Feinn R, Curtis B, Kranzler HR. Balancing risk and bene t in heavy drinkers treated with topiramate: Implications for personalized care. J Clin Psychiatry. 2016;77(3):e278–e282. doi:

10.4088/JCP.15m10053

• SmithRV,HavensJR,WalshSL.Gabapentinmisuse,abuseanddiversion:Asystematicreview.Addiction.2016;111(7):1160–1174.doi:10.1111/add.13324

• StoweZN.Theuseofmoodstabilizersduringbreastfeeding.JClinPsychiatry.2007;68(Suppl.9):22–28.

• YathamLN,KennedySH,ParikhSV,etal.CanadianNetworkforMoodandAnxietyTreatments(CANMAT)andInternationalSocietyforBipolarDisorders(ISBD)collaborativeupdateof

CANMAT guidelines for the management of patients with bipolar disorder: Update 2013. Bipolar Disord. 2013;15(1):1–44. doi:10.1111/bdi.12025

• ZhangL,LiH,LiS,etal.Reproductiveandmetabolicabnormalitiesinwomentakingvalproateforbipolardisorder:Ameta-analysis.EurJObstetGynecolReprodBiol.2016;202:26–31.

doi:10.1016/j.ejogrb.2016.04.038

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Classi cation

DRUGS FOR ADHD

• DrugsforADHDcanbeclassi edasfollows:

Chemical Class

Agent(A)

Page

Psychostimulant

Amphetamine and related drugs (e.g., lisdexamfetamine)

See p. 289

Methylphenidate, dexmethylphenidate(B)

Selective norepinephrine reuptake inhibitor

Atomoxetine

See p. 299

α2 agonist

Clonidine

See p. 307

Guanfacine

Antidepressant

Bupropion

Venlafaxine, desvenlafaxine

See p. 17 See p. 23

Tricyclic agents

See p. 50

Dopaminergic agent

Moda nil Armoda nil

See p. 398

(A) Generic preparations may be available,

Product Availability∗

(B) Not marketed in Canada,

Psychostimulants

Generic Name

Trade Name(A)

Dosage Forms and Strengths

Methylphenidate (MPH)

ACT Methylphenidate ER(C), Apo-Methylphenidate ER(C), PMS-Methylphenidate ER(C), Teva-Methylphenidate ER-C(C) Aptensio XR(B)

Biphentin(C)

Extended-release tablets: 18 mg, 27 mg, 36 mg, 54 mg

Extended-release capsules: 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg Controlled-release capsules: 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 80 mg

Concerta

Cotempla XR-ODT(B)

Extended-release tablets: 18 mg, 27 mg, 36 mg, 54 mg Extended-release orally disintegrating tablets: 8.6 mg, 17.3 mg, 25.9 mg

Foquest(C) Jornay PM(B) Metadate CD(B)

Controlled-release capsules: 25 mg, 35 mg, 45 mg, 55 mg, 70 mg, 85 mg, 100 mg Delayed-release/Extended-release capsules: 20 mg, 40 mg, 60 mg, 80 mg, 100 mg Extended-release capsules: 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg

Metadate ER(B), Ritalin SR(C) Methylin(B)

Sustained-release tablets: 20 mg

Oral solution: 5 mg/5 mL, 10 mg/5 mL

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 289 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Drugs for ADHD

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Psychostimulants (cont.)

Trade Name(A)

Dosage Forms and Strengths

Methylin ER(B) Quillichew ER(B)

Sustained-release tablets: 10 mg, 20 mg Extended-release chewable tablets: 20 mg, 30 mg, 40 mg

Quillivant XR(B) Ritalin

Ritalin LA(B)

Extended-release suspension: 5 mg/mL (after reconstitution) Tablets: 5 mg, 10 mg, 20 mg

Extended-release capsules: 10 mg, 20 mg, 30 mg, 40 mg

Daytrana

Transdermal patch: 10 mg/9 h, 15 mg/9 h, 20 mg/9 h, 30 mg/9 h

Focalin Focalin XR

Tablets: 2.5 mg, 5 mg, 10 mg

Extended-release capsules 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg

Adzenys ER(B) Adzenys XR-ODT(B) Dyanavel XR(B)

Extended-release suspension: 1.25 mg/mL

Extended-release orally disintegrating tablets: 3.1 mg, 6.3 mg, 9.4 mg, 12.5 mg, 15.7 mg, 18.8 mg Extended-release suspension: 2.5 mg/mL

Evekeo(B)

Tablets: 5 mg, 10 mg

Adderall(B) Adderall XR

Tablets(B): 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 30 mg Extended-release capsules: 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg

Mydayis(B)

Extended-release capsules: 12.5 mg, 25 mg, 37.5 mg, 50 mg

Dexedrine Dexedrine Spansules

Tablets: 5 mg, 10 mg(B)

Elixir: 5 mg/5 mL(B)

Extended-release capsules: 5 mg(B), 10 mg, 15 mg

Zenzedi(B)

Tablets: 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30 mg

Vyvanse

Capsules: 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg(B)

Desoxyn

Tablets: 5 mg

Generic Name

Methylphenidate transdermal patch(B) Dexmethylphenidate(B)

Amphetamine

Dextroamphetamine/amphetamine salts (mixed amphetamine salts)

Dextroamphetamine

Lisdexamfetamine Methamphetamine(B) (desoxyephedrine)

∗ Refer to Health Canada’s Drug Product Database or the FDA’s Drugs@FDA for the most current availability information. (A) Generic preparations may be available,

(B) Not marketed in Canada,

Indications‡

( approved)

Attention-de cit/hyperactivity disorder (ADHD) Parkinson’s disease

Narcolepsy

Obesity (amphetamine, dextroamphetamine – USA only) Binge-eating disorder (lisdexamfetamine – USA only)

• Treatment-resistantdepression

• Majordepressioninmedicallyorsurgicallyillpatientsorintheelderly

• Augmentationofcyclicantidepressants,SSRIs,andRIMA

• ADHDinpartialremission(ADHD-PR)inadults

• Chronicfatiguesyndrome,neurasthenia

• Schizophrenia:Negativesymptoms;someimprovementnotedincognitivede cits,mood,andconcentrationwithlowdosesofdextroamphetamine

‡ Indications listed here do not necessarily apply to all psychostimulants or all countries. Please refer to a country’s regulatory database (e.g., US Food and Drug Administration, Health Canada Drug Product Database) for the most current availability information and indications

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

General Comments

• AIDS-relatedneuropsychiatricimpairment:Improvesfatigueandcognition

• Decreasinganger,irritability,andaggressioninbrain-injuredpatients,oppositionalde antdisorder,conductdisorder,andADHD–positiveresults

with methylphenidate

• Inattention and hyperactivity in autism spectrum disorder and intellectual disability – controlled studies suggest methylphenidate has modest

e cacy; adverse e ects may be more problematic in this population

• All psychostimulants, when dosed adequately, are considered to be equally e ective at reducing symptoms of inattention, hyperactivity, and impulsivity

• General response occurs within the rst week; response seen in approximately 75% of children and 25–78% of adults with ADHD (although individuals may respond better to selective drugs)

• Anuntreatedpsychiatricdisorder(moodoranxietydisorder)maydiminishresponsetostimulantsordecreasetheabilitytotoleratethemedication

• Psychostimulantssuggestedtosuppressphysicalandverbalaggressionandreducenegativeorantisocialinteractions

• SeePrecautions(p.295)andContraindications(p.295)regardingpatientrisks

• Carefulmonitoringnecessarywhenusingshort-actingagentsinpatientswithapropensitytoabusedrugsoralcoholorwhomaybedivertingfor

street use; when given to individuals with ADHD, they may help to decrease the risk of developing substance abuse disorder later in life

• Lisdexamfetamine is a prodrug in which d-amphetamine is bonded to L-lysine. Considered to have less potential for abuse and diversion than

short-acting stimulants[1]

• Mechanism of action in treating ADHD is not well understood; methylphenidate blocks the reuptake of norepinephrine (NE) and dopamine (DA) into presynaptic nerve endings. In addition to blocking NE and DA reuptake, amphetamines also promote the release of DA and NE from presynaptic neurons. Increases in DA are suggested to improve attention, decrease distractibility, and modulate motivation, thus improving performance

• ReleaseofDAandNEinsubcorticallimbicareas(e.g.,nucleusaccumbens)proposedasmechanismresponsibleforabusepotentialofthesedrugs

• Seechartp.302

• Seechartp.303

• Treatment is often started at low doses (e.g., 5–10 mg of methylphenidate) in school-aged children and gradually increased over several days in

5 mg increments; initial improvement noted may plateau after 2–3 weeks of continuous use – this does not imply tolerance; patients, caregivers,

and families should compare the plateau to baseline

• Stimulante ectisnotalwaysassociatedwithdose;methylphenidatedosesabove1mg/kg/daymaynotresultinincreasedresponse,however,side

e ects can increase. Doses above 1 mg/kg/day may be tried in those who tolerate the stimulant and have had a moderate response. Some patients

may be short-duration responders or high-dose responders[2]

• To minimize anorexia, give drug with or after meals; food can a ect Tmax and/or Cmax of some formulations (see table p. 305)

• Patients who have problems swallowing pills may use one of several medications formulated as beads (Adderall XR, Aptensio XR, Biphentin,

Dexedrine Spansules, Foquest, Jornay PM, Metadate CD, or Ritalin LA), by opening the capsule, sprinkling the beads on apple sauce or other soft food, and swallowing the mixture without chewing. Lisdexamfetamine capsules may be opened and the contents dispersed in a glass of plain water, orange juice or yogurt. This has the advantage of not only allowing for medication of children who cannot swallow the dose, but also of enabling ne tuning of the dose, and allowing parents to reduce the dose if necessary prior to seeing the physician. The orally disintegrating formulations of mixed amphetamine salts (Adzenys XR-ODT) or methylphenidate (Cotempla XR-ODT) may be dissolved on the tongue and swallowed, and liquid suspensions of amphetamine (Dyanavel XR) and methylphenidate (Quillivant XR) are also available. There is also a methylphenidate extended- release chewable tablet (Quillichew ER). Methylphenidate is also available as a transdermal skin patch (Daytrana) that is applied in the morning and removed 9 h after application (see p. 292).

• JornayPMisadelayed-release/extended-releasemethylphenidateformulationintendedforeveningadministration,resultinginonsetofstimulant action (approximately 10 h after administration) in the morning upon waking

• Divideddosesrequiredwithimmediate-release(IR)preparationsofmethylphenidate(doseapproximatelyevery4h).Importanttodocument“wear- o ” times (changes in behavior/attention, emergence of rebound symptoms) and adjust dosing interval accordingly

• Problems falling asleep occur most frequently when the medication is wearing o and the child experiences rebound irritability or return of symptoms. A small dose of methylphenidate at this time can minimize this e ect. There is a group of children and adults who both nd it easier to go to bed, and easier to fall asleep when given a low dose of stimulant before bedtime

Pharmacology

Dosing

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 291 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Drugs for ADHD

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Psychostimulants (cont.)

• Methylphenidate SR has an erratic release in slightly less than half of patients and has been shown to be somewhat less e ective. However, for patients who are methylphenidate SR responders, the duration of 5 h can carry them through transitions such as lunch or the bus ride home such that they get their next dose before they experience rebound. Methylphenidate IR in adequate doses usually lasts less than 3.5 h and so, if given after breakfast, may wear o before the next dose at lunchtime and, if given after lunch, may wear o before the child is home from school

• The extended-release, sustained-release, or controlled-release formulations may decrease interdose dysphoria or “wear o ” phenomenon (“re- bound” hyperactivity). Supplementation with short-acting preparations may be needed in the morning (to speed up onset) or in the afternoon (to extend duration of action) for some extended-release preparations with a relatively lower proportion of immediate-release stimulant such as Concerta (all others are active within 30–60 min)

• Transdermal patch (Daytrana): Total dose delivered is dependent on patch size and wear time. Dose delivered over 9 h: 10 mg for 27.5 mg patch, 15 mg for 41.3 mg patch, 20 mg for 55 mg patch, and 30 mg for 82.5 mg patch. Dose titration recommended on a weekly basis (9 h wear period/day), as required. Patch can be removed earlier than 9 h for shorter duration of e ect or if late-day side e ects are problematic

Long-Acting Formulations

Drug

Drug1

Formulation

Duration of Effect

Usual Dosing2

Methylphenidate biphasic release

Biphentin, Aptensio XR

Concerta Cotempla XR-ODT

Foquest Metadate CD Ritalin LA

40% immediate-release beads + 60% delayed-release beads in a capsule

22% immediate-release coating + 78% delayed-release osmotic mechanism 25% immediate release + 75% delayed release formulated as an orally disintegrating tablet

20% immediate-release beads + 80% delayed-release beads in a capsule 30% immediate-release beads + 70% delayed-release beads in a capsule 50% immediate-release beads + 50% delayed-release beads in a capsule

10–12 h

10–12 h 12h

16h 8h 6–8 h

Once daily; can open and sprinkle on food

Once daily

Once daily; allow to disintegrate on tongue

Once daily; can open and sprinkle on food Once daily

Once daily; can open and sprinkle on food

Methylphenidate delayed release/extended release

Jornay PM

Beads coated with an extended-release layer and a delayed-release layer

10–14 h (onset delayed by

10 h)

Once daily in the evening; can open and sprinkle on food

Methylphenidate sustained/ slow release

Ritalin SR

Provides a slow continual release of drug from a wax matrix

4–6 h

Multiple daily dosing

ACT Methylphenidate ER, Apo-Methylphenidate ER, PMS-Methylphenidate ER, Teva-Methylphenidate ER-C Methylin ER

Metadate ER Quillichew ER Quillivant XR

Provides a slow continual release of drug from a polymer-coated tablet (though appearance and dosing similar to Concerta, these products do not deliver drug via an osmotic release mechanism)

Provides a slow continual release of drug due to diffusion and erosion from a hydrophilic polymer

Provides a slow continual release of drug from a wax matrix

30% immediate release + 70% delayed release formulated as a chewable tablet 20% immediate release + 80% delayed release formulated as a suspension for reconstitution

10–12 h

4–8 h

4–8 h 8h 12h

Once daily

Multiple daily dosing

Multiple daily dosing Once daily

Once daily

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Drug

Drug1

Formulation

Duration of Effect

Usual Dosing2

Methylphenidate transdermal patch

Daytrana

Drug dispersed in an acrylic adhesive which is dispersed in a silicone adhesive. Total dose delivered is dependent on patch size and wear time (see Dosing p. 303)

Depends on length of time patch applied

Apply patch in a.m., remove after 9 h

Dexmethylphenidate extended-release

Focalin XR

50% immediate-release beads + 50% enteric-coated delayed-release beads in a capsule

10–12 h

Once daily; can open and sprinkle on food

Amphetamine

Adzenys XR-ODT Dyanavel XR

50% immediate release + 50% delayed release formulated as an orally disintegrating tablet

Extended-release suspension

10–12 h upto13h

Once daily; allow to disintegrate on tongue Once daily

Dextroamphetamine/ amphetamine salts

Adderall XR Mydayis

50% immediate-release beads + 50% delayed-release beads in a capsule

33.3% immediate-release beads + 33.3% each of two types of delayed-release beads (pH 5.5 release and pH 7 release) in a capsule

10–12 h 16h

Once daily; can open and sprinkle on food Once daily; can open and sprinkle on food

Dextroamphetamine

Dexedrine Spansules

50% immediate-release beads and 50% sustained-release beads in a capsule

4–9 h

Multiple daily dosing; can open and sprinkle on food

Lisdexamfetamine

Vyvanse

Lisdexamfetamine is an inactive prodrug of d-amphetamine and L-lysine. The drug is converted to active dextroamphetamine as the prodrug molecule is hydrolyzed (cleaving off the amino acid)

10–13 h

Once daily (can open capsule and disperse contents in plain water, orange juice or yogurt); the prolonged duration of action is from its properties as a prodrug and not due to a physical delayed-release formulation

1 See available dosage forms in product availability table p. 289; 2 “Usual” dosing implies: Most common dosing frequency. Note, some “once daily” stimulants are given twice daily in some patients (e.g., adults looking for 18 h/day coverage) and some shorter-acting agents may be used once daily in some situations where a shorter daily duration of coverage is needed

• Itisgenerallyrecommendedtostarttreatmentwithalowdoseofalong-actingpreparationandtitratethedoseslowlytoatherapeuticlevel

• Conversionsbetweendosageformulationsarealwaysapproximationsandaredependentonanumberoffactors

– thepharmacokineticsofeachpreparation,includingthedurationofactionofeachproduct – thepatient’sageandweight(dosingrecommendationsareoftenbasedonweight)

– thepatient’sresponsemayvarybetweenpreparationsofthesamedrug

• Checkspeci cproductlabellingpriortoattemptingconversion.Duetodi erencesinformulationandindrugbaseconcentrations,manyproducts are now considered non-interchangeable, with several product manufacturers recommending re-titration from starting dosages

• Itisalwaysimportanttomonitorbothresponseandadversee ectsateachdosagelevel

Switching Formulations

Dosage Conversion

Immediate-Release Drug

Extended-Release Products (Daily Dose)

Methylphenidate

5 mg bid-tid

Metadate/Methylin ER, Biphentin, or Ritalin LA 10–20 mg, or Metadate CD 10–20 mg, or Concerta 18 mg

10 mg bid-tid 15 mg bid-tid

Metadate/Methylin ER, Biphentin, or Ritalin LA 20–30 mg, or Ritalin SR 20 mg, or Metadate CD 30 mg, or Concerta 27–36 mg Metadate/Methylin ER, Biphentin, or Ritalin LA 30–40 mg, or Ritalin SR 40 mg, or Metadate CD 30–40 mg, or Concerta 36–54 mg

20 mg bid-tid 30 mg bid

Metadate/Methylin ER, Biphentin, or Ritalin LA 40–50 mg, or Ritalin SR 40–60 mg, or Concerta 54–72 mg Metadate/Methylin ER, Biphentin, or Ritalin LA 50–60 mg, or Ritalin SR 60 mg, or Concerta 72 mg*

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 293 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Drugs for ADHD

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Psychostimulants (cont.)

Immediate-Release Drug

Extended-Release Products (Daily Dose)

Dexmethylphenidate

Focalin 2.5 mg bid

Focalin XR 5 mg daily

Dextroamphetamine/amphetamine salts

Adderall 5 mg bid

Adderall XR 10 mg daily

Dextroamphetamine

5mgbid

Dexedrine Spansules 10 mg daily (large inter-patient variance noted in conversion, from 1:1 to about 1:1.5)

* This amount comes from taking 2 × 36 mg tablets and roughly equates to about 15 mg a.m. and 45 mg after lunch of IR methylphenidate

Note: Conversion to methylphenidate transdermal patch (Daytrana) is currently unknown; individual patient titration recommended (see Dosing p. 292)

Conversion to lisdexamfetamine (Vyvanse) not recommended; start patient at 20–30 mg daily and titrate to effective dose

Conversion to methylphenidate extended-release suspension (Quillivant XR) and chewable tablets (Quillichew ER) is not recommended; start patients 6 years of age or older at 20 mg daily and titrate to effective dose.

Conversion to methylphenidate extended-release orally disintegrating tablets (Cotempla XR-ODT) is not recommended; start patients 6 years of age or older at 17.3 mg daily and titrate to effective dose.

Conversion to Jornay PM is not recommended; start patients 6 years of age or older at 20 mg daily administered in the evening and titrate to effective dose

Conversion to amphetamine tablets (Evekeo) or suspension (Dyanavel XR) or amphetamine orally disintegrating tablets (Adzenys XR-ODT) or mixed amphetamine salts extended-release capsules (Mydayis) is not recommended. To avoid substitution errors and overdosage, do not substitute for other amphetamine products on a milligram-per-milligram basis because of different amphetamine base compositions and differing pharmacokinetic pro les

• Seechartp.303

• Large interindividual variation in absorption and bioavailability; food may a ect Tmax and Cmax for some formulations (see table p. 305)

• Transdermal patch releases methylphenidate at a steady rate per hour, related to dose. Absorption and Cmax may increase with chronic dosing; rate

and extent of absorption increase if patch applied to in amed skin or if heat applied over patch

• Lisdexamfetamineisconvertedtod-amphetamineandL-lysinebyenzymatichydrolysis;peakplasmaconcentrationofd-amphetamineafter50mg

dose of lisdexamfetamine is approximately equivalent to 15–30 mg of immediate-release d-amphetamine

• ACTMethylphenidateER,Apo-MethylphenidateER,PMS-MethylphenidateER,andTeva-MethylphenidateER-Caresimilarinappearanceandavail-

able dosage strengths to Concerta, and are marketed as generic forms of Concerta; however, these products are extended-release polymer-coated tablets and do not deliver drug via an osmotic-controlled release mechanism. While they meet Health Canada bioequivalence standards, in single- dose studies, time to peak methylphenidate blood level (Tmax ) may be up to 3 h less with some formulations than with Concerta

• Withthemethylphenidatetransdermalpatch,ittakesabout8hafterpatchapplicationforbloodconcentrationstoreachmaximumlevel.Substan- tial amounts of drug remain in the body for about 6 h after patch removal

• Seechartp.304

• Seechartp.306

• Common adverse e ects include restlessness, irritability, anxiety, insomnia, anorexia, stomachache, tics, headaches, and worsening of aggressive

behavior or hostility at start of therapy. Paradoxical psychiatric e ects such as rebound, restlessness, irritability, anxiety, and increased aggression may be observed. The slower the rate of titration, the less severe the initial side e ects. Many of these psychiatric and somatic side e ects may endure throughout treatment, making drug holidays useful to assess impact of relative risk vs. bene t, and necessitating the regular monitoring of growth

• Drug-induced insomnia [can be managed by changing dose timing or formulation based on expected duration of action; addition of melatonin, sedating antihistamines or trazodone (25–50 mg) at bedtime or clonidine 100 micrograms given 2 h before bedtime]. When stimulants wear o at the end of the day, patient may experience rebound or a period of irritability and return of ADHD symptoms in excess of baseline – this may cause di culty in falling asleep

Pharmacokinetics

Onset & Duration of Action

Adverse Effects

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Discontinuation Syndrome

Precautions

• Anorexia, GI distress, and weight loss are common [can be minimized by taking medication with meals, eating smaller meals more frequently or drinking high-calorie uids (e.g., Boost, Ensure, smoothies made with whole milk), drinking when thirsty and eating before bedtime]; if weight loss is evident (in patients who are not obese), despite attempts to increase caloric intake, and compromising the child’s health or growth, consider switching to a shorter-acting agent that allows for return of appetite late in the day, or use of a non-stimulant such as atomoxetine or guanfacine

• Headachemostcommon2–3hafteradose(tension-likeor“achy”);tendstodecreaseovertime[acetaminophenmaybeusedasrequired]

• Hyperactivereboundcanoccurintheafternoonorevening[anearlierseconddose,morefrequentdosingortheuseofextended-releaseprepara-

tions can be tried]

• Dysphoria or sadness has been noted to occur in patients taking stimulants, both during the day and when they are wearing o ; more common

with amphetamine-based products

• Recent FDA and Health Canada warning re: priapism with methylphenidate dose increase or discontinuation; case reports of priapism in patients

taking amphetamine-based stimulants (though patients were also taking other medications and causality could not be established)

• RecentFDAwarningre:chemicalleukoderma(permanentlossofskincolor)withmethylphenidatepatch(Daytrana)

• Singlecasereportofeosinophilichepatitiswithlisdexamfetamine

• Singlecasereportofsudden,irreversiblehearinglossfollowing rstdoseofmethylphenidateinachild

• Abrupt withdrawal after prolonged use may result in dysphoria, irritability or a rebound in symptoms of ADHD; increase in sleep and appetite reported

• Ifastimulantistakeninconjunctionwithanantipsychotic,suddendiscontinuationofthestimulantmayresultintheemergenceofextrapyramidal symptoms previously masked by the stimulant’s anticholinergic properties and competition for D2 receptors

• Caseofpriapismreportedin16-year-oldeachtimeheforgottotakehisdoseofextended-releasemethylphenidate(Concerta)54mg

• Patients should be screened for cardiovascular risks by history[3] (early cardiac death in the family, syncope, chest pain on exertion, etc.) and given a physical exam. An ECG or cardiology consult should be considered[4] but, if not done, should not necessarily impede therapy if no evidence of cardiac concerns is present. If cardiac risk factors are present, the patient and/or parents should be informed of the relative risk and bene t of their treatment options, and treatment should only proceed with the consent of a cardiologist

• Canadianwarning:ADHDdrugsmayincreaseriskofsuicidalthoughtsandbehavioursinsomepeople;bene tsstilloutweighrisks.Suicidalthinking should be assessed at baseline prior to starting and periodically while on treatment

• Usecautiouslyinpatientswithanxiety,tension,agitation,restlessness,untreatedpsychosisoranorexianervosa/disorderedeating

• May lower the seizure threshold (contradictory data); when starting stimulants in children with ADHD and seizures, ensure adequate seizure

prophylaxis is employed and perform careful monitoring pre and post stimulant treatment for each individual

• Mayprecipitatemanicorhypomanicsymptomsinapatientwithundiagnosedbipolardisorderandexacerbatepsychoticsymptoms

• Chronic abuse in patients can lead to tolerance and psychic dependence; drug dependence is rare; drug abuse or diversion is a risk, especially in

children with comorbid conduct or substance use disorders. Stimulants can be abused orally, intravenously or nasally and may be combined with

other drugs

• Tic disorders; research investigating increased risk of tics with the use of stimulants has yielded contradictory results. Tics tend to wax and wane,

often independent of therapy, though clinicians have commented that stimulants can unmask tics

• Somepatientsbecometoleranttostimulante ectsovertime;mayrequireanincreaseddosageoradrugholiday[2]

• Application of external heat (e.g., heating pad, sauna, etc.) over Daytrana patch results in temperature-dependent increased methylphenidate

release (greater than 2-fold)

• CautionwhenswitchingfromConcertatoACTMethylphenidateER,Apo-MethylphenidateER,PMS-MethylphenidateER,orTeva-Methylphenidate

ER-C formulation as medication delivery system and pharmacokinetics are not the same; the time to peak serum level (Tmax) is several hours less with some of the generic formulations compared to Concerta; Health Canada has received numerous reports of loss of symptom control for patients following switch from Concerta to a generic formulation

• Patients with structural cardiac abnormalities or symptomatic cardiovascular disease, tachyarrhythmias, severe angina pectoris, moderate–severe hypertension

• Usewithcautionandwithcarefulmonitoringinpatientswithahistoryofalcoholand/ordrugabuse

• Severeanxiety,tension,agitation

Contraindications

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 295 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Drugs for ADHD

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Toxicity

Lab Tests/Monitoring Pediatric Considerations

Psychostimulants (cont.)

• Hyperthyroidism,pheochromocytoma,narrow-angleglaucoma

• Duringorwithin14daysoftakingMAOIs

• Seep.307

• Baseline: Height, weight, blood pressure, and pulse and repeat regularly throughout treatment. Patients with a prior or family history of cardiac disease should be further evaluated via ECG and cardiology consult, including echocardiogram as necessary. Cardiac evaluation recommended if patient experiences excessive increase in blood pressure or pulse, exertional chest pain, or unexplained syncope

• Fordetailedinformationontheuseofpsychostimulantsinthispopulation,pleaseseetheClinicalHandbookofPsychotropicDrugsforChildrenand Adolescents[5]

• Psychostimulants used consistently in children and young teenagers over a period of years have been demonstrated to lead to some growth loss. Monitor height and weight (children) to ensure children are growing as per usual growth charts [if more than 10% of body weight is lost in a person of normal height and weight or if ongoing monitoring of the child indicates that they are no longer growing along their expected growth curve, consider dose reduction, periodic drug holidays, or switching treatment]

• May precipitate psychotic symptoms in children with a genetic predisposition or prior history of psychosis; risk of inducing hypomania, mania, depression or a combination (mixed features) in patients with a mood disorder. A recent meta-analysis does not support an association between new onset or worsening tics and psychostimulant use,[6] though data is contradictory. Clinicians may want to consider rechallenging patients who report new onset or worsening of tics with psychostimulants. With support, some of these patients may be able to be successfully established on stimulant treatment

• Useful in the treatment of elderly or medically ill patients with major depression (see Precautions p. 295 and Contraindications p. 295 re cardiac status)

• Dosingbeforebreakfastandlunchmayfacilitatedaytimeactivity

• Initiatedosagegraduallyandincreaseinsmallincrementsevery2–3daysastolerated

• Seep.307

• Ensurethatbeaded,sustained-/extended-release,orosmotic-controlledreleaseformulationsarenotchewedbutopenedandsprinkledonfoodor swallowed whole as appropriate for the dosage form (exception: Quillichew ER is intended to be chewed)

• For patients who have di culty swallowing medications whole, Adderall XR, Aptensio XR, Biphentin, Dexedrine Spansules, Foquest, Jornay PM, Metadate CD, Mydayis, or Ritalin LA can be prescribed; capsule can be opened and the beads sprinkled on apple sauce, yogurt or other soft food and swallowed without chewing. Lisdexamfetamine (Vyvanse) capsules can be opened and the contents dispersed in a glass of plain water, orange juice or yogurt. Other alternatives include orally disintegrating tablets (Adzenys XR-ODT, Cotempla XR-ODT), liquid suspension (Quillivant XR, Dyanavel XR) or chewable tablets (Quillichew ER)

• Monitorforadversee ectsandchangesinconcentration,mood,andactivitylevel;reportanychangesinbehaviororinsleepingoreatinghabits

• In patients with ADHD who drive, improvements in driving have been seen while on medication. Patients with a history of involvement in motor vehicle accidents should be cautioned about driving without rst having taken medication or after medication e ects have worn o (e.g., in the

evening and night time)

• Patientsshouldbeinformedthatabruptdiscontinuationoftreatmentmayleadtoexacerbationofsymptoms

• Doses of psychostimulants in latter part of day (e.g., after noon for extended-release formulations or after 4 p.m. for immediate-release formula-

Geriatric Considerations

Use in Pregnancy♢

Nursing Implications

tions) may cause insomnia

♢ See p. 439 for further information on drug use in pregnancy and e ects on breast milk

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

• MonitorheartrateandBPpriortostartingtreatmentandafterdoseincreases

• PatientsshouldbeadvisedthattheConcertatabletshelldoesnotdissolveandmaybeseeninthestoolafterabowelmovement

• Daytrana patch should be applied (immediately following removal of protective pouch) to clean, dry skin on the hip, 2 h before desired e ect and

patch removed 9 h after application; advise patient not to apply patch to in amed skin and to avoid exposing area of application to external heat (e.g., electric heating pads). Dispose patch by folding together the adhesive side – used patch can be ushed down the toilet (do not ush in areas with septic tank service). NOTE: There have been several reports describing di culties in removing the protective lining to expose the adhesive surface of Daytrana

• MethylphenidateXRsuspension:Reconstitutionrequiredpriortodispensing.Shakebottlevigorouslyfor10secpriortodoseadministration

• AmphetamineXRsuspension:Shakebottlewellpriortodispensingandpriortoeachuse

• Fordetailedpatientinstructionsonpsychostimulants,seethePatientInformationSheet(detailsp.440)

• Clinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterforthesecondagent DRUGS INTERACTING WITH METHYLPHENIDATE AND DEXMETHYLPHENIDATE

Patient Instructions

Drug Interactions

Class of Drug

Example

Interaction Effects

Alcohol

In vitro studies show altered drug release characteristics (84–98% of total methylphenidate dose released within the rst 30–60 min) when taken with alcohol (40% concentration). Interactions are formulation speci c

α2 agonist

Clonidine, guanfacine

Additive effect on sleep, hyperactivity, and aggression associated with ADHD. Consider ECG monitoring. Published case series of sudden death with combination clonidine and methylphenidate use. However, Kapvay (clonidine XR) is FDA approved and Intuniv/Intuniv XR (guanfacine XR) is FDA/Health Canada approved for combination use with stimulants

Antibacterial

Linezolid

Linezolid inhibits MAO enzymes – AVOID combination (discontinue stimulant while linezolid used)

Anticoagulant

Warfarin

Decreased metabolism of anticoagulant Increased INR response

Anticonvulsant

Carbamazepine

Phenobarbital, phenytoin, primidone

Decreased plasma level of methylphenidate due to increased metabolism

Possible increased level of phenytoin, phenobarbital, and primidone due to metabolism inhibition by methylphenidate

Antidepressant

SSRI

SNRI

NaSSA Tricyclic

RIMA

MAOI (Irreversible)

Fluoxetine, sertraline

Desvenlafaxine, duloxetine, venlafaxine

Mirtazapine

Amitriptyline, desipramine

Moclobemide

Phenelzine, tranylcypromine

Potentiated effect in depression, dysthymia, and OCD, in patients with comorbid ADHD; may improve response in treatment-refractory paraphilias and paraphilia-related disorders

Plasma level of antidepressant may be increased

Case report of serotonin syndrome with methylphenidate after one dose of venlafaxine given

May increase agitation and risk of mania, especially in patients with bipolar disorder Used together to augment antidepressant effect

Plasma level of tricyclic antidepressants may be increased due to metabolism inhibition by methylphenidate Cardiovascular effects increased, with combination, in children; monitor blood pressure and ECG

Case reports of neurotoxic effects with imipramine, but considered rare; monitor

Increased blood pressure and enhanced effect if used over prolonged period or in high doses

Release of large amount of norepinephrine while ability to metabolize monoamines blocked by MAOI, leading to hypertensive reaction – AVOID; combination used very RARELY to augment antidepressant therapy with strict monitoring

Antihistamine

Diphenhydramine

Antagonism of sedative effects by stimulant

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 297 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Drugs for ADHD

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Psychostimulants (cont.)

Class of Drug

Example

Interaction Effects

Antipsychotic

General

Antipsychotics can counteract many signs of stimulant toxicity (e.g., anxiety, aggression, visual or auditory hallucinations, psychosis), may impair the stimulatory effect of amphetamines, and have additive adverse effects (e.g., insomnia, restlessness, tremor) Methylphenidate may exacerbate or prolong withdrawal dyskinesia following antipsychotic discontinuation; conversely, following stimulant discontinuation, antipsychotic-related extrapyramidal side effects may emerge

Olanzapine, quetiapine Risperidone

Two case reports of priapism with concurrent use of stimulants

Case reports of rebound dystonia when stimulant medication was withdrawn from patients taking risperidone. May be due to supersensitivity of dopamine receptors and/or removal of anticholinergic activity of stimulant

Disul ram

Case of psychotic-like episode with concurrent use, possibly via disul ram’s action in blocking dopamine-beta-hydroxylase, whose low levels have been associated with ADHD and psychotic symptoms

Herbal preparation

Ephedra, St. John’s Wort, yohimbine Ginkgo biloba

May cause hypertension, arrhythmias, and/or CNS stimulation Seizure threshold may be lowered with combination

Theophylline

Reports of increased tachycardia, palpitations, dizziness, weakness, and agitation

DRUGS INTERACTING WITH DEXTROAMPHETAMINE AND LISDEXAMFETAMINE

Class of Drug

Example

Interaction Effects

Alcohol

In vitro studies show altered drug release characteristics when taken with alcohol (40% concentration). Interactions are formulation speci c

α2 agonist

Clonidine, guanfacine

Acidifying agent

Ammonium chloride, ascorbic acid, fruit juices

Decreased absorption, increased elimination, and decreased plasma level of dextroamphetamine

Alkalinizing agent

Potassium citrate, sodium bicarbonate

Increased absorption, prolonged half-life, decreased elimination, and increased plasma level of dextroamphetamine

Anticonvulsant

Valproic acid

Valproate may attenuate the effects of dextroamphetamine on mood changes, cognitive tasks, and blood pressure, possibly via opposing pharmacological actions on dopamine and norepinephrine release and uptake; clinical signi cance unclear

Antidepressant

SSRI NaSSA

Fluoxetine, sertraline Mirtazapine

Potentiated effect in depression, dysthymia, and OCD, in patients with comorbid ADHD; may improve response in treatment-refractory paraphilias and paraphilia-related disorders

Plasma level of antidepressant may be increased

May increase agitation and risk of mania, especially in patients with bipolar disorder

Tricyclic

RIMA

MAOI (Irreversible)

Amitriptyline, desipramine Moclobemide

Phenelzine, tranylcypromine

May enhance the stimulatory effect of amphetamines. Tricyclics may also potentiate the cardiovascular effects of amphetamines Slightly enhanced effect if used over prolonged period or in high doses

Hypertensive crisis due to increased norepinephrine release while ability to metabolize monoamines is blocked by MAOI; AVOID

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Class of Drug

Example

Interaction Effects

Antipsychotic

Chlorpromazine

Dextroamphetamine can oppose the antipsychotic effects of chlorpromazine with detrimental effects on the control of schizophrenic symptoms; chlorpromazine may antagonize the effects of amphetamines and has been shown to treat amphetamine overdose

β-blocker

Propranolol

Increased blood pressure and tachycardia due to unopposed α stimulation

Urinary acidi er

Ammonium chloride

Increased excretion of dextroamphetamine drugs

Urinary alkalinizer

Acetazolamide, sodium bicarbonate

Decreased excretion of dextroamphetamine; psychoses via amphetamine retention from alkaline urine has been described

Atomoxetine

Product Availability∗

Generic Name

Chemical Class

Trade Name(A)

Dosage Forms and Strengths

Atomoxetine

Selective norepinephrine reuptake inhibitor

Strattera

Capsules: 10 mg, 18 mg, 25 mg, 40 mg, 60 mg, 80 mg, 100 mg

∗ Refer to Health Canada’s Drug Product Database or the FDA’s Drugs@FDA for the most current availability information. (A) Generic preparations may be available

Indications‡

( approved)

General Comments

ADHD in children, adolescents, and adults

• Comorbidanxietydisorder:Mayreduceanxietysymptoms

• MostADHDtreatmentguidelineslistatomoxetineasasecond-lineagent.Maybee ectiveforsomepatientswhohavenotrespondedtostimulant treatment, who have comorbid anxiety, or individuals who have an active comorbid substance use disorder. Bene ts include a lack of euphoria, a lower risk of rebound, a lower risk of induction of tics or psychosis, low abuse potential, and increased somnolence

• Available evidence indicates that stimulants and atomoxetine have both been found to be superior to placebo for reducing the severity of ADHD symptoms on average in the short term

• Hasaslowonsetofactionandresponsemaytakeupto4weeks–titratedosegraduallytohelpmitigateadversee ects(especiallyinpatientswho may be poor CYP2D6 metabolizers: ~10% of the population). Response is rst seen at 4 weeks of full dose and full optimization of drug response requires at least 3 months

• UltrarapidmetabolizersofCYP2D6(28%ofNorthAfricans,Ethiopians,andArabs;upto10%ofCaucasians;3%ofAfricanAmericans,andupto1% of Hispanics, Chinese, and Japanese) would have reduced e cacy of atomoxetine

• Reducesboththeinattentiveandhyperactive/impulsivesymptomclustersofADHD

• Head-to-head studies show greater reductions in ADHD symptoms (net e ect size di erence = 0.3) and a greater percentage of responders with

stimulants when compared to atomoxetine

• A large head-to-head trial of OROS-methylphenidate (Concerta) vs. atomoxetine in over 600 children demonstrated that 40% of children who do

not respond to methylphenidate are responders to atomoxetine, indicating selective response

• Selectively blocks the reuptake of norepinephrine; increases dopamine and norepinephrine in the frontal cortex (without increasing dopamine in subcortical areas) – leads to cognitive enhancement without abuse liability; suggested to be important in regulating attention, impulsivity, and activity levels

Pharmacology

• Nostimulantoreuphoriantactivity–maybeadvantageousinpatientswithcomorbidsubstanceusedisorder

current availability information and indications

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 299 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Drugs for ADHD

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Dosing

Atomoxetine (cont.)

• Seechartp.303

• Dosingisbasedonbodyweight

• Childrenandadolescentsupto70kg:Seetablep.303;donotexceed1.4mg/kgor100mg/day,whicheverisless

• Adults and children over 70 kg: See table p. 303; maximum of 100 mg/day. Doses greater than 100 mg/day have not been found to result in

additional therapeutic bene t

• Inpatientswithmoderatehepaticdysfunction,reducedoseby50%;inseverehepaticdysfunction,reducedoseto25%oftheusualrecommended

dosage

• Nodoseadjustmentrequiredinrenalinsu ciency;mayexacerbatehypertensioninpatientswithend-stagerenaldisease

• If atomoxetine is added to a regimen in combination with drugs that inhibit CYP2D6 (see Drug Interactions p.302): Initiate atomoxetine at

0.5 mg/kg/day as above but do not increase to the usual target dose unless symptoms fail to improve after 4 weeks and the initial dose is well

tolerated

• If a strong CYP2D6 inhibitor such as paroxetine, uoxetine, or bupropion is added to a regimen containing atomoxetine, dosage reduction of

atomoxetine should be considered (see Drug Interactions p. 301)

• For CYP2D6 ultrarapid metabolizers, be alert to reduced e cacy of atomoxetine – there are insu cient data to allow for an adjusted dose to be

calculated, therefore physician may need to prescribe an alternative drug

• Rapidly absorbed; may be taken with or without food – high-fat meal decreases rate but not extent of absorption (Cmax delayed by 3 h and is 37% lower)

• Bioavailability:63%;94%inCYP2D6poormetabolizers

• Proteinbinding:98%foratomoxetineand69%forthehydroxyatomoxetinemetabolite

• Peakplasmalevelreachedin1–2h;3–4hinCYP2D6poormetabolizers

• Half-life = 5 h for atomoxetine and 6–8 h for hydroxyatomoxetine; in CYP2D6 poor metabolizers the values are 21.6 h and 34–40 h, respectively;

metabolized primarily by CYP2D6, also by CYP2C19

• Hepaticdysfunction:2-foldincreaseinatomoxetineAUCinmoderatehepaticinsu ciencyand4-foldincreaseinAUCinseverehepaticdysfunction

(see Dosing above)

• Seetablep.306

• Common: Rhinitis, upper abdominal pain, nausea, vomiting, decreased appetite, weight loss (seen initially, especially if dose titrated too rapidly,

but levels o with time), dizziness, headache, fatigue, emotional lability, insomnia is more common in adults, somnolence in children

• Lessfrequent:Irritability,aggression,sedation,depression,drymouth,constipation,mydriasis,tremor,pruritus,tics,andurinaryretention

• Smallincreasesinbloodpressureandpulsecanoccuratstartoftreatment;usuallyplateauwithtime

• Sexualdysfunction(2%)includingerectiledisturbance,impotence,andabnormalorgasm,casereportofpriapism

• Rarecasesofelevatedhepaticenzymesandbilirubin;severehepaticinjuryreported[7];injuryreversedwhenatomoxetinewithdrawn(nonerequired

liver transplant); one adult died from hepatic and renal failure (the nature of the hepatic injury was considered to be idiosyncratic so that routine

LFT monitoring is of little bene t)

• Increasedriskofsuicidalideationinchildrenandadolescents(seePrecautionsp.300)

• Casereportofatomoxetine-inducedhypothermiainan11-year-oldboy

• Evidencethatnodrugdiscontinuationorwithdrawalsyndromeexistsforatomoxetine.Manufacturerstatesthatatomoxetinemaybediscontinued without tapering of the dose

• Use with caution in patients with cardiovascular disease, including hypertension, arteriosclerosis, and tachyarrhythmias. Do a cardiac history and physical assessment prior to prescribing atomoxetine and evaluate symptoms suggestive of cardiac disease that develop during treatment. DO NOT USE in patients with structural cardiac abnormalities – myocardial infarction, stroke, and deaths reported

Pharmacokinetics

Adverse Effects

Discontinuation Syndrome Precautions

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Contraindications

Toxicity

Lab Tests/Monitoring Pediatric Considerations

Geriatric Considerations

Nursing Implications

Patient Instructions

Drug Interactions

• Duetoriskofhypertension,usecautiouslyinanyconditionthatmaypredisposepatientstohypertension

• Usecautioninpatientswithliverdysfunction–seeDosingabove

• Casesofliverinjuryreported(rare);discontinuedruginpatientswithjaundiceorlaboratoryevidenceofliverinjury–rechallengenotadvised

• Patients should be advised that atomoxetine has been associated with adverse psychiatric e ects such as anger, hostility, irritability or suicidal

ideation and that if these occur the drug dose should be lowered or discontinued. Suicidal thinking should be assessed at baseline prior to starting and periodically while on treatment

• Patients with structural cardiac abnormalities or cardiovascular disease, tachyarrhythmias, severe hypertension or severe angina, current or past history of pheochromocytoma

• ShouldnotbeadministeredtogetherwithaMAOIorwithin2weeksofdiscontinuingaMAOI

• Notrecommendedinpatientswithnarrow-angleglaucomaduetoincreasedriskofmydriasis

• Seep.307

• Symptomsincludeanxiety,tremulousness,drymouth,seizures,andprolongedQTcinterval

• Liverfunctiontestswithanysymptomsorsignofliverdysfunction

• For detailed information on the use of atomoxetine in this population, please see the Clinical Handbook of Psychotropic Drugs for Children and Adolescents[5]

• Safetyande cacyofatomoxetinehasnotbeenestablishedinchildrenlessthan6yearsofage

• Pharmacokineticsinchildrenaresimilartothoseinadults

• Usewithcautioninpatientswithcardiovasculardisease,liverdysfunction,orurinaryout owobstruction

• E ectonhumansunknown

• Unknownifatomoxetineisexcretedinhumanmilk

• Measurepulseandbloodpressureatbaselineandperiodicallyduringtreatment

• Monitorforincreasedirritability,anger,depressionorsuicidalideation

• Monitorgrowthandweightduringtreatment

• Monitorforsignsoflivertoxicity(pruritus,darkurine,jaundice,upperrightquadranttenderness,unexplained u-likesymptoms)

• Manufacturerrecommendscapsulesofatomoxetineshouldnotbeopened(drugpowderisanocularirritant)

• Giveatomoxetinewithoraftermealstominimizestomachache,nausea,andvomiting

• Fordetailedpatientinstructionsonatomoxetine,seethePatientInformationSheet(detailsp.440)

• Clinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterforthesecondagent

Use in Pregnancy♢

Breast Milk

♢ See p. 439 for further information on drug use in pregnancy and e ects on breast milk

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 301 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Drugs for ADHD

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Atomoxetine (cont.)

Class of Drug

Example

Interaction Effects

Antiarrhythmic

Quinidine

Increased plasma level and half-life of atomoxetine due to inhibited metabolism via CYP2D6

Antidepressant

SSRI NDRI

Fluoxetine, paroxetine Bupropion

Increased plasma level and half-life of atomoxetine due to inhibited metabolism via CYP2D6 Increased plasma level and half-life of atomoxetine due to inhibited metabolism via CYP2D6

MAOI

Phenelzine, tranylcypromine

Do not administer concurrently or within 2 weeks of discontinuing a MAOI

Antiretroviral

Non-nucleoside reverse transcriptase inhibitor (NNRTI) Protease inhibitor

Delavirdine Ritonavir

Increased atomoxetine level due to inhibited metabolism via CYP2D6 Increased atomoxetine level due to inhibited metabolism via CYP2D6

β-agonist

Albuterol/salbutamol, levalbuterol

Can potentiate cardiovascular effects, resulting in increased blood pressure and heart rate

Dextromethorphan (DM)

Competitive inhibition of DM metabolism via CYP2D6, with potential for increased plasma level of either drug

QT-prolonging agent

Antiarrhythmics (e.g., amiodarone, sotalol), antimalarials (e.g., chloroquine, me oquine), antipsychotics (quetiapine, thioridazine, ziprasidone), dolasetron, methadone, tacrolimus

Possible additive prolongation of QT interval

Stimulant

Methylphenidate, amphetamine, and related products

Possible potentiation of therapeutic effects and adverse effects such as hypertension and tachycardia. However, combination use recommended as an option by some ADHD treatment guidelines following monotherapy trials with each agent

Comparison of Drugs for ADHD

Methylphenidate

Dexmethylphenidate

Amphetamine salts/Dextroamphetamine/ Lisdexamfetamine/Methamphetamine

Atomoxetine

Pharmacology

Selectively inhibits presynaptic transporters (i.e., reuptake) for DA and NE – dependent on normal neuronal activity

Increases levels of synaptic DA and NE

Selectively inhibits presynaptic transporters (i.e., reuptake)

for DA

and NE – dependent on normal neuronal activity

Increases levels of synaptic DA and NE

Competitive inhibitor and pseudosubstrate for presynaptic transporters (i.e., reuptake) for DA, NE, and 5-HT (though primarily DA). Main amphetamine effects are: 1) depletion of vesicular dopamine, 2) reversal of presynaptic DA transporters, and 3) presynaptic DA transporter inhibition

Selectively blocks reuptake of NE; increases NE and DA in prefrontal cortex

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Methylphenidate

Dexmethylphenidate

Amphetamine salts/Dextroamphetamine/ Lisdexamfetamine/Methamphetamine

Atomoxetine

Dosing

ADHD

Depression Narcolepsy

Start with 2.5–5 mg bid and increase by 2.5–5 mg weekly

Usual dose: 10–60 mg/day or

0.25–1 mg/kg/day body weight (divided doses); up to 3 mg/kg/day has been used in children

Aptensio XR/Biphentin: 10–20 mg q a.m.; can increase by 10 mg weekly to a maximum of 80 mg/day

Concerta: 18–36 mg q a.m.; can increase by 18 mg weekly to a maximum of 72 mg/day (some references support a maximum of

108 mg/day) in adults and 90 mg/day in adolescents)

Cotempla XR-ODT: 17.3 mg q a.m.; may increase by 8.6-17.3 mg in weekly intervals, to maximum of 51.8 mg/day

Daytrana transdermal patch: Week 1, apply

10 mg/9 h patch (for 9 h/day); increase dose in weekly intervals as necessary

Foquest: 25 mg q a.m.; may increase at no less than 5-day intervals to maximum of

100 mg/day

Quillivant XR/Quillichew ER: 20 mg q a.m.; may increase by 10–20 mg weekly to a maximum of 60 mg/day

10–30 mg/day

10–60 mg/day (usual dose: 10 mg 2–3 times/day)

Over age 6: Start with 2.5 mg bid and can increase weekly in 2.5–5 mg increments to a maximum of 20 mg/day (divided dose, given at least q 4h)

Usual dose: 5–20 mg daily divided bid

When switching from methylphenidate, the starting dose of dexmethylphenidate should be half that of methylphenidate

– –

Amphetamine:

Adzenys XR-ODT: Children: 6.3 mg q a.m. Increase by 3.1 or 6.3 mg weekly to maximum of 18.8 mg/day for children or 12.5 mg/day for adolescents. Adults:

12.5 mg q a.m.

Dyanavel XR: Over age 6: Start with 2.5–5 mg q a.m. May increase by 2.5-10 mg every 4–7 days to a maximum of 20 mg/day

Evekeo: Age 3–5: Start with 2.5 mg and increase by 2.5 mg weekly. Over age 6: Start with 5 mg and increase by 5 mg weekly. Usual maximum: 40 mg/day Dextroamphetamine/amphetamine salts:

Adderall: 2.5–5 mg to start and increase by 2.5–5 mg every 3–7 days up to 30 mg/day (given every 4–7 h). In adults up to 40 mg/day (in divided doses)

Adderall XR: 10–30 mg q a.m.

Mydayis: 12.5 mg q a.m.; may increase by 12.5 mg at weekly intervals to maximum of 25 mg/day for adolescents or 50 mg/day for adults Dextroamphetamine:

Age 3–5: Start with 2.5 mg and increase by 2.5 mg weekly. Over age 6: Start with 5 mg and increase by 5 mg weekly. Usual dose: 2.5–40 mg/day or

0.1–0.8 mg/kg (in divided doses) Lisdexamfetamine:

Children age 6 and up, adolescents, and adults: 20–30 mg q a.m. and can increase by 10–20 mg every 7 days to a maximum of 60 mg/day (Canada) or

70 mg/day (USA)

Methamphetamine:

Start with 5 mg daily bid and increase by 5 mg/week. Usual dose: 20–25 mg/day – in divided doses; Gradumet given once daily

Dextroamphetamine: 5–60 mg/day Dextroamphetamine: 5–60 mg/day

Dosing is based on body weight

Children up to 70 kg:

Canadian labeling: Initiate at 0.5 mg/kg/ day for 7–14 days. Based on tolerability, increase to 0.8 mg/kg/day for 7–14 days, and then to 1.2 mg/kg/day, given once daily or bid in the morning and late afternoon. Do not exceed 1.4 mg/kg or 100 mg/day, whichever is less

US labeling: 0.5 mg/kg/day for 3 days, then increase to 1.2 mg/kg/day if tolerated Adolescents and adults over 70 kg: Canadian labeling: Initiate at 40 mg/day for 7–14 days. Based on tolerability, increase to 60 mg/day for 7–14 days, and then to 80 mg/day, given once daily or divided bid in the morning and late afternoon. If response is inadequate after 2–4 weeks, the dose can be increased to a maximum of 100 mg/day

US labeling: 40 mg/day for 3 days, then increase to 80 mg/day. May increase to maximum of 100 mg/day in 2-4 weeks to achieve optimal response

– –

Pharmacokinetics

Bioavailability

30% (range 11–52%)

22–25%

Amphetamine/ Dextroamphetamine: > 90% Lisdexamfetamine: 96.4% Methamphetamine: 65–70%

63–94%

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 303 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Drugs for ADHD

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Comparison of Drugs for ADHD (cont.)

Methylphenidate

Dexmethylphenidate

Amphetamine salts/Dextroamphetamine/ Lisdexamfetamine/Methamphetamine

Atomoxetine

Peak plasma level

Protein binding Onset of effects

Plasma half-life

IR tabs: 0.3–4 h

Slow-release tabs: 1 h Apo-Methylphenidate-ER: 4.63 h PMS-Methylphenidate-ER: 6.5 h Teva-Methylphenidate-ER-C: 4.61 h Aptensio XR/Biphentin: 2 h rst peak, 7 h second peak

Concerta: 1 h initial peak, 6.8 h second peak Cotempla XR-ODT: 5 h

Foquest: 2 h rst peak, 12 h second peak Metadate CD: 1.5 h rst peak, 4.5 h second peak

Quillichew ER: 5 h

Quillivant XR: 5 h

8–15%

0.5–2 h

Absorption from GI tract is slow and incomplete

IR (regular) tabs: 2.9 h mean (range: 2–4 h) SR and Concerta: 3.4 h mean

Daytrana: 3–4 h after removal of patch Metadate CD: 6.8 h mean

Quillichew ER: 5.2 h Quillivant XR: 5.6 h

1–1.5 h (fasting)

12–15% 0.5–2 h

2.2 h

Amphetamine:

Dyanavel XR: 4 h

Evekeo: within 4 h Dextroamphetamine/amphetamine salts: Adderall: 1–2 h

Adderall XR: 7 h

Adzenys XR-ODT: d-amphetamine: 5 h (7 h with food) Mydayis: 8 h

Dextroamphetamine:

Tablets 1–4 h, Spansules: 6–10 h

Lisdexamfetamine: 1 h, d-amphetamine: 3.5 h

12–15%

0.5–2 h

Readily absorbed from the GI tract

Adderall: Saccharate and aspartate salts have a delayed onset

Amphetamine:

Dyanavel XR: Contains d-amphetamine and l-amphetamine with half-lives of 12.4 h and 15.1 h, respectively

Evekeo: 11 h

Dextroamphetamine/amphetamine salts:

Adderall: 6–8 h

Dextroamphetamine: 6–8 h in acidic pH, 18.6–33.6 h in alkaline pH

Lisdexamfetamine: < 1 h; d-amphetamine (after conversion): 10–13 h

Methamphetamine: 6.5–15 h

1–2 h

CYP2D6 poor metabolizers: 3–4 h

Atomoxetine: 98% hydroxyatomoxetine metabolite: 69% Delayed by up to 4 weeks, but then effective continuously with ongoing administration

Atomoxetine = 5 h (CYP2D6 poor metabolizers = 21.6 h) hydroxyatomoxetine = 6–8 h (CYP2D6 poor metabolizers = 34–40 h)

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Methylphenidate

Dexmethylphenidate

Amphetamine salts/Dextroamphetamine/ Lisdexamfetamine/Methamphetamine

Atomoxetine

Duration of action

Metabolism

Hepatic impairment Renal impairment

IR (regular) tablets: 3–5 h

SR: Theoretically 5–8 h, but 3–5 h practically Extended-release formulations: 8–12 h Foquest: 16 h

Hepatic via carboxylesterase CES1A1 to minimally active metabolite

Weak CYP2D6 inhibitor

No change

No adjustment

6–7 h

No change ?

Amphetamine:

Dyanavel XR: Up to 13 h

Evekeo: 4–6 h Dextroamphetamine/amphetamine salts: Adderall: 5–7 h

Adderall XR: 12 h

Mydayis: 16 h

Dextroamphetamine:

Tablets 4–5 h, Spansules: 7–8 h

Lisdexamfetamine: Up to 13 h

Methamphetamine: 6–12 h; effects may continue up to 24 h following administration of large doses

Minor CYP2D6 substrate

(lisdexamfetamine enzymatically converted to active d-amphetamine on erythrocytes)

No change

Decreased excretion

Approx. 24 h

Metabolized primarily by CYP2D6; also by CYP2C19

Moderate: Reduce dose by 50% Severe: Reduce dose by 75% No adjustment

Effect of Food

High-fat meal

Concerta: Delayed Tmax by 1 h and reduced Cmax by 10–30%

Metadate CD: Delayed Tmax by 1 h

Aptensio XR/Biphentin: diminished second peak level, Cmax increased by 28%, AUC by 19% Cotempla XR-ODT: Cmax decreased by 24%, AUC increased by 16%, Tmax decreased by 0.5 h Metadate CD: Cmax increased by 30% Quillichew ER: Tmax unchanged, Cmax increased by 20%, AUC by 4%

Quillivant XR: Tmax increased by 1 h, Cmax by 28%, AUC by 19%

Ritalin and Ritalin LA: Tmax delayed

–

Delayed Tmax

Decreased extent of absorption

Adzenys XR-ODT: Tmax increased by 2–2.5 h, Cmax reduced by 19%

Mydayis: Tmax increased 5 h for d-amphetamine and 4.5 h for l-amphetamine

Lisdexamfetamine: No change

Dyanavel XR: Tmax increased by 1 h, Cmax by 2%, AUC by 6%

Tmax delayed by 3 h

Cmax 37% lower

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 305 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Drugs for ADHD

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Comparison of Drugs for ADHD (cont.)

Methylphenidate

Dexmethylphenidate

Amphetamine salts/Dextroamphetamine/ Lisdexamfetamine/Methamphetamine

Atomoxetine

Adverse Effects

(Dose related)

CNS

GI Cardiovascular

Anticholinergic Endocrine

Other

Nervousness (16%), anxiety, insomnia (up to 28%), restlessness, activation, irritability (up to 26%), headache (up to 14%), tearfulness, drowsiness (10%), rebound depression, may exacerbate mania or psychosis

(See Precautions p. 295)

Cases of suicidal thoughts, hallucinations, and psychotic or violent behavior reported with Concerta

Tourette’s syndrome, tics (up to 10%, mostly with higher doses)

Social withdrawal, dullness, sadness, and irritability reported in children with autism Abdominal pain (up to 23%), nausea, vomiting, and diarrhea (more than 10%), anorexia (up to 41%, dose-related)

Increased heart rate and blood pressure at start of therapy, dizziness (13%), hypotension, palpitations

(See Precautions p. 295)

Dry mouth, blurred vision

Growth delay (height and weight), may occur initially but tends to normalize over time (unless high chronic doses used), weight loss

Upper respiratory infections (pharyngitis (4%), sinusitis (3%), rhinitis (13%), cough (4%)), fever, rash, contact sensitization/dermatitis with Daytrana patch – redness, itching, blistering

Leukopenia, blood dyscrasias, anemia, hair loss, priapism

Drowsiness, headache Fever (5%)

Arthralgia, dyskinesias (See Precautions p. 295)

Abdominal pain (15%), nausea, anorexia (6%)

Increased heart rate and blood pressure at start of therapy (See Precautions p. 295)

Blurred vision

Growth delay, weight loss

Cough, upper respiratory infections, priapism

Nervousness, insomnia, activation, restlessness, anxiety, emotional lability, mania (with high doses), dysphoria, irritability, headache, confusion, delusions, rebound depression; may exacerbate mania or psychosis

(See Precautions p. 295)

Headache

Tremor, Tourette’s syndrome, tics – usually with higher doses

Abdominal pain common; nausea, vomiting, anorexia

Increased heart rate and blood pressure at start of therapy, dizziness, palpitations

(See Precautions p. 295)

Dry mouth, dysgeusia, blurred vision

Growth delay (height and weight), may occur initially but tends to normalize over time (unless high chronic doses used), weight loss, impotence, changes in libido

Urticaria, anemia

Insomnia, dizziness, fatigue, headache, emotional lability

Less common: Drowsiness, irritability, depression, tremor, aggression

Reports of psychotic/manic symptoms (hallucinations, delusions, and mania) in children and adolescents with no prior history of psychotic illness

Case reports of tics; however, patients in clinical trials with baseline tics showed some improvement in tic frequency

Upper abdominal pain, nausea, vomiting, anorexia

Small increases in heart rate and blood pressure at start of treatment

(See Precautions p. 300)

Dry mouth, constipation, mydriasis, urinary retention

Sexual dysfunction, weight loss

Cases of liver damage with elevated AST/ ALT and bilirubin in adults and children Pruritus, rhinitis, priapism

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Methylphenidate

Dexmethylphenidate

Amphetamine salts/Dextroamphetamine/ Lisdexamfetamine/Methamphetamine

Atomoxetine

Toxicity

CNS overstimulation with vomiting, agitation, tremors, hyperre exia, convulsions, confusion, hallucinations, delirium, cardiovascular effects (e.g., hypertension, tachycardia); seizures reported

Supportive therapy should be given

CNS overstimulation with vomiting, agitation, tremors, hyperre exia, convulsions, confusion, hallucinations, delirium, cardiovascular effects (e.g., hypertension, tachycardia) Supportive therapy should be given

Restlessness, dizziness, increased re exes, tremor, insomnia, irritability, assaultiveness, hallucinations, panic, cardiovascular effects, circulatory collapse, convulsions, and coma

Supportive therapy should be given

Anxiety, tremulousness, dry mouth; case of seizures & QTc prolongation

Supportive therapy should be given

Use in Pregnancy♢

No evidence of teratogenicity reported

Safety not established

High doses have embryotoxic and teratogenic potential; use of amphetamine in pregnant animals has been associated with permanent alterations in the central noradrenergic system of the neonate Increased risk of premature delivery and low birth weight; withdrawal reactions in newborn reported

Safety not established

Breastfeeding

No data

Excreted into breast milk; recommended not to breastfeed

No published experience with this drug during breastfeeding; however, there have been reports of no serious adverse effects in 2 breastfed infants

♢ See p. 439 for further information on drug use in pregnancy and effects on breast milk

Product Availability∗

α2 agonists

Generic Name

Chemical Class

Trade Name(A)

Dosage Forms and Strengths

Clonidine

α2 agonist

Catapres, Dixarit(C) Kapvay(B)

Catapres TTS(B)

Tablets: 0.025 mg(C), 0.1 mg, 0.2 mg, 0.3 mg(B) Extended-release tablets: 0.1 mg

Transdermal patch: 0.1 mg/24 h, 0.2 mg/24 h, 0.3 mg/24 h

Guanfacine

Tenex(B)

Tablets: 1 mg, 2 mg

Intuniv(B), Intuniv XR(C)

Extended-release tablets: 1 mg, 2 mg, 3 mg, 4 mg

Indications‡

( approved)

ADHD (clonidine (Kapvay) and guanfacine (Intuniv/Intuniv XR)) – meta-analysis of studies suggests a moderate bene t in children and adolescents; reduced hyperarousal, agitation, aggression, impulsivity, and sleep disturbances; useful in patients with concurrent tic disorders or conduct disorder; minimal bene t on inattentive symptoms

Hypertension (guanfacine – USA only)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 307 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Drugs for ADHD

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

General Comments

α2 agonists (cont.)

• Some bene t apparent in combination with stimulants; may help ameliorate sleep disturbances caused by psychostimulants (Caution – see Drug Interactions p. 310)

• Mayimprovebehaviororimpulsivitywhenusedaloneorincombinationwithmethylphenidate(Caution–seeDrugInteractionsp.310)

• Autism–reportedtobee ectiveforreducinghyperarousalandcontrollingsomeproblematicbehaviorsinchildrenandadults

• Menopausal ushing

• Generalizedanxietydisorder(GAD),panicattacks,phobicdisorders,andobsessive-compulsivedisorders:Ofsomebene t;mayaugmente ectsof

SSRIs and cyclic antidepressants in social phobia; helpful for symptoms of hyperarousal, hypervigilance, aggression, and irritability of PTSD

• Mayrelieveantipsychotic-inducedastheniaandimprovesymptomsoftardivedyskinesia

• Mayhelpdecreaseclozapine-inducedsialorrhea

• Heroin, cocaine, and nicotine withdrawal: Used to reduce agitation, tremor, and diaphoresis, and to increase patient comfort. Opioid antagonists

(e.g., naltrexone) as well as dicyclomine (for stomach cramps) and cyclobenzaprine (for muscle cramps) often given concomitantly

• Reduces the hyperactive/impulsive and aggressive symptoms of ADHD but may be less e ective for inattention problems; considered generally less e ective than psychostimulants and thus second-line treatments, though may be bene cial for some patients who have not responded to stimulant treatment or those with comorbid tic disorder

• Inanxietydisorders,psychologicalsymptomsrespondbetterthansomaticsymptoms;anxiolytice ectsmaybeshort-lived

• Mechanism of action for the treatment of ADHD is unknown; agonizing α2A receptors in the prefrontal cortex appears to improve “signal-to-noise ratio”

• Clonidine is a relatively nonselective α2-adrenergic agonist (α2A, α2B, and α2C receptors). It also has a nity for imidazoline receptors, which may be responsible for some of its sedating and hypotensive action

• Guanfacine is a more selective agonist for postsynaptic α2A receptors in the prefrontal cortex. It has less sedating and hypotensive e ects compared to clonidine

• Bothclonidineandguanfacinestimulateα2-adrenergicreceptorsinthebrainstem.Thisreducessympatheticout owfromtheCNSanddecreases peripheral resistance, renal vascular resistance, heart rate, and blood pressure

• ADHD:

– ClonidineIR:3–10micrograms/kgbodyweightperday(0.05–0.4mg/day)in3–4divideddoses

– ClonidineXR:initially0.1mg/day,mayadjustbyincrementsnolargerthan0.1mg/dayeveryweektomaximumof0.4mg/daybasedonclinical

response. Doses above 0.1 mg/day should be divided equally, or with the larger portion of the split doses given at bedtime

– GuanfacineIR:0.5–4mg/daydividedbid

– GuanfacineXR:initially1mgoncedaily;mayadjustbyincrementsnolargerthan1mgatweeklyintervalsbasedonclinicalresponse,toamaxi-

mum of 4 mg/day in children (as monotherapy or in combination with stimulant) or adolescents (in combination with stimulant) and 7 mg/day in adolescents (as monotherapy). Clinical response is associated with weight-based doses of 0.05–0.08 mg/kg/day. Doses up to 0.12 mg/kg/day may provide additional bene t

• Antisocial behavior/aggression: Clonidine: Children: 0.1–0.4mg/day as tablets (IR: in 3–4 divided doses) or transdermal patch; adults: 0.4– 0.6 mg/day

• Anxietydisorders:Clonidine:0.15–0.5mg/day(IR:in3–4divideddoses)

• Drugdependence:ClonidineIR:0.1–0.3mgtidtoqidforupto7days;nicotinewithdrawal:0.1mgbidto0.4mg/dayfor3–4weeks

• Tic disorders: Clonidine IR: 3–5 micrograms/kg body weight per day in 2–4 divided doses; guanfacine IR: 0.5 mg tid to maximum of 4 mg/day in

3 divided doses

• Clonidineiswellabsorbedorallyandpercutaneously(whenpatchappliedtothearmorchest)

• Peakplasmaleveloforalclonidineoccursin1–3h(IR)or7–8h(XR);therapeuticplasmaconcentrationofclonidinetransdermalpatchoccurwithin

Pharmacology

Dosing

Pharmacokinetics

2–3 days

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Onset & Duration of Action

Adverse Effects

Discontinuation Syndrome

Precautions

Toxicity

Pediatric Considerations

Geriatric Considerations

• Clonidineplasmahalf-lifeis8–12hinchildrenand12–20hinadults;inpatientswithimpairedrenalfunction,half-liferangeis18–41h.Elimination half-life is dose dependent

• Guanfacine is metabolized via CYP3A4; peak plasma level of oral guanfacine occurs in 1-4 h (IR) or 5 h (XR) in children and adolescents, 4–8 h in adults; half-life is 14–18 h in children and adolescents, 10–30 h in adults

• Bioavailability is reduced with guanfacine XR tablets compared to IR tablets, therefore IR and XR forms and their respective dosing guidelines are not considered interchangeable

• OralclonidineIRtablets:Onsetofe ectsoccursin30–60minande ectslastabout6–10h(exceptforXRformulations)

• Clonidinetransdermalpatch:Therapeuticplasmaconcentrationsareattainedwithin2–3daysande ectslastfor7days

• Withclonidineandguanfacine,sedation,dizziness,bradycardia,andhypotensioncommononinitiation(monitorBPandheartrate)–thesee ects are lessened with use of extended-release formulations

• Lesscommonwithbothdrugs:anxiety,irritability,decreasedmemory,headache,drymouth,andlackofenergy

• Dermatologicalreactionsreportedinupto50%ofpatientsusingtransdermalclonidinepatch

• Clonidineandguanfacinemayincreaseagitationandproducedepressivesymptoms

• Casereportsofmaniainducedbyguanfacine

• Withdrawalreactionsmayoccurafterabruptcessationoflong-termclonidineorguanfacinetherapy(over1–2months)

• Taper clonidine and guanfacine (e.g., reduce dose by approximately 25% [round to nearest tablet size] every 3–7 days) on drug discontinuation to

prevent rebound hypertension and insomnia, as well as tic rebound in patients with Tourette’s syndrome

• Casesofreboundpsychoticsymptomsreportedwithbothdrugs

• Case reports (4) of sudden death with combination of methylphenidate and clonidine but causal relationship not established; FDA recommended removal of drug interaction statement regarding methylphenidate and clonidine.[8] Long-acting formulations now FDA/Health Canada approved for adjunctive use with stimulants

• Use with caution in patients with or at risk of CVD, cerebrovascular disease, chronic hepatic or renal impairment or any condition that may predispose to syncope

• Usewithcautionwhenprescribing/transcribingclonidinedoses:highpotentialfor10-folddosingerrorsduetoinadvertentdecimalmisplacement when converting doses between units of micrograms and milligrams

• Signs and symptoms of clonidine or guanfacine overdose occur within 60 min of drug ingestion (with IR tablets; may be delayed with XR tablets) and may persist for up to 48 h or longer

• Symptoms include transient hypertension followed by hypotension, bradycardia, weakness, pallor, sedation, vomiting, hypothermia; can progress to CNS depression, diminished or absent re exes, apnea, respiratory depression, cardiac conduction defects, seizures, and coma

• Supportiveandsymptomatic

• For detailed information on the use of clonidine and guanfacine in this population, please see the Clinical Handbook of Psychotropic Drugs for Children and Adolescents[5]

• Childrenmetabolizeclonidinefasterthanadultsandmayrequiremorefrequentdosing(usually3–4divideddoses/dayforIRformulation)

• Childrenmetabolizeguanfacinefasterthanadultsandmayrequiremorefrequentdosing(2–3divideddoses/dayforIRformulation)

• Usewithcautioninpatientswithcardiovasculardiseaseorchronicrenalfailure

Treatment

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 309 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Drugs for ADHD

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Use in Pregnancy♢

Nursing Implications

α2 agonists (cont.)

• Clonidine: Animal studies suggest teratogenic e ects; no adequate well-controlled studies of clonidine in pregnant women. Clonidine passes the placental barrier and may lower fetus heart rate. Transient rise in blood pressure in the newborn cannot be excluded postpartum

• Clonidinecrossestheplacentaandmaylowertheheartrateofthefetus

• Guanfacine:Noadequatewell-controlledstudiesofguanfacineinpregnantwomen

• Clonidineisdistributedintobreastmilk;e ectsoninfantunknown

• Itisunknownwhetherguanfacineisdistributedintobreastmilk

• Ifusedbynursingmothers,observemilk-fedinfantsforsomnolenceandsedation

• Clonidineandguanfacineshouldnotbediscontinuedsuddenlyduetoriskofreboundhypertensionandinsomnia

• AdvisepatienttoswallowXRformulationswhole,andnottobreak,chew,orcrushXRtablets

• Shouldbetakenwithafullglassofwater.Advisepatienttomaintainadequatehydrationunlessinstructedtorestrict uidintake

• Handleusedtransdermalpatchescarefully(foldinhalfwithstickysidestogetherfordisposal)

• Should the transdermal patch begin to loosen from the skin, apply adhesive overlay over the system to ensure good adhesion over the period of

application

• Monitorforskinreactionsaroundareawhentransdermalpatchisapplied

• AssesspotentialforinteractionswithotherCNSdepressants.Donotdiscontinueabruptly;taper,decreasingdosegradually

• Bioavailability is reduced with XR tablets compared to IR tablets, therefore IR and XR products and their respective dosing guidelines are not

interchangeable

• Fordetailedpatientinstructions,seethePatientInformationSheet(detailsp.440)

• Clinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterforthesecondagent

Breast Milk

Patient Instructions

Drug Interactions

Class of Drug

Example

Interaction Effects

Antibiotic

Clarithromycin, erythromycin Rifampin

Decreased clearance and increased plasma level of guanfacine due to inhibition of CYP3A4 metabolism

Decreased guanfacine levels due to CYP3A4 induction; monitor for signs and symptoms of altered response. With the XR formulation, higher dosages (up to 8 mg/day) and dose increments (2 mg/week) may be required

Anticonvulsant

Carbamazepine Divalproex, valproic acid

Decreased guanfacine levels due to CYP3A4 induction; monitor for signs and symptoms of altered response. With the guanfacine XR formulation, higher dosages (up to 8 mg/day) and dose increments (2 mg/week) may be required

Increased valproate levels; may be due to competition between valproate and guanfacine metabolite (3-hydroxy guanfacine) for glucuronidation enzymes

Antidepressant

Bupropion, desipramine Imipramine, desipramine, SNRI

Clonidine withdrawal may result in excess circulating catecholamines; use caution in combination with noradrenergic or dopaminergic antidepressants

Inhibition of antihypertensive effect of α2A agonist by the antidepressant

Antifungal

Itraconazole, ketoconazole

Decreased clearance and increased plasma level of guanfacine due to inhibition of CYP3A4 metabolism

Antihypertensive

Hydrochlorothiazide, ramipril

Additive hypotension

β-blocker

Propranolol

Additive bradycardia

♢ See p. 439 for further information on drug use in pregnancy and e ects on breast milk

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Class of Drug

Example

Interaction Effects

CNS depressant

Alcohol, antihistamines, benzodiazepines, suvorexant, zolpidem, zopiclone

Additive CNS depressant effects

Stimulant

Dextroamphetamine, methylphenidate

Additive effect on hyperactivity and aggression associated with ADHD

Kapvay (clonidine XR) and Intuniv/Intuniv XR (guanfacine XR) are FDA/Health Canada approved for adjunctive use with stimulant medications

Nonresponse in ADHD

Factors Complicating Response

Augmentation Strategies in ADHD

• Ascertainwhetherdiagnosisiscorrect

• Ascertain if patient is adherent with therapy (speak with caregivers, check with pharmacy for late re lls, count remaining pills in container and

compare to prescription ll date)

• Ensuredosageprescribedistherapeuticallyappropriateandtailorregimentohavepeakserumlevelsoccuratthosetimesofthedaythatsymptoms

are most prominent

• Consider trying a stimulant from an alternate class (methylphenidate class or amphetamine class) if the rst trial was ine ective and the patient

was adhering to therapy recommendations

• Concurrentmedicalorpsychiatriccondition,e.g.,anxietydisorder,bipolardisorder,conductdisorder,autismspectrumdisorder,learningdisability

• Concurrentprescriptiondrugsmayinterferewithe cacy,e.g.,antipsychotics(seeDrugInteractionspp.297–299,301,310)

• Metabolicinducers(e.g.,carbamazepine)maydecreasetheplasmalevelofmethylphenidateorguanfacine

• Highintakeofacidifyingagents(e.g.,fruitjuices,vitaminC)maydecreasethee cacyofamphetaminepreparations

• Substance use, including alcohol and marijuana, may complicate management and treatment selection; need to discontinue substance use to optimize treatment outcomes

• Poore cacywithatomoxetinemaybeduetoultrarapidmetabolismofCYP2D6

• Sidee ectstomedication

• Psychosocial factors may a ect response; nonpharmacological treatment approaches (e.g., behavior modi cation, psychotherapy, and education)

can increase the probability of response

• Additivee ectonhyperactivity,aggression,moodlability,andsleepproblems;studiesindicatee cacyin50–80%ofpatients.Hasbeenfoundhelp- ful in patients with concomitant tic disorders, conduct disorder or oppositional de ant disorder [monitor ECG, heart rate, and blood pressure with combination]

• Kapvay(clonidineXR)andIntuniv/IntunivXR(guanfacineXR)areFDA/HealthCanadaapprovedforadjunctiveusewithstimulantmedications

• Tricyclics (imipramine, nortriptyline, and desipramine) useful in refractory patients or those with concomitant enuresis or bulimia; they may re- duce abnormal movements in patients with tic disorders. There is an increase in the incidence of adverse e ects, including cardiovascular, GI, anticholinergic e ects, and weight gain; use caution and limit quantities prescribed in patients at risk of overdose

• SSRIsorSNRIsmaybee ectiveinadultpatientswithconcomitantmoodoranxietydisorders(e.g.,PTSD)

• Bupropion used to augment e ects of psychostimulants and in patients with concomitant mood disorder, substance abuse, or conduct disorder.

May cause dermatological reactions, exacerbate tics, and increase seizure risk

Augmentation Strategies

Methylphenidate/ Dexmethylphenidate/ Dextroamphetamine + α2 agonist

Psychostimulants + Antidepressants

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 311 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Drugs for ADHD

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Atomoxetine + Stimulants

Psychostimulants + Antipsychotics

Psychostimulants + Mood Stabilizers

Psychostimulants + Buspirone

Further Reading

Augmentation Strategies in ADHD (cont.)

• Useinpatientswhohavepartialreliefofsymptomswithmaximallytolerateddosesofstimulantsandatomoxetineasmonotherapy.Combination may permit lower stimulant doses and allows robust coverage as well as coverage early and late in the day

• Monitorforincreasedbloodpressure,tachycardia,weightloss,andreducedgrowthvelocity

• Second- and third-generation antipsychotics (low doses of risperidone, aripiprazole) have been found useful in patients with comorbid symptoms of dyscontrol, aggression, hyperactivity, and tics. Ensure appropriate metabolic monitoring of antipsychotic therapy completed and discontinue antipsychotic treatment if excessive increases in blood pressure, weight, cholesterol, triglycerides or fasting glucose occur. Stimulants do not mitigate the e ects of antipsychotics on weight and metabolic parameters[9]

• Combination used in patients with comorbid bipolar disorder, conduct disorder, impulsivity, and aggression; infrequent case reports in children include the use of lithium, carbamazepine , and valproate – the possibility of drug interactions should be considered (see Drug Interactions pp. 297– 299); limited likelihood of bene t

• Openstudiessuggestbuspironemayimproverageattacks,impulsivity,inattention,anddisruptivebehavioratdosesof15–30mgdaily

References

1 Jasinski DR, Krishnan S. Human pharmacology of intravenous lisdexamfetamine dimesylate: Abuse liability in adult stimulant abusers. J Psychopharmacol. 2009;23(4):410–418. doi: 10.1177/0269881108093841

2 Weiss MG, Surman CBH, Elbe D. Stimulant ‘rapid metabolizers’: Wrong label, real phenomena. Atten Def Hyperact Disord. 2018;10(2):113–118. doi:10.1007/s12402-017-0242-9

3 Warren AE, Hamilton RM, Bélanger SA, et al. Cardiac risk assessment before the use of stimulant medications in children and youth: A joint position statement by the Canadian Paediatric Society, the Canadian Cardiovascular Society, and the Canadian Academy of Child and Adolescent Psychiatry. Can J Cardiol. 2009;25(11):625–630. Retrieved from https://www.ncbi.nlm.

nih.gov/pmc/articles/PMC2776560/

4 Vetter VL, Elia J., Erickson C, et al. Cardiovascular monitoring of children and adolescents with heart disease receiving medications for attention de cit/hyperactivity disorder [corrected]:

A scienti c statement from the American Heart Association Council on Cardiovascular Disease in the Young Congenital Cardiac Defects Committee and the Council on Cardiovascular

Nursing. Circulation. 2008;117(18):2407–2423. doi:10.1161/CIRCULATIONAHA.107.189473

5 Elbe D, Black TR, McGrane IR, et al. Clinical handbook of psychotropic drugs for children and adolescents. (4th ed.). Boston, MA: Hogrefe Publishing, 2019.

6 Cohen SC, Mulqueen JM, Ferracioli-Oda E, et al. Meta-analysis: Risk of tics associated with psychostimulant use in randomized, placebo-controlled trials. J Am Acad Child Adolesc Psychiatry.

2015; 54(9): 728–736. doi:10.1177/0269881108093841

7 FDA. Postmarket reviews: Atomoxetine. FDA Drug Saf Newsl. 2009;2(1).

Retrieved from http://www.fda.gov/Drugs/DrugSafety/DrugSafetyNewsletter/ucm110235.htm#AtomoxetineMarketedasStrattera:SeriousLiverInjury

8 Diak I-L, Mathis MV. Death with the concomitant use of clonidine or guanfacine and amphetamine/dextroamphetamine or dexmethylphenidate or dextroamphetamine or lisdexam- fetamine or methylphenidate [FDA review. 2010]. Retrieved from http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/PediatricAdvisoryCommittee/

UCM317388.pdf

9 Penzner JB, Dudas M, Saito E, et al. Lack of effect of stimulant combination with second-generation antipsychotics on weight gain, metabolic changes, prolactin levels, and sedation in

youth with clinically relevant aggression or oppositionality. J Child Adolesc Psychopharmacol. 2009;19(5):563–573. doi:10.1177/0269881108093841

Additional Suggested Reading

• AndradeC.Riskofmajorcongenitalmalformationsassociatedwiththeuseofmethylphenidateoramphetaminesinpregnancy.JClinPsychiatry.2018;79(1):18f12108.doi:10.4088/JCP. 18f12108

• BangsME,Tauscher-WisniewskiS,PolzerJ,etal.Meta-analysisofsuicide-relatedbehavioreventsinpatientstreatedwithatomoxetine.JAmAcadChildAdolescPsychiatry.2008;47(2): 209–218. doi:10.1097/chi.0b013e31815d88b2

• CanadianADHDPracticeGuidelines(4thed.).CADDRA2018.Retrievedfromhttps://www.caddra.ca/wp-content/uploads/CADDRA-Guidelines-4th-Edition_-Feb2018.pdf

• ChildressAC,BerrySA.Pharmacotherapyofattention-de cithyperactivitydisorderinadolescents.Drugs.2012;72(3):309–325.doi:10.2165/11599580-000000000-00000

• Childress AC, Sallee FR. Attention-de cit/hyperactivity disorder with inadequate response to stimulants: Approaches to management. CNS Drugs. 2014;28(2):121–129. doi:10.1007/

s40263-013-0130-6

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

• Cortese S, Brown TE, Corkum P, et al. Assessment and management of sleep problems in youths with attention-de cit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2013;52(8):784–796. doi:10.1016/j.jaac.2013.06.001

• ElbeD,MacBrideA,ReddyD.Focusonlisdexamfetamine:Areviewofitsuseinchildandadolescentpsychiatry.JCanAcadChildAdolescPsychiatry.2010;19(4):303–314.Retrievedfrom http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2962544/

• ElbeD,ReddyD.Focusonguanfacineextended-release:Areviewofitsuseinchildandadolescentpsychiatry.JCanAcadChildAdolescPsychiatry.2014;23(1):48–60.Retrievedfrom http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3917669/

• FindlingRL,McBurnettK,WhiteC,etal.Guanfacineextendedreleaseadjunctivetoapsychostimulantinthetreatmentofcomorbidoppositionalsymptomsinchildrenandadolescents with attention-de cit/hyperactivity disorder. J Child Adolesc Psychopharmacol. 2014;24(5):245–252. doi:10.1089/cap.2013.0103

• LopezPL,TorrenteFM,CiapponiA.Cognitive-behaviouralinterventionsforattentionde cithyperactivitydisorder(ADHD)inadults.CochraneDatabaseSystRev.2018;(3):CD010840. doi:10.1002/14651858.CD010840.pub2

• ManKKC,IpP,ChanEW,etal.Effectivenessofpharmacologicaltreatmentforattention-de cit/hyperactivitydisorderonphysicalinjuries:Asystematicreviewandmeta-analysisof observational studies. CNS Drugs. 2017;31(12):1043–1055. doi:10.1007/s40263-017-0485-1

• NewcornJH,KratochvilCJ,AllenAJ,etal.Atomoxetineandosmoticallyreleasedmethylphenidateforthetreatmentofattentionde cithyperactivitydisorder:Acutecomparisonand differential response. Am J Psychiatry. 2008;165(6):721–730. doi:10.1176/appi.ajp.2007.05091676

• PadilhaSCOS,VirtuosoS,ToninFS,etal.Ef cacyandsafetyofdrugsforattentionde cithyperactivitydisorderinchildrenandadolescents:Anetworkmeta-analysis.EurChildAdolesc Psychiatry. 2018;27(10):1335–1345. doi:10.1007/s00787-018-1125-0

• PalumboDR,SalleeFR,PelhamWEJr,etal.Clonidineforattention-de cit/hyperactivitydisorder:I.Ef cacyandtolerabilityoutcomes.JAmAcadChildAdolescPsychiatry.2008;47(2):180– 188. doi:10.1097/chi.0b013e31815d9af7

• Royal College of Psychiatrists in Scotland. ADHD in adults: Good practice guidelines. Retrieved from https://www.rcpsych.ac.uk/docs/default-source/members/divisions/scotland/ adhd_in_adults nal_guidelines_june2017.pdf?sfvrsn=40650449_2

• RostainAL.Attention-de cit/hyperactivitydisorderinadults:Evidence-basedrecommendationsformanagement.PostgradMed.2008;120(3),27–38.doi:10.3810/pgm.2008.09.1905

• SteinMA.TreatingadultADHDwithstimulants.CNSSpectr.2008;13(9Suppl13):8–11.

• StorebøOJ,RamstadE,KroghHB,etal.Methylphenidateforchildrenandadolescentswithattentionde cithyperactivitydisorder(ADHD).CochraneDatabaseSystRev.2015;11:CD009885.

doi:10.1002/14651858.CD009885.pub2

• TorgersenT,GjervanB,LensingMB,etal.OptimalmanagementofADHDinolderadults.NeuropsychiatrDisTreat.2016;12:79–87.doi:10.2147/NDT.S59271

• WolraichML,BrownL,BrownRTetal.ADHD:Clinicalpracticeguidelineforthediagnosis,evaluationandtreatmentofattention-de cit/hyperactivitydisorderinchildrenandadoles-

cents. Pediatrics 2011;128(5):1007–1022. doi:10.1542/peds.2011-2654

• WilliamsAE,GiustJM,Kronenberger,WGetal.Epilepsyandattention-de cithyperactivitydisorder:Links,risks,andchallenges.NeuropsychiatrDisTreat.2016;12:287–296.doi:10.2147/

NDT.S81549

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 313 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Drugs for ADHD

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Classi cation

DRUGS FOR TREATMENT OF DEMENTIA

• Drugsfortreatmentofdementiacanbeclassi edasfollows:

Chemical Class

Agent

Page

Cholinesterase inhibitor

Donepezil Rivastigmine Galantamine

See p. 314

Aminoadamantane

Memantine

See p. 320

Cholinesterase Inhibitors

Product Availability∗

Generic Name

Chemical Class

Trade Name(A)

Dosage Forms and Strengths

Donepezil

Piperidine

Aricept

Tablets: 5 mg, 10 mg, 23 mg(B)

Orally disintegrating tablets: 5 mg, 10 mg

Galantamine (Galanthamine)

Phenanthrene alkaloid

Razadyne(B)

Reminyl ER(C), Razadyne ER(B)

Tablets(B): 4 mg, 8 mg, 12 mg

Liquid(B) : 4 mg/mL

Extended-release capsules: 8 mg, 16 mg, 24 mg

Rivastigmine

Carbamate

Exelon Exelon Patch

Capsules: 1.5 mg, 3 mg, 4.5 mg, 6 mg

Oral solution: 2 mg/mL

Patch: 5 (4.5 mg/24 h), 10 (9.5 mg/24 h), 15 (13.3 mg/24 h)(B)

Indications‡

( approved)

Dementia of Alzheimer’s type – mild, moderate (galantamine, donepezil, rivastigmine), and severe (donepezil, memantine): Symptomatic treatment of mild to moderate disease; no proof of a bene cial e ect on the underlying neurodegenerative process but some disease markers may be positively a ected (e.g., hippocampal volume loss)

Dementia of Parkinson’s disease – mild to moderate (rivastigmine)

Alzheimer’s disease: Treatment of severe disease (donepezil, memantine)

• Memorydysfunctionfollowingbraininjury

• Galantamineanddonepezilsuggestedtoimprovecognitionandbehaviorsandtostabilizeorimproveactivitiesofdailyliving

• Schizophrenia–galantamine(alone,andincombinationwithmemantine)hasbeenshowntoimproveselectivecognitiveimpairmentinpatients

with schizophrenia. Galantamine increases dopaminergic activity and release in the prefrontal cortex in a dose-dependent manner, such bene ts not seen with either donepezil or rivastigmine

‡ Indications listed here do not necessarily apply to all cholinesterase inhibitors or all countries. Please refer to a country’s regulatory database (e.g., US Food and Drug Administration, Health Canada Drug Product Database) for the most current availability information and indications

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

General Comments

• Reversionofneuromuscularblockinge ectsofcurare-typemusclerelaxants(galantamine)

• Substance use disorders – early data suggests that galantamine (as an allosteric potentiator of the nicotinic acetylcholine receptor, especially α7

and α4β2 subtypes) may be bene cial in the treatment of cocaine, opioid, and nicotine addiction

• Autismspectrumdisorder:Double-blindstudiesreportimprovementsinbehaviors,attention,communication,andinteractions

• Donepezilreportedlydecreasedin-hospitalmortality(asaresultofpneumonia)amongolderJapanesepatientswithdementia

• These drugs are suggested to ameliorate behavioral disturbances (such as apathy, depression, anxiety, disinhibition, aberrant motor behavior, delusions, and hallucinations) as well as enhance cognition. Bene ts are lost after drug withdrawal. Therapeutic response following re-initiation of therapy shown to be less than that obtained with initial therapy

• Double-blind placebo-controlled studies involving patients with mild to moderate Alzheimer’s disease showed improvement (i.e., less decline in cognitive ability). Approximately 25% of patients had signi cantly improved attention, interest, orientation, communication, and memory (contro- versy exists over whether cognition enhancers should be used routinely for dementia given their modest e cacy)

• A systematic review of the evidence from randomized, placebo-controlled trials showed a statistically signi cant though modest bene t of donepezil, rivastigmine, and galantamine in the treatment of behavioral and psychological symptoms of Alzheimer’s disease[1]

• Signi canttreatmentbene tsofdonepezildemonstratedinearly-stageAlzheimer’sdiseaseandsupportinitiatingtreatmentearlytoimprovedaily cognitive functioning; shown to have additive e ects with memantine in patients with moderate to severe Alzheimer’s disease

• Theimprovement,onaverage,ismodestandbene tsmaynotbeevidentuntil6–12weeksofcontinuoustreatment.Inlong-termstudies,patients receiving treatment with cholinesterase inhibitors show improvement in cognitive ability after 6 months of therapy but then decline thereafter

• Drugsshouldnotbestoppedjustbecausedementiaseverityincreases

• Adouble-blindstudyconductedinover2,000patientswithmildtomoderateAlzheimer’sdiseaseestablishedthatgalantaminetreatmentresulted

in a signi cantly decreased mortality rate and showed bene ts in cognition and activities of daily living that persisted for 2 years

• Economic analyses suggest that treatment initiated in early stages of Alzheimer’s disease may be cost neutral as a result of patients remaining in

a less severe state of disease for a longer time and delayed institutionalization

• Failuretorespondtooneagentdoesnotprecluderesponsetoanother;open-labelstudiessuggestthatapproximately50%ofpatientsexperiencing

loss of e cacy with one drug respond to subsequent treatment with another agent

• Cholinesteraseinhibitorspromoteluciddreamingandout-of-bodyexperiences

• Vascular dementia: No bene t of donepezil or galantamine on cognitive function. On current evidence, the e cacy on cognitive function and

activities of daily living of cholinesterase inhibitors in people with Huntington’s disease, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), multiple sclerosis, progressive supranuclear palsy or frontotemporal dementia (FTD) is unclear, how- ever, cholinesterase inhibitors are associated with more gastrointestinal side e ects compared with placebo. Worsening of FTD has been reported

• Nobene tinmildcognitiveimpairment(MCI)

• Seechartonp.323

• It is postulated that these compounds increase acetylcholine levels in the brain through inhibition of the enzyme acetylcholinesterase. Both

donepezil and galantamine are reversible inhibitors of acetylcholinesterase, with non-covalent binding to the enzyme. Rivastigmine, on the other hand, has been classi ed as an intermediate-acting agent (pseudo-irreversible). Clinical improvement occurs with between 40% and 70% cholinesterase inhibition (in preclinical studies, they increased extracellular acetylcholine levels in the hippocampus and cerebral cortex)

• Nicotiniccholinergicreceptorsmayregulatecognitivefunctions,suchasattention,andmayincreasethereleaseofneurotransmittersthroughout the brain

• Galantamine is also a positive allosteric modulator of the α4β2 and α7 nicotinic receptors that could lead directly to increased release of acetyl- choline and activation of postsynaptic nicotinic receptors, or act indirectly through its e ects on the release of other neurotransmitters, especially glutamate and dopamine. Galantamine increases dopaminergic activity and release in the prefrontal cortex and hippocampus in a dose-dependent manner

• Cholinesteraseinhibitorswithlessspeci city(e.g.,rivastigmine)maybemoree caciousinmoreadvancedstagesofdementia

• Seechartonp.324

• Withgalantamineandrivastigmine,treatmentisstartedatlowerdoseswithgradualdoseescalationtominimizesidee ects

• E ectsoncognitionandfunctionalactivitiesaredosedependent,whilee ectsonbehavioraldisturbancesarenot

Pharmacology

Dosing

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 315 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Dementia Treatment

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Pharmacokinetics

Pharmacogenomics

Cholinesterase Inhibitors (cont.)

• RivastigminePatch5releasesdrugatarateof4.6mg/24h;Patch10releasesdrugatarateof9.5mg/24h.Whenswitchingfromoraldrug,Patch5 is recommended for patients on less than 6 mg/day and Patch 10 can be used for patients on higher doses; apply patch the day following the last oral dose

• Donepezil 23 mg dose is recommended for patients with moderate to severe disease who have been stabilized on donepezil 10 mg for at least 3 months

• Patients who discontinue galantamine or rivastigmine for longer than several days should be restarted at the lowest daily dose (i.e., 4 mg bid for galantamine and 1.5 mg od or bid for rivastigmine) to reduce the possibility of severe vomiting; dosage should be titrated over a period of 2 months to the maintenance dose

• Fordosinginpatientswithrenaland/orhepaticinsu ciency,seechartp.324

• Seechart,p.324

• Durationofcholinesteraseinhibitiondoesnotre ectplasmahalf-lifeofdrug(e.g.,rivastigminehalf-lifeis1–2h,butcholinesteraseinhibitionlasts

up to 10 h)

• DonepezilandgalantaminearesubstratesforCYP2D6andCYP3A4

• Plasmarivastigminelevelsareapproximately30%higherinelderlymalepatientsthaninyoungadults

• RivastigminePatchproduceslowerpeaklevelsbutmaintainssteadierplasmalevelsthantheoralformulation

• Exposure to galantamine in patients with moderate and severe renal impairment is signi cantly higher than in healthy subjects, and is approxi-

mately 30% higher in patients with moderate hepatic impairment

• Galantamine

– The FDA recommends, but does not require, genetic testing prior to initiating or reinitiating treatment with galantamine. Approximately 7%

of the population has a genetic variation that leads to reduced activity levels of CYP2D6 isozyme. Such individuals have been referred to as poor metabolizers. Galantamine levels are higher in poor metabolizers compared to extensive metabolizers (i.e., AUC of unchanged galantamine increased by 35% and median clearance decreased by 25%)

– Dosageadjustmentisusuallynotnecessaryinpatientsidenti edaspoormetabolizersasthedrugdoseisindividuallytitratedtotolerability

• Donepezil

– Presence of CYP2D6 variants conferring decreased or absent CYP2D6 enzyme activity (intermediate or poor metabolizers) has been associated with greater response to donepezil treatment compared to rapid metabolizers. Analysis of CYP2D6 allele variants may be useful in identifying patients with Alzheimer’s disease who are more likely to respond to donepezil[2]

– InAPOE-ε4allelecarriers,asinglenucleotidepolymorphismrs1080985inthecytochromeP4502D6(CYP2D6)gene,Gallelecarrierswerefound to have increased nonresponse to donepezil

– PatientswiththeGallelehaveapproximately3timesgreaterriskofapoorresponsetodonepeziltreatment

• Seechartonpp.325–326

• Increasedriskofadversee ectswhencholinesteraseinhibitorsusedincombinationwithantipsychotics,antihypertensivesordrugsactingonthe

GI tract[3]

• Most common adverse e ects are due to cholinomimetic activity: nausea, vomiting, diarrhea, constipation (rivastigmine), and anorexia – occur

early in treatment and are associated with rapid dose titration

• Occurmoreofteninpatientsover85yearsofageandinfemales

• Gastrointestinalsymptoms(e.g.,cramping,nausea,vomiting,anddiarrhea)aredosedependent,occurmoreoftenduringdoseescalation,andtend

to resolve with time; they are associated more frequently with the nonselective inhibitor rivastigmine than with donepezil or galantamine [reported to respond to short-term use of propantheline (7.5–15 mg) or domperidone (10 mg tid) – caution due to anticholinergic e ects]; fewer side e ects reported with the lower-dose rivastigmine patch than with the capsules or higher-dose patch – e cacy remains comparable[4]; incidence reported to be 5% higher with donepezil 23 mg vs. 10 mg

Adverse Effects

• Rivastigminehasbeenassociatedwithhepatitis

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Discontinuation Syndrome Precautions

• A cohort study on the use of cholinesterase inhibitors in older adults with dementia showed higher rates of syncope, bradycardia, fall-related injuries, and hip fractures[5]; dizziness and falls reported in 3–7%

• Other side e ects (e.g., CNS, respiratory) occur more often during the maintenance phase and have no clear dose dependence; confusion (more than 4%) with rivastigmine and galantamine

• Aggressionandhallucinationshavebeenreportedinassociationwithrivastigmine.Truncalpurpuricrashreportedwithdonepezil

• Disseminatedcutaneoushypersensitivityreactionshavebeenreportedinassociationwithrivastigmine

• Skinreactions(redness,itching,irritation,swelling)canoccuratapplicationsiteofrivastigminepatch

• Weightloss.Morelikelytooccurathigherdoses

• Sudden worsening of cognitive function and behavior reported following drug withdrawal – suggest that dose be reduced by 25–50% every 1–2 weeks, with close monitoring

• Cautionshouldbeexercisedifanyofthefollowingexists:

– Knownhypersensitivitytoabovecompounds

– Historyoforgeneticpredispositiontosyncope,bradycardia,bradyarrhythmia,sicksinussyndrome,historyofhepaticorrenaldisease,obstructive

urinary disease, conduction disturbances, congestive heart failure, coronary artery disease, asthma, COPD, ulcers or increased risk of ulcers or GI

bleeding (concomitant use of NSAIDS or higher doses of ASA) – Patientistakingdrugsthatsigni cantlyslowheartrate

• Cholinomimeticsmaycausebladderout owobstruction

• Allpatientsshouldbeconsideredatriskforadversee ectsoncardiacconduction,includingbradycardiaandAVblock,duetovagotonice ectson

sinoatrial and atrioventricular nodes

• Withgalantamine:monitorforrespiratoryadverseeventsinpatientswithahistoryofsevereasthmaorobstructivepulmonarydisease

• With rivastigmine: isolated postmarketing reports of patients experiencing disseminated cutaneous hypersensitivity reactions, irrespective of the

route of administration (oral or transdermal). Treatment should be discontinued if such skin reactions occur. Instruct patients and caregivers

accordingly

• Inpatientswhodevelopapplicationsitereactionssuggestiveofallergiccontactdermatitistorivastigminepatchandwhostillrequirerivastigmine,

treatment should be switched to oral rivastigmine only after negative allergy testing and under close medical supervision. Some patients sensitized

to rivastigmine by exposure to patch may not be able to take rivastigmine in any form

• Nauseaandvomiting.Observepatientscloselyatinitiationoftreatmentandafterdoseincreases

• Peptic ulcer disease and GI bleeding. Monitor patients closely for symptoms of active or occult gastrointestinal bleeding, especially those at

increased risk for developing ulcers

• Anesthesia.Exaggerationofmusclerelaxationinducedbysuccinylcholine-typedrugs

• Epilepsy,seizuredisorders.Cholinesteraseinhibitorsarebelievedtohavesomepotentialtocausegeneralizedconvulsions.PatientswithAlzheimer’s

disease should be monitored closely for seizures due to reduced seizure threshold

• Pulmonary conditions. Cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary

disease

• Increasedriskofdeathinpatientswithmildcognitiveimpairment(MCI)(galantamine)

• Donepeziliscontraindicatedinpatientswithknownhypersensitivitytodonepezilhydrochlorideortopiperidinederivatives

• Galantamineiscontraindicatedinpatientswithseverehepaticand/orrenalimpairment(CrCllessthan9mL/min)

• Previousapplicationsitereactionwithrivastigminetransdermalpatchsuggestiveofallergiccontactdermatitis,intheabsenceofnegativeallergy

testing

• Overdose can result in cholinergic crisis characterized by severe nausea, vomiting, salivation, sweating, hypotension, hallucinations, bradycardia, and syncope followed by respiratory depression and convulsions; increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved. Atypical responses in blood pressure and heart rate have been reported

• Hospitalizationand(rarely)deathhavebeenreportedduetoapplicationofmultiplepatchesatthesametime.Ensurepatientsorcaregiversreceive instruction on proper dosing and administration

Contraindications

Toxicity

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 317 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Dementia Treatment

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Management

Pediatric Considerations

Geriatric Considerations

Use in Pregnancy♢

Breast Milk

Nursing Implications

Cholinesterase Inhibitors (cont.)

• Institutegeneralsupportivemeasures

• Treatment:Atropinesulfate1mgto2mgIVwithsubsequentdosesdependingonclinicalresponse.Thevalueofdialysisinoverdosageisnotknown

• In asymptomatic rivastigmine overdose, hold drug for 24 h, then resume treatment. Because of the short half-life of rivastigmine (plasma half-

life of about 3.4 h after patch administration and a duration of acetylcholinesterase inhibition of about 9 h), the value of dialysis in treatment of cholinergic crisis is unknown

• Therearenoadequateandwell-controlledtrialstodocumentthesafetyande cacyofdonepezilhydrochlorideinanyillnessoccurringinchildren

• Cautionshouldbeexercisedandadverseeventscloselymonitoredwhenusingdonepezilindosesover5mgaday

• Galantamineplasmaconcentrationsare30–40%higherintheelderlythaninhealthyyoungsubjects

• Galantaminereportedtoincreasemortalityinpatientswithmildcognitiveimpairmentandshouldnotbeused

• Basedonanimaldata,maycausefetalharm.Adequate,well-controlledhumanstudiesarelacking,andanimalstudieshaveshownrisktothefetus or are lacking as well

• Notrecommendedfornursingwomen

• Advisepatientstotakethedrugasdirected;increasingthedosewillincreaseadversee ectswhileskippingdoseswilldecreasethebene tofthe drug

• Advisepatientsnottostopthemedicationabruptly,aschangesinbehaviorand/orconcentrationcanoccur

• Anticholinergicagents(includingover-the-counterdrugs,e.g.,antinauseants)willreducethee ectsofthesedrugsandshouldbeavoided

• Rivastigmine patches should be kept sealed until use. Apply the rst rivastigmine patch the day following the last oral dose. The location of the

patch should be rotated and the patch applied to the upper or lower back, upper arm, or chest; if there is potential for the patient to remove the patch, apply it onto an inaccessible area. Remove patch after 24 h, prior to applying the next dose – fold it in half with the adhesive sides on the inside and dispose of in waste container; wash hands after handling

• Advisepatientthatrivastigminepatchmaycompromisedrivingability

• Advisepatienttostoptakingrivastigmineandinformdoctorifarashdevelops

• The23mgdonepeziltabletshouldnotbesplit,crushedorchewedbecausethismayincreasetherateofabsorption

• Fordetailedpatientinstructionsoncognitionenhancers,seethePatientInformationSheet(detailsp.440)

• Clinicallysigni cantinteractionsarelistedbelow

Patient Instructions

Drug Interactions

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterforthesecondagent DRUGS INTERACTING WITH DONEPEZIL

Class of Drug

Example

Interaction Effects

Antiarrhythmic

Quinidine

Inhibited metabolism of donepezil via CYP2D6

Antibiotic

Clarithromycin, erythromycin

Inhibited metabolism of donepezil via CYP2D6

Anticholinergic

Benztropine, diphenhydramine

Antagonism of effects

Anticonvulsant

Carbamazepine, phenytoin, phenobarbital

Increased metabolism of donepezil, resulting in decreased ef cacy

♢ See p. 439 for further information on drug use in pregnancy and e ects on breast milk

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Class of Drug

Example

Interaction Effects

Antidepressant

SSRI – uoxetine, paroxetine

May increase plasma level of donepezil by inhibiting metabolism via CYP2D6. Fulminant hepatitis reported in combination with a high dose of sertraline

Case reports of increased GI and CNS adverse effects as well as extrapyramidal symptoms with paroxetine and donepezil

Nefazodone

Inhibited metabolism of donepezil via CYP3A4

Antifungal

Itraconazole, ketoconazole

Inhibited metabolism of donepezil via CYP3A4

Antipsychotic

Risperidone

Exacerbation of EPS; worsening of Parkinson’s disease

Antitubercular drug

Rifampin

Increased metabolism of donepezil, resulting in decreased ef cacy

β-blocker

Propranolol

May potentiate bradycardia; may increase risk of bronchospasm

Cholinergic agonist

Bethanechol

Synergistic effects: Increased nausea, vomiting, and diarrhea

Neuromuscular blocker

Succinylcholine, suxamethonium

Prolonged neuromuscular blockade

DRUGS INTERACTING WITH GALANTAMINE

Class of Drug

Example

Interaction Effects

Antiarrhythmic

Quinidine

Decreased clearance of galantamine (by 25–30%) due to inhibited metabolism via CYP2D6

Antibiotic

Clarithromycin, erythromycin

Increased AUC of galantamine (by 10%) due to inhibited metabolism via CYP3A4

Anticholinergic

Benztropine, chlorpheniramine

Antagonism of effects

Antidepressant

Bupropion

Increased galantamine level possible, due to inhibited metabolism; may increase risk of seizures

Fluvoxamine, nefazodone Paroxetine

Decreased clearance of galantamine (by 25–30%) due to inhibited metabolism via CYP2D6 Increased AUC of galantamine (by 40%) due to inhibited metabolism via CYP2D6

Antifungal

Ketoconazole

Increased AUC of galantamine (by 30%) due to inhibited metabolism via CYP3A4

Antiretroviral

Protease inhibitor

Nel navir, ritonavir

May increase galantamine level due to inhibited metabolism via CYP3A4 Risk of cholinergic adverse effects

β-blocker

Propranolol

May potentiate bradycardia; may increase risk of bronchospasm

H2 antagonist

Cimetidine

Increased AUC of galantamine (by 16%)

Neuromuscular blocker

Succinylcholine, suxamethonium

Prolonged neuromuscular blockade

NSAID

Ibuprofen, ketoprofen

Increased risk of bleeding

DRUGS INTERACTING WITH RIVASTIGMINE

Class of Drug

Example

Interaction Effects

Anticholinergic

Benztropine, diphenhydramine

Antagonism of effects

Antipsychotic

Haloperidol

Exacerbation of EPS

β-blocker

Propranolol

May potentiate bradycardia; may increase risk of bronchospasm

Neuromuscular blocker

Succinylcholine, suxamethonium

Prolonged neuromuscular blockade

Smoking (tobacco)

Increased clearance of rivastigmine by 23%

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 319 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Dementia Treatment

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Memantine

Product Availability∗

Generic Name

Chemical Class

Trade Name

Dosage Forms and Strengths

Memantine

Aminoadamantane

Ebixa(C), Namenda(B) Namenda XR

Tablets:5mg(B) 10mg(C)

Solution(B) : 2 mg/mL

Extended-release capsules(B): 7 mg, 14 mg, 21 mg, 28 mg

Memantine extended release/donepezil

Namzaric(B)

Capsules (memantine extended release/donepezil): 7/10 mg, 14/10 mg, 21/10 mg, 28/10 mg

∗ Refer to Health Canada’s Drug Product Database or the FDA’s Drugs@FDA for the most current availability information. (B) Not marketed in Canada, (C) Not marketed in the USA

Indications‡

( approved)

Dementia of Alzheimer’s type: Symptomatic treatment of moderate to severe disease (memantine shows some e cacy in mild AD)

Memantine extended release/donepezil is indicated for treatment of moderate–severe dementia of Alzheimer’s type in patients stabilized on 10 mg of donepezil hydrochloride once daily

• Vasculardementia:Double-blindstudiesreportbene toncognitivefunction

• Alzheimer’sdisease:Reportedtodecreasedelusions,agitation/aggression,andpsychosisinpatientswithmoderatetoseverediseaseandimprove

behavioral and psychological symptoms of dementia (BPSD)[6]

• DementiawithLewybodies:Showntoimproveglobalclinicalstatusandbehavioralsymptomsinpatientswithmildtomoderatediseaseindouble-

blind studies

• Pain:Memantinehasdemonstratedbene tsindecreasingneuropathicpain,including bromyalgia,indouble-blindstudies

• OCD:ContradictoryresultsreportedwhenmemantineusedasanaugmentingagentwithanSSRIinOCDtreatment

• Bipolardisorder,treatmentresistant:add-onmemantinemayshowantimanicandmood-stabilizinge ects

• Schizophrenia:SeveralRCTsandmeta-analysissuggestthataugmentationwith20mg/daymayimprovepersistentnegativesymptomsandcogni-

tive impairment and bene t general psychopathology of schizophrenia

• Autismspectrumdisorder:Double-blindandopenstudiesreportimprovementsinbehaviors,attention,communication,andinteractions

• Memantine has additive e ects, with cholinesterase inhibitors, in patients with moderate to severe Alzheimer’s disease; reported to signi cantly delay time to nursing home admission[7]

• Shown to modify the progressive symptomatic decline in global status, cognition, function, and behavior in patients with moderate to severe Alzheimer’s disease over 28-week trial

• Fewerviralinfectionsreportedwithmemantineinclinicaltrials(ascomparedtocomparatordrugs)duetoitsantiviralproperties(itbelongstothe same chemical class as amantadine)

• Memantinetreatmentisassociatedwithanincreasedlife-expectancyrelativetodonepeziltreatment

• Fronto-temporaldementia:Nobene tofmemantineoncognitionorbehavior

• Memantine has N-methyl-D-aspartate (NMDA) inhibitory properties thought to contribute to its clinical e ectiveness, and preserves neuronal function by selectively blocking the excitotoxic e ects associated with abnormal glutamate transmission (blocks excessive extrasynaptic activity of the NDMA subtype of glutamate receptors, while largely sparing normal synaptic activity)

• Increasesdopaminelevelsandreportedtohaveantidyskinetic(antiparkinsonian)andantiviralproperties

General Comments

Pharmacology

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Dosing

• Seechart,p.324

• Bidadministrationrecommendedfordosesabove10mg;usualdailydoseis20mg(seetablep.324)

• Asmemantineisexcretedpredominantlybythekidneys,thefollowingdosageadjustmentsarerecommendedinrenalimpairment:

– Inmildlyimpairedrenalfunction(CrCl50–80mL/min),nodosageadjustmentisrequired

– Inmoderaterenalimpairment(CrCl30–49mL/min),thedoseshouldbe10mg/day.Ifwelltoleratedafteratleast7daysoftreatment,andbased

on clinical response, the dose may be increased up to 20 mg/day according to the standard titration scheme – Insevererenalimpairment(CrCl15–29mL/min),thedoseshouldbe10mg/day

• Pleaseseedosingrecommendationsofmemantineextended-releasecapsulesp.324

• Memantine extended release/donepezil recommended dosing is once a day. The capsules can be opened and sprinkled on food for patients who

have di culty swallowing

– For patients stabilized on donepezil and not currently on memantine, the recommended starting dose is 7mg/10mg, taken once a day in

the evening. Increase dose in 7mg increments of the memantine component to the recommended maintenance dose/maximum dose of 28 mg/10 mg once daily. The minimum recommended interval between dose increases is one week. Only increase dose if the previous dose has been well tolerated

– Patients stabilized on both memantine (10 mg twice daily or 28 mg XR once daily) and donepezil 10 mg once daily can be switched to me- mantine extended release/donepezil 28 mg/10 mg, taken once a day in the evening. Patients should start taking the combination product the day following the last dose of memantine and donepezil administered separately. If a patient misses a single dose of memantine extended release/donepezil, the next dose should be taken as scheduled, without doubling the dose

– Severe renal impairment (CrCl 5-29 mL/min, based on the Cockcroft-Gault equation): For patients stabilized on donepezil 10 mg once daily and not currently on memantine, starting dose is 7 mg/10 mg once a day in the evening. Increase to the maintenance dose of 14 mg/10 mg once daily after a minimum of one week. Patients stabilized on memantine (5 mg twice daily or 14 mg XR once daily) and donepezil 10 mg once daily can be switched to memantine extended release/donepezil 14 mg/10 mg, taken once daily in the evening

• Seechart,p.324

• Alkalinizationofurine(e.g.,highantaciduseordrasticdietchange)canreducerenaleliminationofmemantine–monitorurinepH

• TheCYP450enzymesystemdoesnotplayasigni cantroleinthemetabolismofmemantine

• In a study comparing 28 mg once daily memantine XR to 10 mg twice daily memantine immediate release, Cmax and AUC0-24 values were 48% and

33% higher for the XR dosage regimen, respectively

• The terminal elimination half-life increased by 18%, 41%, and 95% in subjects with mild, moderate, and severe renal impairment, respectively,

compared to healthy subjects

• Immediaterelease:

– Crossesblood/brainbarrierreadilyandisdetectableincerebrospinal uidwithin30minofadministration

• Extendedrelease:

– Foodhasnoe ectonoverallabsorption,however,peakplasmaconcentrationsoccurearlywhenadministeredwithfood

– No di erence in the absorption of memantine extended release when the capsule is taken intact or when the contents are sprinkled on apple-

sauce

• Seechart,pp.325–326

• Mostcommon:Confusion,agitation,insomnia,paranoia,mildtomoderatedizziness,andheadaches

• Urinaryincontinenceandurinarytractinfectionsreported

• Bloodandlymphaticsystemdisorders(agranulocytosis,pancytopenia,thromboticthrombocytopenicpurpura)reported

• Casesofdiscontinuationsyndromefollowingabruptcessationofmemantinehavebeendocumented

• Discontinuationsyndromeconsistedofinsomnia,aggressivebehavior,disinhibitedbehavior,anddelusions

• Emergenceofsymptomsasearlyas2daysafterdiscontinuation

Pharmacokinetics

Adverse Effects

Discontinuation Syndrome

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 321 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Dementia Treatment

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Precautions

Memantine (cont.)

• Memantine should be used with caution under conditions that raise urine pH (including alterations by diet, drugs, and the clinical state of the patient). Alkaline urine conditions may decrease the urinary elimination of memantine, resulting in increased plasma levels and a possible increase in adverse e ects

• Memantinehasnotbeensystematicallyevaluatedinpatientswithaseizuredisorder

• ThecombineduseofmemantinewithotherNMDAantagonists(amantadine,ketamine,ordextromethorphan)hasnotbeensystematicallyevalu-

ated and such use should be approached with caution

• Notrecommendedinpatientswithsevererenalimpairment

• Overdose(upto400mg)resultedinCNSe ectsincludingrestlessness,somnolence,stupor,visualhallucinations,seizures,andunconsciousness

• Treatment:Symptomatic

• Eliminationofmemantinecanbeenhancedbyacidi cationofurine

• Nobene tinchildrenandadolescentswithautismspectrumdisorder(ASD)

• Cautioninpatientswithdecreasedrenalfunction

• Monitoradversee ectsclosely

• Notteratogenicinanimals;e ectsinhumansunknown

• E ectunknown

• Minimize the use of antacids (e.g., Milk of Magnesia, Al/Mg products) as alkalinization of urine (pH higher than 8) will reduce elimination and increase the e ects of the drug – monitoring urine pH is recommended by some

• Capsules of memantine extended release and of memantine extended release/donepezil combination can be opened and sprinkled on food for patients who have di culties swallowing

• Fordetailedpatientinstructionsonmemantine,seePatientInformationSheet(detailsonp.440)

• Clinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterforthesecondagent

Contraindications

Toxicity

Management

Pediatric Considerations

Geriatric Considerations

Use in Pregnancy♢

Breast Milk

Nursing Implications

Patient Instructions

Drug Interactions

♢ See p. 439 for further information on drug use in pregnancy and e ects on breast milk

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Class of Drug

Example

Interaction Effects

Alkaline agent

Antacids, sodium bicarbonate, carbonic anhydrase inhibitors

Increased levels of memantine possible as elimination rate decreased signi cantly (by 80%) if pH higher than 8

Aminoadamantane

Amantadine, rimantadine

Do not combine as adverse effects may be enhanced

Anesthetic

Ketamine

Do not combine as adverse effects may be enhanced (additive effects of NMDA receptor blockade)

Antiarrhythmic

Procainamide, quinidine

Increased plasma levels of memantine possible due to competition for excretion via organic cation transporter-2 in the renal tubule

Anticoagulant

Warfarin

Monitor patients for increases in INR or prothrombin times

Anticonvulsant

Valproate

Synergistic effect in seizure suppression reported in animal studies

Anti-infective

Trimethoprim

Increased level of memantine due to competition for excretion via organic cation transporter-2 in the renal tubule

Antimalarial

Quinine

Increased level of memantine due to competition for excretion via organic cation transporter-2 in the renal tubule

Dextromethorphan

Do not combine as adverse effects may be enhanced (additive effects of NMDA receptor blockade)

Diuretic

Hydrochlorothiazide

Reduced excretion of hydrochlorothiazide possible; bioavailability of hydrochlorothiazide reduced by 20%

H2 antagonist

Cimetidine, ranitidine

Increased plasma levels of memantine possible due to competition for excretion via organic cation transporter-2 in the renal tubule

Hypoglycemic agent

Metformin

Theoretical increased level of memantine due to competition for excretion via organic cation transporter-2 in the renal tubule, but one study showed administration of memantine had no effect on the pharmacodynamics activities of glyburide or metformin

Smoking (tobacco)

Increased plasma levels of memantine possible due to competition for excretion via organic cation transporter-2 in the renal tubule

N-methyl-d-aspartate (NMDA) receptor antagonist

Amantadine, dextromethorphan, ketamine

Combined use with other NMDA antagonists has not been systematically evaluated and should be approached with caution

Comparison of Drugs for Treatment of Dementia

Donepezil

Galantamine

Rivastigmine

Memantine

Pharmacology

Piperidine-based

Reversible inhibitor of AChE

AchE > BuChE

Binds to acetylcholinesterase in the brain and has little effect on cholinesterase in serum, heart or small intestine

Phenanthrene alkaloid Reversible inhibitor of AChE AChE > BuChE

Allosteric modulator of central nicotinic receptors (may increase release of acetylcholine presynaptically)

A parasympathomimetic and a reversible cholinesterase inhibitor. Postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by cholinesterase

Acts through uncompetitive NMDA receptor antagonism, binding more effectively than Mg2+ ions at the NMDA receptor. Thus protects against chronically elevated concentrations of glutamate. Also has antagonistic activity at the subtype 3 serotonergic (5-HT3) receptor with a potency similar to that at the NMDA receptor, and lower antagonistic activity at the nicotinic acetylcholine receptor

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 323 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Dementia Treatment

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Comparison of Drugs for Treatment of Dementia (cont.)

Donepezil

Galantamine

Rivastigmine

Memantine

Dosing

Recommended starting dose: 5 mg once daily at bedtime. A dose of 10 mg should not be administered until patient has been onadailydoseof5mgfor4–6weeks.A dose of 23 mg once daily can be administered once patient has been on a dose of 10 mg once daily for at least

3 months

Tablets: Initial dose is 4 mg bid with meals for 4 weeks; increase to 8 mg bid after

4 weeks; if no side effects occur, increase dose to 12 mg bid

In moderate renal or hepatic impairment (Child-Pugh class B): Max. 16 mg/day; avoid if CrCl less than 9 mL/min or Child-Pugh class C

ER capsules: Initial dose is

8 mg/day in a.m. for minimum 4 weeks, increase to initial maintenance dose of 16 mg/day a.m.; if no side effects occur, can increase to 24 mg/day a.m. after further 4 weeks, if necessary (tabs 4mgbid=ER8mg/day) Conversion from tablets/oral solution to ER capsules should occur at the same daily dosage, with the last oral dose taken in the evening and ER capsules once daily started the next a.m.

Oral: Initial dose is 1.5 mg bid, given with meals for 4 weeks; increase by 1.5 mg bid every 4 weeks Usual maintenance dose: 3–6 mg bid (with meals) Patch: Apply patch on intact skin for a 24 h period; replace with a new patch every 24 h

Initiate treatment with Patch 5 (4.6 mg/24 h). After a minimum of 4 weeks, if tolerated, increase dose to Patch 10 (9.5 mg/24 h), which is the minimum effective dose. Following a minimum additional 4 weeks, may increase dosage to maximum dosage of Patch 15 (13.3 mg/24 h)

Mild to moderate Alzheimer’s disease and Parkinson’s disease dementia:

Patch 10 (9.5 mg/24 h) or Patch 15 (13.3 mg/24 h) once daily

Severe Alzheimer’s disease:

Patch 15 (13.3 mg/24 h) once daily

After treatment interruption longer than 3 days, retitrate dosage starting with Patch 5

(4.6 mg/24 h)

When switching from oral drug, Patch 5

(4.6 mg/24 h) is recommended for patients on less than 6 mg/day (do not increase dose for at least 4 weeks). Patch 10 (9.5 mg/24 h) can be used for patients on oral doses above 6 mg/day; apply patch on day following the last oral dose

Consider dose adjustments in patients with mild to moderate hepatic impairment or low body weight (less than 50 kg)

Dose escalation (over 1 month): 5 mg od for 7days,5mgbidfor7days,10mga.m.and 5mgp.m.for7days,then10mgbid;canbe taken with or without food

In renal insuf ciency, see dosing recommendations p. 321

No adjustment in hepatic impairment Switching from tablets to XR capsules requires no titration.

XR starting dose: 7 mg once daily; increase in 7 mg increments after minimum of one week, if well tolerated, up to maximum dose of 28 mg once daily

Recommended that patient on tablets 10 mg twice daily be switched to XR capsules 28 mg once daily on the day following the last dose of a 10 mg tablet

Severe renal impairment (CrCl 5-29 mL/min, based on the Cockcroft-Gault equation): Recommended that patient on 5 mg tablets twice daily be switched to XR capsules 14 mg once daily on the day following the last dose ofa5mgtablet

Memantine extended release/donepezil: Patients stabilized on donepezil (with or without memantine) can be switched to the memantine extended release/donepezil combination. For dosing details, see p. 321

Pharmacokinetics

Bioavailability

Time to peak plasma level (Tmax)

100%; is independent of food

3–4 h (10 mg tablets), 8 h (23 mg tablets

90% (immediate release); food lowers Cmax by 25% and delays Tmax by 1.5 h

ER: Not affected by food Immediate release: 1 h ER=4.5–5h

36%; food delays absorption, lowers Cmax, and increases AUC by 25%

Oral = 1.4–2.6 h

Patch = 10–16 h after rst dose

100%; food has no effect on absorption of memantine

Immediate release: 3–8 h

XR = 9-12 h; peak level occurs earlier when given with food

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Donepezil

Galantamine

Rivastigmine

Memantine

Plasma protein binding

Plasma half-life Liver disease Renal disease

Age Metabolism

96%, predominantly to albumin (75%), and α1-acid glycoprotein (21%). Interaction with drugs that are highly bound to plasma proteins (e.g., warfarin, digoxin) is unlikely 70–80 h in healthy adults; increases after multiple dose administration

Clearance decreased by 20% in patients with liver cirrhosis

Renal impairment has no effect on clearance

Metabolized via CYP2D6 and 3A4 and undergoes glucuronidation. Effects of CYP2D6 genotype: 31.5% slower clearance in poor metabolizers, 24% faster clearance in ultrarapid metabolizers

4 major metabolites, of which 2 are active

28–34%

IR:7–8h,ER:7h

Clearance decreased by 25–30% with liver disease

In moderate and severe renal impairment, AUC increased by 37% and 67%, respectively Clearance about 20% lower in females

Metabolized via CYP2D6 and 3A4

(inhibitors of both pathways increase oral bioavailability of galantamine modestly)

40%

Oral = 1–2 h (in both young and elderly patients) Patch = 3 h after patch removal

Clearance decreased by 60% in patients with liver disease

Clearance decreased by 65% in moderate renal impairment

Metabolized by esterase enzymes – low risk of drug interactions

Phenolic metabolite has approximately 10% of the activity of parent drug

Approx. 45%. Interaction with drugs that are highly bound to plasma proteins (e.g., warfarin, digoxin) is unlikely

Elimination half-life 60–100 h

No dosage adjustment needed in mild or moderate hepatic impairment

Clearance dependent on renal function (see Dosing, p. 321)

Pharmacokinetics in young and elderly subjects are similar

Excreted renally (60–80%). The hepatic microsomal CYP450 enzyme system does not play a signi cant role

Renal elimination rate decreased signi cantly in alkaline pH (higher than 8) No pharmacokinetic interactions with drugs metabolized by CYP isozymes expected

Adverse Effects

CNS

5–10%: Nausea, vomiting, diarrhea, gastric upset, constipation;

> 2%: Anorexia and weight loss (GI effects 5% higher with 23 mg vs. 10 mg dose) 5–10%: Fatigue, headache;

up to 18%: Insomnia;

2–5%: Abnormal dreams, nightmares, somnolence, agitation, activation, depression;

< 2%: Restlessness, aggression, irritability; < 1%: Transient ischemic attack, hypokinesia, seizures

Nightmares reported; manageable by switching from nighttime to morning dosing

10–30%: Nausea, vomiting; 5–10%: Diarrhea;

5–10%: Anorexia;

> 1%: Flatulence

5–10%: Insomnia, headache, depression, fatigue, agitation;

2–5%: Sedation, tremor;

< 1%: Paranoia, delirium, ataxia, vertigo, hypertonia, seizures

Reports of enhanced REM sleep, “lucid dreaming”

10–30%: Nausea, vomiting, diarrhea, abdominal pain;

> 30%: Anorexia (with weight loss, especially in females)

2–10%: Headache;

> 5%: Sedation, asthenia;

> 2%: Anxiety, insomnia, aggression, hallucinations;

> 1%: Tremor, ataxia, abnormal gait Cases of seizures

Case report of Pisa syndrome

> 5%: Diarrhea; 2–10%: Constipation

5–20%: Insomnia, agitation;

> 2%: Headache, confusion;

< 2%: Lethargy

Reports of vivid dreams, nightmares, and hallucinations

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 325 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Dementia Treatment

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Comparison of Drugs for Treatment of Dementia (cont.)

Donepezil

Galantamine

Rivastigmine

Memantine

Cardiovascular

Respiratory

Special senses Skin

Urogenital

Musculoskeletal Liver

Other

Rapid onset of manic symptoms in patients with a history of BD reported

Case report of delirium

Worsening of parkinsonism and abnormal movements (restless legs, stuttering) reported

Case reports of Pisa syndrome

2–10%: Dizziness;

< 2%: Syncope, atrial brillation, hypotension;

< 1%: Arrhythmia, rst degree AV block, torsades de pointes, congestive heart failure, symptomatic sinus bradycardia, supraventricular tachycardia, deep vein thromboses

> 5%: Nasal congestion;

< 2%: Dyspnea;

< 1%: Pulmonary congestion, pneumonia, sleep apnea

< 2%: Blurred vision;

< 1%: Dry eyes, glaucoma

2–10%: Flushing

< 2%: Pruritus and urticaria;

< 2%: Frequent urination, nocturia; < 1%: Prostatic hypertrophy;

> 5%: Incontinence

5–10%: Muscle cramps, pain; < 2%: Arthritis

< 2%: Dehydration;

< 1%: Blood dyscrasias, jaundice, renal failure

5–10%: Dizziness;

> 2%: Bradycardia, syncope (dose-related);

> 1%: Chest pain;

< 1%: Edema, atrial brillation

Case report of QTc prolongation

> 2%: Nasal congestion

> 5%: Urinary tract infection;

> 2%: Hematuria;

> 1%: Incontinence;

< 1%: Urinary retention 5–10%: Muscle cramps

2–5%: Anemia;

< 1%: Blood dyscrasias

10–20%: Dizziness; 2–5%: Syncope

> 2%: Nasal congestion;

< 2%: Dyspnea;

< 1%: Upper respiratory tract infections

> 2%: Tinnitus

> 5%: Increased sweating

Flushing, skin reactions (e.g., rash, redness, in ammation at site of patch application) Disseminated cutaneous hypersensitivity reactions reported irrespective of administration route (oral or transdermal)

> 5%: Urinary tract infection

> 2%: Frequent urination, incontinence

< 1%: Arthralgia, myalgia, pain Has been associated with hepatitis

< 1%: Dehydration, hypokalemia; < 1%: Nose bleeds

2–10%: Dizziness; 2–5%: Syncope

> 2%: Cough

Cases of epidermal necrolysis

> 5%: Incontinence;

> 2%: Urinary tract infections; < 1%: Increased libido

< 1%: hypertonia

Elevated ALT/SGPT

Case of liver failure

Case of aplastic anemia

Cases of pancreatitis and renal failure

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

References

1 Rodda J, Morgan S, Walker Z. Are cholinesterase inhibitors effective in the management of the behavioral and psychological symptoms of dementia in Alzheimer’s disease? A systematic review of randomized, placebo-controlled trials of donepezil, rivastigmine and galantamine. Int Psychogeriatr. 2009;21(5):813–824. doi:10.1017/S1041610209990354

2 Seripa D, Bizzarro A, Pilotto A, et al., Role of cytochrome P4502D6 functional polymorphisms in the ef cacy of donepezil in patients with Alzheimer’s disease. Pharmacogenet Genomics. 2011;21(4):225–230. doi:10.1097/FPC.0b013e32833f984c

3 Pariente A, Sanctussy DJ, Miremont-Salamé G, et al. Factors associated with serious adverse reactions to cholinesterase inhibitors: A study of spontaneous reporting. CNS Drugs. 2010:24(1):55–63. doi:10.2165/11530300-000000000-00000

4 Birks J, Grimley Evans J, Iakovidou V, et al. Rivastigmine for Alzheimer’s disease. Cochrane Database Syst Rev. 2009;2:CD001191. doi:10.1002/14651858.CD001191.pub2

5 Gill SS, Anderson GM, Fischer HD, et al. Syncope and its consequences in patients with dementia receiving cholinesterase inhibitors: A population-based cohort study. Arch Intern Med.

2009;169(9):867–873. doi:10.1001/archinternmed.2009.43

6 Kishi T, Matsunaga S, Iwata N. The effects of memantine on behavioral disturbances in patients with Alzheimer’s disease: A meta-analysis. Neuropsychiatr Dis Treat. 2017;13:1909–1928.

doi:10.2147/NDT.S142839

7 Lopez OL, Becker JT, Wahed AS, et al. Long-term effects of the comcomitant use of memantine with cholinesterase inhibition in Alzheimer disease. J Neurol Neurosurg Psychiatry.

2009;80(6):600–607. doi:10.1136/jnnp.2008.158964

Additional Suggested Reading

• AbeY,ShimokadoK,FushimiK.Donepezilisassociatedwithdecreasedin-hospitalmortalityasaresultofpneumoniaamongolderpatientswithdementia:Aretrospectivecohortstudy. Geriatr Gerontol Int. 2018;18(2):269–275. doi:10.1111/ggi.13177

• BallardD,CorbettA.Managementofneuropsychiatricsymptomsinpeoplewithdementia.CNSDrugs.2010;24(9):729–739.doi:10.2165/11319240-000000000-00000

• BaskysA,ChengJX.Pharmacologicalpreventionandtreatmentofvasculardementia:Approachesandperspectives.ExpGerontol.2012;47(11):887–891.doi:10.1016/j.exger.2012.07.002

• Deardorff WJ, Feen E, Grossberg GT. The use of cholinesterase inhibitors across all stages of Alzheimer’s disease. Drugs Aging. 2015;32(7):537–547. doi:10.1007/s40266-015-0273-x.

doi:10.1007/s40266-015-0273-x

• EmreM,TsolakiM,BonuccelliU,etal.MemantineforpatientswithParkinson’sdiseasedementiaordementiawithLewybodies:Arandomized,double-blind,placebo-controlledtrial.

Lancet Neurol. 2010;9(10):969–977. doi:10.1016/S1474-4422(10)70194-0

• FeldmanHH,PirttilaT,DartiguesJF,etal.Analysesofmortalityriskinpatientswithdementiatreatedwithgalantamine.ActaNeurolScand.2009;119(1):22–31.doi:10.1111/j.1600-0404.

2008.01047.x

• HerrmannN,LanctotK,HoganDB.Pharmacologicalrecommendationsforthesymptomatictreatmentofdementia:TheCanadianConsensusConferenceontheDiagnosisandTreatment

of Dementia 2012. Alzheimers Res Ther. 2013;5(Suppl 1):S5. doi:10.1186/alzrt201

• Huang F, Fu Y. A review of clinical pharmacokinetics and pharmacodynamics of galantamine, a reversible acetylcholinesterase inhibitor for the treatment of Alzheimer’s disease, in

healthy subjects and patients. Curr Clin Pharmacol. 2010;5(2):115–124. doi:10.2174/157488410791110805

• JonesRW.Areviewcomparingthesafetyandtolerabilityofmemantinewiththeacetylcholinesteraseinhibitors.IntJGeriatrPsychiatry.2010;25(6):547–553.doi:10.1002/gps.2384

• LiY,HaiS,ZhouY,etal.Cholinesteraseinhibitorsforrarerdementiasassociatedwithneurologicalconditions.CochraneDatabaseSystRev.2015;(3):CD009444.doi:10.1002/14651858.

CD009444.pub3

• LockhartIA,MitchellSA,KellyS.Safetyandtolerabilityofdonepezil,rivastigmineandgalantamineforpatientswithAlzheimer’sdisease:Systematicreviewofthe’real-world’evidence.

Dement Geriatr Cogn Disord. 2009;28(5):389–403. doi:10.1159/000255578

• McGuinnessB,O’HareJ,CraigD,etal.Cochranereviewon‘Statinsforthetreatmentofdementia’.IntJGeriatrPsychiatry.2013;(28)2:119–126.doi:10.1002/gps.3797

• O’BrienJT,HolmesC,JonesM,etal.Clinicalpracticewithanti-dementiadrugs:Arevised(third)consensusstatementfromtheBritishAssociationforPsychopharmacology.JPsychophar-

macol. 2017;31(2):147–168. doi:10.1177/0269881116680924

• Pasqualetti G, Tognini S, Calsolaro V, et al. Potential drug–drug interactions in Alzheimer patients with behavioral symptoms. Clin Interv Aging. 2015;10:1457–1466. doi:10.2147/CIA.

S87466

• XiaP,ChenHS,ZhangD,etal.MemantinepreferentiallyblocksextrasynapticoversynapticNMDAreceptorcurrentsinhippocampalautapses.JNeurosci.2010;30(33):11246–11250.

doi:10.1523/JNEUROSCI.2488- 10.2010

• ZekryD,GoldG.Managementofmixeddementia.DrugsAging.2010:27(9):715–728.doi:10.2165/11538250-000000000-00000

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 327 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Further Reading

Dementia Treatment

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

SEX-DRIVE DEPRESSANTS

Product Availability∗

Generic Name

Chemical Class

Trade Name(A)

Dosage Forms and Strengths

Cyproterone

Antiandrogen/Progestogen

Androcur(C) Androcur Depot(C)

Tablets: 2 mg, 50 mg Injection (depot): 100 mg/mL

Degarelix

LHRH/GnRH** antagonist

Firmagon

Injection (depot): 80 mg/vial, 120 mg/vial

Finasteride

Anti-androgen; 5-α reductase inhibitor

Proscar

Tablets: 1 mg, 5 mg

Goserelin

LHRH/GnRH agonist

Zoladex, Zoladex LA

Implant (depot): 3.6 mg/vial [1-month implant], 10.8 mg/vial [3-month implant]

Leuprolide

LHRH/GnRH agonist

Lupron Lupron Depot

Eligard

Injection: 5 mg/mL(C)

Injection (depot): 3.75 mg/vial [1-month slow release],

7.5 mg/vial [1-month slow release],

11.25 mg/vial [3-month slow release],

15 mg/vial [1-month slow release](B) ,

22.5 mg/vial [3-month slow release],

30 mg/vial [4-month slow release],

45 mg/vial [6-month slow release](B)

Injection (depot): 7.5 mg/vial [1-month slow release], 22.5 mg/vial [3-month slow release],

30 mg/vial [4-month slow release], 45 mg/vial [6-month slow release](B)

Medroxyprogesterone

Progestogen

Provera

Tablets: 2.5 mg, 5 mg, 10 mg, 100 mg

DepoProvera

Injection (depot): 150 mg/mL, 400 mg/mL(B)

∗ Refer to Health Canada’s Drug Product Database or the FDA’s Drugs@FDA for the most current availability information, (A) Generic preparations may be available, ** LHRH = Luteinizing hormone-releasing hormone, GnRH = gonadotropin-releasing hormone

(B) Not marketed in Canada,

Indications‡

( approved)

General Comments

• Reductionofsexualarousalandlibido(usuallyforsexualo enders)

• Inappropriateordisruptivesexualbehaviorinpatientswithdementia

• Althoughcontrolleddouble-blindstudiesarelacking,giventhenatureofthedi cultiessu eredbytheindividualsbeingtreated,andtheserious- ness of the condition, virtually all of the uncontrolled studies show a signi cant e ect in the same direction, which would be unlikely if this e ect were truly spurious

• Pharmacotherapy may be combined with intensive psychotherapy to possibly improve compliance and outcomes[1, 2]. Treatment of any comorbid psychiatric conditions is recommended

• While medroxyprogesterone and cyproterone are e ective for partial sex drive reduction in non-violent o enders, serious paraphilias in which ablation of testosterone of testicular origin is indicated require treatment with LHRH (GnRH) agonists or antagonists; GnRH analogues have demonstrated a very high e cacy, notably where subjects have failed treatment with psychotherapy and other anti-androgens

‡ Indications listed here do not necessarily apply to all sex-drive depressants or all countries. Please refer to a country’s regulatory database (e.g., US Food and Drug Administration, Health Canada Drug Product Database) for the most current availability information and to know which drugs are indicated in which country

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Pharmacology

Dosing

Adverse Effects

• Evidencefore cacyofserotonergicagents(e.g.,SSRIs)iscontroversialandlimited.SSRIsshouldNOTbeusedaloneinseriouso enders

• Medroxyprogesteroneandcyproteronearenote ectiveinsomepatientsdespitehighdosesandmorethan90%reductionoftestosteronelevels

• Similartoothermedroxyprogesteroneandcyproterone,ethinyloestradiol(0.01mg/daily)maynotbease ectiveinsomepatients

• Antipsychotics:Chlorpromazineisnote ectiveascomparedtobenperidol,whichhasasigni cantlibido-reducinge ect

• Theopioidantagonistnaltrexone(100-200mgperday)mayprovideasafe rststepintreatingadolescentsexualo enders

• Leuprolide and goserelin may cause a transient increase (over 2 weeks or more) in luteinizing hormone and testosterone, followed by a dramatic

decrease and suppression of the hormones (while not considered to be clinically signi cant, the 2-week initial hormone increase does not occur

with LHRH antagonists)

• Longer-actingdepotinjections(e.g.,leuprolide30mgq4months)havedemonstratede cacyintrialswithhigh-risksexo enders

• TheLHRHagonistsandantagonistsareusedforseveralother(nonpsychiatric)indicationssuchasthetreatmentandpreventionofvarioustypesof

prostate cancers (except medroxyprogesterone)

• Rarely,seriouso enderspartlyrefractorytoLHRHagentsmayrequireadditionalperipheraltestosteroneblockadewithagentssuchas nasteride

or other peripheral receptor blockers

• Seek consultation with an internist/endocrinologist prior to initiation of therapy; thereafter, yearly consultation and bone density monitoring is

recommended (see Lab Tests/Monitoring, p. 333)

• Seep.331

• GnRHagonistmedicationisrelativelynon-titratableintermsoftestosteronesuppressione ects

• Depot injections of medroxyprogesterone and cyproterone may initially be prescribed every 2 weeks with monitoring of serum testosterone and

sexual self-report. Often, weekly injection schedule is necessary to achieve good behavioral control and testosterone suppression. Depot injection

of LHRH agonists are available in 1–month, 3–month, 4–month, and 6-month preparations

• Anaphylaxis,whilereportedintheliteraturewithleuprolide,hasrarelybeenobservedinclinicalpractice;however,somecliniciansfeelthatatest

dose of short-acting leuprolide acetate is indicated

• Seep.332

• Themainseriouslong-termsidee ectofLHRHagonistsandantagonistsisdecreasedbonedensitymediatedbytestosteronedepletion.Treatment

with bisphosphonates, calcium, or vitamin D has been found to arrest or even reverse this side e ect. Clear evidence of fractures caused by this

treatment is not reported (it should be remembered that “fracture risk” in densitometry readings is not standardized on this gender/age group).

• Androgendeprivationmayalsoresultinweightgainwithincreasedvisceraladiposity,mildanemia,impairedglucosetolerance,dyslipidemia,and

rarely emotional disturbances[3]

• Oftenimpotenceorrarelygynecomastia

• Medroxyprogesteroneandcyproteronecarryriskofthromboembolism–riskincreasedwithageandsmoking

• QTcprolonagationhasbeenreportedwithGnRHagonist,combinedandrogenblockadeoraGnRHantagonistinthetreatmentofprostatecancer,

with 9–21 millisecond increases in QTc. Hypogonadism rather than a direct drug e ect appears to account for the observed QTc prolongation

• Inappropriatesexualbehaviorsmayoccurinpatientswithdementia.Treatmentmustbeindividualizedbasedonthemedicalstatusoftheindivid- ual, including current drug therapy, as well as the risk this behavior poses to others

• SSRIsortricyclicantidepressantsareconsidered rstchoicefornonthreatening,nonviolentdementedpatientswithproblematicsexualbehaviors[4]. If refractory to these agents, LHRH agonists are preferred due to a more favorable side e ect pro le, including fewer thromboembolic e ects

• Degarelix is supplied as a powder to be reconstituted with sterile water for injection, prior to injecting; the solution should be clear. The drug is administered subcutaneously in the abdominal region that is not exposed to pressure (e.g., from a belt)

• Goserelinpelletisinjectedsubcutaneouslyintotheanteriorabdominalwall

• Leuprolide:Reconstitutedrugwith1mLofdiluentprovided.Shakewell.Suspensionisstablefor24handcanbestoredatroomtemperature.Inject

using 22 gauge needle (or larger). Injection may rarely cause irritation (burning, itching, and swelling)

Geriatric Considerations

Nursing Implications

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 329 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Sex-Drive Depressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Medicolegal Issues

Patient Instructions

Drug Interactions

Sex-Drive Depressants (cont.)

• Medroxyprogesterone: Shake sterile aqueous suspension vigorously just before use to ensure that the dose being given represents a uniform suspension. Inject intramuscularly, preferably to the gluteus maximus, but other muscle tissue such as the deltoid may be used

• CAUTION:Womenwhoare,ormaybe,pregnantshouldnothandlecrushedorbrokentabletsofcyproterone,medroxyprogesteroneor nasteride because of risk of absorption and subsequent potential risk to a male fetus

• Drugmustbetakenconsistentlytomaintaine ect

• Assexdrivereductionisnotanapprovedindicationfortheseagents,gooddocumentationofconsentisessential

• Useofthesedrugsinvolvescomplexissuesinregardtoconsent,asthepatientsareofteninvolvedwiththelegalsystem

• Someoftheagents(GNRHagonist/antagonist)havesexdrivereductionasaformallyapprovedindicationinsomeEuropeanjurisdictions

• Fordetailedpatientinstructionsonsex-drive-depressants,seethePatientInformationSheet(detailsp.440)

• Clinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterforthesecondagent

• Leuprolide considered to have few drug interactions since it is primarily degraded by peptidase enzymes (not CYP450 enzymes) and has a low

degree of protein binding

• FinasterideisaminorCYP3A4substrateandhenceitslevelscanbealteredbyotherdrugsthatinduceorinhibitCYP3A4enzymes

Class of Drug

Example

Interaction Effects

Alcohol

Alcohol may reduce the antiandrogenic effect of cyproterone when used for hypersexuality

Anti-androgen agent

Finasteride

Additive effects on testosterone reduction if utilized with leuprolide or goserelin

Antibiotic

Clarithromycin, erythromycin Rifampin

May increase plasma levels of cyproterone, nasteride, and medroxyprogesterone due to inhibition of CYP3A4

Decreased plasma levels of cyproterone, nasteride, and medroxyprogesterone due to induction of CYP3A4

Anticonvulsant

Carbamazepine, phenytoin

May decrease plasmas level of cyproterone, nasteride, and medroxyprogesterone due to inhibition of CYP3A4

Anti brinolytic

Tranexamic acid

Medroxyprogesterone and cyproterone may enhance the thrombogenic effect of tranexamic acid

Antifungal

Itraconazole, ketoconazole

May increase plasma levels of cyproterone, nasteride, and medroxyprogesterone due to inhibition of CYP3A4

Antiretroviral

Protease inhibitor

Antivirals containing cobicistat Indinavir, nel navir, ritonavir, saquinavir

May increase plasma levels of cyproterone, nasteride, and medroxyprogesterone due to inhibition of CYP3A4

Herbs (with progestogenic properties)

Bloodroot, yucca

May enhance the adverse/toxic effect of progestins

Hypoglycemic

Glyburide, metformin

Diminished therapeutic effect of antidiabetic agent with leuprolide

QT-prolonging agent

Cipro oxacin, pimozide, tetrabenazine, thioridazine, ziprasidone

Androgen deprivation can prolong the QT effect of the drug, leading to severe arrhythmia

St. John’s Wort

May decrease plasmas level of cyproterone, nasteride, and medroxyprogesterone due to induction of CYP3A4

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Comparison of Sex-Drive Depressants

Cyproterone

Degarelix

Finasteride

Goserelin

Leuprolide

Medroxyprogesterone

Pharmacology

A steroidal compound with antiandrogenic, antigonadotropic, and progestin-like activity

GnRH antagonist that reversibly binds to GnRH receptors in the anterior pituitary gland. This reduces LH and FSH secretion, decreasing testosterone production. Note: Testosterone levels DO NOT have an initial are as typically seen with GnRH agonists

A synthetic 5α-reductase inhibitor, an inhibitor of the enzyme that converts peripheral testosterone into 5α-dihydrotestos- terone, a potent androgen

Synthetic analog of GnRH that causes an initial increase in LH and FSH. Chronic administration results in a sustained suppression of pituitary gonadotropins

A synthetic LHRH agonist that acts as a potent inhibitor of gonadotropin secretion. Continuous administration results in suppression of ovarian and testicular steroidogenesis

Inhibits secretion of pituitary gonadotropins by progestational feedback

Dosing

Oral: 100–500 mg/day Depot:

100–600 mg/week

Depot: initial dose = 240 mg sc, maintenance dose = 80 mg sc

5 mg/day

3.6 mg/month; or 10.8 mg q 3 months

Depot: 7.5 mg/month;

22.5 mg q 3 months; 30mgq4months;45mgq 6 months sc

Oral: 100–600 mg/day Depot:

100–700 mg/week IM

Pharmacokinetics

Time to Peak Plasma Level (Tmax)

Oral: 3–4 h Depot: 3 days

2 days

1–2 h)

3.6 mg implant: 12–15 days (males); 8–22 days (females)

Depot: Within 3 h of injection Metabolite: 2–6 h

Oral: 2–4 h Depot: Few days

Protein Binding Metabolism Elimination Half-life (T1/2)

> 95%

via CYP3A4 Oral: 33–42 h Depot: 4 days

90%

via peptidase 53 days

90%

primarily via CYP3A4

5-6 h (age 16-60), 8 h (over age 70)

27%

via hydrolysis

3.6 mg implant: 4.2 h (males); 2–3 h (females)

43-49%

via peptidase Not established

90%

via CYP3A4

Oral: 12–17 h Depot: 50 days

Renal

Not determined

Clearance reduced by 23% if CrCl less than 50 mL/min; dose reduction not recommended in mild to moderate renal impairment. No data in severe renal insuf ciency

Clearance of metabolites decreased; no adjustment in renal impairment

Half-life increased to 12 h in renal impairment

Not determined

No change in dosage

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 331 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Sex-Drive Depressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Comparison of Sex-Drive Depressants (cont.)

Cyproterone

Degarelix

Finasteride

Goserelin

Leuprolide

Medroxyprogesterone

Adverse Effects

CNS

Atrophy of seminiferous tubules with chronic use (possibly reversible if drug stopped) Gynecomastia (15–20%) Decrease in body hair and sebum production, weight gain Thromboembolism Decreased bone density Vitamin B12 de ciency Cardiovascular disease

Fatigue, depression (5–10%)

Irritability

Suicidal ideation

Decreased sperm count, hot ashes, sweating, impotence QT prolongation

Dizziness

Osteoporosis

Increased appetite and weight gain

Pain, erythema, swelling at injection site

Increase in transaminase and GGT

Fatigue, headache, insomnia

Decreased sperm count, impotence, breast tenderness Male breast cancer Dizziness, postural hypotension, edema Decreased libido even after discontinuation of treatment

Lethargy, headache Depression

Decreased sperm count, atrophy of seminiferous tubules, impotence

Hot ashes

Sweating, rash, edema (3%), nausea, other GI effects, loss of body hair, myalgia, anemia, spasms, dyspnea

Decreased bone density Although there has been speculation that the are-up or increase in testosterone after the initial administration of GnRH agonists is signi cant and possibly associated with risk for increased sexual drive and deviant behavior, this observed are-up has not been noted to be clinically signi cant

Prostatic carcinoma, stage B2-C prostatic carcinoma

Lethargy

Decreased sperm count, atrophy of seminiferous tubules, impotence

Hot ashes (60%)

Sweating, rash, edema (3%), nausea, other GI effects, loss of body hair, myalgia, anemia, spasms, lethargy, dyspnea Decreased bone density Although there has been speculation that the are-up or increase in testosterone after the initial administration of GnRH agonists is signi cant and possibly associated with risk for increased sexual drive and deviant behavior, this observed are-up has not been noted to be clinically signi cant

Anxiety, insomnia

Decreased sperm count, hot ashes, sweating, impotence Increased appetite and weight gain

Dyspnea, hypertension, edema, muscle cramps, GI upset Thromboembolism (smoking may increase risk)

Excess salivation

Mild depression, lethargy, nervousness, insomnia, nightmares, headaches

Precautions

May impair carbohydrate metabolism, fasting blood glucose, and glucose tolerance test Hypercalcemia and changes in plasma lipids can occur

Alcohol use may reduce the antiandrogenic effect Deep vein thrombosis and thromboembolism (smoking may increase risk)

Decreased bone density reported

Anti-degarelix antibody development observed in 10% of patients after 1 year; ef cacy and safety appears not affected Long-term androgen deprivation prolongs the QT interval; incidence of QTc interval greater than 450 ms is 20%

Severe hepatic impairment Severe renal impairment

Patients with large residual urine volume and/or severely diminished urinary ow should be carefully monitored for obstructive uropathy Increased risk of high-grade prostate cancer

Transient elevation of BUN, creatinine, testosterone, and acid phosphatase reported (rarely seen)

Hyperglycemia and diabetes, cardiovascular diseases, hypercalcemia

Effect on QT/QTc interval

Long-term androgen deprivation prolongs the QT interval; incidence of QTc interval greater than 450 ms is 20% Hyperglycemia and diabetes, convulsions, allergies to benzyl alcohol (an ingredient of the drug’s vehicle)

May decrease glucose tolerance

Monitor patients with conditions aggravated by uid retention, e.g., asthma, migraine Deep vein thrombosis and thromboembolism (smoking may increase risk)

Depression

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Cyproterone

Degarelix

Finasteride

Goserelin

Leuprolide

Medroxyprogesterone

Contraindications

Liver disease, thromboembolic disorders

Active pituitary pathology

Dubin Johnson syndrome, Rotor syndrome

Previous or existing liver tumors (only if these are not due to metastases from carcinoma of the prostate), history of meningioma, wasting diseases (except inoperable carcinoma of the prostate)

Severe chronic depression

Hypersensitivity to drug Women who are or who may become pregnant

Liver disease, thromboembolic disorders

Active pituitary pathology

Hypersensitivity to drug (rare) Active pituitary pathology Disorders of bone demineralization (relative contraindication)

Liver disease; thromboembolic disorders

Active pituitary pathology

History of or actual myocardial infarction or coronary artery disease

Any ocular lesion arising from ophthalmic vascular disease

Current or history of migraine with focal aura

Toxicity

No reports

Lab Tests/Monitoring

Pretreatment

Chronic

Serum testosterone, prolactin, LH, FSH, liver function, Hb, WBC, glucose, blood pressure, weight

Testosterone: q 6 months LH, FSH, and prolactin: q 6 months

Blood pressure, weight: q 3 months

ECG, Serum testosterone, prolactin, LH, FSH, liver function, Hb, WBC, glucose, baseline serum potassium, calcium and magnesium, blood pressure, weight

Testosterone: q 6 months

LH, FSH, and prolactin: q

6 months

Blood pressure, weight: q

3 months

Prostate-speci c antigen (PSA) periodically

Serum testosterone, prolactin, LH, FSH, liver function, Hb, WBC, glucose, blood pressure, weight

Testosterone: q

6 months

LH, FSH, and prolactin: q 6 months

Blood pressure, weight: q 6 months Prostate-speci c antigen (PSA) periodically

Serum testosterone, prolactin, LH, FSH, ECG, BUN, creatinine, CBC, liver function,

bone density scan

Testosterone: q 1 month for 4 months,

then q 6 months

BUN, creatinine, LH, FSH, and prolactin:

q 6 months

Bone density: q 1-2 years

Serum testosterone, prolactin, LH, FSH, ECG, BUN, creatinine, CBC, liver function,

bone density scan

Testosterone: q 1 month for 4 months, then q 6 months BUN, creatinine, LH, FSH, and prolactin:

q 6 months

Bone density: q 1–2 years Prostate-speci c antigen (PSA) periodically

Serum testosterone, prolactin, LH, FSH, liver function, Hb, WBC, glucose, blood pressure, weight

Testosterone: q

6 months

LH, FSH, and prolactin: q 6 months

Blood pressure, weight: q 6 months

Further Reading

References

1 Codispoti VL. Pharmacology of sexually compulsive behavior. Psychiatr Clin North Am. 2008;31(4):671–679. doi:10.1016/j.psc.2008.06.002

2 Khan O, Ferriter M, Huband N, et al. Pharmacological interventions for those who have sexually offended or are at risk of offending. Cochrane Database Syst Rev. 2015;(2):CD007989.

doi:10.1002/14651858.CD007989.pub2

3 GiltayEJ,GoorenLJ.Potentialsideeffectsofandrogendeprivationtreatmentinsexoffenders.JAmAcadPsychiatryLaw.2009;37(1):53–58.Retrievedfromhttp://www.jaapl.org/content/

37/1/53.long

4 Guay DR. Inappropriate sexual behaviors in cognitively impaired older individuals. Am J Geriatr Pharmacother. 2008;6(5):269–288. doi:10.1016/j.amjopharm.2008.12.004

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 333 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Sex-Drive Depressants

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Sex-Drive Depressants (cont.)

Additional Suggested Reading

• BrikenP,HillA,BernerW.Pharmacotherapyofparaphiliaswithlong-actingagonistsofluteinizinghormone-releasinghormone.Asystematicreview.JClinPsychiatry.2003;64(8):890– 897.

• BrikenP,KafkaMP.Pharmacologicaltreatmentsforparaphilicpatientsandsexualoffenders.CurrOpinPsychiatry.2007;20(6):609–613.doi:10.1097/YCO.0b013e3282f0eb0b

• Degarelix( rmagon)forprostatecancer.MedLettDrugsTher.2009;51(1323):82–83.

• GuayDR.Drugtreatmentofparaphilicandnonparaphilicsexualdisorders.ClinTher.2009;31(1):1–31.doi:10.1016/j.clinthera.2009.01.009

• HoloydaBJ,KellaherDC.Thebiologicaltreatmentofparaphilicdisorders:Anupdatedreview.CurrPsychiatryRep.2016;18(2):19.doi:10.1007/s11920-015-0649-y

• HoutsFW,TallerI,TuckerDEetal.Androgendeprivationtreatmentofsexualbehavior.AdvPsychosomMed.2011;31:149–163.doi:10.1159/000330196

• HsiehAC,RyanCJ.Novelconceptsinandrogenreceptorblockade.CancerJ.2008;14(1):11–14.doi:10.1097/PPO.0b013e318161d13e

• International Association for the Treatment of Sexual Offenders (IATSO). IATSO standards of care for the treatment of adult sex offenders. Vienna, Austria: IATSO. Retrieved from

Click to access iatso_standardsofcare_adult_so.pdf

• TurnerD,PetermannJ,HarrisonK,etal.Pharmacologicaltreatmentofpatientswithparaphilicdisordersandriskofsexualoffending:Aninternationalperspective.WorldJBiolPsychiatry.

2017. Advance online publication. doi:10.1080/15622975.2017.1395069

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Classi cation

DRUGS OF ABUSE

• This chapter gives a general overview of common drugs of abuse and is not intended to deal in detail with all drugs of abuse or to be a complete guide to treatment

• Slangnamesofstreetdrugschangefrequentlyandvarywithcountry,region,anddrugsubculture.Alistofcommondrugnamesisavailablefrom the NIH-sponsored website http://www.drugabuse.gov/drugs-abuse/commonly-abused-drugs/commonly-abused-drugs-chart

• Drugsofabusecanbeclassi edasfollows:

Drug Class

Agent*

Page

Alcohol

(Ethyl) Alcohol

See p. 337

Stimulants

Examples: Amphetamine,methamphetamine,cocaine,(caffeine,ephedrine)

See p. 341

Hallucinogens

Examples: Lysergicaciddiethylamide,cannabis,mescaline,psilocybin

See p. 346

Opioids

Examples: Morphine,oxycodone,hydromorphone,heroin

See p. 354

Inhalants/Aerosols

Examples: Glue,paintthinner

See p. 359

Gamma-hydroxybutyrate

See p. 360

Sedatives/Hypnotics

Examples: Flunitrazepam Barbiturates**

See p. 362 See p. 238

Benzodiazepines**

See p. 222

Nicotine

Examples: Cigarettes,cigars

See p. 363

* Only includes examples of commonly used substances; ** Not dealt with speci cally in this chapter

De nitions

Drug Abuse

Drug Dependence

a) Behavioral aspects b) Physical aspects

General Comments

• While DSM5 combines substance abuse and substance dependence into a single disorder called substance use disorder, the following terms are still commonly used and their de nitions have been retained here for reader’s convenience

• Acute or chronic intake of any substance that: (a) has no recognized medical use, (b) is used inappropriately in terms of its medical indications or its dose. Drug abuse is commonly associated with harm to the individual or others

• Craving or desire for repeated administration of a drug to provide a desired e ect or to avoid discomfort

• A physiological state of adaptation to a drug which usually results in development of tolerance to drug e ects and withdrawal symptoms when

the drug is stopped

• Intensepersistentdruguseassociatedwithastrongdesiretocontinueuse,withdisregardtoconsequencesorpersonalharm

• Phenomenoninwhichincreasingdosesofadrugareneededtoproduceadesirede ectore ectintensitydecreaseswithrepeateduse

• Thee ectwhichanydrugofabusehasonanindividualdependsonalargenumberofvariables: 1. Dose (amount consumed)

2. Potency and purity of drug

3. Route of administration

4. Past experience of the user (this will a ect both physiological and psychological response to drug) 5. Environmental factors, including other people present and concurrent drug use

Addiction

Tolerance

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 335 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Drugs of Abuse

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Detection of Drugs of Abuse

Pharmacology

Adverse Effects

Drugs of Abuse (cont.)

6. Personality and genetic pro le of user

7. Age of user

8. Clinical status of user, i.e., psychiatric illness, recent stress, user’s expectations, and present feelings

• Some users may have di erent experiences with the same drug on di erent occasions. They may encounter both pleasant and unpleasant e ects during the same drug experience

• Many street drugs are adulterated with other chemicals and may not be what the individual thinks they are; potency and purity of street drugs vary greatly

• It remains unclear whether drugs of abuse cause persistent psychiatric disorders in otherwise healthy individuals, or whether they precipitate latent psychiatric illness in predisposed individuals. Overall, in non-treatment community samples, it is estimated that over 50% of drug users have at least one other psychiatric disorder and those with certain psychiatric disorders (e.g., bipolar disorder, schizophrenia) are more likely to abuse substances than the general population

• Dualdiagnosisorconcurrentdisordersrefertotheco-occurrenceofsubstanceusedisorderinapatientwithaseverepsychiatricillness.Substance abuse can occur during any phase of the psychiatric illness; it is associated with a variety of physical/psychosocial problems, can destabilize treatment, and lead to relapse

• Substanceabusehasbeenassociatedwithearlieronsetofschizophrenia,decreasedtreatmentresponsivenessofpositivesymptomsofpsychosis, and poor clinical functioning; similarly decreased treatment responsiveness in bipolar disorder can occur

• Factors a ecting detection of a drug in urine depend on dose and route of administration, drug metabolism, and characteristics of screening and con rmation assays; for instance:

– Amphetaminesinurinecanbepositiveforupto5days

– Cannabis(delta-9-THC)inurinecanbepositive2–4daysafteracuteuseandforupto1–3monthsafterchronicuse

– Cocainecanbepositive,asitsmetabolite,inurineforupto1.5daysafterIVuse,forupto1weekwithstreetdosesusedbydi erentroutes,and

for up to 3 weeks after use of very high doses

– Heroincanbepositive,asitsmetabolite,inurineforupto1.5dayswhenadministeredparenterallyorintranasally

– Prescriptiondrugscansometimescauseunexpectedpositiveresultsduetointerferencewithlabassays(e.g.,quetiapineforamphetamines)

• Researchdatahavedemonstratedthatmostdrugsofabuse(exceptthehallucinogens)increasedopaminelevelsinthenucleusaccumbensofthe brain; the increased dopamine is suggested to be associated with the reinforcing e ects of the drug and contributes to drug craving

• Seepharmacological/psychiatrice ectsunderspeci cdrugs

• Reactionsareunpredictableanddependonthepotencyandpurityofdrugtaken

• Psychiatricreactionssecondarytodrugabusemayoccurmorereadilyinindividualsalreadyatrisk

• Renal, hepatic, cardiorespiratory, neurological, and gastrointestinal complications as well as encephalopathies can occur with chronic abuse of

speci c agents

• Intravenousdrugusersareatriskforinfection,includingcellulitis,endocarditis,hepatitis,andHIV

• Impuritiesinstreetdrugs(especiallyifinhaledorinjected)cancausetissueandorgandamage(bloodvessels,heartvalves,kidney,lungs,andliver)

• Psychologicaldependencecanoccur;thedrugbecomescentraltoaperson’sthoughts,emotions,andactivities,resultingincraving

• Physicaldependencecanoccur;thebodyadaptstothepresenceofthedrugandwithdrawalsymptomsoccurwhenthedrugisstoppedabruptly

• Seespeci cagents

• Identi cation of drug(s) abused is important; some drug withdrawals have the potential to produce life-threatening withdrawal syndromes (e.g.,

alcohol, barbiturates), whereas others are less likely (e.g., opioids, stimulants); toxicology may help in identi cation whenever multiple or combina- tion drug use is suspected

Discontinuation Syndrome

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Treatment

Acute

Long-Term

Further Reading

• Treatment of substance use disorder presents challenges in patients with a diagnosed psychiatric disorder and is best done with an integrated treatment program that combines pharmacotherapy with psychosocial intervention

• Seespeci cagents(refertoTreatmentofSubstanceUseDisorderschapterpp.367–390

• Diagnosismustincludementalstatus,physicalandneurologicalexamination,aswellasadrughistory:Wheneverpossible,collateralhistoryshould

be sought

• Inseverecases,monitorvitalsand uidintake

• Agitationcanbetreatedconservativelybytalkingwiththepatientandprovidingreassuranceuntilthedrugwearso (i.e.,“talkingdown”).When

conservative approaches are inadequate or if symptoms persist, pharmacological intervention should be considered

• Avoidlow-potencyantipsychoticsduetoanticholinergice ects,hypotension,andtachycardia

• The presence of comorbid psychiatric disorders in substance abusers can adversely in uence outcome in treatment of the substance use disorder as well as the psychiatric disorder

Additional Suggested Reading

• AmericanPsychiatricAssociation.Practiceguidelineandresourcesfortreatmentofpatientswithsubstanceusedisorders,2nded.AmJPsychiatry2006;163(8Suppl);1–276.Retrieved from http://www.psychiatryonline.com/pracGuide/pracGuideTopic_5.aspx

• ForrayA,FosterD.Substanceuseintheperinatalperiod.CurrPsychiatryRep.2015;17(11):91.doi:10.1007/s11920-015-0626-5

• NewSouthWalesMinistryofHealth.Clinicalguidelinesforthemanagementofsubstanceuseduringpregnancy,birthandthepostnatalperiod.2014.

Retrieved from http://www.health.nsw.gov.au/mhdao/programs/da/Publications/substance-use-during-pregnancy-guidelines.pdf

• TrachtenbergAI,FlemingMF.Diagnosis&treatmentofdrugabuseinfamilypractice.NationalInstituteOnDrugAbuse.

Retrieved from http://archives.drugabuse.gov/diagnosis-treatment/diagnosis.html

Alcohol

• Slang:Booze,hooch,juice,brew

• Upto50%ofindividualswithalcoholdependencemeetthecriteriaforlifetimediagnosisofmajordepression

• Related problems include withdrawal symptoms, physical violence, loss of control when drinking, surreptitious drinking, change in tolerance to

alcohol, deteriorating job performance, change in social interactions, increased risk for stroke, and injury or death from motor vehicle accidents

• AlcoholactsonnumerouscentralneurotransmissionpathwaysandhasbeenlabeledaCNSdisorganizer

• E ectsofalcoholhaveacloserelationshipwithbloodalcohollevels;impairedjudgmentandimpulsivitycanoccurwithlevelsof4–6mmol/L(20– 30 mg/100 mL); levels of 17 mmol/ (80 mg/100 mL) are associated with slurred speech, incoordination, unsteady gait, and inattention. Higher levels can intensify cognitive de cits, aggressiveness, and cause anterograde amnesia (blackouts)

• E ectsofasingledrinkoccurwithin15minandpeakatapproximately30–60min,dependingonamounttaken;eliminationisabout10galcohol per hour (about 30 mL (1 oz) whiskey or 1 bottle of regular beer). Blood alcohol level declines by 3–7 mmol/L per hour (~ 15 mg/100 mL)

• Disinhibition,relaxation,euphoria,agitation,drowsiness,impairedcognition,judgment,andmemory,perceptualandmotordysfunction

☞ Acutealcoholintakedecreaseshepaticmetabolismofco-administereddrugsbycompetitionformicrosomalenzymes

• Chronic use results in an increased capacity to metabolize alcohol and a concurrent CNS tolerance; psychological as well as physical dependence may occur; hepatic metabolism decreases with liver cirrhosis

☞ Chronicalcoholuseincreaseshepaticmetabolismofco-administereddrugs

General Comments

Pharmacological/ Psychiatric Effects

Acute

Chronic

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 337 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Drugs of Abuse

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Physical

Mental

Pharmacokinetics

Toxicity

Alcohol (cont.)

• Hand tremor, dyspepsia, diarrhea, morning nausea and vomiting, polyuria, impotence, pancreatitis, headache, hepatomegaly, peripheral neuro- pathy

• Memory blackouts, nightmares, insomnia, hallucinations, paranoia, intellectual impairment, dementia, Wernicke-Korsako syndrome, and other organic mental disorders

• Absorptionoccursslowlyfromthestomach,andrapidlyfromtheuppersmallintestine

• Approximately 10% of ingested alcohol is eliminated by rst-pass metabolism (less in females); percentage decreases as amount consumed in-

creases

• Alcoholisdistributedinbody uids(isnotfatsoluble)andthebloodalcoholleveldependsongender,age,andbody uidvolume/fatratio

• Metabolized in the liver primarily by alcohol dehydrogenase, CYP2E1, and CYP450 reductase (also by CYP3A4 and CYP1A2); activity of CYP2E1 is

increased 10-fold in chronic heavy drinkers

• Risk of injury or harm increases with more than 3 standard drinks for females and 4 for males on any single occasion (standard drink = approxi- mately 5 oz or 140 mL wine, a 12 oz bottle of beer, 1.5 oz or 45 mL spirits)[1] ; the legal blood alcohol concentration threshold for impaired driving in the Criminal Code of Canada is 80 mg in 100 mL blood (0.08)

• RiskincreaseswhencombinedwithdrugswithCNSdepressantactivity

• Symptoms include: CNS depression, decreased or absent deep tendon re exes, cardiac dysfunction, ushed skin progressing to cyanosis, hypo-

glycemia, hypothermia, peripheral vasodilation, shock, respiratory depression, and coma

• Occursafterchronicuse

• Moste ectsseenwithin5–7daysafterstopping

• Insomnia,irritability,headache

• Usuallytransientandself-limiting

• PhaseI:Beginswithinhoursofcessationandlasts3–5days.Symptoms:tremor,tachycardia,diaphoresis,labileBP,nausea,vomiting,anxiety

• PhaseII:Perceptualdisturbances(usuallyvisualorauditory)

• PhaseIII:10–15%untreatedalcoholwithdrawalpatientsreachthisphase;seizures(usuallytonic-clonic)last0.5–4minandcanprogresstostatus

epilepticus

• Phase IV: Delirium tremens (DTs) is usually a late complication of untreated alcohol withdrawal; includes autonomic hyperactivity and severe

hyperthermia; mortality associated with alcohol withdrawal reduced due to early treatment preventing delirium tremens

• Wernicke’sencephalopathycanoccurinpatientswiththiaminede ciency

• Patients may experience subtle withdrawal symptoms that can last from weeks to months – include sleep dysregulation, anxiety, irritability, and mood instability

• Cognitiveimpairmentfromchronicalcoholusewillpersistforseveralweeksafterabstinenceisachieved

• Individualsareathighriskforrelapseduringthisperiod

• Hepaticmetabolismofco-administereddrugsmaydecreasefollowingabstinencefromchronicalcoholuse

• Increasedriskofdrugtoxicitypossibleinpatientswithalcohol-inducedliverimpairmentorcirrhosis

• Riskandtypeofdrug-druginteractionvarieswithacuteandchronicalcoholconsumption

Discontinuation Syndrome

Mild Withdrawal

Severe Reactions

Protracted Abstinence Syndrome

Precautions

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Use in Pregnancy♢

Treatment

• Drinkingalcoholwhilepregnantincreasestheriskofproblemsinfetaldevelopment;fetalalcoholspectrumdisorder(FASD)indicatesfullrangeof possible e ects on the fetus; fetal alcohol syndrome (FAS) is characterized by severe e ects of alcohol, including brain damage, facial deformities, and growth de cits. Infants should be reassessed and followed up regularly as early intervention improves long-term educational outcomes

• Withdrawalreactionsreported;seen24–48hafterbirthifmotherisintoxicatedatbirth

• Milklevelsattain90–95%ofbloodlevels;prolongedintakecanbedetrimental

• Inacuteintoxication,minimizestimulation;e ectswilldiminishasbloodalcoholleveldeclines(rateof3–7mmol/Lperhour)

• Withdrawalreactionsfollowingchronicalcoholusemayrequire

a) vitamin supplementation (thiamine 50 mg orally or IM for at least 3 days) to prevent or treat Wernicke-Korsako syndrome (level of evidence 3)

b) benzodiazepine for symptomatic relief (to control agitation) and to prevent seizures (chlordiazepoxide, lorazepam, diazepam, or oxazepam); these drugs reduce mortality, reduce the duration of symptoms, and are associated with fewer complications compared to antipsychotic drugs (level of evidence 1); risk of transferring dependence from alcohol to benzodiazepine is small; loading dose strategy used with diazepam (i.e., patient dosed until light somnolence is achieved (level of evidence 3); its long duration of action prevents breakthrough symptoms and possible

withdrawal seizures)

c) hydration and electrolyte correction

d) high-potency antipsychotic (e.g., haloperidol, zuclopenthixol) to treat behavior disturbances and hallucinations (level of evidence 3)

e) β-blockers may be considered for use in conjunction with benzodiazepines in select patients for control of persistent hypertension or tachycardia

(level of evidence 3)

• SSRIs may be useful as treatment for late-onset alcoholics, or alcoholism complicated by comorbid major depression. Buspirone may have some

utility for treating alcoholics with comorbid anxiety disorder

• Naltrexoneandacamprosatereportedtobee ectiveadjunctstotreatmentforrelapsepreventionfollowingalcoholdetoxi cation,seep.369and

p. 373; the e cacy of each is increased signi cantly when combined with psychosocial treatments

• Seep.371foruseofdisul ramintreatment

• Clinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterforthesecondagent

Breast Milk

Drug Interactions

Class of Drug

Example

Interaction Effects

Analgesic

Acetaminophen Salicylates NSAIDs

Chronic excessive alcohol use increases susceptibility to acetaminophen-induced hepatotoxicity due to enhanced formation of toxic metabolites through CYP2E1 induction

Increased gastric bleeding with ASA; reduced peak plasma concentration of ASA reported

ASA may increase blood alcohol concentration by reducing ethanol oxidation by gastric alcohol dehydrogenase

Increased risk of gastric hemorrhage

Anesthetic

Propofol

Chronic consumption increases the dose of propofol required to induce anesthesia

En urane, halothane

Chronic consumption increases risk of liver damage

Antibiotic

Cephalosporins, metronidazole Doxycycline

Disul ram-like reaction with nausea, hypotension, ushing, headache, tachycardia Chronic alcohol use induces metabolism and decreases plasma level of doxycycline

Anticoagulant

Warfarin

Chronic alcohol use may increase or decrease international normalized ratio (INR) – close monitoring required

Anticonvulsant

Barbiturates, carbamazepine, phenytoin

Additive CNS effects

Chronic ethanol use enhances metabolism of carbamazepine and phenytoin

Antidepressant

Tricyclic

Additive CNS effects, impairment in psychomotor performance Disrupted metabolism of antidepressant

♢ See p. 439 for further information on drug use in pregnancy and e ects on breast milk

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 339 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Drugs of Abuse

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

340

Alcohol (cont.)

Class of Drug Interaction Effects

Example

NaSSA Irreversible MAOIs

Furazolidone, griseofulvin, ketoconazole

Atenolol, metoprolol, prazosin

Verapamil

Haloperidol, olanzapine, quetiapine

Isoniazid

Abacavir

Benzodiazepines (e.g., alprazolam, diazepam, lorazepam

Buspirone

Guanethidine, hydralazine, methyldopa, nitroglycerin

Sedating antihistamines, muscle relaxants, valerian

Premarin (conjugated estrogens)

Cimetidine, ranitidine

Chloral hydrate

Chlorpropamide, glyburide, tolbutamide Metformin

Methotrexate Pimecrolimus, tacrolimus

Antifungal Antihypertensive

α1-blocker, β-blocker Calcium channel blocker

Antipsychotic Antitubercular

Antiviral Ascorbic acid Anxiolytic

Cannabis Cardiovascular drug

CNS depressant

Disul ram

Hormone replacement therapy (HRT)

H2 blocker

Hypnotic Hypoglycemic

Immunosuppressive

Additive CNS effects

Possible risk of hypertensive crisis with consumption of beer or wine, due to tyramine content (see p. 66) Disul ram-like reaction

Acute alcohol ingestion may cause additive hypotensive effects, while chronic moderate–heavy drinking may raise blood pressure and reduce the effectiveness of antihypertensive medications

Verapamil may increase concentration of ethanol due to inhibited metabolism

Additive CNS effects

IM olanzapine given to alcohol-intoxicated patients for agitation was associated with a signi cant decrease in oxygen saturation Extrapyramidal side effects may be worsened by alcohol

Increased risk of hepatotoxicity

Tyramine-containing alcoholic beverages may cause a hypertensive reaction (MAOI)

Disul ram-like reaction

Increased AUC of abacavir (by 41%)

Increased ethanol clearance

Potentiation of CNS effects. Use of lorazepam in intoxicated individuals has been reported to decrease respiration

Combined use with alcohol can cause drowsiness faintness, fatigue, and/or weakness Potentiation of CNS effects; additive detrimental effects on driving performance Increased dizziness or fainting upon standing up

Potentiation of CNS effects. Caution with high doses due to risk of respiratory depression

Flushing, sweating, palpitations, headache due to formation of acetaldehyde (see p. 371)

Both chronic alcohol use and HRT increase the risk of breast cancer, it has been suggested that women on HRT limit their alcohol intake (e.g., less than 1 drink/day)

Inhibit alcohol dehydrogenase in the stomach, reduce rst-pass metabolism of alcohol, and increase gastric emptying

– increased bioavailability of alcohol

Potentiation of CNS effects. Caution with high doses due to risk of respiratory depression

Increased plasma level of metabolite of chloral hydrate (trichloroethanol), which inhibits the metabolism of alcohol and increases blood alcohol levels

Flushing, sweating, palpitations, headache due to formation of acetaldehyde; disul ram-like reaction

Acute alcohol use decreases metabolism of tolbutamide; chronic use increases it

Increased risk of hypoglycemia

Possible increased levels of lactic acid in the blood after alcohol consumption

Increased risk of liver damage

Facial ushing

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Class of Drug

Example

Interaction Effects

Opioid

All opioids

Slow-release opioids (Morphine sustained-release: Kadian)

Additive CNS effects; caution with excessive doses due to risk of respiratory depression

Alcohol can speed the release of opioids into the bloodstream by dissolving the slow-release system (not all products affected; no problems noted with Codeine Contin, Hydromorph Contin, and MS Contin). Use caution with other slow-release products

Methadone

Additive CNS depression

Nitrate

Nitroglycerin

Increased risk of hypotension

Prokinetic agent

Metoclopramide

Increases absorption rate of alcohol by speeding gastric emptying

Stimulant

Caffeine

Cocaine Methylphenidate

While caffeine may oppose some of the CNS depressant effects of alcohol, it does not completely sober up those who have drunk too much, and could even make them more accident-prone

Additive effects; increased heart rate; variable effect on blood pressure

Alcohol may increase levels of methylphenidate (AUC by 25%, maximum serum level by 40%), and may exacerbate the CNS effects of methylphenidate

Further Reading

References

1 Butt P, Beirness D, Gliksman L, et al. (2011). Alcohol and health in Canada: A summary of evidence and guidelines for low-risk drinking. Ottawa, ON: Canadian Centre on Substance Abuse. Retrievedfromhttp://www.ccsa.ca/2011%20CCSA%20Documents/2011-Summary-of-Evidence-and-Guidelines-for-Low-Risk%20Drinking-en.pdf

Additional Suggested Reading

• Alcohol-relateddruginteractions.Pharmacist’sLetter/Prescriber’sLetter.2008;24(1):240106.

• CentreforAddictionandMentalHealth.Exposuretopsychotropicmedicationsandothersubstancesduringpregnancyandlactation:Ahandbookforhealthcareproviders.Toronto

(Canada): Centre for Addiction and Mental Health, 2007.

• KorpiER,denHollanderB,FarooqU,etal.Mechanismsofactionandpersistentneuroplasticitybydrugsofabuse.PharmacolRev.2015;67(4):872–1004.doi:10.1124/pr.115.010967

• Lev-RanS,BalchandK,LefebvreL,etal.Pharmacotherapyofalcoholusedisordersandconcurrentpsychiatricdisorders:Areview.CanJPsychiatry.2012;57(6):342–349.Retrievedfrom

http://publications.cpa- apc.org/media.php?mid=1300

• NationalInstituteonAlcoholAbuseandAlcoholism.ClinicalGuidelines-RelatedResources.Bethesda,MD:NationalInstituteonAlcoholAbuseandAlcoholism.

Retrieved from http://www.niaaa.nih.gov/Publications/EducationTrainingMaterials/Pages/guide.aspx

Stimulants

• Di er,dependingontypeofdrugtaken,dose,androuteofadministration

• E ectsoccurrapidly,especiallywhendrugusedparenterally

• Acutetoxicityreportedwithdosesrangingfrom5to630mgofamphetamine;chronicuserscaningestupto1000mg/day

• Followingacutetoxicity,psychiatricstateusuallyclearswithin1–4weeksofamphetaminediscontinuation

• Elevated BP, tachycardia, increased respiration and temperature, sweating, pallor, tremors, decreased appetite, dilated pupils, reduced fatigue, wakefulness, insomnia, increased sensory awareness, increased or decreased sexual arousal/libido

• Euphoria,exhilaration,alertness,improvedtaskperformance,exacerbationofobsessive-compulsivesymptoms

• Methamphetaminereportedtoinduceparanoiaandhallucinationswhenusedinbinge-likedoses

• Anxiety, excitation, panic attacks, grandiosity, delusions, visual, auditory and tactile hallucinations, paranoia, mania, delirium, increased sense of power, violence

• Fever,sweating,headache, ushing,pallor,hyperactivity,stereotypicbehavior,cardiacarrhythmias,respiratoryfailure,lossofcoordination,collapse, cerebral hemorrhage, convulsions, and death

Pharmacological/ Psychiatric Effects

Physical

Mental

High Doses

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 341 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Drugs of Abuse

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Chronic Use

Complications

Discontinuation Syndrome

Treatment

Drug Interactions

GENERAL

AMPHETAMINES

Stimulants (cont.)

• Decreased appetite and weight, abdominal pain, vomiting, di culty urinating, skin rash, increased risk of stroke, high blood pressure, irregular heart rate, impotence, headache, anxiety, delusions of persecution, violence, dental caries

• Tolerancetophysicale ectsoccursbutvulnerabilitytopsychosisremains

• Chronichigh-doseusecausesphysicaldependence;psychologicaldependencecanoccurevenwithregularlow-doseuse

• Recoveryoccursrapidlyafteramphetaminewithdrawal,butpsychosismaybelasting

• Exacerbationofhypertensionorarrhythmias

• Strokesandretinaldamageduetointensevasospasm,especiallywith“crack”and“ice”

• Withmethamphetamine,cerebralsidee ectsreportedinclude:vasculopathywithorwithoutparenchymalinfarction,hypertensiveencephalopa-

thy, and hemorrhage

• Canexacerbateharmfule ectsofco-occurringinfections,suchasneurologicaldamageinHIVinfection

• Symptoms are very similar to those of major depressive disorder. Include depressed mood, anhedonia, anxiety, hypersomnia, fatigue, irritability, di culty concentrating, craving, and suicidal or homicidal ideation

• Usecalmingtechniques,reassurance,andsupportivemeasures

• Supportive care of excess sympathomimetic stimulation may be required (e.g., BP, temperature); monitor hydration, electrolytes, and for possible

serotonin syndrome

• Forsevereagitationandtopreventseizures,sedatewithbenzodiazepine(e.g.,diazepam,lorazepam)

• Forpsychosis,useahigh-potencyantipsychotic(e.g.,haloperidol);avoidlow-potencyantipsychotics

• Non-pharmacologicaltreatmentapproachesarethecurrentmainstayforthetreatmentofstimulantaddiction

• Agents under investigation with mixed results include GABAergic medications (e.g., vigabatrin, baclofen, topiramate), moda nil, drug vaccines,

disul ram, and cannabidiol

• Clinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterforthesecondagent

Class of Drug

Example

Interaction Effects

Antipsychotic

Diminished pharmacological effects of stimulants

Irreversible MAOI

Phenelzine

Severe palpitations, tachycardia, hypertension, headache, cerebral hemorrhage, agitation, seizures; AVOID. Serotonin syndrome reported with MDA, MDMA

Class of Drug

Example

Interaction Effects

Antidepressant

General Tricyclics

Enhanced antidepressant effect

Increased blood pressure

Enhanced stimulant effects. Increased plasma level of amphetamine Cardiovascular effects increased

MAOI (irreversible)

Release of large amount of norepinephrine while ability to metabolize monoamines blocked by MAOI, leading to hypertensive reaction

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Class of Drug

Example

Interaction Effects

Antihypertensive

Guanethidine

Reversal of hypotensive effects

Antipsychotic

Chlorpromazine

Decreased effects of both agents

Antipsychotics can counteract many signs of stimulant toxicity (e.g., anxiety, aggression, visual or auditory hallucinations, psychosis) and have additive adverse effects (e.g., insomnia, restlessness, tremor)

Urinary acidi er

Ammonium chloride

Increased elimination of amphetamine due to decreased renal tubular reabsorption and increased elimination

Urinary alkalizer

Sodium bicarbonate

Prolonged pharmacological effects of amphetamine due to decreased urinary elimination of unchanged drug

COCAINE

Class of Drug

Alcohol Anorectic

Antibiotic Antidepressant

Antifungal Antipsychotic

Antiretroviral

Non-nucleoside reverse transcriptase inhibitor (NNRTI) Protease inhibitor

Barbiturate β-blocker Cannabis

Catecholamine Disul ram Opioid Sympatholytic

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 343 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Example

Interaction Effects

Additive effects; increased heart rate; variable effect on blood pressure

Mazindol

May decrease craving for cocaine

Increased lethality and convulsant activity reported

Clarithromycin, erythromycin

Combination could result in cocaine overdose, due to inhibition of metabolism via CYP3A4, with rhabdomyolysis, arrhythmia, and cardiovascular collapse[1]

Cyclic, SSRI

Tricyclic: desipramine

Decreased craving

Decreased seizure threshold

Elevated heart rate and diastolic pressure (by 20–30%); increased risk of arrhythmia

Ketoconazole

Combination could result in cocaine overdose, due to inhibition of metabolism via CYP3A4, with rhabdomyolysis, arrhythmia, and cardiovascular collapse[1]

Clozapine, risperidone, ziprasidone

Case reports of EPS, particularly dystonia, with concurrent use of risperidone and ziprasidone, possibly via dopamine depletion from chronic use of cocaine; case report of clozapine causing a dose-dependent increase in plasma concentration of intranasal dose of cocaine, though the positive effects of cocaine were reduced

Nevirapine

Efavirenz, indinavir, ritonavir

Potentially increased metabolism of cocaine to the hepatotoxic metabolite norcocaine, via CYP3A4[1]

Combination could result in cocaine overdose, due to inhibition of metabolism via CYP3A4, with rhabdomyolysis, arrhythmia, and cardiovascular collapse

Reports of enhanced hepatotoxicity

Propranolol

May increase the magnitude of cocaine-induced myocardial ischemia

Increased heart rate; blood pressure increased only with high doses of both drugs Increased plasma level of cocaine and increased subjective reports of euphoria

Norepinephrine

Potentiation of vasoconstriction and cardiac stimulation

Increased plasma level (3-fold) and half-life (60%) of cocaine with possible increased risk of cardiovascular effects

Heroin, morphine

May potentiate cocaine euphoria

Yohimbine

Enhanced effect of cocaine on blood pressure

Drugs of Abuse

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Stimulants (cont.)

Stimulant Agents

Drug

Comments

AMPHETAMINE, DEXTROAMPHETAMINE

(Dexedrine, Dexampex, Biphetamine)

Taken orally as tablet, capsule, sniffed, smoked, injected Slang: Bennies, hearts, pep-pills, dex, beans, benn, truck-drivers, ice, jolly beans, black beauties, crank, pink football, dexies, crosses, hearts, LA turnaround

• Cause the release of monoamines (NE, 5-HT, DA) from central and peripheral neurons

• Onset of action: 30 min after oral ingestion

• Physical effects: Increased heart rate, BP, metabolism, decreased appetite, weight loss, rapid breathing, tremor, loss of coordination

• CNS effects: Euphoria, increased energy and mental alertness, anxiety, insomnia, irritability, restlessness, panic, impulsive or aggressive behavior • Active drug use may be terminated by exhaustion with excessive sleeping

• Tolerance and psychological dependence occur with chronic use

• Excessive doses can lead to heart failure, delirium, psychosis, coma, convulsions, and death

• Pregnancy: Increase in premature births; withdrawal symptoms and behavioral effects (hyperexcitability) noted in offspring

• Breastfeeding: Irritability and poor sleeping pattern reported in infants

METHAMPHETAMINE

(Desoxyephedrine) – Crystal Meth

(Desoxyn, Methampex)

Powder taken as tablets, capsules, liquid, injected, snorted, inhaled, smoked

Slang: Speed, meth, uppers, crystal, shit, moth, crank, crosses, methlies quick, jib, re, chalk, glass, go fast, tweak, yaba

Crystal (“ice”) is methamphetamine washed in a solvent to remove impurities – smoked in a glass pipe, “chased” on aluminium foil or injected

• Synthetic drug related chemically to amphetamine and ephedrine; can be manufactured in “home laboratories” from common household products

• Enhances release of dopamine, norepinephrine, and serotonin[2]

• Very rapid onset of action; can last 10–12 h

• Powerful effects produced are referred to as a “rush”. Used as a club drug at “raves” to increase alertness, energy, sociability, euphoria; has aphrodisiac

effects and causes loss of inhibitions

• A “run” refers to the use of the drug several times a day over a period of several days

• “Ice” can be mixed with cannabis and smoked through a bong or injected

• Physical effects: Tachycardia, tachypnea, diaphoresis, hyperthermia, mydriasis, hypertension; stroke reported

• CNS effects: Anxiety, agitation, confusion, insomnia, delirium, hallucinations, paranoia, violence; powerful psychological dependence and addiction

occurs, particularly with “ice”

• Chronic use can result in weight loss, bruxism, cardiovascular problems, decreases in lung function, pulmonary hypertension, rapid tooth decay (“meth

mouth”), mood disturbances, decreased cognitive functioning, anxiety, psychosis with suicidal or homicidal thoughts; may persist for months after drug

use is stopped; has been associated with neuronal damage

• Users are at high risk of sexually transmitted and blood-borne diseases due to disinhibitory high-risk behaviors that can occur (e.g., shared needles,

multiple partners, unprotected sex)

• Abuse of methamphetamine can produce impaired memory and learning, hyperawareness, hypervigilance, psychomotor agitation, irritability,

aggression. Chronic intoxication (use) may result in a psychotic state with delusions, hallucinations, and delirium

• Toxic effects: Arrhythmias, hypertension, heart failure, hyperthermia, seizures, encephalopathy, rhabdomyolysis (see Complications p. 342)

• After abrupt discontinuation, withdrawal effects peak in 2–3 days and include GI distress, headache, depression, irritability, and poor concentration

• Methamphetamine exposure during pregnancy is associated with decreased growth in infants; withdrawal effects reported in newborns and potentially

developmental delays

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Drug

Comments

COCAINE

Extract from leaves of coca plant

Leaves chewed, applied to mucous membranes Powder taken orally, snorted, smoked, injected Slang: Coke, coca, snow, ake, lady, toot, blow, big C, candy, crack, joy dust, stardust, rock, nose, boulders, bump, bianca, perico, nieve, soda

“Crack”: Free base cocaine

• Inhibits dopamine and serotonin reuptake

• Onset of action and plasma half-life varies depending on route of use (e.g., IV: Peaks in 30 sec, half-life 54 min; snorting: Peaks in 15–30 min, half-life

75 min)

• Metabolized by hydrolysis to its major urinary metabolite, benzoylecgonine

• Crack is a free-based and more potent form of cocaine (volatilized and inhaled)

• Often adulterated with amphetamine, ephedrine, procaine, xylocaine or lidocaine

• Used with heroin, morphine or cannabis for increased intensity

• Used with unitrazepam to moderate stimulatory effect

• CNS effects: Rapid euphoria, increased energy and mental alertness, insomnia, anxiety, agitation, delusion, hallucinations

• Physical effects: Nausea, vomiting, headaches, tachycardia, hypertension, chest pain, pyrexia, diaphoresis, mydriasis, ataxia, anorexia; tactile

hallucinations occur

• Tolerance develops to some effects (appetite), but increased sensitivity (reverse tolerance) develops to others (convulsions, psychosis)

• Powerful psychological dependence occurs; dysphoria can last for weeks

• Depression-like symptoms commonly occur after drug use; dysphoria promotes repetitive use

• Chronic users can develop panic disorder, paranoia, dysphoria, irritability, assaultive behavior, paranoia, and delirium

• Snorting can cause stuffy, runny nose, eczema around nostrils, atrophy of nasal mucosa, bleeding, and perforated septum

• Smokers are susceptible to respiratory symptoms and pulmonary complications

• Sexual dysfunction is common

• Chronic users of “crack” can develop microvascular changes in the eyes, lungs, and brain; respiratory symptoms include asthma and pulmonary

hemorrhage and edema

• Dehydration can occur due to effect on temperature regulation, with possible hyperpyrexia

• Toxic effects: Hypertension, paroxysmal atrial tachycardia, hyperre exia, irregular respiration, hyperthermia, seizures, unconsciousness, death; fatalities

more common with IV use

• Pregnancy: Associated with spontaneous labor and abortion; increase in premature births; infants have lower weight, length, and head circumference,

jitteriness, irritability, poor feeding, EEG abnormalities

• Breastfeeding during cocaine intoxication reported to cause irritability, vomiting, diarrhea, tremulousness, and seizures in infants

KHAT

(Catha edulis) Leaves chewed

• Grows in Africa and the Middle East

• Cathinone is principal psychoactive agent

• Symptoms occur within 3 h and last about 90 min

• Acute symptoms include: euphoria, excitation, grandiosity, increased blood pressure, ushing

• Chronic use can cause: anxiety, agitation, confusion, dysphoria, aggression, visual hallucinations, paranoia

METHYLPHENIDATE

Tablets crushed and snorted, swallowed, injected Slang: Vitamin R, R-ball, skippy, the smart drug, JIF, MPH

•Seep.289

• Large doses can cause psychosis, seizures, stroke, and heart failure

SYMPATHOMIMETICS

(Ephedrine, pseudoephedrine, phenylpropanolamine) Taken as capsules, tablets

Slang: Look alikes, Herbal Bliss, Cloud 9, Herbal X

• Known as Herbal Ecstasy and sold as “natural” alternative to MDMA

• Misrepresented as amphetamines and sold in capsules or tablets that resemble amphetamines • Doses of ingredients vary widely

• Reports of hypertension and seizures; death due to stroke can occur after massive doses

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 345 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Drugs of Abuse

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Stimulants (cont.)

Drug

Comments

SYNTHETIC CATHINONES

Mephedrone (4-methylmethcathinone),

Methylone (3,4-methylenedioxymethcathinone),

MDPV (3,4-methylenedioxypyrovalerone),

ephedrone, ethylcathinone

Sold as capsules, tablets, or white crystalline powder that can be swallowed, snorted or injected

Slang: “Bath salts”, bath powder, plant food, plant fertilizer, Meph, drone, meow, rush, Ivory, Ivory Wave, Cloud 9, (9), Blizzard, Ocean Snow, Scarface, Hurricane Charlie, ne china, Silverback, Blue Magic, vanilla sky, Energy-1, bliss, Bolivian bath, MDPK, MTV, Magic, Maddie, Black Rob, Super Coke, PV and Peeve, Zoom, Bloom, insect repellant, potpourri,vacuum freshener, Heavenly Soak

• Mephedrone and methylone: Nonspeci c substrates of transporters for dopamine, norepinephrine, and serotonin, preventing reuptake

• MDPV: Speci c inhibitor of dopamine and norepinephrine transporters

• Effects similar to other stimulants such as cocaine, methamphetamine, including euphoria, excitement, anxiety, agitation, confusion, psychosis, and

seizures

• CNS effects last 3–4 h, while some physical effects (e.g., tachycardia, hypertension) can last 6–8 h

• Higher doses can produce panic attacks, paranoia, confusion, psychotic delusions, extreme agitation, sometimes progressing to violent behavior, suicidal

thoughts/actions

• Physical effects: Tachycardia, hypertension, vasoconstriction, insomnia, hyper-re exia, nausea, stomach cramps, and digestive problems, anorexia,

bruxism, increased body temperature, chills, sweating, pupil dilation, headache, and tinnitus

• Strong cravings and addiction reported

• Withdrawal symptoms include: Depression, lethargy, headache, anxiety, postural hypotension, and severely bloodshot eyes – usually subside within

4–8 h

Further Reading

References

General Comments

1 Wynn GH, Cozza KL, Zapor MJ, et al. Med-psych drug-drug interactions update. Antiretrovirals, part III: Antiretrovirals and drugs of abuse. Psychosomatics. 2005;46(1):79–87. doi:10.1176/ appi.psy.46.1.79

2 Kish SJ. Pharmacologic mechanism of crystal meth. CMAJ. 2008;178(13):1679–1682. doi:10.1503/cmaj.071675

Additional Suggested Reading

• CoppolaM,MondolaR.Syntheticcathinones:Chemistry,pharmacologyandtoxicologyofanewclassofdesignerdrugsofabusemarketedas“bathsalts”or“plantfood”.ToxicolLett. 2012;211(2):144–149. doi:10.1016/j.toxlet.2012.03.009

• KarilaL,GorelickD,WeinsteinA,etal.Newtreatmentsforcocainedependence:Afocusedreview.IntJNeuropsychopharmacol.2008;11(3):425–438.doi:10.1017/S1461145707008097

• MaxwellJC.Emergingresearchonmethamphetamine.IntDrugTherapyNewsletter.2006;41(3):17–24.

• PanenkaWJ,ProcyshynRM,LecomteT,etal.Methamphetamineuse:Acomprehensivereviewofmolecular,preclinicalandclinical ndings.DrugAlcoholDepend.2013;129(3):167–179.

doi:10.1016/j.drugalcdep.2012.11.016

• ShorterD,KostenTR.Novelpharmacotherapeutictreatmentsforcocaineaddiction.BMCMed.2011;9:119.doi:10.1186/1741-7015-9-119

Hallucinogens

• Cannabis is the most widely used illicit drug of abuse in the world; there have been recent increases in use in North America due to di erent constituencies allowing medical and recreational use

• Thetermmedicalcannabisreferstousingthewholeunprocessedcannabisplantoritsbasicextractstotreatadiseaseorsymptom

• Typicallyprovidedbyalegallyapprovedsupplier

• Dried cannabis and its oil are approved drugs/medicine in Canada. However, reasonable access to a legal source of cannabis is provided when

authorized by a healthcare practitioner

• Medical cannabis has been used to treat chronic pain, muscle spasms, and nausea during chemotherapy, improve appetite in HIV/AIDS, improve

sleep, and improve tics in Tourette’s syndrome. More recent evidence indicates antipsychotic and anti-epileptic e ects of cannabidiol

• CannabisislegalinsomejurisdictionsoftheUSAforuseinPTSD(literaturesuggestsbene tforPTSDsymptomsaswellasworseningofsymptoms)

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Pharmacological/ Psychiatric Effects

Physical

Mental

High Doses

Chronic Use

Discontinuation Syndrome

Treatment

Drug Interactions

CANNABIS

• Di er,dependingontypeofdrugtakenandrouteofadministration(seespeci cagentsbelow)

• E ectsoccurrapidlyandlastfrom30min(e.g.,DMT)toseveraldays(e.g.,PCP)

• Increased BP, tachycardia, dilated pupils, nausea, sweating, ushing, chills, hyperventilation, incoordination, muscle weakness, trembling, numb- ness

• Cannabinoidsmaybee ectivefortreatingneuropathicpain(marketedinCanadaunderthenameofSativexorCesamet[indicatedforchemotherapy- induced nausea and vomiting, as adjunctive treatment for spasticity in multiple sclerosis, and as adjunctive treatment for neuropathic pain]); mixed e ects found on multiple sclerosis symptoms; may have some bene t in Tourette’s syndrome

• Alteration of perception and body awareness, impaired attention and short-term memory, disturbed sense of time, depersonalization, euphoria, mystical or religious experiences, grandiosity, anxiety, panic, visual distortions, hallucinations (primarily visual), erratic behavior, aggression

• Confusion,restlessness,excitement,anxiety,emotionallability,panic,mania,paranoia,“badtrip”

• Cardiacdepressionandrespiratorydepression(mescaline),hypotension,convulsionsandcoma(PCP)

• Anxiety,depression,personalitychanges

• Tolerance(tachyphylaxis)canoccurwithregularuse(exceptwithDMT);reversetolerance(supersensitivity)hasbeendescribed

• “Woolly”thinking,delusions,andhallucinationsreported;maypersistformonthsafterdrugdiscontinuation

• Flashbacks–recurrentpsychoticsymptoms,mayoccuryearsafterdiscontinuation

• Cohort studies suggest that chronic use of cannabis by teenagers is associated with more than 5-fold increase in risk of later-life depression and

anxiety as well as an increased risk of early-onset psychosis

• Regular(weekly)cannabisusehasbeenassociatedwithincreasedriskoftardivedyskinesiainschizophrenicpatientsonantipsychotics

• Thereisevidencethatchroniccannabisusersmightexperiencesustainedde citsinmemoryfunction

• Withdrawal symptoms identi ed in frequent cannabis users consist of irritability, nervousness, anxiety, sleep disturbance, decreased appetite or weight loss, stomach pain, shakiness/tremors, sweating, fever, chills

• Providereassuranceandreductionofthreateningexternalstimuli

• SupportivecareforexcessCNSstimulationmayberequired;monitorhydration,electrolytes,andforpossibleserotoninsyndrome

• Inseverecases,the“trip”shouldbeabortedchemicallyasrapidlyaspossible.Inmildcases,“talkingdown”maybeappropriate

• Usehigh-potencyantipsychotic(e.g.,haloperidol)forpsychoticsymptoms

• Avoid low-potency antipsychotics with anticholinergic and α-adrenergic properties (e.g., chlorpromazine) to minimize hypotension, tachycardia,

disorientation, and seizures

• Usebenzodiazepines(diazepam,lorazepam)tocontrolagitationandtosedate,ifneeded

• Propranololandascorbicacidmayminimizee ectsofPCPandaidinitsexcretion

• Clinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterforthesecondagent

Class of Drug

Example

Interaction Effects

Anticholinergic

Atropine, benztropine, oxybutynin

Increased heart rate and/or hypertension

Antidepressant

Tricyclic: Desipramine MAOI: Tranylcypromine

Case reports of tachycardia, lightheadedness, mood lability, and delirium with combination Cardiac complications reported in children and adolescents

Caution: Cannabis increases serotonin levels and may result in a serotonin syndrome

Antipsychotic

Chlorpromazine, thioridazine

Drugs with anticholinergic and α1-adrenergic properties can cause marked hypotension and increased disorientation

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 347 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Drugs of Abuse

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Hallucinogens (cont.)

Class of Drug

Example

Interaction Effects

Antiretroviral

Protease inhibitor

Indinavir, nel navir

Inhaled marijuana reported to reduce indinavir AUC by 17% and Cmax of nel navir by 21%; no effect on viral load

Barbiturate

Additive effect causing anxiety and hallucinations

CNS depressant

Alcohol, benzodiazepines, hypnotics, opioids

Potentiation of CNS effects; increased impaired judgment

Disul ram

Synergistic CNS stimulation reported, hypomania

Lithium

Clearance of lithium may be decreased

Opioid

Morphine

THC blocks excitation produced by morphine

Smoking (tobacco)

Additive effects on the induction of CYP1A2 isoenzyme; additive increase in heart rate and stimulant effects

Stimulant

Cocaine

Increased heart rate; blood pressure increased with high doses of both drugs; increased plasma level of cocaine and increased subjective reports of euphoria

KETAMINE

Class of Drug

Example

Interaction Effects

Antiretroviral

Protease inhibitor

Nel navir, ritonavir

Elevated levels of ketamine possible due to inhibited metabolism

Benzodiazepine

Diazepam

Prolonged recovery with diazepam due to decreased metabolism

Benzodiazepines may reduce the antidepressant effects of ketamine in the treatment of depression. Possible attenuation of ketamine response from concurrent use of benzodiazepines also suggested

NMDA receptor antagonist

Memantine

Do not combine, as adverse effects may be enhanced; additive effects of NMDA receptor blockade

Opioid

Morphine

Additive respiratory depression; ketamine is a respiratory depressant like morphine, though less potent

LSD

MDA/MDMA

Class of Drug

Example

Interaction Effects

Antidepressant

SSRI: uoxetine

Grand mal seizures reported

Recurrence or worsening of ashbacks reported with uoxetine, sertraline, and paroxetine

Antiretroviral

Protease inhibitor

Ritonavir

Elevated levels of LSD possible due to inhibited metabolism

Class of Drug

Example

Interaction Effects

Alcohol

MDMA may reverse subjective feelings of alcohol sedation without reversing alcohol’s effects on impulsivity or psychomotor skills

Antidepressant

SSRI: uoxetine

Diminished pharmacological effects of MDA

Antiretroviral

Protease inhibitor

Ritonavir

Case reports of increased plasma levels of MDMA due to inhibited metabolism via CYP2D6; death reported

Phosphodiesterase type 5 (PDE5) inhibitor

Sildena l

Anecdotal reports of serious headaches and priapism requiring emergency treatment from the abuse of sildena l and MDMA

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Phencyclidine (PCP)

Class of Drug

Example

Interaction Effects

Acidifying agent

Cranberry juice, ammonium chloride

Increased excretion of PCP

Antiretroviral

Protease inhibitor

Ritonavir

Elevated levels of PCP possible due to inhibited metabolism

Hallucinogenic Agents

Drug

Comments

CANNABIS

Crushed leaves, stems, and owers of female hemp plant (Cannabis sativa)

Smoked (cigarettes or water pipe), swallowed

Slang: Grass, pot, joint, hemp, weed, reefer, smoke, Mary Jane, Indian hay, ace, ganja, gold, J, locoweed, shit, herb, Mexican, ragweed, bhang, sticks, blunt, dope, sinsemilla, skunk, Hydro (hydroponic cannabis)

Hashish – resin from owers and leaves; more potent than cannabis plant

Smoked, cooked, swallowed

Slang: Hash, hash oil, weed oil, weed juice, honey oil, hash brownies, tea, black, solids, grease, smoke, boom, chronic, gangster, hemp

• Over 70 phytocannabinoids in cannabis; delta-9-tetrahydrocannabinol (THC) is the main psychoactive ingredient; high potency (> 20%) forms of cannabis (e.g., “skunk”) increasingly common

• Cannabidiol (CBD) is the second most common psychoactive cannabinoid ingredient in cannabis, typically ranging from 0-13%

• THC undergoes rst-pass metabolism to form psychoactive metabolite 11-OH-THC. Half-life is 24-36 h for infrequent users and up to 10 days for frequent

users. THC and CBD are metabolized primarily by CYP3A4; also by 2D6, 2C9, and 2C19. Weak inhibitor of 3A4, 2C9, and 2C19

• Induces CYP1A2 through activation of the aromatic hydrocarbon receptor

• Effects occur rapidly and last up to several hours; accumulates in fat tissue for up to 4 weeks before being released back into bloodstream; effects may

persist

• Results of short-term controlled trials indicate that smoked cannabis reduces neuropathic pain, improves appetite and caloric intake, especially in

patients with reduced muscle mass, and may relieve spasticity and pain in patients with multiple sclerosis[1]

• THC may have bene cial effects in chemotherapy-induced nausea/vomiting (Cesamet)

• Review of 2 trials suggests THC may have some bene t on the frequency and severity[2] of tics in Tourette’s syndrome

• Tolerance and psychological dependence may occur; reverse tolerance (supersensitivity) described

• Combined with other drugs including PCP, opium, heroin, crack cocaine, or unitrazepam to enhance effect

• CNS effects: Most users experience euphoria with feelings of self-con dence and relaxation; some become dysphoric, anxious, agitated, and suspicious.

Can cause psychotic symptoms with confusion, hallucinations, emotional lability (very prolonged or heavy use can cause serious and potentially

irreversible psychosis)

• Increased craving for sweets

• Chronic use: Bronchitis, weight gain, bloodshot eyes, loss of energy, apathy, “fuzzy” thinking, slow reaction time, impaired judgment, decreased

testosterone in males; increased risk of depression, anxiety, and schizophrenia

• Link between cannabis use and early age at onset of psychosis suggested; results point to cannabis as a dangerous drug in young people at risk of

developing psychosis[3]

• Exogenous THC modulates release of neurotransmitters (including dopamine and glutamate) by interacting with speci c cannabinoid receptors that are

distributed in brain regions implicated in schizophrenia[4]

• Cannabis cigarettes have a higher tar content than ordinary cigarettes and are potentially carcinogenic

• Pregnancy: Can retard fetal growth and cause mild withdrawal reactions in the infant; developmental problems in children born to cannabis-dependent

parents have been reported in some studies

• Breastfeeding: Can reach high levels in breast milk

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 349 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Drugs of Abuse

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Hallucinogens (cont.)

Drug

Comments

CANNABINOIDS, SYNTHETIC

Psychoactive chemicals dissolved in solvent, applied or sprayed to plant material; usually smoked or prepared as a herbal infusion

Slang: K2, Spice, Black Mamba (Turnera diffusa), Bombay Blue, Fake Weed, Genie, Zohai, Bliss, Blaze, JWH -018, -073, -250, Yucatan Fire, Skunk, Moon Rocks

• Synthetic designer drugs that mimic the effects of cannabis

• Contain a mixture of herbs and synthetic cannabinoids, which may include: Cannabicyclohexanol, JWH-018, JWH-073, JWH-200, CP-47,497 or HU-210;

chemicals are frequently changed and concentrations are unpredictable

• Marketed as “synthetic marijuana,” “herbal incense”, “herbal smoking blends” or “potpourri” and sold online, in head shops, and some stores

• Physical effects: 2–3 times more likely to be associated with sympathomimetic effects (i.e., tachycardia and hypertension) than THC; vomiting; high

doses reported to cause convulsions, myocardial infarction[5]

• Contaminant, (1-(5- uoropentyl)-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl) methanone, has been associated with acute kidney injury

• CNS effects: Elevated mood, relaxation, altered perception; anxiety, agitation, confusion, paranoia, and hallucinations reported; psychosis can be

prolonged

• Regular users may experience symptoms of addiction and withdrawal

KETAMINE (Ketalar)

General anesthetic in day surgery

Taken orally as capsules, tablets, powder, crystals, and solution; injected, snorted, smoked

Slang: K, special K, vitamin K, ket, green, jet, kit-kat, cat valiums, Ketalar SV

• NMDA receptor antagonist, prevents glutamate receptor activation, inhibits reuptake of monoamines (5-HT, NE, DA)

• Used as a club drug at “raves” and involved in “date rapes”; most ketamine users are sporadic and polydrug users

• Doses of 60–100 mg injected; consciousness maintained at this dose, but disorientation develops

• Effects start within 60 sec (IV) and 10–20 min (PO); metabolized primarily by CYP2B6 and also by CYP3A4 and 2C9. Weak inhibitor of CYP3A4

• Physical effects: Increased heart rate and blood pressure, nausea, vomiting, increased muscle tone, nystagmus, stereotypic movements, impaired motor

function, numbness; synthetic ketamine linked to serious urinary tract infections and bladder-control problems

• CNS effects: Dream-like state, depersonalization, confusion, hostility, mild delirium, hallucinations, amnesia

• Toxic effects: Severe delirium, respiratory depression, loss of consciousness, catatonia

• IV infusions of ketamine have been found effective in patients with treatment-resistant depression (refer to Unapproved Treatments of Psychiatric

Disorders chapter p. 407

LYSERGIC ACID DIETHYLAMIDE (LSD)

Semi-synthetic drug derived from ergot (grain fungus) White powder used as tablet, capsule, liquid, liquid-impregnated paper, snorted, smoked, inhaled, injected

Slang: Acid, cubes, purple haze, Raggedy Ann, sunshine, yellow sunshine, LBJ, peace pill, big D, blotters, domes, hits, tabs, doses, window-pane, microdot, boomers

• 5-HT2A receptor agonist

• Effects occur in less than 1 h and last 2–18 h

• Physical effects: Mydriasis, nausea, loss of appetite, muscle tension, hyperthermia, hypertension, weakness, numbness, tremors

• CNS effects: Can cause agitation, visual hallucinations, suicidal, homicidal, and irrational behavior, and dysphoria; panic, psychotic reactions can last

several days

• Flashbacks occur without drug being taken

• Tolerance develops rapidly; psychological dependence occurs

• Combined with cocaine, mescaline, or amphetamine to prolong effects

• Pregnancy: Increased risk of spontaneous abortions; congenital abnormalities have been reported

MESCALINE (3,4,5-trimethoxyphenethylamine)

From cactus Lophophora williamsii, San Pedro cactus (Echinopsis pachanoi) and/or the Peruvian torch cactus (Echinopsis peruviana); pure product not readily available Cactus buttons are dried, then sliced, chopped, or ground; used as powder, capsule (masks bitter taste), tablet, solution, inhaled or injected

Slang: Mesc, peyote, buttons, cactus

• Binds to 5-HT2A receptor as a partial agonist and acts on 5-HT2C receptor

• Less potent than LSD, but cross-tolerance reported

• Effects occur 1–2 h after ingestion and last 10–18 h

• Physical effects: Euphoria, time distortion, brilliant colors, weightlessness, headache, dry skin, increased temperature and heart rate, hypotension or

hypertension, numbness, tremors, dizziness, nausea, cardiac and respiratory depression

• CNS effects: Anxiety, disorientation, impaired reality testing, and ashbacks

• Dependence not reported but tolerance to effects occurs quickly

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Drug

Comments

MORNING GLORY SEEDS

Active ingredient is lysergic acid amide; 1/10th as potent as LSD

Seeds eaten whole or ground, mushed, soaked, and solution injected

Slang: Flying saucers, licorice drops, heavenly blue, pearly gates

• Effects occur after 30–90 min when seeds ingested and immediately when solution injected

• Commercial seeds are treated with insecticides, fungicides, and other chemicals and can be poisonous

PHENCYCLIDINE

General anesthetic used in veterinary medicine; often misrepresented as other drugs

Powder, chunks, crystals used as tablets, capsules, liquid, inhaled, snorted, injected (IM or IV)

Slang: PCP, angel dust, hog, horse tranquilizer, animal tranquilizer, peace pill, killer, weed, supergrass, crystal, “CJ”, dust, rocket fuel, boat, love boat

• Antagonist at NMDA receptor

• Effects occur in a few minutes and can last several days to weeks (half-life 18 h); metabolized primarily by CYP3A4 and also by CYP2C11. Weak inhibitor of

CYP2B6

• Frequently sold on street as other drugs (easily synthesized); mis-synthesis yields a product that can cause abdominal cramps, vomiting, coma, and death

• Physical effects: Intermittent vomiting, sialorrhea, loss of appetite, diaphoresis, miosis, nystagmus, hypertension, and ataxia can occur

• CNS effects: Can cause apathy, estrangement, feelings of isolation, indifference to pain, delirium, disorientation with amnesia, schizophrenia-like

psychosis, and violence (often self-directed); can feel intermittently anxious, fearful to euphoric

• Toxic effects: Hypoglycemia, rhabdomyolysis, depression, delirium, CNS depression, coma; deaths have occurred secondary to uncontrollable seizures or

to hypertension resulting in intracranial hemorrhage

• Flashbacks occur

• Psychological dependence occurs

• Pregnancy: Signs of toxicity have been reported in newborns

• Breastfeeding: Drug concentrates in milk and detectable for weeks after heavy use

PSILOCYBIN

From Psilocybe mexicana mushroom

Used as dried mushroom, white crystal, powder, capsule, injection; eaten raw, cooked or steeped as tea

Slang: Magic mushrooms, sacred mushrooms, mushroom, shroom, purple passion

• Chemically related to LSD and DMT (see Tryptamines below); psilocybin is a prodrug for psilocin (4-HO-DMT, 4-hydroxy-dimethyltryptamine)

• Effects occur within 30 min and last several hours

• Partial agonist at 5-HT1A and 5-HT2A receptors

• Effects: Nausea, vomiting, distorted time perceptions (users sometimes think they had a longer trip than the actual effect), nervousness, paranoia, and

ashbacks

• Tolerance develops rapidly; cross-tolerance occurs with LSD

• Mistaken identity with “death-cap” (Amanita) mushroom can result in accidental poisoning

SALVIA DIVINORUM

Member of the mint family

Leaves chewed or crushed and the juice ingested as tea, smoked

Slang: Diviner’s sage, magic mint, Maria Pastora

• Main active ingredient is Salvinorin A; a potent kappa opioid receptor agonist

• Effects, when taken orally, depend on the absorption of Salvinorin A through the oral mucosa as it is inactivated by the GI tract; when absorbed through

oral mucosa, effects detected in 5–10 min, peak at 1 h and subside after 2 h. If inhaled, effects seen after 30 sec, peak in 5–10 min, and subside in

20–30 min; potency increased dramatically when smoked

• Taken in combination with cannabis to prolong effect

• Physical effects: Ataxia, incoherent speech, hysterical laughter, unconsciousness

• CNS effects: Altered perception; can cause dramatic, and sometimes frightening, hallucinogenic experiences with doses higher than 1 mg

TRYPTAMINES

Dimethyltryptamine (DMT), alpha-methyltryptamine (AMT), 5-methyl-di-isopropyl-tryptamine (5-MeO-DIPT) Oil or crystal smoked in a water pipe; oil soaked in parsley; dried and snorted or smoked, used as liquid (tea), injected

Slang: Lunch-hour drug, businessman’s trip, FOXY

(= MeO-DIPT)

• Appear in nature in several plants in South America

• Effects vary widely, depending on amount ingested; occur almost immediately with DMT and last 30–60 min (called “businessman’s trip” due to its short

duration of action)

• Readily destroyed by stomach acids

• Often mixed with cannabis

• CNS effects: Anxiety and panic frequent due to quick onset of effects; produce intense visual hallucinations, loss of awareness of surroundings

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 351 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Drugs of Abuse

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

DRUGS WITH HALLUCINOGENIC AND STIMULANT PROPERTIES

Hallucinogens (cont.)

Drug

Comments

2,5-dimethoxy-4-methylamphetamine (STP/DOM)

Chemically related to both mescaline and amphetamine

Used orally

Slang: Serenity, tranquility, peace

• Effects last 16–24 h

• More potent than mescaline but less potent than LSD

• “Bad trips” occur frequently; prolonged psychotic reactions reported in people with psychiatric history • Tolerance reported; no evidence of dependence

• Anticholinergic effects, exhaustion, convulsions, excitement, and delirium reported

3,4-methylene-dioxyamphetamine (MDA)

Chemically related to both mescaline and amphetamine (synthetic drug)

Used orally as liquid, powder, tablet; injection Slang: Love drug

• Typical doses: 60–120 mg

• Effects occur after 30–60 min (orally), or sooner if injected, and last about 8 h

• CNS effects: Hallucinations and perceptual distortions rare; feeling of peace and tranquility occurs

• High doses: Hyperreactivity to stimuli, agitation, hallucinations, violent and irrational behavior, delirium, convulsions, and coma

3,4-methylene-dioxymethamphetamine (MDMA)

Powder, usually in tablets or capsules; may also be snorted or smoked, “bimped” or cooked on lollypops or paci ers

Slang: Ecstasy, MDMA, “Adam”, XTC, X, E, love drug, businessman’s special, clarity, lover’s speed, hugs, beans

Herbal Ecstasy: MDMA mixed with ephedrine

• Increases levels of serotonin, norepinephrine and, to a lesser extent, dopamine

• Many MDMA products are contaminated with other compounds including dextromethorphan, caffeine, phenylpropanolamine, ephedra, MDA, PMA, ketamine,

methylsalicylate

• Typical dose varies from 50–150 mg

• Onset of effects 30–60 min; duration of action 3–6 h; half-life is about 8 h; metabolized primarily by CYP2D6 and also by CYP1A2, 2B6, and 3A4. May inhibit its

own metabolism via CYP2D6; slow metabolizers of CYP2D6 may develop toxicity at moderate doses due to drug accumulation

• Commonly used at “raves”

• CNS effects: Wakefulness, increases energy and decreases fatigue and sleepiness; creates feelings of euphoria and well-being together with derealization,

depersonalization, impaired memory and learning, and heightened tactile sensations (action believed to be mediated through release of serotonin)

• Common physical effects include: Increased blood pressure and heart rate, increased endurance and sexual arousal, salivation, mydriasis, bruxism, trismus,

increased tension, headache, restless legs, blurred vision, dry mouth, urinary retention, nausea, and suppressed appetite, thirst, and sleep

• Severe physical reactions include: Hypertension, tachycardia, arrhythmia, hyperthermia, seizures; followed by hypotension, ischemic stroke, fatal brain

hemorrhage, and coma; death can occur from excessive physical activity (“raves”) that may result in disseminated intravascular coagulation, rhabdomyolysis,

hyponatremia, acute renal and hepatic failure, and multiple organ failure

• High doses can precipitate panic disorder, hallucinations, paranoid psychosis, aggression, and ashbacks

• After-effects include: Anorexia, drowsiness, muscle aches, generalized fatigue, irritability, anxiety, and depression (last 1–2 days due to half-life of drug of about

8h)

• Tolerance to euphoric effects with chronic use

• Chronic regular use may result in mood swings, depression, impulsivity, and lack of self-control, memory loss, and parkinsonism; can lead to psychological

dependence

• May also stress the immune system and increase susceptibility to infectious diseases

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Drug

Comments

Benzylpiperazine (BZP) and 3-tri uoromethyphenylpiperazine (3-TFMPP) Slang: Peaq, Freq, PureRush, PureSpun

• Promoted as a special tonic and a “natural” alternative to more dangerous street drugs

• Mechanism of action is believed to be similar to MDMA and the effects produced by BZP are comparable to those of amphetamine • Doses of 50–200 mg BZP ingested

• Effects last 4–8 h

• Metabolized via CYP2D6 and COMT

• Physical effects: Nausea, hyperthermia, increased blood pressure, dilated pupils, tingling skin, and decreased appetite

• CNS effects: Alertness, increased euphoria, and paranoia

• With high doses: Hallucinations, respiratory depression, renal toxicity, and convulsions

• Withdrawal effects include: Nausea, headache, fatigue, hangover, confusion, and insomnia

N-ethyl-3,4-methylene-dioxyamphetamine (MDE)

Chemically related to MDMA (synthetic drug) Slang: Eve

• Effects as for MDMA (above)

• Onset of effects within 30 min; duration of action 3–4 h

NBOMes

(N-2-methoxy-benzyl substituted 2C class of hallucinogens) marketed online as “research chemicals” under various names: N-bumb, Smiles, Solaris, Cimbi-5, 251,Bom-25, 2C-I-NBOMe, 25-I-NBOMe, 25I, Pandora, Diviniation, wizard, Smiley Paper

Used sublingually, buccally, and snorted. 25I-NBOMe is often applied to sheets of blotter paper of which small portions (tabs) are held in the mouth to allow absorption through the oral mucosa. There are reports of intravenous injection of 25I-NBOMe solution and smoking the drug in powdered form

• 25I-NBOMe was originally synthesized as a radiotracer for positron emission tomography

• Potent agonists of 5-HT2A receptor with stimulant and hallucinogenic properties – potency varies depending on product (easily synthesized)

• 25I-NBOMe effects usually last 6–10 h if taken sublingually or buccally. When inhaled, effects usually last 4–6 h, but can be signi cantly longer depending on

dosage; durations longer than 12 h reported

• Effects similar to LSD, but more potent; tolerance reported

• Physical effects: tachycardia, hyperpyrexia, mydriasis, increased sex drive

• CNS effects: heightened senses, visual and auditory hallucinations, euphoria

• Higher doses can cause: nausea, hypertension, confusion, paranoia, agitation, aggression, seizures, elevated white blood cell count, elevated creatine kinase,

metabolic acidosis, acute kidney injury, death

NUTMEG

Active ingredient related to trimethoxyamphetamine and to mescaline Seeds eaten whole, ground, powdered; sniffed

• Effects occur slowly and last several hours (duration of hallucinogenic effects is dose related) • Hallucinations are usually preceded by nausea, vomiting, diarrhea, and headache

• Physical effects: Lightheadedness, drowsiness, thirst, and hangover can occur

Paramethoxyamphetamine (PMA)

Synthetic drug

Used as powder, capsules

• Often sold as MDMA but has more pronounced hallucinogenic and stimulant effects

• Metabolized by CYP2D6

• Physical effects: Causes major increase in BP and pulse, hyperthermia, increased and labored breathing • Highly toxic; convulsions, coma, and death reported

Trimethoxyamphetamine (TMA)

Synthetic drug related to mescaline Used orally, as powder, injection

• Effects occur after 2 h

• Often misrepresented as MDA

• More potent than mescaline

• More toxic if injected or higher doses used

• Can cause unprovoked anger and aggression

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 353 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Drugs of Abuse

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Hallucinogens (cont.)

Further Reading

References

General Comments

1 American Medical Association. Use of cannabis for medicinal purposes. Report 3 of the Council on Science and Public Health (I-09). Retrieved from http://www.ama-assn.org/ama1/ pub/upload/mm/443/csaph-report3-i09.pdf

2 Curtis A, Clarke CE, Rickards HE. Cannabinoids for Tourette’s syndrome. Cochrane Database Syst Rev. 2009;4:CD006565. doi:10.1002/14651858.CD006565.pub2

3 González-Pinto A, Vega P, Ibáñez B, et al. Impact of Cannabis and other drugs on age at onset of psychosis. J Clin Psychiatry. 2008;69:1210–1216.

4 Fernandez-Espejo E, Viveros MP, Núñez L, et al. Role of cannabis and endocannabinoids in the genesis of schizophrenia. Psychopharmacology. 2009;206(4):531–549. doi:10.1007/

s00213-009-1612-6

5 Forrester MB, Kleinschmidt K, Schwarz E, et al. Synthetic cannabinoids and marijuana exposures reported to poison centers. Hum Exp Toxicol. 2012;31:1006–1011. doi:10.1177/

0960327111421945

Additional Suggested Reading

• CentreforAddictionandMentalHealth(Toronto,Canada).Informationaboutdrugsandaddiction:Hallucinogens.Retrievedfromhttp://www.camh.net/About_Addiction_Mental_ Health/Drug_and_Addiction_Information/hallucinogens_dyk.html

• CoulstonCM,PerdicesM,TennantCC.Theneuropsychologyofcannabisandothersubstanceuseinschizophrenia:Reviewoftheliteratureandcriticalevaluationofmethodological issues. Aust NZ J Psychiatry. 2007;41(11):869–884. doi:10.1080/00048670701634952

• EuropeanMonitoringCentreforDrugsandDrugAddiction.Understandingthe“Spice”phenomenon.Luxembourg:Of ceforOf cialPublicationsoftheEuropeanCommunities,2009. doi:10.2810/2706. Retrieved from http://www.emcdda.europa.eu/attachements.cfm/att_80086_EN_Spice%20Thematic%20paper%20\T1\textemdash%20 nal%20version.pdf

• FantegrossiWE,MurnaneKS,ReissiqCJ.Thebehavioralpharmacologyofhallucinogens.BiochemPharmacol.2008;75(1):17–33.doi:10.1016/j.bcp.2007.07.018

• Lopez-MorenoJA,González-CuevasG,MorenoJA,etal.Thepharmacologyoftheendocannabinoidsystem:Functionalandstructuralinteractionswithotherneurotransmittersystems

and their repercussions in behavioral addiction. Addict Biol. 2008;13(2):160–187. doi:10.1111/j.1369-1600.2008.00105.x

• McGrath J, Welham J, Scott J, et al. Association between cannabis use and psychosis-related outcomes using sibling pair analysis in a cohort of young adults. Arch Gen Psychiatry.

2010;67(5):440–447. doi:10.1001/archgenpsychiatry.2010.6

• NationalInstituteonDrugAbuse.DrugFacts:MDMA(EcstasyorMolly).Bethesda,MD:USDepartmentofHealthandHumanServices/NationalInstitutesofHealth,2013.Retrieved

fromhttp://www.drugabuse.gov/publications/drugfacts/mdma-ecstasy-or-molly

Opioids

• Highrateofcomorbidity,speci callydepression,alcoholism,andantisocialpersonalitydisorder(oftennotclearifthesearecauseore ect)

• Prescriptionopioidabuse(e.g.,codeine,oxycodone)inthegeneralpopulationisrelativelyhighinNorthAmerica

• Polydruguseandco-dependenceonbenzodiazepinesappearsparticularlycommonamongindividualsinjectingopioids

• High incidence of overdose and deaths reported through illicit use/abuse of prescription opioids (e.g., oxycodone, oxymorphone, fentanyl). Many

“prescription” opioids (e.g., fentanyl) from illicit sources in Asia

• Inmanycountries,naloxonekits(nasalsprayorinjectable)areavailableoverthecounter

• Di erdependingontypeofdrugtaken,thedose,therouteofadministration,andwhethercombinedwithotherdrugs

• Theelderlyaremoresensitivetoe ectsandsidee ectsofopioids

• Analgesia, “rush” sensation followed by relaxation, decreased tension, slow pulse and respiration, increased body temperature, dry mouth, con- stricted pupils, decreased GI motility

• Euphoria,stateofgrati cation,sedation

Pharmacological/ Psychiatric Effects

Physical

Mental

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

High Doses

Chronic Use

Discontinuation Syndrome

Treatment

Drug Interactions

OPIOIDS (GENERAL)

• Respiratorydepression,cardiovascularcomplications,coma,anddeath

• Increasedmortalityassociatedwithhigherprescribedopioiddosesinpatientswithchronicnon-cancerpain[1]

• Generallossofenergy,ambition,anddrive,motorretardation,attentionimpairment,sedation,slurredspeech

• Toleranceandphysicaldependence;withdrawal

• Cross-toleranceoccurswithotheropioids

• Symptoms include: Yawning, runny nose, sneezing, lacrimation, dilated pupils, vasodilation, tachycardia, elevated BP, vomiting and diarrhea, rest- lessness, tremor, chills, piloerection, bone pain, abdominal pain and cramps, anorexia, anxiety, irritability, and insomnia

• Acutesymptomscanlast10–14days(longerwithmethadone)

• Opioidwithdrawalstatesaregenerallynotlife-threatening;“coldturkey”isacceptabletosomeaddicts

• Non-opioidalternatives(e.g.,benzodiazepines,antipsychotics)usuallydonotwork

• Drugsareprescribedforthefollowingreasons:

a) to reverse e ects of toxicity by using opioid antagonists (e.g., naloxone – can precipitate withdrawal) b) to treat the immediate withdrawal reaction (e.g., clonidine, buprenorphine, methadone)

c) to aid in detoxi cation, or for maintenance therapy in a supervised treatment program (e.g., methadone, buprenorphine)

• Clinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterforthesecondagent

Class of Drug

Example

Interaction Effects

Antibiotic

Clarithromycin, erythromycin

Increased plasma concentration of fentanyl, alfentanyl due to inhibited metabolism via CYP3A4, resulting in prolonged analgesia and adverse effects

Increased level of oxycodone (AUC increased 2-fold in young patients and 2.3-fold in elderly patients) via CYP3A4 inhibition of clarithromycin

Anticonvulsant

Carbamazepine Phenytoin

Carbamazepine increases metabolism of codeine, fentanyl, oxycodone, and tramadol via CYP3A4 induction. May result in decreased analgesic effects of fentanyl, oxycodone, and tramadol, while potentially increasing analgesic effects of codeine via increased production of normorphine, a more potent metabolite of codeine

Phenytoin is also a CYP3A4 inducer and may have similar interactions as carbamazepine. Phenytoin has been shown to increase production of norpethidine (AUC increased by 25%), a toxic metabolite of meperidine responsible for adverse effects (e.g., seizures, myoclonus, tremors) via CYP3A4 induction

Antidepressant

MAOI, RIMA

Doxepin, uoxetine, imipramine, maprotiline, paroxetine, venlafaxine

Increased excitation, sweating, and hypotension reported (especially with meperidine, pentazocine); may lead to development of encephalopathy, convulsions, coma, respiratory depression, and serotonin syndrome

Decreased ef cacy of codeine due to inhibition of CYP2D6; must be metabolized to its active metabolite, morphine, (by CYP2D6) for its therapeutic effect

Antiemetic

Metoclopramide Ondansetron

Metoclopramide increases the rate of absorption of oral morphine, increasing its rate of onset and sedative effects. The gastric motility reduction of opioids may antagonize the gastric emptying effects of metoclopramide

Four of ve controlled studies show ondansetron reduced the analgesic ef cacy of tramadol. Tramadol may reduce pain via

enhancing the effects of serotonin on presynaptic 5-HT3 receptors in the spinal dorsal horn, while ondansetron reduces this effect via 5-HT3 receptor antagonism

Antihistamine

Tripelennamine, cyclizine

“Opiate high” reported in combination with opium; euphoria

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 355 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Drugs of Abuse

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Opioids (cont.)

Class of Drug

Example

Interaction Effects

Antipsychotic

FGAs (haloperidol, perphenazine)

Decreased ef cacy of codeine due to inhibition of CYP2D6; must be metabolized to its active metabolite, morphine, (by CYP2D6) for its therapeutic effect

Antiretroviral

Protease inhibitor

Ritonavir

Decreased clearance of opioid due to inhibited metabolism, resulting in increased plasma level (caution with fentanyl, alfentanyl, meperidine, and propoxyphene)

Antitubercular

Rifampin

Rifampin may increase the metabolism of codeine, fentanyl, morphine, oxycodone, and tramadol via CYP2D6 and/or CYP3A4 induction

CNS depressant

Alcohol, sedating antihistamines, benzodiazepines, muscle relaxants

Additive CNS effects; can lead to respiratory depression

Dextromethorphan

Decreased ef cacy of codeine due to inhibition of CYP2D6; must be metabolized to its active metabolite, morphine, (by CYP2D6) for its therapeutic effect

H2 antagonist

Cimetidine

Enhanced effect of opioid and increased adverse effects due to decreased metabolism; 22% decrease in clearance of meperidine

Opioid antagonist

Naloxone, naltrexone, nelmefene

Will precipitate withdrawal reaction

Stimulant

Cocaine

May potentiate cocaine euphoria

Opioids

Drug

Comments

HEROIN

Diacetylmorphine – synthetic derivative of morphine

Injected (IV – “mainlining”, or SC – “skin popping”), smoked, inhaled, taken orally

Slang: “H”, horse, junk, snow, stuff, lady, dope, shill, poppy, smack, scag, black tar, Lady Jane, white stuff, brown sugar, skunk, white horse

• Effects almost immediate following IV injection and last several hours; effects occur in 15–60 min after oral dosing

• Risk of accidental overdose as street preparations contain various concentrations of heroin

• Physical dependence and tolerance occur within 2 weeks; withdrawal occurs within 8–12 h after last dose, peaks in 36–72 h, and can last up to

10 days

• Physical effects: Pain relief, nausea, constipation, staggering gait, and respiratory depression

• CNS effects: Euphoria, drowsiness, and confusion

• Toxicity: Sinus bradycardia or tachycardia, hypertension or hypotension, palpitations, syncope, respiratory depression, coma, and death

• Pregnancy: High rate of spontaneous abortions, premature labor and stillbirths – babies are often small and have an increased mortality risk;

withdrawal symptoms in newborn reported

• Breastfeeding: Tremors, restlessness, vomiting and poor feeding reported in infants

MORPHINE

Principal active component of opium poppy

Taken as powder, capsule, tablet, liquid, injected

Slang: “M”, dreamer, sweet Jesus, junk, morph, Miss Emma, monkey, white stuff

• Effects as for heroin, but slower onset and longer-acting

• Effects occur in 15–60 min after oral dosing and last 1–8 h for immediate-release products; metabolized primarily by UGT1A3 and 2B7; inhibits

metabolism of UGT2B7[2]

• Physical effects: Pain relief, nausea, constipation; with high doses, can get respiratory depression, unconsciousness, and coma

• CNS effects: Drowsiness, confusion, and euphoria

• High dependence liability (second to heroin) due to powerful euphoric and analgesic effects

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Drug

Comments

METHADONE (see p. 380) (Dolophine, Metadol, Methadose) Used as tablets, liquid, injected Slang: The kick pill, dolly, meth

• Drug used in withdrawal and detoxi cation from opioids, but subject to abuse

• Effects occur 30–60 min after oral dosing and last 7–48 h

• Chronic use causes constipation, blurred vision, sweating, decreased libido, menstrual irregularities, joint and bone pain, and sleep disturbances

• Physical dependence and tolerance occur; withdrawal effects peak in 72–96 h, and can last up to 14 days

• Pregnancy: Dosing needs should be reassessed (decreased between weeks 14 and 32 and increased prior to term); withdrawal effects reported in

neonates

• Breastfeeding: Small amounts of methadone enter milk; nurse prior to taking dose or 2–6 h after

OPIUM

Resinous preparation from unripe seed pods of opium poppy; available as dark brown chunks or as powder

Soaked, taken as solution, smoked

Slang: Big O, black stuff, block, gum, hop

• Contains a number of alkaloids including morphine (6–12%) and codeine (0.5–1.5%)

• Physical effects: Nausea common, constipation; with high doses, can get respiratory depression, unconsciousness, and coma • CNS effects: Drowsiness, confusion, and euphoria

OTHER FREQUENTLY ABUSED PRESCRIPTION OPIOIDS AND RELATED DRUGS

Drug

Comments

CODEINE

Methylmorphine

Used orally, liquid, injected

Slang: Schoolboy, 3s, 4s, Captain Cody, Cody

• Naturally occurring alkaloid from opium poppy

• Metabolized primarily by UGT2B7 and also by CYP2D6 and 3A4. Inhibits metabolism of UGT2B7[2]

• Codeine must be metabolized to its active metabolite, morphine (by CYP2D6) for its therapeutic effect. A signi cant proportion of the population are poor or rapid

metabolizers of CYP2D6, resulting in unpredictable opioid effects or adverse effects, including toxicity in ultra-rapid metabolizers

• Common ingredient of both prescription and over-the-counter analgesics and antitussives (e.g., Fiorinal-C, Tylenol #1, etc.; not recommended for children)

• Physical effects: Pain relief, constipation

• CNS effects: Euphoria, drowsiness, and confusion

• Toxic effects: Respiratory depression and arrest, decreased consciousness, coma, and death

• Tolerance develops gradually; physical dependence is infrequent; withdrawal will occur with chronic high-dose use

DEXTROMETHORPHAN

(Robitussin DM)

Used orally

Slang: Robo, robo-trip, poor man’s PCP, candy, CCC, DM, DXM, skittles, triple C, velvet

• Higher doses can cause agitation, euphoria, altered perceptions, ataxia, nystagmus, hypertension, tachycardia, visual disturbances, and disorientation; may progress to panic attacks, delusions, psychotic/manic behavior, hallucinations, paranoia, and seizures

• If combination product abused (e.g. cough/cold preparation) must consider toxic effects of other ingredients

FENTANYL

(Duragesic, Sublimaze)

Slang: Tango, cash, Apache, China girl, China white, dance fever, friend, goodfella, jackpot, murders, murder 8, TNT

• Effects almost immediate following IV injection and last 30–60 min; with IM use, onset slower and duration of action is up to 120 min; exposing application site of fentanyl patch to an external heat source (e.g., heating pad, hot tub) can increase drug absorption and result in increased drug effect

• Metabolized primarily by CYP3A4[2] ; decreased metabolism with potent inhibitors of CYP3A4

• Physical effects: Dizziness, dry mouth, constipation, and GI distress

• CNS effects: Primarily sedation, confusion, and euphoria occurs quickly

• Overdoses have been reported in children who were accidentally exposed to patch due to improper storage or disposal. Toddlers may think the patch is a sticker,

tattoo or bandage

• High doses can produce muscle rigidity (including respiratory muscles) respiratory depression, unconsciousness, and coma

• Risk of serotonin syndrome when used with various serotonergic agents (SSRIs, SNRIs, etc.)

• Fentanyl analogues (e.g., carfentanyl) may be thousands of times more potent than morphine, producing signi cantly more respiratory depression

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 357 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Drugs of Abuse

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Opioids (cont.)

Drug

Comments

HYDROCODONE

(e.g., Novahistex DH, Vicodin) Slang: vike, Watson-387

• Related to codeine but more potent

• An ingredient in prescription antitussive preparations; sought by abusers due to easy availability and purity of product • Metabolized primarily by CYP2D6, 3A4, and by UGTs[2]

• Physical, CNS, and toxic effects as for codeine

• Tolerance develops rapidly

• Lethal dose: 0.5–1.0 g

HYDROMORPHONE

(Dilaudid)

Used orally

Slang: Juice, dillies

• Semisynthetic opioid

• Metabolized by UGT1A3[2]

• At low doses, side effects less common than with other opioids; high doses more toxic due to strong respiratory depressant effect

LEVORPHANOL

(Levo Dromoran)

• Synthetic opioid analgesic with effects similar to morphine

• High doses can produce cardiac arrhythmias, hypotension, respiratory depression, and coma

MEPERIDINE/PETHIDINE

(Demerol)

Synthetic opioid derivative Used orally, injected

Slang: Demmies, pain killer

• Metabolite (normeperidine) is highly toxic; may accumulate with chronic use and cause convulsions

• High doses produce disorientation, hallucinations, respiratory depression, stupor, and coma

• Risk of serotonin syndrome when used with various serotonergic agents (SSRIs, SNRIs, linezolid, etc.) and MAOIs

OXYCODONE

(Percodan, Percocet, OxyNeo, OxyContin (US)) Semisynthetic derivative

Used orally; tablets chewed, crushed and snorted, powder boiled for injection

• An ingredient in combination analgesic products and on its own

• Metabolized by CYP2D6, 3A4, and UGTs[2]

• Very high abuse potential

• Physical effects: Nausea, constipation; with high doses can get respiratory depression and coma • Mental effects: Drowsiness, disorientation, and euphoria

PENTAZOCINE

(Talwin)

Used orally, injected Slang: T’s, big T, Tee, Tea

• Has both agonist and antagonist properties at opioid receptors • Repeated injections can result in tissue damage at injection site • Mixed with tripelennamine

Further Reading

References

1 Gomes T, Mamdani MM, Dhalla IA, et al. Opioid dose and drug-related mortality in patients with nonmalignant pain. Arch Intern Med. 2011;171(7):686–691. doi:10.1001/archinternmed. 2011.117

2 Wynn GH, Cozza KL, Zapor MJ, et al. Med-psych drug-drug interactions update. Antiretrovirals, part III: Antiretrovirals and drugs of abuse. Psychosomatics. 2005;46(1):79–87.

Additional Suggested Reading

• NationalOpioidUseGuidelineGroup(NOUGG).Canadianguidelineforsafeandeffectiveuseofopioidsforchronicnon-cancerpain.2010.Retrievedfromhttp://nationalpaincentre. mcmaster.ca/opioid/

• PredaA.Opioidabuse.MedscapeReference[Articleupdated:December1,2014].Retrievedfromhttp://emedicine.medscape.com/article/287790-overview

• SmelsonDA,DixonL,CraigT,etal.Pharmacologicaltreatmentofschizophreniaandco-occuringsubstanceusedisorders.CNSDrugs.2008;22(11):903–916.

doi:10.2165/00023210-200822110-00002

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

General Comments

Inhalants/Aerosols

• Highrateofpsychopathology,speci callyalcoholism,depression,andantisocialpersonalitydisorder,hasbeendemonstratedinindividualswitha history of solvent use

• Considered“poorman’s”drugofabuse,isinexpensiveandreadilyavailable;primarilyusedbychildrenandinthirdworldcountriestolessenhunger pain

• FourthmostcommonlyabusedsubstanceamongteensinCanada;highuseinAboriginalpopulations

• Useisoftenepisodic,and“fads”determinecurrentinhalantofchoice;usersoftenabuse/misuseotherdrugs

• Nitriteabuseoftenassociatedwith“club”scene;amylnitriteusedtopromotesexualexcitementandorgasm;maycauseatemporarylossofsocial

inhibitions, thereby leading to higher-risk sexual practices

• Glue,gassing,sni ng,chemo,snappers

• Amylandbutylnitrites:Pearls,poppers,rush,lockerroom,Bolt,Kix

• Nitrousoxides:Laughinggas,balloons,whippets

• Volatilegases:Butane,propane,aerosolpropellants

• Solvents:Airplaneglue,gasoline,toluene,printing uid,cleaningsolvents,benzene,acetone,spraypaint(“chroming”),amylnitrite(“poppers”),etc.

• Aerosols:Deodorants,hairspray,freon

• Anestheticgases:Nitrousoxide(laughinggas),chloroform,ether

• “Bagging”–pouringliquidordischarginggasintoplasticbagorballoon

• “Sni ng”–holdingmouthovercontainerasgasisdischarged

• “Hu ng”–holdingasoakedragovermouthornose

• “Torching”–inhalingfumesdischargedfromacigarettelighter,thenignitingtheexhaledair

• Di erdependingontypeofdrugtaken

• Fumessni ed,inhaled;useofplasticbagcanleadtosu ocation

• InhaledproductentersthebloodstreamquicklyviathelungsandCNSpenetrationisrapid–intoxicationoccurswithinminutesandcanlastfrom

a few minutes to an hour

• Drowsiness, dizziness, slurred speech, impaired motor function, muscle weakness, cramps, light sensitivity, headache, nausea or vomiting, saliva- tion, sneezing, coughing, wheezing, decreased breathing and heart rate, hypotension, and cramps

• Fatalitiescanarisefromcardiacarrestorinhalationofvomitwhileunconscious

• Changing levels of awareness, impaired judgment and memory, loss of inhibitions, hallucinations, euphoria, excitation, vivid fantasies, feeling of

invincibility, and delirium

• Lossofconsciousness,convulsions,cardiacarrhythmia,seizures,anddeath

• Fatigue, chronic headaches, encephalopathy, hearing loss, visual impairment, sinusitis, rhinitis, laryngitis, weight loss, kidney and liver damage, bone marrow damage, cardiac arrhythmias, and chronic lung disease

• Inabilitytothinkclearly,memorydisturbances,depression,irritability,hostility,andparanoia

• Tolerancedevelopstodesirede ect;psychologicaldependenceisfrequent

• CNS:Acuteandchronice ectsreported(e.g.,ataxia,peripheralneuropathy)

• Cardiac:AnMIcanoccur,primarilywithuseofhalogenatedsolvents

• Renal:Acidosisandhypokalemia

• Hepatic:Hepatitisandhepaticnecrosis

• Hematologic:Bonemarrowsuppression,primarilywithbenzeneandnitrousoxideuse

• Accidentalsu ocationfromplasticbagusedoverthehead

Slang

Substances Abused

Methods of Use

Pharmacological/ Psychiatric Effects

Physical

Mental

High Doses

Chronic Use

Toxicity

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 359 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Drugs of Abuse

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Use in Pregnancy♢

Inhalants/Aerosols (cont.)

• Associated with increased risk of miscarriage, birth defects, low birth weight, and sudden infant death syndrome (SIDS); in a meta-analysis of 10 studies of maternal solvent exposure, 5 studies showed major malformations

• There is some evidence that prenatal exposure may cause long-term neurodevelopmental impairments, such as de cits in cognitive, speech, and motor skills

• Residualwithdrawalsymptomsreportedinbabiesofmotherswhousedvolatilesubstancesduringpregnancy.Symptomsinbabiesincludeexces- sive and high-pitched crying, sleeplessness, hyperre exia, tremor, hypotonia, and poor feeding

• Riskofinhalantsenteringbreastmilkandexposinginfanttoadversee ects

• E ectsareusuallyshortlasting;usecalmingtechniques,reassurance

• Clinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterforthesecondagent

Additional Suggested Reading

• Centre for Addiction and Mental Health (Toronto, Canada). Resources for professionals: Inhalants. Retrieved from http://www.camh.net/Publications/Resources_for_Professionals/ Pregnancy_Lactation/per_inhalants.html

Gamma-hydroxybutyrate (GHB)/Sodium Oxybate

Narcolepsy: Oral treatment of cataplexy and excessive daytime sleepiness (Xyrem)

• HasbeenusedinEuropetotreatalcoholdependencyatadoseof50mg/day

• Usedforsedationandtotreatopioidwithdrawal

• PrescribinganddispensingrestrictionsapplyforuseofXyreminpatientswithnarcolepsy

• Xyremisavailableasanoralsolutioncontaining500mg/mL

• Abusedasapowdermixedinaliquid;usuallysoldinvialsandtakenorally;hasasaltyorsoapytaste

• Usedforitshallucinogenicandeuphorice ectsatraves

• Meta-analysis of GHB for alcohol dependence reported it was better than naltrexone and disul ram in maintaining abstinence and had a better

e ect on alcohol cravings than disul ram or placebo. Single studies suggest comparable e cacy to benzodiazepines in reducing alcohol withdrawal

syndrome[1]

• Distributedasa“controlleddrug”withgenericnameofsodiumoxybate;improvesnighttimesleepandreducesdaytimesleepattacksandcataplexy

at doses of 6–9 g/night; initial starting doses are recommended to be 4.5 g/night (divided into two doses of 2.25 g each). The second dose is taken 2.5–4 h after the rst

Breast milk

Treatment

Drug Interactions

Class of Drug

Example

Interaction Effects

CNS depressant

Alcohol, benzodiazepines, hypnotics, opioids

Increased impairment of judgment, distortion of reality

Further Reading

Indications

( approved)

General Comments

♢ See p. 439 for further information on drug use in pregnancy and e ects on breast milk

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Slang

Pharmacology

Pharmacological/ Psychiatric Effects

Pharmacokinetics

Adverse Reactions

• Xyrem, being a CNS depressant, should not be used with alcohol or other CNS depressants. Patients should not drive or operate machinery for at least 6 h after taking Xyrem

• Originallyresearchedasananesthetic;showntohavelimitedanalgesice ectsandincreasedseizurerisk

• Promotedillegallyasahealthfoodproduct,anaphrodisiac,andformusclebuilding

• Hasbeenusedin“daterapes”becauseitactsrapidly,producesdisinhibitionandrelaxationofvoluntarymuscles,andcausesanterogradeamnesia

for events that occur under the in uence of the drug

• ProductsconvertedtoGHBinthebodyinclude:Gammabutyrolactone(GBL–alsocalledBlueNitroVitality,GHRevitalizer,GHR,Remforce,Renewtri-

ent, and Gamma G – is sold in health food stores) and the industrial solvent butanediol (BD – also called tetramethylene glycol or Sucol B, and sold as Zen, NRG-3, Soma Solutions, Enliven, and Serenity)

• Liquid ecstasy, liquid X, liquid F, goop, GBH = Grievous Bodily Harm, Easy lay, Ghost Breath, G, Somatomax, Gamma-G, Growth Hormone Booster, Georgia home boy, nature’s Quaalude, G-ri ck, Soapy, Salty Water

• Produced naturally in the body and is a metabolite of gamma aminobutyric acid (GABA); acts on GABAB receptor to potentiate GABAergic e ects

• Reducescataplexy

• Somee ectsofGHBareblockedbyopioidreceptorantagonists

• Deepsleepreportedwithdosesof2.0g

• At10mg/kgproducesanxiolytice ect,musclerelaxation,andamnesia

• At20–30mg/kgincreasesREMandslow-wavesleep

• Stimulatesslow-wavesleep(stages3and4)anddecreasesstage1sleep;withcontinueduse,decreasesREMsleep

• Caution:Dosesabove60mg/kgcanresultinanesthesia,respiratorydepression,andcoma

• Chronicusemayresultintoleranceand/orpsychologicaldependence

• Quicklyabsorbedorally;onsetofactionoccurswithin30min;peakplasmaconcentrationreachedin20–60min

• Food signi cantly decreases the bioavailability of Xyrem (sodium oxybate). Therefore, the rst dose should be taken at least 2 h after eating. To

minimize variability, the drug should be taken consistently in relation to meals

• Eliminationhalf-lifeapproximately20–30min;nolongerdetectedinbloodafter2–8handinurineafter8–12h

• Withhighdoses:Highfrequencyofdropattacks–“victim”suddenlylosesallmuscularcontrolanddropstothe oor,unabletoresistthe“attacker”

• Drowsiness,dizziness,nausea,vomiting,headache,hypotension,bradycardia,hypothermia,ataxia,nystagmus,hypotonia,tremors,musclespasms,

seizures, decreased respiration; symptoms usually resolve within 7 h, but dizziness can persist up to 2 weeks

• Use of sodium oxybate in narcolepsy has been associated with headache, nausea, dizziness, sleepwalking, confusion and urinary incontinence;

worsening of sleep apnea

• Useofhighdosesmayleadtounconsciousnessandcoma(particularlydangerousincombinationwithalcohol)

• Feelingofwell-being,loweredinhibitions,sedation,poorconcentration,confusion,amnesia,euphoria,andhallucinations;cancauseagitationand aggression

• Symptomsoccur1–6hafterabruptcessationandcanlastfor5–15daysafterchronicuse

• Initialsymptomsincludenausea,vomiting,insomnia,anxiety,confusion,and/ortremor;afterchronicuse,symptomscanincludemildtachycardia

and hypertension, and can progress to delirium with auditory and visual hallucinations

• Lowtherapeuticindex;dangerousincombinationwithalcohol

• Overdosescanoccurduetounknownpurityandconcentrationofingestedproduct

• Symptoms:Bradycardia,seizures,apnea,sudden(reversible)comawithabruptawakeningandviolence

Physical

Mental

Discontinuation Syndrome

Toxicity

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 361 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Drugs of Abuse

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Management

Use in Pregnancy♢

Drug Interactions

Gamma-hydroxybutyrate (GHB)/Sodium Oxybate (cont.)

• Comareportedindosesgreaterthan60mg/kg(4g)

• Severaldeathsreportedsecondarytorespiratoryfailure

• Noknownantidote • ScheduleBdrug

• Unknown

• Clinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterforthesecondagent

Breast milk

Class of Drug

Example

Interaction Effects

Antiretroviral

Protease inhibitor

Ritonavir-saquinavir combination

GHB toxicity – may cause bradycardia, respiratory depression, and seizures

Benzodiazepine

Diazepam

Has been used to treat GHB withdrawal; theoretically may worsen respiratory depression

CNS depressant

Alcohol

Synergistic CNS depressant effects can occur, especially with high doses of GHB, leading to respiratory depression

Cannabis

Increased pharmacological effects

Stimulant

Amphetamines

Increased pharmacological effects

Further Reading

References

1 Leone MA, Vigna-Taglianti F, Avanzi G, et al. Gamma-hydroxybutyrate (GHB) for treatment of alcohol withdrawal and prevention of relapses. Cochrane Database Syst Rev. 2010;(2): CD006266. doi:10.1002/14651858.CD006266.pub2

Additional Suggested Reading

General Comments

• •

GahlingerPM.ClubDrugs:MDMA,gamma-hydroxybutyrate(GHB),rohypnol,andketamine.AmFamPhysician.2004;69(11):2619–2627.Retrievedfromhttp://www.aafp.org/afp/2004/ 0601/p2619.html NationalInstituteonDrugAbuse.DrugFacts:Clubdrugs(GHB,ketamine,androhypnol).Bethesda,MD:USDepartmentofHealthandHumanServices/NationalInstitutesofHealth, 2014.Retrievedfrom.http://www.drugabuse.gov/publications/drugfacts/club-drugs-ghb-ketamine-rohypnol

Flunitrazepam (Rohypnol)

Usedasasedative/tranquilizerinsomeEuropeancountries;notmarketedinCanadaortheUSA

Commonly used as a “date-rape” drug because it acts rapidly, produces disinhibition and relaxation of voluntary muscles, and causes anterograde amnesia for events that occur under the in uence of the drug

Alcoholpotentiatesthedrug’se ects

Roo es,R-2s,RochesDos,forget-mepill,MexicanValium,roo nol,rope,rophies ♢ See p. 439 for further information on drug use in pregnancy and e ects on breast milk

Slang

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Method of Use

Pharmacology

Pharmacokinetics

Adverse Reactions

Physical

Mental

Toxicity

Drug Interactions

Further Reading

• Purchased in doses of 1 and 2 mg (legal manufacturers have added blue or green dye to formulation to color beverages and make them murky); illegal manufacturing is common

• Ingested,snortedorinjected

• Addedtoalcoholicbeveragesofunsuspectingvictim

• Fast-actingbenzodiazepine,structurallyrelatedtoclonazepam

• Seep.224

• E ectsbeginin30min,peakwithin2h,andlastupto8h

• Thesereactionsarereportedfollowingrestorationofconsciousness

• Dizziness,impairedmotorskills,“rubberylegs,”weakness,unsteadiness,visualdisturbances,blood-shoteyes,slurredspeech,andurinaryretention

• Decreasedbloodpressureandpulse,slowedbreathing;mayleadtorespiratorydepressionandarrest

• Rapidlossofconsciousnessandamnesia;residualsymptomsincludedrowsiness,fatigue,confusion,impairedmemoryandjudgment,andreduced inhibition

• If some memory of the event remains, the “victim” may describe a disassociation of body and mind – a sensation of being paralyzed, powerless, and unable to resist

• SeeBenzodiazepinesp.226

• SeeBenzodiazepinespp.227–229

Additional Suggested Reading

• GahlingerPM.ClubDrugs:MDMA,gamma-hydroxybutyrate(GHB),rohypnol,andketamine.AmFamPhysician.2004;69(11):2619–2627.Retrievedfromhttp://www.aafp.org/afp/2004/ 0601/p2619.html

Nicotine/Tobacco

• Slang:

E-cigarettes: Vape pipes, hookah pens, e-hookahs

Waterpipe smoking: Shisha, hookah, narghile, goza, hubble bubble

Chewing tobacco: Snu , spit tobacco, smokeless oral tobacco, chad, dip, snarl

• Electronic cigarettes, also known as e-cigarettes or vapor cigarettes, are battery-operated devices that resemble traditional cigarettes. Instead of burning tobacco, they contain cartridges lled with nicotine and other chemicals. When the e-cigarette is used, the liquid chemicals in the cartridge are turned into a vapor or steam that is inhaled by the smoker. The liquid comes in a wide range of avors, from tobacco and co ee to fruit avors. Nicotine content varies widely among products and nicotine exposure depends on the user’s inhalation and experience. There is limited research on their health risks

General Comments

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 363 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Drugs of Abuse

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Pharmacological/ Psychiatric Effects

Pharmacokinetics

Toxicity

Discontinuation Syndrome

Nicotine/Tobacco (cont.)

• FDA has announced that e-cigarette use among youth has reach “epidemic proportions.” Young people who use e-cigarettes are more likely to progress to smoking combustible cigarettes over time; those who use both e-cigarettes and combustible cigarettes may progress toward heavier use of both products, instead of substituting e-cigarettes from combustible ones

• Increasedratesandhigherlevelsofsmokinghavebeenassociatedwithanumberofpsychiatricdisorders,includingschizophrenia,depression,and anxiety disorders, resulting in high rates of morbidity and mortality[1]

• Tobacco smoking is the leading cause of premature death in developed countries; tobacco smoke contains over 4,000 chemicals, approximately 50% are carcinogenic[2]

• Smoking-related diseases include: Cancers (lung, cervix, pancreas, kidneys, bladder, stomach), cardiovascular disease, emphysema, pneumonia, COPD, aortic aneurysms, acute myeloid leukemia, cataracts, and gum disease

• Nicotine is an alkaloid found in the nightshade family of plants (Solanaceae), which constitutes approximately 0.6–3.0% of dry weight of tobacco. In low concentrations (an average cigarette yields about 1 mg of absorbed nicotine), the substance acts as a stimulant in mammals and is the main factor responsible for the dependence-forming properties of tobacco smoking

• By binding to nicotinic acetylcholine receptors, nicotine stimulates the release of many chemical messengers including acetylcholine, nore- pinephrine, epinephrine, vasopressin, arginine, dopamine, autocrine agents, and β-endorphin. This release of neurotransmitters and hormones is responsible for most of nicotine’s e ects. Nicotine appears to enhance concentration and memory, due to the increase of acetylcholine. It also appears to enhance alertness, due to the increases of acetylcholine and norepinephrine. Arousal is increased by the increase of norepinephrine. Pain is reduced by the increases of acetylcholine and β-endorphin

• Asnicotineentersthebody,itisdistributedquicklythroughthebloodstreamandcancrosstheblood-brainbarrier.Onaverage,ittakesabout7sec for nicotine to reach the brain when inhaled

• Theamountofnicotineabsorbedbythebodyfromsmokingdependsonmanyfactors,includingthetypeoftobacco,whetherthesmokeisinhaled, and whether a lter is used. For chewing tobacco, dipping tobacco, snus (moist tobacco powder), and snu (ground tobacco leaves used for inhalation), which are held in the mouth between the lip and gum, or taken in the nose, the amount released into the body tends to be much greater than from smoked tobacco

• NicotineismetabolizedintheliverbyCYP450enzymes(mostlyCYP2A6andalsoCYP2B6).Amajormetaboliteiscotinine;otherprimarymetabolites include nicotine N’-oxide, nornicotine, nicotine isomethonium ion, 2-hydroxynicotine, and nicotine glucuronide. Glucuronidation and oxidative metabolism of nicotine to cotinine are both inhibited by menthol, an additive to mentholated cigarettes, thus increasing the half-life of nicotine in vivo.

• Half-lifeofnicotineinthebodyisaround2h

• It is impossible to overdose on nicotine through smoking alone (though a person can overdose on nicotine through a combination of nicotine patches, nicotine gum, and/or tobacco smoking at the same time)

• Casesofpoisoninghavebeenreportedininfantsandyoungchildrenwithnicotinegum,nicotinepatches,andE-cigarettes

• Approximately 40% of smokers attempt to quit each year, but only 4–7% are likely to be successful on their rst attempt; most relapse in the rst week[3]. Motivational intervention techniques (practical counseling, support, encouragement) appear to be e ective in increasing a patient’s likelihood to try to quit and maintain abstinence

• Nicotinewithdrawalsymptomspeakwithinafewdaysandusuallysubsideafterafewweeks;however,somesymptomscanlastformonths[4]:

– Withdrawal symptoms, lasting a few days to a few weeks: Dizziness, restlessness, anxiety, insomnia, irritability, frustration, anger, di culty

concentrating, drowsiness, cough, dry throat or mouth, constipation, bloating, and bad breath

– Withdrawal symptoms lasting weeks to months: Increased appetite, fatigue, “boredom,” depressed mood, anhedonia, craving for tobacco, and

exacerbation of an underlying psychiatric disorder

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Use in Pregnancy♢

Treatment

Drug Interactions

• Manybehavioralfactorscanalsoa ecttheseverityofwithdrawalsymptoms.Forsomepeople,thefeel,smell,andsightofacigaretteandtheritual of obtaining, handling, lighting, and smoking the cigarette are all associated with the pleasurable e ects of smoking and can make withdrawal or craving worse. Behavioral therapies can help smokers identify environmental triggers of craving so they can employ strategies to prevent or circumvent these symptoms and urges

• Smoking (or exposure to second-hand smoke) during pregnancy results in babies with a lower-than-average birth weight and more health pro- blems, as smoking exposes the baby to chemicals and carcinogens in tobacco and provides less oxygen and nutrients

• Smokershaveagreaterchanceofhavingamiscarriagethannonsmokers.Duringbirth,theyaremorelikelytohavecomplications

• Babies born to mothers who smoked may have more ear infections as well as more colds and respiratory problems; long-term e ects on the

o spring include impaired fertility, type 2 diabetes, obesity, hypertension, learning problems, sleep problems, and neurobehavioral defects[5]

• Childrenregularlyexposedtosecond-handsmokeareatleast50%morelikelytosu erdamagetotheirlungsandtodevelopbreathingproblems

such as asthma[6]

• Tobaccodependenceisachronicproblemthatoftenrequiresrepeatedinterventionsandmultipleattemptstoquit.Behaviortherapies,counseling, and support have shown to improve outcomes

• Medicationswhichhavebeenfoundtobee ectiveas rst-linesmokingcessationtreatmentsinclude[3]: – BupropionSR(seep.17)

– Nicotinereplacementtherapy(gum,lozenge,patch,inhaler;seep.385)

– Partialagonist/antagonist–varenicline(seep.385)

– Second-linetreatmentsinclude:nortriptylineandclonidine

• Polycyclicaromatichydrocarbonsaresomeofthemajorlungcarcinogensfoundintobaccosmoke.TheyarepotentinducersofCYPisoenzyme1A2, and possibly 2E1

• CAUTION;uponsmokingcessation,smokersmayrequireareduceddoseoftheinteractingmedication[7]

Class of Drug

Example

Interaction Effects

Alcohol

Positive correlation reported between cigarette smoking and alcohol use; alcohol potentiates rewarding effects of nicotine

Antidepressant

Fluvoxamine

Decreased plasma level of uvoxamine by 25% due to increased metabolism via CYP1A2

Tricyclic (amitriptyline, imipramine)

Increased clearance of antidepressant due to induction of CYP1A2

Antipsychotic

Clozapine, olanzapine

Chlorpromazine, thioridazine

Decreased plasma level of antipsychotics due to increased metabolism via CYP1A2. Dosage modi cations not routinely recommended but smokers may require higher doses for ef cacy. Caution when patient stops smoking, as level of antipsychotic will increase (case report of serious clozapine toxicity following smoking cessation; serum increases of 72–261% reported); monitor clozapine levels and reduce antipsychotic dose as necessary

Decreased plasma level of chlorpromazine (by 24%) and thioridazine (by 46%) due to induction of metabolism via CYP1A2. Similar interaction with other phenothiazines possible. Caution when patient stops smoking as level of antipsychotic will increase; monitor antipsychotic levels and reduce dose as necessary

Benzodiazepine

Chlordiazepoxide, diazepam

Increased clearance of benzodiazepines due to enzyme induction

Alprazolam

Alprazolam concentration reduced by 50%

Caffeine

Increased metabolism of caffeine

Cannabis

Additive CYP1A2 induction, additive increase in heart rate and stimulant effects

Corticosteroid

Inhaled puffers

Ef cacy of corticosteroid for asthma reduced in smokers

Hormone

Oral contraceptives

Increased risk of serious cardiovascular effects in females over age 35 who smoke 15 or more cigarettes daily

Insulin

Faster onset of action and higher insulin levels in smokers

Theophylline

Decreased plasma level of theophylline due to increased metabolism via CYP1A2

♢ See p. 439 for further information on drug use in pregnancy and e ects on breast milk

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 365 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Drugs of Abuse

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Nicotine/Tobacco (cont.)

Further Reading

References

1 Lawrence D, Mitrou F, Zubrick R. Smoking and mental illness: Results from population surveys in Australia and the United States. BMC Public Health 2009;9:285. doi:10.1186/ 1471-2458-9-285

2 Health Canada. Tobacco scienti c facts. Retrieved from http://www.hc-sc.gc.ca/hc-ps/tobac-tabac/fact-fait/facts-faits-eng.php

3 Fiore MC, Jaen CR, Baker TB, et al. Clinical Practice Guideline: Treating tobacco use and dependence: 2008 Update. Rockville, MD: U.S. Department of Health and Human Services/Public

Health Service, 2008. Retrieved from http://www.surgeongeneral.gov/tobacco/treating_tobacco_use08.pdf

4 Nides M. Update on pharmacologic options for smoking cessation treatment. Am J Med. 2008;121(4 Suppl 1); S20–S31. doi:10.1016/j.amjmed.2008.01.016

5 Bruin JE, Gerstein HC, Holloway AC. Long-term consequences of fetal and neonatal nicotine exposure: A critical review. Toxicol Sci. 2010;116(2):364–374. doi:10.1093/toxsci/kfq103

6 Public Health Agency of Canada. Smoking and Pregnancy. Retrieved from http://www.phac-aspc.gc.ca/hp-gs/know-savoir/smoke-fumer-eng.php

7 Kroon LA. Drug interactions with smoking. Am J Health Syst Pharm. 2007;64(18):1917–1921. doi:10.2146/ajhp060414

Additional Suggested Reading

• NationalInstituteonDrugAbuse.TobaccoAddiction.Bethesda,MD:USDepartmentofHealthandHumanServices/NationalInstitutesofHealth,2009.Retrievedfromhttp://www. drugabuse.gov/researchreports/nicotine/nicotine.html

• Laniado-LaborínR.Smokingcessationintervention:Anevidence-basedapproach.PostgradMed.2010;122(2):74–82.doi:10.3810/pgm.2010.03.2124

• RuddockB.Focusontreatingtobaccouseanddependence.TherapeuticOptions.DrugInformationandResearchCentre,OntarioPharmacists’Association.2008TO1–4.Retrievedfrom

http://www.dirc.ca [subscription required]

• PagliaroLA,PagliaroAM.Pagliaro’scomprehensiveguidetodrugsandsubstancesofabuse(2nded.)Washington,DC:AmericanPharmacistsAssociation,2009.

• Stead LF, Lancaster T. Behavioural interventions as adjuncts to pharmacotherapy for smoking cessation. Cochrane Database Syst Rev. 2012;12:CD009670. doi:10.1002/14651858.

CD009670.pub2

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

TREATMENT OF SUBSTANCE USE DISORDERS

• Drugsavailablefortreatmentofsubstanceusedisordersmaybeclassi edasfollows:

Classi cation

Substance Use Disorder

Alcohol use disorder

Cannabis use disorder

Cocaine use disorder and methamphentamine use disorder Opioid use disorder

Tobacco use disorder

(B) NotmarketedinCanada

Approved Agent

Page

Acamprosate (Campral)

See p. 369

Disul ram(B) (Antabuse) Naltrexone (Revia, Vivitrol(B))

See p. 371 See p. 373

Nalmefene(B)

See p. 371

No approved medication

Buprenorphine (Subutex, Sublocade(B))

See p. 377

Buprenorphine/Naloxone (Bunavail, Suboxone, Zubsolv) Methadone

Naltrexone (Revia, Vivitrol(B))

See p. 377 See p. 380 See p. 373

Bupropion (Zyban)

Nicotine replacement therapies (nicotine patches, gum, lozenges, inhalers) Varenicline tartrate (Champix in Canada/Chantix in the USA)

See p. 17 See p. 385 See p. 385

Substance Use Disorder

Unapproved Agent Under Investigation

Comments

Alcohol use disorder

Baclofen Gabapentin

Pregabalin Sodium oxybate Topiramate

Controversial medication, recent studies and meta-analysis question ef cacy

Evidence suggests that gabapentin could be an effective treatment option for the management of alcohol use disorder; some limited results for its use to treat alcohol withdrawal syndrome

A review of studies shows bene cial effects for alcohol relapse prevention; contradictory results seen for the treatment of withdrawal syndrome; greater bene ts seen in patients with comorbid generalized anxiety disorder

Sodium oxybate is the sodium salt of γ-hydroxybutyric acid (GHB). Used in Italy and Austria for withdrawal and abstinence support, with limited evidence, and an FDA black box warning for respiratory depression and dependence

Evidence suggests that topiramate could be an effective treatment option for the management of alcohol use disorder, while there are limited results for its use to treat alcohol withdrawal syndrome

Varenicline

Encouraging results for combined treatment of tobacco and alcohol dependence

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 367 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Substance Use Treatment

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Treatment of Substance Use Disorders (cont.)

Unapproved Agent Under Investigation

Comments

Dronabinol

Agonist replacement, improved retention in treatment and reduction of withdrawal symptoms; however, no improvement over placebo regarding abstinence

Gabapentin N-acetylcysteine Nabilone Nabiximols (Sativex)

Proof of concept study. Encouraging for use in withdrawal, reductions, craving, cognitive functioning Appears to have potential for cannabis craving and use, with some limited effect size

Agonist replacement, no convincing studies as yet

Agonist replacement during cannabis withdrawal. Withdrawal symptoms decreased; however, no improvement over placebo regarding long-term reduction of cannabis use

Mixed amphetamine salts

Mixed results, reduction in cocaine use, speci cally in individuals with ADHD

Disul ram Methamphetamine (oral)

Very limited evidence in form of reports of decreased cocaine and alcohol use in subjects using both substances

Limited evidence, some reduction in cocaine use and reduced craving reported Single study showing effect in comorbid ADD/ADHD and cocaine use disorder

Methylphenidate N-acetylcysteine

Mixed results; reduced drug craving observed, which may decrease use

May have potential to improve abstinence in individuals who have stopped using, with limited effect size

Clonidine

Injectable opioid agonist therapy (iOAT)

Lofexidine (Lucemyra)

Slow release oral morphine (SROM) (Kadian)

May have a role as an adjunctive maintenance treatment with buprenorphine to increase abstinence duration

Specialist-led approach available in Canada through special access program. It is the highest intensity treatment option available for people with severe IV opioid use disorder who have been unsuccessful at reducing or ceasing illicit opioid use with the assistance of adequately dosed lower-intensity treatment options (i.e., oral opioid agonist therapy)

Only approved for the mitigation of withdrawal symptoms to facilitate abrupt discontinuation of opioids in adults up to 14 days Potential option for individuals who respond poorly to buprenorphine/naloxone (Suboxone) and methadone and may require an alternative treatment approach. Health Canada’s Non-Insured Health Bene ts (NIHB) program includes SROM on its formulary as a treatment option for opioid dependence where methadone and Suboxone are not appropriate or unavailable

Nortriptyline Electronic cigarettes

Equally effective and similar ef cacy to bupropion and NRT

The British National Institute for Health and Care Excellence supports electronic cigarettes for harm reduction; despite some safety concerns, electronic cigarettes may help with smoking cessation, though evidence is limited

Substance Use Disorder

Cannabis use disorder

Cocaine use disorder and methamphetamine use disorder

Opioid use disorder

Tobacco use disorder

General Comments

• No medication has been approved for withdrawal management, but benzodiazepine taper is considered standard in the treatment of alcohol withdrawal, and clonidine is well established as medication to treat opioid and tobacco withdrawal. Methadone and buprenorphine are also used to reduce withdrawal symptoms during opioid taper

• Inpatientswithconcurrent(alsodescribedasdual)disorders(adiagnosedpsychiatricdisorderandasubstanceusedisorder)integratedtreatment is suggested for both disorders, regardless of the status of the concurrent condition

• Given the lack of empirical evidence based on randomized clinical trials, treatment of concurrent conditions is often guided by clinical consensus and evidence established for individuals without concurrent disorders

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Acamprosate

Product Availability∗

Generic Name

Chemical Class

Trade Name

Dosage Forms and Strengths

Acamprosate calcium

Calcium acetyl-homotaurine

Campral

Delayed-release enteric-coated tablets: 333 mg (equiv. to 300 mg acamprosate)

∗ Refer to Health Canada’s Drug Product Database or the FDA’s Drugs@FDA for the most current availability information.

Indications‡

( approved)

General Comments

Alcohol use disorder: Maintenance of abstinence; reduces alcohol cravings and prevents relapse

• Meta-analyseshaveshownthatpatientstreatedwithacamprosatehadsigni cantlyhighercontinuousabstinenceratesthanthoseonplacebo

• Detoxi cationbeforeanacamprosatetrialandagoalofabstinenceratherthancontrolleddrinkingimprovesoutcomewithacamprosate

• May not be e ective in patients who are actively drinking at the start of treatment; it is not e ective for acute withdrawal and does not treat

delirium tremens. Initiate treatment as soon as possible after alcohol withdrawal; treatment should be continued during relapses

• Acamprosatetreatmentshouldbepartofacomprehensivealcoholmanagementprogramthatincludespsychosocialsupport

• Mixedresultsseenwhencombinedwithnaltrexoneastoincreasede cacyandsuccessofabstinence(seeDrugInteractionsp.370);acamprosate

appears more useful in maintaining abstinence as it reduces dysphoric e ects that trigger some patients to resume drinking, while naltrexone

controls alcohol consumption by reducing the pleasurable e ects of alcohol

• Hasbeenusedincombinationwithdisul ramtoincreaseabstinence

• E cacyforpromotingabstinencefromalcoholhasnotbeendemonstratedinpatientswhoabusemultiplesubstances

• N-Methyl-D-aspartate(NMDA)receptormodulator,decreasesactivityatNMDAreceptors

• Decreasesdopaminehyperexcitability

• Restoresglutamatetoneandmodulatesneuronalhyperexcitabilityfollowingwithdrawalfromalcohol,decreasesactivityofglutamate

• Weak inhibitor of presynaptic GABAB receptors in the nucleus accumbens, increases GABA-ergic system

• Adults over 60 kg: 666 mg tid; under 60 kg: 666 mg bid; to minimize GI e ects, can initiate more gradually (i.e., 333 mg tid and increase dose by 1 tablet per week until target dose is reached)

• Hepaticdisorders:Nodosageadjustmentneeded

• Renaldysfunction:Give333mgtidifCrClis30–50mL/min;avoidinpatientswithCrClunder30mL/min

• Bioavailability=11%;foodreducesbioavailabilityby20%,notclinicallysigni cant

• Tmax = 3–9 h once steady state is reached

• Steadystateisreachedin5–7days

• Haslowproteinbinding

• Half-life=20–33h

• Isnotdegradedbytheliverandisprimarilyexcretedasunchangeddrugbythekidneys–notinvolvedinCYP450interactions

• Common:Nausea, atulence,anddiarrhea(doserelatedanddecreaseovertime),headache,asthenia,andpruritus

• Depression,anxiety,insomnia,andsuicidalideationreported

• Lesscommon:Vomiting,dizziness, uctuationsinlibido,maculopapularrash,anorexia,xerostomia,hyperhidrosis,andmetallictaste

Pharmacology

Dosing

Pharmacokinetics

Adverse Effects

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 369 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Substance Use Treatment

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Precautions Contraindications Toxicity

Pediatric Considerations Geriatric Considerations Use in Pregnancy♢

Nursing Implications

Patient Instructions

Drug Interactions

Acamprosate (cont.)

• Syncope,palpitations,peripheraledema

• Weightgain,myalgia,diaphoresis

• Acuterenalfailurereported

• Useofacamprosatedoesnotdiminishwithdrawalsymptoms

• Avoidinsevererenalinsu ciency(CrCllessthan30mL/min)

• Diarrheareportedafteroverdoseof56g

• Providesupportivetreatment

• Notrecommended

• Usecautionandavoidinpatientswithrenalimpairment

• Safety in human pregnancy not established. May be used during pregnancy only after a careful bene t/risk assessment, when the patient cannot abstain from drinking alcohol without being treated with acamprosate and when there is consequently a risk of fetotoxicity or teratogenicity due to alcohol

• Teratogenice ectsweeninanimalstudies

• Notrecommendedinhumansduringpregnancy

• Notknownifexcretedinhumanmilk

• Acamprosatetreatmentshouldbepartofacomprehensivealcoholmanagementprogramthatincludespsychosocialsupport

• Tabletsareenteric-coated,theyshouldnotbebrokenorchewedbutswallowedwhole

• Monitorpatientsforsymptomsofdepressionorsuicidalthinking

• Diarrheaoccurscommonlyduringtherapy,isdoserelatedandgenerallytransient

• Complianceplaysanimportantroleinacamprosatee cacy

• Fordetailedpatientinstructiononacamprosate,seethePatientInformationSheet(detailsonp.440)

• Clinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterforthesecondagent

Breast Milk

Class of Drug

Example

Interaction Effects

Opioid antagonist

Naltrexone

Increased concentrations of acamprosate; Cmax increased by 33% and AUC by 25%; no change in concentration of naltrexone or its metabolite, 6-β-naltrexone. No dosage adjustment needed

♢ See p. 439 for further information on drug use in pregnancy and e ects on breast milk

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Disul ram

Product Availability∗

Generic Name

Trade Name(A)

Dosage Forms and Strengths

Disul ram(B)

Antabuse

Tablets: 250 mg, 500 mg

Indications‡

( approved)

General Comments

Alcohol use disorder: Deterrent

• Comorbidalcoholusedisorderandposttraumaticstressdisorder:Hasshownbene tintreatment

• Doesnottargetcoreofalcoholdependence

• Actsasanaversiveagentorpsychologicaldeterrent;clinicale cacyislimitedduetopoorcompliance

• Superviseddisul rammayhaveshort-terme cacy;long-terme ectsonabstinencerequireevaluation

• Disul ramtreatmentshouldbepartofacomprehensivealcoholmanagementprogramthatincludespsychosocialsupport(levelofevidence1[1])

• Inhibits alcohol metabolism by irreversibly inhibiting acetaldehyde dehydrogenase; the accumulating acetaldehyde produces an unpleasant reac- tion consisting of headache, sweating, ushing, choking, nausea, vomiting, tachycardia, and hypotension

• Responseisproportionaltothedoseandamountofalcoholingested

• Canoccur10–20minafteralcoholingestionandmaylastforseveralhours;maylasttheentiretimealcoholisintheblood

• Increasesbraindopamineconcentrationsbyinhibitingdopaminecatabolizingenzymes,dopamine-β-hydroxylase

• Decreasesnorepinephrine,whichmayplayaroleinanti-craving

• 125–500mgdaily,maintenancetherapymayberequiredformonthstoyears

• Nodosingadjustmentprovidedforrenalorhepaticimpairment.Usewithcautioninacuteorchronicnephritisorhepaticcirrhosis

• Highlylipidsoluble;bioavailability80%

• MetabolizedthroughmultiplestepstoactivemetabolitesviaCYP3A4/5,1A2,2B6,2E1,and avinmonooxygenase

• SelectivelyinhibitsCYP2E1withbothacuteandchronicadministration;withchronicuse,otherenzymes(e.g.,CYP1A2,3A4,andP-gp)mayalsobe

inhibited

• Onsetofaction:upto12h

• Durationofaction:Upto14days,duetoslowrestorationrateofacetaldehydedehydrogenase

• Drowsinessandlethargyfrequent,depression,disorientation,restlessness,excitation,psychosis

• Physical e ects: Neurological toxicity can occur proportional to dose and duration of therapy (e.g., central and peripheral neuropathy, movement

disorders); optic neuritis, headaches, dizziness, skin eruptions, mild gastrointestinal disturbances, impotence, and garlic-like or metallic taste

• Transient elevated liver function tests reported in up to 30% of individuals; hepatitis is rare. Baseline liver function test recommended and repeat

periodically and at rst symptoms or sign of liver dysfunction

• Reversibleencephalopathyandtoxicencephalopathywithconvulsionsandcomamayoccur;isusuallyseenonlyinoverdose

Pharmacology

Dosing

Onset & Duration of Action

Adverse Effects

Pharmacokinetics

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 371 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Substance Use Treatment

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Precautions

Contraindications Toxicity

Lab Tests/Monitoring

Pediatric Considerations Geriatric Considerations

Nursing Implications

Disul ram (cont.)

• Donotgivetointoxicatedindividualsorwithin36hofalcoholconsumption

• Ifalcoholreactionoccurs,generalsupportivemeasuresshouldbeused;inseverehypotension,vasopressoragentsmayberequired

• Usecautiouslyinpulmonarydisorders,liverdisease,renaldisorders,epilepsy,diabetesmellitus,andhypothyroidism

• Patientswithcompromisedliverfunctionorunabletoabstainfromdrinkingareadvisedagainsttakingdisul ram

• Patientsshouldnotdrinkalcoholfortwoweeksafterstoppingdisul ram

• Coronaryocclusion,myocardialdisease,psychosis,hypersensitivity

• Useofalcohol-containingproducts

• Useofmetronidazole

• Alcoholreactionisproportionaltodoseofdrugandalcoholingested;severereactionsmayresultinrespiratorydepression,cardiovascularcollapse, arrhythmias, convulsions, and death

• Liverfunctiontestsatbaselineandafter10–14daysofcommencingtreatment

• MonitorcompleteCBCandserumchemistries

• For detailed information on the use of disul ram in this population, please see the Clinical Handbook of Psychotropic Drugs for Children and Adolescents[2]

• Cardiovasculartolerancedecreaseswithage,thusincreasingtheseverityofthealcoholreactions

• Safetyinpregnancynotestablished,limiteddataonmaternaluseduringpregnancy

• Unknown

• The patient should be made aware of the purpose of this medication and educated about the consequences of drinking; informed consent to treatment is recommended

• Thepatientshouldavoidallproducts(foodanddrugs)containingalcohol,includingtonics,coughsyrups,mouthwashes,andalcohol-basedsauces; exposure to alcohol-containing rubs or organic solvents may also trigger a reaction

• Dailyuninterruptedtherapymustbecontinueduntilthepatienthasestablishedabasisforself-control

• Medication should not be used alone, without proper motivation and supportive therapy; disul ram will not cure alcohol use disorder but acts as

a motivational aid

• Encouragepatienttocarryanidenti cationcardstatingthattheyaretakingdisul ram

• Adisul ram/alcoholreactiongenerallylasts30–60minbutmaybeprolongedinseverereactionsandmaylasttheentiretimealcoholispresentin

the blood

• Fordetailedpatientinstructionsondisul ram,seethePatientInformationSheet(detailsonp.440)

• Clinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterforthesecondagent

Use in Pregnancy♢

Breast Milk

Patient Instructions

Drug Interactions

♢ See p. 439 for further information on drug use in pregnancy and e ects on breast milk

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Example

Interaction Effects

Dilsul ram reaction (tachycardia, shortness of breath, hypotension, ushing); case reports of myocardial infarction

Clarithromycin Metronidazole

Case of toxic epidermal necrolysis

Acute psychosis, ataxia, and confusional states reported

Warfarin

Increased INR response due to reduced metabolism

Phenytoin

Increased phenytoin blood levels and toxicity due to reduced metabolism (carbamazepine and phenobarbital levels not signi cantly affected)

Sertraline oral concentrate Amitriptyline, desipramine Tranylcypromine

Contains alcohol and may cause a disul ram/alcohol reaction

Increased plasma level of antidepressant due to reduced metabolism; neurotoxicity reported with combination Report of delirium, psychosis with combination

Tinidazole

May enhance adverse toxic effect of disul ram

Amprenavir solution

Toxicity reported – formulation contains propylene glycol; metabolism inhibited via aldehyde dehydrogenase

Ritonavir solution Tipranavir

Alcohol-like reaction reported (as formulation contains alcohol Increased toxic effects of tipranavir

Isoniazid

Unsteady gait, incoordination, behavioral changes reported due to reduced metabolism of isoniazid by CYP2E1

Diazepam, alprazolam, chlordiazepoxide, triazolam

Increased activity of benzodiazepine due to decreased clearance (oxazepam, temazepam, and lorazepam not affected)

Reduced clearance of caffeine (by 24–30%) via weak CYP1A2 inhibition, which can cause irritability, insomnia, and anxiety; advise low caffeine intake

Increased plasma level (3- to 6-fold) and half-life (by 60%) of cocaine; increased risk of cardiovascular effects

Tizanidine

Increased serum level of tizanidine which may cause hypotension, bradycardia, and excessive drowsiness

Dextroamphetamine Methylphenidate

Disul ram may inhibit the metabolism and excretion of dextroamphetamine; dextroamphetamine is contraindicated in patients with a history of alcohol abuse

Case of psychotic-like episode with concurrent use, possibly via disul ram’s action in blocking dopamine-β-hydroxylase, whose low levels have been associated with ADHD and psychotic symptoms

Disul ram (a weak CYP1A2 inhibitor) causes a dose-dependent negligible to slight decrease in clearance of theophylline, which may be clinically signi cant and require a dose reduction of theophylline due to its narrow therapeutic index

Class of Drug

Alcohol Antibiotic

Anticoagulant Anticonvulsant

Antidepressant

SSRI

Cyclic

Irreversible MAOIs

Antiparasitic Antiretroviral

Protease inhibitor

Antitubercular Benzodiazepine

Caffeine

Cocaine

Muscle relaxant Stimulant

Theophylline

Naltrexone

Product Availability∗

Generic Name

Trade Name(A)

Dosage Forms and Strengths

Naltrexone

Revia Vivitrol(B)

Tablets: 25 mg(B), 50 mg, 100 mg(B) Extended-release injection: 380 mg

∗ Refer to Health Canada’s Drug Product Database or the FDA’s Drugs@FDA for the most current availability information. (A) Generic preparations may be available,

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 373 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

(B) Not marketed in Canada

Substance Use Treatment

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Indications‡

( approved)

General Comments

Naltrexone (cont.)

Alcohol use disorder: In patients who are able to abstain from alcohol in an outpatient setting prior to initial treatment

Opioid dependence: Treatment adjunct following withdrawal

• Inconsistentresultsfornaltrexoneintreatmentofbulimianervosa

• Investigatedintreatmentofimpulse-controldisorders,e.g.,trichotillomania,kleptomania

• Adolescentsexualo enders–opentrialsuggestsbene tintreatmentwithdosesof100–200mg/day

• In a double-blind RCT study, bupropion (300 mg)/naltrexone (50 mg) combination therapy vs. bupropion (300 mg)/placebo was associated with

signi cantly higher abstinence rates after 7 weeks of treatment

• Usedaloneandcombinedwithvareniclinetodecreasebothalcoholuseandsmokinginheavydrinkers

• Recommendedtobeusedtogetherwithpsychosocialinterventions

• Meta-analyseshaveshownvariablee ectsonabstinence:moderatedecreaseinthenumberofheavydrinkingdayshasbeenshown;maybemore

e ective in patients with high levels of alcohol craving[1] and in males with a family history of alcoholism; double-blind study suggests that it may

not have long-term bene ts in men with chronic severe alcohol dependence

• Patientcomplianceplaysasigni cantroleinthee cacyofnaltrexone

• Mixedresultsseenincombinationwithacamprosateregardingincreasede cacyandsuccessofabstinence(seeDrugInteractionsp.376);naltrex-

one controls alcohol consumption while acamprosate is more useful in maintaining abstinence

• Doesnotattenuatecravingforopioidsorsuppresswithdrawalsymptoms;patientsmustundergodetoxi cationbeforestartingthedrug

• Doesnotproduceeuphoria

• Pretreatmentwithoralnaltrexoneisnotrequiredpriortouseoftheextended-releaseinjection

• Synthetic long-acting antagonist at various opioid receptor sites in the CNS; highest a nity for the μ-opioid receptor – inhibits the positive reinforcement of increased endorphins during alcohol use

• Blocks the “craving” mechanism in the brain, producing less of a high from alcohol; stops the reinforcing e ect of alcohol by blocking the opioid system – promotes abstinence and reduces risk for relapse

• Blocksthee ectsofotheropioidagonists

• Alcoholdependence:50mgoncedaily

• Opioid dependence: Patient must undergo detoxi cation prior to starting naltrexone and be opioid-free for 7–10 days. Initiate dose at 12.5–

25 mg/day and monitor for withdrawal signs; increase dose to 50 mg/day. For supervised administration, maintenance doses of 100 mg every other day or 150 mg every third day can be given

• Theextended-releaseinjectionisformulatedasmicrospheresand380mgisadministeredbyIMinjectionintotheglutealmuscleevery4weeks

• Renal impairment: Mild – no dosing adjustments; moderate–severe – no dosing adjustments per manufacturer’s labeling; however, has not been

studied in moderate–severe renal failure

• Hepaticimpairment:Nodosingadjustmentsaspermanufacturer’slabeling;however,AUCincreases5–10-foldinpatientswithlivercirrhosis

• RapidlyandcompletelyabsorbedfromtheGItract

• Undergoesextensive rst-passmetabolism;onlyabout20%ofdrugreachesthesystemiccirculation

Pharmacology

Dosing

Oral

Injection

Pharmacokinetics

Oral

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Injection

Adverse Effects

• Widelydistributed;only21–28%isproteinbound

• Onsetofe ectoccursin15–30mininchronicmorphineusers

• Durationofe ectisdosedependent;blockadeofopioidreceptorslasts24–72h

• Metabolizedinliver(notviaCYP450);majormetabolite(6-β-naltrexone)isactiveasanopioidantagonist

• Eliminationhalf-lifeis96h;excretedprimarilybythekidneys

• Cautionrecommendedinadministeringthedrugtopatientswithrenalimpairment

• NaltrexoneAUCincreased5-10foldinpatientswithlivercirrhosis

• Firstpeakoccurs2hpostinjection;secondpeakoccurs2–3dayslater;onsetofe ectseenwithin48h

• Eliminationhalf-lifeis5–10daysanddependentontheerosionofthepolymer;plasmaconcentrationsaresustainedforatleast30days

• Commonwithoralnaltrexone:Nauseaandvomiting(approximately10%–morecommoninfemales;maybereducedwithslowerdosetitration), dysphoria

• Commonwithextended-releaseinjection:Nausea,headache,fatigue,pain;andtendernessatinjectionsite,swelling,bruising,pruritusorindura- tions; cellulitis, hematoma, abscess, and necrosis have been reported

• GIe ects:Abdominalpain,cramps,dyspepsia,anorexia,andweightloss;womenaremoresensitivetoGIsidee ects

• CNS e ects: Insomnia, anxiety, depression, confusion, nervousness, fatigue; case reports of naltrexone-induced panic attacks, suicidal thoughts,

and attempted suicide

• Physicale ects:Headache(6.6%),jointandmusclepainorsti ness

• Dose-relatedelevatedenzymesandhepatocellularinjuryreported

• Eosinophilia,casesofeosinophilcpneumonia

• Casesofallergicpneumoniareportedwithinjection

• Nodataavailable

• Since naltrexone is an opioid antagonist, do not give to patients who have used opioids (including tramadol) in the previous 10 days – may result in symptoms of opioid withdrawal

• Donotuseinpatientswithliverdisorders

• Attemptstoovercomeblockadeofnaltrexonewithhighdosesofopioidagonists(e.g.,morphine)mayleadtorespiratorydepressionanddeath

• Patients need to monitor injection site for swelling, tenderness, induration, bruising, pruritus, or redness that worsens or doesn’t improve over

2 weeks

• FDAhasreceivedmanyreportsofinjectionsitereactionssuchascellulitis,induration,hematoma,abscess,andnecrosis

• Patients who have been treated with naltrexone may respond to lower opioid doses (than previously used) when naltrexone is discontinued. This

could potentially lead to accidental overdose

• Patientsreceivingopioidsorthoseinacuteopioidwithdrawal

• Acutehepatitisorliverfailure

• Noexperienceinhumans;800mgdosefor1weekshowednoevidenceoftoxicity

• Riskforseriousinjectionsitereactionincreasedifinjectedsubcutaneouslyorintofattytissueratherthanmuscle

• Baselineliverfunctiontestsrecommended

• Repeatliverfunctiontestsmonthlyfor6months

• Maycausefalsepositiveswithopioidimmunoassays

Discontinuation Syndrome Precautions

Contraindications Toxicity

Lab Tests/Monitoring

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 375 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Substance Use Treatment

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Pediatric Considerations

Geriatric Considerations Use in Pregnancy♢

Nursing Implications

Naltrexone (cont.)

• Hasbeenstudiedinchildrenforaggression,self-injuriousbehavior,autism,andmentalretardation(dose:0.5–2mg/kg/day)

• E ectsnotedwithin rsthourofadministration

• For detailed information on the use of naltrexone in this population, please see the Clinical Handbook of Psychotropic Drugs for Children and

Adolescents[2]

• Nodata

• Noadequateandwell-controlledstudiesinpregnantwomen

• Shouldbeusedinpregnancyonlywhenthepotentialbene tsjustifythepotentialrisktothefetus

• Showntohaveembryocidalandfetotoxice ectsinanimalstudieswhengiven30and60timesthehumandose

• Naltrexoneanditsprimarymetabolite6-β-naltrexoneareexcretedintobreastmilkinverylowconcentrations

• E ects on the nursing infant unknown. Due to the potential for tumorigenicity shown for naltrexone in animal studies, and for the potential of serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or discontinue the drug, taking into account the

importance of the drug to the mother

• Naltrexoneshouldbeusedinconjunctionwithestablishedpsychotherapyorself-helpprograms

• Asnaltrexonedoesnotattenuatecravingforopioidsorsuppresswithdrawalsymptoms,complianceproblemsmayoccur;individualsmustundergo

opioid detoxi cation prior to starting drug

• Patientsshouldbeadvisedtocarrydocumentationstatingthattheyaretakingnaltrexone

• Advisepatientsreceivingextended-releaseinjectionsofnaltrexonethatadministrationoflargedosesofopioidsmayleadtoseriousadversee ects,

coma or death

• Advisepatientstoreportshortnessofbreath,coughing,wheezingorsigni cantrednessanddiscomfortattheinjectionsitetotheirphysician

• Vivitrol injection must be diluted only with the supplied diluent and administered with needle provided in kit. Store kit in the refrigerator; can be

kept at room temperature for no more than 7 days. Once diluted, the injection should be administered IM right away (alternating buttocks); pain

on injection possible; monitor patients for rash or indurations at injection site

• Shouldapatientmissascheduledappointmentforreceivinginjectablenaltrexone,thenextdoseofinjectioncanbegivenassoonaspossible

• Monitorforsignsofdepressionorsuicidalideation

• Naltrexonemaycausefalsepositiveswithopioidimmunoassays

• Fordetailedpatientinstructionsonnaltrexone,seethePatientInformationSheet(detailsonp.440)

• Clinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterforthesecondagent

Breast Milk

Patient Instructions

Drug Interactions

Class of Drug

Example

Interaction Effects

Acamprosate

Increased concentrations of acamprosate; Cmax increased by 33% and AUC by 25%; no clinically signi cant adverse events reported with this combination

Insulin

Case report of increased insulin requirements when given naltrexone (unknown mechanism or clinical signi cance)

Opioid

Codeine, methadone, morphine, etc.

Decreased ef cacy of opioid, may result in opioid withdrawal

♢ See p. 439 for further information on drug use in pregnancy and e ects on breast milk

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Product Availability∗

Buprenorphine

Generic Name

Trade Name(A)

Dosage Forms and Strengths

Buprenorphine

Buprenex(D) Butrans(D) Sublocade

Injection: 0.3 mg/mL

Transdermal patch: 5 micrograms/h

Long-acting injection (pre- lled syringe): 100 mg/0.5 mL, 300 mg/1.5 mL

Subutex(C)

Sublingual tablets: 0.4 mg, 2 mg, 8 mg

Buprenorphine HCl/Naloxone HCl

Bunavail, Suboxone, Suboxone Film, Zubsolv

Sublingual tablets and lm: 2 mg/0.5 mg, 4 mg/1 mg, 8 mg/2 mg, 12 mg/2.5 mg

∗ Refer to Health Canada’s Drug Product Database or the FDA’s Drugs@FDA for the most current availability information. (A) Generic preparations may be available, (C) Not marketed in the USA, (D) Pain indication

Indications‡

( approved)

General Comments

Opioid use disorder; used alone or together with naloxone – sublingual tablets and extended-release once-monthly injection

• Opioidwithdrawal–sublingualtablets

• Analgesicformoderatetoseverepain–transdermalpatchorinjection

• Earlyevidencesuggestsabene tonPTSDsymptomsinindividualswithchronicpainandopioidusedisorder

• Suboxone contains buprenorphine and naloxone in a 4:1 ratio – intended to deter intravenous abuse by attenuating the e ect of buprenorphine and producing withdrawal symptoms if taken IV by those physically dependent on opioids

• Sublocade is indicated for treatment of moderate–severe opioid use disorder in patients who have initiated treatment with a transmucosal buprenorphine-containing product, followed by dose adjustment for a minimum of 7 days

• Reducesuseandcravingforopioids;shouldbecombinedwithconcurrentbehaviortherapiesandpsychosocialprograms

• Consideredase ectiveasmoderatedosesofmethadone;methadoneisconsideredthetreatmentofchoiceinpatientswithhigherlevelsofphysical

dependence

• Maybepreferredforlessdependentusers,lesschaoticlifestylesorcodeinedependency

• Improvementnotedinpsychosocialadjustmentandsocialfunctioning

• Causesminimalwithdrawalsymptomsduetopartialagonistactivity

• Otherformulationsofbuprenorphine(i.e.,injection,patch)arenotapprovedforthetreatmentofopioidaddiction

• Transdermalpatchandbuccal lmhaveawarningregardingQTcprolongationinhigherdoseswhichisnotreportedwithsublingualtablets

• Buprenorphineisapartialμ-opioidreceptoragonistandκ-opioidreceptorantagonist(naloxoneisanopioidantagonist)

• Opioidagoniste ectsincreaselinearlywithincreasingdosesofbuprenorphine,toaplateauor“ceilinge ect”;lessriskoffataloverdose

• When buprenorphine is taken by those physically dependent on opioids, its partial opioid activity will precipitate opioid withdrawal symptoms.

However, if taken while in opioid withdrawal, buprenorphine’s partial agonist e ects will be experienced as relief from withdrawal symptoms

• Ifswitchingtobuprenorphinefrommethadonemaintenance,itisrecommendedthatthemethadonedosebetapereddownto30mgorlessprior

to starting buprenorphine, to minimize withdrawal symptoms[1]

• 4–24mg(buprenorphine)sublinguallygivenoncedaily;duetolonghalf-life,somepatientscanbedosedevery2daysor3timesperweek

Pharmacology

Dosing

current availability information and indications

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 377 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

• Ceilinge ectisusuallyreachedatdosesof16-20mg

Substance Use Treatment

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Pharmacokinetics

Adverse Effects

Discontinuation Syndrome

Precautions

Toxicity

Buprenorphine (cont.)

• Phasesoftreatment:

– InductionPhase:Individualneedstoabstainfromopioidsfor12–24h,dependingonthedurationofactionoftheopioidused,tobeexhibiting

at least mild to moderate withdrawal symptoms prior to rst dose to prevent precipitated withdrawal: 2–4 mg buprenorphine administered

sublingually initially, with another dose later in the day if needed on day 1, and then dose titrated from there based on e ect

– StabilizationPhase:Buprenorphinedoseadjustedinincrements/decrementsof2–4mgtoalevelthatsuppressesbothcravingsandwithdrawal

e ects (4–24 mg/day)

– MaintenancePhase:Patientisonastabledoseofbuprenorphine;thepatientmayrequireinde nitemaintenancetherapy

– Renalimpairment:Nodosingadjustmentsrequired

– Hepatic impairment: No dosing adjustments required for mild–moderate impairment. For severe impairment, use with caution – reduce initial

dose and titration increments. Watch for adverse e ects and toxicity

• Buprenorphineextended-releasesubcutaneousinjection:Recommendeddosingis2monthlyinitialdosesof300mgfollowedby100mgmonthly

maintenance doses. Increasing the maintenance dose to 300 mg may be considered for patients in which the bene ts outweigh the risk

• Sublingual buprenorphine provides moderate bioavailability while sublingual naloxone bioavailability is poor; therefore, buprenorphine’s opioid agonist e ects predominate

• Peak e ects seen in 3–4 h after dosing; Cmax and AUC increase in a linear fashion with dose increases

• Buprenorphineishighlyboundtoplasmaproteins(96%)–primarilytoαandβglobulin

• MetabolizedbyCYP3A4toactivemetabolite,norbuprenorphine,andotherinactiveglucuronidatedmetabolites

• Buprenorphinehalf-life=24–60h(37hmean);naloxonehalf-life=1–2h(mean)

• Mostcommonin rst2–3daysoftherapyandaredoserelated

• Afterthe rstdose,patientmayexperiencesomewithdrawalsymptoms,seepharmacologysectionp.377

• Common: Headache, dizziness, insomnia, somnolence, nausea, vomiting, constipation, sweating, CNS depression, orthostatic hypotension, and

various pains

• Increaseinliverenzymes;casesofhepatitis,acutehepaticinjuryreportedinthecontextofmisuse,particularlyIVuse;monitorliverfunctiontests

periodically

• Lowerriskofrespiratorydepressionandoverdosethanmethadoneduetotheceilinge ect

• Withdrawalsyndromereportedinpatientsonchronictherapyandwithnaloxonecombination

• Causesmilderwithdrawalthanfullopioidantagonists(e.g.,methadone),onsetmaybedelayed

• Symptoms include: Nausea/vomiting, diarrhea, muscle aches/cramps, sweating, lacrimation, rhinorrhea, dilated pupils, yawning, craving, mild

fever, dysphoric mood, insomnia, and irritability

• Buprenorphinecanprecipitatewithdrawalinopioid-dependentindividuals(seepharmacologysectionp.377)

• Chronicadministrationproducesopioid-typedependence,characterizedbywithdrawaluponabruptdiscontinuationorrapidtaper

• Buprenorphine can be abused; if sublingual combination tablets are crushed and injected by opioid-dependent individual, naloxone may exert

e ects and precipitate a withdrawal syndrome

• Usewithcautioninpatientswithcompromisedrespiratoryfunctionorliverdisorder,opioidnaïve,severehepaticimpairment,oracutealcoholism

and delirium tremens

• Buprenorphinedetoxi cationcanoccurfasterthanmethadonedetoxi cation;decreasedoseby2–4mgevery2weeks

• Very high doses can cause respiratory depression, which may be delayed in onset and more prolonged than with other opioids; reversal with naloxone is more di cult due to buprenorphine’s very tight binding to opioid receptors[1]

• Saferinoverdosethanpureagonistsduetopoorbioavailabilityandceilinge ectofagonistaction

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Pediatric Considerations Geriatric Considerations

Use in Pregnancy♢

Nursing Implications

Patient Instructions

Drug Interactions

• Symptomsinclude:Pinpointpupils,sedation,andhypotension;respiratorydepressionanddeathshavebeenreported,particularlywhenbuprenor- phine was misused intravenously or in combination with alcohol or other opioids

• Treatment:Symptomatic

– Monitorforrespiratorydepression

– Naloxonemaynotbee ectiveinreversingrespiratorydepression

• Notrecommendedinchildrenunderage16

• Canadianlabelingdoesnotapproveuseinpatientsunderage18

• Elderlypatientsaremorelikelytoexperienceconfusionanddrowsiness

• Respiratorydepressionoccursmorefrequently

• Long-termusenotrecommended

• Teratogenice ectsreportedinanimalstudies;e ectsinhumansunknown

• Evidence comparing buprenorphine with methadone indicates that buprenorphine is an acceptable treatment for opioid use disorder in pregnant

women

• Neonatalabstinencesyndromemayoccurwithonsetgenerallywithinadayortwoafterbirthandlastingameanof4days

• Buprenorphine/naloxonecombinationnotrecommendedduringpregnancy

• Buprenorphinepassesintomother’smilk;breastfeedingisnotrecommended

• Buprenorphineisanopioidandconsideredtobeacontrolledsubstance

• Buprenorphineshouldbeusedinconjunctionwithbehavior/psychosocialtherapies

• Thetabletsshouldnotbehandled,buttippeddirectlyintothemouthfromamedicinecup;theyshouldbeplaced(alltogether)underthetongue

until dissolved (takes 2–10min); drinking uids prior to taking the tablets may speed up the dissolution process[1]; chewing or swallowing them

reduces the bioavailability of the drug; the patient should not drink for at least 5 min so as to allow the drug to be absorbed

• Educatepatientaboutnotincreasinghis/herdosewithoutphysicianapproval;misuse/abusemayresultintoxicity

• SeriousCNSconsequencesmayoccurifbuprenorphineiscombinedwithbenzodiazepines,hypnoticsoralcohol

• Fordetailedpatientinstructionsonbuprenorphine,seethePatientInformationSheet(detailsp.440)

• Potentiallyclinicallysigni cantinteractionsarelistedbelow

Breast Milk

Class of Drug

Example

Interaction Effects

Antibacterial

Rifampin

Decreased level of buprenorphine possible due to increased metabolism via CYP3A4

Antibiotic

Clarithromycin, erythromycin

Increased levels of buprenorphine possible due to inhibited metabolism via CYP3A4

Antidepressant

SSRI Tricyclic

Citalopram Amitriptyline

May enhance QTc prolongation

May cause additive psychomotor performance impairment and enhanced respiratory depressant effects

Reversible MAOI

Moclobemide

May enhance adverse or toxic effects of MAOIs

Anticonvulsant

Carbamazepine, phenytoin, phenobarbital

Decreased levels of buprenorphine possible due to increased metabolism via CYP3A4

Antifungal

Ketoconazole

Increased Cmax and AUC of buprenorphine reported due to inhibited metabolism via CYP3A4

♢ See p. 439 for further information on drug use in pregnancy and e ects on breast milk

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 379 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Substance Use Treatment

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Buprenorphine (cont.)

Class of Drug

Example

Interaction Effects

Antiretroviral

Non-nucleoside reverse transcriptase inhibitor (NNRTI)

Efavirenz

Decreased level of buprenorphine (50% AUC) via CYP3A4 induction, possible clinical signi cance

Protease inhibitor

Atazanavir

Indinavir, ritonavir, saquinavir

Increased level of buprenorphine and decreased level of atazanavir

Increased level of buprenorphine possible due to inhibited metabolism via CYP3A4

Antipsychotic

Quetiapine

May enhance QTc prolongation

Antitubercular

Rifampin

Decreased level of buprenorphine (70% AUC, 38% Cmax) via CYP3A4 induction, monitor for opiate withdrawal

Anxiolytic

Benzodiazepine

Respiratory depression, coma, and death reported when intravenous or high doses of buprenorphine used in combination

CNS depressant

Alcohol, antipsychotics

CNS depression; deaths have been reported in combination

Opioid

Morphine, meperidine, fentanyl

Low doses of buprenorphine antagonize analgesic effects

High doses are synergistic; increase risk of CNS and respiratory depression

Methadone

Can precipitate withdrawal

Product Availability∗

Methadone

Generic Name

Trade Name(A)

Dosage Forms and Strengths

Methadone

Dolophine(B) Metadol(C)

Methadose

Bulk powder

Oral solution: 5 mg/5 mL, 10 mg/5 mL Injection(B) : 10 mg/mL

Tablets: 5 mg, 10 mg

Oral solution: 1 mg/mL, 10 mg/mL Tablets: 1 mg, 5 mg, 10 mg, 25 mg

Oral solution: 10 mg/mL

Tablets(B): 5 mg, 10 mg, 40 mg (dispersible)

∗ Refer to Health Canada’s Drug Product Database or the FDA’s Drugs@FDA for the most current availability information. (A) Generic preparations may be available,

(B) Not marketed in Canada,

Indications‡

( approved)

Detoxi cation and maintenance treatment in opioid use disorder Treatment of severe pain

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

General Comments

• Usefuldruginopioid-dependentpatientswhodesiremaintenanceopioidtherapy: – E ectiveorallyandcanbeadministeredoncedaily,duetoitslonghalf-life

– Suppresseswithdrawalsymptomsofotheropioids

– Suppresseschroniccravingforopioidswithoutdevelopingtolerance

– Whentakenorallyatappropriatedoses,reducedeuphoriaduetoslowonset

• Patientsreceivingmethadoneremainintreatmentlonger,demonstrateadecreaseduseofillicitopioids,andmaintainsocialstability

• Methadoneisanopioidanditsprescribing,dispensing,andusageisgovernedbyFederalregulations(regulationsvaryindi erentcountries).When

used for opioid dependence, most patients receive their methadone from the pharmacy on a daily basis and are required to drink the contents of the bottle in the presence of the pharmacist. Stable patients may be permitted to carry premeasured individual doses of methadone once the rst dose of each new prescription has been witnessed

• Asyntheticopioidactingontheμ-opioidreceptor

• Analgesicandsedativeproperties–similartootheropioids,butwithalongerdurationofaction

• Relievesopioidwithdrawalsymptomswhileblockingeuphorice ectsincludingthoseofotheradministeredopioids

• Initialdose:20–30mg(lowerifriskfactorsfortoxicity),givenoncedaily;maygiveadditional5–10mgifwithdrawalsymptomsarenotsuppressed or reappear. Do not exceed a total of 40 mg on the rst day

• Levelsaccumulateoverthe rstfewdays,thereforedonotincreasedosestooquickly.Increaseby5–10mgevery3–5daystoastablemaintenance dose

• Dosesbetween60mgand100mgareoftenmoree ectivethanlowerdoses

• Whendosesaregreaterthan80mg,increaseby5–10mgevery5–7days

• Dosingadjustmentsaremadebasedoncravingsandwithdrawalsymptoms.Titratetoadosewhereopiatewithdrawalsymptomsdonotoccurfor

24h

• Usualmaintenancerange:60–120mgdaily

• Oralmethadonedosesareapproximatelytwicetheintravenousdose(duetodecreasedbioavailability)

• Patientsvaryindosagerequirements;dosageisadjustedtocontrolabstinencesymptomswithoutcausingmarkedsedationorrespiratorydepres-

sion

• Inrarecases,patientswhoarerapidmetabolizersofmethadonemayrequireadivided(split)doseratherthanonesingledailydose;thissituation

should be carefully evaluated and monitored for toxicity and respiratory depression

• Whentaperingo methadone,decreasethedosebylessthan10%every10–14days

• Bioavailability:36–100%

• Peakplasmalevel:2–3h

• 85–90%proteinbound

• Half-life: 8–59 h (average: 25 h); half-life increases with repeated dosing. Note: TV is longer than methadone’s duration of action (4–8 h)

• Half-lifeofanalgesice ectis4–8hwithasingledosebutmaybeprolongedwithrepeateddoses

• Metabolizedbytheliver,primarilyviaCYP3A4and2B6,withminoreliminationviaCYP2C19,CYP2D6,otherenzymesmaycontributetomethadone metabolism – see Drug Interactions pp. 383–385

• InhibitsP-gp

• Plasmalevelmeasurementsarenotconsidereduseful(thoughthereisagoodrelationshipbetweendoseandplasmaconcentration)

• Urinetestingmustbedonetodetectillicitdruguseand/orcompliancewithmethadone

• Onsetofe ect:30–60minutes

• Durationofactionincreaseswithchronicuse

Pharmacology

Dosing

Pharmacokinetics

Onset & Duration of Action

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 381 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Substance Use Treatment

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Adverse Effects

CNS Effects

Anticholinergic Effects

Cardiovascular Effects

Endocrine & Metabolic Effects

GI Effects

Urogenital & Sexual Effects

Musculoskeletal Effects

Other Adverse Effects

Discontinuation Syndrome

Methadone (cont.)

• Drowsiness, insomnia, euphoria, dysphoria, confusion, cognitive impairment, depression, seizures, and weakness; tolerance develops to sedating and analgesic e ects

• Withchronicuse:Sleepdisturbances,impairmentinpsychomotorandcognitiveperformancetests

• Headache

• Sweating, ushing

• Chronicconstipation

• Dizziness,lightheadedness,hypotension

• CasesofQTprolongationandtorsadesdepointes–increasedriskwithhigherdoses(morethan150mg/day),drugaccumulation,inpatientswith

pre-existing heart disease, in combination with drugs that increase the QT interval or with drugs that decrease the metabolism of methadone via CYP3A4 (see Drug Interactions pp. 383–385) [baseline ECG recommended; repeat periodically and if dose increased above 150 mg/day]

• Amenorrhea,decreasedlibido

• Hypokalemia,hypomagnesemia,andweightgain

• Nausea,vomiting,anddecreasedappetite

• Constipation

• Impotence,ejaculatoryproblems

• Paininjointsandbones

• Rarely,pulmonaryedemaandrespiratorydepression

• Rapid withdrawal can result in opioid withdrawal syndrome, which includes CNS e ects: Restlessness, agitation, insomnia, headache; autonomic e ects: Increased blood pressure, heart rate, body temperature and respiration, lacrimation, perspiration, congestion, itching, “goose esh”; neuro- logical e ects: Muscle twitching, cramps, tremors; GI e ects: Nausea, vomiting, diarrhea, anorexia

• Symptomsmaybegin24–48hafterthelastdose,peakin72h,andmaylastfor6–7weeks

• Ifnodosingchangesoccurred,considerdruginteractionasapotentialcauseofwithdrawalsymptoms

• Reinstitutedosetopreviouslevel(ifstoppedformorethan3days,titratebackupslowly);restabilizepatientandmonitorwhiletaperingdoseata slower rate

• Clonidinemayamelioratewithdrawalsymptoms

• Methadone has a high physical and psychological dependence liability, therefore withdrawal symptoms will occur on abrupt discontinuation – decrease the dose slowly

• Prior to prescribing methadone, a baseline ECG should be done; repeat within 30 days of treatment and annually, or if patient has unexplained syncope or seizures. Consider discontinuing or reducing the dose if QTc interval is greater than 500 ms. Avoid methadone in patients with a history of structural heart disease, arrhythmia or syncope

• Due to its long half-life, methadone can accumulate to dangerous levels if dose is increased too quickly, without allowing maximal e ects to be assessed at steady state. Peak respiratory depressant e ects occur later and persist longer than peak analgesic e ects

• Methadone detoxi cation may be a lengthy process of approximately 12 weeks; decrease dose by less than 10% every 10–14 days depending on patient response; can use clonidine to decrease withdrawal symptoms

Management

Precautions

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Toxicity

Pediatric Considerations

Geriatric Considerations Use in Pregnancy♢

Nursing Implications

• Withexcessivedoses,candevelopshallowbreathing,pinpointpupils, accidityofskeletalmuscles,lowbloodpressure,slowedheartrate,coldand clammy skin; can progress to cyanosis, coma, severe respiratory depression, circulatory collapse, and cardiac arrest

• For detailed information on the use of methadone in this population, please see the Clinical Handbook of Psychotropic Drugs for Children and Adolescents[2]

• Has been used for postoperative pain in children at doses of 0.2 mg/kg; longer duration of action than with morphine. Drug must be tapered (by 5–10% every 1–2 days) if used for longer than 5–7 days; the patient must be continually assessed for withdrawal symptoms

• MethadonehasahighpotentialfordruginteractionsandisassociatedwithQTintervalprolongation.Inaddition,methadoneisdi culttotitrate because of its large inter-individual variability in pharmacokinetics, particularly in the frail elderly, with a risk for accumulation due to a long elimination half-life

• Methadonetreatmentthroughoutpregnancyreducesriskofperinatalandinfantmortalityinheroin-dependentwomenandisnotassociatedwith adverse postnatal development

• Dosing needs should be assessed during pregnancy: Decreased between weeks 14 and 32, increased prior to term, reduced following birth, and reassessed regularly

• Short-termwithdrawale ectsreportedinapproximately60%ofinfants(notdoserelated);nolong-terme ectsdemonstrated

• Asmallamountofmethadoneentersbreastmilk;nursepriortoadoseofmethadoneor2–6hafterdose

• Methadone must be prescribed in su cient doses, on a maintenance basis, to prevent relapse; long-term treatment may be required. Premature withdrawal may lead to relapse

• MethadoneisanopioidandmustbeprescribedaccordingtoFederalregulations.Manypatientspickuptheirmethadonefromthepharmacyona daily basis and drink the medication in the presence of the pharmacist. Stable patients may be permitted to carry premeasured individual doses of methadone once the rst dose of each new prescription has been witnessed

• Each time the patient is to be medicated, he/she should be assessed for impairment (i.e., drowsiness, slurred speech, forgetfulness, lack of con- centration, disorientation, and ataxia); patients should not be medicated if they appear impaired or smell of alcohol – the physician should be contacted as to management of the patient

• Encouragepatientstocarryacardintheirwalletstatingthattheyaretakingmethadone

• Ifapatientmissesoneormoreappointmentstoreceivehis/herdoseofmethadone,thismayindicateclinicalinstabilityandpossiblerelapse;use

caution due to possible loss of tolerance to drug

• Contacttheprescriberifmorethan2methadonedoseshavebeenmissedorthepatienthasingestedothersubstances

• Fordetailedpatientinstructionsonmethadone,seethePatientInformationSheet(detailsonp.440)

• Clinicallysigni cantinteractionsarelistedbelow

• Formoreinteractioninformationonanygivencombination,alsoseethecorrespondingchapterforthesecondagent

Breast Milk

Patient Instructions

Drug Interactions

Class of Drug

Example

Interaction Effects

Alcohol

Acute alcohol use can decrease methadone metabolism and increase the plasma level – may result in intoxication and respiratory depression

Chronic alcohol use can induce methadone metabolism and decrease the plasma level

May enhance CNS depressant effect

Antacid

Al/Mg antacids

Decreased absorption of methadone

Antiarrhythmic

Quinidine

Possible risk of QT prolongation

♢ See p. 439 for further information on drug use in pregnancy and e ects on breast milk

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 383 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Substance Use Treatment

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

384

Example

Cipro oxacin

Phenytoin, carbamazepine, barbiturates

Desipramine, amitriptyline Fluvoxamine

Fluconazole

Itraconazole

Ketoconazole Voriconazole

Risperidone

Delavirdine

Efavirenz, nevirapine

Abacavir

Didanosine, stavudine

Zidovudine Amprenavir

Indinavir

Lopinavir/ritonavir Nel navir Ritonavir

Ritonavir/saquinavir

Isoniazid Rifampin

Class of Drug

Antibiotic

Anticonvulsant

Antidepressant

Cyclic

SSRI

Antifungal

Antipsychotic Antiretroviral

Non-nucleoside reverse transcriptase inhibitor (NNRTI)

Nucleoside reverse transcriptase inhibitor (NRTI)

Protease inhibitor

Methadone (cont.)

Interaction Effects

Case report of increased methadone adverse reactions (sedation, confusion, and respiratory depression) due to inhibition of CYP1A2 and CYP3A4

Decreased plasma level of methadone due to enhanced metabolism via CYP3A4 and CYP2B6 (phenytoin and barbiturates), via CYP3A4 (carbamazepine). Phenytoin levels may increase by 50%

Increased plasma level of desipramine (by about 108%) due to decreased metabolism via CYP2D6 inhibition

Increased giddiness, euphoria; suspected potentiation of methadone’s “euphoric” effects – abuse with amitriptyline reported Increased plasma level of methadone by (10–100%) with uvoxamine, due to (1) increased clearance, (2) reduced metabolism via CYP3A4 inhibition, and (3) competitive inhibition via CYP2D6

Increase in methadone peak and trough plasma levels by 27% and 48%, respectively; clearance decreased by 24% via inhibition of CYP3A4, may enhance QTc prolongation

Case report of prolonged rate-corrected QT interval leading to torsades de pointes following two doses of itraconazole (200 mg).[3] May increase serum concentration of methadone

May increase serum concentration of methadone

Increase in methadone plasma levels (47% increased AUC); case reports of torsades de pointes

Case reports of precipitation of opioid withdrawal symptoms (mechanism unclear)

Likely to increase methadone levels via inhibition by CYP3A4

Increased clearance of methadone and decreased total concentration (AUC) (by up to 60% with efavirenz and nevirapine) via enzyme induction – withdrawal symptoms reported within 7–10 days

Abacavir levels decreased by 34%, however, clearance remained the same

Methadone plasma level decreased by 23% – may result in withdrawal

Decreased bioavailability of antiretrovirals due to increased degradation in GI tract by methadone (Cmax and AUC decreased by 66% and 63%, respectively, for didanosine, and by 44% and 25% for stavudine)

Inhibited metabolism of AZT by methadone (AUC increased by 43%)

AUC, Cmax, and Cmin of amprenavir decreased by 30%, 27%, and 25%, respectively

Methadone levels decreased an average of 35% with amprenavir/abacavir combination

Variable effects reported on Cmax of indinavir

Reduced AUC of methadone (by 40%)

Methadone AUC decreased by 36% due to increased clearance (attributed to lopinavir) – may result in withdrawal AUC of nelfanavir metabolite decreased by 53% – signi cance unknown

Variable effects on clearance of methadone reported

Displacement from protein binding of methadone and decrease in AUC of both R-methadone and S-methadone Increased plasma level of methadone due to decreased metabolism via CYP3A4

Decreased plasma level of methadone (by up to 50%) due to enhanced metabolism via CYP2D6 and CYP3A4 – may cause withdrawal symptoms

Antitubercular

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Example

Interaction Effects

Clonazepam, diazepam

Enhanced risk of respiratory depression

Combined use suggested to negatively in uence treatment outcomes[4] but by lowering anxiety there may be opportunity to lower methadone dose

Diazepam

“Opiate high” reported with combined use

Decreased metabolism of methadone through inhibition of CYP3A4

Decreased clearance of methadone

Decreased metabolism of methadone through inhibition of CYP3A4 and P-gp

Cimetidine

Decreased clearance of methadone; case reports of apnea with the combination

Zolpidem

Decreased metabolism of methadone through inhibition of CYP3A4

Butorphanol, nalbuphine, pentazocine Morphine

Occurrence of withdrawal symptoms due to partial antagonist effects of these opioids Ef cacy of opioid analgesic reduced; dosage may need to be increased

Naltrexone

Diminished analgesic effect and may precipitate withdrawal

For high-risk combinations, may need to discontinue methadone and initiate buprenorphine treatment

Decreased plasma level of methadone; symptoms of withdrawal reportedbuprenorphine treatment

MDMA

Decreased metabolism of methadone through inhibition of CYP2D6

Ascorbic acid

Increased elimination of methadone

Sodium bicarbonate

Decreased elimination of methadone

Class of Drug

Benzodiazepine

Buprenorphine Disul ram Grapefruit juice H2 antagonist Hypnotic Opioid

Opioid antagonist

QTc prolonging agents St. John’s Wort Stimulant

Urine acidi er

Urine alkalizer

Product Availability∗

Pharmacotherapy for Nicotine/Tobacco Use Disorder

Generic Name

Pharmacological Class

Trade Name(A)

Dosage Forms and Strengths

Nicotine

Nicotine replacement

Commit, Thrive

Nicoderm, Habitrol(B)

Nicorette, Nicorette DS(B), Thrive gum

Lozenges: 2 mg, 4 mg

Transdermal patch: 7 mg/24 h, 14 mg/24 h, 21 mg/24 h Gum:2mg,4mg

Nicorette QuickMist Nicorette, Nicotrol(B)

Sublingual spray: 1 mg/spray

Cartridges: 10 mg (delivers 4 mg nicotine)

Nicotrol NS Electronic cigarettes

Inhalation system: 0.5 mg/spray

Varenicline

Nicotinic receptor partial agonist

Champix(C), Chantix(B)

Tablets: 0.5 mg, 1 mg

Bupropion

Antidepressant

Zyban

Tablets: 150 mg

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 385 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Substance Use Treatment

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Indications‡

( approved)

General Comments

Pharmacotherapy for Nicotine/Tobacco Use Disorder (cont.)

Aid in smoking cessation

• Choice of treatment should be guided by the individual’s preference, contraindications and precautions for use, potential adverse drug reactions, drug interactions, convenience, individual’s previous experience, availability, and cost

• Regardlessofsmokingcessationoptionselected,12-monthabstinenceratesareusually25%orless

• Improvedoutcomesareseenwithcombiningbehavioralcounselingandpharmacotherapy

• Severalcombinationsof rst-linedrugshavebeenshowntobee ectiveinmaintainingabstinence(seePrecautionsp.389),including[5,6,7]:

– Long-term(morethan14weeks)nicotinepatch+nicotinegum,lozengeorspray – Nicotinepatch(6–14weeks)+nicotineinhaler(upto6months)

– Nicotinepatch(6–14weeks)+bupropionSR(upto14weeks)

• Combiningnicotinepatchwithacutedosingformsshowntobemorebene cialwhencomparedtotheuseofasingleformofnicotineproduct

• Long-termuse(upto6months)ofmedicationsmaybehelpfulforsmokerswhoexperiencepersistentwithdrawalsymptomsorwhohaverelapsed

in the past after stopping treatment

• Thereisevidencethatelectroniccigaretteshelpsmokerstostopsmokinglongtermcomparedwithplaceboelectroniccigarettes

• Useofwaterpipesforsmokingcessationinterventionsmaybeanoptionbutrequiresfurtherstudy

Drug Interactions

DRUG INTERACTIONS WITH NRT

Class of Drug

Example

Interaction Effects

Analgesic

Acetaminophen, pentazocine Propoxyphene

Increased levels of analgesic due to inhibition of metabolism, on smoking cessation First-pass metabolism decreased; may require a lower dose

Adrenergic agonist

Isoproterenol, phenylephrine

May require an increase in dose due to a decrease in circulating catecholamine, on smoking cessation

Adrenergic blocker

Labetalol, prazosin

May require a decrease in dose due to a decrease in circulating catecholamines, on smoking cessation

Antidepressant

Imipramine

Increased level of antidepressant due to inhibition of metabolism, on smoking cessation

Antipsychotic

Clozapine, olanzapine

Smoking induces the CYP1A2 enzyme, resulting in lower clozapine and olanzapine levels. Smoking cessation or reduction may therefore result in higher levels of these drugs. Monitor for side effects related to higher levels of clozapine and olanzapine

β-blocker

Propranolol

Increased level of β-blocker due to inhibition of metabolism, on smoking cessation

Caffeine

Increased caffeine levels due to inhibition of metabolism, on smoking cessation

Insulin

May require a decrease in insulin dosage on smoking cessation

Nicotinic receptor partial agonist

Varenicline

Combination can increase adverse effects including nausea, headache, vomiting, dizziness, dyspepsia, and fatigue

Theophylline

Increased level of theophylline due to inhibition of metabolism, on smoking cessation

For DRUG INTERACTIONS with bupropion, see pp. 17–23

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

DRUG INTERACTIONS WITH VARENICLINE

Class of Drug

Example

Interaction Effects

Alcohol

Alcohol intake may increase the risk of patients experiencing psychiatric adverse effects

H2 blocker

Cimetidine, ranitidine

Increased serum concentration of varenicline by 29% due to decreased renal clearance

NRT

Transdermal nicotine

Combination can increase adverse effects including nausea, headache, vomiting, dizziness, dyspepsia, and fatigue

Comparison of Treatments for Nicotine/Tobacco Use Disorder

Nicotine Replacement Therapy (NRT)

Varenicline

Bupropion SR

General Comments

Does not deliver nicotine to the circulation as fast as smoking

Variable plasma levels occur if gum or lozenge chewed/sucked too quickly or too slowly Nicotine inhaler: mimics hand-to-mouth smoking action (coping mechanism)

Nasal spray: Fastest nicotine delivery system

Does not counter the habit/satisfaction of smoking

Adherence rate highest with nicotine patch, moderate with nicotine gum, lozenge and inhaler, and low with nicotine nasal spray

Relieves craving and withdrawal symptoms

Signi cant decrease in smoking satisfaction and psychological reward from smoking reported

Meta-analysis suggests varenicline may increase the odds of quitting over NRT and bupropion

Relieves craving and withdrawal symptoms

Effective in patients with a history of depression

May be used in combination with NRT May minimize weight gain following smoking cessation

Can be used in patients with cardiovascular disease

Pharmacology

Replaces nicotine through various delivery systems

Delivers nicotine that binds to the nicotinic acetylcholine receptor

Partial agonist activity at the α4β2 nicotinic acetylcholine receptor (i.e., agonist activity to a lesser degree than nicotine), while simultaneously preventing nicotine binding (i.e., antagonist activity)

Blocks reuptake of dopamine and noradrenaline

Noncompetitive inhibitor of brain nicotine receptors

Pharmacokinetics

Gum and lozenge: Rate of absorption depends on rate of chewing the gum or sucking the lozenge; time to peak plasma level = 25 min; blood nicotine levels stabilize with repeated use every 30 min

Metabolized by liver, and partly by kidney and lung; plasma half-life = 120 min. Higher levels reported in renal insuf ciency

Inhaler: Peak plasma levels = after continuous inhalation for over 20 min; half-life of primary metabolite, cotinine: 15–20 h

Patch: Eliminates variability of GI absorption; reduces nicotine rst-pass metabolism; effects wear off in 20–24 h. Delivers nicotine slowly and passively over time

Spray: Absorbed very quickly

E-cigarettes: Can deliver levels of nicotine that are comparable to or higher than cigarettes; the average peak plasma level with E-cigarettes appears to be lower than that reported from tobacco cigarette use

Peak plasma levels occur in 3–4 h; bioavailability not affected by food Steady state reached after 4 days Protein binding = 20%

Elimination half-life = 17–24 h 92% excreted unchanged in urine

See p. 18

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 387 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Substance Use Treatment

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Comparison of Treatments for Nicotine/Tobacco Use Disorder (cont.)

Nicotine Replacement Therapy (NRT)

Varenicline

Bupropion SR

Dosing

Dosing comments

Gum:2–4mgq1–2hfor6weeks(max.30pieces/dayofthe2mggum(60mg)or20 pieces/day of the 4 mg gum (80 mg)); 2 mg if smoking < 25 cigarettes/day

Lozenge: At least 9 lozenges/day for 6 weeks (max. 20/day); 2 mg if smoking rst cigarette more than 30 min after waking

Inhaler: 6–16 cartridges/day up to 6 months; each cartridge delivers 4 mg nicotine over 80 inhalations

Patch: 28 mg/24 h for heavy smokers or 14 mg/24 h for light smokers for 6–8 weeks; step-down dosage: 21 mg/24 h x 4 weeks, then 14 mg/24 h x 2 weeks, then 7 mg/24 h x

2 weeks. Studies have been done using up to 42 mg nicotine patch

Spray: 1 spray in each nostril 1–2 times/h. Max.: 5 times/h or 40 times/day (total of 80 sprays/day), each spray delivers 1 mg of nicotine; use initial dose for 8 weeks, then taper over 4–6 weeks

QuickMist: 1-2 sprays/h

With nicotine gum, lozenge or inhaler, do not eat or drink anything but water for 15 min before or after use; acidic beverages decrease absorption

Gum: Bite gum, then chew until “tingle,” then park in cheek for 30–60 sec; repeat for 30 min

Lozenge: Suck lozenge and allow to dissolve slowly; do not chew or swallow lozenge; use tongue to move lozenge from one side of mouth to the other; it should take 20–30 min to dissolve

Spray: Spray into nostrils. The nicotine is quickly absorbed into the nasal membranes

0.5mgdailyx3days,then0.5mgbidx 4 days, then 1 mg bid (morning and supper) for 3 months

Some studies have found 0.5 mg bid as effective as 1 mg bid

If CrCl < 30 mL/min: 0.5 mg/day, max. dose 0.5 mg bid

Start 1 week prior to quit date

Take with food to reduce nausea

Take second dose at supper to minimize insomnia

Total course may be 3-6 months

150mgqa.m.x3days,then150mg bid (given at least 8 h apart) for 7–12 weeks; consider for long-term therapy (up to 6 months after quitting)

Start 1–2 weeks prior to quit date. Target quit date should be after at least 1 week of treatment

Abstinence Rate After 6 Months

13–17%

26%

16.5%

Adverse Effects

Gum or lozenge: Jaw pain, throat irritation, taste perversion, stomatitis, gingivitis, hiccups (10%), dyspepsia, nausea, headache (11%), dizziness, and insomnia

Inhaler: Mouth and throat irritation (small puffs less irritating than long puffs), sneezing, rhinitis, and pharyngitis

Patch: Local skin irritation, insomnia, vivid dreams, and headache Spray: Nose and throat irritation, cough, sneezing, and watery eyes Over 100 trials con rm NRT is not associated with increased cancer risk

Nausea (30%), vomiting, headaches (15%), insomnia (18%), abnormal dreams (13%), somnolence, loss of consciousness, atulence, constipation, dry mouth, dizziness, falls, abnormal spasms and movement; rare hypersensitivity reactions including angioedema, Stevens-Johnson syndrome, and erythema multiforme[8] Changes in behavior, confusion, anxiety, hostility, agitation, restlessness, psychosis, depressed mood and suicidal ideation and acts reported[8]

Possible link to heart attacks, seizures, and diabetes[8]

See p. 19

Insomnia, agitation, headache, dry mouth (10%), disturbed concentration, dizziness, and nausea

Changes in behavior, hostility, agitation, depressed mood and suicidal ideation and acts reported

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Nicotine Replacement Therapy (NRT)

Varenicline

Bupropion SR

Discontinuation

Taper use of NRT gradually to minimize withdrawal symptoms Taper dose of nicotine inhaler during nal 3 months of use

Commonly discontinued after 12 weeks

Commonly discontinued after

7–12 weeks. Some patients require up to 12 months of treatment

Precautions

Caution in patients with recent MI, serious arrhythmias, and unstable angina

Caution in endocrine disorders (e.g., diabetes, hyperthyroidism) due to release of catecholamines

Avoid nicotine spray in patients with severe reactive airway disease; potential for dependence Smoking whilst using NRT can lead to nicotine toxicity with: Headache, nausea, vomiting, abdominal pain, diarrhea, salivation, sweating, ushing, and palpitations

Nicotine addiction may be transferred from cigarettes to gum

Caution in patients with underlying psychiatric disorder or those operating machinery

Reduce dosage in patients with kidney impairment

Black Box Warning: Serious neuropsychiatric events (including depression, suicidal thoughts, and suicide) have been reported

Contraindications

Unstable cardiac conditions

Skin diseases that may complicate patch application

Unstable cardiac conditions

Should not be used by pilots, air traf c controllers, truckers, and bus drivers due to risk of impairment

Anorexia, bulimia, seizures, heavy alcohol use, and use of MAOIs

Use in Adolescents

Little evidence that nicotine replacement is effective in adolescents

Sparse data

Reports of ef cacy in adolescents

Use in Pregnancy♢

Guidelines suggest that nicotine replacement may be used during pregnancy and breastfeeding[9] . These agents are considered much safer than smoking in pregnancy (use suggested even over oral medications for smoking cessation)

Nicotine patch should be removed overnight

Not recommended

♢ See p. 439 for further information on drug use in pregnancy and effects on breast milk

Further Reading

References

1 American Psychiatric Association. Practice guideline and resources for treatment of patients with substance use disorders, 2nd ed. Am J Psychiatry 2006;163(8 Suppl); 1–276. Retrieved from http://www.psychiatryonline.com/pracGuide/pracGuideTopic_5.aspx

2 Elbe D, Black TR, McGrane IR, et al. Clinical handbook of psychotropic drugs for children and adolescents. (4th ed.). Boston, MA: Hogrefe Publishing, 2019.

3 NoorZurani MH, Vicknasingam B, Narayanan S. Itraconazole-induced torsade de pointes in a patient receiving methadone substitution therapy. Drug Alcohol Rev. 2009;28(6):688–690.

doi:10.1111/j.1465-3362.2009.00128.x

4 Brands B, Blake J, Marsh DC, et al. The impact of benzodiazepine use on methadone maintenance treatment outcomes. J Addict Dis. 2008;27(3):37–48. doi:10.1080/10550880802122620

5 Fiore MC, Jaen CR, Baker TB, et al. Clinical Practice Guideline: Treating tobacco use and dependence: 2008 Update. Rockville, MD: U.S. Department of Health and Human Services/Public

Health Service, 2008. Retrieved from http://www.surgeongeneral.gov/tobacco/treating_tobacco_use08.pdf

6 Caldwell BO, Crane J. Combination nicotine metered dose inhaler and nicotine patch for smoking cessation: A randomized controlled trial. Nicotine Tob Res. 2016;18(10):1944–1951.

doi:10.1093/ntr/ntw093

7 Hollands GJ, McDermott MS, Lindson-Hawley N, et al. Interventions to increase adherence to medications for tobacco dependence. Cochrance Database Syst Rev. 2015;2:CD009164.

doi:10.1002/14651858.CD009164.pub2

8 Moore TJ, Cohen MR, Furberg CD. Strong safety signal seen for new varenicline risks. Horsham, PA: Institute for Safe Medication Practices, 2008. Retrieved from http://www.ismp.org/

docs/vareniclinestudy.asp

9 National Institute for Health and Clinical Excellence (NICE). Smoking cessation services in primary care, pharmacies, local authorities and workplaces, particularly for manual working

groups, pregnant women and hard to reach communities. London, UK: NICE, 2008. Retrieved from http://www.nice.org.uk/nicemedia/pdf/PH010guidance.pdf

Additional Suggested Reading

• BrezingCA,LevinFR.Thecurrentstateofpharmacologicaltreatmentsforcannabisusedisorderandwithdrawal.Neuropsychopharmacology.2018;43(1):173–194.doi:10.1038/npp.2017. 212

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 389 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Substance Use Treatment

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Treatment of Substance Use Disorders (cont.)

• BogenDL,PerelJM,HelselJC,etal.Pharmacologicevidencetosupportclinicaldecisionmakingforperipartummethadonetreatment.Psychopharmacology(Berl).2013;225(2):441–451. doi:10.1007/s00213-012-2833-7

• CahillK,StevensS,LancasterT.PharmacologicalTreatmentsforSmokingCessation.JAMA.2014;311(2):193–194.doi:10.1001/jama.2013.283787

• CanadianActionNetworkfortheAdvancement,DisseminationandAdoptionofPractice-informedTobaccoTreatment(CAN-ADAPTT),CentreforAddictionandMentalHealth.Canadian smoking cessation clinical practice guideline. Toronto, ON: Author, 2011. Retrieved from https://www.nicotinedependenceclinic.com/English/CANADAPTT/Guideline/Introduction.aspx

• ClearyBJ,ReynoldsK,EoganM,etal.Methadonedosingandprescribedmedicationuseinaprospectivecohortofopioid-dependentpregnantwomen.Addiction.2013;108(4):762–770.

doi:10.1111/add.12078

• EbbertJO,HatsukamiDK,CroghanIT,etal.CombinationvareniclineandbupropionSRfortobacco-dependencetreatmentincigarettesmokers:Arandomizedtrial.JAMA.2014;311(2):155-

163. doi:10.1001/jama.2013.283185

• FranckJ,Jayaram-LindströmN.Pharmacotherapyforalcoholdependence:Statusofcurrenttreatments.CurrOpinNeurobiol.2013;23(4):692–699.doi:10.1016/j.conb.2013.05.005

• Gowing L, Ali R, White JM. Opioid antagonists under heavy sedation or anaesthesia for opioid withdrawal. Cochrane Database Syst Rev. 2010;(1):CD002022. doi:10.1002/14651858.

CD002022.pub3

• Grant JE, Kim SW, Hartman BK. A double-blind, placebo-controlled study of the opiate antagonist naltrexone in the treatment of pathological gambling urges. J Clin Psychiatry.

2008;69:783–789.

• IacobucciG.Doctorsshouldadvisesmokersonusinge-cigarettes,saysNICE.BMJ.2018;360:k1449.doi:10.1136/bmj.k1449

• JonesHE,KaltenachK,HeilSH,etal.Neonatalabstinencesyndromeaftermethadoneorbuprenorphineexposure.NEnglJMed.2010;363(24):2320–2331.doi:10.1056/NEJMoa1005359

• JørgensenCH,PedersenB,TønnesenH.Theef cacyofdisul ramforthetreatmentofalcoholusedisorder.AlcoholClinExpRes.2011;35(10):1749–1758.doi:10.1111/j.1530-0277.2011.

01523.x

• KalraG,DeSousaA,ShrivastavaA.Disul raminthemanagementofalcoholdependence:Acomprehensiveclinicalreview.OpenJPsychiatr.2014;4(1):43–52.doi:10.4236/ojpsych.2014.

41007

• Lingford-HughesAR,WelchS,PetersL,etal.BAPupdatedguidelines:Evidence-basedguidelinesforthepharmacologicalmanagementofsubstanceabuse,harmfuluse,addictionand

comorbidity: recommendations from BAP. J Psychopharmacol. 2012;26(7):899–952. doi:10.1177/0269881112444324

• Mason BJ, Heyser CJ. The neurobiology, clinical ef cacy and safety of acamprosate in the treatment of alcohol dependence. Expert Opin Drug Saf. 2010;9(1):177–188. doi:10.1517/

14740330903512943

• MattickRP,BreenC,KimberJ,etal.Buprenorphinemaintenanceversusplaceboormethadonemaintenanceforopioiddependence.CochraneDatabaseSystRev.2014;(2):CD002207.

doi:10.1002/14651858.CD002207.pub4

• McCance-Katz EF, Sullivan LE, Nallani S. Drug interactions of clinical importance among the opioids, methadone and buprenorphine, and other frequently prescribed medications:

A review. Am J Addict. 2010;19(1):4–16. doi:10.1111/j.1521-0391.2009.00005.x

• MurphyL,IsaacP,JanecekE,etal.Buprenorphineforthetreatmentofopioiddependence.PharmacyConnection.2012;Winter:21–29.Retrievedfromhttp://www.ocpinfo.com/client/

ocp/OCPHome.nsf/web/Buprenorphine

• O’MalleySS,ZwebenA,FucitoLM,etal.Effectofvareniclinecombinedwithmedicalmanagementonalcoholusedisorderwithcomorbidcigarettesmoking:Arandomizedclinicaltrial.

JAMA psychiatry. 2018;75(2):129–138. doi:10.1001/jamapsychiatry.2017.3544

• RayLA,ChinPF,MiottoK.Naltrexoneforthetreatmentofalcoholism:Clinical ndings,mechanismsofaction,andpharmacogenetics.CNSNeurolDisordDrugTargets.2010;9(1):13–22.

doi:10.2174/187152710790966704

• RoseAK,JonesA.Baclofen:Itseffectivenessinreducingharmfuldrinking,craving,andnegativemood.Ameta-analysis.Addiction.2018;113(8):1396–1406.doi:10.1111/add.14191

• RösnerS,Hackl-HerrwerthA,LeuchtS,etal.Acamprosateforalcoholdependence.CochraneDatabaseSystRev.2010;9:CD004332.doi:10.1002/14651858.CD004332.pub2

• RösnerS,Hackl-HerrwerthA,LeuchtS,etal.Opioidantagonistsforalcoholdependence.CochraneDatabaseSystRev.2010;12:CD001867.doi:10.1002/14651858.CD001867.pub3

• SoghoianS,WienerSW,Diaz-AlcalaJE.Disul ramtoxicity.eMedicine;2016.Retrievedfromhttp://emedicine.medscape.com/article/814525-overview

• VazLR,Leonardi-BeeJ,AveyardP,etal.FactorsassociatedwithsmokingcessationinearlyandlatepregnancyintheSmoking,Nicotine,andPregnancyTrial:Atrialofnicotinereplacement

therapy. Nicotine Tob Res. 2014;16(4)381–389. doi:10.1093/ntr/ntt156

• WilcoxCS,OskooilarN,EricksonJS,etal.Anopen-labelstudyofnaltrexoneandbupropioncombinationtherapyforsmokingcessationinoverweightandobesesubjects.AddictBehav.

2010;35(3):229–234. doi:10.1016/j.addbeh.2009.10.017

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

UNAPPROVED TREATMENTS OF PSYCHIATRIC DISORDERS

Several drugs traditionally used to treat medical conditions have been helpful in ameliorating or preventing symptoms of certain psychiatric disorders. This section presents a summary of some of these drugs and their uses. As a general rule, unapproved treatments should be reserved for patients highly resistant to conventional therapies. Clinicians should be cognizant of medicolegal issues when prescribing drugs for non-approved indications.

Product Availability∗

Adrenergic agents

β-blockers (p. 392) Thyroid hormones (p. 393) Prazosin (p. 394) Doxazosin (p. 395)

Anti-in ammatory agents

Celecoxib

Glucocorticoid (p. 396) Minocycline (p. 396)

Pioglitazone, rosiglitazone (p. 397) Statins (p. 398)

Dopaminergic agents

Armoda nil (p. 398) Moda nil (p. 398) Pramipexole (p. 399)

GABA agents/anticonvulsants

Baclofen (p. 400) Pregabalin Sodium oxybate

Hormones

Estrogen/progesterone (p. 402) Raloxifene (p. 404) Testosterone (p. 405)

NMDA agents

D-cycloserine (p. 406) Dextromethorphan-quinidine Ketamine (p. 407) Pregnenolone (p. 408) Riluzole (p. 408)

Substance Use Disorders

ADHD

Anxiety Disorders

Bipolar Disorder

Dementia

Depression

Schizophrenia

+/C (atenolol & propranolol)

C/S

+/S/C (pindolol) +/S

+ (PTSD) PR (PTSD)

PR/C (PTSD)

PR/C

+/S +/S

S/C +/S

PR/S PR/S/C

+/S +/S

+/S

+/S/C

+/S (females)

PR/C

S/C

+PR/S/C

S/C

+PR

+/S/C

S/C

C (alcohol) +/C (alcohol) + (alcohol)

391

Unapproved Treatments

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Unapproved Treatments of Psychiatric Disorders (cont.)

ADHD

Anxiety Disorders

Bipolar Disorder

Dementia

Depression

Schizophrenia

Substance Use Disorders

5-HT3 antagonists

+/S (granisetron, ondansetron)

+/PR/S (granisetron, ondansetron, tropisetron)

Miscellaneous

ACE inhibitors/ARBs (p. 409)

PR/C

Allopurinol (p. 410) Nalmefene (p. 411)

S/C (mania)

S/C

+/C (alcohol)

∗ Refer to Health Canada’s Drug Product Database or the FDA’s Drugs@FDA for the most current availability information C = contradictory results, P = partial improvement, + = positive, PR = preliminary data, S = synergistic effect

Adrenergic Agents

Have membrane-stabilizing e ect and GABA-mimetic activity; presynaptic 5-HT1A antagonists

• Suggested to inhibit memory consolidation by interfering with protein synthesis; anxiolytic properties may result from its peripheral (autonomic) rather than its central activity – propranolol aids in breaking a vicious cycle of anxiety in which catastrophic misappraisal of bodily sensations of orthosympathetic origin, such as palpitations or increased ventilation, fuel the occurrence of panic attacks

• Propranololdose:Upto320mg/day;atenolol50mg/day

• Propranololandatenololbene cialforsomaticorautonomicallymediatedsymptomsofanxiety(e.g.,tremor,palpitations)asseeninperformance

anxiety and acute panic

• E cacyreportedinadultsandchildrenwithPTSD–propranololtreatmentafterthetraumaticeventreportednottoalterPTSDincidence,although

physiological responses are generally attenuated; early administration reported to treat intrusive memories and reduce severity of later symptoms; recent double-blind, placebo-controlled, randomized clinical trial in 60 adults diagnosed with long-standing PTSD reported positive results with propranolol administered 90 min before a brief memory reactivation session, once a week for 6 consecutive weeks

• Meta-analysissuggestslimiteddataonthebene tofpropranololinlong-termtreatmentofanxietydisorders;noadvantageoverbenzodiazepines reported in the treatment of panic disorders with or without agoraphobia

• Cautioninpatientswithahistory(orfamilyhistory)ofcardiovascularproblems,alcoholuse,andasthma(propranolol)

Argolo FC, Cavalcanti-Ribeiro P, Netto LR, et al. Prevention of posttraumatic stress disorder with propranolol: A meta-analytic review. J Psychosom Res. 2015;79(2):89–93. doi:10.1016/j. jpsychores.2015.04.006

Brunet A, Saumier D, Liu A, et al. Reduction of PTSD symptoms with pre-reactivation propranolol therapy: A randomized controlled trial. Am J Psychiatry. 2018;175(5):427–433. doi: 10.1176/appi.ajp.2017.17050481

de Kleine RA, Rothbaum BO, van Minnen A. Pharmacological enhancement of exposure-based treatment in PTSD: A qualitative review. Eur J Psychotraumatol. 2013;4:21626. doi:10.3402/ ejpt.v4i0.21626

Steenen SA, van Wijk AJ, van der Heijden GJMG, et al. Propranolol for the treatment of anxiety disorders: Systematic review and meta-analysis. J Psychopharmacol. 2016; 30(2):128–139. doi:10.1177/0269881115612236

β-blockers (e.g., propranolol)

Anxiety Disorders

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

• Pindolol dose: 2.5 mg bid to 20 mg daily (5-HT1A and 5-HT1B/1D receptor antagonist)

• Meta-analysis concluded that pindolol accelerates antidepressant response but doesn’t increase the e ectiveness of SSRIs in nonresponsive pa-

tients; data contradictory as lack of e cacy in some studies may be related to dose used and insu cient CNS 5-HT1A receptor occupancy

• Double-blindrandomizedcontrolledstudywithpindolol20mgaddedtovenlafaxinesuggeststhatonlypoormetabolizersofvenlafaxine(i.e.,low

O-desmethylvenlafaxine/venlafaxine ratio) might bene t from pindolol augmentation

• β-blockersareusedtotreatakathisiacausedbySSRIantidepressants

Connolly KR, Thase ME. If at rst you don’t succeed: A review of the evidence for antidepressant augmentation, combination and switching strategies. Drugs. 2011;71(1):43-64. doi: 10.2165/11587620-000000000-00000

Liu Y, Zhou X, Zhu D, et al. Is pindolol augmentation effective in depressed patients resistant to selective serotonin reuptake inhibitors? A systematic review and meta-analysis. See comment in PubMed Commons below Hum Psychopharmacol. 2015;30(3):132–142. doi:10.1002/hup.2465

Martiny K, Lunde M, Bech P, et al. A short-term double-blind randomized controlled pilot trial with active or placebo pindolol in patients treated with venlafaxine for major depression. Nord J Psychiatry. 2012;66(3):147–154. doi:10.3109/08039488.2012.674553

Portella MJ, de Diego-Adeliño J, Ballesteros J, et al. Can we really accelerate and enhance the selective serotonin reuptake inhibitor antidepressant effect?: A randomized clinical trial and a meta-analysis of pindolol in nonresistant depression. J Clin Psychiatry. 2011 Jul;72(7):962-969. doi:10.4088/JCP.09m05827blu

Modulate adrenergic receptor function and permit a given concentration of catecholamines to be more e ective; metabolic enhancers

• Levothyroxinetherapyleadstoasigni cantdeclineinthelevelofin ammatorycytokineswhichmayplayaroleinthepathogenesisofdepression

• Dose: liothyronine (T3 ): 5–50 micrograms/day, L-thyroxine (T4 ) 5–500 micrograms/day

• Augmentation with T3 suggested to be more e cient than with T4 because of individual di erences in thyroid hormone metabolism

• In refractory depression, may potentiate e ects of antidepressants; positive e ects seen in up to 60% of refractory patients within 2 weeks – may

be more bene cial in women than in men; suggested that treatment be discontinued if no response seen after 3 weeks

• Meta-analysisof8studies(4double-blind)ofT3augmentationshowedanabsoluteresponserateof23%inpatientsrefractorytotricyclics;evidence

suggests limited bene t for augmentation of SSRIs

• Case series using higher T3 dose (100 micrograms/day) long term, improved symptoms in 14 of 17 treatment-refractory patients

• Suggested T3 may actually be treating subclinical hypothyroidism; free thyroid hormone concentrations are associated with depression severity

and have an impact on treatment outcome

• Double-blindstudysuggeststhatliothyroninemaypreventECT-inducedmemoryimpairmentinpatientswithMDD

• Negative results reported when T3 added to T4 therapy in hypothyroid patients with depressive symptoms

• Transitorysidee ectscaninclude:Sweating,shaking,anxiety,andtachycardia

• Mayexacerbatemania

Berent D, Zboralski K, Orzechowska A, et al. Thyroid hormones association with depression severity and clinical outcome in patients with major depressive disorder. Mol Biol Rep. 2014;41(4):2419–2425. doi:10.1007/s11033-014-3097-6

Garlow SJ, Dunlop BW, Nemeroff CB. The combination of triiodothyronine (T3) and sertraline is not superior to sertraline monotherapy in the treatment of major depressive disorder. J Psychiatr Res. 2012;46(11):1406–1413. doi:10.1016/j.jpsychires.2012.08.009

Joffe RT. Hormone treatment of depression. Dialogues Clin Neurosci. 2011;13(1):127-138. Retrieved from http://www.dialogues-cns.com/publication/hormone-treatment-of-depression/ Mohagheghi A, Arfaie A, Amiri S, et al. Preventive effect of liothyronine on electroconvulsive therapy-induced memory de cit in patients with major depressive disorder: A double-blind controlled clinical trial. Biomed Res Int. 2015;2015:503918. doi:10.1155/2015/503918

Mowla A, Kalantarhormozi MR, Khazraee S. Clinical characteristics of patients with major depressive disorder with and without hypothyroidism: A comparative study. J Psychiatr Pract. 2011;17(1):67-71. doi:10.1097/01.pra.0000393848.35132.ff

Tayde PS, Bhagwat NM, Sharma P, et al. Hypothyroidism and depression: Are cytokines the link? Indian J Endocrinol Metab. 2017; 21(6):886–892. doi:10.4103/ijem.IJEM_265_17

• Administrationofsupraphysiologicthyroidhormonehasbeensuggestedtoimprovedepressivesymptomsbymodulatingfunctionincomponents of the anterior limbic network

• Dose:liothyronine(T3)(averagedose:90.4micrograms/day,range:13–188micrograms/day;L-thyroxineT4:300–500micrograms/day)

• Controversialresultsseen;responsetotreatmentisusuallyevidentwithinthe rst2weeks

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 393 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Depression

Thyroid Hormones

Depression

Bipolar Disorder

Unapproved Treatments

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Adrenergic Agents (cont.)

• Studies of speci c subgroups of bipolar disorder (rapid cycling, mixed, or depressive bipolar) have reported associations with thyroid antibodies. May be treating unidenti ed hypothyroidism; association reported between elevated T3 hormone and bipolar a ective disorder and that patients with bipolar a ective disorder are 2.55 times more commonly associated with thyroid dysfunction

• HighdoseofL-thyroxinereportedtobeane ectiveadjunctivemaintenancetreatmentofprophylaxis-resistantmooddisorder

• Reportedtoalleviatesymptomsandincreasecyclelengthprimarilyinrapid-cyclingfemalepatients;controversialresultsreportedinmales;adjunc-

tive to other therapies of bipolar disorder

• Retrospective chart review of 159 patients showed that 84% of bipolar II and bipolar NOS patients with treatment-resistant depression improved

when T3 added to their antidepressant regimen; 33% experienced full remission

• Recent review of T3 in bipolar depression reported: 1) improvement in 56%, 75%, and 79% of patients in three open studies, respectively, 2)

improvement in 89% of cases in a retrospective chart review, and 3) improvement in 66% of patients in a mirror-image design study. In the comparative study, T3 performed signi cantly better than placebo. The only randomized double-blind study did not show any substantial di erence between T3 and placebo

• Recommended to regularly assess bone mineral density in postmenopausal women on chronic T4 therapy

Bocchetta A, Traccis F, Mosca E, et al. Bipolar disorder and antithyroid antibodies: Review and case series. Int J Bipolar Disord. 2016;4(1):5. doi:10.1186/s40345-016-0046-4

Chakrabarti S. Thyroid functions and bipolar affective disorder. J Thyroid Res. 2011;2011:306367. doi:10.4061/2011/306367

Chen PH, Huang YJ. Remission of classic rapid cycling bipolar disorder with levothyroxine augmentation therapy in a male patient having clinical hypothyroidism. Neuropsychiatr Dis Treat. 2015;11:339–342. doi:10.2147/NDT.S76973

Khemka D, Ali JA, Koch CA. Primary hypothyroidism associated with acute mania: Case series and literature review. Exp Clin Endocrinol Diabetes. 2011;119(8):513-7. doi:10.1055/ s-0031-1277137

Krishna VN, Thunga R, Unnikrishnan B, et al. Association between bipolar affective disorder and thyroid dysfunction. Asian J Psychiatr. 2013;6(1):42–45. doi:10.1016/j.ajp.2012.08.003 Parmentier T, Sienaert P. The use of triiodothyronine (T3) in the treatment of bipolar depression: A review of the literature. J Affect Disord. 2018;229:410–414. doi:10.1016/j.jad.2017.12.071 Stamm TJ, Lewitzka U, Sauer, et al. Supraphysiologic doses of levothyroxine as adjunctive therapy in bipolar depression: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2014;75(2):162–168. doi:10.4088/JCP.12m08305

α1-adrenergic antagonist

• Dose:Titrategraduallyupto20mg/day;dosesupto48mg/dayhavebeenused(requiresdosing2–4times/dayduetoshorthalf-life)

• High noradrenergic activity may be associated with hyperarousal, trauma nightmares, and sleep disturbances in individuals with PTSD, probably

through the stimulation of α1 adrenergic receptors in the brain prefrontal cortex

• Ameta-analysisconcludesthatPTSD-relatednightmares,sleepdisturbances(hyperarousal,totalsleeptimeandquality),andoverallillnessseverity

show a signi cant response to treatment with prazosin

• Daytimeprazosinreportedtodecreasedistressrelatedtotraumacues

• Caseseriesreportssuccessfuloutcomeusinghigh-dose(upto30and45mg)prazosinforPTSDwithcomorbidtreatment-resistantmooddisorders

• Aretrospectivechartreviewreportedthatprazosinwaswelltoleratedandassociatedwithimprovementsinnightmaresandsleepinyouth(mean

age 13.4 ± 2.9 years; 82% female) with PTSD of whom 76% had a history of sexual abuse and 65% had at least one comorbid psychiatric disorder;

dose ranges of 1-4 mg daily used in children

• Mainsidee ectsreportedincludehypotension,headache,drowsiness,andnausea

Akinsanya A, Marwaha R, Tampi RR. Prazosin in children and adolescents with posttraumatic stress disorder who have nightmares: A systematic review. J Clin Psychopharmacol. 2017;37(1):84–88. doi:10.1097/JCP.0000000000000638

De Berardis D, Marini S, Serroni N, et al. Targeting the noradrenergic system in posttraumatic stress disorder: A systematic review and meta-analysis of prazosin trials. Curr Drug Targets. 2015;16(10):1094–1106. doi:10.2174/1389450116666150506114108

George KC, Kebejian L, Ruth LJ, et al. Meta-analysis of the ef cacy and safety of prazosin versus placebo for the treatment of nightmares and sleep disturbances in adults with posttraumatic stress disorder. J Trauma Dissociation. 2016;17(4):494–510. doi:10.1080/15299732.2016.1141150

Prazosin

Posttraumatic Stress Disorder

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Keeshin BR, Ding Q, Presson AP, et al. Use of prazosin for pediatric PTSD-associated nightmares and sleep disturbances: A retrospective chart review. Neurol Ther. 2017;6(2):247–257. doi:10.1007/s40120-017-0078-4

Koola MM, Varghese SP, Fawcett JA High-dose prazosin for the treatment of post-traumatic stress disorder. Ther Adv Psychopharmacol. 2014;4(1):43–47. doi:10.1177/2045125313500982 Singh B, Hughes AJ, Mehta G, et al. Ef cacy of prazosin in posttraumatic stress disorder: A systematic review and meta-analysis. Prim Care Companion CNS Disord. 2016;18(4). doi: 10.4088/PCC.16r01943

α1-adrenergic antagonist

• Dose:4–16mg/day(haslongerhalf-lifethanprazosin,16–30h,andcanbeusedoncedaily)

• A retrospective chart review of patients with PTSD and/or borderline personality disorder showed a signi cant reduction in trauma-associated

nightmares when treated with doxazosin; 25% of patients treated for 12 weeks had full remission of nightmares

• ApilotstudyinVAveteranssuggestedbene twithdoxazosinXL

Roepke S, Danker-Hopfe H, Repantis D, et al. Doxazosin, an α-1-adrenergic-receptor antagonist, for nightmares in patients with posttraumatic stress disorder and/or borderline personality disorder: A chart review. Pharmacopsychiatry. 2017;50(1):26–31. doi:10.1055/s-0042-107794

Rodgman C, Verrico CD, Holst M, et al. Doxazosin XL reduces symptoms of posttraumatic stress disorder in veterans with PTSD: A pilot clinical trial. J Clin Psychiatry. 2016;77(5):e561–e565. doi:10.4088/JCP.14m09681

Smith C, Koola MM. Evidence for using doxazosin in the treatment of posttraumatic stress disorder, Psychiatr Ann. 2016;46(9):553–555. doi:10.3928/00485713-20160728-01

Anti-in ammatory Agents

Evidence suggests that in ammatory processes and immune responses are involved in the pathophysiology of depression as well as schizophrenia

• Dose:200–400mgdaily

• Openanddouble-blindstudiesshowbene tofcelecoxibintreatingmild–moderatedepressioninpatientswithconcurrentmedicalillness

• Fourstudiesdemonstratedimprovedantidepressanttreatmente ectsforcelecoxibadd-ontreatmentcomparedtoantidepressants+placebo;one

study found that higher levels of the pro-in ammatory marker IL-6 predicted better antidepressant response to adjunctive celecoxib

Andrade C. Antidepressant augmentation with anti-in ammatory agents. J Clin Psychiatry. 2014;75(9):975–977. doi:10.4088/JCP.14f09432

Faridhosseini F, Sadeghi R, Farid L, et al. Celecoxib: A new augmentation strategy for depressive mood episodes. A systematic review and meta-analysis of randomized placebo-controlled trials. Hum Psychopharmacol. 2014;29(3):216–223. doi:10.1002/hup.2401

Köhler O, Krogh J, Mors O, et al. In ammation in depression and the potential for anti-in ammatory treatment. Curr Neuropharmacol. 2016;14(7):732–742. doi:10.2174/1570159X14666151208113700

Majd M, Hashemian F, Hosseini SM, et al. A randomized, double-blind, placebo-controlled trial of celecoxib augmentation of sertraline in treatment of drug-naive depressed women: A pilot study. Iran J Pharm Res. 2015;14(3):891–899. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4518118/s

• The e ect of NSAIDs in bipolar depression remains unclear as clinical studies have yielded mixed results; adjunctive NSAIDs in the treatment of mania have yielded mixed results with anti-manic e ects yet to be consistently demonstrated

Rosenblat JD, McIntyre RS. Bipolar disorder and immune dysfunction: Epidemiological ndings, proposed pathophysiology and clinical implications. Brain Sci. 2017;7(11):pii:E144. doi: 10.3390/brainsci7110144

• Neuroin ammation has been implicated in the neurobiological pathways of schizophrenia. Systematic quantitative reviews and meta-analysis suggest cytokine imbalances in people with schizophrenia relative to controls

• Meta-analysis of 5 randomized DBPC studies of NSAID augmentation (4 used celecoxib, 1 used ASA) of antipsychotic drugs showed NSAIDs can potentially decrease symptom severity in schizophrenia; recent reviews do not encourage the use of aspirin (1000 mg/day)

• Tworecentmeta-analysesof8and6RCTs,respectively,reportthatadjunctivecelecoxibappearstobeane caciousandsafetreatmentinimprov- ing psychotic symptoms, particularly in rst-episode schizophrenia

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 395 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Doxazosin

Posttraumatic Stress Disorder

Celecoxib

Depression

Bipolar disorder

Schizophrenia

Unapproved Treatments

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Glucocorticoid

Posttraumatic Stress Disorder

Minocycline

Anti-in ammatory Agents (cont.)

Andrade C. Anti-in ammatory strategies in the treatment of schizophrenia. See comment in PubMed Commons below Expert Rev Clin Pharmacol. 2016;9(2):161–163. doi:10.1586/ 17512433.2016.1095086

Marini S, De Berardis D, Vellante F, et al. Celecoxib adjunctive treatment to antipsychotics in schizophrenia: A review of randomized clinical add-on trials. Mediators In amm. 2016;2016:3476240. doi:10.1155/2016/3476240

Zheng W, Cai DB, Yang XH, et al. Adjunctive celecoxib for schizophrenia: A meta-analysis of randomized, double-blind, placebo-controlled trials. J Psychiatr Res. 2017;92:139–146. doi: 10.1016/j.jpsychires.2017.04.004

Suggested to restrict retrieval of previous aversive learning episodes

• Hydrocortisone:Dosingandadministrationgiveninsupplementaryfashiontoexposure-basedtreatmentinPTSDpatientshavevariedoutcomes

• Double-blind study suggests that low-dose hydrocortisone (20mg bid), administered within 24h of a trauma, may be a promising approach to the prevention of PTSD in acutely injured trauma patients; suggested to speci cally target avoidance symptoms; meta-analysis reports that hydrocortisone reduces the risk of developing PTSD. Hydrocortisone augmentation of prolonged exposure therapy showed greater reduction in

PTSD symptoms

• Cortisol (up to 25 mg) administered prior to exposure suggested to reduce phobic fears including social phobia; cortisol in uences PTSD-relevant

memory processes and administration of cortisol might be an e ective treatment strategy in reducing intrusive reexperiencing

• Perioperative administration of IV dexamethasone, compared with placebo, during cardiac surgery did not positively or negatively a ect the

prevalence of PTSD and depression

• A 3-year follow-up to determine cumulative incidence of anxiety or depression in 48,207 patients seen in intensive care (exposed pre-admission

to single-agent or combined use of statins, nonsteroidal anti-in ammatory drugs, or glucocorticoids; 1,440 had been glucocorticoid users) showed risk was similar in nonusers compared with users in all drug groups

de Kleine RA, Rothbaum BO, van Minnen A. Pharmacological enhancement of exposure-based treatment in PTSD: A qualitative review. Eur J Psychotraumatol. 2013;4:21626. doi:10.3402/ ejpt.v4i0.21626

Delahanty DL, Gabert-Quillen C, Ostrowski SA, et al. The ef cacy of initial hydrocortisone administration at preventing posttraumatic distress in adult trauma patients: a randomized trial. CNS Spectr. 2013;18(2):103–111. doi:10.1017/S1092852913000096

Holz E, Lass-Hennemann J, Streb M, et al. Effects of acute cortisol administration on perceptual priming of trauma-related material. PLoS One. 2014;9(9):e104864. doi:10.1371/journal. pone.0104864

Kok L, Hillegers MH, Veldhuijzen DS, et al. The effect of dexamethasone on symptoms of posttraumatic stress disorder and depression after cardiac surgery and intensive care admission: Longitudinal follow-up of a randomized controlled trial. Crit Care Med. 2016;44(3):512–520. doi:10.1097/CCM.0000000000001419

Medici CR, Gradus JL, Pedersen L, et al. No impact of preadmission anti-in ammatory drug use on Rrsk of depression and anxiety after critical illness. Crit Care Med. 2017;45(10):1635– 1641. doi:10.1097/CCM.0000000000002571

Sijbrandij M, Kleiboer A, Bisson JI, et al. Pharmacological prevention of post-traumatic stress disorder and acute stress disorder: A systematic review and meta-analysis. Lancet Psychiatry. 2015;2(5):413–421. doi:10.1016/S2215-0366(14)00121-7

Yehuda R, Bierer LM, Pratchett LC, et al. Cortisol augmentation of a psychological treatment for war ghters with posttraumatic stress disorder: Randomized trial showing improved treatment retention and outcome. Psychoneuroendocrinology. 2015;51:589–597. doi:10.1016/j.psyneuen.2014.08.004

Anti-infective drug with anti-in ammatory and neuroprotective properties (including increased neurogenesis and antioxidation, anti-glutamate excitotoxicity, and down-regulation of pro-in ammatory agents); blocks the neurotoxicity of N-methyl-D-aspartate (NMDA) antagonists and may exert a di erential e ect on NMDA signaling pathways; may protect against gray matter loss and modulate fronto-temporal areas involved in the pathophysiology of schizophrenia

• Dose:200mg/day

• Double-blind study reported that 100 mg minocycline bid was safe and e ective in improving mild–moderate depressive symptoms in HIV/AIDS

Depression

patients with mild–moderate depression

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

• A multi-site, 12-week, double-blind, placebo-controlled, pilot trial of adjunctive minocycline in treatment-resistant patients showed positive im- provements in HAMD and CGI scores

• Eighteen clinical studies (including published and unpublished RCTs, open label studies, ongoing clinical trials and a case report) were reviewed; 3 RCTs were analyzed and demonstrated a large antidepressant e ect for minocycline compared to placebo, with good tolerability

• Twoopenlabelstudiesreportedpositiveresultswithminocyclineasadd-ontherapyinpatientswithunipolarpsychoticdepression

Emadi-Kouchak H, Mohammadinejad P, Asadollahi-Amin A, et al. Therapeutic effects of minocycline on mild-to-moderate depression in HIV patients: A double-blind, placebo-controlled, randomized trial. Int Clin Psychopharmacol. 2016;31(1):20–26. doi:10.1097/YIC.0000000000000098

Husain MI, Chaudhry IB, Husain N, et al. Minocycline as an adjunct for treatment-resistant depressive symptoms: A pilot randomised placebo-controlled trial. J Psychopharmacol. 2017;31(9):1166–1175. doi:10.1177/0269881117724352

Miyaoka T, Wake R, Furuya M, et al. Minocycline as adjunctive therapy for patients with unipolar psychotic depression: An open-label study. Prog Neuropsychopharmacol Biol Psychiatry. 2012;37(2):222–226. doi:10.1016/j.pnpbp.2012.02.002

Rosenblat JD, McIntyre RS. Ef cacy and tolerability of minocycline for depression: A systematic review and meta-analysis of clinical trials. J Affect Disord. 2018;227:219–225. doi:10.1016/ j.jad.2017.10.042

Soczynska JK, Kennedy SH, Alsuwaidan M, et al. A pilot, open-label, 8-week study evaluating the ef cacy, safety and tolerability of adjunctive minocycline for the treatment of bipolar I/II depression. Bipolar Disord. 2017;19(3):198–213. doi:10.1111/bdi.12496

• Dose:200mg/day

• Double-blind studies and case series suggest bene t, as an adjunctive medication, on both positive and negative symptoms; signi cant improve-

ment in the BPRS anxiety/depression factor was observed with addition of minocycline to clozapine therapy

• Tworecentmeta-analysesof8and6RCTs,respectively,revealedasigni cantsuperiorityofadjunctiveminocyclinetreatmentoverplaceboforboth

positive and negative symptoms

• Improvementinattentionandmemoryreportedinonestudy,aswellasadecreaseinextrapyramidalsidee ects

• Welltoleratedwithfewsidee ects

Chaudhry IB, Hallak J, Husain N, et al. Minocycline bene ts negative symptoms in early schizophrenia: A randomised double-blind placebo-controlled clinical trial in patients on standard treatment. J Psychopharmacol. 2012;26(9):1185–1193. doi:10.1177/0269881112444941

Chaves C, Marque CR, Maia-de-Oliveira JP, et al. Effects of minocycline add-on treatment on brain morphometry and cerebral perfusion in recent-onset schizophrenia. Schizophr Res. 2015;161(2–3):439–445. doi:10.1016/j.schres.2014.11.031

Kelly DL, Sullivan KM, McEvoy JP, et al. Adjunctive minocycline in clozapine-treated schizophrenia patients with persistent symptoms. J Clin Psychopharmacol. 2015;35(4):374–381. doi: 10.1097/JCP.0000000000000345

Solmi M, Veronese N, Thapa N, et al. Systematic review and meta-analysis of the ef cacy and safety of minocycline in schizophrenia. CNS Spectr. 2017;22(5):415–426. doi:10.1017/ S1092852916000638

Xiang YQ, Zheng W, Wang SB, et al. Adjunctive minocycline for schizophrenia: A meta-analysis of randomized controlled trials. Eur Neuropsychopharmacol. 2017;27(1):8–18. doi:10.1016/ j.euroneuro.2016.11.012

Selective agonists of the nuclear transcription factor peroxisome proliferator-activated receptor-gamma (PPAR-γ) – have anti-in ammatory properties

• Dose:Pioglitazone30mg/day;Rosiglitazone8mg/day

• Fourdouble-blindrandomizedcontrolledtrialssuggestthatpioglitazone,eitheraloneorasadd-ontherapytoconventionaltreatments,wasfound

to be more e ective than placebo and could induce remission of MDD. Improvement in depression scores was associated with improvement in 3 biomarkers of insulin resistance (homeostatic model assessment [HOMA-IR], oral glucose tolerance test, and fasting plasma glucose) and 1 biomarker of in ammation (interleukin-6) among 21 biomarkers studied

• Youngerpatientsmayhavebetterresponse

• Pioglitazonehasbeenassociatedwithseveralsidee ects,includinganincreasedriskforfractures,weightincrease,andcardiovascularevents

Colle R, de Larminat D, Rotenberg S, et al. Pioglitazone could induce remission in major depression: A meta-analysis. Neuropsychiatr Dis Treat. 2016;13:9–16. doi:10.2147/NDT.S121149 Colle R, de Larminat D, Rotenberg S, et al. PPAR-γ agonists for the treatment of major depression: A review. Pharmacopsychiatry. 2017;50(2):49–55. doi:10.1055/s-0042-120120

Lin KW, Wroolie TE, Robakis T, et al. Adjuvant pioglitazone for unremitted depression: Clinical correlates of treatment response. Psychiatry Res. 2015;230(3):846–852. doi:10.1016/j. psychres.2015.10.013

Köhler O, Krogh J, Mors O, et al. In ammation in depression and the potential for anti-in ammatory treatment. Curr Neuropharmacol. 2016;14(7):732–742. doi:10.2174/1570159X14666151208113700

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 397 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Schizophrenia

Pioglitazone/Rosiglitazone

Depression

Unapproved Treatments

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Statins

Armoda nil

Depression

Bipolar Disorder

Moda nil

Anti-in ammatory Agents (cont.)

Statins are also known as HMG-CoA reductase inhibitors and modulate the in ammatory response by decreasing cholesterol synthesis in the liver

• Dose:Lovastatin30mg/day;simvastatin20mg/day

• Earlydatacontradictoryastobene tofstatinadd-ontherapyfortreatingdepression

Köhler O, Krogh J, Mors O, et al. In ammation in depression and the potential for anti-in ammatory treatment. Curr Neuropharmacol. 2016;14(7):732–742. doi:10.2174/1570159X14666151208113700

Köhler-Forsberg O, Gasse C, Berk M, et al. Do statins have antidepressant effects? CNS Drugs. 2017;31(5):335–343. doi:10.1007/s40263-017-0422-3

Dopaminergic Agents

R-enantiomer of moda nil. See moda nil section for mechanism of action

• Dose:150–200mg/day

• Double-blindplacebo-controlledstudiesinpatientswithbipolarIdepressionfoundthatadjunctivearmoda nilimprovedsymptomsandoutcome

measures of depression; a review of the literature shows odds ratio of 1.47; 95% CI, 1.20-1.81; p = .0002 for armoda nil/moda nil

• Sidee ectsincludedheadache,nausea,diarrhea,anxiety,andinsomnia

• WeakinducerofCYP1A2andCYP3A4;weakinhibitorofCYP2C19.DruginteractionreportedwithcarbamazepineviamutualinductionofCYP3A4

Calabrese JR, Frye MA, Yang R, et al. Ef cacy and safety of adjunctive armoda nil in adults with major depressive episodes associated with bipolar 1 disorder: A randomized, double-blind, placebo-controlled, multicenter trial. J Clin Psychiatry. 2014;75(10):1054–1061. doi:10.4088/JCP.13m08951

Darwish M, Bond M, Yang R, et al. Evaluation of the potential for pharmacokinetic drug-drug interaction between armoda nil and carbamazepine in healthy adults. Clin Ther. 2015;37(2):325–337. doi:10.1016/j.clinthera.2014.09.014

Frye MA, Amchin J, Bauer M, et al. Randomized, placebo-controlled, adjunctive study of armoda nil for bipolar I depression: Implications of novel drug design and heterogeneity of concurrent bipolar maintenance treatments. Int J Bipolar Disord. 2015;3(1):34. doi:10.1186/s40345-015-0034-0

Ketter TA, Amchin J, Frye MA, et al. Long-term safety and ef cacy of armoda nil in bipolar depression: A 6-month open-label extension study. J Affect Disord. 2016;197:51–57. doi: 10.1016/j.jad.2016.02.050

McIntyre RS, Lee Y, Zhou AJ, et al. The ef cacy of psychostimulants in major depressive episodes: A systematic review and meta-analysis. J Clin Psychopharmacol. 2017;37(4):412–418. doi:10.1097/JCP.0000000000000723

Niemegeers P, Maudens KE, Morrens M, et al. Pharmacokinetic evaluation or armoda nil for the treatment of bipolar depression. Expert Opin Drug Metab Toxicol. 2012;8(9):1189–1198. doi:10.1517/17425255.2012.708338

Szmulewicz AG, Angriman F, Samamé C, et al. Dopaminergic agents in the treatment of bipolar depression: A systematic review and meta-analysis. Acta Psychiatr Scand. 2017;135(6):527– 538. doi:10.1111/acps.12712

The exact mechanism of action is unclear. Studies have shown it to increase the levels of dopamine in the striatum and nucleus accumbens, norepinephrine in the hypothalamus and ventrolateral preoptic nucleus, and serotonin in the amygdala and frontal cortex. Moda nil also activates glutamatergic circuits while inhibiting GABA neurotransmission

• Dose:100–400mg/day

• Review of double-blind, open label, and retrospective studies suggests moda nil may improve residual fatigue and sedation in patients receiving

antidepressants; may enhance executive function, decrease sleepiness, and improve concentration, mood, and motivation

• Double-blindandopen-labelstudiesshowedbene tinpatientswithatypicaldepression

Depression

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

• A meta-analysis concluded signi cant bene ts of moda nil augmentation on improvements in overall depression scores and remission rates in patients with unipolar major depressive disorder and bipolar depression; a signi cant positive e ect was seen on fatigue symptoms

• Placebo-controlledtrialsuggestsmoda nilplusamoodstabilizermaybemoree ectivefortreatingbipolardepressionwithoutincreasingtherisk of mania

• Mainsidee ectsincludeheadacheandnausea;weightlossreported

• Hasalowabusepotential

• WeakinducerofCYP1A2,2B6,and3A4;maydecreaselevelsofdrugsmetabolizedbytheseenzymes

Abolfazli R, Hosseini M, Ghanizadeh A, et al. Double-blind randomized parallel-group clinical trial of ef cacy of the combination uoxetine plus moda nil versus uoxetine plus placebo in the treatment of major depression. Depress Anxiety. 2011;28(4):297-302. doi:10.1002/da.20801

Goss AJ, Kaser M, Costafreda SG, et al. Moda nil augmentation therapy in unipolar and bipolar depression: A systematic review and meta-analysis of randomized controlled studies. J Clin Psychiatry. 2013;74(11):1101–1107. doi:10.4088/JCP.13r08560

Kleeblatt J, Betzler F, Kilarski LL, et al. Ef cacy of off-label augmentation in unipolar depression: A systematic review of the evidence. Eur Neuropsychopharmacol. 2017;27(5):423–441. doi:10.1016/j.euroneuro.2017.03.003

• Dose:100–425mg/dayindivideddoses

• Bene cial results reported in open and double-blind trials of children aged 5–15; may be useful for inattention, hyperactivity/impulsivity and

oppositional behavior, or when anorexia limits the use of stimulants

• A recent meta-analysis of ve published short-term randomized, double-blind, placebo-controlled trials in children and adolescents showed that

moda nil more signi cantly improved ADHD symptoms at home and in school, compared with placebo

• Maybeassociatedwithanincreasedriskofadversee ectscomparedwithmethylphenidate,dextroamphetamine,andatomoxetine

• Moda nilandcognitive-behavioraltherapyconsideredsecond-linechoicesinpatientswithbipolardisorderandADHD

• Good response reported in double-blind placebo-controlled study of moda nil (mean dose 206.8 mg/day) compared with dextroamphetamine in

adults

• Negativeresultsreportedvs.placebowithmoda nildosesof255,340,425,or510mgdailyinadults

• Common adverse e ects include: Insomnia, headache, nausea, nervousness, hypertension, decreased appetite, and weight loss; serious dermato-

logical reactions have been reported in children and adolescents

Arnold VK, Feifel D, Earl CQ, A 9-week, randomized, double-blind, placebo-controlled, parallel-group, dose- nding study to evaluate the ef cacy and safety of moda nil as treatment for adults with ADHD. J Atten Disord. 2014;18(2):133–144. doi:10.1177/1087054712441969

Bond DJ, Hadjipavlou G, Lam RW, et al. The Canadian Network for Mood and Anxiety Treatments (CANMAT) task force recommendations for the management of patients with mood disorders and comorbid attention-de cit/hyperactivity disorder. Ann Clin Psychiatry. 2012;24(1):23-37. Retrieved from http://www.aacp.com/Abstract.asp?AID=10217

Keen D, Hadijikoumi I. ADHD in children and adolescents. Clin Evid. 2011;2011:0312. Retrieved fromhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3217800/

Wang SM, Han C, Lee SJ, et al. Moda nil for the treatment of attention-de cit/hyperactivity disorder: A meta-analysis. J Psychiatr Res. 2017;84:292–300. doi:10.1016/j.jpsychires.2016. 09.034

D2/D3dopamine receptor agonist; neuroprotective and exerts bene cial e ects on sleep architecture

• Dose:0.375–3mg/day

• A review of open and one double-blind studies suggests e cacy in bipolar and unipolar depression, used alone or in combination with TCAs or

SSRIs; has a large e ect size (0.6–1.1) with a low short-term rate of manic switching in bipolar patients (1% mania and 5% hypomania)

• Double-blind study found modest but statistically signi cant bene t for pramipexole augmentation in treatment-resistant major depressive dis- order using a mixed-e ects linear regression model. However, no statistically signi cant di erence was found using a last-observation-carried-

forward analysis

• Pramipexolereportedtoaugmentantidepressantsintreatment-refractorypatients;higherdoserequiredinsomepatients(3mg/day)

• Positive response reported in a comparative retrospective study assessing the e cacy and safety of pramipexole in the treatment of 14 patients

with resistant depression, in combination with ECT or after a partial response to ECT; one patient became hypomanic

• Bene ciale ectsreportedinseveraldepressionsymptomsinpatientswithParkinson’sdisease

• Highincidenceofnausea;sedationanddizzinessreported;reportsofcompulsivebehaviorsandpsychosis

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 399 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

ADHD

Pramipexole

Depression

Unapproved Treatments

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Dopaminergic Agents (cont.)

Cusin C, Iovieno N, Iosifescu DV, et al. A randomized, double-blind, placebo-controlled trial of pramipexole augmentation in treatment-resistant major depressive disorder. J Clin Psychiatry. 2013;74(7):e636–e41. doi:10.4088/JCP.12m08093

Escalona R, Fawcett J. Pramipexole in treatment-resistant depression, possible role of in ammatory cytokines. Neuropsychopharmacology. 2017;42(1):363. doi:10.1038/npp.2016.217 Fawcett J, Rush AJ, Vukelich J, et al. Clinical experience with high-dosage pramipexole in patients with treatment-resistant depressive episodes in unipolar and bipolar depression. Am J Psychiatry. 2016;173(2):107–111. doi:10.1176/appi.ajp.2015.15060788

Gauthier C, Souaiby L, Advenier-Iakovlev E, et al. Pramipexole and electroconvulsive therapy in treatment-resistant depression. Clin Neuropharmacol. 2017;40(6):264–267. doi:10.1097/ WNF.0000000000000253

Harada T, Ishizaki F, Horie N, et al. New dopamine agonist pramipexole improves parkinsonism and depression in Parkinson’s disease. Hiroshima J Med Sci. 2011;60(4):79-82.

Pae CU. Pramipexole augmentation in treatment-resistant major depressive disorder. Expert Rev Neurother. 2014;14(1):5–8. doi:10.1586/14737175.2014.864556

Tundo A, de Filippis R, Proietti L. Pharmacologic approaches to treatment resistant depression: Evidences and personal experience. World J Psychiatry. 2015;5(3):330–341. doi:10.5498/ wjp.v5.i3.330

• Case report of bene t in the treatment of refractory depression, in combination with mood stabilizers, in a patient with rapid cycling bipolar disorder

• Double-blindstudyshowedimprovementin60%ofbipolarIIdepressedpatientswhenpramipexoleaddedtolithiumtherapy

Dell’Osso B, Ketter TA. Assessing ef cacy/effectiveness and safety/tolerability pro les of adjunctive pramipexole in bipolar depression: Acute versus long-term data. Int Clin Psychophar- macol. 2013;28(6):297–304. doi:10.1097/YIC.0b013e3283639015

Hegde A, Singh A, Ravi M, et al. Pramipexole in the treatment of refractory depression in a patient with rapid cycling bipolar disorder. Indian J Psychol Med. 2015; 37(4):473–474. doi:10.4103/0253- 7176.168614

Mah L, Zarate CA Jr, Nugent AC, et al. Neural mechanisms of antidepressant ef cacy of the dopamine receptor agonist pramipexole in treatment of bipolar depression. Int J Neuropsy- chopharmacol. 2011;14(4):545-551. doi:10.1017/S1461145710001203

GABA Agents/Anticonvulsants

GABAB receptor agonist

• Usualdose:30mg;upto400mg/dayusedinrefractorypatients

• Contradictoryresultsreportedinthetreatmentofalcoholdependence;superiorityoverplacebonotdemonstratedinsomestudies

• Recommended as second-line therapy, at a dose of 300 mg to prevent relapse and reduce drinking, in the 2015 Recommendations of the French

Alcohol Society, issued in partnership with the European Federation of Addiction Societies

• Reportedsafeinpatientswithlivercirrhosis

• Cautionduetopossiblemoodelevatingpropertiesandabusepotential

• Main adverse e ects include drowsiness, dizziness, euphoria, depression, headache, paraesthesias, speech disorders, ataxia, and insomnia – in-

creased with higher doses

Ghosh S, Bhuyan D. Baclofen abuse due to its hypomanic effect in patients with alcohol dependence and comorbid major depressive disorder. Clin Psychopharmacol Neurosci. 2017;15(2):187–189. doi:10.9758/cpn.2017.15.2.187

Liu J, Wang LN. Baclofen for alcohol withdrawal. Cochrane Database Syst Rev. 2017;(8):CD008502. doi:10.1002/14651858.CD008502.pub5

Palpacuer C, Duprez R, Huneau A, et al. Pharmacologically controlled drinking in the treatment of alcohol dependence or alcohol use disorders: A systematic review with direct and network meta-analyses on nalmefene, naltrexone, acamprosate, baclofen and topiramate. Addiction. 2018;113(2):220–237. doi:10.1111/add.13974

Baclofen

Bipolar Disorder

Alcohol Use Disorder

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Pregabalin

Reynaud M, Aubin HJ, Trinquet F, et al. A randomized, placebo-controlled study of high-dose baclofen in alcohol-dependent patients – the ALPADIR study. Alcohol Alcohol. 2017;52(4):439– 446. doi:10.1093/alcalc/agx030

Rolland B, Paille F, Gillet C, et al. Pharmacotherapy for alcohol dependence: The 2015 recommendations of the French Alcohol Society, issued in partnership with the European Federation of Addiction Societies. See comment in PubMed Commons below CNS Neurosci Ther. 2016;22(1):25–37. doi:10.1111/cns.12489

Shukla L, Shukla T, Bokka, S, et al. Correlates of Baclofen Effectiveness in Alcohol Dependence. Indian J Psychol Med. 2015;37(3):370–373. doi:10.4103/0253-7176.162913

Soyka M, Müller CA. Pharmacotherapy of alcoholism – an update on approved and off-label medications. Expert Opin Pharmacother. 2017;18(12):1187–1199. doi:10.1080/14656566.2017. 1349098

Pregabalin binds to the α2δ subunit of the voltage-dependent calcium channel and thus reduces calcium in ux into the nerve terminals; also decreases the release of glutamate, noradrenaline, and substance P; it increases neuronal GABA levels by producing a dose-dependent increase in glutamic acid decarboxylase activity (the enzyme that converts glutamic acid to GABA)

• Dose:150–600mg/day;suggestedthatplateaureachedat300mg

• Double-blindstudiesreporte cacyintreatingsocialanxietydisorderandlong-termtreatmentmaypreventrelapse

• Meta-analysis suggests bene t in generalized anxiety disorder; considered e ective against psychological and somatic anxiety symptoms and

improves sleep maintenance; considered a rst-line agent for the long-term treatment of GAD by the World Federation of Societies of Biological

Psychiatry. Patients with early response to pregabalin are more likely to respond signi cantly at endpoint

• Open-labelanddouble-blindstudiessuggestbene tasaugmentationofantidepressantinpatientswithPTSD

• Double-blindstudiessuggestthatperioperativepregabalin(1or2dosesof150mg)candecreasepreoperativeanxiety,improvesleepquality,and

reduce postoperative pain scores and analgesic usage

• Onsetofactionoccursinabout1weekandismaintainedlongterm

• E cacycomparabletobenzodiazepinesandvenlafaxine,withlesscognitiveandpsychomotorimpairmentthanbenzodiazepines

• Transientsedationanddizzinessreported;weightgain

• Mildwithdrawalsymptomsobserved–withdrawgradually,overatleastaweek

• Canproduceeuphoria;reportsofabuseordependenceinsubstance-seekingindividuals

Baldwin DS, den Boer JA, Lyndon G, et al. Ef cacy and safety of pregabalin in generalised anxiety disorder: A critical review of the literature. J Psychopharmacol. 2015;29(10):1047–1060. doi:10.1177/0269881115598411

Baniasadi M, Hosseini G, Fayyazi Bordbar MR et al. Effect of pregabalin augmentation in treatment of patients with combat-related chronic posttraumatic stress disorder: A randomized controlled trial. J Psychiatr Pract. 2014;20(6):419–427. doi:10.1097/01.pra.0000456590.12998.41

Generoso MB, Trevizol AP, Kasper S, et al. Pregabalin for generalized anxiety disorder: An updated systematic review and meta-analysis. Int Clin Psychopharmacol. 2017;32(1):49–55. doi:10.1097/YIC.0000000000000147

Montgomery SA, Lyndon G, Almas M, et al. Early improvement with pregabalin predicts endpoint response in patients with generalized anxiety disorder: An integrated and predictive data analysis. Int Clin Psychopharmacol. 2017;32(1):41–48. doi:10.1097/YIC.0000000000000144

Oulis P, Mourikis I, Konstantakopoulos G. Pregabalin augmentation in treatment-resistant obsessive-compulsive disorder. Int Clin Psychopharmacol. 2011;26(4):221-224. doi:10.1097/YIC. 0b013e3283466657

Schjerning O, Rosenzweig M, Pottegård A, et al. Abuse potential of pregabalin: A systematic review. CNS Drugs. 2016;30(1):9–25. doi:10.1007/s40263-015-0303-6

Shimony N, Amit U, Minz B, et al. Perioperative pregabalin for reducing pain, analgesic consumption, and anxiety and enhancing sleep quality in elective neurosurgical patients: A prospective, randomized, double-blind, and controlled clinical study. J Neurosurg. 2016;125(6):1513–1522. doi:10.3171/2015.10.JNS151516

• Dose:150–450mg/day;higherdoseshavebeenusedinwithdrawaltreatmentstudies

• A review of studies shows bene cial e ects for alcohol relapse prevention; contradictory results seen for the treatment of withdrawal syndrome;

greater bene ts seen in patients with comorbid generalized anxiety disorder

• Double-blindcomparisonstudywithnaltrexonedemonstratedthatpregabalinshowedgreaterbene tonsymptomsofanxiety,hostility,psychosis,

and abstinence; better outcomes were seen in patients with comorbid psychiatric disorders

• Limitedevidencesupportsaroleofpregabalininthetreatmentofphysicaldependenceandaccompanyingwithdrawalsymptomsassociatedwith

opioids, benzodiazepines, nicotine, cannabinoids, and alcohol

• Trial of pregabalin in detoxi cation from alcohol showed reduced symptoms of withdrawal and of craving; improvement in psychiatric symptoms

reported

• Caution:Potentialforabuseandwithdrawalinpredisposedindividuals

Anxiety Disorders

Alcohol Use Disorder

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 401 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Unapproved Treatments

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Sodium oxybate

Alcohol Use Disorder

Estrogens & Progesterone

GABA Agents/Anticonvulsants (cont.)

Evoy KE, Morrison MD, Saklad SR. Abuse and misuse of pregabalin and gabapentin. Drugs. 2017;77(4):403–426. doi:10.1007/s40265-017-0700-x

Förg A, Hein J, Volkmar K, et al. Ef cacy and safety of pregabalin in the treatment of alcohol withdrawal syndrome: A randomized placebo-controlled trial. Alcohol Alcohol. 2012;47(2):149- 155. doi:10.1093/alcalc/agr153

Freynhagen R, Backonja M, Schug S, et al. Pregabalin for the treatment of drug and alcohol withdrawal symptoms: A comprehensive review. CNS Drugs. 2016;30(12):1191–1200. doi: 10.1007/s40263-016-0390-z

Gimeno C, Dorado ML, Roncero C, et al. Treatment of comorbid alcohol dependence and anxiety disorder: Review of the scienti c evidence and recommendations for treatment. Front Psychiatry. 2017;8:173. doi:10.3389/fpsyt.2017.00173

Schifano F. Misuse and abuse of pregabalin and gabapentin: Cause for concern? CNS Drugs. 2014;28(6):491–496. doi:10.1007/s40263-014-0164-4

Schjerning O, Rosenzweig M, Pottegård A, et al. Abuse potential of pregabalin: A systematic review. CNS Drugs. 2016;30(1):9–25. doi:10.1007/s40263-015-0303-6

The active metabolite of sodium oxybate is gamma-hydroxybutyric acid (GHB) and acts as an agonist at the GABAB receptor complex and the GHB receptor

• Dose:50mg/kgtid

• Resultsofrandomizedcontrolledtrialsindicatethatsodiumoxybateisatleastase ectiveasdiazepamandclomethiazoleinpatientswithalcohol

withdrawal syndrome, rapidly alleviating symptoms, and at least as e ective as naltrexone or disul ram in the maintenance of abstinence in

alcohol-dependent patients

• Reporton7patientstreatedwithsodiumoxybate,incombinationwithnalmefene18mg/day,describedthatduringthe rstmonthofcombined

treatment, two patients were able to achieve alcohol abstinence, 5 were able to suppress and 2 to reduce episodes of heavy drinking days, while

one patient had decreased cravings

• Patientswithalcoholdependenceandborderlinepersonalitydisorderorwhoareinremissionfromheroinorcocaineaddiction,maynotbesuitable

candidates for sodium oxybate therapy because of an increased risk of abuse

Caputo F, Maremmani AG, Addolorato G, et al. Sodium oxybate plus nalmefene for the treatment of alcohol use disorder: A case series. J Psychopharmacol. 2016;30(4):402–409. doi: 10.1177/0269881116629126

Keating GM. Sodium oxybate: A review of its use in alcohol withdrawal syndrome and in the maintenance of abstinence in alcohol dependence. Clin Drug Investig. 2014;34(1):63–80. doi:10.1007/s40261-013-0158-x

Skala K, Caputo F, Mirijello A, et al. Sodium oxybate in the treatment of alcohol dependence: From the alcohol withdrawal syndrome to the alcohol relapse prevention. Expert Opin Pharmacother. 2014;15(2):245–257. doi:10.1517/14656566.2014.863278

Hormones

Estrogens increase central bioavailability of norepinephrine, serotonin, and acetylcholine; may increase binding sites on platelets for antidepressants; estrogens also alter dopamine synthesis, increase its turnover, and modulate dopamine receptor sensitivity. Progesterone enhances serotonergic activity (chronic estrogen use augments activity of progesterone in CNS)

• Dose:Transdermalestrogen100micrograms/day;conjugatedestrogens0.625mg/dayfor21daysfollowedbyprogesterone5mg/day

• Datacontradictoryonbene tofestrogensfordepression;areviewoftheliteraturesuggestssomeevidencetosupporttheantidepressante cacy

of estradiol in perimenopausal but not postmenopausal women

• A number of studies consistently report estrogen therapy to be e ective in improving mood in perimenopausal women. However, its e cacy for

overt depression or during postmenopause is more questionable

• A double-blind study showed that for recently postmenopausal women, hormone replacement therapy did not alter cognition as hypothesized;

however, bene cial mood e ects with small–medium e ect size were noted after 4 years of use of conjugated equine estrogens, but not after 4 years of transdermal estradiol

Depression

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

• Open-labelstudysuggeststhatserumprolactinconcentrationsarepositivelycorrelatedtoseverityofdepressivesymptomsinmenopausalwomen

• A review and meta-analysis reports that longer exposure to endogenous estrogens (i.e., later menopause and a longer reproductive period) is associated with a lower risk of depression in later life; growing evidence from basic and clinical research suggests that uctuations in ovarian

hormones and derived neurosteroids result in alterations in regulation of the HPA axis by GABA, generating greater vulnerability to depression

• Maximumclinicale ectmaytakeupto4weeks

Georgakis MK, Thomopoulos TP, Diamantaras AA, et al. Association of age at menopause and duration of reproductive period with depression after menopause: A systematic review and meta-analysis. JAMA Psychiatry. 2016;73(2):139–149. doi:10.1001/jamapsychiatry.2015.2653

Gleason CE, Dowling NM, Wharton W, et al. Effects of hormone therapy on cognition and mood in recently postmenopausal women: Findings from the randomized, controlled KEEPS- cognitive and affective study. PLoS Med. 2015;12(6):e1001833. doi:10.1371/journal.pmed.1001833

Gordon JL, Girdler SS, Meltzer-Brody SE et al. Ovarian hormone uctuation, neurosteroids, and HPA axis dysregulation in perimenopausal depression: A novel heuristic model. Am J Psychiatry. 2015;172(3):227–236. doi:10.1176/appi.ajp.2014.14070918

Kornstein SG, Toups M, Rush AJ,et al. Do menopausal status and use of hormone therapy affect antidepressant treatment response? Findings from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. J Womens Health (Larchmt). 2013;22(2):121–131. doi:10.1089/jwh.2012.3479

Rubinow DR, Johnson SL, Schmidt PJ et al. Ef cacy of estradiol in perimenopausal depression: So much promise and so few answers. Depress Anxiety. 2015;32(8):539–549. doi:10.1002/ da.22391

Scali J, Ryan J, Carrière I, et al. A prospective study of hormone therapy and depression in community-dwelling elderly women: The Three City Study. J Clin Psychiatry. 2010;71(12):1673– 1679. doi:10.4088/JCP.09m05188blu

Slopien R, Slopien A, Warenik-Szymankiewicz A. Serum prolactin concentration and severity of depression symptoms in climacteric women. Clin Exp Obstet Gynecol. 2015;42(6):749–751. Toffol E, Heikinheimo O, Partonen T. Hormone therapy and mood in perimenopausal and postmenopausal women: A narrative review. Menopause. 2015;22(5):564–578. doi:10.1097/ GME.0000000000000323

• Estrogen promotes cholinergic activity, reduces neuronal loss, improves blood ow, has anti-in ammatory properties, and reduces cholesterol. Estradiol serves as a neurotrophomodulatory substance for basal forebrain cholinergic neurons thought to be involved in learning and memory

• Postmenopausalwomentreatedwithestrogensalone,orincombinationwithprogestin,werefoundtohavehigherrestingcortisolconcentrations than controls matched for time of day. Basal cortisol was a modest predictor of learning and memory; higher cortisol was associated with better recall and fewer memory errors

• Results from trials involving recently postmenopausal women and several large observational studies including women initiating menopausal hormone therapy shortly after menopause suggest that hormone replacement has either a neutral or a bene cial e ect on cognition and mood. In contrast, ndings from several large studies of women aged 65 years and older indicated that both opposed and unopposed conjugated equine estrogens were associated with adverse cognitive e ects and no mood bene ts – data still controversial

• Emerging results seem to suggest that timing of estrogen use may be important; short-term hormone replacement near menopause onset may o er a reasonable strategy to impede development of dementia

• Theassociationbetweenendogenoussexhormonesandbothobjectiveandsubjectivemeasuresofcognitivefunctionwasstudiedin3,044women who were followed up to 23 years in a prospective cohort study. Plasma levels of estrone, estrone sulfate, estradiol, androstenedione, testosterone, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEA-S) were measured between 1989 and 1990, neuropsychologic testing was done between 1999 and 2008, and patients were asked about subjective cognition in 2012; there were no clear associations of endogenous hormone levels at midlife and cognition in later life, although a suggested nding of higher levels of plasma estrone was associated with better cognitive function

• A retrospective analysis of 489,105 Finnish women on postmenopausal hormone therapy (HT) showed that risk of death from vascular dementia was reduced by 37–39% (less than 5 or ≥ 5 years of exposure) with the use of any systemic HT (estradiol only or estradiol-progestin combination), as compared to non-users. Risk of death from Alzheimer’s disease was not reduced with systemic HT use less than 5 years, but was slightly reduced (15%) if HT exposure exceeded 5 years. Age at systemic HT initiation (under 60 vs ≥ 60 years) did not a ect the death risk reductions

Christensen A, Pike CJ. Menopause, obesity and in ammation: Interactive risk factors for Alzheimer’s disease. Front Aging Neurosci. 2015;7:130. doi:10.3389/fnagi.2015.00130 Engler-Chiurazzi EB, Singh M, Simpkins JW. From the 90’s to now: A brief historical perspective on more than two decades of estrogen neuroprotection. Brain Res. 2016;1633:96–100. doi:10.1016/j.brainres.2015.12.044

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 403 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Dementia

Unapproved Treatments

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Hormones (cont.)

Hampson E, Duff-Canning SJ. Salivary cortisol and explicit memory in postmenopausal women using hormone replacement therapy. Psychoneuroendocrinology. 2016;64:99–107. doi: 10.1016/j.psyneuen.2015.11.009

Imtiaz B, Tuppurainen M, Rikkonen T, et al. Postmenopausal hormone therapy and Alzheimer disease: A prospective cohort study. Neurology. 2017;88(11):1062–1068. doi:10.1212/WNL. 0000000000003696

Koyama AK, Tworoger SS, Eliassen AH, et al. Endogenous sex hormones and cognitive function in older women. Alzheimers Dement. 2016;12(7):758–765. doi:10.1016/j.jalz.2015.12.010 Mikkola TS, Savolainen-Peltonen H, Tuomikoski P, et al. Lower death risk for vascular dementia than for Alzheimer’s disease with postmenopausal hormone therapy users. J Clin Endocrinol Metab. 2017;102(3):870–877. doi:10.1210/jc.2016-3590

Pike CJ. Sex and the development of Alzheimer’s disease. J Neurosci Res. 2017; 95(1–2): 671–680. doi:10.1002/jnr.23827

Uchoa MF, Moser VA, Pike CJ. Interactions between in ammation, sex steroids, and Alzheimer’s disease risk factors. Front Neuroendocrinol. 2016;43:60–82. doi:10.1016/j.yfrne.2016.09. 001

• Dose:Conjugatedestrogens0.625mg/day;estradioloral=50–200micrograms/day;17β-estradioltransdermal100–200micrograms/day

• The observation that women have a later onset and lesser symptoms of schizophrenia, and that there is a spike in diagnosis after menopause, has led to the hypothesis that estrogens may have a protective role; women generally require lower doses of an antipsychotic, though a decline in

antipsychotic e cacy has been noted after menopause

• A literature review showed that estrogen augmentation demonstrated signi cant bene ts in patients with schizophrenia for overall, positive,

and negative symptoms. Subgroup analyses yielded signi cant results for estrogens in premenopausal women for overall, positive, and negative

symptoms

• A review of the literature suggests that add-on hormone therapy during the perimenopause in women with schizophrenia ameliorates psychotic

and cognitive symptoms, and may also help a ective symptoms. Vasomotor, genitourinary, and sleep symptoms are also reduced

• Considertheriskofbreastcancerandcardiovasculardisease

Brzezinski A, Brzezinski-Sinai NA, Seeman MV. Treating schizophrenia during menopause. Menopause. 2017;24(5):582–588. doi:10.1097/GME.0000000000000772

Gogos A, Sbisa AM, Sun J, et al. A role for estrogen in schizophrenia: Clinical and preclinical ndings. Int J Endocrinol. 2015;2015:615356. doi:10.1155/2015/615356

González-Rodríguez A, Catalán R, Penadés R, et al. Antipsychotic response worsens with postmenopausal duration in women with schizophrenia. J Clin Psychopharmacol. 2016;36(6):580– 587. doi:10.1097/JCP.0000000000000571

Heringa SM, Begemann MJ, Goverde AJ, et al. Sex hormones and oxytocin augmentation strategies in schizophrenia: A quantitative review. Schizophr Res. 2015;168(3):603–613. doi: 10.1016/j.schres.2015.04.002

McGregor C, Riordan A, Thornton J. Estrogens and the cognitive symptoms of schizophrenia: Possible neuroprotective mechanisms. Front Neuroendocrinol. 2017;47:19–33. doi:10.1016/j. yfrne.2017.06.003

Searles S, Makarewicz JA, Dumas JA. The role of estradiol in schizophrenia diagnosis and symptoms in postmenopausal women. Schizophr Res. 2018;196:35–38. doi:10.1016/j.schres.2017. 05.024

Selective estrogen receptor modulator. Binds estrogen receptor alpha (ESR-α), improves memory and attention, and normalizes cortical and hippocampal activity

• Dose:60–120mg/day

• Review of published studies of adjunctive raloxifene in males and females with schizophrenia shows mixed results in restoring cognition or

reducing symptom severity; bene ts may be related to patient’s age, dosage, and duration of treatment

• Adjunctive raloxifene treatment shown to have bene cial e ects on attention/processing speed and memory for both men and women with

schizophrenia

• Double-blind placebo-controlled studies report contradictory results with raloxifene (120 mg/day) augmentation of antipsychotics in postmeno-

pausal women: Negative results seen in severely decompensated patients with schizophrenia, while positive results reported in refractory

schizophrenia

• Consideration:Smallincreaseintheriskofvenousthromboembolismandendometrialcancer

Kulkarni J, Gavrilidis E, Gwini SM, et al. Effect of adjunctive raloxifene therapy on severity of refractory schizophrenia in women: A randomized clinical trial. JAMA Psychiatry. 2016;73(9):947–954. doi:10.1001/jamapsychiatry.2016.1383

Raloxifene

Schizophrenia

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Usall J, Huerta-Ramos E, Labad J, et al. Raloxifene as an adjunctive treatment for postmenopausal women with schizophrenia: A 24-week double-blind, randomized, parallel, placebo- controlled trial. Schizophr Bull. 2016;42(2):309–317. doi:10.1093/schbul/sbv149

Weickert TW, Weickert CS. Raloxifene improves cognition in schizophrenia: Spurious result or valid effect? Front Psychiatry. 2017;8:202. doi:10.3389/fpsyt.2017.00202

Weiser M, Levi L, Burshtein S, et al. Raloxifene plus antipsychotics versus placebo plus antipsychotics in severely ill decompensated postmenopausal women with schizophrenia or schizoaffective disorder: A randomized controlled trial. J Clin Psychiatry. 2017 Jul;78(7):e758–e765. doi:10.4088/JCP.15m10498

Zhu XM, Zheng W, Li XH, et al. Adjunctive raloxifene for postmenopausal women with schizophrenia: A meta-analysis of randomized, double-blind, placebo-controlled trials. Schizophr Res. 2018;197:288–293. doi:10.1016/j.schres.2018.01.017

Testosterone is a modulator of GABAA receptors and inhibits 5-HT3 receptors centrally

• Testosterone concentrations (total, free, and bioavailable) reported to be lower in males over the age of 45 with MDD; no association found in elderly females

• Dose: 400 mg IM every 2 weeks; testosterone transdermal gel 1% (10 mg/day), dehydroepiandrosterone (DHEA) 30-50 mg/day; route of adminis- tration may play a role in treatment response

• Highrate(i.e.,56%)ofdepressionanddepressivesymptomsdiagnosedinmenreferredforborderlinetestosteronelevels

• A prospective longitudinal study of 3,179 older men, free of clinically signi cant depressive symptoms at baseline, showed that low serum total

testosterone, but not calculated free testosterone, was associated with incident depression over 8.4–10.9 years

• Meta-analysis of data showed a signi cant positive impact of testosterone on mood; e ect more signi cant in men under age 60, and the e ect

size was larger in subthreshold depression compared with major depression

• Datasuggestsbene tasaugmentationstrategyinmenwithlow-normalserumtestosteronerefractorytoSSRIs

• Negativeresultsreportedindouble-blindstudyofhypogonodalmenwithMDD

• A study of 103 women showed an association between postpartum depression and persistent high serum testosterone level 24–28 h following

childbirth (as compared to controls); estradiol and progesterone levels did not show signi cant di erences

Amanatkar HR, Chibnall JT, Seo BW, et al. Impact of exogenous testosterone on mood: A systematic review and meta-analysis of randomized placebo-controlled trials. Ann Clin Psychiatry. 2014;26(1):19–32. Retrieved from http://www.aacp.com/Abstract.asp?AID=11620

Aswathi A, Rajendiren S, Nimesh A, et al. High serum testosterone levels during postpartum period are associated with postpartum depression. Asian J Psychiatr. 2015;17:85–88. doi: 10.1016/j.ajp.2015.08.008

Ford AH, Yeap BB, Flicker L, et al. Prospective longitudinal study of testosterone and incident depression in older men: The Health In Men Study. Psychoneuroendocrinology. 2016;64:57– 65. doi:10.1016/j.psyneuen.2015.11.012

Giltay EJ, van der Mast RC, Lauwen E, et al. Plasma testosterone and the course of major depressive disorder in older men and women. Am J Geriatr Psychiatry. 2017;25(4):425–437. doi:10.1016/j.jagp.2016.12.014

Khera M, Bhattacharya RK, Blick G, et al. The effect of testosterone supplementation on depression symptoms in hypogonadal men from the Testim Registry in the US (TRiUS). Aging Male. 2012;15(1):14–21. doi:10.3109/13685538.2011.606513

• Normalage-relatedtestosteronelossinmenisassociatedwithincreasedriskforseveraldiseasesincludingAlzheimer’s

• Hypogonadal men do not seem to bene t from testosterone supplementation but small-scale, short-term intervention studies in eugonadal men

with and without cognitive impairments have shown promising results

• Arandomized,placebo-controlledcrossoverstudyshowedmodestimprovementonglobalcognitionwithtestosteronetreatmentinoldermen

• Levelsoftestosterone,dihydrotestosterone,estradiol,estrone,SHBG,LH,andFSHweremeasuredinmenaged70yearsandolderatbaseline(2005–

2007; n = 1,705), 2-year follow-up (2007–2009; n = 1,367), and 5-year follow-up (2010–2013; n = 958); a change in all the studied hormones, except for estradiol was signi cantly associated with cognitive decline. Men who had dementia at baseline had signi cantly greater decline in serum testosterone levels

Carcaillon L, Brailly-Tabard S, Ancelin ML, et al. Low testosterone and the risk of dementia in elderly men: Impact of age and education. Alzheimers Dement. 2014;10(5 Suppl.):S306–S314. doi:10.1016/j.jalz.2013.06.006

Giagulli VA, Guastamacchia E, Licchelli B, et al. Serum testosterone and cognitive function in ageing male: Updating the evidence. Recent Pat Endocr Metab Immune Drug Discov. 2016;10(1):22–30. doi:10.2174/1872214810999160603213743

Hsu B, Cumming RG, Waite LM, et al. Longitudinal relationships between reproductive hormones and cognitive decline in older men: The Concord Health and Ageing in Men Project. J Clin Endocrinol Metab. 2015;100(6):2223–2230. doi:10.2174/1871527315666151110125704

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 405 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Testosterone

Depression

Dementia

Unapproved Treatments

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Hormones (cont.)

Pike CJ. Sex and the development of Alzheimer’s disease. J Neurosci Res. 2017; 95(1–2): 671–680. doi:10.1002/jnr.23827

Uchoa MF, Moser VA, Pike CJ. Interactions between in ammation, sex steroids, and Alzheimer’s disease risk factors. Front Neuroendocrinol. 2016;43:60–82. doi:10.1016/j.yfrne.2016.09. 001

Wahjoepramono EJ, Asih PR, Aniwiyanti V, et al. The effects of testosterone supplementation on cognitive functioning in older men. CNS Neurol Disord Drug Targets. 2016;15(3):337–343. doi:10.1016/j.jalz.2013.06.006

NMDA Agents

Acts as a “super agonist” at NMDA receptors containing GluN2C subunits and, under certain conditions, may act as an antagonist at NMDA receptors containing GluN2B subunits

• Studies in animals and clinical trials in patients with anxiety disorders have demonstrated that single or intermittent dosing with D-cycloserine enhances memory consolidation

• Dose:50–500mg/day

• Individualstudieshavereportedpromisingresultsbutmeta-analysesquestionthebene tofD-cycloserineinaugmentingthee ectsofcognitive

and behavioral therapies in the treatment of anxiety disorders in adults, children, and adolescents, including PTSD, panic disorder, social anxiety

disorder, speci c phobia, and OCD; e cacy is not moderated by the concurrent use of antidepressants

• Ameta-analysisofstudiessuggeststhatD-cycloserinemayincreasethespeedore ciencyofexposuretreatment

• Early data suggests intermittent therapy may decrease anxiety, improve negative symptoms of schizophrenia, and enhance learning when com-

bined with cognitive behavioral therapy for delusions or with cognitive remediation

• Mayhelpmaintainsocialskillstraininginautismspectrumdisorder

• Adversee ectsincludesedation,headache,increasedanxiety,andrestlessness

Bürkner PC, Bittner N, Holling H, et al. D-cycloserine augmentation of behavior therapy for anxiety and obsessive-compulsive disorders: A meta-analysis. PLoS One. 2017;12(3):e0173660. doi:10.1371/journal.pone.0173660

Goff DC. D-cycloserine in schizophrenia: New strategies for improving clinical outcomes by enhancing plasticity. Curr Neuropharmacol. 2017;15(1):21–34. doi:10.2174/1570159X14666160225154812

Hofmeijer-Sevink MK, Duits P, Rijkeboer MM, et al. No effects of D-cycloserine enhancement in exposure with response prevention therapy in panic disorder with agoraphobia: A double- blind, randomized controlled Trial. J Clin Psychopharmacol. 2017;37(5):531–539. doi:10.1097/JCP.0000000000000757

Mataix-Cols D, Fernández de la Cruz L, Monzani B, et al. D-cycloserine augmentation of exposure-based cognitive behavior therapy foraAnxiety, obsessive-compulsive, and posttraumatic stress disorders: A systematic review and meta-analysis of individual participant data. JAMA Psychiatry. 2017;74(5):501–510. doi:10.1001/jamapsychiatry.2016.3955

McGuire JF, Wu MS, Piacentini J, et al. A meta-analysis of D-cycloserine in exposure-based treatment: Moderators of treatment ef cacy, response, and diagnostic remission. J Clin Psychiatry. 2017;78(2):196–206. doi:10.4088/JCP.15r10334

Ori R, Amos T, Bergman H, et al. Augmentation of cognitive and behavioural therapies (CBT) with d-cycloserine for anxiety and related disorders. Cochrane Database Syst Rev. 2015;5:CD007803. doi:10.1002/14651858.CD007803.pub2

Wink LK, Minshawi NF, Shaffer RC, et al. D-cycloserine enhances durability of social skills training in autism spectrum disorder. Mol Autism. 2017;8:2. doi:10.1186/s13229-017-0116-1

Dextromethorphan is an NMDA receptor antagonist. Quinidine inhibits the rapid rst-pass metabolism of DM, thus increasing its plasma level; approved in the USA (Nuedexta) for treatment for pseudobulbar a ect (PBA – uncontrollable episodes of crying and/or laughing)

• Agitationandaggressionscoresweresigni cantlyreducedinadouble-blindplacebo-controlledstudyofpatientswithprobableAlzheimer’sdisease; scores also reduced when patients on placebo were provided active drug

• Open-labelstudyshowedDM-Qsigni cantlyreducedpseudobulbara ectsymptomsinpatientswithdementia

D-Cycloserine

Anxiety Disorders

Dextromethorphan-Quinidine (DM-Q)

Dementia

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

• Adverse events included falls, headache, urinary tract infection, and diarrhea; the medication was not associated with cognitive impairment, sedation, or clinically signi cant QTc prolongation

Cummings JL, Lyketsos CG, Peskind ER, et al. Effect of dextromethorphan-quinidine on agitation in patients with Alzheimer disease dementia: A randomized clinical trial. JAMA. 2015;314(12):1242–1254. doi:10.1001/jama.2015.10214

Doody RS, D’Amico S, Cutler AJ, et al. An open-label study to assess safety, tolerability, and effectiveness of dextromethorphan/quinidine for pseudobulbar affect in dementia: PRISM II results. CNS Spectr. 2016;21(6):450–459. doi:10.1017/S1092852915000620

NMDA receptor non-competitive antagonist; has a complex pharmacological pro le and a ects numerous receptors; antidepressant e ects appear to involve the facilitation of glutamatergic neurotransmission in the prefrontal cortex

• Dose: 0.1–0.75 mg/kg administered over 2–100 min (use as a single sub-anesthetic intravenous infusion); intranasal dose: 50–80 mg q 2-3 days; sublingual syrup 8–16 mg/day; other routes include: oral, transmucosal, intramuscular, and subcutaneous

• Evidence supports rapid antidepressant e ects of low-dose intravenous ketamine in major depressive disorder, in bipolar depression and in depression with suicidal ideation; ketamine has demonstrated e cacy in the rapid reduction of suicidal symptoms

• Meta-analysissuggestsketamine’se cacyindepressivedisorders(majordepressivedisorderandbipolardepression),asasingleoraugmentation treatment, in non-ECT studies as well as in ECT studies; as per Cochrane reviews, con dence in the evidence was limited by risk of bias and the small number of participants, despite the promising nature of preliminary results

• Appearstodirectlytargetcoredepressivesymptomssuchassadmood,suicidality,helplessness,andworthlessnessratherthaninducinganonspe- ci c mood-elevating e ect

• Hasbeenused,incombinationwithpropofol,duringECTtreatmentwithvariableresponse

• Antidepressante ectsaretransient(observedwithinhoursofadministration,peakafteraboutaday,andrelapsereportedwithin3–21daysafter

single or multiple use); bene ts can be maintained for weeks to months by continuation of ketamine sessions at 2- to 4-day intervals; case series

suggests that D-cycloserine may prolong the initial clinical response after ketamine

• Repeated infusions of IV ketamine (up to 0.75 mg/kg) have been used to augment current therapy for treatment-resistant depression with some

short-lived response reported; suggested that repeated infusions may o er better response than single infusion

• Sidee ectsincludetransientincreaseinbloodpressureandheartrate,light-headedness,sedation,confusion,emotionalblunting,anddissociative symptoms; acute impairments of working, episodic, and semantic memory have been reported in recreational users as well as healthy volunteers

and may persist with chronic use. Case report of mania in patient with unipolar major depression

• Drugs that induce CYP2B6 and CYP3A4 may reduce exposure to ketamine whilst drugs that inhibit these enzymes may increase exposure to ke-

tamine; concurrent benzodiazepines may diminish the antidepressant bene ts of ketamine, drugs (such as lamotrigine) that inhibit glutamatergic

signaling may reduce the adverse e ects of ketamine

• Concernsexistregardingthepotentialforabuseofketamine;casereportofMDDfollowingchronicabuseofketamine

Andrade C. Ketamine for depression, 1: Clinical summary of issues related to ef cacy, adverse effects, and mechanism of action. J Clin Psychiatry. 2017;78(4):e415–e419. doi:10.4088/JCP. 17f11567

Andrade C. Ketamine for depression, 2: Diagnostic and contextual indications. J Clin Psychiatry. 2017;78(5):e555–e558. doi:10.4088/JCP.17f11629

Andrade C. Ketamine for depression, 4: In what dose, at what rate, by what route, for how long, and at what frequency? J Clin Psychiatry. 2017;78(7):e852–e857. doi:10.4088/JCP.17f11738 Andrade C. Ketamine for depression, 5: Potential pharmacokinetic and pharmacodynamic drug interactions. J Clin Psychiatry. 2017;78(7):e858–e861. doi:10.4088/JCP.17f11802

Banwari G, Desai P, Patidar P, et al. Ketamine-induced affective switch in a patient with treatment-resistant depression. Indian J Pharmacol. 2015;47(4):454–455. doi:10.4103/0253-7613. 161277

Cusin C, Ionescu DF, Pavone KJ, et al. Ketamine augmentation for outpatients with treatment-resistant depression: Preliminary evidence for two-step intravenous dose escalation. See comment in PubMed Commons below Aust N Z J Psychiatry. 2017;51(1):55–64. doi:10.1177/0004867416631828

Ionescu DF, and Papakostas GI. Experimental medication treatment approaches for depression. Transl Psychiatry. 2017;7(3):e1068. doi:10.1038/tp.2017.33

Li CT, Chen MH, Lin WC, et al. The effects of low-dose ketamine on the prefrontal cortex and amygdala in treatment-resistant depression: A randomized controlled study. Hum Brain Mapp. 2016;37(3):1080–1090. doi:10.1002/hbm.23085

Mathew SJ, Shah A, Lapidus K, et al. Ketamine for treatment-resistant unipolar depression: Current evidence. CNS Drugs. 2012;26(3):189–204. doi:10.2165/11599770-000000000-00000 Sanacora G, Frye, MA, McDonald W, et al. A consensus statement on the use of ketamine in the treatment of mood disorders. JAMA Psychiatry. 2017;74(4):399–405. doi:10.1001/ jamapsychiatry.2017.0080

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 407 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Ketamine

Depression

Unapproved Treatments

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

NMDA Agents (cont.)

Neurosteroid; modulates excitatory glutaminergic NMDA receptors (reduces the response of the GABAA receptor)

• Dose:30–50mg/day

• Early studies suggest promise as an adjunctive treatment in schizophrenia and schizoa ective disorder; improvement noted in both positive and

negative symptoms

• Low-dose (30mg/day) augmentation also demonstrated signi cant amelioration of EPS and improvement in attention and working memory

performance

• A double-blind study using pregnenolone 50 mg with L-theanine 400 mg (vs. placebo) to augment current antipsychotics in patients with chronic

schizophrenia or schizoa ective disorder demonstrated signi cant improvement in negative symptoms such as blunted a ect, alogia, and anhedo- nia. Add-on pregnenolone/L-theanine also was signi cantly associated with a reduction of anxiety scores related to such as anxious mood, tension, and cardiovascular symptoms as well as an increase in general functioning

• Negativeresultsreportedinarandomizeddouble-blindclinicaltrialof82femaleinpatientswithchronicschizophrenia

Kardashev A, Ratner Y, Ritsner MS. Add-on pregnenolone with L-theanine to antipsychotic therapy relieves negative and anxiety symptoms of schizophrenia: An 8-week, randomized, double-blind, placebo-controlled trial. Clin Schizophr Relat Psychoses. 2015 Jul 28. [Epub ahead of print]. doi:10.3371/CSRP.KARA.070415

Kashani L, Shams N, Moazen-Zadeh E, et al. Pregnenolone as an adjunct to risperidone for treatment of women with schizophrenia: A randomized double-blind placebo-controlled clinical trial. J Psychiatr Res. 2017;94:70–77. doi:10.1016/j.jpsychires.2017.06.011

Keller WR, Kum LM, Wehring HJ, et al. A review of anti-in ammatory agents for symptoms of schizophrenia. J Psychopharmacol. 2013;27(4):337–342. doi:10.1177/0269881112467089

Riluzole (1) inactivates voltage-dependent sodium channels on glutamatergic nerve terminals, thereby blocking glutamatergic neurotransmission, (2) blocks some of the postsynaptic e ects of glutamic acid by noncompetitive blockade of the NMDA receptors, and (3) blocks GABA reuptake

• Dose:50–100mgbid

• Severalstudieshaveshowne cacyinthetreatmentofOCD,trichotillomania,eatingdisordersandskin-picking

• Open-label study, case series, and double-blind study suggest bene t of riluzole augmentation in adults with treatment-refractory OCD; data

contradictory as in another double-blind study, clinical improvement was not found to be statistically signi cant though a trend towards bene t

was seen in secondary analysis. No bene t reported when used, at a maximum dose of 100 mg/day, to augment therapy in children with OCD

• Open-labelstudieshaveshowne cacyassoletreatmentoraugmentingagentinGAD

• Riluzole is well tolerated by adults and children; common side e ects include headache, nausea, and fatigue. Elevations in transaminase levels

reported but none resulted in drug discontinuation; pancreatitis reported in children

Coric V, Milanovic S, Wasylink S, et al. Bene cial effects of the antiglutamatergic agent riluzole in a patient diagnosed with obsessive-compulsive disorder and major depressive disorder. Psychopharmacology (Berl). 2003;167:219–220. doi:10.1007/s00213-003-1396-z

Emamzadehfard S, Kamaloo A, Paydary K, et al. Riluzole in augmentation of uvoxamine for moderate to severe obsessive-compulsive disorder: Randomized, double-blind, placebo- controlled study. Psychiatry Clin Neurosci. 2016;70(8):332–341. doi:10.1111/pcn.12394

Grant PJ, Joseph LA, Farmer CA, et al. 12-week, placebo-controlled trial of add-on riluzole in the treatment of childhood-onset obsessive-compulsive disorder. Neuropsychopharmacology. 2014;39(6):1453–1459. doi:10.1038/npp.2013.343

Grant P, Song JY, Swedo SE. Review of the use of the glutamate antagonist riluzole in psychiatric disorders and a description of recent use in childhood obsessive-compulsive disorder. J Child Adolesc Psychopharmacol. 2010;20(4):309–315. doi:10.1089/cap.2010.0009

Pittenger C, Bloch MH, Wasylink S, et al. Riluzole augmentation in treatment-refractory obsessive-compulsive disorder: A pilot randomized placebo-controlled trial. J Clin Psychiatry. 2015;76(8):1075–1084. doi:10.4088/JCP.14m09123

Rynn M, Pulia co A, Heleniak C, et al. Advances in pharmacotherapy for pediatric anxiety disorders. Depress Anxiety. 2011;28:76–87. doi:10.1002/da.20769

• Dose:50–200mg/day

• Double-blindandopen-labelstudiesandcasereportssuggestpossibleroleforriluzoleasaugmentationtherapyinmoderate–severemajordepres-

Pregnenolone

Schizophrenia

Riluzole

Anxiety Disorders

Depression

sive disorder

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

• No change in severity of depressive symptoms reported in a double-blind placebo-controlled study of patients with bipolar depression receiving riluzole compared with placebo

Ionescu DF, Papakostas GI. Experimental medication treatment approaches for depression. Transl Psychiatry. 2017;7(3): e1068. doi:10.1038/tp.2017.33

Park LT, Lener MS, Hopkins M, et al. A double-blind, placebo-controlled, pilot study of riluzole Mmnotherapy for acute bipolar depression. J Clin Psychopharmacol. 2017;37(3):355–358. doi:10.1097/JCP.0000000000000693

Salardini E, Zeinoddini A, Mohammadinejad P, et al. Riluzole combination therapy for moderate-to-severe major depressive disorder: A randomized, double-blind, placebo-controlled trial. J Psychiatr Res. 2016;75:24–30. doi:10.1016/j.jpsychires.2016.01.003

5-HT3 Antagonists

5-HT3 receptor antagonists cause increased release of norepinephrine (NE), acetylcholine (ACh), and serotonin (5-HT) within various brain circuits

• Dose:Ondansetron1–8mg/day;granisetron1mgbid

• OndansetronhasbeenusedtoaugmentSSRIsforOCDinseveraltherapeuticstudies,andgranisetroninonetrial.Bothdrugsshowedsomee cacy

in open studies and superiority to placebo in double-blind studies

Andrade C. Ondansetron augmentation of serotonin reuptake inhibitors as a treatment strategy in obsessive-compulsive disorder. J Clin Psychiatry. 2015;76(1):e72–e75. doi:10.4088/JCP. 14f09704

Serata D, Kotzalidis GD, Rapinesi C, et al. Are 5-HT3 antagonists effective in obsessive-compulsive disorder? A systematic review of literature. Hum Psychopharmacol. 2015;30(2):70–84. doi:10.1002/hup.2461

• Granisetron1mgbid,ondansetron4–16mg,ortropisetron5–20mgusedincombinationwithantipsychotic

• Meta-analysis of 5-HT3 antagonist studies in stable schizophrenia patients shows that augmentation is associated with signi cant reduction in

negative symptoms, general psychopathology, and total symptom ratings without reduction in positive symptom ratings

• Primarysidee ectwasconstipationwithcombinationtherapy

Andrade C. Nonsteroidal anti-in ammatory drugs and 5-HT3 serotonin receptor antagonists as innovative antipsychotic augmentation treatments for schizophrenia. J Clin Psychiatry. 2014;75(7):e707–e709. doi:10.4088/JCP.14f09292

Garay RP, Bourin M, de Paillette E, et al. Potential serotonergic agents for the treatment of schizophrenia. See comment in PubMed Commons below Expert Opin Investig Drugs. 2016;25(2):159–170. doi:10.1517/13543784.2016.1121995

Miscellaneous

The rennin-angiotensin pathway is suggested to be involved in mediating stress and anxiety, and possibly depression (in addition to its e ect on cardiovascular regulation)

• DatasuggestsanassociationbetweentheprescriptionofanACEinhibitororARBanddecreasedsymptomsofPTSD.Otherbloodpressuremedica- tion (e.g., β-blockers, CA-channel blockers, and diuretics) did not have a similar e ect

• The renin-angiotensin system may be important in PTSD, as ACE-inhibitor/ARB usage has been associated with lower symptoms. Individuals with the CC rs4311 genotype appear to bene t more with ACE-Inhibitors/ARBs

• Meta-analysis of 11 studies reported that when compared with placebo or other antihypertensive medications, ARBs and ACE inhibitors were associated with improved overall quality of life, positive wellbeing, and decreased anxiety

Brownstein DJ, Salagre E, Köhler C, et al. Blockade of the angiotensin system improves mental health domain of quality of life: A meta-analysis of randomized clinical trials. Aust N Z J Psychiatry. 2018;52(1):24–38. doi:10.1177/0004867417721654

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 409 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Granisetron, Ondansetron, Tropisetron

Anxiety Disorders

Schizophrenia

ACE inhibitors/ARBs

Anxiety Disorders

Unapproved Treatments

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Miscellaneous (cont.)

Khoury NM, Marvar PJ, Gillespie CF, et al. The rennin-angiotensin pathway in posttraumatic stress disorder: Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are associated with fewer traumatic stress symptoms. J Clin Psychiat. 2012;73(6):849-855. doi:10.4088/JCP.11mo07316

Nylocks KM, Michopoulos V, Rothbaum AO, et al. An angiotensin-converting enzyme (ACE) polymorphism may mitigate the effects of angiotensin-pathway medications on posttraumatic stress symptoms. Am J Med Genet B Neuropsychiatr Genet. 2015;168B(4):307–315. doi:10.1002/ajmg.b.32313

• Preliminary evidence suggests a role for the angiotensin system in the pathophysiology of MDD; ACE inhibitors and ARBs suggested to reduce oxidative and in ammatory stress and enhance neurogenesis

• CasereportsandobservationalstudiesshowthatACEinhibitorsandARBsmayhavepositivee ectsondepression,whereasotherantihypertensive agents do not; no placebo-controlled double-blind studies to date

• Data contradictory; in a randomised placebo-controlled trial of citalopram in 284 coronary heart disease patients with MDD, the use of ACE inhibitors predicted a worse response to citalopram

Vian J, Pereira C, Chavarria V, et al. The renin–angiotensin system: A possible new target for depression. BMC Med. 2017;15(1):144. doi:10.1186/s12916-017-0916-3

Xanthine oxidase inhibitor – suggested to increase adenosine, a neuromodulator of dopaminergic and glutamatergic systems. May have neuropro- tective e ect due to antioxidant properties

• Dose:300mgoncedailyorbid

• There is evidence of increased uric acid levels in drug-naïve subjects with bipolar disorder during their rst manic episode; association between

manic symptoms, uric acid excretion, hyperuricemia, and gout has been described

• In patients with acute mania, the probability of remission after 4 weeks was 23 times higher in the treatment group (i.e., sodium valproate 15–

20 mg/kg + 300 mg allopurinol twice a day) compared to the control group (i.e., sodium valproate 15–20 mg/kg + placebo)

• Two meta-analyses were done of 5 studies; suggest that allopurinol may have some e cacy as an adjunct in reducing mania symptoms during

acute manic episodes, particularly in patients with a more severe form of mania

• Negative results reported in double-blind study. In some studies, subjects with restricted ca eine use showed a greater e ect size compared to

ca eine users

Bartoli F, Crocamo C, Clerici M, et al. Allopurinol as add-on treatment for mania symptoms in bipolar disorder: Systematic review and meta-analysis of randomised controlled trials. Br J Psychiatry. 2017;210(1):10–15. doi:10.1192/bjp.bp.115.180281

Chen AT, Malmstrom T, Nasrallah HA. Allopurinol augmentation in acute mania: A meta-analysis of placebo-controlled trials. J Affect Disord. 2018;226:245–250. doi:10.1016/j.jad.2017. 09.034

Jahangard L, Soroush S, Haghighi M, et al. In a double-blind, randomized and placebo-controlled trial, adjuvant allopurinol improved symptoms of mania in in-patients suffering from bipolar disorder. Eur Neuropsychopharmacol. 2014;24(8):1210–1221. doi:10.1016/j.euroneuro.2014.05.013

Weiser M, Burshtein S, Gershon AA et al. Allopurinol for mania: A randomized trial of allopurinol versus placebo as add-on treatment to mood stabilizers and/or antipsychotic agents in manic patients with bipolar disorder. Bipolar Disord. 2014;16(4):441–447. doi:10.1111/bdi.12202

• Dose:300mgoncedailyorbid

• Though double-blind studies and case series suggest the addition of allopurinol to an antipsychotic in treatment-refractory patients results in

improvement in positive symptoms, a systematic review of trials concluded that allopurinol failed to show superiority to placebo in all primary

outcome measures in schizophrenia

• Skinrashseenin3%ofpatients;earlyleukocytosis,eosinophilia,andincreasedaminotransferaseactivityreported

Hirota T, Kishi T. Adenosine hypothesis in schizophrenia and bipolar disorder: A systematic review and meta-analysis of randomized controlled trial of adjuvant purinergic modulators. Schizophr Res. 2013;149(1–3):88–95. doi:10.1016/j.schres.2013.06.038

Weiser M, Gershon AA, Rubenstein K, et al. A randomized controlled trial of allopurinol vs. placebo added on to antipsychotics in patients with schizophrenia or schizoaffective disorder. Schizophr Res. 2012;138(1):35–38. doi:10.1016/j.schres.2012.02.014

Depression

Allopurinol

Bipolar Disorder

Schizophrenia

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Nalmefene

Opioid antagonist (a mu-and delta receptor antagonist and partial agonist at the κ-receptor)

• Dose:18–20mg/dayprn

• Treatmentisbasedonas-neededconcept:Patientstakeonetablet(18mg)eachdaytheyperceiveariskofdrinkingalcohol,preferably1–2hprior

to anticipated time of drinking, but otherwise as soon as drinking has started. Maximum of 1 tablet per day

• ApprovedintheEuropeanUniontoreducealcoholconsumptioninalcohol-dependentadultswithahighdrinkingrisklevel;currentlynotavailable

in Canada or the USA

• As-neededusesigni cantlyreducedboththenumberofheavydrinkingdaysandtotalalcoholconsumptioninalcohol-dependentpatientswithat

least a high drinking risk level at screening and randomization

• Anindirectmeta-analysisindicatesanadvantageofnalmefeneovernaltrexone;anothermeta-analysissuggestslimitede cacyofnalmefene

• Acaseseriessuggeststhatthecombinationofnalmefeneplussodiumoxybatemayimproveresponse

• Nalmefenemustnotbeusedinpatientstakingopioidmedicines,inpatientswhohaveacurrentorrecentaddictiontoopioids,patientswithacute

opioid withdrawal symptoms, or in patients suspected to have used opioids recently. It must also not be used in patients with severe liver or kidney

impairment or a recent history of acute alcohol withdrawal syndrome (including hallucinations, seizures ( ts), and tremors)

• Sidee ectsincludefatigueanddrowsiness/sleepiness

Brodtkorb TH, Bell M, Irving AH, et al. The cost effectiveness of nalmefene for reduction of alcohol consumption in alcohol-dependent patients with high or very high drinking-risk levels from a UK societal perspective. CNS Drugs. 2016;30(2):163–177. doi:10.1007/s40263-016-0310-2

Mann K, Torup L, Sørensen P, et al. Nalmefene for the management of alcohol dependence: Review on its pharmacology, mechanism of action and meta-analysis on its clinical ef cacy. Eur Neuropsychopharmacol. 2016;26(12):1941–1949. doi:10.1016/j.euroneuro.2016.10.008

Palpacuer C, Laviolle B, Boussageon R, et al. Risks and bene ts of nalmefene in the treatment of adult alcohol dependence: A systematic literature review and meta-analysis of published and unpublished double-blind randomized controlled trials. PLoS Med. 2015;12(12):e1001924. doi:10.1371/journal.pmed.1001924

Soyka M, Müller CA. Pharmacotherapy of alcoholism – an update on approved and off-label medications. Expert Opin Pharmacother. 2017;18(12):1187–1199. doi:10.1080/14656566.2017. 1349098

Alcohol Use Disorder

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 411 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Unapproved Treatments

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

General Comments

NATURAL HEALTH PRODUCTS

Although pharmacotherapy is generally the rst line of treatment for psychiatric disorders, an increasing number of patients are turning to natural health products (NHPs). Most NHP use is self-prescribed (60%) and undisclosed to health care providers (75%). In one study, 34% of users took NHPs to treat a mood disorder, while almost half of the users also took concurrent prescription medication. Another study found that 63% of patients hospitalized for psychiatric indications had used complementary alternative medicine, or CAM, within the past year, with 79% of patients not disclosing their use to their psychiatrist. The widespread use of NHPs for mental illnesses makes it necessary for health care providers to understand their bene ts and risks and look for relevant drug–NHP interactions.

This chapter looks at the evidence and safety of some commonly used NHPs that are used for a variety of conditions. Although in most cases the optimum dose of the natural health product (herb or supplement) is not known, the most frequently studied dose is provided, along with the proposed mechanism of action.

Drug

ADHD

Alzheimer’s Disease

Anxiety

Bipolar Disorder

Depression

Schizophrenia

Sleep Disorders

Ginkgo Biloba (p. 412)

C/+

PR/+

PR/S/+

Kava Kava (p. 414)

+/SC

Melatonin (p. 415)

C/+

Omega-3 Fatty Acids (p. 416)

C/S/+

S-Adenosyl-L-Methionine (p. 419)

C/S/+

St. John’s Wort (p. 420)

PR/C

+†

Valerian (p. 421)

C/+

Vitamins (p. 423) Vitamin B

PR/S

PR/+

Vitamin B9 Vitamin C Vitamin E

PR PR C

PR/S

PR PR/S

† Mild to moderate depression only;

C = contradictory results, + = positive ndings, PR = preliminary data, S = synergistic/adjunctive effect, SC = signi cant safety concerns

Further Reading

Indications

( approved)

References

• McCrea CE, Pritchard ME. Concurrent herb-prescription medication use and health care provider disclosure among university students. Complement Ther Med. 2011;19(1):32–36. doi: 10.1016/j.ctim.2010.12.005

Ginkgo Biloba

• Anoverviewof12systematicreviews(totalof59RCTs)concludedthatextractofGinkgobiloba(EGb)haspotentiallybene ciale ectsoverplacebo on cognitive performance, ADLs, and clinical global impression in the treatment of dementia. Most studies used a dose of 240 mg/day and were of 22 weeks or longer. Findings include:

Alzheimer’s Disease/Dementia

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Anxiety Disorders

Schizophrenia

General Comments

– Overallmagnitudeofe ectwasconsideredsmalltomoderateandthequalityofevidencewasfairlylow(highriskofbiasandheterogeneity) – Greaterbene twasobservedinolderpersonswithmildtomoderatedementia

– PersonswithdementiatakingEGbdidnotexperienceanimprovedqualityoflife

– Nosu cientevidencesupportsfavorablee ectsifusedforlessthan22weeks

• Dementiaprevention:

– Ginkgo evaluation of memory study followed 3,069 participants above age 72 for over 6 years, who received EGb 761 (120 mg bid) or placebo;

assessed cognitive decline, functional disability, incidence of CVD and stroke, and total mortality, and showed that ginkgo did not result in less

cognitive decline and was ine ective in reducing the development of dementia and Alzheimer’s disease

– PatientscomplainingofcognitivedeclineweregivenEGb761(120mgbid)ormatchedplaceboandfollowedfor5years.Theriskofprogression

to Alzheimer’s disease was comparable in both groups

• Comparedtoconventionaltherapy:

– Although ginkgo has been shown to be as e cacious and tolerable as donepezil in the treatment of mild to moderate Alzheimer’s disease, (160 mg EGb 761 extract; n = 20) after 6 months, larger patient samples are required to con rm these ndings

– Patientssu eringfromAlzheimer’sdementiaweregivenginkgo(120mg/day)orrivastigmine(4.5mg/day)forsixmonths.Onlypatientstaking the cholinesterase inhibitor reported signi cant improvements in Mini-Mental State Examination (MMSE) and Short Mental Test (SMT) scores

• A double-blind RCT (n = 107) using ginkgo extract EGb 761 for 4 weeks showed that participants’ HAM-A total scores decreased signi cantly compared to placebo

• Areviewandmeta-analysissuggeststhattheadditionofginkgotoantipsychotictherapy(haloperidol,chlorpromazine,clozapine)producessignif- icant moderate improvement in total and negative symptoms of chronic schizophrenia (average length of study = 8 weeks)

• Reportedtobee ectiveinreducingsymptomsoftardivedyskinesiainpatientswithschizophrenia(AIMStotalscorereducedin51.3%ofpatients)

• Activeginkgolidesareobtainedfromtheleavesofoneoftheoldestdeciduoustreeintheworld(ginkgo–alsocalledMaidenhairtreeorkewtree)

• AvailablebyprescriptioninmanypartsofEurope

• Hasbeensafelyusedforupto6years

• Oneofthemostpopularnaturalproductsusedbythegeriatricpopulation

• Appearstoincreasevascularcirculation,haswelldocumentedantioxidantandfreeradicalscavenginge ects;inhibitsadenosinediphosphate-and collagen-induced platelet aggregation; also inhibits binding of platelet activating factor, decreasing blood coagulation

• Popular extract from ginkgo leaves (EGb 371) has exhibited neuroprotective e ects, including protecting hippocampal neurons against cell death induced by β-amyloid

• Alzheimer’sdisease:

– Dosesstudied:120–240mg/daydividedin2–3doses – Maytake6–8weekstoseeaclinicale ect

• Anxiety:240–480mg/dayused

• Schizophrenia:

– Dosesstudied:120–360mg/day(giventid)

– Most studies use ginkgo extracts EGb 761 or LI 1370. Both are similar and contain approximately 24-25% avone glycosides and 6% terpene

lactones

• Adversee ectsarerareandmayinclude:mildGIupset,headache,dizziness,palpitations,constipation,andallergicskinreactions

• Serious cases of bleeding reported; hence CAUTION with patients on anticoagulant/anti-platelet drugs; may increase bleeding times; clinical

signi cance is controversial

• ToavoidGIsidee ects,startat120mg

Pharmacology

Dosing

Adverse Effects

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 413 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Natural Health Products

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Drug Interactions

Further Reading

Ginkgo Biloba (cont.)

• Interactions:InhibitorofCYP2C9andinducerofCYP2C19andCYP1A2;mayinteractwithdrugsmetabolizedbytheseisoenzymes:Decreaseslevels of omeprazole, ritonavir, and tolbutamide; may inhibit metabolism of warfarin; may potentiate drugs that lower the seizure threshold. Avoid with talinolol – shown to increase levels by 36% in one study

References

• NasabNM,BahrammiMA,Nikpour,etal.Ef cacyofrivastigmineincomparisontoginkgofortreatingAlzheimer’sdementia.JPakMedAssoc.2012;62(7):677–680.

• SinghV,SinghSP,ChanK.Reviewandmeta-analysisofusageofginkgoasanadjuncttherapyinchronicschizophrenia.IntJNeuropsychopharmacol.2010;13(2):251–271.doi:10.1017/

S1461145709990654

• WeinmannS,RollS,SchwarzbachC,etal.EffectsofGinkgobilobaindementia:Systematicreviewandmeta-analysis.BMCGeriatr.2010;10:14.doi:10.1186/1471-2318-10-14

• WoelkH,ArnoldtKH,KieserM,etal.GinkgobilobaspecialextractEGb761ingeneralizedanxietydisorderandadjustmentdisorderwithanxiousmood:Arandomized,double-blind,

placebo-controlled trial. J Psychiatr Res. 2007;41(6):472–480. doi:10.1016/j.jpsychires.2006.05.004

• YuanQ,WangC,ShiJ,etal.EffectsofGinkgobilobaondementia:Anoverviewofsystematicreviews.JEthnopharmacol.2017;195:1–9.doi:10.1016/j.jep.2016.12.005

• Zhang WF, Tan YL, Zhang XY, et al. Extract of ginkgo biloba treatment for tardive dyskinesia in schizophrenia: A randomized, double-blind, placebo-controlled trial. J Clin Psychiatry.

2011;72(5):615–621. doi:10.4088/JCP.09m05125yel

Kava Kava

• In a 6-week double-blind RCT, kava modestly reduced generalized anxiety disorder compared with the placebo group (p = 0.046), with a greater reduction in the HAM-A scale seen in patients with moderate–severe GAD (p = 0.02)

• Meta-analysis (n = 7) concludes that kava extract is an e ective symptomatic treatment for anxiety when compared to placebo as shown by decreased HAM-A scores (p = 0.05)

• Comparedtoplacebo,kavaextractWS1490(200mgdaily)signi cantlyimprovedsleepdisturbancesassociatedwithanxietyina4-weekrandom- ized, placebo-controlled, double-blind study

• Anothermeta-analysis(n=6)foundthatWS1490(300mg/day)wassigni cantlymoree ective(OR=3.3)thanplaceboatimprovingnon-psychotic anxiety disorders, using Hamilton Anxiety Scale (HAM-A) scores

• Madefromtherhizome,roots,andstemofPipermethysticum;activeconstituentkavalactones

• Used throughout the Paci c Islands as a ceremonial drink to induce relaxation and sleep and to decrease anxiety; may have anticonvulsant and

muscle-relaxant activity

• Hasbeenusedsafelyintrialsupto24weeks

• CNSe ectsappeartobemediatedbytheblockageofvoltage-gatedsodiumandcalciumchannels,ultimatelysuppressingglutamaterelease

• ThekavalactonesdesmethoxyyangoninandmethysticinarebelievedtoblockMAO-Bmetabolism,producingpsychotropice ects

• Sedativeandantianxietypropertiesmayresultfromkava’se ectsonfacilitatingGABAtransmissionbyincreasingthenumberofGABAsites

• Mostclinicaltrialshaveusedkavaextractstandardizedto70%kavalactones;300mgdividedinthreedoses(delivering210mgkavalactones/day)

Indications

( approved)

Anxiety Disorders

General Comments

Pharmacology

Dosing

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Adverse Effects

• Adversee ectsatlowerdosesarerareandtransient.Theyincludegastricdiscomfort,dizziness,and,withchronicuse,yellowskindiscoloration

• Dosesabove400mg/day:Dry akingskin,redeyes,facialpu ness,muscleweakness,dystonicreactions,dyskinesias,andchoreoathetosis

• Doesnotadverselya ectcognition,mentalacuityorcoordination

• Caution: Numerous reports of liver dysfunction and death with kava use; it is uncertain whether these reactions have occurred at recommended

doses or higher ones; for this reason, the US Food and Drug Administration (FDA) has issued warnings about kava use; sold as a homeopathic product in Canada

– Livertoxicityismorefrequentlyassociatedwithprolongeduseofveryhighdoses – Unclearwhichpatientsaresusceptibletoadverselivere ects

– Untilmoreinformationaboutitssafetyisknown,kavauseshouldbediscouraged – Patientswantingtotryitneedperiodicliverfunctiontests

• AvoidconcurrentusewithCNSdepressants(includingalcoholandbenzodiazepines),showntoincreasesidee ectsandtoxicity

• Preliminary evidence reports that Kava kava can inhibit CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A4, and may interact with levodopa, alprazolam, and

paroxetine

References

• NaturalMedicinesDatabase:Kavamonograph.Retrievedfromhttp://www.naturaldatabase.com

• PittlerMH,ErnstE.Kavaextractvsplacebofortreatinganxiety.CochraneDatabaseSystRev.2003;1:CD003383.doi:10.1002/14651858.CD003383

• SarrisJ,StoughC,BousmanCAetal.Kavainthetreatmentofgeneralizedanxietydisorder:Adouble-blind,randomized,placebo-controlledstudy.JClinPsychopharmacol.2013;33(5):643–

648. doi:10.1097/JCP.0b013e318291be67

Melatonin

• Ingeneral,melatonin’se ectsonsleeparemodestandclinicalsigni canceisquestionable

• Inprimaryinsomnia,melatoninhasbeenshowntodecreasesleeplatency(timetofallasleep)overtheshortterm(4weeksorless)byapproximately

15 min. Clinical signi cance is questionable

• A meta-analysis (19 studies) demonstrated that melatonin signi cantly improved sleep in patients with primary sleep disorders compared to

placebo:

– Reducedsleep-onsetlatencyby~7–9min

– Increasedtotalsleeptime:8.25min

– Improvedsleepquality

– Trialswithlongerdurationandhigherdosesreportedgreatere ects

• May be more useful in the elderly (who sometimes have decreased nocturnal secretion of melatonin); found not to be e ective in patients with sleep disturbances and dementia

• Maybehelpfulformedicallyillpatientswithinsomniaforwhomconventionalhypnoticsmaybeproblematic

• Casereportssuggestmelatoninmayfacilitatewithdrawalfrombenzodiazepines(whichcandecreasenocturnalmelatoninproduction)

• Earlydatasuggestitmaybebene cialinchildrenwithADHDandinmulti-disabledchildren(withneurologicalorbehavioraldisorders)withsevere

insomnia in doses of 2–10 mg, and in autism spectrum disorder

Drug Interactions

Further Reading

Indications

( approved)

Sleep Disorders

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 415 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Natural Health Products

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

General Comments

Melatonin (cont.)

• Hormoneproducedbythepinealglandinvolvedinregulationofcircadianrhythms

• Alsousedforjetlag

• There is no well-known standardization for melatonin and many brands have been found to contain impurities as well as dissimilar amounts of

actual hormone (http://www.consumerlab.com/ is a useful reference to look for brand quality)

• Synthesisandreleaseofmelatoninisstimulatedbydarkness(useroomdarkeningshades)andinhibitedbylight

• Acts on MT1 and MT2 receptors in the hypothalamic suprachiasmatic nuclei (master circadian clock site)

• Actstoresetthecircadianclockand”trigger”theonsetofsleep

• Melatoninlevelstypicallypeakbetween2and4a.m.;physiologically,levelsarehighestbetween1and3yearsofage

• Insomnia:0.3–10mg/day(0.3mg=physiologicaldose)taken30–120minbeforebedtime;exogenousmelatonindoesnotappeartoa ectendoge- nous production or secretion of melatonin

• Peakplasmaconcentrationsachievedwithin60min;metabolizedbytheliver;eliminationhalf-life=20–50min

• Immediate-release products may help individuals having di culty falling asleep, while sustained-release or long-acting formulation is better for

people having trouble staying asleep

• Adversee ectsarerare(likelysafewhenusedforshortdurationatdosesof5mg/dayorless)

• Athigherdoses:Abdominalcramps,headache,dizziness,daytimefatigue,andincreasedirritability

• Atveryhighdoses(morethan75mg)canexacerbatedepression,causecoagulationabnormalities,andinhibitovulation

• Caution in patients taking warfarin or other agents that a ect coagulation; CNS depressants (including benzodiazepines and alcohol) should be avoided

References

• BendzLM,ScatesAC.Melatonintreatmentforinsomniainpediatricpatientswithattention-de cit/hyperactivitydisorder.AnnPharmacother.2010;44(1):185–191.doi:10.1345/aph.1M365 • Ferracioli-OdaE,QawasmiA,BlochMH.Meta-analysis:Melatoninforthetreatmentofprimarysleepdisorders.PLoSOne.2013;8(5):e63773.doi:10.1371/journal.pone.0063773

• WasdellMB,JanJE,BombenMM,etal.Arandomized,placebo-controlledtrialofcontrolledreleasemelatonintreatmentofdelayedsleepphasesyndromeandimpairedsleepmainte-

nance in children with neurodevelopmental disabilities. J Pineal Res. 2008 Jan;44(1):57–64.doi:10.1111/j.1600-079X.2007.00528.x

Omega-3 Polyunsaturated Fatty Acids

• Suggestedthatrelativede cienciesinPUFA(mainlyEPA)maybeimplicatedinsomeofthebehavioralandlearningproblemsassociatedwithADHD

• Reviewwith13trials(n=1011)concludedthatthereisverylittleevidencethat shoilsaloneprovidebene tforchildren/adolescentswithADHD

• The combination of omega-3 fatty acids ( sh oils 400 mg) and omega-6 fatty acids (evening primrose oil, 100 mg) 6 capsules daily was shown to

be the most e ective at treating symptoms of ADHD

Pharmacology

Dosing

Adverse Effects Drug Interactions

Further Reading

Indications

( approved)

ADHD

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Alzheimer’s Disease

Bipolar Disorder

Depression

Schizophrenia

General Comments

• Datasuggestarelationshipbetweenhighconsumptionofunsaturatedfattyacidsandadecreasedriskofcognitiveimpairment

• Epidemiologicalevidencesupportstheideathatomega-3polyunsaturatedfattyacidsmayplayaroleinmaintainingadequatecognitivefunction-

ing in predementia syndromes, but not when the AD process has already taken over

• Preliminary double-blind study suggests that patients with BD who took supplements of sh oil, in addition to their usual medication, had a signi cantly longer period of remission than those on placebo

• Epidemiological data suggest a relationship between consumption of seafood and decreased lifetime prevalence of depression, bipolar I and II disorder, and bipolar spectrum disorder; contradictory data reported as to e cacy and dosage in depressed and rapid-cycling BD

• Systematic review identi ed 5 studies of highly variable methodological quality. Only one 12-week study was of su cient quality and showed positive e ects for treating depression (not mania) when omega-3 PUFAs (1g ethyl-EPA/day) were used as an adjunct to conventional mood stabilizers

• InanotherRCT,patientswithbipolardisorderandrapidcyclingtookEPA6mg/dayinadditiontotheirconventionaltreatment(for4months),there were no signi cant di erences in depression or manic symptoms compared to treatment plus placebo

• Epidemiologicalstudiessuggestthathigh shconsumptioniscorrelatedwithdecreaseddepression

• Evidenceintreatmentofdepressioniscon icting,largelyduetosupplementpreparation,diagnosis(includingwithorwithoutothercomorbidities),

and severity of depression. Other limitations include di erent study lengths

– Greatere ectshavebeenfoundwhenpatientswerediagnosedwithMDD(asopposedtoself-identi ed)

– In a review of 19 studies, patients treated with supplements containing 60% or more EPA showed a signi cant e ect, but not those with

supplements containing less than 60% EPA

– A Cochrane meta-analysis of 26 RCTs concluded that there was a small to modest e ect that Omega-3 fatty acids are e ective as a treatment

for MDD and that their clinical signi cance is questionable at this time

• Mixedresultswhenusedasanadjuncttoconventionaltherapy:

– Patientstakingsertraline(50mg)plusomega-3(55%EPA,2g/day)vs.placebofoundnoadditionalbene ts

– Patientstakingomega-3(80%EPA,2g/day)pluscitalopram(8weeks)showedasigni cantreductioninHAM-Dscorescomparedtoplacebo

– Inpatientstaking1gEPAor20mg uoxetineoracombinationofboth(8weeks),thecombinationofbothwassigni cantlybetterthaneither

uoxetine or EPA alone after 4 weeks of treatment

• Evidencesuggeststhatlowlevelsofomega-3fattyacidsarecorrelatedwithdepressivesymptomsduringpregnancyandafterdelivery;suggested

to be safe to use during pregnancy

• Preliminary data suggest a relationship between high consumption of omega-3 fatty acids and less severe symptoms of schizophrenia; ethyl-EPA suggested to inhibit phospholipase A2, an enzyme found to be overactive in patients with schizophrenia and may be responsible for depletion of arachidonic acid from brain and red cell phospholipids in these patients

• In a small double-blind placebo-controlled randomized 6-month study, an intervention with omega-3 fatty acids (using 2.2 g EPA + DHA per day) signi cantly improved the level of functioning (measured by PANSS) in rst-episode schizophrenia patients compared to placebo

• Ameta-analysisof6studiesconcludedthatEPAdidnotimprovethesymptomsofschizophrenia

• Asystematicreviewthatincluded8studiesrangingfrom6to16weeksreportedthatwhenanydoseofEPAorethyl-EPAiscomparedtoplacebo,the

need for antipsychotics appears to be reduced for subjects taking the omega-3 fatty acids; changes in global and mental state are not consistent

• Randomized placebo-controlled study suggests that long-chain omega-3 fatty acids (EPA 1.2 g/day) may reduce the progression to rst-episode

psychotic disorder in adolescents and young adults with subthreshold psychosis

• Supplementation of a mixture of EPA/DHA (180:120 mg) in combination with vitamins E and C (400 units:500 mg) bid for 4 months reported to

signi cantly reduce psychopathology in patients with schizophrenia

• Reviewofdouble-blindstudiessuggestsethyl-EPA(atadoseof2g/day)canaugmente ectsofclozapineintreatment-refractorypatients

• N-3fattyacidde ciencieshavebeenreportedinpeoplewithawiderangeofmentaldisordersbyseveralstudies

• Thehumanbodyisnotabletosynthesizeomega-3polyunsaturatedfattyacids(PUFAs)

• N-3PUFAsareresponsibleforapproximately20%ofthebrain’sdryweightand33%ofallfatsintheCNS

• BestsourceforPUFAsisfatty sh(e.g.,mackerel,halibut,salmon),asthiscontainseicosapentaenoicacid(EPA)anddocosahexaenoicacids(DHA)

• Other sources are green leafy vegetables, nuts, axseed oil, and canola oil; all contain alpha-linolenic acid (ALA), which can be converted (only 5–

10%) to EPA and DHA

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 417 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Natural Health Products

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Pharmacology

Dosing

Adverse Effects

Drug Interactions

Further Reading

Omega-3 Polyunsaturated Fatty Acids (cont.)

• Positivee ectsondepressiveillnessesarebelievedtobearesultofchangestocellmembranestructureandfunction,impactingparticularlycellular

communication, in ammatory processes, and neurotransmitter activities

• Bipolardisorder:1–2g/day(EPA)

• Depression:1–4g/day(EPA+DHA)

• Schizophrenia:1–4g/day(EPA+DHA)

• Alzheimer’sdisease:1–4g/day(EPA+DHA)

• TheratioofEPA:DHAisimportant;over60%(EPA)hasbeenshowntobebetterinclinicaltrials

• One serving of sh (100 g or 3.5 oz) contains approximately 1 g EPA/DHA. Fresh sh is always best but patients may need to supplement in order

to get higher doses

• Welltoleratedinadultsandchildrenatdosesof3-4g/day;mildgastrointestinale ects

• Fishyaftertaste,belching(takewithmealsorfreezetohelpwiththis)

• Mayincreasebleedingriskathigherdoses(morethan3g/day)

• Riskofhypomanianotedinafewcases,butnosuchinstancesreportedinsystematicreviewsormeta-analysesinbipolardepression

• Hypotensiveagents:canlowerbloodpressure,resultinginadditivee ects

• Highdoses(morethan3g/day)mayincreaseLDLcholesterollevelsby5–10%

References

• Amminger GP, Schäfer MR, Papageorgiou K, et al. Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: A randomized, placebo-controlled trial. Arch Gen Psychiatry. 2010;67(2):146–154. doi:10.1001/archgenpsychiatry.2009.192

• AppletonKM,SallisHM,PerryR,etal.Omega-3fattyacidsfordepressioninadults.CochraneDatabaseSystRev.2015;(11):CD004692.doi:10.1002/14651858.CD004692.pub4

• BlochMH,HannestadJ.Omega-3fattyacidsforthetreatmentofdepression:Systematicreviewandmeta-analysis.MolPsychiatry.2012;17(12):1272–1282.doi:10.1038/mp.2011.100

• CiappolinoV,DelvecchioG,AgostoniC,etal.Theroleofn-3polyunsaturatedfattyacids(n-3PUFAs)inaffectivedisorders.JAffectDisord.2017;224:32–47.doi:10.1016/j.jad.2016.12.034

• GertsikL,PolandRE,BreseeC,etal.Omega-3fattyacidaugmentationofcitalopramtreatmentforpatientswithmajordepressivedisorder.JClinPsychopharmacol.2012;32(1):61–64.

doi:10.1097/JCP.0b013e31823f3b5f

• Gillies D, Sinn JKH, Lad SS, et al. Polyunsaturated fatty acids (PUFA) for attention de cit hyperactivity disorder (ADHD) in children and adolescents. Cochrane Database Syst Rev.

2012;(7):CD007986. doi:10.1002/14651858.CD007986.pub2

• JazayeriS,Tehrani-DoostM,KeshavarzSA,etal.Comparisonoftherapeuticeffectsofomega-3fattyacideicosapentaenoicacidand uoxetine,separatelyandincombination,inmajor

depressive disorder. Aust N Z J Psychiatry. 2008;42(3):192–198. doi:10.1080/00048670701827275

• Lin PY, Mischoulon D, Freeman MP, et al. Are omega-3 fatty acids antidepressants or just mood-improving agents? The effect depends upon diagnosis, supplement preparation, and

severity of depression. Mol Psychiatry. 2012;17(12):1161–1163. doi:10.1038/mp.2012.111

• MartinsJG,BentsenH,PuriBK.Eicosapentaenoicacidappearstobethekeyomega-3fattyacidcomponentassociatedwithef cacyinmajordepressivedisorder:AcritiqueofBlochand

Hannestad and updated meta-analysis. Mol Psychiatry. 2012;17(12):1144–1149. doi:10.1038/mp.2012.25

• MontgomeryP,RichardsonAJ.Omega-3fattyacidsforbipolardisorder.CochraneDatabaseSystRev.2008;2:CD005169.doi:10.1002/14651858.CD005169.pub2

• MorrisMC,EvansDA,TangneyCC,etal.Fishconsumptionandcognitivedeclinewithageinalargecommunitystudy.ArchNeurol.2005;62(12):1849–1853.

• Pawelczyk T, Grancow-Grabka M, Kotlicka-Antczak M, et al. A randomized controlled study of the ef cacy of si-month supplementation with concentrated sh oil rich in omega-3

polyunsaturated fatty acids in rst episode schizophrenia. J Psychiatr Res. 2016;73:34–44. doi:10.1016/j.jpsychires.2015.11.013

• RavindranAV,LamRW,FilteauMJ,etal.CanadianNetworkforMoodandAnxietyTreatments(CANMAT)Clinicalguidelinesforthemanagementofmajordepressivedisorderinadults.V.

Complementary and alternative medicine treatments. J Affect Disord. 2009;117(Suppl. 1):S54–64. doi:10.1016/j.jad.2009.06.040

• RossBM,SeguinJ,SieswerdaLE.Omega-3fattyacidsastreatmentsformentalillness:Whichdisorderandwhichfattyacid?LipidsHealthDis.2007;6:21.doi:10.1186/1476-511X-6-21

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Indications

( approved)

• SchuchardtJP,HussM,Stauss-GraboM,etal.Signi canceoflong-chainpolyunsaturatedfattyacids(PUFAs)forthedevelopmentandbehaviourofchildren.EurJPediatr.2010;169(2): 149–164. doi:10.1007/s00431-009-1035-8

• SolfrizziV,FrisardiV,CapursoC,etal.Dietaryfattyacidsandpredementiasyndromes.Scienti cWorldJournal.2009;9:792–810.

• Syblette ME, Ellis SP, Geant AL, et al. Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J Clin Psych. 2011;72(12):1577–1584. doi:10.4088/JCP.

10m06634

S-Adenosyl-L-Methionine (SAMe)

• Systematic review of 6 studies suggests comparable e cacy to tricyclic antidepressants and more e ective than placebo for mild to moderate depression (trials lasted up to 8 weeks)

• PreliminaryevidenceindicatesthatSAMe(800mgbidfor6weeks)maybeasafeande ectiveadjuncttoSSRIsfornonresponderstoSSRIsalone

• A12-week,3-armedtrialofSAMe(1600–3200mg),escitalopram(10–20mg)orplaceboshowednosigni cantdi erencesinresponserates

• Ina2016Cochranereviewof8RCTs,SAMewascomparedtoplacebo,desipramine,escitalopram,andimipramine:

– TherewerenochangesinsymptomsfrombaselinetoendoftreatmentwithSAMeorplacebo

– Nodi erenceine ectivenessbetweenSAMeandimipramineorescitalopram

– SAMewasmoree ectivethanplacebowhenusedasanadd-ontoSSRIs

– Giventheabsenceofhigh-qualityevidence,theuseofSAMeintreatmentofdepressionshouldbeinvestigatedfurther

• Inanotherreview(2017),12/19placebo-controlledtrialsshowedSAMewassigni cantlymoree ectivethanplaceboandcomparabletoTCAs

• LowserumandCSFlevelsofSAMereportedinpatientswithMDD

• Canbefoundinproteinfoodsources(e.g.,beef)

• WidelyprescribedasanantidepressantinEuropebutsoldoverthecounterinNorthAmerica

• Usedmostcommonlyfortreatmentofdepressionandosteoarthritis

• SAMeisanaminoacidthatactsasamethyldonorneededinthesynthesisofmonoaminetransmitters(dopamine,norepinephrine,andserotonin) and membrane phospholipids)

• Abnormalmethylationhasbeenimplicatedasapotentialpathogenicmechanismindepressionanddementia

• Mayincreasemembrane uidityandin uencemonoamineandphospholipidmetabolism;mayincreasetheturnoverofserotonin,norepinephrine,

and dopamine

• FormildtomoderateMDD,thelowestdoseshowntobee ectiveis800mg/day,andforsevereMDD1600mg/day(in2-3divideddoses)

• Rapid onset reported (~ 10 days); response may depend on folate and vitamin B12 levels

• Although tosylate salt is the most commercially available, the butanedisulfonate salt has been shown to be the most stable and to have superior

bioavailability

• Generallywelltolerated

• HigherdosescancauseGIe ects,headache,tachycardia,anxiety,restlessness,insomnia,andfatigue

• Noweightgainreported

• Contraindication:bipolardisorder,duetocasereportsoftheinductionofmaniathroughSAMetreatment

• Antidepressantdrugs(avoidduetopossibleserotoninsyndrome)

• SAMemaymethylatelevodopa,leadingtoadecreasedresponse

Depression

General Comments

Pharmacology

Dosing

Adverse Effects

Drug Interactions

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 419 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Natural Health Products

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

S-Adenosyl-L-Methionine (SAMe) (cont.)

Further Reading

References

Indications

( approved)

• BazzanAJ,ZabreckyG,MontiDA,etal.Currentevidenceregardingthemanagementofmoodandanxietydisordersusingcomplementaryandalternativemedicine.ExpertRev.Neurother. 2014;14(4):411–423. doi:10.1586/14737175.2014.892420

• BottiglieriT.Folate,vitaminB12,andS-adenosylmethionine.PsychiatrClinNorthAm.2013;36(1):1–13.doi:10.1016/j.psc.2012.12.001

• CarpenterDJ.St.John’swortandS-adenosylmethionineas“natural”alternativestoconventionalantidepressantsintheeraofthesuicidalityboxedwarning:Whatistheevidencefor

clinically relevant bene t? Altern Med Rev. 2011;16(1):17–39. Retrieved from http://www.altmedrev.com/publications/16/1/17.pdf

• GaliziaI,OldaniL,MacritchieK,etal.S-adneosylmethionine(SAMe)fordepressioninadults.CochraneDatabaseSystRev.2016;(10):CD011286.Retrievedfromdoi:10.1002/14651858.

CD011286.pub2

• Mischoulon D, Price LH, Carpenter LL, et al. A double-blind, randomized, placebo-controlled clinical trial of S-adenosyl-L-methionine (SAMe) versus escitalopram in major depressive

disorder. J Clin Psychiatry. 2014;75(4):370–376. doi:10.4088/JCP.13m08591

• NaturalMedicinesDatabase:SAMeMonograph.Retrievedfromhttp://www.naturaldatabase.com

• Papakostas GI, Mischoulon D, Shyu I, et al. S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive

disorder: A double-blind, randomized clinical trial. Am J Psychiatry. 2010; 167(8):889–891. doi:10.1176/appi.ajp.2009.09081198

• RavindranAV,LamRW,FilteauMJ,etal.CanadianNetworkforMoodandAnxietyTreatments(CANMAT)Clinicalguidelinesforthemanagementofmajordepressivedisorderinadults.V.

Complementary and alternative medicine treatments. J Affect Disord. 2009;117(Suppl. 1):S54–64. doi:10.1016/j.jad.2009.06.040

• RavindranAV,daSilvaTL.Complementaryandalternativetherapiesasadd-ontopharmacotherapyformoodandanxietydisorders:Asystematicreview.JAffectDisord.2013;150(3):707–

719. doi:10.1016/j.jad.2013.05.042

• SharmaA,GerbargP,BottiglieriT,etal.S-adenosylmethionineforneuropsychiatricdisorders:Aclinician-orientedreviewofresearch.JClinPsychiatry.2017;78(6):e656–e667.doi:10.4088/

JCP.16r11113

St. John’s Wort

• Inconsistentresultsandweakdatareportedonthee cacyofSt.John’swortinthetreatmentofanxietydisorders

• Overall,thiswell-researchedherbhasbeenshowntobesuperiortoplaceboandase ectiveasSSRIsformajordepression(mildtomoderate)

• A2008Cochranemeta-analysisof29clinicaltrialsfoundSt.John’swort(SJW)extractstobesuperiortoplaceboinpatientswithmajordepression,

similarly e ective as standard antidepressants, and better tolerated than standard antidepressants

• A more recent review (2017) supports the Cochrane ndings. In 27 trials, SJW was given to patients with mild–moderate depression for up to

12 weeks. SJW had response and remission rates similar to SSRIs. In addition, SJW was as e ective as SSRI treatment at ameliorating depressive

symptoms (measured by HAM-D) and had a signi cantly lower discontinuation rate compared to SSRIs

• CANMAT 2016 guidelines recommend St. John’s wort as rst-line monotherapy for MDD (mild to moderate: Level 1 evidence) and as adjuvant

therapy for MDD (moderate and higher severity: Level 2 evidence)

• St.John’swortdoesnotseemtobee ectiveinseveredepressionaccordingto2well-donetrials

• Nostudiestodateonuseasadjuvanttherapywithconventionaltherapies

• ExtractsofHypericumperforatumL.(St.John’swort)havebeenusedhistoricallytotreatdepressivedisorders;someformulationsareonlyavailable by prescription in Europe

• Thisextractisthebest-known”natural”antidepressantandisnowusedtotreatdepression,anxiety,andsleepdisorders

Anxiety Disorders

Depression

General Comments

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Pharmacology

Dosing

Adverse Effects

Drug Interactions

Further Reading

• Bothhypericumandhyperforinhavebeenshowntobeactiveinseveralanimalstudies;however,itisbelievedthatatleast7constituentscontribute to its overall e ect

• Inhibitsreuptakeofserotonin,norepinephrine,dopamine,GABA,andL-glutamate

• Downregulatesmonaminereceptors(weakere ect)

• Most clinical trials have used 300 mg of standardized 0.3% hypericin or 2–5% hyperforin taken 3 times per day; dose has been increased to 1200- 1800 mg after 2 weeks if no response

• E ectisusuallyseenafter10–14days(withsigni cantclinicalresponseseenat4–6weeks)

• Ingeneral,bettertolerabilityandfeweradversee ectsthanwithconventionalantidepressants:

– Gastrointestinaldiscomfort,confusion,fatigue

– Photosensitivity(inlargedoses:2-4g/day);fair-skinnedindividualsshoulduseprotectivemeasuresagainstsunlight – Maycauseinsomnia(decreasedoseortakeinthemorning)

– Maycauseinducedhypomania(indepression)andmania(inoccultbipolardisorder)

• Contraindications: pregnancy, lactation, Alzheimer’s disease, schizophrenia (case reports of inducing psychosis), and bipolar disorder (case reports of hypomania or mania)

• Hypericumhasmanypossiblemajordruginteractions–besttoavoidusingthisnaturalproductiftakingothermedications

• Potent inducer of CYP3A4 (and, to a lesser extent, CYP2C9 and CYP1A2), and the P-glycoprotein transporter; reported to decrease plasma level of drugs metabolized by these systems, including cyclosporine (30–70% decrease has resulted in rejection of transplanted organ); also reported to decrease plasma level of indinavir (57% decrease in AUC), digoxin (up to 25% decrease in AUC), theophylline, imatinib, irinotecan, amitriptyline, barbiturates, alprazolam, methadone, opioids, phenytoin, and warfarin; breakthrough bleeding and cases of pregnancy reported in patients on oral

contraceptives; may interact with other drugs metabolized by these enzymes

• Severalcasesofserotoninsyndromereportedincombinationwithserotonergicdrugs

References

• IzzoAA,ErnstE.Interactionsbetweenherbalmedicinesandprescribeddrugs:Anupdatedsystematicreview.Drugs.2009;69(13):1777–1798.doi:10.2165/11317010-000000000-00000 • LindeK,BernerMM,KristonL.StJohn’swortformajordepression.CochraneDatabaseSystRev.2008;(4):CD000448.doi:10.1002/14651858.CD000448.pub3

• NaturalMedicinesDatabase:St.John’swortmonograph.Retrievedfromhttp://www.naturaldatabase.com

• NgQX,VenkatanarayananN,HoCY.ClinicaluseofHypericumperforatum(St.John’swort)indepression:Ameta-analysis.JAffectDisord.2017;210:211–221.doi:10.1016/j.jad.2016.12.048 • SarrisJ,KavanaghDJ.KavaandSt.John’swort:Currentevidenceforuseinmoodandanxietydisorders.JAlternComplementMed.2009;15(8):827–836.doi:10.1089/acm.2009.0066

Valerian

• Placebo-controlled RCT compared valerian (mean dose 81.3 mg/day), diazepam (6.5 mg/day) and placebo for 4 weeks. Patients receiving valerian and diazepam had signi cant improvement in HAM-A scores (but not total anxiety scores)

• In a 2017 pilot double-blind RCT with 51 HIV-positive patients beginning efavirenz, valerian extract (530 mg/day) taken for 4 weeks signi cantly reduced anxiety using validated questionnaires

• Useinbenzodiazepinewithdrawalquestionable:

– 19patientswithchronicinsomniaweretaperedo benzodiazepinesovera2-weekperiod

– 2weeksafterinitiatingplaceboor300mg/dayvalerian,sleeplatencywassuperiorintheplacebogroup

Indications

( approved)

Anxiety Disorders

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 421 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Natural Health Products

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Sleep Disorders

General Comments

Valerian (cont.)

• Systematic review and meta-analysis (18 RCTs) reported subjective improvement in sleep quality when outcome was measured as a dichotomous variable (yes or no) – e cacy has not been shown with objective measurements. No di erence in seep latency or quality when measured with visual analogue scale

• Anotherrecentmeta-analysis(14RCTs)foundnoimprovementinsleeponsetlatency,duration,e ciencyorqualitycomparedtoplacebo

• Several placebo-controlled crossover studies show improvement in sleep quality, decrease in sleep latency, and a decrease in the number of awak-

enings; response better in females and individuals less than 40 years of age; some studies did not show bene t

• Valerianconsistsoftheroots,rhizomes(undergroundstems),andstolonsfromtheplantValerianao cinalis

• TherapeuticusesforinsomniadescribedbyHippocratesandGalen(2ndcentury)

• Traditionallyusedforinsomnia,anxiety,seizures,andmigraine

• Wellstudiedbutmajorityofstudiesareofpoorquality

• Active ingredients associated with sedative properties thought to be valepotriates, mono- and sesquiterpenes (e.g., valerenic acid), and pyridine alkaloids

• MayenhanceGABAreleaseanddecreaseuptake

• AbletoalterbindingatbenzodiazepinereceptorandcauseCNSdepression(mechanismofactionunclear)

• Dose:200–1200mg/day

• Usualdose400–900mgtaken2hbeforebedtime

• Welltoleratedforupto6weeks

• Adversee ectsincludenausea,excitability,blurredvision,headache

• Adviseagainststoppingsuddenly:withdrawalsymptomsincludingdelirium,visualhallucinations,andcardiaccomplicationsreportedafterabrupt

discontinuation of chronic use

• Nodetrimentale ectsondrivingperformancewereseenaftertakingvalerian(comparedtoplacebo)

• Contraindications:

– Liverdysfunctionreported;usewithcautioninpatientswithahistoryofliverdisease–periodicliverfunctiontestsrecommended – Surgery:discontinue2weekspriortosurgery(duetoCNSdepressante ects)

– Pregnancyandbreastfeeding

• AvoidusingincombinationwithbenzodiazepinesorotherCNSdepressants

• Willpotentiatethee ectsofotherCNSdrugs

References

• Ahmadi M, Khalili H, Abbasian L, et al. Effect of valerian in preventing neuropsychiatric adverse effects of efavirenz in HIV-positive patients. Ann Pharmacother. 2017;51(6):457–464. doi:10.1177/1060028017696105

• Fernández-San-MartínMI,Masa-FontR,Palacios-SolerL,etal.Effectivenessofvalerianoninsomnia:Ameta-analysisofrandomizedplacebo-controlledtrials.SleepMed.2010;11(6):505– 511. doi:10.1016/j.sleep.2009.12.009

• LeachMJ,PageAT.Herbalmedicineforinsomnia:Asystematicreviewandmeta-analysis.SleepMedRev.2015;24:1–12.doi:10.1016/j.smrv.2014.12.003

• NaturalMedicinesComprehensiveDatabase:Valerianmonograph.Retrievedfromhttp://www.naturaldatabase.com

• ThomasK,CanedoJ,PerryP,etal.Effectsofvalerianonsubjectivesedation, eldsobrietytestinganddrivingsimulatorperformance.AccidAnalPrev.2016;92:240–244.doi:10.1016/j.

aap.2016.01.019

• TonaryA,JackS,CunninghamD,etal.Naturalhealthproductsandadversereactions:Update.CanadianAdverseReactionNewsletter.2009;19(1):2–3.

Pharmacology

Dosing

Adverse Effects

Drug Interactions

Further Reading

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Indications

( approved)

Vitamins

• VitaminEshowntoreducecelldeathassociatedwithβ-amyloidprotein

• Amyloiddepositioninthebrainhasbeenshowntobesigni cantlyreducedinpeoplewithhigherintakeofvitaminDandvitaminB12

• A meta-analysis of 106 studies showed signi cant reductions in the concentration of 6 vitamins in plasma in patients with Alzheimer’s disease

relative to healthy controls. These include Vitamins A, B12, C, D, E, and Folate (B9)

• ReducedprevalenceofdementiareportedinindividualswhousedvitaminCandEsupplementswithorwithoutadditionalmultivitamins

• Meta-analysis suggests there is no evidence of e cacy of vitamin E in the prevention or treatment of people with Alzheimer’s disease or mild

cognitive impairment

• Alongitudinalstudyinelderlypeoplefoundthattakinghighdosesoffolicacid(morethantherecommendeddailyamount)signi cantlyreduced

the risk of developing Alzheimer’s disease

• Vitamin B supplementation was successful at lowering serum homocysteine (a potential risk factor for cognitive impairment) in 4 RCTs, but no

signi cant changes in MMSE scores were found

• Vitamin B9 (folate):

– Despiteaknownlinkbetweenfolatede ciencyanddepression,ithasbeenpoorlystudied(moststudieslookatmultivitamincomplexes)

– Small systematic review: RCTs suggest that folic acid, in combination with antidepressants, may reduce residual symptoms of depression,

especially in individuals with low folate levels; greater response rate reported in women

– 5-MTHFreportedtobee ectiveasmonotherapyoraugmentationtherapyindouble-blindtrials

– AnotherreviewconcludedthataddingfolatetoanantidepressantreducedtheHAM-Dscoresonaveragebyafurther2.65points

• VitaminB:

– LowlevelsofVitaminBhavebeenreportedinpatientswithschizophrenia

– Vitamin B6 may act as an antioxidant and free radical scavenger and reactive carbonyl compounds are believed to contribute to the pathogenesis

of schizophrenia

– Pooled e ects of 18 RCTs showed that Vitamin B supplementation (B6, B8, and B12) reduced symptoms signi cantly more than control groups

and meta-regression analyses indicated that shorter illness duration was associated with greater Vitamin B e ectiveness (p = .001). Authors

conclude that there is preliminary evidence

• VitaminC:

– Reportsthatascorbicacidindosesupto8g/daymayantagonizedopamineneurotransmissionandpotentiatetheactivityoftheantipsychotic (may antagonize the metabolism of the antipsychotic). Supplementation of vitamin C with atypical antipsychotics reported to increase ascorbic acid levels, reduce oxidative stress, and improve BPRS scores

• VitaminDde ciencieshavebeenreportedinpatientswithschizophrenia

• VitaminE:

– Data contradictory on bene t of vitamin E for tardive dyskinesia; suggest vitamin E may protect against worsening of tardive dyskinesia. Combination of vitamins E and C (400 units: 500 mg) plus omega-3 fatty acids reported to decrease psychopathology patients with schizophrenia

• Vitamin B9 (folate):

– Anaturallyoccurringwater-solubleBvitaminfoundinleafyvegetables,fruits,andlegumes

– Availableasfolicacid(syntheticform),5-MTHF(5-methyltetrahydrofolate),andfolinicacid

– Folatede ciencyhasbeenassociatedwithdepression,poorcognitivefunction,andschizophrenia

– Lowfolatelevelshavebeenlinkedtoatrophyofthecerebralcortex,morenotablyinpeoplewithneocorticallesionsrelatedtoAlzheimer’sdisease

Alzheimer’s Disease/Dementia

Depression

Schizophrenia

General Comments

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 423 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Natural Health Products

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Pharmacology

Dosing

Further Reading

Vitamins (cont.)

• Vitamin B9 (folate):

– Reducesthelevelofhomocysteine,anaminoacidbelievedtoexacerbatesomepsychiatricsymptoms

– Folic and folinic acid are converted to L-methylfolate, which crosses the blood/brain barrier and activates enzymes needed to synthesize

dopamine, norepinephrine, and serotonin

– ParticipatesinmethylationofhomocysteineandsynthesisofmethionineandSAMe

• Depression:Toenhanceresponsetoantidepressants,200–500micrograms/dayoffolicacid • Alzheimer’sdisease:unclearatthistime

References

• AkhondzadehS,GerbargPL,Brown,RP.Nutrientsforpreventionandtreatmentofmentalhealthdisorders.PsychiatrClinNorthAm.2013;36(1):25–36.doi:10.1016/j.psc.2012.12.003

• BrownHE,RoffmanJL.Emergingtreatmentsinschizophrenia:Highlightsfromrecentsupplementationandpreventiontrials.HarvRevPsychiatry.2016;24(2):e1–e7.doi:10.1097/HRP.

0000000000000101

• Cherniack EP, Troen BR, Florez HJ, et al. Some new food for thought: The role of vitamin D in the mental health of older adults. Curr Psychiatry Rep. 2009;11(1):12–19. doi:10.1007/

s11920-009-0003-3

• FarinaN,IsaacGM,ClarkAR,etal.VitaminEforAlzheimer’sdementiaandmildcognitiveimpairment.CochraneDatabaseSystRev.2012;11:CD002854.doi:10.1002/14651858.CD002854.

pub3

• FavaM,MischoulonD.Evidenceforfolateincombinationwithantidepressantsatinitiationoftherapy.JClinPsychiatry.2010;71(11):e31.doi:10.4088/JCP.8157tx4c

• FavaM,MischoulonD.Folateindepression:Ef cacy,safety,differencesinformulations,andclinicalissues.JClinPsychiatry.2009;70(Suppl.5):12–17.doi:10.4088/JCP.8157su1c.03

• FenechM.Vitaminsassociatedwithbrainaging,mildcognitiveimpairment,andAlzheimerDisease:Biomarkers,epidemiologicalandexperimentalevidence,plausiblemechanisms,and

Kkowledge gaps. Adv Nutr. 2017;8(6):958–970. doi:10.3945/an.117.015610

• FirthJ,StubbsB,SarrisJ,etal.Theeffectsofvitaminandmineralsupplementationonsymptomsofschizophrenia:Asystematicreviewandmeta-analysis.PsycholMed.2017;47(9):1515–

1527. doi:10.1017/S0033291717000022

• Humble MB, Gustafsson S, Bejerot S. Low serum levels of 25-hydroxyvitamin D (25-OHD) among psychiatric out-patients in Sweden: Relations with season, age, ethnic origin and

psychiatric diagnosis. J Steroid Biochem Mol Biol. 2010;121(1–2):467–470. doi:10.1016/j.jsbmb.2010.03.013

• Zhang DM, Ye JX, Mu JS, et al. Ef cacy of vitamin B supplementation on cognition in elderly patients with cognitive-related diseases. J Geriatr Psychiatry Neurol. 2017;30(1):50–59.

doi:10.1177/0891988716673466

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

PHARMACOGENOMIC INFORMATION FOR COMMON PSYCHOTROPIC DRUGS

General Comments

• Responsestopsychotropicdrugsarein uencedbyanarrayoffactorsincludingage,sex,ethnicity,nutritionalstatus,smokingandalcoholorother drug use. In addition, there is now strong evidence for the role of genetic variability in individual responses to psychotropic drugs.[1] With genetic testing becoming more widely available in the clinical setting (e.g., see [2]), it is important that prescribers have easy access to pharmacogenomic information. Searching available databases often requires specialized knowledge and could be time consuming. This chapter is a brief summary of genetic polymorphisms associated with the metabolism, side e ects, and e ectiveness of commonly prescribed psychotropic drugs. Information was obtained from pertinent publications produced by Health Canada/Santé Canada (HCSC; https://www.canada.ca/en/health-canada.html), US Food and Drug Administration (FDA)[3], Clinical Pharmacogenetics Implementation Consortium (CPIC)[4, 5], Dutch Pharmacogenetics Working Group (DPWG)[6], PharmGKB database[7] as well as US National Library of Medicine – National Institutes of Health databases

• Information on pharmacokinetic e ects of CYP2C9, CYP2C19, CYP2D6, and CYP3A4 enzymes responsible for the metabolism of a substantial majority of psychotropic drugs that is provided here pertains to highly polymorphic genes encoding these enzymes. For more details on CYP polymorphisms, refer to the Pharmacogene Variation (PharmVar) Consortium database (https://www.pharmvar.org/).

• Informationongeneticpolymorphismsassociatedwithpharmacodynamicpropertiesofpsychotropicdrugswasincludedinthissummaryifitwas unambiguous, did not fail replication, and had statistical signi cance of p > .05. Genes listed here are commonly interrogated for polymorphisms by commercial genotyping laboratories. Lists of such laboratories and available genetic tests can be found in the Genetic Test Registry database (https://www.ncbi.nlm.nih.gov/gtr/) and also on the International Society of Genetic Genealogy (ISOGG) wiki page (https://isogg.org/wiki/List_of_ DNA_testing_companies).

• Referencestogeographic/ethnic/racialdistributionofgenotypesandphenotypes(e.g.,“Caucasian”)representacustomaryuseofthesetermsand do not necessarily correspond to the 1000Genomes (http://www.internationalgenome.org/) terminology.

• MEDpicker is an innovative tool designed to help prescribers select the most appropriate medications based on a patient’s drug metabolizer phenotype.[8] It does not require special knowledge of pharmacogenomics and is easy to use. All interactions are shown in a graphic format. In addition, MEDpicker can factor in drug–drug interactions and show dose adjustment recommendations, warnings, and precautions. For full details on MEDpicker and how to acquire the software, see http://www.medpicker.com

• Genelist:

– ANKK1:ankyrinrepeatandkinasedomaincontaining1

– COMT:catechol-O-methyltransferase

– CYP2C9:cytochromeP450,subfamilyIIC,polypeptide9

– CYP2C19:cytochromeP450,subfamilyIIC,polypeptide19

– CYP2D6:cytochromeP450,subfamilyIID,polypeptide6

– CYP3A4:cytochromeP450,subfamilyIIIA,polypeptide4HTR1A-5-hydroxytryptaminereceptor1A – DRD2:dopaminereceptorD2

– HTR1A:5-hydroxytryptaminereceptor1A

– HTR2A:5-hydroxytryptaminereceptor2A

– HTR2C:5-hydroxytryptaminereceptor2C

– OPRM1:opioidreceptor,MU-1

– TPH2:tryptophanhydroxylase2

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 425 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Pharmacogenomics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Genotype E ects on Pharmacokinetic Properties of Psychotropic Drugs∗

Biomarkers

CYP2D6

CYP2C19

Phenotypes

Ultrarapid metabolizer

Extensive metabolizer

Intermediate metabolizer

Poor metabolizer

Ultrarapid metabolizer

Extensive metabolizer

Intermediate metabolizer

Poor metabolizer

Phenotype de nitions

Duplications of functional alleles

Two functional alleles or two reduced function alleles; or one functional and one nonfunctional allele; or one functional and one reduced function allele

One reduced function allele and one nonfunctional allele

Two nonfunctional alleles

Two gain-of-function alleles or one functional allele and one gain-of-function allele

Two functional alleles

One functional allele and one nonfunctional allele

Two nonfunctional alleles

Clinical signi cance

Reduced effectiveness

Expected effectiveness

Risk of phenoconversion#

Signi cant side effects, toxicity

Reduced effectiveness

Expected effectiveness

Risk of phenoconversion#

Signi cant side effects, toxicity

Phenotype frequencies##

African Americans

1.0–2.4

24.0–90.0

0.0–19.0

75.0

25.0

7.0

Caucasians East Asians Hispanics

0.7–5.6 0.9–1.3 2.2–6.6

33.4–83.8 8.0–49.0 ND

1.0–2.0 38.1–70.0 ND

3.0–10.0 0.0–1.0 ND

20.0 0.3–4.0 17.2

87.0 50–61.8 70.0–90.0

13.0 ~50.0 ND

2.0 15.2–24.0 ND

Saudi Arabians, Ethiopians

21.0–29.0

3.0–9.0

1.0–2.0

# Substances that inhibit CYP2D6/CYP2D19 activity may convert intermediate metabolizers to poor metabolizers, ## Phenotype frequencies among geographic/ethnic/racial groups (in % of general population).[9, 10, 11, 12, 13] Columns correspond to the phenotypes listed above.

ND = No data available

∗ De nitions of drug metabolizer phenotypes

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Pharmacogenomics-Based Dose Adjustment Recommendations and Guidelines∗

Drug(s) and genotypes with effects on their metabolism

Aripiprazole

CYP2D6 poor metabolizers

CYP2D6 poor metabolizers, concomitant use of CYP3A4 inhibitors

Atomoxetine

CYP2D6 poor metabolizers

Concomitant use of CYP2D6 inhibitors

CYP2D6 ultrarapid metabolizers

Brexpiprazole

CYP2D6 poor metabolizers

CYP2D6 poor metabolizers, concomitant use of CYP3A4 inhibitors

Carbamazepine

HLA-A and HLA-B

Cariprazine

CYP2D6 poor metabolizers

Concomitant use of CYP3A4 inhibitors

Carisoprodol

CYP2C19 poor metabolizers

Citalopram

CYP2C19 ultrarapid metabolizers CYP2C19 poor metabolizers

Concomitant use of CYP2C19 inhibitor CYP2D6 poor metabolizers

Recommendations

Reduce usual dosage by half, then adjust to receive favorable clinical response

In patients who are also taking strong/moderate CYP3A4 inhibitors, administer a quarter of the usual dose

10-fold higher AUC and 5-fold higher peak concentration compared with extensive metabolizers

Initiate at 0.5 mg/kg/day and only increase to the usual target dose of 1.2 mg/kg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated In children and adolescents up to 70 kg body weight administered strong CYP2D6 inhibitors (e.g., uoxetine, paroxetine, quinidine), initiate at 0.5 mg/kg/day and only increase to the usual target dose of 1.2 mg/kg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated

Be alert to reduced ef cacy or select alternative drug (e.g., methylphenidate, clonidine)

Reduce usual dosage by half

In patients who are also taking strong/moderate CYP3A4 inhibitors, administer a quarter of the usual dose

There is a moderate association between HLA-A*3101 and the risk of developing hypersensitivity reactions to carbamazepine.

Screening of patients with ancestry in genetically at-risk populations (patients of Asian descent) for the presence of the HLA-B*1502 allele should be carried out prior to treatment due to a high risk of serious and sometimes fatal dermatologic reactions

No clinically relevant effect on cariprazine pharmacokinetics

If a strong CYP3A4 inhibitor is initiated, reduce current cariprazine dosage by half

4-fold increase in exposure to carisoprodol, and concomitant 50% reduced exposure to meprobamate compared to extensive CYP2C19 metabolizers

Consider an alternative drug not predominantly metabolized by CYP2C19

Recommended maximum dose is 20 mg/day (due to increased citalopram exposure, which leads to a greater risk for QT prolongation, a potentially fatal abnormality in the heart’s electrical activity)

Recommended maximum dose is 20 mg/day for patients taking cimetidine or another CYP2C19 inhibitor (due to increased citalopram exposure, which leads to a greater risk for QT prolongation, a potentially fatal abnormality in the heart’s electrical activity)

Steady state levels not signi cantly different in poor vs. extensive metabolizers of CYP2D6

∗ The table shows genotype e ects on psychotropic drug metabolism. Annotations re ect published dose adjustment recommendations and guidelines from Health Canada/Santé Canada (HCSC), US Food and Drug Administration (FDA), Clinical Pharmacogenetics Implementation Consortium (CPIC), and Dutch Pharmacogenetics Working Group (DPWG). Blank spaces = no dose adjustment guidelines are currently available

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 427 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Pharmacogenomics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Pharmacogenomics-Based Dose Adjustment Recommendations and Guidelines∗ (cont.)

Drug(s) and genotypes with effects on their metabolism

Clozapine

CYP2D6 poor metabolizers Concomitant use of substrates,

inducers or inhibitors of CYP1A2

CYP3A4

CYP2D6

Codeine

CYP2D6 ultrarapid metabolizers

CYP2D6 extensive metabolizers CYP2D6 intermediate metabolizers

CYP2D6 poor metabolizers

Desvenlafaxine

CYP2D6 poor metabolizers

Diazepam

CYP2C19

CYP3A4

Divalproex

POLG

Testing required

Dronabinol

CYP2C9 variant carriers

Duloxetine

CYP2D6 poor metabolizers

Recommendations

Dose reduction may be necessary

The drug label notes to use caution when clozapine is administered concomitantly with drugs that induce or inhibit these enzymes

Use caution when co-administering with other drugs that are metabolized by CYP2D6 as their levels may be increased. Lower than usual dosing of such drugs may be necessary. These include speci c antidepressants, carbamazepine, phenothiazines, and Type 1C antiarrhythmics (e.g., encainide, ecainide, propafenone)

Increased formation of morphine following codeine administration, leading to higher risk of toxicity, therefore avoid codeine use. Alternatives that are not affected by this CYP2D6 phenotype include opioids that are not metabolized by CYP2D6 (including buprenorphine, fentanyl, hydromorphone, methadone, morphine, and oxymorphone), along with non-opioid analgesics

Black box warning in FDA-approved drug label that respiratory depression and death have occurred in children who received codeine following a tonsillectomy and/or adenoidectomy and who had evidence of being CYP2D6 ultrarapid metabolizers, and also that deaths have occurred in nursing infants exposed to high levels of morphine in breast milk because their mothers were CYP2D6 ultrarapid metabolizers

Normal morphine formation. Use label-recommended age- or weight-speci c dosing

Reduced morphine formation. Use label-recommended age- or weight-speci c dosing. If no response, consider alternative analgesics such as morphine or a non-opioid. Monitor tramadol use for response

Greatly reduced morphine formation following codeine administration, leading to insuf cient pain relief, therefore avoid codeine use. Alternatives that are not affected by this CYP2D6 phenotype include opioids that are not metabolized by CYP2D6 (including buprenorphine, fentanyl, hydromorphone, methadone, morphine, and oxymorphone), along with non-opioid analgesics. Tramadol, and to a lesser extent hydrocodone and oxycodone, are not good alternatives because their metabolism is affected by CYP2D6 activity; these agents should be avoided

Similar pharmacokinetics in CYP2D6 poor and extensive metabolizers

FDA-approved drug label notes that diazepam is metabolized by CYP2C19 and CYP3A4, and that interindividual variation in clearance of the drug is likely attributable to CYP2C19 or CYP3A4 genetic variability

Contraindicated in individuals with known mitochondrial disorders caused by mutations in mitochondrial DNA polymerase gamma (POLG), and suspected POLG-related disorders in children under 2 years old. POLG-related disorders should be suspected in patients with a family history or suggestive symptoms, including (but not limited to) unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy, cerebellar ataxia, ophthalmoplegia or complicated migraine with occipital aura

Published data suggest that systemic clearance of dronabinol may be reduced and concentrations increased in the presence of CYP2C9 genetic polymorphism. Monitoring for increased adverse reactions is recommended in patients known to carry genetic variants associated with diminished CYP2C9 function

Duloxetine is metabolized by CYP2D6 and CYP1A2. Concomitant administration with uvoxamine (a potent CYP1A2 inhibitor) to CYP2D6 poor metabolizers resulted in a 6-fold increase in duloxetine AUC and Cmax

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Recommendations

30 mg once daily resulted in 1.7-fold higher mean Cmax than the mean Cmax for the maximum recommended therapeutic dose at steady state (20 mg)

Drug exposure under a supratherapeutic 30 mg dose is similar to the steady state concentrations expected in CYP2C19 poor metabolizers following a therapeutic dose of 20 mg

In a study on 8 female poor metabolizers, Cmax and AUC0-inf of ibanserin 100 mg once daily decreased 23% and 18%, respectively, compared to exposures among 8 extensive metabolizers

Increased exposure to the drug as compared to extensive metabolizers. Increase monitoring for adverse reactions (e.g., hypotension). Half-life increased to 13.5 h (from 11.1 h in extensive metabolizers)

Fluoxetine inhibits CYP2D6 activity and may thus make individuals with normal CYP2D6 metabolic activity resemble poor metabolizers (phenoconversion) Co-administration of uoxetine with other drugs that are metabolized by CYP2D6, including certain antidepressants (e.g., SSRIs and tricyclics), antipsychotics (e.g., phenothiazines and most atypicals), and antiarrhythmics (e.g., ecainide, propafenone, and others) may lead to drug interactions and should be approached with caution

If a patient is receiving uoxetine concurrently or has taken it in the previous 5 weeks, initiate medications with a relatively narrow therapeutic index that are predominantly metabolized by the CYP2D6 system at the low end of the dose range

Thioridazine should not be administered with uoxetine or within a minimum of 5 weeks after uoxetine discontinuation, due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine

If uoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need for a decreased dose of the original medication should be considered. Drugs with a narrow therapeutic index represent the greatest concern (e.g., ecainide, propafenone, tricyclics, vinblastine)

Use caution in treating patients with low CYP2D6 activity and those receiving other medications known to inhibit CYP2D6

Drug exposures approximately 50% higher than for extensive metabolizers. However, no dosage adjustment necessary as dose is individually titrated to tolerability

Increased exposure to iloperidone compared with extensive metabolizers. Dose should be reduced by half

Risk of QT prolongation

Risk of QT prolongation. Caution is warranted when prescribing iloperidone with drugs that inhibit its metabolism

Moda nil reversibly inhibits CYP2C19 at pharmacologically relevant concentrations. CYP2C19 is also reversibly inhibited, with similar potency, by a circulating metabolite, moda nil sulfone. Although the maximum plasma concentrations of moda nil sulfone are much lower than those of parent moda nil, the combined effect of both compounds could produce sustained partial inhibition of the enzyme. Drugs that are largely eliminated via CYP2C19 metabolism, such as diazepam, propranolol, phenytoin (also via CYP2C9) or S-mephenytoin may have prolonged elimination upon co-administration with moda nil and may require dosage reduction and monitoring for toxicity

Drug(s) and genotypes with effects on their metabolism

Escitalopram

CYP2C19 poor metabolizers

Flibanserin

CYP2C9 poor metabolizers

CYP2C19 poor metabolizers

Fluoxetine

CYP2D6 poor and intermediate metabolizers

and/or

Concomitant use of CYP2D6 inhibitors and substrates

Fluvoxamine

CYP2D6 poor and intermediate metabolizers

and

Concomitant use of CYP2D6 inhibitors

Galantamine

CYP2D6 poor metabolizers

Iloperidone

CYP2D6 poor metabolizers

Concomitant use of CYP2D6

inhibitors

Moda nil

CYP2C19

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 429 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Pharmacogenomics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Pharmacogenomics-Based Dose Adjustment Recommendations and Guidelines∗ (cont.)

Drug(s) and genotypes with effects on their metabolism

Recommendations

CYP2D6 poor metabolizers

Concomitant use of drugs cleared by CYP1A2

CYP2B6

CYP3A4

CYP2C19 provides an ancillary pathway for the metabolism of certain tricyclic antidepressants (e.g., clomipramine and desipramine) that are primarily metabolized by CYP2D6. In tricyclic-treated patients who are CYP2D6 poor metabolizers, the amount of metabolism by CYP2C19 may be substantially increased. Moda nil inhibition of CYP2C19 may cause elevation of tricyclics levels in this subset of patients. Reduction in tricyclic dose might be needed

Moda nil induces CYP1A2, CYP2B6, and CYP3A4 in a concentration-dependent manner. Exercise caution when co-administering moda nil with drugs that depend on these three enzymes for their clearance since lower blood levels of such drugs could result

Nefazodone

CYP2D6

Concomitant use of CYP3A4 substrates

No adjustment required based on CYP2D6 metabolizer status

Nefazodone inhibits CYP3A4. It is recommended that nefazodone not be used in combination with astemizole, cisapride, pimozide, or terfenadine

Nuedexta (dextromethorphan + quinidine)

CYP2D6 poor metabolizers

The quinidine component of Nuedexta is a CYP2D6 inhibitor used to increase the plasma availability of dextromethorphan, which is metabolized by CYP2D6. Therefore, CYP2D6 poor metabolizers may be at risk of experiencing toxicity. The quinidine component of Nuedexta is not expected to contribute to the effectiveness of Nuedexta in CYP2D6 poor metabolizers, but adverse events of the quinidine are still possible. In patients who may be at risk of signi cant toxicity due to quinidine, genotyping to determine if they are poor metabolizers should be considered prior to deciding to treat with Nuedexta

Oxcarbazepine

HLA-B*1502 allele carriers

These patients may be at increased risk for Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) with oxcarbazepine treatment. Frequency of the HLA-B*1502 allele varies:

above 15% in the Philippines and in some Malaysian populations

approximately 8% in Thai populations

2–12% in Han Chinese populations

approximately 6% in India

approximately 2% in Korea

negligible in people of European descent, several African populations, indigenous peoples of the Americas, Hispanic populations, and in Japanese (less than 1%)

Testing for the presence of the HLA-B*1502 allele should be considered in patients with ancestry in genetically at-risk populations, prior to initiating treatment with oxcarbazepine. Use of oxcarbazepine should be avoided in HLA-B*1502 carriers unless the bene ts clearly outweigh the risks. Also consider avoiding the use of other drugs associated with SJS/TEN in HLA-B*1502 carriers when alternative therapies are available

Paroxetine

CYP2D6 substrates and inhibitors

Co-administration of paroxetine with other drugs that are metabolized by CYP2D6, including certain drugs effective in the treatment of major depressive disorder (e.g., amitriptyline, desipramine, uoxetine, imipramine, and nortriptyline), phenothiazines, risperidone, tamoxifen and Type 1C antiarrhythmics (e.g., encainide, ecainide, and propafenone), or CYP2D6 inhibitors (e.g., quinidine), should be approached with caution.

Thioridazine and paroxetine should not be co-administered, due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated thioridazine plasma levels

Tamoxifen is a prodrug requiring metabolic activation by CYP2D6. Inhibition of CYP2D6 by paroxetine may lead to reduced plasma concentrations of an active metabolite (endoxifen) and hence reduced ef cacy of tamoxifen

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Recommendations

Increased metabolism of paroxetine to less active compounds, compared to extensive metabolizers. Low or undetectable plasma concentrations of paroxetine may increase probability of pharmacotherapy failure

If paroxetine use is warranted, consider a 50% reduction of recommended starting dose and titrate to response

Higher plasma concentrations of antipsychotic drugs at usual doses, which may correlate with emergence of adverse effects

Plasma concentrations of antipsychotics may be acutely increased by concomitant administration of other drugs that inhibit CYP2D6 activity. Among these are tricyclic

antidepressants and SSRIs (e.g., uoxetine, sertraline and paroxetine). Close monitoring is essential when prescribing such drugs to patients already receiving antipsychotic therapy, and dose reduction may become necessary to avoid toxicity. Lower than usual doses of either the antipsychotic or the other drug may be required

Doses should not exceed 0.05 mg/kg/day in children or 4 mg/day in adults. Doses should not be increased at intervals of less than 14 days CYP2D6 genotyping should be performed if pimozide is to be used at higher doses

Risperidone is metabolized to 9-hydroxyrisperidone by CYP2D6. Co-administration of drugs that inhibit or induce CYP2D6 may alter the plasma concentration of risperidone

Initiate therapy with recommended starting dose. If patient does not respond to recommended maintenance dosing, consider alternative drug not predominantly metabolized by CYP2C19

Consider a 50% reduction of recommended starting dose and titrate to response or select alternative drug not predominantly metabolized by CYP2C19

Contraindicated in patients with reduced CYP2D6 activity, equally co-administration with drugs that may inhibit CYP2D6 or by some other mechanism interfere with thoridazine clearance

Life-threatening respiratory depression and death have occurred in children who received tramadol. It is contraindicated in children less than 12 years old, and below age 18 following tonsillectomy and/or adenoidectomy. Avoid use in adolescents aged 12–18 who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol

Prevalence of CYP2D6 ultrarapid metabolizer phenotype varies widely (see table above p. 426). These individuals convert tramadol into its active metabolite, odesmethyltramadol (M1), more rapidly and completely than other people, which results in higher than expected serum M1 levels. Even at labeled dosage regimens, ultrarapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing). Therefore, ultrarapid CYP2D6 metabolizers should not use tramadol

CYP2D6 poor metabolizers may have higher plasma concentrations of tricyclic antidepressants. Monitor plasma levels Monitor plasma levels when tricyclics are co-administered with a CYP2D6 inhibitor

Drug(s) and genotypes with effects on their metabolism

CYP2D6 ultrarapid metabolizers

CYP2D6 poor metabolizers

Perphenazine

CYP2D6 poor metabolizers Concomitant use of CYP2D6 inhibitors

Pimozide

CYP2D6 poor metabolizers

Testing required

Risperidone

Concomitant use of CYP2D6

inhibitors/inducers

Sertraline

CYP2C19 ultrarapid metabolizers

CYP2C19 poor metabolizers

Thioridazine

CYP2D6 poor metabolizers

Tramadol

CYP2D6 ultrarapid metabolizers

Tricyclics

Amitriptyline Clomipramine Desipramine Doxepin Imipramine Trimipramine)

CYP2D6 poor metabolizers Concomitant use of CYP2D6 inhibitors

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 431 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Pharmacogenomics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Pharmacogenomics-Based Dose Adjustment Recommendations and Guidelines∗ (cont.)

Drug(s) and genotypes with effects on their metabolism

Recommendations

Valbenazine

CYP2D6 poor metabolizers

Concomitant use of CYP2D6 and CYP3A4 inhibitors

Valbenazine concentrations may be higher and QT prolongation clinically signi cant; dose reduction may be necessary. Consider reducing the dose based on tolerability. Valbenazine concentrations may be higher and QT prolongation clinically signi cant; dose reduction may be necessary

Venlafaxine

Concomitant use of CYP2D6 and CYP3A4 inhibitors

No dosage adjustment required

Vortioxetine

CYP2D6 poor metabolizers

Concomitant use of CYP2D6 inhibitors/inducers

Maximum recommended dose is 10 mg/day

Reduce dose by if patient is receiving a strong CYP2D6 inhibitor (e.g., bupropion, uoxetine, paroxetine, or quinidine)

Consider dose increase if a strong CYP inducer (e.g., carbamazepine, phenytoin, or rifampin) is co-administered; the maximum dose is not recommended to exceed three times the original dose

Genotype E ects on Pharmacokinetic Properties of Psychotropic Drugs∗

Gene

Genotype or Allele

Drug

Effect

Reference(a)

ANKK1 (DRD2)(b)

rs1800497

Allele A

rs1800497 Genotypes AA and AG

rs1800497 Allele A

Clozapine Olanzapine Risperidone

Bripiprazole Bromperidol Chlorpromazine Clozapine Haloperidol Nemonapride Olanzapine Risperidone

Increased likelihood of weight gain in schizophrenia or schizoaffective disorder

Increased risk of hyperprolactinemia (OR = 3.0)

No response to antipsychotics in schizophrenia

PMID: 20714340[14] PMID: 15146457[15] PMID: 19339912[16]

PMID: 20194480[17]

COMT

rs4680

Allele G

rs4680

Genotypes AA and AG

Fluvoxamine

Most antipsychotics

Decreased response in depressive disorders at 4th week of treatment

Decreased risk of tardive dyskinesia when treated with antipsychotics in schizophrenia (OR = 0.66)

PMID: 20619611[18] PMID: 18180754[19]

∗ Genes that are commonly interrogated for polymorphisms associated with antidepressant, antipsychotic, and opiate receptor ligand e ectiveness or adverse e ects

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Gene

Genotype or Allele

Drug

Effect

Reference(a)

HTR1A

rs10042486 Genotype CC rs1364043 Genotype TT

Fluvoxamine Milnacipran Paroxetine

Increased response in depression

PMID: 18484082[20]

HTR2A

rs7997012 Allele G rs17288723 Genotype CC rs6314 Genotype AG

rs7997012 Allele G

A combination of antidepressants, antipsychotics, and mood stabilizers Most antidepressants

Paroxetine Venlafaxine XR

Increased likelihood of remission in depressive disorders Increased likelihood of remission in depressive disorders Increased likelihood of remission in major depressive disorder

Better response at 6 months of treatment in generalized anxiety disorder (OR = 4.72)

PMID: 19924111[21] PMID: 19924111[21] PMID: 18253134[22] PMID: 22006095[23]

HTR2C

rs1414334 Allele C

Clozapine Risperidone

Most antipsychotics

Increased risk of metabolic syndrome when treated with clozapine (OR = 9.2) or risperidone (OR = 5.35)

Increased likelihood of metabolic syndrome (OR = 3.73)

PMID: 20680028[24] PMID: 17632216[25]

OPRM1

rs1799971

Genotypes GG and AG

Naltrexone

Increased response to naltrexone (OR = 5.75) in individuals with alcohol use disorder

PMID: 18250251[26]

TPH2

rs10897346 Allele C

Mirtazapine Venlafaxine

Increased response in major depressive disorder (OR = 2.6)

PMID: 18496129[27]

(a) References to original studies are provided as PubMed IDs (PMID) (b) Also known as Taq1A, restriction fragment length polymorphism [RFLP], which has been associated with a reduction in D2 receptor density. Taq1A RFLP lies 10 kB downstream of DRD2 and may therefore fall within a different coding region than the DRD2 gene. ANKK1 is within this downstream region. The DRD2 Taq1A RFLP causes an amino acid substitution in ANKK1 product (p.Glu713Lys), which may affect substrate-binding speci city

Further Reading

References

1 2

3 4

6 7 8 9

10 11 12

13 14

Ravyn D, Ravyn V, Lowney R, et al. CYP450 pharmacogenetic treatment strategies for antipsychotics: A review of the evidence. Schizophrenia Res. 2013.149(1–3):1–14. doi:10.1016/j.schres. 2013.06.0351

Shuldiner AR, Palmer K, Pakyz RE, et al. Implementation of pharmacogenetics: The University of Maryland personalized anti-platelet pharmacogenetics program. Am J Med Genet C Semin Med Genet. 2014;166(1):76–84. doi:10.1002/ajmg.c.31396

FDA. Table of pharmacogenomic biomarkers in drug labeling. Retrieved from: https://www.fda.gov/Drugs/ScienceResearch/ucm572698.htm

Relling MV, Klein TE. CPIC: Clinical Pharmacogenetics Implementation Consortium of the Pharmacogenomics Research Network. Clin Pharmacol Ther. 2011;89(3):464–467. doi:10.1038/ clpt.2010.279

Hicks JK, Bishop JR, Sangkuhl K, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and dosing of selective serotonin reuptake inhibitors. Clin Pharmacol Ther. 2015;98(2):127–134. doi:10.1002/cpt.147

Swen JJ, Nijenhuis M, de Boer A, et al. Pharmacogenetics: From bench to byte – an update of guidelines. Clin Pharmacol Ther. 2011;89(5):662–673. doi:10.1038/clpt.2011.34 Whirl-Carrillo M, McDonagh EM, Hebert JM, et al. Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther. 2012;92(4):414–417. doi:10.1038/clpt.2012.96

Baskys A. Application of pharmacogenetics in clinical practice: Problems and solutions. J Neural Transm (Vienna). 2018. Advance online publication. doi:10.1007/s00702-018-1894-0

Teh LK, Bertilsson L. Pharmacogenomics of CYP2D6: Molecular genetics, interethnic differences and clinical importance. Drug Metab Pharmacokinet. 2012;27(1):55–67. doi:10.2133/dmpk. DMPK-11-RV-121

McGraw J, Waller D. Cytochrome P450 variations in different ethnic populations. Expert Opin Drug Metab Toxicol. 2012;8(3):371–382. doi:10.1517/17425255.2012.657626

Mrazek DA. Psychiatric pharmacogenomics. New York: Oxford University Press, 2010

Bernard S, Neville KA, Nguyen AT, et al. Interethnic differences in genetic polymorphisms of CYP2D6 in the U.S. population: Clinical implications. Oncologist. 2006;11(2):126–135. doi: 10.1634/theoncologist.11- 2- 126

Claudio-Campos K, Duconge J, Cadilla CL, et al. Pharmacogenetics of drug-metabolizing enzymes in US Hispanics. Drug Metab Pers Ther. 2015;30(2):87–105. doi:10.1515/dmdi-2014-0023 Müller DJ, Zai CC, Sicard M, et al. Systematic analysis of dopamine receptor genes (DRD1-DRD5) in antipsychotic-induced weight gain. Pharmacogenomics J. 2012;12(2):156–164. doi: 10.1038/tpj.2010.65

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 433 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Pharmacogenomics

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Pharmacogenomic Information for Common Psychotropic Drugs (cont.)

15 16 17 18 19 20 21 22 23 24 25 26 27

Neville MJ, Johnstone EC, Walton RT. Identi cation and characterization of ANKK1: a novel kinase gene closely linked to DRD2 on chromosome band 11q23.1. Hum Mutat. 2004;23(6):540– 545. doi:10.1002/humu.20039

Calarge CA, Ellingrod VL, Acion L, et al. Variants of the dopamine D2 receptor gene and risperidone-induced hyperprolactinemia in children and adolescents. Pharmacogenet Genomics. 2009;19(5):373–382. doi:10.1097/FPC.0b013e328329a60f

Zhang JP, Lencz T, Malhotra AK. D2 receptor genetic variation and clinical response to antipsychotic drug treatment: A meta-analysis. Am J Psychiatry. 2010;167(7):763–772. doi:10.1176/ appi.ajp.2009.09040598

Benedetti F, Dallaspezia S, Colombo C, et al. Effect of catechol-O-methyltransferase Val(108/158)Met polymorphism on antidepressant ef cacy of uvoxamine. Eur Psychiatry. 2010;25(8): 476–478. doi:10.1016/j.eurpsy.2009.12.007

Bakker PR, van Harten PN, van Os J. Antipsychotic-induced tardive dyskinesia and polymorphic variations in COMT, DRD2, CYP1A2 and MnSOD genes: A meta-analysis of pharmacogenetic interactions. Mol Psychiatry. 2008;13(5):544–556. doi:10.1038/sj.mp.4002142

Kato M, Fukuda T, Wakeno M, et al. Effect of 5-HT1A gene polymorphisms on antidepressant response in major depressive disorder. Am J Med Genet B Neuropsychiatr Genet. 2009;150B(1):115–123. doi:10.1002/ajmg.b.30783

Horstmann S, Lucae S, Menke A, et al. Polymorphisms in GRIK4, HTR2A, and FKBP5 show interactive effects in predicting remission to antidepressant treatment. Neuropsychopharmacol- ogy. 2010;35(3):727–740. doi:10.1038/npp.2009.180

Wilkie MJ, Smith G, Day RK, et al. Polymorphisms in the SLC6A4 and HTR2A genes in uence treatment outcome following antidepressant therapy. Pharmacogenomics J. 2009;9(1):61–70. doi:10.1038/sj.tpj.6500491

Lohoff FW, Aquino TD, Narasimhan S, et al. Serotonin receptor 2A (HTR2A) gene polymorphism predicts treatment response to venlafaxine XR in generalized anxiety disorder. Pharma- cogenomics J. 2013;13(1):21–26. doi:10.1038/tpj.2011.47

Risselada AJ, Vehof J, Bruggeman R, et al. Association between HTR2C gene polymorphisms and the metabolic syndrome in patients using antipsychotics: a replication study. Pharma- cogenomics J. 2012;12(1):62–67. doi:10.1038/tpj.2010.66

Mulder H, Franke B, van der Beek AA, et al. The association between HTR2C gene polymorphisms and the metabolic syndrome in patients with schizophrenia. J Clin Psychopharmacol. 2007;27(4):338–343. doi:10.1097/JCP.0b013e3180a76dc0

Anton RF, Oroszi G, O’Malley S, et al. An evaluation of mu-opioid receptor (OPRM1) as a predictor of naltrexone response in the treatment of alcohol dependence: Results from the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) study. Arch Gen Psychiatry. 2008;65(2):135–144. doi:10.1001/archpsyc.65.2.135

Tzvetkov MV, Brockmöller J, Roots I, et al. Common genetic variations in human brain-speci c tryptophan hydroxylase-2 and response to antidepressant treatment. Pharmacogenet Genomics. 2008;18(6):495–506. doi:10.1097/FPC.0b013e3282fb02cb

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

ACE

ADHD

ADL Agranulocytosis Akathisia

Akinesia Alopecia ALT/SGPT

Amenorrhea ANC

Anorexia Anterocollis Anticholinergic Antiemetic ARB Arrhythmia

Arteriosclerosis

Arthralgia ASA AST/SGOT

Asterixis

Asthenia Ataxia

Atherosclerosis Atypical depression

AUC

Angiotensin-converting enzyme

Attention de cit hyperactivity disorder

Activities of daily living

Reduction of neutrophil white blood cells to very low levels Inability to relax, compulsion to change position, motor restlessness

Absence of voluntary muscle movement

Hair loss

Alanine aminotransferase/serum glutamic pyruvic transaminase

Absence of menstruation

Absolute neutrophil count

Lack of appetite for food

Forward spasm of the neck

Block e ects of acetylcholine

Helps prevent nausea and vomiting

Angiotensin receptor blocker

Any variation of the normal rhythm (usually of the heart beat)

Hardening and degeneration of the arteries due to brous tissue formation

Pain in the joints

Acetylsalicylic acid

Aspartate aminotransferase/serum glutamic oxaloacetic transaminase

Abnormal tremor consisting of involuntary jerking movements, especially in the hands, frequently occurring with impending hepatic coma and other forms of metabolic encephalopathy; also called apping tremor

Weakness, fatigue

Incoordination, especially the inability to coordinate voluntary muscular action

Degeneration of the walls of the arteries due to fatty deposits

As per DSM-5, patient has mood reactivity and at least 2

of the following symptoms: increased appetite or weight, hypersomnia, leaden paralysis and a long-standing pattern of extreme sensitivity to perceived interpersonal rejection Area under the concentration vs time curve (on graph depicting drug in the plasma after a single dose) – represents the extent of systemic exposure of the body to the drug

Autonomic

BAD

Ballismus Bioavailability

Bipolar I disorder Bipolar II disorder

Blepharospasm

BMI (body mass index) BPH

BPRS

Bradycardia

Brugada syndrome

Bruxism BUN Cataplexy CBC

CBT

CHD Choreiform Choreoathetosis

Chronic brain syndrome CI

Clearance

CNS

CNS depression

COPD Cortex Coryza

CrCl

CSF

CVD Cycloplegia CYP

The part of the nervous system that is functionally independent of thought control (involuntary) Bipolar a ective disorder

Bipolar disorder

Jerking, twisting

The fraction of an administered dose of unchanged drug that reaches the systemic circulation

Cyclical mood disorder with depression alternating with mania or mixed mania

Cyclical mood disorder with depression alternating with hypomania

Forceful sustained eye closure

Weight (in kg) divided by height (in m2)

Benign prostatic hyperplasia

Brief Psychiatric Rating Scale

Abnormally slow heart beat

Cardiac conduction disorder that can lead to sudden cardiac death

Teeth clenching, grinding

Blood urea nitrogen

Loss of muscle tone and collapse

Complete blood count

Cognitive-behavioral therapy

Coronary heart disease

Purposeless, uncontrolled sinuous movements,

Slow, repeated, involuntary sinuous movements or twitching of muscles

Irreversible damage to brain cells = dementia

Con dence interval

Rate at which drug is removed from the body (depends on rate of metabolism by liver and elimination from body) Central nervous system

Drowsiness, ataxia, incoordination, slowing of respiration which in severe cases may lead to coma and death

Chronic obstructive pulmonary disorder

The external layer (super cial gray matter) of the brain “Head cold,” acute catarrhal in ammation of nasal

mucosa

Creatinine clearance

Cerebrospinal uid

Cardiovascular disease

Paralysis of accommodation of the eye

Cytochrome P450 enzymes, involved in drug metabolism

435

GLOSSARY

Glossary

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

436

DBPC DDAVP Dermatitis Diaphoresis Diplopia DLPFC DRESS Dysarthria Dysgeusia Dyspepsia

Dysphagia Dyskinesia Dystonia

ECG

ECT EEG

Edema Elimination

Emesis Endocrine Enzyme

Enuresis Eosinophilia myalgia

syndrome (EMS)

Epigastric Epistaxis

EPS

ER Exacerbation Extrapyramidal

Extrapyramidal syndrome FAS

Fasciculation

FASD

Fibrosis

Dopamine

Double-blind placebo-controlled

Desmopressin acetate

In ammation of the skin

Perspiration

Double vision

Dorsolateral prefrontal cortex

Drug reaction with eosinophilia and systemic symptoms Impaired, di cult speech

Unpleasant taste

Pain or discomfort in upper abdomen or chest (gas, feeling of fullness, or burning pain)

Di culty in swallowing

Abnormal movements, i.e., twitching, grimacing, spasm Disordered muscle tone leading to spasms or postural change

Electrocardiogram (tracing of electrical activity of the heart muscle)

Electroconvulsive therapy, “shock therapy” Electroencephalogram (tracing of electrical activity of the brain)

Swelling of body tissues due to accumulation of uid Excretion or removal of drug (and/or metabolites) from the body, usually by the kidneys

Vomiting

A gland that secretes internally, a ductless gland

Organic compound that acts upon speci c uids, tissues, or chemicals in the body to facilitate chemical action Involuntary discharge of urine

Connective tissue disease with eosinophilia and myalgia (Eosinophils are blood cells that are usually in low quantities)

Referring to the upper middle region of the abdomen

Nose bleed

Extrapyramidal side e ects

Extended release

Increase in severity of symptoms or disease

Refers to certain nuclei of the brain close to the pyramidal tract

Parkinsonian-like e ects of drugs

Fetal alcohol syndrome

Twitching of muscles

Fetal alcohol spectrum disorder

Formation of brous or scar tissue

First-pass e ect

FSH GABA

GAD Galactorrhea GERD

GFR

Glaucoma Glomerular

Glossodynia

GnRH Gynecomastia Half-life

HAM-A

HAM-D

HDL

Histological Hypercalcemia Hyperkinetic Hyperparathyroidism Hyperre exia Hypertension Hyperthyroid Hypertrophy Hypesthesia Hypnotic Hypospadias

Hypotension Hypothyroid Induration INR

IR Jaundice

Drugs absorbed from the intestine rst pass through the liver; a portion of the drug is metabolized before it can act on receptors

Follicle-stimulating hormone

Gamma-amino butyric acid; an inhibitory neuro- transmitter

Generalized anxiety disorder

Excretion of milk from breasts Gastroesophageal re ux disease

Glomerular ltration rate

Gastrointestinal

Increased pressure within the eye

Pertaining to small blood vessels of the kidney that serve as ltering structures in the excretion of urine

Burning mouth syndrome – a persistent tingling or burning sensation in the lips, tongue or entire mouth Gonadotropin-releasing hormone

Increase in breast size in males

Time required to decrease the plasma concentration of a drug by 50% (depends on drug clearance and volume of distribution)

Hamilton Anxiety Rating Scale

Hamilton Depression Rating Scale High-density lipoprotein

Pertaining to microscopic tissue anatomy An excessive amount of calcium in the blood Abnormal increase in activity

Increased secretion of the parathyroid Increased action of the re exes

High blood pressure

Excessive activity of the thyroid gland Enlargement

Diminished sensitivity to tactile stimuli

Inducing sleep

Developmental abnormality in males in which the urethra opens on the under surface of the penis or in the perineum

Low blood pressure

Insu ciency of thyroid secretion

Area of hardened tissue

International normalized ratio; measures coagulation of blood

Immediate release

Yellow skin caused by excess of bile pigment

Glossary (cont.)

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Kindling

LDH

LDL

LFTs

LHRH

Libido

Limbic system

Leukocytosis

Leukopenia

Macrosomia

MADRS

Manic depressive psychosis

MAOI

MDD

Metabolic syndrome

Metabolism

Metabolites

MI Micrographia Miosis MMSE Myalgia Mydriasis Narcolepsy Nephritis NMDA

NMS

NRT

Epileptogenesis caused by adaptive changes in neurons producing repeated electrical discharges

Lactate dehydrogenase (an enzyme)

Low-density lipoprotein

Liver function tests

Luteinizing hormone-releasing hormone

Luteinizing hormone

Drive or energy usually associated with sexual interest

A system of brain structures common to the brains of all mammals (deals with emotions)

Increase in the white blood cells in the blood

Decrease in the white blood cells in the blood

Birth weight of infant more than 4 kg

Montgomery Åsberg Depression Rating Scale

Conspicuous mood swings ranging from normal to elation or depression, or alternating of the two; in DSM-IV, called bipolar a ective disorder

Monoamine oxidase (an enzyme) inhibitor

Major depressive disorder

An interrelated cluster of CVD risk factors that include abdominal obesity, dyslipidemia, hypertension, and impaired glucose tolerance (also called insulin resistance syndrome, syndrome X, or dysmetabolic syndrome); see

p. 141 for diagnostic criteria

Chemical processes living organisms utilize to maintain life. Drug metabolism is the biochemical process by which living organisms modify pharmaceutical substances. For example, drug metabolism often converts fat-soluble drugs into more water-soluble drugs, which can more readily be excreted by the kidneys. Most psychotropic drugs are metabolized by cytochrome P450 enzymes

Resultant by-products of metabolism; metabolites can be either active substances or nonactive agents

Myocardial infarction

Decrease in size of hand writing; may be a form of akinesia Constricted pupils

Mini-Mental State Examination

Tenderness or pain in muscles

Dilated pupils

Condition marked by an uncontrollable desire to sleep In ammation of the kidneys

N-methyl-D-aspartate

Neuroleptic malignant syndrome – rare disorder charac- terized by autonomic dysfunction (e.g., tachycardia and hypertension), hyperthermia, altered consciousness, and muscle rigidity with an increase in creatine kinase (CK) and myoglobinuria

Nicotine replacement therapy

Nystagmus

OCD

Oculogyric crisis Occipital

ODT Ophthalmoplegia Opisthotonus

Oral hypoesthesia

OROS

Orthostatic hypotension

Osteomalacia PANSS

Palinopsia Papilledema Paresthesia

Parkinsonism

Perioral

Peripheral neuropathy Petechiae

P-gp

Photophobia Photosensitivity

Piloerection

Pisa syndrome

PMS

Polydipsia

Polyuria

“Poop-out” syndrome Postural hypotension Priapism

Prostatic hypertrophy Pruritus

Psychosis

Psychomotor excitement Psychomotor retardation

Involuntary movement of the eyeball or abnormal movement on testing

Obsessive-compulsive disorder

Oral contraceptive

Rolling up of the eyes and the inability to focus

In the back part of the head

Oral disintegrating tablets

Paralysis of the extraocular eye muscles

Arching (spasm) of the body due to contraction of back muscles

Diminished oral sensitivity

Osmotic-controlled release oral delivery system

Faintness caused by suddenly standing erect (leading to a drop in blood pressure)

Rickets

Positive and negative syndrome scale used in the diagnosis and monitoring of symptoms of schizophrenia

Visual perseveration,“tracking” or shimmering

Edema of the optic disc

Feeling of “pins and needles,” tingling or sti ness in distal extremities

A condition marked by mask-like facial appearance, tremor, change in gait and posture (resembles Parkinson’s disease) Panic disorder (with/without agoraphobia)

Around the mouth

Pathological changes in the peripheral nervous system Small purplish hemorrhagic spots on skin

P-glycoprotein; a protein that transports molecules through cell membranes (e.g., in and out of speci c body organs) Sensitivity of the eyes to light

Light sensitive

Protease inhibitor

“Goose-bumps” or hair standing up

A condition where an individual leans to one side Premenstrual syndrome

Excessive drinking

Excessive urination

Tolerance to e ects (tachyphylaxis)

Lowered blood pressure caused by a change in position Abnormal, continued erection of the penis

Enlargement of the prostate gland

Itching

A major mental disorder of organic or emotional origin

in which there is a departure from normal patterns of thinking, feeling and acting; commonly characterized by loss of contact with reality

Physical and emotional overactivity

Slowing of physical and psychological reactions

437

Glossary

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

PTSD

Pyloric

Rabbit syndrome RCT

RDBCT Retardation Retrocollis

Schizophrenia

Sedative

Serotonin syndrome

SIADH

Sialorrhea

SIDS

Social AD Somnambulism SR

Stereotypic Syncope T2DM Tachycardia Tachyphylaxis

Prothrombin time; used to determine the blood’s coagula- tion tendency (extrinsic pathway)

Posttraumatic stress disorder

Referring to the lower opening of the stomach

Tremor of the lower lip

Randomized controlled trial

Randomized double-blind controlled trial

Slowing

Spasm of neck muscles causing the head to twist up and back

A severe disorder of psychotic depth characterized by a retreat from reality with delusions and hallucinations Producing calming of activity or excitement Hypermetabolic syndrome resulting from serotonergic excess; symptoms include: Disorientation, confusion, agitation, tremor, myoclonus, hyperre exia, twitching, shivering, ataxia, hyperactivity

Syndrome of inappropriate secretion of antidiuretic hormone

Excessive ow of saliva

Sudden infant death syndrome

Sublingual

Social anxiety disorder

Sleepwalking

Sustained release

Rhythmic and repetitive

A sudden loss of strength or fainting

Type 2 diabetes mellitus

Abnormally rapid heart rate

Tolerance to e ects

Tardive dyskinesia Tardive dystonia

TCA

Therapeutic index

TIA Tinnitus Torticollis Tortipelvis Tracking

TRH Trismus

TSH UGT

Ulceration

Vasoconstrictor

Volume of distribution (Vd)

WBC Wernicke-Korsako

syndrome XR

Persistent dyskinetic movements that appear late in neuroleptic therapy

Persistent abnormal muscle tone that appears late in neuroleptic therapy

Tricyclic antidepressant

Tardive dyskinesia

Ratio of median lethal dose of a drug to its median e ective

Glossary (cont.)

dose: i.e., median lethal dose

therapeutic index = Transient ischemic attack

median e ective dose

A noise in the ears (ringing, buzzing, or roaring)

Spasm on one side of the neck causing the head to twist Twisting of pelvis due to muscle spasm

A reaction in which the medication leaves the original injection site and moves to another

Thyrotropin-releasing hormone, releases TSH and prolactin Severe spasm of the muscles of the jaw resembling tetanus (lock jaw); jaw clenching

Thyroid-stimulating hormone

Uridine diphosphate glucuronosyltransferase, enzyme involved in drug metabolism

An open lesion on the skin or mucous membrane

Causes narrowing of the blood vessels

The theoretical volume that a drug would have to occupy to provide the same concentration as it currently is in blood plasma

White blood cell count

Syndrome characterized by confusion, ataxia, ophthalmo- plegia, recent memory impairment, and confabulation Extended release

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

DRUG USE IN PREGNANCY AND EFFECTS ON BREAST MILK

Drug labeling

• The FDA has replaced the product letter categories (A, B, C, D and X) used to classify the risks of using prescription drugs during pregnancy with the following three detailed subsections, as outlined in the Pregnancy and Lactation Labeling Rule (PLLR):

– Pregnancy: This subsection provides information relevant to the use of the drug in pregnant women, such as dosing and potential risks to the developing fetus, as well

as information about whether there is a registry that collects and maintains data on how pregnant women are a ected when they use the drug or biological product.

Information in drug labeling about the existence of any pregnancy registries was previously recommended but not required

– Lactation:Thissubsectionprovidesinformationaboutusingthedrugwhilebreastfeeding,suchastheamountofdruginbreastmilkandpotentiale ectsonthebreastfed

child

– Females and Males of Reproductive Potential: This subsection includes information about pregnancy testing, contraception, and infertility as it relates to the drug. This

information was previously included in labeling, but there was no consistent placement for it

• The “Pregnancy” and “Lactation” subsections include three subheadings: “risk summary,” “clinical considerations,” and “data.” These subheadings provide more detailed

information regarding, for example, human and animal data on the use of the drug, and speci c adverse reactions of concern for pregnant or breastfeeding women

List of pregnancy exposure registries

• Forinformationalpurposes,theFDAmaintainsalistofpregnancyexposureregistriesat https://www.fda.gov/ScienceResearch/SpecialTopics/WomensHealthResearch/ucm134848.htm that may provide useful information on various agents

Further Reading

Additional Suggested Reading

Print resources

• American College of Obstetricians and Gynecologists (ACOG). Use of psychiatric medications during pregnancy and lactation. (ACOG practice bulletin no. 92). Obstet Gynecol. 2008;111(4):1001-1020. doi:10.1097/AOG.0b013e31816fd910

• BriggsGG,FreemanRK,YaffeSJ.Drugsinpregnancyandlactation:Areferenceguidetofetalandneonatalrisk.(9thed.)Philadelphia,PA:LippincottWilliams&Wilkins,2011.

• HaleTW.Medicationsandmothers’milk.(15thed.)Amarillo,TX:PharmasoftMedicalPublishing,2012.

Online resources (freely accessible)

• Motherisk[ACanadianclinical,research,andteachingprogramdedicatedtoantenataldrug,chemical,anddiseaseriskcounseling].Retrievedfromhttp://www.motherisk.org

• LactMed[AUSNationalLibraryofMedicinedatabaseofdrugsandotherchemicalstowhichbreastfeedingmothersmaybeexposed.Includesinformationonthelevelsofsuchsubstances

in breast milk and infant blood, and the possible adverse effects in the nursing infant]. Retrieved from http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT

• Exposuretopsychotropicmedicationsandothersubstancesduringpregnancyandlactation:Ahandbookforhealthcareproviders[ACanadianresourcedevelopedbytheCentrefor Addiction and Mental Health in Toronto and the Motherisk Program]. Retrieved from http://www.camhx.ca/Publications/Resources_for_Professionals/Pregnancy_Lactation/index.html

Online resources (subscription required)

• REPROTOX[AdatabasedevelopedbytheReproductiveToxicologyCenterinWashington,DC,USAforitsmembers,whichcontainssummariesontheeffectsofmedications,chemicals, infections, and physical agents on pregnancy, reproduction, and development]. Retrieved from http://www.reprotox.org

• TERIS-TeratogenInformationSystem[DevelopedbytheUniversityofWashington,Seattle,WA,USA;providescurrentinformationontheteratogeniceffectsofdrugsandenvironmental agents]. Retrieved from http://depts.washington.edu/terisweb/teris/index.html

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 439 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Pregnancy Resources

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

PATIENT INFORMATION SHEETS

The Patient Information Sheets contain information that may be passed on to patients about some of the most frequently used psychotropic medications as well as three nonpharmacological interventions. The sheets are designed to be easily understood by patients, give details on such matters as the uses of the drug, how quickly it starts working, how long it should be taken, side e ects and what to do if they occur, what to do if a dose is forgotten, drug interactions, and precautions. Information sheets such as these, of course, cannot replace a proper consultation with and advice from the physician or other medical professional, but can serve as a useful tool to increase compliance, improve e cacy, and enhance safety.

The authors and the publisher welcome feedback and suggestions from readers (for contact addresses, see the front of the book).

Printable pdf les of Patient Information Sheets on the drugs and classes of drugs shown at the right can be found at the end of this PDF e-book.

The Patient Information Sheets may be reproduced by users of the Clinical Handbook of Psychotropic Drugs for their own clinical practice but not for any commercial use.

The following Patient Information Sheets are available:

1. Acamprosate

2. Anticonvulsant Mood Stabilizers

3. Antiparkinsonian Agents for Treating Extrapyramidal Side E ects 4. Antipsychotics

5. Anxiolytics and Benzodiazepines

6. Atomoxetine

7. Bright Light Therapy

8. Buprenorphine

9. Bupropion

10. Buspirone

11. Clonidine and Guanfacine

12. Clozapine

13. Cyclic Antidepressants

14. Deutetrabenazine

15. Disul ram

16. Drugs for Treatment of Dementia

17. Electroconvulsive Therapy

18. Esketamine

19. Hypnotics/Sedatives

20. Lithium

21. L-Tryptophan

22. MAOI Antidepressants

23. Methadone

24. Mirtazapine

25. Moclobemide

26. Naltrexone

27. Pimavanserin

28. Psychostimulants

29. Repetitive Transcranial Magnetic Stimulation 30. SARI Antidepressants

31. Selegiline Transdermal

32. Sex-Drive Depressants

33. SNRI Antidepressants

34. SSRI Antidepressants

35. Valbenazine

36. Vilazodone

37. Vortioxetine

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

APPENDIX: NEUROSCIENCE-BASED NOMENCLATURE (NbN)

In 2010, the European College of Neuropsychopharmacology (ECNP; https://www.ecnp.eu/) established a Taskforce on Nomenclature to address a topic that had been of growing concern within the worldwide neuropsychopharmacological community for some time – that the existing nomenclature of psychotropic medications, whose origins date back to the 1950s, did not adequately re ect the underlying neuroscience of these drugs.

This concern essentially centered on two aspects: that inadequate nomenclature, on the one hand, made it more di cult to nd innovative treatments (and subsequently obtain approval for them) whilst, on the other hand, it was confusing patients (who were, e.g., wondering why they were being prescribed an antidepressant for their anxiety, as the primary indications of most psychiatric drugs are not unique) and exacerbating noncompliance – all of which ultimately negatively impacts patient welfare.

The Taskforce, consisting of representatives from the American College of Neuropsychopharmacology (ACNP; https://acnp.org/), the Asian College of Neuropsychopharmacology (AsCNP; http://ascnp.org/), the International College of Neuropsychopharmacology (CINP; https://cinp.org/), ECNP (ECNP; https://www.ecnp.eu/), and the International Union of Basic and Clinical Pharmacology (IUPHAR; https://iuphar.org/) presented a proposal for a new neuroscience-based nomenclature at the 27th European College of Neuropsy- chopharmacology (ECNP) Congress in Berlin, Germany, on October 19, 2014.

This new multi-axial approach to drug classi cation based on pharmacological mode of action is still very much a work in progress and has inherent exibility to grow as needed. In terms of prescribing practice, an emphasis on mechanism might provide an extra stimulus for every prescribing clinician to think what they are doing when they prescribe for patients.

As an introduction to the proposed new classi cation, the table below lists commonly prescribed psychotropic medications together with their pharmacological targets and modes of action.

Generic Name Mode of Action

Pharmacological Target

Glutamate multifunctional Melatonin multifunctional GABA

Dopamine

Serotonin multifunctional

Norepinephrine multifunctional Dopamine multifunctional Dopamine multifunctional

Dopamine

Dopamine multifunctional Norepinephrine

Dopamine multifunctional Opioid

Dopamine multifunctional

Serotonin

GABA multifunctional Dopamine multifunctional

GABA

Dopamine multifunctional

Serotonin

Acamprosate

Agomelatine

Alprazolam

Amisulpride

Amitriptyline

Amoxapine

Amphetamine (D) and (D,L) Aripiprazole

Multimodal: NMDA receptor antagonist, GABA modulator

Multimodal: Melatonin receptor agonist, serotonin receptor antagonist

Benzodiazepine receptor agonist (GABAA receptor positive allosteric modulator)

Dopamine D2 receptor antagonist

Serotonin and norepinephrine reuptake inhibitor

Norepinephrine and serotonin reuptake inhibitor

Multimodal: Dopamine and norepinephrine reuptake inhibitor, dopamine and norepinephrine releaser Dopamine and serotonin receptor partial agonist

Dopamine reuptake inhibitor

Dopamine and serotonin receptor antagonist

Norepinephrine reuptake inhibitor

Dopamine and serotonin receptor partial agonist

Receptor partial agonist (μ), receptor antagonist (κ,d)

Multimodal: Dopamine reuptake inhibitor, dopamine and norepinephrine releaser

5-HT1A receptor partial agonist

Voltage-gated sodium and calcium channel blocker

Dopamine and serotonin receptor partial agonist

Benzodiazepine receptor agonist (GABAA receptor positive allosteric modulator)

Dopamine receptor antagonist, other receptors antagonist

Armoda nil

Asenapine

Atomoxetine

Brexpiprazole

Buprenorphine

Bupropion

Buspirone

Carbamazepine

Cariprazine

Chlordiazepoxide

Chlorpromazine

Citalopram Serotonin reuptake inhibitor

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 441 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Appendix

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Pharmacological Target

Serotonin multifunctional

GABA Norepinephrine

GABA

Dopamine multifunctional Norepinephrine

Serotonin multifunctional GABA

Acetylcholine

Serotonin multifunctional Norepinephrine multifunctional Serotonin multifunctional

Serotonin GABA GABA

GABA Serotonin

Dopamine Dopamine GABA

Serotonin Glutamate Acetylcholine

Norepinephrine Dopamine Histamine

Dopamine multifunctional Serotonin multifunctional Serotonin multifunctional

Glutamate

Norepinephrine multifunctional Dopamine multifunctional

Lithium multifunctional Norepinephrine

Generic Name

Clomipramine Clonazepam Clonidine Clorazepate Clozapine Desipramine Desvenlafaxine Diazepam Donepezil Dosulepin Doxepin Duloxetine Escitalopram Estazolam Eszopiclone Flunitrazepam Fluoxetine Flupenthixol Fluphenazine Flurazepam Fluvoxamine Gabapentin Galantamine Guanfacine Haloperidol Hydroxyzine Iloperidone Imipramine Isocarboxazid Lamotrigine Levomilnacipran Lisdexamfetamine Lithium Lofepramine

Appendix: Neuroscience-Based Nomenclature (NbN) (cont.)

Mode of Action

Serotonin and norepinephrine reuptake inhibitor

Benzodiazepine receptor agonist (GABAA receptor positive allosteric modulator) Norepinephrine α-2 receptor agonist

Benzodiazepine receptor agonist (GABAA receptor positive allosteric modulator) Dopamine and serotonin receptor antagonist, other receptors antagonist Norepinephrine reuptake inhibitor

Serotonin and norepinephrine reuptake inhibitor

Benzodiazepine receptor agonist (GABAA receptor positive allosteric modulator) Acetylcholinesterase enzyme inhibitor

Serotonin and norepinephrine reuptake inhibitor

Norepinephrine and serotonin reuptake inhibitor

Serotonin and norepinephrine reuptake inhibitor

Serotonin reuptake inhibitor

Benzodiazepine receptor agonist (GABAA receptor positive allosteric modulator) Benzodiazepine receptor agonist (GABAA receptor positive allosteric modulator) Benzodiazepine receptor agonist (GABAA receptor positive allosteric modulator) Serotonin reuptake inhibitor

Dopamine D2 receptor antagonist

Benzodiazepine receptor agonist (GABAA receptor positive allosteric modulator) Serotonin reuptake inhibitor

Voltage-gated calcium channel blocker

Acetylcholinesterase enzyme inhibitor

Norepinephrine α-2 receptor agonist

Dopamine D2 receptor antagonist

Histamine receptor antagonist

Dopamine and serotonin receptor antagonist

Serotonin and norepinephrine reuptake inhibitor

Monoamine oxidase type A and type B enzyme inhibitor

Voltage-gated sodium channel blocker

Norepinephrine and serotonin reuptake inhibitor

Multimodal: Dopamine and norepinephrine reuptake inhibitor, dopamine releaser Enzyme active site interactions

Norepinephrine reuptake inhibitor

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Pharmacological Target

GABA GABA

Dopamine multifunctional Dopamine multifunctional Norepinephrine

Melatonin

Glutamate multifunctional Dopamine multifunctional

Norepinephrine multifunctional GABA

Norepinephrine multifunctional

Norepinephrine multifunctional Serotonin multifunctional Dopamine

Opioid multifunctional Opioid multifunctional

Serotonin multifunctional Norepinephrine multifunctional Dopamine multifunctional

GABA

GABA multifunctional Dopamine multifunctional

Serotonin

Dopamine multifunctional Dopamine

Serotonin multifunctional Serotonin

Dopamine

Dopamine Glutamate

Norepinephrine multifunctional GABA

Dopamine multifunctional

Melatonin Norepinephrine Dopamine multifunctional

Acetylcholine multifunctional

Generic Name Mode of Action

Lorazepam

Lormetazepam

Loxapine

Lurasidone

Maprotiline

Melatonin

Memantine

Methylphenidate (D) and (D,L) Mianserin

Benzodiazepine receptor agonist (GABAA receptor positive allosteric modulator) Benzodiazepine receptor agonist (GABAA receptor positive allosteric modulator) Dopamine and serotonin receptor antagonist

Dopamine and serotonin receptor antagonist

Norepinephrine reuptake inhibitor

Melatonin M1 and M2 receptor agonist

NMDA receptor antagonist

Multimodal: Dopamine and norepinephrine reuptake inhibitor, dopamine releaser

Multimodal: Norepinephrine alpha-2 receptor antagonist and norepinephrine reuptake inhibitor Benzodiazepine receptor agonist (GABAA receptor positive allosteric modulator) Norepinephrine and serotonin reuptake inhibitor

Midazolam

Milnacipran

Mirtazapine

Moclobemide

Moda nil

Nalmefene

Naltrexone

Nefazodone

Nortriptyline

Olanzapine

Oxazepam

Oxcarbazepine

Paliperidone

Paroxetine

Perospirone

Perphenazine

Phenelzine

Pimavanserin

Pimozide

Pipotiazine

Pregabalin

Protriptyline

Quazepam

Quetiapine

Ramelteon

Reboxetine

Risperidone

Rivastigmine Acetylcholinesterase and butyrylacetylcholinesterase enzyme inhibitor

Norepinephrine α-2, 5-HT2A , 5-HT2C , 5-HT3 , receptor antagonist Reversible monoamine oxidase type A inhibitor

Dopamine reuptake inhibitor

μ, δ receptor antagonist, and κ receptor partial agonist Opioid receptor antagonist

5-HT2 and 5-HT1A receptor antagonist

Norepinephrine and serotonin reuptake inhibitor

Dopamine and serotonin receptor antagonist, other receptors antagonist

Benzodiazepine receptor agonist (GABAA receptor positive allosteric modulator)

Voltage-gated sodium and calcium channel blocker

Dopamine and serotonin receptor antagonist

Serotonin reuptake inhibitor

Dopamine and serotonin receptor antagonist

Dopamine D2 receptor antagonist

Monoamine oxidase type A and type B enzyme inhibitor

5-HT2A receptor antagonist

Dopamine D2 receptor antagonist

Voltage-gated calcium channel blocker

Norepinephrine and serotonin reuptake inhibitor

Benzodiazepine receptor agonist (GABAA receptor positive allosteric modulator)

Dopamine and serotonin receptor antagonist, Norepinephrine reuptake inhibitor (active metabolite) Melatonin M1 and M2 receptor agonist

Norepinephrine reuptake inhibitor

Dopamine and serotonin receptor antagonist

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 443 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

Appendix

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, &

Appendix: Neuroscience-Based Nomenclature (NbN) (cont.)

Pharmacological Target

Norepinephrine multifunctional Dopamine multifunctional

Serotonin

GABA multifunctional Dopamine

GABA

Dopamine multifunctional Glutamate

Serotonin multifunctional Serotonin multifunctional

GABA

Dopamine

Serotonin multifunctional

Glutamate

Acetylcholine

Serotonin multifunctional

Serotonin multifunctional Serotonin multifunctional

GABA

Dopamine multifunctional GABA

GABA

Dopamine multifunctional Dopamine

Generic Name

Selegiline

Sertindole

Sertraline

Sodium oxybate (GHB) Sulpiride

Temazepam Thioridazine Tianeptine Tranylcypromine Trazodone Triazolam Tri uoperazine Trimipramine Valproate Varenicline Venlafaxine Vilazodone Vortioxetine

Zaleplon Ziprasidone Zolpidem Zopiclone Zotepine Zuclopenthixol

Further Reading

Mode of Action

Monoamine oxidase type B and Type A enzyme inhibitor Dopamine and serotonin receptor antagonist

Serotonin reuptake inhibitor

GABAB and Gamma-hydroxybutyrate (GHB) receptor agonist Dopamine D2 receptor antagonist

Benzodiazepine receptor agonist (GABAA receptor positive allosteric modulator) Dopamine and serotonin receptor antagonist, other receptors antagonist

Yet to be determined

Multimodal: Monoamine oxidase type A and type B inhibitor, dopamine releaser Multimodal: 5-HT2 receptor antagonist, 5-HT1A partial agonist

Benzodiazepine receptor agonist (GABAA receptor positive allosteric modulator) Dopamine D2 receptor antagonist

5-HT2 and D2 receptor antagonist

Yet to be determine

Acetylcholine receptor partial agonist

Serotonin and norepinephrine reuptake inhibitor

Multimodal: Serotonin reuptake inhibitor and 5-HT1A receptor partial agonist

Multimodal: Serotonin reuptake inhibitor, 5-HT3, 5-HT7, and 5-HT1D receptor antagonist, 5-HT1A and 5-HT1B receptor partial agonist

Benzodiazepine receptor agonist (GABAA receptor positive allosteric modulator)

Dopamine and serotonin receptor antagonist

Benzodiazepine receptor agonist (GABAA receptor positive allosteric modulator)

Dopamine and serotonin receptor antagonist

Dopamine D2 receptor antagonist

Additional Suggested Reading

• ZoharJ,NuttDJ,KupferDJ,etal.Aproposalforanupdatedneuropsychopharmacologicalnomenclature.EurNeuropsychopharmacology.2014;24(7):1005–1014.doi:10.1016/j.euroneuro. 2013.08.004

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Adzenys XR-ODT

see Amphetamines

Aerosols 335, 359–360 Agomelatine 2, 441 Akineton see Biperiden Albuterol 302

Alcohol 9, 15, 20, 21, 27, 29, 34, 46, 55, 69, 76, 130, 157, 161, 172, 223, 226–228, 239, 260, 265, 272, 295, 297, 298, 311, 330, 332, 335, 337–341, 343, 348, 356, 360–362, 369–374, 379, 383, 389, 415, 416

– Interactions 36, 37, 50, 57, 58, 130, 157, 228, 243, 260, 275, 277–279, 330, 339–341, 360, 362, 380, 383

– Withdrawal treatment

230, 231, 233, 265, 291, 337–339, 365, 368, 371, 372, 374, 387, 401

Amino acids 204 Aminophylline 262

Antacids 212, 227, 268, 272, 277, 279, 321–323, 383

Anti-alcohol drugs 367–376 Antiandrogens 328–333 Antiarrhythmics 212

– Interactions 11, 21, 29, 57,

126, 131, 151, 170, 175, 273, 277, 302, 318, 319, 323, 383, 428–430

Anti-asthma drugs 68 Antibiotics 11, 21, 29, 36, 41,

45, 49, 57, 63, 68, 73, 102, 126, 151–152, 170, 212, 227, 236, 242, 245, 260, 273, 275, 310, 318, 319, 330, 339, 343, 355, 373, 379, 384

Anticholinergics 10, 21, 29, 33–36, 63, 68, 78–81, 96, 111, 112, 118, 119, 122, 127, 130, 137, 138, 145, 152, 177, 198, 203, 207–220, 244, 267, 284, 306, 311, 316, 318–319, 337, 347, 352, 382

Anticoagulants 11–12, 29, 36, 41, 45, 49, 57, 97, 127, 152, 242, 273, 275, 297, 323, 339, 373

Anticonvulsant mood stabilizers

see Anticonvulsants

Anticonvulsants 12, 21, 29, 81, 88, 94–95, 97, 127, 199, 221, 234, 235, 253, 262–287, 298, 310, 318, 323, 330, 339, 355, 391, 400–401, 414, 440

– Interactions 21, 36, 49, 57, 68, 73, 95, 98, 107, 152–153, 170, 212, 227, 242, 260, 273, 278, 297, 373, 379, 384

– Tables 277–279–286, 287

Antidepressants 2–89, 89, 90, 93–97, 100, 104, 105, 107, 116, 127, 133, 134, 154, 171, 198, 199, 221, 234, 236, 242, 244, 253–256, 260, 273, 277, 279, 280, 289, 297, 308–311, 319, 339–340, 342, 343, 347, 348, 365, 373, 385, 393, 394, 398, 399, 401–402, 419, 420, 423, 433, 440

Abacavir

Abilify

Acamprosate 339, 367,

Acidifying agents

349

Alfentanyl 356 Aliphatic phenothiazines

Acyclovir 276

Adapin Adasuve Adderall

α-blockers 69, 340 α-methyltryptamine 351 Alprazolam 14, 37, 58,

222–229, 274, 340, 365, 373,

415, 421, 441

– Tables 229

Amantadine 6–8, 21, 54, 121,

142, 143, 204, 208–210, 212, 213, 214, 217, 320, 322, 323

340, 384

see Aripiprazole

Amiodarone 175, 302 Amisulpride

441

126, 151, 170,

134, 139, 200,

369–370, 374, 376, 440, 441 Acamprosate calcium 369 ACE inhibitors 57, 69, 260,

392, 409

Acetaldehyde 340 Acetaminophen 277, 339, 357 Acetazolamide 36, 58, 260,

261, 274, 279, 299 Acetylcholine 7, 42, 88, 94,

126, 151, 170, 209, 315, 323,

364, 387, 402 Acetylcholinesterase 318, 323 Acetylcholinesterase inhibitors

126, 151, 170

Acetylsalicylic acid 7, 9, 11, 27,

29, 34, 48, 261, 277, 317, 339 – Interactions 41

AChE see Acetylcholinesterase

2, 12, 50–59, 69, 107, 116, 128, 142, 155,

298, 311, 20, 55, 62,

see Doxepin see Loxapine

109, α2 agonists 29, 298, 307–311

Activated charcoal

126, 146, 151, 211, 212, 269

115

Alkaline agents 323 Allopurinol 392, 410 Alosetron 13

see Dextroamphetamine/

amphetamine salts Adderall XR

see Dextroamphetamine/

amphetamine salts

ADHD, Drugs for 289–312 – Tables 302–307 Adrenergic agents 391, 392 Adsorbents 126, 151, 212 Adzenys ER

– Tables Ambien Amiloride

214, 215, 217 see Zolpidem

65, 256, 261

Anorexiants Antabuse

11, 245

see Disul ram

445

see Amphetamines

* Page numbers in bold type indicate main entries.

INDEX OF DRUGS*

– Tables 77, 80, 84 Amphetamines 16, 63, 70,

72, 73, 76, 131, 133, 160, 173, 289–307, 311, 335, 336, 341–345, 352–353, 362, 441

– Interactions 260, 342–343 – Tables 302–307 Amprenavir 373, 384

AMT see α-methyltryptamine Amylinomimetics 126, 151 Anafranil see Clomipramine Analgesics 11, 16, 19, 29, 45,

51, 59, 106, 117, 131, 243, 277, 339, 356–358, 361, 377, 380, 382, 385, 386

Androcur see Cyproterone Androcur Depot

see Cyproterone Anesthetics 57, 63, 68,

96–98, 105, 125, 126, 227, 273, 275, 277, 323, 339, 350, 351, 359, 361

– Tables 77, 79–87 Antidiabetics

see Hypoglycemics Antiemetics 13, 41, 50, 260,

355

Anti brinolytic 330 Antifungals 13, 29, 36, 41,

45, 50, 57, 128, 155, 171, 213, 228, 236, 242, 274, 310, 319, 330, 340, 343, 379, 384

Antihistamines 13, 15, 29, 36, 37, 57, 58, 68, 127, 130, 152, 155, 157, 171, 208, 212, 227, 228, 238–243, 294, 297, 311, 340, 355, 356

– Interactions 68

– Tables 246–247, 250 Antihypertensives 35–36, 50,

58, 69, 78, 95, 98, 128, 155, 260–261, 274, 310, 316, 340, 343

Amitriptyline

199, 236, 245, 273, 276, 297,

298, 365, 373, 379, 384, 421,

430, 431, 441

– Tables 77, 80, 83 Amlodipine 37 Ammonium chloride

– –

Augmentation 87–89, 102, 290

Interactions 11–17, 21–23, 29–31, 35–37, 40–41, 45, 49–50, 57–59, 63, 68–70, 73, 76, 98, 102, 107, 127–128, 152, 212, 227–228, 245, 273, 276, 278, 297–298, 302, 355, 373, 379, 384, 386, 428

298, Amoxapine 50–59, 80, 122,

299, 343, 349 441

Index of Drugs

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

446

55, 69, 95, 96, 142, 126, 151, 212

– Interactions 29, 113, 213, 276

Anti-infective 323 Anti-in ammatory agents

391, 395 Antimalarials 302, 323

Antivirals

340

261, 274, 276, 278, 14, 37, 41, 58, 73,

Atropine 318, 347

Attapulgite Austedo

319, 339, 340, 343, 386, 391,

392, 409

Betamethasone 158, 172 Bethanechol 7, 53–54, 56,

112, 119, 121, 138, 143, 211,

319

Biguanides 279

– Interactions 12, 21, 29, 45, 57, 63, 68, 98, 106, 107, 154, 171, 212, 242, 302, 432

– Tables 77, 79, 82, 387–389 Buspar see Buspirone Buspirone 6–8, 14, 42, 58, 69,

73, 89, 157, 221, 234–236,

312, 339, 340, 440, 441

– Interactions 37, 41, 63,

129, 236

Butorphanol 385 Butyrophenone 109, 115 – Tables 191 Butyrylcholinesterase 323

Cabergoline 120, 141 Ca eine 11, 15, 28, 35, 54,

56, 68, 94, 98, 112, 130, 157, 206, 213, 227, 228, 239, 241, 243, 255, 259, 261, 335, 341, 352, 365, 373, 386

Calcitonin 261 Calcium channel blockers

204, 340, 409

– Interactions 15, 30, 41, 58,

85, 128, 130, 157, 228, 236,

261, 274, 278

Calcium iodide 261 Campral see Acamprosate

calcium

Candesartan 260 Cannabidiol see Cannabis Cannabinoids see Cannabis Cannabinoids, synthetic 350 Cannabis 15, 58, 130, 335,

336, 340, 343–346, 347–349,

351, 362, 365

– Interactions 347–348 Captopril 66, 119, 140, 260 Carbamate 314 Carbamazepine 12, 21, 33,

36, 41, 44, 45, 49, 53, 57, 68, 73, 85, 88, 95, 98, 127, 152, 170, 227, 242, 253, 255, 260, 262–287, 297, 310–312, 318, 330, 339, 355, 373, 379, 384, 398, 441

Antinauseants Antineoplastic 274 Antiparasitic 373 Antiparkinsonian agents

229–233

12, 29, 36, 41, 45,

Azithromycin

Biperiden

218

– Tables Biphentin

208, 209, 210, 214, 215

127, 128, 138, 152, 155, 171,

203–216, 440

– Tables 214

Antiplatelets 13, 22, 30, 50 Antipsychotics 6, 29, 30, 57,

87–89, 93, 104, 107, 109–201, 203, 205–207, 209, 211, 223, 243, 244, 253, 255, 257, 261, 264, 277, 299, 302, 311–312, 319, 337, 339, 342, 343, 347, 355, 356, 365, 380, 408, 410, 413, 417, 423, 432, 433, 440

– Augmentation 198–201

– Interactions 13–14, 22, 30,

36, 41, 50, 58, 63, 69, 98, 102, 126–131, 151–160, 170–173, 175, 213, 228, 236, 274, 276, 298, 340, 347, 380, 384, 386

– Tables 176, 180, 181, 185–192, 205–207

Antipsychotics, Depot

– Tables 191–192 Antipyretics 211 Antiretrovirals 14, 30, 37, 58,

129, 156, 172, 236, 302, 319, 330, 343, 348–349, 356, 362, 373

– Interactions 22, 41, 228, 243, 274, 276, 278, 380, 384 Antituberculars 14, 22, 129,

157, 172, 213, 236, 243, 274, 276, 319, 340, 356, 373, 380, 384

Antitussives 68, 357, 358

Aplenzin

Appetite suppressants Aprepitant 157 Aptensio XR

Barbiturates 12, 36, 57, 69, 226–228, 238, 243, 267, 335, 339, 343, 348, 384, 421

– Tables 247–248, 250 Belladonna alkaloid 129, 157 Belsomra see Suvorexant Benadryl

see Diphenhydramine Benperidol 329 Benzisothiazol 109, 132 Benzisoxazole 109, 132, 193 Benzodiazepines 6, 14, 20,

22, 32, 55, 76, 95–97, 139, 145, 149, 157, 172, 198, 203, 204, 208, 209, 211, 221, 222–233, 234–235, 238–241, 243, 258, 261, 274, 276, 311, 335, 339, 340, 342, 347, 348, 354–356, 360, 363, 365, 368, 373, 379, 385, 392, 401, 407, 415, 416, 421, 422, 440

– Interactions 37, 50, 58, 98, 129, 157, 227–229, 236, 360, 362, 373, 380

– Tables 214, 229–233 Benzothiazolylpiperazine

109, 132

Benztropine 13, 55, 142, 146,

205, 208, 209–211, 214, 217, 318–319, 347

214, 215, 217 146, 302

see Methylphenidate Biphetamine

see Dextroamphetamine Bisarylsulfanyl amine 41

Bismuth subsalicylate Bisoprolol 261 Bisphosphonates 329

BLT see Bright light therapy Boceprevir 129, 156, 172 Botulinum toxin 204 Brexanolone 2 Brexpiprazole 89, 109,

161–173, 253, 441

– Tables 176, 181, 189, 427 Bright light therapy 100–102,

440

Brintellix see Vortioxetine Bripiprazole 432

Brisdelle see Paroxetine

22, 131, 159, 95, 318

– Interactions 14, 63, 69, 129, 157, 226, 227–229, 236,

13, 21, 29, 36, 57, 63, 68, 118,

see Bupropion 68

Anxiolytics

145, 221–236, 239, 243, 308, 340, 361, 380, 440

see Deutetrabenazine Aventyl see Nortriptyline Azapirone 129

Baclofen

400

276

– Tables Apixaban 57, 273

57, 126, 227 59, 204, 367, 391,

see Methylphenidate Aricept see Donepezil Aripiprazole 14, 30, 89, 109,

112, 120, 128, 156, 161–173,

200, 243, 253, 274, 312, 441 – Interactions 170–173, 213 – Tables 176, 181, 189,

193–196, 427

Aristada see Aripiprazole Aristada Initio

see Aripiprazole Armoda nil 76, 289, 391,

398, 441

Artane see Trihexyphenidyl ASA see Acetylsalicylic acid Ascorbic acid see Vitamin C Asenapine 13, 109, 110, 129,

132–149, 253, 441

– Interactions 128, 129, 151,

152, 154–156, 159, 160

– Tables 176, 181, 185 Asendin see Amoxapine Astemizole 430

Atarax see Hydroxyzine Atazanavir 129, 156, 172,

243, 274, 278, 380

Atenolol 255, 340, 391, 392 Ativan see Lorazepam Atomoxetine 16, 23, 63, 289,

295, 299–302, 304, 311, 312,

399, 440, 441

– Tables 302–307, 427 Atorvastatin 37

277

– Tables β-agonists β-blockers

15, 22, 30, 69, 95, 96, 98, 119, 128–129, 172,

203–207, 208, 214, 228, 243, 255, 261, 264, 274, 299, 310,

14, 222–230 69, 120, 138,

141, 142 Bromperidol 432 BuChE

see Butyrylcholinesterase Bunavail see Buprenorphine Buprenorphine 275, 355, 367,

368, 377–380, 385, 440, 441 – Interactions 379 Bupropion 2, 6, 17–23, 44,

51, 79, 82, 88, 289, 300, 310, 311, 319, 365, 367, 368, 374, 385–387, 440, 441

Bromazepam

– Tables 230 Bromocriptine

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

– Interactions 175, 212, 273–275, 277–279, 428, 432

– Tables 263–265, 270, 279–287, 427

Carbapenems 275

Carbatrol see Carbamazepine Carbolith see Lithium Carbonic anhydrase inhibitors

Cholestyramine 37, 58, 126, 151, 212

Cholinergics 19, 54, 55, 122, 130, 145, 167, 197, 198, 315,

318

297, 298, 307–311, 355, 365,

368, 382, 440, 442 Clopidogrel 13, 22, 30, 50 Clopixol see Zuclopenthixol Clopixol Acuphase

see Zuclopenthixol Clopixol Depot

see Zuclopenthixol Clorazepate 222–231, 442 – Tables 231

Clozapine 13, 30, 51, 58, 93,

95–98, 107, 109, 110, 112, 120, 123, 132–159, 171, 176, 188, 197–200, 207, 228, 253, 261, 274, 276, 308, 343, 365, 386, 417, 432, 433, 440, 442

– Interactions 36, 213, 269 – Tables 147, 176, 181, 185,

428

Clozaril see Clozapine

CNS depressants 15, 37, 50,

58, 69, 76, 111, 130, 157, 172, 227–228, 243, 269, 311, 338, 340, 348, 356, 360, 362, 380, 415, 422

Cobicistat 274, 278

Cocaine 70, 85, 160, 161, 205,

217, 265, 335, 336, 341,

342–345, 348–350, 356, 373 – Interactions 131, 343 Codeine 16, 59, 68, 131, 213,

243, 341, 354–358, 376, 377 – Tables 428

Cogentin see Benztropine Cognition enhancers

314–326

Commit see Nicotine

replacement therapy Compoz

see Diphenhydramine Concerta

see Methylphenidate

Crack 342, 345, 349 Cyclic antidepressants

Desipramine 2, 12, 22, 29, 50–59, 63, 69, 88, 227, 242, 273, 297, 298, 310, 311, 343, 347, 373, 384, 419, 430, 431, 442

– Tables 77, 80, 83 Desmopressin 15, 45, 256,

261, 274 Desoxyephedrine

see Methamphetamine Desoxyn

see Methamphetamine Desvenlafaxine 2, 23–31, 77,

127, 260, 289, 297, 442 – Tables 79, 83, 428 Desyrel see Trazodone Deutetrabenazine 203,

207–210, 212, 213, 218, 440 – Interactions 212, 213

– Tables 216 Dexamethasone 274, 396 Dexampex

see Dextroamphetamine Dexedrine

see Dextroamphetamine Dexmethylphenidate

289–299, 303, 311

– Interactions 297

– Tables 302–307 Dextroamphetamine 8, 31,

50, 243, 290–299, 303–305,

311, 341–345, 373, 399

– Interactions 260, 298–299 – Tables 302–307 Dextroamphetamine/

amphetamine salts 290,

293, 294, 303–305, 368

– Tables 302–307 Dextromethorphan 16, 63,

69, 73, 302, 322, 323, 352,

356, 357

– Tables 430 Dextromethorphan-quinidine

(DM-Q) 391, 406 Diacetylmorphine 356 Diastat see Diazepam Diazemuls see Diazepam

268, 279, 284, 323 Cardesartan 260 Cardiac glycosides

95, – Interactions 213, 318–319

15, 37, 41, Cariprazine 109, 161–173,

15, 308 23, 274

213, 228, 279, 421 Carfentanyl 357

253, 441

– Tables 176, 181, 189, 427 Carisoprodol

– Tables 427

Carvediolol 261 Caspofungin 274

Catapres see Clonidine

CYP450 inducers CYP450 inhibitors Cyproheptadine

Catecholamines 343, 389, 393

218

– Tables 215 Cyproterone 328–333

254, 310, Celecoxib 261, 391, 395

– Tables

Dabigatran 57, 273 Dalfopristin

Cathinone 345 Celexa see Citalopram

11–17, 127, – Tables 77, 79, 82, 427

331–333

12, 29, 36, 41, 45,

227, 273

see Flurazepam

Cephalosporins 339 Champix see Varenicline Chantix see Varenicline

278

Clarithromycin 11, 29, 36, 39,

Dalmane

Danazol 273

Darunavir 14, 129, 156, 172,

Chloral hydrate

340

15, 238–243, 37, 242

243, 274, 278

D-cycloserine 391, 406, 407 DDAVP see Desmopressin Decongestants 68 Degarelix 328–333

– Tables 331–333 Delavirdine 30, 37, 129, 156,

274, 278, 302, 384 Demeclocycline 119, 140 Dementia treatment

314–326 – Tables

see Medroxyprogesterone

– Interactions

– Tables 246, 250 Chloramphenicol 227 Chlordiazepoxide 222–230,

276, 339, 365, 373, 441

– Interactions

– Tables 230

Chloroquine Chlorpheniramine 319 Chlorpromazine 13, 22, 36,

227–229 22, 159, 302

58, 102, 109–111, 115–131, 145, 156, 190, 243, 261, 299, 343, 347, 365, 432, 441

– Interactions 126, 128, 175, 213

– Tables 176, 180, 182 Chlorpropamide 102, 340

385, 442

– Interactions

15, 22, 140, see Methylphenidate

Co-trimoxazole 212

323–326

see Pethidine see Valproate

Cholinesterase inhibitors 314–319, 413

35–37, 57–58, 63, 69, 98, 128, 155, 227, 260, 273, 343, 373, 384

– Tables 77, 80, 83–84

– Tables 323–326 Cimetidine 15, 30, 41, 50, 58,

63, 130, 158, 173, 228, 243, 275, 277, 319, 323, 340, 356, 385

Cipralex see Escitalopram Cipralex Meltz

see Escitalopram Cipro oxacin 21, 29, 57, 126,

151, 227, 242, 330, 384 Cisapride 430

Cisplatin 274

Citalopram 2, 3–17, 42, 57,

62, 63, 68, 88, 89, 102, 127, 154, 171, 199, 260, 273, 379,

441

41, 57, 126, 152, 160, 170, 175, 212, 227, 236, 242, 273, 275, 310, 318, 319, 330, 343, 355, 373, 379

Clobazam 170, 273 Clomethiazole 402 Clomipramine 12, 50–59, 62,

63, 69, 80, 155, 221, 236, 431,

442

– Interactions 57–59

– Tables 77, 80, 83, 86 Clonazepam 5, 10, 33, 53, 55,

65, 206, 207, 208, 214, 222–230, 273, 274, 276, 363,

Cyclizine 355 Cyclobenzaprine Cyclophosphamide Cyclosporine 15, 236, 275,

421

Cymbalta see Duloxetine

41, 45 45

– Interactions

107, 129, 157, – Tables 214, 215, 218, 230

Corticosteroids 274, 365

Demerol Depacon Depakene Depakote DepoProvera

227–229, 261

Clonidine 29, 36, 50, 54, 58,

Cortisol 396 Cotempla XR-ODT

see Valproate see Valproate

78, 128, 142, 155, 204, 289,

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 447 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

2–59, – Interactions 12, 22, 29,

78, 128, 276, 290, 440 – Augmentation 88

5, 7–9, 54, 65, 121, 143, 208, 212, 214,

Index of Drugs

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

448

Diazepam 14, 22, 55, 96, 98, 129, 146, 157, 206, 208, 214, 218, 222–231, 236, 276, 339, 340, 342, 347, 348, 362, 365, 373, 385, 402, 421, 442

– Interactions 227–229 – Tables 216, 231, 428 Diazepam intensol

132

Dibenzothiazepine Dibenzoxazepine

Dolasetron

302

13, 50, 159, 260, see Methadone

ECT see Electroconvulsive therapy

Edluar see Zolpidem Edoxaban 273

Efavirenz 14, 22, 30, 129, 156,

274, 278, 343, 380, 384 E exor see Venlafaxine E exor XR see Venlafaxine Elavil see Amitriptyline Elbasvir 274, 278 Electroconvulsive therapy

89, 93–98, 105, 138, 200,

204, 226, 257, 440

Eligard see Leuprolide Elvitegravir 274, 278 EMSAM see Selegiline Enalapril 57, 260 Encainide

– Interactions 428, 430 Endoxifen 16

En urane 57, 126 Enoxacin 29

Ephedra 298, 352 Ephedrine 63, 70, 73, 143,

335, 344, 345, 352 Epinephrine 59, 63, 70, 131,

146, 160, 262

Epitol see Carbamazepine Epival see Valproate Eplenerone 261

Epoxide 269, 273, 277 Equetro see Carbamazepine Ergotamine 15 Erythromycin 11, 36, 41, 57,

85, 126, 152, 170, 227, 236, 273, 275, 310, 318, 319, 330, 343, 355, 379

Escitalopram 2, 3–15, 43, 57, 63, 171, 221, 260, 277, 419, 442

– Interactions 12, 127 – Tables 77, 79, 82, 429

– Interactions 228

– Tables 231

Estradiol 130, 158, 246, 275,

278, 402, 403

Estrogens 22, 58, 130, 158,

204, 228, 279, 340, 391, 402,

Flecainide 428–430 Flibanserin

11, 21, 29, 429

see Diazepam Dibenzodiazepine Dibenzo-oxepino pyrrole 109,

238–243, 442 242

50, 84, 109, Diclofenac 261, 275

115

Dicyclomine 308

Didanosine 384 Diethylstilboestrol 246 Digoxin 15, 37, 41, 213, 228,

279, 421

Dihydroergotamine 15 Dilaudid see Hydromorphone Diltiazem 15, 58, 130, 157,

204, 228, 236, 261, 274 Dimethyltryptamine 347, 351 Diphenhydramine 13, 29, 57,

68, 205, 208–218, 238–243,

250, 297, 318, 319

– Interactions 242–243 – Tables 216, 246, 250 Diphenoxylate 69 Diphenylbutylpiperidines

109, 115

Disopyramide 175, 273 Disul ram 130, 157, 228, 339,

340, 343, 348, 360, 367–369,

371–373, 385, 402, 440

– Interactions 298, 373 Diuretics 7, 97, 128, 130, 155,

256, 409

– Interactions 30, 41, 45, 69,

102, 130, 146, 157, 257, 261,

274, 278, 279, 323 Divalproex see Valproate Dixarit see Clonidine

DMT see Dimethyltryptamine Docusate see Stool softeners

Etrafon

Etravirine

Evekeo

Evening primrose oil 416 Exelon see Rivastigmine Extrapyramidal side e ects,

109, 132 109, 132

66,

Dolophine Dolutegravir

DOM (25-dimethoxy-4-

274, 278 methylamphetamine)

see Flupenthixol see Flupenthixol decanoate

Fluconazole

– Interactions 13, 29, 45, 57,

128, 155, 171, 228, 242, 274,

384

Fludrocortisone 54, 65, 67,

140

Flumazenil 95, 226, 243 Flunitrazepam 335, 345, 349,

362–363, 442

Fluoxetine 2–17, 22, 27, 29,

34, 36, 45, 49, 57, 63, 68, 82, 88, 89, 98, 102, 105, 127, 154, 171, 228, 236, 242, 260, 273, 276, 300, 302, 319, 348, 355, 442

– Interactions 11–17, 127, 212, 297, 298, 430–432

– Tables 77, 79, 82, 85, 429 Fluoxetine/olanzapine

combination 3, 4, 88,

132–134, 253

Flupenthixol 115–131, 180,

191–192, 274, 442

– Interactions 213

– Tables 176, 180, 182 Flupenthixol decanoate 115 – Tables 191–192 Fluphenazine 13, 58,

115–131, 154, 156, 180,

191–192, 243, 442

– Tables 176, 180, 182 Fluphenazine decanoate 115,

118

– Tables 191–192 Flurazepam 222–232, 442

– Tables 232

Fluvoxamine 2, 3–17, 29, 36,

49, 57, 63, 68, 82, 154, 171, 199, 204, 228, 236, 242, 245, 260, 273, 319, 365, 384, 432, 433, 442

347–349, 352 Domperidone 316 Donepezil 6, 126, 151, 170,

314–319, 320, 413, 442

– Interactions 213, 318–319 – Tables 323–326 Dopamine 2, 4, 17–19,

21–24, 33, 42, 54, 60, 64, 67, 69–71, 88, 94, 105, 109, 118, 120, 126, 128, 131, 137, 138, 141, 143, 146, 151, 155, 160, 162, 171, 203, 208–210, 291, 299, 302, 320, 336, 345, 349, 352, 369, 371, 387, 398, 399, 402, 419, 421, 423

403, 404

Eszopiclone

– Interactions

– Tables 247, 250 Ethopropazine 208–219 – Tables 214, 216, 219 Ethosuximide 273, 275 Ethyl eicosapentaenoic acid

(E-EPA) 200, 417 Etomidate 95, 96

Dopamine agonists Dopaminergic agents

138, 208 289,

see Amphetamines agents for treating

391, 398

Dosulepin 442

Doxazosin 78, 391, 395 Doxepin 50–59, 84, 155, 238,

273, 276, 355, 431, 442 – Tables 77, 80, 84 Doxorubicin 274

203–220 – Tables

Doxycycline 273, 339

102, 242, 260, 238, 246, 250

Doxylamine Dronabinol 368 – Tables 428

Felbamate Felodipine Fentanyl Fetzima

Fetzima Titration

Droperidol Drysol 54 Duloxetine

119, 159

2, 12, 23–30, 46,

261, 278

262, 354–357, 380

77, 98, 127, 171, 245, 260,

297, 442

– Interactions 29–30 – Tables 79, 83, 428

Duragesic Dyanavel XR

see Levomilnacipran see Levomilnacipran

see Fentanyl see Amphetamines

73–76, 81, 84, Eslicarbazepine 273

Esomeprazole 159 Estazolam 222–229, 442

FGAs 109–112, 115–131, 134, 137, 138, 180, 197, 205, 206, 209, 356

– Interactions 41, 126–131, 212

– Tables 176, 191–192 Finasteride 328–333

Ebixa Ecstasy

440

– Tables 77

– Tables Fiorinal-C Firmagon

331–333 357

see Degarelix

see Memantine see MDMA

Esketamine

see Perphenazine 129, 156, 274, 278

214, 215, 217 Famotidine 142, 173, 228,

266, 275

Fanapt see Iloperidone Fanatrex FusePaq

see Gabapentin FazaClo see Clozapine

273, 275

Fluanxol Fluanxol depot

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

– Interactions 11, 127, 428 – Tables 77, 79, 429 Focalin

see Dexmethylphenidate Focalin XR

see Dexmethylphenidate

Glue 335, 359–360

Hashish see Cannabis

Ifosfamide 23 Iloperidone 14, 109, 132,

133, 135, 140, 141, 143, 148,

151, 154, 155, 157, 158, 442 – Interactions 129, 151–160 – Tables 176, 181, 185, 429 Imatinib 274, 421 Imipramine 2, 12, 22, 29,

51–59, 85, 121, 143, 227, 273, 297, 310, 311, 355, 365, 386, 419, 431, 442

– Interactions 430

– Tables 77, 80, 84 Immunostimulators 261 Immunosuppressants 15,

236, 275, 340

Imovane see Zopiclone Impril see Imipramine Inderal see Propranolol Inderal LA see Propranolol Indinavir 30, 37, 129, 156,

172, 236, 274, 278, 330, 343,

348, 380, 384, 421

– Interactions 175, 228, 243 Indolalkylamine 37 Indomethacin 261 In uenza vaccine 275 Ingrezza see Valbenazine Inhalants 335, 359–360

– Interactions 360 Injectable opioid agonist

therapy (iOAT) 368 InnoPran XL see Propranolol Inositol 254

Insomnal

see Diphenhydramine

Insulin 15, 58, 69, 96, 97, 120,

139–141, 204, 256, 266, 283,

284, 365, 376, 386

Integrase inhibitors 274, 278 Intermezzo see Zolpidem Intuniv see Guanfacine Invega see Paliperidone Invega Sustenna

see Paliperidone Invega Trinza

see Paliperidone Iodide salt 261

Ipecac 55, 146

Irenka see Duloxetine Irinotecan 274, 421 Isocarboxazid 57, 60, 64–70,

212, 442

– Tables 81, 84

Iso urane 273

Isoniazid 129, 228, 274, 276,

Folate

Foquest For vo Fosamprenavir

see Vitamin B9

see Methylphenidate

62, 67, – Interactions 41, 213, 278

see Bupropion

14, 129, 156,

Granisetron

409

Grapefruit

– Interactions

13, 50, 260, 392, 11, 15, 32, 35,

102, 261, 298

Heroin 308, 335, 336, 343,

340, 373, 384 Isoproterenol Isotretinoin

– Interactions Itraconazole

59, 70

262, 275

172

Fosinopril 260 Fosphenytoin 260 Furazolidone 340 Furosemide 261, 278, 279

GABA 37, 42, 94, 221, 229, 239, 254, 280, 361, 369, 398, 401, 414, 421, 422

GABA agonists 229, 400

GABA

Gabapentin 98, 107, 221,

37, 39, 41, 58, 125, 130, 149, 158, 169, 172, 228, 236, 243, 275, 385

Grazoprevir 274, 278 Griseofulvin 340 Guanabenz 50 Guanethidine 36, 58, 69, 78,

340, 343

Guanfacine 49, 50, 276, 289,

345, 349, 356

Hetlioz see Tasimelteon

receptor modulator 253, 263–287, 367, 368, 442

– Interactions 277

295, 297, 298, 307–311, 440, 442

– Tables 270, 279–287 Gabapentin enacarbil 263

Galantamine 314–319, 442

H2 antagonists

130, 158, 173, 228, 277, 323, 340

– Interactions

– Tables 323–326, 429 Galanthamine

replacement therapy Halcion see Triazolam Haldol see Haloperidol Haldol decanoate

see Haloperidol decanoate

41, 213

16, 275, 277,

95, 227, 322, 323, 347–350, 391, 407

see Galantamine Gammabutyrolactone 361 Gamma-hydroxybutyrate

158, 172, 396 16, 335,

– Interactions 348 Ketoconazole

– Interactions 13, 29, 36, 41,

45, 50, 57, 128, 155, 171, 175, 213, 228, 236, 242, 274, 310, 319, 330, 340, 343, 379, 384

Ketoprofen 319 Ketorolac 261 Khat 341–345

335, 360–362, 367, 402, 444 – Interactions 362 Gati oxacin 175

Ge tinib 274

Geodon see Ziprasidone GHB

see Gamma-hydroxybutyrate Ginkgo biloba 15, 22, 37, 54, 158, 200, 204, 207, 298, 412

Ginseng 8, 54, 69, 213, 278 Glevaprevir 274, 278 Glucocorticoids 158, 172,

391, 396 Glucosamine 41

Hallucinogens

15, 335, 347

354, 358

Hydroxyzine 155, 238–243,

247, 250, 442

– Tables 247

Hypnotics 98, 172, 224,

238–251, 265, 277, 335, 348,

360, 379, 415, 440

– Interactions 15, 22, 30, 37,

58, 130, 157, 242–243, 277,

385

– Tables 246–251 Hypoglycemics 69, 95, 97,

126, 151, 319

15, 30, 58, 63, Habitrol see Nicotine

– Interactions Hydrocodone 354, 358

Hydrocortisone Hydromorphone

Kemadrin Ketalar Ketamine

340

Hormones 22, 58, 118, 119,

130, 140, 158, 228, 235, 240, 246, 261, 275, 278–279, 328, 329, 361, 364, 365, 391, 402, 416

5-HT2A inverse agonist antipsychotic 174–175

– Tables 190

Hydralazine 340 Hydrochlorothiazide 45, 102,

130, 274, 279, 310, 323

Glutamate 369, 414

42, 280, 320, 350, 16, 330, 340

Hawthorn

– Interactions

213

Glyburide

Glycopyrrolate 95 Goserelin 328–333

– Interactions 330

– Tables 331–333 Gralise see Gabapentin

Hemangeol Hemangiol Henbane

– Interactions 213 Herbal preparations

346–353

– Interactions Haloperidol

13, 30, 36, 58, 107, 109, 111, 115–131, 134, 154, 156, 172, 180, 191–192, 213, 236, 261, 274, 276, 319,

Khedezla Klonopin

Labetalol

Lactulose

– Interactions 261 Lamictal see Lamotrigine

339, 340, 342, 347, 356, 432,

442

– Tables 176, 180, 182, 183

see Desvenlafaxine see Clonazepam

Haloperidol decanoate

115,

102, 120, 141, 323, 330, 340

58, 78 112, 212

122

– Tables Halothane

191–192 273, 339

Ibuprofen

41, 261, 275, 319 449

Horizant enacarbil

see Propranolol see Propranolol

see Gabapentin Hormone replacement therapy

29, 57, 128, 155, 171, 175, 213, 228, 236, 242, 269, 274, 310, 319, 330,

384

Jornay PM

see Methylphenidate

Kaolin-pectin 126, 151, 212 Kapvay see Clonidine

Kava kava 15, 229, 412, 414,

415

– Interactions 130, 213

see Procyclidine see Ketamine

– Interactions

Index of Drugs

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

450

see Leuprolide 109, 132–137,

Lamotrigine 88, 98, 127, 152, 170, 199, 221, 253, 263–287, 407, 442

– Interactions 276–278 – Tables 270, 279–287 Lansoprazole 229 Lapatinib 274

Lithane see Lithium

Lithium 15, 60, 89, 93, 95, 97,

130, 133, 158, 173, 199, 223, 229, 244–246, 253–262, 264, 287, 312, 348, 440, 442

– Interactions 30, 58, 69, 98, 130, 158, 246, 260–262, 275, 277, 348

– Tables 287 Lithium carbonate

see Lithium

Lithium citrate see Lithium Lithmax see Lithium Lithobid see Lithium Lofepramine 442

Lofexidine 368

Lomitapide 30

Loperamide 155, 256 Lopinavir 129, 156, 172, 243,

274, 278, 384

Lorazepam 5, 55, 95, 96, 98,

125, 129, 146, 157, 172, 205, 206, 208, 214, 222–232, 243, 276, 339, 340, 342, 347, 373, 443

– Interactions 227–229 – Tables 216, 219, 232 Lormetazepam 443 Losartan 260

16, 160 see Loxapine

Lupron Depot Lurasidone

Melatonin 16, 100, 101, 204, 239, 244, 412, 415–416, 443

Mellaril see Thioridazine Memantine 200, 314, 315,

320–326, 348, 443

– Interactions 322

– Tables 323–326 5-MeO-DIPT (5-methyl-di-iso-

propyl-tryptamine) 351 Meperidine 30, 41, 45, 63, 69,

73, 96, 354–356, 358, 380 – Interactions 262 Mescaline 335, 347, 350,

352–353 Metadate CD

see Methylphenidate Metadate ER

see Methylphenidate Metadol see Methadone Metamucil see Psyllium Metaxalone 261 Metformin 141, 142, 266,

323, 330, 340

Methadone 16, 59, 131, 146,

159, 173, 243, 265, 275, 302, 341, 355, 357, 367, 368, 376–380–385, 421, 440

Methylmorphine 357 Methylphenidate 6, 8, 16, 23,

31, 50, 59, 63, 70, 90, 131, 160, 173, 201, 243, 275, 289–298, 302–305, 308, 311, 341–345, 368, 373, 399, 443

– Interactions 41, 262, 297 – Tables 302–307

– Transdermal 295 Methyphenidate 76 Metoclopramide 16, 30, 131,

159, 173, 207, 260, 341, 355 – Interactions 41 Metoprolol 15, 22, 172, 243,

Largactil Latuda Laxatives

see Chlorpromazine see Lurasidone

141, 143, 148, 149, 154, 155,

157, 158, 253, 443

– Interactions 36

– Tables 176, 181, 185 Luvox see Fluvoxamine Luvox CR see Fluvoxamine Lysergic acid diethylamide

15, 335, 347–350–352 – Interactions 348

Maalox see Antacids Macrolides 36, 126, 152 Manerix see Moclobemide Mannitol 261

MAO-B inhibitors 2, 16, 30, 37, 59, 60, 63, 69, 70, 84, 440

MAOIs 2–3, 13, 29, 36, 44, 60, 64–70, 72, 73, 85, 87, 88, 90, 95–96, 102, 107, 296, 301, 302, 340, 342, 347, 358, 389, 440

– Interactions 13, 22, 29, 36, 41, 50, 57, 63, 68–70, 76, 98, 102, 128, 155, 212, 236, 245, 260, 269, 273, 297, 298, 302, 340, 355, 373, 379

– Tables 81, 84, 87 Maprotiline 2, 51–59, 80,

155, 355, 443

– Tables 77, 80, 84 Marijuana see Cannabis Marplan see Isocarboxazid Mazindol 343

MDA 69, 347–349, 352, 353 – Interactions 348

MDE 347–349, 353

MDMA 69, 342, 345,

347–349, 352, 353, 361, 385 – Interactions 348 Medroxyprogesterone

328–333

– Tables 331–333 Medroxyprogesterone acetate

275

Mefenamic acid 261 Me oquine 22, 302

52, 53, 56, 112, 119, 138, 212, 262

L-carnitine 269

L-deprenyl see Selegiline L-dopa 21, 63, 69, 229 Lectopam see Bromazepam Ledipasvir 274, 278 Leuprolide 328–333

– Interactions 330

– Tables 331–333 Levarterenol

see Norepinephrine Levate see Amitriptyline Levetiracetam 204, 207 Levo Dromoran

see Levorphanol

Levodopa

419

261, 340 Metronidazole

260, 273, 339,

Levo oxacin Levomilnacipran

46–50, 69, 88, 154, 199, 206,

238, 433, 440, 443

– Interactions 49, 297, 298

– Tables 77, 80, 83 Moclobemide 2, 9, 13, 26, 29,

36, 60–63, 81, 84, 89, 128,

245, 260, 297, 440, 443

– Interactions 41, 62, 298,

379

– Tables Moda nil

36, 77, 260, 442 – Tables 79, 83

109, 115–131, 274, – Interactions 126–131

see Methamphetamine Methamphetamine 46,

290–299, 303–305, 335,

341–344, 368

– Tables 302–307 Methohexital 95 Methotrexate 340 Methotrimeprazine 115–131 – Tables 176, 180, 183 Methyldopa 36, 58, 260, 340 Methylene blue

– Interactions 16, 22, 30, 37,

39, 41, 44, 45, 50, 63, 69, 261 Methylin

see Methylphenidate Methylin ER

see Methylphenidate

128, 162, 171, 415, 126, 151

– Interactions

383–385 Methadose Methampex

213, 262, see Methadone

see Antacids Milnacipran Minocycline Mirtazapine

433, 443

391, 396–397 2, 8, 12, 29, 42,

2, 23, 24, 25, Levonorgestrel 278

Lovastatin Loxapac Loxapine

Levorphanol 358 Levothyroxine see L-thyroxine Lexapro see Escitalopram LHRH agonists 328–333 Librium see Chlordiazepoxide Licorice

– Interactions 15, 30, 69 Lidocaine 11, 262, 345 Linezolid 11, 21, 29, 36, 39,

41, 44, 45, 49, 57, 63, 68, 73,

236, 245, 297, 358 Liothyronine 17, 90, 95, 393 Lisdexamfetamine 290, 291,

293–296, 298, 303–305, 442 – Tables 302–307

Lisinopril 155, 260

443

– Tables 176, 180, 183

Loxitane see Loxapine LSD see Lysergic acid

diethylamide

L-thyroxine 90, 255, 393–394 L-tryptophan 15, 37, 59, 63,

69, 78, 90, 98, 102, 238, 240,

241, 244–246, 440

– Interactions 15, 30, 37, 59,

63, 98, 102, 245, 261

81, 84

6, 76, 89, 160, 275,

– Tables Ludiomil Lunesta Lupron

247, 250

see Maprotiline

see Eszopiclone see Leuprolide

see Nitrazepam see Oral lubricants

372, 373 Mexiletine 11 Mianserin 443 Miconazole 57 Midazolam 14, 443 Midodrine 54

Milk of magnesia

289, 391, 398, 399, 443 – Tables 429

Modecate decanoate

see Fluphenazine see Fluphenazine

Moditen

Mogadon

MoiStir

Monoamine oxidase B inhibitor

see MAO-B inhibitors

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Monoamine oxidase inhibitors see MAOIs

Mood stabilizers 9, 65, 93, 133, 198, 253–287, 312, 399, 433

Morning glory 347–351 Morphine 16, 59, 243, 277,

335, 341, 343, 345, 348, 354–358, 368, 375–376, 380, 383, 385, 428

Moxi oxacin – Interactions

260

NDRI 2, 17–23, 79, 87–88, 154, 171

– Interactions 12, 21–23, 29, 45, 57, 63, 68, 98, 212, 242, 302

– Tables 77, 79, 82, 86 Nefazodone 2, 12, 29, 31–37,

63, 88, 128, 154, 228, 273,

NMDA agents 391

NMDA receptor antagonists

2, 73, 323, 348, 350 – Tables 77, 81, 84 N-methyl-D-aspartate

see NMDA

Nodoz see Ca eine Non-nucleoside reverse

transcriptase inhibitor (NNRTI) 14, 22, 30, 37, 129, 156, 274, 278, 302, 343, 380, 384

Norclozapine

276

193, 228, 253, 274, 276, 277,

298, 340, 365, 386, 432, 443 – Interactions 36, 50, 159,

213

– Tables 193–196

– Interactions 278

– Tables 270, 279–287, 430 Oxprenolol 261

Oxtellar XR

see Oxcarbazepine Oxtriphylline 262 Oxybutynin 54, 59, 143, 347 Oxycodone 16, 335, 354–356,

358

Oxymorphone 16, 354 OxyNeo see Oxycodone

Paint thinner 335 Paliperidone 14, 112, 128,

129, 132, 135, 137, 142, 146, 148–152, 154–156, 172, 253, 443

– Interactions 129, 156, 159 – Tables 176, 181, 186,

193–196

Pancuronium 262, 275 Paramethoxyamphetamine

347–349, 352, 353

Parnate see Tranylcypromine Paroxetine 2, 3–17, 29, 36,

45, 57, 68, 82, 102, 149, 154, 156, 158, 171, 221, 242, 260, 300, 302, 319, 348, 355, 415, 433, 443

– Interactions 11–17, 127, 212, 431, 432

– Tables 77, 79, 82, 430 Parsitan see Ethopropazine Paxil see Paroxetine

Paxil CR see Paroxetine

PCP see Phencyclidine Pentazocine 16, 63, 354–355,

358, 385, 386 Pentobarbital 238–250

Muscle relaxants

215, 216, 231, 261, 275, 315, 356, 373, 414

Nembutal see Pentobarbital Nemonapride 432 Neostigmine 7, 54, 121, 143 Neuleptil see Periciazine Neuroleptics

275, 414 Ondansetron

Mydayis

see Dextroamphetamine/ amphetamine salts

Nabilone 368 Nabiximols 368 N-acetylcysteine 368 Nadolol see β-blockers Nalbuphine 385

see Antipsychotics Neuromuscular blockers

355, 392, 409

Opioid analgesics 358, 385

Opioids 16, 30, 37, 41, 45, 50, 59, 63, 68–69, 73, 76, 130–131, 157, 159, 172, 173, 226, 229, 243, 246, 265, 275, 277–278, 308, 335, 341, 343, 348, 349, 351, 354–358, 360, 361, 374–385, 411, 421

– Interactions 23, 50, 213,

Nalmefene 411, 443

356, 367, 392, 269, 355, 356, 367,

274, 276, 278, 343, 384 Niacin 244, 250 Nicardipine 30 Nicoderm see Nicotine

replacement therapy Nicorette see Nicotine replacement therapy

Nicorette QuickMist

see Nicotine replacement therapy

Nicotine 23, 51, 69, 131, 308, 335, 364, 365, 386–389

Nicotine replacement therapy 365, 367, 368, 385–386, 389

– Tables 387–389 Nicotrol see Nicotine replacement therapy

Nifedipine 15, 58, 261, 274 Niravam see Alprazolam Nitrazepam 222–232

262, 355–356

– Withdrawal treatment Opium see Opioids

OraCare D see Oral lubricants Oral contraceptives

– Interactions 58, 130, 158,

228, 246, 275, 278–279, 365,

421

Oral lubricants 53, 119, 138,

211

Orap see Pimozide Orexin receptor antagonist

238

Orfenace see Orphenadrine Orlistat 142

Orphenadrine 21, 208–216

Naloxone 377–379 Naltrexone

368

308, 339, 356, 360, 367, 369, 370, 373–376, 385, 401, 402, 411, 433, 440,

443

– Interactions 376

– Tables 433

Namenda see Memantine Namenda XR see Memantine Namzaric see Memantine Naproxen 41, 261

Nardil see Phenelzine N-arylpiperazine 109

NaSSA 2, 29, 46–50, 73, 83,

87–88, 154, 340

– Interactions 12, 49–50, 69,

245, 297, 298

– Tables 77, 80, 83, 86 Navane see Thiothixene NBOMes 353

see Oxycodone see Oxycodone

126, 151, 175, 59, 69, 95,

Nel navir

274, 278, 319, 330, 348, 384

151, 154, 157, 2, 4, 17–19,

– Interactions 41

Omega-6 fatty acids Omeprazole 16, 59, 159, 229,

319, 443 – Tables

77, 79, 83, 430

22, 129, 156, 172,

Omega-3 fatty acids 204, 412, 416–419

89, 200, 416

262, Neurontin see Gabapentin

Nor oxacin 151 Nor uoxetine 5, 6 Normeperidine 358 Norpramin see Desipramine Nortriptyline 2, 22, 51–59,

63, 84, 88, 93, 98, 155, 273,

276, 311, 365, 368, 443 – Interactions 430

– Tables 77, 80, 84 Novahistex DH

see Hydrocodone Nozinan

see Methotrimeprazine NSAIDs 395

– Interactions 7, 9, 11, 16, 27,

30, 34, 41, 44, 45, 48, 258,

261, 275, 317, 319, 339 Nucleoside reverse

transcriptase inhibitor (NRTI)

276, 384

Nuedexta see Dextromethor-

phan-quinidine (DM-Q) Nuplazid see Pimavanserin

319

Nevirapine 14, 22, 129, 156,

– Interactions

– Tables 232

Nitroglycerin

Nizatidine 142, 158, 228, 275 NMDA 209, 320, 323, 350,

351

Nutmeg Nytol

347–349, 353

see Diphenhydramine

– Tables Oxazepam 373, 443

214, 216, 219 222–233, 339,

Percocet

Percodan

Periactin

Periciazine

– Tables

Peripheral nerve blocker 262 Perospirone 443

This document is for personal use only. Reproduction or distribution is not permitted. From Ric M. Procyshyn, Kalyna Z. Bezchlibnyk-Butler, & 451 J. Joel Jeffries: Clinical Handbook of Psychotropic Drugs, 23rd edition (ISBN 9781616765613) © 2019 Hogrefe Publishing.

228 340, 341

see Cyproheptadine 109, 115–183

Norepinephrine

23, 29, 42, 46, 59, 60, 63, 69, 70, 94, 131, 146, 160, 209, 289, 291, 297–299, 302, 343, 352, 398, 402, 419, 421

13, 42, 50, 260, Opiates see Opioids

O oxacin 57

Olanzapine 3, 14, 42, 88, 109,

112, 132–159, 160, 172, 190,

– Tables

Oxcarbazepine 73, 153, 170,

176, 181, 186, Oleptro see Trazodone

233

253, 263–287, 443

176, 180, 183

Index of Drugs

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

452

Perphenazine 13, 36, 58, 109, 115, 116, 117, 124, 125, 127, 129–131, 243, 261, 356, 443

Pimozide 13, 58, 109, 111, 115–131, 156, 330, 443

– Interactions 36, 41, 430

– Tables 176, 180, 184, 431 Pindolol 15, 89, 129, 391, 393

Promethazine 238 – Tables 247

Propafenone – Interactions

– Interactions 36

– Tables 176, 181, 187 Quillichew ER

see Methylphenidate Quillivant XR

see Methylphenidate Quinapril 260

Quinidine 11, 29, 45, 57, 126,

151, 170, 273, 302, 318, 319,

323, 383, 430 – Interactions

Rifampin 14, 22, 41, 44, 45, 59, 129, 157, 172, 228, 236, 243, 274–276, 278, 310, 319, 330, 356, 379, 380, 384

– Interactions 175, 213, 432 Rifapentine 129, 157 Rilpivirine 274, 278

Riluzole 391, 408

RIMA 2, 60–63, 73, 87–88, 96, 290

– Interactions 13, 29, 36, 62–63, 128, 155, 245, 260, 297, 298, 355

– Tables 81, 84, 87 Risperdal see Risperidone Risperdal Consta

see Risperidone Risperidone 14, 22, 30, 88,

98, 109, 110, 116, 132–160, 172, 181, 193, 243, 253, 261, 274, 298, 312, 319, 343, 384, 432, 433, 443

– Interactions 36, 276, 430 – Tables 176, 181, 187,

193–196, 431

Ritalin see Methylphenidate Ritalin LA

see Methylphenidate Ritalin SR

see Methylphenidate Ritonavir 14, 22, 30, 37, 41, 58, 129, 156, 172, 236, 274,

276, 278, 302, 319, 330, 343, 348, 349, 356, 362, 373, 380,

– Tables

Pethidine

Pexeva

Peyote 347

Phencyclidine 347–351 Phenelzine 2, 13, 22, 29, 36,

11, 21, 29, 57, Propantheline 316

Pibrentasvir Pilocarpine Pimavanserin

131, 159, Prolixin see Fluphenazine

176, 180, 183, 431 see Meperidine

428–430

Propofol 95, 98, 275, 339,

407

Propoxyphene

386

see Paroxetine

50, 57, 60, 64–69, 76, 85, 98,

Pioglitazone 391, 397 Piperazine phenothiazine – Tables 115, 191 Piperidine phenothiazine Pipotiazine 443 Piracetam 204

109 115

229, 354–356, 6, 15, 30, 55, 98,

155, 236, 260, 273, 297, 302,

342, 443

– Interactions 41, 68–69,

212, 298

– Tables 81, 84

Phenergan see Promethazine Phenobarbital 12, 21, 57, 127,

153, 170, 273, 277–279, 297,

318, 373, 379

– Interactions 276–278 Phenothiazines 109, 115,

117, 120–122, 124, 126–129,

131, 156, 261, 274, 276, 365 – Interactions 128, 428–430 Phentermine 11, 50 Phentolamine 66 Phenylephrine 59, 70, 73,

131, 146, 160, 386 Phenylpiperazine 109,

161–165, 193 Phenylpropanolamine 73,

345, 352

Phenyltriazine 221 Phenytoin 12, 21, 36, 41, 44,

45, 49, 57, 127, 153, 170, 227, 242, 260, 273, 277–279, 297, 318, 330, 339, 355, 373, 379, 384, 421

– Interactions 175, 212, 276–278, 432

Phosphodiesterase type 5 (PDE5) inhibitor 16, 37, 348

274, 278

53, 119, 138, 211

Propranolol

119, 129, 140, 172, 204, 206–208, 209, 213, 217, 219, 228, 255, 261, 266, 274, 299, 310, 319, 347, 386, 391, 392

175, 212, 430, Quinine 275, 323

109, 174–175, Pimecrolimus 340

341

440, 443

– Tables 190

Prolixin decanoate

see Fluphenazine decanoate

PMA see Paramethoxyam- phetamine

Potassium 6, 33, 123, 146, 280

432

– Interactions Pramipexole

399

Pramlintide

Pravastatin Prazosin

394

213, 262, 298 128, 171, 391,

Propylene glycol 224

Proscar see Finasteride ProSom see Estazolam Protease inhibitors 14, 22, 30,

37, 41, 45, 58, 129, 156, 172, 302, 319, 330, 343, 348, 349, 356, 362, 373

– Interactions 228, 236, 243, 274, 276, 278, 380, 384

Proton pump inhibitor 16, 59, 159, 229, 275

Protriptyline 51–59, 443 – Tables 77, 80, 84 Provera

see Medroxyprogesterone Prozac see Fluoxetine

Prozac Weekly see Fluoxetine Pseudoephedrine 23, 70, 73,

143, 345

Psilocybin 335, 347–349, 351 Psychostimulants 6, 76, 90,

289–299, 308, 311, 312, 440 – Interactions 297–299

302–307

52, 119, 212, 262

6, 65, 204, 207, Quazepam 443

Qudexy XR see Topiramate Quetiapine 69, 88, 109, 110,

123, 132–160, 172, 243, 253, 274, 298, 302, 340, 380, 443

Quinolones Quinupristin

126, 151, 227 227, 273

126, 151 16, 37

Raloxifene

Raltegravir

Ramelteon

– Interactions 242

– Tables 248, 251 Ramipril 260, 310 Ranitidine 158, 228, 266,

78, 340, 386, 391, Prednisolone 274

Prednisone Pregabalin 401, 443

15, 158, 172

46, 221, 367, 391,

275, 323, 340, 387 Ranolazine 159, 172 Rasagiline 50

Razadyne see Galantamine Razadyne ER

see Galantamine Reboxetine 443

Remeron see Mirtazapine Remifentanil 95

Reminyl ER see Galantamine Repetitive transcranial

magnetic stimulation (rTMS)

90, 93, 104–107, 440

– Interactions 107 Reserpine 204

– Interactions 58, 69, 213 Restlessness 46

Restoril see Temazepam Resveratrol 204

Retinoids

– Interactions 262

Revia see Naltrexone Rexulti see Brexpiprazole Rifabutin 129, 157

Pregnenolone Primatine P

391, 408

see Anti-asthma

drugs

Primidone

Pristiq see Desvenlafaxine Probenecid 229 Procainamide

– Interactions 57, 175, 277,

323

Procaine 125, 345 Procyclidine 13, 208–216,

273, 276–279, 297

219

– Tables 214, 216, 219 Prodiem see Psyllium Progesterone 22, 58, 391, 402 Progestogens 328–333 Proguanil 16

Prokinetic agents

– Tables Psyllium Pyridoxine

384, 414

– Interactions Rivaroxaban

273

– Interactions Rivastigmine

228, 243 12, 29, 36, 57,

41, 45

126, 151, 170,

250

314–319, 413, 443

– Interactions 213, 319

– Tables 323–326

Rivotril see Clonazepam Rizatriptan 17, 31, 63, 70 Rocuronium 95 Rocuronium bromide 96 Rohypnol see Flunitrazepam

391, 404

274, 278

15, 238–243, 443

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Rolaids see Antacids Ropinirole 128, 155, 171 Rosiglitazone 391, 397 Rozerem see Ramelteon rTMS see Repetitive

transcranial magnetic stimulation

S-adenosyl-L-methionine

68–70, 72, 73, 78, 89, 94, 105, 154, 155, 159, 160, 197, 209, 244–246, 250, 297, 342, 344, 345, 347, 352, 355, 358, 398, 402, 419, 421, 440

335, 344–345, 348, 364, 365,

386–389

SNRIs 2, 6, 17, 23–31, 73, 83,

87–88, 90, 127, 154, 171, 221,

234, 245, 311, 357, 358, 440 – Interactions 12, 22, 29, 36, 49, 57, 63, 69, 102, 242, 260,

276, 297

– Tables 77, 79, 83, 86 Sodium bicarbonate 262,

268, 285, 299, 323, 343, 385

Stimulants 41, 68, 69, 131, 201, 243, 279, 289–299, 308, 311, 312, 335, 341–345, 348, 352, 353, 364, 373, 399

– Interactions 16, 31, 50, 59, 63, 160, 173, 262, 275, 291, 295, 297, 299, 302, 342–343, 356, 362, 385

– Tables 302–307 Stiripentol 29

Stool softeners 119, 138 STP 347–349, 352

Tasimelteon 238–242

– Tables 248, 251

TCAs see Tricyclics

Tegretol see Carbamazepine Tegretol XR

see Carbamazepine Telaprevir 129, 156, 172 Telithromycin 29, 126, 152,

170

Temazepam 222–233, 373, 444 – Tables 233

Temsirolimus 274

Tenex see Guanfacine Terazosin 54, 126, 142, 151 Terbina ne 13, 57, 155, 171 Terfenadine 430

Teril see Carbamazepine Testosterone 90, 240, 251,

266, 268, 284, 328–330, 332,

333, 349, 391, 405 Tetrabenazine 70, 204, 207,

330

– Interactions 213 Tetracyclics 46, 51, 84 Tetracycline 102, 152, 260,

273

Tetrahydrocannabinol see Cannabis

TGAs 89, 110, 112, 118, 128, 138, 156, 161–173, 205–207 – Interactions 170–173, 175

– Tables 176, 193–196

THC see Cannabis Theophylline 17, 23, 98, 239,

262, 275, 298, 365, 373, 386,

421

Thiamine 95, 338, 339 Thiazide diuretics 36, 58, 261 Thienobenzodiazepine 109,

132

Thiopental 98, 277 Thioridazine 13, 22, 30, 58,

110, 115–131, 156, 302, 330,

347, 365, 444

– Interactions 213, 429, 430 – Tables 176, 180, 184, 431

412, 419

Salbutamol

Salicylates

Saliment

Salvia 347–349, 351 Salvinorin A 351

Saphris see Asenapine Saquinavir 129, 156, 172,

274, 276, 278, 330, 362, 380,

384

– Interactions 243 Sarafem see Fluoxetine Sargramostim

– Interactions 261

SARIs 2, 12, 31–37, 73, 83,

87–88, 128, 228, 440

– Interactions 12, 29, 35–37,

63, 69, 98, 154, 236, 273

– Tables 77, 79, 83, 86 Sativex see Nabiximols Secobarbital 238–250 Seconal see Secobarbital Sedatives 9, 32, 68–69, 98,

145, 215, 216, 225, 238–251,

265, 335, 362, 440

– Interactions 15, 22, 30,

242–243

– Tables 246–251

– Withdrawal 223

Selegiline 2, 16, 30, 37, 50, 59,

60, 63, 69, 70–73, 81, 84, 201,

444

– Interactions 212

– Transdermal 71, 72

Serax see Oxazepam Seroquel see Quetiapine Serotonin 2–4, 9, 11–17, 23,

24, 27, 29–32, 34, 36, 37, 42, 46, 49, 50, 55, 57–63, 66,

stimulator (SMS) 2, 41–45,

128, 154

– Interactions 22

– Tables 77, 80, 83, 86 Serotonin-1A partial

agonist/serotonin reuptake

inhibitor (SPARI) 2, 37–41 – Interactions 273

– Tables 77, 80, 83, 86 Sertindole 444

Sertraline 2, 3–17, 26, 36, 49,

57, 68, 85, 102, 154, 171, 221, 228, 242, 260, 273, 277, 348, 373, 444

– Interactions 11–17, 127, 278, 297, 298, 431

– Tables 77, 79, 82, 431 Serzone see Nefazodone Sevo urane 273 Sex-drive depressants

328–333, 440

– Interactions 330

SGAs 88, 109, 110, 112, 118,

120, 128, 129, 132–160, 162,

205–207, 312

– Interactions 50, 151–160 – Tables 176, 193–196 Sibutramine 11, 245 Sildena l 7–8, 16, 37, 121,

143, 348

Silenor see Doxepin Simeprevir 129, 156, 172 Simply Sleep

see Diphenhydramine Simvastatin 16, 37, 160 Sinequan see Doxepin Sirolimus 275

Smoking 4, 7, 16–18, 20–21, 23, 50, 51, 119, 121, 131, 159, 231, 265, 266, 319, 323, 332,

63, 70 277, 339

– Interactions Sodium chloride Sodium oxybate

298

54, 67, 125 360–362,

Strattera

Sublimaze

Sublinox

Sublocade

Suboxone

Subutex

Succinylcholine 69, 95, 262,

317–319 Sulfamethoxazole

see Oral lubricants

see Atomoxetine see Fentanyl

Serotonin antagonists 50, 440

2, 31, Serotonin modulator and

391, 402, 411 Sodium salts 262 Sodium valproate Sofosbuvir 274, 278 Sominex

see Diphenhydramine Sonata see Zaleplon

Sotalol 302

– Interactions 175 Spironolactone 256, 261 Spravato see Esketamine SSRIs 2, 3–17, 19, 22, 26, 27,

29, 34, 36, 43, 44, 47, 49, 52, 55, 73, 79, 82, 84, 85, 89, 107, 154, 199, 206, 221, 234, 235, 265, 290, 308, 311, 319, 329, 339, 343, 357, 358, 393, 405, 419, 420, 440

– Interactions 11–17, 22, 29, 36, 45, 57, 63, 68, 98, 102, 127, 154, 171, 212, 228, 236, 242, 245, 260, 273, 276, 297, 298, 302, 348, 373, 379, 384, 429, 431

– Tables 77, 79, 82, 85

see Zolpidem

see Buprenorphine

St. John’s Wort

420

69, 330, 412, 16, 31, 63, 73,

131 T3 see Liothyronine

– Interactions

102, 160, 175, 213, 229, 236, 275, 298

Tacrolimus 131, 159, 275, 302, 340

Talinolol 414

Talwin see Pentazocine Tamoxifen 16, 59, 430 Tamsulosin 26

Statins 16, 37, 160, 391, 398

Stavudine Stelazine

276, 384

see Tri uoperazine

453

204

see Buprenorphine see Buprenorphine

– Interactions Sulfonylureas

277

Sulindac 261

Sulpiride 444

Sumatriptan 17, 31, 59, 63, 70 Surmontil see Trimipramine Suvorexant 238–243, 311

– Interactions 242

– Tables 248, 251 Suxamethonium 319 Symbyax see Fluoxetine/

olanzapine combination Symmetrel see Amantadine Sympathomimetics 23, 59,

63, 70, 72, 73, 78, 146, 160,

239, 341–345 – Interactions

212

16, 37, 59, 70,

Index of Drugs

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

454

Thiothixene 109, 115–131, 243, 274

– Tables 176, 180, 184 Thioxanthenes 109, 115–131,

Triadapin see Doxepin Triamterene 261

– Interactions 213 Triazolam 14, 58, 222–233,

Viibryd see Vilazodone Vilazodone 2, 37–41, 77, 87,

273, 440, 444

– Tables 77, 80, 83 Vinblastine

– Interactions 429 Vistaril see Hydroxyzine

423 412, 423

412, 423, 424 423

Zaleplon 238–243, 444 – Interactions 242–243

249, 251 see Selegiline

191

– Tables Thrive

373, 444

– Interactions

– Tables 233 Trichloroethanol

Tricyclics 27, 50–59, 60, 64,

66, 73, 85, 88–90, 128, 221, 245, 260, 269, 289, 311, 329, 339, 342–343, 347, 365, 393, 399, 419

– Interactions 12, 22, 29, 57, 63, 69, 98, 236, 242, 297, 298, 379, 429–431

– Tables 83, 86, 431 Tri uoperazine 115–131, 444 – Interactions 128, 213

– Tables 176, 180, 184 Trihexyphenidyl 142, 143,

207, 209–219

– Tables 214, 217, 219 Triiodothyronine

see Liothyronine

Trilafon see Perphenazine Trileptal see Lamotrigine Trimethoprim

– Interactions 212, 323 Trimethoxyamphetamine

347–349, 353 Trimipramine

Unisom

see Diphenhydramine

Urea 10

Urecholine see Bethanechol

– Tables Zelapar Zeldox Zenzedi

176, 191 see Nicotine

37, 227 246, 340

Urinary acidi ers

385

Urinary alkalizers 343, 385

299, 343, 262, 299,

Vitamin A Vitamin B Vitamin B9 Vitamin B12 Vitamin C

see Ziprasidone see Dextroamphetamine

replacement therapy Thyroid hormones 17, 90,

142, 275, 391, 393–394 Thyrotropin 17

Thyroxine 17, 284

Tiagabine 273

Tianeptine 444

Tinidazole 373

Tipranavir 129, 156, 172, 373 Tizanidine 11, 373

TMA

see Trimethoxyamphetamine

Tobacco

– Withdrawal treatment 368 Tofranil see Imipramine Tolbutamide 16, 37, 59, 70,

277, 340, 414

Tolterodine 17, 31, 143 Topamax see Topiramate Topiramate 12, 98, 142, 153,

199, 253, 260, 263–287, 367 – Interactions 212, 276, 279 – Tables 270, 279–287 Tramadol 16, 30, 37, 41, 50,

59, 63, 69, 73, 131, 159, 246,

275, 355, 356, 375

– Interactions 213, 262

– Tables 431

Trandolopril 260

Tranxene see Clorazepate Tranylcypromine 2, 13, 36, 50,

57, 60, 64–69, 76, 102, 128, 155, 236, 245, 260, 297, 302, 347, 373, 444

– Interactions 41, 69, 298 – Tables 81, 84

Trazodone 2, 12, 29, 31–37,

69, 88, 98, 154, 236, 273,

294, 444

– Interactions 128

– Tables 77, 79, 83

203, 207, 209, – Interactions 212, 213

– Tables 217, 220, 432 Valepotriates 422

Valerian 340, 412, 421–422 – Interactions 213

Valium see Diazepam Valproate 12, 33, 53, 57, 65,

95, 98, 127, 153, 170, 199, 227, 253, 254, 260, 262, 263–287, 298, 310, 312, 323, 410, 444

– Interactions 21, 57, 107, 127, 273, 275–277–279

– Tables 262–265, 270,

279–287, 428

Valproic acid see Valproate Valsartan 260

Varenicline 365, 367, 374,

385–389, 444

– Tables 387–389 Velpatasvir 274, 278 Venlafaxine 2, 12, 22, 23–31,

36, 49, 63, 69, 77, 83, 93, 102, 127, 154, 160, 171, 221, 242, 260, 276, 289, 297, 355, 433, 444

– Interactions 29, 57

– Tables 77, 79, 83, 432 Verapamil 15, 30, 41, 58, 130,

143, 157, 236, 261, 274, 340 – Interactions 278 Versacloz see Clozapine Vesicular monoamine

transporter 2 (VMAT2)

inhibitors 208, 209, 211 – Interactions 213

Zidovudine 261, 276, 384 Ziprasidone 14, 69, 88, 109,

110, 128, 129, 131, 132–160, 172, 253, 274, 302, 330, 343, 444

– Interactions 129, 151–160, 175

– Tables 176, 181, 188 Zoladex see Goserelin Zoladex LA see Goserelin Zolmitriptan 59, 63, 70 Zoloft see Sertraline Zolpidem 15, 22, 30, 59, 204,

238–243, 277, 311, 385, 444 – Interactions 242

155, 431, 444

– Interactions

– Tables 77, 80, 84

Trintellix see Vortioxetine Tripelennamine 355, 358 Triptans 17, 31, 59, 63, 70 Trokendi XR see Topiramate Troleandomycin 227 Tropicamide 142

Tropisetron 392, 409 Tryptamines 347–349, 351 Tryptan see L-tryptophan Tryptophan see L-tryptophan Tums see Antacids

Tylenol see Acetaminophen Tyramine 61,62,66–67,70,340

12, 29, 36, 41, 45, 49, 57, 127, 152, 242, 273,

Zotepine 444

Zubsolv see Buprenorphine Zuclopenthixol 115–131, 158,

180, 191–192, 274, 339, 444 – Interactions 126–131

– Tables 176, 180, 184 Zuclopenthixol acetate

– Tables 184 Zuclopenthixol decanoate

29, 51–59, 128, 58

Warfarin

– Interactions

444

– Tables 249, 251

Valbenazine

210, 212, 213, 440

298, 311, 340, 347, 385, 412, 417, 423

Vitamin D 329, 423

VitaminE 204,207,412,417,423 Vitamins 65, 286, 311, 329,

339, 350, 412, 419, 423–424 Vivactil see Protriptyline Vivitrol see Naltrexone Voriconazole

– Interactions 269, 384

128, 155, 171, 2, 22, 41–45, 77,

Vortioxetine

87, 128, 154, 440, 444

– Tables

Zolpimist

Zonalon

Zonisamide 204, 273, 279 Zopiclone 98, 238–243, 311,

– Tables 77, 80, 83, 432 Voxilaprevir 274, 278 Vraylar see Cariprazine Vyvanse

see Lisdexamfetamine

249, 251

see Zolpidem

275, 297, 323, 339, 373, 414,

416, 421 Wellbutrin

see Bupropion see Alprazolam

Xanax

Xanax TS

Xanax XR see Alprazolam Xanthurenic acid 245, 246 Xylocaine 345

Xyrem

see Alprazolam

see Gamma-hydroxybutyrate

– Tables

Zulresso

Zyban

Zyprexa

Zyprexa IntraMuscular

Yohimbine 298, 343

7–8, 54, 121, 143,

see Olanzapine see Olanzapine

see Doxepin – Interactions 242

191–192

see Brexanolone see Bupropion

Zyprexa Zydis see Olanzapine

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Acamprosate

What is this drug used for?

Acamprosate is primarily used in the treatment of alcohol dependence, where it reduces alcohol cravings and can prevent relapse.

Acamprosate has been shown to maintain abstinence if taken, as directed, as part of a treatment program that includes counseling and support.

How quickly will the drug start working?

Acamprosate is usually prescribed after an individual has been withdrawn from alcohol use. It is not e ective if the person is actively drinking, nor will it treat withdrawal symptoms. It reduces cravings for alcohol.

How long should you take this medication?

Acamprosate is usually prescribed for a set period of time (months) to help the individual remain alcohol-free. Do not increase or decrease your dose of medication without discussing this with your doctor.

What side effects may happen?

Side e ects may happen with any drug. They are not usually serious and do not happen to everyone. Side e ects may sometimes occur before bene cial e ects of the medication are noticed. If you think you may be having a side e ect, speak to your doctor or pharmacist as they can help you decrease it or cope with it.

Common side e ect that should be reported to your doctor at the NEXT VISIT include:

• Upsetstomach,nausea,gas,diarrhea–ifthesesymptoms continue, your doctor may need to adjust your dose.

• Headache–thistendstobetemporaryandcanbemanagedby taking pain medicine (aspirin, acetaminophen, ibuprofen) as required. If the headache persists or is “troubling,” contact your doctor.

• Increasedanxiety,sleepingdi culties–someindividualsmay feel nervous or have di culty sleeping for a few days after starting this medication.

• Itching,skinrash.

Rare side e ects you should report to your doctor RIGHT AWAY include:

• Severeanxiety,changeinyourmoodorbehavior,suicidal thoughts

Let your doctor know right away if you miss your period or think you may be pregnant, plan to become pregnant or are breastfeeding.

What should you do if you forget to take a dose of your medication?

If you are taking the medication 3 times a day with meals and miss taking your dose by more than 2 hours, skip the missed dose and continue with your next scheduled dose.

Is this drug safe to take with other medication?

Because acamprosate can change the e ect of other medication or may be a ected by other medication, always check with your doctor or pharmacist before taking other drugs, including those you can buy without a prescription such as cold remedies and herbal preparations. Always inform any doctor or dentist that you see that you are taking acamprosate.

Precautions/considerations

1. This drug may impair the mental and physical abilities and reaction time required for driving or operating other machinery. Avoid these activities if you feel drowsy or slowed down.

2. Do not change your dose or stop the drug suddenly without discussing this with your doctor.

3. Should you restart drinking during treatment, continue taking the acamprosate but notify your doctor as soon as possible.

4. Report any changes in mood or behavior to your doctor. What else do I need to know about acamprosate?

1. Do not cut, crush or chew acamprosate but swallow the tablets whole.

2. Store your medication in a clean, dry area at room temperature. Keep all medication out of reach of children.

If you have any questions regarding this medication, please ask your doctor, pharmacist or nurse.

From: Procyshyn RM, Bezchlibnyk-Butler KZ, Jeffries JJ. Clinical Handbook of Psychotropic Drugs, 23rd edition, © 2019 Hogrefe Publishing. This document may be reproduced for personal clinical use. No other reproduction or distribution is permitted.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Anticonvulsant Mood Stabilizers

The name of your medication is ________________________.

What is this drug used for?

Anticonvulsants can be used to treat symptoms of acute mania and in the long-term control or prevention of bipolar disorder. They are also used to treat seizure disorders as well as certain pain syndromes (e.g., trigeminal neuralgia – carbamazepine; migraines – valproate).

Though not approved for these indications, these drugs have also been found to be useful in the treatment of several other conditions, including: Add-on therapy with antidepressants to treat depression, add-on therapy with antipsychotics to treat schizophrenia, withdrawal reactions from alcohol or sedatives/hypnotics, and in behavior disturbances such as chronic aggression or impulsivity. Ask your doctor if you are not sure why you are taking this drug.

How does your doctor decide on the dosage?

The dose of the medication is di erent for every patient and is based on the amount of drug in the blood (for some of these drugs) as well as your response to treatment. You may initially take your medication 2 or 3 times a day; after several weeks, your doctor may decide to prescribe the drug once daily.

How often will you need to have blood levels done with carbamazepine and valproate?

Your doctor will measure the drug level in the blood on a regular basis during the rst few months until the dose is stable. Thereafter, drug levels will be done at least once a year or whenever there is a change in drug therapy.

What do the blood levels mean?

The carbamazepine level that is usually found to be e ective for most patients is between 17 and 50 umol/L (4–12 ug/mL). The valproate level that is usually found to be e ective for most patients is between 350 and 875 umol/L (50–125 ug/mL).

On the morning of your blood test, take the morning dose of your medication after the test to avoid inaccurate results.

Blood levels usually do not need to be tested if you are being treated with lamotrigine, topiramate or gabapentin.

How quickly will the drug start working?

Control of manic symptoms or stabilization of mood may require up to 14 days of treatment. Because these medications need time to work, do not decrease or increase the dose or stop the medication without discussing this with your doctor. Improvement in seizures and pain symptoms as well as aggression/impulsivity also occur gradually.

How long should you take this medication?

This depends on what type of illness you have and how well you do. Following the rst episode of mania, it is recommended that these drugs be continued for a minimum of 1 year; this decreases the chance of having another episode. Your doctor may then decrease the drug slowly and monitor for any symptoms; if none occur, the drug can gradually be stopped. For individuals who have had several or severe episodes of mania or depression, medication may need to be continued inde nitely.

Long-term treatment is generally recommended for recurring depression, seizure disorder, and aggression/impulsivity.

What side effects may happen?

Common side e ects that should be reported to your doctor at the NEXT VISIT include:

• Feelingsleepy,tired,di cultyconcentrating–thisproblem usually goes away with time. Use of other drugs that make you drowsy will worsen the problem. Avoid driving a car or operating machinery if drowsiness persists.

• Dizziness–getupfromalyingorsittingpositionslowly; dangle your legs over the edge of the bed for a few minutes before getting up. Sit or lie down if dizziness persists or if you feel faint – then call your doctor.

• Problemswithbalanceorunsteadiness–discussthiswithyour doctor as this may require a change in your dosage.

• Blurredvision–thisusuallyhappenswhenyou rststartthe drug and tends to be temporary. Reading under a bright light or at a distance may help; a magnifying glass can be of temporary use. If the problem lasts for more than a few weeks, let your doctor know.

• Drymouth–sourcandyandsugarlessgumhelpincreasesaliva in your mouth. Do not drink sugar-containing drinks as they may give you cavities and increase your weight. Drink water and brush your teeth regularly.

• Nauseaorheartburn–ifthishappens,takethemedication with food. If vomiting or diarrhea occur and last for more than 24 hours, call your doctor.

• Muscletremor–speaktoyourdoctorasthismayrequirea change in your dosage.

• Changesinhairtexture,hairloss(valproate).

• Changesinyourmenstrualcycle(valproate).

• Changesinsexdriveorsexualperformance–discussthiswith

your doctor.

• Weight/appetitechanges–watchthetypeoffoodyoueat;

avoid foods with high fat content (e.g., cakes and pastry). • Periods of hyperventilation or rapid breathing.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Anticonvulsant Mood Stabilizers

Rare side e ects you should report to your doctor RIGHT AWAY include:

• Soremouth,gumsorthroat,mouthulcersorsores

• Skinrashoritching,swellingoftheface,skinblisteringor crusting (especially with carbamazepine and lamotrigine)

• Severestomachpain,nausea,vomiting,lossofappetite

• Feelingtired,weak,feverishorlikeyouhavethe u

• Feelingconfusedordisorientedorhavingtrouble ndingthe

right words you want to say

• Uncomfortabletinglingsensationsin ngersortoes

• Easybruising,bleeding,appearanceofsplotchypurplish

darkening of the skin

• Yellowingoftheskinoreyes;dark-coloredurine(pee)

• Unusualeyemovements

• Suddenblurringofvisionand/orpainfulorredeyes

• Feelingverydizzyorfalling/fainting

Let your doctor know right away if you miss your period or think you may be pregnant, plan to become pregnant or are breastfeeding.

What should you do if you forget to take a dose of your medication?

If you take your total dose of medication in the morning or at bedtime and you forget to take it for more than 6 hours, skip the missed dose and continue with your schedule the next day. DO NOT DOUBLE THE DOSE. If you take the drug several times a day, take the missed dose when you remember, then continue with your regular schedule.

Is this drug safe to take with other medication?

Because these drugs can change the e ect of other medication or may be a ected by other medication, always check with your doctor or pharmacist before taking other drugs, including those you can buy without a prescription such as cold remedies and herbal preparations . Always inform any doctor or dentist that you see that you are taking this drug.

Precautions/considerations

1. Do not change your dose or stop the drug suddenly without speaking with your doctor, as this may result in withdrawal symptoms such as anxiety, irritability, and changes in mood.

2. These drugs may impair the mental and physical abilities and reaction time required for driving a car or operating other machinery. Avoid these activities if you feel drowsy or slowed down.

3. This drug may increase the e ects of alcohol, making you more sleepy, dizzy, and lightheaded. If taken together with alcohol, this may make it dangerous for you to drive, operate machinery, or perform tasks that require careful attention.

4. Report any changes in mood or behavior to your doctor.

What else do I need to know about anticonvulsants?

1. Avoid drinking grapefruit juice while on carbamazepine as it can change the e ect of carbamazepine in your body.

2. If you are on liquid carbamazepine, do not mix it with any other liquid medication.

3. The liquid form of valproic acid should not be mixed with carbonated beverages, such as soda pop; this may cause an unpleasant taste or mouth irritation.

4. Unless you are prescribed a chewable tablet, capsules or tablets should be swallowed whole; do not break, chew or crush them; chewing capsules can cause irritation in the mouth and throat; extended-release capsules can be opened and sprinkled on food.

5. Gabapentin should not be taken within 2 hours of an antacid (e.g., Tums, Rolaids, Maalox).

6. If you are taking topiramate, drink plenty of uids before and during activities such as exercise or exposure to warm temperatures. Avoid the regular use of antacids (e.g., Tums, Maalox).

7. To treat occasional pain, avoid the use of ASA (aspirin and related products) if you are taking divalproex or valproic acid, as it can a ect the amount of this drug in your body; acetaminophen (Tylenol) or ibuprofen (Motrin, Advil) are safer alternatives.

8. On the morning when blood is drawn for an anticonvulsant level, withhold your morning dose of the drug until after the blood draw.

9. Store your medication in a clean, dry area at room temperature. Keep all medication out of the reach of children.

If you have any questions regarding this medication, please ask your doctor, pharmacist or nurse.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Antiparkinsonian Agents for Treating Extrapyramidal Side E ects

The name of your medication is ______________________.

What is this drug used for?

This drug is called an antiparkinsonian drug. It is used to treat a group of side e ects, known as extrapyramidal side e ects (or EPSE) that can happen when taking antipsychotic drugs. EPSE a ect your muscles and can cause:

• Musclespasmsortightening(thisusuallyhappensintheneck – can make your neck tip back or turn to the side; eyes – can make your eyes to roll back up in your head; or tongue – can make your tongue feel bigger than normal, making it hard to swallow)

• Musclesti ness,tremorsorshaking,andashu ingwalk.

• Feelingrestlessorunabletositstill.

How quickly will the drug start working?

When given by injection, this drug works very fast, usually in 10 or 15 minutes. When swallowed as a pill, the drug should make you feel better within 1 hour.

How long should you take this medication?

Many people only take this drug for 2–3 weeks to prevent or treat EPS when an antipsychotic drug is rst started. Your doctor may lower the dose of this drug to see if any signs of EPS return; if not, you may be able to stop this drug. Do not change the dose of this drug without talking to your doctor rst.

Some people may need to take this drug for a longer time because they are more “sensitive” or more likely to get EPS. Other people only have to take it for short periods from time to time. (e.g., for 1 week after getting an antipsychotic by injection).

What side effects may happen?

Side e ects may happen with any drug. They are not usually serious and do not happen to everyone. Side e ects may sometimes occur before bene cial e ects of the medication are noticed. Many side e ects get better or go away over time. If you think you may be having a side e ect, speak to your doctor or pharmacist as they can help you decrease it or cope with it.

Common side e ects than should be reported to your doctor at the NEXT visit include:

• Drymouth–sugarlesshardcandyorgum,icecubesor popsicles can help. Do not drink sugar-containing drinks to help your dry mouth as they may give you cavities and increase your weight. Brush your teeth daily and visit your dentist regularly.

• Blurredvision–mayhappenwhenyou rststarttotakethis drug and may last for 1–2 weeks. Reading under a bright light or moving the book further away to read may help. If the problem lasts for more than a few weeks let your doctor know.

• Constipation–drinkplentyofwater,trytoincreasethe amount of ber in your diet (like fruit, vegetables or bran), and exercise your abdominal muscles. Some individuals nd a bulk

laxative like psyllium (e.g., Metamucil) or PEG 3350 (e.g., Miralax, Pegalax) or a stool softener like docusate (e.g., Colace, Surfak) helps regulate their bowels. If this does not work or if you go more than 3 days without having a bowel movement, speak to your doctor or pharmacist.

• Feelingsleepyortired–thisusuallygoesawayovertime.Be careful if your are driving or operating heavy machinery during times when you need to be wide awake.

• Nauseaorheartburn–trytakingyourdrugwithfoodifthis happens.

Less common side e ects that should be reported to your doctor RIGHT AWAY include:

• Feelingconfused,havingmemorylossornoticinganincrease in your psychosis symptoms

• Goingmorethan3dayswithouthavingabowelmovement • Goingadaywithoutpeeing

• Getting a skin rash

Let your doctor know right away if you miss your period or think you may be pregnant, plan to become pregnant or are breastfeeding.

Is this drug safe to take with other medication?

Antiparkinsonian drugs can change the e ect of other drugs that you are taking or they may be a ected by other drugs. Always check with your doctor or pharmacist before taking any drugs, including those that you are taking or plan to take, those you can buy without a prescription (like cold remedies), and herbals (like St. John’s Wort, ginseng, and many others).

What else do I need to know about antiparkinsonian drugs?

1. Do not change your dose or stop it without talking to your doctor.

2. This drug may increase the e ects of alcohol, making you more sleepy and less alert.

3. This drug may a ect your body’s ability to control body temperature, so avoid places that are very hot and humid like saunas.

4. Keep your antiparkinsonian drugs in a clean, dry area at room temperature. Keep all medication out of the reach of children.

If you have any questions about this drug, please ask your doctor, pharmacist or nurse.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Antipsychotics

Thenameofyourmedicationis________________________.

What is this drug used for?

The main use of this drug is to treat psychosis. Psychosis can be a part of many illnesses like schizophrenia, major depression, and bipolar disorder. Ask your doctor if you are not sure why you are taking this drug.

What symptoms will this drug help control?

Symptoms of psychosis may not be the same for each person. Some symptoms of psychosis that this drug can help with are: • Hearingvoices,seeingthingsorsmelling,tastingorfeeling

things that are not real (hallucinations).

• Feelingthatsomeoneistryingtohurtyouorisfollowingyou

or that people are talking about you or that you have special

powers or are famous (delusions).

• Findingithardtothinkclearly,havingthoughtsthatare

speeded up or feeling like you don’t have control of your

thoughts.

• Becomingeasilyupsetoroverexcited.

• Showingdiminishedinterestinyourselforothers.

Your doctor may choose to use this medication for reasons not listed here. If you are not sure why this drug is being prescribed for you, please ask your doctor. These drugs are now frequently used to improve symptoms of depression, usually together with an antidepressant.

How quickly will the drug start working?

Some symptoms of psychosis may get better before others. Over the rst few weeks, you may nd that you sleep better and have fewer mood changes (feel too angry, sad or happy or have too much energy). Slowly, over the next 2–8 weeks, hallucinations or delusions fade away and your thoughts become clearer.

Because antipsychotics take time to work, do NOT change your dose or stop your medication without talking to your doctor.

How long should you take this medication?

This depends on what type of illness you have and how well you do. Ifyouaretakingthisdrugtotreatpsychosisforthe rsttimeand do well on it, your doctor will likely want you to stay on it for at least 1–2 years. This will help stop you from getting sick again. If you have had symptoms of psychosis for many years or symptoms that go away but then come back, you may need to stay on this drugforalongtime.Talkwithyourdoctorabouthowlongyou should stay on this medication.

How do you take this drug?

Antipsychotic drugs come in di erent forms:

• Fast-actinginjection–usedtocontrolsymptomsquickly.

• Liquidformorquick-meltingtablet–usuallyusedforpeople

who can’t swallow tablets easily.

• Tablets–themostcommonwaytotakethisdrug.

• Sublingualtablets–tabletsthatdissolveormeltunderthe

tongue without the need to swallow

• Long-actingordepotinjection–drugisgiveninaninjection

once every 2–12 weeks. This is helpful if you can’t remember to take your drug every day.

What side effects may happen?

Side e ects may happen with any drug. Side e ects may sometimes occur before bene cial e ects of the medication are noticed. Many side e ects get better or go away over time. If you think you may be having a side e ect, speak to your doctor or pharmacist as they can help you decrease it or cope with it.

Common side e ects of some antipsychotic drugs that you should tell your doctor about RIGHT AWAY are:

Extrapyramidal Side E ects (or EPSE): There are di erent kinds of EPSE. Try not to be scared if these happen to you because they can be treated

• Onekind,calledacutedystonia,canmakeyourmusclessti . This can make your neck tip back or turn to the side or cause your eyes to roll back up in your head or make your tongue feel bigger than normal, making it hard to swallow. This kind of EPSE most often happens in the rst week that you start to take antipsychotc drugs. Call your doctor right away if you think you have this and they will give you another medicine that should make you feel better within 10–15 minutes. If you experience di culty breathing related to this reaction, go to your nearest hospital emergency room or call an ambulance.

• AnotherkindofEPSE,calledakathisia,maymakeyoufeel restless, dgety or unable to sit still

• AnotherkindofEPSE,calledparkinsonism,maymakeyour hands shake or your body feel sti and slow

Common side e ects that you should tell your doctor about at the NEXT VISIT include:

• Feelingsleepyortired–thisusuallygoesawayovertime.Be careful driving or during times when you need to be wide awake.

• Feelingdizzy–youmay ndyougetdizzyorfeelfaintwhen you get up too fast from sitting or lying down. Getting up more slowly or sitting on the side of your bed with your feet on the oor before getting up will help. This side e ect usually goes away over time.

• Drymouth–sugarlesshardcandyorgum,icecubesor popsicles can help. Do not drink sugar-containing soft drinks to help your dry mouth as they may give you cavities and increase your weight. Brush your teeth daily and visit your dentist regularly.

• Constipation–drinkplentyofwater,trytoincreasethe amount of ber in your diet (like fruit, vegetables or bran), and exercise your abdominal muscles. Some individuals nd a bulk laxative like psyllium (e.g., Metamucil) or PEG 3350 (e.g., Miralax, Pegalax) or a stool softener like docusate (e.g., Colace, Surfak) helps regulate their bowels. If this does not work or if

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Antipsychotics

you go more than 3 days without having a bowel movement,

speak to your doctor or pharmacist.

• Weightgain–thebestwaytolimitweightgainistowatch

how much you eat and avoid eating fatty foods (like cakes, ice cream) or foods high in sugar (like soft drinks or energy drinks). Exercise can also help. Your doctor may check your weight, cholesterol (a type of body fat), and sugar levels from time to time.

• Increasedthirstorpeeingmoreoften–letyourdoctorknow. Your doctor may want to check your blood sugar.

• Nauseaorheartburn–trytakingyourdrugwithfoodifthis happens.

• E ectsinwomen–someantipsychoticdrugsmaycause changes in how regular your monthly periods are or cause you to miss your period. It may also cause your breasts to leak milk. Let your doctor know if this happens to you as these e ects can be treated.

• Tardivedyskinesias–mayoccurinpeopletakingantipsychotic drugs (usually the older agents) for many years. Tardive dyskinesias happen when some of your body muscles, usually in your face (lips and tongue), move on their own, without you making them do so. Your doctor may periodically examine you for any signs of tardive dyskinesia as picking them up early and taking action (depending on how you are doing, your doctor may decide to stop your drug or change to another drug) can help increase the chance that this side e ect will go away.

Rare side e ects you should tell your doctor about RIGHT AWAY are:

• Skinrashoritching

• Reallybadheadache

• Constantdizzinessorfainting,breathingtoofastorfeelinglike

your heart is skipping or missing beats

• Fever,nausea,vomiting,appetitelossorfeelingtired,confused,

really thirsty, weak or like you have a u

• Soremouth,gumsorthroat

• Yellowtingeintheeyesortotheskin;dark-coloredurine(pee) • Goingmorethanadaywithoutpeeing

• Goingmorethan3dayswithouthavingabowelmovement

• Fever(temperaturehigherthan38degreesCelsius)with

muscle sti ness

• Suddenweaknessornumbingintheface,armsorlegsor

di culty seeing or talking

Let your doctor know right away if you miss your period or think you may be pregnant, plan to become pregnant or are breastfeeding.

What should you do if you forget to take a dose of your medication?

If it is almost time for your next dose, just skip the missed one. Do NOT take two doses at the same time.

Is this drug safe to take with other medication?

Antipsychotic drugs can change the e ect of other drugs that you are taking or they may be a ected by other drugs. Always check with your doctor or pharmacist before taking any drugs, including those that you are taking or plan to take, those you can buy without a prescription (like cold remedies), and herbals (like

St. John’s Wort, ginseng, and many others).

What else do I need to know about antipsychotic drugs?

1. Do not change your dose or stop it without talking to your doctor.

2. If you take asenapine (Saphris) let the tablet melt under your tongue and do not eat or drink for 10 minutes afterwards. Most other antipsychotic drugs can be taken with meals or with water, milk or orange juice. Do NOT take them with apple juice or grapefruit juice as these may change the amount of drug in your body.

3. If you take ziprasidone (Geodon) or lurasidone (Latuda), make sure you take your tablets with meals. If you take risperidone liquid (Risperdal oral solution), do NOT take it with colas or with tea.

4. Risperidone, olanzapine, and aripiprazole oral disintegrating tables (Risperdal M-tab, Zyprexa Zydis, and Abilify Discmelt) dissolve rapidly in saliva and can be taken with or without liquid. They can also break easily. Do NOT push tablets through foil backing as this could damage tablets. Use dry hands to remove tablet and immediately place tablet on tongue.

5. Do not split, crush or chew quetiapine (Seroquel XR) or paliperidone (Invega) tablets.

6. If you take paliperidone (Invega), you may see some of the tablet in your stool. This is normal because the tablet does not dissolve all the way.

7. Do not break or crush your drug unless you have been told to do it by your doctor.

8. This drug may increase the e ects of alcohol, making you more sleepy and less alert.

9. This drug may a ect your body’s ability to control body temperature, so avoid places that are very hot and humid like saunas.

10. Antacids (like Diovol, Maalox, amphogel, etc.) may lower the amount of drug in your body. Take your antacid at least 2 hours before or 1 hour after taking your antipsychotic drug to avoid this.

11. Some people may get bad sunburn even without being in direct sun for a long time. Avoid direct sun, wear protective clothes, and use sunscreen.

12. Drinking a lot of ca eine (co ee, teas, colas, etc.) can cause you to become easily upset or jittery and make it harder for this drug to work.

13. Cigarette smoking can change the amount of drug in your body, so let your doctor know if you smoke or if you stop smoking or change how much you smoke.

14. Stopping your drug all of a sudden (“cold turkey”) may make you ill. Talk to your doctor or pharmacist rst about how to stop it safely.

15. Keep your antipsychotic drugs in a clean, dry area at room temperature. Keep all medication out of the reach of children.

If you have any questions about antipsychotic drugs, please ask your doctor, pharmacist or nurse.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Anxiolytics and Benzodiazepines

Thenameofyourmedicationis________________________.

What is this drug used for?

This medication is used to treat symptoms of anxiety. Anxiety is a normal human response to stress and is considered necessary for e ective functioning and coping with daily activities. It may, however, be a symptom of many other disorders, both medical and psychiatric. There are many di erent types of anxiety and there are many di erent approaches to treating it. Anxiolytics can help relieve the symptoms of anxiety but will not get rid of its cause. In usually prescribed doses, they help to calm and relax the individual; in high doses, these drugs may be used to induce sleep. Benzodiazepines may also be used as muscle relaxants, to stop seizures, and before some diagnostic procedures. Ask your doctor if you are not sure why you are taking this drug.

How quickly will the drug start working?

Anxiolytic drugs can reduce agitation and induce calm or sedation usually within an hour. Sometimes they have to be given by injection or dissolved under the tongue for a quicker e ect.

How long should you take this medication?

Anxiety is usually self-limiting; often when the cause of anxiety is treated or eliminated, symptoms of anxiety will decrease. Therefore, anxiolytics are usually prescribed for a limited period of time. Many individuals take the medication only when needed (during periods of excessive stress) rather than on a daily basis. Tolerance or loss of e ectiveness can occur in some individuals if the medication is used continuously beyond 4 months. If you have been taking the medication for a continuous period of time, your doctor may try to reduce the dose of this drug slowly to see if the anxiety symptoms return; if not, the dosage may be further reduced and you may be advised to stop using this medication. Do not increase the dose or stop the drug without consulting with your doctor.

Some patients need to use an anxiolytic drug for longer time periods because of the type of anxiety they may be experiencing. Others require anxiolytic medication only from time to time, i.e., as needed.

What side effects may happen?

Side e ects may happen with any drug. They are not usually serious and do not happen to everyone. Side e ects may sometimes occur before bene cial e ects of the medication are noticed. Many side e ects get better or go away over time. If you think you may be having a side e ect, speak to your doctor or pharmacist as they can help you decrease it or cope with it.

Common side e ects that should be reported to your doctor at the NEXT VISIT include:

• Feelingsleepyandtired–thisproblemgoesawaywhenthe dose is reduced. Use of other drugs that make you drowsy will worsen the problem. Avoid driving a car or operating machinery if drowsiness persists.

• Muscleincoordination,weaknessordizziness–informyour doctor; an adjustment in your dosage may be needed.

• Forgetfulness,memorylapses–informyourdoctor.

• Slurredspeech–anadjustmentinyourdosagemaybeneeded. • Nauseaorheartburn–ifthishappens,takethemedication

with food.

Less common side e ects that you should report to your doctor RIGHT AWAY include:

• Disorientation,confusion,worseningofmemory,blackouts, di culty learning new things or amnesia

• Nervousness,excitement,restlessnessoranybehaviorchanges

• Incoordinationleadingtofalls • Skinrash

Let your doctor know right away if you miss your period or think you may be pregnant, plan to become pregnant or are breastfeeding.

Is this drug safe to take with other medication?

Precautions/considerations

1. Do not change your dose or stop the drug suddenly without talking to your doctor, especially if you have been on the medication for a number of months or have been taking high doses. Anxiolytics need to be withdrawn gradually to prevent withdrawal reactions.

2. Check with your doctor or pharmacist before taking other drugs, including drugs you can buy without a prescription such as cold remedies and herbal preparations.

3. This drug may impair the mental and physical abilities required for driving a car or operating machinery. Avoid these activities if you feel drowsy or slowed down.

4. This drug may increase the e ects of alcohol, making you more sleepy, dizzy, and lightheaded.

What else do I need to know about antianxiety drugs?

1. Take your medication with meals or with water, milk orange or apple juice. Avoid grapefruit juice as it may change the e ects of the drug in your body.

2. If you are taking sublingual lorazepam, dissolve the tablet under your tongue. The tablet will dissolve within 20 seconds, but you should not swallow for 2 minutes so the drug can be absorbed.

3. If you are taking extended-release alprazolam (Xanax XR) or clorazepate (Tranxene SD), do not cut, crush or chew the tablet. Rather, swallow it whole. Take this drug at the same time in relation to your meals (preferably in the morning).

4. Clonazepam or alprazolam oral disintegrating tablet: Do not remove the blister from the outer pouch until you are ready to take an orally disintegrating tablet. Make sure that your hands are dry when you open the blister pack. Do not push the tablet through the foil but peel back the foil on the blister pack and

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Anxiolytics and Benzodiazepines

place the tablet onto your tongue. The tablet dissolves quickly and can be swallowed with saliva. It may be taken with or without water. Take the tablet immediately after opening the blister pack. Do not store the removed tablet for future use. If you are only taking a half tablet for your dose, throw away the other half. Do not save it for later use.

5. Drinking a lot of ca eine (co ee, tea, colas, etc.) can cause you to become easily upset or jittery and make it harder for this drug to work.

6. Store your medication in a clean, dry area at room temperature. Keep all medication out of the reach of children.

If you have any questions regarding this medication, please ask your doctor, pharmacist or nurse.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Atomoxetine

What is this drug used for?

Atomoxetine is used primarily in the treatment of attention de cit/hyperactivity disorder (ADHD) in children and adults. Though not approved for this indication, atomoxetine may reduce anxiety symptoms.

How quickly will the drug start working?

Some response to atomoxetine is usually noted within the rst 3–4 weeks of treatment of ADHD.

How does your doctor decide on the dosage?

Atomoxetine comes in a capsule; the dose is based on how you respond to initial low doses and is guided by your body weight. The capsule is usually taken once or twice a day, with or without food. Do not increase or decrease the dose without speaking to your doctor.

How long should you take this medication?

Atomoxetine is usually prescribed for a period of several months to years.

What side effects may happen?

Common side e ects that should be reported to your doctor at the NEXT VISIT include:

• Increasedanxiety,agitationorexcitability–someindividuals may feel nervous or have di culty sleeping for a few days after starting this medication.

• Headache–thistendstobetemporaryandcanbemanagedby taking pain medicine (e.g., acetaminophen or ibuprofen) when required. If the headache persists or is “troubling,” contact your doctor.

• Nausea,abdominalpain,vomiting–trytakingyourmedication with food; if symptoms persist, speak to your doctor.

• Lossofappetite,weightloss–eatingsmallermealsmore frequently or drinking liquid nutritional supplements may help.

• Feelingsleepyandtired–theproblemusuallygoesawaywith time, however, your doctor may suggest you take your medication at bedtime. Use of other drugs that make you drowsy will worsen the problem. Avoid operating machinery or tasks that require alertness if drowsiness persists.

• Di cultyrememberingthings–speaktoyourdoctor.

Rare side e ects you should report to your doctor RIGHT AWAY include:

• Fastorirregularheartbeat

• Skinrashwithswelling,itching

• Sorenessofthemouth,gumsorthroat

• Anyunusualbruisingorbleeding,appearanceofsplotchy

purplish darkening of the skin

• Tendernessontherightsideofyourabdomen,fatigue,

weakness, fever or u-like symptoms accompanied by nausea,

vomiting or loss of appetite

• Yellowtingeintheeyesortotheskin;dark-coloredurine(pee) • Severe agitation, restlessness or irritability

• Going12hoursormorewithoutpeeing

• Apersistentorpainfulerectionofthepenisthatcontinuesfor

longer than 4 hours

• Switchinmoodtoanunusualstateofhappiness,excitement,

irritability, a marked disturbance in sleep or thoughts of suicide

Let your doctor know as soon as possible if you miss your period or think you may be pregnant, plan to become pregnant or are breastfeeding.

What should you do if you forget to take a dose of your medication?

If you take atomoxetine more than once a day and you forget to take a dose by more than 6 hours, skip the missed dose and continue with your regular schedule. DO NOT DOUBLE THE DOSE.

Is this drug safe to take with other medication?

Because atomoxetine can change the e ect of other medication or may be a ected by other medication, always check with your doctor or pharmacist before taking other drugs, including those you can buy without a prescription such as cold remedies and herbal preparations. Always inform any doctor or dentist that you see that you are taking atomoxetine.

Precautions/considerations

1. This medication should not be used in patients who have high blood pressure, heart disease or abnormalities, hardening of the arteries or an overactive thyroid.

2. Report to your doctor any changes in sleeping or eating habits or changes in mood or behavior.

3. Do not change your dose or stop atomoxetine without speaking with your doctor.

4. Use caution while performing tasks requiring alertness as atomoxetine can mask fatigue.

5. This drug may interact with medication prescribed by your dentist, so let him/her know the name of the drug you are taking.

What else do I need to know about atomoxetine?

1. Swallow the capsules whole; do not open the capsules as the powder inside may irritate your eyes.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Atomoxetine

2. Take atomoxetine with or after meals to lessen stomach upset, nausea or vomiting.

3. Store your medication in a clean dry area at room temperature. Keep all medication out of reach of children.

If you have any questions regarding this medication, please ask your doctor, pharmacist or nurse.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Bright Light Therapy (BLT)

What is bright light therapy used for?

Bright light therapy is a procedure used primarily to treat patients with a form of depression called seasonal a ective disorder.

It has also been used to treat milder “winter blues,” premenstrual syndrome, and some sleeping disorders.

How do you use bright light therapy?

There are a number of di erent BLT products on the market, including light visors, standard light boxes, or dawn simulators (your doctor will tell you what units may be best for you). These units deliver up to 10,000 lux units of illumination; it is of utmost importance that only UV- ltered light be used.

You will wear the visor or sit near the light source for a period of 20–60 minutes each day during the time of year when you typically experience symptoms of seasonal depression. (Your doctor will tell you when to begin using the light source and whether to use it in the early morning or evening.)

It is not necessary for you to glance directly at the light source; you may read, eat or perform other activities during exposure.

How does bright light therapy work?

Asinthecaseofmanymedicaltreatments,theactualwaythat BLTrelievessymptomsofdepressionisnottotallyunderstood. Several theories have been suggested related primarily to an e ect on the “light-dark” hormone melatonin and to the ability of bright light to reset the body’s internal clock.

How effective is bright light therapy?

Studies comparing the e ectiveness of BLT and drug therapy in seasonal a ective disorder have consistently shown that BLT is the most e ective treatment for this form of depression. Most patients begin to see improvement in their symptoms after 1–3 weeks of daily exposure to the light.

How safe is bright light therapy and what are the potential side effects?

BLT is considered a very safe procedure and studies over several years have shown no damage to the eyes from the light source. Side e ects that can occur include:

• Nausea–ifsevere,useanantinauseant(e.g.,dimenhydrinate) prior to light exposure.

• Headache–acetaminophencanbeused.

• Eye strain, blurred vision, itchy or stingy eyes – this tends to

occur early in treatment and goes away with time. If it continues to be bothersome, sit further away from the light source or decrease the time you spend under the light until the problem no longer occurs.

• Skin irritation – tends to occur in people with sensitive skin or blondes and redheads. You may need to decrease your exposure to the light until the skin problem resolves; then you can gradually increase the time spent under the light.

• Nervousness – let your doctor know if this problem continues. If you feel stimulated or anxious following BLT, contact your doctor before continuing with the treatment.

What else do I need to know about bright light therapy?

• BLTshouldbeusedundersupervisionfromyourdoctor.

• Ensureyouunderstandhow,when,andforhowlongyouareto

use the light visor or standard light box. Ask your doctor to explain anything about the treatment that you do not understand.

• DonotoveruseBLT.

• AsmedicationcaninteractwithBLT,ensureyourdoctoris

aware of all medication you are taking, including drugs you can buy without a prescription and herbal preparations.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Buprenorphine

What is this drug used for?

Buprenorphine is primarily used as a substitute drug in the treatment of opioid-dependent patients who desire maintenance therapy. It suppresses cravings for opioids and can aid in the withdrawal process. Buprenorphine is part of a complete addiction treatment program that also includes behavior therapy and counseling. It has been demonstrated that buprenorphine is bene cial in helping patients avoid illicit opioid use and helps them become socially stable.

How is it supplied?

Buprenorphine is available as two di erent preparations: Subutex, which is a sublingual tablet of buprenorphine, and Suboxone, which is a combination of sublingual buprenorphine and sublingual naloxone. Your doctor will determine which preparation is most appropriate for you.

Buprenorphine is an opioid and its dispensing and usage is governed by Federal regulations.

How quickly will the drug start working?

Buprenorphine will be started once you have abstained from opioids for 12–24 hours and are in the early stages of withdrawal. The dose will be determined by your doctor, and will be given once daily. Put the tablets under your tongue and let them melt; this will take 2–10 minutes. Do not chew or swallow the tablets, as this will change the e ect of the drug.

Any changes in dosage of buprenorphine will be determined by your response, i.e., a decrease in cravings and no withdrawal symptoms. You should see a response within the rst 2 weeks. Follow your doctor’s directions exactly; do not increase or decrease your dose as either severe adverse e ects or withdrawal e ects could occur.

How long should you take this medication?

The length of time buprenorphine is prescribed varies among individuals and depends on a number of factors, including how well they do in therapy. Some patients receive buprenorphine for several months, while most may require it for several years. Any decreases in dose should be done very gradually under the direction of your doctor.

What side effects may happen?

Common side e ects that should be reported to your doctor at the NEXT VISIT include:

• Energizedfeeling,insomnia–someindividualsmayfeel nervous or have di culty sleeping for a few days after starting this medication.

• Nausea, stomach pain – if this happens, take the medication after eating.

• Drowsiness–thisproblemgoesawaywithtime.Useofother drugs that make you sleepy will worsen the problem. Avoid driving a car or operating machinery if drowsiness persists.

• Sweating–youmaysweatmorethanusual;frequent showering, use of deodorants may help.

• Paininjoints,muscles–temporaryuseofnon-opioidpain medicine (e.g., ASA, acetaminophen, ibuprofen) may help.

Rare side e ects you should report to your doctor RIGHT AWAY include:

• Feelingfaint,dizzy,andconfused

• Slowed,di cultbreathing

• Yellowtingeintheeyesortotheskin;dark-coloredurine(pee) • Sore mouth, gums or throat

• Skin rash or itching, swelling of the face

• Nausea, vomiting, loss of appetite, accompanied by feeling

tired, weak, feverish or like you have the u.

Let your doctor know right away if you miss your period or think you may be pregnant, plan to become pregnant or are breastfeeding.

What should you do if you forget to take a dose of your medication?

If you miss a dose, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take two doses at once unless told to do so by your doctor.

Missed doses as well as extra doses can cause withdrawal reactions which include: Nausea/vomiting, diarrhea, muscle aches and cramps, sweating, tearing of the eyes, running nose, dilated pupils, yawning, craving, mild fever, irritability, and insomnia. If you have a combination of these symptoms, call your doctor right away or your local emergency number.

Is this drug safe to take with other medication?

Because buprenorphine can change the e ect of other medication or may be a ected by other medication, always check with your doctor or pharmacist before taking other drugs, including those you can buy without a prescription such as cold remedies and herbal preparations. Always inform any doctor or dentist that you see that you are taking this medication.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Buprenorphine

Precautions/considerations

1. It is important to carry a card in your wallet, stating that you are taking buprenorphine, in case of emergency.

2. DO NOT drink alcohol or take tranquilizers or sedatives while you are on buprenorphine, as serious reactions can occur.

3. Do not share this medication with anyone and store it out of reach of children (preferably in a locked cupboard or desk); buprenorphine can be poisonous to other individuals.

4. Do not change the dose or stop the drug suddenly without speaking to your doctor. Taking higher doses can precipitate a withdrawal syndrome; misuse/abuse may result in poisoning.

5. You can develop dependence from taking buprenorphine, so withdrawal symptoms can occur if you stop the drug suddenly.

6. Buprenorphine can cause death from overdose or if it is injected.

7. You may feel drowsy while taking buprenorphine; do not drive a car or perform tasks requiring alertness if you feel drowsy or slowed down.

What else do I need to know about buprenorphine?

1. The tablets should not be handled, but placed directly in the mouth; they should be placed (all together) under the tongue until dissolved (this takes 2–10 minutes); drinking uids prior to taking the tablets may speed up the dissolution process; chewing or swallowing them reduces the e ect of the drug; do not drink for at least 5 minutes afterwards so as to allow the drug to be absorbed.

If you have any questions regarding this medication, please ask your doctor, pharmacist or nurse.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Bupropion

Bupropion belongs to a class of antidepressants called selective norepinephrine dopamine reuptake inhibitors (NDRI).

What is this drug used for?

Bupropion is mainly used in the treatment of major depressive disorder and bipolar depression. It has also been approved for use in the management of smoking cessation.

Though not approved for these indications, bupropion has also been found useful in children and adults with attention de cit/ hyperactivity disorder, and has been used as an add-on treatment to increase the e ects of other classes of antidepressants. Ask your doctor if you are not sure why you are taking this drug.

How quickly will the drug start working?

Bupropion is usually prescribed twice a day, morning and afternoon or once a day if you are using an extended-release tablet. It begins to improve sleep and appetite and to increase energy within 1–2 weeks; however, feelings of depression may take 4–6 weeks to improve. Because antidepressants take time to work, do not decrease or increase the dose or stop the medication without discussing this with your doctor.

Improvement in smoking cessation/withdrawal also occurs over a period of 6 weeks.

How long should you take this medication?

This depends on what type of illness you have and how well you do.

Following the rst episode of depression, it is recommended that antidepressants be continued for a minimum of 1 year; this decreases the chance of having another episode. Your doctor may then decrease the drug slowly and monitor for any symptoms of depression; if none occur, the drug can gradually be stopped.

For individuals who have had several episodes of depression, antidepressant medication should be continued inde nitely. DO NOT STOP taking your medication if you are feeling better, without rst discussing this with your doctor.

Use of bupropion for smoking cessation is recommended as a one-time treatment for a period of 12 weeks.

What side effects may happen?

Common side e ects that should be reported to your doctor at the NEXT VISIT include:

• Energizing/agitatedfeeling–someindividualsmayfeel nervous or have di culty sleeping for a few days after starting this medication. Report this to your doctor; he/she may advise you to take the medication in the morning.

• Vividdreamsornightmares–thiscanoccuratthestartof treatment.

• Headache – this can be managed by taking pain medicine (e.g., aspirin, acetaminophen) as required. If the headache persists or is “troubling,” contact your doctor.

• Muscletremor,twitching–speaktoyourdoctorasthismay require a change in your dosage.

• Nauseaorheartburn–ifthishappens,takethemedication with food.

• Lossofappetite.

• Drymouth–sourcandyandsugarlessgumhelpincreasesaliva

in your mouth. Do not drink sweet drinks like colas as they may give you cavities and increase your weight. Drink water and brush your teeth regularly.

• Sweating–youmaysweatmorethanusual;frequent showering, use of deodorants may help.

• Bloodpressure–aslightincreaseinbloodpressurecanoccur with this drug. If you are taking medication for high blood pressure, tell your doctor, as this medication may have to be adjusted.

Rare side e ects you should report to your doctor RIGHT AWAY include:

• Persistent,troublingheadache

• Seizures;theseusuallyoccurwithhighdoses–shouldyou

have a seizure, stop taking bupropion and contact your doctor

• Chestpain,shortnessofbreath

• Soremouth,gumsorthroat

• Skinrashoritching,swellingoftheface

• Nausea,vomiting,lossofappetite,fatigue,weakness,feveror

u-like symptoms

• Musclepainandtendernessorjointpainaccompaniedbyfever

and rash

• Yellowtingeintheeyesortotheskin;dark-coloredurine(pee)

• Tinglinginthehandsandfeet,severemuscletwitching

• Severeagitation,restlessness,irritabilityorthoughtsofsuicide

• Switchinmoodtoanunusualstateofhappiness,excitement,

irritability or problems sleeping

Let your doctor know right away if you miss your period or think you may be pregnant, plan to become pregnant or are breastfeeding.

What should you do if you forget to take a dose of your medication?

If you take the sustained-release form of bupropion (Aplenzin, For vo, Wellbutrin SR, Zyban) and take this medication twice daily, and you forget to take the morning dose by more than

4 hours, skip the missed dose and continue with your schedule for the evening dose. If you miss the evening dose by more than

4 hours, skip the missed dose and continue with your schedule the next day. DO NOT DOUBLE THE DOSE as seizures may occur.

Is this drug safe to take with other medication?

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Bupropion

remedies and herbal preparations. Always inform any doctor or dentist that you see that you are taking an antidepressant drug.

Precautions/considerations

1. Do not change your dose without talking with your health care provider (e.g., doctor, pharmacist, nurse).

2. Do not stop this drug suddenly (without discussing it with your health care advisor), as this may result in withdrawal symptoms such as muscle aches, chills, tingling in your hands or feet, nausea, vomiting, and dizziness.

3. Report any changes in mood or behavior to your doctor.

4. Inform your doctor of all medications you are taking including

all drugs prescribed by any doctor as well as over-the-counter

and herbal preparations.

5. This drug may interact with medication prescribed by your

dentist, so let him/her know the name of the drug you are taking.

What else do I need to know about bupropion?

1. If you are taking a sustained-release or extended-release tablet of bupropion, swallow it whole; do not split, crush or chew the tablet, as this will a ect the action of the medication.

2. If you have been told by your doctor to break a bupropion sustained-release tablet in half, do so just prior to taking this medication; throw out the second half unless you can use it within 24 hours (store the half tablet in a tightly closed container away from light).

3. It is best not to drink alcohol at all, or to drink very moderately, while taking bupropion. The risk of seizures is increased if you drink a lot of alcohol and suddenly stop.

4. Excessive use of ca einated foods, drugs or beverages may increase anxiety and agitation and confuse the diagnosis.

5. Store your medication in a clean, dry area at room temperature and away from high humidity, as tablets can deteriorate. Keep all medication out of the reach of children.

If you have any questions regarding this medication, please ask your doctor, pharmacist or nurse.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Buspirone

Buspirone is an anti-anxiety drug (anxiolytic).

What is this drug used for?

Buspirone is used to treat symptoms of chronic anxiety. Anxiety is a normal human response to stress and is considered necessary for e ective functioning and coping with daily activities. It may, however, be a symptom of many other disorders, both medical and psychiatric. There are many di erent types of anxiety and there are many di erent approaches to treating it.

Though not approved for these indications, buspirone has also been found e ective in other conditions, including social phobia, agitation, irritability, aggression, and antisocial behavior. It has been used alone or in combination with antidepressants in the treatment of depression. Ask your doctor if you are not sure why you are taking this drug.

How quickly will the drug start working?

Buspirone causes a gradual improvement in symptoms of anxiety and can reduce agitation and induce calm usually within

1–2 weeks. The maximum e ect is seen after 3–4 weeks. Improvement in symptoms of other disorders for which buspirone may be prescribed occur gradually over several weeks.

How long should you take this medication?

This depends on what type of illness you have and how well you do.

Anxiety is usually self-limiting; often when the cause of anxiety is treated or eliminated, symptoms of anxiety will decrease. Therefore, anxiolytics are usually prescribed for a limited period of time. To maintain e ectiveness, buspirone cannot be taken only when needed (during periods of excessive stress), but needs to be taken on a daily basis. Your doctor may try to reduce the dose of this drug to see if the anxiety symptoms return; if not, the dosage may be further reduced and you may be advised to stop using this medication. Do not increase the dose or stop the drug without consulting with your doctor.

Some patients need to use an anxiolytic drug for longer time periods because of the type of anxiety they may be experiencing. Long-term treatment is generally recommended for certain other indications such as social phobia or antisocial behavior.

What side effects may happen?

Common side e ects that should be reported to your doctor at the NEXT VISIT include:

• Feelingsleepyandtired–thisproblemgoesawaywithtimeor when the dose is reduced. Avoid driving a car or operating machinery if drowsiness persists.

• Headache – tends to be temporary and can be managed by taking pain medicine (e.g., aspirin, acetaminophen) when required.

• Nauseaorheartburn–ifthishappens,takethemedication with food.

• Dizziness, lightheadedness – sit or lie down; if symptoms persist, contact your doctor.

• Energized/agitated feeling – some individuals may feel nervous for a few days after starting this medication. Report this to your doctor.

• Tingling or numbing in ngers or toes – report this to your doctor.

Less common side e ects that you should report to your doctor RIGHT AWAY include:

• Severeagitation,excitementoranychangesinbehavior

Let your doctor know right away if you miss your period or think you may be pregnant, plan to become pregnant or are breastfeeding.

What should you do if you forget to take a dose of your medication?

If you take your total dose of buspirone at bedtime and you forget to take your medication, skip the missed dose and continue with your schedule the next day. DO NOT DOUBLE THE DOSE. If you take the drug several times a day, take the missed dose when you remember, then continue with your regular schedule.

Is this drug safe to take with other medication?

Because this drug can change the e ect of other medication, or may be a ected by other medication, always check with your doctor or pharmacist before taking other drugs, including those you can buy without a prescription such as cold remedies and herbal preparations. Always inform any doctor or dentist that you see that you are taking this drug.

What else do I need to know about buspirone?

1. Do not increase your dose without consulting your doctor.

2. Take your medication at the same time each day in relation to

your meals (i.e., always with or without food).

3. Take your medication with water, milk orange or apple juice.

Avoid grapefruit juice as it may change the e ects of the drug

in your body.

4. Drinking a lot of ca eine (co ee, tea, colas, etc.) can cause you

to become easily upset or jittery and make it harder for this

drug to work.

5. This drug may increase the e ects of alcohol, making you more

sleepy, dizzy, and lightheaded.

6. Store your medication in a clean, dry area at room

temperature. Keep all medication out of the reach of children.

If you have any questions regarding this medication, please ask your doctor, pharmacist or nurse.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Clonidine and Guanfacine

What are these drug used for?

Clonidine and guanfacine are used in the treatment of attention de cit/hyperactivity disorder (ADHD) and tic disorder in children and adults. They have also been found e ective for controlling some problematic behaviors in children and adults with autism, in decreasing symptoms in certain anxiety disorders as well as in schizophrenia, and in increasing patient comfort during heroin and nicotine withdrawal. Ask your doctor if you are not sure why you are taking this drug.

How quickly will the drug start working?

Some response is usually noted within the rst week of treatment of ADHD and tends to increase over the next 3 weeks.

How does your doctor decide on the dosage?

Clonidine comes in both a tablet and a transdermal patch. The dose is based on body weight. The tablet is usually taken once or twice daily (extended release forms) or several times a day (short-acting form), while the patch is applied to the upper arm or chest and is left there for a period of one week. Guanfacine is available as fast-release or extended-release tablets. The dose is increased slowly until response is achieved.

Do not increase or decrease the dose without speaking to your doctor. Do not take o the patch mid-week unless you have been told to do so by your doctor.

How long should you take this medication?

These drugs are usually prescribed for a period of several years for ADHD. The length of use for other indications varies.

What side effects may happen?

Common side e ects that should be reported to your doctor at the NEXT VISIT include:

• Feelingsleepyandtired–theproblemgoesawaywithtime. Use of other drugs that make you drowsy will worsen the problem. Avoid operating machinery if drowsiness persists.

• Drymouth–sourcandy,mints,andsugarlessgumhelp increase saliva in your mouth. Do not drink sugar-containing drinks as they may give you cavities and increase your weight. Drink water and brush your teeth regularly.

• Headache–thistendstobetemporaryandcanbemanagedby taking pain medicine (e.g., acetaminophen or ibuprofen) when

required. If the headache persists or is “troubling,” contact your

doctor.

• Skinreactions–thesemayincluderedness,scaling,and

blistering. Rotate site of patch application

Rare side e ects you should report to your doctor RIGHT AWAY include:

• Fast,slow,orirregularheartbeat

• Skinrashwithswelling,itching

• Soremouth,gumsorthroat

• Anyunusualbruisingorbleeding,appearanceofsplotchy

purplish darkening of the skin

• Nausea,vomiting,lossofappetite,feelingtired,weak,feverish

or like you have the u

• Yellowtingeintheeyesortotheskin;dark-coloredurine(pee) • Severeagitation,restlessnessorirritability

Let your doctor know right away if you miss your period or think you may be pregnant, plan to become pregnant or are breastfeeding.

What should you do if you forget to take a dose of your medication?

If you take clonidine more than once a day and you forget to take a dose by more than 6 hours, skip the missed dose and continue with your regular schedule. DO NOT DOUBLE THE DOSE.

If you take guanfacine once a day and you forget to take a dose by more than 6 hours, skip the missed dose and continue with your regularly scheduled dose the next day. DO NOT DOUBLE THE DOSE.

Is this drug safe to take with other medication?

Because clonidine and guanfacine can change the e ect of other medication or may be a ected by other medication, always check with your doctor or pharmacist before taking other drugs, including those you can buy without a prescription such as cold remedies and herbal preparations. Always inform any doctor or dentist you see that you are taking this drug.

Precautions/considerations

1. Report to your doctor any changes in sleeping or eating habits or changes in mood or behavior.

2. Do not change your dose or stop the drug suddenly, without speaking with your doctor, as it may result in withdrawal symptoms including insomnia and changes in blood pressure. If you need to stop taking this medication, your doctor will tell you how to gradually reduce your dosage to prevent changes in blood pressure.

3. Use caution while performing tasks requiring alertness as clonidine can cause fatigue.

4. Clonidine and guanfacine may increase the e ects of alcohol, making you more sleepy, dizzy, and lightheaded. If taken together with alcohol, this may make it dangerous for you to drive, operate machinery, or perform tasks that require careful attention

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Clonidine and Guanfacine

What else do I need to know about this medication?

1. If using the clonidine patch and it begins to loosen from the skin after application, apply adhesive tape directly over the patch to make sure it stays on for the rest of the week.

2. Take o the used patch before applying a new patch to the skin. Handle used transdermal patches carefully; fold the patch in half with the sticky sides together, and place inside a baggie prior to discarding. Wash hands carefully after handling. Keep out of reach of children.

3. Do not crush or chew extended-release tablets, but swallow them whole. Do not crush, split or chew the tablet.

4. Store your medication in a clean dry area at room temperature. Keep all medication out of reach of children.

If you have any questions regarding this medication, please ask your doctor, pharmacist or nurse.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Clozapine

Clozapine belongs to the class of drugs called antipsychotics. What is this drug used for?

The main use of this drug is to treat psychosis. Psychosis can be a part of many illnesses like schizophrenia or bipolar disorder. Clozapine is most often used in people when other antipsychotic drugs don’t work well enough. Ask your doctor if you are not sure why you are taking this drug.

What symptoms will this drug help control?

Symptoms of psychosis may not be the same for each person. Some symptoms of psychosis that this drug can help with are: • Hearingvoices,seeingthingsorsmelling,tastingorfeeling

things that are not real (hallucinations).

• Feeling that someone is trying to hurt you or is following you

or that people are talking about you or that you have special

powers or are famous (delusions).

• Finding it hard to think clearly, having thoughts that are

speeded up or feeling like you don’t have control of your

thoughts.

• Becoming easily upset or overexcited.

• Showing no interest in yourself or others.

How quickly will the drug start working?

Because antipsychotics take time to work, do NOT change your dose or stop your medication without talking to your doctor.

How long should you take this medication?

People who take clozapine have often had symptoms of psychosis for a long time and may need to stay on this drug long term. Your doctor may change your dose from time to time based on how well you are doing and on the results of blood tests that you have. DO NOT CHANGE the dose or STOP taking clozapine without talking to your doctor rst. Stopping clozapine all at once (“cold turkey”) may cause you to feel ill.

Why do I need blood tests with clozapine? Why can I only get a small supply at a time?

Clozapine can cause a rare side e ect called agranulocytosis. This can happen in 1 out of every 100 people that take clozapine. It causes the number of white blood cells (a type of cell in your blood) to drop too low. This makes it harder for your body to ght o an infection. Blood tests must be done regularly so your doctor can check your white blood cells. Usually, a blood test must be done once a week for the rst 26 weeks, then once every 2 weeks for the next 26 weeks, then every four weeks after that, while you

stay on the drug. Sometimes your doctor may want you to get extra blood tests depending on how you feel or if your white blood cells drop in number. It is also very important to call your doctor if you get any signs of infection such as fever, sore throat or mouth sores. Always let your doctor and pharmacist know you are taking clozapine before taking other drugs.

What side effects may happen?

Common side e ects that you should tell your doctor about at the NEXT VISIT include:

• Feelingsleepyortired–thisusuallygoesawayovertime.Be careful if you are driving or operating heavy machinery during times when you need to be wide awake.

• Feeling dizzy – you may nd you get dizzy or feel faint when you get up too fast from sitting or lying down. Getting up more slowly or sitting on the side of your bed with your feet on the oor before getting up will help. This side e ect usually goes away over time.

• Drooling–oftenoccursatnight.Useatowelonthepillow when sleeping. Drooling may occasionally occur while you are awake. If this is bothersome, talk to your doctor or pharmacist about other ways of dealing with this.

• Weightgain–thebestwaytolimitweightgainistowatch how much you eat and avoid eating fatty foods (like cakes, ice cream) or foods high in sugar (like soft drinks or energy drinks). Exercise can also help. Your doctor may check your weight, cholesterol, (a type of body fat) and sugar levels from time to time.

• Increased thirst or peeing more often – let your doctor know. Your doctor may want to check your blood sugar.

• Nausea or heartburn – try taking your drug with food if this happens.

Rare side e ects you should tell your doctor about RIGHT AWAY are:

• Soremouth,gumsorthroat

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Clozapine

• Feelingtiredorweak,feveror u-likesymptomsorothersigns of having an infection

• Feelinglikeyourheartisbeatingtofast,chestpainorproblems breathing

• Havingablackout, torseizure

• Skinrashoritching

• Reallybadheadache

• Constantdizzinessorfainting

• Yellowtingeintheeyesortotheskin;dark-coloredurine(pee)

• Goingadayormorewithoutpeeing

• Goingmorethan2or3dayswithouthavingabowel

movement

• Neworworseneddistressingthoughtsorcompulsive

behaviors

Tardive dyskinesia: This is a movement disorder that may occur in people who have taken some antipsychotic drugs for many years. Tardive dyskinesia happens when some of your body muscles, usually in your face (lips and tongue), move on their own, without you making them do so. The chance of this happening with clozapine is very low and sometimes clozapine may be used to help treat it.

Let your doctor know right away if you miss your period or think you may be pregnant, plan to become pregnant or are breastfeeding.

What should you do if you forget to take a dose of your medication?

If you miss a dose and remember within 2 hours, take the dose right away. Otherwise skip the missed dose. Do NOT take two doses at the same time. If you have stopped taking clozapine for more than 2 days, do not re-start taking clozapine on your own. Speak to your doctor or pharmacist about what to do.

Is this drug safe to take with other medication?

Clozapine can change the e ect of other drugs that you are taking or it may be a ected by other drugs. Always check with your doctor or pharmacist before taking any drugs, including those that you are taking or plan to take, those you can buy without a prescription (like cold remedies or medications for fever), and herbals (like St. John’s Wort, ginseng, and many others).

WhatelsedoIneedtoknowaboutclozapine?

1. Do not change your dose or stop it without talking to your doctor.

2. Take clozapine with meals or with water, milk or orange juice. Do NOT take it with grapefruit juice as this may change the amount of drug in your body.

3. Do not break or crush clozapine unless you have been told to do it by your doctor. If you are taking clozapine oral disintegrating tablets (FazaClo), do not push the tablet through the foil blister pack. Remove FazaClo by peeling back the foil and gently removing the tablet. Use dry hands to remove the tablet and immediately place the tablet on your tongue and let it melt. No water is needed to take FazaClo.

4. Clozapine may increase the e ects of alcohol, making you more sleepy and less alert.

5. Clozapine may a ect your body’s ability to control body temperature, so avoid places that are very hot and humid like saunas.

6. Antacids (like Diovol, Maalox, amphogel, etc.) may lower the amount of clozapine in your body. Take your antacid at least 2 hours before or 1 hour after taking clozapine to avoid this.

7. Drinking a lot of ca eine (co ee, teas, colas, etc.) can cause you to become easily upset or jittery and make it harder for clozapine to work.

8. Cigarette smoking can change the amount of clozapine in your body, so let your doctor know if you smoke or if you stop smoking or change how much you smoke.

9. Stopping your drug all of a sudden (“cold turkey”) may make you ill. Talk to your doctor or pharmacist rst about how to stop it safely.

10. Keep your antipsychotic drugs in a clean, dry area at room temperature. Keep all medication out of the reach of children.

If you have any questions about clozapine, please ask your doctor, pharmacist or nurse.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Cyclic Antidepressants

The name of your medication is ________________________.

What is this drug used for?

Cyclic antidepressants are primarily used in the treatment of major depressive disorder and bipolar depression.

Certain drugs in this class have also been found e ective in several other disorders including obsessive-compulsive disorder, panic disorder, bulimia, social phobia, bed wetting, and premenstrual dysphoria as well as management of chronic pain conditions (e.g., migraines, neuropathic pain). Ask your doctor if you are not sure why you are taking this drug.

How quickly will the drug start working?

Antidepressants begin to improve sleep and appetite and to increase energy within 1–2 weeks; however, feelings of depression may take 4–6 weeks to improve. Because antidepressants take time to work, do not decrease or increase the dose or stop the medication without discussing this with your doctor. Improvement in symptoms of obsessive-compulsive disorder, panic disorder, and bulimia as well as pain management also occur gradually.

How long should you take this medication?

This depends on what type of illness you have and how well you do.

Following the rst episode of depression it is recommended that antidepressants be continued for a minimum of 1 year; this decreases the chance of having another episode. Your doctor may then decrease the drug slowly and monitor for any symptoms of depression; if none occur, the drug can gradually be stopped.

Long-term treatment is generally recommended for obsessive- compulsive disorder, panic disorder, bulimia, pain management, and persistent bedwetting in children.

What side effects may happen?

Common side e ects that should be reported to your doctor at the NEXT VISIT include:

• Feelingdrowsyortired–thisproblemgoesawaywithtime. Use of other drugs that make you drowsy will worsen the problem. Avoid driving a car or operating machinery until you know how the drug a ects you. If drowsiness persists your doctor may advise you to take the medication at bedtime.

• Energizing/agitated feeling – some individuals may feel nervous or have di culty sleeping for a few days after starting

this medication. Report this to your doctor; he/she may advise

you to take the medication in the morning.

• Blurredvision–thisusuallyhappenswhenyou rststartthe

drug and tends to be temporary. Reading under a bright light or at a distance may help; a magnifying glass can be of temporary use. If the problem lasts more than a few weeks, let your doctor know.

• Drymouth–sourcandyandsugarlessgumhelpincreasesaliva in your mouth. Do not drink sweet drinks like colas as they may give you cavities and increase your weight. Drink water and brush your teeth regularly.

• Headache–thistendstobetemporaryandcanbemanagedby taking pain medicine (aspirin, acetaminophen) when required.

• Nauseaorheartburn–ifthishappens,takethemedication with food.

• Sweating–youmaysweatmorethanusual;frequent showering, use of deodorants may help.

• Muscletremor,twitching–speaktoyourdoctorasthismay require a change in your dosage.

• Changesinsexdriveorsexualperformance–discussthiswith your doctor.

• Nightmares–canbemanagedbychangingthetimeyoutake your drug, speak with your doctor.

Rare side e ects you should report to your doctor RIGHT AWAY include:

• Soremouth,gumsorthroat

• Skinrashoritching,swellingoftheface

• Nausea,vomiting,lossofappetite,fatigue,weakness,feveror

u-like symptoms

• Yellowtingeintheeyesortotheskin;dark-coloredurine(pee) • Going12hoursormorewithoutpeeing

• Inabilitytohaveabowelmovement(formorethan2–3days)

• Tinglinginthehandsandfeet,severemuscletwitching

• Severeagitation,restlessness,irritabilityorthoughtsofsuicide • Switchinmoodtoanunusualstateofhappiness,excitement,

irritability or problems sleeping

Let your doctor know right away if you miss your period or think you may be pregnant, plan to become pregnant or are breastfeeding.

What should you do if you forget to take a dose of your medication?

If you take your total dose of this medication in the morning and you forget to take it for more than 6 hours, skip the missed dose

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Cyclic Antidepressants

and continue with your schedule the next day. DO NOT DOUBLE THE DOSE. If you take the drug several times a day, take the missed dose when you remember, then continue with your regular schedule.

Is this drug safe to take with other medication?

Because antidepressant drugs can change the e ect of other medication or may be a ected by other medication, always check with your doctor or pharmacist before taking other drugs, including those you can buy without a prescription such as cold remedies and herbal preparations. Always inform any doctor or dentist that you see that you are taking an antidepressant drug.

Precautions/considerations

1. Do not change your dose without talking with your health care provider (e.g., doctor, pharmacist, nurse).

3. This drug may impair the mental and physical abilities required for driving a car or operating machinery. Avoid these activities if you feel drowsy or slowed down.

4. This drug may increase the e ects of alcohol, making you more sleepy, dizzy, and lightheaded.

5. Report any changes in mood or behavior to your doctor.

6. This drug may interact with medication prescribed by your dentist, so let him/her know the name of the drug you are

taking.

What else do I need to know about cyclic antidepressants?

1. Take your drug with meals or with water, milk orange or apple juice; avoid grapefruit juice as it may change the e ect of the drug in your body.

2. Avoid taking high- ber foods (e.g., bran) or laxatives (e.g., psyllium) together with your medication, as this may reduce the antidepressant e ect.

3. Avoid exposure to extreme heat and humidity since this drug may a ect your body’s ability to regulate temperature.

4. Excessive use of ca einated foods, drugs or beverages may increase anxiety and agitation and confuse the diagnosis.

5. Store your medication in a clean, dry area at room temperature. Keep all medication out of the reach of children.

If you have any questions regarding this medication, please ask your doctor, pharmacist or nurse.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Deutetrabenazine

Thenameofyourmedicationis_______________________.

What is this drug used for?

Deutetrabenazine is a medication used to treat the involuntary movements (chorea) of Huntington’s disease. Deutetrabenazine does not cure the cause of the involuntary movements, and it does not treat other symptoms of Huntington’s disease, such as problems with thinking or emotions.

It is also used to treat movement in the face, tongue, or other body parts that cannot be controlled (tardive dyskinesia).

How quickly will the drug start working?

Deutetrabenazine may begin to reduce involuntary/ uncontrollable movements after 4 weeks, but it may take up to 12 weeks to feel the full e ect.

Because this medication takes time to work, do NOT change your dose or stop your medication without talking to your doctor.

How long should you take this medication?

This may depend on how e ective deutetrabenazine is at reducing your involuntary/uncontrollable movements.

Talk with your doctor about how long you should stay on this medication.

How do you take this drug?

Rare side e ects you should report to your doctor RIGHT AWAY are:

• Depressionandsuicidalthoughtsoractionsinpeoplewith Huntington’s disease

• Fast,slow,orirregularheartbeat

• Dizzinessorfainting

• Shortnessofbreath

• Restlessness–youmaygetaconditionwhereyoufeelastrong

urge to move. This is called akathisia.

• ParkinsonisminpeoplewithHuntington’sdisease.Symptoms

include: slight shaking, body sti ness, trouble moving, or

keeping your balance.

• NeurolepticMalignantSyndrome.Callyourdoctorrightaway

and go to the nearest emergency room if you develop these signs and symptoms that do not have another obvious cause

– Highfever

– Sti muscles

– Problemsthinking

– Veryfastorunevenheartbeat – Increasedsweating

Let your doctor know right away if you miss your period or think you may be pregnant, plan to become pregnant or are breastfeeding.

Deutetrabenzaine is a titrated medication, meaning that your

dose may be adjusted throughout the rst few weeks of

treatment until your doctor identi es the dose that is appropriate medication? for you. Each dosing schedule is individualized. Take

deutetrabenazine with food and swallow the tablet whole with

water. Do not chew, crush, or break the tablets before swallowing.

If you cannot swallow the tablets whole, tell your doctor. You may

need a di erent medicine.

What side effects may happen?

Side e ects may happen with any drug. They may sometimes occur before bene cial e ects of the medication are noticed. Many side e ects get better or go away over time. If you think you may be having a side e ect, speak to your doctor or pharmacist as they can help you decrease it or cope with it.

Common side e ects that should be reported to your doctor at the NEXT VISIT include:

• Feelingsleepyortired–thisproblemgoesawaywithtime.Use of other drugs that make you drowsy will worsen the problem. Avoid driving a car or operating machinery until you know how the drug a ects you. Drinking alcohol and taking other drugs that may also cause sleepiness while you are taking deutetrabenazine may increase any sleepiness caused by deutetrabenazine. If drowsiness persists, your doctor may advise you to take the medication at bedtime.

• Diarrhea

Is this drug safe to take with other medication?

Because deutetrabenazine can change the e ect of other medication or may be a ected by other medication, always check with your doctor or pharmacist before taking other drugs, including those you can buy without a prescription such as cold remedies and herbal preparations. Always inform any doctor or dentist that you see that you are taking this medication.

What else do I need to know about deutetrabenazine?

1. Do not change your dose without talking with your health care provider (e.g., doctor, pharmacist, nurse).

2. Do not start taking deutetrabenazine if you are depressed (have untreated depression or depression that is not well controlled by medicine) or have suicidal thoughts. Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts or feelings. This is especially important when deutetrabenzine is started and when the dose is changed. Call you doctor right away if you become depressed,

What should you do if you forget to take a dose of your

If you forget to take a dose of your medication, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. DO NOT take two doses at the same time.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Deutetrabenazine

have unusual changes in mood or behavior, or have thoughts

of suicide.

3. Do not cut, crush or chew deutetrabenazine tablets. Swallow

them whole.

4. Antacids (like Diovol, Maalox, amphogel, etc.) may lower the

amount of deutetrabenazine in your body. Take your antacid at least 2 hours before or 1 hour after taking deutetrabenazine to avoid this.

5. This drug may cause sleepiness. Do not drive, operate heavy machinery, or do other dangerous activities until you know how deutetrabenazine a ects you.

6. Store your medication in a clean, dry area at room temperature. Keep all medication out of the reach of children.

If you have any questions regarding this medication, please ask your doctor, pharmacist or nurse.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Disul ram

What is this drug used for?

Disul ram is primarily used as a deterrent to alcohol use/abuse. Disul ram has been shown to maintain abstinence if taken, as directed, as part of a treatment program that includes counseling and support.

How quickly will the drug start working?

Disul ram inhibits the breakdown of alcohol in the body, resulting in a build-up of a chemical called acetaldehyde; this results in an unpleasant reaction when alcohol is consumed. The reaction can occur 10–20 minutes after drinking alcohol and may last up to 2 hours.

The reaction consists of: Flushing, choking, nausea, vomiting, increased heart rate and decreased blood pressure (dizziness).

How long should you take this medication?

Disul ram is usually prescribed for a set period of time to help the individual stop the use of alcohol. Do not decrease or increase the dose without discussing this with your doctor.

What side effects may happen?

Common side e ects that should be reported to your doctor at the NEXT VISIT include:

• Feelingsleepy,tired,depressed–thisproblemgoesawaywith time. Use of other drugs that make you drowsy will worsen the problem. Avoid driving a car or operating machinery if drowsiness persists.

• Energizing/agitatedfeeling–someindividualsmayfeel nervous or have di culty sleeping for a few days after starting this medication.

• Headache–temporaryuseofpainmedicine(e.g., acetaminophen, ASA).

• Garlic-liketaste.

Rare side e ects you should report to your doctor RIGHT AWAY include:

• Yellowtingeintheeyesortotheskin;dark-coloredurine(pee) • Soremouth,gumsorthroat

• Skinrash,itchingorswellingoftheface

• Feelingtired,weak,feverishorlikeyouhavethe u,associated

with nausea, vomiting, and loss of appetite

Let your doctor know right away if you miss your period or think you may be pregnant, plan to become pregnant or are breastfeeding.

What should you do if you forget to take a dose of your medication?

If you take your total dose of the drug in the morning and you forget to take it for more than 6 hours, skip the missed dose and continue with your schedule the next day. DO NOT DOUBLE THE DOSE.

Is this drug safe to take with other medication?

Because disul ram can change the e ect of other medication or may be a ected by other medication, always check with your doctor or pharmacist before taking other drugs, including those you can buy without a prescription such as cold remedies and herbal preparations. Always inform any doctor or dentist that you see that you are taking this medication.

Precautions/considerations

1. Do not change your dose or stop the drug without speaking to your doctor.

2. Report to your doctor any changes in sleeping or eating habits or changes in mood or behavior.

3. Avoid all products (food and drugs) containing alcohol, including tonics, cough syrups, mouth washes, and alcohol-based sauces. A delay in the reaction may be as long as 24 hours.

4. Exposure to alcohol-containing rubs or solvents (e.g., after-shave) may trigger a reaction.

What else do I need to know about disul ram?

1. Carry an identi cation card stating the name of the drug you are taking.

2. Store your medication in a clean, dry area at room temperature. Keep all medication out of the reach of children.

If you have any questions regarding this medication, please ask your doctor, pharmacist or nurse.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Drugs for Treatment of Dementia

Thenameofyourmedicationis________________________.

What is this drug used for?

Cognition enhancers are primarily used to treat symptoms of mild to severe Alzheimer’s dementia. They have also been found of bene t in treating some of the behavioral and psychological disturbances seen in patients with dementia.

How quickly will the drug start working?

Improvement in concentration, attention, and activities of daily living is noted over a period of several weeks. Because these drugs take time to work do not decrease or increase the dose without discussing this with your doctor.

How does your doctor decide on the dosage?

The drug is started at a low dose to minimize the chance of side e ects. The dose can be increased after several weeks if minimal improvement is seen.

How long should you take this medication?

Cognition enhancers are usually prescribed for a period of several years.

What side effects may happen?

Common side e ects that should be reported to your doctor at the NEXT VISIT include:

• Energizing/agitatedfeeling,excitability–someindividualsmay feel nervous or have di culty sleeping for a few days after starting this medication or after a dose increase. If you are taking the medication in the evening, your doctor may decide to prescribe it earlier in the day.

• Nightmaresorvividdreams–letyourdoctorknow;thetime you take the drug or your dose may need to be adjusted.

• Headache–thistendstobetemporaryandcanbemanagedby taking pain medicine (aspirin, acetaminophen) when required. If the headache persists or is “troubling,” contact your doctor.

• Nausea,vomiting,stomachpains,heartburncanoccurwhen treatment is started or after a dose increase; if this happens, take the medication with food or milk.

• Diarrheaorconstipation, atulence.

• Lossofappetite,weightloss–takingthemedicationafter

meals, eating smaller meals more frequently or drinking high

calorie drinks may help.

• Feelingtired,weak.

• Muscleachesorcramps–canbemanagedbytakingpain

medicine when required.

• Nasalcongestion. • Hot ushes.

Rare side e ects you should report to your doctor RIGHT AWAY include:

• Yellowtingeintheeyesortotheskin;dark-coloredurine(pee) • Soremouth,gumsorthroat

• Skinrashoritching,swellingoftheface

• Nausea,vomiting,lossofappetite,fatigue,weakness,feveror

u-like symptoms

• Severe agitation or restless

• Feelingdizzyorfaintorepisodesoffalling

What should you do if you forget to take a dose of your medication?

If you take your total dose of the drug in the morning and you forget to take it for more than 6 hours, skip the missed dose and continue with your schedule the next day. DO NOT DOUBLE THE DOSE. If you take the drug several times a day, take the missed dose when you remember, then continue with your regular schedule.

Is this drug safe to take with other medication?

Because these drugs can change the e ect of other medication or may be a ected by other medication, always check with your doctor or pharmacist before taking other drugs, including those you can buy without a prescription such as cold remedies and herbal preparations. Always inform any doctor or dentist that you see that you are taking a cognition enhancer.

Precautions/considerations

1. Do not change your dose or stop the drug without speaking with your doctor.

2. Report to your doctor any changes in sleeping or eating habits or changes in mood or behavior.

3. Do not stop your drug suddenly as this may result in changes in behavior and/or concentration. If rivastigmine was stopped for more than 3 days, DO NOT restart without speaking to your doctor.

4. This drug may interact with medication prescribed by your dentist, so let him/her know the name of the drug you are taking.

5. Do not take any other medication (including drugs you can buy without a prescription and herbal products) without talking to your doctor or pharmacist.

What else do I need to know about drugs for dementia?

1. Extended-release capsules of galantamine or memantine should not be broken, chewed or crushed but should be swallowed whole.

2. Donepezil oral disintegrating tablets should be placed under the tongue and can be taken with or without liquid.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Drugs for Treatment of Dementia

3. The area where the rivastigmine patch is applied should be rotated to other parts of the body routinely. If there is concern of the patch being removed prematurely or inadvertently, then it is suggested that a caregiver place the patch where the patient cannot easily remove it. Ensure the patch is removed after 24 hours and prior to applying the next dose. When removing the patch, fold it in half with the adhesive side on the inside and dispose of in waste container; wash hands after handling. Keep out of reach of children.

4. If you are prescribed memantine, do not use antacids (e.g., Tums, Rolaids, Maalox) excessively as they may a ect the action of memantine.

5. Store your medication in a clean, dry area at room temperature. Keep all medication out of the reach of children.

If you have any questions regarding this medication, please ask your doctor, pharmacist or nurse.

Practical recommendations for caregivers to decrease agitation and improve communication with patients with dementia

1. Decrease stimulation and change the environment to maintain safety.

2. Maintain physical comfort.

3. Slow down your pace and simplify your actions (i.e., one

demand at a time).

4. Use simple direct statements; limit choices. Speak clearly and

slowly and allow time for response.

5. Match verbal and nonverbal signals; maintain eye contact and

relaxed posture.

6. Identify situations/actions that result in agitation; change

these if possible.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Electroconvulsive Therapy (ECT)

What is ECT used for?

ECT is a procedure used primarily to treat patients with severe depression. It has also been found e ective in the manic phase of bipolar depression and in some patients with schizophrenia.

What is the ECT procedure?

ECT is given to the patient while under a general anesthetic that has put him/her to sleep; a muscle relaxant is also given to prevent injury to the muscles, bones, and joints.

ECT involves passing a small, controlled electric current between two metal discs (electrodes) which are applied on the surface of the scalp. The two electrodes may be placed on one side of the head for unilateral ECT or on both sides of the forehead for bilateral ECT. The electric current passes between the two electrodes and through part of the brain in order to stimulate the brain; that electrical stimulation induces a convulsion or seizure which usually lasts 20–90 seconds.

The procedure takes approximately 10 minutes from the time the anesthetic is given until its e ect wears o . Oxygen is given throughout this time and the patient is monitored continuously by the physician. The treatment is not painful and the electric current and seizure are not felt by the patient.

How does ECT work?

As is the case with many medical treatments, the actual way that ECT relieves symptoms of illness is not totally understood. ECT a ects some of the chemicals which transfer impulses or messages between nerve cells in the brain, perhaps more strongly and quickly than some medications. The treatment may correct some of the changes in these chemicals which accompany some mental illnesses.

How effective is ECT?

Studies comparing the e ectiveness of ECT and drug therapy in depression have consistently shown that ECT is the most e ective treatment of depression, especially in patients whose illness does not respond adequately to drug treatment.

The total number of treatments required to get the full bene t from ECT may range from 6 to 20, depending on the patient’s diagnosis and response to treatment. In some patients, improvements may be seen after 3 treatments; however, a full course is generally recommended to obtain a full response. Some patients require ongoing periodic ECT treatments to maintain their improvement.

How safe is ECT and what are the potential side effects?

ECT is considered safe when given according to modern standards. It has been given safely to elderly patients as well as to patients during pregnancy, with proper monitoring. Side e ects that can occur include the following:

• Memory–themostcommonsidee ectseenfollowingECTis some degree of memory loss. Recovery from that memory loss begins a few weeks after treatment and is usually complete in most patients after 6–9 months. There may be a permanent loss of memory for details of some events, particularly those which occurred some time before and during the weeks ECT treatment was given. Also, there may be some di culty learning and remembering new information for a short period after ECT. However, the ability to acquire and retain new memories recovers completely, usually a few months after treatment. A very small number of patients report severe problems with memory that remain for months or years.

• Confusion–somepatientsexperienceabriefperiodof confusion after waking from the anesthetic.

• Headache–common,butnotusuallysevere.

• Muscleaches–usuallymostsigni cantafterthe rst

treatment and not usually severe.

• Increasedheartrateandbloodpressure–thiscanoccurduring

treatment and last for several minutes. Monitoring of patients during and following ECT includes temperature, pulse, blood pressure, and electrocardiogram (ECG).

• Prolongedseizure–occursrarely;seizureactivityismonitored during the procedure by an electroencephalogram (EEG). Rarely, a patient may have a spontaneous seizure following ECT.

• Dentalinjury(e.g.,brokenteeth)orbonefractures–occurvery rarely.

The risk of death is very rare (2–4 per 100,000 treatments) and is similar to that seen with any treatment given under a brief general anesthetic.

What else do I need to know about the ECT procedure?

1. Make sure that you understand the information that has been provided to you by your doctor or nurse regarding ECT; ask them to explain anything about the treatment which you do not understand.

2. Do not eat or drink anything for approximately 8 hours before each treatment (and nothing after midnight).

3. Any essential medication (e.g., for high blood pressure) which your doctor has told you must be taken before ECT, should be swallowed only with a very small sip of water.

4. Any other medication which you usually take in the morning should not be taken until after the ECT procedure.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Esketamine

Thenameofyourmedicationis________________________.

What is this drug used for?

Esketamine is a medicine, used along with an antidepressant taken by mouth, for treatment-resistant depression in adults.

How quickly will the drug start working?

Unlike other antidepressants, esketamine may begin to reduce your symptoms of depression as soon as 24 hours from the start of treatment.

How long should you take this medication?

This will depend on how e ective esketamine is at reducing or eliminating your symptoms of depression.

Talk with your doctor about how long you should stay on this medication.

How do you take this drug?

• Youwilladministeresketaminenasalsprayyourself,underthe supervision of a healthcare provider in a healthcare setting. Your healthcare provider will show you how to use the nasal spray device.

• Yourhealthcareproviderwilltellyouhowmuchesketamine you will take and when you will take it.

• Followyourtreatmentscheduleexactlyasyourhealthcare provider tells you to.

• Duringandaftereachuseoftheesketaminenasalspraydevice you will be checked by a healthcare provider who will decide when you are ready to leave the healthcare setting.

• Youwillneedtoplanforacaregiverorfamilymembertodrive you home after taking esketamine.

• Suicidalthoughtsoractions

• Problemswiththinkingclearlyorremembering

• Bladderproblemssuchastroubleurinating,frequentorurgent

need to urinate, pain when urinating, or urinating frequently at night.

Common side e ects of esketamine when used along with an antidepressant taken by mouth are listed below. If these occur, they usually happen right after taking esketamine and go away the same day:

• Nauseaandvomiting

• Anxiety

• Lackofenergy

• Increasedbloodpressure

Let your doctor know right away if you miss your period or think you may be pregnant, plan to become pregnant or are breastfeeding.

What should you do if you forget to take a dose of your medication?

If you miss an esketamine treatment, your healthcare provider may change your dose and treatment schedule.

Is this drug safe to take with other medication?

• Somepeopletakingesketaminegetnauseaandvomiting.You WhatelsedoIneedtoknowaboutesketamine?

should not eat for at least 2 hours before taking esketamine

and not drink liquids 30 minutes before taking esketamine. • Ifyoutakeanasalcorticosteroidornasaldecongestant

medicine, take these medicine at last 1 hour before taking esketamine.

What side effects may happen?

Serious side e ects that should be reported to your doctor RIGHT AWAY are:

• Sedationanddissociation.Esketaminemaycausesleepiness (sedation), fainting, dizziness, spinning sensation, anxiety, or feeling disconnected from yourself, your thoughts, feelings, space, and time (dissociation).

• Abuseandmisuse.Thereisariskforabuseandphysicaland psychological dependence with esketamine treatment.

Before you take esketamine, tell you healthcare provider about all of your medical conditions, including if you:

1. Have heart or brain problems including high blood pressure,

slow or fast heartbeats, chest pain, lightheadedness, fainting, history of heart attack, history of stroke, heart valve disease or failure.

2. Have liver problems.

3. Have ever had a condition called “psychosis” (see, feel, or hear

things that are not there, or believe in things that are not true).

4. Are pregnant or plan to become pregnant. Esketamine may

harm your baby. You should not take esketamine if you are

pregnant.

5. Are breastfeeding or plan to breastfeed. You should be not be

breastfeeding during treatment with esketamine.

Tell you healthcare provider if you have ever abused or been dependent on alcohol, prescription medicines, or street drugs.

If you have any questions regarding this medication, please ask your doctor, pharmacist or nurse.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Hypnotics/Sedatives

The name of your medication is ________________________.

What is this drug used for?

This medication is used to treat sleep problems, such as problems falling asleep or remaining asleep for a reasonable number of hours or waking up often during the night. Sleeping problems occur in most individuals from time to time. If, however, sleeping problems persist, this may be a symptom of some other disorder, either medical or psychiatric.

A person may have di culty in falling asleep because of stress or anxiety felt during the day, pain, physical discomfort or changes in daily routine (e.g., jet-lag, changes in work shifts, etc.). Any disease that causes pain (e.g., ulcers) or breathing di culties (e.g., asthma or a cold) can interfere with continuous sleep. Stimulant drugs, including ca eine, may also contribute to problems falling asleep; other medications may change sleep patterns when they are stopped (e.g., antidepressants, antipsychotics). Sleep will improve when these causes have been identi ed, corrected or treated.

Problems remaining asleep may be due to age, as older people tend to sleep less at night. Certain disorders, including depression, may also a ect sleep.

Hypnotic/sedatives are similar to anxiolytic drugs but tend to cause more drowsiness and incoordination; certain antianxiety drugs are sometimes given to treat sleep problems.

How quickly will the drug start working?

Hypnotics/sedatives can induce calm or sedation usually within an hour. As some drugs act quickly, take the medication just prior to going to bed and relax in bed until the drug takes e ect.

How long should you take this medication?

Sleep problems are usually self-limiting; often when the cause of sleep di culties is treated or eliminated, sleep will improve. Therefore, hypnotic/sedatives are usually prescribed for a limited period of time. Many individuals take the medication only when needed (during periods of insomnia) rather than on a daily basis. It is suggested that once you have slept well for 2 or 3 nights in a row, try to get to sleep without taking the sedative/hypnotic. Tolerance or loss of e ectiveness can occur in some individuals if the medication is used every day beyond 4 months. Individuals taking hypnotics for long periods of time have a risk of developing dependence – they may have di culty stopping the medication and may experience withdrawal symptoms.

If you have been taking the medication every day for a period of time, your doctor may try to reduce the dose of this drug slowly to see if sleeping problems persist; if not, the dosage may be further reduced and you may be advised to stop using this medication. Do not increase the dose or stop the drug without consulting with your doctor.

Some patients need to use a sedative/hypnotic drug for longer time periods because of the type of problems they may be experiencing. Others require it only from time to time, i.e., as needed.

What side effects may happen?

Common side e ects that you should report to your doctor at the NEXT VISIT include:

• Morninghangover,feelingsleepyandtired–thisproblemmay lessen with time; inform your doctor. Use of other drugs that make you drowsy will worsen the problem. Avoid driving a car or operating machinery if drowsiness persists.

• Muscle incoordination, weakness, lightheadedness or dizziness – inform your doctor; a change in your dosage may be needed.

• Forgetfulness, memory lapses – inform your doctor.

• Slurred speech – a change in your dosage may be needed. • Nausea or heartburn – if this happens, take the medication

with food.

• Bittertaste–canoccurwithcertaindrugs(e.g.,zopiclone).

Avoid milk in the morning to lessen this e ect.

Less common side e ects that you should report to your doctor RIGHT AWAY include:

• Disorientation,confusion,worseningofyourmemory,periods of blackouts or amnesia

• Nervousness,excitement,agitation,hallucinationsorany behavior changes

• Worseningofdepression,suicidalthoughts

• Incoordinationleadingtofalls

• Skinrash

• Rareincidentsofsleepwalking,driving,andfoodbingingwhile

“asleep” have been reported.

Let your doctor know right away if you miss your period or think you may be pregnant, plan to become pregnant or are breastfeeding.

Is this drug safe to take with other medication?

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Hypnotics/Sedatives

Precautions/considerations

1. Do not increase your dose without consulting your doctor.

2. Check with your doctor or pharmacist before taking other

drugs, including drugs you can buy without prescription such

as cold remedies and herbal preparations.

3. Speak to your doctor if you begin having sleeping problems

after starting any new medication (e.g., for a medical

condition).

4. This drug may impair the mental and physical abilities required

for driving a car or operating machinery. Avoid these activities

if you feel drowsy or slowed down.

5. This drug may increase the e ects of alcohol, making you more

sleepy, dizzy, and lightheaded. If taken together with alcohol, this may make it dangerous for you to drive, operate machinery, or perform tasks that require careful attention.

6. Do not stop taking this drug suddenly, especially if you have been on the medication for a number of months or have been taking high doses. Hypnotics /sedatives need to be withdrawn gradually to prevent withdrawal reactions.

What else do I need to know about hypnotics/sedatives?

1. Take your medication about half an hour before bedtime; do not smoke in bed afterwards.

2. If you are taking sublingual forms of zolpidem (e.g., Edluar, Intermezzo, Sublinox) the tablet should be placed under the tongue, where it will disintegrate. The tablet should not be taken with water. The tablet should not be taken with or immediately after a meal.

3. If you are prescribed zolpidem (Ambien CR) or ramelteon (Rozerem), do not split, crush or chew the tablet but swallow it whole.

4. If you are taking ramelteon or zaleplon (Sonata), do not consume a high-fat meal within 1 hour of taking this medication.

5. Drinking a lot of ca eine (co ee, tea, colas, etc.) can cause you to become easily upset or jittery and make it harder for this drug to work.

6. Store your medication in a clean, dry area at room temperature. Keep all medication out of the reach of children.

Some non-drug methods to help you sleep include:

1. Avoid taking ca eine-containing drinks or foods (e.g., chocolate) after 6 p.m. and avoid heavy meals several hours before bedtime. A warm glass of milk is e ective for some people.

2. Napping and sleeping during the day will make restful sleep at night di cult. Keep active during the day and exercise regularly.

3. Engage in relaxing activities prior to bedtime such a reading, listening to music or taking a warm bath. Strenuous exercise (e.g., jogging) immediately before bedtime may make it di cult to get to sleep.

4. Establish a routine or normal pattern of sleeping and waking. 5. Use the bed and bedroom only for sleep and sexual activity. 6. Minimize external stimulation which might disturb sleep. If

necessary, use dark shades over windows or wear earplugs. 7. Once in bed, make sure you are comfortable (i.e., not too hot

or cold); use a rm mattress.

8. Relaxation techniques (e.g., muscle relaxation exercises, yoga)

may be helpful in decreasing anxiety and promoting sleep.

9. If you have problems getting to sleep, rather than tossing and turning in bed, have some warm milk, read a book, listen to music or try relaxation techniques until you again begin to

feel tired.

10. Don’t worry about the amount of sleep you are getting as the

amount will vary from day to day. The more you worry the more anxious you will get and this may make it harder for you to fall asleep.

If you have any questions regarding this medication, please ask your doctor, pharmacist or nurse.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Lithium

Lithium is classi ed as a mood stabilizer. It is a simple element, found in nature, and is also present in small amounts in the human body.

What is this drug used for?

Lithium is used primarily to treat symptoms of acute mania and in the long-term control or prevention of bipolar depression. Though not approved for these indications, lithium has also been found to augment the e ects of antidepressants in depression and obsessive-compulsive disorder, and is useful in the treatment of cluster headaches as well as chronic aggression or impulsivity. Ask your doctor if you are not sure why you are taking this drug.

How does your doctor decide on the dosage?

The dose of lithium is di erent for every patient and is based on how much lithium is in your blood, as well as the response to treatment. Your doctor will measure the lithium level in your blood on a regular basis during the rst few months. The lithium level that is usually found to be e ective for most patients is between 0.6 and 1.2 mmol/L (mEq/L).

You may initially take your medication 2 or 3 times a day; after several weeks, your doctor may decide to prescribe lithium once daily. It is important to drink 8–12 cups of uid daily when taking lithium (e.g., water, juice, milk, broth, etc.).

On the morning of your lithium blood test, take the morning dose of lithium after the test to avoid inaccurate results.

How quickly will the drug start working?

Control of manic symptoms may require up to 14 days of treatment. Because lithium takes time to work, do not decrease or increase the dose or stop the medication without discussing this with your doctor.

Improvement in symptoms of depression, obsessive-compulsive disorder, and cluster headaches as well as aggression/impulsivity also occur gradually.

How long should you take this medication?

This depends on what type of illness you have and how well you do.

Following the rst episode of mania, it is recommended that lithium be continued for a minimum of 1 year; this decreases the chance of having another episode. Your doctor may then decrease the drug slowly and monitor for any symptoms; if none occur, the drug can gradually be stopped.

For individuals who have had several episodes of mania or depression, lithium may need to be continued inde nitely. Long-term treatment is generally recommended for recurring depression, obsessive-compulsive disorder, cluster headaches or aggression/impulsivity.

DO NOT STOP taking your medication if you are feeling better, without rst discussing this with your doctor.

What side effects may happen?

Common side e ects that should be reported to your doctor at the NEXT VISIT include:

• Feelingtired,di cultyconcentrating–thisproblemusually goes away with time. Use of other drugs that make you drowsy will worsen the problem. Avoid driving a car or operating machinery if drowsiness persists.

• Nauseaorheartburn–ifthishappens,takethemedication with food. If vomiting or diarrhea occur and persist for more than 24 hours, call your doctor.

• Muscle tremor, weakness, shakiness, sti ness – speak to your doctor as this may require a change in your dosage.

• Changes in sex drive or sexual performance – discuss this with your doctor.

• Weight changes – watch the type of food you eat; avoid foods with a high fat content (e.g., cakes and pastry).

• Increased thirst and increase in how often you pee – discuss this with your doctor.

• Skin changes, e.g., dry skin, acne, rashes.

Side e ects you should report RIGHT AWAY, as they may indicate the amount of lithium in the body is higher than it should be, include:

• Lossofbalance

• Slurredspeech

• Visualdisturbances(e.g.,doublevision)

• Nausea,vomiting,stomachache

• Waterystools,diarrhea(morethantwiceaday)

• Abnormalgeneralweaknessordrowsiness

• Markedtrembling(e.g.,shakingthatinterfereswithholdinga

cup), muscle twitches, jaw shaking.

IF THESE OCCUR CALL YOUR DOCTOR RIGHT AWAY. If you cannot reach your doctor, stop taking lithium until you get in touch with him/her. Drink plenty of uids and snack on salty foods (e.g., chips, crackers). If symptoms continue to get worse or if they do not clear within 12 hours, go to the Emergency Department of the nearest hospital. A clinical check-up and a blood test may show the cause of the problem.

Rare side e ects you should report to your doctor RIGHT AWAY include:

• Soremouth,gumsorthroat

• Skinrashoritching,swellingoftheface

• Nausea,vomiting,lossofappetite,feelingtired,weak,feverish

or like you have the u

• Swellingoftheneck(goiter)

• Abnormallyfrequentneedtopeeandincreasedthirst(e.g.,

having to get up in the night several times to pee)

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Lithium

Let your doctor know right away if you miss your period or think you may be pregnant, plan to become pregnant or are breastfeeding.

What should you do if you forget to take a dose of your medication?

If you take your total dose of lithium in the morning or evening and you forget to take it for more than 6 hours, skip the missed dose and continue with your schedule the next day. DO NOT DOUBLE THE DOSE. If you take the drug several times a day, take the missed dose when you remember, then continue with your regular schedule.

Is this drug safe to take with other medication?

Because lithium can change the e ect of other medication or may be a ected by other medication, always check with your doctor or pharmacist before taking other drugs, including over-the-counter medication such as cold remedies and herbal preparations. Always inform any doctor or dentist that you see that you are taking lithium.

Precautions/considerations

1. Do not change your dose or stop the drug without talking to your doctor.

2. This drug may impair the mental and physical abilities and reaction time required for driving a car or operating other machinery. Avoid these activities if you feel drowsy or slowed down.

3. Do not stop your drug suddenly as this may result in withdrawal symptoms such as anxiety, irritability, and changes in mood.

4. Report any changes in mood or behavior to your doctor.

What else do I need to know about lithium?

1. It is important to drink 8–12 cups of uids daily (e.g., water, juice, milk, broth, etc.).

2. Limit the number of ca einated liquids you drink (e.g., co ee, tea, colas), and avoid excessive alcohol use.

3. To treat occasional pain, avoid the use of nonsteroidal anti-in ammatory drugs (e.g., ibuprofen or Motrin, Advil) as they can a ect the blood level of lithium and may result in toxicity. Acetaminophen is a safer alternative.

4. Do not change your salt intake during your treatment without rst speaking to your doctor (e.g., avoid no-salt or low-salt diets).

5. If you have the u, especially if vomiting or diarrhea occur, check with your doctor regarding your lithium dose.

6. Use extra care in hot weather and during activities that cause you to sweat heavily (e.g., hot baths, saunas, exercising). The loss of too much water and salt from your body may lead to changes in the level of lithium in your body and increase side e ects, some of which may be serious.

7. If you take sustained-release lithium tablets tablets (e.g., Lithobid, Lithmax), the tablets should be swallowed whole and not chewed or crushed. Lithmax tablets may be split.

8. On the morning when blood is drawn for a lithium level, withhold your morning dose of lithium until after the blood draw.

9. Store your medication in a clean, dry area at room temperature. Keep all medication out of the reach of children.

If you have any questions regarding this medication, please ask your doctor, pharmacist or nurse.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on L-Tryptophan

L-tryptophan is an amino acid, a natural body chemical. What is this drug used for?

L-tryptophan is used primarily as an add-on therapy to treat symptoms of acute mania or depression, and in the long-term control or prophylaxis of bipolar depression.

Though not approved for these indications, L-tryptophan has also been found to be useful as a sedative in insomnia and in behavior disturbances, such as chronic aggression or antisocial behavior. Ask your doctor if you are not sure why you are taking this drug.

How quickly will the drug start working?

Control of manic symptoms may require up to 14 days of treatment. Because L-tryptophan takes time to work, do not decrease or increase the dose or stop the medication without discussing this with your doctor.

Improvement in sleep disorders tends to occur relatively quickly (with the rst dose). Bene ts in behavior disturbances occur gradually.

How long should you take this medication?

This depends on what type of illness you have and how well you do.

L-tryptophan is often prescribed to increase the e ectiveness of an antidepressant, an antipsychotic or another mood stabilizer. Long-term treatment is generally recommended for recurring depression or mood disorder.

As sleep problems are usually self-limiting, many individuals take L-tryptophan only when needed (during periods of insomnia). Long-term treatment is generally recommended for treatment of behavior disturbances.

What side effects may happen?

Common side e ects that should be reported to your doctor at the NEXT VISIT include:

• Feelingsleepyandtired,di cultyconcentrating–thisproblem goes away with time. Use of other drugs that make you drowsy will worsen the problem. Avoid driving a car or operating machinery if drowsiness persists.

• Problems with balance or unsteadiness, incoordination

– discuss this with your doctor as this may require a change in your dosage.

• Nauseaorheartburn–ifthishappens,takethemedication with food.

• Drymouth–sourcandyandsugarlessgumhelpincreasesaliva in your mouth. Do not drink sugar-containing drinks as they

may give you cavities and increase your weight. Drink water

and brush your teeth regularly.

Rare side e ects you should report to your doctor RIGHT AWAY include:

• Muscletwitches,tremor,incoordination,shivering,confusion • Soremouth,gumsorthroat,mouthulcersorsores

• Skinrashoritching,swellingoftheface

• Vomiting,stomachpain

• Feelingtired,weak,feverishorlikeyouhavethe u

• Yellowingoftheskinoreyes;dark-coloredurine(pee)

• Severedizziness

• Switchinmoodtoanunusualstateofhappiness,excitement

or irritability

Let your doctor know right away if you miss your period or think you may be pregnant, plan to become pregnant or are breastfeeding.

What should you do if you forget to take a dose of your medication?

If you take your total dose of L-tryptophan in the evening and you forget to take it that evening, skip the missed dose and continue with your schedule the next day. DO NOT DOUBLE THE DOSE. If you take the drug several times a day, take the missed dose when you remember, then continue with your regular schedule.

Is this drug safe to use with other medication?

Because L -tryptophan can change the e ect of other medication or may be a ected by other medication, always check with your doctor or pharmacist before taking other drugs, including those you can buy without a prescription (such as cold remedies and herbal preparations). Always inform any doctor or dentist you see that you are taking this drug.

Precautions/considerations

1. Do not change your dose or stop the drug without speaking to your doctor.

2. This drug may impair the mental and physical abilities and reaction time required for driving a car or operating other machinery. Avoid these activities if you feel drowsy or slowed down.

3. Let your doctor know before starting any protein-reduced diets as these can interfere with the action of this medication.

4. Report any changes in mood or behavior to your doctor. 5. Store your medication in a clean, dry area at room

temperature. Keep all medication out of the reach of children.

If you have any questions regarding this medication, please ask your doctor, pharmacist or nurse.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on MAOI Antidepressants

The name of your medication is ________________________. It belongs to a class of antidepressants called monoamine oxidase inhibitors (MAOI).

What is this drug used for?

This medication is primarily used in the treatment of major depressive disorders bipolar depression. It has also been approved for the management of atypical depression, phobic anxiety states or social anxiety disorder.

Though not approved for these indications, MAOIs have also been found e ective in persistent depressive disorder (dysthymia), panic disorder and obsessive-compulsive disorder. Ask your doctor if you are not sure why you are taking this drug.

How quickly will the drug start working?

MAOIs begin to improve sleep and appetite and to increase energy within about one week; however, feelings of depression may take from 4 to 6 weeks to improve. Because antidepressants take time to work, do not decrease or increase the dose or stop the medication without discussing this with your doctor. Improvement in symptoms of atypical depression, phobic anxiety or social phobia, persistent depressive disorder (dysthymia), panic disorder and obsessive-compulsive disorder also occur gradually.

How long should you take this medication?

This depends on what type of illness you have and how well you do.

Following the rst episode of depression it is recommended that antidepressants be continued for a minimum of one year; this decreases the chance of being ill again. Your doctor may then decrease the drug slowly and monitor for any symptoms of depression; if none occur, the drug can gradually be stopped. For individuals who have had several episodes of depression, antidepressant medication should be continued inde nitely.

DO NOT STOP taking your medication if you are feeling better, without rst discussing this with your doctor. Long-term treatment is generally recommended for atypical depression, phobic anxiety or social phobia, persistent depressive disorder (dysthymia), panic disorder or obsessive-compulsive disorder.

What side effects may happen?

Common side e ects that should be reported to your doctor at the NEXT VISIT include:

• Feelingsleepyortired–thisproblemgoesawaywithtime.Use of other drugs that make you drowsy will worsen the problem. Avoid driving a car or operating machinery until you know how

the drug a ects you. If drowsiness persists your doctor may

advise you to take the medication at bedtime.

• Energizing/agitated feeling – some individuals may feel

nervous or have di culty sleeping for a few days after starting this medication. Report this to your doctor; he/she may advise you to take the medication in the morning and afternoon (rather than the evening).

• Headache–thiscanbemanagedbytakingpainmedicine(e.g., aspirin, acetaminophen) as required. If the headache persists or is “troubling”, contact your doctor.

• Nauseaorheartburn–ifthishappens,takethemedication with food.

• Dry mouth – sour candy and sugarless gum help increase saliva in your mouth. Do not drink sweet drinks like colas as they may give you cavities and increase your weight. Drink water and brush your teeth regularly.

• Muscletremor,twitching,jerking–speaktoyourdoctorasthis may require a change in your dosage.

• Sweating–youmaysweatmorethanusual;frequent showering, use of deodorants may help.

• Lossofappetite.

Rare side e ects you should report to your doctor RIGHT AWAY include:

• Persistent,throbbingheadache

• Soremouth,gums,orthroat

• Skinrashoritching,swellingoftheface

• Nausea,vomiting,lossofappetite,feelingtired,weak,feverish,

or like you have the u

• Yellow tinge in the eyes or to the skin; dark-colored urine (pee) • Going a day or more without peeing

• Severe agitation, restlessness, irritability or thoughts of suicide • Switch in mood to an unusual state of happiness, excitement,

irritability or problems sleeping

Let your doctor know right away if you miss your period or think you may be pregnant, plan to become pregnant or are breastfeeding.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on MAOI Antidepressants

Caution

Certain foods and drugs contain chemicals which are broken down by the enzyme monoamine oxidase. Since this drug inhibits this enzyme, these chemicals increase in the body and may raise the blood pressure and cause a severe reaction called a hypertensive crisis.

Listed below are the foods and drugs which should be avoided while taking this drug.

Do not eat the following foods:

• Allmaturedoragedcheeses(Cheddar,Brick,Blue,Stilton,

Camembert, Roquefort)

• Broadbeanpods(e.g.,FavaBeans)

• Concentratedyeastextracts(“Marmite”)

• Sausage(ifaged,especiallysalami,mortadella,pastrami,

summer sausage), other unrefrigerated fermented meats,

game meat that has been hung, aged liver

• Driedsalted sh,pickledherring

• Sauerkraut

• Soysauceorsoybeancondiments,tofu

• Packetsoup(especiallymiso)

• Tap(draft)beer,alcohol-freebeer

• Improperlystoredorspoiledmeat,poultry,or sh

Wait for 14 days after stopping a MAOI drug before restarting to eat the above foods.

Hypertensive reactions have been reported, by some individuals, with the following foods; try small portions to determine if these foods will cause a reaction:

• Smoked sh,caviar,snails,tinned sh,shrimppaste • Yogurt

• Meattenderizers

• Meatextract(“Bovril,”“Oxo”)

• Homemaderedwine,Chianti,canned/bottledbeer,sherry, champagne

• Cheeses(e.g.,Parmesan,Muenster,Swiss,Gruyere,Mozzarella, Feta)

• Pepperoni

• Overripefruit,avocados,raspberries,bananas,plums,canned

gs and raisins, orange pulp, tomatoes • Asianfoods

• Spinach,eggplant

It is SAFE to use the following foods, in moderate amounts (only if fresh):

• Cottagecheese,creamcheese,farmer’scheese,processed cheese, Cheez Whiz, ricotta, Havarti, Boursin, Brie without rind, Gorgonzola

• Liver(aslongasitisfresh),freshorprocessedmeats,poultryor sh (e.g., hot dogs, bologna)

• Spirits, liquor (in moderation)

• Soy milk

• Sour cream

• Salad dressings

• Worcestershire sauce

• Yeast-leavened bread

Make sure all food is fresh, stored properly, and eaten soon after being purchased. Never touch food that is fermented or possibly “o .” Avoid restaurant sauces, gravy and soup.

Do not use the following drugs, which you can buy without a prescription, unless you have spoken to your doctor or pharmacist:

• Cold remedies, decongestants (including nasal sprays and drops), some anti-histamines and cough medicine

• Opioidpainkillers(e.g.,productscontainingcodeine)

• Allstimulantsincludingpep-pills(Wake-ups,Nodoz),or

appetite suppressants

• Anti-asthmadrugs(PrimatineP)

• Sleepaidsandsedatives(Sominex,Nytol)

• Yeast,dietarysupplements(e.g.,Ultrafast,Optifast)

It is SAFE to use:

• PlainASA(aspirin),acetaminophen(e.g.,Tylenol),oribuprofen

(e.g., Motrin, Advil)

• Antacids(e.g.,Tums,Maalox) • Throatlozenges

If a hypertensive reaction (high blood pressure) should occur, the symptoms usually come on suddenly, so be alert for these signs:

• Severe,throbbingheadachewhichstartsatthebackofthe head and radiates forward; often the headache is accompanied by nausea and vomiting

• Sti neck

• Heartpalpitations,fastheartbeat,chestpain

• Sweating,coldandclammyskin

• Enlarged(dilated)pupilsoftheeyes

• Suddenunexplainednosebleeds

If a combination of these symptoms does occur, contact your doctor IMMEDIATELY; if you are unable to do so, go to the Emergency Department of your nearest hospital.

What should you do if you forget to take a dose of your medication?

If you take your total dose of this medication in the morning and you forget to take it for more than 6 h, skip the missed dose and continue with your schedule the next day. DO NOT DOUBLE THE DOSE. If you take the drug several times a day, take the missed dose when you remember, then continue with your regular schedule.

Is this drug safe to take with other medication?

Because antidepressant drugs can change the e ect of other medication, or may be a ected by other medication, always check with your doctor or pharmacist before taking other drugs, including those you can buy without a prescription such as cold remedies and herbal preparations. Always inform any doctor or dentist that you see that you are taking an antidepressant drug.

Precautions/considerations

1. Do not increase or decrease your dose without consulting your doctor.

2. Be aware of foods which you cannot eat while taking this medication.

3. Take no other medication (including those you can buy without a prescription or herbal products) without speaking with your doctor or pharmacist. Avoid all products containing dextromethorphan (DM).

4. This drug may impair the mental and physical abilities required for driving a car or operating machinery. Avoid these activities if you feel drowsy or slowed down.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on MAOI Antidepressants

5. This drug may interact with medication prescribed by your dentist, so let him/her know the name of the drug you are taking.

6. This drug may impair the mental and physical abilities required for driving a car or operating other machinery. Avoid these activities if you feel drowsy or slowed down.

7. Do not stop your drug suddenly as this may result in withdrawal symptoms such as muscle aches, chills, tingling in your hands or feet, nausea, vomiting, and dizziness.

8. Report any changes in mood or behavior to your doctor.

9. Store your medication in a clean, dry area at room

temperature. Keep all medication out of the reach of children.

10. If you are to have surgery you will probably have to discontinue

the medication 10 days before.

If you have any questions regarding this medication, please ask

your doctor, pharmacist or nurse.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Methadone

What is this drug used for?

Methadone is primarily used as a substitute drug in the treatment of opioid-dependent patients who desire maintenance therapy. It blocks the e ect of the highly addicting opioids (e.g. heroin, oxycodone). It suppresses withdrawal symptoms of other opioid analgesics as well as the craving for opioids. Methadone is part of a complete addiction treatment program that also includes behavior therapy and counseling. It has been shown that methadone helps patients avoid illicit opioid use and helps them attain social stability.

On occasion methadone is prescribed for severe chronic pain. Ask your doctor if you are not sure why you are taking this drug.

How quickly will the drug start working?

Methadone blocks the “craving” and withdrawal reactions from opioids immediately. Methadone is started at a low dose and increased gradually, based on e ectiveness, to a maintenance dose. It is then usually prescribed once daily.

Why is methadone given on a daily basis?

Methadone is an opioid and its dispensing and usage is governed by Federal regulations. It is prepared as a liquid, and in some locations, is dispensed mixed with orange juice. At rst, patients receive their methadone from the pharmacy on a daily basis and are required to drink the contents of the bottle in the presence of the pharmacist. After a period where there has been no substance abuse, patients may receive up to 7 days’ supply.

How long should you take this medication?

The length of time methadone is prescribed varies among individuals and depends on a number of factors, including their progress in therapy; some patients receive methadone for several months, while most may require it for several years. Any decreases in dose should be done very gradually under the direction of your doctor.

What side effects may happen?

Common side e ects that should be reported to your doctor at the NEXT VISIT include:

• Feelingtired,confusion,depression–thisproblemgoesaway with time. Use of other drugs that make you drowsy will worsen the problem. Avoid driving a car or operating machinery if drowsiness persists.

• Energizedfeeling,insomnia–someindividualsmayfeel nervous or have di culty sleeping for a few days after starting this medication.

• Dizziness, lightheadedness, weakness – this should go away with time.

• Jointandmusclepain–temporaryuseofnon-opioidpain medicine may help (e.g., ASA, acetaminophen, ibuprofen).

• Nauseaandvomiting–ifthishappens,takethemedication after eating.

• Lossofappetite,weightloss–takingthemedicationafter meals, eating smaller meals more frequently or drinking high calorie drinks may help.

• Changesinsexdriveorsexualperformance–thoughrare, should this problem occur, discuss it with your doctor.

• Changestothemenstrualcycle.

• Sweating, ushing–youmaysweatmorethanusual;frequent

showering, use of deodorants and talcum powder may help. • Constipation–drinkplentyofwater,trytoincreasethe

amount of ber in your diet (like fruit, vegetables or bran), and exercise your abdominal muscles. Some individuals nd a bulk laxative like psyllium (e.g., Metamucil) or PEG 3350 (e.g., Miralax, Pegalax) or a stool softener like docusate (e.g., Colace, Surfak) helps regulate their bowels. If this does not work or if you go more than 3 days without having a bowel movement, speak to your doctor or pharmacist.

• Muscletwitching.

Rare side e ects you should report to your doctor RIGHT AWAY include:

• Combinationofsymptomsthatincludedizziness,fainting spells, palpitations, nausea, and vomiting

• Yellowtingeintheeyesortotheskin;dark-coloredurine(pee)

• Soremouth,gumsorthroat

• Sloweddi cultbreathing

• Skinrashoritching,swellingoftheface

• Feelingtired,weak,feverishorlikeyouhavethe u,associated with nausea, vomiting, and loss of appetite

Let your doctor know right away if you miss your period or think you may be pregnant, plan to become pregnant or are breastfeeding.

What should you do if you forget to take a dose of your medication?

It is important to take methadone at approximately the same time each day, on a daily basis. Missing a dose can result in a withdrawal reaction, consisting of restlessness, insomnia, nausea, vomiting, headache, increased perspiration, congestion, “goose esh,” abdominal cramps, and muscle and bone pain.

Is this drug safe to take with other medication?

Because methadone can change the e ect of other medication or may be a ected by other medication, always check with your doctor or pharmacist before taking other drugs, including those you can buy without a prescription such as cold remedies and herbal preparations. Always inform any doctor or dentist that you see that you are taking this medication. It is important to carry a card in your wallet, stating that you are taking methadone, in cases of emergency.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Methadone

Precautions/considerations

1. Do not share this medication with anyone. If you receive “carries” of methadone, store them out of the reach of children (preferably in a lockable compartment in the refrigerator); methadone can be lethally poisonous to individuals who do not take opioids. Misuse/abuse may result in poisoning.

2. Report to your doctor any changes in sleeping or eating habits or changes in mood or behavior.

3. This drug may impair the mental and physical abilities and reaction time required for driving or operating other machinery. Avoid these activities if you feel drowsy or slowed down.

4. This drug may increase the e ects of alcohol, making you more sleepy, dizzy, and lightheaded. If taken together with alcohol, this may make it dangerous for you to drive, operate machinery, or perform tasks that require careful attention.

What else do I need know about methadone?

1. Carry an identi cation card stating the name of the drug you are taking and ensure every doctor and dentist you visit is aware you are taking methadone.

2. Avoid grapefruit juice while taking methadone.

If you have any questions regarding this medication, please ask

your doctor, pharmacist or nurse.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Mirtazapine

Mirtazapine belongs to a class of antidepressants called noradrenergic/speci c serotonergic antidepressants (NaSSA).

What is this drug used for?

Mirtazapine is primarily used in the treatment of major depressive disorder and bipolar depression.

Though not approved for these indications, mirtazapine has also been found e ective in several anxiety disorders including obsessive-compulsive disorder, panic disorder, generalized anxiety disorder, and posttraumatic stress disorder. Ask your doctor if you are not sure why you are taking this drug.

How quickly will the drug start working?

Mirtazapine begins to improve sleep and appetite and to increase energy within 1–2 weeks; however, feelings of depression may take 4–6 weeks to improve. Because antidepressants take time to work, do not decrease or increase the dose or stop the medication without discussing this with your doctor.

Improvement in symptoms of anxiety disorders also occur gradually over several weeks.

How long should you take this medication?

This depends on what type of illness you have and how well you do.

Long-term treatment is generally recommended for anxiety disorders.

What side effects may happen?

Common side e ects that should be reported to your doctor at the NEXT VISIT include:

• Dry mouth – sour candy and sugarless gum help increase saliva in your mouth. Do not drink sweet drinks like colas as they may

give you cavities and increase your weight. Drink water and

brush your teeth regularly.

• Constipation–drinkplentyofwater,trytoincreasethe

• Increasedappetiteandweightgain–monitoryourfoodintake and try to avoid foods with a high fat content (e.g., cakes and pastry).

• Jointpainorworseningofarthritis–discussthiswithyour doctor.

Rare side e ects you should report to your doctor RIGHT AWAY include:

• Soremouth,gumsorthroat,mouthulcers

• Skinrashoritching,swellingoftheface

• Nausea,vomiting,lossofappetite,feelingtired,weak,feverish

or like you have the u

• Yellowtingeintheeyesortotheskin;dark-coloredurine(pee) • Severeagitation,restlessness,irritabilityorthoughtsofsuicide • Switchinmoodtoanunusualstateofhappiness,excitement,

irritability or problems sleeping

Let your doctor know right away if you miss your period or think you may be pregnant, plan to become pregnant or are breastfeeding.

What should you do if you forget to take a dose of your medication?

If you take your total dose of this medication at bedtime and you forget to take your medication, skip the missed dose and continue with your schedule the next day. DO NOT DOUBLE THE DOSE. If you take the drug several times a day, take the missed dose when you remember, then continue with your regular schedule.

Is this drug safe to take with other medication?

Precautions/considerations

1. Do not change your dose without talking with your health care provider (e.g., doctor, pharmacist, nurse).

2. Do not stop this drug suddenly (without discussing it with your health care provider), as this may result in withdrawal symptoms such as muscle aches, chills, tingling in your hands or feet, nausea, vomiting, and dizziness.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Mirtazapine

3. This drug may impair the mental and physical abilities required for driving a car or operating machinery. Avoid these activities if you feel drowsy or slowed down.

4. This drug may increase the e ects of alcohol, making you more sleepy, dizzy, and lightheaded.

5. Report any changes in mood or behavior to your doctor.

6. This drug may interact with medication prescribed by your dentist, so let him/her know the name of the drug you are

taking.

What else do I need to know about mirtazapine?

1. Mirtazapine oral disintegrating tablets dissolve rapidly in saliva and can be taken with or without liquid, chewed or allowed to dissolve.

2. Excessive use of ca einated foods, drugs or beverages may increase anxiety and agitation and confuse the diagnosis.

3. Store your medication in a clean, dry area at room temperature. Keep all medication out of the reach of children.

If you have any questions regarding this medication, please ask your doctor, pharmacist or nurse.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Moclobemide

Moclobemide belongs to a class of antidepressants called reversible inhibitors of monoamine oxidase-A (RIMA).

What is this drug used for?

Moclobemide is primarily used in the treatment of major depressive disorder and bipolar depression. It has also been approved for use in the management of persistent depressive disorder (also knows as dysthymia).

Though not approved for these indications, moclobemide has also been found e ective in seasonal a ective disorder and social phobia. Ask your doctor if you are not sure why you are taking this drug.

How quickly will the drug start working?

Moclobemide begins to improve sleep and appetite and to increase energy within 1–2 weeks; however, feelings of depression may take 4–6 weeks to improve. Because antidepressants take time to work, do not decrease or increase the dose or stop the medication without discussing this with your doctor. Improvement in symptoms of seasonal a ective disorder and social phobia also occur gradually.

When should I take this medication?

Moclobemide is usually prescribed to be taken twice daily, morning and evening. Take this drug after meals to minimize side e ects such as nausea.

How long should you take this medication?

This depends on what type of illness you have and how well you do.

Long-term treatment is generally recommended for social phobia, while cyclical therapy may be e ective for seasonal a ective disorder.

What side effects may happen?

Common side e ects that should be reported to your doctor at the NEXT VISIT include:

• Energizing/agitated feeling – some individuals may feel nervous or have di culty sleeping for a few days after starting this medication. Report this to your doctor; he/she may advise you to take the medication in the morning and afternoon (rather than the evening).

• Headache–thiscanbemanagedbytakingpainmedicine(e.g., aspirin, acetaminophen) as required. If the headache persists or is “troubling,” contact your doctor.

• Nauseaorheartburn–ifthishappens,takethemedication with food.

• Sweating–youmaysweatmorethanusual;frequent showering, use of deodorants may help.

Rare side e ects you should report to your doctor RIGHT AWAY include:

• Persistent,throbbingheadache

• Soremouth,gumsorthroat

• Skinrashoritching,swellingoftheface

• Nausea,vomiting,lossofappetite,feelingtired,weak,feverish

or like you have the u

• Yellowtingeintheeyesortotheskin;dark-coloredurine(pee) • Severeagitation,restlessness,irritabilityorthoughtsofsuicide • Switchinmoodtoanunusualstateofhappiness,excitement,

irritability or problems sleeping

Let your doctor know right away if you miss your period or think you may be pregnant, plan to become pregnant or are breastfeeding.

Treatment with moclobemide does NOT require special diet restrictions as with other MAOIs. However, you should avoid eating excessive amounts of aged, overripe cheeses or yeast extracts. If a hypertensive reaction (high blood pressure) should occur, the symptoms usually come on suddenly, so be alert for these signs:

• Severe,throbbingheadachewhichstartsatthebackofthe head and moves toward the front. Often nausea and vomiting occur at the same time

• Sti neck

• Heartpalpitations,fastheartbeat,chestpain

• Sweating,coldandclammyskin

• Enlarged(dilated)pupilsoftheeyes • Suddenunexplainednosebleeds

If a combination of these symptoms does occur, contact your doctor IMMEDIATELY; if you are unable to do so, go to the Emergency Department of your nearest hospital. Moclobemide should always be taken after meals to avoid any food-related side e ects (e.g., headaches).

Side e ects may happen with any drug. They are not usually

serious and do not happen to everyone. Side e ects may

sometimes occur before bene cial e ects of the medication are

noticed. If you think you may be having a side e ect, speak to

your doctor or pharmacist as they can help you decrease it or medication? cope with it.

What should you do if you forget to take a dose of your

If you take your total dose of antidepressant in the morning and you forget to take it for more than 6 hours, skip the missed dose and continue with your schedule the next day. DO NOT DOUBLE

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Moclobemide

THE DOSE. If you take the drug several times a day, take the missed dose when you remember, then continue with your regular schedule.

Is this drug safe to take with other medication?

Precautions/considerations

1. Do not change your dose without talking with your health care provider (e.g., doctor, pharmacist, nurse).

3. Report any changes in mood or behavior to your doctor.

4. This drug may impair the mental and physical abilities required

for driving a car or operating machinery. Avoid these activities

if you feel drowsy or slowed down.

5. This drug may interact with medication prescribed by your

dentist, so let him/her know the name of the drug you are

taking.

6. Take no other medication (including drugs you buy without a

prescription or herbal products) without consulting with your doctor or pharmacist. Avoid all products containing dextromethorphan (DM).

What else do I need to know about moclobemide?

1. Take moclobemide after food to decrease potential side e ects; a big meal should not be eaten after taking moclobemide.

2. Store your medication in a clean, dry area at room temperature. Keep all medication out of the reach of children.

If you have any questions regarding this medication, please ask your doctor, pharmacist or nurse.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Naltrexone

Whatisthisdrugusedfor?

Naltrexone is mainly used as an aid in the treatment of alcohol dependence or addiction to opioids. Naltrexone has been shown to maintain abstinence if taken, as directed, as part of a treatment program that includes counseling and support. Though not approved for these indications, naltrexone has also been used in the treatment of behavior and impulse-control disorders and obsessive-compulsive disorder. It is available as an oral tablet and (in the USA) as a monthly injection. Ask your doctor if you are not sure why you are taking this drug.

How quickly will the drug start working?

Naltrexone blocks the “craving” for alcohol and opioids. It does not suppress withdrawal symptoms that can occur in an opioid user and should not be used in anyone who has used opioids in the previous 10 days; these individuals must undergo detoxi cation programs before starting naltrexone. Naltrexone is started at a low dose and increased gradually based on e ectiveness. Onset of response is quick (within the hour).

How long should you take this medication?

Naltrexone is usually prescribed for a set period of time to help the individual discontinue the use of alcohol or opioids. Naltrexone is used for a prolonged period of time in the treatment of behavior and impulse-control problems and obsessive-compulsive disorder. Do not decrease or increase the dose without discussing this with your doctor.

What side effects may happen?

Common side e ects that should be reported to your doctor at the NEXT VISIT include:

• Nervousness,anxiety,problemssleeping–someindividuals may feel nervous or have di culty sleeping for a few days after starting this medication.

• Headache – temporary use of pain medicine (e.g., aspirin, acetaminophen ) may be required; contact your doctor if headaches occur frequently or are “troubling.”

• Joint and muscle pain or sti ness – temporary use of pain medicine may be required.

• Stomachpain,cramps,nausea,andvomiting–ifthishappens, take the medication with food or milk.

• Weightloss.

• Pain,tenderness,itchinessatsiteofinjection;occasionallya lump can be felt.

Rare side e ects you should report to your doctor RIGHT AWAY include:

• Yellowtingeintheeyesortotheskin;dark-coloredurine(pee) • Soremouth,gumsorthroat

• Skinrashoritching,swellingoftheface

• Nausea,vomiting,lossofappetite,fatigue,weakness,feveror

u-like symptoms

• Shortnessofbreath,persistentcoughingandwheezing

Let your doctor know right away if you miss your period or think you may be pregnant, plan to become pregnant or are breastfeeding.

What should you do if you forget to take a dose of your medication?

Is this drug safe to take with other medication?

Because naltrexone can change the e ect of other medication or may be a ected by other medication, always check with your doctor or pharmacist before taking other drugs, including those you can buy without a prescription such as cold remedies and herbal preparations. Always inform any doctor or dentist that you see that you are taking this medication.

Precautions/considerations

1. Do not change your dose or stop taking naltrexone without speaking to your doctor.

2. Report to your doctor any changes in sleeping or eating habits or changes in mood or behavior.

3. Do NOT use opioid preparations while taking oral or injectable naltrexone as this may cause serious adverse e ects including coma and death.

What else do I need to know about naltrexone?

1. Limit the use of nonprescription pain medicine such as aspirin, acetaminophen (Tylenol) or nonsteroidal anti-in ammatories (e.g., Motrin).

2. Carry an identi cation card stating the name of the drug you are taking.

3. Store your medication in a clean, dry area at room temperature. Keep all medication out of the reach of children.

If you have any questions regarding this medication, please ask your doctor, pharmacist or nurse.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Pimavanserin

The name of your medication is _______________________.

What is this drug used for?

Pimavanserin is a medicine that is used to treat hallucination and delusions associated with Parkinson’s disease psychosis. These nonmotor symptoms happen when a person with Parkinson’s disease begins to have hallucinations (such as seeing or hearing things that are not there) and/or delusions such as believing things that are not real).

How quickly will the drug start working?

Pimavanserin may begin to reduce hallucinations and delusions after 2 weeks, but it may take up to 6 weeks to feel the full e ect. Because this medication takes time to work, do NOT change your dose or stop your medication without talking to your doctor.

How long should you take this medication?

This may depend on how e ective pimavanserin is at reducing or eliminating your hallucinations and/or delusions.

Talk with your doctor about how long you should stay on this medication.

How do you take this drug?

Pimavanserin is usually taken once daily (2 tablets), at a time that you choose, or as prescribed by your doctor. You may take this medicine with or without food.

What side effects may happen?

Common side e ects that you should report to your doctor RIGHT AWAY are:

• Swellingoflegsorarms–elevateyourlegs(orarms)abovethe level of your head a few times a day. Sleep with a pillow under your legs at night.

• Hallucinations

• Confusion

Common side e ects that should be reported to your doctor at the NEXT VISIT include:

• Nausea–trytakingyourdrugwithfoodifthishappens.

• Constipation–drinkplentyofwater,trytoincreasethe

you go more than 3 days without having a bowel movement,

speak to your doctor or pharmacist. • Changeinwalkingandbalance

Rare side e ects you should report to your doctor RIGHT AWAY are:

• Fast,slow,orirregularheartbeat • Dizzinessorfainting

• Shortnessofbreath

Let your doctor know right away if you miss your period or think you may be pregnant, plan to become pregnant or are breastfeeding.

What should you do if you forget to take a dose of your medication?

If you forget to take a dose of your medication, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to you regular dosing schedule. DO NOT take two doses at the same time.

Is this drug safe to take with other medication?

Because pimavanserin can change the e ect of other medication or may be a ected by other medication, always check with your doctor or pharmacist before taking other drugs, including those you can buy without a prescription such as cold remedies and herbal preparations. Always inform any doctor or dentist that you see that you are taking this medication.

What else do I need to know about pimavanserin?

1. Do not change your dose without talking with your health care provider (e.g., doctor, pharmacist, nurse).

2. Do not break or crush pimavanserin unless you have been told to do so by your doctor.

3. Antacids (like Diovol, Maalox, amphogel, etc.) may lower the amount of pimavanserin in your body. Take your antacid at least 2 hours before or 1 hour after taking pimavanserin to avoid this.

4. Store your medication in a clean, dry area at room temperature. Keep all medication out of the reach of children.

If you have any questions regarding this medication, please ask your doctor, pharmacist or nurse.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Psychostimulants

The name of your medication is ________________________.

What is this drug used for?

Psychostimulants are primarily used in the treatment of attention de cit/hyperactivity disorder (ADHD) in children and adults. These drugs are also approved for use in other conditions such as Parkinson’s disease and narcolepsy (a sleeping disorder).

Though they are currently not approved for this indication, psychostimulants have been found useful as add-on therapy in the treatment of depression. Ask your doctor if you are not sure why you are taking this drug.

How quickly will the drug start working?

Some response to psychostimulants is usually noted within the rst week of treatment of ADHD and tends to increase over the next 3 weeks.

How does your doctor decide on the dosage?

Psychostimulants come in various preparations including short-acting and slow-release (i.e., Spansules or extended-release) forms as well as a skin patch (Daytrana – available in the US only). The dose is sometimes based on body weight and is given once daily (for slow-release forms) or several times a day (short-acting forms). Take the drug exactly as prescribed; do not increase or decrease the dose without speaking to your doctor.

How long should you take this medication?

Psychostimulants are usually prescribed for a period of several years. Some clinicians may prescribe “drug holidays” to individuals on this medication (i.e., the drug is temporarily not taken at certain times such as vacations, etc.), in situations when side e ects may be of concern.

What side effects may happen?

Common side e ects that should be reported to your doctor at the NEXT VISIT include:

• Energizing/agitatedfeeling,excitability–someindividualsmay feel nervous or have di culty sleeping for a few days after starting this medication. If you are taking the medication in the late afternoon or evening, your doctor may decide to prescribe it earlier in the day.

• Increasedheartrate–speaktoyourdoctor.

• Headache–thistendstobetemporaryandcanbemanagedby

taking pain medicine (acetaminophen or ibuprofen) when required. If the headache persists or is “troubling,” contact your

doctor. Blood pressure should be checked by your doctor before

and after starting, and following dose increases.

• Nauseaorheartburn–ifthishappens,takethemedication

with food or milk.

• Drymouth–sourcandy,mints,andsugarlessgumhelp

increase saliva in your mouth. Do not drink sugar-containing drinks as they may give you cavities and increase your weight. Drink water and brush your teeth regularly.

• Lossofappetite,weightloss–takingthemedicationafter meals, eating smaller meals more frequently or drinking liquid nutritional supplements may help.

• Respiratorysymptomsincludingsorethroat,coughingorsinus pain.

• Decreasedgrowth.

• Skinirritationandrasheswithtopicalpatch(Daytrana).

Rare side e ects you should report to your doctor RIGHT AWAY include:

• Fastorirregularheartbeat

• Dizziness,feelingfaintorlightheaded

• Muscletwitches,ticsormovementproblems

• Persistentthrobbingheadache

• Soremouth,gumsorthroat

• Skinrashoritching,swellingofthefacewithoralformand

topical patch

• Anyunusualbruisingorbleeding,appearanceofsplotchy

purplish darkening of the skin

• Tiredness, weakness, fever or feeling like you have the u,

associated with nausea, vomiting, loss of appetite

• Yellow tinge in the eyes or to the skin; dark-colored urine (pee) • Severe agitation or restlessness

• A persistent or painful erection of the penis that continues for

longer than 4 hours

• Aswitchinmoodtoanunusualstateofhappinessor

irritability; uctuations in mood.

Let your doctor know right away if you miss your period or think you may be pregnant, plan to become pregnant or are breastfeeding.

What should you do if you forget to take a dose of your medication?

If you take the psychostimulant 2–3 times a day and forget to take a dose by more than 4 hours, skip the missed dose and continue with your regular schedule. DO NOT DOUBLE THE DOSE. The skin patch (Daytrana) is placed on the body in the morning and removed 9 hours later.

Is this drug safe to take with other medication?

Because psychostimulants can change the e ect of other medication or may be a ected by other medication, always check

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Psychostimulants

with your doctor or pharmacist before taking other drugs, including those you can buy without a prescription such as cold remedies and herbal preparations. Always inform any doctor or dentist that you see that you are taking a psychostimulant drug.

Precautions/considerations

1. This medication should not be used in patients who have high blood pressure, heart disease or abnormalities, hardening of the arteries or an overactive thyroid. If there is a history of heart problems in your family, tell your doctor before taking this medication.

2. Do not change your dose or stop taking this medication without talking to your doctor.

3. Use caution while driving or performing tasks requiring alertness as these drugs can mask symptoms of fatigue and impair concentration.

4. Report to your doctor any changes in sleeping or eating habits or changes in mood or behavior.

5. Unless instructed otherwise, do not stop your medication suddenly as this may result in withdrawal symptoms that include changes in mood and behavior.

6. This drug may interact with medication prescribed by your dentist, so let him/her know the name of the drug you are taking.

7. If using the Daytrana patch, it takes about 8 hours after applying the patch before blood concentrations reach a maximum level. Furthermore, substantial amounts of drug remain in the body for about 6 hours after patch removal.

What else do I need to know about psychostimulants?

1. Do not chew or crush the tablets or capsules unless speci cally told to do so by your doctor.

2. If you have di culty swallowing medication, your doctor may prescribe a chewable tablet, a liquid form, an orally disintegrating tablet, or a capsule that can be opened and the beads from it sprinkled on apple sauce and swallowed without chewing, or a capsule that can be opened and the contents mixed in a glass of water, orange juice or yogurt and swallowed.

3. If you are prescribed the skin patch (Daytrana), it should be applied to clean, dry skin on the hip immediately upon removal from the protective pouch; do not apply to skin areas that are in amed or broken. The patch should not be exposed to external heat sources (e.g., heating pads, hot tubs); used patches need to be discarded carefully, according to package instructions. There may occasionally be some di culties removing the patch.

4. If you take Concerta, you may notice the tablet shell in your stool. This is normal; the tablet shell does not dissolve but the contents of the tablet are fully absorbed.

5. Store your medication in a clean, dry area at room temperature. Keep all medication out of the reach of children.

If you have any questions regarding this medication, please ask your doctor, pharmacist or nurse.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Repetitive Transcranial Magnetic Stimulation (rTMS)

What is rTMS used for?

rTMS is a brain stimulation procedure used to treat patients with depression. There is some preliminary evidence suggesting it can also help reduce hearing voices (auditory hallucinations) in patients with schizophrenia.

How do you use rTMS?

A wire coil (inside insulated plastic) is held over the skull and an electrical current is pulsed through the coil to generate a magnetic eld. This magnetic eld induces an electric current in parts of the brain. No anesthetic is required during this procedure. Individuals are awake and alert throughout the procedure and there is no recovery period once the treatment is nished. You may resume normal activity, including operating a motor vehicle, immediately after rTMS is completed. Depending on the type of rTMS given, each treatment may take anywhere from 15 to 45 minutes and is repeated on a daily basis for 10–40 days.

How does rTMS work?

As in the case of many medical and psychiatric treatments, the actual way that rTMS relieves symptoms of depression is not totally understood.

It is thought that rTMS may stimulate nerve cells in the brain to release certain brain chemicals (serotonin and dopamine) that are important in stabilizing mood or may alter the excitability of a part of the brain called the cortex.

How effective is rTMS?

Studies comparing the e ectiveness of rTMS to other forms of treatment of depression, including electroconvulsive therapy, suggest that rTMS is an e ective treatment for depression. Most patients begin to see improvement in their symptoms after a few sessions.

How safe is rTMS and what are the potential side effects?

rTMS is considered a safe procedure. Side e ects, though uncommon, can occur in certain individuals.

Side e ects of rTMS may include:

• Headache–acetaminophenoraspirincanbeused,butare usually not necessary.

• Painaroundthesiteofcoilplacementcanoccurwitheach magnetic pulse if very high-intensity stimulation is used – let your doctor know.

• Short-termneckpain,eyepain,toothache,andmuscle twitches can occasionally occur.

• Lossofhearingsensitivityispossibleifhearingprotectionis not used – use of foam earplugs during the procedure should prevent this e ect.

• Worseningdepressionortheappearanceofhypomaniaare rare – if your mood becomes unusually sad or elevated following rTMS, contact your doctor.

• Nodeteriorationinmemoryhasbeenreported.

The long-term e ects of exposure to high-power magnetic elds are not known; however, the magnetic eld strength of rTMS is similar to that of an MR (magnetic resonance) imaging scanner. To date no health hazards have been identi ed for patients or sta who have been exposed to the magnetic elds of an MR scanner.

What else do I need to know about rTMS?

1. Make sure you understand the information that has been provided to you by your doctor or nurse regarding rTMS. Ask them to explain anything about the treatment that you do not understand.

2. Ensure your doctor is aware of all medication you are taking, including drugs you can buy without a prescription and herbal preparations. Some medications may increase the risk of seizures during some types of rTMS.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on SARI Antidepressants

The name of your medication is _______________________. It belongs to a class of antidepressants called serotonin-2 antagonist/reuptake inhibitors (SARI).

What is this drug used for?

SARI antidepressants are used in the treatment of major depressive disorder and bipolar depression. Though currently not approved for these indications, these drugs have also been found e ective in several other disorders including dysthymia, premenstrual dysphoria or depression, social phobia, posttraumatic stress disorder, and acute and chronic insomnia as well as disruptive and impulsive behavior. Ask your doctor if you are not sure why you are taking this drug.

How quickly will the drug start working?

Antidepressants begin to improve sleep and appetite and to increase energy within 1–2 weeks; however, feelings of depression may take 4–6 weeks to improve. Because antidepressants take time to work, do not decrease or increase the dose or stop the medication without discussing this with your doctor. Improvement in symptoms of premenstrual dysphoria or impulsive behavior also occur gradually.

How long should you take this medication?

This depends on what type of illness you have and how well you do.

What side effects may happen?

Common side e ects that should be reported to your doctor at the NEXT VISIT include:

• Energizing/agitatedfeeling–someindividualsmayfeel nervous or have di culty sleeping for a few days after starting this medication.

• Headache – this tends to be temporary and can be managed by taking pain medicine (such as aspirin, acetaminophen) when required. If the headache persists or is “troubling,” contact your doctor.

• Nauseaorheartburn–ifthishappens,takethemedication with food.

• Muscletremor,twitching–speaktoyourdoctorasthismay require a change in your dosage.

• Changesinsexdriveorsexualperformance–thoughrare, should this problem occur, discuss it with your doctor.

• Lossofappetite.

Rare side e ects you should report to your doctor RIGHT AWAY include:

• Soremouth,gumsorthroat

• Skinrashoritching,swellingoftheface

• Anyunusualbruisingorbleeding

• Episodesofdizzinessorfalling

• Nausea,vomiting,lossofappetite,feelingtired,weak,feverish

or like you have the u

• Persistentabdominalpain,palestools

• Yellowtingeintheeyesortotheskin;dark-coloredurine(pee) • Tinglinginthehandsandfeet,severemuscletwitching

• Apersistenterectionthatcontinuesbeyond4hours

• Severeagitation,restlessness,irritabilityorthoughtsofsuicide • Switchinmoodtoanunusualstateofhappiness,excitement,

irritability or problems sleeping

Let your doctor know right away if you miss your period or think you may be pregnant, plan to become pregnant or are breastfeeding.

What should you do if you forget to take a dose of your medication?

If you take your total dose of this medication in the morning and you forget to take it for more than 6 hours, skip the missed dose and continue with your schedule the next day. DO NOT DOUBLE THE DOSE. If you take the drug several times a day, take the missed dose when you remember, then continue with your regular schedule.

Is this drug safe to take with other medication?

Because SARI antidepressant drugs can change the e ect of other medication or may be a ected by other medication, always check with your doctor or pharmacist before taking other drugs, including those you can buy without a prescription such as cold remedies and herbal preparations. Always inform any doctor or dentist that you see that you are taking an antidepressant drug.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on SARI Antidepressants

Precautions/considerations

1. Do not change your dose without talking with your health care provider (e.g., doctor, pharmacist, nurse).

2. Do not stop your drug suddenly (without discussing it with your health care advisor), as this may result in withdrawal symptoms such as muscle aches, chills, tingling in your hands or feet, nausea, vomiting, and dizziness.

3. This drug may impair the mental and physical abilities required for driving a car or operating machinery. Avoid these activities if you feel drowsy or slowed down.

5. Report any changes in mood or behavior to your doctor.

6. This drug may interact with medication prescribed by your dentist, so let him/her know the name of the drug you are

taking.

What else do I need to know about SARI antidepressants?

1. Take your drug with water, milk orange or apple juice; avoid grapefruit juice as it may change the e ect of the drug in your body.

2. If you are taking the extended-release tablet, do not break, chew or crush the drug but swallow it whole.

3. Excessive use of ca einated foods, drugs or beverages may increase anxiety and agitation and confuse the diagnosis.

4. Store your medication in a clean, dry area at room temperature. Keep all medication out of the reach of children.

If you have any questions regarding this medication, please ask your doctor, pharmacist or nurse.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Transdermal Selegiline

The name of your medication is selegiline. It belongs to a class of antidepressants called monoamine oxidase-B inhibitors (MAO-B).

What is this drug used for?

Selegiline transdermal (EMSAM) comes as a skin patch and is used to treat major depression. The skin patch delivers the medicine through your skin and into your bloodstream.

Your doctor will prescribe a dose of EMSAM based on your condition; he/she may change your dose if needed. Ask your doctor if you are not sure why you are taking this drug.

How quickly will the drug start working?

Though selegiline may begin to improve sleep and appetite and to increase energy within about one week, feelings of depression may take from 4 to 6 weeks to improve.

How long should you take this medication?

This depends on what type of illness you have and how well you do.

DO NOT STOP taking your medication if you are feeling better, without rst discussing this with your doctor.

How do you use the transdermal patch?

Carefully read and follow the instructions, which are given to you with the patch.

1. EMSAM should be applied to dry, intact skin on the upper torso

(below the neck and above the waist), upper thigh or the outer surface of the upper arm. A new application site should be selected with each new patch to avoid re-application to the same area.

2. Apply the patch at approximately the same time each day to an area of skin that is not hairy, oily, irritated, broken, scarred or calloused. Do not place the patch where your clothing is tight which could cause the patch to rub o .

3. Only one EMSAM patch should be worn at a time. Carefully dispose of used patches, as instructed.

4. Avoid exposing the EMSAM application site to external sources of direct heat, such as heating pads or electric blankets, heat lamps, saunas, hot tubs, heated water beds, and prolonged direct sunlight.

What side effects may happen?

Side e ects may happen with any drug. They are not usually serious and do not happen to everyone. Side e ects may

sometimes occur before bene cial e ects of the medication are noticed. If you think you may be having a side e ect, speak to your doctor or pharmacist as they can help you decrease it or cope with it.

Common side e ect that should be reported to your doctor at the NEXT VISIT include:

• Itching,skinrashorotherskinreactionsatthesiteof application of patch; change the site where you apply the patch regularly

• Dizziness,lightheadedness–getupfromlyingorsitting positions slowly. Let your doctor know if the dizziness occurs frequently, or you feel faint

• Stomachupset,diarrhea–ifthesesymptomscontinue,your doctor may need to adjust the dose

• Headache–thistendstobetemporaryandcanbemanagedby taking pain medicine (Aspirin, acetaminophen, ibuprofen) as required. If the headache persists or is “troubling,” contact your doctor.

• Drymouth,sorethroat–Sourcandyandsugarlessgumhelp increase saliva in your mouth. Do not drink sweet drinks like colas as they may give you cavities and help put on weight. Drink water and brush your teeth regularly.

• Sleepingdi culties–someindividualsmayfeelnervousor have di culty sleeping for a few days after starting this medication. Your doctor may advise you to remove the patch at bedtime if your sleeping di culties continue

Rare side e ects you should report to your doctor RIGHT AWAY include:

• Suddenonsetofsevereheadache,nausea,sti neck,afast heartbeat or a change in the way your heart beats (palpitations), a lot of sweating, and confusion. If you suddenly have these symptoms, remove the patch and get medical care right away

• Highfeverorsweating

• Tremors, muscle sti ness, or movements you cannot control

• Convulsions (or seizures)

• Increased anxiety, agitation, increase in suicidal thoughts

• Switch in mood to an unusual state of happiness, excitement,

irritability

• Symptoms which indicate that you may have too much

selegiline in your body include: excitement, irritability, nervousness, insomnia, dizziness, severe headache, hallucinations, sweating, light-headedness, fainting, or seizures

Let your doctor know right away if you miss your period or think you may be pregnant, plan to become pregnant or are breastfeeding.

Caution

Certain foods and drugs contain chemicals which are broken down by the enzyme monoamine oxidase. In higher doses (usually over 6 mg/day) this drug can inhibit this enzyme, thereby increasing these chemicals in the body, and may raise the blood pressure and cause a severe reaction called a hypertensive crisis. Discuss the need for dietary restrictions with your doctor.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Transdermal Selegiline

Listedbelowarethefoodsanddrugsthatmustbeused cautiouslyoravoidedwhileonthisdrug.

Do not eat the following foods if your drug dose is above 6mg/day(andusecautiouslyifyouareonalowerdose):

• Allmaturedoragedcheeses(Cheddar,Brick,Blue,Stilton, Camembert,Roquefort)

• Broadbeanpods(e.g.,FavaBeans)

• Concentratedyeastextracts(“Marmite”)

• Sausage(ifaged,especiallysalami,mortadella,pastrami,

summer sausage), other unrefrigerated fermented meats,

gamemeatthathasbeenhung,agedliver

• Dried salted sh, pickled herring

• Sauerkraut

• Soy sauce or soybean condiments, tofu

• Packet soup (especially miso)

• Tap (draft) beer, alcohol-free beer

• Improperlystoredorspoiledmeat,poultry,or sh

Wait for 14 days after stopping a MAOI drug before restarting to eat the above foods.

Hypertensive reactions have been reported, by some individuals, with the following foods; try small portions to determine if these foods will cause a reaction:

• Smoked sh,caviar,snails,tinned sh,shrimppaste • Yogurt

• Meattenderizers

• Meatextract(“Bovril,”“Oxo”)

• Homemaderedwine,Chianti,canned/bottledbeer,sherry, champagne

• Cheeses(e.g.,Parmesan,Muenster,Swiss,Gruyere,Mozzarella, Feta)

• Pepperoni

• Overripefruit,avocados,raspberries,bananas,plums,canned

gs and raisins, orange pulp, tomatoes • Asianfoods

• Spinach,eggplant

It is SAFE to use the following foods, in moderate amounts (only if fresh):

• Cottagecheese,creamcheese,farmer’scheese,processed cheese, Cheez Whiz, ricotta, Havarti, Boursin, Brie without rind, Gorgonzola

• Liver(aslongasitisfresh),freshorprocessedmeats,poultryor sh (e.g., hot dogs, bologna)

• Spirits,liquor(inmoderation)

• Soymilk

• Sourcream

• Saladdressings

• Worcestershiresauce

• Yeast-leavenedbread

Make sure all food is fresh, stored properly, and eaten soon after being purchased. Never touch food that is fermented or possibly “o .” Avoid restaurant sauces, gravy and soup.

Do not use the following drugs, which you can buy without a prescription, unless you have spoken to your doctor or pharmacist:

• Coldremedies,decongestants(includingnasalspraysand drops), some anti-histamines and cough medicine

• Opioidpainkillers(e.g.,productscontainingcodeine)

• Allstimulantsincludingpep-pills(Wake-ups,Nodoz),or

appetite suppressants

• Anti-asthmadrugs(PrimatineP)

• Sleepaidsandsedatives(Sominex,Nytol)

• Yeast,dietarysupplements(e.g.,Ultrafast,Optifast)

It is SAFE to use:

• PlainASA(aspirin),acetaminophen(e.g.,Tylenol),oribuprofen

(e.g.,Motrin,Advil)

• Antacids(e.g.,Tums,Maalox) • Throatlozenges

Ifahypertensivereaction(highbloodpressure)shouldoccur,the symptoms usually come on suddenly, so be alert for these signs:

• Severe,throbbingheadachewhichstartsatthebackofthe head and radiates forward; often the headache is accompanied by nausea and vomiting

• Sti neck

• Heart palpitations, fast heart beat, chest pain • Sweating, cold and clammy skin

• Enlarged (dilated) pupils of the eyes

• Sudden unexplained nose bleeds

If a combination of these symptoms does occur, contact your doctor IMMEDIATELY; if you are unable to do so, go to the Emergency Department of your nearest hospital.

What should you do if you forget to take a dose of your medication?

Should you forget to apply the patch at your usual time in the morning, apply it as soon as you remember to do so, unless it is almost time for the next dose. Replace this patch with a new one on the following day, at your usual time. Do not use extra medicine (or use more than one patch) to make up the missed dose.

Is this drug safe to take with other medication?

Because selegiline can change the e ect of other medication, or may be a ected by other medication, always check with your doctor of pharmacist before taking other drugs, including those you can buy without a prescription such as cold remedies and herbal preparations. Always inform any doctor or dentist that you see that you are using selegiline patches.

Precautions/considerations

1. It is important that you understand how to use and apply an EMSAM Patch. Read the instruction provided with your medication carefully, and ask your doctor, nurse or pharmacist if there is something that you do not understand.

2. Use EMSAM exactly as prescribed by your doctor. Use only one patch at a time. Change the patch once a day (every 24 hours). Choose a time of day that works best for you. Do not stop the drug suddenly without discussing this with your doctor.

3. Do not take other medicines while using EMSAM or for 2 weeks after you stop using it unless your doctor has told you it is okay.

4. Do not drive or operate dangerous machinery until you know how the selegiline patch a ects you. It may reduce your judgment, ability to think, or coordination. Drinking alcoholic beverages is not recommended while using this drug.

5. Tell your doctor if you plan to have surgery. Also, tell your surgeon that you take EMSAM. EMSAM should be stopped 10 days before you have elective surgery.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Transdermal Selegiline

6. Avoid exposing the EMSAM application site to external sources of direct heat, such as heating pads or electric blankets, heat lamps, saunas, hot tubs, heated waterbeds, and prolonged direct sunlight.

7. Discuss the need for dietary restrictions with your doctor.

8. Store your medication in a clean, dry area at room temperature, in its sealed pouch until use. Keep the patch out of the reach of

children and away from pets.

If you have any questions regarding this medication, please ask your doctor, pharmacist or nurse.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Sex-Drive Depressants

Thenameofyourmedicationis________________________.

What is this drug used for?

These drugs are primarily used to reduce sexual arousal and libido.

How quickly will the drug start working?

These drugs interfere with the formation of the hormone testosterone in the body; their e ect on sexual arousal and libido is noted over a period of several weeks. Because these drugs take time to work, do not decrease or increase the dose without discussing this with your doctor.

How does your doctor decide on the dosage?

These drugs are available in di erent forms, including tablets and long-acting injections. For oral tablets, the dose of the drug is increased gradually until a good response is noted. A testosterone test or your own report of the e ects, can determine the correct dosage. The injection may be given either monthly or every

3 months.

How long should you take this medication?

Sex-drive depressants are usually prescribed for a period of several years.

What side effects may happen?

Common side e ects that should be reported to your doctor at the NEXT VISIT include:

• Sweating,hot ushes

• Impotence

• Muscleachesorspasms–canbemanagedbytakingpain

medicine when required (e.g., aspirin, acetaminophen) • Swollenbreasts

• Decreaseinbodyhair

• Feelingtired,depressedmood

• Nervousness,problemssleeping

Rare side e ects you should report to your doctor RIGHT AWAY include:

• Yellowtingeintheeyesortotheskin;dark-coloredurine(pee) • Soremouth,gumsorthroat

• Skinrashoritching,swellingoftheface

• Nausea,vomiting,lossofappetite,feelingtired,weak,feverish

or like you have the u

• Changesinyourconcentration

• Changeinmusclemovementoractivity • Swellingorpaininthelegs

What should you do if you forget to take a dose of your medication?

If you take your total dose of the drug in the morning and you forget to take it for more than 6 hours, skip the missed dose and continue with your schedule the next day. DO NOT DOUBLE THE DOSE.

If you miss your injection, contact your doctor and try to get an injection as soon as possible.

Is this drug safe to take with other medication?

Because these drugs can change the e ect of other medication or may be a ected by other medication, always check with your doctor or pharmacist before taking other drugs, including those you can buy without a prescription such as cold remedies and herbal preparations. Always inform any doctor or dentist that you see that you are taking this medication.

Precautions/considerations

1. Do not change your dose or stop the drug without speaking to your doctor. The drug needs to be taken regularly to have a bene cial e ect.

2. Report to your doctor any changes in sleeping or eating habits or changes in mood or behavior.

What else do I need to know about sex-drive depressants?

1. Store your medication in a clean, dry area at room temperature. Keep all medication out of the reach of children.

If you have any questions regarding this medication, please ask your doctor, pharmacist or nurse.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on SNRI Antidepressants

The name of your medication is ________________________. It belongs to a class of antidepressants called selective serotonin and norepinephrine reuptake inhibitors (SNRI).

What is this drug used for?

SNRIs are primarily used in the treatment of major depressive disorder, bipolar depression, generalized anxiety disorder or social anxiety disorder, panic disorder, neuropathic pain, musculoskeletal pain, and bromyalgia in adults.

Though not approved for these indications, some of these drugs have also been found e ective in several other disorders including obsessive-compulsive disorder, premenstrual dysphoric disorder, pain syndromes, and in children and adults with attention de cit/hyperactivity disorder. Ask your doctor if you are not sure why you are taking this drug.

How quickly will the drug start working?

SNRIs begin to improve sleep and appetite and to increase energy within 1–2 weeks; however, feelings of depression may take

4–6 weeks to improve. Because antidepressants take time to work, do not decrease or increase the dose or stop the medication without discussing this with your doctor.

Improvement in symptoms of obsessive-compulsive disorder, panic disorder, social phobia, and symptoms of pain also occur gradually over several weeks.

How long should you take this medication?

This depends on what type of illness you have and how well you do.

Long-term treatment is generally recommended for obsessive- compulsive disorder, panic disorder, and social phobia.

What side effects may happen?

Common side e ects that should be reported to your doctor at the NEXT VISIT include:

• Energizing/agitatedfeeling–someindividualsmayfeel nervous or have di culty sleeping for a few days after starting

this medication. Report this to your doctor; he/she may advise

you to take the medication in the morning.

• Headache – this can be managed by taking pain medicine (e.g.,

aspirin, acetaminophen) as required. If the headache persists

or is “troubling,” contact your doctor.

• Nauseaorheartburn–ifthishappens,takethemedication

with food.

• Drymouth–sourcandyandsugarlessgumhelpincreasesaliva

in your mouth. Do not drink sweet drinks like colas as they may give you cavities and increase your weight. Drink water and brush your teeth regularly.

• Sweating–youmaysweatmorethanusual;frequent showering, use of deodorants may help.

• Bloodpressure–aslightincreaseinbloodpressurecanoccur with this drug. If you are taking medication for high blood pressure, tell your doctor, as this medication may have to be adjusted.

• Changesinsexdriveorsexualperformance–discussthiswith your doctor.

Rare side e ects you should report to your doctor RIGHT AWAY include:

• Persistent,troublingheadache

• Soremouth,gumsorthroat

• Skinrashoritching,swellingoftheface

• Nausea,vomiting,diarrhea,lossofappetite,feelingtired,

weak, feverish or like you have the u

• Sharporpersistentstomachpainorcramps

• Yellowtingeintheeyesortotheskin;dark-coloredurine(pee) • Tinglinginthehandsandfeet,severemuscletwitching,

tremor, shivering, and loss of balance

• Racingheart/pulse

• Going12hoursormorewithoutpeeing

• Severeagitation,restlessness,anxiety,panic,irritabilityor

thoughts of suicide

• Switchinmoodtoanunusualstateofhappiness,excitement,

irritability or problems sleeping

Let your doctor know right away if you miss your period or think you may be pregnant, plan to become pregnant or are breastfeeding.

What should you do if you forget to take a dose of your medication?

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on SNRI Antidepressants

missed dose when you remember, then continue with your regular schedule.

Is this drug safe to take with other medication?

Precautions/considerations

1. Do not change your dose without talking with your health care provider (e.g., doctor, pharmacist, nurse).

3. This drug may impair the mental and physical abilities required for driving a car or operating machinery. Avoid these activities if you feel drowsy or slowed down.

4. This drug may increase the e ects of alcohol, making you more sleepy, dizzy, and lightheaded.

5. Report any changes in mood or behavior to your doctor.

6. This drug may interact with medication prescribed by your dentist, so let him/her know the name of the drug you are

taking.

What else do I need to know about SNRI antidepressants?

1. If you are taking sustained-release tablets of venlafaxine or desvenlafaxine or extended/delayed-release capsules of venlafaxine, duloxetine, or levomilnacipran, do not break, chew or crush the drug but swallow it whole.

2. If you are taking desvenlafaxine, you may notice the empty tablet in your stool. This is normal.

3. Excessive use of ca einated foods, drugs or beverages may increase anxiety and agitation and confuse the diagnosis.

4. Store your medication in a clean, dry area at room temperature. Keep all medication out of the reach of children.

If you have any questions regarding this medication, please ask your doctor, pharmacist or nurse.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on SSRI Antidepressants

The name of your medication is ________________________. It belongs to a class of antidepressants called selective serotoninreuptakeinhibitors(SSRI).

What is this drug used for?

SSRI antidepressants are used in the treatment of a number of disorders including:

• Majordepressivedisorder,bipolardepression • Generalizedanxietydisorder

• Obsessive-compulsivedisorder

• Panicdisorder

• Bulimia

• Socialphobia

• Premenstrualdysphoriaordepression • Posttraumaticstressdisorder

These drugs are also used to treat several other disorders. Ask your doctor if you are not sure why you are taking this drug.

How quickly will the drug start working?

Antidepressants begin to improve sleep and appetite and to increase energy within 1–2 weeks; however, feelings of depression may take 4–6 weeks to improve. Because antidepressants take time to work, do not decrease or increase the dose or stop the medication without discussing this with your doctor. Improvement in symptoms related to anxiety disorders such as obsessive-compulsive disorder, panic disorder, social phobia, and symptoms of bulimia also occurs gradually.

How long should you take this medication?

This depends on what type of illness you have and how well you do.

Long-term treatment is generally recommended for obsessive- compulsive disorder, panic disorder, and bulimia.

What side effects may happen?

Common side e ects that should be reported to your doctor at the NEXT VISIT include:

• Headache–thistendstobetemporaryandcanbemanagedby taking pain medicine (such as aspirin, acetaminophen) when required. If the headache persists or is “troubling,” contact your doctor.

• Nauseaorheartburn–ifthishappens,takethemedication with food.

• Muscletremor,twitching–speaktoyourdoctorasthismay require a change in your dosage.

• Changesinsexdriveorsexualperformance–discussthiswith your doctor.

• Sweating–youmaysweatmorethanusual;frequent showering, use of deodorants may help.

• Nightmares–canbemanagedbychangingthetimeyoutake your drug, speak with your doctor.

• Lossofappetite.

Rare side e ects you should report to your doctor RIGHT AWAY include:

• Soremouth,gumsorthroat

• Skinrashoritching,swellingoftheface

• Anyunusualbruisingorbleeding,increasednosebleedsor

blood in your stool

• Nausea, vomiting, loss of appetite, feeling tired, weak, feverish

or like you have the u

• Yellow tinge in the eyes or to the skin; dark-colored urine (pee) • Going a day or more without peeing

• Tingling in the hands and feet, severe muscle twitching

• Severeagitation,restlessness,irritabilityorthoughtsofsuicide • Switchinmoodtoanunusualstateofhappiness,excitement,

irritability or problems sleeping

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on SSRI Antidepressants

Let your doctor know right away if you miss your period or think you may be pregnant, plan to become pregnant or are breastfeeding.

What should you do if you forget to take a dose of your medication?

Is this drug safe to take with other medication?

Because SSRI antidepressant drugs can change the e ect of other medication, or may be a ected by other medication, always check with your doctor or pharmacist before taking other drugs, including those you can buy without a prescription, such as cold remedies and herbal preparations. Always inform any doctor or dentist that you see that you are taking an antidepressant drug.

Precautions/considerations

1. Do not change your dose without talking with your health care provider (e.g., doctor, pharmacist, nurse).

3. Take your drug with meals or with water, milk, orange or apple juice; avoid grapefruit juice as it may change the e ect of the drug in your body.

4. If you are taking a controlled-release medication (e.g., Paxil CR, Luvox CR, Symbyax), or enteric-coated uoxetine, swallow the drug whole. Do not split, crush or chew the tablet/capsule, as this will a ect the action of the medication.

5. This drug may impair the mental and physical abilities required for driving a car or operating machinery. Avoid these activities if you feel drowsy or slowed down.

6. This drug may increase the e ects of alcohol, making you more sleepy, dizzy, and lightheaded.

7. Report any changes in mood or behavior to your doctor.

8. This drug may interact with medication prescribed by your dentist, so let him/her know the name of the drug you are

taking.

9. Oral disintegrating tablets of citalopram should be placed

under the tongue and may be taken with or without liquid. 10. Excessive use of ca einated foods, drugs or beverages may

increase anxiety and agitation and confuse the diagnosis. 11. Store your medication in a clean, dry area at room

temperature. Keep all medication out of the reach of children.

If you have any questions regarding this medication, please ask your doctor, pharmacist or nurse.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Valbenazine

Thenameofyourmedicationis_______________________.

What is this drug used for?

Valbenazine is a medication used to treat adults with movements in the face, tongue, or other body parts that cannot be controlled (tardive dyskinesia).

How quickly will the drug start working?

Valbenazine may begin to reduce uncontrollable movements after 2 weeks, but it may take up to 6 weeks to feel the full e ect. Because this medication takes time to work, do NOT change your dose or stop your medication without talking to your doctor.

How long should you take this medication?

This may depend on how e ective valbenazine is at reducing or eliminating your uncontrollable movements.

Talk with your doctor about how long you should stay on this medication.

How do you take this drug?

Valbenazine is usually taken once daily, at a time that you choose, or as prescribed by your doctor. You may take this medicine with or without food.

What side effects may happen?

Common side e ects that should be reported to your doctor at the NEXT VISIT include:

• Change in walking and balance

• Drymouth–sourcandyandsugarlessgumhelpincreasesaliva

in your mouth. Do not drink sweet drinks like colas as they may give you cavities and increase your weight. Drink water and brush your teeth regularly

• Headache–thiscanbemanagedbytakingpainmedicine(e.g., acetaminophen or ibuprofen) as required. If the headache persists or is “troubling,” contact your doctor.

• Feelingsofrestlessness

• Blurredvision–thisusuallyhappenswhenyou rststartthe

drug and tends to be temporary. Reading under a bright light or at a distance may help; a magnifying glass can be of temporary use. If the problem lasts for more than a few weeks, let your doctor know.

Rare side e ects you should report to your doctor RIGHT AWAY are:

• Fast,slow,orirregularheartbeat • Dizzinessorfainting

• Shortnessofbreath

Let your doctor know right away if you miss your period or think you may be pregnant, plan to become pregnant or are breastfeeding.

What should you do if you forget to take a dose of your medication?

Is this drug safe to take with other medication?

Because valbenazine can change the e ect of other medication or may be a ected by other medication, always check with your doctor or pharmacist before taking other drugs, including those you can buy without a prescription such as cold remedies and herbal preparations. Always inform any doctor or dentist that you see that you are taking this medication.

What else do I need to know about valbenazine?

1. Do not change your dose without talking with your health care provider (e.g., doctor, pharmacist, nurse).

2. Antacids (like Diovol, Maalox, amphogel, etc.) may lower the amount of valbenazine in your body. Take your antacid at least 2 hours before or 1 hour after taking valbenazine to avoid this.

3. This drug may cause sleepiness. Do not drive, operate heavy machinery, or do other dangerous activities until you know how valbenazine a ects you.

4. Store your medication in a clean, dry area at room temperature. Keep all medication out of the reach of children.

If you have any questions regarding this medication, please ask your doctor, pharmacist or nurse.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Vilazodone

Vilazodone belongs to a class of antidepressants called serotonin-1A partial agonist/serotonin reuptake inhibitor (SPARI).

What is this drug used for?

Vilazodone is used in the treatment of major depressive disorder.

How quickly will the drug start working?

Vilazodone begins to improve sleep and appetite and to increase energy within 1–2 weeks; however, feelings of depression may take 4–6 weeks to improve. Because antidepressants take time to work, do not decrease or increase the dose or stop the medication without discussing this with your doctor.

How long should you take this medication?

DO NOT STOP taking your medication if you are feeling better without rst discussing this with your doctor.

What side effects may happen?

Common side e ects that should be reported to your doctor at the NEXT VISIT include:

• Nausea, heartburn – if this happens, take the medication with food.

• Loose stools, diarrhea – a bulking agent, such as psyllium (Metamucil) can help. If diarrhea persists, contact your doctor.

• Dizziness, lightheaded feeling – get up from a lying or sitting position slowly; dangle your legs over the edge of the bed for a few minutes before getting up. Sit or lie down if dizziness persists or if you feel faint, then contact your doctor.

• Headache – this can be managed by taking pain medicine (e.g., aspirin, acetaminophen) as required. If the headache persists or is “troubling,” contact your doctor.

• Feeling sleepy or tired – this problem goes away with time. Use of other drugs that make you drowsy will worsen the problem. Avoid driving a car or operating machinery until you know how

the drug a ects you. If drowsiness persists, your doctor may

advise you to take the medication at bedtime.

• Changesinsexdriveorsexualperformance–discussthiswith

your doctor.

Rare side e ects you should report to your doctor RIGHT AWAY include:

• Soremouth,gumsorthroat

• Skinrashoritching,swellingoftheface,di cultybreathing • Any unusual bruising or bleeding, increased nosebleeds or

blood in your stool

• Nausea,vomiting,lossofappetite,feelingtired,weak,feverish

or like you have the u

• Yellowtingeintheeyesortotheskin;dark-coloredurine(pee) • Goingadayormorewithoutpeeing

• Tinglinginthehandsandfeet,severemuscletwitching

• Severeagitation,restlessness,irritabilityorthoughtsofsuicide • Switchinmoodtoanunusualstateofhappiness,excitement,

irritability or problems sleeping

Let your doctor know right away if you miss your period or think you may be pregnant, plan to become pregnant or are breastfeeding.

What should you do if you forget to take a dose of your medication?

Is this drug safe to take with other medication?

Precautions/considerations

1. Do not change your dose without talking with your health care provider (e.g., doctor, pharmacist, nurse).

3. This drug may impair the mental and physical abilities required for driving a car or operating machinery. Avoid these activities if you feel drowsy or slowed down.

5. Avoid grapefruit juice as it may change the e ect of the drug in your body.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Vilazodone

6. Report any changes in mood or behavior to your doctor.

7. This drug may interact with medication prescribed by your dentist, so let him/her know the name of the drug you are

taking.

What else do I need to know about vilazodone?

1. Excessive use of ca einated foods, drugs or beverages may increase anxiety and agitation and confuse the diagnosis.

2. Store your medication in a clean, dry area at room temperature. Keep all medication out of the reach of children.

If you have any questions regarding this medication, please ask your doctor, pharmacist or nurse.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Vortioxetine

Vortioxetine belongs to a class of antidepressants called serotonin modulator and stimulator (SMS).

What is this drug used for?

Vortioxetine is used in the treatment of major depressive disorder. Though not approved for this indication, vortioxetine is also used in the treatment of generalized anxiety disorder.

Howquicklywillthedrugstartworking?

Vortioxetine begins to improve sleep and appetite and to increase energy within 1–2 weeks; however, feelings of depression may take 4–6 weeks to improve. Because antidepressants take time to work, do not decrease or increase the dose or stop the medication without discussing this with your doctor.

Improvement in symptoms of anxiety disorders also occur gradually over several weeks.

How long should you take this medication?

DO NOT STOP taking your medication if you are feeling better without rst discussing this with your doctor.

Long-term treatment is generally recommended for anxiety disorders.

What side effects may happen?

Common side e ects that should be reported to your doctor at the NEXT VISIT include:

• Nausea,heartburn–ifthishappens,takethemedicationwith food. If vomiting occurs regularly, contact your doctor.

• Loosestools,diarrhea–abulkingagent,suchaspsyllium (Metamucil) can help. If diarrhea persists, contact your doctor.

• Dizziness,lightheadedfeeling–getupfromalyingorsitting position slowly; dangle your legs over the edge of the bed for a few minutes before getting up. Sit or lie down if dizziness persists or if you feel faint, then contact your doctor.

• Headache–thiscanbemanagedbytakingpainmedicine(e.g., acetaminophen or ibuprofen) as required. If the headache persists or is “troubling,” contact your doctor.

• Drymouth–sourcandyandsugarlessgumhelpincreasesaliva in your mouth. Do not drink sweet drinks like colas as they may

give you cavities and increase your weight. Drink water and

brush your teeth regularly

• Constipation–drinkplentyofwater,trytoincreasethe

• Changesinsexdriveorsexualperformance–discussthiswith your doctor.

Rare side e ects you should report to your doctor RIGHT AWAY include:

• Soremouth,gumsorthroat

• Skin rash or itching, swelling of the face, di culty breathing • Any unusual bruising or bleeding, increased nosebleeds or

blood in your stool

• Nausea,vomiting,lossofappetite,feelingtired,weak,feverish

or like you have the u

• Yellowtingeintheeyesortotheskin;dark-coloredurine(pee) • Eyepain,visionchanges,orswellingorrednessinoraround

the eye

• Goingadayormorewithoutpeeing

• Tinglinginthehandsandfeet,severemuscletwitching,

seizures

• Confusion,decreasedcoordination,fainting,hallucinations,

headache, memory problems, mental or mood changes, sluggishness, trouble concentrating, or weakness – may indicate low levels of sodium in the body

• Severeagitation,restlessness,irritabilityorthoughtsofsuicide • Switchinmoodtoanunusualstateofhappiness,excitement,

irritability or problems sleeping

Let your doctor know right away if you miss your period or think you may be pregnant, plan to become pregnant or are breastfeeding.

What should you do if you forget to take a dose of your medication?

Is this drug safe to take with other medication?

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

Patient Information on Vortioxetine

Precautions/considerations

1. Do not change your dose without talking with your health care provider (e.g., doctor, pharmacist, nurse).

2. Do not stop this drug suddenly (without discussing it with your health care provider).

4. Report any changes in mood or behavior to your doctor.

5. This drug may interact with medication prescribed by your dentist, so let him/her know the name of the drug you are

taking.

What else do I need to know about vortioxetine?

1. Excessive use of ca einated foods, drugs or beverages may increase anxiety and agitation and confuse the diagnosis.

2. Store your medication in a clean, dry area at room temperature. Keep all medication out of the reach of children.

If you have any questions regarding this medication, please ask your doctor, pharmacist or nurse.

Ericka Teleg / 192.133.45.2 (2020-04-01 16:57)

deemag and chest clinic

Clinical Handbook of Psychotropic Drugs

Pages

Leave a comment Cancel reply

SEARCH THIS SITE

Recent Posts

categores

alexaVerifyID”

facebook page

Goodreads

Follow Blog via Email

Blogroll

dr.pkgupta

contact information

Flickr Photos

archives

Follow me on Twitter

twitter

list of top posts

CLICK HERE for more interaction on media

google

deemag and chest clinic

Clinical Handbook of Psychotropic Drugs

Share this:

Related

Pages

Leave a comment Cancel reply

SEARCH THIS SITE

Recent Posts

categores

alexaVerifyID”

facebook page

Goodreads

Follow Blog via Email

Blogroll

dr.pkgupta

contact information

Flickr Photos

archives

Follow me on Twitter

twitter

list of top posts

CLICK HERE for more interaction on media

google