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)

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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

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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

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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

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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

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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

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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

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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

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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

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Antidepressants

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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

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• 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

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Hematologic Effects

Endocrine & Metabolic Effects

GI Effects

Urogenital & Sexual Effects

Antidepressants

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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

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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

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Antidepressants

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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

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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

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Antidepressants

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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

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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.

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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.

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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

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Antidepressants

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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.

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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

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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

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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

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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

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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

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Antidepressants

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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

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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

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Antidepressants

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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

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Antidepressants

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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)

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Antidepressants

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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

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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

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Antidepressants

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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

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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

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Priapism reported,

Shortened QTc interval,

Antidepressants

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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)

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Antidepressants

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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)

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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

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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

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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

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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

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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

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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.

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Antipsychotics

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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

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Antipsychotics

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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

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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

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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

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Antipsychotics

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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

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Cardiovascular Effects

Endocrine & Metabolic Effects

Antipsychotics

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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

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• 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

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GI Effects

Urogenital & Sexual Effects

Ocular Effects

Hematological Effects

Antipsychotics

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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]

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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

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Antipsychotics

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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

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• 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

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Nursing Implications

Oral

Short-acting IM

Long-acting IM

Intravenous

Antipsychotics

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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

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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

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Antipsychotics

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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

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Antipsychotics

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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

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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

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Antipsychotics

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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

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Antipsychotics

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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

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Antipsychotics

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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

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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

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• 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

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Antipsychotics

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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

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Urogenital & Sexual Effects

Ocular Effects

Hematological Effects

Antipsychotics

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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

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Antipsychotics

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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

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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

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Antipsychotics

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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

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• 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

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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

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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

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Antipsychotics

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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

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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

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Antipsychotics

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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

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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

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Antipsychotics

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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

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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

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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

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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

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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

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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

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Antipsychotics

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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

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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

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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

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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

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Antipsychotics

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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

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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

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Antipsychotics

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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)

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Antipsychotics

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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

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Antipsychotics

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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)

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Antipsychotics

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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

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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)

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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

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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

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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

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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

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Antipsychotics

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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

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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

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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:

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Extrapyramidal

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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

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Extrapyramidal

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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

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Extrapyramidal

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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

∗ 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

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

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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

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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

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Extrapyramidal

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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

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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)

–

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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

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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

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Anxiolytics

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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

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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

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Anxiolytics

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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

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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

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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

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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 th

deemagclinic

Clinical Handbook of Psychotropic Drugs