STAHL€TM S ESSENTIAL PSYCHOPHARMACOLOGY Prescriberâ€TM s Guide

STAHL€TM S ESSENTIAL PSYCHOPHARMACOLOGY Prescriberâ€TM s Guide

SEVENTH EDITION

With the range of psychotropic drugs expanding and the usages of existing medications diversifying, we are pleased to present this very latest edition of what has become the indispensable formulary in psychopharmacology.

This new edition features several new compounds as well as information about new formulations, new indications, and new warnings for existing drugs.

With its easy-to-use, template-driven navigation system, the Prescriberâ€TM s Guide combines evidence-based data with clinically informed advice to support everyone prescribing in the field of mental health.

Stephen M. Stahl is Professor of Psychiatry and Neuroscience at the University of California, Riverside and San Diego and Honorary Visiting Senior Fellow in Psychiatry at the University of Cambridge, UK. He has conducted various research projects awarded by the National Institute of Mental Health, Veterans Affairs, and the pharmaceutical industry. Author of more than 500 articles and chapters, Dr Stahl is also the author of the bestseller Stahlâ€TM s Essential Psychopharmacology .

STAHL€TM S ESSENTIAL PSYCHOPHARMACOLOGY

Prescriberâ€TM s Guide

SEVENTH EDITION

Stephen M. Stahl

University of California at Riverside and at San Diego, Riverside and San Diego, California

Editorial assistant

Meghan M. Grady

With illustrations by

Nancy Muntner

University Printing House, Cambridge CB2 8BS, United Kingdom

One Liberty Plaza, 20th Floor, New York, NY 10006, USA

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India

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Cambridge University Press is part of the University of Cambridge.

It furthers the Universityâ€TM s mission by disseminating knowledge in the pursuit of education, learning, and research at the highest international levels of excellence.

http://www.cambridge.org

Information on this title: http://www.cambridge.org/9781316618134

© Stephen M. Stahl 2005, 2006, 2009, 2011, 2014, 2017, 2021

This publication is in copyright. Subject to statutory exception and to the provisions of relevant collective licensing agreements, no reproduction of any part may take place without the written permission of Cambridge University Press.

First published 2005

Revised and updated edition published 2006 Third edition published 2009

Fourth edition published 2011

Fifth edition published 2014

Sixth edition published 2017 Seventh edition published 2021

Printed in the United Kingdom by TJ Books Ltd, Padstow Cornwall

A catalog record for this publication is available from the British Library.

ISBN 978-1-108-92601-0 Paperback ISBN 978-1-108-92602-7 Spiral

Additional resources for this publication at http://www.stahlonline.org

Every effort has been made in preparing this book to provide accurate and up-to-date information that is in accord with accepted standards and practice at the time of publication. Although case histories are drawn from actual cases, every effort has been made to disguise the identities of the individuals involved. Nevertheless, the authors, editors, and publishers can make no warranties that the information contained herein is totally free from error, not least because clinical standards are constantly changing through research and regulation. The authors, editors, and publishers therefore disclaim all liability for direct or consequential damages resulting from the use of material contained in this book. Readers are strongly advised to pay careful attention to information provided by the manufacturer of any drugs or equipment that they plan to use.

Cambridge University Press has no responsibility for the persistence or accuracy of URLs for external or third-party Internet Web sites referred to in this publication, and does not guarantee that any content on such Web sites is, or will remain, accurate or appropriate.

Contents

Introduction

List of icons

1 acamprosate

2 agomelatine

3 alprazolam

4 amisulpride

5 amitriptyline

6 amoxapine

7 amphetamine (d) 8 amphetamine (d,l) 9 aripiprazole

10 armodafinil

11 asenapine

12 atomoxetine

13 benztropine

14 blonanserin

15 bremelanotide 16 brexanolone

17 brexpiprazole

18 buprenorphine 19 bupropion

20 buspirone

21 caprylidene

22 carbamazepine 23 cariprazine

24 chlordiazepoxide 25 chlorpromazine

26 citalopram

27 clomipramine

28 clonazepam

29 clonidine

30 clorazepate

31 clozapine

32 cyamemazine

33 desipramine

34 desvenlafaxine

35 deutetrabenazine 36 dextromethorphan 37 diazepam

38 diphenhydramine 39 disulfiram

40 donepezil

41 dothiepin

42 doxepin

43 duloxetine

44 escitalopram

45 esketamine

46 estazolam

47 eszopiclone

48 flibanserin

49 flumazenil

50 flunitrazepam

51 fluoxetine

52 flupenthixol

53 fluphenazine

54 flurazepam 55 fluvoxamine 56 gabapentin 57 galantamine 58 guanfacine 59 haloperidol 60 hydroxyzine 61 iloperidone 62 imipramine 63 isocarboxazid 64 ketamine

65 lamotrigine

66 lemborexant

67 levetiracetam

68 levomilnacipran 69 lisdexamfetamine 70 lithium

71 lofepramine 72 lofexidine 73 loflazepate 74 lorazepam 75 loxapine

76 lumateperone

77 lurasidone

78 maprotiline

79 memantine

80 methylfolate (l)

81 methylphenidate (d)

82 methylphenidate (d,l) 83 mianserin

84 midazolam

85 milnacipran

86 mirtazapine

87 moclobemide

88 modafinil

89 molindone

90 nalmefene

91 naltrexone

92 naltrexone/bupropion

93 nefazodone

94 nortriptyline

95 olanzapine

96 oxazepam

97 oxcarbazepine

98 paliperidone

99 paroxetine

100 perospirone

101 perphenazine

102 phenelzine

103 phentermine/topiramate 104 pimavanserin

105 pimozide

106 pipothiazine

107 pitolisant

108 prazosin

109 pregabalin

110 propranolol

111 protriptyline 112 quazepam

113 quetiapine

114 ramelteon

115 reboxetine

116 risperidone

117 rivastigmine 118 selegiline

119 sertindole

120 sertraline

121 sildenafil

122 sodium oxybate 123 solriamfetol 124 sulpiride

125 suvorexant

126 tasimelteon

127 temazepam

128 thioridazine

129 thiothixene

130 tiagabine

131 tianeptine

132 topiramate

133 tranylcypromine 134 trazodone

135 triazolam

136 trifluoperazine 137 trihexyphenidyl

138 triiodothyronine 139 trimipramine 140 valbenazine 141 valproate

142 varenicline 143 venlafaxine 144 vilazodone 145 vortioxetine 146 zaleplon

147 ziprasidone 148 zolpidem

149 zonisamide 150 zopiclone

151 zotepine

152 zuclopenthixol

Index by Drug Name Index by Use

Index by Class Abbreviations

Introduction

This Guide is intended to complement Stahlâ€TM s Essential

Psychopharmacology . Stahlâ€TM s Essential Psychopharmacology emphasizes mechanisms of action and how psychotropic drugs work upon receptors and enzymes in the brain. This Guide gives practical information on how to use these drugs in clinical practice.

It would be impossible to include all available information about any drug in a single work, and no attempt is made here to be comprehensive. The purpose of this Guide is instead to integrate the art of clinical practice with the science of psycho-pharmacology. That means including only essential facts in order to keep things short. Unfortunately it also means excluding less critical facts as well as extraneous information, which may nevertheless be useful to the reader but would make the book too long and dilute the most important information. In deciding what to include and what to omit, the author has drawn upon common sense and 30 years of clinical experience with patients. He has also consulted with many experienced clinicians and analyzed the evidence from controlled clinical trials and regulatory filings with government agencies.

In order to meet the needs of the clinician and to facilitate future updates of this Guide , the opinions of readers are sincerely solicited. Feedback can be emailed to customerservice@neiglobal.com. Specifically, are the best and most essential psychotropic drugs included here? Do you find any factual errors? Are there agreements or disagreements with any of the opinions expressed here? Are there suggestions for any additional tips or pearls for future editions? Any and all suggestions and comments are welcomed.

All of the selected drugs are presented in the same format in order to facilitate rapid access to information. Specifically, each drug is broken down into five sections, each designated by a unique color background: Therapeutics, Side Effects, Dosing and Use, Special Populations, and The Art of Psychopharmacology, followed by key references.

Therapeutics covers the brand names in major countries; the class of drug; what it is commonly prescribed and approved for by the United States Food and Drug Administration (FDA); how the drug works; how long it takes to work; what to do if it works or if it doesnâ€TM t work; the best augmenting combinations for partial response or treatment resistance; and the tests (if any) that are required.

Side Effects explains how the drug causes side effects; gives a list of notable, life-threatening, or dangerous side effects; gives a specific rating for weight gain or sedation; and gives advice about how to handle side effects, including best augmenting agents for side effects.

Dosing and Use gives the usual dosing range; dosage forms; how to dose and dosing tips; symptoms of overdose; long-term use; if habit forming, how to stop; pharmacokinetics; drug interactions; when not to use; and other warnings or precautions.

Special Populations gives specific information about any possible renal, hepatic, and cardiac impairments, and any precautions to be taken for treating the elderly, children, adolescents, and pregnant and breast-feeding women.

The Art of Psychopharmacology gives the authorâ€TM s opinions on issues such as the potential advantages and disadvantages of any one drug, the primary target symptoms, and clinical pearls to get the best out of a drug.

In addition, drugs for which switching between medications can be complicated have a special section called The Art of Switching, which includes clinical pearls and graphical representations to help guide the switching process.

There is a list of icons used in this Guide following this Introduction and at the back of the Guide are several indices. The first is an index by drug name, giving both generic names (uncapitalized) and trade names (capitalized and followed by the generic name in parentheses). The second is an index of common uses for the generic drugs included in the Guide and is organized by disorder/symptom. Agents that are approved by the FDA for a particular use are shown in bold. The third index is organized by drug class and lists all the agents that fall within each particular class. In addition to these indices there is a list of abbreviations.

Readers are encouraged to consult standard references 1 and comprehensive psychiatry and pharmacology textbooks for more in-depth information. They are also reminded that the Art of Psychopharmacology section is the authorâ€TM s opinion.

It is strongly advised that readers familiarize themselves with the standard use of these drugs before attempting any of the more exotic uses discussed, such as unusual drug combinations and doses. Reading about both drugs before augmenting one with the other is also strongly recommended. Todayâ€TM s psychopharmacologist should also regularly track blood pressure, weight, and body mass index for most of his or her patients. The dutiful clinician will also check out the drug interactions of non-central nervous system (CNS) drugs with those that act in the CNS, including any prescribed by other clinicians.

Certain drugs may be for experts only, and these might include clozapine, thioridazine, pimozide, nefazodone, and monoamine oxidase (MAO) inhibitors, among others. Off-label uses not approved by the FDA and inadequately studied doses or combinations of drugs may also be for the expert only, who can weigh risks and benefits in the presence of sometimes vague and conflicting evidence. Pregnant or nursing women, or people with two or more psychiatric illnesses, substance abuse, and/or a concomitant medical illness may be suitable patients for the expert only. Controlled substances also require expertise. Use your best judgment as to your level of expertise and realize that we are all learning in this rapidly advancing field. The practice of medicine is often not so much a science as it is an art. It is important to stay within the standards of medical care for the field, and also within your personal comfort zone, while trying to help extremely ill and often difficult patients with medicines that can relieve their suffering and sometimes transform their lives.

Finally, this book is intended to be genuinely helpful for practitioners of psychopharmacology by providing them with the mixture of facts and opinions selected by the author. Ultimately, prescribing choices are the readerâ€TM s responsibility. Every effort has been made in preparing this book to provide accurate and up-to-date information in accord with accepted standards and practice at the time of publication. Nevertheless, the psychopharmacology field is evolving rapidly and the author and publisher make no warranties that the information contained herein is totally free from error, not least because clinical standards are constantly changing through research and regulation. Furthermore, the author and publisher disclaim any responsibility for the continued currency of this information and disclaim all liability for any and all damages, including direct or

consequential damages, resulting from the use of information contained in this book. Doctors recommending and patients using these drugs are strongly advised to pay careful attention to, and consult information provided by, the manufacturer.

1 For example, Physicianâ€TM s Desk Reference and Martindale: The Complete Drug Reference .

List of icons

agomelatine

alcohol dependence treatment alpha adrenergic blocker

alpha 2 agonist

anticonvulsant antiparkinson/anticholinergic benzodiazepine

benzodiazepine receptor antagonist beta blocker

cholinesterase inhibitor

dopamine 2 antagonist

dopamine 2 partial agonist dual orexin receptor antagonist flibanserin

histaminic

lithium

medical food

melanocortin receptor agonist l-methylfolate

modafinil (wake-promoter) monoamine oxidase inhibitor naltrexone/bupropion

nefazodone (serotonin antagonist/reuptake inhibitor) neuroactive steroid

nicotinic partial agonist

N-methyl-D-aspartate antagonist

noradrenergic and specific serotonergic antidepressant norepinephrine and dopamine reuptake inhibitor phentermine/topiramate

phosphodiesterase inhibitor

pimavanserin

sedative-hypnotic

selective norepinephrine reuptake inhibitor selective serotonin reuptake inhibitor

serotonin-dopamine antagonist

serotonin and norepinephrine reuptake inhibitor serotonin 1A partial agonist

serotonin partial agonist reuptake inhibitor

sodium oxybate

stimulant

thyroid hormone

trazodone (serotonin antagonist/reuptake inhibitor) tricyclic/tetracyclic antidepressant

vesicular monoamine transporter 2 inhibitor vortioxetine

How the drug works, mechanism of action

Best augmenting agents to add for partial response or treatment resistance

Life-threatening or dangerous side effects

Weight Gain : Degrees of weight gain associated with the drug, with unusual signifying that weight gain has been reported but is not expected; not unusual signifying that weight gain occurs in a significant minority; common signifying that many experience weight gain and/or it can be significant in amount; and problematic signifying that weight gain occurs frequently, can be significant in amount, and may be a health problem in some patients

Sedation : Degrees of sedation associated with the drug, with unusual signifying that sedation has been reported but is not expected; not unusual signifying that sedation occurs in a significant minority; common signifying that many experience sedation and/or it can be significant in amount; and problematic signifying that sedation occurs frequently, can be significant in amount, and may be a health problem in some patients

Tips for dosing based on the clinical expertise of the author

Drug interactions that may occur

Warnings and precautions regarding use of the drug

Dosing and other information specific to children and adolescents Information regarding use of the drug during pregnancy

Clinical pearls of information based on the clinical expertise of the author The art of switching

Suggested reading

Acamprosate

Campral

Therapeutics Brands

see index for additional brand names

Not in USA

Generic?

Class

Neuroscience-based Nomenclature: glutamate multimodal (Glu- MM)

Alcohol dependence treatment

Commonly Prescribed for

(bold for FDA approved)

Maintenance of alcohol abstinence

How the Drug Works

Theoretically reduces excitatory glutamate neurotransmission and increases inhibitory gamma-aminobutyric acid (GABA) neurotransmission

Binds to and blocks certain glutamate receptors, including metabotropic glutamate receptors

Because withdrawal of alcohol following chronic administration can lead to excessive glutamate activity and deficient GABA activity, acamprosate can act as “ artificial alcohol†to mitigate these effects

How Long Until It Works

Has demonstrated efficacy in trials lasting between 13 and 52 weeks

If It Works

Increases abstinence from alcohol

If It Doesnâ€TM t Work

Evaluate for and address contributing factors Consider switching to another agent Consider augmenting with naltrexone

Best Augmenting Combos for Partial Response or Treatment Resistance

Naltrexone

Augmentation therapy may be more effective than monotherapy

Augmentation with behavioral, educational, and/or supportive therapy in groups or as an individual is probably key to successful

treatment

Tests

Side Effects

How Drug Causes Side Effects

Theoretically, behavioral side effects due to changes in neurotransmitter concentrations at receptors in parts of the brain and body other than those that cause therapeutic actions

Gastrointestinal side effects may be related to large doses of a drug that is an amino acid derivative, increasing osmotic absorption in the gastrointestinal tract

Notable Side Effects

Diarrhea, nausea Anxiety, depression

Life-Threatening or Dangerous Side Effects

Suicidal ideation and behavior (suicidality)

Weight Gain

None for healthy individuals

Reported but not expected

Sedation

What to Do About Side Effects

Wait

Adjust dose

If side effects persist, discontinue use

Best Augmenting Agents for Side Effects

Dose reduction or switching to another agent may be more effective since most side effects cannot be improved with an augmenting agent

Dosing and Use Usual Dosage Range

666 mg three times daily (>60 kg) 666 mg two times daily (<60 kg)

Dosage Forms

Reported but not expected

Tablet 333 mg

How to Dose

Patient should begin treatment as soon as possible after achieving abstinence

Recommended dose is 666 mg three times daily; titration is not required

Dosing Tips

Providing educational materials and counseling in combination with acamprosate treatment can increase the chances of success

Patients should be advised to continue treatment even if relapse occurs, and to disclose any renewed drinking

Although absorption of acamprosate is not affected by food, it may aid adherence if patients who regularly eat three meals per day take each dose with a meal

Adherence with three times daily dosing can be a problem; having patient focus on frequent oral dosing of drug rather than frequent drinking may be helpful in some patients

Overdose

Limited available data; diarrhea

Long-Term Use

Has been studied in trials up to 1 year

No

Taper not necessary

Habit Forming

How to Stop

Pharmacokinetics

Terminal half-life 20– 33 hours Excreted unchanged via the kidneys

Drug Interactions

Does not inhibit hepatic enzymes, and thus is unlikely to affect plasma concentrations of drugs metabolized by those enzymes

Is not hepatically metabolized and thus is unlikely to be affected by drugs that induce or inhibit hepatic enzymes

Concomitant administration with naltrexone may increase plasma levels of acamprosate, but this does not appear to be clinically significant and dose adjustment is not recommended

Other Warnings/Precautions

Monitor patients for emergence of depressed mood or suicidal ideation and behavior (suicidality)

Use cautiously in individuals with known psychiatric illness

Do Not Use

If patient has severe renal impairment

If there is a proven allergy to acamprosate

Special Populations Renal Impairment

For moderate impairment, recommended dose is 333 mg three times daily

Contraindicated in severe impairment

Hepatic Impairment

Dose adjustment not generally necessary

Cardiac Impairment

Limited data available

Elderly

Some patients may tolerate lower doses better Consider monitoring renal function

Children and Adolescents

Safety and efficacy have not been established

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women

In animal studies, acamprosate demonstrated teratogenicity in doses approximately equal to the human dose (rat studies) and in doses approximately 3 times the human dose (rabbit studies)

Pregnant women needing to stop drinking may consider behavioral therapy before pharmacotherapy

Not generally recommended for use during pregnancy, especially during first trimester

Breast Feeding

Unknown if acamprosate is secreted in human breast milk, but all psychotropics are assumed to be secreted in breast milk

Recommended either to discontinue drug or bottle feed

The Art of Psychopharmacology Potential Advantages

Individuals who have recently abstained from alcohol For the chronic daily drinker

Potential Disadvantages

Individuals who are not abstinent at time of treatment initiation For binge drinkers

Primary Target Symptoms

Alcohol dependence

Pearls

Because acamprosate serves as “ artificial alcohol,†it may be less effective in situations in which the individual has not yet abstained from alcohol or suffers a relapse

Thus acamprosate may be a preferred treatment if the goal is complete abstinence, but may not be preferred if the goal is reduced- risk drinking

Suggested Reading

Anton RF , Oâ€TM Malley SS , Ciraulo DA , et al. Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial . JAMA 2006 ;295 (17 ): 2003 – 17.

Kranzler HR , Gage A . Acamprosate efficacy in alcohol-dependent patients: summary of results from three pivotal trials . Am J Addictions 2008 ; 17 :70 – 6.

Rosner S , Leucht P , Soyka M . Acamprosate supports abstinence, naltrexone prevents excessive drinking: evidence from a met-analysis with unreported outcomes . J Psychopharmacol 2008 ;22 :11 – 23 .

Agomelatine

Valdoxan

Therapeutics Brands

No

Generic?

Class

see index for additional brand names

Neuroscience-based Nomenclature: melatonin multimodal (Mel- MM)

Agonist at melatonergic 1 and melatonergic 2 receptors Antagonist at 5HT2C receptors

Commonly Prescribed for

(bold for FDA approved)

Depression

Generalized anxiety disorder

How the Drug Works

Actions at both melatonergic and 5HT2C receptors may be synergistic and increase norepinephrine and dopamine neurotransmission in the prefrontal cortex; may resynchronize circadian rhythms that are disturbed in depression

No influence on extracellular levels of serotonin

How Long Until It Works

Daytime functioning, anhedonia, and sleep can improve from the first week of treatment

Onset of full therapeutic actions in depression is usually not immediate, but often delayed 2– 4 weeks

May continue to work for many years to prevent relapse of symptoms

If It Works

The goal of treatment is complete remission of current symptoms as well as prevention of future relapses

Treatment most often reduces or even eliminates symptoms, but not a cure since symptoms can recur after medicine is stopped

Continue treatment until all symptoms are gone (remission)

Once symptoms are gone, continue treating for 1 year for the first episode of depression

For second and subsequent episodes of depression, treatment may need to be indefinite

If It Doesnâ€TM t Work

Many patients have only a partial response where some symptoms are improved but others persist (especially insomnia, fatigue, and problems concentrating)

Other patients may be nonresponders, sometimes called treatment- resistant or treatment-refractory

Consider increasing dose as early as 2 weeks after initiating treatment if response is insufficient (decision on dose increase has to be balanced with a higher risk of transaminase elevation; any dose increase should be made on an individual patient benefit/risk basis and with strict respect of liver function tests monitoring)

Consider switching to another agent or adding an appropriate augmenting agent

Consider psychotherapy

Consider evaluation for another diagnosis or for a comorbid condition (e.g., medical illness, substance abuse, etc.)

Some patients may experience apparent lack of consistent efficacy due to activation of latent or underlying bipolar disorder, and require antidepressant discontinuation and a switch to a mood stabilizer

Best Augmenting Combos for Partial Response or Treatment Resistance

SSRIs (excluding fluvoxamine), SNRIs, bupropion, reboxetine, atomoxetine (use combinations of antidepressant with caution as

this may activate bipolar disorder and suicidal ideation)

Modafinil, especially for fatigue, sleepiness, and lack of concentration

Mood stabilizers or atypical antipsychotics for bipolar depression, psychotic depression, or treatment-resistant depression

Benzodiazepines

Tests

Liver function tests before initiation of treatment and then at 3 weeks, 6 weeks, 12 weeks, 24 weeks, and thereafter when clinically indicated

When increasing the dose, liver function tests should be performed at the same frequency as when initiating treatment

Liver function tests should be repeated within 48 hours in any patient who develops raised transaminases

Side Effects

How Drug Causes Side Effects

Adverse reactions usually mild to moderate and occur within the first 2 weeks of treatment

Actions at melatonergic receptors and at 5HT2C receptors could contibute to the side effects described below

Notable Side Effects

Nausea and dizziness are most common

Other adverse reactions are somnolence, fatigue, insomnia, headache, anxiety, diarrhea, constipation, upper abdominal pain, vomiting, hyperhidrosis

Increase of transaminase levels

Life-Threatening or Dangerous Side Effects âœ1⁄2 Rare hepatitis, hepatic failure

Theoretically rare induction of mania (class warning)

Rare activation of suicidal ideation and behavior (suicidality) (short- term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo beyond age 24) (class warning)

Weight Gain

Occurs in significant minority

In clinical studies, weight changes were similar to those in placebo Cases of weight decrease have been reported

Sedation (Somnolence)

Occurs in significant minority

Generally transient

May be more likely to cause fatigue than sedation

What to Do About Side Effects

Wait

Wait

Stop if transaminase levels reach 3 times the upper limit of normal Switch to another drug

Best Augmenting Agents for Side Effects

Often best to try another antidepressant monotherapy prior to resorting to augmentation strategies to treat side effects

Many side effects are time-dependent (i.e., they start immediately upon dosing and upon each dose increase, but go away with time)

Many side effects cannot be improved with an augmenting agent

Therotically activation and agitation may represent the induction of a bipolar state, especially a mixed dysphoric bipolar II condition sometimes associated with suicidal ideation, and require the addition of lithium, a mood stabilizer or an atypical antipsychotic, and/or discontinuation of agomelatine (class warning)

Dosing and Use

Usual Dosage Range

25– 50 mg/day at bedtime

Tablet 25 mg

Dosage Forms

How to Dose

Initial 25 mg/day at bedtime; after 2 weeks can increase to 50 mg/day at bedtime

Dosing Tips

If intolerable anxiety, insomnia, agitation, akathisia, or activation occur upon either dosing initiation or discontinuation, consider the possibility of activated bipolar disorder and switch to a mood stabilizer or an atypical antipsychotic

Overdose

Drowsiness and epigastralgia; fatigue, agitation, anxiety, tension, dizziness, cyanosis, or malaise have also been reported

Long-Term Use

Treatment up to 12 months has been found to decrease rate of relapse

No

Habit Forming

No need to taper dose

How to Stop

Pharmacokinetics

Half-life 1– 2 hours

Metabolized primarily by CYP450 1A2

Drug Interactions

Use of agomelatine with potent CYP450 1A2 inhibitors (e.g., fluvoxamine) is contraindicated

Tramadol increases the risk of seizures in patients taking an antidepressant (class warning)

Other Warnings/Precautions

Use with caution in patients with hepatic injury risk factors, such as obesity/overweight/non-alcoholic fatty liver disease, diabetes, patients who drink large quantities of alcohol and/or have alcohol use disorder, or who take medication associated with risk of hepatic injury. Doctors should ask their patients if they have ever had liver problems

If symptoms or signs of potential liver injury (dark urine, light- colored stools, yellow skin/eyes, pain in upper right belly, sustained new-onset and unexplained fatigue) are present, agomelatine should be discontinued immediately

Use caution in patients with pretreatment elevated transaminases (> the upper limit of the normal range and ❤ times the upper limit of the normal range)

Discontinue treatment if serum transaminases increase to 3 times the upper limit of normal; liver function tests should be performed regularly until serum transaminases return to normal

Agomelatine should be administered at bedtime

Use with caution in patients with bipolar disorder unless treated with concomitant mood-stabilizing agent

When treating children off label (an unapproved use), carefully weigh the risks and benefits of pharmacological treatment against the risks and benefits of nontreatment with antidepressants and make sure to document this in the patientâ€TM s chart

Whenever possible, warn patients and their caregivers about the possibility of activating side effects, and advise them to report such symptoms immediately

Monitor patients for activation of suicidal ideation, especially children and adolescents

Do Not Use

If patient has hepatic impairment

If patient has transaminase levels >3 times the upper limit of normal

If patient is taking a potent CYP450 1A2 inhibitor (e.g., fluvoxamine, ciprofloxacin)

If patient is taking an MAO inhibitor (MAOI)

If patient has galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption

If there is a proven allergy to agomelatine

Special Populations Renal Impairment

Drug should be used with caution

Contraindicated

Hepatic Impairment

Cardiac Impairment

Dose adjustment not necessary

Elderly

Efficacy and safety have been established (< 75 years old) Dose adjustment not necessary

Should not be used in patients age 75 years and older Should not be used in elderly patients with dementia

Children and Adolescents

Carefully weigh the risks and benefits of pharmacological treatment against the risks and benefits of nontreatment with antidepressants and make sure to document this in the patientâ€TM s chart

Monitor patients face-to-face regularly, particularly during the first several weeks of treatment

Safety and efficacy have not been established and it is not recommended

Pregnancy

Controlled studies have not been conducted in pregnant women

Not generally recommended for use during pregnancy, especially during first trimester

Must weigh the risk of treatment (first trimester fetal development, third trimester newborn delivery) to the child against the risk of no treatment (recurrence of depression, maternal health, infant bonding) to the mother and child

For many patients this may mean continuing treatment during pregnancy

Breast Feeding

Unknown if agomelatine is secreted in human breast milk, but all psychotropics are assumed to be secreted in breast milk

Therefore, breast feeding or drug needs to be discontinued

Immediate postpartum period is a high-risk time for depression, especially in women who have had prior depressive episodes, so drug may need to be reinstituted late in the third trimester or shortly after childbirth to prevent a recurrence during the postpartum period

The Art of Psychopharmacology Potential Advantages

Patients with lack of energy, anhedonia, anxious comorbidity, and sleep-wake disturbances

Patients particularly concerned about sexual side effects or weight gain

Potential Disadvantages

Patients with hepatic impairment

Primary Target Symptoms

Depressed mood, anhedonia Functioning

Anxiety within depression

Pearls

Agomelatine represents a novel approach to depression through a novel pharmacologic profile, agonist at melatonergic MT1 / MT2

receptors and antagonist at 5HT2C receptors acting synergistically

This synergy provides agomelatine with a distinctive efficacy profile, different from conventional antidepressants with potentially an early and continuous improvement over time

Agomelatine improves anhedonia early in treatment Improves anxiety in major depressive disorder

May be fewer withdrawals/discontinuations for adverse events than with other antidepressants

No significant effect on cardiac parameters such as blood pressure and heart rate

Some data suggest that agomelatine may be specially efficacious in achieving functional remission

Agomelatine may improve sleep quality by promoting proper maintenance of circadian rhythms underlying a normal sleep-wake cycle

Suggested Reading

DeBodinat C , Guardiola-Lemaitre B , Mocaer E , et al. Agomelatine, the first melatonergic antidepressant: discovery, characterization, and development . Nat Rev Drug Discov 2010 ;9 :628– 42 .

Goodwin GM , Emsley R , Rembry S , Rouillon F. Agomelatine prevents relapse in patients with major depressive disorder without evidence of a

discontinuation syndrome: a 24-week randomized, double-blind, placebo- controlled trial . J Clin Psychiatry 2009 ;70 :1128 – 37.

Kennedy SH , Avedisova A , Belaà ̄di C , Picarel-Blanchot F , de Bodinat C. Sustained efficacy of agomelatine 10 mg, 25 mg, and 25– 50 mg on depressive symptoms and functional outcomes in patients with major depressive disorder . A placebo-controlled study over 6 months. Neuropsychopharmacol 2016 ;26 (2 ):378– 89 .

Khoo AL , Zhou HJ , Teng M , et al. Network meta-analysis and cost- effectiveness analysis of new generation antidepressants . CNS Drugs 2015 ;29 (8 ):695 – 712 .

Martinotti G , Sepede G , Gambi F , et al. Agomelatine versus venlafaxine XR in the treatment of anhedonia in major depressive disorder: a pilot study . J Clin Psychopharmacol 2012 ;32 (4 ):487– 91 .

Racagni G , Riva MA , Molteni R , et al. Mode of action of agomelatine: synergy between melatonergic and 5-HT2C receptors . World J Biol Psychiatry 2011 ;12 (8 ):574– 87 .

Stahl SM . Mechanism of action of agomelatine: a novel antidepressant exploiting synergy between monoaminergic and melatonergic properties . CNS Spectr 2014 ;19 :207– 12

Stahl SM , Fava M , Trivedi M , et al. Agomelatine in the treatment of major depressive disorder. An 8 week, multicenter, randomized, placebo- controlled trial . J Clin Psychiatry 2010 ;71 (5 ):616– 26 .

Stein DJ , Picarel-Blanchot F , Kennedy SH . Efficacy of the novel antidepressant agomelatine on anxiety symptoms in major depression . Hum Psychopharmacol 2013 ;28 (2 ):151– 9 .

Taylor D , Sparshatt A , Varma S , Olofinjana O . Antidepressant efficacy of agomelatine: meta-analysis of published and unpublished studies . BMJ 2014 ;348 :g2496.

Alprazolam

XanaxXanax XR

Therapeutics Brands

Yes

Generic?

Class

see index for additional brand names

Neuroscience-based Nomenclature: GABA positive allosteric modulator (GABA-PAM)

Benzodiazepine (anxiolytic)

Commonly Prescribed for

(bold for FDA approved)

Generalized anxiety disorder (IR) Panic disorder (IR and XR)

Other anxiety disorders

Anxiety associated with depression Premenstrual dysphoric disorder

Irritable bowel syndrome and other somatic symptoms associated with anxiety disorders

Insomnia

Acute mania (adjunctive) Acute psychosis (adjunctive) Catatonia

How the Drug Works

Binds to benzodiazepine receptors at the GABA-A ligand-gated chloride channel complex

Enhances the inhibitory effects of GABA

Boosts chloride conductance through GABA-regulated channels

Inhibits neuronal activity presumably in amygdala-centered fear circuits to provide therapeutic benefits in anxiety disorders

How Long Until It Works

Some immediate relief with first dosing is common; can take several weeks with daily dosing for maximal therapeutic benefit

If It Works

For short-term symptoms of anxiety – after a few weeks, discontinue use or use on an “ as-needed†basis

For chronic anxiety disorders, the goal of treatment is complete remission of symptoms as well as prevention of future relapses

For chronic anxiety disorders, treatment most often reduces or even eliminates symptoms, but not a cure since symptoms can recur after medicine stopped

For long-term symptoms of anxiety, consider switching to an SSRI or SNRI for long-term maintenance

If long-term maintenance with a benzodiazepine is necessary, continue treatment for 6 months after symptoms resolve, and then taper dose slowly

If symptoms reemerge, consider treatment with an SSRI or SNRI, or consider restarting the benzodiazepine; sometimes benzodiazepines have to be used in combination with SSRIs or SNRIs for best results

If It Doesnâ€TM t Work

Consider switching to another agent or adding an appropriate augmenting agent

Consider psychotherapy, especially cognitive behavioral psychotherapy

Consider presence of concomitant substance abuse

Consider presence of alprazolam abuse

Consider another diagnosis, such as a comorbid medical condition

Best Augmenting Combos for Partial Response or Treatment Resistance

Benzodiazepines are frequently used as augmenting agents for antipsychotics and mood stabilizers in the treatment of psychotic and bipolar disorders

Benzodiazepines are frequently used as augmenting agents for SSRIs and SNRIs in the treatment of anxiety disorders

Not generally rational to combine with other benzodiazepines

Caution if using as an anxiolytic concomitantly with other sedative hypnotics for sleep

Could consider augmenting alprazolam with either gabapentin or pregabalin for treatment of anxiety disorders

Tests

In patients with seizure disorders, concomitant medical illness, and/or those with multiple concomitant long-term medications, periodic liver tests and blood counts may be prudent

Side Effects

How Drug Causes Side Effects

Same mechanism for side effects as for therapeutic effects – namely due to excessive actions at benzodiazepine receptors

Long-term adaptations in benzodiazepine receptors may explain the development of dependence, tolerance, and withdrawal

Side effects are generally immediate, but immediate side effects often disappear in time

Notable Side Effects âœ1⁄2 Sedation, fatigue, depression

âœ1⁄2 Dizziness, ataxia, slurred speech, weakness âœ1⁄2 Forgetfulness, confusion

âœ1⁄2 Hyperexcitability, nervousness

Rare hallucinations, mania Rare hypotension Hypersalivation, dry mouth

Life-Threatening or Dangerous Side Effects

Respiratory depression, especially when taken with CNS depressants in overdose

Rare hepatic dysfunction, renal dysfunction, blood dyscrasias

Weight Gain

Reported but not expected

Sedation

Occurs in significant minority

Especially at initiation of treatment or when dose increases Tolerance often develops over time

What to Do About Side Effects

Wait

Wait

Wait

Lower the dose

Switch to alprazolam XR

Take largest dose at bedtime to avoid sedative effects during the day Switch to another agent

Administer flumazenil if side effects are severe or life-threatening

Best Augmenting Agents for Side Effects

Many side effects cannot be improved with an augmenting agent

Dosing and Use

Usual Dosage Range

Anxiety: alprazolam IR: 1– 4 mg/day

Panic: alprazolam IR: 5– 6 mg/day Panic: alprazolam XR: 3– 6 mg/day

Dosage Forms

Alprazolam IR tablet 0.25 mg scored, 0.4 mg (Japan), 0.5 mg scored, 0.8 mg (Japan), 1 mg scored, 2 mg multiscored

Alprazolam IR solution, concentrate 1 mg/mL

Alprazolam XR (extended-release) tablet 0.5 mg, 1 mg, 2 mg, 3 mg

How to Dose

For anxiety, alprazolam IR should be started at 0.75– 1.5 mg/day divided into 3 doses; increase dose every 3– 4 days until desired efficacy is reached; maximum dose generally 4 mg/day

For panic, alprazolam IR should be started at 1.5 mg/day divided into 3 doses; increase 1 mg or less every 3– 4 days until desired efficacy is reached, increasing by smaller amounts for dosage over 4 mg/day; may require as much as 10 mg/day for desired efficacy in difficult cases

For panic, alprazolam XR should be started at 0.5– 1 mg/day once daily in the morning; dose may be increased by 1 mg/day every 3– 4 days until desired efficacy is reached; maximum dose generally 10 mg/day

Dosing Tips

Use lowest possible effective dose for the shortest possible period of time (a benzodiazepine-sparing strategy)

Assess need for continued treatment regularly

Risk of dependence may increase with dose and duration of treatment

For interdose symptoms of anxiety, can either increase dose or maintain same total daily dose but divide into more frequent doses, or give as extended-release formulation

Can also use an as-needed occasional “ top-up†dose for interdose anxiety

Because panic disorder can require doses higher than 4 mg/day, the risk of dependence may be greater in these patients

Some severely ill patients may require 8 mg/day or more

Extended-release formulation only needs to be taken once or twice daily

Do not break or chew XR tablets as this will alter controlled-release properties

Frequency of dosing in practice is often greater than predicted from half-life, as duration of biological activity is often shorter than pharmacokinetic terminal half-life

Alprazolam and alprazolam XR generally dosed about one-tenth the dosage of diazepam

âœ1⁄2 Alprazolam and alprazolam XR generally dosed about twice the dosage of clonazepam

Overdose

Fatalities have been reported both in monotherapy and in conjunction with alcohol; sedation, confusion, poor coordination, diminished reflexes, coma

Long-Term Use

Risk of dependence, particularly for treatment periods longer than 12 weeks and especially in patients with past or current polysubstance abuse

Habit Forming

Alprazolam is a Schedule IV drug

Patients may develop dependence and/or tolerance with long-term use

How to Stop

Seizures may rarely occur on withdrawal, especially if withdrawal is abrupt; greater risk for doses above 4 mg and in those with additional risks for seizures, including those with a history of seizures

Taper by 0.5 mg every 3 days to reduce chances of withdrawal effects

For difficult-to-taper cases, consider reducing dose much more slowly after reaching 3 mg/day, perhaps by as little as 0.25 mg per week or less (not for XR)

For other patients with severe problems discontinuing a benzodiazepine, dosing may need to be tapered over many months (i.e., reduce dose by 1% every 3 days by crushing tablet and suspending or dissolving in 100 mL of fruit juice and then disposing of 1 mL and drinking the rest; 3– 7 days later, dispose of 2 mL, and so on). This is both a form of very slow biological tapering and a form of behavioral desensitization. Not for XR

Be sure to differentiate reemergence of symptoms requiring reinstitution of treatment from withdrawal symptoms

Benzodiazepine-dependent anxiety patients and insulin-dependent diabetics are not addicted to their medications. When benzodiazepine-dependent patients stop their medication, disease symptoms can reemerge, disease symptoms can worsen (rebound), and/or withdrawal symptoms can emerge

Pharmacokinetics

Metabolized by CYP450 3A4 Inactive metabolites

Elimination half-life 12– 15 hours

Food does not affect absorption

Drug Interactions

Increased depressive effects when taken with other CNS depressants (see Warnings below)

Inhibitors of CYP450 3A, such as nefazodone, fluvoxamine, fluoxetine, and even grapefruit juice, may decrease clearance of alprazolam and thereby raise alprazolam plasma levels and enhance sedative side effects; alprazolam dose may need to be lowered

Thus, azole antifungal agents (such as ketoconazole and itraconazole), macrolide antibiotics, and protease inhibitors may also raise alprazolam plasma levels

Inducers of CYP450 3A, such as carbamazepine, may increase clearance of alprazolam and lower alprazolam plasma levels and possibly reduce therapeutic effects

Other Warnings/Precautions

Boxed warning regarding the increased risk of CNS depressant effects when benzodiazepines and opioid medications are used together, including specifically the risk of slowed or difficulty breathing and death

If alternatives to the combined use of benzodiazepines and opioids are not available, clinicians should limit the dosage and duration of each drug to the minimum possible while still achieving therapeutic efficacy

Patients and their caregivers should be warned to seek medical attention if unusual dizziness, lightheadedness, sedation, slowed or difficulty breathing, or unresponsiveness occur

Dosage changes should be made in collaboration with prescriber

Use with caution in patients with pulmonary disease; rare reports of death after initiation of benzodiazepines in patients with severe pulmonary impairment

History of drug or alcohol abuse often creates greater risk for dependency

Hypomania and mania have occurred in depressed patients taking alprazolam

Use only with extreme caution if patient has obstructive sleep apnea

Some depressed patients may experience a worsening of suicidal ideation

Some patients may exhibit abnormal thinking or behavioral changes similar to those caused by other CNS depressants (i.e., either depressant actions or disinhibiting actions)

Do Not Use

If patient has angle-closure glaucoma

If patient is taking ketoconazole or itraconazole (azole antifungal agents)

If there is a proven allergy to alprazolam or any benzodiazepine

Special Populations Renal Impairment

Drug should be used with caution

Hepatic Impairment

Should begin with lower starting dose (0.5– 0.75 mg/day in 2 or 3 divided doses)

Cardiac Impairment

Benzodiazepines have been used to treat anxiety associated with acute myocardial infarction

Elderly

Should begin with lower starting dose (0.5– 0.75 mg/day in 2 or 3 divided doses) and be monitored closely

Children and Adolescents

Safety and efficacy not established but often used, especially short- term and at the lower end of the dosing scale

Long-term effects of alprazolam in children/adolescents are unknown

Should generally receive lower doses and be more closely monitored

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Possible increased risk of birth defects when benzodiazepines are taken during pregnancy

Because of the potential risks, alprazolam is not generally recommended as treatment for anxiety during pregnancy, especially during first trimester

Drug should be tapered if discontinued

Infants whose mothers received a benzodiazepine late in pregnancy may experience withdrawal effects

Neonatal flaccidity has been reported in infants whose mothers took a benzodiazepine during pregnancy

Seizures, even mild seizures, may cause harm to the embryo/fetus

Breast Feeding

Some drug is found in motherâ€TM s breast milk

âœ1⁄2 Recommended either to discontinue drug or bottle feed

Effects on infant have been observed and include feeding difficulties, sedation, and weight loss

The Art of Psychopharmacology Potential Advantages

Rapid onset of action

Less sedation than some other benzodiazepines

Availability of an XR formulation with longer duration of action

Potential Disadvantages

Euphoria may lead to abuse

Abuse especially risky in past or present substance abusers

Primary Target Symptoms

Panic attacks Anxiety

Pearls

âœ1⁄2 One of the most popular benzodiazepines for anxiety, especially

among primary care physicians and psychiatrists

Is a very useful adjunct to SSRIs and SNRIs in the treatment of numerous anxiety disorders

Not effective for treating psychosis as a monotherapy, but can be used as an adjunct to antipsychotics

Not effective for treating bipolar disorder as a monotherapy, but can be used as an adjunct to mood stabilizers and antipsychotics

May both cause depression and treat depression in different patients

Risk of seizure is greatest during the first 3 days after discontinuation of alprazolam, especially in those with prior seizures, head injuries, or withdrawal from drugs of abuse

Clinical duration of action may be shorter than plasma half-life, leading to dosing more frequently than 2– 3 times daily in some patients, especially for immediate-release alprazolam

Adding fluvoxamine, fluoxetine, or nefazodone can increase alprazolam levels and make the patient very sleepy unless the alprazolam dose is lowered by half or more

When using to treat insomnia, remember that insomnia may be a symptom of some other primary disorder itself, and thus warrant evaluation for comorbid psychiatric and/or medical conditions

âœ1⁄2 Alprazolam XR may be less sedating than immediate-release alprazolam

âœ1⁄2 Alprazolam XR may be dosed less frequently than immediate- release alprazolam, and lead to less interdose breakthrough symptoms and less “ clock-watching†in anxious patients

Slower rises in plasma drug levels for alprazolam XR have the potential to reduce euphoria/abuse liability, but this has not been proven

Slower falls in plasma drug levels for alprazolam XR have the potential to facilitate drug discontinuation by reducing withdrawal symptoms, but this has not been proven

âœ1⁄2 Alprozolam XR generally has longer biological duration of action than clonazepam

âœ1⁄2 If clonazepam can be considered a “ long-acting alprazolam- like anxiolytic,†then alprazolam XR can be considered “ an even longer-acting clonazepam-like anxiolytic†with the potential of improved tolerability features in terms of less euphoria, abuse, dependence, and withdrawal problems, but this has not been proven

Though not systematically studied, benzodiazepines have been used effectively to treat catatonia and are the initial recommended treatment

Suggested Reading

DeVane CL , Ware MR , Lydiard RB . Pharmacokinetics, pharmacodynamics, and treatment issues of benzodiazepines: alprazolam, adinazolam, and clonazepam . Psychopharmacol Bull 1991 ;27 :463– 73 .

Greenblatt DJ , Wright CE . Clinical pharmacokinetics of alprazolam. Therapeutic implications . Clin Pharmacokinet 1993 ; 24 :453– 71 .

Jonas JM , Cohon MS . A comparison of the safety and efficacy of alprazolam versus other agents in the treatment of anxiety, panic, and

depression: a review of the literature . J Clin Psychiatry 1993 ;54 (Suppl):S25 – 45.

Klein E . The role of extended-release benzodiazepines in the treatment of anxiety: a risk-benefit evaluation with a focus on extended-release alprazolam . J Clin Psychiatry 2002 ;63 (Suppl 14):S27 – 33 .

Speigel DA . Efficacy studies of alprazolam in panic disorder . Psychopharmacol Bull 1998 ; 34 :191– 5 .

van Marwijk H , Allick G , Wegman F , Bax A , Riphagen II . Alprazolam for depression . Cochrane Database Syst Rev 2012 ; (7) :CD007139.

Amisulpride

Solian

Barhemsys

see index for additional brand names

Therapeutics Brands

Yes

Generic?

Class

Neuroscience-based Nomenclature: dopamine receptor antagonist (D-RAn)

Atypical antipsychotic (benzamide; possibly a dopamine stabilizer and dopamine partial agonist)

Commonly Prescribed for

(bold for FDA approved)

Prevention of postoperative nausea and vomiting (PONV) (monotherapy or with antiemetic of a different class) (Barhemsys injection)

Treatment of PONV in patients who have received antiemetic prophylaxis with an agent of a different class or have not received prophylaxis (Barhemsys injection)

Schizophrenia, acute and chronic (outside of USA, especially Europe)

Dysthymia

How the Drug Works

Theoretically blocks presynaptic dopamine 2 receptors at low doses

Theoretically blocks postsynaptic dopamine 2 receptors at higher doses

âœ1⁄2 May be a partial agonist at dopamine 2 receptors, which would theoretically reduce dopamine output when dopamine concentrations are high and increase dopamine output when dopamine concentrations are low

Blocks dopamine 3 receptors, which may contribute to its clinical actions

âœ1⁄2 Unlike other atypical antipsychotics, amisulpride does not have potent actions at serotonin 2A or serotonin 1A receptors

âœ1⁄2 Does have antagonist actions at serotonin 7 receptors and serotonin 2B receptors, which may contribute to antidepressant effects

How Long Until It Works

Psychotic symptoms can improve within 1 week, but it may take several weeks for full effect on behavior as well as on cognition and affective stabilization

Classically recommended to wait at least 4– 6 weeks to determine efficacy of drug, but in practice some patients require up to 16– 20 weeks to show a good response, especially on negative or cognitive symptoms

If It Works

Most often reduces positive symptoms in schizophrenia but does not eliminate them

Can improve negative symptoms, as well as aggressive, cognitive, and affective symptoms in schizophrenia

Most schizophrenic patients do not have a total remission of symptoms but rather a reduction of symptoms by about a third

Perhaps 5– 15% of schizophrenic patients can experience an overall improvement of greater than 50– 60%, especially when receiving stable treatment for more than a year

Such patients are considered super-responders or “ awakeners†since they may be well enough to be employed, live independently, and sustain long-term relationships

Continue treatment until reaching a plateau of improvement

After reaching a satisfactory plateau, continue treatment for at least a year after first episode of psychosis

For second and subsequent episodes of psychosis, treatment may need to be indefinite

Even for first episodes of psychosis, it may be preferable to continue treatment indefinitely to avoid subsequent episodes

If It Doesnâ€TM t Work

Try one of the other first-line atypical antipsychotics

If two or more antipsychotic monotherapies do not work, consider clozapine

Some patients may require treatment with a conventional antipsychotic

If no atypical antipsychotic is effective, consider higher doses or augmentation with valproate or lamotrigine

Consider noncompliance and switch to another antipsychotic with fewer side effects or to an antipsychotic that can be given by depot injection

Consider initiating rehabilitation and psychotherapy such as cognitive remediation

Consider presence of concomitant drug abuse

Best Augmenting Combos for Partial Response or Treatment Resistance

Valproic acid (valproate, divalproex, divalproex ER)

Augmentation of amisulpride has not been systematically studied

Other mood-stabilizing anticonvulsants (carbamazepine, oxcarbazepine, lamotrigine)

Lithium Benzodiazepines

Tests

âœ1⁄2 Although risk of diabetes and dyslipidemia with amisulpride has not been systematically studied, monitoring as for all other atypical antipsychotics is suggested

Before starting an atypical antipsychotic âœ1⁄2 Weigh all patients and track BMI during treatment

Get baseline personal and family history of diabetes, obesity, dyslipidemia, hypertension, and cardiovascular disease

Get waistline circumference (at umbilicus), blood pressure, fasting plasma glucose, and fasting lipid profile

Determine if the patient

is overweight (BMI 25.0– 29.9)

is obese (BMI ≥ 30)

has pre-diabetes (fasting plasma glucose 100– 125 mg/dL) has diabetes (fasting plasma glucose ≥ 126 mg/dL)

has hypertension (BP >140/90 mmHg)

has dyslipidemia (increased total cholesterol, LDL cholesterol, and triglycerides; decreased HDL cholesterol)

Treat or refer such patients for treatment, including nutrition and weight management, physical activity counseling, smoking cessation, and medical management

Monitoring after starting an atypical antipsychotic âœ1⁄2 BMI monthly for 3 months, then quarterly

Consider monitoring fasting triglycerides monthly for several months in patients at high risk for metabolic complications and when initiating or switching antipsychotics

Blood pressure, fasting plasma glucose, fasting lipids within 3 months and then annually, but earlier and more frequently for patients with diabetes or who have gained >5% initial weight

Treat or refer for treatment and consider switching to another atypical antipsychotic for patients who become overweight, obese, pre-diabetic, diabetic, hypertensive, or dyslipidemic while receiving an atypical antipsychotic

âœ1⁄2 Even in patients without known diabetes, be vigilant for the rare but life-threatening onset of diabetic ketoacidosis, which always requires immediate treatment by monitoring for the rapid onset of polyuria, polydipsia, weight loss, nausea, vomiting, dehydration, rapid respiration, weakness and clouding of sensorium, even coma

ECGs may be useful for selected patients (e.g., those with personal or family history of QTc prolongation; cardiac arrhythmia; recent myocardial infarction; uncompensated heart failure; or taking agents that prolong QTc interval such as pimozide, thioridazine, selected antiarrhythmics, moxifloxacin, sparfloxacin, etc.)

Patients at risk for electrolyte disturbances (e.g., patients on diuretic therapy) should have baseline and periodic serum potassium and magnesium measurements

Patients with low white blood cell count (WBC) or history of drug- induced leukopenia/neutropenia should have complete blood count (CBC) monitored frequently during the first few months and amisulpride should be discontinued at the first sign of decline of WBC in the absence of other causative factors

Patients should be monitored periodically for the development of abnormal movements of tardive dyskinesia, using neurological exam and the AIMS (Abnormal Involuntary Movement Scale)

Side Effects

How Drug Causes Side Effects

Acute blockade of dopamine 2 receptors in the striatum can cause drug-induced parkinsonism, dystonia, or akathisia

Chronic blockade of dopamine 2 receptors in the striatum can cause tardive dyskinesia

By blocking dopamine 2 receptors in the pituitary, it can cause elevations in prolactin

Mechanism of weight gain and increased incidence of diabetes and dyslipidemia with atypical antipsychotics is unknown, and risks vary based on the particular agent

Notable Side Effects âœ1⁄2 Drug-induced parkinsonism

âœ1⁄2 Galactorrhea, amenorrhea

âœ1⁄2 Atypical antipsychotics may increase the risk for diabetes and dyslipidemia, although the specific risks associated with amisulpride are unknown

Insomnia, sedation, agitation, anxiety

Constipation, weight gain

Tardive dyskinesia

Risk of potentially irreversible involuntary dyskinetic movements may increase with cumulative dose and treatment duration

Life-Threatening or Dangerous Side Effects

Rare neuroleptic malignant syndrome (NMS) may cause hyperpyrexia, muscle rigidity, delirium, and autonomic instability with elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure

Rare seizures

Dose-dependent QTc prolongation

As a class, antipsychotics are associated with an increased risk of death and cerebrovascular events in elderly patients with dementia; not approved for treatment of dementia-related psychosis

Occurs in significant minority

Weight Gain

Sedation

Many experience and/or can be significant in amount, especially at high doses

Wait

Wait

Wait

Lower the dose

What to Do About Side Effects

For drug-induced parkinsonism, add an anticholinergic agent

Beta blockers, benzodiazepines, or 5HT2A antagonists (e.g., mirtazapine, cyproheptadine) may reduce akathisia

Take more of the dose at bedtime to help reduce daytime sedation

Weight loss, exercise programs, and medical management for high BMIs, diabetes, dyslipidemia

Metformin may help prevent or reverse antipsychotic-induced weight gain

Switch to another atypical antipsychotic

Best Augmenting Agents for Side Effects

Benztropine, trihexyphenidyl, or amantadine for drug-induced parkinsonism

Beta blockers, benzodiazepines, or 5HT2A antagonists (e.g., mirtazapine, cyproheptadine) for akathisia

Valbenazine or deutetrabenazine for tardive dyskinesia

Many side effects cannot be improved with an augmenting agent

Dosing And Use Usual Dosage Range

Schizophrenia: 400– 800 mg/day in 2 doses Negative symptoms only: 50– 300 mg/day Dysthymia: 50 mg/day

Dosage Forms

Different formulations may be available in different markets

Tablet 50 mg, 100 mg, 200 mg, 400 mg Oral solution 100 mg/mL

How to Dose

Initial 400– 800 mg/day in 2 doses; daily doses above 400 mg should be divided in 2; maximum generally 1200 mg/day

See also the Switching section below, after Pearls

Dosing Tips

âœ1⁄2 Efficacy for negative symptoms in schizophrenia may be achieved at lower doses, while efficacy for positive symptoms may require higher doses

Patients receiving low doses may only need to take the drug once daily

âœ1⁄2 For dysthymia and depression, use only low doses âœ1⁄2 Dose-dependent QTc prolongation, so use with caution,

especially at higher doses (>800 mg/day)

âœ1⁄2 Amisulpride may accumulate in patients with renal insufficiency, requiring lower dosing or switching to another antipsychotic to avoid QTc prolongation in these patients

Rather than raise the dose above normal dosing in acutely agitated patients requiring acute antipsychotic actions, consider short-term (one dose or more) augmentation with a benzodiazepine or another antipsychotic, especially intramuscularly

Rather than raise the dose above normal dosing in partial responders, consider augmentation with a mood-stabilizing anticonvulsant, such as valproate, topiramate, or lamotrigine

Children and elderly should generally be dosed at the lower end of the dosage spectrum

Treatment should be suspended if absolute neutrophil count falls below 1000/mm3

Overdose

Sedation, coma, hypotension, drug-induced parkinsonism

Long-Term Use

Amisulpride is used for both acute and chronic schizophrenia treatment

Should periodically reevaluate long-term usefulness in individual patients, but treatment may need to continue for many years

No

Habit Forming

How to Stop

See Switching section of individual agents for how to stop amisulpride

Rapid discontinuation may lead to rebound psychosis and worsening of symptoms

Pharmacokinetics

Elimination half-life approximately 12 hours Excreted largely unchanged

Drug Interactions

Can decrease the effects of levodopa, dopamine agonists

Can increase the effects of antihypertensive drugs

CNS effects may be increased if used with a CNS depressant

May enhance QTc prolongation of other drugs capable of prolonging QTc interval

Since amisulpride is only weakly metabolized, few drug interactions that could raise amisulpride plasma levels are expected

Other Warnings/Precautions

Use cautiously in patients with alcohol withdrawal or convulsive disorders because of possible lowering of seizure threshold

If signs of neuroleptic malignant syndrome develop, treatment should be immediately discontinued

Because amisulpride may dose-dependently prolong QTc interval, use with caution in patients who have bradycardia or who are taking

drugs that can induce bradycardia (e.g., beta blockers, calcium channel blockers, clonidine, digitalis)

Because amisulpride may dose-dependently prolong QTc interval, use with caution in patients who have hypokalemia and/or hypomagnesemia or who are taking drugs that can induce hypokalemia and/or magnesemia (e.g., diuretics, stimulant laxatives, intravenous amphotericin B, glucocorticoids, tetracosactide)

Use only with caution if at all in Parkinsonâ€TM s disease or Lewy body dementia, especially at high doses

Atypical antipsychotics have the potential for cognitive and motor impairment, especially related to sedation

Atypical antipsychotics can cause body temperature dysregulation; use caution in patients who may experience conditions that increase body temperature (e.g., strenuous exercise, saunas, extreme heat, dehydration, or concomitant anticholinergic medication)

Antipsychotics may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls; for patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment, and recurrently for patients on long-term antipsychotic therapy

As with any antipsychotic, use with caution in patients with history of seizures

Do Not Use

If patient has pheochromocytoma

If patient has prolactin-dependent tumor If patient is pregnant or nursing

If patient is taking agents capable of significantly prolonging QTc interval (e.g., pimozide; thioridazine; selected antiarrhythmics such as quinidine, disopyramide, amiodarone, and sotalol; selected antibiotics such as moxifloxacin and sparfloxacin)

If there is a history of QTc prolongation or cardiac arrhythmia, recent acute myocardial infarction, uncompensated heart failure

If patient is taking cisapride, intravenous erythromycin, or pentamidine

In children

If there is a proven allergy to amisulpride

Special Populations Renal Impairment

Use with caution; drug may accumulate

Amisulpride is eliminated by the renal route; in cases of severe renal insufficiency, the dose should be decreased and intermittent treatment or switching to another antipsychotic should be considered

Hepatic Impairment

Use with caution, but dose adjustment not generally necessary

Cardiac Impairment

Amisulpride produces a dose-dependent prolongation of QTc interval, which may be enhanced by the existence of bradycardia, hypokalemia, congenital or acquired long QTc interval, which should be evaluated prior to administering amisulpride

Use with caution if treating concomitantly with a medication likely to produce prolonged bradycardia, hypokalemia, slowing of intracardiac conduction, or prolongation of the QTc interval

Avoid amisulpride in patients with a known history of QTc prolongation, recent acute myocardial infarction, and uncompensated heart failure

Elderly

Some patients may be more susceptible to sedative and hypotensive effects

Although atypical antipsychotics are commonly used for behavioral disturbances in dementia, no agent has been approved for treatment of elderly patients with behavioral symptoms of dementia such as agitation

Elderly patients with dementia-related psychosis treated with atypical antipsychotics are at an increased risk of death compared to

placebo, and also have an increased risk of cerebrovascular events

Children and Adolescents

Efficacy and safety not established under age 18

Pregnancy

Although animal studies have not shown teratogenic effect, amisulpride is not recommended for use during pregnancy

There is a risk of abnormal muscle movements and withdrawal symptoms in newborns whose mothers took an antipsychotic during the third trimester; symptoms may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty feeding

Psychotic symptoms may worsen during pregnancy and some form of treatment may be necessary

Breast Feeding

Unknown if amisulpride is secreted in human breast milk, but all psychotropics are assumed to be secreted in breast milk

âœ1⁄2 Recommended either to discontinue drug or bottle feed

The Art of Psychopharmacology Potential Advantages

Not as clearly associated with weight gain as some other atypical antipsychotics

For patients who are responsive to low-dose activation effects that reduce negative symptoms and depression

Potential Disadvantages

Patients who have difficulty being compliant with twice daily dosing

Patients for whom elevated prolactin may not be desired (e.g., possibly pregnant patients; pubescent girls with amenorrhea; postmenopausal women with low estrogen who do not take estrogen replacement therapy)

Patients with severe renal impairment

Primary Target Symptoms

Positive symptoms of psychosis Negative symptoms of psychosis Depressive symptoms

Pearls

âœ1⁄2 Efficacy has been particularly well demonstrated in patients with

predominantly negative symptoms

âœ1⁄2 The increase in prolactin caused by amisulpride may cause menstruation to stop

For treatment-resistant patients with inadequate responses to clozapine, amisulpride may be a preferred augmentation option

Risks of diabetes and dyslipidemia not well studied, but does not seem to cause as much weight gain as some other atypical antipsychotics

Has atypical antipsychotic properties (i.e., antipsychotic action without a high incidence of drug-induced parkinsonism), especially at low doses, but not a serotonin dopamine antagonist

Mediates its atypical antipsychotic properties via novel actions on dopamine receptors, perhaps dopamine stabilizing partial agonist actions on dopamine 2 receptors

May be more of a dopamine 2 antagonist than aripiprazole, but less of a dopamine 2 antagonist than other atypical or conventional antipsychotics

Low-dose activating actions may be beneficial for negative symptoms in schizophrenia

Very low doses may be useful in dysthymia

Compared to sulpiride, amisulpride has better oral bioavailability and more potency, thus allowing lower dosing, less weight gain, and a lower risk of drug-induced parkinsonism

Compared to other atypical antipsychotics with potent serotonin 2A antagonism, amisulpride may have more drug-induced parkinsonism and prolactin elevation, but may still be classified as an atypical antipsychotic, particularly at low doses

Patients have very similar antipsychotic responses to any conventional antipsychotic, which is different from atypical antipsychotics where antipsychotic responses of individual patients can occasionally vary greatly from one atypical antipsychotic to another

Patients with inadequate responses to atypical antipsychotics may benefit from determination of plasma drug levels and, if low, a dosage increase even beyond the usual prescribing limits

Patients with inadequate responses to atypical antipsychotics may also benefit from a trial of augmentation with a conventional antipsychotic or switching to a conventional antipsychotic

However, long-term polypharmacy with a combination of a conventional antipsychotic with an atypical antipsychotic may combine their side effects without clearly augmenting the efficacy of either

For treatment-resistant patients, especially those with impulsivity, aggression, violence, and self-harm, long-term polypharmacy with 2 atypical antipsychotics or with 1 atypical antipsychotic and 1 conventional antipsychotic may be useful or even necessary while closely monitoring

In such cases, it may be beneficial to combine 1 depot antipsychotic with 1 oral antipsychotic

Although a frequent practice by some prescribers, adding two conventional antipsychotics together has little rationale and may reduce tolerability without clearly enhancing efficacy

The Art of Switching

Switching from Oral Antipsychotics to Amisulpride

It is advisable to begin amisulpride at an intermediate dose and build the dose rapidly over 3– 7 days

Clinical experience has shown that asenapine, quetiapine, and olanzapine should be tapered off slowly over a period of 3– 4 weeks, to allow patients to readapt to the withdrawal of blocking cholinergic, histaminergic, and alpha 1 receptors

Clozapine should always be tapered off slowly, over a period of 4 weeks or more

* Benzodiazepine or anticholinergic medication can be administered during cross-titration to help alleviate side effects such as insomnia, agitation, and/or psychosis

Suggested Reading

Huhn M , Nikolakopoulou A , Schneider-Thoma J , et al. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis . Lancet 2019 ;394:939– 51 .

Komossa K , Rummel-Kluge C , Hunder H , et al. Amisulpride versus other atypical antipsychotics for schizophrenia . Cochrane Database Syst Rev 2010 ;(1):CD006624.

Leucht S , Pitschel-Walz G , Engel RR , Kissling W . Amisulpride, an unusual “ atypical†antipsychotic: a meta-analysis of randomized controlled trials . Am J Psychiatry 2002 ;159 (2 ):180– 90 .

Amitriptyline

Elavil

Therapeutics Brands

see index for additional brand names

Yes

Generic?

Class

Neuroscience-based Nomenclature: serotonin, norepinephrine multimodal (SN-MM)

Tricyclic antidepressant (TCA)

Serotonin and norepinephrine/noradrenaline reuptake inhibitor

Commonly Prescribed for

(bold for FDA approved)

Depression

Endogenous depression

âœ1⁄2 Neuropathic pain/chronic pain âœ1⁄2 Fibromyalgia

âœ1⁄2 Headache

âœ1⁄2 Low back pain/neck pain

Anxiety

Insomnia

Treatment-resistant depression

How the Drug Works

Boosts neurotransmitters serotonin and norepinephrine/noradrenaline

Blocks serotonin reuptake pump (serotonin transporter), presumably increasing serotonergic neurotransmission

Blocks norepinephrine reuptake pump (norepinephrine transporter), presumably increasing noradrenergic neurotransmission

Presumably desensitizes both serotonin 1A receptors and beta adrenergic receptors

Since dopamine is inactivated by norepinephrine reuptake in frontal cortex, which largely lacks dopamine transporters, amitriptyline can increase dopamine neurotransmission in this part of the brain

How Long Until It Works

May have immediate effects in treating insomnia or anxiety

Onset of therapeutic actions usually not immediate, but often delayed 2– 4 weeks

If it is not working within 6– 8 weeks for depression, it may require a dosage increase or it may not work at all

May continue to work for many years to prevent relapse of symptoms

If It Works

The goal of treatment of depression is complete remission of current symptoms as well as prevention of future relapses

The goal of treatment of chronic pain conditions such as neuropathic pain, fibromyalgia, headaches, low back pain, and neck pain is to reduce symptoms as much as possible, especially in combination with other treatments

Treatment of depression most often reduces or even eliminates symptoms, but not a cure since symptoms can recur after medicine stopped

Treatment of chronic pain conditions such as neuropathic pain, fibromyalgia, headache, low back pain, and neck pain may reduce symptoms, but rarely eliminates them completely, and is not a cure since symptoms can recur after medicine is stopped

Continue treatment of depression until all symptoms are gone (remission)

Once symptoms of depression are gone, continue treating for 1 year for the first episode of depression

For second and subsequent episodes of depression, treatment may need to be indefinite

Use in anxiety disorders and chronic pain conditions such as neuropathic pain, fibromyalgia, headache, low back pain, and neck pain may also need to be indefinite, but long-term treatment is not well studied in these conditions

If It Doesnâ€TM t Work

Many depressed patients have only a partial response where some symptoms are improved but others persist (especially insomnia, fatigue, and problems concentrating)

Other depressed patients may be nonresponders, sometimes called treatment-resistant or treatment-refractory

Consider increasing dose, switching to another agent, or adding an appropriate augmenting agent

Consider psychotherapy

Consider evaluation for another diagnosis or for a comorbid condition (e.g., medical illness, substance abuse, etc.)

Some patients may experience apparent lack of consistent efficacy due to activation of latent or underlying bipolar disorder, and require antidepressant discontinuation and a switch to a mood stabilizer

Best Augmenting Combos for Partial Response or Treatment Resistance

Lithium, buspirone, thyroid hormone (for depression)

Gabapentin, tiagabine, other anticonvulsants, even opiates if done by experts while monitoring carefully in difficult cases (for chronic pain)

Tests

Baseline ECG is recommended for patients over age 50

âœ1⁄2 Since tricyclic and tetracyclic antidepressants are frequently associated with weight gain, before starting treatment, weigh all patients and determine if the patient is already overweight (BMI 25.0– 29.9) or obese (BMI ≥ 30)

Before giving a drug that can cause weight gain to an overweight or obese patient, consider determining whether the patient already has pre-diabetes (fasting plasma glucose 100– 125 mg/dL), diabetes (fasting plasma glucose ≥ 126 mg/dL), or dyslipidemia (increased total cholesterol, LDL cholesterol, and triglycerides; decreased HDL cholesterol), and treat or refer such patients for treatment, including nutrition and weight management, physical activity counseling, smoking cessation, and medical management

âœ1⁄2 Monitor weight and BMI during treatment

âœ1⁄2 While giving a drug to a patient who has gained >5% of initial weight, consider evaluating for the presence of pre-diabetes, diabetes, or dyslipidemia, or consider switching to a different antidepressant

ECGs may be useful for selected patients (e.g., those with personal or family history of QTc prolongation; cardiac arrhythmia; recent myocardial infarction; uncompensated heart failure; or taking agents that prolong QTc interval such as pimozide, thioridazine, selected antiarrhythmics, moxifloxacin, sparfloxacin, etc.)

Patients at risk for electrolyte disturbances (e.g., patients on diuretic therapy) should have baseline and periodic serum potassium and magnesium measurements

Side Effects

How Drug Causes Side Effects

Anticholinergic activity may explain sedative effects, dry mouth, constipation, and blurred vision

Sedative effects and weight gain may be due to antihistamine properties

Blockade of alpha adrenergic 1 receptors may explain dizziness, sedation, and hypotension

Cardiac arrhythmias and seizures, especially in overdose, may be caused by blockade of ion channels

Notable Side Effects

Blurred vision, constipation, urinary retention, increased appetite, dry mouth, nausea, diarrhea, heartburn, unusual taste in mouth,

weight gain

Fatigue, weakness, dizziness, sedation, headache, anxiety, nervousness, restlessness

Sexual dysfunction (impotence, change in libido) Sweating, rash, itching

Life-Threatening or Dangerous Side Effects

Paralytic ileus, hyperthermia (TCAs + anticholinergic agents) Lowered seizure threshold and rare seizures

Orthostatic hypotension, sudden death, arrhythmias, tachycardia QTc prolongation

Hepatic failure, drug-induced parkinsonism Increased intraocular pressure

Rare induction of mania

Rare activation of suicidal ideation and behavior (suicidality) (short- term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo beyond age 24)

Weight Gain

Many experience and/or can be significant in amount Can increase appetite and carbohydrate craving

Sedation

Many experience and/or can be significant in amount Tolerance to sedative effects may develop with long-term use

What to Do About Side Effects

Wait

Wait

Wait

Lower the dose

Switch to an SSRI or newer antidepressant

Best Augmenting Agents for Side Effects

Many side effects cannot be improved with an augmenting agent

50– 150 mg/day

Dosing and Use Usual Dosage Range

Dosage Forms

Tablet 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg

How to Dose

Initial 25 mg/day at bedtime; increase by 25 mg every 3– 7 days

75 mg/day in divided doses; increase to 150 mg/day; maximum 300 mg/day

Dosing Tips

If given in a single dose, should generally be administered at bedtime because of its sedative properties

If given in split doses, largest dose should generally be given at bedtime because of its sedative properties

If patients experience nightmares, split dose and do not give large dose at bedtime

Patients treated for chronic pain may only require lower doses

If intolerable anxiety, insomnia, agitation, akathisia, or activation occur upon either dosing initiation or discontinuation, consider the possibility of activated bipolar disorder, and switch to a mood stabilizer or an atypical antipsychotic

Overdose

Death may occur; CNS depression, convulsions, cardiac dysrhythmias, severe hypotension, ECG changes, coma

Safe

Long-Term Use

No

Habit Forming

How to Stop

Taper to avoid withdrawal effects

Even with gradual dose reduction, some withdrawal symptoms may appear within the first 2 weeks

Many patients tolerate 50% dose reduction for 3 days, then another 50% reduction for 3 days, then discontinuation

If withdrawal symptoms emerge during discontinuation, raise dose to stop symptoms and then restart withdrawal much more slowly

Pharmacokinetics

Substrate for CYP450 2D6 and 1A2 Plasma half-life 10– 28 hours

Metabolized to an active metabolite, nortriptyline, which is predominantly a norepinephrine reuptake inhibitor, by demethylation via CYP450 1A2

Food does not affect absorption

Drug Interactions

Tramadol increases the risk of seizures in patients taking TCAs

Use of TCAs with anticholinergic drugs may result in paralytic ileus or hyperthermia

Fluoxetine, paroxetine, bupropion, duloxetine, and other CYP450 2D6 inhibitors may increase TCA concentrations

Fluvoxamine, a CYP450 1A2 inhibitor, can decrease the conversion of amitriptyline to nortriptyline and increase amitriptyline plasma concentrations

Cimetidine may increase plasma concentrations of TCAs and cause anticholinergic symptoms

Phenothiazines or haloperidol may raise TCA blood concentrations

May alter effects of antihypertensive drugs; may inhibit hypotensive effects of clonidine

Use of TCAs with sympathomimetic agents may increase sympathetic activity

Methylphenidate may inhibit metabolism of TCAs

Activation and agitation, especially following switching or adding antidepressants, may represent the induction of a bipolar state, especially a mixed dysphoric bipolar II condition sometimes associated with suicidal ideation, and require the addition of lithium, a mood stabilizer or an atypical antipsychotic, and/or discontinuation of amitriptyline

Other Warnings/Precautions

Add or initiate other antidepressants with caution for up to 2 weeks after discontinuing amitriptyline

Generally, do not use with MAOIs, including 14 days after MAOIs are stopped; do not start an MAOI for at least 5 half-lives (5 to 7 days for most drugs) after discontinuing amitriptyline, but see Pearls

Use with caution in patients with history of seizures, urinary retention, angle-closure glaucoma, hyperthyroidism

TCAs can increase QTc interval, especially at toxic doses, which can be attained not only by overdose but also by combining with drugs that inhibit TCA metabolism via CYP450 2D6, potentially causing torsade de pointes-type arrhythmia or sudden death

Because TCAs can prolong QTc interval, use with caution in patients who have bradycardia or who are taking drugs that can induce bradycardia (e.g., beta blockers, calcium channel blockers, clonidine, digitalis)

Because TCAs can prolong QTc interval, use with caution in patients who have hypokalemia and/or hypomagnesemia, or who are taking drugs that can induce hypokalemia and/or magnesemia (e.g., diuretics, stimulant laxatives, intravenous amphotericin B, glucocorticoids, tetracosactide)

When treating children, carefully weigh the risks and benefits of pharmacological treatment against the risks and benefits of nontreatment with antidepressants and make sure to document this in the patientâ€TM s chart

Distribute the brochures provided by the FDA and the drug companies

Whenever possible, warn patients and their caregivers about the possibility of activating side effects, and advise them to report such symptoms immediately

Monitor patients for activation of suicidal ideation, especially children and adolescents

Do Not Use

If patient is recovering from myocardial infarction

If patient is taking agents capable of significantly prolonging QTc interval (e.g., pimozide, thioridazine, selected antiarrhythmics, moxifloxacin, sparfloxacin)

If there is a history of QTc prolongation or cardiac arrhythmia, recent acute myocardial infarction, uncompensated heart failure

If patient is taking drugs that inhibit TCA metabolism, including CYP450 2D6 inhibitors, except by an expert

If there is reduced CYP450 2D6 function, such as patients who are poor 2D6 metabolizers, except by an expert and at low doses

If there is a proven allergy to amitriptyline or nortriptyline

Special Populations Renal Impairment

Use with caution; may need to lower dose

Hepatic Impairment

Use with caution; may need to lower dose

Cardiac Impairment

Baseline ECG is recommended

TCAs have been reported to cause arrhythmias, prolongation of conduction time, orthostatic hypotension, sinus tachycardia, and heart failure, especially in the diseased heart

Myocardial infarction and stroke have been reported with TCAs

TCAs produce QTc prolongation, which may be enhanced by the existence of bradycardia, hypokalemia, congenital or acquired long QTc interval, which should be evaluated prior to administering amitriptyline

Use with caution if treating concomitantly with a medication likely to produce prolonged bradycardia, hypokalemia, slowing of intracardiac conduction, or prolongation of the QTc interval

Avoid TCAs in patients with a known history of QTc prolongation, recent acute myocardial infarction, and uncompensated heart failure

TCAs may cause a sustained increase in heart rate in patients with ischemic heart disease and may worsen (decrease) heart rate variability, an independent risk of mortality in cardiac populations

Since SSRIs may improve (increase) heart rate variability in patients following a myocardial infarct and may improve survival as well as mood in patients with acute angina or following a myocardial infarction, these are more appropriate agents for cardiac population than tricyclic/tetracyclic antidepressants

âœ1⁄2 Risk/benefit ratio may not justify use of TCAs in cardiac impairment

Elderly

Baseline ECG is recommended for patients over age 50

May be more sensitive to anticholinergic, cardiovascular, hypotensive, and sedative effects

Initial dose 50 mg/day; increase gradually up to 100 mg/day

Reduction in the risk of suicidality with antidepressants compared to placebo in adults age 65 and older

Children and Adolescents

Carefully weigh the risks and benefits of pharmacological treatment against the risks and benefits of nontreatment with antidepressants and make sure to document this in the patientâ€TM s chart

Use with caution, observing for activation of known or unknown bipolar disorder and/or suicidal ideation, and inform parents or guardians of this risk so they can help observe child or adolescent patients

Monitor patients face-to-face regularly, particularly during the first several weeks of treatment

Not generally recommended for use under age 12

Several studies show lack of efficacy of TCAs for depression

May be used to treat enuresis or hyperactive/impulsive behaviors

Some cases of sudden death have occurred in children taking TCAs

Adolescents: initial dose 50 mg/day; increase gradually up to 100 mg/day

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women Crosses the placenta

Adverse effects have been reported in infants whose mothers took a TCA (lethargy, withdrawal symptoms, fetal malformations)

Must weigh the risk of treatment (first trimester fetal development, third trimester newborn delivery) to the child against the risk of no

treatment (recurrence of depression, maternal health, infant bonding) to the mother and child

For many patients this may mean continuing treatment during pregnancy

National Pregnancy Registry for Antidepressants: 1-866-961-2388,

https://womensmentalhealth.org/research/pregnancyregistry/antidepr essants

Breast Feeding

Some drug is found in motherâ€TM s breast milk

âœ1⁄2 Recommended either to discontinue drug or bottle feed

Immediate postpartum period is a high-risk time for depression, especially in women who have had prior depressive episodes, so drug may need to be reinstituted late in the third trimester or shortly after childbirth to prevent a recurrence during the postpartum period

Must weigh benefits of breast feeding with risks and benefits of antidepressant treatment versus nontreatment to both the infant and the mother

For many patients this may mean continuing treatment during breast feeding

The Art of Psychopharmacology Potential Advantages

Patients with insomnia

Severe or treatment-resistant depression

Patients with a wide variety of chronic pain syndromes

Potential Disadvantages

Pediatric and geriatric patients Patients concerned with weight gain Cardiac patients

Primary Target Symptoms

Depressed mood Symptoms of anxiety Somatic symptoms Chronic pain Insomnia

Pearls

Was once one of the most widely prescribed agents for depression

Remains one of the most favored TCAs for treating headache and a wide variety of chronic pain syndromes, including neuropathic pain, fibromyalgia, migraine, neck pain, and low back pain

âœ1⁄2 Preference of some prescribers for amitriptyline over other tricyclic/tetracyclic antidepressants for the treatment of chronic pain syndromes is based more upon art and anecdote rather than controlled clinical trials, since many TCAs/tetracylics may be effective for chronic pain syndromes

TCAs are no longer generally considered a first-line treatment option for depression because of their side effect profile

âœ1⁄2 Amitriptyline has been shown to be effective in primary insomnia

TCAs may aggravate psychotic symptoms

Alcohol should be avoided because of additive CNS effects

Underweight patients may be more susceptible to adverse cardiovascular effects

Children, patients with inadequate hydration, and patients with cardiac disease may be more susceptible to TCA-induced cardiotoxicity than healthy adults

For the expert only: although generally prohibited, a heroic but potentially dangerous treatment for severely treatment-resistant patients is to give a tricyclic/tetracyclic antidepressant other than clomipramine simultaneously with an MAOI for patients who fail to respond to numerous other antidepressants

If this option is elected, start the MAOI with the tricyclic/tetracyclic antidepressant simultaneously at low doses after appropriate drug

washout, then alternately increase doses of these agents every few days to a week as tolerated

Although very strict dietary and concomitant drug restrictions must be observed to prevent hypertensive crises and serotonin syndrome, the most common side effects of MAOI/tricyclic or tetracyclic combinations may be weight gain and orthostatic hypotension

Patients on TCAs should be aware that they may experience symptoms such as photosensitivity or blue-green urine

SSRIs may be more effective than TCAs in women, and TCAs may be more effective than SSRIs in men

Since tricyclic/tetracyclic antidepressants are substrates for CYP450 2D6, and 7% of the population (especially Caucasians) may have a genetic variant leading to reduced activity of 2D6, such patients may not safely tolerate normal doses of tricyclic/tetracyclic antidepressants and may require dose reduction

Phenotypic testing may be necessary to detect this genetic variant prior to dosing with a tricyclic/tetracyclic antidepressant, especially in vulnerable populations such as children, elderly, cardiac populations, and those on concomitant medications

Patients who seem to have extraordinarily severe side effects at normal or low doses may have this phenotypic CYP450 2D6 variant and require low doses or switching to another antidepressant not metabolized by 2D6

Suggested Reading

Guaiana G , Barbui C , Hotopf M. Amitriptyline for depression . Cochrane

Database Syst Rev 2007 ;(3):CD004186 .

Hauser W , Petzke F , Uceyler N , Sommer C. Comparative efficacy and acceptability of amitriptyline, duloxetine and milnacipran in fibromyalgia syndrome: a systematic review with meta-analysis . Rheumatology (Oxford) 2011 ;50 (3 ):532– 43 .

Torrente Castells E , Vazquez Delgado E , Gay Escoda C. Use of amitriptyline for the treatment of chronic tension-type headache. Review of the literature . Med Oral Patol Oral Cir Bucal 2008 ;13 (9 ):E567 – 72.

Amoxapine

Asendin

Therapeutics Brands

see index for additional brand names

Yes

Generic?

Class

Neuroscience-based Nomenclature: norepinephrine, serotonin reuptake inhibitor (SN-RI)

Tricyclic antidepressant (TCA), sometimes classified as a tetracyclic antidepressant

Norepinephrine/noradrenaline reuptake inhibitor Serotonin 2A antagonist

Parent drug and especially an active metabolite are dopamine 2 antagonists

Commonly Prescribed for

(bold for FDA approved)

Neurotic or reactive depressive disorder Endogenous and psychotic depressions Depression accompanied by anxiety or agitation Depressive phase of bipolar disorder

Anxiety

Insomnia

Neuropathic pain/chronic pain Treatment-resistant depression

How the Drug Works

Boosts neurotransmitter norepinephrine/noradrenaline

Blocks norepinephrine reuptake pump (norepinephrine transporter), presumably increasing noradrenergic neurotransmission

Since dopamine is inactivated by norepinephrine reuptake in frontal cortex, which largely lacks dopamine transporters, amoxapine can thus increase dopamine neurotransmission in this part of the brain

A more potent inhibitor of norepinephrine reuptake pump than serotonin reuptake pump (serotonin transporter)

At high doses may also boost neurotransmitter serotonin and presumably increase serotonergic neurotransmission

Blocks dopamine 2 receptors, reducing positive symptoms of psychosis

How Long Until It Works

Onset of therapeutic actions usually not immediate, but often delayed 2– 4 weeks

If it is not working within 6– 8 weeks for depression, it may require a dosage increase or it may not work at all

May continue to work for many years to prevent relapse of symptoms

If It Works

The goal of treatment is complete remission of current symptoms as well as prevention of future relapses

Treatment most often reduces or even eliminates symptoms, but not a cure since symptoms can recur after medicine stopped

Continue treatment until all symptoms are gone (remission)

Once symptoms are gone, continue treating for 1 year for the first episode of depression

For second and subsequent episodes of depression, treatment may need to be indefinite

Use in anxiety disorders may also need to be indefinite

If It Doesnâ€TM t Work

Many patients have only a partial response where some symptoms are improved but others persist (especially insomnia, fatigue, and

problems concentrating)

Other patients may be nonresponders, sometimes called treatment- resistant or treatment-refractory

Consider increasing dose, switching to another agent, or adding an appropriate augmenting agent

Consider psychotherapy

Consider evaluation for another diagnosis or for a comorbid condition (e.g., medical illness, substance abuse, etc.)

Some patients may experience apparent lack of consistent efficacy due to activation of latent or underlying bipolar disorder, and require antidepressant discontinuation and a switch to a mood stabilizer

Best Augmenting Combos for Partial Response or Treatment Resistance

Lithium, buspirone, thyroid hormone

Tests

Baseline ECG is recommended for patients over age 50

âœ1⁄2 Since tricyclic and tetracyclic antidepressants are frequently associated with weight gain, before starting treatment, weigh all patients and determine if the patient is already overweight (BMI 25.0– 29.9) or obese (BMI ≥ 30)

Before giving a drug that can cause weight gain to an overweight or obese patient, consider determining whether the patient already has

pre-diabetes (fasting plasma glucose 100– 125 mg/dL), diabetes (fasting plasma glucose ≥ 126 mg/dL), or dyslipidemia (increased total cholesterol, LDL cholesterol, and triglycerides; decreased HDL cholesterol), and treat or refer such patients for treatment, including nutrition and weight management, physical activity counseling, smoking cessation, and medical management

âœ1⁄2 Monitor weight and BMI during treatment

âœ1⁄2 While giving a drug to a patient who has gained >5% of initial weight, consider evaluating for the presence of pre-diabetes, diabetes, or dyslipidemia, or consider switching to a different antidepressant

ECGs may be useful for selected patients (e.g., those with personal or family history of QTc prolongation; cardiac arrhythmia; recent myocardial infarction; uncompensated heart failure; or taking agents that prolong QTc interval such as pimozide, thioridazine, selected antiarrhythmics, moxifloxacin, sparfloxacin, etc.)

Patients at risk for electrolyte disturbances (e.g., patients on diuretic therapy) should have baseline and periodic serum potassium and magnesium measurements

Side Effects

How Drug Causes Side Effects

Anticholinergic activity may explain sedative effects, dry mouth, constipation, and blurred vision

Sedative effects and weight gain may be due to antihistamine properties

Blockade of alpha adrenergic 1 receptors may explain dizziness, sedation, and hypotension

Cardiac arrhythmias and seizures, especially in overdose, may be caused by blockade of ion channels

Notable Side Effects

Blurred vision, constipation, urinary retention, increased appetite, dry mouth, nausea, diarrhea, heartburn, unusual taste in mouth, weight gain

Fatigue, weakness, dizziness, sedation, headache, anxiety, nervousness, restlessness

Sexual dysfunction, sweating

âœ1⁄2 Can cause drug-induced parkinsonism, akathisia, and theoretically, tardive dyskinesia

Life-Threatening or Dangerous Side Effects

Paralytic ileus, hyperthermia (TCAs/tetracyclics + anticholinergic agents)

Lowered seizure threshold and rare seizures

Orthostatic hypotension, sudden death, arrhythmias, tachycardia QTc prolongation

Hepatic failure, drug-induced parkinsonism Increased intraocular pressure

Rare induction of mania

Rare activation of suicidal ideation and behavior (suicidality) (short- term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo beyond age 24)

Weight Gain

Many experience and/or can be significant in amount Can increase appetite and carbohydrate craving

Sedation

Many experience and/or can be significant in amount Tolerance to sedative effect may develop with long-term use

What to Do About Side Effects

Wait

Wait

Wait

Lower the dose

Switch to an SSRI or newer antidepressant

Best Augmenting Agents for Side Effects

Many side effects cannot be improved with an augmenting agent

May use anticholinergics for drug-induced parkinsonism, or switch to another antidepressant

200– 300 mg/day

Dosing and Use Usual Dosage Range

Dosage Forms

Tablet 25 mg, 50 mg, 100 mg, 150 mg

How to Dose

Initial 25 mg 2– 3 times/day; increase gradually to 100 mg 2– 3 times/day or a single dose at bedtime; maximum 400 mg/day (may dose up to 600 mg/day in inpatients)

Dosing Tips

If given in a single dose, should generally be administered at bedtime because of its sedative properties

If given in split doses, largest dose should generally be given at bedtime because of its sedative properties

If patients experience nightmares, split dose and do not give large dose at bedtime

If intolerable anxiety, insomnia, agitation, akathisia, or activation occur upon either dosing initiation or discontinuation, consider the possibility of activated bipolar disorder, and switch to a mood stabilizer or an atypical antipsychotic

Overdose

Death may occur; convulsions, cardiac dysrhythmias, severe hypotension, CNS depression, coma, changes in ECG

Long-Term Use

Generally safe

Some patients may develop withdrawal dyskinesias when discontinuing amoxapine after long-term use

Habit Forming

Some patients may develop tolerance

How to Stop

Taper to avoid withdrawal effects

Even with gradual dose reduction some withdrawal symptoms may appear within the first 2 weeks

Many patients tolerate 50% dose reduction for 3 days, then another 50% reduction for 3 days, then discontinuation

If withdrawal symptoms emerge during discontinuation, raise dose to stop symptoms and then restart withdrawal much more slowly

Pharmacokinetics

Substrate for CYP450 2D6

Half-life of parent drug approximately 8 hours

âœ1⁄2 7- and 8-hydroxymetabolites are active and possess serotonin 2A and dopamine 2 antagonist properties, similar to atypical antipsychotics

âœ1⁄2 Amoxapine is the N-desmethyl metabolite of the conventional antipsychotic loxapine

Half-life of the active metabolites approximately 24 hours

Drug Interactions

Tramadol increases the risk of seizures in patients taking TCAs

Use of TCAs/tetracyclics with anticholinergic drugs may result in paralytic ileus or hyperthermia

Fluoxetine, paroxetine, bupropion, duloxetine, and other CYP450 2D6 inhibitors may increase TCA/tetracyclic concentrations

Cimetidine may increase plasma concentrations of TCAs/tetracyclics and cause anticholinergic symptoms

Phenothiazines or haloperidol may raise TCA/tetracyclic blood concentrations

May alter effects of antihypertensive drugs; may inhibit hypotensive effects of clonidine

Use of TCAs/tetracyclics with sympathomimetic agents may increase sympathetic activity

Methylphenidate may inhibit metabolism of TCAs/tetracyclics

Activation and agitation, especially following switching or adding antidepressants, may represent the induction of a bipolar state, especially a mixed dysphoric bipolar II condition sometimes associated with suicidal ideation, and require the addition of lithium, a mood stabilizer or an atypical antipsychotic, and/or discontinuation of amoxapine

Other Warnings/Precautions

Add or initiate other antidepressants with caution for up to 2 weeks after discontinuing amoxapine

Generally, do not use with MAOIs, including 14 days after MAOIs are stopped; do not start an MAOI for at least 5 half-lives (5 to 7 days for most drugs) after discontinuing amoxapine, but see Pearls

Use with caution in patients with history of seizure, urinary retention, angle-closure glaucoma, hyperthyroidism

TCAs/tetracyclics can increase QTc interval, especially at toxic doses, which can be attained not only by overdose but also by

combining with drugs that inhibit its metabolism via CYP450 2D6, potentially causing torsade de pointes-type arrhythmia or sudden death

Because TCAs/tetracyclics can prolong QTc interval, use with caution in patients who have bradycardia or who are taking drugs that can induce bradycardia (e.g., beta blockers, calcium channel blockers, clonidine, digitalis)

Because TCAs/tetracyclics can prolong QTc interval, use with caution in patients who have hypokalemia and/or hypomagnesemia, or who are taking drugs that can induce hypokalemia and/or magnesemia (e.g., diuretics, stimulant laxatives, intravenous amphotericin B, glucocorticoids, tetracosactide)

When treating children, carefully weigh the risks and benefits of pharmacological treatment against the risks and benefits of nontreatment with antidepressants and make sure to document this in the patientâ€TM s chart

Distribute the brochures provided by the FDA and the drug companies

Whenever possible, warn patients and their caregivers about the possibility of activating side effects, and advise them to report such symptoms immediately

Monitor patients for activation of suicidal ideation, especially children and adolescents

Do Not Use

If patient is recovering from myocardial infarction

If patient is taking agents capable of significantly prolonging QTc interval (e.g., pimozide, thioridazine, selected antiarrhythmics, moxifloxacin, sparfloxacin)

If there is a history of QTc prolongation or cardiac arrhythmia, recent acute myocardial infarction, uncompensated heart failure

If patient is taking drugs that inhibit TCA/tetracyclic metabolism, including CYP450 2D6 inhibitors, except by an expert

If there is reduced CYP450 2D6 function, such as patients who are poor 2D6 metabolizers, except by an expert and at low doses

If there is a proven allergy to amoxapine or loxapine

Special Populations Renal Impairment

Use with caution – may require lower than usual adult dose

Hepatic Impairment

Use with caution – may require lower than usual adult dose

Cardiac Impairment

Baseline ECG is recommended

TCAs/tetracyclics have been reported to cause arrhythmias, prolongation of conduction time, orthostatic hypotension, sinus tachycardia, and heart failure, especially in the diseased heart

Myocardial infarction and stroke have been reported with TCAs/tetracyclics

TCAs/tetracyclics produce QTc prolongation, which may be enhanced by the existence of bradycardia, hypokalemia, congenital or acquired long QTc interval, which should be evaluated prior to administering amoxapine

Use with caution if treating concomitantly with a medication likely to produce prolonged bradycardia, hypokalemia, slowing of intracardiac conduction, or prolongation of the QTc interval

Avoid TCAs/tetracyclics in patients with a known history of QTc prolongation, recent acute myocardial infarction, and uncompensated heart failure

TCAs/tetracyclics may cause a sustained increase in heart rate in patients with ischemic heart disease and may worsen (decrease) heart rate variability, an independent risk of mortality in cardiac populations

Since SSRIs may improve (increase) heart rate variability in patients following a myocardial infarct and may improve survival as well as mood in patients with acute angina or following a myocardial infarction, these are more appropriate agents for cardiac population than tricyclic/tetracyclic antidepressants

âœ1⁄2 Risk/benefit ratio may not justify use of TCAs/tetracyclics in cardiac impairment

Elderly

Baseline ECG is recommended for patients over age 50

May be more sensitive to anticholinergic, cardiovascular, hypotensive, and sedative effects

Initial dose 25 mg/day at bedtime; increase by 25 mg/day each week; maximum dose 300 mg/day

Children and Adolescents

Carefully weigh the risks and benefits of pharmacological treatment against the risks and benefits of nontreatment with antidepressants and make sure to document this in the patientâ€TM s chart

Use with caution, observing for activation of known or unknown bipolar disorder and/or suicidal ideation, and inform parents or guardians of this risk so they can help observe child or adolescent patients

Monitor patients face-to-face regularly, particularly during the first several weeks of treatment

Not generally recommended for use under age 16

Several studies show lack of efficacy of TCAs/tetracyclics for depression

May be used to treat enuresis or hyperactive/impulsive behaviors

Some cases of sudden death have occurred in children taking TCAs/tetracyclics

Adolescents: initial 25– 50 mg/day; increase gradually to 100 mg/day in divided doses or single dose at bedtime

Pregnancy

Controlled studies have not been conducted in pregnant women

Some animal studies show adverse effects

Amoxapine crosses the placenta

Adverse effects have been reported in infants whose mothers took a TCA (lethargy, withdrawal symptoms, fetal malformations)

Evaluate for treatment with an antidepressant with a better risk/benefit ratio

National Pregnancy Registry for Antidepressants: 1-866-961-2388,

https://womensmentalhealth.org/research/pregnancyregistry/antidepr essants

Breast Feeding

Some drug is found in motherâ€TM s breast milk

âœ1⁄2 Recommended either to discontinue drug or bottle feed

Immediate postpartum period is a high-risk time for depression, especially in women who have had prior depressive episodes, so

drug may need to be reinstituted late in the third trimester or shortly after childbirth to prevent a recurrence during the postpartum period

Evaluate for treatment with an antidepressant with a better risk/benefit ratio

The Art of Psychopharmacology Potential Advantages

Severe or treatment-resistant depression Treatment-resistant psychotic depression

Potential Disadvantages

Pediatric and geriatric patients

Patients concerned with weight gain

Cardiac patients

Patients with Parkinsonâ€TM s disease or tardive dyskinesia

Depressed mood

Primary Target Symptoms

Pearls

Tricyclic/tetracyclic antidepressants are no longer generally considered a first-line treatment option for depression because of

their side effect profile

Tricyclic/tetracyclic antidepressants continue to be useful for severe or treatment-resistant depression

âœ1⁄2 Because of potential drug-induced parkinsonism, akathisia, and theoretical risk of tardive dyskinesia, first consider other TCAs/tetracyclics for long-term use in general and for treatment of chronic patients

TCAs may aggravate psychotic symptoms

Alcohol should be avoided because of additive CNS effects

Underweight patients may be more susceptible to adverse cardiovascular effects

Children, patients with inadequate hydration, and patients with cardiac disease may be more susceptible to TCA-induced cardiotoxicity than healthy adults

For the expert only: although generally prohibited, a heroic but potentially dangerous treatment for severely treatment-resistant patients is to give a tricyclic/tetracyclic antidepressant other than clomipramine simultaneously with an MAOI for patients who fail to respond to numerous other antidepressants

Use of MAOIs with clomipramine is always prohibited because of the risk of serotonin syndrome and death

Amoxapine may be the preferred trycyclic/tetracyclic antidepressant to combine with an MAOI in heroic cases due to its theoretically protective 5HT2A antagonist properties

If this option is elected, start the MAOI with the tricyclic/tetracyclic antidepressant simultaneously at low doses after appropriate drug washout, then alternately increase doses of these agents every few days to a week as tolerated

Although very strict dietary and concomitant drug restrictions must be observed to prevent hypertensive crises and serotonin syndrome, the most common side effects of MAOI/tricyclic or tetracyclic combinations may be weight gain and orthostatic hypotension

Patients on TCAs/tetracyclics should be aware that they may experience symptoms such as photosensitivity or blue-green urine

SSRIs may be more effective than TCAs/tetracyclics in women, and TCAs/tetracyclics may be more effective than SSRIs in men

âœ1⁄2 May cause some motor effects, possibly due to effects on dopamine receptors

âœ1⁄2 Amoxapine may have a faster onset of action than some other antidepressants

âœ1⁄2 May be pharmacologically similar to an atypical antipsychotic in some patients

âœ1⁄2 At high doses, patients who form high concentrations of active metabolites may have akathisia or drug-induced parkinsonism, and possibly develop tardive dyskinesia

âœ1⁄2 Structurally and pharmacologically related to the antipsychotic loxapine

Since tricyclic/tetracyclic antidepressants are substrates for CYP450 2D6, and 7% of the population (especially Caucasians) may have a genetic variant leading to reduced activity of 2D6, such patients may not safely tolerate normal doses of tricyclic/tetracyclic antidepressants and may require dose reduction

Phenotypic testing may be necessary to detect this genetic variant prior to dosing with a tricyclic/tetracyclic antidepressant, especially in vulnerable populations such as children, elderly, cardiac populations, and those on concomitant medications

Patients who seem to have extraordinarily severe side effects at normal or low doses may have this phenotypic CYP450 2D6 variant and require low doses or switching to another antidepressant not metabolized by 2D6

Suggested Reading

Anderson IM . Meta-analytical studies on new antidepressants . Br Med

Bull 2001 ; 57 :161– 78 .

Anderson IM . Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability . J Aff Disorders 2000 ;58 :19 – 36 .

Hayes PE , Kristoff CA . Adverse reactions to five new antidepressants . Clin Pharm 1986 ; 5 :471– 80 .

Jue SG , Dawson GW , Brogden RN . Amoxapine: a review of its pharmacology and efficacy in depressed states . Drugs 1982 ;24 :1 – 23 .

Amphetamine (D)

Dexedrine

Dexedrine Spansules

Zenzedi

ProCentra

see index for additional brand names

Therapeutics Brands

Yes

Generic?

Class

Neuroscience-based Nomenclature: dopamine, norepinephrine reuptake inhibitor and releaser (DN-RIRe)

Stimulant

Commonly Prescribed for

(bold for FDA approved)

Attention deficit hyperactivity disorder (ADHD) (ages 6 and older or 3 and older depending on formulation)

Narcolepsy (ages 6 and older)

Treatment-resistant depression

How the Drug Works

âœ1⁄2 Increases norepinephrine and especially dopamine actions by

blocking their reuptake and facilitating their release

Enhancement of dopamine and norepinephrine actions in certain brain regions may improve attention, concentration, executive function, and wakefulness (e.g., dorsolateral prefrontal cortex)

Enhancement of dopamine actions in other brain regions (e.g., basal ganglia) may improve hyperactivity

Enhancement of dopamine and norepinephrine in yet other brain regions (e.g., medial prefrontal cortex, hypothalamus) may improve depression, fatigue, and sleepiness

How Long Until It Works

Some immediate effects can be seen with first dosing

Can take several weeks to attain maximum therapeutic benefit

If It Works (for ADHD)

The goal of treatment of ADHD is reduction of symptoms of inattentiveness, motor hyperactivity, and/or impulsiveness that disrupt social, school, and/or occupational functioning

Continue treatment until all symptoms are under control or improvement is stable and then continue treatment indefinitely as long as improvement persists

Reevaluate the need for treatment periodically

Treatment for ADHD begun in childhood may need to be continued into adolescence and adulthood if continued benefit is documented

If It Doesnâ€TM t Work (for ADHD)

Consider adjusting dose or switching to another formulation of d- amphetamine or to another agent

Consider behavioral therapy

Consider the presence of noncompliance and counsel patient and parents

Consider evaluation for another diagnosis or for a comorbid condition (e.g., bipolar disorder, substance abuse, medical illness, etc.)

âœ1⁄2 Some ADHD patients and some depressed patients may experience lack of consistent efficacy due to activation of latent or underlying bipolar disorder, and require either augmenting with a mood stabilizer or switching to a mood stabilizer

Best Augmenting Combos for Partial Response or Treatment Resistance

âœ1⁄2 Best to attempt other monotherapies prior to augmenting

For the expert, can combine immediate-release formulation with a sustained-release formulation of d-amphetamine for ADHD

For the expert, can combine with modafinil or atomoxetine for ADHD

For the expert, can occasionally combine with atypical antipsychotics in highly treatment-resistant cases of bipolar disorder or ADHD

For the expert, can combine with antidepressants to boost antidepressant efficacy in highly treatment-resistant cases of depression while carefully monitoring patient

Tests

Before treatment, assess for presence of cardiac disease (history, family history, physical exam)

Blood pressure should be monitored regularly In children, monitor weight and height

Side Effects

How Drug Causes Side Effects

Increases in norepinephrine peripherally can cause autonomic side effects, including tremor, tachycardia, hypertension, and cardiac arrhythmias

Increases in norepinephrine and dopamine centrally can cause CNS side effects such as insomnia, agitation, psychosis, and substance abuse

Notable Side Effects

âœ1⁄2 Insomnia, headache, exacerbation of tics, nervousness,

irritability, overstimulation, tremor, dizziness

Anorexia, nausea, dry mouth, constipation, diarrhea, weight loss

Can temporarily slow normal growth in children (controversial)

Sexual dysfunction long-term (impotence, libido changes) but can also improve sexual dysfunction short-term

Life-Threatening or Dangerous Side Effects

Psychotic episodes, especially with parenteral abuse

Seizures

Palpitations, tachycardia, hypertension

Rare activation of hypomania, mania, or suicidal ideation (controversial)

Cardiovascular adverse effects, sudden death in patients with preexisting cardiac structural abnormalities

Weight Gain

Reported but not expected

Some patients may experience weight loss

Sedation

Reported but not expected

Activation much more common than sedation

What to Do About Side Effects

Wait

Adjust dose

Switch to a long-acting stimulant

Switch to another agent

For insomnia, avoid dosing in afternoon/evening

Best Augmenting Agents for Side Effects

Beta blockers for peripheral autonomic side effects

Dose reduction or switching to another agent may be more effective since most side effects cannot be improved with an augmenting agent

Dosing and Use

Usual Dosage Range

Narcolepsy: 5– 60 mg/day (divided doses for tablet, once daily morning dose for Spansule capsule)

ADHD: 5– 40 mg/day (divided doses for tablet, once daily morning dose for Spansule capsule)

Dosage Forms

Immediate-release tablet 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30 mg

Extended-release capsule 5 mg, 10 mg, 15 mg Immediate-release oral solution 5 mg/5 mL

How to Dose

Narcolepsy, ages 12 and older (Spansule capsule or tablet): initial 10 mg/day; can increase by 10 mg each week; give first dose on waking; tablet is administered in divided doses

Narcolepsy, ages 6 to 12 (tablet IR): initial 5 mg/day; can increase by 5 mg each week; administered in divided doses

ADHD, ages 6 and older (Spansule capsule or tablet): initial 5 mg/day; can increase by 5 mg each week; give first dose on waking

ADHD, ages 3 to 5 (tablet IR): initial 2.5 mg/day; can increase by 2.5 mg each week; administered in divided doses

Dosing Tips

Clinical duration of action often differs from pharmacokinetic half- life

âœ1⁄2 Immediate-release dextroamphetamine has 3– 6 hour duration of clinical action

âœ1⁄2 Sustained-release dextroamphetamine (Dexedrine Spansule) has up to 8-hour duration of clinical action

Tablets contain tartrazine, which may cause allergic reactions, particularly in patients allergic to aspirin

Dexedrine Spansules are controlled-release and should therefore not be chewed but rather should only be swallowed whole

âœ1⁄2 Controlled-release delivery of dextroamphetamine may be sufficiently long in duration to allow elimination of lunchtime dosing in many but not all patients

âœ1⁄2 This innovation can be an important practical element in stimulant utilization, eliminating the hassle and pragmatic difficulties of lunchtime dosing at school, including storage problems, potential diversion, and the need for a medical professional to supervise dosing away from home

Avoid dosing late in the day because of the risk of insomnia

âœ1⁄2 May be possible to dose only during the school week for some ADHD patients

Off-label uses are dosed the same as for ADHD

âœ1⁄2 May be able to give drug holidays over the summer in order to reassess therapeutic utility and effects on growth and to allow catch-up from any growth suppression as well as to assess any other side effects and the need to reinstitute stimulant treatment for the next school term However, most studies show that parental height is what determines a patientâ€TM s final height, and that most children/adolescents taking stimulants reach their expected height, just more slowly than children/adolescents not exposed to stimulants

Side effects are generally dose-related

Taking with food may delay peak actions for 2– 3 hours

Overdose

Rarely fatal; panic, hyperreflexia, rhabdomyolysis, rapid respiration, confusion, coma, hallucination, convulsion, arrhythmia, change in blood pressure, circulatory collapse

Long-Term Use

Often used long-term for ADHD when ongoing monitoring documents continued efficacy

Dependence and/or abuse may develop

Tolerance to therapeutic effects may develop in some patients

Long-term stimulant use may be associated with growth suppression in children (controversial)

Periodic monitoring of weight, blood pressure, CBC, platelet counts, and liver function may be prudent

Habit Forming

High abuse potential, Schedule II drug

Patients may develop tolerance, psychological dependence

How to Stop

Taper to avoid withdrawal effects

Withdrawal following chronic therapeutic use may unmask symptoms of the underlying disorder and may require follow-up and reinstitution of treatment

Careful supervision is required during withdrawal from abusive use since severe depression may occur

Pharmacokinetics

Half-life approximately 10– 12 hours

Drug Interactions

May affect blood pressure and should be used cautiously with agents used to control blood pressure

Gastrointestinal acidifying agents (guanethidine, reserpine, glutamic acid, ascorbic acid, fruit juices, etc.) and urinary acidifying agents (ammonium chloride, sodium phosphate, etc.) lower amphetamine

plasma levels, so such agents can be useful to administer after an overdose but may also lower therapeutic efficacy of amphetamines

Gastrointestinal alkalinizing agents (sodium bicarbonate, etc.) and urinary alkalinizing agents (acetazolamide, some thiazides) increase amphetamine plasma levels and potentiate amphetamineâ€TM s actions

Desipramine and protryptiline can cause striking and sustained increases in brain concentrations of d-amphetamine and may also add to d-amphetamineâ€TM s cardiovascular effects

Theoretically, other agents with norepinephrine reuptake blocking properties, such as venlafaxine, duloxetine, atomoxetine, milnacipran, and reboxetine, could also add to amphetamineâ€TM s CNS and cardiovascular effects

Amphetamines may counteract the sedative effects of antihistamines

Haloperidol, chlorpromazine, and lithium may inhibit stimulatory effects of amphetamines

Theoretically, atypical antipsychotics should also inhibit stimulatory effects of amphetamines

Theoretically, amphetamines could inhibit the antipsychotic actions of antipsychotics

Theoretically, amphetamines could inhibit the mood-stabilizing actions of atypical antipsychotics in some patients

Combinations of amphetamines with mood stabilizers (lithium, anticonvulsants, atypical antipsychotics) is generally something for

experts only, when monitoring patients closely and when other options fail

Absorption of phenobarbital, phenytoin, and ethosuximide is delayed by amphetamines

Amphetamines inhibit adrenergic blockers and enhance adrenergic effects of norepinephrine

Amphetamines may antagonize hypotensive effects of veratrum alkaloids and other antihypertensives

Amphetamines increase the analgesic effects of meperidine

Amphetamines contribute to excessive CNS stimulation if used with large doses of propoxyphene

Amphetamines can raise plasma corticosteroid levels

MAOIs slow absorption of amphetamines and thus potentiate their actions, which can cause headache, hypertension, and rarely hypertensive crisis and malignant hyperthermia, sometimes with fatal results

Use with MAOIs, including within 14 days of MAOI use, is not advised, but this can sometimes be considered by experts who monitor depressed patients closely when other treatment options for depression fail

Other Warnings/Precautions

Use with caution in patients with any degree of hypertension, hyperthyroidism, or history of drug abuse

Children who are not growing or gaining weight should stop treatment, at least temporarily

May worsen motor and phonic tics

May worsen symptoms of thought disorder and behavioral disturbance in psychotic patients

Stimulants have a high potential for abuse and must be used with caution in anyone with a current or past history of substance abuse or alcoholism or in emotionally unstable patients

Administration of stimulants for prolonged periods of time should be avoided whenever possible or done only with close monitoring, as it may lead to marked tolerance and drug dependence, including psychological dependence with varying degrees of abnormal behavior

Particular attention should be paid to the possibility of subjects obtaining stimulants for nontherapeutic use or distribution to others and the drugs should in general be prescribed sparingly with documentation of appropriate use

Usual dosing has been associated with sudden death in children with structural cardiac abnormalities

Not an appropriate first-line treatment for depression or for normal fatigue

May lower the seizure threshold

Emergence or worsening of activation and agitation may represent the induction of a bipolar state, especially a mixed dysphoric bipolar

II condition sometimes associated with suicidal ideation, and require the addition of a mood stabilizer and/or discontinuation of d- amphetamine

Do Not Use

If patient has extreme anxiety or agitation

If patient has motor tics or Touretteâ€TM s syndrome or if there is a family history of Touretteâ€TM s, unless administered by an expert in cases when the potential benefits for ADHD outweigh the risks of worsening tics

Should generally not be administered with an MAOI, including within 14 days of MAOI use, except in heroic circumstances and by an expert

If patient has arteriosclerosis, cardiovascular disease, or severe hypertension

If patient has glaucoma

If patient has structural cardiac abnormalities

If there is a proven allergy to any sympathomimetic agent

Special Populations

Renal Impairment

No dose adjustment necessary

Use with caution

Hepatic Impairment

Cardiac Impairment

Use with caution, particularly in patients with recent myocardial infarction or other conditions that could be negatively affected by increased blood pressure

Do not use in patients with structural cardiac abnormalities

Elderly

Some patients may tolerate lower doses better

Children and Adolescents

Safety and efficacy not established in children under age 3 Use in young children should be reserved for the expert

d-amphetamine may worsen symptoms of behavioral disturbance and thought disorder in psychotic children

Half-life and duration of clinical action tend to be shorter in younger children

d-amphetamine has acute effects on growth hormone; long-term effects are unknown but weight and height should be monitored during long-term treatment

Narcolepsy: ages 6– 12: initial 5 mg/day; increase by 5 mg each week

ADHD: ages 3– 5: initial 2.5 mg/day; increase by 2.5 mg each week

Usual dosing has been associated with sudden death in children with structural cardiac abnormalities

American Heart Association recommends ECG prior to initiating stimulant treatment in children, although not all experts agree

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women

There is a greater risk of premature birth and low birth weight in infants whose mothers take d-amphetamine during pregnancy

Infants whose mothers take d-amphetamine during pregnancy may experience withdrawal symptoms

In animal studies, d-amphetamine caused delayed skeletal ossification and decreased post-weaning weight gain in rats; no major malformations occurred in rat or rabbit studies

Use in women of childbearing potential requires weighing potential benefits to the mother against potential risks to the fetus

âœ1⁄2 For ADHD patients, d-amphetamine should generally be discontinued before anticipated pregnancies

Breast Feeding

Some drug is found in motherâ€TM s breast milk

âœ1⁄2 Recommended either to discontinue drug or bottle feed

If infant shows signs of irritability, drug may need to be discontinued

The Art of Psychopharmacology Potential Advantages

May work in ADHD patients unresponsive to other stimulants

Established long-term efficacy of immediate-release and Spansule formulations

Potential Disadvantages

Patients with current or past substance abuse

Patients with current or past bipolar disorder or psychosis Patients with anorexia

Patients with insomnia

Primary Target Symptoms

Concentration, attention span Motor hyperactivity Impulsiveness

Physical and mental fatigue Daytime sleepiness Depression

Pearls

âœ1⁄2 May be useful for treatment of depressive symptoms in medically

ill elderly patients

âœ1⁄2 May be useful for treatment of post-stroke depression

âœ1⁄2 A classical augmentation strategy for treatment-refractory depression

âœ1⁄2 Specifically, may be useful for treatment of cognitive dysfunction and fatigue as residual symptoms of major depressive disorder unresponsive to multiple prior treatments

âœ1⁄2 May also be useful for the treatment of cognitive impairment, depressive symptoms, and severe fatigue in patients with HIV infection and in cancer patients

Can be used to potentiate opioid analgesia and reduce sedation, particularly in end-of-life management

Some patients respond to or tolerate d-amphetamin better than methylphenidate and vice versa

Some patients may benefit from an occasional addition of 5– 10 mg of immediate-release d-amphetamine to their daily base of sustained-release Dexedrine Spansules

âœ1⁄2 Despite warnings, can be a useful adjunct to MAOIs for heroic treatment of highly refractory mood disorders when monitored with vigilance

âœ1⁄2 Can reverse sexual dysfunction caused by psychiatric illness and by some drugs such as SSRIs, including decreased libido, erectile dysfunction, delayed ejaculation, and anorgasmia

Atypical antipsychotics may be useful in treating stimulant or psychotic consequences of overdose

Drug abuse may actually be lower in ADHD adolescents treated with stimulants than in ADHD adolescents who are not treated

Suggested Reading

Fry JM . Treatment modalities for narcolepsy . Neurology 1998 ;50 (2

Suppl 1 ):S43 – 8.

Greenhill LL , Pliszka S , Dulcan MK , et al. Practice parameter for the use of stimulant medications in the treatment of children, adolescents, and adults . J Am Acad Child Adolesc Psychiatry 2002 ;41 (2 ):S26 – 49 .

Jadad AR , Boyle M , Cunningham C , Kim M , Schachar R . Treatment of attention-deficit/hyperactivity disorder . Evid Rep Technol Assess (Summ) 1999 ;11 :i – viii , 1 – 341 .

Stiefel G , Besag FM . Cardiovascular effects of methylphenidate, amphetamines, and atomoxetine in the treatment of attention-deficit hyperactivity disorder . Drug Saf 2010 ;33 (10 ):821– 42 .

Vinson DC . Therapy for attention-deficit hyperactivity disorder . Arch Fam Med 1994 ;3 :445– 51 .

Wender PH , Wolf LE , Wasserstein J . Adults with ADHD. An overview . Ann NY Acad Sci 2001 ;931 :1 – 16 .

Amphetamine (D,L)

Adderall

Adderall XR Evekeo Adzenys-XR-ODT Dyanavel XR Mydayis

Adzenys ER

Therapeutics Brands

Yes

Generic?

Class

see index for additional brand names

Neuroscience-based Nomenclature: dopamine, norepinephrine reuptake inhibitor and releaser (DN-RIRe)

Stimulant

Commonly Prescribed for

(bold for FDA approved)

Attention deficit hyperactivity disorder (ADHD) in patients ages 3 and older (Adderall, Evekeo)

ADHD in children ages 6– 17 (Dyanavel XR)

ADHD in patients ages 6 and older (Adderall XR, Evekeo, Adzenys XR-ODT, Adzenys ER)

ADHD in patients ages 13 and older (Mydayis) Narcolepsy in patients ages 6 and older (Adderall, Evekeo) Exogenous obesity in patients ages 12 and older (Evekeo) Treatment-resistant depression

How the Drug Works

âœ1⁄2 Increases norepinephrine and especially dopamine actions by

blocking their reuptake and facilitating their release

Enhancement of dopamine and norepinephrine actions in certain brain regions (e.g., dorsolateral prefrontal cortex) may improve attention, concentration, executive function, and wakefulness

Enhancement of dopamine actions in other brain regions (e.g., basal ganglia) may improve hyperactivity

Enhancement of dopamine and norepinephrine in yet other brain regions (e.g., medial prefrontal cortex, hypothalamus) may improve depression, fatigue, and sleepiness

How Long Until It Works

Some immediate effects can be seen with first dosing

Can take several weeks to attain maximum therapeutic benefit

If It Works (for ADHD)

The goal of treatment of ADHD is reduction of symptoms of inattentiveness, motor hyperactivity, and/or impulsiveness that disrupt social, school, and/or occupational functioning

Continue treatment until all symptoms are under control or improvement is stable and then continue treatment indefinitely as long as improvement persists

Reevaluate the need for treatment periodically

Treatment for ADHD begun in childhood may need to be continued into adolescence and adulthood if continued benefit is documented

If It Doesnâ€TM t Work (for ADHD)

Consider adjusting dose or switching to another formulation of d,l- amphetamine or to another agent

Consider behavioral therapy

Consider the presence of noncompliance and counsel patient and parents

Consider evaluation for another diagnosis or for a comorbid condition (e.g., bipolar disorder, substance abuse, medical illness,

etc.)

âœ1⁄2 Some ADHD patients and some depressed patients may experience lack of consistent efficacy due to activation of latent or underlying bipolar disorder, and require either augmenting with a mood stabilizer or switching to a mood stabilizer

Best Augmenting Combos for Partial Response or Treatment Resistance

Best to attempt other monotherapies prior to augmenting

For the expert, can combine immediate-release formulation with a sustained-release formulation of d,l-amphetamine for ADHD

For the expert, can combine with modafinil or atomoxetine for ADHD

For the expert, can occasionally combine with atypical antipsychotics in highly treatment-resistant cases of bipolar disorder or ADHD

For the expert, can combine with antidepressants to boost antidepressant efficacy in highly treatment-resistant cases of depression while carefully monitoring patient

Tests

Before treatment, assess for presence of cardiac disease (history, family history, physical exam)

Blood pressure should be monitored regularly

In children, monitor weight and height

Side Effects

How Drug Causes Side Effects

Increases in norepinephrine peripherally can cause autonomic side effects, including tremor, tachycardia, hypertension, and cardiac arrhythmias

Increases in norepinephrine and dopamine centrally can cause CNS side effects such as insomnia, agitation, psychosis, and substance abuse

Notable Side Effects

âœ1⁄2 Insomnia, headache, exacerbation of tics, nervousness,

irritability, overstimulation, tremor, dizziness

Anorexia, nausea, dry mouth, constipation, diarrhea, weight loss

Can temporarily slow normal growth in children (controversial)

Sexual dysfunction long-term (impotence, libido changes) but can also improve sexual dysfunction short-term

Life-Threatening or Dangerous Side Effects

Psychotic episodes, especially with parenteral abuse Seizures

Palpitations, tachycardia, hypertension

Rare activation of hypomania, mania, or suicidal ideation (controversial)

Cardiovascular adverse effects, sudden death in patients with preexisting cardiac structural abnormalities

Weight Gain

Reported but not expected

Some patients may experience weight loss

Sedation

Reported but not expected

Activation much more common than sedation

What to Do About Side Effects

Wait

Adjust dose

Switch to a long-acting stimulant

Switch to another agent

For insomnia, avoid dosing in afternoon/evening

Best Augmenting Agents for Side Effects

Beta blockers for peripheral autonomic side effects

Dose reduction or switching to another agent may be more effective since most side effects cannot be improved with an augmenting agent

Dosing and Use Usual Dosage Range

Narcolepsy: 5– 60 mg/day in divided doses

ADHD: varies by formulation; see How to Dose section Exogenous obesity: 30 mg/day in divided doses

Dosage Forms

Immediate-release Adderall tablet 5 mg double-scored, 7.5 mg double-scored, 10 mg double-scored, 12.5 mg double-scored, 15 mg double-scored, 20 mg double-scored, 30 mg double-scored

Immediate-release Evekeo tablet 5 mg scored, 10 mg double-scored

Extended-release orally disintegrating tablet (Adzenys XR-ODT) 3.1 mg, 6.3 mg, 9.4 mg, 12.5 mg, 15.7 mg, 18.8 mg

Extended-release tablet (Adderal XR) 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg

Extended-release capsule (Mydayis) 12.5 mg, 25 mg, 37.5 mg, 50 mg

Extended-release oral suspension (Dynavel XR) 2.5 mg/mL Extended-release oral suspension (Adzenys ER) 1.25 mg/mL

How to Dose

Immediate-release Adderall or Evekeo in ADHD (ages 6 and older): initial 5 mg once or twice per day; can increase by 5 mg each week; maximum dose generally 40 mg/day; split daily dose with first dose on waking and every 4– 6 hours thereafter

Immediate-release Evekeo in ADHD (ages 3 to 5): initial 2.5 mg/day; can increase by 2.5 mg each week; administered in divided doses

Immediate-release Adderall or Evekeo in narcolepsy (ages 12 and older): initial 10 mg/day; can increase by 10 mg each week; split daily dose with first dose on waking and every 4– 6 hours thereafter

Immediate-release Evekeo in narcolepsy (ages 6 to 12): initial 5 mg/day; can increase by 5 mg each week; administered in divided doses

Extended-release tablet in ADHD: initial 10 mg/day in the morning; can increase by 5– 10 mg/day at weekly intervals; maximum dose generally 30 mg/day

Extended-release oral suspension in ADHD (Dynavel XR): initial 2.5 mg or 5 mg once in the morning; can increase by 2.5– 10 mg/day every 4– 7 days; maximum recommended dose 20 mg/day

Extended-release oral suspension in pediatric ADHD (Adzenys ER): initial 6.3 mg once in the morning; maximum dose 18.8 mg/day for patients ages 6 to 12 years and 12.5 mg/day for patients ages 13 to 17 years

Extended-release oral suspension in adult ADHD (Adzenys ER): 12.5 mg once daily in the morning

Extended-release orally disintegrating tablet in ADHD: initial 6.3 mg once in the morning; maximum dose 18.8 mg/day for patients ages 6– 12 or 12.5 mg/day for patients ages 13 and older

Extended-release capsule in adult ADHD: initial dose 12.5 mg immediately upon waking; can increase daily dose weekly by 12.5 mg; maximum recommended daily dose 50 mg

Extended-release capsule in ADHD (ages 13 to 17): initial dose 12.5 mg immediately upon waking; can increase daily dose weekly by 12.5 mg; maximum recommended daily dose 25 mg

Immediate-release Evekeo in exogenous obesity (ages 12 and older): usual daily dose 30 mg; taken in divided doses of 5– 10 mg, 30– 60 minutes before meals

Dosing Tips

Clinical duration of action often differs from pharmacokinetic half- life

âœ1⁄2 Immediate-release d,l-amphetamine has 3– 6 hour duration of clinical action

âœ1⁄2 Extended-release d,l-amphetamine has up to 8-hour duration of clinical action

Adderall XR is controlled-release and should therefore not be chewed but rather should only be swallowed whole

Extended-release oral suspension (Dyanavel XR) and extended- release orally disintegrating tablet (Adzenys XR-ODT) should not be substituted for other amphetamine products on a mg-per-mg basis due to differing amphetamine base compositions and pharmacokinetic profiles

âœ1⁄2 Controlled-release delivery of d,l-amphetamine is sufficiently long in duration to allow elimination of lunchtime dosing

âœ1⁄2 This innovation can be an important practical element in stimulant utilization, eliminating the hassle and pragmatic difficulties of lunchtime dosing at school, including storage problems, potential diversion, and the need for a medical professional to supervise dosing away from home

Avoid dosing late in the day because of the risk of insomnia

May be possible to dose only during the school week for some ADHD patients

Off-label uses are dosed the same as for ADHD

âœ1⁄2 May be able to give drug holidays over the summer in order to reassess therapeutic utility and effects on growth and to allow catch-up from any growth suppression as well as to assess any other side effects and the need to reinstitute stimulant treatment for the next school term

However, most studies show that parental height is what determines a patientâ€TM s final height, and that most children/adolescents taking stimulants reach their expected height, just more slowly than children/adolescents not exposed to stimulants

Side effects are generally dose-related

Taking with food may delay peak actions for 2– 3 hours

Overdose

Rarely fatal; panic, hyperreflexia, rhabdomyolysis, rapid respiration, confusion, coma, hallucinations, convulsions, arrhythmia, change in blood pressure, circulatory collapse

Long-Term Use

Often used long-term for ADHD when ongoing monitoring documents continued efficacy

Dependence and/or abuse may develop

Tolerance to therapeutic effects may develop in some patients

Long-term stimulant use may be associated with growth suppression in children (controversial)

Periodic monitoring of weight, blood pressure, CBC, platelet counts, and liver function may be prudent

Habit Forming

High abuse potential, Schedule II drug

Patients may develop tolerance, psychological dependence

How to Stop

Taper to avoid withdrawal effects

Withdrawal following chronic therapeutic use may unmask symptoms of the underlying disorder and may require follow-up and reinstitution of treatment

Careful supervision is required during withdrawal from abusive use since severe depression may occur

Pharmacokinetics

Adderall and Adderall XR are a mixture of d-amphetamine and l- amphetamine salts in the ratio of 3:1

A single dose of Adderall XR 20 mg gives drug levels of both d- amphetamine and l-amphetamine comparable to Adderall immediate-release 20 mg administered in 2 divided doses 4 hours apart

In adults, half-life for d-amphetamine is 10 hours and for l- amphetamine is 13 hours

For children ages 6– 12, half-life for d-amphetamine is 9 hours and for l-amphetamine is 11 hours

Substrate for CYP450 2D6

Drug Interactions

May affect blood pressure and should be used cautiously with agents used to control blood pressure

Gastrointestinal acidifying agents (guanethidine, reserpine, glutamic acid, ascorbic acid, fruit juices, etc.) and urinary acidifying agents (ammonium chloride, sodium phosphate, etc.) lower amphetamine plasma levels, so such agents can be useful to administer after an overdose but may also lower therapeutic efficacy of amphetamines

Gastrointestinal alkalinizing agents (sodium bicarbonate, etc.) and urinary alkalinizing agents (acetazolamide, some thiazides) increase amphetamine plasma levels and potentiate amphetamineâ€TM s actions

Desipramine and protryptiline can cause striking and sustained increases in brain concentrations of amphetamine and may also add to amphetamineâ€TM s cardiovascular effects

Theoretically, other agents with norepinephrine reuptake blocking properties, such as venlafaxine, duloxetine, atomoxetine, milnacipran, and reboxetine, could also add to amphetamineâ€TM s CNS and cardiovascular effects

Amphetamines may counteract the sedative effects of antihistamines

Haloperidol, chlorpromazine, and lithium may inhibit stimulatory effects of amphetamines

Theoretically, atypical antipsychotics should also inhibit stimulatory effects of amphetamines

Theoretically, amphetamines could inhibit the antipsychotic actions of antipsychotics

Theoretically, amphetamines could inhibit the mood-stabilizing actions of atypical antipsychotics in some patients

Combinations of amphetamines with mood stabilizers (lithium, anticonvulsants, atypical antipsychotics) is generally something for experts only, when monitoring patients closely and when other options fail

Absorption of phenobarbital, phenytoin, and ethosuximide is delayed by amphetamines

Amphetamines inhibit adrenergic blockers and enhance adrenergic effects of norepinephrine

Amphetamines may antagonize hypotensive effects of veratrum alkaloids and other antihypertensives

Amphetamines increase the analgesic effects of meperidine

Amphetamines contribute to excessive CNS stimulation if used with large doses of propoxyphene

Amphetamines can raise plasma corticosteroid levels

MAOIs slow absorption of amphetamines and thus potentiate their actions, which can cause headache, hypertension, and rarely hypertensive crisis and malignant hyperthermia, sometimes with fatal results

Use with MAOIs, including within 14 days of MAOI use, is not advised, but this can sometimes be considered by experts who monitor depressed patients closely when other treatment options for depression fail

Other Warnings/Precautions

Use with caution in patients with any degree of hypertension, hyperthyroidism, or history of drug abuse

Children who are not growing or gaining weight should stop treatment, at least temporarily

May worsen motor and phonic tics

May worsen symptoms of thought disorder and behavioral disturbance in psychotic patients

Stimulants have a high potential for abuse and must be used with caution in anyone with a current or past history of substance abuse or alcoholism or in emotionally unstable patients

Administration of stimulants for prolonged periods of time should be avoided whenever possible or done only with close monitoring, as it may lead to marked tolerance and drug dependence, including

psychological dependence with varying degrees of abnormal behavior

Particular attention should be paid to the possibility of subjects obtaining stimulants for nontherapeutic use or distribution to others and the drugs should in general be prescribed sparingly with documentation of appropriate use

Usual dosing has been associated with sudden death in children with structural cardiac abnormalities

Not an appropriate first-line treatment for depression or for normal fatigue

May lower the seizure threshold

Emergence or worsening of activation and agitation may represent the induction of a bipolar state, especially a mixed dysphoric bipolar II condition sometimes associated with suicidal ideation, and require the addition of a mood stabilizer and/or discontinuation of d,l- amphetamine

Half-life and duration of clinical action tend to be shorter in younger children

Do Not Use

If patient has extreme anxiety or agitation

If patient has motor tics or Touretteâ€TM s syndrome or if there is a family history of Touretteâ€TM s, unless administered by an expert in

cases when the potential benefits for ADHD outweigh the risks of worsening tics

Should generally not be administered with an MAOI, including within 14 days of MAOI use, except in heroic circumstances and by an expert

If patient has arteriosclerosis, cardiovascular disease, or severe hypertension

If patient has glaucoma

If patient has structural cardiac abnormalities

If there is a proven allergy to any sympathomimetic agent

Special Populations Renal Impairment

No dose adjustment necessary

Hepatic Impairment

No dose adjustment necessary

Cardiac Impairment

Use with caution, particularly in patients with recent myocardial infarction or other conditions that could be negatively affected by increased blood pressure

Do not use in patients with structural cardiac abnormalities

Elderly

Some patients may tolerate lower doses better

Children and Adolescents

Safety and efficacy not established under age 3

Use in young children should be reserved for the expert

d,l-amphetamine may worsen symptoms of behavioral disturbance and thought disorder in psychotic children

Half-life and duration of clinical action tend to be shorter in younger children

d,l-amphetamine has acute effects on growth hormone; long-term effects are unknown but weight and height should be monitored during long-term treatment

ADHD: ages 3– 5: initial 2.5 mg/day; can increase by 2.5 mg each week

Narcolepsy: ages 6– 12: initial 5 mg/day; increase by 5 mg each week

Usual dosing has been associated with sudden death in children with structural cardiac abnormalities

American Heart Association recommends ECG prior to initiating stimulant treatment in children, although not all experts agree

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women

Infants whose mothers take d,l-amphetamine during pregnancy may experience withdrawal symptoms

In rat and rabbit studies, amphetamine d,l did not affect embryofetal development or survival throughout organogenesis at doses of approximately one and a half and eight times the maximum recommended human dose of 30 mg/day (child)

In animal studies, d-amphetamine caused delayed skeletal ossification and decreased post-weaning weight gain in rats; no major malformations occurred in rat or rabbit studies

Use in women of childbearing potential requires weighing potential benefits to the mother against potential risks to the fetus

âœ1⁄2 For ADHD patients, d,l-amphetamine should generally be discontinued before anticipated pregnancies

Breast Feeding

Some drug is found in motherâ€TM s breast milk

âœ1⁄2 Recommended either to discontinue drug or bottle feed If infant shows signs of irritability, drug may need to be

discontinued

The Art of Psychopharmacology Potential Advantages

May work in ADHD patients unresponsive to other stimulants, including pure d-amphetamine sulfate

Multiple formulation options

Potential Disadvantages

Patients with current or past substance abuse

Patients with current or past bipolar disorder or psychosis Patients with anorexia

Patients with insomnia

Primary Target Symptoms

Concentration, attention span Motor hyperactivity Impulsiveness

Physical and mental fatigue

Daytime sleepiness Depression

Pearls

âœ1⁄2 May be useful for treatment of depressive symptoms in medically

ill elderly patients

âœ1⁄2 May be useful for treatment of post-stroke depression

âœ1⁄2 A classical augmentation strategy for treatment-refractory depression

âœ1⁄2 Specifically, may be useful for treatment of cognitive dysfunction and fatigue as residual symptoms of major depressive disorder unresponsive to multiple prior treatments

âœ1⁄2 May also be useful for the treatment of cognitive impairment, depressive symptoms, and severe fatigue in patients with HIV infection and in cancer patients

Can be used to potentiate opioid analgesia and reduce sedation, particularly in end-of-life management

âœ1⁄2 Despite warnings, can be a useful adjunct to MAOIs for heroic treatment of highly refractory mood disorders when monitored with vigilance

âœ1⁄2 Can reverse sexual dysfunction caused by psychiatric illness and by some drugs such as SSRIs, including decreased libido, erectile dysfunction, delayed ejaculation, and anorgasmia

Atypical antipsychotics may be useful in treating stimulant or psychotic consequences of overdose

Drug abuse may actually be lower in ADHD adolescents treated with stimulants than in ADHD adolescents who are not treated

Some patients respond to or tolerate d,l-amphetamine better than methylphenidate and vice versa

âœ1⁄2 Adderall and Adderall XR are a mixture of d-amphetamine and l- amphetamine salts in the ratio of 3:1

âœ1⁄2 Specifically, Adderall and Adderall XR combine 1 part dextroamphetamine saccharate, 1 part dextroamphetamine sulfate, 1 part d,l-amphetamine aspartate, and 1 part d,l-amphetamine sulfate

âœ1⁄2 This mixture of salts may have a different pharmacologic profile, including mechanism of therapeutic action and duration of action, compared to pure dextroamphetamine, which is given as the sulfate salt

âœ1⁄2 Specifically, d-amphetamine may have more profound action on dopamine than norepinephrine whereas l-amphetamine may have a more balanced action on both dopamine and norepinephrine

âœ1⁄2 Theoretically, this could lead to relatively more noradrenergic actions of the Adderall mixture of amphetamine salts than that of pure dextroamphetamine sulfate, but this is unproven and of no clear clinical significance

Nevertheless, some patients may respond to or tolerate Adderall/Adderall XR differently than they do pure dextro-

amphetamine sulfate

Adderall XR capsules also contain 2 types of drug-containing beads designed to give a double-pulsed delivery of amphetamines to prolong their release

Suggested Reading

Fry JM . Treatment modalities for narcolepsy . Neurology 1998 ;50 (2

Suppl 1):S43– 8 .

Greenhill LL , Pliszka S , Dulcan MK , et al. Practice parameter for the use of stimulant medications in the treatment of children, adolescents, and adults . J Am Acad Child Adolesc Psychiatry 2002 ;41 (2 Suppl):S26 – 49 .

Jadad AR , Boyle M , Cunningham C , Kim M , Schachar R . Treatment of attention-deficit/hyperactivity disorder . Evid Rep Technol Assess (Summ) 1999 ;11:i – viii,1 – 341 .

Stiefel G , Besag FM. Cardiovascular effects of methylphenidate, amphetamines, and atomoxetine in the treatment of attention-deficit hyperactivity disorder . Drug Saf 2010 ;33 (10 ):821– 42 .

Vinson DC . Therapy for attention-deficit hyperactivity disorder . Arch Fam Med 1994 ;3 :445– 51 .

Wender PH , Wolf LE , Wasserstein J . Adults with ADHD. An overview . Ann NY Acad Sci 2001 ;931 :1 – 16 .

Aripiprazole

Abilify

Abilify Maintena

Aristada

see index for additional brand names

Therapeutics Brands

Yes

Generic?

Class

Neuroscience-based Nomenclature: dopamine, serotonin receptor partial agonist (DS-RPA)

Dopamine partial agonist (dopamine-serotonin partial agonist, dopamine stabilizer, atypical antipsychotic, third-generation antipsychotic; sometimes included as a second-generation antipsychotic; also a mood stabilizer)

Commonly Prescribed for

(bold for FDA approved)

Schizophrenia (adults) (Abilify, Abilify Maintena, Aristada, Aristada Initio)

Schizophrenia (ages 13 to 17) (Abilify) Maintaining stability in schizophrenia (Abilify)

Acute mania/mixed mania (ages 10 and older; monotherapy and adjunct) (Abilify)

Bipolar maintenance [monotherapy (Abilify, Abilify Maintena) and adjunct (Abilify)]

Depression (adjunct) (Abilify)

Autism-related irritability in children ages 6 to 17 (Abilify)

Touretteâ€TM s disorder in children ages 6 to 18 (Abilify)

Acute agitation associated with schizophrenia or bipolar disorder (IM Abilify)

Bipolar depression

Other psychotic disorders

Behavioral disturbances in dementias

Behavioral disturbances in children and adolescents Disorders associated with problems with impulse control Posttraumatic stress disorder (PTSD) Obsessive-compulsive disorder (adjunct to SSRIs)

How the Drug Works

âœ1⁄2 Partial agonism at dopamine 2 receptors

Theoretically reduces dopamine output when dopamine concentrations are high, thus improving positive symptoms and mediating antipsychotic actions

Theoretically increases dopamine output when dopamine concentrations are low, thus improving cognitive, negative, and mood symptoms

Interactions at a myriad of other neurotransmitter receptors may contribute to aripiprazoleâ€TM s efficacy

Actions at dopamine 3 receptors could theoretically contribute to aripiprazoleâ€TM s efficacy

Partial agonism at 5HT1A receptors may be relevant at clinical doses

Blocks serotonin 2A receptors, causing enhancement of dopamine release in certain brain regions and thus reducing motor side effects and possibly improving cognitive and affective symptoms

Blockade of serotonin type 2C and 7 receptors as well as partial agonist actions at 5HT1A receptors may contribute to antidepressant actions

How Long Until It Works

Psychotic and manic symptoms can improve within 1 week, but it may take several weeks for full effect on behavior as well as on cognition and affective stabilization

Classically recommended to wait at least 4– 6 weeks to determine efficacy of drug, but in practice some patients require up to 16– 20 weeks to show a good response, especially on negative or cognitive symptoms

If It Works

Most often reduces positive symptoms in schizophrenia but does not eliminate them

Can improve negative symptoms, as well as aggressive, cognitive, and affective symptoms in schizophrenia

Most schizophrenic patients do not have a total remission of symptoms but rather a reduction of symptoms by about a third

Perhaps 5– 15% of schizophrenic patients can experience an overall improvement of greater than 50– 60%, especially when receiving stable treatment for more than a year

Such patients are considered super-responders or “ awakeners†since they may be well enough to be employed, live independently, and sustain long-term relationships

Many bipolar patients may experience a reduction of symptoms by half or more

Treatment may not only reduce mania but also prevent recurrences of mania in bipolar disorder

Continue treatment until reaching a plateau of improvement

After reaching a satisfactory plateau, continue treatment for at least a year after first episode of psychosis

For second and subsequent episodes of psychosis, treatment may need to be indefinite

Even for first episodes of psychosis, it may be preferable to continue treatment indefinitely to avoid subsequent episodes

If It Doesnâ€TM t Work

Try one of the other atypical antipsychotics

If two or more antipsychotic monotherapies do not work, consider clozapine

Some patients may require treatment with a conventional antipsychotic

If no first-line atypical antipsychotic is effective, consider higher doses or augmentation with valproate or lamotrigine

Consider noncompliance and switch to another antipsychotic with fewer side effects or to an antipsychotic that can be given by depot injection

Consider initiating rehabilitation and psychotherapy such as cognitive remediation

Consider presence of concomitant drug abuse

Best Augmenting Combos for Partial Response or Treatment Resistance

Valproic acid (valproate, divalproex, divalproex ER)

Other mood-stabilizing anticonvulsants (carbamazepine, oxcarbazepine, lamotrigine)

Topiramate Lithium Benzodiazepines

Tests

Before starting an atypical antipsychotic

âœ1⁄2 Weigh all patients and track BMI during treatment

Get baseline personal and family history of diabetes, obesity,

dyslipidemia, hypertension, and cardiovascular disease

âœ1⁄2 Get waist circumference (at umbilicus), blood pressure, fasting plasma glucose, and fasting lipid profile

Determine if the patient

is overweight (BMI 25.0– 29.9)

is obese (BMI ≥ 30)

has pre-diabetes (fasting plasma glucose 100– 125 mg/dL) has diabetes (fasting plasma glucose ≥ 126 mg/dL)

has hypertension (BP >140/90 mmHg)

has dyslipidemia (increased total cholesterol, LDL cholesterol, and triglycerides; decreased HDL cholesterol)

Treat or refer such patients for treatment, including nutrition and weight management, physical activity counseling, smoking cessation, and medical management

Monitoring after starting an atypical antipsychotic âœ1⁄2 BMI monthly for 3 months, then quarterly

âœ1⁄2 Consider monitoring fasting triglycerides monthly for several months in patients at high risk for metabolic complications and when initiating or switching antipsychotics

âœ1⁄2 Blood pressure, fasting plasma glucose, fasting lipids within 3 months and then annually, but earlier and more frequently for patients with diabetes or who have gained >5% of initial weight

Treat or refer for treatment and consider switching to another atypical antipsychotic for patients who become overweight, obese, pre-diabetic, diabetic, hypertensive, or dyslipidemic while receiving an atypical antipsychotic

âœ1⁄2 Even in patients without known diabetes, be vigilant for the rare but life-threatening onset of diabetic ketoacidosis, which always requires immediate treatment, by monitoring for the rapid onset of polyuria, polydipsia, weight loss, nausea, vomiting, dehydration, rapid respiration, weakness and clouding of sensorium, even coma

Patients with low white blood cell count (WBC) or history of drug- induced leukopenia/neutropenia should have complete blood count (CBC) monitored frequently during the first few months and aripiprazole should be discontinued at the first sign of decline of WBC in the absence of other causative factors

Patients should be monitored periodically for the development of abnormal movements of tardive dyskinesia, using neurological exam and the AIMS (Abnormal Involuntary Movement Scale)

Side Effects

How Drug Causes Side Effects

Blocking alpha 1 adrenergic receptors can cause dizziness, hypotension, and syncope

Partial agonist actions at dopamine 2 receptors in the striatum can cause akathisia and drug-induced parkinsonism

Partial agonist actions at dopamine 2 receptors can also cause nausea, occasional vomiting, and activating side effects

Mechanism of weight gain and increased incidence of diabetes and dyslipidemia with atypical antipsychotics is unknown, and risks vary based on the particular agent

Notable Side Effects âœ1⁄2 Dizziness, insomnia, akathisia, activation

âœ1⁄2 Nausea, vomiting

Orthostatic hypotension, occasionally during initial dosing

Constipation

Headache, asthenia, sedation

Tardive dyskinesia (reduced risk compared to conventional antipsychotics)

Risk of potentially irreversible involuntary dyskinetic movements may increase with cumulative dose and treatment duration

Life-Threatening or Dangerous Side Effects

Rare impulse control problems

Rare neuroleptic malignant syndrome (NMS) may cause hyperpyrexia, muscle rigidity, delirium, and autonomic instability with elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure

Rare seizures

As a class, antipsychotics are associated with an increased risk of death and cerebrovascular events in elderly patients with dementia; not approved for treatment of dementia-related psychosis

As a class, antidepressants have been reported to increase the risk of suicidal thoughts and behaviors in children and young adults

Weight Gain

Reported in a few patients, especially those with low BMIs, but not expected

Less frequent and less severe than for most other antipsychotics May be more risk of weight gain in children than in adults

Sedation

Reported in a few patients but not expected

May be less than for some other antipsychotics, but never say never Can be activating

Wait

Wait

Wait

Reduce the dose

What to Do About Side Effects

Anticholinergics may reduce drug-induced parkinsonism when present

Beta blockers, benzodiazepines, or 5HT2A antagonists (e.g., mirtazapine, cyproheptadine) may reduce akathisia

Weight loss, exercise programs, and medical management for high BMIs, diabetes, dyslipidemia

Metformin may help prevent or reverse antipsychotic-induced weight gain

Switch to another atypical antipsychotic

Best Augmenting Agents for Side Effects

Benztropine, trihexyphenidyl, or amantadine for drug-induced parkinsonism

Beta blockers, benzodiazepines, or 5HT2A antagonists (e.g., mirtazapine, cyproheptadine) for akathisia

Valbenazine or deutetrabenazine for tardive dyskinesia

Many side effects cannot be improved with an augmenting agent

Dosing and Use Usual Dosage Range

15– 30 mg/day for schizophrenia and mania

2– 10 mg/day for augmenting SSRIs/SNRIs in depression

5– 15 mg/day for autism

5– 20 mg/day for Touretteâ€TM s disorder

300– 400 mg/4 weeks (LAI Maintena; see Aripiprazole Depot Formulations after Pearls for dosing and use)

441 mg, 662 mg, or 882 mg administered monthly; 882 mg administered every 6 weeks; or 1064 mg administered every 2

months (LAI Aristada; see Aripiprazole Depot Formulations after Pearls for dosing and use)

Aristada Initio: single 675 mg injection combined with a 30 mg oral dose (on the same day as the first maintenance-dose injection or up to 10 days later)

Dosage Forms

Tablet 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg Orally disintegrating tablet 10 mg, 15 mg

Oral solution 1 mg/mL

Injection 9.75 mg/1.3 mL

Depot (Maintena) 300 mg, 400 mg

Depot (Aristada) 441 mg, 662 mg, 882 mg, 1064 mg Single-dose injection (Initio) 675 mg

How to Dose – Oral and Acute IM

Schizophrenia, mania: initial approved recommendation is 10– 15 mg/day; maximum approved dose 30 mg/day

Depression (adjunct): initial dose 2– 5 mg/day; can increase by 5 mg/day at intervals of no less than 1 week; maximum dose 15 mg/day

Autism: initial dose 2 mg/day; can increase by 5 mg/day at intervals of no less than 1 week; maximum dose 15 mg/day

Touretteâ€TM s disorder (patients weighing less than 50 kg): initial dose 2 mg/day; after 2 days increase to 5 mg/day; after 1 additional week can increase to 10 mg/day if needed

Touretteâ€TM s disorder (patients weighing more than 50 kg): initial dose 2 mg/day; after 2 days increase to 5 mg/day; after 5 additional days can increase to 10 mg/day; can increase by 5 mg/day at intervals of no less than 1 week; maximum dose 20 mg/day

Agitation: 9.75 mg/1.3 mL; maximum 30 mg/day

Oral solution: solution doses can be substituted for tablet doses on a mg-per-mg basis up to 25 mg; patients receiving 30 mg tablet should receive 25 mg solution

Dosing Tips – Oral

âœ1⁄2 For some, less may be more: frequently, patients not acutely psychotic may need to be dosed lower (e.g., 2.5– 10 mg/day) in order to avoid akathisia and activation and for maximum tolerability

For others, more may be more: rarely, patients may need to be dosed higher than 30 mg/day for optimum efficacy

Consider administering 1– 5 mg as the oral solution for children and adolescents, as well as for adults very sensitive to side effects

âœ1⁄2 Although studies suggest patients switching to aripiprazole from another antipsychotic can do well with rapid switch or with cross- titration, clinical experience suggests many patients may do best by adding either an intermediate or full dose of aripiprazole to the

maintenance dose of the first antipsychotic for at least several days and possibly as long as 3 or 4 weeks prior to slow down-titration of the first antipsychotic. See also the Switching section below, after Pearls

Rather than raise the dose above normal dosing in acutely agitated patients requiring acute antipsychotic actions, consider short-term (one dose or more) augmentation with a benzodiazepine or another antipsychotic, especially intramuscularly

Rather than raise the dose above normal dosing in partial responders, consider augmentation with a mood-stabilizing anticonvulsant, such as valproate, topiramate, or lamotrigine

Children and elderly should generally be dosed at the lower end of the dosage spectrum

Due to its very long half-life, aripiprazole will take longer to reach steady state when initiating dosing, and longer to wash out when stopping dosing, than other atypical antipsychotics

Treatment should be suspended if absolute neutrophil count falls below 1000/mm3

Overdose

No fatalities have been reported; sedation, vomiting

Long-Term Use

Approved to delay relapse in long-term treatment of schizophrenia Approved for long-term maintenance in bipolar disorder

Often used for long-term maintenance in various behavioral disorders

Should periodically reevaluate long-term usefulness in individual patients, but treatment may need to continue for many years

No

Habit Forming

How to Stop

See Switching section of individual agents for how to stop aripiprazole

Rapid discontinuation could theoretically lead to rebound psychosis and worsening of symptoms, but less likely with aripiprazole due to its long half-life

Pharmacokinetics

Metabolized primarily by CYP450 2D6 and CYP450 3A4

Mean elimination half-life 75 hours (aripiprazole) and 94 hours (major metabolite dehydro-aripiprazole)

Food does not affect absorption

Drug Interactions

Ketaconazole and possibly other CYP450 3A4 inhibitors such as nefazodone, fluvoxamine, and fluoxetine may increase plasma

levels of aripiprazole

Carbamazepine and possibly other inducers of CYP450 3A4 may decrease plasma levels of aripiprazole

Quinidine and possibly other inhibitors of CYP450 2D6 such as paroxetine, fluoxetine, and duloxetine may increase plasma levels of aripiprazole

Aripiprazole may enhance the effects of antihypertensive drugs Aripiprazole may antagonize levodopa, dopamine agonists

Other Warnings/Precautions

There have been reports of problems with impulse control in patients taking aripiprazole, including compulsive gambling, shopping, binge eating, and sexual activity; use caution when prescribing to patients at high risk for impulse-control problems (e.g., patients with bipolar disorder, impulsive personality, obsessive-compulsive disorder, substance use disorders) and monitor all patients for emergence of these symptoms; dose should be lowered or discontinued if impulse-control problems manifest

Use with caution in patients with conditions that predispose to hypotension (dehydration, overheating)

Atypical antipsychotics have the potential for cognitive and motor impairment, especially related to sedation

Atypical antipsychotics can cause body temperature dysregulation; use caution in patients who may experience conditions that increase

body temperature (e.g., strenuous exercise, saunas, extreme heat, dehydration, or concomitant anticholinergic medication)

Dysphagia has been associated with antipsychotic use, and aripiprazole should be used cautiously in patients at risk for aspiration pneumonia

Monitor patients for activation of suicidal ideation, especially children and adolescents

As with any antipsychotic, use with caution in patients with history of seizures

Antipsychotics may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls; for patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment, and recurrently for patients on long-term antipsychotic therapy

Do Not Use

If there is a proven allergy to aripiprazole

Special Populations

Renal Impairment

Dose adjustment not necessary

Hepatic Impairment

Dose adjustment not necessary

Cardiac Impairment

Use in patients with cardiac impairment has not been studied, so use with caution because of risk of orthostatic hypotension

Use with caution if patient is taking concomitant antihypertensive or alpha 1 antagonist

Elderly

Dose adjustment generally not necessary, but some elderly patients may tolerate lower doses better

Although atypical antipsychotics are commonly used for behavioral disturbances in dementia, no agent has been approved for treatment of elderly patients with behavioral symptoms of dementia such as agitation

Elderly patients with dementia-related psychosis treated with atypical antipsychotics are at an increased risk of death compared to placebo, and also have an increased risk of cerebrovascular events

Consider pimavanserin for dementia-related psychosis or Parkinson’s disease psychosis instead of an atypical antipsychotic

Children and Adolescents

Approved for use in schizophrenia (ages 13 and older), manic/mixed episodes (ages 10 and older), irritability associated with autism (ages 6– 17), and treatment of Touretteâ€TM s disorder (ages 6– 18)

Clinical experience and early data suggest aripiprazole may be safe and effective for behavioral disturbances in children and adolescents, especially at lower doses

Children and adolescents using aripiprazole may need to be monitored more often than adults and may tolerate lower doses better

May be more risk of weight gain in children than in adults

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women

There is a risk of abnormal muscle movements and withdrawal symptoms in newborns whose mothers took an antipsychotic during the third trimester; symptoms may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty feeding

In animal studies, aripiprazole demonstrated developmental toxicity, including possible teratogenic effects, at doses higher than the maximum recommended human dose

Psychotic symptoms may worsen during pregnancy and some form of treatment may be necessary

Aripiprazole may be preferable to anticonvulsant mood stabilizers if treatment is required during pregnancy

National Pregnancy Registry for Atypical Antipsychotics: 1-866- 961-2388, https://womensmentalhealth.org/research/pregnancyregistry/atypical antipsychotic

Breast Feeding

Some drug is found in motherâ€TM s breast milk

âœ1⁄2 Recommended either to discontinue drug or bottle feed

Infants of women who choose to breast feed while on aripiprazole should be monitored for possible adverse effects

The Art of Psychopharmacology Potential Advantages

Some cases of psychosis and bipolar disorder refractory to treatment with other antipsychotics

âœ1⁄2 Patients concerned about gaining weight and patients who are already obese or overweight

âœ1⁄2 Patients with diabetes

âœ1⁄2 Patients with dyslipidemia (especially elevated triglycerides)

Patients requiring rapid onset of antipsychotic action without dosage titration

âœ1⁄2 Patients who wish to avoid sedation Potential Disadvantages

Patients in whom sedation is desired

May be more difficult to dose for children, elderly, or “ off-

label†uses

Primary Target Symptoms

Positive symptoms of psychosis

Negative symptoms of psychosis

Cognitive symptoms

Unstable mood (both depression and mania) Aggressive symptoms

Pearls

âœ1⁄2 Approved as an adjunct treatment for depression (e.g., to SSRIs, SNRIs)

May work better in 2– 10 mg/day range than at higher doses for augmenting SSRIs/SNRIs in treatment-resistant unipolar depression

Frequently used for bipolar depression as augmenting agent to lithium, valproate. and/or lamotrigine

âœ1⁄2 Well accepted in clinical practice when wanting to avoid weight gain because less weight gain than most other antipsychotics

âœ1⁄2 Well accepted in clinical practice when wanting to avoid sedation because less sedation than most other antipsychotics at all doses

âœ1⁄2 Can even be activating, which can be reduced by lowering the dose or starting at a lower dose

If sedation is desired, a benzodiazepine can be added short-term at the initiation of treatment until symptoms of agitation and insomnia are stabilized or intermittently as needed

âœ1⁄2 May not have diabetes or dyslipidemia risk, but monitoring is still indicated

Anecdotal reports of utility in treatment-resistant cases of psychosis Has a very favorable tolerability profile in clinical practice

Favorable tolerability profile leading to “ off-label†uses for many indications other than schizophrenia (e.g., bipolar II disorder, including hypomanic, mixed, rapid cycling, and depressed phases; treatment-resistant depression; anxiety disorders)

A short-acting intramuscular formulation is available as well as long-acting depot

Lacks D1 antagonist, anticholinergic, and antihistamine properties, which may explain relative lack of sedation or cognitive side effects in most patients

High affinity of aripiprazole for D2 receptors means that combining with other D2 antagonist antipsychotics could reverse their actions and thus often makes sense not to combine with other antipsychotics

An exception to this is in case of hyperprolactinemia or galactorrhea, when administration of even low dose (1– 5 mg) can reverse the hyperprolactinemia/galactorrhea of other antipsychotics, also proving that aripiprazole interferes with the D2 actions of other antipsychotics

Abilify Maintena (depot) may be particularly well suited to early- onset psychosis/first-episode psychosis to reduce rehospitalizations and to enhance adherence with relatively low side effect burden

Aristada can be initiated in one day using two injections and one pill (Aristada formulation plus Initio single-dose injection plus a 30 mg oral pill); this avoids the need for any further oral medication or for a follow-up injection for another 4, 6, or 8 weeks

Aristada might be the formulation of choice for patients on the last day of hospitalization or incarceration, obviating the need for further treatment or follow-up until the next LAI injection of Aristada is due

Depot Formulations

Vehicle Tmax

T1/2 with multiple dosing

Time to reach steady state

Able to be loaded

Dosing schedule (maintenance)

Injection site

Needle gauge Dosage forms

Injection volume

Monohydrate (Maintena)

Water

6.5– 7.1 days 29.9– 46.5 days

No

4 weeks

Intramuscular gluteal

21

300 mg, 400 mg

200 mg/mL; range 0.8 mL (160 mg)– 2 mL (400 mg)

Lauroxil (Aristada)

Water

44.1– 50.0 days 29.2– 34.9 days

4 monthly injections

Yes, with Initio formulation

4– 6 weeks

Intramuscular injection in deltoid (441 mg dose only) or gluteal (441, 662, or 882 mg)

20 or 21

441 mg, 662 mg, 882 mg, 1064 mg

441 mg/1.6 mL; 662 mg/2.4 mL; 882 mg/3.2 mL, 1064 mg/3.9 mL

Usual Dosage Range

300– 400 mg/4 weeks (monohydrate Maintena)

441 mg, 662 mg, or 882 mg administered monthly; 882 mg administered every 6 weeks; or 1064 mg administered every 2 months

Aristada Initio: single 675 mg injection combined with a 30 mg oral dose (on the same day as the first maintenance-dose injection or up to 10 days later)

How to Dose

Not recommended for patients who have not first demonstrated tolerability to oral aripiprazole (in clinical trials, 2 oral or short- acting IM doses are generally used to establish tolerability)

Maintena: loading is not possible, necessitating oral coverage for 14 days

Conversion from oral to Maintena: administer initial 400 mg injection along with an overlapping 14-day dosing of oral aripiprazole

Aristada: loading is not possible, necessitating either oral coverage for 21 days or use of the single-dose injection

Conversion from oral to Aristada with oral supplementation: administer initial injection (441 mg, 662 mg, 882 mg, or 1064 mg) along with an overlapping 21-day dosing of oral aripiprazole

Conversion from oral to Aristada with the single-dose injection (Initio): administer the 675 mg single-dose injection in combination with a 30 mg oral dose; the first maintenance aripiprazole lauroxil injection can be administered on the same day as the single-dose injection or up to 10 days later; avoid injecting both the single-dose injection and maintenance-dose injection into the same deltoid or gluteal muscle

Dosing Tips

With LAIs, the absorption rate constant is slower than the elimination rate constant, thus resulting in “ flip-flop†kinetics – i.e., time to steady state is a function of absorption rate, while concentration at steady state is a function of elimination rate

The rate-limiting step for plasma drug levels for LAIs is not drug metabolism, but rather slow absorption from the injection site

In general, 5 half-lives of any medication are needed to achieve 97% of steady-state levels

The long half-lives of depot antipsychotics mean that one must either adequately load the dose (if possible) or provide oral supplementation

The failure to adequately load the dose leads either to prolonged cross-titration from oral antipsychotic or to sub-therapeutic antipsychotic plasma levels for weeks or months in patients who are not receiving (or adhering to) oral supplementation

Because plasma antipsychotic levels increase gradually over time, dose requirements may ultimately decrease from initial; obtaining periodic plasma levels can be beneficial to prevent unnecessary plasma level creep

The time to get a blood level for patients receiving LAI is the morning of the day they will receive their next injection

Advantages: refrigeration not required; option of 6-week injections with Aristada

Disadvantages: both formulations require oral coverage

Downward dose adjustment is needed for poor CYP450 2D6 metabolizers and patients taking strong CYP450 2D6 or 3A4 inhibitors; avoid use with strong CYP450 3A4 inducers, as this can lead to sub-therapeutic plasma levels

Maintena: CYP450 Dose Adjustment

Poor 2D6 metabolizers

Patients taking strong 2D6 OR 3A4 inhibitors

Poor 2D6 metabolizers taking concomitant 3A4 inhibitors

Adjusted dose for patients taking 300 mg

N/A 200 mg

N/A

Adjusted dose for patients taking 400 mg

300 mg 300 mg

200 mg

Maintena: CYP450 Dose Adjustment

Patients taking 2D6 AND 3A4 inhibitors

Patients taking 3A4 inducers

Adjusted dose for patients taking 300 mg

160 mg

Avoid

Adjusted dose for patients taking 400 mg

200 mg

Avoid

Aristada: CYP450 Dose Adjustment

Adjusted dose for patients taking 441 mg

N/A N/A

Adjusted dose for patients taking 662 mg

N/A 441 mg

Adjusted dose for patients taking 1064

Adjusted

dose for

patients

taking 882

mg mg

Poor 2D6 metabolizers

Patients taking strong 2D6 OR 3A4 inhibitors

N/A 662 mg

N/A 882 mg

Aristada: CYP450 Dose Adjustment

Adjusted dose for patients taking 441 mg

N/A

N/A

662 mg

Adjusted dose for patients taking 662 mg

441 mg

Avoid

N/A

Adjusted dose for patients taking 1064

Adjusted

dose for

patients

taking 882

mg mg

Poor 2D6 metabolizers taking concomitant 3A4 inhibitors

Patients taking 2D6 AND 3A4 inhibitors

Patients taking 3A4 inducers

441 mg

Avoid

N/A

441 mg

Avoid

N/A

Switching from Oral Antipsychotics to Aripiprazole Depot Formulations

Discontinuation of oral antipsychotic can begin following oral coverage of 14 days (Maintena) or 21 days (Aristada)

How to discontinue oral formulations

Down-titration is not required for: amisulpride, aripiprazole, brexpiprazole, cariprazine, paliperidone ER

1-week down-titration is required for: iloperidone, lurasidone, risperidone, ziprasidone

3– 4-week down-titration is required for: asenapine, olanzapine, quetiapine

4+-week down-titration is required for: clozapine

For patients taking benzodiazepine or anticholinergic medication, this can be continued during cross-titration to help alleviate side effects such as insomnia, agitation, and/or psychosis. Once the patient is stable on LAI, these can be tapered one at a time as appropriate

The Art of Switching

Switching from Oral Antipsychotics to Aripiprazole

It is advisable to begin aripiprazole at an intermediate dose and build the dose rapidly over 3– 7 days

Clinical experience has shown that asenapine, quetiapine, and olanzapine should be tapered off slowly over a period of 3– 4 weeks, to allow patients to readapt to the withdrawal of blocking cholinergic, histaminergic, and alpha 1 receptors

Clozapine should always be tapered off slowly, over a period of 4 weeks or more

* Benzodiazepine or anticholinergic medication can be administered during cross-titration to help alleviate side effects such as insomnia, agitation, and/or psychosis

Suggested Reading

El-Sayeh HG , Morganti C. Aripiprazole for schizophrenia . Cochrane

Database Syst Rev 2006 ;(2) :CD004578 .

Huhn M , Nikolakopoulou A , Schneider-Thoma J , et al. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis . Lancet 2019 ;394 :939– 51 .

Kane JM , Sanchez R , Perry PP , et al. Aripiprazole intramuscular depot as maintenance treatment in patients with schizophrenia: a 52-week, multicenter, randomized, double-blind, placebo-controlled study . J Clin Psychiatry 2012 ;73 (5 ):617– 24 .

Marcus RN , McQuade RD , Carson WH , et al. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a second

multicenter, randomized, double-blind, placebo-controlled study . J Clin Psychopharmacol 2008 ;28 (2 ):156– 65 .

Montastruc F , Nie R , Loo S , et al. Association of aripiprazole with the risk for psychiatric hospitalization, self-harm, or suicide . JAMA Psychiatry 2019 ;76 (4 ):409– 17 .

Nasrallah HA . Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles . Mol Psychiatry 2008 ;13 (1 ):27 – 35 .

Armodafinil

Nuvigil

Therapeutics Brands

see index for additional brand names

Yes

Generic?

Class

Neuroscience-based Nomenclature: dopamine reuptake inhibitor (D- RI)

Wake-promoting

Commonly Prescribed for

(bold for FDA approved)

Reducing excessive sleepiness in patients with narcolepsy and shift work sleep disorder

Reducing excessive sleepiness in patients with obstructive sleep apnea/hypopnea syndrome (OSAHS) (adjunct to standard treatment for underlying airway obstruction)

Attention deficit hyperactivity disorder (ADHD) Fatigue and sleepiness in depression

Fatigue in multiple sclerosis

Bipolar depression

How the Drug Works

Unknown, but clearly different from classical stimulants such as methylphenidate and amphetamine

Binds to and requires the presence of the dopamine transporter; also requires the presence of alpha adrenergic receptors

Hypothetically acts as an inhibitor of the dopamine transporter

Increases neuronal activity selectively in the hypothalamus

âœ1⁄2 Presumably enhances activity in hypothalamic wakefulness center (TMN, tuberomammillary nucleus) within the hypothalamic sleep-wake switch by an unknown mechanism

âœ1⁄2 Activates tuberomammillary nucleus neurons that release histamine

âœ1⁄2 Activates other hypothalamic neurons that release orexin/hypocretin

How Long Until It Works

Can immediately reduce daytime sleepiness and improve cognitive task performance within 2 hours of first dosing

Can take several days to optimize dosing and clinical improvement

If It Works

âœ1⁄2 Improves daytime sleepiness and may improve attention as well

as fatigue

âœ1⁄2 Does not generally prevent one from falling asleep when needed

May not completely normalize wakefulness

Treat until improvement stabilizes and then continue treatment indefinitely as long as improvement persists (studies support at least 12 weeks of treatment)

If It Doesnâ€TM t Work

âœ1⁄2 Change dose; some patients may do better with an increased dose

but some may actually do better with a decreased dose

Augment or consider an alternative treatment for daytime sleepiness, fatigue, or ADHD

Best Augmenting Combos for Partial Response or Treatment Resistance

âœ1⁄2 Armodafinil is itself an adjunct to standard treatments for OSAHS; if continuous positive airway pressure (CPAP) is the treatment of choice, a maximal effort to treat first with CPAP should be made prior to initiating armodafinil and CPAP should be continued after initiation of armodafinil

âœ1⁄2 Armodafinil is itself an augmenting therapy to antidepressants for residual sleepiness and fatigue in major depressive disorder

âœ1⁄2 Armodafinil is itself an augmenting therapy to mood stabilizers for bipolar depression

Best to attempt another monotherapy prior to augmenting with other drugs in the treatment of sleepiness associated with sleep disorders or problems concentrating in ADHD

Combination of armodafinil with stimulants such as methylphenidate or amphetamine or with atomoxetine for ADHD has not been systematically studied

However, such combinations may be useful options for experts, with close monitoring, when numerous monotherapies for sleepiness or ADHD have failed

Tests

Side Effects

How Drug Causes Side Effects

None for healthy individuals

Unknown

CNS side effects presumably due to excessive CNS actions on various neurotransmitter systems

Notable Side Effects

âœ1⁄2 Headache

Anxiety, dizziness, insomnia Dry mouth, diarrhea, nausea

Life-Threatening or Dangerous Side Effects

Transient ECG ischemic changes in patients with mitral valve prolapse or left ventricular hypertrophy have been reported (rare)

Rare activation of (hypo)mania, anxiety, hallucinations, or suicidal ideation

Rare severe dermatologic reactions (Stevens-Johnson syndrome and others)

Angioedema, anaphylactoid reactions, and multi-organ hypersensitivity reactions have been reported

Weight Gain

Sedation

Reported but not expected

Patients are usually awakened and some may be activated

Reported but not expected

Wait

Lower the dose

What to Do About Side Effects

For activation or insomnia, do not give in the evening

If unacceptable side effects persist, discontinue use

For life-threatening or dangerous side effects, discountinue immediately (e.g., at first sign of a drug-related rash)

Best Augmenting Agents for Side Effects

Many side effects cannot be improved with an augmenting agent

150– 250 mg/day

Dosing And Use Usual Dosage Range

Dosage Forms

Tablet 50 mg, 100 mg, 150 mg, 200 mg, 250 mg

How to Dose

Titration up or down only necessary if not optimally efficacious at the standard starting dose of 150 mg once a day

For OSA and narcolepsy, give as a single dose in the morning

For shift work sleep disorder, give as a single dose 1 hour prior to the start of the work shift

Dosing Tips

âœ1⁄2 For sleepiness, more may be more: higher doses may be better

than lower doses in patients with daytime sleepiness in sleep disorders

âœ1⁄2 For problems concentrating and fatigue, less may be more: lower doses may be paradoxically better than higher in some patients

At high doses, may slightly induce its own metabolism, possibly by actions of inducing CYP450 3A4

Dose may creep upward in some patients with long-term treatment due to autoinduction; drug holiday may restore efficacy at original dose

Pharmacokinetics and clinical experience suggest armodafinil has longer duration of action than racemic modafinil, generally requiring only once daily administration

Overdose

Agitation, insomnia, increase in hemodynamic parameters

Postmarketing experience includes CNS symptoms, such as restlessness, disorientation, confusion, excitation, and hallucinations; digestive changes, such as nausea and diarrhea; and cardiovascular changes, such as tachycardia, bradycardia, hypertension, and chest pain

Long-Term Use

The need for continued treatment should be reevaluated periodically

Habit Forming

Schedule IV; may have some potential for abuse but unusual in clinical practice

How to Stop

Taper not necessary; patients may have sleepiness on discontinuation

Pharmacokinetics

Metabolized by the liver

Elimination half-life approximately 15 hours Inhibits CYP450 2C19

Induces CYP450 3A4 (and slightly 1A2)

Drug Interactions

May increase plasma levels of drugs metabolized by CYP450 2C19 (e.g., diazepam, phenytoin, propranolol)

May decrease plasma levels of CYP450 3A4 substrates such as ethinyl estradiol and triazolam

Due to induction of CYP450 3A4, effectiveness of steroidal contraceptives may be reduced by armodafinil, including 1 month after discontinuation

Inducers or inhibitors of CYP450 3A4 may affect levels of armodafinil (e.g., carbamazepine may lower modafinil plasma levels; fluvoxamine and fluoxetine may raise armodafinil plasma levels)

Armodafinil may slightly reduce its own levels by autoinduction of CYP450 3A4

Patients on armodafinil and warfarin should have prothrombin times monitored

Methylphenidate and dextroamphetamine may delay absorption of armodafinil by an hour

âœ1⁄2 However, coadministration with methylphenidate or dextroamphetamine does not significantly change the pharmacokinetics of armodafinil or either stimulant

Interaction studies with MAOIs have not been performed, but MAOIs can be given with armodafinil by experts with cautious monitoring

Other Warnings/Precautions

Patients with history of drug abuse should be monitored closely

Armodafinil may cause CNS effects similar to those caused by other CNS agents (e.g., changes in mood and, theoretically, activation of

psychosis, mania, or suicidal ideation)

Armodafinil should be used in patients with sleep disorders that have been completely evaluated for narcolepsy, OSAHS, and shift work sleep disorder

In OSAHS patients for whom CPAP is the treatment of choice, a maximal effort to treat first with CPAP should be made prior to initiating armodafinil, and then CPAP should be continued after initiating armodafinil

The effectiveness of hormonal contraceptives may be reduced when used with armodafinil and for 1 month after discontinuation of armodafinil

Armodafinil is not a replacement for sleep

Do Not Use

If there is a proven allergy to armodafinil or modafinil

Use with caution

Special Populations Renal Impairment

Hepatic Impairment

Reduce dose in severely impaired patients

Use with caution

Cardiac Impairment

Not recommended for use in patients with a history of left ventricular hypertrophy, ischemic ECG changes, chest pain, arrhythmias, or recent myocardial infarction

Elderly

Limited experience in patients over 65

Clearance of armodafinil may be reduced in elderly patients

Children and Adolescents

Safety and efficacy have not been established

Can be used cautiously by experts for children and adolescents

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women

Intrauterine growth restriction and spontaneous abortion have been reported with armodafinil and modafinil

In animal studies, developmental toxicity was observed at clinically relevant plasma exposures

Use in women of childbearing potential requires weighing potential benefits to the mother against potential risks to the fetus

âœ1⁄2 Generally, armodafinil should be discontinued prior to anticipated pregnancies

Breast Feeding

Unknown if armodafinil is secreted in human breast milk, but all psychotropics are assumed to be secreted in breast milk

âœ1⁄2 Recommended either to discontinue drug or bottle feed

The Art of Psychopharmacology Potential Advantages

Selective for areas of brain involved in sleep/wake promotion Less activating and less abuse potential than stimulants

Potential Disadvantages

May not work as well as stimulants in some patients

Sleepiness

Primary Target Symptoms

Concentration

Physical and mental fatigue

Pearls

Armodafinil is the longer-lasting R enantiomer of racemic modafinil

Armodafinil maintains high plasma concentrations later in the day than does modafinil on a mg-to-mg basis, which could theoretically result in improved wakefulness throughout the day with armodafinil compared to modafinil

âœ1⁄2 Armodafinil is not a replacement for sleep

âœ1⁄2 The treatment for sleep deprivation is sleep, not armodafinil

Controlled studies suggest armodafinil improves attention in OSAHS and shift work sleep disorder, but controlled studies of attention have not been performed in ADHD or major depressive disorder

Controlled studies of racemic modafinil in ADHD suggest improvement in attention

âœ1⁄2 May be useful to treat fatigue in patients with depression as well as other disorders, such as multiple sclerosis, myotonic dystrophy, HIV/AIDS

May be useful in treating sleepiness associated with opioid analgesia, particularly in end-of-life management

Subjective sensation associated with armodafinil is usually one of normal wakefulness, not of stimulation, although jitteriness can rarely occur

âœ1⁄2 Compared to traditional stimulants, armodafinil has a novel mechanism of action, novel therapeutic uses, and less abuse potential

Alpha 1 antagonists such as prazosin may block the therapeutic actions of armodafinil

Some controlled trials suggest efficacy in bipolar depression as an adjunct to atypical antipsychotics

Suggested Reading

Darwish M , Kirby M , Hellriegel ET , Robertson P Jr . Interaction profile of armodafinil with medications metabolized by cytochrome P450 enzymes 1A2, 3A4, and 2C19 in healthy subjects . Clin Pharmacokinet 2008 ;47 (1 ):61 – 74 .

Darwish M , Kirby M , Hellriegel ET , Robertson P Jr. Armodafinil and modafinil have substantially different pharmacokinetic profiles despite having the same terminal half-lives: analysis of data from three randomized, single-dose, pharmacokinetic studies . Clin Drug Investig 2009 ;29 (9 ):613– 23 .

Garnock-Jones KP , Dhillon S , Scott LJ . Armodafinil . CNS Drugs 2009 ;23 (9 ):793 – 803 .

Asenapine

No

Generic?

Class

SaphrisSecuado (transdermal)

see index for additional brand names

Therapeutics Brands

Neuroscience-based Nomenclature: dopamine, serotonin, norepinephrine receptor antagonist (DSN-RAn)

Atypical antipsychotic (serotonin-dopamine antagonist; second- generation antipsychotics; also a mood stabilizer)

Commonly Prescribed for

(bold for FDA approved)

Schizophrenia, adults (Saphris, Secuado)

Acute mania/mixed mania, monotherapy, ages 10 to 17 and in adults (Saphris)

Acute mania/mixed mania, adjunct to lithium or valproate, adults (Saphris)

Bipolar maintenance, adults (Saphris)

Other psychotic disorders

Bipolar maintenance

Bipolar depression

Treatment-resistant depression

Behavioral disturbances in dementia

Behavioral disturbances in children and adolescents Disorders associated with problems with impulse control Posttraumatic stress disorder

How the Drug Works

Blocks dopamine 2 receptors, reducing positive symptoms of psychosis and stabilizing affective symptoms

Blocks serotonin 2A receptors, causing enhancement of dopamine release in certain brain regions and thus reducing motor side effects and possibly improving cognitive and affective symptoms

Interactions at a myriad of other neurotransmitter receptors may contribute to asenapineâ€TM s efficacy

Partial agonist at 5HT1A receptors, which may be beneficial for mood, anxiety, and cognition in a number of disorders

âœ1⁄2 Serotonin 2C, serotonin 7, and alpha 2 antagonist properties may contribute to antidepressant actions

How Long Until It Works

Psychotic symptoms can improve within 1 week, but it may take several weeks for full effect on behavior as well as on cognition

Classically recommended to wait at least 4– 6 weeks to determine efficacy of drug, but in practice some patients may require up to 16– 20 weeks to show a good response, especially on negative or cognitive symptoms

If It Works

Most often reduces positive symptoms but does not eliminate them

Can improve negative symptoms, as well as aggressive, cognitive, and affective symptoms in schizophrenia

Most schizophrenia patients do not have a total remission of symptoms but rather a reduction of symptoms by about a third

Perhaps 5– 15% of schizophrenia patients can experience an overall improvement of greater than 50– 60%, especially when receiving stable treatment for more than a year

Such patients are considered super-responders or “ awakeners†since they may be well enough to be employed, live independently, and sustain long-term relationships

Many bipolar patients may experience a reduction of symptoms by half or more

Continue treatment until reaching a plateau of improvement

After reaching a satisfactory plateau, continue treatment for at least a year after first episode of psychosis

For second and subsequent episodes of psychosis, treatment may need to be indefinite

Even for first episodes of psychosis, it may be preferable to continue treatment indefinitely to avoid subsequent episodes

Treatment may not only reduce mania but also prevent recurrences of mania in bipolar disorder

If It Doesnâ€TM t Work

Try one of the other atypical antipsychotics

If 2 or more antipsychotic monotherapies do not work, consider clozapine

Some patients may require treatment with a conventional antipsychotic

If no first-line atypical antipsychotic is effective, consider higher doses or augmentation with valproate or lamotrigine

Consider noncompliance and switch to another antipsychotic with fewer side effects or to an antipsychotic that can be given by depot injection

Consider initiating rehabilitation and psychotherapy such as cognitive remediation

Consider presence of concomitant drug abuse

Best Augmenting Combos for Partial Response or Treatment Resistance

Valproic acid (valproate, divalproex, divalproex ER)

Other mood-stabilizing anticonvulsants (carbamazepine, oxcarbazepine, lamotrigine)

Lithium Topiramate Benzodiazepines

Tests

Before starting an atypical antipsychotic

âœ1⁄2 Weigh all patients and track BMI during treatment

Get baseline personal and family history of diabetes, obesity,

dyslipidemia, hypertension, and cardiovascular disease

âœ1⁄2 Get waist circumference (at umbilicus), blood pressure, fasting plasma glucose, and fasting lipid profile

Determine if the patient

is overweight (BMI 25.0– 29.9)

is obese (BMI ≥ 30)

has pre-diabetes (fasting plasma glucose 100– 125 mg/dL)

has diabetes (fasting plasma glucose ≥ 126 mg/dL)

has hypertension (BP >140/90 mmHg)

has dyslipidemia (increased total cholesterol, LDL cholesterol, and triglycerides; decreased HDL cholesterol)

Treat or refer such patients for treatment, including nutrition and weight management, physical activity counseling, smoking cessation, and medical management

Monitoring after starting an atypical antipsychotic âœ1⁄2 BMI monthly for 3 months, then quarterly

âœ1⁄2 Consider monitoring fasting triglycerides monthly for several months in patients at high risk for metabolic complications and when initiating or switching antipsychotics

âœ1⁄2 Blood pressure, fasting plasma glucose, fasting lipids within 3 months and then annually, but earlier and more frequently for patients with diabetes or who have gained >5% of initial weight

Treat or refer for treatment and consider switching to another atypical antipsychotic for patients who become overweight, obese, pre-diabetic, diabetic, hypertensive, or dyslipidemic while receiving an atypical antipsychotic

âœ1⁄2 Even in patients without known diabetes, be vigilant for the rare but life-threatening onset of diabetic ketoacidosis, which always requires immediate treatment, by monitoring for the rapid onset of polyuria, polydipsia, weight loss, nausea, vomiting, dehydration, rapid respiration, weakness and clouding of sensorium, even coma

Patients with low white blood cell count (WBC) or history of drug- induced leukopenia/neutropenia should have complete blood count (CBC) monitored frequently during the first few months and asenapine should be discontinued at the first sign of decline in WBC in the absence of other causative factors

Patients should be monitored periodically for the development of abnormal movements of tardive dyskinesia, using neurological exam and the AIMS (Abnormal Involuntary Movement Scale)

Side Effects

How Drug Causes Side Effects

Acute blockade of dopamine 2 receptors in the striatum can cause drug-induced parkinsonism, dystonia, or akathisia

Chronic blockade of dopamine 2 receptors in the striatum can cause tardive dyskinesia

By blocking dopamine 2 receptors in the pituitary, it can cause elevations in prolactin

Blocking alpha 1 adrenergic receptors can cause dizziness, hypotension, and syncope

Mechanism of weight gain and increased incidence of diabetes and dyslipidemia with atypical antipsychotics is unknown, and risks vary based on the particular agent

Notable Side Effects

âœ1⁄2 Sedation, dizziness Oral hypoesthesia

Application site reactions (oral ulcers, blisters, peeling/sloughing, inflammation for sublingual; irritation, burning for transdermal)

âœ1⁄2 Drug-induced parkinsonism, akathisia

âœ1⁄2 May increase risk for diabetes and dyslipidemia

Tardive dyskinesia (reduced risk compared to conventional antipsychotics)

Risk of potentially irreversible involuntary dyskinetic movements may increase with cumulative dose and treatment duration

Orthostatic hypotension

Life-Threatening or Dangerous Side Effects

Type 1 hypersensitivity reactions (anaphylaxis, angioedema, low blood pressure, rapid heart rate, swollen tongue, difficulty breathing, wheezing, rash)

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients taking atypical antipsychotics

As a class, antipsychotics are associated with an increased risk of death and cerebrovascular events in elderly patients with dementia; not approved for treatment of dementia-related psychosis

Rare neuroleptic malignant syndrome (NMS) may cause hyperpyrexia, muscle rigidity, delirium, and autonomic instability with elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure

Rare seizures

Weight Gain

Occurs in a significant minority

May be less than for some antipsychotics, more than for others

Sedation

Many experience and/or can be significant in amount

Wait Wait

What to Do About Side Effects

Wait

Anticholinergics may reduce drug-induced parkinsonism when present

Beta blockers, benzodiazepines, or 5HT2A antagonists (e.g., mirtazapine, cyproheptadine) may reduce akathisia

Weight loss, exercise programs, and medical management for high BMIs, diabetes, dyslipidemia

Metformin may help prevent or reverse antipsychotic-induced weight gain

Switch to another atypical antipsychotic

Best Augmenting Agents for Side Effects

Beta blockers, benzodiazepines, or 5HT2A antagonists (e.g., mirtazapine, cyproheptadine) for akathisia

Benztropine, trihexyphenidyl, or amantadine for drug-induced parkinsonism

Valbenazine or deutetrabenazine for tardive dyskinesia

Many side effects cannot be improved with an augmenting agent

Dosing and Use Usual Dosage Range

Schizophrenia and bipolar mania (sublingual): 10– 20 mg/day in 2 divided doses

Schizophrenia (transdermal): 3.8 mg/24 hours

Dosage Forms

Sublingual tablet 2.5 mg, 5 mg, 10 mg

Transdermal system 3.8 mg/24 hours, 5.7 mg/24 hours, 7.6 mg/24 hours

How to Dose – Sublingual

Must be administered sublingually; patients may not eat or drink for 10 minutes following administration

Schizophrenia: initial 10 mg/day in 2 divided doses; maximum dose generally 20 mg/day in 2 divided doses; limited experience with once daily administration

Bipolar mania (adults, monotherapy): initial 20 mg/day in 2 divided doses; can reduce dose to 10 mg/day in 2 divided doses if there are adverse effects

Bipolar mania (adults, adjunct): initial 10 mg/day in 2 divided doses; can increase to 20 mg/day in 2 divided doses

Bipolar mania (children, monotherapy): initial 5 mg/day in 2 divided doses; after 3 days can increase to 10 mg/day in 2 divided doses; after 3 more days can increase to 20 mg/day in 2 divided doses

Pediatric patients may be more sensitive to dystonia with initial dosing if the recommended titration schedule is not followed

How to Dose – Transdermal

Apply one Secuado transdermal system every 24 hours to one of the following sites: hip, abdomen, upper arm, or lower back area

Recommended starting dose: 3.8 mg/24 hours

After 1 week, may increase to 5.7 mg/24 hours or 7.6 mg/24 hours

Dosing Tips – Sublingual

Asenapine is not absorbed after swallowing (less than 2% bioavailable orally) and thus must be administered sublingually (35% bioavailable), as swallowing would render asenapine inactive

Patients should be instructed to place the tablet under the tongue and allow it to dissolve completely, which will occur in seconds; tablet should not be divided, crushed, chewed, or swallowed

Patients may not eat or drink for 10 minutes following sublingual administration so that the drug in the oral cavity can be absorbed locally and not washed into the stomach (where it would not be absorbed)

Once daily use seems theoretically possible because the half-life of asenapine is 13– 39 hours, but this has not been extensively studied and may be limited by the need to expose the limited

sublingual surface area to a limited amount of sublingual drug dosage

Some patients may respond to doses greater than 20 mg/day but no single administration should be greater than 10 mg, thus necessitating 3 or 4 separate daily doses

Rather than raise the dose above normal dosing in acutely agitated patients requiring acute antipsychotic actions, consider short-term (one dose or more) augmentation with a benzodiazepine or another antipsychotic, especially intramuscularly

Rather than raise the dose above normal dosing in partial responders, consider augmentation with a mood-stabilizing anticonvulsant, such as valproate, topiramate, or lamotrigine

Children and elderly should generally be dosed at the lower end of the dosage spectrum

Due to rapid onset of action, can be used as a rapid acting “ prn†or “ as needed†dose for agitation or transient worsening of psychosis or mania instead of an injection

Treatment should be suspended if absolute neutrophil count falls below 1000/mm3

Dosing Tips – Transdermal

Based on the average exposure (AUC) of asenapine, Secuado 3.8 mg/24 hours corresponds to 5 mg twice daily of sublingual

asenapine, and Secuado 7.6 mg/24 hours corresponds to 10 mg twice daily of sublingual asenapine

Instruct patient to select a different transdermal system application site each day to limit the occurrence of skin reactions

Do not cut Secuado; the whole transdermal system should be applied

Discard Secuado by folding the used transdermal system so that the adhesive side sticks to itself, and dispose of safely

If irritation or a burning sensation occurs while wearing Secuado, remove the system and apply a new transdermal system to a new application site

Showering is permitted, but the use of Secuado during swimming or taking a bath has not been evaluated

Treatment should be suspended if absolute neutrophil count falls below 1000/mm3

Agitation, confusion

Overdose

Long-Term Use

Should periodically reevaluate long-term usefulness in individual patients, but treatment may need to continue for many years

Habit Forming

No

How to Stop

Down-titration, over 2– 4 weeks when possible, especially when simultaneously beginning a new antipsychotic while switching (i.e., cross-titration)

Rapid discontinuation could theoretically lead to rebound psychosis and worsening of symptoms

Pharmacokinetics

Half-life 13– 39 hours Inhibits CYP450 2D6 Substrate for CYP450 1A2

Optimal bioavailability is with sublingual administration (~35%); if food or liquid is consumed within 10 minutes of administration bioavailability decreases to 28%; bioavailability decreases to 2% if swallowed

Transdermal: maximum asenapine concentrations are typically reached between 12 and 24 hours, with sustained concentrations during wear time (24 hours); following removal, elimination half- life is approximately 30 hours

Drug Interactions

May increase effects of antihypertensive agents

May antagonize levodopa, dopamine agonists

CYP450 1A2 inhibitors (e.g., fluvoxamine) can raise asenapine levels

Via CYP450 2D6 inhibition, asenapine could theoretically interfere with the analgesic effects of codeine, and increase the plasma levels of some beta blockers and of atomoxetine

Via CYP450 2D6 inhibition, asenapine could theoretically increase concentrations of thioridazine and cause dangerous cardiac arrhythmias

Other Warnings/Precautions

Use with caution in patients with conditions that predispose to hypotension (dehydration, overheating)

Atypical antipsychotics have the potential for cognitive and motor impairment, especially related to sedation

Atypical antipsychotics can cause body temperature dysregulation; use caution in patients who may experience conditions that increase body temperature (e.g., strenuous exercise, saunas, extreme heat, dehydration, or concomitant anticholinergic medication)

Dysphagia has been associated with antipsychotic use, and asenapine should be used cautiously in patients at risk for aspiration pneumonia

As with any antipsychotic, use with caution in patients with history of seizures

Antipsychotics may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls; for patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment, and recurrently for patients on long-term antipsychotic therapy

Avoid exposing transdermal system to external heat sources during wear, because both the rate and extent of absorption are increased

During wear time or immediately after removal of transdermal system, local skin reactions may occur

Do Not Use

Severe hepatic impairment (Child-Pugh C)

If there is a proven allergy to asenapine or any components in the transdermal system

Special Populations Renal Impairment

Dose adjustment not generally necessary

Hepatic Impairment

No dose adjustment necessary for mild to moderate impairment Contraindicated in patients with severe hepatic impairment

Cardiac Impairment

Use in patients with cardiac impairment has not been studied, so use with caution because of risk of orthostatic hypotension

Use with caution if patient is taking concomitant antihypertensive or alpha 1 antagonist

Elderly

Some patients may tolerate lower doses better

Although atypical antipsychotics are commonly used for behavioral disturbances in dementia, no agent has been approved for treatment of elderly patients with behavioral symptoms of dementia such as agitation

Elderly patients with dementia-related psychosis treated with atypical antipsychotics are at an increased risk of death compared to placebo, and also have an increased risk of cerebrovascular events

Consider pimavanserin for dementia-related psychosis or Parkinson’s disease psychosis instead of an atypical antipsychotic

Children and Adolescents

Transdermal asenapine is approved only in adults

Sublingual asenapine is approved to treat acute manic/mixed episodes of bipolar I disorder in children ages 10 and older

Efficacy of sublingual asenapine for schizophrenia was not demonstrated in an 8-week, placebo-controlled, double-blind trial in

adolescent patients ages 12 to 17 years

Children and adolescents using asenapine may need to be monitored more often than adults and may tolerate lower doses better

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women

There is a risk of abnormal muscle movements and withdrawal symptoms in newborns whose mothers took an antipsychotic during the third trimester; symptoms may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty feeding

In animal studies, asenapine increased post-implantation loss and decreased pup weight and survival at doses similar to or less than recommended clinical doses; there was no increase in the incidence of structural abnormalities

Psychotic symptoms may worsen during pregnancy and some form of treatment may be necessary

National Pregnancy Registry for Atypical Antipsychotics: 1-866- 961-2388, https://womensmentalhealth.org/research/pregnancyregistry/atypical antipsychotic/

Breast Feeding

Unknown if asenapine is secreted in human breast milk, but all psychotropics are assumed to be secreted in breast milk

âœ1⁄2 Recommended either to discontinue drug or bottle feed Infants of women who choose to breast feed while on asenapine

should be monitored for possible adverse effects

The Art of Psychopharmacology Potential Advantages

Patients requiring rapid onset of antipsychotic action without dosage titration

Potential Disadvantages

Patients who are less likely to be adherent

Efficacy for schizophrenia was not demonstrated in an 8-week, placebo-controlled, double-blind trial in adolescent patients ages 12 to 17 years

Primary Target Symptoms

Positive symptoms of psychosis

Negative symptoms of psychosis

Cognitive symptoms

Unstable mood (both depression and mania) Aggressive symptoms

Pearls

Asenapineâ€TM s chemical structure is related to the antidepressant mirtazapine and it shares many of the same pharmacologic binding properties of mirtazapine plus many others

Not approved for depression, but binding properties suggest potential use in treatment-resistant and bipolar depression

Sublingual administration may require prescribing asenapine to reliable, adherent patients, or those who have someone who can supervise drug administration

Asenapine has a more rapid onset of action (Cmax) when given sublingually than most atypical antipsychotics do when given orally, and thus may be suitable for use as a prn (as needed) agent to treat acute agitation in patients with schizophrenia when an injection is not possible

Patients with inadequate responses to atypical antipsychotics may benefit from determination of plasma drug levels and, if low, a dosage increase even beyond the usual prescribing limits

Patients with inadequate responses to atypical antipsychotics may also benefit from a trial of augmentation with a conventional antipsychotic or switching to a conventional antipsychotic

However, long-term polypharmacy with a combination of a conventional antipsychotic with an atypical antipsychotic may combine their side effects without clearly augmenting the efficacy of either

For treatment-resistant patients, especially those with impulsivity, aggression, violence, and self-harm, long-term polypharmacy with 2 atypical antipsychotics or with 1 atypical antipsychotic and 1 conventional antipsychotic may be useful or even necessary while closely monitoring

In such cases, it may be beneficial to combine 1 depot antipsychotic with 1 oral antipsychotic

Although a frequent practice by some prescribers, adding 2 conventional antipsychotics together has little rationale and may reduce tolerability without clearly enhancing efficacy

The Art of Switching

Switching from Oral Antipsychotics to Asenapine

With amisulpride, aripiprazole, brexpiprazole, cariprazine, lumateperone, and paliperidone ER, immediate stop is possible; begin asenapine at middle dose

With risperidone, ziprasidone, iloperidone, and luasidone, begin asenapine gradually, titrating over at least 2 weeks to allow patients to become tolerant to the sedating effect

* May need to taper clozapine slowly over 4 weeks or longer

Suggested Reading

Citrome L . Asenapine for schizophrenia and bipolar disorder: a review of the efficacy and safety profile for this newly approved sublingually absorbed second-generation antipsychotic . Int J Clin Pract 2009 ;63 (12 ):1762– 84 .

Huhn M , Nikolakopoulou A , Schneider-Thoma J , et al. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis . Lancet 2019 ;394 :939– 51 .

Shahid M , Walker GB , Zorn SH , Wong EH . Asenapine: a novel psychopharmacologic agent with a unique human receptor signature . J

Psychopharmacol 2009 ;23 (1 ):65 – 73 .

Tarazi F , Stahl SM . Iloperidone, asenapine and lurasidone: a primer on their current status . Exp Opin Pharmacother 2012 ;13 (13 ):1911– 22 .

Atomoxetine

Strattera

Therapeutics Brands

see index for additional brand names

Yes

Generic?

Class

Neuroscience-based Nomenclature: norepinephrine reuptake inhibitor (N-RI)

Selective norepinephrine reuptake inhibitor (NRI)

Commonly Prescribed for

(bold for FDA approved)

Attention deficit hyperactivity disorder (ADHD) in adults and children over 6

Treatment-resistant depression

How the Drug Works

Boosts neurotransmitter norepinephrine/noradrenaline and may also increase dopamine in prefrontal cortex

Blocks norepinephrine reuptake pumps, also known as norepinephrine transporters

Presumably this increases noradrenergic neurotransmission

Since dopamine is inactivated by norepinephrine reuptake in frontal cortex, which largely lacks dopamine transporters, atomoxetine can also increase dopamine neurotransmission in this part of the brain

How Long Until It Works

âœ1⁄2 Onset of therapeutic actions in ADHD can be seen as early as the

first day of dosing

Therapeutic actions may continue to improve for 8– 12 weeks If it is not working within 6– 8 weeks, it may not work at all

If It Works

The goal of treatment of ADHD is reduction of symptoms of inattentiveness, motor hyperactivity, and/or impulsiveness that disrupt social, school, and/or occupational functioning

Continue treatment until all symptoms are under control or improvement is stable and then continue treatment indefinitely as long as improvement persists

Reevaluate the need for treatment periodically

Treatment for ADHD begun in childhood may need to be continued into adolescence and adulthood if continued benefit is documented

If It Doesnâ€TM t Work

Consider adjusting dose or switching to another agent Consider behavioral therapy

Consider the presence of noncompliance and counsel patient and parents

Consider evaluation for another diagnosis or for a comorbid condition (e.g., bipolar disorder, substance abuse, medical illness, etc.)

Some patients may experience apparent lack of consistent efficacy due to activation of latent or underlying bipolar disorder, and require atomoxetine discontinuation and a switch to a mood stabilizer

Best Augmenting Combos for Partial Response or Treatment Resistance

âœ1⁄2 Best to attempt other monotherapies prior to augmenting

SSRIs, SNRIs, or mirtazapine for treatment-resistant depression (use combinations of antidepressants with atomoxetine with caution as this may theoretically activate bipolar disorder and suicidal ideation)

Mood stabilizers or atypical antipsychotics for comorbid bipolar disorder

For the expert, can combine with modafinil, methylphenidate, or amphetamine for ADHD

Tests

None recommended for healthy patients

May be prudent to monitor blood pressure and pulse when initiating treatment and until dosage increments have stabilized

Side Effects

How Drug Causes Side Effects

Norepinephrine increases in parts of the brain and body and at receptors other than those that cause therapeutic actions (e.g., unwanted actions of norepinephrine on acetylcholine release causing decreased appetite, increased heart rate and blood pressure, dry mouth, urinary retention, etc.)

Most side effects are immediate but often go away with time

Lack of enhancing dopamine activity in limbic areas theoretically explains atomoxetineâ€TM s lack of abuse potential

Notable Side Effects âœ1⁄2 Sedation, fatigue (particularly in children)

âœ1⁄2 Decreased appetite âœ1⁄2 Rare priapism

Increased heart rate (6– 9 beats/min)

Increased blood pressure (2– 4 mmHg)

Insomnia, dizziness, anxiety, agitation, aggression, irritability

Dry mouth, constipation, nausea, vomiting, abdominal pain, dyspepsia

Urinary hesitancy, urinary retention (older men) Dysmenorrhea, sweating

Sexual dysfunction (men: decreased libido, erectile disturbance, impotence, ejaculatory dysfunction, abnormal orgasm; women: decreased libido, abnormal orgasm)

Life-Threatening or Dangerous Side Effects

Increased heart rate and hypertension

Orthostatic hypotension

Severe liver damage (rare)

Hypomania and, theoretically, rare induction of mania

Rare activation of suicidal ideation and behavior (suicidality) (short- term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo beyond age 24)

Weight Gain

Reported but not expected

Patients may experience weight loss

Sedation

Occurs in significant minority, particularly in children

Wait

Wait

Wait

Lower the dose

What to Do About Side Effects

If giving once daily, can change to split dose twice daily

If atomoxetine is sedating, take at night to reduce daytime drowsiness

In a few weeks, switch or add other drugs

Best Augmenting Agents for Side Effects

For urinary hesitancy, give an alpha 1 blocker such as tamsulosin

Often best to try another monotherapy prior to resorting to augmentation strategies to treat side effects

Many side effects are dose-dependent (i.e., they increase as dose increases, or they reemerge until tolerance redevelops)

Many side effects are time-dependent (i.e., they start immediately upon dosing and upon each dose increase, but go away with time)

Activation and agitation may represent the induction of a bipolar state, especially a mixed dysphoric bipolar II condition sometimes associated with suicidal ideation, and require the addition of lithium, a mood stabilizer or an atypical antipsychotic, and/or discontinuation of atomoxetine

Dosing and Use Usual Dosage Range

0.5– 1.2 mg/kg/day in children up to 70 kg; 40– 100 mg/day in adults

Dosage Forms

Capsule 10 mg, 18 mg, 25 mg, 40 mg, 60 mg, 80 mg, 100 mg

How to Dose

For children 70 kg or less: initial dose 0.5 mg/kg per day; after 7 days can increase to 1.2 mg/kg per day either once in the morning or divided; maximum dose 1.4 mg/kg per day or 100 mg/day, whichever is less

For adults and children over 70 kg: initial dose 40 mg/day; after 7 days can increase to 80 mg/day once in the morning or divided; after

2– 4 weeks can increase to 100 mg/day if necessary; maximum daily dose 100 mg

Dosing Tips

Can be given once a day in the morning

âœ1⁄2 Efficacy with once daily dosing despite a half-life of 5 hours suggests therapeutic effects persist beyond direct pharmacologic effects, unlike stimulants whose effects are generally closely correlated with plasma drug levels

Once daily dosing may increase gastrointestinal side effects

Lower starting dose allows detection of those patients who may be especially sensitive to side effects such as tachycardia and increased blood pressure

Patients especially sensitive to the side effects of atomoxetine may include those individuals deficient in the enzyme that metabolizes atomoxetine, CYP450 2D6 (i.e., 7% of Caucasians and 2% of African Americans)

In such individuals, drug should be titrated slowly to tolerability and effectiveness

Other individuals may require up to 1.8 mg/kg total daily dose

Overdose

No fatalities have been reported as monotherapy; sedation, agitation, hyperactivity, abnormal behavior, gastrointestinal symptoms

Safe

No

Taper not necessary

Long-Term Use

Habit Forming

How to Stop

Pharmacokinetics

Metabolized by CYP450 2D6 Half-life approximately 5 hours Food does not affect absorption

Drug Interactions

Tramadol increases the risk of seizures in patients taking an antidepressant

Plasma concentrations of atomoxetine may be increased by drugs that inhibit CYP450 2D6 (e.g., paroxetine, fluoxetine), so atomoxetine dose may need to be reduced if coadministered

Coadministration of atomoxetine and oral or IV albuterol may lead to increases in heart rate and blood pressure

Coadministration with methylphenidate does not increase cardiovascular side effects beyond those seen with methylphenidate alone

Use with caution with MAOIs, including 14 days after MAOIs are stopped (for the expert)

Other Warnings/Precautions

Growth (height and weight) should be monitored during treatment with atomoxetine; for patients who are not growing or gaining weight satisfactorily, interruption of treatment should be considered

Use with caution in patients with hypertension, tachycardia, cardiovascular disease, or cerebrovascular disease

Use with caution in patients with bipolar disorder

Use with caution in patients with urinary retention, benign prostatic hypertrophy

Rare reports of hepatotoxicity; although causality has not been established, atomoxetine should be discontinued in patients who develop jaundice or other evidence of significant liver dysfunction

Use with caution with antihypertensive drugs

Increased risk of sudden death has been reported in children with structural cardiac abnormalities or other serious heart conditions

When treating children, carefully weigh the risks and benefits of pharmacological treatment against the risks and benefits of

nontreatment and make sure to document this in the patientâ€TM s chart

Distribute the brochures provided by the FDA and the drug companies

Whenever possible, warn patients and their caregivers about the possibility of activating side effects, and advise them to report such symptoms immediately

Monitor patients for activation of suicidal ideation, especially children and adolescents

Do Not Use

If patient is taking an MAOI (except as noted under Drug Interactions)

If patient has pheochromocytoma or history of pheochromocytoma

If patient has a severe cardiovascular disorder that might deteriorate with clinically important increases in heart rate and blood pressure

If patient has angle-closure glaucoma

If there is a proven allergy to atomoxetine

Special Populations

Renal Impairment

Dose adjustment not generally necessary

Hepatic Impairment

For patients with moderate liver impairment, dose should be reduced to 50% of normal dose

For patients with severe liver impairment, dose should be reduced to 25% of normal dose

Cardiac Impairment

Use with caution because atomoxetine can increase heart rate and blood pressure

Do not use in patients with structural cardiac abnormalities

Elderly

Some patients may tolerate lower doses better

Reduction in the risk of suicidality with antidepressants compared to placebo in adults age 65 and older

Children and Adolescents

Approved to treat ADHD in children over age 6 Recommended target dose is 1.2 mg/kg per day

Do not use in children with structural cardiac abnormalities or other serious cardiac problems

Carefully weigh the risks and benefits of pharmacological treatment against the risks and benefits of nontreatment and make sure to

document this in the patientâ€TM s chart

Monitor patients face-to-face regularly, particularly during the first several weeks of treatment

Use with caution, observing for activation of known or unknown bipolar disorder and/or suicidal ideation, and inform parents or guardians of this risk so they can help observe child or adolescent patients

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women Some animal studies have shown adverse effects

Use in women of childbearing potential requires weighing potential benefits to the mother against potential risks to the fetus

âœ1⁄2 For women of childbearing potential, atomoxetine should generally be discontinued before anticipated pregnancies

Breast Feeding

Unknown if atomoxetine is secreted in human breast milk, but all psychotropics are assumed to be secreted in breast milk

âœ1⁄2 Recommend either to discontinue drug or bottle feed

The Art of Psychopharmacology Potential Advantages

No known abuse potential

Potential Disadvantages

May not act as rapidly as stimulants when initiating treatment in some patients

Primary Target Symptoms

Concentration, attention span Motor hyperactivity Depressed mood

Pearls

âœ1⁄2 Unlike stimulants approved for ADHD, atomoxetine does not

have abuse potential and is not a scheduled substance

âœ1⁄2 Despite its name as a selective norepinephrine reuptake inhibitor, atomoxetine enhances both dopamine and norepinephrine in frontal

cortex, presumably accounting for its therapeutic actions on attention and concentration

Since dopamine is inactivated by norepinephrine reuptake in frontal cortex, which largely lacks dopamine transporters, atomoxetine can increase dopamine as well as norepinephrine in this part of the brain, presumably causing therapeutic actions in ADHD

Since dopamine is inactivated by dopamine reuptake in nucleus accumbens, which largely lacks norepinephrine transporters, atomoxetine does not increase dopamine in this part of the brain, presumably explaining why atomoxetine lacks abuse potential

Atomoxetineâ€TM s known mechanism of action as a selective norepinephrine reuptake inhibitor suggests its efficacy as an antidepressant

Pro-noradrenergic actions may be theoretically useful for the treatment of chronic pain

Atomoxetineâ€TM s mechanism of action and its potential antidepressant actions suggest it has the potential to destabilize latent or undiagnosed bipolar disorder, similar to the known actions of proven antidepressants

Thus, administer with caution to ADHD patients who may also have bipolar disorder

Unlike stimulants, atomoxetine may not exacerbate tics in Touretteâ€TM s syndrome patients with comorbid ADHD

Urinary retention in men over 50 with borderline urine flow has been observed with other agents with potent norepinephrine reuptake blocking properties (e.g., reboxetine, milnacipran), so administer atomoxetine with caution to these patients

Atomoxetine was originally called tomoxetine but the name was changed to avoid potential confusion with tamoxifen, which might lead to errors in drug dispensing

Suggested Reading

Garnock-Jones KP , Keating GM . Atomoxetine: a review of its use in attention-deficit hyperactivity disorder in children and adolescents . Paediatr Drugs 2009 ;11 (3 ):203– 26 .

Kelsey D , Sumner C , Casat C , et al. Once daily atomoxetine treatment for children with attention deficit hyperactivity behavior including an assessment of evening and morning behavior: a double-blind, placebo- controlled trial . Pediatrics 2004 ;114 :el – 8.

Michelson D , Adler L L , Spencer T , et al. Atomoxetine in adults with ADHD: two randomized, placebo-controlled studies . Biol Psychiatry 2003 ;53 (2 ):112– 20 .

Michelson D , Buitelaar JK , Danckaerts M , et al. Relapse prevention in pediatric patients with ADHD treated with atomoxetine: a randomized, double-blind, placebo-controlled study . J Am Acad Child Adolesc Psychiatry 2004 ;43 (7 ):896 – 904 .

Stiefel G , Besag FM . Cardiovascular effects of methylphenidate, amphetamines, and atomoxetine in the treatment of attention-deficit hyperactivity disorder . Drug Saf 2010 ;33 (10 ):821– 42 .

Benztropine

Cogentin

Therapeutics Brands

Yes

Generic?

Class

see index for additional brand names

Antiparkinson agent; anticholinergic

Commonly Prescribed for

(bold for FDA approved)

Extrapyramidal disorders (drug-induced parkinsonism) Parkinsonism

Acute dystonic reactions

Idiopathic generalized dystonia

Focal dystonias Dopa-responsive dystonia

How the Drug Works

Diminishes the excess acetylcholine activity caused by removal of dopamine inhibition when dopamine receptors are blocked

May also inhibit the reuptake and storage of dopamine at central dopamine receptors, prolonging dopamine action

How Long Until It Works

For drug-induced parkinsonism and in Parkinsonâ€TM s disease, onset of action can be within minutes or hours

If It Works

Does not lessen the ability of antipsychotics to cause tardive dyskinesia

If It Doesnâ€TM t Work

Consider switching to trihexyphenidyl, diphenhydramine, or a benzodiazepine

Disorders that develop after prolonged antipsychotic use may not respond to treatment

Consider discontinuing the agent that precipitated the parkinsonism

Best Augmenting Combos for Partial Response or Treatment Resistance

Reduces motor side effects

If ineffective, switch to another agent rather than augment Benztropine is itself an augmenting agent to antipsychotics

Tests

Side Effects

How Drug Causes Side Effects

Prevents the action of acetylcholine on muscarinic receptors

Notable Side Effects

Dry mouth, blurred vision, diplopia

Confusion, hallucinations

Constipation, nausea, vomiting

Dilation of colon/paralytic ileus/bowel obstruction Erectile dysfunction

Life-Threatening or Dangerous Side Effects

Angle-closure glaucoma

Heat stroke, especially in elderly patients Tachycardia, cardiac arrhythmias, hypotension

None for healthy individuals

Urinary retention

Anticholinergic agents such as benztropine can exacerbate or unmask tardive dyskinesia

Weight Gain

Sedation

Many experience and/or can be significant in amount

What to Do About Side Effects

For confusion or hallucinations, discontinue use

For sedation, lower the dose and/or take the entire dose at night

For dry mouth, chew gum or drink water

For urinary retention, obtain a urological evaluation; may need to discontinue use

Best Augmenting Agents for Side Effects

Many side effects cannot be improved with an augmenting agent

Dosing and Use

Reported but not expected

Usual Dosage Range

Drug-induced parkinsonism: 2– 8 mg/day Parkinsonism: 0.5– 6 mg/day

Dosage Forms

Tablet 0.5 mg, 1 mg, 2 mg Injection 1 mg/mL

How to Dose

Drug-induced parkinsonism: 1– 4 mg once or twice daily; can be given orally or parenterally

Parkinsonism (oral): initial 0.5 mg once daily; increase by 0.5 mg at 5– 6 day intervals until desired efficacy is reached

Dosing Tips

If drug-induced parkinsonism occurs soon after initiation of a neuroleptic drug, it is likely to be transient; thus, attempt to withdraw benztropine after 1– 2 weeks to determine if still needed

Patients may take benztropine once daily at night to improve sleep and allow for earlier rising in the morning

Taking benztropine with meals can reduce side effects

Intramuscular and intravenous dosing are equally effective and fast- acting

Overdose

Circulatory collapse, cardiac arrest, respiratory depression or arrest, psychosis, shock, coma, seizure, ataxia, combativeness, anhidrosis and hyperthermia, fever, dysphagia, decreased bowel sounds, sluggish pupils

Long-Term Use

Safe

Effectiveness may decrease over time (years), and side effects such as sedation and cognitive impairment may worsen

No

Taper not necessary

Habit Forming

How to Stop

Pharmacokinetics

Half-life 36 hours, although greatest effect lasts about 6– 8 hours Metabolism is not well understood

Drug Interactions

Use with amantadine may increase side effects

Benztropine and all other anticholinergic agents may increase serum levels and effects of digoxin

Can lower concentration of haloperidol and other phenothiazines, causing worsening of schizophrenia symptoms

Can decrease gastric motility, resulting in increased gastric deactivation of levodopa and reduction in efficacy

Other Warnings/Precautions

Use with caution in hot weather, as benztropine may increase susceptibility to heat stroke

Anticholinergic agents have additive effects when used with drugs of abuse such as cannabinoids, barbiturates, opioids, and alcohol

Do Not Use

In patients with glaucoma, particularly angle-closure glaucoma

In patients with pyloric or duodenal obstruction, stenosing peptic ulcers, prostate hypertrophy or bladder neck obstructions, achalasia, or megacolon

If there is a proven allergy to benztropine

Special Populations

Renal Impairment

No known effects, but use with caution

Hepatic Impairment

No known effects, but use with caution

Cardiac Impairment

Use with caution in patients with known arrhythmias, especially tachycardia

Elderly

Use with caution

Elderly patients may be more susceptible to side effects

Children and Adolescents

Do not use in children ages 3 and younger

Generalized dystonias may respond to anticholinergic treatment, and young patients usually tolerate the medication better than the elderly

Usual dose is 0.05 mg/kg once or twice daily

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women

Breast Feeding

Unknown if benztropine is secreted in human breast milk, but all psychotropics are assumed to be secreted in breast milk

âœ1⁄2 Recommended either to discontinue drug or bottle feed unless the potential benefit to the mother justifies the potential risk to the child

Infants of women who choose to breast feed while on benztropine should be monitored for possible adverse effects

The Art of Psychopharmacology Potential Advantages

Drug-induced parkinsonism, particularly in acute setting

Potential Disadvantages

Patients with long-standing drug-induced parkinsonism may not respond to treatment

Generalized dystonias (less established as treatment than trihexyphenidyl)

Primary Target Symptoms

Tremor, akinesia, rigidity, drooling

Pearls

First-line agent for drug-induced parkinsonism related to antipsychotic use

Useful adjunct in younger Parkinsonâ€TM s patients with tremor, but trihexyphenidyl is more commonly used

Useful in the treatment of post-encephalitic Parkinsonâ€TM s disease and for drug-induced parkinsonism, but not for tardive dyskinesias

Post-encephalitic Parkinsonâ€TM s patients usually tolerate higher doses better than idiopathic Parkinsonâ€TM s patients

Generalized dystonias are more likely to benefit from anticholinergic therapy than focal dystonias; trihexyphenidyl is used more commonly than benztropine

Sedation limits use, especially in older patients Patients with cognitive impairment may do poorly

Can cause cognitive side effects with chronic use, so periodic trials of discontinuation may be useful to justify continuous use, especially in institutional settings when used as an adjunct to antipsychotics

Can be abused in institutional or correctional settings

Commonly used in an oral or intramuscular formulation as needed with concomitant antipsychotics to reduce or prevent drug-induced parkinsonism

Suggested Reading

Brocks DR . Anticholinergic drugs used in Parkinsonâ€TM s disease: an overlooked class of drugs from a pharmacokinetic perspective . J Pharm Pharm Sci 1999 ;2 (2 ):39 – 46 .

Colosimo C , Gori MC , Inghilleri M . Postencephalitic tremor and delayed- onset parkinsonism . Parkinsonism Relat Disord 1999 ;5 (3 ):123– 4 .

Costa J , EspÃrito-Santo C , Borges A , et al. Botulinum toxin type A versus anticholinergics for cervical dystonia . Cochrane Database Syst Rev 2005 ;(1):CD004312 .

Hai NT , Kim J , Park ES , Chi SC . Formulation and biopharmaceutical evaluation of transdermal patch containing benztropine . Int J Pharm 2008 ;357 (1– 2 ):55 – 60 .

Blonanserin

Lonasen

Therapeutics Brands

No

Generic?

Class

see index for additional brand names

Atypical antipsychotic (serotonin dopamine antagonist; second- generation antipsychotic; also a potential mood stabilizer)

Commonly Prescribed for

(bold for FDA approved)

Schizophrenia

Acute mania/mixed mania Other psychotic disorders Bipolar maintenance

Bipolar depression Treatment-resistant depression

Behavioral disturbances in dementia

Behavioral disturbances in children and adolescents Disorders associated with problems with impulse control

How the Drug Works

Blocks dopamine 2 receptors, reducing positive symptoms of psychosis and stabilizing affective symptoms

Blocks serotonin 2A receptors, causing enhancement of dopamine release in certain brain regions and thus reducing motor side effects and possibly improving cognition and affective symptoms

Actions at dopamine 3 receptors could theoretically contribute to blonanserinâ€TM s efficacy

How Long Until It Works

Psychotic symptoms can improve within 1 week, but it may take several weeks for full effect on behavior as well as on cognition

Classically recommended to wait at least 4– 6 weeks to determine efficacy of drug, but in practice some patients may require up to 16– 20 weeks to show a good response, especially on negative or cognitive symptoms

If It Works

Most often reduces positive symptoms but does not eliminate them

Can improve negative symptoms, as well as aggressive, cognitive, and affective symptoms in schizophrenia

Most schizophrenia patients do not have a total remission of symptoms but rather a reduction of symptoms by about a third

Perhaps 5– 15% of schizophrenia patients can experience an overall improvement of greater than 50– 60%, especially when receiving stable treatment for more than a year

Such patients are considered super-responders or “ awakeners†since they may be well enough to be employed, live independently, and sustain long-term relationships

Continue treatment until reaching a plateau of improvement

After reaching a satisfactory plateau, continue treatment for at least a year after first episode of psychosis

For second and subsequent episodes of psychosis, treatment may need to be indefinite

Even for first episodes of psychosis, it may be preferable to continue treatment

If It Doesnâ€TM t Work

Try one of the other atypical antipsychotics

If 2 or more antipsychotic monotherapies do not work, consider clozapine

Some patients may require treatment with a conventional antipsychotic

If no first-line atypical antipsychotic is effective, consider higher doses or augmentation with valproate or lamotrigine

Consider noncompliance and switch to another antipsychotic with fewer side effects or to an antipsychotic that can be given by depot injection

Consider initiating rehabilitation and psychotherapy such as cognitive remediation

Consider presence of concomitant drug abuse

Best Augmenting Combos for Partial Response or Treatment Resistance

Valproic acid (valproate, divalproex, divalproex ER)

Mood-stabilizing anticonvulsants (carbamazepine, oxcarbazepine, lamotrigine)

Topiramate Lithium Benzodiazepines

Tests

Before starting any atypical antipsychotic

âœ1⁄2 Weigh all patients and track BMI during treatment

Get baseline personal and family history of diabetes, obesity,

dyslipidemia, hypertension, and cardiovascular disease

âœ1⁄2 Get waist circumference (at umbilicus), blood pressure, fasting plasma glucose, and fasting lipid profile

Determine if the patient

is overweight (BMI 25.0– 29.9)

is obese (BMI ≥ 30)

has pre-diabetes (fasting plasma glucose 100– 125 mg/dL)

has diabetes (fasting plasma glucose ≥ 126 mg/dL)

has hypertension (BP >140/90 mmHg)

has dyslipidemia (increased total cholesterol, LDL cholesterol, and triglycerides; decreased HDL cholesterol)

Treat or refer such patients for treatment, including nutrition and weight management, physical activity counseling, smoking cessation, and medical management

Monitoring after starting any atypical antipsychotic âœ1⁄2 BMI monthly for 3 months, then quarterly

âœ1⁄2 Consider monitoring fasting triglycerides monthly for several months in patients at high risk for metabolic complications and when initiating or switching antipsychotics

âœ1⁄2 Blood pressure, fasting plasma glucose, fasting lipids within 3 months and then annually, but earlier and more frequently for patients with diabetes or who have gained >5% of initial weight

Treat or refer for treatment and consider switching to another atypical antipsychotic for patients who become overweight, obese, pre-diabetic, diabetic, hypertensive, or dyslipidemic while receiving an atypical antipsychotic

âœ1⁄2 Even in patients without known diabetes, be vigilant for the rare but life-threatening onset of diabetic ketoacidosis, which always requires immediate treatment, by monitoring for the rapid onset of polyuria, polydipsia, weight loss, nausea, vomiting, dehydration, rapid respiration, weakness and clouding of sensorium, even coma

Patients with low white blood cell count (WBC) or history of drug- induced leukopenia/neutropenia should have complete blood count (CBC) monitored frequently during the first few months, and blonanserin should be discontinued at the first sign of decline in WBC in the absence of other causative factors

Patients should be monitored periodically for the development of abnormal movements of tardive dyskinesia, using neurological exam and the AIMS (Abnormal Involuntary Movement Scale)

Side Effects

How Drug Causes Side Effects

Acute blockade of dopamine 2 receptors in the striatum can cause drug-induced parkinsonism, dystonia, or akathisia

Chronic blockade of dopamine 2 receptors in the striatum can cause tardive dyskinesia

By blocking dopamine 2 receptors in the pituitary, it can cause elevations in prolactin

Mechanism of weight gain and increased incidence of diabetes and dyslipidemia with atypical antipsychotics is unknown, and risks vary based on the particular agent

Notable Side Effects

Akathisia, drug-induced parkinsonism

Insomnia, anxiety, sedation

Urinary retention

Tardive dyskinesia (TD) (reduced risk compared to conventional antipsychotics)

Risk of potentially irreversible involuntary dyskinetic movements may increase with cumulative dose and treatment duration

Life-Threatening or Dangerous Side Effects

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients taking atypical antipsychotics

As a class, antipsychotics are associated with an increased risk of death and cerebrovascular events in elderly patients with dementia; not approved for treatment of dementia-related psychosis

Rare neuroleptic malignant syndrome (NMS) may cause hyperpyrexia, muscle rigidity, delirium, and autonomic instability with elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure

Rare seizures

Weight Gain

Sedation

Many experience and/or can be significant in amount

What to Do About Side Effects

Wait Wait Wait

Anticholinergics may reduce drug-induced parkinsonism when present

Reported but not expected

Beta blockers, benzodiazepines, or 5HT2A antagonists (e.g., mirtazapine, cyproheptadine) may reduce akathisia

Weight loss, exercise programs, and medical management for high BMIs, diabetes, dyslipidemia

Metformin may help prevent or reverse antipsychotic-induced weight gain

Switch to another atypical antipsychotic

Best Augmenting Agents for Side Effects

Beta blockers, benzodiazepines, or 5HT2A antagonists (e.g., mirtazapine, cyproheptadine) for akathisia

Benztropine, trihexyphenidyl, or amantadine for drug-induced parkinsonism

Valbenazine or deutetrabenazine for tardive dyskinesia

Many side effects cannot be improved with an augmenting agent

Dosing and Use Usual Dosage Range

8– 16 mg/day divided in 2 doses

Tablet 2 mg, 4 mg, 8 mg

Dosage Forms

Powder 20 mg per 1 g powder

How to Dose

Initial 8 mg/day divided in 2 doses; maintenance dose 8– 16 mg/day divided in 2 doses; maximum dose 24 mg/day

Blonanserin should be taken after a meal, as maximum concentrations are increased in the fed state; however, because the increase in systemic exposure continues until at least 4 hours after food intake, blonanserin can be taken before bedtime

Dosing Tips

Start with twice daily dosing; once stabilized, some patients do well with 1 dose given at night

Rather than raise the dose above normal dosing in acutely agitated patients requiring acute antipsychotic actions, consider short-term (one dose or more) augmentation with a benzodiazepine or another antipsychotic, especially intramuscularly

Rather than raise the dose above normal dosing in partial responders, consider augmentation with a mood-stabilizing anticonvulsant, such as valproate, topiramate, or lamotrigine

Children and elderly should generally be dosed at the lower end of the dosage spectrum

Treatment should be suspended if absolute neutrophil count falls below 1000/mm3

Limited data

Overdose

Long-Term Use

Not extensively studied past 56 weeks, but long-term maintenance treatment is often necessary for schizophrenia

Should periodically reevaluate long-term usefulness in individual patients, but treatment may need to continue for many years

No

Habit Forming

How to Stop

Down-titration, especially when simultaneously beginning a new antipsychotic while switching (i.e., cross-titration)

Rapid discontinuation could theoretically lead to rebound psychosis and worsening of symptoms

Pharmacokinetics

Elimination half-life 10– 16 hours after single dose Metabolized by CYP450 3A4

Drug Interactions

CYP450 3A4 inducers, such as carbamazepine, can lower the plasma levels of blonanserin

CYP450 3A4 inhibitors, such as ketoconazole, nefazodone, fluvoxamine, and fluoxetine, can increase plasma levels of blonanserin

May increase effects of antihypertensive agents May antagonize levodopa, dopamine agonists

Other Warnings/Precautions

Use with caution in patients with conditions that predispose to hypotension (dehydration, overheating)

Atypical antipsychotics have the potential for cognitive and motor impairment, especially related to sedation

Atypical antipsychotics can cause body temperature dysregulation; use caution in patients who may experience conditions that increase body temperature (e.g., strenuous exercise, saunas, extreme heat, dehydration, or concomitant anticholinergic medication)

Dysphagia has been associated with antipsychotic use, and blonanserin should be used cautiously in patients at risk for aspiration pneumonia

Antipsychotics may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls; for patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic

treatment, and recurrently for patients on long-term antipsychotic therapy

As with any antipsychotic, use with caution in patients with history of seizures

Do Not Use

In conjunction with adrenaline/epinephrine If patient is taking ketoconazole

If there is a proven allergy to blonanserin

Not studied

Special Populations Renal Impairment

Hepatic Impairment

Use with caution; may need to lower dose

Cardiac Impairment

Use in patients with cardiac impairment has not been studied, so use with caution

Elderly

Some patients may tolerate lower doses better

Although atypical antipsychotics are commonly used for behavioral disturbances in dementia, no agent has been approved for treatment of elderly patients with behavioral symptoms of dementia such as agitation

Elderly patients with dementia-related psychosis treated with atypical antipsychotics are at an increased risk of death compared to placebo and also have an increased risk of cerebrovascular events

Children and Adolescents

Safety and efficacy have not been established

Children and adolescents using blonanserin may need to be monitored more often than adults and may tolerate lower doses better

Pregnancy

Controlled studies have not been conducted in pregnant women

Psychotic symptoms may worsen during pregnancy, and some form of treatment may be necessary

Breast Feeding

Unknown if blonanserin is secreted in human breast milk, but all psychotropics are assumed to be secreted in breast milk

âœ1⁄2 Recommended either to discontinue drug or bottle feed unless the potential benefit to the mother justifies the potential risk to the child

Infants of women who choose to breast feed while on blonanserin should be monitored for possible adverse effects

The Art of Psychopharmacology Potential Advantages

May be useful when other antipsychotics have failed to provide adequate response or have not been tolerated

Potential Disadvantages

Patients who require once daily dosing from the initiation of treatment

Patients who require intramuscular administration

Primary Target Symptoms

Positive symptoms of psychosis

Negative symptoms of psychosis

Cognitive symptoms

Unstable mood (both depression and mania) Aggressive symptoms

Pearls

Relatively selective binding profile

Not approved for mania, but almost all atypical antipsychotics approved for acute treatment of schizophrenia have proven effective in the acute treatment of mania as well

Blonanserinâ€TM s binding affinity for D2 dopamine receptors (0.14 nM) is greater than for D3 receptors (0.49 nM); however, it is one of the very few antipsychotics in which the binding affinity for D3 receptors is greater than dopamineâ€TM s binding affinity for D3 receptors (~60 nM)

D3 antagonist actions have been hypothetically associated with improvement in negative, cognitive, and affective symptoms

Suggested Reading

Deeks ED , Keating GM . Blonanserin. A review of its use in the management of schizophrenia . CNS Drugs 2010 ;24 (1 ):65 – 84 .

Hida H , Mouri A , Mori K , et al. Blonanserin ameliorates phencyclidine- induced visual-recognition memory deficits: the complex mechanism of blonanserin action involving D3-5-HT2A and D1-NMDA receptors in the mPFC . Neuropsychopharmacology 2015 ;40 (3 ):601– 13 .

Kishi T , Matsuda Y , Nakamura H , Iwata N. Blonanserin for schizophrenia: a systematic review and meta-analysis of double-blind, randomized, controlled trials . J Psychiatr Res 2013 ;47 (2 ):149– 54 .

Yang J , Bahk WM , Cho HS , et al. Efficacy and tolerability of blonanserin in the patients with schizophrenia: a randomized, double-blind, risperidone- compared trial . Clin Neuropharmacol 2010 ;33 (4 ):169– 75 .

Bremelanotide

Vyleesi

Therapeutics Brands

No

Generic?

Class

see index for additional brand names

Nonselective melanocortin receptor agonist

Commonly Prescribed for

(bold for FDA approved)

Acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women

How the Drug Works

Bremelanotide is a nonselective melanocortin receptor agonist; at therapeutic doses, bremelanotide binding to melanocortin 1 and 4 receptors is most relevant

Sexual dysfunction is theoretically linked to an imbalance in central excitatory and inhibitory sexual signals

HSDD hypothetically results from excessive inhibitory signals, inadequate excitatory signals, or a combination of the two

Melanocortin receptors are located in the medial preoptic area of the hypothalamus, which is implicated in the sexual behavior of both sexes; stimulation of those receptors leads to dopamine release

How Long Until It Works

Should be used at least 45 minutes before anticipated sexual activity; duration of efficacy after each dose is unknown and optimal window for bremelanotide administration has not been established

If It Works

Increases ratings on sexual desire scores Reduces distress related to sexual dysfunction

If It Doesnâ€TM t Work

If there is no improvement after 8 weeks, discontinue use

Best Augmenting Combos for Partial Response or Treatment Resistance

None known

Tests

Blood pressure and risk for cardiovascular disease should be evaluated before initiation and periodically during treatment

Side Effects

How Drug Causes Side Effects

Binding at melanocortin 1 receptors on melanocytes leads to melanin expression and increased pigmentation

Notable Side Effects

Nausea

Flushing

Injection site reactions

Headache

Vomiting

Hyperpigmentation (higher risk with daily dosing)

Life-Threatening or Dangerous Side Effects

Transient increase in blood pressure and decrease in heart rate

Weight Gain

None

Sedation

What to Do About Side Effects

Reported but not expected

Wait

In most cases nausea improves after the first dose; for persistent or severe nausea, consider discontinuation or initiating antiemetic therapy

For hyperpigmentation, consider discontinuation Switch to another treatment option

Best Augmenting Agents for Side Effects

Antiemetic medication

Dosing and Use Usual Dosage Range

1.75 mg as needed, at least 45 minutes before anticipated sexual activity

Dosage Forms

Subcutaneous injection 1.75 mg/0.3 mL in a single-dose autoinjector

How to Dose

Patient should self-inject 1.75 mg subcutaneously in the abdomen or thigh using the autoinjector, as needed, at least 45 minutes before anticipated sexual activity

Dosing Tips

Do not administer more than one dose in 24 hours

Not recommended to administer more than 8 doses per month

Duration of efficacy after each dose is unknown and the optimal window for bremelanotide administration has not been established

Patient should be advised to visually inspect the drug product prior to administration, and to discard if the solution is cloudy or discolored or if visible particles are observed

Overdose

Limited data; nausea, focal hyperpigmentation, and more pronounced blood pressure increases are more likely with higher doses

Long-Term Use

Safe and effective in controlled trials (24 weeks) and open-label extension studies lasting an additional 52 weeks

No

Habit Forming

How to Stop

Bremelanotide is administered as needed

Pharmacokinetics

Tmax is approximately 1 hour

Mean terminal half-life approximately 2.7 hours

Absorption is not affected by injection site (thigh or abdomen)

Drug Interactions

Bremelanotide may slow gastric emptying, which could impact the rate and extent of absorption of concomitantly administered oral medications

Bremelanotide may significantly decrease exposure to oral naltrexone, so avoid use with orally administered naltrexone- containing products

Other Warnings/Precautions

Bremelanotide can cause transient increase in blood pressure and decrease in heart rate, which occurs after each dose and usually resolves within 12 hours; patients should be evaluated for cardiovascular risk before and periodically during treatment; treatment should not be initiated in those at high risk for cardiovascular disease

Focal hyperpigmentation can occur, with greater risk in patients with darker skin and with daily dosing; resolution was not confirmed in some patients; consider discontinuation if hyperpigmentation develops

Nausea can be severe enough to require antiemetic therapy or treatment discontinuation; for most patients in clinical trials it improved with the second dose; for persistent nausea, consider discontinuation or initiation of antiemetic therapy

Do Not Use

In patients with uncontrolled hypertension or known cardiovascular disease

If there is a proven allergy to bremelanotide

Special Populations

Renal Impairment

Dose adjustment not necessary for mild to moderate impairment

Use with caution in patients with severe impairment

Hepatic Impairment

Dose adjustment not necessary for mild to moderate impairment Use with caution in patients with severe impairment

Contraindicated

Cardiac Impairment

Elderly

Not approved for use in postmenopausal women, and safety and efficacy have not been established

Children and Adolescents

Safety and efficacy have not been established

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women

In clinical trials of up to 12 months, 7 pregnancies were reported; among these 7 pregnancies, no major congenital anomalies were reported; there was one spontaneous abortion (miscarriage), five full-term live births, and one outcome unknown as it was lost to follow-up

When administered to pregnant dogs during organogenesis, embryofetal toxicity occurred at doses approximately 16 times the maximum recommended human dose (MRHD)

When administered to pregnant mice during pregnancy and lactation, developmental effects occurred at doses approximately 125 times the MRHD

Advise patients to discontinue bremelanotide if pregnancy is suspected

Pregnancy registry for bremelanotide: 1-877-411-2510

Breast Feeding

Unknown if bremelanotide is secreted in human breast milk, but all psychotropics are assumed to be secreted in breast milk

Bremelanotide is dosed episodically (average 2– 3 times per month) and has a half-life of 2.7 hours

The Art of Psychopharmacology Potential Advantages

Can be taken as needed

For patients who do not respond to flibanserin

Potential Disadvantages

Patients with cardiovascular disease

Patients taking oral medications for which gastric absorption is relevant (e.g., antibiotics)

Patients who do not like injections

Primary Target Symptoms

Reduced sexual desire

Pearls

Bremelanotide is not approved for treatment in postmenopausal women or in men and is not indicated to enhance sexual performance

If not effective for HSDD, consider avoiding any concomitant use of agents that either enhance serotonin activity (such as SSRIs or SNRIs) or diminish dopamine activity (such as antipsychotics)

In women of childbearing potential who are or are likely to become sexually active, should inform about risk of harm to the fetus and monitor contraceptive status

Patients should be counseled that bremelanotide offers no protection against sexually transmitted diseases

No studies, but theoretically possible to combine with flibanserin for partial responders to either drug

Suggested Reading

Kingsberg SA , Clayton AH , Portman D , et al. Bremelanotide for the treatment of hypoactive sexual desire disorder: two randomized phase 3 trials . Obstet Gynecol 2019 ;134 (5 ):899 – 908 .

Simon JA , Kingsberg SA , Portman D , et al. Long-term safety and efficacy of bremelanotide for hypoactive sexual desire disorder . Obstet Gynecol 2019 ;134 (5 ):909– 17 .

Weinberger JM , Houman J , Caron AT , et al. Female sexual dysfunction and the placebo effect: a meta-analysis . Obstet Gynecol 2018 ;132 (2 ):453– 8 .

Brexanolone

Zulresso

Therapeutics Brands

see index for additional brand names

No

Neuroactive steroid

Generic?

Class

Commonly Prescribed for

(bold for FDA approved)

Postpartum depression

How the Drug Works

Positive allosteric modulator at neuroactive steroid sites on both gamma-aminobutyric acid (GABA) A benzodiazepine-sensitive and benzodiazepine-insensitive ligand-gated ion channels

Benzodiazepine-insensitive GABA-A receptor subtypes (with Î ́ subunits and α 4 or α 6 subunits) are located extrasynaptically,

where they capture not only GABA that diffuses away from the synapse, but also neuroactive steroids synthesized and released by glia

GABA binding at these receptors hypothetically regulates tonic inhibition

Brexanolone binds to the neuroactive steroid site, acting as a positive allosteric modulator to enhance the effects of GABA binding, i.e., to increase tonic GABAergic tone

Only known therapeutic agent for depression with positive allosteric modulation of the benzodiazepine-insensitive GABA-A receptor

How Long Until It Works

Clinical improvement may be evident as early as 12– 24 hours into the infusion

Improvement may continue over the 60-hour infusion regimen

If It Works

In clinical trials, antidepressant effect was sustained at 30 days post- infusion

If It Doesnâ€TM t Work

Consider psychotherapy and/or initiating treatment with an oral antidepressant

Best Augmenting Combos for Partial Response or Treatment Resistance

Brexanolone is a short-term treatment

Some patients may require initiation of a longer-term oral antidepressant

Tests

Side Effects

How Drug Causes Side Effects

Same mechanism for side effects as for therapeutic effects – namely due to excessive actions at GABA-A receptors

Notable Side Effects

Sedation, dizziness, dry mouth, flushing/hot flush

Life-Threatening or Dangerous Side Effects

Excessive sedation or sudden loss of consciousness Syncope, presyncope

Theoretical activation or emergence of suicidal ideation

Weight Gain

None for healthy individuals

None

Sedation

Many experience and/or can be significant in amount

Excessive sedation with sudden loss of consciousness can occur

What to Do About Side Effects

If excessive sedation occurs at any time during the infusion, stop the infusion until the symptoms resolve; the infusion may be resumed at the same or lower dose as clinically appropriate

If hypoxia occurs at any time during the infusion, immediately stop the infusion; after hypoxia, the infusion should not be resumed

For other side effects, consider a maximum dose of 60 Î1⁄4 g/kg/hour (hours 24 to 52)

None

Best Augmenting Agents for Side Effects

Dosing and Use Usual Dosage Range

Administered as a continuous intravenous infusion over 60 hours, titrated from 30 Î1⁄4 g/kg/hour up to 90 Î1⁄4 g/kg/hour and back down to 30 Î1⁄4 g/kg/hour on a set schedule (see How to Dose)

Dosage Forms

Injection 100 mg/20 mL (5 mg/mL) single-dose vial

How to Dose

Healthcare provider must be available on site for the duration of the infusion in order to continuously monitor the patient and intervene as necessary

0 to 4 hours: initial dose 30 Î1⁄4 g/kg/hour

4 to 24 hours: increase dosage to 60 Î1⁄4 g/kg/hour

24 to 52 hours: increase dosage to 90 Î1⁄4 g/kg/hour; alternatively consider 60 Î1⁄4 g/kg/hour for those who do not tolerate 90 Î1⁄4 g/kg/hour

52 to 56 hours: decrease dosage to 60 Î1⁄4 g/kg/hour 56 to 60 hours: decrease dosage to 30 Î1⁄4 g/kg/hour Dilution is required prior to administration

Dosing Tips

Because of the risk of excessive sedation and loss of consciousness, patients must be monitored continuously for the duration of the infusion

Monitor patients for hypoxia using continuous pulse oximetry equipped with an alarm

Monitor for excessive sedation every 2 hours during planned, non- sleep periods

Initiate brexanolone early enough during the day to allow for recognition of excessive sedation

Patients must be accompanied during interactions with their children

Brexanolone is supplied as a concentrated solution that must be diluted prior to administration; after dilution the product can be stored in infusion bags under refrigerated conditions for up to 96 hours; however, because the diluted product can be used for only 12 hours at room temperature, each 60-hour infusion will require preparation of at least 5 infusion bags

Limited data

Overdose

Long-Term Use

Not intended for long-term use

Schedule IV

Habit Forming

How to Stop

Down-titrate per the standard dosing regimen (see How to Dose)

Pharmacokinetics

Terminal half-life approximately 9 hours

Extensively metabolized by non-CYP-based pathways; metabolites are inactive

Drug Interactions

Increased depressive effects when taken with other CNS depressants

Other Warnings/Precautions

Brexanolone can cause excessive sedation and sudden loss of consciousness; for that reason, brexanolone is available only through a Risk Evaluation and Mitigation Strategy (REMS); the patient must be enrolled in the program prior to administration of brexanolone

Brexanolone can cause hypoxia; monitor patients using pulse oximetry and stop the infusion if hypoxia occurs

Do Not Use

If there is a proven allergy to brexanolone

Special Populations

Renal Impairment

Dose adjustment not necessary for mild, moderate, or severe renal impairment

Avoid use in patients with end-stage renal disease, due to the potential accumulation of the stabilizing agent, betadex sulfobutyl ether sodium

Hepatic Impairment

Dose adjustment not necessary

Cardiac Impairment

Use in patients with cardiac impairment has not been studied, so use with caution

Not studied

Elderly

Children and Adolescents

Safety and efficacy have not been established

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy

letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women

In animal studies, malformations were not seen in rats or rabbits at levels up to 5 and 6 times the maximum recommended human dose (MRHD), respectively

Developmental toxicities were seen in rats and rabbits at 5 and ≥ 3 times the MRHD, respectively, and reproductive toxicities were seen in rabbits at ≥ 3 the MRHD

When administered during pregnancy and lactation in rats, lower pup survival occurred at doses ≥ 2 times the MRHD and a neurobehavioral deficit in female offspring occurred at doses 5 times the MRHD

In published animal studies, administration of other drugs that enhance GABAergic inhibition to neonatal rats caused widespread apoptotic neurodegeneration during the period of brain development that corresponds to the third trimester of pregnancy in humans

National Pregnancy Registry for Antidepressants: 1-866-961-2388,

https://womensmentalhealth.org/research/pregnancyregistry/antidepr essants

Breast Feeding

Some drug is found in motherâ€TM s breast milk

In a study of 12 healthy adult lactating women treated with intravenous brexanolone according to the recommended 60-hour regimen, concentrations of brexanolone in breast milk were low (≤ 10 ng/mL) in ≥ 95% of women; the calculated maximum relative infant dose during infusion was 1– 2%

The Art of Psychopharmacology Potential Advantages

Rapid response

Potential Disadvantages

Can only be administered in a Zulresso REMS-certified healthcare setting

Depressed mood

Primary Target Symptoms

Pearls

Brexanolone is the first medication approved for the treatment of postpartum depression

Brexanolone is first-in-class as an antidepressant with a GABAergic mechanism

A related neuroactive steroid is currently being studied in an oral formulation for the treatment of postpartum depression and unipolar depression

Suggested Reading

Cooper MC , Kilvert HS , Hodgkins P , Roskell NS , Eldar-Lissai A . Using matching-adjusted indirect comparisons and network meta-analyses to compare efficacy of brexanolone injection with selective serotonin reuptake inhibitors for treating postpartum depression . CNS Drugs 2019 ;33 (10 ):1039– 52 .

Meltzer-Brody S , Colquhoun H , Riesenberg R , et al. Brexanolone injection in post-partum depression: two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials . Lancet 2018 ;392 (10152 ):1058– 70 .

Zheng W , Cai DB , Zheng W , et al. Brexanolone for postpartum depression: a meta-analysis of randomized controlled studies . Psychiatry Res 2019 ;279 :83– 9 .

Zorumski CF , Paul SM , Covey DF , Mennerick S . Neurosteroids as novel antidepressants and anxiolytics: GABA-A receptors and beyond . Neurobiol Stress 2019 ;11 :100196 .

Brexpiprazole

Rexulti

Therapeutics Brands

No

Generic?

Class

see index for additional brand names

Dopamine partial agonist (dopamine-serotonin partial agonist, dopamine stabilizer, atypical antipsychotic, third-generation antipsychotic; sometimes included as a second-generation antipsychotic; also a potential mood stabilizer)

Commonly Prescribed for

(bold for FDA approved)

Schizophrenia

Treatment-resistant depression (adjunct) Acute mania/mixed mania

Other psychotic disorders

Bipolar maintenance

Bipolar depression

Behavioral disturbances in dementia

Behavioral disturbances in children and adolescents Disorders associated with problems with impulse control Posttraumatic stress disorder

How the Drug Works âœ1⁄2 Partial agonism at dopamine 2 receptors

Theoretically reduces dopamine output when dopamine concentrations are high, thus improving positive symptoms and mediating antipsychotic actions

Theoretically increases dopamine output when dopamine concentrations are low, thus improving cognitive, negative, and mood symptoms

Interactions at a myriad of other neurotransmitter receptors may contribute to brexpiprazoleâ€TM s efficacy

Partial agonist at 5HT1A receptors, which may be beneficial for mood, anxiety, and cognition in a number of disorders

Blocks serotonin 2A receptors, causing enhancement of dopamine release in certain brain regions and thus reducing motor side effects and possibly improving cognitive and affective symptoms

Blockade of alpha 1B receptors may reduce arousal symptoms in posttraumatic stress disorder and in agitation associated with dementia as well as motor side effects such as akathisia

Blockade of alpha 2C receptors may contribute to antidepressant actions

Actions at dopamine 3 receptors could theoretically contribute to brexpiprazoleâ€TM s efficacy

Blocks serotonin 7 receptors, which may be beneficial for mood, cognitive impairment, and negative symptoms in schizophrenia, and also in bipolar disorder and major depressive disorder

How Long Until It Works

Psychotic symptoms can improve within 1 week, but it may take several weeks for full effect on behavior as well as on cognition

For psychosis, classically recommended to wait at least 4– 6 weeks to determine efficacy of drug, but in practice some patients may require up to 16– 20 weeks to show a good response, especially on negative or cognitive symptoms

For depression, onset of therapeutic actions usually not immediate, but often delayed 2– 4 weeks

If It Works – for Schizophrenia

Most often reduces positive symptoms but does not eliminate them

Can improve negative symptoms, as well as aggressive, cognitive, and affective symptoms in schizophrenia

Most schizophrenia patients do not have a total remission of symptoms but rather a reduction of symptoms by about a third

Perhaps 5– 15% of schizophrenia patients can experience an overall improvement of greater than 50– 60%, especially when receiving stable treatment for more than a year

Such patients are considered super-responders or “ awakeners†since they may be well enough to be employed, live independently, and sustain long-term relationships

Continue treatment until reaching a plateau of improvement

After reaching a satisfactory plateau, continue treatment for at least a year after first episode of psychosis

For second and subsequent episodes of psychosis, treatment may need to be indefinite

Even for first episodes of psychosis, it may be preferable to continue treatment

If It Works – for Depression

The goal of treatment is complete remission of current symptoms as well as prevention of future relapses

Treatment most often reduces or even eliminates symptoms, but not a cure since symptoms can recur after medicine stopped

Continue treatment until all symptoms are gone (remission) or significantly reduced

Once symptoms are gone, continue treating for 1 year for the first episode of depression

For second and subsequent episodes of depression, treatment may need to be indefinite

If It Doesnâ€TM t Work – for Schizophrenia

Try one of the other atypical antipsychotics

If 2 or more antipsychotic monotherapies do not work, consider clozapine

Some patients may require treatment with a conventional antipsychotic

If no first-line atypical antipsychotic is effective, consider higher doses or augmentation with valproate or lamotrigine

Consider noncompliance and switch to another antipsychotic with fewer side effects or to an antipsychotic that can be given by depot injection

Consider initiating rehabilitation and psychotherapy Consider presence of concomitant drug abuse

If It Doesnâ€TM t Work – for Depression

Some patients may be nonresponders, sometimes called treatment- resistant or treatment-refractory

Some patients who have an initial response may relapse even though they continue treatment, sometimes called “ poop-outâ€

Consider psychotherapy

Consider evaluation for another diagnosis or for a comorbid condition (e.g., medical illness, substance abuse, etc.)

Some patients may experience apparent lack of consistent efficacy due to activation of latent or underlying bipolar disorder

Best Augmenting Combos for Partial Response or Treatment Resistance

For depression, brexpiprazole is itself an augmenting agent Valproic acid (valproate, divalproex, divalproex ER)

Mood-stabilizing anticonvulsants (carbamazepine, oxcarbazepine, lamotrigine)

Lithium Topiramate Benzodiazepines

Tests

Before starting any atypical antipsychotic

âœ1⁄2 Weigh all patients and track BMI during treatment

Get baseline personal and family history of diabetes, obesity,

dyslipidemia, hypertension, and cardiovascular disease

âœ1⁄2 Get waist circumference (at umbilicus), blood pressure, fasting plasma glucose, and fasting lipid profile

Determine if the patient

is overweight (BMI 25.0– 29.9)

is obese (BMI ≥ 30)

has pre-diabetes (fasting plasma glucose 100– 125 mg/dL)

has diabetes (fasting plasma glucose ≥ 126 mg/dL)

has hypertension (BP >140/90 mmHg)

has dyslipidemia (increased total cholesterol, LDL cholesterol, and

triglycerides; decreased HDL cholesterol)

Treat or refer such patients for treatment, including nutrition and weight management, physical activity counseling, smoking cessation, and medical management

Monitoring after starting any atypical antipsychotic âœ1⁄2 BMI monthly for 3 months, then quarterly

âœ1⁄2 Consider monitoring fasting triglycerides monthly for several months in patients at high risk for metabolic complications and when

initiating or switching antipsychotics

âœ1⁄2 Blood pressure, fasting plasma glucose, fasting lipids within 3 months and then annually, but earlier and more frequently for patients with diabetes or who have gained >5% of initial weight

Treat or refer for treatment and consider switching to another atypical antipsychotic for patients who become overweight, obese, pre-diabetic, diabetic, hypertensive, or dyslipidemic while receiving an atypical antipsychotic

âœ1⁄2 Even in patients without known diabetes, be vigilant for the rare but life-threatening onset of diabetic ketoacidosis, which always requires immediate treatment, by monitoring for the rapid onset of polyuria, polydipsia, weight loss, nausea, vomiting, dehydration, rapid respiration, weakness and clouding of sensorium, even coma

Patients with low white blood cell count (WBC) or history of drug- induced leukopenia/neutropenia should have complete blood count (CBC) monitored frequently during the first few months and brexpiprazole should be discontinued at the first sign of decline in WBC in the absence of other causative factors

Patients should be monitored periodically for the development of abnormal movements of tardive dyskinesia, using neurological exam and the AIMS (Abnormal Involuntary Movement Scale)

Side Effects

How Drug Causes Side Effects

Blocking alpha 1 adrenergic receptors can cause dizziness, hypotension, and syncope

Partial agonist actions at dopamine 2 receptors in the striatum can cause akathisia and drug-induced parkinsonism

Partial agonist actions at dopamine 2 receptors and 5HT1A receptors can also cause nausea, occasional vomiting, and activating side effects

Mechanism of weight gain and increased incidence of diabetes and dyslipidemia with atypical antipsychotics is unknown, and risks vary based on the particular agent

Notable Side Effects

Weight gain

Akathisia (dose-dependent), restlessness (dose-dependent), anxiety

Sedation, headache

Tardive dyskinesia (TD) (reduced risk compared to conventional antipsychotics)

Risk of potentially irreversible involuntary dyskinetic movements may increase with cumulative dose and treatment duration

Life-Threatening or Dangerous Side Effects

Rare impulse control problems

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients taking atypical antipsychotics

As a class, antipsychotics are associated with an increased risk of death and cerebrovascular events in elderly patients with dementia; not approved for treatment of dementia-related psychosis

As a class, antidepressants have been reported to increase the risk of suicidal thoughts and behaviors in children and young adults

Rare neuroleptic malignant syndrome (NMS) may cause hyperpyrexia, muscle rigidity, delirium, and autonomic instability with elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure

Rare seizures

Occurs in a significant minority

Occurs in a significant minority

Weight Gain

Sedation

Wait Wait Wait

What to Do About Side Effects

Anticholinergics may reduce drug-induced parkinsonism when present

Beta blockers, benzodiazepines, or 5HT2A antagonists (e.g., mirtazapine, cyproheptadine) may reduce akathisia

Weight loss, exercise programs, and medical management for high BMIs, diabetes, dyslipidemia

Metformin may help prevent or reverse antipsychotic-induced weight gain

Switch to another atypical antipsychotic

Best Augmenting Agents for Side Effects

Benztropine, trihexyphenidyl, or amantadine for drug-induced parkinsonism

Beta blockers, benzodiazepines, or 5HT2A antagonists (e.g., mirtazapine, cyproheptadine) for akathisia

Valbenazine or deutetrabenazine for tardive dyskinesia

Many side effects cannot be improved with an augmenting agent

Dosing and Use Usual Dosage Range

Schizophrenia: 2– 4 mg once daily Depression: 2 mg once daily

Dosage Forms

Tablet 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg

How to Dose

Schizophrenia: Initial 1 mg once daily for days 1– 4; increase to 2 mg once daily for days 5– 7; increase to 4 mg once daily on day 8; maximum dose 4 mg once daily

Depression: initial 0.5– 1 mg once daily; increase in weekly intervals up to 1 mg once daily and then up to 2 mg once daily; maximum dose 3 mg once daily

Dosing Tips

Can be taken with or without foodRather than raise the dose above normal dosing in acutely agitated patients requiring acute antipsychotic actions, consider short-term (one dose or more) augmentation with a benzodiazepine or another antipsychotic, especially intramuscularlyRather than raise the dose above normal dosing in partial responders, consider augmentation with a mood- stabilizing anticonvulsant, such as valproate, topiramate, or lamotrigine Children and elderly should generally be dosed at the lower end of the dosage spectrumTreatment should be suspended if absolute neutrophil count falls below 1000/mm3

Limited experience

Overdose

Long-Term Use

Safety and efficacy demonstrated in schizophrenia in a maintenance study lasting over 1 year

Should periodically reevaluate long-term usefulness in individual patients, but treatment may need to continue for many years

No

Habit Forming

How to Stop

Because clinical experience is lacking, down-titration may be prudent, especially when simultaneously beginning a new antipsychotic while switching (i.e., cross-titration)

However, the long half-life suggests that it may be possible to stop brexpiprazole abruptly

See Switching section of individual agents for how to stop brexpiprazole

Rapid discontinuation could theoretically lead to rebound psychosis and worsening of symptoms, but less likely with brexpiprazole due to its long half-life

Pharmacokinetics

Mean half-life 91 hours (brexpiprazole) and 86 hours (major metabolite DM-3411)

Metabolized primarily by CYP450 2D6 and CYP450 3A4

Drug Interactions

In patients receiving a strong/moderate CYP450 3A4 inhibitor (e.g., ketaconazole), brexpiprazole should be administered at half the usual dose

In patients receiving a strong CYP450 3A4 inducer (e.g., carbamazepine), brexpiprazole should be administered at double the usual dose

In patients with schizophrenia who are receiving a strong/moderate CYP450 2D6 inhibitor (e.g., quinidine) or who are known CYP450 2D6 poor metabolizers, brexpiprazole should be administered at half the usual dose

However, clinical trials in major depressive disorder took into account the potential concomitant administration of strong CYP450 2D6 inhibitors (e.g., paroxetine, fluoxetine), so the dose of brexpiprazole does not need to be adjusted in these cases

In patients receiving both a strong/moderate CYP450 3A4 inhibitor and a strong/moderate CYP450 2D6 inhibitor, brexpiprazole should be administered at one-quarter the usual dose

In patients receiving a strong/moderate CYP450 3A4 inhibitor who are known CYP450 2D6 poor metabolizers, brexpiprazole should be administered at one-quarter the usual dose

May increase effects of antihypertensive agents

May antagonize levodopa, dopamine agonists

Other Warnings/Precautions

There have been reports of problems with impulse control in patients taking aripiprazole, including compulsive gambling, shopping, binge eating, and sexual activity; use caution when prescribing to patients at high risk for impulse-control problems (e.g., patients with bipolar disorder, impulsive personality, obsessive-compulsive disorder, substance use disorders) and monitor all patients for emergence of these symptoms; dose should be lowered or discontinued if impulse-control problems manifest

Monitor patients for activation of suicidal ideation, especially children and adolescents

Use with caution in patients with conditions that predispose to hypotension (dehydration, overheating)

Atypical antipsychotics have the potential for cognitive and motor impairment, especially related to sedation

Atypical antipsychotics can cause body temperature dysregulation; use caution in patients who may experience conditions that increase body temperature (e.g., strenuous exercise, saunas, extreme heat, dehydration, or concomitant anticholinergic medication)

Dysphagia has been associated with antipsychotic use, and brexpiprazole should be used cautiously in patients at risk for aspiration pneumonia

As with any antipsychotic, use with caution in patients with history of seizures

Antipsychotics may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls; for patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment, and recurrently for patients on long-term antipsychotic therapy

Do Not Use

If there is a proven allergy to brexpiprazole

Special Populations Renal Impairment

Moderate, severe, or end-stage: maximum recommended dose for depression is 2 mg once daily and for schizophrenia is 3 mg once daily

Hepatic Impairment

Moderate to severe: maximum recommended dose for depression is 2 mg once daily and for schizophrenia is 3 mg once daily

Cardiac Impairment

Use in patients with cardiac impairment has not been studied, so use with caution because of risk of orthostatic hypotension

Use with caution if patient is taking concomitant antihypertensive or alpha 1 antagonist

Elderly

Some elderly patients may tolerate lower doses better

Although atypical antipsychotics are commonly used for behavioral disturbances in dementia, no agent has been approved for treatment of elderly patients with behavioral symptoms of dementia such as agitation

Elderly patients with dementia-related psychosis treated with atypical antipsychotics are at an increased risk of death compared to placebo, and also have an increased risk of cerebrovascular events

Consider pimavanserin for dementia-related psychosis or Parkinsonâ€TM s disease psychosis instead of an atypical antipsychotic

Children and Adolescents

Safety and efficacy have not been established

Children and adolescents using brexpiprazole may need to be monitored more often than adults and may tolerate lower doses better

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women

In animal studies, brexpiprazole did not demonstrate teratogenicity

There is a risk of abnormal muscle movements and withdrawal symptoms in newborns whose mothers took an antipsychotic during the third trimester; symptoms may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty feeding

Psychotic symptoms may worsen during pregnancy and some form of treatment may be necessary

Brexpiprazole may be preferable to anticonvulsant mood stabilizers if treatment is required during pregnancy

National Pregnancy Registry for Atypical Antipsychotics: 1-866- 961-2388, http://womensmentalhealth.org/research/pregnancyregistry/atypicala ntipsychotic/

Breast Feeding

Unknown if brexpiprazole is secreted in human breast milk, but all psychotropics are assumed to be secreted in breast milk

âœ1⁄2 Recommended either to discontinue drug or bottle feed unless the potential benefit to the mother justifies the potential risk to the child

Infants of women who choose to breast feed while on brexpiprazole should be monitored for possible adverse effects

The Art of Psychopharmacology Potential Advantages

For patients who do not tolerate aripiprazole or cariprazine

Expensive

Potential Disadvantages

Primary Target Symptoms

Positive symptoms of psychosis

Negative symptoms of psychosis

Cognitive symptoms

Unstable mood (both depression and mania) Aggressive symptoms

Pearls

Approved as an adjunct treatment for depression

Animal data suggest that brexpiprazole may improve cognitive impairment in schizophrenia

Brexpiprazole is in late-stage clinical testing for agitation associated with Alzheimer dementia

Brexpiprazole has shown evidence of efficacy especially in combination with sertraline for posttraumatic stress disorder

Not approved for mania, but almost all atypical antipsychotics approved for acute treatment of schizophrenia have proven effective in the acute treatment of mania as well

Pharmacological differences from aripiprazole suggest less akathisia with brexpiprazole, but no head-to-head trials

Compared to aripiprazole, brexpiprazole has more potent binding of several receptor sites relative to dopamine 2 receptor binding, namely 5HT1A, 5HT2A, and alpha 1 receptors; however, the clinical significance of these differences is still under investigation

The Art of Switching

Switching from Oral Antipsychotics to Brexpiprazole

It is advisable to begin brexpiprazole at an intermediate dose and build the dose rapidly over 3– 7 days

Clinical experience has shown that asenapine, quetiapine, and olanzapine should be tapered off slowly over a period of 3– 4

weeks, to allow patients to readapt to the withdrawal of blocking cholinergic, histaminergic, and alpha 1 receptors

Clozapine should always be tapered off slowly, over a period of 4 weeks or more

* Benzodiazepine or anticholinergic medication can be administered during cross-titration to help alleviate side effects such as insomnia, agitation, and/or psychosis

Suggested Reading

Huhn M , Nikolakopoulou A , Schneider-Thoma J , et al. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis . Lancet 2019 ;394 :939– 51 .

Kane JM , Skuban A , Ouyang J , et al. A multicenter, randomized, double- blind, controlled phase 3 trial of fixed-dose brexpiprazole for the treatment of adults with acute schizophrenia . Schizophr Res 2015 ;164 (1 – 3):127– 35 .

Kishi T , Sakuma K , Nomura I , et al. Brexpiprazole as adjunctive treatment for major depressive disorder following treatment failure with at least one antidepressant in the current episode: a systematic review and meta-analysis . Int J Neuropsychopharmacol 2019 ;22 (11 ):698 – 709 .

Ward K , Citrome L . Brexpiprazole for the maintenance treatment of adults with schizophrenia: an evidence-based review and place in therapy . Neuropsychiatr Dis Treat 2019 ;15 :247– 57 .

Buprenorphine

Therapeutics Brands

Suboxone (with naloxone) Probuphine (implant)

Sublocade (subcutaneous injection)

see index for additional brand names

Generic?

Yes (not for implant or injection)

Class

mu opioid receptor partial agonist

Commonly Prescribed for

(bold for FDA approved)

Induction of treatment for opioid dependence (Bunavail only) Maintenance treatment of opioid dependence (sublingual)

Maintenance treatment of opioid dependence in patients who have achieved and sustained prolonged clinical stability on low-

to-moderate doses (no more than 8 mg) of a transmucosal buprenorphine-containing product (implant)

Moderate to severe opioid use disorder in patients who have initiated treatment with a transmucosal buprenorphine- containing product, followed by dose adjustment for a minimum of 7 days (injection)

How the Drug Works

Binds with strong affinity to the mu opioid receptor, preventing exogenous opioids from binding there and thus preventing the pleasurable effects of opioid consumption

Because buprenorphine is a partial agonist, it can cause immediate withdrawal in a patient currently taking opioids (i.e., reduces receptor stimulation in the presence of a full agonist) but can relieve withdrawal if a patient is already experiencing it (i.e., increases receptor stimulation in the absence of a full agonist)

Buprenorphine is also an antagonist at the kappa opioid receptor

In combination with naloxone: naloxone is a mu opioid receptor antagonist and can therefore block the effects of buprenorphine; however, because naloxone has poor sublingual bioavailability, it does not interfere with buprenorphineâ€TM s effects when used properly. Naloxone does have good parenteral bioavailability; thus, if one tries to administer the buprenorphine/naloxone formulation intravenously, naloxone will prevent any rewarding effects from buprenorphine

How Long Until It Works

Effects on withdrawal can be immediate

Effects on reducing opioid use disorder/dependence can take many months of treatment

If It Works

Reduces cravings, decreases opioid consumption Reduces effects of opioid withdrawal

Diminishes rewarding effects of opioid consumption

If It Doesnâ€TM t Work

Evaluate for and address contributing factors

Consider switching to another agent

If patients receiving the implant feel a need for supplemental dosing, they should be evaluated and transmucosal buprenorphine should be considered

Best Augmenting Combos for Partial Response or Treatment Resistance

Augmentation with behavioral, educational, and/or supportive therapy in groups or as an individual is probably key to successful treatment

Buprenorphine can be prescribed in combination with naloxone (Suboxone) to decrease the potential for abuse or diversion

Tests

Liver function tests at baseline and during treatment

Side Effects

How Drug Causes Side Effects

Binding at mu opioid receptors

Notable Side Effects

Headache, constipation, nausea

Oral hypoesthesia, glossodynia

Orthostatic hypotension

Implant specific: insertion site pain, pruritis, erythema

Life-Threatening or Dangerous Side Effects

Respiratory depression Hepatotoxicity

Reported but not expected

Weight Gain

Sedation

Many experience and/or can be significant in amount

What to Do About Side Effects

Wait

Reduce dose

Switch to another agent

Best Augmenting Agents for Side Effects

Dose reduction or switching to another agent may be more effective since most side effects cannot be improved with an augmenting agent

Dosing and Use Usual Dosage Range

Sublingual: 8– 32 mg/day

Implant: 4 implants intended to be in place for 6 months Injection: maintenance dose is 100– 300 mg monthly

Dosage Forms

Sublingual tablet 2 mg, 8 mg

Sublingual tablet (with naloxone) 2 mg/ 0.5 mg, 8 mg/ 2 mg

Sublingual film (with naloxone) 2 mg/0.5 mg, 4 mg/1 mg, 8 mg/2 mg, 12 mg/3 mg

Each implant is 26 mm in length and 2.5 mm diameter and contains 74.2 mg of buprenorphine (equivalent to 80 mg of buprenorphine hydrochloride)

Injection 100 mg/0.5 mL, 300 mg/1.5 mL

How to Dose – Sublingual

Patients must be in a mild withdrawal state prior to starting bupre

Initiation (7 days)

Buprenorphine

Buprenorphine/naloxone

Day 1

8 mg

8 mg/2 mg

Day 2

12 or 16 mg

12 mg/3 mg or 16 mg/4 mg

Days 3– 7

Increase in increments of 4 mg; maximum 32 mg

Increase in increments of 4 mg/1 mg; maximum 32 mg/8 mg

norphine

Observe patient for at least 2 hours with initial dose, then have 1– 2 visits in first week

Achieve the lowest dose that eliminates withdrawal symptoms and illicit opioid use

Stabilization (up to 2 months) and maintenance dose is generally 8– 24 mg (8 mg/2 mg up to 24 mg/6 mg for buprenorphine/naloxone)

During stabilization patients should be seen once per week During maintenance patients should be seen biweekly or monthly

Dosing Tips – Sublingual

Buprenorphine must be administered sublingually, as swallowing reduces its bioavailability

Patients should be instructed to place the sublingual formulation under the tongue and allow it to dissolve completely; the formulation should not be divided, crushed, chewed, or swallowed

Can be dosed less often than once daily; one should double the dose for each additional 24-hour interval

Buprenorphine alone is often used to initiate treatment, while buprenorphine/naloxone is preferred for stabilization and maintenance treatment

Only buprenorphine with naloxone should be used for unsupervised administration, unless the patient has a proven allergy to naloxone

Can be distributed through cliniciansâ€TM offices by those who obtain a DEA DATA 2000 waiver

Patients being switched between the 2 sublingual formulations (tablet and film) should be started on the same dose as the previously administered product; however, because the sublingual film has greater bioavailability than the sublingual tablet, patients must be monitored for over-medication (when switching from tablet to film) or under-medication (when switching from film to tablet); dose adjustment may be necessary

How to Dose – Implant

Patient must have achieved and sustained prolonged clinical stability on transmucosal buprenorphine

Four implants are inserted subdermally in the inner side of the upper arm for 6 months of treatment and are removed by the end of the sixth month

Dosing Tips – Implant

Implants must be inserted and removed by trained healthcare providers who are certified in the Probuphine REMS program; information is available at http://www.probuphinerems.com or 1-844-859- 6341

Patients must currently be on a maintenance dose of 8 mg/day or less of transmucosal buprenorphine and should not be transitioned to a lower dose for the sole purpose of transitioning to the implant

Patients should be on a stable transmucosal buprenorphine dose (8 mg/day or less) for 3 months or longer without any need for supplemental dosing or adjustments

Examine the insertion site 1 week after implant insertion for signs of infection or other problems

Patients should not receive prescriptions for transmucosal buprenorphine for as-needed use; patients who feel a need for supplemental dosing should be evaluated and alternative treatment should be considered

For continued treatment, new implants may be inserted subdermally in an area of the inner side of either upper arm that has not been previously used at the time of removal

If new implants are not inserted on the same day as removal, then patients should be maintained on their previous dosage of transmucosal buprenorphine

After one insertion in each arm, most patients should be transitioned back to transmucosal buprenorphine if continued treatment is desired, as there is no experience with re-insertion into previously used administration sites or insertion into sites other than the upper arm

How to Dose – Injection

Two monthly initial doses of 300 mg, followed by 100 mg monthly maintenance dose; can increase monthly maintenance dose to 300 mg if benefits outweigh risks

Should be administered subcutaneously in the abdominal region; should not be administered intravenously or intramuscularly

Dosing Tips – Injection

There should be a minimum of 26 days between doses

Occasional delays in dosing of up to 2 weeks are not expected to have clinically significant impact on treatment effects

Overdose

Can be fatal (less common than with methadone); respiratory depression, sedation, constricted pupils, bradycardia, hypotension, coma

Long-Term Use

Maintenance treatment may be required; typical maintenance period is up to 2 years but may need to be indefinite

Habit Forming

Buprenorphine is a Schedule III drug Can cause physical dependence

How to Stop

Patients may experience a mild withdrawal syndrome if buprenorphine is stopped abruptly

Taper to avoid withdrawal effects

Pharmacokinetics

Metabolized by CYP450 3A4

Elimination half-life of sublingual buprenorphine is 24– 42 hours Elimination half-life of naloxone is 2– 12 hours

Implant: Tmax is 12 hours; time to steady state is 4 weeks

Drug Interactions

Increased depressive effects, particularly respiratory depression, have occurred when taken with benzodiazepines or other CNS depressants; prescribe the lowest effective dose and shortest duration if taken concomitantly

Plasma concentrations of buprenorphine may be increased by drugs that inhibit CYP450 3A4, so buprenorphine dose may need to be reduced if coadministered

Patients taking a CYP450 3A4 inhibitor who transfer to the implant should be monitored to ensure that plasma buprenorphine levels are adequate

If a CYP450 3A4 inhibitor is initiated in a patient with the implant, the patient should be monitored for signs of over-medication

If a CYP450 3A4 inhibitor is discontinued in a patient with the implant, the patient should be monitored for signs of withdrawal

Plasma concentrations of buprenorphine may be reduced by drugs that induce CYP450 3A4, so buprenorphine dose may need to be increased if coadministered

Patients taking a CYP450 3A4 inducer who transfer to the implant should be monitored to ensure that plasma buprenorphine levels are not excessive

If a CYP450 3A4 inducer is initiated in a patient with the implant, the patient should be monitored for signs of withdrawal

If a CYP450 3A4 inducer is discontinued in a patient with the implant, the patient should be monitored for signs of over- medication

Other Warnings/Precautions

Increased risk of CNS depressant effects when benzodiazepines and opioid medications are used together, including specifically the risk of slowed or difficult breathing and death

If alternatives to the combined use of benzodiazepines and opioids are not available, clinicians should limit the dosage and duration of each drug to the minimum possible while still achieving therapeutic efficacy

Although the risk is lower, buprenorphine can be abused in a manner similar to other opioids

Parenteral misuse of buprenorphine/naloxone may result in marked opioid withdrawal syndrome

To prevent withdrawal in patients dependent on opioids, patients must be in a mild withdrawal state prior to initiating treatment

Attempts by patients to overcome blockade of opioid receptors by taking large amounts of exogenous opioids could lead to opioid intoxication or even fatal overdose

Use with caution in patients with compromised respiratory function

Risk of respiratory depression is increased with concomitant use of CNS depressants, particularly with parenteral administration

Can cause severe, possibly fatal respiratory depression in children who are accidentally exposed to it

Withdrawal symptoms can occur when switching from methadone to buprenorphine

Buprenorphine may elevate cerebrospinal fluid pressure and should be used with caution in patients with head injury, intracranial lesions, and other circumstances when cerebrospinal pressure may be increased

Buprenorphine may increase intracholedochal pressure and should be administered with caution to patients with dysfunction of the biliary tract

Use with caution in debilitated patients and those with myxedema or hypothyroidism, adrenal cortical insufficiency (e.g., Addisonâ€TM s disease); CNS depression or coma; toxic psychoses; prostatic hypertrophy or urethral stricture; acute alcoholism; delirium tremens; or kyphoscoliosis

Use the implant with caution in patients with a history of keloid formation, connective tissue disease, or history of recurrent recurrent methicillin-resistant Staphylococens aureus (MRSA) infections

Rare nerve damage and migration resulting in embolism and death may occur due to improper insertion of the implant in the upper arm; local migration, protrusion, and expulsion can also occur as a result of improper or incomplete insertion; protrusion and expulsion may occur as a result of infection

In the event that an implant is expelled, the patient should store it in a plastic bag out of reach of children and bring it to their healthcare provider to ensure that the entire implant was expelled

The prescribing healthcare provider will need to monitor the patient until the implant is replaced

Do Not Use

As an analgesic

If the patient is naive to opioid use

If there is a proven allergy to buprenorphine

If patient has severe hepatic impairment (buprenorphine/naloxone combinations only)

If there is a proven allergy to naloxone (buprenorphine/naloxone combinations only)

Special Populations Renal Impairment

Dose adjustment not necessary

Hepatic Impairment

In patients with moderate to severe impairment, plasma levels of buprenorphine can be higher and half-life can be longer; thus, these patients should be monitored for signs and symptoms of toxicity or overdose

For severe impairment, the dose should be reduced

Because dose adjustment is not possible with the implant, it is not recommended for use in patients with moderate to severe hepatic impairment

Hepatic impairment results in reduced clearance of naloxone, so patients with severe impairment should not take buprenorphine/naloxone combinations; caution is warranted for patients with moderate impairment

Use with caution

Use with caution

Cardiac Impairment

Elderly

Some patients may tolerate lower doses better

Children and Adolescents

Safety and efficacy have not been established

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women Buprenorphine may be preferable to methadone in pregnant women

Neonatal withdrawal has been reported following use of buprenorphine during pregnancy

In animal studies, adverse events have been observed at clinically relevant doses; no clear teratogenic effects were seen, but increases in skeletal abnormalities were observed in rats and rabbits given daily buprenorphine at doses 5.4 and 10.8 times the maximum human recommended dose

Not generally recommended for use during pregnancy, especially during first trimester

Breast Feeding

Some drug is found in motherâ€TM s breast milk

âœ1⁄2 Recommended either to discontinue drug or bottle feed

The Art of Psychopharmacology Potential Advantages

Patients with mild to moderate physical dependence

Potential Disadvantages

Patients unable to tolerate mild withdrawal symptoms

Primary Target Symptoms

Opioid dependence

Pearls

Considered a “ take home†medication that generally has less stigma and better adherence than methadone

Relatively convenient to administer, with flexible dosing and ease of discontinuation

Suggested Reading

Bonhomme J , Shim RS , Gooden R , Tyus D , Rust G. Opioid addiction and abuse in primary care practice: a comparison of methadone and buprenorphine as treatment options . J Natl Med Assoc 2012 ;104 (7– 8):342– 50 .

Jones HE , Finnegan LP , Kaltenbach K. Methadone and buprenorphine for the management of opioid dependence in pregnancy . Drugs 2012 ;72 (6 ):747– 57 .

Kraus ML , Alford DP , Kotz MM , et al. Statement of the American Society of Addiction Medicine Consensus Panel on the use of buprenorphine in office-based treatment of opioid addiction . J Addict Med 2011 ;5 (4 ):254– 63 .

Yokell MA , Zaller ND , Green TC , Rich JD. Buprenorphine and buprenorphine/naloxone diversion, misuse, and illicit use: an international review . Curr Drug Abuse Rev 2011 ;4 (1 ):28 – 41 .

Bupropion

WellbutrinWellbutrin SRWellbutrin XL Zyban

Aplenzin

see index for additional brand names

Therapeutics Brands

Yes

Generic?

Class

Neuroscience-based Nomenclature: dopamine reuptake inhibitor and releaser (D-RIRe)

NDRI (norepinephrine and dopamine reuptake inhibitor); antidepressant; smoking cessation treatment

Commonly Prescribed for

(bold for FDA approved)

Major depressive disorder (bupropion, bupropion SR, and bupropion XL)

Seasonal affective disorder (bupropion XL) Nicotine addiction (bupropion SR)

Bipolar depression

Attention deficit hyperactivity disorder (ADHD) Sexual dysfunction

How the Drug Works

Boosts neurotransmitters norepinephrine/noradrenaline and dopamine

Blocks norepinephrine reuptake pump (norepinephrine transporter), presumably increasing norepinephrine neurotransmission

Since dopamine is inactivated by norepinephrine reuptake in frontal cortex, which largely lacks dopamine transporters, bupropion can increase dopamine neurotransmission in this part of the brain

Blocks dopamine reuptake pump (dopamine transporter), presumably increasing dopaminergic neurotransmission

How Long Until It Works

Onset of therapeutic actions usually not immediate, but often delayed 2– 4 weeks

If it is not working within 6– 8 weeks for depression, it may require a dosage increase or it may not work at all

May continue to work for many years to prevent relapse of symptoms

If It Works

The goal of treatment of depression is complete remission of current symptoms as well as prevention of future relapses

Treatment of depression most often reduces or even eliminates symptoms, but is not a cure since symptoms can recur after medicine stopped

Continue treatment of depression until all symptoms are gone (remission)

Once symptoms of depression are gone, continue treating for 1 year for the first episode of depression

For second and subsequent episodes of depression, treatment may need to be indefinite

Treatment for nicotine addiction should consist of a single treatment for 6 weeks

If It Doesnâ€TM t Work

Many patients have only a partial response where some symptoms are improved but others persist (especially insomnia, fatigue, and problems concentrating)

Other patients may be nonresponders, sometimes called treatment- resistant or treatment-refractory

Some patients who have an initial response may relapse even though they continue treatment, sometimes called “ poop-outâ€

Consider increasing dose, switching to another agent, or adding an appropriate augmenting agent

Consider psychotherapy

Consider evaluation for another diagnosis or for a comorbid condition (e.g., medical illness, substance abuse, etc.)

Some patients may experience apparent lack of consistent efficacy due to activation of latent or underlying bipolar disorder, and require antidepressant discontinuation and a switch to a mood stabilizer, although this may be a less frequent problem with bupropion than with other antidepressants

Best Augmenting Combos for Partial Response or Treatment Resistance

Trazodone for residual insomnia

Benzodiazepines for residual anxiety

âœ1⁄2 Can be added to SSRIs to reverse SSRI-induced sexual dysfunction, SSRI-induced apathy (use combinations of antidepressants with caution as this may activate bipolar disorder and suicidal ideation)

âœ1⁄2 Can be added to SSRIs to treat partial responders

âœ1⁄2 Often used as an augmenting agent to mood stabilizers and/or atypical antipsychotics in bipolar depression

Mood stabilizers or atypical antipsychotics can also be added to bupropion for psychotic depression or treatment-resistant depression

Hypnotics for insomnia

Mirtazapine, modafinil, atomoxetine (add with caution and at lower doses since bupropion could theoretically raise atomoxetine levels) both for residual symptoms of depression and attention deficit disorder

Tests

Recommended to assess blood pressure at baseline and periodically during treatment

Side Effects

How Drug Causes Side Effects

Side effects are probably caused in part by actions of norepinephrine and dopamine in brain areas with undesired effects (e.g., insomnia, tremor, agitation, headache, dizziness)

Side effects are probably also caused in part by actions of norepinephrine in the periphery with undesired effects (e.g., sympathetic and parasympathetic effects such as dry mouth, constipation, nausea, anorexia, sweating)

Most side effects are immediate but often go away with time

Notable Side Effects

Dry mouth, constipation, nausea, weight loss, anorexia, myalgia

Insomnia, dizziness, headache, agitation, anxiety, tremor, abdominal pain, tinnitus

Sweating, rash Hypertension

Life-Threatening or Dangerous Side Effects

Rare seizures (higher incidence for immediate-release than for sustained-release; risk increases with doses above the recommended maximums; risk increases for patients with predisposing factors)

Anaphylactoid/anaphylactic reactions and Stevens-Johnson syndrome have been reported

Hypomania (more likely in bipolar patients but perhaps less common than with some other antidepressants)

Rare induction of mania

Rare activation of suicidal ideation and behavior (suicidality) (short- term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo beyond age 24)

Weight Gain

Reported but not expected

âœ1⁄2 Patients may experience weight loss Sedation

Reported but not expected

What to Do About Side Effects

Wait

Wait

Wait

Keep dose as low as possible

Take no later than mid-afternoon to avoid insomnia Switch to another drug

Best Augmenting Agents for Side Effects

Often best to try another antidepressant monotherapy prior to resorting to augmentation strategies to treat side effects

Trazodone or a hypnotic for drug-induced insomnia

Mirtazapine for insomnia, agitation, and gastrointestinal side effects Benzodiazepines or buspirone for drug-induced anxiety, agitation

Many side effects are dose-dependent (i.e., they increase as dose increases, or they reemerge until tolerance redevelops)

Many side effects are time-dependent (i.e., they start immediately upon dosing and upon each dose increase, but go away with time)

Activation and agitation may represent the induction of a bipolar state, especially a mixed dysphoric bipolar II condition sometimes associated with suicidal ideation, and require the addition of lithium, a mood stabilizer or an atypical antipsychotic, and/or discontinuation of bupropion

Dosing and Use Usual Dosage Range

Bupropion: 225– 450 mg in 3 divided doses (maximum single dose 150 mg)

Bupropion SR: 200– 450 mg in 2 divided doses (maximum single dose 200 mg)

Bupropion XL: 150– 450 mg once daily (maximum single dose 450 mg)

Bupropion hydrobromide: 174– 522 mg once daily (maximum single dose 522 mg)

Dosage Forms

Bupropion: tablet 75 mg, 100 mg

Bupropion SR (sustained-release): tablet 100 mg, 150 mg, 200 mg Bupropion XL (extended-release): tablet 150 mg, 300 mg, 450 mg

Bupropion hydrobromide (extended-release): tablet 174 mg, 378 mg, 522 mg

How to Dose

Depression: for bupropion immediate-release, dosing should be in divided doses, starting at 75 mg twice daily, increasing to 100 mg twice daily, then to 100 mg 3 times daily; maximum dose 450 mg per day

Depression: for bupropion SR, initial dose 100 mg twice a day, increase to 150 mg twice a day after at least 3 days; wait 4 weeks or longer to ensure drug effects before increasing dose; maximum dose 400 mg total per day

Depression: for bupropion XL, initial dose 150 mg once daily in the morning; can increase to 300 mg once daily after 4 days; maximum single dose 450 mg once daily

Depression: for bupropion hydrobromide, initial dose 174 mg once daily in the morning; can increase to 522 mg administered as a single dose

Nicotine addiction (for bupropion SR): initial dose 150 mg/day once a day, increase to 150 mg twice a day after at least 3 days; maximum dose 300 mg/day; bupropion treatment should begin 1– 2 weeks before smoking is discontinued

Dosing Tips

XL formulation has replaced immediate-release and SR formulations as the preferred option

XL is best dosed once a day, whereas SR is best dosed twice daily, and immediate-release is best dosed 3 times daily

Dosing higher than 450 mg/day (400 mg/day SR) increases seizure risk

Patients who do not respond to 450 mg/day should discontinue use or get blood levels of bupropion and its major active metabolite 6- hydroxy-bupropion

If levels of parent drug and active metabolite are low despite dosing at 450 mg/day, experts can prudently increase dosing beyond the therapeutic range while monitoring closely, informing the patient of the potential risk of seizures and weighing risk/benefit ratios in difficult-to-treat patients

When used for bipolar depression, it is usually as an augmenting agent to mood stabilizers, lithium, and/or atypical antipsychotics

For smoking cessation, may be used in conjunction with nicotine replacement therapy

Do not break or chew SR or XL tablets as this will alter controlled- release properties

The more anxious and agitated the patient, the lower the starting dose, the slower the titration, and the more likely the need for a concomitant agent such as trazodone or a benzodiazepine

If intolerable anxiety, insomnia, agitation, akathisia, or activation occur upon either dosing initiation or discontinuation, consider the possibility of activated bipolar disorder and switch to a mood stabilizer or an atypical antipsychotic

Overdose

Rarely lethal; seizures, cardiac disturbances, hallucinations, loss of consciousness

Long-Term Use

For smoking cessation, treatment for up to 6 months has been found to be effective

For depression, treatment up to 1 year has been found to decrease rate of relapse

Habit Forming

No

Can be abused by individuals who crush and then snort or inject it

How to Stop

Tapering is prudent to avoid withdrawal effects, but no well- documented tolerance, dependence, or withdrawal reactions

Pharmacokinetics

Inhibits CYP450 2D6

Parent half-life 10– 14 hours Metabolite half-life 20– 27 hours Food does not affect absorption

Drug Interactions

Tramadol increases the risk of seizures in patients taking an antidepressant

Can increase TCA levels; use with caution with TCAs or when switching from a TCA to bupropion

Use with caution with MAOIs, including 14 days after MAOIs are stopped (for the expert)

There is increased risk of hypertensive reaction if bupropion is used in conjunction with MAOIs or other drugs that increase norepinephrine

There may be an increased risk of hypertension if bupropion is combined with nicotine replacement therapy

Via CYP450 2D6 inhibition, bupropion could theoretically interfere with the analgesic actions of codeine, and increase the plasma levels of some beta blockers and of atomoxetine

Via CYP450 2D6 inhibition, bupropion could theoretically increase concentrations of thioridazine and cause dangerous cardiac arrhythmias

Other Warnings/Precautions

Use cautiously with other drugs that increase seizure risk (TCAs, lithium, phenothiazines, thioxanthenes, some antipsychotics)

Bupropion should be used with caution in patients taking levodopa or amantadine, as these agents can potentially enhance dopamine neurotransmission and be activating

Do not use if patient has severe insomnia

Use with caution in patients with bipolar disorder unless treated with concomitant mood-stabilizing agent

When treating children, carefully weigh the risks and benefits of pharmacological treatment against the risks and benefits of nontreatment and make sure to document this in the patientâ€TM s chart

Distribute the brochures provided by the FDA and the drug companies

Whenever possible, warn patients and their caregivers about the possibility of activating side effects, and advise them to report such symptoms immediately

Monitor patients for activation of suicidal ideation, especially children and adolescents

Discontinuing smoking may lead to pharmacokinetic or pharmacodynamic changes in other drugs the patient is taking, which could potentially require dose adjustment

Do Not Use

Zyban or Aplenzin in combination with each other or with any formulation of Wellbutrin

If patient has history of seizures

If patient is anorexic or bulimic, either currently or in the past, but see Pearls

If patient is abruptly discontinuing alcohol, sedative use, or anticonvulsant medication

If patient has had recent head injury If patient has a nervous system tumor

If patient is taking an MAOI (except as noted under Drug Interactions)

If patient is taking thioridazine

If there is a proven allergy to bupropion

Special Populations Renal Impairment

Lower initial dose, perhaps give less frequently Drug concentration may be increased

Patient should be monitored closely

Hepatic Impairment

Lower initial dose, perhaps give less frequently Patient should be monitored closely

In severe hepatic cirrhosis, bupropion XL should be administered at no more than 150 mg every other day

Cardiac Impairment

Limited available data

Evidence of rise in supine blood pressure Use with caution

Elderly

Some patients may tolerate lower doses better

Reduction in the risk of suicidality with antidepressants compared to placebo in adults age 65 and older

Children and Adolescents

Carefully weigh the risks and benefits of pharmacological treatment against the risks and benefits of nontreatment with antidepressants and make sure to document this in the patientâ€TM s chart

Monitor patients face-to-face regularly, particularly during the first several weeks of treatment

Use with caution, observing for activation of known or unknown bipolar disorder and/or suicidal ideation, and inform parents or

guardians of this risk so they can help observe child or adolescent patients

Safety and efficacy have not been established

May be used for ADHD in children or adolescents

May be used for smoking cessation in adolescents

Preliminary research suggests efficacy in comorbid depression and ADHD

Dosage may follow adult pattern for adolescents

Children may require lower doses initially, with a maximum dose of 300 mg/day

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women

Epidemiological studies do not indicate increased risk of congenital malformations overall or of cardiovascular malformations

In animal studies, no clear evidence of teratogenicity has been observed; however, slightly increased incidences of fetal

malformations and skeletal variations were observed in rabbit studies at doses approximately equal to and greater than the maximum recommended human doses, and greater and decreased fetal weights were observed in rat studies at doses greater than the maximum recommended human doses

Pregnant women wishing to stop smoking may consider behavioral therapy before pharmacotherapy

Not generally recommended for use during pregnancy, especially during first trimester

Must weigh the risk of treatment (first trimester fetal development, third trimester newborn delivery) to the child against the risk of no treatment (recurrence of depression, maternal health, infant bonding) to the mother and child

For many patients this may mean continuing treatment during pregnancy

National Pregnancy Registry for Antidepressants: 1-866-961-2388,

https://womensmentalhealth.org/research/pregnancyregistry/antidepr essants

Breast Feeding

Some drug is found in motherâ€TM s breast milk

If child becomes irritable or sedated, breast feeding or drug may need to be discontinued

Immediate postpartum period is a high-risk time for depression, especially in women who have had prior depressive episodes, so drug may need to be reinstituted late in the third trimester or shortly after childbirth to prevent a recurrence during the postpartum period

Must weigh benefits of breast feeding with risks and benefits of antidepressant treatment versus nontreatment to both the infant and the mother

For many patients, this may mean continuing treatment during breast feeding

The Art of Psychopharmacology Potential Advantages

Retarded depression

Atypical depression

Bipolar depression

Patients concerned about sexual dysfunction Patients concerned about weight gain

Potential Disadvantages

Patients experiencing weight loss associated with their depression Patients who are excessively activated

Primary Target Symptoms

Depressed mood

Sleep disturbance, especially hypersomnia Cravings associated with nicotine withdrawal Cognitive functioning

Pearls

âœ1⁄2 May be effective if SSRIs have failed or for SSRI “ poop-

outâ€

Less likely to produce hypomania than some other antidepressants

âœ1⁄2 May improve cognitive slowing/pseudodementia âœ1⁄2 Reduces hypersomnia and fatigue

Approved to help reduce craving during smoking cessation Anecdotal use in attention deficit disorder

May cause sexual dysfunction only infrequently

May exacerbate tics

Bupropion may not be as effective in anxiety disorders as many other antidepressants

Prohibition for use in eating disorders due to increased risk of seizures is related to past observations when bupropion immediate- release was dosed at especially high levels to low body weight patients with active anorexia nervosa

Current practice suggests that patients of normal BMI without additional risk factors for seizures can benefit from bupropion, especially if given prudent doses of the XL formulation; such treatment should be administered by experts, and patients should be monitored closely and informed of the potential risks

Recently approved hydrobromide salt formulation of bupropion may facilitate high dosing for difficult-to-treat patients, as it allows administration of single-pill doses up to 450 mg equivalency to bupropion hydrochloride salt (522 mg tablet), unlike bupropion hydrochloride controlled-release formulations for which the biggest dose in a single pill is 300 mg

As bromide salts have anticonvulsant properties, hydrobromide salts of bupropion could theoretically reduce risk of seizures, but this has not been proven

The active enantiomer of the principal active metabolite [(+)-6- hydroxy-bupropion] is in clinical development as a novel antidepressant

The combination of bupropion and naltrexone has demonstrated efficacy as a treatment for obesity and is currently being evaluated in a long-term study to assess the cardiovascular health outcomes of this treatment

Phase 2 trials of the combination of bupropion and zonisamide for the treatment of obesity have been completed

Suggested Reading

Clayton AH . Extended-release bupropion: an antidepressant with a broad spectrum of therapeutic activity? Expert Opin Pharmacother 2007 ;8 (4 ):457– 66 .

Ferry L , Johnston JA . Efficacy and safety of bupropion SR for smoking cessation: data from clinical trials and five years of postmarketing experience . Int J Clin Pract 2003 ;57 (3 ):224– 30 .

Foley KF , DeSanty KP , Kast RE . Bupropion: pharmacology and therapeutic applications . Expert Rev Neurother 2006 ;6 (9 ):1249– 65 .

Jefferson JW , Pradko JF . Muir KT. Bupropion for major depressive disorder: pharmacokinetic and formulation considerations . Clin Ther 2005 ;27 (11 ):1685– 95 .

Papakostas GI , Nutt DJ , Hallett LA , et al. Resolution of sleepiness and fatigue in major depressive disorder: a comparison of bupropion and the selective serotonin reuptake inhibitors . Biol Psychiatry 2006 ;60 (12 ):1350– 5 .

Buspirone

BuSpar

Therapeutics Brands

Yes

Generic?

Class

see index for additional brand names

Neuroscience-based Nomenclature: serotonin receptor partial agonist (S-RPA)

Anxiolytic (azapirone; serotonin 1A partial agonist; serotonin stabilizer)

Commonly Prescribed for

(bold for FDA approved)

Management of anxiety disorders Short-term treatment of symptoms of anxiety Mixed anxiety and depression Treatment-resistant depression (adjunctive)

How the Drug Works

Binds to serotonin type 1A receptors

Partial agonist actions postsynaptically may theoretically diminish serotonergic activity and contribute to anxiolytic actions

Partial agonist actions at presynaptic somatodendritic serotonin autoreceptors may theoretically enhance serotonergic activity and contribute to antidepressant actions

How Long Until It Works

Generally takes within 2– 4 weeks to achieve efficacy

If it is not working within 6– 8 weeks, it may require a dosage increase or it may not work at all

If It Works

The goal of treatment is complete remission of symptoms as well as prevention of future relapses

Treatment most often reduces or even eliminates symptoms, but not a cure since symptoms can recur after medicine stopped

Chronic anxiety disorders may require long-term maintenance with buspirone to control symptoms

If It Doesnâ€TM t Work

Consider switching to another agent (a benzodiazepine or antidepressant)

Best Augmenting Combos for Partial Response or Treatment Resistance

Sedative hypnotic for insomnia

Buspirone is often given as an augmenting agent to SSRIs or SNRIs

Tests

Side Effects

How Drug Causes Side Effects

Serotonin partial agonist actions in parts of the brain and body and at receptors other than those that cause therapeutic actions

Notable Side Effects

âœ1⁄2 Dizziness, headache, nervousness, sedation, excitement

Nausea Restlessness

Life-Threatening or Dangerous Side Effects

None for healthy individuals

Rare cardiac symptoms

Weight Gain

Reported but not expected

Sedation

Occurs in significant minority

What to Do About Side Effects

Wait

Wait

Wait

Lower the dose

Give total daily dose divided into 3, 4, or more doses Switch to another agent

Best Augmenting Agents for Side Effects

Many side effects cannot be improved with an augmenting agent

20– 30 mg/day

Dosing and Use Usual Dosage Range

Dosage Forms

Tablet 5 mg scored, 10 mg scored, 15 mg multiscored, 30 mg multiscored

How to Dose

Initial 15 mg twice a day; increase in 5 mg/day increments every 2– 3 days until desired efficacy is reached; maximum dose generally 60 mg/day

Dosing Tips

Requires dosing 2– 3 times a day for full effect

Absorption is affected by food, so administration with or without food should be consistent

Overdose

No deaths reported in monotherapy; sedation, dizziness, small pupils, nausea, vomiting

Long-Term Use

Limited data suggest that it is safe

No

Habit Forming

How to Stop

Taper generally not necessary

Pharmacokinetics

Metabolized primarily by CYP450 3A4 Elimination half-life approximately 2– 3 hours Absorption is affected by food

Drug Interactions

Use with caution with MAOIs, including 14 days after MAOIs are stopped (for the expert)

CYP450 3A4 inhibitors (e.g., fluxotine, fluvoxamine, nefazodone) may reduce clearance of buspirone and raise its plasma levels, so the dose of buspirone may need to be lowered when given concomitantly with these agents

CYP450 3A4 inducers (e.g., carbamazepine) may increase clearance of buspirone, so the dose of buspirone may need to be raised

Buspirone may increase plasma concentrations of haloperidol

Buspirone may raise levels of nordiazepam, the active metabolite of diazepam, which may result in increased symptoms of dizziness, headache, or nausea

None

Other Warnings/Precautions

Do Not Use

If patient is taking an MAOI (except as noted under Drug Interactions)

If there is a proven allergy to buspirone

Special Populations Renal Impairment

Use with caution

Not recommended for patients with severe renal impairment

Hepatic Impairment

Use with caution

Not recommended for patients with severe hepatic impairment

Cardiac Impairment

Buspirone has been used to treat hostility in patients with cardiac impairment

Elderly

Some patients may tolerate lower doses better

Children and Adolescents

Studies in children age 6– 17 do not show significant reduction in anxiety symptoms in generalized anxiety disorder (GAD)

Safety profile in children encourages use

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women Animal studies have not shown adverse effects

Not generally recommended in pregnancy, but may be safer than some other options

Breast Feeding

Some drug is found in motherâ€TM s breast milk

Trace amounts may be present in nursing children whose mothers are on buspirone

If child becomes irritable or sedated, breast feeding or drug may need to be discontinued

The Art of Psychopharmacology Potential Advantages

Safety profile

Lack of dependence, withdrawal

Lack of sexual dysfunction or weight gain

Potential Disadvantages

Takes 4 weeks for results, whereas benzodiazepines have immediate effects

Primary Target Symptoms

Anxiety

Pearls

âœ1⁄2 Buspirone does not appear to cause dependence and shows

virtually no withdrawal symptoms

May have less severe side effects than benzodiazepines

âœ1⁄2 Generally lack of sexual dysfunction

Buspirone may reduce sexual dysfunction associated with GAD and

with serotonergic antidepressants

Sedative effects may be more likely at doses above 20 mg/day

May have less anxiolytic efficacy than benzodiazepines for some patients

Buspirone is generally reserved as an augmenting agent to treat anxiety

Suggested Reading

Apter JT , Allen LA . Buspirone: future directions . J Clin

Psychopharmacol 1999 ;19 :86 – 93 .

Mahmood I , Sahaiwalla C . Clinical pharmacokinetics and pharmacodynamics of buspirone, an anxiolytic drug . Clin Pharmacokinet 1999 ;36 :277– 87 .

Pecknold JC . A risk-benefit assessment of buspirone in the treatment of anxiety disorders . Drug Saf 1997 ;16 :118– 32 .

Sramek JJ , Hong WW , Hamid S , Nape B , Cutler NR . Meta-analysis of the safety and tolerability of two dose regimens of buspirone in patients with persistent anxiety . Depress Anxiety 1999 ;9 :131– 4 .

Caprylidene

Axona

Therapeutics Brands

see index for additional brand names

No

Medical food Cognitive enhancer

Generic?

Class

Commonly Prescribed for

(bold for FDA approved)

Dietary management of metabolic processes associated with Alzheimer disease (mild to moderate)

Mild cognitive impairment

How the Drug Works

Induces hyperketonemia and provides an alternative energy substrate to glucose in the brain

Caprylidene is processed in the gut, resulting in medium-chain fatty acids that pass to the liver and undergo obligate oxidation, ultimately being formed into ketone bodies (acetoacetate and beta- hydroxybutyric acid (BHB))

Ketone bodies cross the blood– brain barrier and are taken up by neurons and enter the mitochondria, where they increase mitochondrial efficiency

Ketone bodies also generate ATP and increase pools of acetyl-CoA and acetylcholine

How Long Until It Works

May begin working immediately

If It Works

May improve or stabilize memory and cognitive function, but does not reverse the degenerative process

If It Doesnâ€TM t Work

Consider a cholinesterase inhibitor or memantine

Best Augmenting Combos for Partial Response or Treatment Resistance

Cholinesterase inhibitors or memantine

Tests

Triglyceride levels should be monitored periodically for individuals who meet multiple criteria for metabolic syndrome (i.e., elevated waist circumference, elevated triglycerides, high blood pressure, reduced fasting HDL, and/or elevated fasting glucose)

Side Effects

How Drug Causes Side Effects

Caprylidene is processed in the gut, which may contribute to gastrointestinal side effects

Notable Side Effects

Diarrhea, flatulence, dyspepsia Nausea, headache

Life-Threatening or Dangerous Side Effects

None for healthy individuals

None reported

Weight Gain

Reported but not expected

Some patients may experience weight loss

Sedation

What to Do About Side Effects

Take it with food

Sip it slowly over approximately 30 minutes Consider lowering the dose

Best Augmenting Agents for Side Effects

Many side effects cannot be improved with an augmenting agent Over-the-counter simethicone, antacids, or antidiarrheals

Reported but not expected

40 g/day

Powder 40 g/packet

Dosing and Use Usual Dosage Range

Dosage Forms

How to Dose

One 40 g packet of caprylidene should be fully mixed with 4– 8 oz of liquid; dosing should occur shortly after a meal (preferably breakfast or lunch)

Dosing Tips

Each 40 g packet of caprylidene powder contains 20 g of medium- chain triglycerides (MCTs)

Gastrointestinal side effects are reduced if caprylidene is taken with food and/or sipped slowly over approximately 30 minutes

Some patients may require a lower starting dose in order to improve tolerability

Overdose

No fatalities have been reported; diarrhea, sometimes severe

Long-Term Use

Not studied

Drug may lose effectiveness as the course of Alzheimer disease progresses

No

Habit Forming

Taper not necessary

How to Stop

Pharmacokinetics

Absorbed in the gut; metabolized in the liver Crosses the blood– brain barrier

None reported

Drug Interactions

Other Warnings/Precautions

Use with caution in patients with known hypersensitivity to palm or coconut oil

Use with caution in patients at risk for ketoacidosis (e.g., alcoholics, patients with poorly controlled diabetes)

Use with caution in patients with a history of gastrointestinal inflammatory conditions

Do Not Use

If there is a proven allergy to caprylidene, milk, or soy

Special Populations Renal Impairment

Not studied

Not studied

Not studied

Hepatic Impairment

Cardiac Impairment

Elderly

Dose adjustment not necessary

Children and Adolescents

Safety and efficacy have not been established

Pregnancy

Controlled studies have not been conducted in pregnant women Animal studies have not shown teratogenic effects

Breast Feeding

Unknown if caprylidene is secreted in human breast milk

The Art of Psychopharmacology Potential Advantages

Patients with residual memory problems on Alzheimer treatment

Potential Disadvantages

Patients with gastrointestinal disorders

Primary Target Symptoms

Memory loss in Alzheimer disease Memory loss in mild cognitive impairment

Pearls

Dramatic reversal of symptoms of Alzheimer disease is not generally seen with caprylidene

âœ1⁄2 Perhaps only 50% of Alzheimer patients are diagnosed, and only 50% of those diagnosed are treated, and then only for 200 days in a disease that lasts 7– 10 years

Must evaluate lack of efficacy and loss of efficacy over months, not weeks

Patients who complain themselves of memory problems may have depression, whereas patients whose spouses or children complain of the patientâ€TM s memory problems may have Alzheimer disease

Treat the patient but ask the caregiver about efficacy What you see may depend upon how early you treat

The first symptoms of Alzheimer disease are generally mood changes; thus, Alzheimer disease may initially be diagnosed as depression

Women may experience cognitive symptoms in perimenopause as a result of hormonal changes that are not a sign of dementia or Alzheimer disease

If treatment with antidepressants fails to improve apathy and depressed mood in the elderly, it is possible that this represents early Alzheimer disease

Delay in progression in Alzheimer disease is not evidence of disease-modifying actions of caprylidene

The most prominent side effects of caprylidene are gastrointestinal effects, which are usually mild and transient

Weight loss can be a problem in Alzheimer patients with debilitation and muscle wasting

Suggested Reading

Henderson ST . Ketone bodies as therapeutic for Alzheimerâ€TM s disease . Neurotherapeutics 2008 ;5 (3 ):470– 80 .

Traul KA , Driedger A , Ingle DL , Nakhasi D. Review of the toxicoogic properties of medium-chain triglycerides . Food Chem Toxicol 2000 ;38 :79 – 98 .

Carbamazepine

Therapeutics Brands

Tegretol

Carbatrol

Equetro

see index for additional brand names

Generic?

Yes (not for extended-release formulation)

Class

Neuroscience-based Nomenclature: glutamate, voltage-gated sodium and calcium channel blocker (Glu-CB)

Anticonvulsant, antineuralgic for chronic pain, voltage-sensitive sodium channel antagonist

Commonly Prescribed for

(bold for FDA approved)

Partial seizures with complex symptomatology Generalized tonic– clonic seizures (grand mal)

Mixed seizure patterns

Pain associated with true trigeminal neuralgia Acute mania/mixed mania (Equetro) Glossopharyngeal neuralgia

Bipolar depression

Bipolar maintenance

Psychosis, schizophrenia (adjunctive)

How the Drug Works

âœ1⁄2 Acts as a use-dependent blocker of voltage-sensitive sodium

channels

âœ1⁄2 Interacts with the open channel conformation of voltage-sensitive sodium channels

âœ1⁄2 Interacts at a specific site of the alpha pore-forming subunit of voltage-sensitive sodium channels

Inhibits release of glutamate

How Long Until It Works

For acute mania, effects should occur within a few weeks

May take several weeks to months to optimize an effect on mood stabilization

Should reduce seizures by 2 weeks

If It Works

The goal of treatment is complete remission of symptoms (e.g., seizures, mania, pain)

Continue treatment until all symptoms are gone or until improvement is stable and then continue treating indefinitely as long as improvement persists

Continue treatment indefinitely to avoid recurrence of mania and seizures

Treatment of chronic neuropathic pain most often reduces but does not eliminate pain and is not a cure since symptoms usually recur after medicine stopped

If It Doesnâ€TM t Work (for Bipolar Disorder)

âœ1⁄2 Many patients have only a partial response where some symptoms are improved but others persist or continue to wax and wane without stabilization of mood

Other patients may be nonresponders, sometimes called treatment- resistant or treatment-refractory

Consider increasing dose, switching to another agent, or adding an appropriate augmenting agent

Consider adding psychotherapy

Consider biofeedback or hypnosis for pain

For bipolar disorder, consider the presence of noncompliance and counsel patient

Switch to another mood stabilizer with fewer side effects or to extended-release carbamazepine

Consider evaluation for another diagnosis or for a comorbid condition (e.g., medical illness, substance abuse, etc.)

Best Augmenting Combos for Partial Response or Treatment Resistance

Lithium

Atypical antipsychotics (especially risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole)

Valproate (carbamazepine can decrease valproate levels)

Lamotrigine (carbamazepine can decrease lamotrigine levels)

âœ1⁄2 Antidepressants (with caution because antidepressants can destabilize mood in some patients, including induction of rapid cycling or suicidal ideation; in particular consider bupropion; also SSRIs, SNRIs, others; generally avoid TCAs, MAOIs)

Tests

âœ1⁄2 Before starting: blood count, liver, kidney, and thyroid function

tests

During treatment: blood count every 2– 4 weeks for 2 months, then every 3– 6 months throughout treatment

During treatment: liver, kidney, and thyroid function tests every 6– 12 months

Consider monitoring sodium levels because of possibility of hyponatremia

âœ1⁄2 Before starting: individuals with ancestry across broad areas of Asia should consider screening for the presence of the HLA-B* 1502 allele; those with HLA-B*1502 should not be treated with carbamazepine

Side Effects

How Drug Causes Side Effects

CNS side effects theoretically due to excessive actions at voltage- sensitive sodium channels

Major metabolite (carbamazepine-10, 11 epoxide) may be the cause of many side effects

Mild anticholinergic effects may contribute to sedation, blurred vision

Notable Side Effects

âœ1⁄2 Sedation, dizziness, confusion, unsteadiness, headache

âœ1⁄2 Nausea, vomiting, diarrhea Blurred vision

âœ1⁄2 Benign leukopenia (transient; in up to 10%) âœ1⁄2 Rash

Life-Threatening or Dangerous Side Effects âœ1⁄2 Rare aplastic anemia, agranulocytosis (unusual bleeding or

bruising, mouth sores, infections, fever, sore throat)

âœ1⁄2 Rare severe dermatologic reactions (purpura, Stevens-Johnson syndrome)

Rare anaphylaxis and angioedema Rare cardiac problems

Rare induction of psychosis or mania

âœ1⁄2 SIADH (syndrome of inappropriate antidiuretic hormone secretion) with hyponatremia

Increased frequency of generalized convulsions (in patients with atypical absence seizures)

Rare activation of suicidal ideation and behavior (suicidality)

Weight Gain

Occurs in significant minority

Sedation

Frequent and can be significant in amount Some patients may not tolerate it Dose-related

Can wear off with time, but commonly does not wear off at high doses

CNS side effects significantly lower with controlled-release formulation (e.g., Equetro, Carbatrol)

What to Do About Side Effects

Wait

Wait

Wait

Take with food or split dose to avoid gastrointestinal effects Extended-release carbamazepine can be sprinkled on soft food Take at night to reduce daytime sedation

Switch to another agent or to extended-release carbamazepine

Best Augmenting Agents for Side Effects

Many side effects cannot be improved with an augmenting agent

Dosing and Use Usual Dosage Range

400– 1200 mg/day

Under age 6: 10– 20 mg/kg per day

Dosage Forms

Tablet 100 mg, 200 mg

Tablet 100 mg chewable, 200 mg chewable Extended-release tablet 100 mg, 200 mg, 400 mg Extended-release capsule 100 mg, 200 mg, 300 mg Oral suspension 100 mg/5mL (450 mL)

How to Dose

For bipolar disorder and seizures (ages 13 and older): initial 200 mg twice daily (tablet) or 1 teaspoon (100 mg) 4 times a day (suspension); each week increase by up to 200 mg/day in divided doses (2 doses for extended-release formulation, 3– 4 doses for other tablets); maximum dose generally 1200 mg/day for adults and 1000 mg/day for children under age 15; maintenance dose generally 800– 1200 mg/day for adults; some patients may require up to 1600 mg/day

Seizures (under age 13): see Children and Adolescents

Trigeminal neuralgia: initial 100 mg twice daily (tablet) or 0.5 teaspoon (50 mg) 4 times a day; each week increase by up to 200 mg/day in divided doses (100 mg every 12 hours for tablet formulations, 50 mg 4 times a day for suspension formulation); maximum dose generally 1200 mg/day

Lower initial dose and slower titration should be used for carbamazepine suspension

Dosing Tips

Higher peak levels occur with the suspension formulation than with the same dose of the tablet formulation, so suspension should generally be started at a lower dose and titrated slowly

Take carbamazepine with food to avoid gastrointestinal effects

âœ1⁄2 Slow dose titration may delay onset of therapeutic action but enhance tolerability to sedating side effects

Controlled-release formulations (e.g., Equetro, Carbatrol) can significantly reduce sedation and other CNS side effects

Should titrate slowly in the presence of other sedating agents, such as other anticonvulsants, in order to best tolerate additive sedative side effects

âœ1⁄2 Can sometimes minimize the impact of carbamazepine upon the bone marrow by dosing slowly and monitoring closely when initiating treatment; initial trend to leukopenia/neutropenia may reverse with continued conservative dosing over time and allow subsequent dosage increases with careful monitoring

âœ1⁄2 Carbamazepine often requires a dosage adjustment upward with time, as the drug induces its own metabolism, thus lowering its own plasma levels over the first several weeks to months of treatment

Do not break or chew carbamazepine extended-release tablets as this will alter controlled-release properties

Overdose

Can be fatal (lowest known fatal dose in adults is 3.2 g, in adolescents is 4 g, and in children is 1.6 g); nausea, vomiting, involuntary movements, irregular heartbeat, urinary retention, trouble breathing, sedation, coma

Long-Term Use

May lower sex drive

Monitoring of liver, kidney, thyroid functions, blood counts, and sodium may be required

No

Habit Forming

How to Stop

Taper; may need to adjust dosage of concurrent medications as carbamazepine is being discontinued

âœ1⁄2 Rapid discontinuation may increase the risk of relapse in bipolar disorder

Epilepsy patients may seize upon withdrawal, especially if withdrawal is abrupt

Discontinuation symptoms uncommon

Pharmacokinetics

Metabolized in the liver, primarily by CYP450 3A4

Renally excreted

Active metabolite (carbamazepine-10,11 epoxide)

Initial half-life 26– 65 hours (35– 40 hours for extended-release formulation); half-life 12– 17 hours with repeated doses

Half-life of active metabolite is approximately 34 hours

âœ1⁄2 Is not only a substrate for CYP450 3A4, but also an inducer of CYP450 3A4

âœ1⁄2 Thus, carbamazepine induces its own metabolism, often requiring an upward dosage adjustment

Is also an inducer of CYP450 2C9 and weakly of 1A2 and 2C19 Food does not affect absorption

Drug Interactions

Enzyme-inducing antiepileptic drugs (carbamazepine itself as well as phenobarbital, phenytoin, and primidone) may increase the clearance of carbamazepine and lower its plasma levels

CYP450 3A4 inducers, such as carbamazepine itself, can lower the plasma levels of carbamazepine

CYP450 3A4 inhibitors, such as nefazodone, fluvoxamine, and fluoxetine, can increase plasma levels of carbamazepine

Carbamazepine can increase plasma levels of clomipramine, phenytoin, primidone

Carbamazepine can decrease plasma levels of acetaminophen, clozapine, benzodiazepines, dicumarol, doxycycline, theophylline, warfarin, rivaroxaban, apixaban, dabigatran, edoxaban, and haloperidol as well as other anticonvulsants such as phensuximide, methsuximide, ethosuximide, phenytoin, tiagabine, topiramate, lamotrigine, and valproate

Carbamazepine can decrease plasma levels of hormonal contraceptives and adversely affect their efficacy

Combined use of carbamazepine with other anticonvulsants may lead to altered thyroid function

Combined use of carbamazepine and lithium may increase risk of neurotoxic effects

Depressive effects are increased by other CNS depressants (alcohol, MAOIs, other anticonvulsants, etc.)

Combined use of carbamazepine suspension with liquid formulations of chlorpromazine has been shown to result in excretion of an orange rubbery precipitate; because of this, combined use of carbamazepine suspension with any liquid medicine is not recommended

Other Warnings/Precautions

âœ1⁄2 Patients should be monitored carefully for signs of unusual bleeding or bruising, mouth sores, infections, fever, or sore throat, as the risk of aplastic anemia and agranulocytosis with carbamazepine use is 5– 8 times greater than in the general population (risk in the

untreated general population is 6 patients per 1 million per year for agranulocytosis and 2 patients per 1 million per year for aplastic anemia)

Because carbamazepine has a tricyclic chemical structure, use with caution with MAOIs, including 14 days after MAOIs are stopped (for the expert)

May exacerbate angle-closure glaucoma

Because carbamazepine can lower plasma levels of hormonal contraceptives, it may also reduce their effectiveness

May need to restrict fluid intake because of risk of developing syndrome of inappropriate antidiuretic hormone secretion, hyponatremia and its complications

Use with caution in patients with mixed seizure disorders that include atypical absence seizures because carbamazepine has been associated with increased frequency of generalized convulsions in such patients

Individuals with the HLA-B*1502 allele are at increased risk of developing Stevens-Johnson syndrome and toxic epidermal necrolysis

Whenever possible, warn patients and their caregivers about the possibility of activating side effects, and advise them to report such side effects immediately

Do Not Use

If patient has history of bone marrow suppression

If patient tests positive for the HLA-B*1502 allele

If there is a proven allergy to any tricyclic compound

If there is a proven allergy to carbamazepine

Suspension: in patients with hereditary problems with fructose intolerance

Special Populations Renal Impairment

Carbamazepine is renally secreted, so the dose may need to be lowered

Hepatic Impairment

Drug should be used with caution

Rare cases of hepatic failure have occurred

Cardiac Impairment

Drug should be used with caution

Elderly

Some patients may tolerate lower doses better

Elderly patients may be more susceptible to adverse effects

Children and Adolescents

Approved use for epilepsy; therapeutic range of total carbamazepine in plasma is considered the same for children and adults

Ages 6– 12: initial dose 100 mg twice daily (tablets) or 0.5 teaspoon (50 mg) 4 times a day (suspension); each week increase by up to 100 mg/day in divided doses (2 doses for extended-release formulation, 3– 4 doses for all other formulations); maximum dose generally 1000 mg/day; maintenance dose generally 400– 800 mg/day

Ages 5 and younger: initial 10– 20 mg/kg per day in divided doses (2– 3 doses for tablet formulations, 4 doses for suspension); increase weekly as needed; maximum dose generally 35 mg/kg/day

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

âœ1⁄2 Use during first trimester may raise risk of neural tube defects (e.g., spina bifida) or other congenital anomalies

Use in women of childbearing potential requires weighing potential benefits to the mother against the risks to the fetus

âœ1⁄2 If drug is continued, perform tests to detect birth defects

âœ1⁄2 If drug is continued, start on folate 1 mg/day early in pregnancy

to reduce risk of neural tube defects

Antiepileptic Drug Pregnancy Registry: 1-888-233-2334,

http://www.aedpregnancyregistry.org

Use of anticonvulsants in combination may cause a higher prevalence of teratogenic effects than anticonvulsant monotherapy

Taper drug if discontinuing

Seizures, even mild seizures, may cause harm to the embryo/fetus

âœ1⁄2 For bipolar patients, carbamazepine should generally be discontinued before anticipated pregnancies

Recurrent bipolar illness during pregnancy can be quite disruptive

For bipolar patients, given the risk of relapse in the postpartum period, some form of mood stabilizer treatment may need to be restarted immediately after delivery if patient is unmedicated during pregnancy

âœ1⁄2 Atypical antipsychotics may be preferable to lithium or anticonvulsants such as carbamazepine if treatment of bipolar disorder is required during pregnancy

Bipolar symptoms may recur or worsen during pregnancy and some form of treatment may be necessary

Breast Feeding

Some drug is found in motherâ€TM s breast milk

âœ1⁄2 Recommended either to discontinue drug or bottle feed

If drug is continued while breast feeding, infant should be monitored for possible adverse effects, including hematological effects

If infant shows signs of irritability or sedation, drug may need to be discontinued

Some cases of neonatal seizures, respiratory depression, vomiting, and diarrhea have been reported in infants whose mothers received carbamazepine during pregnancy

âœ1⁄2 Bipolar disorder may recur during the postpartum period, particularly if there is a history of prior postpartum episodes of either depression or psychosis

Relapse rates may be lower in women who receive prophylactic treatment for postpartum episodes of bipolar disorder

Atypical antipsychotics and anticonvulsants such as valproate may be safer than carbamazepine during the postpartum period when breast feeding

The Art of Psychopharmacology Potential Advantages

Treatment-resistant bipolar and psychotic disorders

Potential Disadvantages

Patients who do not wish to or cannot comply with blood testing and close monitoring

Patients who cannot tolerate sedation Pregnant patients

Primary Target Symptoms

Incidence of seizures

Unstable mood, especially mania Pain

Pearls

Carbamazepine was the first anticonvulsant widely used for the treatment of bipolar disorder and is now formally approved for acute mania and mixed mania

âœ1⁄2 An extended-release formulation has better evidence of efficacy and improved tolerability in bipolar disorder than does immediate- release carbamazepine

Dosage frequency as well as sedation, diplopia, confusion, and ataxia may be reduced with extended-release carbamazepine

Risk of serious side effects is greatest in the first few months of treatment

Common side effects such as sedation often abate after a few months

âœ1⁄2 May be effective in patients who fail to respond to lithium or other mood stabilizers

May be effective for the depressed phase of bipolar disorder and for maintenance in bipolar disorder

Can be complicated to use with concomitant medications

Suggested Reading

Leucht S , McGrath J , White P , Kissling W . Carbamazepine for schizophrenia and schizoaffective psychoses . Cochrane Database Syst Rev 2002 ;(3 ):CD001258 .

Marson AG , Williamson PR , Hutton JL , Clough HE , Chadwick DW . Carbamazepine versus valproate monotherapy for epilepsy . Cochrane Database Syst Rev 2000 ;(3 ):CD001030 .

Smith LA , Cornelius V , Warnock A , Tacchi MJ , Taylor D . Pharmacological interventions for acute bipolar mania: a systematic review of randomized placebo-controlled trials . Bipolar Disord 2007 ;9 (6 ):551– 60 .

Weisler RH , Kalali AH , Ketter TA . A multicenter, randomized, double- blind, placebo-controlled trial of extended-release carbamazepine capsules as monotherapy for bipolar disorder patients with manic or mixed episodes . J Clin Psychiatry 2004 ;65 :478– 84 .

Cariprazine

Vraylar

Therapeutics Brands

No

Generic?

Class

see index for additional brand names

Neuroscience-based Nomenclature: dopamine, serotonin, norepinephrine receptor partial agonist

Dopamine partial agonist (dopamine-serotonin partial agonist, dopamine stabilizer, atypical antipsychotic, third- generation antipsychotic; sometimes included as a second-generation antipsychotic; also a potential mood stabilizer)

Commonly Prescribed for

(bold for FDA approved)

Schizophrenia, acute and maintenance Acute mania/mixed mania

Bipolar depression (bipolar I disorder)

Bipolar depressive episodes with mixed features (subsyndromal manic symptoms)

Bipolar maintenance

Major depressive episodes (unipolar) with mixed features (subsyndromal manic symptoms)

Manic episodes with mixed features (subsyndromal depressive symptoms)

Other psychotic disorders

Negative symptoms of schizophrenia

Treatment-resistant depression

Augmentation of other antidepressants in (unipolar) major depressive disorder

Behavioral disturbances in dementia

Behavioral disturbances in children and adolescents Disorders associated with problems with impulse control Posttraumatic stress disorder

How the Drug Works âœ1⁄2 Partial agonism at dopamine 2 receptors

Theoretically reduces dopamine output when dopamine concentrations are high, thus improving positive symptoms and

mediating antipsychotic actions

Theoretically increases dopamine output when dopamine concentrations are low, thus improving cognitive, negative, and mood symptoms

Preferentially binds to dopamine 3 over dopamine 2 receptors at low doses; the clinical significance is unknown but could theoretically contribute to cariprazineâ€TM s efficacy for negative symptoms. D3 partial agonism could theoretically be useful for treating cognition, mood, emotions, and reward/substance use

Interactions at a myriad of other neurotransmitter receptors may contribute to cariprazineâ€TM s efficacy

Cariprazine also has high affinity for the serotonin 1A (partial agonist) and 2B (antagonist) receptors

Blocks serotonin 2A receptors, causing enhancement of dopamine release in certain brain regions and thus reducing motor side effects and possibly improving cognitive and affective symptoms

How Long Until It Works

Psychotic, and manic and depressive symptoms can improve within 1 week, but it may take several weeks for full effect on behavior as well as on cognition

Classically recommended to wait at least 4– 6 weeks to determine full antipsychotic and antidepressant efficacy of drug, but in practice

some patients require up to 16– 20 weeks to show a good response, especially on negative or cognitive symptoms

If It Works

Most often reduces positive symptoms but does not eliminate them

May reduce and eliminate acute manic symptoms and depressive symptoms

Can improve negative symptoms, as well as aggressive, cognitive, and affective symptoms in schizophrenia

Most schizophrenia patients do not have a total remission of symptoms but rather a reduction of symptoms by about a third

Perhaps 5– 15% of schizophrenia patients can experience an overall improvement of greater than 50– 60%, especially when receiving stable treatment for more than a year

Such patients are considered super-responders or “ awakeners†since they may be well enough to be employed, live independently, and sustain long-term relationships

Continue treatment until reaching a plateau of improvement

After reaching a satisfactory plateau, continue treatment for at least a year after first episode of psychosis

For second and subsequent episodes of psychosis, treatment may need to be indefinite

Even for first episodes of psychosis, it may be preferable to continue treatment

If It Works – for Bipolar Depression

The goal of treatment is complete remission of current symptoms as well as prevention of future relapses

Treatment most often reduces or even eliminates symptoms, but not a cure since symptoms can recur after medicine stopped

Continue treatment until all symptoms are gone (remission) or significantly reduced

Once symptoms are gone, continue treating for 1 year for the first episode of depression

For second and subsequent episodes of depression, treatment may need to be indefinite

If It Doesnâ€TM t Work

Try one of the other atypical antipsychotics

If 2 or more antipsychotic monotherapies do not work, consider clozapine

Some patients may require treatment with a conventional antipsychotic

If no first-line atypical antipsychotic is effective for schizophrenia, consider higher doses or augmentation with valproate or lamotrigine

Consider lithium and anticonvulsant mood stabilizers for mania

Consider noncompliance and switch to another antipsychotic with fewer side effects or to an antipsychotic that can be given by depot injection

Consider initiating rehabilitation and psychotherapy Consider presence of concomitant drug abuse

If It Doesnâ€TM t Work – for Bipolar Depression

Some patients may be nonresponders, sometimes called treatment- resistant or treatment-refractory

Some patients who have an initial response may relapse even though they continue treatment, sometimes called “ poop-outâ€

Consider psychotherapy

Consider evaluation for another diagnosis or for a comorbid condition (e.g., medical illness, substance abuse, etc.)

Best Augmenting Combos for Partial Response or Treatment Resistance

Valproic acid (valproate, divalproex, divalproex ER) Lamotrigine

Topiramate

Lithium

Benzodiazepines

Tests

Before starting any atypical antipsychotic

âœ1⁄2 Weigh all patients and track BMI during treatment

Get baseline personal and family history of diabetes, obesity,

dyslipidemia, hypertension, and cardiovascular disease

âœ1⁄2 Get waist circumference (at umbilicus), blood pressure, fasting plasma glucose, and fasting lipid profile

Determine if the patient

is overweight (BMI 25.0– 29.9)

is obese (BMI ≥ 30)

has pre-diabetes (fasting plasma glucose 100– 125 mg/dL)

has diabetes (fasting plasma glucose ≥ 126 mg/dL)

has hypertension (BP >140/90 mmHg)

has dyslipidemia (increased total cholesterol, LDL cholesterol, and triglycerides; decreased HDL cholesterol)

Treat or refer such patients for treatment, including nutrition and weight management, physical activity counseling, smoking cessation, and medical management

Monitoring after starting any atypical antipsychotic âœ1⁄2 BMI monthly for 3 months, then quarterly

âœ1⁄2 Consider monitoring fasting triglycerides monthly for several months in patients at high risk for metabolic complications and when initiating or switching antipsychotics

âœ1⁄2 Blood pressure, fasting plasma glucose, fasting lipids within 3 months and then annually, but earlier and more frequently for patients with diabetes or who have gained >5% of initial weight

Treat or refer for treatment and consider switching to another atypical antipsychotic for patients who become overweight, obese, pre-diabetic, diabetic, hypertensive, or dyslipidemic while receiving an atypical antipsychotic

âœ1⁄2 Even in patients without known diabetes, be vigilant for the rare but life-threatening onset of diabetic ketoacidosis, which always requires immediate treatment, by monitoring for the rapid onset of polyuria, polydipsia, weight loss, nausea, vomiting, dehydration, rapid respiration, weakness and clouding of sensorium, even coma

Patients with low white blood cell count (WBC) or history of drug- induced leukopenia/neutropenia should have complete blood count (CBC) monitored frequently during the first few months and cariprazine should be discontinued at the first sign of decline in WBC in the absence of other causative factors

Patients should be monitored periodically for the development of abnormal movements of tardive dyskinesia, using neurological exam and the AIMS (Abnormal Involuntary Movement Scale)

Side Effects

How Drug Causes Side Effects

Partial agonist actions at dopamine 2 receptors in the striatum can cause akathisia and drug-induced parkinsonism

Partial agonist actions at dopamine 2 receptors can also cause nausea, occasional vomiting, and activating side effects

Mechanism of weight gain and increased incidence of diabetes and dyslipidemia with atypical antipsychotics is unknown, and risks vary based on the particular agent

Notable Side Effects

Akathisia, drug-induced parkinsonism, restlessness

Gastrointestinal distress

Sedation

Tardive dyskinesia (TD) (reduced risk compared to conventional antipsychotics)

Risk of potentially irreversible involuntary dyskinetic movements may increase with cumulative dose and treatment duration

Side effects may theoretically appear several weeks after initiating cariprazine, because plasma levels and major active metabolites accumulate over time

Life-Threatening or Dangerous Side Effects

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients taking atypical antipsychotics

Rare neuroleptic malignant syndrome (NMS) may cause hyperpyrexia, muscle rigidity, delirium, and autonomic instability with elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure

Rare seizures

As a class, antipsychotics are associated with an increased risk of death and cerebrovascular events in elderly patients with dementia; not approved for treatment of dementia-related psychosis

As a class, antidepressants have been reported to increase the risk of suicidal thoughts and behaviors in children and young adults

Weight Gain

Reported but not expected

Occurs in significant minority

Sedation

Wait Wait

What to Do About Side Effects

Wait

Anticholinergics may reduce drug-induced parkinsonism when present

Beta blockers, benzodiazepines, or 5HT2A antagonists (e.g., mirtazapine, cyproheptadine) may reduce akathisia

Weight loss, exercise programs, and medical management for high BMIs, diabetes, dyslipidemia

Metformin may help prevent or reverse antipsychotic-induced weight gain

Switch to another atypical antipsychotic

Best Augmenting Agents for Side Effects

Benztropine, trihexyphenidyl, or amantadine for drug-induced parkinsonism

Beta blockers, benzodiazepines, or 5HT2A antagonists (e.g., mirtazapine, cyproheptadine) for akathisia

Valbenazine or deutetrabenazine for tardive dyskinesia

Many side effects cannot be improved with an augmenting agent

Dosing and Use

Usual Dosage Range

Schizophrenia: 1.5– 6 mg once daily

Bipolar mania: 3– 6 mg once daily Bipolar depression: 1.5– 3 mg once daily

Dosage Forms

Capsule 1.5 mg, 3 mg, 4.5 mg, 6 mg

How to Dose

Schizophrenia: initial 1.5 mg once daily; can increase to 3 mg once daily on day 2; should increase in 1.5– 3 mg increments to reach therapeutic dose (recommended dose 1.5– 6 mg once daily)

Bipolar mania: initial 1.5 mg once daily; can increase to 3 mg once daily on day 2; can increase in 1.5– 3 mg increments to reach therapeutic dose (recommended dose 3– 6 mg once daily)

Bipolar depression: initial 1.5 mg once daily; can increase to 3 mg once daily on day 15 if clinically warranted (recommended dose 1.5– 3 mg once daily)

Dosing Tips

Because of its long half-life, and the especially long half-life of one of its active metabolites, monitor for adverse effects and response for several weeks after starting cariprazine and with each dosage change; also washout of active drug will take several weeks

Because of its long half-life, missing a few doses may not be as detrimental compared to other antipsychotics

Dosing for bipolar depression is generally lower than for schizophrenia or bipolar mania

For bipolar depression without mixed features, 1.5 mg/day dose may be adequate for many patients

For bipolar depression with mixed features, 3.0 mg/day may be a better dose for some patients

In general, the more manic features, the higher the dose in bipolar disorder, and dose can be adjusted according to this principle as the patient waxes and wanes symptoms of mania and depression

Some patients with schizophrenia or acute bipolar mania may benefit from doses higher than 6.0 mg/day, as cariprazine has been studied up to 12 mg/day, but it is not approved for this use and side effects are definitely dose-related and in general therapeutic effects for the majority of patients do not justify dosing over 6.0 mg/day

Slow titration from 1.5 mg/day to 3.0 mg/day in bipolar depression produced much less akathisia compared to rapid dose increases in studies of mania and schizophrenia

Can be taken with or without food

Rather than raise the dose above normal dosing in acutely agitated patients requiring acute antipsychotic actions, consider short-term (one dose or more) augmentation with a benzodiazepine or another antipsychotic, especially intramuscularly

Rather than raise the dose above normal dosing in partial responders, consider augmentation with a mood-stabilizing

anticonvulsant, such as valproate, topiramate, or lamotrigine

Children and elderly should generally be dosed at the lower end of the dosage spectrum

Treatment should be suspended if absolute neutrophil count falls below 1000/mm3

Limited experience

Overdose

Long-Term Use

Approved for maintenance treatment of schizophrenia in adults

Should periodically reevaluate long-term usefulness in individual patients, but treatment may need to continue for many years

No

Habit Forming

How to Stop

Because clinical experience is lacking, down-titration may be prudent, especially when simultaneously beginning a new antipsychotic while switching (i.e., cross-titration)

However, the long half-lives of cariprazine and its two active metabolites suggest that it may be possible to stop cariprazine abruptly

See Switching section of individual agents for how to stop cariprazine

Rapid discontinuation could theoretically lead to rebound psychosis and worsening of symptoms, but less likely with cariprazine due to its long half-life

Pharmacokinetics

Metabolized by CYP450 3A4 into two long-lasting active metabolites

Based on time to reach steady state, half-life for cariprazine is 2– 4 days and for one of its active metabolites, didesmethyl cariprazine (DDCAR), is 1– 3 weeks

Drug Interactions

Initiating a strong CYP450 3A4 inhibitor in patients on a stable dose of cariprazine: reduce the current dose of cariprazine by half (for patients taking 4.5 mg, reduce to either 1.5 mg or 3 mg once daily; for patients taking 1.5 mg once daily, reduce to 1.5 mg every other day)

Initiating cariprazine in patients taking a strong CYP450 3A4 inhibitor: administer 1.5 mg on day 1; do not dose on day 2; administer 1.5 mg on day 3 and on day 4; maximum dose 3 mg once daily

Concomitant use of cariprazine and a CYP450 3A4 inducer is not recommended

May increase effects of antihypertensive agents May antagonize levodopa, dopamine agonists

Other Warnings/Precautions

Use with caution in patients with conditions that predispose to hypotension (dehydration, overheating)

Atypical antipsychotics have the potential for cognitive and motor impairment, especially related to sedation

Atypical antipsychotics can cause body temperature dysregulation; use caution in patients who may experience conditions that increase body temperature (e.g., strenuous exercise, saunas, extreme heat, dehydration, or concomitant anticholinergic medication)

Monitor patients for activation of suicidal ideation, especially children and adolescents

Dysphagia has been associated with antipsychotic use, and cariprazine should be used cautiously in patients at risk for aspiration pneumonia

Antipsychotics may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls; for patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment, and recurrently for patients on long-term antipsychotic therapy

As with any antipsychotic, use with caution in patients with history of seizures

Do Not Use

If there is a proven allergy to cariprazine

Special Populations Renal Impairment

Mild to moderate impairment (creatinine clearance <30 mL/minute): no dose adjustment necessary

Severe or end-stage: not recommended

Hepatic Impairment

Mild to moderate impairment (Child-Pugh score between 5 and 9): no dose adjustment necessary

Severe: not recommended

Cardiac Impairment

Use in patients with cardiac impairment has not been studied, so use with caution because of risk of orthostatic hypotension

Use with caution if patient is taking concomitant antihypertensive or alpha 1 antagonist

Elderly

Some elderly patients may tolerate lower doses better

Although atypical antipsychotics are commonly used for behavioral disturbances in dementia, no atypical antipsychotic has been approved for treatment of elderly patients with behavioral symptoms of dementia such as agitation

Elderly patients with dementia-related psychosis treated with atypical antipsychotics are at an increased risk of death compared to placebo, and also have an increased risk of cerebrovascular events

Consider pimavanserin for dementia-related psychosis or Parkinsonâ€TM s disease psychosis instead of an atypical antipsychotic

Children and Adolescents

Safety and efficacy have not been established

Children and adolescents using cariprazine may need to be monitored more often than adults and may tolerate lower doses better

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR

or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women

In rats, administration of cariprazine during organogenesis caused malformations, lower pup survival, and developmental delays at exposures less than the human exposure at maximum recommended human dose (6 mg/day); cariprazine was not teratogenic in rabbits at doses up to 4.6 times the maximum recommended human dose

There is a risk of abnormal muscle movements and withdrawal symptoms in newborns whose mothers took an antipsychotic during the third trimester; symptoms may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty feeding

Psychotic symptoms may worsen during pregnancy and some form of treatment may be necessary

National Pregnancy Registry for Atypical Antipsychotics: 1-866- 961-2388, https://womensmentalhealth.org/research/pregnancyregistry/atypical antipsychotic

Breast Feeding

Unknown if cariprazine is secreted in human breast milk, but all psychotropics are assumed to be secreted in breast milk

âœ1⁄2 Recommended either to discontinue drug or bottle feed unless the potential benefit to the mother justifies the potential risk to the child

Infants of women who choose to breast feed while on cariprazine should be monitored for possible adverse effects

The Art of Psychopharmacology Potential Advantages

For patients who do not tolerate aripiprazole or brexpiprazole for schizophrenia

For patients who do not tolerate quetiapine, lurasidone, or olanzapine for bipolar depression

Possibly negative symptoms in schizophrenia

Possibly mixed mood states such as depression or mania with mixed features

Expensive

Potential Disadvantages

Primary Target Symptoms

Positive symptoms of psychosis Negative symptoms of psychosis Symptoms of acute mania/mixed mania

Cognitive symptoms

Unstable mood (both depression and mania)

Aggressive symptoms

Bipolar depression

Mixtures of manic and depressive symptoms in bipolar disorder

Pearls

Cariprazine is metabolized into a very long-lasting active metabolite; it is therefore possible that adverse events could appear several weeks after initiation of cariprazine due to accumulation of cariprazine and major metabolites over time

It is also possible that cariprazine or its very long-lasting active metabolites could be developed as an “ oral depot,†namely a very long-lasting oral formulation for weekly or even monthly oral administration

Based on short-term clinical trials, cariprazine appears to have a favorable metabolic profile, with changes in triglycerides, fasting glucose, and cholesterol similar to placebo; little or no weight gain in bipolar depression, and a small amount of weight gain in bipolar mania and schizophrenia studies especially at higher doses

Approved as a monotherapy for bipolar depression, with post hoc analyses showing efficacy in bipolar depression with mixed features

Approved as a monotherapy for acute bipolar mania, with post hoc analyses showing efficacy in bipolar mania with mixed features

May be one of the best choices for treatment across the spectrum of bipolar disorder, from bipolar depression, to mixed states of bipolar depression and mania, to acute bipolar mania

Cariprazine is in late-stage testing for augmentation of SSRIs/SNRIs in unipolar major depression

Approved in Europe for the negative symptoms of schizophrenia

D3-preferring (over D2) actions represent a novel pharmacologic profile among antipsychotics, especially at lower doses; clinical advantages of this profile remain to be determined but animal models suggest that targeting D3 receptors may have advantages for mood, cognition, negative symptoms, and substance abuse

All antipsychotics bind to the D3 receptor in vitro, but cariprazine has affinity for the D3 receptor much greater than dopamine itself has for the D3 receptor. Cariprazine is the most potent antipsychotic and one of the only antipsychotics with functional D3 partial agonism in vivo in the living human brain. This means that at therapeutic dosing, cariprazine may have a unique action as a partial agonist at the D3 receptor

Cariprazine may exert its efficacy across the bipolar spectrum by partial agonist actions at D2 receptors, mostly blocking them in limbic areas, to treat mania and psychosis while having simultaneous partial agonist actions at D3 receptors, especially in the substantia nigra/ventral tegmental area, leading to enhanced dopamine release in prefrontal cortex to treat mood, cognition, and

negative symptoms in both schizophrenia and across the mood disorder spectrum

The Art of Switching

Switching from Oral Antipsychotics to Cariprazine

It is advisable to begin cariprazine at an intermediate dose and build the dose rapidly over 3– 7 days

Clinical experience has shown that asenapine, quetiapine, and olanzapine should be tapered off slowly over a period of 3– 4 weeks, to allow patients to readapt to the withdrawal of blocking cholinergic, histaminergic, and alpha 1 receptors

Clozapine should always be tapered off slowly, over a period of 4 weeks or more

All antipsychotics bind to the D3 receptor in vitro, but cariprazine has affinity for the D3 receptor much greater than dopamine itself has for the D3 receptor. Cariprazine is the most potent antipsychotic and one of the only antipsychotics with functional D3 partial agonism in vivo in the living human brain. This means that at therapeutic dosing, cariprazine may have a unique action as partial agonist at the D3 receptor

* Benzodiazepine or anticholinergic medication can be administered during cross-titration to help alleviate side effects such as insomnia, agitation, and/or psychosis

Suggested Reading

Choi YK , Adham N , Kiss B , Gyertyán I , Tarazi FI. Long-term effects of cariprazine exposure on dopamine receptor subtypes . CNS Spectr 2014 ;19 (3 ):268– 77 .

Citrome L. Cariprazine in schizophrenia: clinical efficacy, tolerability, and place in therapy . Adv Ther 2013 ;30 (2 ):114– 26 .

Earley WR , Burgess MV , Khan B , et al. Efficacy and safety of cariprazine in bipolar I depression: a double-blind, placebo-controlled phase 3 study. Bipolar Disord 2020 ;22(4):372– 84. doi: 10.1111/bdi.12852 .

Huhn M , Nikolakopoulou A , Schneider-Thoma J , et al. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis . Lancet 2019 ;394 :939– 51 .

McIntyre RS , Suppes T , Earley W , Patel M , Stahl SM. Cariprazine efficacy in bipolar I depression with and without concurrent manic symptoms: post hoc analysis of 3 randomized, placebo-controlled studies. CNS Spectr 2019 ;1– 9. doi:10.1017/S1092852919001287 .

Stahl SM , Drugs for psychosis and mood: unique actions at D3, D2, and D1 dopamine receptor subtypes, CNS Spectr 2017 ;22:375– 84.

Stahl SM , Laredo S , Morrissette DA . Cariprazine as a treatment across the bipolar I spectrum from depression to mania: mechanism of action and review of clinical data . Ther Adv Psychopharmacol 2020 ;10 :2045125320905752 . doi: 10.1177/2045125320905752 . eCollection 2020.

Vieta E , Durgam S , Lu K , et al. Effect of cariprazine across the symptoms of mania in bipolar I disorder: analyses of pooled data from phase II/III trials . Eur Neuropsychopharmacol 2015 ;25 (11 ):1882 – 91.

Vieta E , Earley WR , Burgess MV , et al. Longterm safety and tolerability of cariprazine as adjunctive therapy in major depressive disorder. Int Clin Psychopharmacol 2019 ;34(2):76– 83.

Chlordiazepoxide

Yes

Generic?

Class

Limbitrol

Librium

Librax

see index for additional brand names

Therapeutics Brands

Neuroscience-based Nomenclature: GABA positive allosteric modulator (GABA-PAM)

Benzodiazepine (anxiolytic)

Commonly Prescribed for

(bold for FDA approved)

Anxiety disorders

Symptoms of anxiety

Preoperative apprehension and anxiety

Withdrawal symptoms of acute alcoholism

Catatonia

How the Drug Works

Binds to benzodiazepine receptors at the GABA-A ligand-gated chloride channel complex

Enhances the inhibitory effects of GABA

Boosts chloride conductance through GABA-regulated channels

Inhibits neuronal activity presumably in amygdala-centered fear circuits to provide therapeutic benefits in anxiety disorders

How Long Until It Works

Some immediate relief with first dosing is common; can take several weeks with daily dosing for maximal therapeutic benefit

If It Works

For short-term symptoms of anxiety – after a few weeks, discontinue use or use on an “ as-needed†basis

For chronic anxiety disorders, the goal of treatment is complete remission of symptoms as well as prevention of future relapses

For chronic anxiety disorders, treatment most often reduces or even eliminates symptoms, but not a cure since symptoms can recur after medicine stopped

For long-term symptoms of anxiety, consider switching to an SSRI or SNRI for long-term maintenance

If long-term maintenance with a benzodiazepine is necessary, continue treatment for 6 months after symptoms resolve, and then taper dose slowly

If symptoms reemerge, consider treatment with an SSRI or SNRI, or consider restarting the benzodiazepine; sometimes benzodiazepines have to be used in combination with SSRIs or SNRIs for best results

If It Doesnâ€TM t Work

Consider switching to another agent or adding an appropriate augmenting agent

Consider psychotherapy, especially cognitive behavioral psychotherapy

Consider presence of concomitant substance abuse

Consider presence of chlordiazepoxide abuse

Consider another diagnosis, such as a comorbid medical condition

Best Augmenting Combos for Partial Response or Treatment Resistance

Benzodiazepines are frequently used as augmenting agents for antipsychotics and mood stabilizers in the treatment of psychotic and bipolar disorders

Benzodiazepines are frequently used as augmenting agents for SSRIs and SNRIs in the treatment of anxiety disorders

Not generally rational to combine with other benzodiazepines

Caution if using as an anxiolytic concomitantly with other sedative hypnotics for sleep

Tests

In patients with seizure disorders, concomitant medical illness, and/or those with multiple concomitant long-term medications, periodic liver tests and blood counts may be prudent

Side Effects

How Drug Causes Side Effects

Same mechanism for side effects as for therapeutic effects – namely due to excessive actions at benzodiazepine receptors

Long-term adaptations in benzodiazepine receptors may explain the development of dependence, tolerance, and withdrawal

Side effects are generally immediate, but immediate side effects often disappear in time

Notable Side Effects âœ1⁄2 Sedation, fatigue, depression

âœ1⁄2 Dizziness, ataxia, slurred speech, weakness

âœ1⁄2 Forgetfulness, confusion

âœ1⁄2 Hyperexcitability, nervousness

Rare hallucinations, mania Rare hypotension Hypersalivation, dry mouth

Life-Threatening or Dangerous Side Effects

Respiratory depression, especially when taken with CNS depressants in overdose

Rare hepatic dysfunction, renal dysfunction, blood dyscrasias

Weight Gain

Sedation

Many experience and/or can be significant in amount Especially at initiation of treatment or when dose increases Tolerance often develops over time

Reported but not expected

Wait

What to Do About Side Effects

Wait

Wait

Lower the dose

Take largest dose at bedtime to avoid sedative effects during the day Switch to another agent

Administer flumazenil if side effects are severe or life-threatening

Best Augmenting Agents for Side Effects

Many side effects cannot be improved with an augmenting agent

Dosing and Use Usual Dosage Range

Mild to moderate anxiety: 15– 40 mg/day in 3– 4 doses Severe anxiety: 60– 100 mg/day in 3– 4 doses

Dosage Forms

Capsule 2.5 mg, 5 mg, 10 mg, 25 mg

How to Dose

Mild to moderate anxiety: 15– 40 mg/day in 3– 4 doses Severe anxiety: 60– 100 mg/day in 3– 4 doses

Dosing Tips

Use lowest possible effective dose for the shortest possible period of time (a benzodiazepine-sparing strategy)

Assess need for continued treatment regularly

Risk of dependence may increase with dose and duration of treatment

For interdose symptoms of anxiety, can either increase dose or maintain same total daily dose but divide into more frequent doses

Can also use an as-needed occasional “ top-up†dose for interdose anxiety

Because anxiety disorders can require higher doses, the risk of dependence may be greater in these patients

Some severely ill patients may require doses higher than the generally recommended maximum dose

Frequency of dosing in practice is often greater than predicted from half-life, as duration of biological activity is often shorter than pharmacokinetic terminal half-life

Overdose

Fatalities can occur; hypotension, tiredness, ataxia, confusion, coma

Long-Term Use

Evidence of efficacy for up to 16 weeks

Risk of dependence, particularly for treatment periods longer than 12 weeks, and especially in patients with past or current polysubstance abuse

Habit Forming

Chlordiazepoxide is a Schedule IV drug

Patients may develop dependence and/or tolerance with long-term use

How to Stop

Patients with history of seizure may seize upon withdrawal, especially if withdrawal is abrupt

Taper by 10 mg every 3 days to reduce chances of withdrawal effects

For difficult-to-taper patients, consider reducing dose much more slowly after reaching 20 mg/day, perhaps by as little as 5 mg per week or less

For other patients with severe problems discontinuing a benzodiazepine, dosing may need to be tapered over many months (i.e., reduce dose by 1% every 3 days by crushing tablet and suspending or dissolving in 100 mL of fruit juice and then disposing of 1 mL and drinking the rest; 3– 7 days later, dispose of 2 mL, and so on). This is both a form of very slow biological tapering and a form of behavioral desensitization

Be sure to differentiate reemergence of symptoms requiring reinstitution of treatment from withdrawal symptoms

Benzodiazepine-dependent anxiety patients and insulin-dependent diabetics are not addicted to their medications. When benzodiazepine-dependent patients stop their medication, disease symptoms can reemerge, disease symptoms can worsen (rebound), and/or withdrawal symptoms can emerge

Pharmacokinetics

Elimination half-life 24– 48 hours

Drug Interactions

Increased depressive effects when taken with other CNS depressants (see Warnings below)

Other Warnings/Precautions

Boxed warning regarding the increased risk of CNS depressant effects when benzodiazepines and opioid medications are used together, including specifically the risk of slowed or difficulty breathing and death

If alternatives to the combined use of benzodiazepines and opioids are not available, clinicians should limit the dosage and duration of each drug to the minimum possible while still achieving therapeutic efficacy

Patients and their caregivers should be warned to seek medical attention if unusual dizziness, lightheadedness, sedation, slowed or difficulty breathing, or unresponsiveness occur

Dosage changes should be made in collaboration with prescriber

Use with caution in patients with pulmonary disease; rare reports of death after initiation of benzodiazepines in patients with severe pulmonary impairment

History of drug or alcohol abuse often creates greater risk for dependency

Some depressed patients may experience a worsening of suicidal ideation

Some patients may exhibit abnormal thinking or behavioral changes similar to those caused by other CNS depressants (i.e., either depressant actions or disinhibiting actions)

Do Not Use

If patient has angle-closure glaucoma

If there is a proven allergy to chlordiazepoxide or any benzodiazepine

Special Populations

Renal Impairment

Initial 10– 20 mg/day in 2– 4 doses; increase as needed

Hepatic Impairment

Initial 10– 20 mg/day in 2– 4 doses; increase as needed

Cardiac Impairment

Benzodiazepines have been used to treat anxiety associated with acute myocardial infarction

Elderly

Initial 10– 20 mg/day in 2– 4 doses; increase as needed Elderly patients may be more sensitive to sedative effects

Children and Adolescents

Not recommended for use in children under age 6

Initial 10– 20 mg/day in 2– 4 doses; may increase to 20– 30 mg/day in 2– 3 doses if ineffective

Hyperactive children should be monitored for paradoxical effects

Long-term effects of chlordiazepoxide in children/adolescents are unknown

Should generally receive lower doses and be more closely monitored

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Possible increased risk of birth defects when benzodiazepines are taken during pregnancy

Because of the potential risks, chlordiazepoxide is not generally recommended as treatment for anxiety during pregnancy, especially during first trimester

Drug should be tapered if discontinued

Infants whose mothers received a benzodiazepine late in pregnancy may experience withdrawal effects

Neonatal flaccidity has been reported in infants whose mothers took a benzodiazepine during pregnancy

Seizures, even mild seizures, may cause harm to the embryo/fetus

Breast Feeding

Unknown if chlordiazepoxide is secreted in human breast milk, but all psychotropics are assumed to be secreted in breast milk

âœ1⁄2 Recommended either to discontinue drug or bottle feed

Effects of benzodiazepines on nursing infants have been reported and include feeding difficulties, sedation, and weight loss

The Art of Psychopharmacology Potential Advantages

Rapid onset of action

Potential Disadvantages

Euphoria may lead to abuse

Abuse especially risky in past or present substance abusers

Panic attacks Anxiety

Primary Target Symptoms

Pearls

Can be a useful adjunct to SSRIs and SNRIs in the treatment of numerous anxiety disorders, but not used as frequently as some other benzodiazepines

Not effective for treating psychosis as a monotherapy, but can be used as an adjunct to antipsychotics

Not effective for treating bipolar disorder as a monotherapy, but can be used as an adjunct to mood stabilizers and antipsychotics

Can both cause depression and treat depression in different patients

When using to treat insomnia, remember that insomnia may be a symptom of some other primary disorder itself, and thus warrant

evaluation for comorbid psychiatric and/or medical conditions âœ1⁄2 Remains a viable treatment option for alcohol withdrawal

Though not systematically studied, benzodiazepines have been used effectively to treat catatonia and are the initial recommended treatment

Suggested Reading

Baskin SI , Esdale A. Is chlordiazepoxide the rational choice among benzodiazepines ? Pharmacotherapy 1982 ;2 :110– 19 .

Erstad BL , Cotugno CL. Management of alcohol withdrawal . Am J Health Syst Pharm 1995 ;52 :697 – 709 .

Fraser AD. Use and abuse of the benzodiazepines . Ther Drug Monit 1998 ;20 :481– 9 .

Murray JB. Effects of valium and librium on human psychomotor and cognitive functions . Genet Psychol Monogr 1984 ;109 (2D Half):167– 97 .

Chlorpromazine

Thorazine

Therapeutics Brands

see index for additional brand names

Yes

Generic?

Class

Neuroscience-based Nomenclature: dopamine and serotonin receptor antagonist (DS-RAn)

Conventional antipsychotic (neuroleptic, phenothiazine, dopamine 2 antagonist, antiemetic)

Commonly Prescribed for

(bold for FDA approved)

Schizophrenia (oral)

Severe behavioral problems associated with oppositional defiant disorder or other disruptive behavioral disorders, or for attention deficit hyperactivity disorder (ADHD) in pediatric patients who show excessive motor activity with accompanying

conduct disorders (oral, intramuscular for acute, severe agitation in hospitalized patients)

Acute psychosis (intramuscular)

Nausea, vomiting (oral, rectal, intramuscular, intravenous) Acute intermittent porphyria (oral, intramuscular) Tetanus (intramuscular, adjunct)

Intractable hiccups (oral, intramuscular, intravenous) Bipolar disorder

Restlessness and apprehension before surgery

How the Drug Works

Blocks dopamine 2 receptors, reducing positive symptoms of psychosis and improving other behaviors

Combination of dopamine D2, histamine H1, and cholinergic M1 blockade in the vomiting center may reduce nausea and vomiting

How Long Until It Works

Psychotic symptoms can improve within 1 week, but it may take several weeks for full effect on behavior

Immediate and short-term (a few hours) relief of severe behavioral problems if given during an acute exacerbation on an “ as needed†prn basis (most common use in children)

Actions on nausea and vomiting are immediate

If It Works

Most often reduces positive symptoms in schizophrenia but does not eliminate them

Most schizophrenic patients do not have a total remission of symptoms but rather a reduction of symptoms by about a third

Continue treatment in schizophrenia until reaching a plateau of improvement

After reaching a satisfactory plateau, continue treatment for at least a year after first episode of psychosis in schizophrenia

For second and subsequent episodes of psychosis in schizophrenia, treatment may need to be indefinite

Reduces symptoms of acute psychotic mania but not proven as a mood stabilizer or as an effective maintenance treatment in bipolar disorder

After reducing acute psychotic symptoms in mania, switch to a mood stabilizer and/or an atypical antipsychotic for mood stabilization and maintenance

If It Doesnâ€TM t Work

Consider trying one of the first-line atypical antipsychotics Consider trying another conventional antipsychotic

If 2 or more antipsychotic monotherapies do not work, consider clozapine

Best Augmenting Combos for Partial Response or Treatment Resistance

Augmentation of conventional antipsychotics has not been systematically studied

Addition of a mood-stabilizing anticonvulsant such as valproate, carbamazepine, or lamotrigine may be helpful in both schizophrenia and bipolar mania

Augmentation with lithium in bipolar mania may be helpful Addition of a benzodiazepine, especially short-term for agitation

Tests

âœ1⁄2 Since conventional antipsychotics are frequently associated with weight gain, before starting treatment, weigh all patients and determine if the patient is already overweight (BMI 25.0– 29.9) or obese (BMI ≥ 30)

Before giving a drug that can cause weight gain to an overweight or obese patient, consider determining whether the patient already has pre-diabetes (fasting plasma glucose 100– 125 mg/dL), diabetes (fasting plasma glucose ≥ 126 mg/dL), or dyslipidemia (increased total cholesterol, LDL cholesterol, and triglycerides; decreased HDL cholesterol), and treat or refer such patients for treatment, including nutrition and weight management, physical activity counseling, smoking cessation, and medical management

âœ1⁄2 Monitor weight and BMI during treatment

âœ1⁄2 Consider monitoring fasting triglycerides monthly for several months in patients at high risk for metabolic complications and when initiating or switching antipsychotics

âœ1⁄2 While giving a drug to a patient who has gained >5% of initial weight, consider evaluating for the presence of pre-diabetes, diabetes, or dyslipidemia, or consider switching to a different antipsychotic

Should check blood pressure in the elderly before starting and for the first few weeks of treatment

Monitoring elevated prolactin levels of dubious clinical benefit

Phenothiazines may cause false-positive phenylketonuria results

Patients with low white blood cell count (WBC) or history of drug- induced leukopenia/neutropenia should have complete blood count (CBC) monitored frequently during the first few months and chlorpromazine should be discontinued at the first sign of decline of WBC in the absence of other causative factors

Patients should be monitored periodically for the development of abnormal movements of tardive dyskinesia, using neurological exam and the AIMS (Abnormal Involuntary Movement Scale)

Side Effects

How Drug Causes Side Effects

Acute blockade of dopamine 2 receptors in the striatum can cause drug-induced parkinsonism, dystonia, or akathisia

Chronic blockade of dopamine 2 receptors in the striatum can cause tardive dyskinesia

By blocking dopamine 2 receptors excessively in the mesocortical and mesolimbic dopamine pathways, especially at high doses, it can cause worsening of negative and cognitive symptoms (neuroleptic- induced deficit syndrome)

Blocking muscarinic cholinergic receptors can cause dry mouth, blurred vision, urinary retention, constipation, and paralytic ileus

Antihistaminic actions may cause sedation, weight gain

Blocking alpha 1 adrenergic receptors can cause dizziness, hypotension, and syncope

Mechanism of weight gain and any possible increased incidence of diabetes or dyslipidemia with conventional antipsychotics is unknown

Notable Side Effects âœ1⁄2 Neuroleptic-induced deficit syndrome

âœ1⁄2 Akathisia

âœ1⁄2 Priapism

âœ1⁄2 Drug-induced parkinsonism âœ1⁄2 Galactorrhea, amenorrhea

Dizziness, sedation, impaired memory

Dry mouth, constipation, urinary retention, blurred vision

Decreased sweating

Sexual dysfunction

Hypotension, tachycardia, syncope

Weight gain

Tardive dyskinesia

Risk of potentially irreversible involuntary dyskinetic movements may increase with cumulative dose and treatment duration

Life-Threatening or Dangerous Side Effects

Rare neuroleptic malignant syndrome (NMS) may cause hyperpyrexia, muscle rigidity, delirium, and autonomic instability with elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure

Rare jaundice, agranulocytosis Rare seizures

As a class, antipsychotics are associated with an increased risk of death and cerebrovascular events in elderly patients with dementia; not approved for treatment of dementia-related psychosis

Weight Gain

Many experience and/or can be significant in amount

Sedation

Tolerance to sedation can develop over time

Wait

Wait

Wait

What to Do About Side Effects

For drug-induced parkinsonism, add an anticholinergic agent

Beta blockers, benzodiazepines, or 5HT2A antagonists (e.g., mirtazapine, cyproheptadine) may reduce akathisia

Reduce the dose

For sedation, give at night

Switch to an atypical antipsychotic

Weight loss, exercise programs, and medical management for high BMIs, diabetes dyslipidemia

Metformin may help prevent or reverse antipsychotic-induced weight gain

Best Augmenting Agents for Side Effects

Benztropine, trihexyphenidyl, or amantadine for drug-induced parkinsonism

Beta blockers, benzodiazepines, or 5HT2A antagonists (e.g., mirtazapine, cyproheptadine) for akathisia

Valbenazine or deutetrabenazine for tardive dyskinesia

Many side effects cannot be improved with an augmenting agent

200– 800 mg/day

Dosing and Use Usual Dosage Range

Dosage Forms

Tablet 10 mg, 25 mg, 50 mg, 100 mg, 200 mg Capsule 30 mg, 75 mg, 150 mg (not in USA) Ampoule 25 mg/mL; 1 mL, 2 mL

Liquid 10 mg/5 mL (discontinued in USA) Suppository 25 mg, 100 mg (discontinued in USA)

How to Dose

Psychosis: increase dose until symptoms are controlled; after 2 weeks reduce to lowest effective dose

Psychosis (intramuscular): varies by severity of symptoms and inpatient/outpatient status

Dosing Tips

Low doses may have more sedative actions than antipsychotic actions

Low doses have been used to provide short-term relief of daytime agitation and anxiety and to enhance sedative hypnotic actions in nonpsychotic patients, but other treatment options such as atypical antipsychotics are now preferred

Higher doses may induce or worsen negative symptoms of schizophrenia

Can be taken with or without food

Ampoules contain sulfites that may cause allergic reactions, particularly in patients with asthma

One of the few antipsychotics available as a suppository

Rather than raise the dose above normal dosing in acutely agitated patients requiring acute antipsychotic actions, consider short-term (one dose or more) augmentation with a benzodiazepine or another antipsychotic, especially intramuscularly

Rather than raise the dose above normal dosing in partial responders, consider augmentation with a mood-stabilizing anticonvulsant, such as valproate, topiramate, or lamotrigine

Children and elderly should generally be dosed at the lower end of the dosage spectrum

Treatment should be suspended if absolute neutrophil count falls below 1000/mm3

Overdose

Drug-induced parkinsonism, sedation, hypotension, coma, respiratory depression

Long-Term Use

Should periodically reevaluate long-term usefulness in individual patients, but treatment may need to continue for many years

No

Habit Forming

How to Stop

Slow down-titration of oral formulation (over 6– 8 weeks), especially when simultaneously beginning a new antipsychotic while switching (i.e., cross-titration)

Rapid oral discontinuation may lead to rebound psychosis and worsening of symptoms

If antiparkinson agents are being used, they should be continued for a few weeks after chlorpromazine is discontinued

Pharmacokinetics

Half-life approximately 8– 33 hours

Drug Interactions

May decrease the effects of levodopa, dopamine agonists

May increase the effects of antihypertensive drugs except for guanethidine, whose antihypertensive actions chlorpromazine may antagonize

Additive effects may occur if used with CNS depressants

Some pressor agents (e.g., epinephrine) may interact with chlorpromazine to lower blood pressure

Alcohol and diuretics may increase the risk of hypotension

Reduces effects of anticoagulants

May reduce phenytoin metabolism and increase phenytoin levels

Plasma levels of chlorpromazine and propranolol may increase if used concomitantly

Some patients taking a neuroleptic and lithium have developed an encephalopathic syndrome similar to neuroleptic malignant syndrome

Other Warnings/Precautions

If signs of neuroleptic malignant syndrome develop, treatment should be immediately discontinued

Use cautiously in patients with alcohol withdrawal or convulsive disorders because of possible lowering of seizure threshold

Use with caution in patients with respiratory disorders, glaucoma, or urinary retention

Use with caution in patients with hematological disease Avoid extreme heat exposure

Avoid undue exposure to sunlight

Antiemetic effect of chlorpromazine may mask signs of other disorders or overdose; suppression of cough reflex may cause asphyxia

Use only with caution if at all in Parkinsonâ€TM s disease or Lewy body dementia

Antipsychotics may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls; for patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment, and recurrently for patients on long-term antipsychotic therapy

As with any antipsychotic, use with caution in patients with history of seizures

Do Not Use

If patient is in a comatose state

If patient is taking metrizamide or large doses of CNS depressants If patient shows signs of Reyeâ€TM s syndrome

If patient has a sulfite hypersensitivity (injectable preparations)

If there is a proven allergy to chlorpromazine

If there is a known sensitivity to any phenothiazine

Use with caution

Use with caution

Special Populations Renal Impairment

Hepatic Impairment

Cardiac Impairment

Cardiovascular toxicity can occur, especially orthostatic hypotension

Elderly

Lower doses should be used and patient should be monitored closely Often do not tolerate sedating actions of chlorpromazine

Although conventional antipsychotics are commonly used for behavioral disturbances in dementia, no agent has been approved for treatment of elderly patients with behavioral symptoms of dementia such as agitation

Elderly patients with dementia-related psychosis treated with antipsychotics are at an increased risk of death compared to placebo, and also have an increased risk of cerebrovascular events

Children and Adolescents

Can be used cautiously in children or adolescents over age 1 with severe behavioral problems

Oral – 0.25 mg/lb every 4– 6 hours as needed; rectal – 0.5 mg/lb every 6– 8 hours as needed; IM – 0.25 mg/lb every 6– 8 hours as needed; maximum 40 mg/day (under 5), 75 mg/day (5– 12)

Do not use if patient shows signs of Reyeâ€TM s syndrome Generally consider second-line after atypical antipsychotics

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women

There is a risk of abnormal muscle movements and withdrawal symptoms in newborns whose mothers took an antipsychotic during the third trimester; symptoms may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty feeding

Reports of drug-induced parkinsonism, jaundice, hyperreflexia, hyporeflexia in infants whose mothers took a phenothiazine during pregnancy

Chlorpromazine should generally not be used during the first trimester

Chlorpromazine should be used during pregnancy only if clearly needed

Psychotic symptoms may worsen during pregnancy and some form of treatment may be necessary

Atypical antipsychotics may be preferable to conventional antipsychotics or anticonvulsant mood stabilizers if treatment is required during pregnancy

Breast Feeding

Some drug is found in motherâ€TM s breast milk

Effects on infant have been observed (dystonia, tardive dyskinesia, sedation)

âœ1⁄2 Recommended either to discontinue drug or bottle feed

The Art of Psychopharmacology

Potential Advantages

Intramuscular formulation for emergency use

Patients who require sedation for behavioral control

Potential Disadvantages

Patients with tardive dyskinesia

Children

Elderly

Patients who wish to avoid sedation

Patients who wish to avoid anticholinergic side effects, especially patients on clozapine

Primary Target Symptoms

Positive symptoms of psychosis Motor and autonomic hyperactivity Violent or aggressive behavior

Pearls

Chlorpromazine is one of the earliest classical conventional antipsychotics

Chlorpromazine has a broad spectrum of efficacy, but risk of tardive dyskinesia and the availability of alternative treatments make its utilization outside of psychosis a short-term and second-line treatment option

Adding chlorpromazine as the choice for patients who require sedation or behavioral control, either as a daily or as a prn (as needed) treatment, should be avoided in order to reduce the chances of potentially fatal paralytic ileus in patients on concomitant anticholinergics, including antipsychotic drugs with anticholinergic properties such as clozapine

Chlorpromazine is a low-potency phenothiazine

Sedative actions of low-potency phenothiazines are an important aspect of their therapeutic actions in some patients and side effect profile in others

Low-potency phenothiazines like chlorpromazine have a greater risk of cardiovascular side effects

Patients have very similar antipsychotic responses to any conventional antipsychotic, which is different from atypical antipsychotics where antipsychotic responses of individual patients can occasionally vary greatly from one atypical antipsychotic to another

Patients with inadequate responses to atypical antipsychotics may benefit from a trial of augmentation with a conventional antipsychotic such as chlorpromazine or from switching to a conventional antipsychotic such as chlorpromazine

However, long-term polypharmacy with a combination of a conventional antipsychotic such as chlorpromazine with an atypical antipsychotic may combine their side effects without clearly augmenting the efficacy of either

For treatment-resistant patients, especially those with impulsivity, aggression, violence, and self-harm, long-term polypharmacy with 2 atypical antipsychotics or with 1 atypical antipsychotic and 1 conventional antipsychotic may be useful or even necessary while closely monitoring

In such cases, it may be beneficial to combine 1 depot antipsychotic with 1 oral antipsychotic

Suggested Reading

Adams CE , Awad G , Rathbone J , Thornley B. Chlorpromazine versus placebo for schizophrenia . Cochrane Database Syst Rev 2007 ;18 (2 ):CD000284 .

Ahmed U , Jones H , Adams CE. Chlorpromazine for psychosis induced aggression or agitation . Cochrane Database Syst Rev 2010 ;14 (4 ):CD007445 .

Huhn M , Nikolakopoulou A , Schneider-Thoma J , et al. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis . Lancet 2019 ;394 :939– 51 .

Leucht C , Kitzmantel M , Chua L , Kane J , Leucht S. Haloperidol versus chlorpromazine for schizophrenia . Cochrane Database Syst Rev 2008 ;23 (1 ):CD004278 .

Liu X , De Haan S. Chlorpromazine dose for people with schizophrenia . Cochrane Database Syst Rev 2009 ;15 (2 ):CD007778 .

Citalopram

Celexa

Therapeutics Brands

Yes

Generic?

Class

see index for additional brand names

Neuroscience-based Nomenclature: serotonin reuptake inhibitor (S- RI)

SSRI (selective serotonin reuptake inhibitor); often classified as an antidepressant, but it is not just an antidepressant

Commonly Prescribed for

(bold for FDA approved)

Depression

Premenstrual dysphoric disorder (PMDD) Obsessive-compulsive disorder (OCD) Panic disorder

Generalized anxiety disorder (GAD) Posttraumatic stress disorder (PTSD) Social anxiety disorder (social phobia)

How the Drug Works

Boosts neurotransmitter serotonin

Blocks serotonin reuptake pump (serotonin transporter)

Desensitizes serotonin receptors, especially serotonin 1A autoreceptors

Presumably increases serotonergic neurotransmission

âœ1⁄2 Citalopram also has mild antagonist actions at H1 histamine receptors

âœ1⁄2 Citalopramâ€TM s inactive R enantiomer may interfere with the therapeutic actions of the active S enantiomer at serotonin reuptake pumps

How Long Until It Works

Onset of therapeutic actions usually not immediate, but often delayed 2– 4 weeks

If it is not working within 6– 8 weeks, it may require a dosage increase or it may not work at all

May continue to work for many years to prevent relapse of symptoms

If It Works

The goal of treatment is complete remission of current symptoms as well as prevention of future relapses

Treatment most often reduces or even eliminates symptoms, but not a cure since symptoms can recur after medicine stopped

Continue treatment until all symptoms are gone (remission) or significantly reduced (e.g., OCD, PTSD)

Once symptoms are gone, continue treating for 1 year for the first episode of depression

For second and subsequent episodes of depression, treatment may need to be indefinite

Use in anxiety disorders may also need to be indefinite

If It Doesnâ€TM t Work

Many patients have only a partial response where some symptoms are improved but others persist (especially insomnia, fatigue, and problems concentrating in depression)

Other patients may be nonresponders, sometimes called treatment- resistant or treatment-refractory

Some patients who have an initial response may relapse even though they continue treatment, sometimes called “ poop-outâ€

Consider increasing dose, switching to another agent, or adding an appropriate augmenting agent

Consider psychotherapy

Consider evaluation for another diagnosis or for a comorbid condition (e.g., medical illness, substance abuse, etc.)

Some patients may experience apparent lack of consistent efficacy due to activation of latent or underlying bipolar disorder, and require antidepressant discontinuation and a switch to a mood stabilizer

Best Augmenting Combos for Partial Response or Treatment Resistance

Trazodone, especially for insomnia

Bupropion, mirtazapine, reboxetine, or atomoxetine (add with caution and at lower doses since citalopram could theoretically raise atomoxetine levels); use combinations of antidepressants with caution as this may activate bipolar disorder and suicidal ideation

Modafinil, especially for fatigue, sleepiness, and lack of concentration

Mood stabilizers or atypical antipsychotics for bipolar depression, psychotic depression, treatment-resistant depression, or treatment- resistant anxiety disorders

Benzodiazepines

If all else fails for anxiety disorders, consider gabapentin or tiagabine

Hypnotics for insomnia

Classically, lithium, buspirone, or thyroid hormone

Tests

Side Effects

How Drug Causes Side Effects

Theoretically due to increases in serotonin concentrations at serotonin receptors in parts of the brain and body other than those that cause therapeutic actions (e.g., unwanted actions of serotonin in sleep centers causing insomnia, unwanted actions of serotonin in the gut causing diarrhea, etc.)

Increasing serotonin can cause diminished dopamine release and might contribute to emotional flattening, cognitive slowing, and apathy in some patients

Most side effects are immediate but often go away with time, in contrast to most therapeutic effects which are delayed and are enhanced over time

âœ1⁄2 Citalopramâ€TM s unique mild antihistamine properties may contribute to sedation and fatigue in some patients

Notable Side Effects

Sexual dysfunction (dose-dependent; men: delayed ejaculation, erectile dysfunction; men and women: decreased sexual desire, anorgasmia)

None for healthy individuals

Gastrointestinal (decreased appetite, nausea, diarrhea, constipation, dry mouth)

Mostly CNS (dose-dependent insomnia but also sedation, agitation, tremors, headache, dizziness)

Activation (short-term; patients with diagnosed or undiagnosed bipolar or psychotic disorders may be more vulnerable to CNS- activating actions of SSRIs)

Sweating (dose-dependent) Bruising and rare bleeding

Rare hyponatremia (mostly in elderly patients and generally reversible on discontinuation of citalopram)

SIADH (syndrome of inappropriate antidiuretic hormone secretion)

Life-Threatening or Dangerous Side Effects

Rare seizures

Rare induction of mania

Rare activation of suicidal ideation and behavior (suicidality) (short- term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo beyond age 24)

Weight Gain

Reported but not expected

Citalopram has been associated with both weight gain and weight loss in various studies, but is relatively weight neutral overall

Sedation

Occurs in significant minority

What to Do About Side Effects

Wait

Wait

Wait

Take in the morning if nighttime insomnia Take at night if daytime sedation

In a few weeks, switch to another agent or add other drugs

Best Augmenting Agents for Side Effects

Often best to try another SSRI or another antidepressant monotherapy prior to resorting to augmentation strategies to treat side effects

Trazodone or a hypnotic for insomnia

Bupropion, sildenafil, vardenafil, or tadalafil for sexual dysfunction Bupropion for emotional flattening, cognitive slowing, or apathy Mirtazapine for insomnia, agitation, and gastrointestinal side effects

Benzodiazepines for jitteriness and anxiety, especially at initiation of treatment and especially for anxious patients

Many side effects are dose-dependent (i.e., they increase as dose increases, or they reemerge until tolerance redevelops)

Many side effects are time-dependent (i.e., they start immediately upon dosing and upon each dose increase, but go away with time)

Activation and agitation may represent the induction of a bipolar state, especially a mixed dysphoric bipolar II condition sometimes associated with suicidal ideation, and require the addition of lithium, a mood stabilizer or an atypical antipsychotic, and/or discontinuation of citalopram

20– 40 mg/day

Dosing and Use Usual Dosage Range

Dosage Forms

Tablet 10 mg, 20 mg scored, 40 mg scored Solution 10 mg/5 mL

How to Dose

Initial 20 mg/day; increase by 20 mg/day after 1 or more weeks; maximum 40 mg/day; single-dose administration, morning or

evening

Dosing Tips

Citalopram should no longer be prescribed at doses greater than 40 mg/day because if can cause abnormal changes in the electrical activity of the heart

Some controversy with FDA dosage limit of 40 mg/day, and higher doses may be prescribed by experts

Tablets are scored, so to save costs, give 10 mg as half of 20 mg tablet or 20 mg as half of 40 mg tablet, since the tablets cost about the same in many markets

Many patients respond better to 40 mg than to 20 mg

Given once daily, any time of day when best tolerated by the individual

If intolerable anxiety, insomnia, agitation, akathisia, or activation occur upon either dosing initiation or discontinuation, consider the possibility of activated bipolar disorder and switch to a mood stabilizer or an atypical antipsychotic

Overdose

Rare fatalities have been reported with citalopram overdose, both alone and in combination with other drugs

Vomiting, sedation, heart rhythm disturbances, dizziness, sweating, nausea, tremor

Rarely amnesia, confusion, coma, convulsions

Safe

No

Long-Term Use

Habit Forming

How to Stop

Taper not usually necessary

However, tapering to avoid potential withdrawal reactions generally prudent

Many patients tolerate 50% dose reduction for 3 days, then another 50% reduction for 3 days, then discontinuation

If withdrawal symptoms emerge during discontinuation, raise dose to stop symptoms and then restart withdrawal much more slowly

Pharmacokinetics

Parent drug has 23– 45 hour half-life Weak inhibitor of CYP450 2D6 Metabolized by CYP450 3A4 and 2C19

Drug Interactions

Tramadol increases the risk of seizures in patients taking an antidepressant

Can increase TCA levels; use with caution with TCAs

Can cause a fatal “ serotonin syndrome†when combined with MAOIs, so do not use with MAOIs or at least for 14 days after MAOIs are stopped

Do not start an MAOI for at least 5 half-lives (5 to 7 days for most drugs) after discontinuing citalopram

May displace highly protein-bound drugs (e.g., warfarin)

Can rarely cause weakness, hyperreflexia, and incoordination when combined with sumatriptan or possibly other triptans, requiring careful monitoring of patient

Possible increased risk of bleeding especially when combined with anticoagulants (e.g., warfarin, NSAIDs)

NSAIDs may impair effectiveness of SSRIs

Should not be dosed above 20 mg/day in patients taking a CYP450 2C19 inhibitor (e.g., cimetidine) due to risk of QT prolongation

Via CYP450 2D6 inhibition, citalopram could theoretically interfere with the analgesic actions of codeine, and increase the plasma levels of some beta blockers and of atomoxetine

Via CYP450 2D6 inhibition, citalopram could theoretically increase concentrations of thioridazine and cause dangerous cardiac arrhythmias

Other Warnings/Precautions

Use with caution in patients with history of seizures

Use with caution in patients with bipolar disorder unless treated with concomitant mood-stabilizing agent

When treating children, carefully weigh the risks and benefits of pharmacological treatment against the risks and benefits of nontreatment with antidepressants and make sure to document this in the patientâ€TM s chart

Distribute the brochures provided by the FDA and the drug companies

Whenever possible, warn patients and their caregivers about the possibility of activating side effects, and advise them to report such symptoms immediately

Monitor patients for activation of suicidal ideation, especially children and adolescents

Do Not Use

If patient is taking an MAOI

If patient is taking thioridazine or pimozide

If there is a proven allergy to citalopram or escitalopram

Special Populations

Renal Impairment

No dose adjustment for mild to moderate impairment Use cautiously in patients with severe impairment

Hepatic Impairment

Should not be used at doses greater than 20 mg/day

May need to dose cautiously at the lower end of the dose range in some patients for maximal tolerability

Cardiac Impairment

May cause abnormal changes in the electrical activity of the heart at doses greater than 40 mg/day

Treating depression with SSRIs in patients with acute angina or following myocardial infarction may reduce cardiac events and improve survival as well as mood

Elderly

Doses greater than 20 mg/day should not be used in patients over age 60 years

May need to dose at the lower end of the dose range in some patients for maximal tolerability

Risk of SIADH with SSRIs is higher in the elderly

Citalopram may be an especially well-tolerated SSRI in the elderly

Reduction in the risk of suicidality with antidepressants compared to placebo in adults age 65 and older

Children and Adolescents

Carefully weigh the risks and benefits of pharmacological treatment against the risks and benefits of nontreatment with antidepressants and make sure to document this in the patientâ€TM s chart

Monitor patients face-to-face regularly, particularly during the first several weeks of treatment

Use with caution, observing for activation of known or unknown bipolar disorder and/or suicidal ideation, and inform parents or guardians of this risk so they can help observe child or adolescent patients

Not specifically approved, but preliminary data suggest citalopram is safe and effective in children and adolescents with OCD and with depression

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women

Not generally recommended for use during pregnancy, especially during first trimester

Nonetheless, continuous treatment during pregnancy may be necessary and has not been proven to be harmful to the fetus

At delivery there may be more bleeding in the mother and transient irritability or sedation in the newborn

Must weigh the risk of treatment (first trimester fetal development, third trimester newborn delivery) to the child against the risk of no treatment (recurrence of depression, maternal health, infant bonding) to the mother and child

For many patients, this may mean continuing treatment during pregnancy

Exposure to SSRIs early in pregnancy may be associated with increased risk of septal heart defects (absolute risk is small)

SSRI use beyond the 20th week of pregnancy may be associated with increased risk of pulmonary hypertension in newborns, although this is not proven

Exposure to SSRIs late in pregnancy may be associated with increased risk of gestational hypertension and preeclampsia

Neonates exposed to SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding; reported symptoms are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome, and include respiratory

distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying

National Pregnancy Registry for Antidepressants: 1-866-961-2388,

https://womensmentalhealth.org/research/pregnancyregistry/antidepr essants

Breast Feeding

Some drug is found in motherâ€TM s breast milk

Trace amounts may be present in nursing children whose mothers are on citalopram

If child becomes irritable or sedated, breast feeding or drug may need to be discontinued

Immediate postpartum period is a high-risk time for depression, especially in women who have had prior depressive episodes, so drug may need to be reinstituted late in the third trimester or shortly after childbirth to prevent a recurrence during the postpartum period

Must weigh benefits of breast feeding with risks and benefits of antidepressant treatment versus nontreatment to both the infant and the mother

For many patients, this may mean continuing treatment during breast feeding

The Art of Psychopharmacology Potential Advantages

Elderly patients

Patients excessively activated or sedated by other SSRIs

Potential Disadvantages

May require dosage titration to attain optimal efficacy Can be sedating in some patients

Primary Target Symptoms

Depressed mood

Anxiety

Panic attacks, avoidant behavior, reexperiencing, hyperarousal Sleep disturbance, both insomnia and hypersomnia

Pearls

âœ1⁄2 May be more tolerable than some other antidepressants

May have less sexual dysfunction than some other SSRIs

May be especially well tolerated in the elderly âœ1⁄2 May be less well tolerated than escitalopram

Documentation of efficacy in anxiety disorders is less comprehensive than for escitalopram and other SSRIs

Can cause cognitive and affective “ flatteningâ€

Some evidence suggests that citalopram treatment during only the luteal phase may be more effective than continuous treatment for patients with PMDD

SSRIs may be less effective in women over 50, especially if they are not taking estrogen

SSRIs may be useful for hot flushes in perimenopausal women

Nonresponse to citalopram in elderly may require consideration of mild cognitive impairment or Alzheimer disease

Suggested Reading

Cipriani A , Purgato M , Furukawa TA , et al. Citalopram versus other anti- depressive agents for depression . Cochrane Database Syst Rev 2012 ;11 (7 ):CD006534 .

Rush AJ , Trivedi MH , Wisniewski SR . Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report . Am J Psychiatry 2006 ;163 (11 ):1905 – 17.

Vieweg WV , Hasnain M , Howland RH , et al. Citalopram, QTc interval prolongation, and torsade de pointes. How should we apply the recent FDA ruling? Am J Med 2012 ;125 (9 ):859– 68 .

Clomipramine

Anafranil

Therapeutics Brands

see index for additional brand names

Yes

Generic?

Class

Neuroscience-based Nomenclature: serotonin reuptake inhibitor (SRI)

Tricyclic antidepressant (TCA)

Parent drug is a potent serotonin reuptake inhibitor

Active metabolite is a potent norepinephrine/noradrenaline reuptake inhibitor

Commonly Prescribed for

(bold for FDA approved)

âœ1⁄2 Obsessive-compulsive disorder

Depression

âœ1⁄2 Severe and treatment-resistant depression âœ1⁄2 Cataplexy syndrome

Anxiety

Insomnia

Neuropathic pain/chronic pain

How the Drug Works

Boosts neurotransmitters serotonin and norepinephrine/noradrenaline

Blocks serotonin reuptake pump (serotonin transporter), presumably increasing serotonergic neurotransmission

Blocks norepinephrine reuptake pump (norepinephrine transporter), presumably increasing noradrenergic neurotransmission

Presumably desensitizes both serotonin 1A receptors and beta adrenergic receptors

Since dopamine is inactivated by norepinephrine reuptake in frontal cortex, which largely lacks dopamine transporters, clomipramine can increase dopamine neurotransmission in this part of the brain

How Long Until It Works

May have immediate effects in treating insomnia or anxiety

Onset of therapeutic actions in depression usually not immediate, but often delayed 2 to 4 weeks

Onset of therapeutic action in OCD can be delayed 6 to 12 weeks

If it is not working for depression within 6 to 8 weeks, it may require a dosage increase or it may not work at all

If it is not working for OCD within 12 weeks, it may not work at all

May continue to work for many years to prevent relapse of symptoms

If It Works

The goal of treatment of depression is complete remission of current symptoms as well as prevention of future relapses

Treatment most often reduces or even eliminates symptoms, but not a cure since symptoms can recur after medicine stopped

Although the goal of treatment of OCD is also complete remission of symptoms, this may be less likely than in depression

The goal of treatment of chronic neuropathic pain is to reduce symptoms as much as possible, especially in combination with other treatments

Continue treatment of depression until all symptoms are gone (remission)

Once symptoms of depression are gone, continue treating for 1 year for the first episode of depression

For second and subsequent episodes of depression, treatment may need to be indefinite

Use in OCD may also need to be indefinite, starting from the time of initial treatment

Use in other anxiety disorders and chronic pain may also need to be indefinite, but long-term treatment is not well studied in these conditions

If It Doesnâ€TM t Work

Many patients have only a partial response where some symptoms are improved but others persist (especially insomnia, fatigue, and problems concentrating)

Other patients may be nonresponders, sometimes called treatment- resistant or treatment-refractory

Consider increasing dose, switching to another agent, or adding an appropriate augmenting agent

Consider psychotherapy, especially behavioral therapy in OCD

Consider evaluation for another diagnosis or for a comorbid condition (e.g., medical illness, substance abuse, etc.)

Some patients may experience apparent lack of consistent efficacy due to activation of latent or underlying bipolar disorder, and require antidepressant discontinuation and a switch to a mood stabilizer

Best Augmenting Combos for Partial Response or Treatment Resistance

Lithium, buspirone, hormone (for depression and OCD)

For the expert: consider cautious addition of fluvoxamine for treatment-resistant OCD

Thyroid hormone (for depression) Atypical antipsychotics (for OCD)

Tests

Baseline ECG is recommended for patients over age 50

âœ1⁄2 Monitoring of plasma drug levels is potentially available at specialty laboratories for the expert

âœ1⁄2 Since tricyclic and tetracyclic antidepressants are frequently associated with weight gain, before starting treatment, weigh all patients and determine if the patient is already overweight (BMI 25.0– 29.9) or obese (BMI ≥ 30)

Before giving a drug that can cause weight gain to an overweight or obese patient, consider determining whether the patient already has pre-diabetes (fasting plasma glucose 100– 125 mg/dL), diabetes (fasting plasma glucose ≥ 126 mg/dL), or dyslipidemia (increased total cholesterol, LDL cholesterol, and triglycerides; decreased HDL cholesterol), and treat or refer such patients for treatment, including nutrition and weight management, physical activity counseling, smoking cessation, and medical management

âœ1⁄2 Weight and BMI during treatment

âœ1⁄2 While giving a drug to a patient who has gained >5% of initial weight, consider evaluating for the presence of pre-diabetes, diabetes,

or dyslipidemia, or consider switching to a different antidepressant

ECGs may be useful for selected patients (e.g., those with personal or family history of QTc prolongation; cardiac arrhythmia; recent myocardial infarction; uncompensated heart failure; or taking agents that prolong QTc interval such as pimozide, thioridazine, selected antiarrhythmics, moxifloxacin, sparfloxacin, etc.)

Patients at risk for electrolyte disturbances (e.g., patients on diuretic therapy) should have baseline and periodic serum potassium and magnesium measurements

Side Effects

How Drug Causes Side Effects

Anticholinergic activity may explain sedative effects, dry mouth, constipation, and blurred vision

Sedative effects and weight gain may be due to antihistamine properties

Blockade of alpha adrenergic 1 receptors may explain dizziness, sedation, and hypotension

Cardiac arrhythmias and seizures, especially in overdose, may be caused by blockade of ion channels

Notable Side Effects

Blurred vision, constipation, urinary retention, increased appetite, dry mouth, nausea, diarrhea, heartburn, unusual taste in mouth, weight gain

Fatigue, weakness, dizziness, sedation, headache, anxiety, nervousness, restlessness

Sexual dysfunction, sweating

Life-Threatening or Dangerous Side Effects

Paralytic ileus, hyperthermia (TCAs + anticholinergic agents) Lowered seizure threshold and rare seizures

Orthostatic hypotension, sudden death, arrhythmias, tachycardia QTc prolongation

Hepatic failure, drug-induced parkinsonism Increased intraocular pressure

Rare induction of mania

Rare activation of suicidal ideation and behavior (suicidality) (short- term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo beyond age 24)

Weight Gain

Many experience and/or can be significant in amount Can increase appetite and carbohydrate craving

Sedation

Many experience and/or can be significant in amount Tolerance to sedative effect may develop with long-term use

What to Do About Side Effects

Wait

Wait

Wait

Lower the dose

Switch to an SSRI or newer antidepressant

Best Augmenting Agents for Side Effects

Many side effects cannot be improved with an augmenting agent

100– 200 mg/day

Dosing and Use Usual Dosage Range

Dosage Forms

Capsule 25 mg, 50 mg, 75 mg

How to Dose

Initial 25 mg/day; increase over 2 weeks to 100 mg/day; maximum dose generally 250 mg/day

Dosing Tips

If given in a single dose, should generally be administered at bedtime because of its sedative properties

If given in split doses, largest dose should generally be given at bedtime because of its sedative properties

If patients experience nightmares, split dose and do not give large dose at bedtime

Patients treated for chronic pain may only require lower doses

âœ1⁄2 Patients treated for OCD may often require doses at the high end of the range (e.g., 200– 250 mg/day)

Risk of seizure increases with dose, especially with clomipramine at doses above 250 mg/day

âœ1⁄2 Dose of 300 mg may be associated with up to 7/1000 incidence of seizures, a generally unacceptable risk

If intolerable anxiety, insomnia, agitation, akathisia, or activation occur upon either dosing initiation or discontinuation, consider the possibility of activated bipolar disorder, and switch to a mood stabilizer or an atypical antipsychotic

Overdose

Death may occur; convulsions, cardiac dysrhythmias, severe hypotension, CNS depression, coma, changes in ECG

Long-Term Use

Limited data but appears to be efficacious and safe long-term

No

Habit Forming

How to Stop

Taper to avoid withdrawal effects

Even with gradual dose reduction some withdrawal symptoms may appear within the first 2 weeks

Many patients tolerate 50% dose reduction for 3 days, then another 50% reduction for 3 days, then discontinuation

If withdrawal symptoms emerge during discontinuation, raise dose to stop symptoms and then restart withdrawal much more slowly

Pharmacokinetics

Substrate for CYP450 2D6 and 1A2

Metabolized to an active metabolite, desmethyl-clomipramine, a predominantly norepinephrine reuptake inhibitor, by demethylation via CYP450 1A2

Inhibits CYP450 2D6

Half-life approximately 17– 28 hours Food does not affect absorption

Drug Interactions

Tramadol increases the risk of seizures in patients taking TCAs

Can cause a fatal “ serotonin syndrome†when combined with MAOIs, so do not use with MAOIs or at least for 14 days after MAOIs are stopped

Do not start an MAOI for at least 5 half-lives (5 to 7 days for most drugs) after discontinuing clomipramine

Use of TCAs with anticholinergic drugs may result in paralytic ileus or hyperthermia

Fluoxetine, paroxetine, bupropion, duloxetine, and other CYP450 2D6 inhibitors may increase TCA concentrations

Fluvoxamine, a CYP450 1A2 inhibitor, can decrease the conversion of clomipramine to desmethyl-clomipramine, and increase clomipramine plasma concentrations

Cimetidine may increase plasma concentrations of TCAs and cause anticholinergic symptoms

Phenothiazines or haloperidol may raise TCA blood concentrations May alter effects of antihypertensive drugs

Use of TCAs with sympathomimetic agents may increase sympathetic activity

TCAs may inhibit hypotensive effects of clonidine Methylphenidate may inhibit metabolism of TCAs

Activation and agitation, especially following switching or adding antidepressants, may represent the induction of a bipolar state, especially a mixed dysphoric bipolar II condition sometimes associated with suicidal ideation, and require the addition of lithium, a mood stabilizer or an atypical antipsychotic, and/or discontinuation of clomipramine

Other Warnings/Precautions

Add or initiate other antidepressants with caution for up to 2 weeks after discontinuing clomipramine

Use with caution in patients with history of seizures, urinary retention, angle-closure glaucoma, hyperthyroidism

TCAs can increase QTc interval, especially at toxic doses, which can be attained not only by overdose but also by combining with drugs that inhibit TCA metabolism via CYP450 2D6, potentially causing torsade de pointes-type arrhythmia or sudden death

Because TCAs can prolong QTc interval, use with caution in patients who have bradycardia or who are taking drugs that can induce bradycardia (e.g., beta blockers, calcium channel blockers, clonidine, digitalis)

Because TCAs can prolong QTc interval, use with caution in patients who have hypokalemia and/or hypomagnesemia or who are taking drugs that can induce hypokalemia and/or magnesemia (e.g., diuretics, stimulant laxatives, intravenous amphotericin B, glucocorticoids, tetracosactide)

When treating children, carefully weigh the risks and benefits of pharmacological treatment against the risks and benefits of nontreatment with antidepressants and make sure to document this in the patientâ€TM s chart

Distribute the brochures provided by the FDA and the drug companies

Whenever possible, warn patients and their caregivers about the possibility of activating side effects, and advise them to report such symptoms immediately

Monitor patients for activation of suicidal ideation, especially children and adolescents

Do Not Use

If patient is taking an MAOI

If patient is recovering from myocardial infarction

If patient is taking agents capable of significantly prolonging QTc interval (e.g., pimozide, thioridazine, selected antiarrhythmics, moxifloxacin, sparfloxacin)

If there is a history of QTc prolongation or cardiac arrhythmia, recent acute myocardial infarction, uncompensated heart failure

If patient is taking drugs that inhibit TCA metabolism, including CYP450 2D6 inhibitors, except by an expert

If there is reduced CYP450 2D6 function, such as patients who are poor 2D6 metabolizers, except by an expert and at low doses

If there is a proven allergy to clomipramine

Use with caution

Use with caution

Special Populations Renal Impairment

Hepatic Impairment

Cardiac Impairment

Baseline ECG is recommended

TCAs have been reported to cause arrhythmias, prolongation of conduction time, orthostatic hypotension, sinus tachycardia, and heart failure, especially in the diseased heart

Myocardial infarction and stroke have been reported with TCAs

TCAs produce QTc prolongation, which may be enhanced by the existence of bradycardia, hypokalemia, congenital or acquired long QTc interval, which should be evaluated prior to administering clomipramine

Use with caution if treating concomitantly with a medication likely to produce prolonged bradycardia, hypokalemia, slowing of intracardiac conduction, or prolongation of the QTc interval

Avoid TCAs in patients with a known history of QTc prolongation, recent acute myocardial infarction, and uncompensated heart failure

TCAs may cause a sustained increase in heart rate in patients with ischemic heart disease and may worsen (decrease) heart rate variability, an independent risk of mortality in cardiac populations

Since SSRIs may improve (increase) heart rate variability in patients following a myocardial infarct and may improve survival as well as mood in patients with acute angina or following a myocardial infarction, these are more appropriate agents for cardiac population than tricyclic/tetracyclic antidepressants

âœ1⁄2 Risk/benefit ratio may not justify use of TCAs in cardiac impairment

Elderly

Baseline ECG is recommended for patients over age 50

May be more sensitive to anticholinergic, cardiovascular, hypotensive, and sedative effects

Dose may need to be lower than usual adult dose, at least initially

Reduction in the risk of suicidality with antidepressants compared to placebo in adults age 65 and older

Children and Adolescents

Carefully weigh the risks and benefits of pharmacological treatment against the risks and benefits of nontreatment with antidepressants and make sure to document this in the patientâ€TM s chart

Monitor patients face-to-face regularly, particularly during the first several weeks of treatment

Use with caution, observing for activation of known or unknown bipolar disorder and/or suicidal ideation, and inform parents or guardians of this risk so they can help observe child or adolescent patients

Not recommended for use in children under age 10

Several studies show lack of efficacy of TCAs for depression

May be used to treat enuresis or hyperactive/impulsive behaviors Effective for OCD in children

Some cases of sudden death have occurred in children taking TCAs

Dose in children/adolescents should be titrated to a maximum of 100 mg/day or 3 mg/kg per day after 2 weeks, after which dose can then be titrated up to a maximum of 200 mg/day or 3 mg/kg per day

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women Clomipramine crosses the placenta

Adverse effects have been reported in infants whose mothers took a TCA (lethargy, withdrawal symptoms, fetal malformations)

Must weigh the risk of treatment (first trimester fetal development, third trimester newborn delivery) to the child against the risk of no treatment (recurrence of depression, worsening of OCD, maternal health, infant bonding) to the mother and child

For many patients this may mean continuing treatment during pregnancy

National Pregnancy Registry for Antidepressants: 1-866-961-2388,

https://womensmentalhealth.org/research/pregnancyregistry/antidepr essants

Breast Feeding

Some drug is found in motherâ€TM s breast milk

âœ1⁄2 Recommended either to discontinue drug or bottle feed

Immediate postpartum period is a high-risk time for depression and worsening of OCD, especially in women who have had prior depressive episodes or OCD symptoms, so drug may need to be reinstituted late in the third trimester or shortly after childbirth to prevent a recurrence or exacerbation during the postpartum period

Must weigh benefits of breast feeding with risks and benefits of antidepressant treatment versus nontreatment to both the infant and the mother

For many patients this may mean continuing treatment during breast feeding

The Art of Psychopharmacology Potential Advantages

Patients with insomnia

Severe or treatment-resistant depression Patients with comorbid OCD and depression Patients with cataplexy

Potential Disadvantages

Pediatric and geriatric patients Patients concerned with weight gain Cardiac patients

Patients with seizure disorders

Primary Target Symptoms

Depressed mood Obsessive thoughts Compulsive behaviors

Pearls

âœ1⁄2 The only TCA with proven efficacy in OCD

Normally, clomipramine (CMI), a potent serotonin reuptake blocker, at steady state is metabolized extensively to its active metabolite desmethyl-clomipramine (de-CMI), a potent nonadrenaline reuptake blocker, by the enzyme CYP450 1A2

Thus, at steady state, plasma drug activity is generally more noradrenergic (with higher de-CMI levels) than serotonergic (with lower parent CMI levels)

Addition of the SSRI and CYP450 1A2 inhibitor fluvoxamine blocks this conversion and results in higher CMI levels than de-CMI levels

For the expert only: addition of the SSRI fluvoxamine to CMI in treatment-resistant OCD can powerfully enhance serotonergic activity, not only due to the inherent additive pharmacodynamic serotonergic activity of fluvoxamine added to CMI, but also due to a favorable pharmacokinetic interaction inhibiting CYP450 1A2 and

thus converting CMIâ€TM s metabolism to a more powerful serotonergic portfolio of parent drug

âœ1⁄2 One of the most favored TCAs for treating severe depression TCAs are no longer generally considered a first-line treatment

option for depression because of their side effect profile

TCAs continue to be useful for severe or treatment-resistant depression

TCAs are often a first-line treatment option for chronic pain

âœ1⁄2 Unique among TCAs, clomipramine has a potentially fatal interaction with MAOIs in addition to the danger of hypertension characteristic of all MAOI-TCA combinations

âœ1⁄2 A potentially fatal serotonin syndrome with high fever, seizures, and coma, analogous to that caused by SSRIs and MAOIs, can occur with clomipramine and SSRIs, presumably due to clomipramineâ€TM s potent serotonin reuptake blocking properties

TCAs may aggravate psychotic symptoms

Alcohol should be avoided because of additive CNS effects

Underweight patients may be more susceptible to adverse cardiovascular effects

Children, patients with inadequate hydration, and patients with cardiac disease may be more susceptible to TCA-induced cardiotoxicity than healthy adults

Patients on TCAs should be aware that they may experience symptoms such as photosensitivity or blue-green urine

SSRIs may be more effective than TCAs in women, and TCAs may be more effective than SSRIs in men

Since tricyclic/tetracyclic antidepressants are substrates for CYP450 2D6, and 7% of the population (especially Caucasians) may have a genetic variant leading to reduced activity of 2D6, such patients may not safely tolerate normal doses of tricyclic/tetracyclic antidepressants and may require dose reduction

Phenotypic testing may be necessary to detect this genetic variant prior to dosing with a tricyclic/tetracyclic antidepressant, especially in vulnerable populations such as children, elderly, cardiac populations, and those on concomitant medications

Patients who seem to have extraordinarily severe side effects at normal or low doses may have this phenotypic CYP450 2D6 variant and require low doses or switching to another antidepressant not metabolized by 2D6

Suggested Reading

Anderson IM . Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability . J Aff Disorders 2000 ;58 :19 – 36 .

Anderson IM . Meta-analytical studies on new antidepressants . Br Med Bull 2001 ;57 :161– 78 .

Cox BJ , Swinson RP , Morrison B , Lee PS . Clomipramine, fluoxetine, and behavior therapy in the treatment of obsessive-compulsive disorder: a meta-analysis . J Behav Ther Exp Psychiatry 1993 ;24 :149– 53 .

Feinberg M . Clomipramine for obsessive-compulsive disorder . Am Fam Physician 1991 ; 43 :1735– 8 .

Clonazepam

Klonopin

Therapeutics Brands

Yes

Generic?

Class

see index for additional brand names

Neuroscience-based Nomenclature: GABA positive allosteric modulator (GABA-PAM)

Benzodiazepine (anxiolytic, anticonvulsant)

Commonly Prescribed for

(bold for FDA approved)

Panic disorder, with or without agoraphobia Lennox-Gastaut syndrome (petit mal variant) Akinetic seizure

Myoclonic seizure

Absence seizure (petit mal)

Atonic seizures

Other seizure disorders Other anxiety disorders Acute mania (adjunctive) Acute psychosis (adjunctive) Insomnia

Catatonia

How the Drug Works

Binds to benzodiazepine receptors at the GABA-A ligand-gated chloride channel complex

Enhances the inhibitory effects of GABA

Boosts chloride conductance through GABA-regulated channels

Inhibits neuronal activity presumably in amygdala-centered fear circuits to provide therapeutic benefits in anxiety disorders

Inhibitory actions in cerebral cortex may provide therapeutic benefits in seizure disorders

How Long Until It Works

Some immediate relief with first dosing is common; can take several weeks with daily dosing for maximal therapeutic benefit

If It Works

For short-term symptoms of anxiety – after a few weeks, discontinue use or use on an “ as-needed†basis

For chronic anxiety disorders, the goal of treatment is complete remission of symptoms as well as prevention of future relapses

For chronic anxiety disorders, treatment most often reduces or even eliminates symptoms, but not a cure since symptoms can recur after medicine stopped

For long-term symptoms of anxiety, consider switching to an SSRI or SNRI for long-term maintenance

If long-term maintenance with a benzodiazepine is necessary, continue treatment for 6 months after symptoms resolve, and then taper dose slowly

If symptoms reemerge, consider treatment with an SSRI or SNRI, or consider restarting the benzodiazepine; sometimes benzodiazepines have to be used in combination with SSRIs or SNRIs for best results

For long-term treatment of seizure disorders, development of tolerance dose escalation and loss of efficacy necessitating adding or switching to other anticonvulsants is not uncommon

If It Doesnâ€TM t Work

Consider switching to another agent or adding an appropriate augmenting agent

Consider psychotherapy, especially cognitive behavioral psychotherapy

Consider presence of concomitant substance abuse

Consider presence of clonazepam abuse

Consider another diagnosis such as a comorbid medical condition

Best Augmenting Combos for Partial Response or Treatment Resistance

Benzodiazepines are frequently used as augmenting agents for antipsychotics and mood stabilizers in the treatment of psychotic and bipolar disorders

Benzodiazepines are frequently used as augmenting agents for SSRIs and SNRIs in the treatment of anxiety disorders

Not generally rational to combine with other benzodiazepines

Caution if using as an anxiolytic concomitantly with other sedative hypnotics for sleep

Clonazepam is commonly combined with other anticonvulsants for the treatment of seizure disorders

Tests

In patients with seizure disorders, concomitant medical illness, and/or those with multiple concomitant long-term medications, periodic liver tests and blood counts may be prudent

Side Effects

How Drug Causes Side Effects

Same mechanism for side effects as for therapeutic effects – namely due to excessive actions at benzodiazepine receptors

Long-term adaptations in benzodiazepine receptors may explain the development of dependence, tolerance, and withdrawal

Side effects are generally immediate, but immediate side effects often disappear in time

Notable Side Effects âœ1⁄2 Sedation, fatigue, depression

âœ1⁄2 Dizziness, ataxia, slurred speech, weakness âœ1⁄2 Forgetfulness, confusion

âœ1⁄2 Hyperexcitability, nervousness

Rare hallucinations, mania Rare hypotension Hypersalivation, dry mouth

Life-Threatening or Dangerous Side Effects

Respiratory depression, especially when taken with CNS depressants in overdose

Rare hepatic dysfunction, renal dysfunction, blood dyscrasias Grand mal seizures

Weight Gain

Sedation

Occurs in significant minority

Especially at initiation of treatment or when dose increases Tolerance often develops over time

What to Do About Side Effects

Wait

Wait

Wait

Lower the dose

Take largest dose at bedtime to avoid sedative effects during the day Switch to another agent

Administer flumazenil if side effects are severe or life-threatening

Best Augmenting Agents for Side Effects

Many side effects cannot be improved with an augmenting agent

Reported but not expected

Dosing and Use Usual Dosage Range

Seizures: dependent on individual response of patient, up to 20 mg/day

Panic: 0.5– 2 mg/day either as divided doses or once at bedtime

Dosage Forms

Tablet 0.5 mg scored, 1 mg, 2 mg

Disintegrating (wafer) 0.125 mg, 0.25 mg, 0.5 mg, 1 mg, 2 mg

How to Dose

Seizures – 1.5 mg divided into 3 doses, raise by 0.5 mg every 3 days until desired effect is reached; divide into 3 even doses or else give largest dose at bedtime; maximum dose generally 20 mg/day

Panic – 1 mg/day; start at 0.25 mg divided into 2 doses, raise to 1 mg after 3 days; dose either twice daily or once at bedtime; maximum dose generally 4 mg/day

Dosing Tips

For anxiety disorders, use lowest possible effective dose for the shortest possible period of time (a benzodiazepine-sparing strategy)

Assess need for continuous treatment regularly

Risk of dependence may increase with dose and duration of treatment

For interdose symptoms of anxiety, can either increase dose or maintain same daily dose but divide into more frequent doses

Can also use an as-needed occasional “ top-up†dose for interdose anxiety

Because seizure disorder can require doses much higher than 2 mg/day, the risk of dependence may be greater in these patients

Because panic disorder can require doses somewhat higher than 2 mg/day, the risk of dependence may be greater in these patients than in anxiety patients maintained at lower doses

Some severely ill seizure patients may require more than 20 mg/day Some severely ill panic patients may require 4 mg/day or more

Frequency of dosing in practice is often greater than predicted from half-life, as duration of biological activity is often shorter than pharmacokinetic terminal half-life

âœ1⁄2 Clonazepam is generally dosed half the dosage of alprazolam Escalation of dose may be necessary if tolerance develops in seizure

disorders

Escalation of dose usually not necessary in anxiety disorders, as tolerance to clonazepam does not generally develop in the treatment of anxiety disorders

âœ1⁄2 Available as an oral disintegrating wafer

Overdose

Rarely fatal in monotherapy; sedation, confusion, coma, diminished reflexes

Long-Term Use

May lose efficacy for seizures; dose increase may restore efficacy

Risk of dependence, particularly for treatment periods longer than 12 weeks and especially in patients with past or current polysubstance abuse

Habit Forming

Clonazepam is a Schedule IV drug

Patients may develop dependence and/or tolerance with long-term use

How to Stop

Patients with history of seizures may seize upon withdrawal, especially if withdrawal is abrupt

Taper by 0.25 mg every 3 days to reduce chances of withdrawal effects

For difficult-to-taper cases, consider reducing dose much more slowly after reaching 1.5 mg/day, perhaps by as little as 0.125 mg per week or less

For other patients with severe problems discontinuing a benzodiazepine, dosing may need to be tapered over many months (i.e., reduce dose by 1% every 3 days by crushing tablet and suspending or dissolving in 100 mL of fruit juice and then disposing of 1 mL and drinking the rest; 3– 7 days later, dispose of 2 mL, and so on). This is both a form of very slow biological tapering and a form of behavioral desensitization

Be sure to differentiate reemergence of symptoms requiring reinstitution of treatment from withdrawal symptoms

Benzodiazepine-dependent anxiety patients and insulin-dependent diabetics are not addicted to their medications. When benzodiazepine-dependent patients stop their medication, disease symptoms can reemerge, disease symptoms can worsen (rebound), and/or withdrawal symptoms can emerge

Pharmacokinetics

Long half-life compared to other benzodiazepine anxiolytics (elimination half-life approximately 30– 40 hours)

Substrate for CYP450 3A4 Food does not affect absorption

Drug Interactions

Increased depressive effects when taken with other CNS depressants (see Warnings below)

Inhibitors of CYP450 3A4 may affect the clearance of clonazepam, but dosage adjustment usually not necessary

Flumazenil (used to reverse the effects of benzodiazepines) may precipitate seizures and should not be used in patients treated for seizure disorders with clonazepam

Use of clonazepam with valproate may cause absence status

Other Warnings/Precautions

Boxed warning regarding the increased risk of CNS depressant effects when benzodiazepines and opioid medications are used together, including specifically the risk of slowed or difficulty breathing and death

If alternatives to the combined use of benzodiazepines and opioids are not available, clinicians should limit the dosage and duration of each drug to the minimum possible while still achieving therapeutic efficacy

Patients and their caregivers should be warned to seek medical attention if unusual dizziness, lightheadedness, sedation, slowed or difficulty breathing, or unresponsiveness occur

Dosage changes should be made in collaboration with prescriber

Use with caution in patients with pulmonary disease; rare reports of death after initiation of benzodiazepines in patients with severe pulmonary impairment

History of drug or alcohol abuse often creates greater risk for dependency

Clonazepam may induce grand mal seizures in patients with multiple seizure disorders

Use only with extreme caution if patient has obstructive sleep apnea

Some depressed patients may experience a worsening of suicidal ideation

Some patients may exhibit abnormal thinking or behavioral changes similar to those caused by other CNS depressants (i.e., either depressant actions or disinhibiting actions)

Do Not Use

If patient has angle-closure glaucoma

If patient has severe liver disease

If there is a proven allergy to clonazepam or any benzodiazepine

Special Populations Renal Impairment

Dose should be reduced

Hepatic Impairment

Dose should be reduced

Cardiac Impairment

Benzodiazepines have been used to treat anxiety associated with acute myocardial infarction

Elderly

Should receive lower doses and be monitored

Children and Adolescents

Seizures – up to 10 years or 30 kg – 0.01– 0.03 mg/kg per day divided into 2– 3 doses; maximum dose 0.05 mg/kg per day

Safety and efficacy not established in panic disorder

For anxiety, children and adolescents should generally receive lower doses and be more closely monitored

Long-term effects of clonazepam in children/adolescents are unknown

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Possible increased risk of birth defects when benzodiazepines are taken during pregnancy

Because of the potential risks, clonazepam is not generally recommended as treatment for anxiety during pregnancy, especially during first trimester

Drug should be tapered if discontinued

Infants whose mothers received a benzodiazepine late in pregnancy may experience withdrawal effects

Neonatal flaccidity has been reported in infants whose mothers took a benzodiazepine during pregnancy

Seizures, even mild seizures, may cause harm to the embryo/fetus

Breast Feeding

Some drug is found in motherâ€TM s breast milk

âœ1⁄2 Recommended either to discontinue drug or bottle feed

Effects on infant have been observed and include feeding difficulties, sedation, and weight loss

The Art of Psychopharmacology Potential Advantages

Rapid onset of action

Less sedation than some other benzodiazepines

Longer duration of action than some other benzodiazepines Availability of oral disintegrating wafer

Potential Disadvantages

Development of tolerance may require dose increases, especially in seizure disorders

Abuse especially risky in past or present substance abusers

Primary Target Symptoms

Frequency and duration of seizures

Spike and wave discharges in absence seizures (petit mal) Panic attacks

Anxiety

Pearls

âœ1⁄2 One of the most popular benzodiazepines for anxiety, especially

among psychiatrists

Is a very useful adjunct to SSRIs and SNRIs in the treatment of numerous anxiety disorders

Not effective for treating psychosis as a monotherapy, but can be used as an adjunct to antipsychotics

Not effective for treating bipolar disorder as a monotherapy, but can be used as an adjunct to mood stabilizers and antipsychotics

Generally used as second-line treatment for petit mal seizures if succinimides are ineffective

Can be used as an adjunct or as monotherapy for seizure disorders

Clonazepam is the only benzodiazepine that is used as a solo maintenance treatment for seizure disorders

âœ1⁄2 Easier to taper than some other benzodiazepines because of long half-life

âœ1⁄2 May have less abuse potential than some other benzodiazepines âœ1⁄2 May cause less depression, euphoria, or dependence than some

other benzodiazepines

âœ1⁄2 Clonazepam is often considered a “ longer-acting alprazolam- like anxiolytic†with improved tolerability features in terms of less euphoria, abuse, dependence, and withdrawal problems, but this has not been proven

When using to treat insomnia, remember that insomnia may be a symptom of some other primary disorder itself, and thus warrant evaluation for comorbid psychiatric and/or medical conditions

Though not systematically studied, benzodiazepines have been used effectively to treat catatonia and are the initial recommended treatment

Suggested Reading

Davidson JR , Moroz G. Pivotal studies of clonazepam in panic disorder . Psychopharmacol Bull 1998 ;34 :169– 74 .

DeVane CL , Ware MR , Lydiard RB. Pharmacokinetics, pharmacodynamics, and treatment issues of benzodiazepines: alprazolam, adinazolam, and clonazepam . Psychopharmacol Bull 1991 ;27 :463– 73 .

Iqbal MM , Sobhan T , Ryals T. Effects of commonly used benzodiazepines on the fetus, the neonate, and the nursing infant . Psychiatr Serv 2002 ;53 :39 – 49 .

Panayiotopoulos CP. Treatment of typical absence seizures and related epileptic syndromes . Paediatr Drugs 2001 ;3 :379 – 403 .

Clonidine

Duraclon (injection)

Catapres

Kapvay

see index for additional brand names

Therapeutics Brands

Yes (not for transdermal)

Generic?

Class

Neuroscience-based Nomenclature: norepinephrine receptor agonist (N-RA)

Antihypertensive; centrally acting alpha 2 agonist hypotensive agent, nonstimulant for ADHD

Commonly Prescribed for

(bold for FDA approved)

Hypertension

Attention deficit hyperactivity disorder (ADHD) (Kapvay, ages 6 to 17)

Attention deficit hyperactivity disorder (ADHD)

Touretteâ€TM s syndrome

Substance withdrawal, including opiates and alcohol

Anxiety disorders, including posttraumatic stress disorder (PTSD) and social anxiety disorder

Clozapine-induced hypersalivation Menopausal flushing

Severe pain in cancer patients that is not adequately relieved by opioid analgesics alone (combination with opiates)

How the Drug Works

For ADHD, theoretically has central actions on postsynaptic alpha 2 receptors in the prefrontal cortex

For hypertension, stimulates alpha 2 adrenergic receptors in the brain stem, reducing sympathetic outflow from the CNS and decreasing peripheral resistance, renal vascular resistance, heart rate, and blood pressure

An imidazoline, so also interacts at imidazoline receptors

How Long Until It Works

For ADHD, can take a few weeks to see maximum therapeutic benefits

Blood pressure may be lowered 30– 60 minutes after first dose; greatest reduction seen after 2– 4 hours

May take several weeks to control blood pressure adequately

If It Works

The goal of treatment of ADHD is reduction of symptoms of inattentiveness, motor hyperactivity, and/or impulsiveness that disrupt social, school, and/or occupational functioning

Continue treatment until all symptoms are under control or improvement is stable and then continue treatment indefinitely as long as improvement persists

Reevaluate the need for treatment periodically

Treatment for ADHD begun in childhood may need to be continued into adolescence and adulthood if continued benefit is documented

For hypertension, continue treatment indefinitely and check blood pressure regularly

If It Doesnâ€TM t Work

Consider adjusting dose or switching to another agent Consider behavioral therapy

Consider the presence of noncompliance and counsel patient and parents

Consider evaluation for another diagnosis or for a comorbid condition (e.g., bipolar disorder, substance abuse, medical illness, etc.)

Best Augmenting Combos for Partial Response or Treatment Resistance

Best to attempt another monotherapy prior to augmenting for ADHD

Possibly combination with stimulants (with caution as benefits of combination poorly documented and there are some reports of serious adverse events)

Combinations for ADHD should be for the expert, while monitoring the patient closely, and when other treatment options have failed

Chlorthalidone, thiazide-type diuretics, and furosemide for hypertension

Tests

Blood pressure should be checked regularly during treatment

Side Effects

How Drug Causes Side Effects

Excessive actions on alpha 2 receptors and/or on imidazoline receptors

Notable Side Effects

âœ1⁄2 Dry mouth

âœ1⁄2 Dizziness, constipation, sedation

Weakness, fatigue, impotence, loss of libido, insomnia, headache Major depression

Dermatologic reactions (especially with transdermal clonidine) Hypotension, occasional syncope

Tachycardia Nervousness, agitation Nausea, vomiting

Life-Threatening or Dangerous Side Effects

Sinus bradycardia, atrioventricular block

During withdrawal, hypertensive encephalopathy, cerebrovascular accidents, and death (rare)

Weight Gain

Reported but not expected

Sedation

Many experience and/or can be significant in amount Some patients may not tolerate it

Can abate with time

What to Do About Side Effects

Wait

Take larger dose at bedtime to avoid daytime sedation

Switch to another medication with better evidence of efficacy

âœ1⁄2 For withdrawal and discontinuation reactions, may need to reinstate clonidine and taper very slowly when stabilized

Best Augmenting Agents for Side Effects

Dose reduction or switching to another agent may be more effective since most side effects cannot be improved with an augmenting agent

Dosing and Use

Usual Dosage Range

Extended-release for ADHD: 0.1– 0.4 mg/day in divided doses

Immediate-release for hypertension: 0.2– 0.6 mg/day in divided doses

Opioid withdrawal: 0.1 mg 3 times daily (can be higher in inpatient setting)

Dosage Forms

Extended-release tablet 0.1 mg, 0.2 mg

Immediate-release tablet 0.1 mg scored, 0.2 mg scored, 0.3 mg scored

Topical (7 day administration) 0.1 mg/24 hours, 0.2 mg/24 hours, 0.3 mg/24 hours

Injection 0.1 mg/mL, 0.5 mg/mL

How to Dose

Oral (for ADHD): initial 0.1 mg at bedtime; can increase by 0.1 mg/day each week with dosing divided and larger dose at bedtime; maximum dose generally 0.4 mg/day in divided doses

For opioid withdrawal: 0.1 mg 3 times daily; next dose should be withheld if blood pressure falls below 90/60 mmHg; outpatients should not be given more than a 3-day supply, detoxification can usually be achieved in 4– 6 days for short-acting opioids

Oral (for hypertension): initial 0.1 mg in 2 divided doses, morning and night; can increase by 0.1 mg/day each week; maximum dose generally 2.4 mg/day

Topical (for hypertension): apply once every 7 days in hairless area; change location with each application

Injection (for hypertension): initial 30 Î1⁄4 g/hour; maximum 40 Î1⁄4 g/hour; 500 mg/mL must be diluted

Dosing Tips

Extended-release tablet should not be chewed, crushed, or broken before swallowing, as this could alter controlled-release properties

Do not substitute different clonidine products for each other on a mg-per-mg basis, because they have different pharmacokinetic profiles

Adverse effects are dose-related and usually transient

The last dose of the day should occur at bedtime so that blood pressure is controlled overnight

If clonidine is terminated abruptly, rebound hypertension may occur within 2– 4 days, so taper dose in decrements of no more than 0.1 mg every 3 to 7 days when discontinuing

Using clonidine in combination with another antihypertensive agent may attenuate the development of tolerance to clonidineâ€TM s antihypertensive effects

The likelihood of severe discontinuation reactions with CNS and cardiovascular symptoms may be greater after administration of high doses of clonidine

âœ1⁄2 In patients who have developed localized contact sensitization to transdermal clonidine, continuing transdermal dosing on other skin areas or substituting with oral clonidine may be associated with the development of a generalized skin rash, urticaria, or angioedema

âœ1⁄2 If administered with a beta blocker, stop the beta blocker first for several days before the gradual discontinuation of clonidine in cases of planned discontinuation

Overdose

Hypotension, hypertension, miosis, respiratory depression, seizures, bradycardia, hypothermia, coma, sedation, decreased reflexes, weakness, irritability, dysrhythmia

Long-Term Use

Patients may develop tolerance to the antihypertensive effects

âœ1⁄2 Studies have not established the utility of clonidine for long-term CNS uses

âœ1⁄2 Be aware that forgetting to take clonidine or running out of medication can lead to abrupt discontinuation and associated withdrawal reactions and complications

Habit Forming

Reports of some abuse by opiate addicts

Reports of some abuse by non-opioid-dependent patients

How to Stop

âœ1⁄2 Discontinuation reactions are common and sometimes severe

Sudden discontinuation can result in nervousness, agitation, headache, and tremor, with rapid rise in blood pressure

Rare instances of hypertensive encephalopathy, cerebrovascular accident, and death have been reported after clonidine withdrawal

Taper over 2– 4 days or longer to avoid rebound effects (nervousness, increased blood pressure)

If administered with a beta blocker, stop the beta blocker first for several days before the gradual discontinuation of clonidine

Pharmacokinetics

Half-life 12– 16 hours Metabolized by the liver Excreted renally

Drug Interactions

The likelihood of severe discontinuation reactions with CNS and cardiovascular symptoms may be greater when clonidine is combined with beta blocker treatment

Increased depressive and sedative effects when taken with other CNS depressants

TCAs may reduce the hypotensive effects of clonidine

Corneal lesions in rats increased by use of clonidine with amitriptyline

Use of clonidine with agents that affect sinus node function or AV nodal function (e.g., digitalis, calcium channel blockers, beta blockers) may result in bradycardia or AV block

Other Warnings/Precautions

There have been cases of hypertensive encephalopathy, cerebrovascular accidents, and death after abrupt discontinuation

If used with a beta blocker, the beta blocker should be stopped several days before tapering clonidine

In patients who have developed localized contact sensitization to transdermal clonidine, continuing transdermal dosing on other skin areas or substituting with oral clonidine may be associated with the development of a generalized skin rash, urticaria, or angioedema

Use with caution in patients at risk for hypotension, heart block, and bradycardia

Be aware that forgetting to take clonidine or running out of medication can lead to abrupt discontinuation and associated withdrawal reactions and complications

Injection is not recommended for use in managing obstetrical, postpartum, or peri-operative pain

Certain transdermal patches containing even small traces of aluminum or other metals in the adhesive backing can cause skin

burns if worn during MRI, so warn patients taking the transdermal formulation about this possibility and advise them to disclose this information if they need an MRI

Do Not Use

If there is a proven allergy to clonidine

Special Populations Renal Impairment

Use with caution and possibly reduce dose

Use with caution

Hepatic Impairment

Cardiac Impairment

Use with caution in patients with recent myocardial infarction, severe coronary insufficiency, cerebrovascular disease

Elderly

Elderly patients may tolerate a lower initial dose better Elderly patients may be more sensitive to sedative effects

Children and Adolescents

Safety and efficacy not established for children under age 6

Children may be more sensitive to hypertensive effects of withdrawing treatment

âœ1⁄2 Because children commonly have gastrointestinal illnesses that lead to vomiting, they may be more likely to abruptly discontinue clonidine and therefore be more susceptible to hypertensive episodes resulting from abrupt inability to take medication

Children may be more likely to experience CNS depression with overdose and may even exhibit signs of toxicity with 0.1 mg of clonidine

Injection may be used in pediatric cancer patients with severe pain unresponsive to other medications

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women Some animal studies have shown adverse effects

Use in women of childbearing potential requires weighing potential benefits to the mother against potential risks to the fetus

âœ1⁄2 For ADHD patients, clonidine should generally be discontinued before anticipated pregnancies

Breast Feeding

Some drug is found in motherâ€TM s breast milk

No adverse effects have been reported in nursing infants

If irritability or sedation develop in nursing infant, may need to discontinue drug or bottle feed

The Art of Psychopharmacology Potential Advantages

Not a controlled substance

Potential Disadvantages

Not well studied in adults with ADHD Withdrawal reactions

Noncompliant patients

Patients on concomitant CNS medications

Primary Target Symptoms

Concentration Motor hyperactivity

Oppositional and impulsive behavior High blood pressure

Pearls

âœ1⁄2 Clonidine extended-release is approved for ADHD in children

ages 6– 17

As monotherapy or in combination with methylphenidate for ADHD with conduct disorder or oppositional defiant disorder, may improve aggression, oppositional, and conduct disorder symptoms

Clonidine is sometimes used in combination with stimulants to reduce side effects and enhance therapeutic effects on motor hyperactivity

Doses of 0.1 mg in 3 divided doses have been reported to reduce stimulant-induced insomnia as well as impulsivity

âœ1⁄2 Clonidine may also be effective for treatment of tic disorders, including Touretteâ€TM s syndrome

May suppress tics especially in severe Touretteâ€TM s syndrome, and may be even better at reducing explosive violent behaviors in Touretteâ€TM s syndrome

Sedation is often unacceptable in various patients despite improvement in CNS symptoms and leads to discontinuation of treatment, especially for ADHD and Touretteâ€TM s syndrome

Considered an investigational treatment for most other CNS applications

May block the autonomic symptoms in anxiety and panic disorders (e.g., palpitations, sweating) and improve subjective anxiety as well

May be useful in decreasing the autonomic arousal of PTSD

May be useful as an as-needed medication for stage fright or other predictable socially phobic situations

May also be useful when added to SSRIs for reducing arousal and dissociative symptoms in PTSD

May block autonomic symptoms of opioid withdrawal (e.g., palpitations, sweating) especially in inpatients, but muscle aches, irritability, and insomnia may not be well suppressed by clonidine

Often prescribed with naltrexone to suppress symptoms of opioid withdrawal; this requires monitoring of the patient for 8 hours on the first day due to the potential severity of naltrexone-induced withdrawal and the potential blood pressure effects of clonidine

May be useful in decreasing the hypertension, tachycardia, and tremulousness associated with alcohol withdrawal, but not the seizures or delirium tremens in complicated alcohol withdrawal

Clonidine may improve social relationships, affectual responses, and sensory responses in autistic disorder

Clonidine may reduce the incidence of menopausal flushing

Growth hormone response to clonidine may be reduced during menses

Clonidine stimulates growth hormone secretion (no chronic effects have been observed)

Alcohol may reduce the effects of clonidine on growth hormone

âœ1⁄2 Guanfacine is a related centrally active alpha 2 agonist hypotensive agent that has been used for similar CNS applications but has not been as widely investigated or used as clonidine

âœ1⁄2 Guanfacine may be tolerated better than clonidine in some patients (e.g., sedation) or it may work better in some patients for CNS applications than clonidine, but no head-to-head trials

Suggested Reading

American Psychiatric Association . Practice guideline for the treatment of patients with substance use disorders, second edition . Am J Psychiatry 2007 ;164 (4 ):1 – 86 .

Burris JF . The USA experience with the clonidine transdermal therapeutic system . Clin Auton Res 1993 ;3 :391– 6 .

Croxtall JD. Clonidine extended-release: in attention-deficit hyperactivity disorder . Paediatr Drugs 2011 ;13 (5 ):329– 36 .

Gavras I , Manolis AJ , Gayras H . The alpha2-adrenergic receptors in hypertension and heart failure: experimental and clinical studies . J Hypertens 2001 ;19 :2115– 24 .

Neil MJ. Clonidine: clinical pharmacology and therapeutic use in pain management . Curr Clin Pharmacol 2011 ;6 (4 ):280– 7 .

Clorazepate

Azene

Tranxene

see index for additional brand names

Therapeutics Brands

Yes

Generic?

Class

Neuroscience-based Nomenclature: GABA positive allosteric modulator (GABA-PAM)

Benzodiazepine (anxiolytic)

Commonly Prescribed for

(bold for FDA approved)

Anxiety disorder Symptoms of anxiety Acute alcohol withdrawal Partial seizures (adjunct)

Catatonia

How the Drug Works

Binds to benzodiazepine receptors at the GABA-A ligand-gated chloride channel complex

Enhances the inhibitory effects of GABA

Boosts chloride conductance through GABA-regulated channels

Inhibits neuronal activity presumably in amygdala-centered fear circuits to provide therapeutic benefits in anxiety disorders

How Long Until It Works

Some immediate relief with first dosing is common; can take several weeks with daily dosing for maximal therapeutic benefit

If It Works

For short-term symptoms of anxiety – after a few weeks, discontinue use or use on an “ as-needed†basis

For chronic anxiety disorders, the goal of treatment is complete remission of symptoms as well as prevention of future relapses

For chronic anxiety disorders, treatment most often reduces or even eliminates symptoms, but not a cure since symptoms can recur after medicine stopped

For long-term symptoms of anxiety, consider switching to an SSRI or SNRI for long-term maintenance

If long-term maintenance with a benzodiazepine is necessary, continue treatment for 6 months after symptoms resolve, and then taper dose slowly

If symptoms reemerge, consider treatment with an SSRI or SNRI, or consider restarting the benzodiazepine; sometimes benzodiazepines have to be used in combination with SSRIs or SNRIs for best results

If It Doesnâ€TM t Work

Consider switching to another agent or adding an appropriate augmenting agent

Consider psychotherapy, especially cognitive behavioral psychotherapy

Consider presence of concomitant substance abuse

Consider presence of clorazepate abuse

Consider another diagnosis, such as a comorbid medical condition

Best Augmenting Combos for Partial Response or Treatment Resistance

Benzodiazepines are frequently used as augmenting agents for antipsychotics and mood stabilizers in the treatment of psychotic and bipolar disorders

Benzodiazepines are frequently used as augmenting agents for SSRIs and SNRIs in the treatment of anxiety disorders

Not generally rational to combine with other benzodiazepines

Caution if using as an anxiolytic concomitantly with other sedative hypnotics for sleep

Tests

In patients with seizure disorders, concomitant medical illness, and/or those with multiple concomitant long-term medications, periodic liver tests and blood counts may be prudent

Side Effects

How Drug Causes Side Effects

Same mechanism for side effects as for therapeutic effects – namely due to excessive actions at benzodiazepine receptors

Long-term adaptations in benzodiazepine receptors may explain the development of dependence, tolerance, and withdrawal

Side effects are generally immediate, but immediate side effects often disappear in time

Notable Side Effects

Sedation, fatigue, depression

Dizziness, ataxia, slurred speech, weakness Forgetfulness, confusion

Nervousness

Rare hallucinations, mania

Rare hypotension Hypersalivation, dry mouth

Life-Threatening or Dangerous Side Effects

Respiratory depression, especially when taken with CNS depressants in overdose

Rare hepatic dysfunction, renal dysfunction, blood dyscrasias

Weight Gain

Sedation

Many experience and/or can be significant in amount Especially at initiation of treatment or when dose increases Tolerance often develops over time

Reported but not expected

Wait

Wait

Wait

Lower the dose

What to Do About Side Effects

Take largest dose at bedtime to avoid sedative effects during the day Switch to another agent

Administer flumazenil if side effects are severe or life-threatening

Best Augmenting Agents for Side Effects

Many side effects cannot be improved with an augmenting agent

Dosing and Use Usual Dosage Range

Anxiety: 15– 60 mg/day in divided doses

Alcohol withdrawal: 30– 60 mg/day in divided doses

Dosage Forms

Tablet 3.75 mg scored, 7.5 mg scored, 15 mg scored

How to Dose

Anxiety: initial 15 mg/day in divided doses; adjust dose as needed on subsequent days; single-dose tablet may be given once daily at bedtime after patient is stable; maximum generally 90 mg/day

Alcohol withdrawal: initial 30 mg, then 30– 60 mg in divided doses; second day 45– 90 mg in divided doses; third day 22.5– 45 mg in divided doses; fourth day 15– 30 mg in divided doses;

after fourth day decrease dose gradually and discontinue when patient is stable; maximum generally 90 mg/day

Epilepsy: initial 7.5 mg 3 times/day; increase by 7.5 mg weekly; maximum generally 90 mg/day

Dosing Tips

Use lowest possible effective dose for the shortest possible period of time (a benzodiazepine-sparing strategy)

Assess need for continued treatment regularly

Risk of dependence may increase with dose and duration of treatment

For interdose symptoms of anxiety, can either increase dose or maintain same total daily dose but divide into more frequent doses

Can also use an as-needed occasional “ top-up†dose for interdose anxiety

Because anxiety disorders can require higher doses, the risk of dependence may be greater in these patients

Frequency of dosing in practice is often greater than predicted from half-life, as duration of biological activity is often shorter than pharmacokinetic terminal half-life

Overdose

Fatalities can occur; hypotension, tiredness, ataxia, confusion, coma

Long-Term Use

Evidence of efficacy for up to 16 weeks

Risk of dependence, particularly for periods longer than 12 weeks and especially in patients with past or current polysubstance abuse

Habit Forming

Clorazepate is a Schedule IV drug

Patients may develop dependence and/or tolerance with long-term use

How to Stop

Patients with history of seizure may seize upon withdrawal, especially if withdrawal is abrupt

Taper by 7.5 mg every 3 days to reduce chances of withdrawal effects

For difficult-to-taper cases, consider reducing dose much more slowly after reaching 30 mg/day, perhaps by as little as 3.75 mg per week or less

For other patients with severe problems discontinuing a benzodiazepine, dosing may need to be tapered over many months (i.e., reduce dose by 1% every 3 days by crushing tablet and suspending or dissolving in 100 mL of fruit juice and then disposing of 1 mL and drinking the rest; 3– 7 days later, dispose of 2 mL,

and so on). This is both a form of very slow biological tapering and a form of behavioral desensitization

Be sure to differentiate reemergence of symptoms requiring reinstitution of treatment from withdrawal symptoms

Benzodiazepine-dependent anxiety patients and insulin-dependent diabetics are not addicted to their medications. When benzodiazepine-dependent patients stop their medication, disease symptoms can reemerge, disease symptoms can worsen (rebound), and/or withdrawal symptoms can emerge

Pharmacokinetics

Elimination half-life 40– 50 hours

Drug Interactions

Increased depressive effects when taken with other CNS depressants (see Warnings below)

Other Warnings/Precautions

Boxed warning regarding the increased risk of CNS depressant effects when benzodiazepines and opioid medications are used together, including specifically the risk of slowed or difficulty breathing and death

If alternatives to the combined use of benzodiazepines and opioids are not available, clinicians should limit the dosage and duration of

each drug to the minimum possible while still achieving therapeutic efficacy

Patients and their caregivers should be warned to seek medical attention if unusual dizziness, lightheadedness, sedation, slowed or difficulty breathing, or unresponsiveness occur

Dosage changes should be made in collaboration with prescriber

Use with caution in patients with pulmonary disease; rare reports of death after initiation of benzodiazepines in patients with severe pulmonary impairment

History of drug or alcohol abuse often creates greater risk for dependency

Some depressed patients may experience a worsening of suicidal ideation

Some patients may exhibit abnormal thinking or behavioral changes similar to those caused by other CNS depressants (i.e., either depressant actions or disinhibiting actions)

Do Not Use

If patient has angle-closure glaucoma

If there is a proven allergy to clorazepate or any benzodiazepine

Special Populations Renal Impairment

Initial 7.5– 15 mg/day in divided doses or in 1 dose at bedtime

Hepatic Impairment

Initial 7.5– 15 mg/day in divided doses or in 1 dose at bedtime

Cardiac Impairment

Benzodiazepines have been used to treat anxiety associated with acute myocardial infarction

Elderly

Initial 7.5– 15 mg/day in divided doses or in 1 dose at bedtime

Children and Adolescents

Not recommended for use in children under age 9 Recommended initial dose: 7.5 mg twice a day

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Possible increased risk of birth defects when benzodiazepines are taken during pregnancy

Because of the potential risks, clorazepate is not generally recommended as treatment for anxiety during pregnancy, especially during first trimester

Drug should be tapered if discontinued

Infants whose mothers received a benzodiazepine late in pregnancy may experience withdrawal effects

Neonatal flaccidity has been reported in infants whose mothers took a benzodiazepine during pregnancy

Seizures, even mild seizures, may cause harm to the embryo/fetus

Breast Feeding

Some drug is found in motherâ€TM s breast milk Recommended either to discontinue drug or bottle feed

Effects of benzodiazepines on nursing infants have been reported and include feeding difficulties, sedation, and weight loss

The Art of Psychopharmacology

Potential Advantages

Rapid onset of action

Potential Disadvantages

Euphoria may lead to abuse

Abuse especially risky in past or present substance abusers

Primary Target Symptoms

Panic attacks

Anxiety

Incidence of seizures (adjunct)

Pearls

Can be very useful as an adjunct to SSRIs and SNRIs in the treatment of numerous anxiety disorders

Not effective for treating psychosis as a monotherapy, but can be used as an adjunct to antipsychotics

Not effective for treating bipolar disorder as a monotherapy, but can be used as an adjunct to mood stabilizers and antipsychotics

More commonly used than some other benzodiazepines for treating alcohol withdrawal

May both cause depression and treat depression in different patients

When using to treat insomnia, remember that insomnia may be a symptom of some other primary disorder itself, and thus warrant evaluation for comorbid psychiatric and/or medical conditions

Though not systematically studied, benzodiazepines have been used effectively to treat catatonia and are the initial recommended treatment

Suggested Reading

Griffith JL , Murray GB . Clorazepate in the treatment of complex partial seizures with psychic symptomatology . J Nerv Ment Dis 1985 ;173 :185 – 6 .

Kiejna A , Kantorska-Janiec M , Malyszczak K . [The use of chlorazepate dipotassium (Tranxene) in the states of restlessness and agitation] . Psychiatr Pol 1997 ;31 :753 – 60 .

Mielke L , Breinbauer B , Schubert M , et al. [Comparison of the effectiveness of orally administered clorazepate dipotassium and nordiazepam on preoperative anxiety] . Anaesthesiol Reanim 1995 ;20 :144 – 8 .

Rickels K , Schweizer E , Csanalosi I , Case WG , Chung H . Long-term treatment of anxiety and risk of withdrawal. Prospective comparison of clorazepate and buspirone . Arch Gen Psychiatry 1988 ;45 :444 – 50 .

Clozapine

Clozaril

Leponex

Versacloz (oral suspension)

Fazaclo ODT (oral disintegrating tablet) see index for additional brand names

Therapeutics Brands

Yes

Generic?

Class

Neuroscience-based Nomenclature: dopamine, serotonin, norepinephrine receptor antagonist (DSN-RAn)

Atypical antipsychotic (serotonin-dopamine antagonist; second- generation antipsychotic; also a mood stabilizer)

Commonly Prescribed for

(bold for FDA approved)

Treatment-resistant schizophrenia

Reduction in risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder

Treatment-resistant bipolar disorder

Violent aggressive patients with psychosis and other brain disorders not responsive to other treatments

How the Drug Works

Blocks dopamine 2 receptors, reducing positive symptoms of psychosis and stabilizing affective symptoms

Blocks serotonin 2A receptors, causing enhancement of dopamine release in certain brain regions and thus reducing motor side effects and possibly improving cognitive and affective symptoms

Interactions at a myriad of other neurotransmitter receptors may contribute to clozapineâ€TM s efficacy

âœ1⁄2 Specifically, interactions at 5HT2C and 5HT1A receptors may contribute to efficacy for cognitive and affective symptoms in some patients

Mechanism of efficacy for psychotic patients who do not respond to other antipsychotics is unknown but is presumed to be a mechanism other than D2 antagonism

How Long Until It Works

Likelihood of response depends on achieving trough plasma levels of at least 350 ng/mL

Median time to response after achieving therapeutic plasma levels (350 ng/mL) is approximately 3 weeks

If there is no response after 3 weeks of therapeutic plasma levels, recheck plasma levels and continue titration

If It Works

In strictly defined refractory schizophrenia, 50– 60% of patients will respond to clozapine

The response rate to other atypical antipsychotic in the refractory patient population ranges from 0– 9%

Can improve negative symptoms, as well as aggressive, cognitive, and affective symptoms in schizophrenia

Most schizophrenic patients do not have a total remission of symptoms but rather a reduction of symptoms by about a third

Many patients with bipolar disorder and other disorders with psychotic, aggressive, violent, impulsive, and other types of behavioral disturbances may respond to clozapine when other agents have failed

Perhaps 5– 15% of schizophrenic patients can experience an overall improvement of greater than 50– 60%, especially when receiving stable treatment for more than a year

âœ1⁄2 Such patients are considered super-responders or “ awakeners†since they may be well enough to be employed, live independently, and sustain long-term relationships; superresponders

are anecdotally reported more often with clozapine than with some other antipsychotics

Many bipolar patients may experience a reduction of symptoms by half or more

Treatment may not only reduce mania but also prevent recurrences of mania in bipolar disorder

If It Doesnâ€TM t Work

Obtain clozapine plasma levels and continue titration Levels greater than 700 ng/mL are often not well tolerated

No evidence to support dosing that results in plasma levels greater than 1000 ng/mL

Some patients may require treatment with a conventional antipsychotic

Some patients may require augmentation with a conventional antipsychotic or with an atypical antipsychotic (especially risperidone or amisulpride), but these are the most refractory of all psychotic patients and such treatment can be expensive

âœ1⁄2 Consider augmentation with valproate, lamotrigine, or topiramate, but use caution with valproate as it can also cause bone marrow suppression and be sedating

Consider noncompliance and switch to another antipsychotic with fewer side effects or to an antipsychotic that can be given by depot injection

Consider initiating rehabilitation and psychotherapy such as cognitive remediation

Consider presence of concomitant drug abuse

Best Augmenting Combos for Partial Response or Treatment Resistance

Valproic acid (valproate, divalproex, divalproex ER) Lamotrigine

Topiramate

Conventional antipsychotics

Benzodiazepines Lithium

Tests

Evaluate bowel function before starting a patient on clozapine Lower ANC threshold for starting clozapine:

General population: ≥ 1500/ÂμL

Benign ethnic neutropenia (BEN): ≥ 1000/ÂμL Testing for myocarditis:

Myocarditis is rare and only occurs in the first 6 weeks of treatment

Baseline: check troponin I/T, C-reactive protein (CRP)

Weekly troponin I/T and CRP for the first month

Fever is usually benign and self-limited; suspicion of myocarditis should only be raised based on elevated troponin and other features of myocarditis

Clozapine should be stopped if troponin ≥ 2× upper limits of normal or CRP >100 mg/L

Cardiomyopathy is a late complication; consider annual ECG

Before starting an atypical antipsychotic âœ1⁄2 Weigh all patients and track BMI during treatment

Get baseline personal and family history of diabetes, obesity, dyslipidemia, hypertension, and cardiovascular disease

âœ1⁄2 Get waist circumference (at umbilicus), blood pressure, fasting plasma glucose, and fasting lipid profile

Determine if the patient

is overweight (BMI 25.0– 29.9)

is obese (BMI ≥ 30)

has pre-diabetes (fasting plasma glucose 100– 125 mg/dL) has diabetes (fasting plasma glucose ≥ 126 mg/dL)

has hypertension (BP >140/90 mmHg)

has dyslipidemia (increased total cholesterol, LDL cholesterol, and triglycerides; decreased HDL cholesterol)

Treat or refer such patients for treatment, including nutrition and weight management, physical activity counseling, smoking cessation, and medical management

Monitoring after starting an atypical antipsychotic âœ1⁄2 BMI monthly for 3 months, then quarterly

âœ1⁄2 Consider monitoring fasting triglycerides monthly for several months in patients at high risk for metabolic complications and when initiating or switching antipsychotics

âœ1⁄2 Blood pressure, fasting plasma glucose, fasting lipids within 3 months and then annually, but earlier and more frequently for patients with diabetes or who have gained >5% of initial weight

Treat or refer for treatment and consider switching to another atypical antipsychotic for patients who become overweight, obese, pre-diabetic, diabetic, hypertensive, or dyslipidemic while receiving an atypical antipsychotic

âœ1⁄2 Even in patients without known diabetes, be vigilant for the rare but life-threatening onset of diabetic ketoacidosis, which always requires immediate treatment, by monitoring for the rapid onset of polyuria, polydipsia, weight loss, nausea, vomiting, dehydration, rapid respiration, weakness and clouding of sensorium, even coma

Liver function testing, ECG, general physical exam, and assessment of baseline cardiac status before starting treatment

Liver tests may be necessary during treatment in patients who develop nausea, vomiting, or anorexia

Patients should be monitored periodically for the development of abnormal movements of tardive dyskinesia, using neurological exam and the AIMS (Abnormal Involuntary Movement Scale)

Side effects

How Drug Causes Side Effects

Blocking alpha 1 adrenergic receptors can cause dizziness, hypotension, and syncope

Blocking muscarinic cholinergic receptors can cause dry mouth, blurred vision, urinary retention, constipation, and paralytic ileus

By blocking histamine 1 receptors in the brain, it can cause sedation and possibly weight gain

Mechanism of weight gain and increased incidence of diabetes and dyslipidemia with atypical antipsychotics is unknown, and risks vary based on the particular agent

Insulin regulation may be impaired by blocking pancreatic M3 muscarinic receptors

Orthostasis Sialorrhea

Notable Side Effects

Constipation

Sedation

Tachycardia

Weight gain

Dyslipidemia and hyperglycemia Benign fever (~20%)

Tardive dyskinesia (reduced risk compared to other antipsychotics)

Risk of potentially irreversible involuntary dyskinetic movements may increase with cumulative dose and treatment duration

Life-Threatening or Dangerous Side Effects

Severe neutropenia

Myocarditis (only in first 6 weeks of treatment) Paralytic ileus

Seizures (risk increases with dose)

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients taking atypical antipsychotics

Pulmonary embolism (may include deep vein thrombosis or respiratory symptoms)

Dilated cardiomyopathy

Rare neuroleptic malignant syndrome (NMS) may cause hyperpyrexia, muscle rigidity, delirium, and autonomic instability with elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure (more likely when clozapine is used with another agent)

As a class, antipsychotics are associated with an increased risk of death and cerebrovascular events in elderly patients with dementia; not approved for treatment of dementia-related psychosis

Weight Gain

Frequent and can be significant in amount

May increase risk for aspiration events

Should be managed aggressively

Can become a health problem in some

More than for some other antipsychotics, but never say always as not a problem in everyone

Sedation

Frequent and can be significant in amount Some patients may not tolerate it

More than for some other antipsychotics, but never say always as not a problem in everyone

Can wear off over time

Can reemerge as dose increases and then wear off again over time

What to Do About Side Effects

Slow titration to minimize orthostasis and sedation

Minimize use of other alpha 1 antagonists

If orthostasis remains a problem, Florines 0.1– 0.3 mg qd for volume expansion (contraindicated in congestive heart failure)

Take at bedtime to help reduce daytime sedation Sialorrhea management

Atropine 1% drops, 1– 3 drops sublingually at bedtime; can use up to 3 times per day if needed

Ipratropium bromide 0.06% spray, 1– 3 sprays intra-orally at bedtime; can use up to 3 times per day if needed

Avoid use of systemic anticholinergic agents, which increase risk of ileus (benztropine, glycopyrrolate, etc.)

Consider novel use of botulinum toxin injections for severe cases

Constipation management

Avoid psyllium as it may worsen symptoms

All patients should receive docusate 250 mg when starting clozapine

If needed, add Miralax 17 g

If docusate + Miralax are ineffective, add either bisacodyl or sennosides

If constipation still remains a problem, prescribe lubiprostone 8– 24 Î1⁄4 g twice per day

Advise patients to contact a healthcare professional right away if they have difficulty having a bowel movement, do not have a bowel movement at least three times a week or less than their normal frequency, or are unable to pass gas

Weight gain and metabolic effects

Consider prophylactic metformin; start at 500 mg for 1 week, then increase dose

All patients should be referred for lifestyle management and exercise

Tachycardia

Atenolol 12.5 mg qd, increase to keep resting HR <100 bpm

Chest pain during the first 6 weeks Obtain workup for myocarditis Fever

In the absence of elevated troponin and myocarditis symptoms, fever is usually self-limited and there is no need to stop clozapine

Seizures

Valproate for myoclonic or generalized seizures

Avoid phenytoin and carbamazepine because of kinetic interactions

Best Augmenting Agents for Side Effects

Beta blockers, benzodiazepines, or 5HT2A antagonists (e.g., mirtazapine, cyproheptadine) for akathisia

Valbenazine or deutetrabenazine for tardive dyskinesia

Many side effects cannot be improved with an augmenting agent

Dosing and use Usual Dosage Range

Depends on plasma levels; threshold for response is trough plasma level of 350 ng/mL

Dosage Forms

Tablet 12.5 mg, 25 mg scored, 50 mg, 100 mg scored, 200 mg

Orally disintegrating tablet 12.5 mg, 25 mg, 100 mg, 150 mg, 200 mg

Oral suspension 50 mg/mL

How to Dose

Initial 25 mg at night; increase by 25– 50 mg/day every 48– 72 hours as tolerated

Obtain trough plasma level on 200 mg at bedtime

Threshold for response is 350 ng/mL

Levels greater than 700 ng/mL are often not well tolerated

No evidence to support dosing that results in plasma levels greater than 1000 ng/mL

Doses greater than 500 mg per day may require a split dose See also The Art of Switching, after Pearls

Dosing Tips

Because of the monitoring schedule, prescriptions are generally given 1 week at a time for the first 6 months, then every 2 weeks for months 6– 12, and then monthly after 12 months

Plasma half-life suggests twice daily administration, but in practice it may be given once a day at night

Prior to initiating treatment with clozapine, a baseline ANC must be at least 1500/ÂμL for the general population and at least 1000/ÂμL for patients with documented benign ethnic neutropenia (BEN)

Recommended ANC Monitoring for the General Population ANC Level Recommendation ANC Monitoring

Recommended ANC Monitoring for the General Population ANC Level Recommendation ANC Monitoring

Normal range

(at least 1500/ ÂμL)

Initiate treatment

If treatment is interrupted for <30 days, continue monitoring as before

If treatment is interrupted for 30 days or more, monitor as if new patient

First 6 months: weekly

Second 6 months: every 2 weeks After 1 year: every month

Mild neutropenia

(1000– 1499/ÂμL) Continue treatment

Confirm all initial reports of ANC <1500/Î1⁄4 L with a repeat ANC measurement within 24 hours

Monitor 3 times/week until ANC ≥ 1500/ÂμL

Once ANC ≥ 1500/ÂμL, return to patientâ€TM s last “ normal range†ANC monitoring interval

Moderate neutropenia

(500– 999/ÂμL)

Interrupt treatment for suspected clozapine-induced neutropenia

Recommend hematology consultation

Confirm all initial reports of ANC <1500/Î1⁄4 L with a repeat ANC measurement within 24 hours

Monitor ANC daily until ≥ 1000/ÂμL THEN

Monitor 3 times/week until ANC ≥ 1500/ÂμL

Once ANC ≥ 1500/ÂμL, check ANC weekly for 4 weeks, then return to patientâ€TM s last “ normal range†ANC monitoring interval

Severe neutropenia

(<500/ÂμL)

Interrupt treatment for suspected clozapine-induced neutropenia

Recommend hematology consultation

Do not rechallenge unless prescriber determines benefits outweigh risks

Confirm all initial reports of ANC <1500/Î1⁄4 L with a repeat ANC measurement within 24 hours

Monitor ANC daily until ≥ 1000/ÂμL THEN

Monitor 3 times/week until ANC ≥ 1500/ÂμL

If patient is rechallenged, resume treatment as a new patient under

“ normal range†monitoring once ANC ≥ 1500/ÂμL

Recommended ANC Monitoring for BEN Patients ANC Level Recommendation ANC Monitoring

ANC Level

Normal BEN range

(established

ANC baseline ≥ 1000/ ÂμL)

Recommendation

Obtain at

least 2 baseline ANC levels before initiating treatment

If treatment

is interrupted for <30 days, continue monitoring as before

If treatment

is interrupted for 30 days or more, monitor as if new patient

Continue treatment

ANC Monitoring

First 6 months: weekly

Second 6

months: every 2 weeks

After 1 year: every month

Recommended ANC Monitoring for BEN Patients

BEN neutropenia

Confirm all

initial reports of ANC <1500/Î1⁄4

(500– 999/ Recommend

Recommended ANC Monitoring for BEN Patients

ÂμL)

ANC Level

hematology Recocmomnseunltdaatitoinon

ANC Monitoring

L with a repeat ANC measurement within 24 hours

Monitor 3

times/week until ANC ≥ 1000/ÂμL or ≥ patientâ€TM s known baseline

Once ANC â‰

¥ 1000/ÂμL or above patientâ€TM s known baseline, check ANC weekly for 4 weeks, then return to patientâ€TM s last “ normal BEN range†ANC monitoring interval

BEN severe Interrupt

Recommended ANC Monitoring for BEN Patients

neutropenia

treatment Recofmormendation

suspected clozapine- induced neutropenia

Recommend

hematology consultation

Do not

rechallenge unless prescriber determines benefits outweigh risks

ANC Level

ANC Monitoring

Confirm all

initial reports of ANC <1500/Î1⁄4 L with a repeat ANC measurement within 24 hours

Monitor ANC

daily until ≥ 500/ÂμL THEN

Monitor 3

times/week until ANC ≥ patientâ€TM s baseline

If patient is

rechallenged, resume treatment as a new patient under “ normal BEN range†monitoring once ANC ≥ 1000/ÂμL or at

(<500/ÂμL)

Recommended ANC Monitoring for BEN Patients ANC Level Recommendation ANC Monitoring

patientâ€TM s known baseline

If treatment is discontinued for more than 2 days, reinitiate with 12.5 mg once or twice daily; if that dose is tolerated, the dose may be increased to the previously therapeutic dose more quickly than recommended for initial treatment

If abrupt discontinuation of clozapine is necessary, the patient must be covered for cholinergic rebound; those with higher clozapine plasma levels may need extremely high doses of anticholinergic medications to prevent delirium and other rebound symptoms

Slow off-titration is preferred if possible to avoid cholinergic rebound and rebound psychosis

Rather than raise the dose above normal dosing in acutely agitated patients requiring acute antipsychotic actions, consider short-term (one dose or more) augmentation with a benzodiazepine or another antipsychotic, especially intramuscularly

Rather than raise the dose above normal dosing in partial responders, consider augmentation with a mood-stabilizing anticonvulsant, such as valproate, topiramate, or lamotrigine

For treatment resistance, consider obtaining plasma drug levels to guide dosing above recommended levels

Overdose

Sometimes lethal; changes in heart rhythm, excess salivation, respiratory depression, altered state of consciousness

Long-Term Use

Treatment to reduce risk of suicidal behavior should be continued for at least 2 years

Medication of choice for treatment-refractory schizophrenia

No

Habit Forming

How to Stop

See The Art of Switching section of individual agents for how to stop clozapine, generally over at least 4 weeks

See Tables for guidance on stopping due to neutropenia

âœ1⁄2 Rapid discontinuation may lead to rebound psychosis and worsening of symptoms

Pharmacokinetics

Half-life 5– 16 hours

Metabolized primarily by CYP450 1A2 and to a lesser extent by CYP450 2D6 and 3A4

Drug Interactions

Use clozapine plasma levels to guide treatment due to propensity for drug interactions

In the presence of a strong CYP450 1A2 inhibitor (e.g., fluvoxamine, ciprofloxacin): use 1/3 the dose of clozapine

In the presence of a strong CYP450 1A2 inducer (e.g., cigarette smoke), clozapine plasma levels are decreased

May need to decrease clozapine dose by up to 50% during periods of extended smoking cessation (>1 week)

Strong CYP450 2D6 inhibitors (e.g., bupropion, duloxetine, paroxetine, fluoxetine) can raise clozapine levels; dose adjustment may be necessary

Strong CYP450 3A4 inhibitors (e.g., ketoconazole) can raise clozapine levels; dose adjustment may be necessary

Clozapine may enhance effects of antihypertensive drugs May antagonize levodopa, dopamine agonists

Other Warnings/Precautions

Use with caution in patients on other anticholinergic agents (benztropine, trihexyphenidyl, olanzapine, quetiapine, chlorpromazine, oxybutynin, and other antimuscarinics)

Constipation caused by clozapine can uncommonly lead to serious bowel complications, so advise patients of the risk and the need to stay hydrated, question patients about their bowel movements throughout treatment, and advise them to contact a healthcare

professional right away if they have difficulty having a bowel movement, do not have a bowel movement at least three times a week or less than their normal frequency, or are unable to pass gas

Should not be used in conjunction with agents that are known to cause neutropenia

Myocarditis is rare and only occurs in the first 6 weeks of treatment Cardiomyopathy is a late complication (consider annual ECG)

Use with caution in patients with glaucoma

Use with caution in patients with enlarged prostate

Use with caution in patients with conditions that predispose to hypotension (dehydration, overheating)

Atypical antipsychotics have the potential for cognitive and motor impairment, especially related to sedation

Atypical antipsychotics can cause body temperature dysregulation; use caution in patients who may experience conditions that increase body temperature (e.g., strenuous exercise, saunas, extreme heat, dehydration, or concomitant anticholinergic medication)

Dysphagia has been associated with antipsychotic use, and clozapine should be used cautiously in patients at risk for aspiration pneumonia

Antipsychotics may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls; for patients with diseases, conditions, or medications that could exacerbate these

effects, complete fall risk assessments when initiating antipsychotic treatment, and recurrently for patients on long-term antipsychotic therapy

As with any antipsychotic, use with caution in patients with history of seizures

Do Not Use

In patients with myeloproliferative disorder In patients with uncontrolled epilepsy

In patients with paralytic ileus

In patients with CNS depression

If there is a proven allergy to clozapine

Special populations Renal Impairment

Should be used with caution

Hepatic Impairment

Should be used with caution

Cardiac Impairment

Use in patients with cardiac impairment has not been studied, so use with caution because of risk of orthostatic hypotension

Use with caution if patient is taking concomitant antihypertensive or alpha 1 antagonist

Elderly

Some patients may tolerate lower doses better

Although atypical antipsychotics are commonly used for behavioral disturbances in dementia, no agent has been approved for treatment of elderly patients with behavioral symptoms of dementia such as agitation

Elderly patients with dementia-related psychosis treated with atypical antipsychotics are at an increased risk of death compared to placebo, and also have an increased risk of cerebrovascular events

Consider pimavanserin for dementia-related psychosis or Parkinson’s disease psychosis instead of an atypical antipsychotic

Children and Adolescents

Safety and efficacy have not been established

Preliminary research has suggested efficacy in early-onset treatment-resistant schizophrenia

Children and adolescents using clozapine may need to be monitored more often than adults and may tolerate lower doses better

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women

There is a risk of abnormal muscle movements and withdrawal symptoms in newborns whose mothers took an antipsychotic during the third trimester; symptoms may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty feeding

Animal studies have not shown adverse effects

Psychotic symptoms may worsen during pregnancy and some form of treatment may be necessary

Clozapine should be used only when the potential benefits outweigh potential risks to the fetus

National Pregnancy Registry for Atypical Antipsychotics: 1-866- 961-2388, https://womensmentalhealth.org/research/pregnancyregistry/atypical antipsychotic

Breast Feeding

Unknown if clozapine is secreted in human breast milk, but all psychotropics are assumed to be secreted in breast milk

âœ1⁄2 Recommended either to discontinue drug or bottle feed Infants of women who choose to breast feed while on clozapine

should be monitored for possible adverse effects

The art of psychopharmacology Potential Advantages

âœ1⁄2 Treatment-resistant schizophrenia âœ1⁄2 Violent, aggressive patients

âœ1⁄2 Patients with tardive dyskinesia âœ1⁄2 Patients with suicidal behavior

Potential Disadvantages

âœ1⁄2 Patients with diabetes, obesity, and/or dyslipidemia

Sialorrhea, sedation, and orthostatis may be intolerable for some

Primary Target Symptoms

Positive symptoms of psychosis Negative symptoms of psychosis Cognitive symptoms

Unstable mood (both depression and mania) Suicidal behavior

Aggressive symptoms

Pearls

âœ1⁄2 Clozapine is the gold standard treatment for refractory

schizophrenia

âœ1⁄2 Clozapine is not used first-line due to side effects and monitoring burden

âœ1⁄2 However, some studies have shown that clozapine was associated with the lowest risk of mortality among the antipsychotics, causing the study authors to question if its use should continue to be restricted to resistant cases

May reduce violence and aggression in difficult cases, including forensic cases

âœ1⁄2 Reduces suicide in schizophrenia

May reduce substance abuse

May improve tardive dyskinesia

Little or no prolactin elevation, motor side effects, or tardive dyskinesia

Clinical improvements often continue slowly over several years

Cigarette smoke can decrease clozapine levels and patients may be at risk for relapse if they begin or increase smoking

More weight gain than many other antipsychotics – does not mean every patient gains weight

Patients can have much better responses to clozapine than to any other agent, but not always

For treatment-resistant patients, especially those with impulsivity, aggression, violence, and self-harm, long-term polypharmacy with 2 atypical antipsychotics or with 1 atypical antipsychotic and 1 conventional antipsychotic may be useful or even necessary while closely monitoring

In such cases, it may be beneficial to combine 1 depot antipsychotic with 1 oral antipsychotic

To treat constipation and reduce risk of paralytic ileus and bowel obstruction, taper off other anticholinergic agents and start all patients routinely on docusate

The US FDA has changed the requirements for monitoring, prescribing, dispensing, and receiving clozapine in order to address concerns related to neutropenia; in addition to updating the prescribing information for clozapine, the FDA has approved a new, shared Risk Evaluation and Mitigation Strategy (REMS)

The Clozapine REMS program replaces the six existing clozapine registries, which are maintained by individual clozapine manufacturers. Prescribers, pharmacies, and patients will now be required to enroll in a single centralized program; patients already treated with clozapine will be automatically transferred. In order to prescribe and dispense clozapine, prescribers and pharmacies will be

required to be certified in the Clozapine REMS program. Visit the Clozapine REMS program homepage for more information.

The Art of Switching

Switching from Oral Antipsychotics to Clozapine

With amisulpride, aripiprazole, brexpiprazole, cariprazine, lumateperone, and paliperidone ER, immediate stop is possible; begin clozapine at middle dose

With risperidone, ziprasidone, iloperidone, and lurasidone, begin clozapine gradually, titrating over at least 2 weeks to allow patients to become tolerant to the sedating effect

* Benzodiazepine or anticholinergic medication can be administered during cross-titration to help alleviate side effects such as insomnia, agitation, and/or psychosis. However, use with caution in combination with clozapine as this can increase the risk of circulatory collapse

Suggested Reading

Huhn M , Nikolakopoulou A , Schneider-Thoma J , et al. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis . Lancet 2019 ;394 :939 -51 .

Masuda T , Misawa F , Takase M , Kane JM , Correll CU . Association with hospitalization and all-cause discontinuation among patients with schizophrenia on clozapine vs other oral second-generation antipsychotics: a systematic review and meta-analysis of cohort studies . JAMA Psychiatry 2019 ;76 :1052 – 62 . doi: 10.1001/jamapsychiatry.2019.1702 .

Meyer JM , Stahl SM . Stahl’s handbooks: the clozapine handbook . New York, NY : Cambridge University Press ; 2019 .

Ronaldson KJ , Fitzgerald PD , McNeil JJ . Clozapine-induced myocarditis, a widely overlooked adverse reaction . Acta Psychiatr Scand 2015 ;132 :231– 40 .

Rosenheck RA , Davis S , Covell N , et al. Does switching to a new antipsychotic improve outcomes? Data from the CATIE Trial . Schizophr Res 2009 ;170 (1 ):22 – 9.

Schulte P . What is an adequate trial with clozapine?: therapeutic drug monitoring and time to response in treatment-refractory schizophrenia . Clin Pharmacokinet 2003 ;42 :607– 18 .

Tiihonen J , Lonnqvist J , Wahlbeck K , et al. 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11

study) . Lancet 2009 ; 374 (9690 ):620 – 7 .

Cyamemazine

Tercian

Therapeutics Brands

see index for additional brand names

Not in USA

Generic?

Class

Conventional antipsychotic (neuroleptic, phenothiazine, dopamine 2 antagonist, serotonin dopamine antagonist)

Commonly Prescribed for

(bold for FDA approved)

Schizophrenia

âœ1⁄2 Anxiety associated with psychosis (short-term)

Anxiety associated with nonpsychotic disorders, including mood disorders and personality disorders (short-term)

Severe depression Bipolar disorder

Other psychotic disorders

Acute agitation/aggression (injection) Benzodiazepine withdrawal

How the Drug Works

Blocks dopamine 2 receptors, reducing positive symptoms of psychosis

âœ1⁄2 Although classified as a conventional antipsychotic, cyamemazine is a potent serotonin 2A antagonist

Affinity at a myriad of other neurotransmitter receptors may contribute to cyamemazineâ€TM s efficacy

âœ1⁄2 Specifically, antagonist actions at 5HT2C receptors may contribute to notable anxiolytic effects in many patients

5HT2C antagonist actions may also contribute to antidepressant actions in severe depression and to improvement of cognitive and negative symptoms of schizophrenia in some patients

How Long Until It Works

Psychotic symptoms can improve with high doses within 1 week, but it may take several weeks for full effect on behavior

Anxiolytic actions can improve with low doses within 1 week, but it may take several days to weeks for full effect on behavior

If It Works

High doses most often reduce positive symptoms in schizophrenia but do not eliminate them

Low doses most often reduce anxiety symptoms in psychotic and nonpsychotic disorders

Most schizophrenia patients do not have a total remission of symptoms but rather a reduction of symptoms by about a third

Continue treatment in schizophrenia until reaching a plateau of improvement

After reaching a satisfactory plateau, continue treatment for at least a year, after first episode of psychosis in schizophrenia

For second and subsequent episodes of psychosis in schizophrenia, treatment may need to be indefinite

For symptomatic treatment of anxiety in psychotic and nonpsychotic disorders, treatment may also need to be indefinite while monitoring the risks versus the benefits of long-term treatment

Reduces symptoms of acute psychotic mania but not proven as a mood stabilizer or as an effective maintenance treatment in bipolar disorder

After reducing acute psychotic symptoms in mania, consider switching to a mood stabilizer and/or an atypical antipsychotic for long-term mood stabilization and maintenance

If It Doesnâ€TM t Work

For treatment of psychotic symptoms, consider trying one of the first-line atypical antipsychotics (risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone, amisulpiride)

Consider trying another conventional antipsychotic

If 2 or more antipsychotic monotherapies do not work, consider clozapine

For treatment of anxiety symptoms, consider adding a benzodiazepine or switching to a benzodiazepine

Best Augmenting Combos for Partial Response or Treatment Resistance

Generally, best to switch to another agent

Augmentation of conventional antipsychotics has not been systematically studied

Addition of a mood-stabilizing anticonvulsant such as valproate, carbamazepine, or lamotrigine may be helpful in both schizophrenia and bipolar mania

Augmentation with lithium in bipolar mania may be helpful Addition of a benzodiazepine, especially for short-term agitation Addition of antidepressants for severe depression

Tests

âœ1⁄2 Since conventional antipsychotics are frequently associated with weight gain, before starting treatment, weigh all patients and determine if the patient is already overweight (BMI 25.0– 29.9) or obese BMI ≥ 30)

Before giving a drug that can cause weight gain to an overweight or obese patient, consider determining whether the patient already has pre-diabetes (fasting glucose 100– 125 mg/dL), diabetes (fasting plasma glucose ≥ 126 mg/dL), or dyslipidemia (increased total cholesterol, LDL cholesterol, and triglycerides; decreased HDL cholesterol), and treat or refer such patients for treatment, including nutrition and weight management, physical activity counseling, smoking cessation, and medical management

âœ1⁄2 Monitor weight and BMI during treatment

âœ1⁄2 Consider monitoring fasting triglycerides monthly for several months in patients at high risk for metabolic complications and when initiating or switching antipsychotics

âœ1⁄2 While giving a drug to a patient who has gained >5% of initial weight, consider evaluating for the presence of pre-diabetes, diabetes, or dyslipidemia, or consider switching to a different antipsychotic

Should check blood pressure in the elderly before starting and for the first few weeks of treatment

Monitoring elevated prolactin levels of dubious clinical benefit

Patients with low white blood cell count (WBC) or history of drug- induced leukopenia/neutropenia should have complete blood count

(CBC) monitored frequently during the first few months and cyamemazine should be discontinued at the first sign of decline of WBC in the absence of other causative factors

Side effects

How Drug Causes Side Effects

By blocking dopamine 2 receptors in the striatum, it can cause motor side effects at antipsychotic (high) doses

Much lower propensity to cause motor side effects at low doses used to treat anxiety

By blocking dopamine 2 receptors in the pituitary, it can cause elevations in prolactin, but unlike other conventional antipsychotics, prolactin elevations at low doses of cyamemazine are uncommon or transient

By blocking dopamine 2 receptors excessively in the mesocortical and mesolimbic dopamine pathways, especially at high doses, it can cause worsening of negative and cognitive symptoms (neuroleptic- induced deficit syndrome)

Anticholinergic actions, especially at high doses, may cause sedation, blurred vision, constipation, dry mouth

Antihistamine actions may contribute to anxiolytic actions at low doses and to sedation and weight gain at high doses

By blocking alpha 1 adrenergic receptors, cyamemazine can cause dizziness, sedation, and hypotension especially at high doses

Mechanism of weight gain and any possible increased incidence of diabetes and dyslipidemia with conventional antipsychotics is unknown

Notable Side Effects

âœ1⁄2 Neuroleptic-induced deficit syndrome (unusual at low doses)

Akathisia

Drug-induced parkinsonism, tardive dyskinesia (unusual at low doses)

Galactorrhea, amenorrhea (unusual at low doses) Hypotension, tachycardia (unusual at low doses)

Dry mouth, constipation, vision disturbance, urinary retention Sedation

Decreased sweating

Weight gain (may be unusual at low doses)

Sexual dysfunction

Metabolic effects, glucose tolerance

Life-Threatening or Dangerous Side Effects

Rare neuroleptic malignant syndrome

Rare seizures

Rare jaundice, agranulocytosis

Increased risk of death and cerebrovascular events in elderly patients with dementia-related psychosis

Weight Gain

Reported but not expected especially at low doses

Sedation

Many experience and/or can be significant in amount, especially at high doses

Sedation is usually dose-dependent and may not be experienced as sedation but as anxiolytic actions on anxiety and aggression at low doses where cyamemazine may function as an atypical antipsychotic (e.g., <300 mg/day; especially 25– 100 mg/day)

What to Do About Side Effects

Wait

Wait

Wait

For motor symptoms, add an anticholinergic agent

Reduce the dose

For sedation, give at night

Switch to an atypical antipsychotic

Weight loss, exercise programs, and medical management for high BMIs, diabetes, dyslipidemia

Best Augmenting Agents for Side Effects

Benztropine or trihexyphenidyl for motor side effects Benzodiazepines may be helpful for akathisia

Many side effects cannot be improved with an augmenting agent

Dosing and use Usual Dosage Range

50– 300 mg at bedtime for treatment of psychosis 25– 100 mg for anxiety; duration of treatment 4 weeks Children (ages 6 and older): 1– 4 mg/kg per day Injection: 25– 100 mg/day

Tablet 25 mg, 100 mg Oral solution 40 mg/mL

Dosage Forms

Injection 50 mg/5 mL

How to Dose

Psychosis: usual maintenance dose 50– 300 mg at bedtime; maximum dose 600 mg/day divided into 2 or 3 doses; after 2 weeks consider reducing to lowest effective dose

Anxiety (adults): usual dose 25– 100 mg/day; reduce dose if unacceptable sedation; maximum duration of treatment 4 weeks

Anxiety (children): usual dose 1– 4 mg/kg per day

Dosing Tips

Has conventional antipsychotic properties at originally recommended high doses (300– 600 mg/day)

âœ1⁄2 Binding studies, PET studies, and clinical observations suggest that cyamemazine may be “ atypical†with low motor side effects or prolactin elevations at low doses (below 300 mg/day)

âœ1⁄2 Clinical evidence suggests substantial anxiolytic benefits at 25– 100 mg/day in many patients

âœ1⁄2 Clinical evidence suggests low risk of drug-induced parkinsonism, little prolactin elevation yet demonstrable anxiolytic, anti-aggression, and antidepressant actions at doses below 300 mg/day

Robust antipsychotic actions on positive symptoms may require dosing above 300 mg/day

Low doses up to 100 mg/day may be used to augment partial responders to other conventional or atypical antipsychotics, especially for anxiolytic actions

Treatment should be suspended if absolute neutrophil count falls below 1000/mm3

Overdose

Drug-induced parkinsonism, sedation, hypotension, coma, respiratory depression

Long-Term Use

Some side effects may be irreversible (e.g., tardive dyskinesia)

No

Habit Forming

How to Stop

Slow down-titration (over 6– 8 weeks), especially when simultaneously beginning a new antipsychotic while switching (i.e., cross-titration)

Rapid oral discontinuation of high doses of phenothiazines in psychotic patients may lead to rebound psychosis and worsening of symptoms

If antiparkinsonian agents are being used, they should generally be continued for a few weeks after high-dose cyamemazine is discontinued

Half-life 10 hours

Pharmacokinetics

Drug Interactions

May decrease the effects of levodopa; contraindicated for use with dopamine agonists other than levodopa

May increase the effects of antihypertensive drugs except for guanethidine, whose antihypertensive actions phenothiazines may antagonize

May enhance QTc prolongation of other drugs capable of prolonging QTc interval

Additive effects may occur if used with CNS depressants

Anticholinergic effects may occur if used with atropine or related compounds

Some patients taking a neuroleptic and lithium have developed an encephalopathic syndrome similar to neuroleptic malignant syndrome

Epinephrine may lower blood pressure; diuretics and alcohol may increase risk of hypotension when administered with a phenothiazine

Other Warnings/Precautions

If signs of neuroleptic malignant syndrome develop, treatment should be immediately discontinued

Use cautiously in patients with respiratory disorders

Use cautiously in patients with alcohol withdrawal or convulsive disorders because phenothiazines can lower seizure threshold

Do not use epinephrine in event of overdose as interaction with some pressor agents may lower blood pressure

Avoid undue exposure to sunlight Avoid extreme heat exposure

Use with caution in patients with respiratory disorders, glaucoma, or urinary retention

Antiemetic effects of phenothiazines may mask signs of other disorders or overdose; suppression of cough reflex may cause asphyxia

Observe for signs of ocular toxicity (corneal and lenticular deposits) as for other phenothiazines

Use only with caution or at low doses, if at all, in Parkinsonâ€TM s disease or Lewy body dementia

Because cyamemazine may dose-dependently prolong QTc interval, use with caution in patients who have bradycardia or who are taking drugs that can induce bradycardia (e.g., beta blockers, calcium channel blockers, clonidine, digitalis)

Because cyamemazine may dose-dependently prolong QTc interval, use with caution in patients who have hyperkalemia and/or hypomagnesemia or who are taking drugs that can induce hypokalemia and/or magnesemia (e.g., diuretics, stimulant laxatives, intravenous amphotericin B, glucocorticoids, tetracosaclides)

Cyamemazine can increase the QTc interval, potentially causing torsade de pointes-type arrhythmia or sudden death

Do Not Use

If there is a history of QTc prolongation or cardiac arrhythmia, recent acute myocardial infarction, uncompensated heart failure

âœ1⁄2 If QTc interval greater than 450 msec or if taking an agent capable of prolonging the QTc interval

If patient is taking sultopride

If patient is in a comatose state or has CNS depression

If there is the presence of blood dyscrasias, bone marrow depression, or liver disease

If there is subcortical brain damage

If patient has sensitivity to or intolerance of gluten (tablets contain gluten)

If patient has congenital galactosemy, does not adequately absorb glucose/galactose, or has lactase deficit (tablets contain lactose)

If patient is intolerant of fructose, does not adequately absorb glucose/galactose, or has sugar-isomaltase deficit (oral solution only; oral solution contains saccharose)

If there is a proven allergy to cyamemazine

If there is a known sensitivity to any phenothiazine

Use with caution

Use with caution

Special populations Renal Impairment

Hepatic Impairment

Cardiac Impairment

Cardiovacular toxicity can occur, especially orthostatic hypotension

Elderly

Elderly patients may be more susceptible to adverse effects

Lower doses should be used and patient should be monitored closely Generally, doses above 100 mg/day are not recommended

Elderly patients with dementia-related psychosis treated with antipsychotics are at an increased risk of death compared to placebo,

and also have an increased risk of cerebrovascular events

Children and Adolescents

Sometimes used for severe behavioral disturbances in children ages 6 and older

Oral solution is preferable to the other formulations

Pregnancy

There is a risk of abnormal muscle movements and withdrawal symptoms in newborns whose mothers took an antipsychotic during the third trimester; symptoms may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty feeding

Reports of drug-induced parkinsonism, jaundice, hyperreflexia, hyporeflexia in infants whose mothers took a phenothiazine during pregnancy

Phenothiazines should only be used during pregnancy if clearly needed

Psychotic symptoms may worsen during pregnancy and some form of treatment may be necessary

Atypical antipsychotics may be preferable to phenothiazines or anticonvulsant mood stabilizers if treatment is required during pregnancy

Breast Feeding

Unknown if cyamemazine is secreted in human breast milk, but all psychotropics are assumed to be secreted in breast milk

âœ1⁄2 Recommended either to discontinue drug or bottle feed

The art of psychopharmacology Potential Advantages

For anxiety in patients with psychotic illnesses For anxiety in patients with nonpsychotic illnesses For severe depression

Potential Disadvantages

Patients with tardive dyskinesia Children

Elderly

Primary Target Symptoms

Anxiety associated with psychosis Anxiety

Aggression

Agitation

Positive symptoms of psychosis Severe depression

Pearls

One of the most frequently prescribed antipsychotics in France, especially as a low-dose anxiolytic for psychotic patients

âœ1⁄2 Appears to have unique anxiolytic actions at low doses without rebound anxiety following discontinuation

âœ1⁄2 Low doses rarely associated with motor side effects or with prolactin elevation

âœ1⁄2 Recently discovered to be a serotonin dopamine antagonist with more potent binding of 5HT2A and 5HT2C receptors than D2 receptors (binding studies and PET scans)

Low doses appear to saturate 5HT2A receptors in frontal cortex while not saturating D2 receptors in the striatum, accounting for apparent atypical antipsychotic and anxiolytic properties at low doses

May be useful second-line therapy in facilitating benzodiazepine withdrawal for those patients in whom substitution with another benzodiazepine is not effective or is not appropriate

Suggested Reading

Hameg A , Bayle F , Nuss P , Dupuis P , et al. Affinity of cyamemazine, an anxiolytic antipsychotic drug, for human recombinant dopamine vs. serotonin receptor subtypes . Biochem Pharmacol 2003 ;65 (3 ):435– 40 .

Hode Y , Reimold M , Demazieres A , et al. A positron emission tomography (PET) study of cerebral dopamine D2 and serotonine 5-HT2A receptor occupancy in patients treated with cyamemazine (Tercian) . Psychopharmacology (Berl) 2005 ;180 (2 ):377– 84 .

Lemoine P , Kermadi I , Garcia-Acosta S , Garay RP , Dib M . Double- blind, comparative study of cyamemazine vs. bromazepam in the benzodiazepine withdrawal syndrome . Prog Neuropsychopharmacol Biol Psychiatry 2006 ;30 (1 ):131 – 7 .

Desipramine

Norpramin

Therapeutics Brands

Yes

Generic?

Class

see index for additional brand names

Neuroscience-based Nomenclature: norepinephrine reuptake inhibitor (N-RI)

Tricyclic antidepressant (TCA)

Predominantly a norepinephrine/noradrenaline reuptake inhibitor

Commonly Prescribed for

(bold for FDA approved)

Depression

Anxiety

Insomnia

Neuropathic pain/chronic pain

Treatment-resistant depression

How the Drug Works

Boosts neurotransmitter norepinephrine/noradrenaline

Blocks norepinephrine reuptake pump (norepinephrine transporter), presumably increasing noradrenergic neurotransmission

Since dopamine is inactivated by norepinephrine reuptake in frontal cortex, which largely lacks dopamine transporters, desipramine can thus increase dopamine neurotransmission in this part of the brain

A more potent inhibitor of norepinephrine reuptake pump than serotonin reuptake pump (serotonin transporter)

At high doses may also boost neurotransmitter serotonin and presumably increase serotonergic neurotransmission

How Long Until It Works

May have immediate effects in treating insomnia or anxiety

Onset of therapeutic actions usually not immediate, but often delayed 2– 4 weeks

If it is not working within 6– 8 weeks for depression, it may require a dosage increase or it may not work at all

May continue to work for many years to prevent relapse of symptoms

If It Works

The goal of treatment of depression is complete remission of current symptoms as well as prevention of future relapses

The goal of treatment of chronic neuropathic pain is to reduce symptoms as much as possible, especially in combination with other treatments

Treatment of depression most often reduces or even eliminates symptoms, but not a cure since symptoms can recur after medicine stopped

Treatment of chronic neuropathic pain may reduce symptoms, but rarely eliminates them completely, and is not a cure since symptoms can recur after medicine is stopped

Continue treatment of depression until all symptoms are gone (remission)

Once symptoms of depression are gone, continue treating for 1 year for the first episode of depression

For second and subsequent episodes of depression, treatment may need to be indefinite

Use in anxiety disorders and chronic pain may also need to be indefinite, but long-term treatment is not well studied in these conditions

If It Doesnâ€TM t Work

Many depressed patients have only a partial response where some symptoms are improved but others persist (especially insomnia,

fatigue, and problems concentrating)

Other depressed patients may be nonresponders, sometimes called treatment-resistant or treatment-refractory

Consider increasing dose, switching to another agent, or adding an appropriate augmenting agent

Consider psychotherapy

Consider evaluation for another diagnosis or for a comorbid condition (e.g., medical illness, substance abuse, etc.)

Some patients may experience apparent lack of consistent efficacy due to activation of latent or underlying bipolar disorder, and require antidepressant discontinuation and a switch to a mood stabilizer

Best Augmenting Combos for Partial Response or Treatment Resistance

Lithium, buspirone, thyroid hormone (for depression)

Gabapentin, tiagabine, other anticonvulsants, even opiates if done by experts while monitoring carefully in difficult cases (for chronic pain)

Tests

Baseline ECG is recommended for patients over age 50 âœ1⁄2 Monitoring of plasma drug levels is available

âœ1⁄2 Since tricyclic and tetracyclic antidepressants are frequently associated with weight gain, before starting treatment, weigh all patients and determine if the patient is already overweight (BMI 25.0– 29.9) or obese (BMI ≥ 30)

Before giving a drug that can cause weight gain to an overweight or obese patient, consider determining whether the patient already has pre-diabetes (fasting plasma glucose 100– 125 mg/dL), diabetes (fasting plasma glucose ≥ 126 mg/dL), or dyslipidemia (increased total cholesterol, LDL cholesterol, and triglycerides; decreased HDL cholesterol), and treat or refer such patients for treatment, including nutrition and weight management, physical activity counseling, smoking cessation, and medical management

âœ1⁄2 Monitor weight and BMI during treatment

âœ1⁄2 While giving a drug to a patient who has gained >5% of initial weight, consider evaluating for the presence of pre-diabetes, diabetes, or dyslipidemia, or consider switching to a different antidepressant

ECGs may be useful for selected patients (e.g., those with personal or family history of QTc prolongation; cardiac arrhythmia; recent myocardial infarction; uncompensated heart failure; or taking agents that prolong QTc interval such as pimozide, thioridazine, selected antiarrhythmics, moxifloxacin, sparfloxacin, etc.)

Patients at risk for electrolyte disturbances (e.g., patients on diuretic therapy) should have baseline and periodic serum potassium and magnesium measurements

Side effects

How Drug Causes Side Effects

âœ1⁄2 Anticholinergic activity for desipramine may be somewhat less than for some other TCAs, yet can still explain the presence, if lower incidence, of sedative effects, dry mouth, constipation, and blurred vision

Sedative effects and weight gain may be due to antihistamine properties

Blockade of alpha adrenergic 1 receptors may explain dizziness, sedation, and hypotension

Cardiac arrhythmias and seizures, especially in overdose, may be caused by blockade of ion channels

Notable Side Effects

Blurred vision, constipation, urinary retention, increased appetite, dry mouth, nausea, diarrhea, heartburn, unusual taste in mouth, weight gain

Fatigue, weakness, dizziness, sedation, headache, anxiety, nervousness, restlessness

Sexual dysfunction, sweating

Life-Threatening or Dangerous Side Effects

Paralytic ileus, hyperthermia (TCAs + anticholinergic agents)

Lowered seizure threshold and rare seizures

Orthostatic hypotension, sudden death, arrhythmias, tachycardia QTc prolongation

Hepatic failure, drug-induced parkinsonism

Increased intraocular pressure

Blood dyscrasias

Rare induction of mania

Rare activation of suicidal ideation and behavior (suicidality) (short- term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo beyond age 24)

Weight Gain

Many experience and/or can be significant in amount Can increase appetite and carbohydrate craving

Sedation

Many experience and/or can be significant in amount Tolerance to sedative effects may develop with long-term use

Wait

What to Do About Side Effects

Wait

Wait

Lower the dose

Switch to an SSRI or newer antidepressant

Best Augmenting Agents for Side Effects

Many side effects cannot be improved with an augmenting agent

Dosing and use Usual Dosage Range

100– 200 mg/day (for depression) 50– 150 mg/day (for chronic pain)

Dosage Forms

Tablet 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg

How to Dose

Initial 25 mg/day at bedtime; increase by 25 mg every 3– 7 days

75 mg/day once daily or in divided doses; gradually increase dose to achieve desired therapeutic effect; maximum dose 300 mg/day

Dosing Tips

If given in a single dose, should generally be administered at bedtime because of its sedative properties

If given in split doses, largest dose should generally be given at bedtime because of its sedative properties

If patients experience nightmares, split dose and do not give large dose at bedtime

Patients treated for chronic pain may only require lower doses (e.g., 50– 75 mg/day)

Risk of seizure increases with dose

âœ1⁄2 Monitoring plasma levels of desipramine is recommended in patients who do not respond to the usual dose or whose treatment is regarded as urgent

If intolerable anxiety, insomnia, agitation, akathisia, or activation occur upon either dosing initiation or discontinuation, consider the possibility of activated bipolar disorder, and switch to a mood stabilizer or an atypical antipsychotic

Overdose

Death may occur, and may be more likely than with other TCAs; convulsions, cardiac dysrhythmias, severe hypotension, CNS depression, coma, changes in ECG

Safe

Long-Term Use

No

Habit Forming

How to Stop

Taper to avoid withdrawal effects

Even with gradual dose reduction some withdrawal symptoms may appear within the first 2 weeks

Many patients tolerate 50% dose reduction for 3 days, then another 50% reduction for 3 days, then discontinuation

If withdrawal symptoms emerge during discontinuation, raise dose to stop symptoms and then restart withdrawal much more slowly

Pharmacokinetics

Substrate for CYP450 2D6 and 1A2

Is the active metabolite of imipramine, formed by demethylation via CYP450 1A2

Half-life approximately 24 hours Food does not affect absorption

Drug Interactions

Tramadol increases the risk of seizures in patients taking TCAs

Use of TCAs with anticholinergic drugs may result in paralytic ileus or hyperthermia

Fluoxetine, paroxetine, bupropion, duloxetine, and other CYP450 2D6 inhibitors may increase TCA concentrations

Cimetidine may increase plasma concentrations of TCAs and cause anticholinergic symptoms

Phenothiazines or haloperidol may raise TCA blood concentrations

May alter effects of antihypertensive drugs; may inhibit hypotensive effects of clonidine

Use of TCAs with sympathomimetic agents may increase sympathetic activity

Methylphenidate may inhibit metabolism of TCAs

Activation and agitation, especially following switching or adding antidepressants, may represent the induction of a bipolar state, especially a mixed dysphoric bipolar II condition sometimes associated with suicidal ideation, and require the addition of lithium, a mood stabilizer or an atypical antipsychotic, and/or discontinuation of desipramine

Other Warnings/Precautions

Add or initiate other antidepressants with caution for up to 2 weeks after discontinuing desipramine

Generally, do not use with MAOIs, including 14 days after MAOIs are stopped; do not start an MAOI for at least 5 half-lives (5 to 7 days for most drugs) after discontinuing desipramine, but see Pearls

Use with caution in patients with history of seizures, urinary retention, angle-closure glaucoma, hyperthyroidism

Use caution when prescibing in patients with a family history of sudden death, cardiac dysrhythmias, and cardiac conduction disturbances

Some patients may have seizures before cardiac dysrhythmias and death

TCAs can increase QTc interval, especially at toxic doses, which can be attained not only by overdose but also by combining with drugs that inhibit TCA metabolism via CYP450 2D6, potentially causing torsade de pointes-type arrhythmia or sudden death

Because TCAs can prolong QTc interval, use with caution in patients who have bradycardia or who are taking drugs that can induce bradycardia (e.g., beta blockers, calcium channel blockers, clonidine, digitalis)

Because TCAs can prolong QTc interval, use with caution in patients who have hypokalemia and/or hypomagnesemia or who are taking drugs that can induce hypokalemia and/or magnesemia (e.g., diuretics, stimulant laxatives, intravenous amphotericin B, glucocorticoids, tetracosactide)

When treating children, carefully weigh the risks and benefits of pharmacological treatment against the risks and benefits of nontreatment with antidepressants and make sure to document this in the patientâ€TM s chart

Distribute the brochures provided by the FDA and the drug companies

Whenever possible, warn patients and their caregivers about the possibility of activating side effects, and advise them to report such symptoms immediately

Monitor patients for activation of suicidal ideation, especially children and adolescents

Do Not Use

If patient is recovering from myocardial infarction

If patient is taking agents capable of significantly prolonging QTc interval (e.g., pimozide, thioridazine, selected antiarrhythmics, moxifloxacin, sparfloxacin)

If there is a history of QTc prolongation or cardiac arrhythmia, recent acute myocardial infarction, uncompensated heart failure

If patient is taking drugs that inhibit TCA metabolism, including CYP450 2D6 inhibitors, except by an expert

If there is reduced CYP450 2D6 function, such as patients who are poor 2D6 metabolizers, except by an expert and at low doses

If there is a proven allergy to desipramine, imipramine, or lofepramine

Special populations

Renal Impairment

Use with caution; may need to lower dose May need to monitor plasma levels

Hepatic Impairment

Use with caution; may need to lower dose May need to monitor plasma levels

Cardiac Impairment

Baseline ECG is recommended

TCAs have been reported to cause arrhythmias, prolongation of conduction time, orthostatic hypotension, sinus tachycardia, and heart failure, especially in the diseased heart

Myocardial infarction and stroke have been reported with TCAs

TCAs produce QTc prolongation, which may be enhanced by the existence of bradycardia, hypokalemia, congenital or acquired long QTc interval, which should be evaluated prior to administering desipramine

Use with caution if treating concomitantly with a medication likely to produce prolonged bradycardia, hypokalemia, slowing of intracardiac conduction, or prolongation of the QTc interval

Avoid TCAs in patients with a known history of QTc prolongation, recent acute myocardial infarction, and uncompensated heart failure

TCAs may cause a sustained increase in heart rate in patients with ischemic heart disease and may worsen (decrease) heart rate variability, an independent risk of mortality in cardiac populations

Since SSRIs may improve (increase) heart rate variability in patients following a myocardial infarct and may improve survival as well as mood in patients with acute angina or following a myocardial infarction, these are more appropriate agents for cardiac population than tricyclic/tetracyclic antidepressants

âœ1⁄2 Risk/benefit ratio may not justify use of TCAs in cardiac impairment

Elderly

Baseline ECG is recommended for patients over age 50

May be more sensitive to anticholinergic, cardiovascular, hypotensive, and sedative effects

Initial dose 25– 50 mg/day, raise to 100 mg/day; maximum 150 mg/day

May be useful to monitor plasma levels in elderly patients

Reduction in the risk of suicidality with antidepressants compared to placebo in adults age 65 and older

Children and Adolescents

Carefully weigh the risks and benefits of pharmacological treatment against the risks and benefits of nontreatment with antidepressants

and make sure to document this in the patientâ€TM s chart

Monitor patients face-to-face regularly, particularly during the first several weeks of treatment

Use with caution, observing for activation of known or unknown bipolar disorder and/or suicidal ideation, and inform parents or guardians of this risk so they can help observe child or adolescent patients

Not recommended for use in children under age 12

Several studies show lack of efficacy of TCAs for depression

May be used to treat enuresis or hyperactive/impulsive behaviors

May reduce tic symptoms

Some cases of sudden death have occurred in children taking TCAs

Adolescents: initial dose 25– 50 mg/day, increase to 100 mg/day; maximum dose 150 mg/day

May be useful to monitor plasma levels in children and adolescents

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women Crosses the placenta

Adverse effects have been reported in infants whose mothers took a TCA (lethargy, withdrawal symptoms, fetal malformations)

Must weigh the risk of treatment (first trimester fetal development, third trimester newborn delivery) to the child against the risk of no treatment (recurrence of depression, maternal health, infant bonding) to the mother and child

For many patients this may mean continuing treatment during pregnancy

National Pregnancy Registry for Antidepressants: 1-866-961-2388,

https://womensmentalhealth.org/research/pregnancyregistry/antidepr essants

Breast Feeding

Some drug is found in motherâ€TM s breast milk

âœ1⁄2 Recommended either to discontinue drug or bottle feed

Immediate postpartum period is a high-risk time for depression, especially in women who have had prior depressive episodes, so drug may need to be reinstituted late in the third trimester or shortly after childbirth to prevent a recurrence during the postpartum period

Must weigh benefits of breast feeding with risks and benefits of antidepressant treatment versus nontreatment to both the infant and the mother

For many patients this may mean continuing treatment during breast feeding

The art of psychopharmacology Potential Advantages

Patients with insomnia

Severe or treatment-resistant depression

Patients for whom therapeutic drug monitoring is desirable

Potential Disadvantages

Pediatric and geriatric patients Patients concerned with weight gain Cardiac patients

Depressed mood Chronic pain

Primary Target Symptoms

Pearls

TCAs are often a first-line treatment option for chronic pain

TCAs are no longer generally considered a first-line option for depression because of their side effect profile

TCAs continue to be useful for severe or treatment-resistant depression

Noradrenergic reuptake inhibitors such as desipramine can be used as a second-line treatment for smoking cessation, cocaine dependence, and attention deficit disorder

TCAs may aggravate psychotic symptoms

Alcohol should be avoided because of additive CNS effects

Underweight patients may be more susceptible to adverse cardiovascular effects

Children, patients with inadequate hydration, and patients with cardiac disease may be more susceptible to TCA-induced cardiotoxicity than healthy adults

For the expert only: although generally prohibited, a heroic but potentially dangerous treatment for severely treatment-resistant patients is to give a tricyclic/tetracyclic antidepressant other than clomipramine simultaneously with an MAOI for patients who fail to respond to numerous other antidepressants

If this option is elected, start the MAOI with the tricyclic/tetracyclic antidepressant simultaneously at low doses after appropriate drug washout, then alternately increase doses of these agents every few days to a week as tolerated

Although very strict dietary and concomitant drug restrictions must be observed to prevent hypertensive crises and serotonin syndrome,

the most common side effects of MAOI/tricyclic or tetracyclic combinations may be weight gain and orthostatic hypotension

Patients on TCAs should be aware that they may experience symptoms such as photosensitivity or blue-green urine

SSRIs may be more effective than TCAs in women, and TCAs may be more effective than SSRIs in men

Not recommended for first-line use in children with ADHD because of the availability of safer treatments with better documented efficacy and because of desipramineâ€TM s potential for sudden death in children

âœ1⁄2 Desipramine is one of the few TCAs where monitoring of plasma drug levels has been well studied

âœ1⁄2 Fewer anticholinergic side effects than some other TCAs

Since tricyclic/tetracyclic antidepressants are substrates for CYP450 2D6, and 7% of the population (especially Caucasians) may have a genetic variant leading to reduced activity of 2D6, such patients may not safely tolerate normal doses of tricyclic/tetracyclic antidepressants and may require dose reduction

Phenotypic testing may be necessary to detect this genetic variant prior to dosing with a tricyclic/tetracyclic antidepressant, especially in vulnerable populations such as children, elderly, cardiac populations, and those on concomitant medications

Patients who seem to have extraordinarily severe side effects at normal or low doses may have this phenotypic CYP450 2D6 variant

and require low doses or switching to another antidepressant not metabolized by 2D6

Suggested Reading

Anderson IM . Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability . J Aff Disorders 2000 ;58 :19 – 36 .

Anderson IM . Meta-analytical studies on new antidepressants . Br Med Bull 2001 ;57 :161– 78 .

Janowsky DS , Byerley B . Desipramine: an overview . J Clin Psychiatry 1984 ;45 :3 – 9.

Levin FR , Lehman AF . Meta-analysis of desipramine as an adjunct in the treatment of cocaine addiction . J Clin Psychopharmacol 1991 ;11 :374 – 8.

Desvenlafaxine

Pristiq

Therapeutics Brands

see index for additional brand names

Yes

Generic?

Class

Neuroscience-based Nomenclature: serotonin norepinephrine reuptake inhibitor (SN-RI)

SNRI (dual serotonin and norepinephrine reuptake inhibitor); often classified as an antidepressant, but it is not just an antidepressant

Commonly Prescribed for

(bold for FDA approved)

Major depressive disorder

Vasomotor symptoms

Fibromyalgia

Generalized anxiety disorder (GAD)

Social anxiety disorder (social phobia) Panic disorder

Posttraumatic stress disorder (PTSD) Premenstrual dysphoric disorder (PMDD)

How the Drug Works

Boosts neurotransmitters serotonin, norepinephrine/noradrenaline, and dopamine

Blocks serotonin reuptake pump (serotonin transporter), presumably increasing serotonergic neurotransmission

Blocks norepinephrine reuptake pump (norepinephrine transporter), presumably increasing noradrenergic neurotransmission

Desensitizes both serotonin 1A receptors and beta adrenergic receptors

Since dopamine is inactivated by norepinephrine reuptake in frontal cortex, which largely lacks dopamine transporters, desvenlafaxine can increase dopamine neurotransmission in this part of the brain

How Long Until It Works

Onset of therapeutic actions usually not immediate, but often delayed 2– 4 weeks

If it is not working within 6 or 8 weeks for depression, it may require a dosage increase or it may not work at all

May continue to work for many years to prevent relapse of depressive symptoms

Vasomotor symptoms in perimenopausal women with or without depression may improve within 1 week

If It Works

The goal of treatment is complete remission of current symptoms as well as prevention of future relapses

Treatment most often reduces or even eliminates symptoms, but not a cure since symptoms can recur after medicine stopped

Continue treatment until all symptoms are gone (remission) or significantly reduced

Once symptoms are gone, continue treating for 1 year for the first episode of depression

For second and subsequent episodes of depression, treatment may need to be indefinite

If It Doesnâ€TM t Work

Many patients have only a partial response where some symptoms are improved but others persist (especially insomnia, fatigue, and problems concentrating)

Other patients may be nonresponders, sometimes called treatment- resistant or treatment-refractory

Some patients who have an initial response may relapse even though they continue treatment, sometimes called “ poop-outâ€

Consider increasing dose, switching to another agent, or adding an appropriate augmenting agent

Consider psychotherapy

Consider evaluation for another diagnosis or for a comorbid condition (e.g., medical illness, substance abuse, etc.)

Some patients may experience apparent lack of consistent efficacy due to activation of latent or underlying bipolar disorder, and require antidepressant discontinuation and switch to a mood stabilizer

Best Augmenting Combos for Partial Response or Treatment Resistance

Mirtazapine (“ California rocket fuel†; a potentially powerful dual serotonin and norepinephrine combination, but observe for activation of bipolar disorder and suicidal ideation)

Bupropion, reboxetine, nortriptyline, desipramine, maprotiline, atomoxetine (all potentially powerful enhancers of noradrenergic action, but observe for activation of bipolar disorder and suicidal ideation)

Modafinil, especially for fatigue, sleepiness, and lack of concentration

Mood stabilizers or atypical antipsychotics for bipolar depression, psychotic depression, or treatment-resistant depression

Benzodiazepines

If all else fails for anxiety disorders, consider gabapentin or tiagabine

Hypnotics or trazodone for insomnia

Classically, lithium, buspirone, or thyroid hormone

Tests

Check blood pressure before initiating treatment and regularly during treatment

Side effects

How Drug Causes Side Effects

Theoretically due to increases in serotonin and norepinephrine concentrations at receptors in parts of the brain and body other than those that cause therapeutic actions (e.g., unwanted actions of serotonin in sleep centers causing insomnia, unwanted actions of norepinephrine on acetylcholine release causing constipation and dry mouth, etc.)

Most side effects are immediate but often go away with time

Notable Side Effects

Most side effects increase with higher doses, at least transiently Insomnia, sedation, anxiety, dizziness

Nausea, vomiting, constipation, decreased appetite

Sexual dysfunction (abnormal ejaculation/orgasm, impotence) Sweating

SIADH (syndrome of inappropriate antidiuretic hormone secretion) Hyponatremia

Increase in blood pressure

Life-Threatening or Dangerous Side Effects

Rare seizures

Rare induction of hypomania

Rare activation of suicidal ideation and behavior (suicidality) (short- term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo beyond age 24)

Weight Gain

Sedation

Occurs in significant minority

May also be activating in some patients

Reported but not expected

What to Do About Side Effects

Wait

Wait

Wait

Lower the dose

In a few weeks, switch or add other drugs

Best Augmenting Agents for Side Effects

Often best to try another antidepressant monotherapy prior to resorting to augmentation strategies to treat side effects

Trazodone or a hypnotic for insomnia

Bupropion, sildenafil, vardenafil, or tadalafil for sexual dysfunction

Benzodiazepines for jitteriness and anxiety, especially at initiation of treatment and especially for anxious patients

Mirtazapine for insomnia, agitation, and gastrointestinal side effects

Many side effects are dose-dependent (i.e., they increase as dose increases, or they reemerge until tolerance redevelops)

Many side effects are time-dependent (i.e., they start immediately upon dosing and upon each dose increase, but go away with time)

Activation and agitation may represent the induction of a bipolar state, especially a mixed dysphoric bipolar II condition sometimes associated with suicidal ideation, and require the addition of lithium,

a mood stabilizer or an atypical antipsychotic, and/or discontinuation of desvenlafaxine

Dosing and use Usual Dosage Range

Depression: 50 mg once daily

Dosage Forms

Tablet (extended-release) 25 mg, 50 mg, 100 mg

How to Dose

Initial dose 50 mg once daily; maximum recommended dose generally 100 mg once daily; doses up to 400 mg once daily have been shown to be effective but higher doses are associated with increased side effects

Dosing Tips

Desvenlafaxine is the active metabolite O-desmethylvenlafaxine (ODV) of venlafaxine, and is formed as the result of CYP450 2D6

More potent at the serotonin transporter (SERT) than at the norepinephrine transporter (NET), but has greater inhibition of NET relative to SERT compared to venlafaxine

Nonresponders at lower doses may try higher doses to be assured of the benefits of dual SNRI action

For vasomotor symptoms, current data suggest that a dose of 100 mg/day is effective

Do not break or chew tablets, as this will alter controlled-release properties

For some patients with severe problems discontinuing desvenlafaxine, it may be useful to add an SSRI with a long half- life, especially fluoxetine, prior to taper of desvenlafaxine. While maintaining fluoxetine dosing, first slowly taper desvenlafaxine and then taper fluoxetine

Be sure to differentiate between reemergence of symptoms requiring reinstitution of treatment and withdrawal symptoms

May dose up to 400 mg/day in patients who do not respond to lower doses, if tolerated

Overdose

No fatalities have been reported as monotherapy; headache, vomiting, agitation, dizziness, nausea, constipation, diarrhea, dry mouth, paresthesia, tachycardia

Desvenlafaxine is the active metabolite of venlafaxine; fatal toxicity index data from the UK suggest a higher rate of deaths from overdose with venlafaxine than with SSRIs; it is unknown whether

this is related to differences in patients who receive venlafaxine or to potential cardiovascular toxicity of venlafaxine

Long-Term Use

See doctor regularly to monitor blood pressure

No

Habit Forming

How to Stop

Taper to avoid withdrawal effects (dizziness, nausea, diarrhea, sweating, anxiety, irritability)

Recommended taper schedule is to give a fully daily dose (50 mg) less frequently

If withdrawal symptoms emerge during discontinuation, raise dose to stop symptoms and then restart withdrawal much more slowly

Pharmacokinetics

Active metabolite of venlafaxine Half-life 9– 13 hours

Minimally metabolized by CYP450 3A4 Food does not affect absorption

Drug Interactions

Tramadol increases the risk of seizures in patients taking an antidepressant

Can cause a fatal “ serotonin syndrome†when combined with MAOIs, so do not use with MAOIs or for at least 14 days after MAOIs are stopped

Do not start an MAOI for at least 5 half-lives (5 to 7 days for most drugs) after discontinuing desvenlafaxine

Can rarely cause weakness, hyperreflexia, and incoordination when combined with sumatriptan or possibly other triptans, requiring careful monitoring of patient

Possible increased risk of bleeding, especially when combined with anticoagulants (e.g., warfarin, NSAIDs)

NSAIDs may impair effectiveness of SSRIs

Potent inhibitors of CYP450 3A4 may increase plasma levels of desvenlafaxine, but the clinical significance of this is unknown

Few known adverse drug interactions

False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients taking desvenlafaxine, due to a lack of specificity of the screening tests. False-positive test results may be expected for several days following discontinuation of desvenlafaxine

Other Warnings/Precautions

Use with caution in patients with history of seizure Use with caution in patients with heart disease

Use with caution in patients with bipolar disorder unless treated with concomitant mood-stabilizing agent

When treating children, carefully weigh the risks and benefits of pharmacological treatment against the risks and benefits of nontreatment with antidepressants and make sure to document this in the patientâ€TM s chart

Distribute the brochures provided by the FDA and the drug companies

Whenever possible, warn patients and their caregivers about the possibility of activating side effects, and advise them to report such symptoms immediately

Monitor patients for activation of suicidal ideation, especially children and adolescents

Do Not Use

If patient has uncontrolled angle-closure glaucoma

If patient is taking an MAOI

If there is a proven allergy to desvenlafaxine or venlafaxine

Special populations

Renal Impairment

For moderate impairment, recommended dose is 50 mg/day

For severe impairment, recommended dose is 50 mg every other day

Patients on dialysis should not receive subsequent dose until dialysis is completed

Hepatic Impairment

Doses greater than 100 mg/day not recommended

Cardiac Impairment

Drug should be used with caution

Hypertension should be controlled prior to initiation of desvenlafaxine and should be monitored regularly during treatment

Desvenlafaxine has a dose-dependent effect on increasing blood pressure

Desvenlafaxine is the active metabolite of venlafaxine, which is contraindicated in patients with heart disease in the UK

Venlafaxine can block cardiac ion channels in vitro and worsens (i.e., reduces) heart rate variability in depression, perhaps due to norepinephrine reuptake inhibition

Elderly

Some patients may tolerate lower doses better

Risk of SIADH with SSRIs is higher in the elderly

Reduction in the risk of suicidality with antidepressants compared to placebo in adults age 65 and older

Children and Adolescents

Carefully weigh the risks and benefits of pharmacological treatment against the risks and benefits of nontreatment with antidepressants and make sure to document this in the patientâ€TM s chart

Monitor patients face-to-face regularly, particularly during the first several weeks of treatment

Use with caution, observing for activation of known or unknown bipolar disorder and/or suicidal ideation, and inform parents or guardians of this risk so they can help observe child or adolescent patients

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women

In animal studies, there was no evidence of teratogenicity at plasma exposure up to 19 times (rat) and 0.5 times (rabbit) the exposure at a usual adult dose; however, fetotoxicity and pup deaths occurred in rats at 4.5 times the exposure at a usual adult dose

Not generally recommended for use during pregnancy, especially during first trimester

Nonetheless, continuous treatment during pregnancy may be necessary and has not been proven to be harmful to the fetus

Must weigh the risk of treatment (first trimester fetal development, third trimester newborn delivery) to the child against the risk of no treatment (recurrence of depression, maternal health, infant bonding) to the mother and child

For many patients this may mean continuing treatment during pregnancy

Exposure to SSRIs late in pregnancy may be associated with increased risk of gestational hypertension and preeclampsia

Neonates exposed to SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding; reported symptoms are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome, and include respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying

National Pregnancy Registry for Antidepressants: 1-866-961-2388,

https://womensmentalhealth.org/research/pregnancyregistry/antidepr essants

Breast Feeding

Some drug is found in motherâ€TM s breast milk

Trace amounts may be present in nursing children whose mothers are on desvenlafaxine

If child becomes irritable or sedated, breast feeding or drug may need to be discontinued

Immediate postpartum period is a high-risk time for depression, especially in women who have had prior depressive episodes, so drug may need to be reinstituted late in the third trimester or shortly after childbirth to prevent a recurrence during the postpartum period

Must weigh benefits of breast feeding with risks and benefits of antidepressant treatment versus nontreatment to both the infant and the mother

For many patients, this may mean continuing treatment during breast feeding

The art of psychopharmacology

Potential Advantages

Patients with retarded depression

Patients with atypical depression

Patients with depression may have higher remission rates on SNRIs than on SSRIs

Depressed patients with somatic symptoms, fatigue, and pain Depressed patients with vasomotor symptoms

Patients who do not respond or remit on treatment with SSRIs

Potential Disadvantages

Patients sensitive to nausea

Patients with borderline or uncontrolled hypertension Patients with cardiac disease

Primary Target Symptoms

Depressed mood

Energy, motivation, and interest Sleep disturbance

Physical symptoms

Pain

Pearls

Because desvenlafaxine is only minimally metabolized by CYP450 3A4 and is not metabolized at all by CYP450 2D6, as venlafaxine

is, it should have more consistent plasma levels than venlafaxine

In addition, although desvenlafaxine, like venlafaxine, is more potent at the serotonin transporter (SERT) than the norepinephrine transporter (NET), it has relatively greater actions on NET versus SERT than venlafaxine does at comparable doses

The greater potency for NET may make it a preferable agent for conditions theoretically associated with targeting norepinephrine actions, such as vasomotor symptoms and fibromyalgia

May be particularly helpful for hot flushes in perimenopausal women

May be effective in patients who fail to respond to SSRIs

May be used in combination with other antidepressants for treatment-refractory cases

May be effective in a broad array of anxiety disorders and possibly adult ADHD, although it has not been studied in these conditions

May be associated with higher depression remission rates than SSRIs

Because of recent studies from the UK that suggest a higher rate of deaths from overdose with venlafaxine than with SSRIs, and because of its potential to affect heart function, venlafaxine can only be prescribed in the UK by specialist doctors and is contraindicated there in patients with heart disease

Overdose data are from fatal toxicity index studies, which do not take into account patient characteristics or whether drug use was

first- or second-line

Venlafaxineâ€TM s toxicity in overdose is less than that for TCAs

Suggested Reading

Deecher DC , Beyer CE , Johnston G , et al. Desvenlafaxine succinate: a new serotonin and norepinephrine reuptake inhibitor . J Pharmacol Exp Ther 2006 ;318 (2 ):657– 65 .

Lieberman DZ , Montgomery SA , Tourian KA , et al. A pooled analysis of two placebo-controlled trials of desvenlafaxine in major depressive disorder . Int Clin Psychopharmacol 2008 ;23 (4 ):188– 97 .

Speroff L , Gass M , Constantine G . Efficacy and tolerability of desvenlafaxine succinate treatment for menopausal vasomotor symptoms: a randomized controlled trial . Obstet Gynecol 2008 ;111 (1 ):77 – 87 .

Deutetrabenazine

Austedo

Therapeutics Brands

see index for additional brand names

No

Generic?

Class

Vesicular monoamine transporter 2 (VMAT2) inhibitor

Commonly Prescribed for

(bold for FDA approved)

Tardive dyskinesia in adults

Chorea associated with Huntingtonâ€TM s disease

How the Drug Works

Deutetrabenazine is a selective and reversible inhibitor of the vesicular monoamine transporter 2 (VMAT2), which packages monoamines, including dopamine, into synaptic vesicles of presynaptic neurons in the central nervous system

How Long Until It Works

In clinical trials deutetrabenazine separated from placebo as early as weeks 2– 4

If It Works

Patients should experience a significant reduction in the total Abnormal Involuntary Movement Scale (AIMS) score

If It Doesnâ€TM t Work

If tardive dyskinesia does not reverse with deutetrabenazine, then other management options include valbenazine, tetrabenazine, reserpine, clonazepam, amantadine, botulinum toxin injections for focal dystonia symptoms, or ginkgo biloba

Some patients may require suppressive therapy, in which the offending antipsychotic is reinstituted or its dose raised; this should only be considered if the symptoms are very severe and cause marked functional impact (e.g., inability to eat; mouth sores from rubbing); this can make tardive dyskinesia worse in the long run, but the short- term benefits may justify the risk for certain patients

Best Augmenting Combos for Partial Response or Treatment Resistance

Deutetrabenazine is itself an augmenting agent to treat a side effect of antipsychotic drugs

Tests

None for healthy individuals

No need for CYP450 2D6 testing

For patients at risk for QT prolongation: assess the QT interval before and after increasing the total dosage above 24 mg/day

Side effects

How Drug Causes Side Effects

Theoretically due to increases in monoamine concentrations at receptors in parts of the brain and body other than those that cause therapeutic actions

Depletion of dopamine due to long-term inhibition of VMAT2 may also be responsible for some side effects

Notable Side Effects

Sedation, fatigue, dizziness, insomnia, nasopharyngitis Diarrhea, dry mouth

Life-Threatening or Dangerous Side Effects

QT prolongation, although the degree of QT prolongation is not clinically significant at concentrations expected with recommended dosing

Neuroleptic malignant syndrome (NMS) (has not been observed in patients taking deutetrabenazine, but has been observed in patients taking tetrabenazine)

Risk of depression and suicidal thoughts and behavior in patients with Huntingtonâ€TM s disease

Weight Gain

Sedation

Many experience and/or can be significant in amount

Reported but not expected

Wait

Wait

Wait

What to Do About Side Effects

Reduce dose or discontinue if agitation, akathisia, restlessness, or parkinsonism occurs

Best Augmenting Agents for Side Effects

Deutetrabenazine is itself an augmenting agent to treat a side effect of antipsychotic drugs

Dosing and use Usual Dosage Range

Tardive dyskinesia: 12– 48 mg/day in two divided doses

Chorea associated with Huntingtonâ€TM s disease: 6– 48 mg/day (in two divided doses for total daily dosages of 12 mg or more)

Dosage Forms

Tablet 6 mg, 9 mg, 12 mg

How to Dose

Tardive dyskinesia: initial dose 12 mg in two divided doses; titrate by 6 mg/day in weekly intervals; maximum recommended dose is 48 mg/day in two divided doses

Chorea associated with Huntingtonâ€TM s disease: initial dose 6 mg once daily; titrate by 6 mg/day in weekly intervals; doses above 12 mg/day should be administered in two divided doses; maximum recommended dose is 48 mg/day in two divided doses

Dosing Tips

Should be taken with food because that is how clinical trials were conducted; however, food has no effect on the AUC of deutetrabenazineâ€TM s active metabolites, but increased Cmax by 50%

Tablet should be swallowed whole and should not be chewed or crushed

If switching from tetrabenazine: discontinue tetrabenazine and initiate deutetrabenazine the next day:

Current tetrabenazine daily dose 12.5 mg

25 mg

37.5 mg

50 mg 62.5 mg 75 mg 87.5 mg 100 mg

Initial deutetrabenazine dose 6 mg once daily

6 mg twice daily

9 mg twice daily

If switching from reserpine: at least 20 days should stopping reserpine before starting deutetrabenazine

Overdose

Limited experience

Overdose with tetrabenazine: acute dystonia, oculogyric crisis, nausea and vomiting, sweating, sedation, hypotension, confusion,

12 mg twice 15 mg twice 18 mg twice 21 mg twice 24 mg twice

daily daily daily daily daily

elapse after

diarrhea, hallucinations, rubor, and tremor have been reported

Long-Term Use

Long-term clinical trials have not been conducted

No

Taper not necessary

Habit Forming

How to Stop

Pharmacokinetics

Deutetrabenazine is a deuterated from of tetrabenazine

Deuteration is a process in which the stable isotope deuterium replaces selected hydrogen atoms, resulting in a compound with similar pharmacodynamic effects but different pharmacokinetic profiles, because the carbon– deuterium covalent bond requires 8 times more energy to break than a carbon– hydrogen bond

Substitution of deuterium for hydrogen slows the breakdown of metabolites; thus, the active metabolites of deutetrabenazine have longer half-lives and greater absorption than those of tetrabenazine

Deutetrabenazine is broken down into 4 metabolites

Half-life of total (a+b)-HTBZ from deutetrabenazine is approximately 9 to 10 hours

Metabolized by CYP450 2D6, but deuteration means that, unlike tetrabenazine, CYP450 2D6 genotyping is not necessary

Drug Interactions

Strong CYP450 2D6 inhibitors (e.g., paroxetine, fluoxetine) may increase exposure to deutetrabenazine; maximum recommended dose in patients taking strong CYP450 2D6 inhibitors or who are known CYP2D6 poor metabolizers is 36 mg/day

May be additive sedative effects if deutetrabenazine is given concomitantly with alcohol or other sedating drugs

Other Warnings/Precautions

May cause an increase in QT interval, although the degree of QT prolongation is not clinically significant at concentrations expected with recommended dosing

Avoid use in patients with congenital long QT syndrome or with arrhythmias associated with a prolonged QT interval

For patients at increased risk of prolonged QT interval, assess the QT interval before and after increasing the total dose above 24 mg/day

Due to the increased risk of depression and suicidality in patients with Huntingtonâ€TM s disease who take deutetrabenazine, one should monitor for the emergence or worsening of depression, suicidality, or unusual changes in behavior; patients and caregivers should be informed of the risk of depression and suicidality and told to report behaviors of concern promptly

Do Not Use

In patients with Huntingtonâ€TM s disease who are suicidal or have untreated/inadequately treated depression

In patients with hepatic impairment

If patient is taking a monoamine oxidase inhibitor (MAOI) If patient is taking reserpine, tetrabenazine, or valbenazine If there is a proven allergy to deutetrabenazine

Not evaluated

Contraindicated

Special populations Renal Impairment

Hepatic Impairment

Cardiac Impairment

May cause an increase in QT interval; avoid use in patients with congenital long QT syndrome or with arrhythmias associated with a prolonged QT interval

For patients at risk for QT prolongation: assess the QT interval before and after increasing the total dosage above 24 mg/day

Elderly

Some patients may tolerate lower doses better

Children and Adolescents

Safety and efficacy have not been established

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women

In rat studies, no malformations were observed when deutetrabenazine was administered during the period of organogenesis at doses up to 6 times the maximum recommended human dose

In rat studies, administration of tetrabenazine during organogenesis through lactation produced an increase in the number of stillborn pups and postnatal pup mortalities

Breast Feeding

Unknown if deutetrabenazine is secreted in human breast milk, but all psychotropics are assumed to be secreted in breast milk

The art of psychopharmacology Potential Advantages

Multiple doses for flexible dosing No CYP450 3A4 drug interactions

Potential Disadvantages

Expensive

Requires twice daily dosing (12 mg/day and above)

Carries a black box warning for depression and suicidality in patients with Huntingtonâ€TM s disease

Primary Target Symptoms

Repetitive involuntary movements of tardive dyskinesia (usually associated with lower facial and distal extremity musculature, e.g., tongue protrusion, writhing of tongue, lip smacking, chewing, blinking, and grimacing)

Pearls

In clinical trials, deutetrabenazine was well tolerated, with low rates of psychiatric adverse events, including anxiety

Unlike with tetrabenazine, clinical trials with deutetrabenazine did not result in reports of depression or suicidal ideation

The safety profile of deutetrabenazine appears similar regardless of whether a concomitant antipsychotic drug is administered

At therapeutic doses, deutetrabenazineâ€TM s active metabolites bind predominantly to VMAT2, with low D2 dopamine receptor blockade

Deutetrabenazineâ€TM s active metabolites have moderate blockade of 5HT7; the clinical significance of this is unknown, although 5HT7 antagonism has been associated with antidepressant and pro-cognitive actions in animal models

Can rarely cause akathisia

Suggested Reading

Anderson KE , Stamler D , Davis MD , et al. Deutetrabenazine for treatment of involuntary movements in patients with tardive dyskinesia (AIM-TD): a double-blind, randomised, placebo-controlled, phase 3 trial . Lancet Psychiatry 2017 ;4 (8 ):595 – 604 .

Fernandez HH , Factor SA , Hauser RA , et al. Randomized controlled trial of deutetrabenazine for tardive dyskinesia: the ARM-TD study . Neurology 2017 ;88 (21 ):2003 – 10 .

Frank S , Stamler D , Kayson E , et al. Safety of converting from tetrabenazine to deutetrabenazine for the treatment of chorea . JAMA Neurol 2017 ;74 (8 ):977 – 82 .

Huntington Study Group, Frank S , Testa CM , et al. Effect of deutetrabenazine on chorea among patients with Huntington disease: a randomized clinical trial. JAMA 2016 ;316 (1 ):40 – 50 .

Meyer JM . Forgotten but not gone: new developments in the understanding and treatment of tardive dyskinesia . CNS Spectr 2016 ;21 (S1 ):13 – 24 .

Dextromethorphan

Nuedexta (in combination with quinidine)

see index for additional brand names

Therapeutics Brands

No

Generic?

Class

Noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist and sigma 1 agonist

Commonly Prescribed for

(bold for FDA approved)

Pseudobulbar affect (PBA)

Diabetic peripheral neuropathic pain

Unstable mood and affect in PTSD and mild traumatic brain injury Third-line for treatment-resistant depression

How the Drug Works

Dextromethorphan reduces glutamate neurotransmission through blocking NMDA receptors and by acting as an agonist at sigma 1 receptors

Dextromethorphan also has affinity for the serotonin transporter and may therefore modulate serotonin levels

Quinidine increases availability of dextromethorphan by inhibiting its metabolism via CYP450 2D6

How Long Until It Works

In clinical trials the rate of pseudobulbar affect episodes was significantly decreased beginning at day 15

If It Works

Reduces the frequency and severity of episodes of uncontrollable laughing and/or crying

If It Doesnâ€TM t Work

Consider switching to a TCA or an SSRI

Best Augmenting Combos for Partial Response or Treatment Resistance

Often best to attempt another monotherapy prior to resorting to augmentation strategies

Tests

None for healthy individuals

Side effects

How Drug Causes Side Effects

Presumably mechanism-related, including central actions at sigma and NMDA receptors causing dissociative symptoms, euphoria, or sedation

Notable Side Effects

Dizziness, asthenia Diarrhea, vomiting Cough, peripheral edema Urinary tract infection Euphoria

Life-Threatening or Dangerous Side Effects

Immune-mediated thrombocytopenia Hepatotoxicity

Dose-dependent QT prolongation

Weight Gain

Reported but not expected

Sedation

What to Do About Side Effects

Wait

Wait

Wait

In a few weeks, switch to another agent or add other drugs

Best Augmenting Agents for Side Effects

Often best to try another agent prior to resorting to augmentation strategies to treat side effects

Many side effects are dose-dependent (i.e., they increase as dose increases, or they reemerge until tolerance redevelops)

Many side effects are time-dependent (i.e., they start immediately upon dosing and upon each dose increase, but go away with time)

Dosing and use Usual Dosage Range

Reported but not expected

20 mg/10 mg twice per day

Dosage Forms

Capsule 20 mg/10 mg (dextromethorphan/quinidine)

How to Dose

Initial 20 mg/10 mg once per day; after 7 days increase to 20 mg/10 mg twice per day

Dosing Tips

Some patients may tolerate and respond to doses higher than the approved doses, but few controlled studies of high doses

Overdose

Nausea, dizziness, headache, ventricular arrhythmias, hypotension, coma, respiratory depression, seizures, tachycardia, hyperexcitability, toxic psychosis

Not evaluated

No

Long-Term Use

Habit Forming

Taper not necessary

How to Stop

Pharmacokinetics

Elimination half-life of dextromethorphan is approximately 13 hours Elimination half-life of quinidine is approximately 7 hours

Dextromethorphan is metabolized by CYP450 2D6, while quinidine inhibits CYP450 2D6

Quinidine is metabolized by CYP450 3A4

Drug Interactions

Via CYP450 2D6 inhibition, dextromethorphan/quinidine could increase plasma concentrations of drugs metabolized by CYP450 2D6 (e.g., desipramine), potentially requiring dose reduction of the substrate

Can cause a fatal “ serotonin syndrome†when combined with MAOIs, so do not use with MAOIs or for at least 14 days after MAOIs are stopped

Do not start an MAOI for at least 5 half-lives (5 to 7 days for most drugs) after discontinuing dextromethorphan/quinidine

Via P-glycoprotein inhibition, quinidine could increase plasma concentrations of P-glycoprotein substrates such as digoxin, potentially requiring dose reduction of the substrate

Can theoretically cause serotonin syndrome when combined with serotonin reuptake inhibitors, but not well studied

Other Warnings/Precautions

Quinidine can cause immune-mediated thrombocytopenia that can be severe or fatal; dextromethorphan/quinidine should be discontinued immediately if thrombocytopenia occurs unless it is clearly not drug-related, and should not be restarted in sensitized patients

Quinidine has been associated with a lupus-like syndrome involving polyarthritis

ECG should be monitored if patient must take an agent that prolongs QT interval or that inhibits CYP450 3A4

Anticholinergic effects of quinidine may lead to worsening in myasthenia gravis and other sensitive conditions

Do Not Use

If patient is taking an MAOI

If patient is taking another medication containing quinidine, quinine, or mefloquine

If patient has a history of quinidine, quinine, or mefloquine-induced thrombocytopenia, hepatitis, or other hypersensitivity reaction

If patient has prolonged QT interval, congenital long QT syndrome, history suggestive of torsade de pointes, or heart failure

If patient has complete atrioventricular (AV) block without implanted pacemaker, or patients at high risk of complete AV block

If patient is taking a drug that prolongs QT interval and is metabolized by CYP450 2D6 (e.g., thioridazine, pimozide)

If there is a proven allergy to dextromethorphan or quinidine

Special populations Renal Impairment

Dose adjustment not necessary in patients with mild to moderate impairment

Hepatic Impairment

Dose adjustment not necessary in patients with mild to moderate impairment

Cardiac Impairment

Contraindicated in patients with prolonged QT interval, congenital long QT syndrome, history suggestive of torsade de pointes, and heart failure

Monitor ECG in patients with left ventricular hypertrophy or left ventricular dysfunction

Elderly

Some patients may tolerate lower doses better

Children and Adolescents

Safety and efficacy have not been established

Use with caution, observing for activation of known or unknown bipolar disorder and/or suicidal ideation, and strongly consider informing parents or guardian of this risk so they can help observe child or adolescent patients

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women Some animal studies have shown adverse effects

Breast Feeding

Unknown if dextromethorphan/quinidine is secreted in human breast milk, but all psychotropics are assumed to be secreted in breast milk

If child becomes irritable or sedated, breast feeding or drug may need to be discontinued

Must weigh benefits of breast feeding with risks and benefits of antidepressant treatment versus nontreatment to both the infant and the mother

The art of psychopharmacology Potential Advantages

No other approved agent for PBA

Potential Disadvantages

CYP450 2D6 poor metabolizers may require dose reduction

In patients with past substance abuse, especially of dextromethorphan, ketamine, or PCP

Primary Target Symptoms

Uncontrollable crying Uncontrollable laughter

Pearls

Quinidine is intended to increase the actions of dextromethorphan by inhibiting its metabolism by CYP450 2D6; therefore, poor metabolizers of CYP450 2D6 may not benefit as much from this treatment while still experiencing adverse effects associated with quinidine

Affective instability in Alzheimer disease may be treatable with this agent, including agitation, allowing antipsychotics to be avoided in this population

Some men express emotional lability as laughter and anger rather than laughter and crying

Affective instability in PTSD and in mild traumatic brain injury may be improved by dextromethorphan/quinidine

Similar binding properties to ketamine suggest possible efficacy in both treatment-resistant depression and chronic pain

Suggested Reading

Brooks BR , Thisted RA , Appel SH , et al. Treatment of pseudobulbar affect in ALS with dextromethorphan/quinidine: a randomized trial . Neurology 2004 ;63 (8 ):1364 – 70.

Garnock-Jones KP . Dextromethorphan/quinidine in pseudobulbar affect . CNS Drugs 2011 ;25 (5 ):435– 45 .

The Medical Letter Inc . Dextromethorphan/quinidine (neudexta) for pseudobulbar affect . Med Lett Drugs Ther 2011 ;53 (1366 ):46 – 7.

Pioro EP , Brooks BR , Cummings J , et al. Dextromethorphan plus ultra low-dose quinidine reduces pseudobulbar affect . Ann Neurol 2010 ;68 (5 ):693– 702 .

Diazepam

Valium

Diastat

see index for additional brand names

Yes (not Diastat)

Generic?

Class

Therapeutics Brands

Neuroscience-based Nomenclature: GABA positive allosteric modulator (GABA-PAM)

Benzodiazepine (anxiolytic, muscle relaxant, anticonvulsant)

Commonly Prescribed for

(bold for FDA approved)

Anxiety disorder

Symptoms of anxiety (short-term)

Acute agitation, tremor, impending or acute delirium tremens and hallucinosis in acute alcohol withdrawal

Skeletal muscle spasm due to reflex spasm to local pathology Spasticity caused by upper motor neuron disorder

Athetosis

Stiff-person syndrome

Convulsive disorder (adjunctive)

Anxiety during endoscopic procedures (adjunctive) (injection only)

Preoperative anxiety (injection only)

Anxiety relief prior to cardioversion (intravenous) Initial treatment of status epilepticus (injection only) Insomnia

Catatonia

How the Drug Works

Binds to benzodiazepine receptors at the GABA-A ligand-gated chloride channel complex

Enhances the inhibitory effects of GABA

Boosts chloride conductance through GABA-regulated channels

Inhibits neuronal activity presumably in amygdala-centered fear circuits to provide therapeutic benefits in anxiety disorders

Inhibiting actions in cerebral cortex may provide therapeutic benefits in seizure disorders

Inhibitory actions in spinal cord may provide therapeutic benefits for muscle spasms

How Long Until It Works

Some immediate relief with first dosing is common; can take several weeks with daily dosing for maximal therapeutic benefit

If It Works

For short-term symptoms of anxiety or muscle spasms – after a few weeks, discontinue use or use on an “ as-needed†basis

Chronic muscle spasms may require chronic diazepam treatment

For chronic anxiety disorders, the goal of treatment is complete remission of symptoms as well as prevention of future relapses

For chronic anxiety disorders, treatment most often reduces or even eliminates symptoms, but not a cure since symptoms can recur after medicine stopped

For long-term symptoms of anxiety, consider switching to an SSRI or SNRI for long-term maintenance

If long-term maintenance with a benzodiazepine is necessary, continue treatment for 6 months after symptoms resolve, and then taper dose slowly

If symptoms reemerge, consider treatment with an SSRI or SNRI, or consider restarting the benzodiazepine; sometimes benzodiazepines have to be used in combination with SSRIs or SNRIs for best results

If It Doesnâ€TM t Work

Consider switching to another agent or adding an appropriate augmenting agent

Consider psychotherapy, especially cognitive behavioral psychotherapy

Consider presence of concomitant substance abuse

Consider presence of diazepam abuse

Consider another diagnosis, such as a comorbid medical condition

Best Augmenting Combos for Partial Response or Treatment Resistance

Benzodiazepines are frequently used as augmenting agents for antipsychotics and mood stabilizers in the treatment of psychotic and bipolar disorders

Benzodiazepines are frequently used as augmenting agents for SSRIs and SNRIs in the treatment of anxiety disorders

Not generally rational to combine with other benzodiazepines

Caution if using as an anxiolytic concomitantly with other sedative hypnotics for sleep

Tests

In patients with seizure disorders, concomitant medical illness, and/or those with multiple concomitant long-term medications, periodic liver tests and blood counts may be prudent

Side effects

How Drug Causes Side Effects

Same mechanism for side effects as for therapeutic effects – namely due to excessive actions at benzodiazepine receptors

Long-term adaptations in benzodiazepine receptors may explain the development of dependence, tolerance, and withdrawal

Side effects are generally immediate, but immediate side effects often disappear in time

Notable Side Effects âœ1⁄2 Sedation, fatigue, depression

âœ1⁄2 Dizziness, ataxia, slurred speech, weakness âœ1⁄2 Forgetfulness, confusion

âœ1⁄2 Hyperexcitability, nervousness

âœ1⁄2 Pain at injection site

Rare hallucinations, mania Rare hypotension Hypersalivation, dry mouth

Life-Threatening or Dangerous Side Effects

Respiratory depression, especially when taken with CNS depressants in overdose

Rare hepatic dysfunction, renal dysfunction, blood dyscrasias

Weight Gain

Sedation

Many experience and/or can be significant in amount Especially at initiation of treatment or when dose increases Tolerance often develops over time

What to Do About Side Effects

Wait

Wait

Wait

Lower the dose

Take largest dose at bedtime to avoid sedative effects during the day Switch to another agent

Administer flumazenil if side effects are severe or life-threatening

Best Augmenting Agents for Side Effects

Many side effects cannot be improved with an augmenting agent

Reported but not expected

Dosing and use Usual Dosage Range

Oral: 4– 40 mg/day in divided doses

Intravenous (adults): 5 mg/minute

Intravenous (children): 0.25 mg/kg every 3 minutes

Dosage Forms

Tablet 2 mg, 5 mg, 10 mg

Nasal 5 mg/spray, 7.5 mg/spray, 20 mg/spray Concentrate 5 mg/mL

Solution 5 mg/5 mL

Injection vial 5 mg/mL, 10 mg/2 mL, 50 mg/10 mL Rectal gel 2.5 mg/0.5 mL, 10 mg/2 mL, 20 mg/4 mL

How to Dose

Oral (anxiety, muscle spasm, seizure): 2– 10 mg, 2– 4 times/day

Oral (alcohol withdrawal): initial 10 mg, 3– 4 times/day for 1 day; reduce to 5 mg, 3– 4 times/day; continue treatment as needed

Liquid formulation should be mixed with water or fruit juice, applesauce, or pudding

Because of risk of respiratory depression, rectal diazepam treatment should not be given more than once in 5 days or more than twice

during a treatment course, especially for alcohol withdrawal or status epilepticus

Dosing Tips

âœ1⁄2 Only benzodiazepine with a formulation specifically for rectal

administration

âœ1⁄2 One of the few benzodiazepines available in an oral liquid formulation

âœ1⁄2 One of the few benzodiazepines available in an injectable formulation

Diazepam injection is intended for acute use; patients who require long-term treatment should be switched to the oral formulation

Use lowest possible effective dose for the shortest possible period of time (a benzodiazepine-sparing strategy)

Assess need for continued treatment regularly

Risk of dependence may increase with dose and duration of treatment

For interdose symptoms of anxiety, can either increase dose or maintain same total daily dose but divide into more frequent doses

Can also use an as-needed occasional “ top-up†dose for interdose anxiety

Because some anxiety disorder patients and muscle spasm patients can require doses higher than 40 mg/day or more, the risk of

dependence may be greater in these patients

Frequency of dosing in practice is often greater than predicted from half-life, as duration of biological activity is often shorter than pharmacokinetic terminal half-life

Overdose

Fatalities can occur; hypotension, tiredness, ataxia, confusion, coma

Long-Term Use

Evidence of efficacy up to 16 weeks

Risk of dependence, particularly for treatment periods longer than 12 weeks and especially in patients with past or current polysubstance abuse

Not recommended for long-term treatment of seizure disorders

Habit Forming

Diazepam is a Schedule IV drug

Patients may develop dependence and/or tolerance with long-term use

How to Stop

Patients with history of seizure may seize upon withdrawal, especially if withdrawal is abrupt

Taper by 2 mg every 3 days to reduce chances of withdrawal effects

For difficult-to-taper cases, consider reducing dose much more slowly after reaching 20 mg/day, perhaps by as little as 0.5– 1 mg every week or less

For other patients with severe problems discontinuing a benzodiazepine, dosing may need to be tapered over many months (i.e., reduce dose by 1% every 3 days by crushing tablet and suspending or dissolving in 100 mL of fruit juice and then disposing of 1 mL and drinking the rest; 3– 7 days later, dispose of 2 mL, and so on). This is both a form of very slow biological tapering and a form of behavioral desensitization

Be sure to differentiate reemergence of symptoms requiring reinstitution of treatment from withdrawal symptoms

Benzodiazepine-dependent anxiety patients and insulin-dependent diabetics are not addicted to their medications. When benzodiazepine-dependent patients stop their medication, disease symptoms can reemerge, disease symptoms can worsen (rebound), and/or withdrawal symptoms can emerge

Pharmacokinetics

Elimination half-life 20– 50 hours Substrate for CYP450 2C19 and 3A4 Food does not affect absorption

Drug Interactions

Increased depressive effects when taken with other CNS depressants (see Warnings below)

Cimetidine may reduce the clearance and raise the levels of diazepam

Flumazenil (used to reverse the effects of benzodiazepines) may precipitate seizures and should not be used in patients treated for seizure disorders with diazepam

Other Warnings/Precautions

Boxed warning regarding the increased risk of CNS depressant effects when benzodiazepines and opioid medications are used together, including specifically the risk of slowed or difficulty breathing and death

If alternatives to the combined use of benzodiazepines and opioids are not available, clinicians should limit the dosage and duration of each drug to the minimum possible while still achieving therapeutic efficacy

Patients and their caregivers should be warned to seek medical attention if unusual dizziness, lightheadedness, sedation, slowed or difficulty breathing, or unresponsiveness occur

Dosage changes should be made in collaboration with prescriber

Use with caution in patients with pulmonary disease; rare reports of death after initiation of benzodiazepines in patients with severe

pulmonary impairment

History of drug or alcohol abuse often creates greater risk for dependency

Some depressed patients may experience a worsening of suicidal ideation

Some patients may exhibit abnormal thinking or behavioral changes similar to those caused by other CNS depressants (i.e., either depressant actions or disinhibiting actions)

Do Not Use

If angle-closure glaucoma

If there is a proven allergy to diazepam or any benzodiazepine

Special populations Renal Impairment

Initial 2– 2.5 mg, 1– 2 times/day; increase gradually as needed

Hepatic Impairment

Initial 2– 2.5 mg, 1– 2 times/day; increase gradually as needed

Cardiac Impairment

Benzodiazepines have been used to treat anxiety associated with acute myocardial infarction

Diazepam may be used as an adjunct during cardiovascular emergencies

Elderly

Initial 2– 2.5 mg, 1– 2 times/day; increase gradually as needed

Children and Adolescents

6 months and up: initial 1– 2.5 mg, 3– 4 times/day; increase gradually as needed

Parenteral: 30 days or older

Rectal: 2 years or older

Long-term effects of diazepam in children/adolescents are unknown

Should generally receive lower doses and be more closely monitored

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Possible increased risk of birth defects when benzodiazepines are taken during pregnancy

Because of the potential risks, diazepam is not generally recommended as treatment for anxiety during pregnancy, especially during first trimester

Drug should be tapered if discontinued

Infants whose mothers received a benzodiazepine late in pregnancy may experience withdrawal effects

Neonatal flaccidity has been reported in infants whose mothers took a benzodiazepine during pregnancy

Seizures, even mild seizures, may cause harm to the embryo/fetus

Breast Feeding

Unknown if diazepam is secreted in human breast milk, but all psychotropics are assumed to be secreted in breast milk

âœ1⁄2 Recommended either to discontinue drug or bottle feed Effects of benzodiazepines on nursing infants have been reported

and include feeding difficulties, sedation, and weight loss

The art of psychopharmacology

Potential Advantages

Rapid onset of action

Availability of oral liquid, rectal, and injectable dosage formulations

Potential Disadvantages

Euphoria may lead to abuse

Abuse especially risky in past or present substance abusers

Can be sedating at doses necessary to treat moderately severe anxiety disorders

Primary Target Symptoms

Panic attacks

Anxiety

Incidence of seizures (adjunct) Muscle spasms

Pearls

Can be a useful adjunct to SSRIs and SNRIs in the treatment of numerous anxiety disorders, but not used as frequently as other benzodiazepines for this purpose

Not effective for treating psychosis as a monotherapy, but can be used as an adjunct to antipsychotics

Not effective for treating bipolar disorder as a monotherapy, but can be used as an adjunct to mood stabilizers and antipsychotics

âœ1⁄2 Diazepam is often the first-choice benzodiazepine to treat status epilepticus, and is administered either intravenously or rectally

Because diazepam suppresses stage 4 sleep, it may prevent night terrors in adults

May both cause depression and treat depression in different patients

Was once one of the most commonly prescribed drugs in the world and the most commonly prescribed benzodiazepine

âœ1⁄2 Remains a popular benzodiazepine for treating muscle spasms A commonly used benzodiazepine to treat sleep disorders

âœ1⁄2 Remains a popular benzodiazepine to treat acute alcohol withdrawal

Not especially useful as an oral anticonvulsant

âœ1⁄2 Multiple dosage formulations (oral tablet, oral liquid, rectal gel, injectable) allow more flexibility of administration compared to most other benzodiazepines

When using to treat insomnia, remember that insomnia may be a symptom of some other primary disorder itself, and thus warrant evaluation for comorbid psychiatric and/or medical conditions

Though not systematically studied, benzodiazepines have been used effectively to treat catatonia and are the initial recommended treatment

Suggested Reading

Ashton H . Guidelines for the rational use of benzodiazepines. When and what to use . Drugs 1994 ;48 :25 – 40 .

De Negri M , Baglietto MG . Treatment of status epilepticus in children . Paediatr Drugs 2001 ;3 :411– 20 .

Mandelli M , Tognoni G , Garattini S . Clinical pharmacokinetics of diazepam . Clin Pharmacokinet 1978 ;3 :72 – 91 .

Rey E , Treluver JM , Pons G . Pharmacokinetic optimization of benzodiazepine therapy for acute seizures. Focus on delivery routes . Clin Pharmacokinet 1999 ;36 :409– 24 .

Diphenhydramine

BenadrylSominex

Therapeutics Brands

Yes

Generic?

Class

see index for additional brand names

Antihistamine; anticholinergic agent

Commonly Prescribed for

(bold for FDA approved)

Allergy symptoms

Motion sickness Occasional sleeplessness Antiparkinsonism Drug-induced parkinsonism

How the Drug Works (for drug-induced parkinsonism)

Diminishes the excess acetylcholine activity caused by removal of dopamine inhibition when dopamine receptors are blocked

Also has potent histamine 1 antagonist properties

How Long Until It Works

For drug-induced parkinsonism and in Parkinsonâ€TM s disease, onset of action can be within minutes or hours

If It Works (for drug-induced parkinsonism)

Reduces motor side effects

Does not lessen the ability of antipsychotics to cause tardive dyskinesia

If It Doesnâ€TM t Work (for drug-induced parkinsonism)

Consider switching to trihexyphenidyl, benztropine, or a benzodiazepine

Disorders that develop after prolonged antipsychotic use may not respond to treatment

Consider discontinuing the agent that precipitated the parkinsonism

Best Augmenting Combos for Partial Response or Treatment Resistance

If ineffective, switch to another agent rather than augment Diphenhydramine itself is an augmenting agent to antipsychotics

Tests

Side effects

How Drug Causes Side Effects

Blocking histamine 1 receptors can cause sedation

Preventing the action of acetylcholine on muscarinic receptors can cause anticholinergic effects such as dry mouth, blurred vision, constipation

Notable Side Effects

Sedation, dizziness Constipation, nausea

Dry mouth, blurred vision

Life-Threatening or Dangerous Side Effects

Rare convulsions (at high doses) Urinary retention

Tachycardia, cardiac arrhythmias Confusion

Paralytic ileus/bowel obstruction

None for healthy individuals

Weight Gain

Frequent and can be significant in amount

Sedation

Many experience and/or can be significant in amount

What to Do About Side Effects

For confusion or hallucinations, discontinue use

For sedation, lower the dose and/or take the entire dose at night

For dry mouth, chew gum or drink water

For urinary retention, obtain a urological evaluation; may need to discontinue use

Best Augmenting Agents for Side Effects

Many side effects cannot be improved with an augmenting agent

Dosing and use Usual Dosage Range

Oral: 50 mg/day Injection: 10– 50 mg

Injection 50 mg/mL

Capsule 50 mg

Elixir 12.5 mg/5 mL

Dosage Forms

Also available in formulations in combination with other medications

How to Dose

Injection: 10– 50 mg intravenously at a rate not exceeding 25 mg/min or deep intramuscularly; can dose at 100 mg if required; maximum daily dose 400 mg

Dosing Tips

If drug-induced parkinsonism occurs soon after initiation of a neuroleptic drug, it is likely to be transient; thus, attempt to withdraw diphenhydramine after 1– 2 weeks to determine if still needed

The injection should be used for parkinsonism only if oral therapy is impossible or contraindicated

Overdose

CNS depression, CNS stimulation (more likely in pediatric patients), dry mouth, dilated pupils, flushing, gastrointestinal symptoms

Safe

Long-Term Use

Effectiveness may decrease over time, even after a few doses, but side effects such as cognitive impairment and sedation may persist

No

Habit Forming

How to Stop

Tapering generally not necessary

Pharmacokinetics

Plasma half-life approximately 8 hours; may be longer in children and in the elderly

Drug Interactions

May potentiate the effects of other CNS depressants

If anticholinergic agents are used with diphenhydramine, the anticholinergic effects may be enhanced

Other Warnings/Precautions

Use with caution in patients with a history of bronchial asthma, lower respiratory disease, increased intraocular pressure, hyperthyroidism, cardiovascular disease, or hypertension

May have additive effects if taken with anticholinergic agents

Do Not Use

In neonates or premature infants

In patients with glaucoma, particularly angle-closure glaucoma

In patients with pyloric or duodenal obstruction, stenosing peptic ulcers, prostate hypertrophy, or bladder neck obstructions

If patient is taking an MAOI

If there is a proven allergy to diphenhydramine

Special populations Renal Impairment

No dose adjustment necessary

Hepatic Impairment

No dose adjustment necessary

Cardiac Impairment

Not systematically evaluated in patients with cardiac impairment

Elderly

If patient is breast feeding

Some patients may tolerate lower doses better

Diphenhydramine injection is preferred for parkinsonism in the elderly who are unable to tolerate more potent agents

Children and Adolescents

Not recommended for children under age 12

Injection: 5 mg/kg/24 hours or 150 mg/m2 /24 hours; maximum daily dose 300 mg; divide into 4 doses; can be given intravenously at a rate not exceeding 25 mg/min, or deep intramuscularly

Contraindicated in neonates and premature infants

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women Animal studies have not shown adverse effects

Contraindicated

Breast Feeding

The art of psychopharmacology Potential Advantages

Mild cases of parkinsonism

Potential Disadvantages

Can be too sedating for some patients

Can cause confusion in elderly patients and in patients with dementia

Primary Target Symptoms

Drug-induced parkinsonism

Pearls

Can be useful for occasional insomnia

Patients with cognitive impairment may do poorly

Can cause cognitive side effects with chronic use, so periodic trials of discontinuation may be useful to justify continuous use, especially in institutional settings when used as an adjunct to antipsychotics

Can be abused in institutional or correctional settings

Suggested Reading

Gonzalez F. Diphenhydramine may be useful as a palliative treatment for patients dying with Parkinsonâ€TM s disease and tremors: a case report and discussion . Am J Hosp Palliat Care 2010 ;26 (6 ):474 – 5 .

Disulfiram

Antabuse

Therapeutics Brands

see index for additional brand names

Generic?

Class

Commonly Prescribed for

(bold for FDA approved)

Maintenance of alcohol abstinence

How the Drug Works

Irreversibly inhibits aldehyde dehydrogenase, the enzyme involved in second-stage metabolism of alcohol

Alcohol is metabolized to acetaldehyde, which in turn is metabolized by aldehyde dehydrogenase; thus, disulfiram blocks this second-stage metabolism

Yes

Alcohol dependence treatment

If alcohol is consumed by a patient taking disulfiram, toxic levels of acetaldehyde build up, causing unpleasant side effects

This aversive experience ideally leads to negative conditioning, in which patients abstain from alcohol in order to avoid the unpleasant effects

How Long Until It Works

Disulfiramâ€TM s effects are immediate; patients should not take disulfiram until at least 12 hours after drinking

If It Works

Increases abstinence from alcohol

If It Doesnâ€TM t Work

Patients who drink alcohol while taking disulfiram can experience side effects, including alcohol toxicity

Evaluate for and address contributing factors Consider switching to another agent

Best Augmenting Combos for Partial Response or Treatment Resistance

Augmentation with behavioral, educational, and/or supportive therapy in groups or as an individual is probably key to successful treatment

Tests

Baseline and follow-up liver function tests

Side effects

How Drug Causes Side Effects

When alcohol is consumed by a patient taking disulfiram, levels of acetaldehyde build up, causing side effects of alcohol toxicity

One of disulfiramâ€TM s metabolites is carbon disulfide, which may be excreted through the lungs; this could account for the side effect of metallic taste

Notable Side Effects

Metallic taste, dermatitis, sedation

Flushing, headache, tachycardia, nausea, vomiting (if alcohol is consumed)

Life-Threatening or Dangerous Side Effects

Hepatotoxicity

Myocardial infarction, congestive heart failure, respiratory depression, other signs of alcohol toxicity (if alcohol is consumed)

Weight Gain

Reported but not expected

Sedation

Occurs in significant minority

What to Do About Side Effects

Wait

Reduce dose

Take at night to reduce sedation

Best Augmenting Agents for Side Effects

Dose reduction or switching to another agent may be more effective since most side effects cannot be improved with an augmenting agent

Dosing and use Usual Dosage Range

250– 500 mg/day; 1-year duration

Dosage Forms

Tablet 250 mg, 500 mg scored

How to Dose

The patient should not take disulfiram until at least 12 hours after drinking

Initial 250– 500 mg/day for 1– 2 weeks

Usually dosed in the morning but can be dosed at night if sedation is a problem

Maintenance dose usually 250 mg/day; maximum dose 500 mg/day

Dosing Tips

The patient must be fully informed of the disulfiram-alcohol reaction

The patient should be advised not to consume any food or beverages containing alcohol or to use any alcohol-containing preparations (e.g., cough syrup)

The patient should be warned that reactions may occur up to 2 weeks after disulfiram is stopped

The patient should carry an emergency card stating that he or she is taking disulfiram

Unknown

Overdose

Long-Term Use

Maintenance treatment should be continued until the patient is recovered

No

Taper not necessary

Habit Forming

How to Stop

A disulfiram-alcohol reaction may occur for up to 2 weeks after disulfiram is stopped

Pharmacokinetics

Half-life of parent drug is 60– 120 hours

Half-life of metabolites is 13.9 hours (diethyldithiocarbamate) and 8.9 hours (carbon disulfide)

Drug Interactions

Disulfiram may increase blood levels of phenytoin; baseline and follow-up levels of phenytoin should be taken

Disulfiram may prolong prothrombin time, requiring dose adjustment of oral anticoagulants

Use with isoniazid may lead to unsteady gait or change in mental status

Other Warnings/Precautions

Disulfiram should not be given to a patient in a state of alcohol intoxication or without the patientâ€TM s full knowledge

Not recommended for patients older than age 60 or for those with severe pulmonary disease, chronic renal failure, diabetes, peripheral neuropathy, seizures, cirrhosis, or portal hypertension

Use with extreme caution in patients with hypothyroidism, epilepsy, cerebral damage

Patients taking disulfiram should not be exposed to ethylene dibromide or its vapors, as this has resulted in a higher incidence of tumors in rats

Do Not Use

If the patient is in a state of alcohol intoxication

Without the patientâ€TM s full knowledge

For at least 12 hours after the patient last drank

If patient is taking metronidazole, amprenavir, ritonavir, or sertraline If patient has psychosis

If patient has cardiovascular disease

If there is a proven allergy to disulfiram

If there is a proven allergy to thiuram derivatives

Special populations Renal Impairment

Not recommended for patients with chronic renal failure

Not recommended

Contraindicated

Hepatic Impairment

Cardiac Impairment

Elderly

Not generally recommended for patients older than age 60 Some patients may tolerate lower doses better

Children and Adolescents

Safety and efficacy have not been established

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR

or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women Some animal studies have shown adverse effects

Pregnant women needing to stop drinking may consider behavioral therapy before pharmacotherapy

Not generally recommended for use during pregnancy, especially during first trimester

Breast Feeding

Unknown if disulfiram is secreted in human breast milk, but all psychotropics are assumed to be secreted in breast milk

âœ1⁄2 Recommended either to discontinue drug or bottle feed

The art of psychopharmacology Potential Advantages

Individuals who are motivated to abstain from alcohol

Potential Disadvantages

Adherence rates can be low

Primary Target Symptoms

Alcohol dependence

Pearls

Some evidence of efficacy in comorbid alcohol use disorder and PTSD

Preliminary evidence of efficacy for use in cocaine dependence, both alone and comorbid with alcohol use disorder

Suggested Reading

Barth KS , Malcolm RJ . Disulfiram: an old therapeutic with new applications . CNS Neurol Disord Drug Targets 2010 ;9 (1 ):5 – 12.

Jorgensen CH , Pedersen B , Tonnesen H. The efficacy of disulfiram for the treatment of alcohol use disorder . Alcohol Clin Exp Res 2011 ;35 (10 ):1749 – 58.

Pani PP , Troqu E , Vacca R , et al. Disulfiram for the treatment of cocaine dependence . Cochrane Database Syst Rev 2010 ;20 (1 ):CD007024 .

Donepezil

Yes

Generic?

Class

Aricept

Memac

see index for additional brand names

Therapeutics Brands

Neuroscience-based Nomenclature: acetylcholine enzyme inhibitor (ACh-EI)

Cholinesterase inhibitor (selective acetylcholinesterase inhibitor); cognitive enhancer

Commonly Prescribed for

(bold for FDA approved)

Alzheimer disease (mild, moderate, and severe)

Memory disorders in other conditions Mild cognitive impairment

How the Drug Works

âœ1⁄2 Reversibly but noncompetitively inhibits centrally active

acetylcholinesterase (AChE), making more acetylcholine available

Increased availability of acetylcholine compensates in part for degenerating cholinergic neurons in neocortex that regulate memory

Does not inhibit butyrylcholinesterase

May release growth factors or interfere with amyloid deposition

How Long Until It Works

May take up to 6 weeks before any improvement in baseline memory or behavior is evident

May take months before any stabilization in degenerative course is evident

If It Works

May improve symptoms and slow progression of disease, but does not reverse the degenerative process

If It Doesnâ€TM t Work

Consider adjusting dose, switching to a different cholinesterase inhibitor, or adding an appropriate augmenting agent

Reconsider diagnosis and rule out other conditions such as depression or a dementia other than Alzheimer disease

Best Augmenting Combos for Partial Response or Treatment Resistance

âœ1⁄2 Atypical antipsychotics to reduce behavioral disturbances âœ1⁄2 Antidepressants if concomitant depression, apathy, or lack of

interest

âœ1⁄2 Memantine for moderate to severe Alzheimer disease

Divalproex, carbamazepine, or oxcarbazepine for behavioral disturbances

Not rational to combine with another cholinesterase inhibitor

Tests

Side effects

How Drug Causes Side Effects

Peripheral inhibition of acetylcholinesterase can cause gastrointestinal side effects

Central inhibition of acetylcholinesterase may contribute to nausea, vomiting, weight loss, and sleep disturbances

Notable Side Effects

âœ1⁄2 Nausea, diarrhea, vomiting, appetite loss, increased gastric acid secretion, weight loss

None for healthy individuals

Insomnia, dizziness

Muscle cramps, fatigue, depression, abnormal dreams

Life-Threatening or Dangerous Side Effects

Rare seizures Rare syncope

Weight Gain

Reported but not expected

Some patients may experience weight loss

Sedation

What to Do About Side Effects

Wait

Wait

Wait

Take in daytime to reduce insomnia Use slower dose titration

Reported but not expected

Consider lowering dose, switching to a different agent, or adding an appropriate augmenting agent

Best Augmenting Agents for Side Effects

Hypnotics or trazodone may improve insomnia

Many side effects cannot be improved with an augmenting agent

5– 10 mg at night

Dosing and use Usual Dosage Range

Dosage Forms

Tablet 5 mg, 10 mg, 23 mg

Orally disintegrating tablet 5 mg, 10 mg

Namzaric extended-release (combination memantine/donepezil) 7 mg/10 mg, 14 mg/10 mg, 21 mg/10 mg, 28 mg/10 mg

How to Dose

Initial 5 mg/day; may increase to 10 mg/day after 4– 6 weeks

Namzaric, for patients already on donepezil 10 mg once daily: initial dose 7 mg/10 mg once daily in the evening; increase weekly in 7 mg increments; maximum dose 28 mg/10 mg

Namzaric, for patients already on memantine (10 mg twice per day or 28 mg extended-release once per day) and donepezil 10 mg once daily: can switch to 28 mg/10 mg once daily in the evening

Dosing Tips

Side effects occur more frequently at higher doses than at lower doses

Slower titration (e.g., 6 weeks to 10 mg/day) may reduce the risk of side effects

Food does not affect the absorption of donepezil

Probably best to utilize highest tolerated dose within the usual dosage range

Some off-label uses for cognitive disturbances other than Alzheimer disease have anecdotally utilized doses higher than 10 mg/day

âœ1⁄2 When switching to another cholinesterase inhibitor, probably best to cross-titrate from one to the other to prevent precipitous decline in function if the patient washes out of one drug entirely

Namzaric can be taken with or without food, whole or sprinkled on applesauce; do not divide, chew, or crush

Overdose

Can be lethal; nausea, vomiting, excess salivation, sweating, hypotension, bradycardia, collapse, convulsions, muscle weakness (weakness of respiratory muscles can lead to death)

Long-Term Use

Drug may lose effectiveness in slowing degenerative course of Alzheimer disease after 6 months

Can be effective in some patients for several years

No

Habit Forming

How to Stop

Taper to avoid withdrawal effects

Discontinuation may lead to notable deterioration in memory and behavior, which may not be restored when drug is restarted or another cholinesterase inhibitor is initiated

Pharmacokinetics

Metabolized by CYP450 2D6 and CYP450 3A4 Elimination half-life approximately 70 hours

Drug Interactions

Donepezil may increase the effects of anesthetics and should be discontinued prior to surgery

Inhibitors of CYP450 2D6 and CYP450 3A4 may inhibit donepezil metabolism and increase its plasma levels

Inducers of CYP450 2D6 and CYP450 3A4 may increase clearance of donepezil and decrease its plasma levels

Donepezil may interact with anticholinergic agents and the combination may decrease the efficacy of both

May have synergistic effect if administered with cholinomimetics (e.g., bethanechol)

Bradycardia may occur if combined with beta blockers

Theoretically, could reduce the efficacy of levodopa in Parkinsonâ€TM s disease

Not rational to combine with another cholinesterase inhibitor

Other Warnings/Precautions

May exacerbate asthma or other pulmonary disease

Increased gastric acid secretion may increase the risk of ulcers

Bradycardia or heart block may occur in patients with or without cardiac impairment

Do Not Use

If there is a proven allergy to donepezil

Special populations Renal Impairment

Few data available but dose adjustment is most likely unnecessary

Severe renal impairment: the recommended maintenance dose for Namzaric is 14 mg/10 mg once daily in the evening

Hepatic Impairment

Few data available; may need to lower dose

Cardiac Impairment

Should be used with caution

Syncopal episodes have been reported with the use of donepezil

Elderly

Some patients may tolerate lower doses better

Use of cholinesterase inhibitors may be associated with increased rates of syncope, bradycardia, pacemaker insertion, and hip fracture in older adults with dementia

Children and Adolescents

Safety and efficacy have not been established

Preliminary reports of efficacy as an adjunct in attention deficit hyperactivity disorder (ADHD) (ages 8– 17)

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women

âœ1⁄2 Not recommended for use in pregnant women or women of childbearing potential

Breast Feeding

Unknown if donepezil is secreted in human breast milk, but all psychotropics are assumed to be secreted in breast milk

âœ1⁄2 Recommended either to discontinue drug or bottle feed Donepezil is not recommended for use in nursing women

The art of psychopharmacology Potential Advantages

Once a day dosing

May be used in vascular dementia

May work in some patients who do not respond to other cholinesterase inhibitors

May work in some patients who do not tolerate other cholinesterase inhibitors

Potential Disadvantages

Patients with insomnia

Primary Target Symptoms

Memory loss in Alzheimer disease Behavioral symptoms in Alzheimer disease Memory loss in other dementias

Pearls

A fixed-dose combination of memantine extended-release and donepezil (Namzaric) has been approved for the treatment of moderate to severe Alzheimer dementia in patients stabilized on memantine and donepezil

Dramatic reversal of symptoms of Alzheimer disease is not generally seen with cholinesterase inhibitors

Can lead to therapeutic nihilism among prescribers and lack of an appropriate trial of a cholinesterase inhibitor

âœ1⁄2 Perhaps only 50% of Alzheimer patients are diagnosed, and only 50% of those diagnosed are treated, and only 50% of those treated are given a cholinesterase inhibitor, and then only for 200 days in a disease that lasts 7– 10 years

Must evaluate lack of efficacy and loss of efficacy over months, not weeks

âœ1⁄2 Treats behavioral and psychological symptoms of Alzheimer dementia as well as cognitive symptoms (i.e., especially apathy, disinhibition, delusions, anxiety, cooperation, pacing)

Patients who complain themselves of memory problems may have depression, whereas patients whose spouses or children complain of the patientâ€TM s memory problems may have Alzheimer disease

Treat the patient but ask the caregiver about efficacy What you see may depend upon how early you treat

The first symptoms of Alzheimer disease are generally mood changes; thus, Alzheimer disease may initially be diagnosed as depression

Women may experience cognitive symptoms in perimenopause as a result of hormonal changes that are not a sign of dementia or Alzheimer disease

Aggressively treat concomitant symptoms with augmentation (e.g., atypical antipsychotics for agitation, antidepressants for depression)

If treatment with antidepressants fails to improve apathy and depressed mood in the elderly, it is possible that this represents early Alzheimer disease and a cholinesterase inhibitor like donepezil may be helpful

What to expect from a cholinesterase inhibitor:

Patients do not generally improve dramatically although this can be observed in a significant minority of patients

Onset of behavioral problems and nursing home placement can be delayed

Functional outcomes, including activities of daily living, can be preserved

Caregiver burden and stress can be reduced

Delay in progression in Alzheimer disease is not evidence of disease-modifying actions of cholinesterase inhibition

Cholinesterase inhibitors like donepezil depend upon the presence of intact targets for acetylcholine for maximum effectiveness and thus may be most effective in the early stages of Alzheimer disease

The most prominent side effects of donepezil are gastrointestinal effects, which are usually mild and transient

âœ1⁄2 May cause more sleep disturbances than some other cholinesterase inhibitors

For patients with intolerable side effects, generally allow a washout period with resolution of side effects prior to switching to another cholinesterase inhibitor

Weight loss can be a problem in Alzheimer patients with debilitation and muscle wasting

Women over 85, particularly with low body weights, may experience more adverse effects

Use with caution in underweight or frail patients

Cognitive improvement may be linked to substantial (>65%) inhibition of acetylcholinesterase

Donepezil has greater action on CNS acetylcholinesterase than on peripheral acetylcholinesterase

Some Alzheimer patients who fail to respond to donepezil may respond to another cholinesterase inhibitor

Some Alzheimer patients who fail to respond to another cholinesterase inhibitor may respond when switched to donepezil

To prevent potential clinical deterioration, generally switch from long-term treatment with one cholinesterase inhibitor to another without a washout period

âœ1⁄2 Donepezil may slow the progression of mild cognitive impairment to Alzheimer disease

âœ1⁄2 May be useful for dementia with Lewy bodies (DLB, constituted by early loss of attentiveness and visual perception with possible hallucinations, Parkinson-like movement problems, fluctuating cognition such as daytime drowsiness and lethargy, staring into space for long periods, episodes of disorganized speech)

May decrease delusions, apathy, agitation, and hallucinations in dementia with Lewy bodies

âœ1⁄2 May be useful for vascular dementia (e.g., acute onset with slow stepwise progression that has plateaus, often with gait abnormalities, focal signs, imbalance, and urinary incontinence)

May be helpful for dementia in Downâ€TM s syndrome

Suggestions of utility in some cases of treatment-resistant bipolar disorder

Theoretically, may be useful for ADHD, but not yet proven

Theoretically, could be useful in any memory condition characterized by cholinergic deficiency (e.g., some cases of brain injury, cancer chemotherapy-induced cognitive changes, etc.)

Suggested Reading

Bentue-Ferrer D , Tribut O , Polard E , Allain H . Clinically significant drug interactions with cholinesterase inhibitors: a guide for neurologists . CNS Drugs 2003 ;17 :947– 63 .

Birks JS , Harvey R . Donepezil for dementia due to Alzheimerâ€TM s disease . Cochrane Database Syst Rev 2003 ;(1):CD001190 .

Bonner LT , Peskind ER . Pharmacologic treatments of dementia . Med Clin North Am 2002 ;86 :657– 74 .

Jones RW . Have cholinergic therapies reached their clinical boundary in Alzheimerâ€TM s disease ? Int J Geriatr Psychiatry 2003 ;18 (Suppl 1):S7 – 13.

Seltzer B . Donepezil: an update . Expert Opin Pharmacother 2007 ;8 (7 ):1011 – 23.

Dothiepin

Prothiaden

Therapeutics Brands

see index for additional brand names

In UK

Generic?

Class

Neuroscience-based Nomenclature: serotonin, norepinephrine multimodal (SN-MM)

Tricyclic antidepressant (TCA)

Serotonin and norepinephrine/noradrenaline reuptake inhibitor

Commonly Prescribed for

(bold for FDA approved)

Major depressive disorder Anxiety

Insomnia

Neuropathic pain/chronic pain

Treatment-resistant depression

How the Drug Works

Boosts neurotransmitters serotonin and norepinephrine/noradrenaline

Blocks serotonin reuptake pump (serotonin transporter), presumably increasing serotonergic neurotransmission

Blocks norepinephrine reuptake pump (norepinephrine transporter), presumably increasing noradrenergic neurotransmission

Presumably desensitizes both serotonin 1A receptors and beta adrenergic receptors

Since dopamine is inactivated by norepinephrine reuptake in frontal cortex, which largely lacks dopamine transporters, dothiepin can increase dopamine neurotransmission in this part of the brain

How Long Until It Works

May have immediate effects in treating insomnia or anxiety

Onset of therapeutic actions usually not immediate, but often delayed 2– 4 weeks

If it is not working within 6– 8 weeks for depression, it may require a dosage increase or it may not work at all

May continue to work for many years to prevent relapse of symptoms

If It Works

The goal of treatment of depression is complete remission of current symptoms as well as prevention of future relapses

The goal of treatment of chronic neuropathic pain is to reduce symptoms as much as possible, especially in combination with other treatments

Treatment of depression most often reduces or even eliminates symptoms, but not a cure since symptoms can recur after medicine stopped

Treatment of chronic neuropathic pain may reduce symptoms, but rarely eliminates them completely, and is not a cure since symptoms can recur after medicine is stopped

Continue treatment of depression until all symptoms are gone (remission)

Once symptoms of depression are gone, continue treating for 1 year for the first episode of depression

For second and subsequent episodes of depression, treatment may need to be indefinite

Use in anxiety disorders and chronic pain may also need to be indefinite, but long-term treatment is not well studied in these conditions

If It Doesnâ€TM t Work

Many depressed patients have only a partial response where some symptoms are improved but others persist (especially insomnia, fatigue, and problems concentrating)

Other depressed patients may be nonresponders, sometimes called treatment-resistant or treatment-refractory

Consider increasing dose, switching to another agent, or adding an appropriate augmenting agent

Consider psychotherapy

Consider evaluation for another diagnosis or for a comorbid condition (e.g., medical illness, substance abuse, etc.)

Some patients may experience apparent lack of consistent efficacy due to activation of latent or underlying bipolar disorder, and require antidepressant discontinuation and a switch to a mood stabilizer

Best Augmenting Combos for Partial Response or Treatment Resistance

Lithium, buspirone, thyroid hormone (for depression)

Gabapentin, tiagabine, other anticonvulsants, even opiates if done by experts while monitoring carefully in difficult cases (for chronic pain)

Tests

Baseline ECG is recommended for patients over age 50

âœ1⁄2 Since tricyclic and tetracyclic antidepressants are frequently associated with weight gain, before starting treatment, weigh all patients and determine if the patient is already overweight (BMI 25.0– 29.9) or obese (BMI ≥ 30)

Before giving a drug that can cause weight gain to an overweight or obese patient, consider determining whether the patient already has pre-diabetes (fasting plasma glucose 100– 125 mg/dL), diabetes (fasting plasma glucose ≥ 126 mg/dL), or dyslipidemia (increased total cholesterol, LDL cholesterol, and triglycerides; decreased HDL cholesterol), and treat or refer such patients for treatment including nutrition and weight management, physical activity counseling, smoking cessation, and medical management

âœ1⁄2 Monitor weight and BMI during treatment

âœ1⁄2 While giving a drug to a patient who has gained >5% of initial weight, consider evaluating for the presence of pre-diabetes, diabetes, or dyslipidemia, or consider switching to a different antidepressant

ECGs may be useful for selected patients (e.g., those with personal or family history of QTc prolongation; cardiac arrhythmia; recent myocardial infarction; uncompensated heart failure; or taking agents that prolong QTc interval such as pimozide, thioridazine, selected antiarrhythmics, moxifloxacin, sparfloxacin, etc.)

Patients at risk for electrolyte disturbances (e.g., patients on diuretic therapy) should have baseline and periodic serum potassium and magnesium measurements

Side effects

How Drug Causes Side Effects

Anticholinergic activity may explain sedative effects, dry mouth, constipation, and blurred vision

Sedative effects and weight gain may be due to antihistamine properties

Blockade of alpha adrenergic 1 receptors may explain dizziness, sedation, and hypotension

Cardiac arrhythmias and seizures, especially in overdose, may be caused by blockade of ion channels

Notable Side Effects

Blurred vision, constipation, urinary retention, increased appetite, dry mouth, nausea, diarrhea, heartburn, unusual taste in mouth, weight gain

Fatigue, weakness, dizziness, sedation, headache, anxiety, nervousness, restlessness

Sexual dysfunction, sweating

Life-Threatening or Dangerous Side Effects

Paralytic ileus, hyperthermia (TCAs + anticholinergic agents) Lowered seizure threshold and rare seizures

Orthostatic hypotension, sudden death, arrhythmias, tachycardia

QTc prolongation

Hepatic failure, drug-induced parkinsonism Increased intraocular pressure

Rare induction of mania

Rare activation of suicidal ideation and behavior (suicidality) (short- term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo beyond age 24)

Weight Gain

Many experience and/or can be significant in amount Can increase appetite and carbohydrate craving

Sedation

Many experience and/or can be significant in amount Tolerance to sedative effect may develop with long-term use

Wait

Wait

Wait

Lower the dose

What to Do About Side Effects

Switch to an SSRI or newer antidepressant

Best Augmenting Agents for Side Effects

Many side effects cannot be improved with an augmenting agent

75– 150 mg/day

Capsule 25 mg Tablet 75 mg

Dosing and use Usual Dosage Range

Dosage Forms

How to Dose

75 mg/day once daily or in divided doses; gradually increase dose to achieve desired therapeutic effect; maximum dose 300 mg/day

Dosing Tips

If given in a single dose, should generally be administered at bedtime because of its sedative properties

If given in split doses, largest dose should generally be given at bedtime because of its sedative properties

If patients experience nightmares, split dose and do not give large dose at bedtime

Patients treated for chronic pain may only require lower doses Risk of seizure increases with dose

If intolerable anxiety, insomnia, agitation, akathisia, or activation occur upon either dosing initiation or discontinuation, consider the possibility of activated bipolar disorder, and switch to a mood stabilizer or an atypical antipsychotic

Overdose

Death may occur; convulsions, cardiac dysrhythmias, severe hypotension, CNS depression, coma, changes in ECG

Safe

No

Long-Term Use

Habit Forming

How to Stop

Taper to avoid withdrawal effects

Even with gradual dose reduction some withdrawal symptoms may appear within the first 2 weeks

Many patients tolerate 50% dose reduction for 3 days, then another 50% reduction for 3 days, then discontinuation

If withdrawal symptoms emerge during discontinuation, raise dose to stop symptoms and then restart withdrawal much more slowly

Pharmacokinetics

Substrate for CYP450 2D6

Half-life approximately 14– 40 hours

Drug Interactions

Tramadol increases the risk of seizures in patients taking TCAs

Use of TCAs with anticholinergic drugs may result in paralytic ileus or hyperthermia

Fluoxetine, paroxetine, bupropion, duloxetine, and other CYP450 2D6 inhibitors may increase TCA concentrations

Cimetidine may increase plasma concentrations of TCAs and cause anticholinergic symptoms

Phenothiazines or haloperidol may raise TCA blood concentrations

May alter effects of antihypertensive drugs; may inhibit hypotensive effects of clonidine

Use of TCAs with sympathomimetic agents may increase sympathetic activity

Methylphenidate may inhibit metabolism of TCAs

Activation and agitation, especially following switching or adding antidepressants, may represent the induction of a bipolar state, especially a mixed dysphoric bipolar II condition sometimes associated with suicidal ideation, and require the addition of lithium, a mood stabilizer or an atypical antipsychotic, and/or discontinuation of dothiepin

Other Warnings/Precautions

Add or initiate other antidepressants with caution for up to 2 weeks after discontinuing dothiepin

Generally, do not use with MAOIs, including 14 days after MAOIs are stopped; do not start an MAOI for at least 5 half-lives (5 to 7 days for most drugs) after discontinuing dothiepin, but see Pearls

Use with caution in patients with history of seizures, urinary retention, angle-closure glaucoma, hyperthyroidism, and in patients recovering from myocardial infarction

TCAs can increase QTc interval, especially at toxic doses, which can be attained not only by overdose but also by combining with drugs that inhibit TCA metabolism via CYP450 2D6, potentially causing torsade de pointes-type arrhythmia or sudden death

Because TCAs can prolong QTc interval, use with caution in patients who have bradycardia or who are taking drugs that can induce bradycardia (e.g., beta blockers, calcium channel blockers, clonidine, digitalis)

Because TCAs can prolong QTc interval, use with caution in patients who have hypokalemia and/or hypomagnesemia or who are taking drugs that can induce hypokalemia and/or magnesemia (e.g., diuretics, stimulant laxatives, intravenous amphotericin B, glucocorticoids, tetracosactide)

When treating children, carefully weigh the risks and benefits of pharmacological treatment against the risks and benefits of nontreatment with antidepressants and make sure to document this in the patientâ€TM s chart

Distribute the brochures provided by the FDA and the drug companies

Whenever possible, warn patients and their caregivers about the possibility of activating side effects, and advise them to report such symptoms immediately

Monitor patients for activation of suicidal ideation, especially children and adolescents

Do Not Use

If patient is recovering from myocardial infarction

If patient is taking agents capable of significantly prolonging QTc interval (e.g., pimozide, thioridazine, selected antiarrhythmics, moxifloxacin, sparfloxacin)

If there is a history of QTc prolongation or cardiac arrhythmia, recent acute myocardial infarction, uncompensated heart failure

If patient is taking drugs that inhibit TCA metabolism, including CYP450 2D6 inhibitors, except by an expert

If there is reduced CYP450 2D6 function, such as patients who are poor 2D6 metabolizers, except by an expert and at low doses

If there is a proven allergy to dothiepin

Use with caution

Use with caution

Special populations Renal Impairment

Hepatic Impairment

Cardiac Impairment

Baseline ECG is recommended

TCAs have been reported to cause arrhythmias, prolongation of conduction time, orthostatic hypotension, sinus tachycardia, and heart failure, especially in the diseased heart

Myocardial infarction and stroke have been reported with TCAs

TCAs produce QTc prolongation, which may be enhanced by the existence of bradycardia, hypokalemia, congenital or acquired long QTc interval, which should be evaluated prior to administering dothiepin

Use with caution if treating concomitantly with a medication likely to produce prolonged bradycardia, hypokalemia, slowing of intracardiac conduction, or prolongation of the QTc interval

Avoid TCAs in patients with a known history of QTc prolongation, recent acute myocardial infarction, and uncompensated heart failure

TCAs may cause a sustained increase in heart rate in patients with ischemic heart disease and may worsen (decrease) heart rate variability, an independent risk of mortality in cardiac populations

Since SSRIs may improve (increase) heart rate variability in patients following a myocardial infarct and may improve survival as well as mood in patients with acute angina or following a myocardial infarction, these are more appropriate agents for cardiac population than tricyclic/tetracyclic antidepressants

âœ1⁄2 Risk/benefit ratio may not justify use of TCAs in cardiac impairment

Elderly

Baseline ECG is recommended for patients over age 50

May be more sensitive to anticholinergic, cardiovascular, hypotensive, and sedative effects

Reduction in the risk of suicidality with antidepressants compared to placebo in adults age 65 and older

Children and Adolescents

Carefully weigh the risks and benefits of pharmacological treatment against the risks and benefits of nontreatment with antidepressants and make sure to document this in the patientâ€TM s chart

Monitor patients face-to-face regularly, particularly during the first several weeks of treatment

Use with caution, observing for activation of known or unknown bipolar disorder and/or suicidal ideation, and inform parents or guardians of this risk so they can help observe child or adolescent patients

Not recommended for use in children under age 18

Several studies show lack of efficacy of TCAs for depression

May be used to treat enuresis or hyperactive/impulsive behaviors Some cases of sudden death have occurred in children taking TCAs

Pregnancy

Controlled studies have not been conducted in pregnant women Crosses the placenta

Adverse effects have been reported in infants whose mothers took a TCA (lethargy, withdrawal symptoms, fetal malformations)

Not generally recommended for use during pregnancy, especially during first trimester

Must weigh the risk of treatment (first trimester fetal development, third trimester newborn delivery) to the child against the risk of no

treatment (recurrence of depression, maternal health, infant bonding) to the mother and child

For many patients this may mean continuing treatment during pregnancy

National Pregnancy Registry for Antidepressants: 1-866-961-2388,

https://womensmentalhealth.org/research/pregnancyregistry/antidepr essants

Breast Feeding

Some drug is found in motherâ€TM s breast milk

âœ1⁄2 Recommended either to discontinue drug or bottle feed

Immediate postpartum period is a high-risk time for depression, especially in women who have had prior depressive episodes, so drug may need to be reinstituted late in the third trimester or shortly after childbirth to prevent a recurrence during the postpartum period

Must weigh benefits of breast feeding with risks and benefits of antidepressant treatment versus nontreatment to both the infant and the mother

For many patients this may mean continuing treatment during breast feeding

The art of psychopharmacology Potential Advantages

Patients with insomnia

Severe or treatment-resistant depression Anxious depression

Potential Disadvantages

Pediatric and geriatric patients Patients concerned with weight gain Cardiac patients

Primary Target Symptoms

Depressed mood Chronic pain

Pearls

âœ1⁄2 Close structural similarity to amitriptyline

TCAs are often a first-line treatment option for chronic pain

TCAs are no longer generally considered a first-line option for depression because of their side effect profile

TCAs continue to be useful for severe or treatment-resistant depression

TCAs may aggravate psychotic symptoms

Alcohol should be avoided because of additive CNS effects

Underweight patients may be more susceptible to adverse cardiovascular effects

Children, patients with inadequate hydration, and patients with cardiac disease may be more susceptible to TCA-induced cardiotoxicity than healthy adults

For the expert only: a heroic treatment (but potentially dangerous) for severely treatment-resistant patients is to give simultaneously with MAOIs for patients who fail to respond to numerous other antidepressants, but generally recommend a different TCA than dothiepin for this use

If this option is elected, start the MAOI with the tricyclic/tetracyclic antidepressant simultaneously at low doses after appropriate drug washout, then alternately increase doses of these agents every few days to a week as tolerated

Although very strict dietary and concomitant drug restrictions must be observed to prevent hypertensive crises and serotonin syndrome, the most common side effects of MAOI and tricyclic/tetracyclic antidepressant combinations may be weight gain and orthostatic hypotension

Patients on TCAs should be aware that they may experience symptoms such as photosensitivity or blue-green urine

SSRIs may be more effective than TCAs in women, and TCAs may be more effective than SSRIs in men

Since tricyclic/tetracyclic antidepressants are substrates for CYP450 2D6, and 7% of the population (especially Caucasians) may have a genetic variant leading to reduced activity of 2D6, such patients may not safely tolerate normal doses of tricyclic/tetracyclic antidepressants and may require dose reduction

Phenotypic testing may be necessary to detect this genetic variant prior to dosing with a tricyclic/tetracyclic antidepressant, especially in vulnerable populations such as children, elderly, cardiac populations, and those on concomitant medications

Patients who seem to have extraordinarily severe side effects at normal or low doses may have this phenotypic CYP450 2D6 variant and require low doses or switching to another antidepressant not metabolized by 2D6

Suggested Reading

Anderson IM . Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability . J Aff Disorders 2000 ;58 :19 – 36 .

Anderson IM . Meta-analytical studies on new antidepressants . Br Med Bull 2001 ; 57 :161– 78 .

Donovan S , Dearden L , Richardson L . The tolerability of dothiepin: a review of clinical studies between 1963 and 1990 in over 13,000 depressed patients . Prog Neuropsychopharmacol Biol Psychiatry 1994 ; 18 :1143 – 62.

Lancaster SG , Gonzalez JP . Dothiepin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness . Drugs 1989 ;38 :123– 47 .

Doxepin

SinequanSilenor

Therapeutics Brands

Yes

Generic?

Class

see index for additional brand names

Neuroscience-based Nomenclature: serotonin, norepinephrine multimodal (SN-MM)

Tricyclic antidepressant (TCA)

Serotonin and norepinephrine/noradrenaline reuptake inhibitor Antihistamine

Commonly Prescribed for

(bold for FDA approved)

Psychoneurotic patient with depression and/or anxiety Depression and/or anxiety associated with alcoholism Depression and/or anxiety associated with organic disease

Psychotic depressive disorders with associated anxiety Involutional depression

Manic-depressive disorder

Insomnia (difficulty with sleep maintenance) (Silenor only)

âœ1⁄2 Pruritus/itching (topical) Dermatitis, atopic (topical)

Lichen simplex chronicus (topical) Anxiety

Neuropathic pain/chronic pain Treatment-resistant depression

How the Drug Works

At antidepressant doses:

Boosts neurotransmitters serotonin and norepinephrine/noradrenaline

Blocks serotonin reuptake pump (serotonin transporter), presumably increasing serotonergic neurotransmission

Blocks norepinephrine reuptake pump (norepinephrine transporter), presumably increasing noradrenergic neurotransmission

Presumably desensitizes both serotonin 1A receptors and beta adrenergic receptors

Since dopamine is inactivated by norepinephrine reuptake in frontal cortex, which largely lacks dopamine transporters, doxepin can thus increase dopamine neurotransmission in this part of the brain

May be effective in treating skin conditions because of its strong antihistamine properties

At hypnotic doses (3– 6 mg/day):

Selectively and potently blocks histamine 1 receptors, presumably decreasing wakefulness and thus promoting sleep

How Long Until It Works

May have immediate effects in treating insomnia or anxiety

Onset of therapeutic actions in depression is usually not immediate, but often delayed 2– 4 weeks

If it is not working within 6– 8 weeks for depression, it may require a dosage increase or it may not work at all

May continue to work for many years to prevent relapse of depressive symptoms

May also work long-term for insomnia (studied for up to 12 weeks)

If It Works

The goal of treatment of depression is complete remission of current symptoms as well as prevention of future relapses

The goal of treatment of insomnia is to improve quality of sleep, including effects on total wake-time and number of nighttime awakenings

The goal of treatment of chronic neuropathic pain is to reduce symptoms as much as possible, especially in combination with other treatments

Treatment of depression most often reduces or even eliminates symptoms, but not a cure since symptoms can recur after medicine stopped

Treatment of chronic neuropathic pain may reduce symptoms, but rarely eliminates them completely, and is not a cure since symptoms can recur after medicine is stopped

Continue treatment of depression until all symptoms are gone (remission)

Once symptoms of depression are gone, continue treating for 1 year for the first episode of depression

For second and subsequent episodes of depression, treatment may need to be indefinite

Use in anxiety disorders, chronic pain, and skin conditions may also need to be indefinite, but long-term treatment is not well studied in these conditions

If It Doesnâ€TM t Work

Many depressed patients have only a partial response where some symptoms are improved but others persist (especially insomnia, fatigue, and problems concentrating)

Other depressed patients may be nonresponders, sometimes called treatment-resistant or treatment-refractory

Consider increasing dose, switching to another agent, or adding an appropriate augmenting agent

Consider psychotherapy

Consider evaluation for another diagnosis or for a comorbid condition (e.g., medical illness, substance abuse, etc.)

Some patients may experience apparent lack of consistent efficacy due to activation of latent or underlying bipolar disorder, and require antidepressant discontinuation and a switch to a mood stabilizer

If insomnia does not improve after 7– 10 days, it may be a manifestation of a primary psychiatric or physical illness such as obstructive sleep apnea or restless leg syndrome, which requires independent evaluation

Best Augmenting Combos for Partial Response or Treatment Resistance

Lithium, buspirone, thyroid hormone (for depression) Trazodone, GABA-ergic sedative hypnotics (for insomnia)

Gabapentin, tiagabine, other anticonvulsants, even opiates if done by experts while monitoring carefully in difficult cases (for chronic

pain)

Tests

Baseline ECG is recommended for patients over age 50 (not for Silenor)

âœ1⁄2 Since tricyclic and tetracyclic antidepressants are frequently associated with weight gain, before starting treatment, weigh all patients and determine if the patient is already overweight (BMI 25.0– 29.9) or obese (BMI ≥ 30)

Before giving a drug that can cause weight gain to an overweight or obese patient, consider determining whether the patient already has pre-diabetes (fasting plasma glucose 100– 125 mg/dL), diabetes (fasting plasma glucose ≥ 126 mg/dL), or dyslipidemia (increased total cholesterol, LDL cholesterol, and triglycerides; decreased HDL cholesterol), and treat or refer such patients for treatment including nutrition and weight management, physical activity counseling, smoking cessation, and medical management

âœ1⁄2 Monitor weight and BMI during treatment

âœ1⁄2 While giving a drug to a patient who has gained >5% of initial weight, consider evaluating for the presence of pre-diabetes, diabetes, or dyslipidemia, or consider switching to a different antidepressant

ECGs may be useful for selected patients (e.g., those with personal or family history of QTc prolongation; cardiac arrhythmia; recent myocardial infarction; uncompensated heart failure; or taking agents

that prolong QTc interval such as pimozide, thioridazine, selected antiarrhythmics, moxifloxacin, sparfloxacin, etc.)

Patients at risk for electrolyte disturbances (e.g., patients on diuretic therapy) should have baseline and periodic serum potassium and magnesium measurements

Side effects

How Drug Causes Side Effects

At antidepressant doses, anticholinergic activity may explain sedative effects, dry mouth, constipation, and blurred vision

Sedative effects and weight gain may be due to antihistamine properties

At antidepressant doses, blockade of alpha adrenergic 1 receptors may explain dizziness, sedation, and hypotension

Cardiac arrhythmias and seizures, especially in overdose, may be caused by blockade of ion channels

Notable Side Effects Antidepressant Doses

Blurred vision, constipation, urinary retention, increased appetite, dry mouth, nausea, diarrhea, heartburn, unusual taste in mouth, weight gain

Fatigue, weakness, dizziness, sedation, headache, anxiety, nervousness, restlessness

Sexual dysfunction, sweating

Topical: burning, stinging, itching, or swelling at application site

Hypnotic Doses

Few side effects at low doses (3– 6 mg/day), the most common being somnolence/sedation

Life-Threatening or Dangerous Side Effects

Paralytic ileus, hyperthermia (TCAs + anticholinergic agents) Lowered seizure threshold and rare seizures

Orthostatic hypotension, sudden death, arrhythmias, tachycardia QTc prolongation

Hepatic failure, drug-induced parkinsonism

Increased intraocular pressure, increased psychotic symptoms Rare induction of mania

Rare activation of suicidal ideation and behavior (suicidality) (short- term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo beyond age 24)

Weight Gain

Many experience and/or can be significant in amount (antidepressant doses)

Can increase appetite and carbohydrate craving Weight gain is unusual at hypnotic doses

Sedation

Many experience and/or can be significant in amount Tolerance to sedative effect may develop with long-term use Sedation is not unusual at hypnotic doses

What to Do About Side Effects

Wait

Wait

Wait

Lower the dose

Switch to an SSRI or newer antidepressant Switch to another hypnotic

Best Augmenting Agents for Side Effects

Many side effects cannot be improved with an augmenting agent

Dosing and use Usual Dosage Range

75– 150 mg/day for depression 3– 6 mg at bedtime for insomnia

Dosage Forms

Capsule 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg Solution 10 mg/mL

Topical 5%

Tablet 3 mg, 6 mg

How to Dose

Initial 25 mg/day at bedtime; increase by 25 mg every 3– 7 days

75 mg/day; increase gradually until desired efficacy is achieved; can be dosed once a day at bedtime or in divided doses; maximum dose 300 mg/day

Topical: apply thin film 4 times a day (or every 3– 4 hours while awake)

Insomnia: 6 mg once daily, 30 minutes before bedtime; should not be taken within 3 hours of a meal; maximum dose 6 mg/day

Dosing Tips

If given in a single antidepressant dose, should generally be administered at bedtime because of its sedative properties

If given in split antidepressant doses, largest dose should generally be given at bedtime because of its sedative properties

If patients experience nightmares, split antidepressant dose and do not give large dose at bedtime

Patients treated for chronic pain may only require lower doses

Patients treated for insomnia may benefit from doses of 3– 6 mg at bedtime

Liquid formulation should be diluted with water or juice, excluding grape juice

150 mg capsule available only for maintenance use, not initial therapy

âœ1⁄2 Topical administration is absorbed systematically and can cause the same systematic side effects as oral administration

If intolerable anxiety, insomnia, agitation, akathisia, or activation occur upon either dosing initiation or discontinuation, consider the possibility of activated bipolar disorder, and switch to a mood stabilizer or an atypical antipsychotic

Overdose

Death may occur; convulsions, cardiac dysrhythmias, severe hypotension, CNS depression, coma, changes in ECG

Safe

No

Long-Term Use

Habit Forming

How to Stop

At antidepressant doses, taper to avoid withdrawal effects

Even with gradual dose reduction some withdrawal symptoms may appear within the first 2 weeks

Many patients tolerate 50% dose reduction for 3 days, then another 50% reduction for 3 days, then discontinuation

If withdrawal symptoms emerge during discontinuation, raise dose to stop symptoms and then restart withdrawal much more slowly

Taper not necessary for low doses (3– 6 mg/day); withdrawal effects generally not observed

Pharmacokinetics

Substrate for CYP450 2D6

Half-life approximately 8– 24 hours

Drug Interactions

Tramadol increases the risk of seizures in patients taking TCAs

Use of TCAs with anticholinergic drugs may result in paralytic ileus or hyperthermia

Fluoxetine, paroxetine, bupropion, duloxetine, and other CYP450 2D6 inhibitors may increase TCA concentrations

Cimetidine may increase plasma concentrations of TCAs and cause anticholinergic symptoms

Phenothiazines or haloperidol may raise TCA blood concentrations

May alter effects of antihypertensive drugs; may inhibit hypotensive effects of clonidine

Use with sympathomimetic agents may increase sympathetic activity

Methylphenidate may inhibit metabolism of TCAs

Most drug interactions may be less likely at low doses (1– 6 mg/day) due to the lack of effects on receptors other than the histamine 1 receptors

Activation and agitation, especially following switching or adding antidepressants, may represent the induction of a bipolar state, especially a mixed dysphoric bipolar II condition sometimes associated with suicidal ideation, and require the addition of lithium, a mood stabilizer or an atypical antipsychotic, and/or discontinuation of doxepin

Other Warnings/Precautions

Add or initiate other antidepressants with caution for up to 2 weeks after discontinuing doxepin

Generally, do not use with MAOIs, including 14 days after MAOIs are stopped; do not start an MAOI for at least 5 half-lives (5 to 7 days for most drugs) after discontinuing doxepin, but see Pearls

Use with caution in patients with history of seizures, urinary retention, angle-closure glaucoma, hyperthyroidism

TCAs can increase QTc interval, especially at toxic doses, which can be attained not only by overdose but also by combining with drugs that inhibit TCA metabolism via CYP450 2D6, potentially causing torsade de pointes-type arrhythmia or sudden death

Because TCAs can prolong QTc interval, use with caution in patients who have bradycardia or who are taking drugs that can induce bradycardia (e.g., beta blockers, calcium channel blockers, clonidine, digitalis)

Because TCAs can prolong QTc interval, use with caution in patients who have hypokalemia and/or hypomagnesemia or who are taking drugs that can induce hypokalemia and/or magnesemia (e.g., diuretics, stimulant laxatives, intravenous amphotericin B, glucocorticoids, tetracosactide)

When treating children, carefully weigh the risks and benefits of pharmacological treatment against the risks and benefits of nontreatment with antidepressants and make sure to document this in the patientâ€TM s chart

Distribute the brochures provided by the FDA and the drug companies

Whenever possible, warn patients and their caregivers about the possibility of activating side effects, and advise them to report such symptoms immediately

Monitor patients for activation of suicidal ideation, especially children and adolescents

Do Not Use

If patient is recovering from myocardial infarction

If patient is taking agents capable of significantly prolonging QTc interval (e.g., pimozide, thioridazine, selected antiarrhythmics, moxifloxacin, sparfloxacin)

If there is a history of QTc prolongation or cardiac arrhythmia, recent acute myocardial infarction, uncompensated heart failure

If patient is taking drugs that inhibit TCA metabolism, including CYP450 2D6 inhibitors, except by an expert

If there is reduced CYP450 2D6 function, such as patients who are poor 2D6 metabolizers, except by an expert and at low doses

If patient has angle-closure glaucoma or severe urinary retention If there is a proven allergy to doxepin

Special populations

Use with caution

Renal Impairment

Hepatic Impairment

Use with caution – may need lower than usual adult dose

Cardiac Impairment

Baseline ECG is recommended (not for Silenor)

TCAs have been reported to cause arrhythmias, prolongation of conduction time, orthostatic hypotension, sinus tachycardia, and heart failure, especially in the diseased heart

Myocardial infarction and stroke have been reported with TCAs

TCAs produce QTc prolongation, which may be enhanced by the existence of bradycardia, hypokalemia, congenital or acquired long QTc interval, which should be evaluated prior to administering doxepin

Use with caution if treating concomitantly with a medication likely to produce prolonged bradycardia, hypokalemia, slowing of intracardiac conduction, or prolongation of the QTc interval

Avoid TCAs in patients with a known history of QTc prolongation, recent acute myocardial infarction, and uncompensated heart failure

TCAs may cause a sustained increase in heart rate in patients with ischemic heart disease and may worsen (decrease) heart rate variability, an independent risk of mortality in cardiac populations

Since SSRIs may improve (increase) heart rate variability in patients following a myocardial infarct and may improve survival as well as mood in patients with acute angina or following a myocardial infarction, these are more appropriate agents for cardiac population than tricyclic/tetracyclic antidepressants

âœ1⁄2 Risk/benefit ratio may not justify use of TCAs in cardiac impairment

Elderly

Baseline ECG is recommended for patients over age 50 (not for Silenor)

May be more sensitive to anticholinergic, cardiovascular, hypotensive, and sedative effects

Low-dose doxepin (3– 6 mg/day) has been studied and found effective for insomnia in elderly patients; recommended dose is 3 mg/day

Reduction in the risk of suicidality with antidepressants compared to placebo in adults age 65 and older

Children and Adolescents

Carefully weigh the risks and benefits of pharmacological treatment against the risks and benefits of nontreatment with antidepressants and make sure to document this in the patientâ€TM s chart

Monitor patients face-to-face regularly, particularly during the first several weeks of treatment

Use with caution, observing for activation of known or unknown bipolar disorder and/or suicidal ideation, and inform parents or guardians of this risk so they can help observe child or adolescent patients

Not recommended for use in children under age 12

Several studies show lack of efficacy of TCAs for depression

May be used to treat enuresis or hyperactive/impulsive behaviors Some cases of sudden death have occurred in children taking TCAs Initial dose 25– 50 mg/day; maximum 100 mg/day

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women Crosses the placenta

Adverse effects have been reported in infants whose mothers took a TCA (lethargy, withdrawal symptoms, fetal malformations)

Not generally recommended for use during pregnancy, especially during first trimester

Must weigh the risk of treatment (first trimester fetal development, third trimester newborn delivery) to the child against the risk of no treatment (recurrence of depression, maternal health, infant bonding) to the mother and child

For many patients this may mean continuing treatment during pregnancy for depression

National Pregnancy Registry for Antidepressants: 1-866-961-2388,

https://womensmentalhealth.org/research/pregnancyregistry/antidepr essants

Breast Feeding

Some drug is found in motherâ€TM s breast milk

Significant drug levels have been detected in some nursing infants âœ1⁄2 Recommended either to discontinue drug or bottle feed

Immediate postpartum period is a high-risk time for depression, especially in women who have had prior depressive episodes, so drug may need to be reinstituted late in the third trimester or shortly after childbirth to prevent a recurrence during the postpartum period

Must weigh benefits of breast feeding with risks and benefits of antidepressant treatment versus nontreatment to both the infant and the mother

For many patients this may mean continuing treatment during breast feeding

The art of psychopharmacology Potential Advantages

Patients with insomnia

Severe or treatment-resistant depression Patients with neurodermatitis and itching

Potential Disadvantages

Pediatric and geriatric patients Patients concerned with weight gain Cardiac patients

Primary Target Symptoms

Depressed mood Anxiety

Disturbed sleep, energy Somatic symptoms Itching skin

Pearls

âœ1⁄2 Only TCA available in topical formulation

âœ1⁄2 Topical administration may reduce symptoms in patients with

various neuro-dermatitis syndromes, especially itching

Although low doses are specifically approved for sleep maintenance in insomnia they may also work for sleep onset in insomnia

At low doses, one of the few hypnotics that is not a controlled substance, because it has no risk of dependence, withdrawal, or abuse

At low doses, there is no tolerance to hypnotic actions seen At low doses, there is little or no weight gain

At low doses doxepin is selective for the histamine 1 receptor and thus can improve sleep without causing side effects associated with other neurotransmitter systems

In particular, low-dose doxepin does not appear to cause anticholinergic symptoms, memory impairment, or weight gain, nor is there evidence of tolerance, rebound insomnia, or withdrawal effects

TCAs are often a first-line treatment option for chronic pain

TCAs are no longer generally considered a first-line option for depression because of their side effect profile

TCAs continue to be useful for severe or treatment-resistant depression

TCAs may aggravate psychotic symptoms

Alcohol should be avoided because of additive CNS effects

Underweight patients may be more susceptible to adverse cardiovascular effects

Children, patients with inadequate hydration, and patients with cardiac disease may be more susceptible to TCA-induced cardiotoxicity than healthy adults

For the expert only: although generally prohibited, a heroic but potentially dangerous treatment for severely treatment-resistant patients is to give a tricyclic/tetracyclic antidepressant other than clomipramine simultaneously with an MAOI for patients who fail to respond to numerous other antidepressants

If this option is elected, start the MAOI with the tricyclic/tetracyclic antidepressant simultaneously at low doses after appropriate drug washout, then alternately increase doses of these agents every few days to a week as tolerated

Although very strict dietary and concomitant drug restrictions must be observed to prevent hypertensive crises and serotonin syndrome, the most common side effects of MAOI/tricyclic or tetracyclic combinations may be weight gain and orthostatic hypotension

Patients on TCAs should be aware that they may experience symptoms such as photosensitivity or blue-green urine

SSRIs may be more effective than TCAs in women, and TCAs may be more effective than SSRIs in men

Since tricyclic/tetracyclic antidepressants are substrates for CYP450 2D6, and 7% of the population (especially Caucasians) may have a genetic variant leading to reduced activity of 2D6, such patients may not safely tolerate normal doses of tricyclic/tetracyclic antidepressants and may require dose reduction

Phenotypic testing may be necessary to detect this genetic variant prior to dosing with a tricyclic/tetracyclic antidepressant, especially in vulnerable populations such as children, elderly, cardiac populations, and those on concomitant medications

Patients who seem to have extraordinarily severe side effects at normal or low doses may have this phenotypic CYP450 2D6 variant and require low doses or switching to another antidepressant not metabolized by 2D6

Suggested Reading

Anderson IM . Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability . J Aff Disorders 2000 ;58 :19 – 36 .

Anderson IM . Meta-analytical studies on new antidepressants . Br Med Bull 2001 ;57 :161– 78 .

Godfrey RG . A guide to the understanding and use of tricyclic antidepressants in the overall management of fibromyalgia and other chronic pain syndromes . Arch Intern Med 1996 ;156 :1047 – 52.

Roth T , Rogowski R , Hull S , et al. Efficacy and safety of doxepin 1 mg, 3 mg, and 6 mg in adults with primary insomnia . Sleep 2007 ;30 (11 ):1555 – 61.

Singh H , Becker PM . Novel therapeutic usage of low-dose doxepin hydrochloride . Expert Opin Investig Drugs 2007 ;16 (8 ):1295 – 305.

Stahl SM . Selective histamine 1 antagonism: novel hypnotic and pharmacologic actions challenge classical notions of antihistamines . CNS Spectr 2008 ;13 (12 ):855– 65 .

Duloxetine

Cymbalta

Therapeutics Brands

Yes

Generic?

Class

see index for additional brand names

Neuroscience-based Nomenclature: serotonin norepinephrine reuptake inhibitor (SN-RI)

SNRI (dual serotonin and norepinephrine reuptake inhibitor); may be classified as an antidepressant, but it is not just an antidepressant

Commonly Prescribed for

(bold for FDA approved)

Major depressive disorder

Diabetic peripheral neuropathic pain (DPNP) Fibromyalgia

Generalized anxiety disorder, acute and maintenance

Chronic musculoskeletal pain

Stress urinary incontinence Neuropathic pain/chronic pain Other anxiety disorders

How the Drug Works

Boosts neurotransmitters serotonin, norepinephrine/noradrenaline, and dopamine

Blocks serotonin reuptake pump (serotonin transporter), presumably increasing serotonergic neurotransmission

Blocks norepinephrine reuptake pump (norepinephrine transporter), presumably increasing noradrenergic neurotransmission

Presumably desensitizes both serotonin 1A receptors and beta adrenergic receptors

Since dopamine is inactivated by norepinephrine reuptake in frontal cortex, which largely lacks dopamine transporters, duloxetine can increase dopamine neurotransmission in this part of the brain

Weakly blocks dopamine reuptake pump (dopamine transporter), and may increase dopamine neurotransmission

How Long Until It Works

Onset of therapeutic actions usually not immediate, but often delayed 2– 4 weeks for depression

If it is not working within 6– 8 weeks for depression, it may require a dosage increase or it may not work at all

Can reduce neuropathic pain within a week, but onset can take longer

May continue to work for many years to prevent relapse of depressive symptoms or prevent worsening of painful symptoms

Vasomotor symptoms in perimenopausal women with or without depression may improve within 1 week

If It Works

The goal of treatment of depression and anxiety disorders is complete remission of current symptoms as well as prevention of future relapses

The goal of treatment of diabetic peripheral neuropathic pain and fibromyalgia and chronic neuropathic pain is to reduce symptoms as much as possible, especially in combination with other treatments

Treatment of depression most often reduces or even eliminates symptoms, but is not a cure since symptoms can recur after medicine stopped

Treatment of diabetic peripheral neuropathic pain, fibromyalgia, and chronic neuropathic pain may reduce symptoms, but rarely eliminates them completely, and is not a cure since symptoms can recur after medicine is stopped

Continue treatment of depression and anxiety disorders until all symptoms are gone (remission)

Once symptoms of depression are gone, continue treating for 1 year for the first episode of depression

For second and subsequent episodes of depression, treatment may need to be indefinite

Use in anxiety disorders may also need to be indefinite

Use in diabetic peripheral neuropathic pain, fibromyalgia, and chronic neuropathic pain may also need to be indefinite, but long- term treatment is not well studied in these conditions

If It Doesnâ€TM t Work

Many patients have only a partial response where some symptoms are improved but others persist (especially insomnia, fatigue, and problems concentrating)

Other patients may be nonresponders, sometimes called treatment- resistant or treatment-refractory

Some depressed patients who have an initial response may relapse even though they continue treatment, sometimes called “ poop- outâ€

Consider increasing dose, switching to another agent, or adding an appropriate augmenting agent

Consider psychotherapy for depression or biofeedback or hypnosis for pain

Consider evaluation for another diagnosis or for a comorbid condition (e.g., medical illness, substance abuse, etc.)

Consider the presence of noncompliance and counsel the patient

Some patients may experience apparent lack of consistent efficacy due to activation of latent or underlying bipolar disorder, and require antidepressant discontinuation and a switch to a mood stabilizer

Best Augmenting Combos for Partial Response or Treatment Resistance

Augmentation experience is limited compared to other antidepressants and treatments for neuropathic pain

Adding other agents to duloxetine for treating depression could follow the same practice for augmenting SSRIs or other SNRIs if done by experts while monitoring carefully in difficult cases

Although no controlled studies and little clinical experience, adding other agents for treating diabetic peripheral neuropathic pain and fibromyalgia and neuropathic pain could theoretically include gabapentin, pregabalin, and tiagabine, if done by experts while monitoring carefully in difficult cases

Mirtazapine (“ California rocket fuel†for depression; a potentially powerful dual serotonin and norepinephrine combination, but observe for activation of bipolar disorder and suicidal ideation)

Bupropion, reboxetine, nortriptyline, desipramine, maprotiline, atomoxetine (all potentially powerful enhancers of noradrenergic action for depression, but observe for activation of bipolar disorder and suicidal ideation)

Modafinil, especially for fatigue, sleepiness, and lack of concentration

Mood stabilizers or atypical antipsychotics for bipolar depression, psychotic depression, or treatment-resistant depression

Benzodiazepines

If all else fails for anxiety disorders, consider gabapentin, pregabalin, or tiagabine

Hypnotics or trazodone for insomnia

Classically, lithium, buspirone, or thyroid hormone for depression

Tests

Check blood pressure before initiating treatment and regularly during treatment

Side Effects

How Drug Causes Side Effects

Theoretically due to increases in serotonin and norepinephrine concentrations at receptors in parts of the brain and body other than those that cause therapeutic actions (e.g., unwanted actions of

serotonin in sleep centers causing insomnia, unwanted actions of norepinephrine on acetylcholine release causing decreased appetite, increased blood pressure, urinary retention, etc.)

Most side effects are immediate but often go away with time

Notable Side Effects

Nausea, diarrhea, decreased appetite, dry mouth, constipation (dose- dependent)

Insomnia, sedation, dizziness

Sexual dysfunction (men: abnormal ejaculation/orgasm, impotence, decreased libido; women: abnormal orgasm)

Sweating

Increase in blood pressure (up to 2 mmHg) Urinary retention

Life-Threatening or Dangerous Side Effects

Rare seizures

Rare induction of hypomania

Rare activation of suicidal ideation, suicide attempts, and completed suicide

Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo beyond age 24

Weight Gain

Sedation

Occurs in significant minority

May also be activating in some patients

What to Do About Side Effects

Wait

Wait

Wait

Lower the dose

In a few weeks, switch or add other drugs

Best Augmenting Agents for Side Effects

For urinary hesitancy, give an alpha 1 blocker such as tamsulosin

Often best to try another antidepressant monotherapy prior to resorting to augmentation strategies to treat side effects

Trazodone or a hypnotic for insomnia

Bupropion, sildenafil, vardenafil, or tadalafil for sexual dysfunction

Reported but not expected

Benzodiazepines for jitteriness and anxiety, especially at initiation of treatment and especially for anxious patients

Mirtazapine for insomnia, agitation, and gastrointestinal side effects

Many side effects are dose-dependent (i.e., they increase as dose increases, or they reemerge until tolerance redevelops)

Many side effects are time-dependent (i.e., they start immediately upon dosing and upon each dose increase, but go away with time)

Activation and agitation may represent the induction of a bipolar state, especially a mixed dysphoric bipolar II condition sometimes associated with suicidal ideation, and require the addition of lithium, a mood stabilizer or an atypical antipsychotic, and/or discontinuation of duloxetine

Dosing and Use Usual Dosage Range

40– 60 mg/day in 1– 2 doses for depression

60 mg once daily for diabetic peripheral neuropathic pain and fibromyalgia

60 mg once daily for generalized anxiety disorder 40 mg twice daily for stress urinary incontinence

Dosage Forms

Capsule 20 mg, 30 mg, 40 mg, 60 mg

How to Dose

For depression, initial 40 mg/day in 2 doses; can increase to 60 mg/day in 1– 2 doses if necessary; maximum dose generally 120 mg/day

For neuropathic pain and fibromyalgia initial 30 mg once daily; increase to 60 mg once daily after 1 week; maximum dose generally 60 mg/day

For generalized anxiety, initial 60 mg once daily; maximum dose generally 120 mg/day

Dosing Tips

Studies have not demonstrated increased efficacy beyond 60 mg/day

Some patients may require up to or more than 120 mg/day, but clinical experience is quite limited with high dosing

In relapse prevention studies in depression, a significant percentage of patients who relapsed on 60 mg/day responded and remitted when the dose was increased to 120 mg/day

In neuropathic pain and fibromyalgia doses above 60 mg/day have been associated with increased side effects without an increase in efficacy

Some studies suggest that both serotonin and norepinephrine reuptake blockade are present at 40– 60 mg/day

Do not chew or crush and do not sprinkle on food or mix with food, but rather always swallow whole to avoid affecting enteric coating

Some patients may require dosing above 120 mg/day in 2 divided doses, but this should be done with caution and by experts

Overdose

Rare fatalities have been reported; serotonin syndrome, sedation, vomiting, seizures, coma, change in blood pressure

Long-Term Use

Blood pressure should be monitored regularly

No

Habit Forming

How to Stop

Taper to avoid withdrawal effects (dizziness, nausea, vomiting, headache, paresthesias, irritability)

Many patients tolerate 50% dose reduction for 3 days, then another 50% reduction for 3 days, then discontinuation

If withdrawal symptoms emerge during discontinuation, raise dose to stop symptoms and then restart withdrawal much more slowly

Pharmacokinetics

Elimination half-life approximately 12 hours Metabolized mainly by CYP450 2D6 and CYP450 1A2

Inhibitor of CYP450 2D6 (probably clinically significant) and CYP450 1A2 (probably not clinically significant)

Absorption may be delayed by up to 3 hours and clearance may be increased by one-third after an evening dose as compared to a morning dose

Food does not affect absorption

Drug Interactions

Can increase TCA levels; use with caution with TCAs or when switching from a TCA to duloxetine

Can cause a fatal “ serotonin syndrome†when combined with MAOIs, so do not use with MAOIs or for at least 14 days after MAOIs are stopped

Possible increased risk of bleeding, especially when combined with anticoagulants (e.g., warfarin, NSAIDs)

Do not start an MAOI for at least 5 half-lives (5 to 7 days for most drugs) after discontinuing duloxetine

Inhibitors of CYP450 1A2, such as fluvoxamine, increase plasma levels of duloxetine and may require a dosage reduction of duloxetine

Cigarette smoking induces CYP450 1A2 and may reduce plasma levels of duloxetine, but dosage modifications are not recommended for smokers

Inhibitors of CYP450 2D6, such as paroxetine, fluoxetine, and quinidine, may increase plasma levels of duloxetine and require a dosage reduction of duloxetine

Via CYP450 1A2 inhibition, duloxetine could theoretically reduce clearance of theophylline and clozapine; however, studies of coadministration with theophylline did not demonstrate significant effects of duloxetine on theophylline pharmacokinetics

Via CYP450 2D6 inhibition, duloxetine could theoretically interfere with the analgesic actions of codeine, and increase the plasma levels of some beta blockers and of atomoxetine

Via CYP450 2D6 inhibition, duloxetine could theoretically increase concentrations of thioridazine and cause dangerous cardiac arrhythmias

Other Warnings/Precautions

Use with caution in patients with history of seizures

Use with caution in patients with bipolar disorder unless treated with concomitant mood-stabilizing agent

Rare reports of hepatotoxicity; although causality has not been established, duloxetine should be discontinued in patients who develop jaundice or other evidence of significant liver dysfunction

When treating children, carefully weigh the risks and benefits of pharmacological treatment against the risks and benefits of nontreatment with antidepressants and make sure to document this in the patientâ€TM s chart

Distribute the brochures provided by the FDA and the drug companies

Whenever possible, warn patients and their caregivers about the possibility of activating side effects, and advise them to report such symptoms immediately

Monitor patients for activation of suicidal ideation, especially children and adolescents

Duloxetine may increase blood pressure, so blood pressure should be monitored during treatment

Do Not Use

If patient has uncontrolled angle-closure glaucoma If patient has substantial alcohol use

If patient is taking an MAOI

If patient is taking thioridazine

If there is a proven allergy to duloxetine

Special Populations

Renal Impairment

Dose adjustment generally not necessary for mild to moderate impairment

Not recommended for use in patients with end-stage renal disease (requiring dialysis) or severe renal impairment

Hepatic Impairment

Not to be administered to patients with any hepatic insufficiency Not recommended for use in patients with substantial alcohol use Increased risk of elevation of serum transaminase levels

Cardiac Impairment

Drug should be used with caution Duloxetine may raise blood pressure

Elderly

Some patients may tolerate lower doses better

Reduction in the risk of suicidality with antidepressants compared to placebo in adults age 65 and older

Children and Adolescents

Carefully weigh the risks and benefits of pharmacological treatment against the risks and benefits of nontreatment with antidepressants

and make sure to document this in the patientâ€TM s chart

Monitor patients face-to-face regularly, particularly during the first several weeks of treatment

Use with caution, observing for activation of known or unknown bipolar disorder and/or suicidal ideation, and inform parents or guardians of this risk so they can help observe child or adolescent patients

Not studied, but can be used by experts

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women

Not generally recommended for use during pregnancy, especially during first trimester

Nonetheless, continuous treatment during pregnancy may be necessary and has not been proven to be harmful to the fetus

Must weigh the risk of treatment (first trimester fetal development, third trimester newborn delivery) to the child against the risk of no

treatment (recurrence of depression, maternal health, infant bonding) to the mother and child

For many patients this may mean continuing treatment during pregnancy

Neonates exposed to SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding; reported symptoms are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome, and include respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying

National Pregnancy Registry for Antidepressants: 1-866-961-2388,

https://womensmentalhealth.org/research/pregnancyregistry/atypical antipsychotic

Breast Feeding

Some drug is found in motherâ€TM s breast milk

If child becomes irritable or sedated, breast feeding or drug may need to be discontinued

Immediate postpartum period is a high-risk time for depression, especially in women who have had prior depressive episodes, so drug may need to be reinstituted late in the third trimester or shortly after childbirth to prevent a recurrence during the postpartum period

Must weigh benefits of breast feeding with risks and benefits of antidepressant treatment versus nontreatment to both the infant and the mother

For many patients, this may mean continuing treatment during breast feeding

The Art of Psychopharmacology Potential Advantages

Patients with physical symptoms of depression Patients with retarded depression

Patients with atypical depression

Patients with comorbid anxiety

Patients with depression may have higher remission rates on SNRIs than on SSRIs

Depressed patients with somatic symptoms, fatigue, and pain

Patients who do not respond or do not remit on treatment with SSRIs

Potential Disadvantages

Patients with urologic disorders, prostate disorders (e.g., older men) Patients sensitive to nausea

Primary Target Symptoms

Depressed mood

Energy, motivation, and interest Sleep disturbance

Anxiety

Physical symptoms

Pain

Pearls

Duloxetine has well-documented efficacy for the painful physical symptoms of depression

Duloxetine has only somewhat greater potency for serotonin reuptake blockade than for norepinephrine reuptake blockade, but this is of unclear clinical significance as a differentiator from other SNRIs

No head-to-head studies, but may have less hypertension than venlafaxine XR

Powerful pro-noradrenergic actions may occur at doses greater than 60 mg/day

Not well studied in ADHD, but may be effective

Approved in many countries for stress urinary incontinence

Patients may have higher remission rate for depression on SNRIs than on SSRIs

Add or switch to or from pro-noradrenergic agents (e.g., atomoxetine, reboxetine, other SNRIs, mirtazapine, maprotiline, nortriptyline, desipramine, bupropion) with caution

Add or switch to or from CYP450 2D6 substrates with caution (e.g., atomoxetine, maprotiline, nortriptyline, desipramine)

Mechanism of action as SNRI suggests it may be effective in some patients who fail to respond to SSRIs

Suggested Reading

Arnold LM , Pritchett YL , Dâ€TM Souza DN , et al. Duloxetine for the treatment of fibromyalgia in women: pooled results from two randomized, placebo-controlled trials . J Womens Health (Larchmt) 2007 ;16 (8 ):1145 – 56.

Bymaster FP , Dreshfield-Ahmad LJ , Threlkeld PG , et al. Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors . Neuropsychopharmacology 2001 ;25 (6 ):871– 80 .

Hartford J , Kornstein S , Liebowitz M , et al. Duloxetine as an SNRI treatment for generalized anxiety disorder: results from placebo and active- controlled trial . Int Clin Psychopharmacol 2007 ;22 (3 ):167– 74 .

Muller N , Schennach R , Riedel M , Moller HJ . Duloxetine in the treatment of major psychiatric and neuropathic disorders . Expert Rev

Neurother 2008 ;8 (4 ):527– 36 .

Zinner NR . Duloxetine: a serotonin-noradrenaline re-uptake inhibitor for the treatment of stress urinary incontinence . Expert Opin Investig Drugs 2003 ;12 (9 ):1559 – 66.

Escitalopram

Lexapro

Therapeutics Brands

Yes

Generic?

Class

see index for additional brand names

Neuroscience-based Nomenclature: serotonin reuptake inhibitor (S- RI)

SSRI (selective serotonin reuptake inhibitor); often classified as an antidepressant, but it is not just an antidepressant

Commonly Prescribed for

(bold for FDA approved)

Major depressive disorder (ages 12 and older) Generalized anxiety disorder (GAD)

Panic disorder

Obsessive-compulsive disorder (OCD)

Posttraumatic stress disorder (PTSD) Social anxiety disorder (social phobia) Premenstrual dysphoric disorder (PMDD)

How the Drug Works

Boosts neurotransmitter serotonin

Blocks serotonin reuptake pump (serotonin transporter)

Desensitizes serotonin receptors, especially serotonin 1A autoreceptors

Presumably increases serotonergic neurotransmission

How Long Until It Works

Onset of therapeutic actions usually not immediate, but often delayed 2– 4 weeks

If it is not working within 6– 8 weeks, it may require a dosage increase or it may not work at all

May continue to work for many years to prevent relapse of symptoms

If It Works

The goal of treatment is complete remission of current symptoms as well as prevention of future relapses

Treatment most often reduces or even eliminates symptoms, but not a cure since symptoms can recur after medicine stopped

Continue treatment until all symptoms are gone (remission) or significantly reduced (e.g., OCD, PTSD)

Once symptoms are gone, continue treating for 1 year for the first episode of depression

For second and subsequent episodes of depression, treatment may need to be indefinite

Use in anxiety disorders may also need to be indefinite

If It Doesnâ€TM t Work

Many patients have only a partial response where some symptoms are improved but others persist (especially insomnia, fatigue, and problems concentrating in depression)

Other patients may be nonresponders, sometimes called treatment- resistant or treatment-refractory

Some patients who have an initial response may relapse even though they continue treatment, sometimes called “ poop-outâ€

Consider increasing dose, switching to another agent, or adding an appropriate augmenting agent

Consider psychotherapy

Consider evaluation for another diagnosis or for a comorbid condition (e.g., medical illness, substance abuse, etc.)

Some patients may experience apparent lack of consistent efficacy due to activation of latent or underlying bipolar disorder, and require antidepressant discontinuation and a switch to a mood stabilizer

Best Augmenting Combos for Partial Response or Treatment Resistance

Trazodone, especially for insomnia

Bupropion, mirtazapine, reboxetine, or atomoxetine (use combinations of antidepressants with caution as this may activate bipolar disorder and suicidal ideation)

Modafinil, especially for fatigue, sleepiness, and lack of concentration

Mood stabilizers or atypical antipsychotics for bipolar depression, psychotic depression, treatment-resistant depression, or treatment- resistant anxiety disorders

Benzodiazepines

If all else fails for anxiety disorders, consider gabapentin or tiagabine

Hypnotics for insomnia

Classically, lithium, buspirone, or thyroid hormone

Tests

None for healthy individuals

Side effects

How Drug Causes Side Effects

Theoretically due to increases in serotonin concentrations at serotonin receptors in parts of the brain and body other than those that cause therapeutic actions (e.g., unwanted actions of serotonin in sleep centers causing insomnia, unwanted actions of serotonin in the gut causing diarrhea, etc.)

Increasing serotonin can cause diminished dopamine release and might contribute to emotional flattening, cognitive slowing, and apathy in some patients

Most side effects are immediate but often go away with time, in contrast to most therapeutic effects which are delayed and are enhanced over time

âœ1⁄2 As escitalopram has no known important secondary pharmacologic properties, its side effects are presumably all mediated by its serotonin reuptake blockade

Notable Side Effects

Sexual dysfunction (men: delayed ejaculation, erectile dysfunction; men and women: decreased sexual desire, anorgasmia)

Gastrointestinal (decreased appetite, nausea, diarrhea, constipation, dry mouth)

Mostly central nervous system (insomnia but also sedation, agitation, tremors, headache, dizziness)

Note: patients with diagnosed or undiagnosed bipolar or psychotic disorders may be more vulnerable to CNS-activating actions of SSRIs

Autonomic (sweating) Bruising and rare bleeding

Rare hyponatremia (mostly in elderly patients and generally reversible on discontinuation of escitalopram

SIADH (syndrome of inappropriate antidiuretic hormone secretion)

Life-Threatening or Dangerous Side Effects

Rare seizures

Rare induction of mania

Rare activation of suicidal ideation and behavior (suicidality) (short- term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo beyond age 24)

Weight Gain

Sedation

Reported but not expected

Reported but not expected

What to Do About Side Effects

Wait

Wait

Wait

In a few weeks, switch to another agent or add other drugs

Best Augmenting Agents for Side Effects

Often best to try another SSRI or another antidepressant monotherapy prior to resorting to augmentation strategies to treat side effects

Trazodone or a hypnotic for insomnia

Bupropion, sildenafil, vardenafil, or tadalafil for sexual dysfunction

Bupropion for emotional flattening, cognitive slowing, or apathy

Mirtazapine for insomnia, agitation, and gastrointestinal side effects

Benzodiazepines for jitteriness and anxiety, especially at initiation of treatment and especially for anxious patients

Many side effects are dose-dependent (i.e., they increase as dose increases, or they reemerge until tolerance redevelops)

Many side effects are time-dependent (i.e., they start immediately upon dosing and upon each dose increase, but go away with time)

Activation and agitation may represent the induction of a bipolar state, especially a mixed dysphoric bipolar II condition sometimes associated with suicidal ideation, and require the addition of lithium,

a mood stabilizer or an atypical antipsychotic, and/or discontinuation of escitalopram

10– 20 mg/day

Dosing and use Usual Dosage Range

Dosage Forms

Tablet 5 mg, 10 mg (scored), 20 mg (scored) Oral solution 5 mg/5 mL

How to Dose

Initial 10 mg/day; increase to 20 mg/day if necessary; single-dose administration, morning or evening

Dosing Tips

Given once daily, any time of day tolerated

âœ1⁄2 10 mg of escitalopram may be comparable in efficacy to 40 mg of citalopram with fewer side effects

Thus, give an adequate trial of 10 mg prior to giving 20 mg Some patients require dosing with 30 or 40 mg

If intolerable anxiety, insomnia, agitation, akathisia, or activation occur upon either dosing initiation or discontinuation, consider the possibility of activated bipolar disorder and switch to a mood stabilizer or an atypical antipsychotic

Overdose

Rare fatalities have been reported; symptoms include convulsions, coma, dizziness, hypotension, insomnia, nausea, vomiting, sinus tachycardia, somnolence, and ECG changes

Safe

No

Long-Term Use

Habit Forming

How to Stop

Taper not usually necessary

However, tapering to avoid potential withdrawal reactions generally prudent

Many patients tolerate 50% dose reduction for 3 days, then another 50% reduction for 3 days, then discontinuation

If withdrawal symptoms emerge during discontinuation, raise dose to stop symptoms and then restart withdrawal much more slowly

Pharmacokinetics

Mean terminal half-life 27– 32 hours

Steady-state plasma concentrations achieved within 1 week Substrate for CYP450 2C19 and 3A4

No significant actions on CYP450 enzymes

Food does not affect absorption

Drug Interactions

Tramadol increases the risk of seizures in patients taking an antidepressant

Can cause a fatal “ serotonin syndrome†when combined with MAOIs, so do not use with MAOIs or for at least 14 days after MAOIs are stopped

Do not start an MAOI for at least 5 half-lives (5 to 7 days for most drugs) after discontinuing escitalopram

Could theoretically cause weakness, hyperreflexia, and incoordination when combined with sumatriptan or possibly other triptans, requiring careful monitoring of patient

Possible increased risk of bleeding, especially when combined with anticoagulants (e.g., warfarin, NSAIDs)

NSAIDs may impair effectiveness of SSRIs Few known adverse drug interactions

Other Warnings/Precautions

Use with caution in patients with history of seizures

Use with caution in patients with bipolar disorder unless treated with concomitant mood-stabilizing agent

When treating children, carefully weigh the risks and benefits of pharmacological treatment against the risks and benefits of nontreatment with antidepressants and make sure to document this in the patientâ€TM s chart

Distribute the brochures provided by the FDA and the drug companies

Whenever possible, warn patients and their caregivers about the possibility of activating side effects, and advise them to report such symptoms immediately

Monitor patients for activation of suicidal ideation, especially children and adolescents

Do Not Use

If patient is taking an MAOI

If patient is taking pimozide

If there is a proven allergy to escitalopram or citalopram

Special populations

Renal Impairment

No dose adjustment for mild to moderate impairment Use cautiously in patients with severe impairment

Hepatic Impairment

Recommended dose 10 mg/day

Cardiac Impairment

Not systematically evaluated in patients with cardiac impairment

Preliminary data suggest that citalopram is safe in patients with cardiac impairment, suggesting that escitalopram is also safe

Treating depression with SSRIs in patients with acute angina or following myocardial infarction may reduce cardiac events and improve survival as well as mood

Elderly

Recommended dose 10 mg/day

Risk of SIADH with SSRIs is higher in the elderly

Reduction in the risk of suicidality with antidepressants compared to placebo in adults age 65 and older

Children and Adolescents

Approved for depression in adolescents ages 12– 17

Carefully weigh the risks and benefits of pharmacological treatment against the risks and benefits of nontreatment with antidepressants and make sure to document this in the patientâ€TM s chart

Monitor patients face-to-face regularly, particularly during the first several weeks of treatment

Use with caution, observing for activation of known or unknown bipolar disorder and/or suicidal ideation, and inform parents or guardians of this risk so they can help observe child or adolescent patients

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women

Not generally recommended for use during pregnancy, especially during first trimester

Nonetheless, continuous treatment during pregnancy may be necessary and has not been proven to be harmful to the fetus

At delivery there may be more bleeding in the mother and transient irritability or sedation in the newborn

Must weigh the risk of treatment (first trimester fetal development, third trimester newborn delivery) to the child against the risk of no treatment (recurrence of depression, maternal health, infant bonding) to the mother and child

For many patients, this may mean continuing treatment during pregnancy

Exposure to SSRIs early in pregnancy may be associated with increased risk of septal heart defects (absolute risk is small)

SSRI use beyond the 20th week of pregnancy may be associated with increased risk of pulmonary hypertension in newborns, although this is not proven

Exposure to SSRIs late in pregnancy may be associated with increased risk of gestational hypertension and preeclampsia

Neonates exposed to SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding; reported symptoms are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome, and include respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying

National Pregnancy Registry for Antidepressants: 1-866-961-2388,

https://womensmentalhealth.org/research/pregnancyregistry/antidepr essants

Breast Feeding

Some drug is found in motherâ€TM s breast milk

Trace amounts may be present in nursing children whose mothers are on escitalopram

If child becomes irritable or sedated, breast feeding or drug may need to be discontinued

Immediate postpartum period is a high-risk time for depression, especially in women who have had prior depressive episodes, so drug may need to be reinstituted late in the third trimester or shortly after childbirth to prevent a recurrence during the postpartum period

Must weigh benefits of breast feeding with risks and benefits of antidepressant treatment versus nontreatment to both the infant and the mother

For many patients, this may mean continuing treatment during breast feeding

The art of psychopharmacology Potential Advantages

Patients taking concomitant medications (few drug interactions and fewer even than with citalopram)

Patients requiring faster onset of action

Potential Disadvantages

More expensive than citalopram in markets where citalopram is generic

Primary Target Symptoms

Depressed mood

Anxiety

Panic attacks, avoidant behavior, reexperiencing, hyperarousal Sleep disturbance, both insomnia and hypersomnia

Pearls

âœ1⁄2 May be among the best-tolerated antidepressants

May have less sexual dysfunction than some other SSRIs May be better tolerated than citalopram

Can cause cognitive and affective “ flatteningâ€

âœ1⁄2 R-citalopram may interfere with the binding of S-citalopram at the serotonin transporter

âœ1⁄2 For this reason, S-citalopram may be more than twice as potent as R,S-citalopram (i.e., citalopram)

Thus, 10 mg starting dose of S-citalopram may have the therapeutic efficacy of 40 mg of R,S-citalopram

Thus, escitalopram may have faster onset and better efficacy with reduced side effects compared to R,S-citalopram

Some data may actually suggest remission rates comparable to SNRIs, but this is not proven

âœ1⁄2 Escitalopram is commonly used with augmenting agents, as it is the SSRI with the least interaction at either CYP450 2D6 or 3A4, therefore causing fewer pharmacokinetically mediated drug interactions with augmenting agents than other SSRIs

SSRIs may be less effective in women over 50, especially if they are not taking estrogen

SSRIs may be useful for hot flushes in perimenopausal women

Some postmenopausal womenâ€TM s depression will respond better to escitalopram plus estrogen augmentation than to escitalopram alone

Nonresponse to escitalopram in elderly may require consideration of mild cognitive impairment or Alzheimer disease

Suggested Reading

Baldwin DS , Reines EH , Guiton C , Weiller E. Escitalopram therapy for major depression and anxiety disorders . Ann Pharmacother 2007 ;41 (10 ):1583 – 92.

Bareggi SR , Mundo E , Dellâ€TM Osso B , Altamura AC . The use of escitalopram beyond major depression: pharmacological aspects, efficacy and tolerability in anxiety disorders . Expert Opin Drug Metab Toxicol 2007 ;3 (5 ):741– 53 .

Burke WJ . Escitalopram . Expert Opin Investig Drugs 2002 ;11 (10 ):1477 – 86.

Esketamine

Spravato

Therapeutics Brands

see index for additional brand names

No

Generic?

Class

N-methyl-D-aspartate (NMDA) receptor antagonist

Commonly Prescribed for

(bold for FDA approved)

Treatment-resistant depression in adults (adjunct)

Depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior (adjunct)

How the Drug Works

Esketamine is a nonselective, noncompetitive open channel inhibitor of the NMDA receptor; specifically, it binds to the phencyclidine site of the NMDA receptor

This leads to downstream glutamate release and consequent stimulation of other glutamate receptors, including AMPA receptors

Theoretically, esketamine may have antidepressant effects because activation of AMPA receptors leads to activation of signal transduction cascades, including mTORC1, and an increase in growth factors such as BDNF that cause the expression of synaptic proteins and an increase in the density of dendritic spines

How Long Until It Works

Antidepressant effects can occur within 24 hours

If It Works

Can immediately alleviate depressed mood and suicidal ideation

If It Doesnâ€TM t Work

Try a traditional antidepressant or stimulation therapy

Best Augmenting Combos for Partial Response or Treatment Resistance

Esketamine itself is an augmenting agent

Tests

Assess blood pressure prior to dosing: if baseline blood pressure is elevated (e.g., >140 mmHg systolic, >90 mmHg diastolic), consider the risks of short-term increases in blood pressure and benefit of

esketamine treatment in patients with treatment-resistant depression, and do not administer esketamine if an increase in blood pressure or intracranial pressure poses a serious risk

Given its potential to induce dissociative effects, carefully assess patients with psychosis before administering esketamine

Side effects

How Drug Causes Side Effects

Direct effect on NMDA receptors

Notable Side Effects

Dissociation, dizziness, sedation, vertigo, anxiety, lethargy, feeling drunk, numbness, hypoesthesia

Nausea, vomiting

Lower urinary tract symptoms, including increased frequency of urination (pollakiuria)

Life-Threatening or Dangerous Side Effects

Dissociation, sedation (requires monitoring for at least 2 hours at each treatment session)

Increased blood pressure (peak at approximately 40 minutes post- administration and lasts approximately 4 hours)

Short-term cognitive impairment (generally resolves by 2 hours post-dose)

Weight Gain

Sedation

Many experience and/or can be significant in amount

What to Do About Side Effects

Use lower dose (56 mg rather than 84 mg)

For CNS side effects, discontinuation of nonessential centrally acting medications may help

If blood pressure remains high, promptly seek assistance from practitioners experienced in blood pressure management

Refer patients experiencing symptoms of a hypertensive crisis (e.g., chest pain, shortness of breath) or hypertensive encephalopathy (e.g., sudden severe headache, visual disturbances, seizures, diminished consciousness, or focal neurological deficits) immediately for emergency care

Best Augmenting Agents for Side Effects

Reported but not expected

Many side effects cannot be improved with an augmenting agent

Dosing and use Usual Dosage Range

Induction phase (weeks 1– 4): administer twice per week; day 1 starting dose 56 mg; subsequent doses 56 mg or 84 mg

Maintenance phase (weeks 5– 8): administer once weekly; 56 mg or 84 mg

Maintenance phase (weeks 9 and after): administer every 2 weeks or once weekly (use least frequent dosing to maintain remission/response); 56 mg or 84 mg

Dosage Forms

56 mg dose kit: unit-dose carton containing two 28 mg nasal spray devices

84 mg dose kit: unit-dose carton containing three 28 mg nasal spray devices

How to Dose

Given in conjunction with an oral antidepressant

Administered intranasally under the supervision of a healthcare provider

Each nasal spray device delivers 2 sprays containing a total of 28 mg of esketamine

To prevent loss of medication, do not prime the device before use

Patient should recline head at about 45 degrees during administration to keep medication inside the nose

Patient should blow nose before first device only

After patient self-administers both sprays (one in each nostril), check that the indicator shows no green dots; if there is a green dot, have patient spray again into the second nostril

Use 2 devices (for a 56 mg dose) or 3 devices (for a 84 mg dose) with a 5-minute rest period between each device

Blood pressure must be assessed before administration; if blood pressure is elevated, weigh the risks vs. benefits of esketamine administration

Reassess blood pressure 40 minutes post-administration and thereafter as clinically warranted

Patients must be monitored for at least 2 hours at each treatment session, followed by an assessment to determine when the patient is clinically stable and ready to leave the healthcare facility; this is due to the risks of sedation, dissociation, and hypertension

If blood pressure is decreasing and patient is clinically stable for at least 2 hours, the patient may be discharged; if not, continue to monitor

Advise the patient not to engage in potentially hazardous activities, such as driving or operating machinery, until the next day after a restful sleep; patients will need to arrange transportation home

Dosing Tips

Nausea and vomiting are potential side effects, so advise patients to avoid food for at least 2 hours before administration and liquids for at least 30 minutes before administration

Nasal corticosteroid or nasal decongestant should not be used within an hour prior to administration of esketamine

If a patient misses treatment sessions and there is a worsening of symptoms, consider returning to the previous dosing schedule (i.e., every 2 weeks to once weekly, weekly to twice weekly)

Evidence of therapeutic benefit should be evaluated at the end of the induction phase to determine the need for continued treatment

Overdose

With racemic ketamine, symptoms of overdose include restlessness, psychosis, hallucinations, stupor, respiratory depression

Long-Term Use

Long-term cognitive effects of esketamine have not been evaluated beyond 1 year

Long-term cognitive and memory impairment have been reported with repeated ketamine misuse or abuse

Habit Forming

Esketamine is a Schedule III drug and is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS)

Taper not necessary

How to Stop

Pharmacokinetics

Time to maximum plasma concentration is approximately 20– 40 minutes after the last administered nasal spray

Mean terminal half-life 7– 12 hours

Metabolized primarily by CYP450 2B6 and CYP450 3A4, and to a lesser extent by CYP450 2C9 and 2C19

No significant actions on CYP450 enzymes, although esketamine has modest induction effects on CYP450 2B6 and 3A4 in human hepatocytes

Drug Interactions

Little potential to affect metabolism of drugs cleared by CYP450 enzymes

Use with caution with other drugs that are NMDA antagonists (amantadine, memantine, dextromethorphan)

Esketamine may increase the effects of other sedatives, including benzodiazepines, barbiturates, opioids, anesthetics, and alcohol

Concomitant use with stimulants or monoamine oxidase inhibitors may increase blood pressure

Other Warnings/Precautions

Because of the risks of sedation and dissociation and of abuse and misuse, esketamine is only available through a restricted program under a REMS; healthcare settings and pharmacies must be certified in the REMS program, and pharmacies must only dispense esketamine to healthcare settings that are certified in the program

Esketamine can raise blood pressure; patients with cardiovascular and cerebrovascular conditions and risk factors may be at an increased risk of associated adverse effects

Blood pressure should be monitored for at least 2 hours post- administration of esketamine, and prompt medical care should be sought if blood pressure remains high; refer patients experiencing symptoms of a hypertensive crisis or hypertensive encephalopathy for immediate emergency care

In patients with a history of hypertensive encephalopathy, more intensive monitoring, including more frequent blood pressure and symptom assessment, is warranted because these patients are at higher

risk for developing encephalopathy with even small increases in blood pressure

Because of the risks of delayed or prolonged sedation and dissociation, patients must be monitored for at least 2 hours at each treatment session, followed by an assessment to determine when the patient is clinically stable and ready to leave the healthcare facility

Because of the risk of dissociation, carefully assess patients with psychosis before administering esketamine and only initiate treatment if the potential benefits outweigh the risks

Monitor patients for activation of suicidal ideation

Esketamine may impair attention, judgment, thinking, reaction speed, and motor skills

Esketamine may impair ability to drive and operate machinery; patients should not drive or operate machinery until the next day after a restful sleep

When treating children, carefully weigh the risks and benefits of pharmacological treatment against the risks and benefits of nontreatment with antidepressants and make sure to document this in the patientâ€TM s chart

Distribute the brochures provided by the FDA and the drug companies

Whenever possible, warn patients and their caregivers about the possibility of activating side effects, and advise them to report such symptoms immediately

Monitor patients for activation of suicidal ideation, especially children and adolescents

Do Not Use

If patient has aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial and peripheral arterial vessels) or arteriovenous malformation

If patient has intracerebral hemorrhage

If there is a proven allergy to esketamine or ketamine

Special populations Renal Impairment

No dose adjustment necessary

Hepatic Impairment

Patients with moderate impairment may need to be monitored for adverse reactions for a longer period of time

Not recommended for use in patients with severe impairment

Cardiac Impairment

Contraindicated in patients with aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial and peripheral arterial vessels) or arteriovenous malformation

Patients with cardiovascular and cerebrovascular conditions and risk factors may be at an increased risk of associated adverse effects

Elderly

In clinical trials, no differences were observed in safety profile between patients aged 65 years and older and patients younger than 65 years

In clinical trials, Cmax and AUC values were higher in patients aged 65 years and older than in patients younger than 65 years

Children and Adolescents

Safety and efficacy have not been established

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women Not recommended for use during pregnancy

In pregnant primates, use of NMDA receptor antagonists during the period of peak brain development increased neuronal apoptosis in

the developing brain of the fetuses

In rabbits, skeletal malformations were observed when ketamine was administered intranasally at estimated esketamine exposures of 0.3 times the maximum recommended human dose

In rats, delay in sensorimotor development in pups was observed when esketamine was administered intranasally at exposures similar to the maximum recommended human dose

Because of the risk for fetal harm, consider pregnancy planning and prevention in females of reproductive potential

National Pregnancy Registry for Antidepressants: 1-866-961-2388,

https://womensmentalhealth.org/research/pregnancyregistry/antidepr essants

Breast Feeding

Some drug is found in motherâ€TM s breast milk

Animal studies have shown neurotoxicity in juvenile animals when NMDA antagonists were administered during a window of vulnerability that correlates with exposures in the third trimester through the first several months of life, but this window may extend out to approximately 3 years of age in humans

Recommended either to discontinue drug or bottle feed

The art of psychopharmacology

Potential Advantages

Severely treatment-resistant depression, suicidal ideation

Potential Disadvantages

Only available through a restricted program under a REMS

Must be administered in the presence of a healthcare professional Requires monitoring for at least 2 hours post-administration

Primary Target Symptoms

Treatment-resistant depression

Pearls

Esketamine is the “ s†enantiomer of ketamine

Esketamine is not approved as an anesthetic, and its safety or efficacy

as an anesthetic has not been established

In clinical trials, treatment-resistant depression was defined as a DSM- 5 diagnosis for major depressive disorder (MDD) in patients who have not responded adequately to at least two different antidepressants of adequate dose and duration in the current depressive episode

Several studies suggest rapid reduction of depressive symptoms in patients with MDD who have active suicidal ideation with intent

Studies of esketamine or IV ketamine administered during psychotherapy sessions suggest potential improvement of substance

and alcohol abuse

Suggested Reading

Canuso CM Canuso CM , Singh JB Singh JB , Fedgchin M Fedgchin M , et al. Efficacy and safety of esketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide: results of a double-blind, randomized, placebo-controlled study . Am J Psychiatry 2018 ;175 (7 ):620 – 30 .

Daly EJ Daly EJ , Trivedi MH Trivedi MH , Janik A Janik A , et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial . JAMA Psychiatry 2019 ;76 :893 – 903 . doi: 10.1001/jamapsychiatry.2019.1189 .

Fedgchin M Fedgchin M , Trivedi M Trivedi M , Daly E Daly E , et al. Efficacy and safety of fixed-dose esketamine nasal spray combined with a new oral antidepressant in treatment-resistant depression: results of a randomized, double-blind, active-controlled study (TRANSFORM-1) . Int J Neuropsychopharmacol 2019 ;22 (10 ):616 – 30 .

Ochs-Ross R Ochs-Ross R , Daly EJ Daly EJ , Zhang Y Zhang Y , et al. Efficacy and safety of esketamine nasal spray plus an oral antidepressant in elderly patients with treatment-resistant depression – TRANSFORM-3 . Am J Geriatr Psychiatry 2019 ;28 (2 ):121 – 41 .

Popova V Popova V , Daly EJ Daly EJ , Trivedi M Trivedi M , et al. Efficacy and safety of flexibly dose esketamine nasal spray combined with

a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study . Am J Psychiatry 2019 ;176 (6 ):428 – 38 .

Estazolam

ProSom

Therapeutics Brands

Yes

Generic?

Class

see index for additional brand names

Neuroscience-based Nomenclature: GABA positive allosteric modulator (GABA-PAM)

Benzodiazepine (hypnotic)

Commonly Prescribed for

(bold for FDA approved)

Insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings, and/or early morning awakenings

Catatonia

How the Drug Works

Binds to benzodiazepine receptors at the GABA-A ligand-gated chloride channel complex

Enhances the inhibitory effects of GABA

Boosts chloride conductance through GABA-regulated channels

Inhibitory actions in sleep centers may provide sedative hypnotic effects

How Long Until It Works

Generally takes effect in less than an hour

If It Works

Effects on total wake-time and number of nighttime awakenings may be decreased over time

If It Doesnâ€TM t Work

If insomnia does not improve after 7– 10 days, it may be a manifestation of a primary psychiatric or physical illness such as obstructive sleep apnea or restless leg syndrome, which requires independent evaluation

Increase the dose Improve sleep hygiene Switch to another agent

Improves quality of sleep

Best Augmenting Combos for Partial Response or Treatment Resistance

Generally, best to switch to another agent

Trazodone

Agents with antihistamine actions (e.g., diphenhydramine, TCAs)

Tests

In patients with seizure disorders, concomitant medical illness, and/or those with multiple concomitant long-term medications, periodic liver tests and blood counts may be prudent

Side effects

How Drug Causes Side Effects

Same mechanism for side effects as for therapeutic effects – namely due to excessive actions at benzodiazepine receptors

Actions at benzodiazepine receptors that carry over to the next day can cause daytime sedation, amnesia, and ataxia

Long-term adaptations in benzodiazepine receptors may explain the development of dependence, tolerance, and withdrawal

Notable Side Effects âœ1⁄2 Sedation, fatigue, depression

âœ1⁄2 Dizziness, ataxia, slurred speech, weakness

âœ1⁄2 Forgetfulness, confusion

âœ1⁄2 Hyperexcitability, nervousness

Rare hallucinations, mania

Rare hypotension

Hypersalivation, dry mouth

Rebound insomnia when withdrawing from long-term treatment

Life-Threatening or Dangerous Side Effects

Respiratory depression, especially when taken with CNS depressants in overdose

Rare hepatic dysfunction, renal dysfunction, blood dyscrasias

Weight Gain

Sedation

Many experience and/or can be significant in amount

Reported but not expected

Wait

What to Do About Side Effects

To avoid problems with memory, take estazolam only if planning to have a full nightâ€TM s sleep

Lower the dose

Switch to a shorter-acting sedative hypnotic

Switch to a non-benzodiazepine hypnotic

Administer flumazenil if side effects are severe or life-threatening

Best Augmenting Agents for Side Effects

Many side effects cannot be improved with an augmenting agent

Dosing and use Usual Dosage Range

1– 2 mg/day at bedtime

Dosage Forms

Tablet 1 mg scored, 2 mg scored

How to Dose

Initial 1 mg/day at bedtime; increase to 2 mg/day at bedtime if ineffective

Dosing Tips

Use lowest possible effective dose and assess need for continued treatment regularly

Estazolam should generally not be prescribed in quantities greater than a 1-month supply

Patients with lower body weights may require lower doses

Risk of dependence may increase with dose and duration of treatment

Overdose

No death reported in monotherapy; sedation, slurred speech, poor coordination, confusion, coma, respiratory depression

Long-Term Use

Not generally intended for long-term use Evidence of efficacy up to 12 weeks

Habit Forming

Estazolam is a Schedule IV drug

Some patients may develop dependence and/or tolerance; risk may be greater with higher doses

History of drug addiction may increase risk of dependence

How to Stop

If taken for more than a few weeks, taper to reduce chances of withdrawal effects

Patients with seizure history may seize upon sudden withdrawal

Rebound insomnia may occur the first 1– 2 nights after stopping

For patients with severe problems discontinuing a benzodiazepine, dosing may need to be tapered over many months (i.e., reduce dose by 1% every 3 days by crushing tablet and suspending or dissolving in 100 mL of fruit juice and then disposing of 1 mL and drinking the rest; 3– 7 days later, dispose of 2 mL, and so on). This is both a form of very slow biological tapering and a form of behavioral desensitization

Pharmacokinetics

Half-life 10– 24 hours Inactive metabolites

Drug Interactions

Increased clearance and thus decreased estazolam levels in smokers

Increased depressive effects when taken with other CNS depressants (see Warnings below)

Other Warnings/Precautions

Boxed warning regarding the increased risk of CNS depressant effects when benzodiazepines and opioid medications are used

together, including specifically the risk of slowed or difficulty breathing and death

If alternatives to the combined use of benzodiazepines and opioids are not available, clinicians should limit the dosage and duration of each drug to the minimum possible while still achieving therapeutic efficacy

Patients and their caregivers should be warned to seek medical attention if unusual dizziness, lightheadedness, sedation, slowed or difficulty breathing, or unresponsiveness occur

Insomnia may be a symptom of a primary disorder, rather than a primary disorder itself

Some patients may exhibit abnormal thinking or behavioral changes similar to those caused by other CNS depressants (i.e., either depressant actions or disinhibiting actions)

Some depressed patients may experience a worsening of suicidal ideation

Use only with extreme caution in patients with impaired respiratory function or obstructive sleep apnea

Estazolam should be administered only at bedtime

Do Not Use

If patient is pregnant

If patient has angle-closure glaucoma

If there is a proven allergy to estazolam or any benzodiazepine

Special populations Renal Impairment

Drug should be used with caution

Hepatic Impairment

Drug should be used with caution

Cardiac Impairment

Benzodiazepines have been used to treat insomnia associated with acute myocardial infarction

Elderly

No dose adjustment in healthy patients

Debilitated patients: recommended initial dose of 0.5 mg/day

Children and Adolescents

Safety and efficacy have not been established

Long-term effects of estazolam in children/adolescents are unknown

Should generally receive lower doses and be more closely monitored

Pregnancy

Contraindicated for use in pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Infants whose mothers received a benzodiazepine late in pregnancy may experience withdrawal effects

Neonatal flaccidity has been reported in infants whose mothers took a benzodiazepine during pregnancy

Breast Feeding

Unknown if estazolam is secreted in human breast milk, but all psychotropics are assumed to be secreted in breast milk

âœ1⁄2 Recommended either to discontinue drug or bottle feed Effects on infant have been observed and include feeding

difficulties, sedation, and weight loss

The art of psychopharmacology Potential Advantages

Transient insomnia

Potential Disadvantages

Smokers (may need higher dose)

Primary Target Symptoms

Time to sleep onset Total sleep time Nighttime awakenings

Pearls

If tolerance develops, it may result in increased anxiety during the day and/or increased wakefulness during the latter part of the night

Best short-term use is for less than 10 consecutive days, and for less than half of the nights in a month

Drug holidays may restore drug effectiveness if tolerance develops

Though not systematically studied, benzodiazepines have been used effectively to treat catatonia and are the initial recommended treatment

Suggested Reading

Pierce MW , Shu VS . Efficacy of estazolam. The United States clinical experience . Am J Med 1990 ;88 :S6 – 11.

Pierce MW , Shu VS , Groves LJ . Safety of estazolam. The United States clinical experience . Am J Med 1990 ;88 :S12 – 17.

Vogel GW , Morris D . The effects of estazolam on sleep, performance, and memory: a long-term sleep laboratory study of elderly insomniacs . J Clin Pharmacol 1992 ;32 :647– 51 .

Eszopiclone

Lunesta

Therapeutics Brands

Yes

Generic?

Class

see index for additional brand names

Neuroscience-based Nomenclature: GABA positive allosteric modulator (GABA-PAM)

Non-benzodiazepine hypnotic; alpha 1 isoform selective agonist of GABA-A/benzodiazepine receptors

Commonly Prescribed for

(bold for FDA approved)

Insomnia

Primary insomnia Chronic insomnia Transient insomnia

Insomnia secondary to psychiatric or medical conditions Residual insomnia following treatment with antidepressants

How the Drug Works

May bind selectively to a subtype of the benzodiazepine receptor, the alpha 1 isoform

May enhance GABA inhibitory actions that provide sedative hypnotic effects more selectively than other actions of GABA

Boosts chloride conductance through GABA-regulated channels

Inhibitory actions in sleep centers may provide sedative hypnotic effects

How Long Until It Works

Generally takes effect in less than an hour

If It Works

Effects on total wake-time and number of nighttime awakenings may be decreased over time

If It Doesnâ€TM t Work

If insomnia does not improve after 7– 10 days, it may be a manifestation of a primary psychiatric or physical illness such as

Improves quality of sleep

obstructive sleep apnea or restless leg syndrome, which requires independent evaluation

Increase the dose Improve sleep hygiene Switch to another agent

Best Augmenting Combos for Partial Response or Treatment Resistance

Generally, best to switch to another agent

Trazodone

Agents with antihistamine actions (e.g., diphenhydramine, TCAs)

Tests

Side effects

How Drug Causes Side Effects

Actions at benzodiazepine receptors that carry over to the next day can cause daytime sedation, amnesia, and ataxia

âœ1⁄2 Chronic studies of eszopiclone suggest lack of notable tolerance or dependence developing over time

None for healthy individuals

âœ1⁄2 Unpleasant taste Sedation

Notable Side Effects

Dizziness Dose-dependent amnesia Nervousness

Dry mouth, headache

Life-Threatening or Dangerous Side Effects

Respiratory depression, especially when taken with other CNS depressants in overdose

Rare angioedema

Weight Gain

Sedation

Many experience and/or can be significant in amount

Next-day carryover sedation following nighttime dosing uncommon

What to Do About Side Effects

Reported but not expected

Wait

To avoid problems with memory, take eszopiclone only if planning to have a full nightâ€TM s sleep

Lower the dose

Switch to a shorter-acting sedative hypnotic

Administer flumazenil if side effects are severe or life-threatening

Best Augmenting Agents for Side Effects

Many side effects cannot be improved with an augmenting agent

Dosing and Use Usual Dosage Range

2– 3 mg at bedtime

Tablet 1 mg, 2 mg, 3 mg

Dosage Forms

How to Dose

No titration, take dose at bedtime

Dosing Tips

Not restricted to short-term use

No notable development of tolerance or dependence seen in studies up to 6 months

Recent study adding eszopiclone to patients with major depression and only a partial response to fluoxetine showed improvement not only in residual insomnia, but in other residual symptoms of depression as well

Most studies were done with 3 mg dose or less at night, but some patients with insomnia associated with psychiatric disorders may require higher dosing

However, doses higher than 3 mg may be associated with carryover effects, hallucinations, or other CNS adverse effects

To avoid problems with memory or carryover sedation, only take eszopiclone if planning to have a full nightâ€TM s sleep

Most notable side effect may be unpleasant taste

Other side effects can include sedation, dizziness, dose-dependent amnesia, nervousness, dry mouth, and headache

Overdose

Few reports of eszopiclone overdose, but probably similar to zopiclone overdose

Rare fatalities have been reported in zopiclone overdose

Symptoms associated with zopiclone overdose include clumsiness, mood changes, sedation, weakness, breathing trouble, unconsciousness

Long-Term Use

No development of tolerance was seen in studies up to 6 months

Habit Forming

Eszopiclone is a Schedule IV drug

Some patients could develop dependence and/or tolerance with drugs of this class; risk may be theoretically greater with higher doses

History of drug addiction may theoretically increase risk of dependence

How to Stop

Rebound insomnia may occur the first night after stopping

If taken for more than a few weeks, taper to reduce chances of withdrawal effects

Pharmacokinetics

Metabolized by CYP450 3A4 and 2E1

Terminal elimination half-life approximately 6 hours

Heavy high-fat meal slows absorption, which could reduce effect on sleep latency

Drug Interactions

Increased depressive effects when taken with other CNS depressants

Inhibitors of CYP450 3A4, such as nefazodone and fluvoxamine, could increase plasma levels of eszopiclone

Inducers of CYP450 3A4, such as rifampicin, could decrease plasma levels of eszopiclone

Other Warnings/Precautions

Insomnia may be a symptom of a primary disorder, rather than a primary disorder itself

Some patients may exhibit abnormal thinking or behavioral changes similar to those caused by other CNS depressants (i.e., either depressant actions or disinhibiting actions)

Some depressed patients may experience a worsening of suicidal ideation

Use only with caution in patients with impaired respiratory function or obstructive sleep apnea

Eszopiclone should only be administered at bedtime

Rare angioedema has occurred with sedative hypnotic use and could potentially cause fatal airway obstruction if it involves the throat, glottis, or larynx; thus if angioedema occurs treatment should be discontinued

Sleep driving and other complex behaviors, such as eating and preparing food and making phone calls, have been reported in patients taking sedative hypnotics; in some cases these behaviors

have resulted in serious injury or death, prompting the FDA to require a black box warning

Do Not Use

If the patient has experienced an episode of complex sleep behaviors after taking a sleep medication

If there is a proven allergy to eszopiclone or zopiclone

Special populations Renal Impairment

Dose adjustment not generally necessary

Hepatic Impairment

Dose adjustment not generally recommended for mild-to-moderate hepatic impairment

For severe impairment, recommended initial dose 1 mg at bedtime; maximum dose 2 mg at bedtime

Cardiac Impairment

Dosage adjustment may not be necessary

Elderly

May be more susceptible to adverse effects

Initial dose 1 mg at bedtime; maximum dose generally 2 mg at bedtime

Children and Adolescents

Safety and efficacy have not been established

Long-term effects of eszopiclone in children/adolescents are unknown

Should generally receive lower doses and be more closely monitored

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women

Infants whose mothers took sedative hypnotics during pregnancy may experience some withdrawal symptoms

Neonatal flaccidity has been reported in infants whose mothers took sedative hypnotics during pregnancy

Breast Feeding

Unknown if eszopiclone is secreted in human breast milk, but all psychotropics are assumed to be secreted in breast milk

âœ1⁄2 Recommended either to discontinue drug or bottle feed

The art of psychopharmacology Potential Advantages

Primary insomnia

Chronic insomnia

Those who require long-term treatment

Those with depression whose insomnia does not resolve with antidepressant treatment

Potential Disadvantages

More expensive than some other sedative hypnotics

Primary Target Symptoms

Time to sleep onset Nighttime awakenings Total sleep time

Pearls

âœ1⁄2 May be preferred over benzodiazepines because of its rapid onset of action, short duration of effect, and safety profile

Eszopiclone is the best documented agent to be safe for long-term use, with little or no suggestion of tolerance, dependence, or abuse

May even be safe to consider in patients with a past history of substance abuse who require treatment with a hypnotic

May be preferred over benzodiazepine hypnotics, which all cause tolerance, dependence, and abuse as a class

Not a benzodiazepine itself but binds to the benzodiazepine receptor May be a preferred agent in primary insomnia

Targeting insomnia may prevent the onset of depression and maintain remission after recovery from depression

Rebound insomnia does not appear to be common

Suggested Reading

Eszopiclone: esopiclone, estorra, S-zopiclone, zopiclone– Sepracor . Drugs R D 2005 ;6 (2 ):111– 15 .

Krystal AD , Walsh JK , Laska E , et al. Sustained efficacy of eszopiclone over 6 months of nightly treatment: results of a randomized, double-blind, placebo-controlled study in adults with chronic insomnia . Sleep 2003 ;26 (7 ):793 – 9 .

Zammit GK , McNabb LJ , Caron J , Amato DA , Roth T . Efficacy and safety of eszopiclone across 6-weeks of treatment for primary insomnia . Curr Med Res Opin 2004 ;20 (12 ):1979 – 91.

Flibanserin

Addyi

Therapeutics Brands

No

Generic?

Class

see index for additional brand names

Serotonin 1A agonist and serotonin 2A antagonist

Commonly Prescribed for

(bold for FDA approved)

Acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women

How the Drug Works

Sexual dysfunction is theoretically linked to an imbalance in central excitatory and inhibitory sexual signals

HSDD hypothetically results from excessive inhibitory signals, inadequate excitatory signals, or a combination of the two

Flibanserin hypothetically counteracts this imbalance in HSDD through its ability to both reduce inhibitory signals and enhance excitatory signals

Specifically, flibanserin increases the release of dopamine and norepinephrine, which are excitatory sexual signals, and reduces the release of serotonin, an inhibitory sexual signal

How Long Until It Works

In clinical trials, improvement was seen at 4 weeks

If It Works

Increases number of satisfying sexual events and ratings on sexual desire scores

Reduces distress related to sexual dysfunction

If It Doesnâ€TM t Work

If there is no improvement after 8 weeks, discontinue use

Best Augmenting Combos for Partial Response or Treatment Resistance

None known

Theoretically, bupropion augmentation could be considered, but no published trials

Tests

Side effects

How Drug Causes Side Effects

Most common side effects (e.g., notable side effects below) likely caused by 5HT1A agonism and/or 5HT2A antagonism

Hypotension, dizziness, and syncope of flibanserin as a monotherapy is theoretically related to its 5HT1A agonist actions

Weak alpha 1 antagonist actions may also contribute to hypotension and dizziness of flibanserin, especially when given in combination with alcohol, which is contraindicated

Notable Side Effects

Somnolence Nausea Fatigue Insomnia Dry mouth

Life-Threatening or Dangerous Side Effects

None for healthy individuals

Dizziness, syncope, especially when combined with alcohol (contraindicated)

Reported but not expected

Weight Gain

Sedation

Many experience and/or can be significant in amount

Wait

Wait

Wait

What to Do About Side Effects

Review any concomitant medications and consider reducing the dose or discontinuing agents that may be interacting with flibanserin

Switch to another treatment option

Best Augmenting Agents for Side Effects

Many side effects cannot be improved with an augmenting agent

Dosing and use Usual Dosage Range

100 mg once daily at bedtime

Tablet 100 mg

Dosage Forms

How to Dose

Flibanserin is dosed at bedtime to reduce the risk of hypotension, syncope, and somnolence

Limited experience

Not studied

Overdose

Long-Term Use

However, flibanserin is recommended for long-term use with close monitoring

No

Habit Forming

How to Stop

Taper not necessary but may be better tolerated in some patients

Pharmacokinetics

Metabolized primarily by CYP450 3A4 and to a lesser extent by CYP450 2C19

Mean terminal half-life approximately 11 hours

Drug Interactions

The risk of hypotension, syncope, and CNS depression with flibanserin is increased in the presence of alcohol; therefore, the concomitant use of alcohol and flibanserin is contraindicated

The risk of hypotension, syncope, and CNS depression with flibanserin is increased in the presence of moderate or strong CYP450 3A4 inhibitors; therefore, the concomitant use of moderate/strong CYP450 3A4 inhibitors and flibanserin is contraindicated

If the patient requires a moderate or strong CYP450 3A4 inhibitor, flibanserin should be discontinued at least 2 days prior to starting the CYP450 3A4 inhibitor

If the patient is taking a moderate or strong CYP450 3A4 inhibitor, it should be discontinued 2 weeks prior to starting flibanserin

Concomitant use of flibanserin and weak CYP450 3A4 inhibitors may increase flibanserin exposure, potentially increasing risk of adverse effects

Concomitant use of flibanserin and CNS depressants may increase the risk of adverse effects such as somnolence

Concomitant use of flibanserin and CYP450 3A4 inducers may decrease exposure to flibanserin and is not recommended

Concomitant use of flibanserin and CYP450 2C19 inhibitors may increase flibanserin exposure, potentially increasing risk of adverse effects

Use of flibanserin in patients who are poor CYP450 2C19 metabolizers may increase flibanserin exposure, potentially increasing risk of adverse effects

Concomitant use of flibanserin and P-glycoprotein substrates (e.g., digoxin) may increase concentrations of the P-glycoprotein substrate; monitoring is required for P-glycoprotein substrates that have narrow therapeutic index (e.g., digoxin)

Other Warnings/Precautions

Flibanserin can cause severe hypotension and loss of consciousness, with increased risk in the presence of alcohol or CYP450 3A4 inhibitors; for that reason, flibanserin is available only through a Risk Evaluation and Mitigation Strategy (REMS), which includes elements to assure safe use (ETASU)

Do Not Use

In the presence of alcohol

With moderate/strong CYP450 3A4 inhibitors In patients with hepatic impairment

If there is a proven allergy to flibanserin

Special Populations Renal Impairment

Exposure may be increased

Hepatic Impairment

Contraindicated; flibanserin exposure increases 4.5-fold in patients with hepatic impairment

Cardiac Impairment

Use in patients with cardiac impairment has not been studied

Elderly

Not approved for use in postmenopausal women

Some elderly patients may theoretically tolerate lower doses better but this has not been formally studied

Children and Adolescents

Safety and efficacy have not been established

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women

In animal studies, fetal toxicity occurred only in the presence of significant maternal toxicity including reductions in weight gain and sedation

In animal studies, decreased fetal weight, structural anomalies, and increases in fetal loss occurred with flibanserin at exposures greater than 15 times those achieved with recommended human doses

Breast Feeding

Unknown if flibanserin is secreted in human breast milk, but all psychotropics are assumed to be secreted in breast milk

Breast feeding is not recommended during treatment with flibanserin

The art of psychopharmacology

Potential Advantages

Patients who do not like injections

Potential Disadvantages

Patients who drink alcohol

Patients who take concomitant medications that may interact with flibanserinâ€TM s pharmacokinetic and pharmacodynamic properties

Primary Target Symptoms

Reduced sexual desire

Pearls

Flibanserin is not approved for treatment in postmenopausal women or in men and is not indicated to enhance sexual performance

May act on reward circuits in the CNS to enhance motivation and interest

If not effective for HSDD, consider avoiding any concomitant use of agents that either enhance serotonin activity (such as SSRIs or SNRIs) or diminish dopamine activity (such as antipsychotics)

Theoretically, may wish to avoid concomitant use with agents that have potent alpha 1 antagonist actions that may enhance the possibility of hypotension

Suggested Reading

Simon JA , Thorp J , Millheiser L . Flibanserin for premenopausal hypoactive sexual desire disorder: pooled analysis of clinical trials . J

Womens Health (Larchmt) 2019 ;28 (6 ):769– 77 .

Stahl SM . Mechanism of action of flibanserin, a multifunctional serotonin agonist and antagonist (MSAA), in hypoactive sexual desire disorder . CNS Spectr 2015 ;20 (1 ):1 – 6 .

Stahl SM , Sommer B , Allers KA . Multifunctional pharmacology of flibanserin: possible mechanism of therapeutic action in Hypoactive Sexual Desire Disorder . J Sex Med 2011 ;8 :15 – 27 .

Weinberger JM , Houman J , Caron AT , et al. Female sexual dysfunction and the placebo effect: a meta-analysis . Obstet Gynecol 2018 ;132 (2 ):453– 8 .

Flumazenil

Romazicon

Anexate

Lanexat

see index for additional brand names

Therapeutics Brands

Yes

Generic?

Class

Benzodiazepine receptor antagonist

Commonly Prescribed for

(bold for FDA approved)

Reversal of sedative effects of benzodiazepines after general anesthesia has been induced and/or maintained with benzodiazepines

Reversal of sedative effects of benzodiazepines after sedation has been produced with benzodiazepines for diagnostic and

therapeutic procedures

Management of benzodiazepine overdose

Reversal of conscious sedation induced with benzodiazepines (pediatric patients)

How the Drug Works

Blocks benzodiazepine receptors at GABA-A ligand-gated chloride channel complex, preventing benzodiazepines from binding there

How Long Until It Works

Onset of action 1– 2 minutes; peak effect 6– 10 minutes

If It Works

âœ1⁄2 Reverses sedation and psychomotor retardation rapidly, but may

not restore memory completely

âœ1⁄2 Patients treated for benzodiazepine overdose may experience CNS excitation

âœ1⁄2 Patients who receive flumazenil to reverse benzodiazepine effects should be monitored for up to 2 hours for resedation, respiratory depression, or other lingering benzodiazepine effects

Flumazenil has not been shown to treat hypoventilation due to benzodiazepine treatment

If It Doesnâ€TM t Work

Sedation is most likely not due to a benzodiazepine, and treatment with flumazenil should be discontinued and other causes of sedation investigated

Best Augmenting Combos for Partial Response or Treatment Resistance

None – flumazenil is basically used as a monotherapy antidote to reverse the actions of benzodiazepines

Tests

Side effects

How Drug Causes Side Effects

Blocks benzodiazepine receptors at GABA-A ligand-gated chloride channel complex, preventing benzodiazepines from binding there

Notable Side Effects

May precipitate benzodiazepine withdrawal in patients dependent upon or tolerant to benzodiazepines

Dizziness, injection site pain, sweating, headache, blurred vision

Life-Threatening or Dangerous Side Effects

None for healthy individuals

Seizures

Death (majority occurred in patients with severe underlying disease or who overdosed with non-benzodiazepines)

Cardiac dysrhythmia

Weight Gain

Sedation

Patients may experience resedation if the effects of flumazenil wear off before the effects of the benzodiazepine

What to Do About Side Effects

Monitor patient

Restrict ambulation because of dizziness, blurred vision, and possibility of resedation

Best Augmenting Agents for Side Effects

None – augmenting agents are not appropriate to treat side effects associated with flumazenil use

Reported but not expected

Reported but not expected

Dosing and use Usual Dosage Range

0.4– 1 mg generally causes complete antagonism of therapeutic doses of benzodiazepines

1– 3 mg generally reverses benzodiazepine overdose

Dosage Forms

Intravenous 0.1 mg/mL– 5 mL multiple-use vial, 10 mL multiple- use vial

How to Dose

Conscious sedation, general anesthesia: 0.2 mg (2 mL) over 15 seconds; can administer 0.2 mg again after 45 seconds; can administer 0.2 mg each additional 60 seconds; maximum 1 mg

Benzodiazepine overdose: 0.2 mg over 30 seconds; can administer 0.3 mg over next 30 seconds; can administer 0.5 mg over 30 seconds after 1 minute; maximum 5 mg

Dosing Tips

May need to administer follow-up doses to reverse actions of benzodiazepines that have a longer half-life than flumazenil (i.e., longer than 1 hour)

Overdose

Anxiety, agitation, increased muscle tone, hyperesthesia, convulsions

Long-Term Use

Not a long-term treatment

No

N/A

Habit Forming

How to Stop

Pharmacokinetics

Terminal half-life 41– 79 minutes

Drug Interactions

Food increases its clearance

Other Warnings/Precautions

Flumazenil may induce seizures, particularly in patients tolerant to or dependent on benzodiazepines, or who have overdosed on cyclic antidepressants, received recent/repeated doses of parenteral benzodiazepines, or have jerking or convulsion during overdose

Patients dependent on benzodiazepines or receiving benzodiazepines to suppress seizures in cyclic antidepressant overdose should receive the minimally effective dose of flumazenil

Use with caution in patients with head injury

Greater risk of resedation if administered to a patient who took a long-acting benzodiazepine or a large dose of a short-acting benzodiazepine

Flumazenil may induce panic attacks in patients with panic disorder

Use with caution in cases of mixed overdose because toxic effects of other drugs used in overdose (e.g., convulsions) may appear when the effects of the benzodiazepine are reversed

Do Not Use

Should not be used until after effects of neuromuscular blockers have been reversed

If benzodiazepine was prescribed to control a life-threatening condition (e.g., status epilepticus, intracranial pressure)

If there is a high risk of seizure

If patient exhibits signs of serious cyclic antidepressant overdose If there is a proven allergy to flumazenil or benzodiazepines

Special populations

Renal Impairment

Dosage adjustment may not be necessary

Hepatic Impairment

Prolongation of half-life

Moderate: clearance reduced by half Severe: clearance reduced by three-quarters

Cardiac Impairment

Dosage adjustment may not be necessary

Elderly

Dosage adjustment may not be necessary

Children and Adolescents

More variability of pharmacokinetics than in adults

Safety and efficacy established for reversal of conscious sedation for children over age 1

Initial 0.01 mg/kg (up to 0.2 mg) over 15 seconds; same dosing pattern as adults; maximum 0.05 mg/kg or 1 mg

Safety and efficacy for reversal of benzodiazepine overdose, general anesthesia induction or resuscitation of a newborn have not been

established, but anecdotal data suggest similar safety and efficacy as for conscious sedation

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women

Not recommended to treat the effects of benzodiazepines during labor and delivery because the effects on the infant have not been studied

Breast Feeding

Unknown if flumazenil is secreted in human breast milk, but all psychotropics are assumed to be secreted in breast milk

If treatment with flumazenil is necessary, it should be administered with caution

The art of psychopharmacology Potential Advantages

To reverse a low dose of a short-acting benzodiazepine

Potential Disadvantages

May be too short-acting

Primary Target Symptoms

Effects of benzodiazepines

Sedative effects

Recall and psychomotor impairments Ventilatory depression

Pearls

Can precipitate benzodiazepine withdrawal seizures âœ1⁄2 Can wear off before the benzodiazepine it is reversing

âœ1⁄2 Can precipitate anxiety or panic in conscious patients with anxiety disorders

Suggested Reading

Malizia AL , Nutt DJ . The effects of flumazenil in neuropsychiatric disorders . Clin Neuropharmacol 1995 ;18 :215– 32 .

McCloy RF . Reversal of conscious sedation by flumazenil: current status and future prospects . Acta Anaesthesiol Scand Suppl 1995 ;108 :35 – 42 .

Weinbroum AA , Flaishon R , Sorkine P , Szold O , Rudick V . A risk- benefit assessment of flumazenil in the management of benzodiazepine overdose . Drug Saf 1997 ;17 :181– 96 .

Whitwam JG . Flumazenil and midazolam in anaesthesia . Acta Anaesthesiol Scand Suppl 1995 ;108 :15 – 22 .

Whitwam JG , Amrein R . Pharmacology of flumazenil . Acta Anaesthesiol Scand Suppl 1995 ;108 :3 – 14.

Flunitrazepam

Rohypnol

Therapeutics Brands

see index for additional brand names

No

Generic?

Class

Neuroscience-based Nomenclature: GABA positive allosteric modulator (GABA-PAM)

Benzodiazepine (hypnotic)

Commonly Prescribed for

(bold for FDA approved)

Short-term treatment of insomnia (severe, disabling) Catatonia

How the Drug Works

Binds to benzodiazepine receptors at the GABA-A ligand-gated chloride channel complex

Enhances the inhibitory effects of GABA

Boosts chloride conductance through GABA-regulated channels

Inhibitory actions in sleep centers may provide sedative hypnotic effects

How Long Until It Works

Generally takes effect in less than an hour

If It Works

Effects on total wake-time and number of nighttime awakenings may be decreased over time

If It Doesnâ€TM t Work

If insomnia does not improve after 7– 10 days, it may be a manifestation of a primary psychiatric or physical illness such as obstructive sleep apnea or restless leg syndrome, which requires independent evaluation

Increase the dose Improve sleep hygiene Switch to another agent

Improves quality of sleep

Best Augmenting Combos for Partial Response or Treatment Resistance

Generally, best to switch to another agent

Trazodone

Agents with antihistamine actions (e.g., diphenhydramine, TCAs)

Tests

In patients with seizure disorders, concomitant medical illness, and/or those with multiple concomitant long-term medications, periodic liver tests and blood counts may be prudent

Side Effects

How Drug Causes Side Effects

Same mechanism for side effects as for therapeutic effects – namely due to excessive actions at benzodiazepine receptors

Actions at benzodiazepine receptors that carry over to the next day can cause daytime sedation, amnesia, and ataxia

Long-term adaptations in benzodiazepine receptors may explain the development of dependence, tolerance, and withdrawal

Notable Side Effects âœ1⁄2 Sedation, fatigue, depression

âœ1⁄2 Dizziness, ataxia, slurred speech, weakness

âœ1⁄2 Forgetfulness, confusion

âœ1⁄2 Hyperexcitability, nervousness

Rare hallucinations, mania

Rare hypotension

Hypersalivation, dry mouth

Rebound insomnia when withdrawing from long-term treatment

Life-Threatening or Dangerous Side Effects

Respiratory depression, especially when taken with CNS depressants in overdose

Rare hepatic dysfunction, renal dysfunction, blood dyscrasias

Weight Gain

Sedation

Many experience and/or can be significant in amount

Reported but not expected

Wait

What to Do About Side Effects

To avoid problems with memory, only take flunitrazepam if planning to have a full nightâ€TM s sleep

Lower the dose

Switch to a shorter-acting sedative hypnotic

Switch to a non-benzodiazepine hypnotic

Administer flumazenil if side effects are severe or life-threatening

Best Augmenting Agents for Side Effects

Many side effects cannot be improved with an augmenting agent

Dosing And Use Usual Dosage Range

0.5– 1 mg/day at bedtime

Dosage Forms

Tablet 0.5 mg, 1 mg, 2 mg, 4 mg

How to Dose

Initial 0.5– 1 mg/day at bedtime; maximum generally 2 mg/day at bedtime

Dosing Tips

Use lowest possible effective dose and assess need for continued treatment regularly

Flunitrazepam should generally not be prescribed in quantities greater than a 1-month supply

Patients with lower body weights may require lower doses

Risk of dependence may increase with dose and duration of treatment

Use doses over 1 mg only in exceptional circumstances

Patients who request or who require doses over 1 mg may be more likely to have present or past substance abuse

Flunitrazepam is 10 times more potent than diazepam

Overdose

Sedation, slurred speech, poor coordination, confusion, coma, respiratory depression

Long-Term Use

Not generally intended for long-term use Use is not recommended to exceed 4 weeks

Habit Forming

Some patients may develop dependence and/or tolerance; risk may be greater with higher doses

History of drug addiction may increase risk of dependence

Currently classified as Schedule III by the World Health Organization

Currently classified as a Schedule IV drug in the USA, but not legally available in the USA

How to Stop

If taken for more than a few weeks, taper to reduce chances of withdrawal effects

Patients with seizure history may seize upon sudden withdrawal

Rebound insomnia may occur the first 1– 2 nights after stopping

For patients with severe problems discontinuing a benzodiazepine, dosing may need to be tapered over many months (i.e., reduce dose by 1% every 3 days by crushing tablet and suspending or dissolving in 100 mL of fruit juice and then disposing of 1 mL and drinking the rest; 3– 7 days later, dispose of 2 mL, and so on). This is both a form of very slow biological tapering and a form of behavioral desensitization

Pharmacokinetics

Elimination half-life 16– 35 hours Half-life of active metabolite 23– 33 hours

Drug Interactions

Increased depressive effects when taken with other CNS depressants (see Warnings below)

Cisapride may hasten the absorption of flunitrazepam and thus cause a temporary increase in the sedative effects of flunitrazepam

Other Warnings/Precautions

Boxed warning regarding the increased risk of CNS depressant effects when benzodiazepines and opioid medications are used together, including specifically the risk of slowed or difficulty breathing and death

If alternatives to the combined use of benzodiazepines and opioids are not available, clinicians should limit the dosage and duration of each drug to the minimum possible while still achieving therapeutic efficacy

Patients and their caregivers should be warned to seek medical attention if unusual dizziness, lightheadedness, sedation, slowed or difficulty breathing, or unresponsiveness occur

Insomnia may be a symptom of a primary disorder, rather than a primary disorder itself

Some patients may exhibit abnormal thinking or behavioral changes similar to those caused by other CNS depressants (i.e., either depressant actions or disinhibiting actions)

Some depressed patients may experience a worsening of suicidal ideation

Use only with extreme caution in patients with impaired respiratory function or obstructive sleep apnea

Flunitrazepam should be administered only at bedtime

Do Not Use

If patient is pregnant

If patient has severe chronic hypercapnia, myasthenia gravis, severe respiratory insufficiency, sleep apnea, or severe hepatic insufficiency

In children

If patient has angle-closure glaucoma

If there is a proven allergy to flunitrazepam or any benzodiazepine

Special Populations Renal Impairment

Drug should be used with caution

Hepatic Impairment

Dose should be lowered

Should not be used in patients with severe hepatic insufficiency, as it may precipitate encephalopathy

Cardiac Impairment

Benzodiazepines have been used to treat insomnia associated with acute myocardial infarction

Elderly

Initial starting dose 0.5 mg at bedtime; maximum generally 1 mg/day at bedtime

Paradoxical reactions with restlessness and agitation are more likely to occur in the elderly

Children and Adolescents

Safety and efficacy have not been established

Not recommended for use in children or adolescents

Paradoxical reactions with restlessness and agitation are more likely to occur in children

Pregnancy

Positive evidence of risk to human fetus; contraindicated for use in pregnancy

Infants whose mothers received a benzodiazepine late in pregnancy may experience withdrawal effects

Neonatal flaccidity has been reported in infants whose mothers took a benzodiazepine during pregnancy

Breast Feeding

Unknown if flunitrazepam is secreted in human breast milk, but all psychotropics are assumed to be secreted in breast milk

âœ1⁄2 Recommended either to discontinue drug or bottle feed Effects on infant have been observed and include feeding

difficulties, sedation, and weight loss

The Art of Psychopharmacology Potential Advantages

For severe, disabling insomnia unresponsive to other sedative hypnotics

Potential Disadvantages

For those who need treatment for longer than a few weeks For those with current or past substance abuse

Primary Target Symptoms

Time to sleep onset Total sleep time Nighttime awakenings

Pearls

âœ1⁄2 Psychiatric symptoms and “ paradoxical†reactions may be quite severe with flunitrazepam and may be more frequent than with other benzodiazepines

âœ1⁄2 “ Paradoxical†reactions include symptoms such as restlessness, agitation, irritability, aggressiveness, delusions, rage, nightmares, hallucinations, psychosis, inappropriate behavior, and other adverse behavioral effects

Although legally available in Europe, Mexico, South America, and many other countries, it is not legally available in the USA

Although currently classified as a Schedule IV drug, the US Drug Enforcement Administration is considering reclassifying it as Schedule I

âœ1⁄2 Has earned a reputation as a “ date rape drug†in which sexual predators have allegedly slipped flunitrazepam into womenâ€TM s drinks to induce sexual relations

âœ1⁄2 Flunitrazepam, especially in combination with alcohol, is claimed to reduce the womanâ€TM s judgment, inhibitions, or physical ability to resist sexual advances, as well as to reduce or eliminate her recall of the events

âœ1⁄2 Until 1999 was colorless, but a colorimetric compound is now added that turns the drug blue when added to a liquid, making it obvious that a drink was tampered with

Illicit use since 1999 has fallen in part due to this additive

Illicit use has also fallen in the USA due to the Drug-Induced Rape Prevention and Punishment Act of 1996, making it punishable to commit a violent crime using a controlled substance such as flunitrazepam

Street names for flunitrazepam, based in part upon its trade name of Rohypnol, manufacturer Roche, and the presence of RO-2 on the surface of the tablets, include “ roofies,†“ ruffies,†“ roapies,†“ la roacha,†“ roach-2,†“ Mexican valium,†“ rope,†“ roache vitamins,†and others

If tolerance develops, it may result in increased anxiety during the day and/or increased wakefulness during the latter part of the night

Best short-term use is for less than 10 consecutive days, and for less than half of the nights in a month

Drug holidays may restore drug effectiveness if tolerance develops

Though not systematically studied, benzodiazepines have been used effectively to treat catatonia and are the initial recommended treatment

Suggested Reading

Simmons MM , Cupp MJ . Use and abuse of flunitrazepam . Ann

Pharmacother 1998 ;32 (1 ):117– 19 .

Woods JH , Winger G . Abuse liability of flunitrazepam . J Clin Psychopharmacol 1997 ;17 (3 Suppl 2):S1 – 57.

Fluoxetine

Prozac

Prozac weekly

Sarafem

see index for additional brand names

Therapeutics Brands

Yes

Generic?

Class

Neuroscience-based Nomenclature: serotonin reuptake inhibitor (S- RI)

SSRI (selective serotonin reuptake inhibitor); often classified as an antidepressant, but it is not just an antidepressant

Commonly Prescribed for

(bold for FDA approved)

Major depressive disorder (ages 8 and older) Obsessive-compulsive disorder (OCD) (ages 7 and older)

Premenstrual dysphoric disorder (PMDD)

Bulimia nervosa

Panic disorder

Bipolar depression [in combination with olanzapine (Symbyax)]

Treatment-resistant depression [in combination with olanzapine (Symbyax)]

Social anxiety disorder (social phobia) Posttraumatic stress disorder (PTSD)

How the Drug Works

Boosts neurotransmitter serotonin

Blocks serotonin reuptake pump (serotonin transporter) Desensitizes serotonin receptors, especially serotonin 1A receptors Presumably increases serotonergic neurotransmission

âœ1⁄2 Fluoxetine also has antagonist properties at 5HT2C receptors, which could increase norepinephrine and dopamine neurotransmission

How Long Until It Works

âœ1⁄2 Some patients may experience increased energy or activation

early after initiation of treatment

Onset of therapeutic actions usually not immediate, but often delayed 2– 4 weeks

If it is not working within 6– 8 weeks, it may require a dosage increase or it may not work at all

May continue to work for many years to prevent relapse of symptoms

If It Works

The goal of treatment is complete remission of current symptoms as well as prevention of future relapses

Treatment most often reduces or even eliminates symptoms, but not a cure since symptoms can recur after medicine stopped

Continue treatment until all symptoms are gone (remission) or significantly reduced (e.g., OCD, PTSD)

Once symptoms are gone, continue treating for 1 year for the first episode of depression

For second and subsequent episodes of depression, treatment may need to be indefinite

For anxiety disorders and bulimia, treatment may also need to be indefinite

If It Doesnâ€TM t Work

Many patients have only a partial response where some symptoms are improved but others persist (especially insomnia, fatigue, and problems concentrating in depression)

Other patients may be nonresponders, sometimes called treatment- resistant or treatment-refractory

Some patients who have an initial response may relapse even though they continue treatment, sometimes called “ poop-outâ€

Consider increasing dose, switching to another agent, or adding an appropriate augmenting agent

Consider psychotherapy

Consider evaluation for another diagnosis or for a comorbid condition (e.g., medical illness, substance abuse, etc.)

Some patients may experience apparent lack of consistent efficacy due to activation of latent or underlying bipolar disorder, and require antidepressant discontinuation and a switch to a mood stabilizer

Best Augmenting Combos for Partial Response or Treatment Resistance

Trazodone, especially for insomnia

Bupropion, mirtazapine, reboxetine, or atomoxetine (add with caution and at lower doses since fluoxetine could theoretically raise atomoxetine levels); use combinations of antidepressants with caution as this may activate bipolar disorder and suicidal ideation

Modafinil, especially for fatigue, sleepiness, and lack of concentration

Mood stabilizers or atypical antipsychotics for bipolar depression, psychotic depression, treatment-resistant depression, or treatment-

resistant anxiety disorders

âœ1⁄2 Fluoxetine has been specifically studied in combination with olanzapine (olanzapine/fluoxetine combination) with excellent results for bipolar depression, treatment-resistant unipolar depression, and psychotic depression

Benzodiazepines

If all else fails for anxiety disorders, consider gabapentin or tiagabine

Hypnotics for insomnia

Classically, lithium, buspirone, or thyroid hormone

Tests

Side Effects

How Drug Causes Side Effects

Theoretically due to increases in serotonin concentrations at serotonin receptors in parts of the brain and body other than those that cause therapeutic actions (e.g., unwanted actions of serotonin in sleep centers causing insomnia, unwanted actions of serotonin in the gut causing diarrhea, etc.)

Increasing serotonin can cause diminished dopamine release and might contribute to emotional flattening, cognitive slowing, and

None for healthy individuals

apathy in some patients

Most side effects are immediate but often go away with time, in contrast to most therapeutic effects which are delayed and are enhanced over time

âœ1⁄2 Fluoxetineâ€TM s unique 5HT2C antagonist properties could contribute to agitation, anxiety, and undesirable activation, especially early in dosing

Notable Side Effects

Sexual dysfunction (men: delayed ejaculation, erectile dysfunction; men and women: decreased sexual desire, anorgasmia)

Gastrointestinal (decreased appetite, nausea, diarrhea, constipation, dry mouth)

Mostly CNS (insomnia but also sedation, agitation, tremors, headache, dizziness)

Note: patients with diagnosed or undiagnosed bipolar or psychotic disorders may be more vulnerable to CNS-activating actions of SSRIs

Autonomic (sweating)

Bruising and rare bleeding

SIADH (syndrome of inappropriate antidiuretic hormone secretion)

Life-Threatening or Dangerous Side Effects

Rare seizures

Rare induction of mania

Rare activation of suicidal ideation and behavior (suicidality) (short- term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo beyond age 24)

Weight Gain

Reported but not expected

Possible weight loss, especially short-term

Sedation

What to Do About Side Effects

Reported but not expected

Wait

Wait

Wait

If fluoxetine is activating, take in the morning to help reduce insomnia

Reduce dose to 10 mg, and either stay at this dose if tolerated and effective, or consider increasing again to 20 mg or more if tolerated

but not effective at 10 mg

In a few weeks, switch or add other drugs

Best Augmenting Agents for Side Effects

Often best to try another SSRI or another antidepressant monotherapy prior to resorting to augmentation strategies to treat side effects

Trazodone or a hypnotic for insomnia

Bupropion, sildenafil, vardenafil, or tadalafil for sexual dysfunction

Bupropion for emotional flattening, cognitive slowing, or apathy

Mirtazapine for insomnia, agitation, and gastrointestinal side effects

Benzodiazepines for jitteriness and anxiety, especially at initiation of treatment and especially for anxious patients

Many side effects are dose-dependent (i.e., they increase as dose increases, or they reemerge until tolerance redevelops)

Many side effects are time-dependent (i.e., they start immediately upon dosing and upon each dose increase, but go away with time)

Activation and agitation may represent the induction of a bipolar state, especially a mixed dysphoric bipolar II condition sometimes associated with suicidal ideation, and require the addition of lithium, a mood stabilizer or an atypical antipsychotic, and/or discontinuation of fluoxetine

Dosing And Use Usual Dosage Range

20– 80 mg for depression and anxiety disorders 60– 80 mg for bulimia

Dosage Forms

Capsule 10 mg, 20 mg, 40 mg

Tablet 10 mg, 15 mg, 20 mg, 60 mg Liquid 20 mg/5 mL– 120 mL bottles Weekly capsule 90 mg

Olanzapine/fluoxetine combination capsule (mg equivalent olanzapine/mg equivalent fluoxetine) 3 mg/25 mg, 6 mg/25 mg, 6 mg/50 mg, 12 mg/25 mg, 12 mg/50 mg

How to Dose

Depression and OCD: initial dose 20 mg/day in morning, usually wait a few weeks to assess drug effects before increasing dose; maximum dose generally 80 mg/day

Bulimia: initial dose 60 mg/day in morning; some patients may need to begin at lower dose and titrate over several days

Dosing Tips

The long half-lives of fluoxetine and its active metabolites mean that dose changes will not be fully reflected in plasma for several weeks, lengthening titration to final dose and extending withdrawal from treatment

Give once daily, often in the mornings, but at any time of day tolerated

Often available in capsules, not tablets, so unable to break capsules in half

Occasional patients are dosed above 80 mg

Liquid formulation easiest for doses below 10 mg when used for cases that are very intolerant to fluoxetine or for very slow up-and down-titration needs

âœ1⁄2 For some patients, weekly dosing with the weekly formulation may enhance compliance

The more anxious and agitated the patient, the lower the starting dose, the slower the titration, and the more likely the need for a concomitant agent such as trazodone or a benzodiazepine

If intolerable anxiety, insomnia, agitation, akathisia, or activation occur upon either dosing initiation or discontinuation, consider the possibility of activated bipolar disorder and switch to a mood stabilizer or an atypical antipsychotic

Overdose

Rarely lethal in monotherapy overdose; respiratory depression especially with alcohol, ataxia, sedation, possible seizures

Safe

No

Long-Term Use

Habit Forming

How to Stop

Taper rarely necessary since fluoxetine tapers itself after immediate discontinuation, due to the long half-life of fluoxetine and its active metabolites

Pharmacokinetics

Active metabolite (norfluoxetine) has 2 week half-life Parent drug has 2– 3 day half-life

Inhibits CYP450 2D6

Inhibits CYP450 3A4

Drug Interactions

Tramadol increases the risk of seizures in patients taking an antidepressant

Can increase TCA levels; use with caution with TCAs or when switching from a TCA to fluoxetine

Can cause a fatal “ serotonin syndrome†when combined with MAOIs, so do not use with MAOIs or for at least 14 days after MAOIs are stopped

Do not start an MAOI for at least 5 weeks after discontinuing fluoxetine

May displace highly protein-bound drugs (e.g., warfarin)

Can rarely cause weakness, hyperreflexia, and incoordination when combined with sumatriptan, or possibly with other triptans, requiring careful monitoring of patient

Possible increased risk of bleeding, especially when combined with anticoagulants (e.g.,warfarin, NSAIDs)

NSAIDs may impair effectiveness of SSRIs

Via CYP450 2D6 inhibition, could theoretically interfere with the analgesic actions of codeine, and increase the plasma levels of some beta blockers and of atomoxetine

Via CYP450 2D6 inhibition, fluoxetine could theoretically increase concentrations of thioridazine and cause dangerous cardiac arrhythmias

May reduce the clearance of diazepam or trazodone, thus increasing their levels

Via CYP450 3A4 inhibition, may increase the levels of alprazolam, buspirone, and triazolam

Via CYP450 3A4 inhibition, fluoxetine could theoretically increase concentrations of certain cholesterol-lowering HMG CoA reductase inhibitors, especially simvastatin, atorvastatin, and lovastatin, but not pravastatin or fluvastatin, which would increase the risk of rhabdomyolysis; thus, coadministration of fluoxetine with certain HMG CoA reductase inhibitors should proceed with caution

Via CYP450 3A4 inhibition, fluoxetine could theoretically increase the concentrations of pimozide, and cause QTc prolongation and dangerous cardiac arrhythmias

Other Warnings/Precautions

âœ1⁄2 Add or initiate other antidepressants with caution for up to 5

weeks after discontinuing fluoxetine

Use with caution in patients with history of seizure

Use with caution in patients with bipolar disorder unless treated with concomitant mood-stabilizing agent

When treating children, carefully weigh the risks and benefits of pharmacological treatment against the risks and benefits of nontreatment with antidepressants and make sure to document this in the patientâ€TM s chart

Distribute the brochures provided by the FDA and the drug companies

Whenever possible, warn patients and their caregivers about the possibility of activating side effects, and advise them to report such symptoms immediately

Monitor patients for activation of suicidal ideation, especially children and adolescents

Do Not Use

If patient is taking an MAOI

If patient is taking thioridazine

If patient is taking pimozide

If patient is taking tamoxifen

If there is a proven allergy to fluoxetine

Special Populations Renal Impairment

No dose adjustment

Not removed by hemodialysis

Hepatic Impairment

Lower dose or give less frequently, perhaps by half

Cardiac Impairment

Preliminary research suggests that fluoxetine is safe in these patients

Treating depression with SSRIs in patients with acute angina or following myocardial infarction may reduce cardiac events and improve survival as well as mood

Elderly

Some patients may tolerate lower doses better Risk of SIADH with SSRIs is higher in the elderly

Reduction in the risk of suicidality with antidepressants compared to placebo in adults age 65 and older

Children and Adolescents

Carefully weigh the risks and benefits of pharmacological treatment against the risks and benefits of nontreatment with antidepressants and make sure to document this in the patientâ€TM s chart

Monitor patients face-to-face regularly, particularly during the first several weeks of treatment

Use with caution, observing for activation of known or unknown bipolar disorder and/or suicidal ideation, and inform parents or guardians of this risk so they can help observe child or adolescent patients

Approved for OCD and depression

Adolescents often receive adult dose, but doses slightly lower for children

Children taking fluoxetine may have slower growth; long-term effects are unknown

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women

Not generally recommended for use during pregnancy, especially during first trimester

Nonetheless, continuous treatment during pregnancy may be necessary and has not been proven to be harmful to the fetus

Current patient registries of children whose mothers took fluoxetine during pregnancy do not show adverse consequences

At delivery there may be more bleeding in the mother and transient irritability or sedation in the newborn

Must weigh the risk of treatment (first trimester fetal development, third trimester newborn delivery) to the child against the risk of no treatment (recurrence of depression, maternal health, infant bonding) to the mother and child

For many patients this may mean continuing treatment during pregnancy

Exposure to SSRIs early in pregnancy may be associated with increased risk of septal heart defects (absolute risk is small)

SSRI use beyond the 20th week of pregnancy may be associated with increased risk of pulmonary hypertension in newborns, although this is not proven

Exposure to SSRIs late in pregnancy may be associated with increased risk of gestational hypertension and preeclampsia

Neonates exposed to SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding; reported symptoms are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome, and include respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying

National Pregnancy Registry for Antidepressants: 1-866-961-2388,

https://womensmentalhealth.org/research/pregnancyregistry/antidepr essants

Breast Feeding

Some drug is found in motherâ€TM s breast milk

Trace amounts may be present in nursing children whose mothers are on fluoxetine

If child becomes irritable or sedated, breast feeding or drug may need to be discontinued

Immediate postpartum period is a high-risk time for depression, especially in women who have had prior depressive episodes, so drug may need to be reinstituted late in the third trimester or shortly after childbirth to prevent a recurrence during the postpartum period

Must weigh benefits of breast feeding with risks and benefits of antidepressant treatment versus nontreatment to both the infant and the mother

For many patients this may mean continuing treatment during breast feeding

The art of Psychopharmacology Potential Advantages

Patients with atypical depression (hypersomnia, increased appetite) Patients with fatigue and low energy

Patients with comorbid eating and affective disorders

Generic is less expensive than brand name where available Patients for whom weekly administration is desired

Children with OCD or depression

Potential Disadvantages

Patients with anorexia

Initiating treatment in anxious, agitated patients Initiating treatment in severe insomnia

Primary Target Symptoms

Depressed mood

Energy, motivation, and interest

Anxiety (eventually, but can actually increase anxiety, especially short-term)

Sleep disturbance, both insomnia and hypersomnia (eventually, but may actually cause insomnia, especially short-term)

Pearls

âœ1⁄2 May be a first-line choice for atypical depression (e.g.,

hypersomnia, hyperphagia, low energy, mood reactivity) Consider avoiding in agitated insomniacs

Can cause cognitive and affective “ flatteningâ€

Not as well tolerated as some other SSRIs for panic disorder and other anxiety disorders, especially when dosing is initiated, unless given with co-therapies such as benzodiazepines or trazodone

Long half-life; even longer-lasting active metabolite

âœ1⁄2 Actions at 5HT2C receptors may explain its activating properties

âœ1⁄2 Actions at 5HT2C receptors may explain in part fluoxetineâ€TM s efficacy in combination with olanzapine for bipolar depression and treatment-resistant depression, since both agents have this property

For sexual dysfunction, can augment with bupropion, sildenafil, vardenafil, or tadalafil, or switch to a non-SSRI such as bupropion or mirtazapine

Mood disorders can be associated with eating disorders (especially in adolescent females) and be treated successfully with fluoxetine

SSRIs may be less effective in women over 50, especially if they are not taking estrogen

SSRIs may be useful for hot flushes in perimenopausal women

Some postmenopausal womenâ€TM s depression will respond better to fluoxetine plus estrogen augmentation than to fluoxetine alone

Nonresponse to fluoxetine in elderly may require consideration of mild cognitive impairment or Alzheimer disease

SSRIs may not cause as many patients to attain remission of depression as some other classes of antidepressants (e.g., SNRIs)

A single pill containing both fluoxetine and olanzapine is available for combination treatment of bipolar depression, psychotic depression, and treatment-resistant unipolar depression

Suggested Reading

Anderson IM . Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability . J Affect Disord 2000 ;58 :19 – 36 .

Beasley CM Jr, Ball SG , Nilsson ME , et al. Fluoxetine and adult suicidality revisited: an updated meta-analysis using expanded data sources from placebo-controlled trials . J Clin Psychopharmacol 2007 ;27 (6 ):682 – 6 .

March JS , Silva S , Petrycki S , et al. The treatment for adolescents with depression study (TADS): long-term effectiveness and safety outcomes . Arch Gen Psychiatry 2007 ;64 (10 ):1132 – 43.

Wagstaff AJ , Goa KL . Once-weekly fluoxetine . Drugs 2001 ;61 :2221 – 8.

Flupenthixol

Depixol

Therapeutics Brands

No

Generic?

Class

see index for additional brand names

Neuroscience-based Nomenclature: dopamine receptor antagonist (D-RAn)

Conventional antipsychotic (neuroleptic, thioxanthene, dopamine 2 antagonist)

Commonly Prescribed for

(bold for FDA approved)

Schizophrenia Depression (low dose) Other psychotic disorders Bipolar disorder

How the Drug Works

Blocks dopamine 2 receptors, reducing positive symptoms of psychosis

How Long Until It Works

With injection, psychotic symptoms can improve within a few days, but it may take 1– 2 weeks for notable improvement

With oral formulation, psychotic symptoms can improve within 1 week, but it may take several weeks for full effect on behavior

If It Works

Most often reduces positive symptoms in schizophrenia but does not eliminate them

Most schizophrenic patients do not have a total remission of symptoms but rather a reduction of symptoms by about a third

Continue treatment in schizophrenia until reaching a plateau of improvement

After reaching a satisfactory plateau, continue treatment for at least a year after first episode of psychosis in schizophrenia

For second and subsequent episodes of psychosis in schizophrenia, treatment may need to be indefinite

Reduces symptoms of acute psychotic mania but not proven as a mood stabilizer or as an effective maintenance treatment in bipolar disorder

After reducing acute psychotic symptoms in mania, switch to a mood stabilizer and/or an atypical antipsychotic for mood stabilization and maintenance

If It Doesnâ€TM t Work

Consider trying one of the first-line atypical antipsychotics Consider trying another conventional antipsychotic

If 2 or more antipsychotic monotherapies do not work, consider clozapine

Best Augmenting Combos for Partial Response or Treatment Resistance

Augmentation of conventional antipsychotics has not been systematically studied

Addition of a mood-stabilizing anticonvulsant such as valproate, carbamazepine, or lamotrigine may be helpful in both schizophrenia and bipolar mania

Augmentation with lithium in bipolar mania may be helpful Addition of a benzodiazepine, especially short-term for agitation

Tests

âœ1⁄2 Since conventional antipsychotics are frequently associated with weight gain, before starting treatment, weigh all patients and determine

if the patient is already overweight (BMI 25.0– 29.9) or obese (BMI ≥ 30)

Before giving a drug that can cause weight gain to an overweight or obese patient, consider determining whether the patient already has pre-diabetes (fasting plasma glucose 100– 125 mg/dL), diabetes (fasting plasma glucose ≥ 126 mg/dL), or dyslipidemia (increased total cholesterol, LDL cholesterol, and triglycerides; decreased HDL cholesterol), and treat or refer such patients for treatment, including nutrition and weight management, physical activity counseling, smoking cessation, and medical management

âœ1⁄2 Monitor weight and BMI during treatment

âœ1⁄2 Consider monitoring fasting triglycerides monthly for several months in patients at high risk for metabolic complications and when initiating or switching antipsychotics

âœ1⁄2 While giving a drug to a patient who has gained >5% of initial weight, consider evaluating for the presence of pre-diabetes, diabetes, or dyslipidemia, or consider switching to a different antipsychotic

Monitoring elevated prolactin levels of dubious clinical benefit

Patients with low white blood cell count (WBC) or history of drug- induced leukopenia/neutropenia should have complete blood count (CBC) monitored frequently during the first few months and flupenthixol should be discontinued at the first sign of decline of WBC in the absence of other causative factors

Patients should be monitored periodically for the development of abnormal movements of tardive dyskinesia, using neurological exam and the AIMS (Abnormal Involuntary Movement Scale)

Side Effects

How Drug Causes Side Effects

Acute blockade of dopamine 2 receptors in the striatum can cause drug-induced parkinsonism, dystonia, or akathisia

Chronic blockade of dopamine 2 receptors in the striatum can cause tardive dyskinesia

By blocking dopamine 2 receptors in the pituitary, it can cause elevations in prolactin

By blocking dopamine 2 receptors excessively in the mesocortical and mesolimbic dopamine pathways, especially at high doses, it can cause worsening of negative and cognitive symptoms (neuroleptic- induced deficit syndrome)

Blocking muscarinic cholinergic receptors can cause dry mouth, blurred vision, urinary retention, constipation, and paralytic ileus

Antihistaminic actions may cause sedation, weight gain

Blocking alpha 1 adrenergic receptors can cause dizziness, hypotension, and syncope

Mechanism of weight gain and any possible increased incidence of diabetes or dyslipidemia with conventional antipsychotics is

unknown

Notable Side Effects âœ1⁄2 Neuroleptic-induced deficit syndrome

âœ1⁄2 Drug-induced parkinsonism

âœ1⁄2 Insomnia, restlessness, agitation, sedation

âœ1⁄2 Tardive dyskinesia (risk increases with duration of treatment and with dose)

âœ1⁄2 Risk of potentially irreversible involuntary dyskinetic movements may increase with cumulative dose and treatment duration

âœ1⁄2 Galactorrhea, amenorrhea Tachycardia

Weight gain

Hypomania

Rare eosinophilia

Life-Threatening or Dangerous Side Effects

Rare neuroleptic malignant syndrome (NMS) may cause hyperpyrexia, muscle rigidity, delirium, and autonomic instability with elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure

Rare seizures

Rare jaundice, leukopenia

As a class, antipsychotics are associated with an increased risk of death and cerebrovascular events in elderly patients with dementia; not approved for treatment of dementia-related psychosis

Weight Gain

Many experience and/or can be significant in amount

Sedation

Occurs in significant minority

Wait

Wait

Wait

What to Do About Side Effects

For drug-induced parkinsonism, add an anticholinergic agent

Beta blockers, benzodiazepines, or 5HT2A antagonists (e.g., mirtazapine, cyproheptadine) may reduce akathisia

Reduce the dose

For sedation, give at night

Switch to an atypical antipsychotic

Weight loss, exercise programs, and medical management for high BMIs, diabetes, dyslipidemia

Metformin may help prevent or reverse antipsychotic-induced weight gain

Best Augmenting Agents for Side Effects

Benztropine, trihexyphenidyl, or amantadine for drug-induced parkinsonism

Beta blockers, benzodiazepines, or 5HT2A antagonists (e.g., mirtazapine, cyproheptadine) for akathisia

Valbenazine or deutetrabenazine for tardive dyskinesia

Many side effects cannot be improved with an augmenting agent

Dosing And Use Usual Dosage Range

Oral 3– 6 mg/day in divided doses Intramuscular 40– 120 mg every 1– 4 weeks

Dosage Forms

Tablet 0.5 mg, 3 mg

Injection 20 mg/mL, 100 mg/mL

How to Dose

Oral: initial 1 mg 3 times a day; increase by 1 mg every 2– 3 days; maximum generally 18 mg/day

Intramuscular: initial dose 20 mg for patients who have not been exposed to long-acting depot antipsychotics, 40 mg for patients who have previously demonstrated tolerance to long-acting depot antipsychotics; after 4– 10 days can give additional 20 mg dose; maximum 200 mg every 1– 4 weeks

Dosing Tips

The peak of action for the decanoate is usually 7– 10 days, and doses generally have to be administered every 2– 3 weeks

May have more activating effects at low doses, which can sometimes be useful as a second-line, short-term treatment of depression

Some evidence that flupenthixol may improve anxiety and depression at low doses

Rather than raise the dose above normal dosing in acutely agitated patients requiring acute antipsychotic actions, consider short-term (one dose or more) augmentation with a benzodiazepine or another antipsychotic, especially intramuscularly

Rather than raise the dose above normal dosing in partial responders, consider augmentation with a mood-stabilizing anticonvulsant, such as valproate, topiramate, or lamotrigine

Children and elderly should generally be dosed at the lower end of the dosage spectrum

Treatment should be suspended if absolute neutrophil count falls below 1000/mm3

Overdose

Agitation, confusion, sedation, drug-induced parkinsonism, respiratory collapse, circulatory collapse

Long-Term Use

Should periodically reevaluate long-term usefulness in individual patients, but treatment may need to continue for many years

No

Habit Forming

How to Stop

Slow down-titration of oral formulation (over 6– 8 weeks), especially when simultaneously beginning a new antipsychotic while switching (i.e., cross-titration)

Rapid oral discontinuation may lead to rebound psychosis and worsening of symptoms

If antiparkinson agents are being used, they should be continued for a few weeks after flupenthixol is discontinued

Pharmacokinetics

Oral: maximum plasma concentrations within 3– 8 hours

Intramuscular: rate-limiting half-life approximately 8 days with single dose, approximately 17 days with multiple doses

Drug Interactions

May decrease the effects of levodopa, dopamine agonists

May increase the effects of antihypertensive drugs except for guanethidine, whose antihypertensive actions flupenthixol may antagonize

CNS effects may be increased if used with other CNS depressants Combined use with epinephrine may lower blood pressure Ritonavir may increase plasma levels of flupenthixol

May increase carbamazepine plasma levels

Some patients taking a neuroleptic and lithium have developed an encephalopathic syndrome similar to neuroleptic malignant syndrome

Other Warnings/Precautions

If signs of neuroleptic malignant syndrome develop, treatment should be immediately discontinued

Use cautiously in patients with alcohol withdrawal or convulsive disorders because of possible lowering of seizure threshold

In epilepsy patients, dose 10– 20 mg every 15 days for intramuscular formulation

Use with caution if at all in patients with Parkinsonâ€TM s disease, severe arteriosclerosis, or Lewy body dementia

Possible antiemetic effect of flupenthixol may mask signs of other disorders or overdose; suppression of cough reflex may cause asphyxia

Avoid extreme heat exposure

Do not use epinephrine in event of overdose as interaction with some pressor agents may lower blood pressure

Antipsychotics may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls; for patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment, and recurrently for patients on long-term antipsychotic therapy

As with any antipsychotic, use with caution in patients with history of seizures

Do Not Use

If patient is taking a large concomitant dose of a sedative hypnotic If patient has CNS depression

If patient is comatose or if there is brain damage

If there is blood dyscrasia

If patient has pheochromocytoma

If patient has liver damage

If patient has a severe cardiovascular disorder If patient has renal insufficiency

If patient has cerebrovascular insufficiency

If there is a proven allergy to flupenthixol

Special Populations Renal Impairment

Oral: recommended to take half or less of usual adult dose

Intramuscular: recommended dose schedule generally 10– 20 mg every 15 days

Hepatic Impairment

Use with caution

Oral: recommended to take half or less of usual adult dose

Cardiac Impairment

Use with caution

Oral: recommended to take half or less of usual adult dose

Elderly

Intramuscular: recommended initial dose generally 5 mg; recommended dose schedule generally 10– 20 mg every 15 days

Oral: recommended to take half or less of usual adult dose

Although conventional antipsychotics are commonly used for behavioral disturbances in dementia, no agent has been approved for treatment of elderly patients with behavioral symptoms of dementia such as agitation

Elderly patients with dementia-related psychosis treated with antipsychotics are at increased risk of death compared to placebo, and also have an increased risk of cerebrovascular events

Children and Adolescents

Not recommended for use in children

Pregnancy

Not recommended for use during pregnancy

There is a risk of abnormal muscle movements and withdrawal symptoms in newborns whose mothers took an antipsychotic during the third trimester; symptoms may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty feeding

Reports of drug-induced parkinsonism, jaundice, hyperreflexia, hyporeflexia in infants whose mothers took a conventional

antipsychotic during pregnancy

Psychotic symptoms may worsen during pregnancy and some form of treatment may be necessary

Atypical antipsychotics may be preferable to conventional antipsychotics or anticonvulsant mood stabilizers if treatment is required during pregnancy

Breast Feeding

Some drug is found in motherâ€TM s breast milk

âœ1⁄2 Recommended either to discontinue drug or bottle feed

The Art Of Psychopharmacology Potential Advantages

Noncompliant patients

Potential Disadvantages

Children

Elderly

Patients with tardive dyskinesia

Primary Target Symptoms

Positive symptoms of psychosis

Negative symptoms of psychosis Aggressive symptoms

Pearls

Less sedation and orthostatic hypotension but more drug-induced parkinsonism than some other conventional antipsychotics

Patients have very similar antipsychotic responses to any conventional antipsychotic, which is different from atypical antipsychotics where antipsychotic responses of individual patients can occasionally vary greatly from one atypical antipsychotic to another

Patients with inadequate responses to atypical antipsychotics may benefit from a trial of augmentation with a conventional antipsychotic such as flupenthixol or from switching to a conventional antipsychotic such as flupenthixol

However, long-term polypharmacy with a combination of a conventional antipsychotic such as flupenthixol with an atypical antipsychotic may combine their side effects without clearly augmenting the efficacy of either

For treatment-resistant patients, especially those with impulsivity, aggression, violence, and self-harm, long-term polypharmacy with 2 atypical antipsychotics or with 1 atypical antipsychotic and 1 conventional antipsychotic may be useful or even necessary while closely monitoring

In such cases, it may be beneficial to combine 1 depot antipsychotic with 1 oral antipsychotic

Although a frequent practice by some prescribers, adding 2 conventional antipsychotics together has little rationale and may reduce tolerability without clearly enhancing efficacy

Suggested Reading

Gerlach J . Depot neuroleptics in relapse prevention: advantages and disadvantages . Int Clin Psychopharmacol 1995 ;(9 Suppl 5):S17 – 20.

Huhn M , Nikolakopoulou A , Schneider-Thoma J , et al. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis . Lancet 2019 ;394 :939– 51 .

Quraishi S , David A . Depot flupenthixol decanoate for schizophrenia or other similar psychotic disorders . Cochrane Database Syst Rev 2000 ; (2):CD001470 .

Soyka M , De Vry J . Flupenthixol as a potential pharmacotreatment of alcohol and cocaine abuse/dependence . Eur Neuropsychopharmacol 2000 ;10 (5 ):325– 32 .

Fluphenazine

Prolixin

Therapeutics Brands

see index for additional brand names

Yes

Generic?

Class

Conventional antipsychotic (neuroleptic, phenothiazine, dopamine 2 antagonist)

Commonly Prescribed for

(bold for FDA approved)

Psychotic disorders

Bipolar disorder

How the Drug Works

Blocks dopamine 2 receptors, reducing positive symptoms of psychosis

How Long Until It Works

Psychotic symptoms can improve within 1 week, but it may take several weeks for full effect on behavior

If It Works

Most often reduces positive symptoms in schizophrenia but does not eliminate them

Most schizophrenic patients do not have a total remission of symptoms but rather a reduction of symptoms by about a third

Continue treatment in schizophrenia until reaching a plateau of improvement

After reaching a satisfactory plateau, continue treatment for at least a year after first episode of psychosis in schizophrenia

For second and subsequent episodes of psychosis in schizophrenia, treatment may need to be indefinite

Reduces symptoms of acute psychotic mania but not proven as a mood stabilizer or as an effective maintenance treatment in bipolar disorder

After reducing acute psychotic symptoms in mania, switch to a mood stabilizer and/or an atypical antipsychotic for mood stabilization and maintenance

If It Doesnâ€TM t Work

Consider trying one of the first-line atypical antipsychotics

Consider trying another conventional antipsychotic

If 2 or more antipsychotic monotherapies do not work, consider clozapine

Best Augmenting Combos for Partial Response or Treatment Resistance

Augmentation of conventional antipsychotics has not been systematically studied

Addition of a mood-stabilizing anticonvulsant such as valproate, carbamazepine, or lamotrigine may be helpful in both schizophrenia and bipolar mania

Augmentation with lithium in bipolar mania may be helpful Addition of a benzodiazepine, especially short-term for agitation

Tests

âœ1⁄2 Since conventional antipsychotics are frequently associated with weight gain, before starting treatment, weigh all patients and determine if the patient is already overweight (BMI 25.0– 29.9) or obese (BMI ≥ 30)

Before giving a drug that can cause weight gain to an overweight or obese patient, consider determining whether the patient already has pre-diabetes (fasting plasma glucose 100– 125 mg/dL), diabetes (fasting plasma glucose ≥ 126 mg/dL), or dyslipidemia (increased total cholesterol, LDL cholesterol, and triglycerides;

decreased HDL cholesterol), and treat or refer such patients for treatment, including nutrition and weight management, physical activity counseling, smoking cessation, and medical management

âœ1⁄2 Monitor weight and BMI during treatment

âœ1⁄2 Consider monitoring fasting triglycerides monthly for several months in patients at high risk for metabolic complications and when initiating or switching anitpsychotics

âœ1⁄2 While giving a drug to a patient who has gained >5% of initial weight, consider evaluating for the presence of pre-diabetes, diabetes, or dyslipidemia, or consider switching to a different antipsychotic

Should check blood pressure in the elderly before starting and for the first few weeks of treatment

Monitoring elevated prolactin levels of dubious clinical benefit

Phenothiazines may cause false-positive phenylketonuria results

Patients with low white blood cell count (WBC) or history of drug- induced leukopenia/neutropenia should have complete blood count (CBC) monitored frequently during the first few months and fluphenazine should be discontinued at the first sign of decline of WBC in the absence of other causative factors

Patients should be monitored periodically for the development of abnormal movements of tardive dyskinesia, using neurological exam and the AIMS (Abnormal Involuntary Movement Scale)

Side Effects

How Drug Causes Side Effects

Acute blockade of dopamine 2 receptors in the striatum can cause drug-induced parkinsonism, dystonia, or akathisia

Chronic blockade of dopamine 2 receptors in the striatum can cause tardive dyskinesia

By blocking dopamine 2 receptors in the pituitary, it can cause elevations in prolactin

By blocking dopamine 2 receptors excessively in the mesocortical and mesolimbic dopamine pathways, especially at high doses, it can cause worsening of negative and cognitive symptoms (neuroleptic- induced deficit syndrome)

Blocking muscarinic cholinergic receptors can cause dry mouth, blurred vision, urinary retention, constipation, and paralytic ileus

Antihistaminic actions may cause sedation, weight gain

Blocking alpha 1 adrenergic receptors can cause dizziness, hypotension, and syncope

Mechanism of weight gain and any possible increased incidence of diabetes or dyslipidemia with conventional antipsychotics is unknown

Notable Side Effects âœ1⁄2 Neuroleptic-induced deficit syndrome

âœ1⁄2 Akathisia

âœ1⁄2 Priapism

âœ1⁄2 Drug-induced parkinsonism

âœ1⁄2 Tardive dyskinesia, tardive dystonia

âœ1⁄2 Risk of potentially irreversible involuntary dyskinetic movements may increase with cumulative dose and treatment duration

âœ1⁄2 Galactorrhea, amenorrhea

Dizziness, sedation

Dry mouth, constipation, urinary retention, blurred vision Decreased sweating, depression

Sexual dysfunction

Hypotension, tachycardia, syncope

Weight gain

Life-Threatening or Dangerous Side Effects

Rare neuroleptic malignant syndrome (NMS) may cause hyperpyrexia, muscle rigidity, delirium, and autonomic instability with elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure

Rare jaundice, agranulocytosis Rare seizures

As a class, antipsychotics are associated with an increased risk of death and cerebrovascular events in elderly patients with dementia; not approved for treatment of dementia-related psychosis

Weight Gain

Occurs in significant minority

Sedation

Occurs in significant minority

Wait

Wait

Wait

What to Do About Side Effects

For drug-induced parkinsonism, add an anticholinergic agent

Beta blockers, benzodiazepines, or 5HT2A antagonists (e.g., mirtazapine, cyproheptadine) may reduce akathisia

Reduce the dose

For sedation, take at night

Switch to an atypical antipsychotic

Weight loss, exercise programs, and medical management for high BMIs, diabetes, dyslipidemia

Metformin may help prevent or reverse antipsychotic-induced weight gain

Best Augmenting Agents for Side Effects

Benztropine, trihexyphenidyl, or amantadine for drug-induced parkinsonism

Beta blockers, benzodiazepines, or 5HT2A antagonists (e.g., mirtazapine, cyproheptadine) for akathisia

Valbenazine or deutetrabenazine for tardive dyskinesia

Many side effects cannot be improved with an augmenting agent

Dosing And Use Usual Dosage Range

Oral: 1– 20 mg/day maintenance Intramuscular: generally 1/3 to 1/2 the oral dose

Decanoate for intramuscular or subcutaneous administration:12.5– 100 mg/2 weeks maintenance (see Fluphenazine Decanoate section after Pearls for dosing and use)

Dosage Forms

Tablet 1 mg, 2.5 mg scored, 5 mg scored, 10 mg scored

Decanoate for long-acting intramuscular or subcutaneous administration 25 mg/mL

Injection for acute intramuscular administration 2.5 mg/mL Elixir 2.5 mg/5 mL

Concentrate 5 mg/mL

How to Dose

Oral: initial 0.5– 10 mg/day in divided doses; maximum 40 mg/day

Intramuscular (short-acting): initial 1.25 mg; 2.5– 10 mg/day can be given in divided doses every 6– 8 hours; maximum dose generally 10 mg/day

Dosing Tips – Oral

Patients receiving atypical antipsychotics may occasionally require a “ top-up†of a conventional antipsychotic to control aggression or violent behavior

Fluphenazine tablets 2.5 mg, 5 mg, and 10 mg contain tartrazine, which can cause allergic reactions, especially in patients sensitive to aspirin

Oral solution should not be mixed with drinks containing caffeine, tannic acid (tea), or pectinates (apple juice)

Rather than raise the dose above normal dosing in acutely agitated patients requiring acute antipsychotic actions, consider short-term (one dose or more) augmentation with a benzodiazepine or another antipsychotic, especially intramuscularly

Rather than raise the dose above normal dosing in partial responders, consider augmentation with a mood-stabilizing anticonvulsant, such as valproate, topiramate, or lamotrigine

Children and elderly should generally be dosed at the lower end of the dosage spectrum

For treatment resistance, consider obtaining plasma drug levels to guide dosing above recommended levels

Treatment should be suspended if absolute neutrophil count falls below 1000/mm3

Overdose

Drug-induced parkinsonism, coma, hypotension, sedation, seizures, respiratory depression

Long-Term Use

Should periodically reevaluate long-term usefulness in individual patients, but treatment may need to continue for many years

No

Habit Forming

How to Stop

Slow down-titration of oral formulation (over 6 to 8 weeks), especially when simultaneously beginning a new antipsychotic while switching (i.e., cross-titration)

Rapid oral discontinuation may lead to rebound psychosis and worsening of symptoms

If antiparkinson agents are being used, they should be continued for a few weeks after fluphenazine is discontinued

Pharmacokinetics

Mean half-life of oral formulation approximately 15 hours

Mean half-life of intramuscular formulation approximately 6.8– 9.6 days

Drug Interactions

May decrease the effects of levodopa, dopamine agonists

May increase the effects of antihypertensive drugs except for guanethidine, whose antihypertensive actions fluphenazine may antagonize

Additive effects may occur if used with CNS depressants

Additive anticholinergic effects may occur if used with atropine or related compounds

Alcohol and diuretics may increase the risk of hypotension

Some patients taking a neuroleptic and lithium have developed an encephalopathic syndrome similar to neuroleptic malignant syndrome

Combined use with epinephrine may lower blood pressure

Other Warnings/Precautions

If signs of neuroleptic malignant syndrome develop, treatment should be immediately discontinued

Use cautiously in patients with alcohol withdrawal or convulsive disorders because of possible lowering of seizure threshold

Avoid undue exposure to sunlight

Use cautiously in patients with respiratory disorders

Avoid extreme heat exposure

Antiemetic effect can mask signs of other disorders or overdose

Do not use epinephrine in event of overdose as interaction with some pressor agents may lower blood pressure

Use only with caution if at all in Parkinsonâ€TM s disease or Lewy body dementia

Antipsychotics may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls; for patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic

treatment, and recurrently for patients on long-term antipsychotic therapy

As with any antipsychotic, use with caution in patients with history of seizures

Do Not Use

If patient is in a comatose state or has CNS depression

If patient is taking cabergoline, pergolide, or metrizamide

If there is a proven allergy to fluphenazine

If there is a known sensitivity to any phenothiazine

Decanoate and enanthate injectable formulations are contraindicated in children under age 12

Special Populations Renal Impairment

Use with caution; titration should be slower

Hepatic Impairment

Use with caution; titration should be slower

Cardiac Impairment

Cardiovascular toxicity can occur, especially orthostatic hypotension

Elderly

Titration should be slower; lower initial dose (1– 2.5 mg/day) Elderly patients may be more susceptible to adverse effects

Although conventional antipsychotics are commonly used for behavioral disturbances in dementia, no agent has been approved for treatment of elderly patients with behavioral symptoms of dementia such as agitation

Elderly patients with dementia-related psychosis treated with antipsychotics are at an increased risk of death compared to placebo, and also have an increased risk of cerebrovascular events

Children and Adolescents

Safety and efficacy not established

Decanoate and enanthate injectable formulations are contraindicated in children under age 12

Generally consider second-line after atypical antipsychotics

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

There is a risk of abnormal muscle movements and withdrawal symptoms in newborns whose mothers took an antipsychotic during the third trimester; symptoms may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty feeding

Reports of drug-induced parkinsonism, jaundice, hyperreflexia, hyporeflexia in infants whose mothers took a phenothiazine during pregnancy

Fluphenazine should only be used during pregnancy if clearly indicated

Psychotic symptoms may worsen during pregnancy and some form of treatment may be necessary

Atypical antipsychotics may be preferable to conventional antipsychotics or anticonvulsant mood stabilizers if treatment is required during pregnancy

Breast Feeding

Some drug is found in motherâ€TM s breast milk

Effects on infant have been observed (dystonia, tardive dyskinesia, sedation)

âœ1⁄2 Recommended either to discontinue drug or bottle feed

The Art Of Psychopharmacology

Potential Advantages

Intramuscular formulation for emergency use

Relatively rapid onset of LAI (but see fluphenazine decanoate after Pearls section)

Potential Disadvantages

Patients with tardive dyskinesia Children

Elderly

Primary Target Symptoms

Positive symptoms of psychosis Motor and autonomic hyperactivity Violent or aggressive behavior

Pearls

Fluphenazine is a high-potency phenothiazine

Less risk of sedation and orthostatic hypotension but greater risk of drug-induced parkinsonism than with low-potency phenothiazines

Not shown to be effective for behavioral problems in mental retardation

Patients have very similar antipsychotic responses to any conventional antipsychotic, which is different from atypical

antipsychotics where antipsychotic responses of individual patients can occasionally vary greatly from one atypical antipsychotic to another

Patients with inadequate responses to atypical antipsychotics may benefit from a trial of augmentation with a conventional antipsychotic such as fluphenazine or from switching to a conventional antipsychotic such as fluphenazine

However, long-term polypharmacy with a combination of a conventional antipsychotic such as fluphenazine with an atypical antipsychotic may combine their side effects without clearly augmenting the efficacy of either

For treatment-resistant patients, especially those with impulsivity, aggression, violence, and self-harm, long-term polypharmacy with 2 atypical antipsychotics or with 1 atypical antipsychotic and 1 conventional antipsychotic may be useful or even necessary while closely monitoring

In such cases, it may be beneficial to combine 1 depot antipsychotic with 1 oral antipsychotic

Although a frequent practice by some prescribers, adding 2 conventional antipsychotics together has little rationale and may reduce tolerability without clearly enhancing efficacy

Fluphenazine Decanoate

Vehicle Sesame Oil

Tmax

T1/2 with multiple dosing Able to be loaded

Time to reach steady state Dosing schedule (maintenance) Injection site

Needle gauge

Dosage forms

Injection volume

0.3– 1.5 days

14 days

Yes

4– 6 weeks with loading 2 weeks

Intramuscular or subcutaneous 21

25 mg

25 mg/mL

Usual Dosage Range

12.5– 100 mg/2 weeks maintenance

How to Dose

Conversion from oral: can either supplement with oral formulation at half-dose for at least 2 weeks OR use weekly loading injections of 1.6 times the oral daily dose (mg/day) for 4– 6 weeks

Dosing Tips

With LAIs, the absorption rate constant is slower than the elimination rate constant, thus resulting in “ flip-flop†kinetics

– i.e., time to steady state is a function of absorption rate, while concentration at steady state is a function of elimination rate

In general, 5 half-lives of any medication are needed to achieve 97% of steady-state levels

The long half-lives of depot antipsychotics mean that one must either adequately load the dose (if possible) or provide oral supplementation

The failure to adequately load the dose leads either to prolonged cross-titration from oral antipsychotic or to sub-therapeutic antipsychotic plasma levels for weeks or months in patients who are not receiving (or adhering to) oral supplementation

Because plasma antipsychotic levels increase gradually over time, dose requirements may ultimately decrease from initial; obtaining periodic plasma levels can be beneficial to prevent unnecessary plasma level creep

The time to get a blood level for patients receiving LAI is the morning of the day they will receive their next injection

Advantages: early peak (see following graph) may be beneficial in the management of acute patients

Disadvantages: early peak also carries risk of drug-induced parkinsonism or akathisia in first 48 hours; 2-week injection schedule; higher incidence of local site reactions (due to sesame oil vehicle)

Response threshold is 0.81 ng/mL; plasma levels greater than 2– 3 ng/mL are generally not well tolerated, although treatment-resistant cases might tolerate and respond to plasma levels up to 4 ng/mL, which is the point of futility if no response and even if tolerated

The Art Of Switching

Switching from Oral Antipsychotics to Fluphenazine Decanoate

Discontinuation of oral antipsychotic can begin immediately if adequate loading is pursued; otherwise, supplement with oral formulation at half-dose for at least 2 weeks

How to discontinue oral formulations

Down-titration is not required for: amisulpride, aripiprazole, brexpiprazole, cariprazine, paliperidone ER

1-week down-titration is required for: iloperidone, lurasidone, risperidone, ziprasidone

3– 4-week down-titration is required for: asenapine, olanzapine, quetiapine

4+-week down-titration is required for: clozapine

For patients taking benzodiazepine or anticholinergic medication, this can be continued during cross-titration to help alleviate side effects such as insomnia, agitation, and/or psychosis. Once the patient is stable on LAI, these can be tapered one at a time as appropriate.

Suggested Reading

David A , Adams CE , Eisenbruch M , Quraishi S , Rathbone J. Depot fluphenazine decanoate and enanthate for schizophrenia . Cochrane Database Syst Rev 2005 ;25 (1 ):CD000307 .

Ereshefsky L , Saklad SR , Jann MW . Future of depot neuroleptic therapy: pharmacokinetic and pharmacodynamic approaches . J Clin Psychiatry 1984 ;45 (Suppl):50 – 9.

Huhn M , Nikolakopoulou A , Schneider-Thoma J , et al. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis . Lancet 2019 ;394 :939– 51 .

Matar HE , Almerie MQ. Oral fluphenazine versus placebo for schizophrenia . Cochrane Database Syst Rev 2007 ;24 (1 ):CD006352 .

Meyer JM . Converting oral to long-acting injectable antipsychotics: a guide for the perplexed . CNS Spectr 2017 ;22 (S1):14 – 28 .

Milton GV , Jann MW . Emergency treatment of psychotic symptoms. Pharmacokinetic considerations for antipsychotic drugs . Clin Pharmacokinet 1995 ;28 (6 ):494– 504 .

Flurazepam

Dalmane

Therapeutics Brands

Yes

Generic?

Class

see index for additional brand names

Neuroscience-based Nomenclature: GABA positive allosteric modulator (GABA-PAM)

Benzodiazepine (hypnotic)

Commonly Prescribed for

(bold for FDA approved)

Insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings, and/or early morning awakening

Recurring insomnia or poor sleeping habits

Acute or chronic medical situations requiring restful sleep Catatonia

How the Drug Works

Binds to benzodiazepine receptors at the GABA-A ligand-gated chloride channel complex

Enhances the inhibitory effects of GABA

Boosts chloride conductance through GABA-regulated channels

Inhibitory actions in sleep centers may provide sedative hypnotic effects

How Long Until It Works

Generally takes effect in less than an hour

If It Works

Effects on total wake-time and number of nighttime awakenings may be decreased over time

If It Doesnâ€TM t Work

If insomnia does not improve after 7– 10 days, it may be a manifestation of a primary psychiatric or physical illness such as obstructive sleep apnea or restless leg syndrome, which requires independent evaluation

Increase the dose Improve sleep hygiene

Improves quality of sleep

Switch to another agent

Best Augmenting Combos for Partial Response or Treatment Resistance

Generally, best to switch to another agent

Trazodone

Agents with antihistamine actions (e.g., diphenhydramine, TCAs)

Tests

In patients with seizure disorders, concomitant medical illness, and/or those with multiple concomitant long-term medications, periodic liver tests and blood counts may be prudent

Side Effects

How Drug Causes Side Effects

Same mechanism for side effects as for therapeutic effects – namely due to excessive actions at benzodiazepine receptors

Actions at benzodiazepine receptors that carry over to the next day can cause daytime sedation, amnesia, and ataxia

Long-term adaptations in benzodiazepine receptors may explain the development of dependence, tolerance, and withdrawal

Notable Side Effects

âœ1⁄2 Sedation, fatigue, depression

âœ1⁄2 Dizziness, ataxia, slurred speech, weakness âœ1⁄2 Forgetfulness, confusion

âœ1⁄2 Hyperexcitability, nervousness

Rare hallucinations, mania

Rare hypotension

Hypersalivation, dry mouth

Rebound insomnia when withdrawing from long-term treatment

Life-Threatening or Dangerous Side Effects

Respiratory depression, especially when taken with CNS depressants in overdose

Rare hepatic dysfunction, renal dysfunction, blood dyscrasias

Weight Gain

Sedation

Many experience and/or can be significant in amount

What to Do About Side Effects

Reported but not expected

Wait

To avoid problems with memory, only take flurazepam if planning to have a full nightâ€TM s sleep

Lower the dose

Switch to a shorter-acting sedative hypnotic

Switch to a non-benzodiazepine hypnotic

Administer flumazenil if side effects are severe or life-threatening

Best Augmenting Agents for Side Effects

Many side effects cannot be improved with an augmenting agent

Dosing And Use Usual Dosage Range

15– 30 mg/day at bedtime for 7– 10 days

Capsule 15 mg, 30 mg

Dosage Forms

How to Dose

15 mg/day at bedtime; may increase to 30 mg/day at bedtime if ineffective

Dosing Tips

âœ1⁄2 Because flurazepam tends to accumulate over time, perhaps not

the best hypnotic for chronic nightly use

Use lowest possible effective dose and assess need for continued treatment regularly

Flurazepam should generally not be prescribed in quantities greater than a 1-month supply

Patients with lower body weights may require lower doses

Risk of dependence may increase with dose and duration of treatment

Overdose

No death reported in monotherapy; sedation, slurred speech, poor coordination, confusion, coma, respiratory depression

Long-Term Use

Not generally intended for long-term use

âœ1⁄2 Because of its relatively longer half-life, flurazepam may cause some daytime sedation and/or impaired motor/cognitive function, and may do so progressively over time

Habit Forming

Flurazepam is a Schedule IV drug

Some patients may develop dependence and/or tolerance; risk may be greater with higher doses

History of drug addiction may increase risk of dependence

How to Stop

If taken for more than a few weeks, taper to reduce chances of withdrawal effects

Patients with seizure history may seize upon sudden withdrawal

Rebound insomnia may occur the first 1– 2 nights after stopping

For patients with severe problems discontinuing a benzodiazepine, dosing may need to be tapered over many months (i.e., reduce dose by 1% every 3 days by crushing tablet and suspending or dissolving in 100 mL of fruit juice and then disposing of 1 mL and drinking the rest; 3– 7 days later, dispose of 2 mL, and so on). This is both a form of very slow biological tapering and a form of behavioral desensitization

Pharmacokinetics

Elimination half-life approximately 24– 100 hours Active metabolites

Drug Interactions

Cimetidine may decrease flurazepam clearance and thus raise flurazepam levels

Flurazepam and kava combined use may affect clearance of either drug

Increased depressive effects when taken with other CNS depressants (see Warnings below)

Other Warnings/Precautions

Boxed warning regarding the increased risk of CNS depressant effects when benzodiazepines and opioid medications are used together, including specifically the risk of slowed or difficulty breathing and death

If alternatives to the combined use of benzodiazepines and opioids are not available, clinicians should limit the dosage and duration of each drug to the minimum possible while still achieving therapeutic efficacy

Patients and their caregivers should be warned to seek medical attention if unusual dizziness, lightheadedness, sedation, slowed or difficulty breathing, or unresponsiveness occur

Insomnia may be a symptom of a primary disorder, rather than a primary disorder itself

Some patients may exhibit abnormal thinking or behavioral changes similar to those caused by other CNS depressants (i.e., either depressant actions or disinhibiting actions)

Some depressed patients may experience a worsening of suicidal ideation

Use only with extreme caution in patients with impaired respiratory function or obstructive sleep apnea

Flurazepam should be administered only at bedtime

Do Not Use

If patient is pregnant

If patient has angle-closure glaucoma

If there is a proven allergy to flurazepam or any benzodiazepine

Special Populations Renal Impairment

Recommended dose: 15 mg/day

Hepatic Impairment

Recommended dose: 15 mg/day

Cardiac Impairment

Benzodiazepines have been used to treat insomnia associated with acute myocardial infarction

Elderly

Recommended dose: 15 mg/day

Children and Adolescents

Safety and efficacy have not been established

Long-term effects of flurazepam in children/adolescents are unknown

Should generally receive lower doses and be more closely monitored

Pregnancy

Contraindicated for use in pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Infants whose mothers received a benzodiazepine late in pregnancy may experience withdrawal effects

Neonatal flaccidity has been reported in infants whose mothers took a benzodiazepine during pregnancy

Breast Feeding

Unknown if flurazepam is secreted in human breast milk, but all psychotropics are assumed to be secreted in breast milk

âœ1⁄2 Recommended either to discontinue drug or bottle feed

Effects on infant have been observed and include feeding difficulties, sedation, and weight loss

The Art Of Psychopharmacology Potential Advantages

Transient insomnia

Potential Disadvantages

Chronic nightly insomnia

Primary Target Symptoms

Time to sleep onset Total sleep time Nighttime awakenings

Pearls

âœ1⁄2 Flurazepam has a longer half-life than some other sedative hypnotics, so it may be less likely to cause rebound insomnia on discontinuation

Flurazepam may not be as effective on the first night as it is on subsequent nights

Was once one of the most widely used hypnotics

âœ1⁄2 Long-term accumulation of flurazepam and its active metabolites may cause insidious onset of confusion or falls, especially in the elderly

Though not systematically studied, benzodiazepines have been used effectively to treat catatonia and are the initial recommended treatment

Suggested Reading

Greenblatt DJ . Pharmacology of benzodiazepine hypnotics . J Clin

Psychiatry 1992 ;53 (Suppl):S7 – 13.

Hilbert JM , Battista D . Quazepam and flurazepam: differential pharmacokinetic and pharmacodynamic characteristics . J Clin Psychiatry 1991 ;52 (Suppl):S21 – 6.

Johnson LC , Chernik DA , Sateia MJ . Sleep, performance, and plasma levels in chronic insomniacs during 14-day use of flurazepam and midazolam: an introduction . J Clin Psychopharmacol 1990 ;10 (4 Suppl):S5 – 9.

Roth T , Roehrs TA . A review of the safety profiles of benzodiazepine hypnotics . J Clin Psychiatry 1991 ;52 (Suppl):S38 – 41.

Fluvoxamine

Therapeutics Brands

Luvox

Luvox CR

see index for additional brand names

Generic?

Class

Neuroscience-based Nomenclature: serotonin reuptake inhibitor (S- RI)

SSRI (selective serotonin reuptake inhibitor); often classified as an antidepressant, but it is not just an antidepressant

Commonly Prescribed for

(bold for FDA approved)

Obsessive-compulsive disorder (OCD)(fluvoxamine and fluvoxamine CR)

Social anxiety disorder (fluvoxamine CR)

Yes (not for fluvoxamine CR)

Depression

Panic disorder

Generalized anxiety disorder (GAD) Posttraumatic stress disorder (PTSD)

How the Drug Works

Boosts neurotransmitter serotonin

Blocks serotonin reuptake pump (serotonin transporter) Desensitizes serotonin receptors, especially serotonin 1A receptors Presumably increases serotonergic neurotransmission

âœ1⁄2 Fluvoxamine also binds at sigma 1 receptors How Long Until It Works

âœ1⁄2 Some patients may experience relief of insomnia or anxiety early after initiation of treatment

Onset of therapeutic actions usually not immediate, but often delayed 2– 4 weeks

If it is not working within 6– 8 weeks, it may require a dosage increase or it may not work at all

May continue to work for many years to prevent relapse of symptoms

If It Works

The goal of treatment is complete remission of current symptoms as well as prevention of future relapses

Treatment most often reduces or even eliminates symptoms, but not a cure since symptoms can recur after medicine stopped

Continue treatment until all symptoms are gone (remission) or significantly reduced (e.g., OCD)

Once symptoms are gone, continue treating for 1 year for the first episode of depression

For second and subsequent episodes of depression, treatment may need to be indefinite

Use in anxiety disorders may also need to be indefinite

If It Doesnâ€TM t Work

Many patients have only a partial response where some symptoms are improved but others persist (especially insomnia, fatigue, and problems concentrating in depression)

Other patients may be nonresponders, sometimes called treatment- resistant or treatment-refractory

Some patients who have an initial response may relapse even though they continue treatment, sometimes called “ poop-outâ€

Consider increasing dose, switching to another agent, or adding an appropriate augmenting agent

Consider psychotherapy

Consider evaluation for another diagnosis or for a comorbid condition (e.g., medical illness, substance abuse, etc.)

Some patients may experience apparent lack of consistent efficacy due to activation of latent or underlying bipolar disorder, and require antidepressant discontinuation and a switch to a mood stabilizer

Best Augmenting Combos for Partial Response or Treatment Resistance

For the expert, consider cautious addition of clomipramine for treatment-resistant OCD

Trazodone, especially for insomnia

Bupropion, mirtazapine, reboxetine, or atomoxetine (use combinations of antidepressants with caution as this may activate bipolar disorder and suicidal ideation)

Modafinil, especially for fatigue, sleepiness, and lack of concentration

Mood stabilizers or atypical antipsychotics for bipolar depression, psychotic depression, treatment-resistant depression, or treatment- resistant anxiety disorders

Benzodiazepines

If all else fails for anxiety disorders, consider gabapentin or tiagabine

Hypnotics for insomnia

Classically, lithium, buspirone, or thyroid hormone

In Europe and Japan, augmentation is more commonly administered for the treatment of depression and anxiety disorders, especially with benzodiazepines and lithium

In the USA, augmentation is more commonly administered for the treatment of OCD, especially with atypical antipsychotics, buspirone, or even clomipramine; clomipramine should be added with caution and at low doses as fluvoxamine can alter clomipramine metabolism and raise its levels

Tests

Side Effects

How Drug Causes Side Effects

Theoretically due to increases in serotonin concentrations at serotonin receptors in parts of the brain and body other than those that cause therapeutic actions (e.g., unwanted actions of serotonin in sleep centers causing insomnia, unwanted actions of serotonin in the gut causing diarrhea, etc.)

Increasing serotonin can cause diminished dopamine release and might contribute to emotional flattening, cognitive slowing, and apathy in some patients

Most side effects are immediate but often go away with time, in contrast to most therapeutic effects which are delayed and are

None for healthy individuals

enhanced over time

âœ1⁄2 Fluvoxamineâ€TM s sigma 1 agonist properties may contribute to sedation and fatigue in some patients

Notable Side Effects

Sexual dysfunction (men: delayed ejaculation, erectile dysfunction; men and women: decreased sexual desire, anorgasmia)

Gastrointestinal (decreased appetite, nausea, diarrhea, constipation, dry mouth)

Mostly CNS (insomnia but also sedation, agitation, tremors, headache, dizziness)

Note: patients with diagnosed or undiagnosed bipolar or psychotic disorders may be more vulnerable to CNS-activating actions of SSRIs

Autonomic (sweating) Bruising and rare bleeding Rare hyponatremia

Life-Threatening or Dangerous Side Effects

Rare seizures

Rare induction of mania

Rare activation of suicidal ideation and behavior (suicidality) (short- term studies did not show an increase in the risk of suicidality with

antidepressants compared to placebo beyond age 24)

Weight Gain

Reported but not expected

Patients may actually experience weight loss

Sedation

Many experience and/or can be significant in amount

What to Do About Side Effects

Wait

Wait

Wait

If fluvoxamine is sedating, take at night to reduce drowsiness Reduce dose

In a few weeks, switch or add other drugs

Best Augmenting Agents for Side Effects

Often best to try another SSRI or another antidepressant monotherapy prior to resorting to augmentation strategies to treat side effects

Trazodone or a hypnotic for insomnia

Bupropion, sildenafil, vardenafil, or tadalafil for sexual dysfunction

Bupropion for emotional flattening, cognitive slowing, or apathy

Mirtazapine for insomnia, agitation, and gastrointestinal side effects

Benzodiazepines for jitteriness and anxiety, especially at initiation of treatment and especially for anxious patients

Many side effects are dose-dependent (i.e., they increase as dose increases, or they reemerge until tolerance redevelops)

Many side effects are time-dependent (i.e., they start immediately upon dosing and upon each dose increase, but go away with time)

Activation and agitation may represent the induction of a bipolar state, especially a mixed dysphoric bipolar II condition sometimes associated with suicidal ideation, and require the addition of lithium, a mood stabilizer or an atypical antipsychotic, and/or discontinuation of fluvoxamine

Dosing And Use Usual Dosage Range

100– 300 mg/day for OCD

100– 200 mg/day for depression

100– 300 mg/day for social anxiety disorder

Dosage Forms

Tablet 25 mg, 50 mg scored, 100 mg scored Controlled-release capsule 100 mg, 150 mg

How to Dose

For immediate-release, initial 50 mg/day; increase by 50 mg/day in 4– 7 days; usually wait a few weeks to assess drug effects before increasing dose further, but can increase by 50 mg/day every 4– 7 days until desired efficacy is reached; maximum 300 mg/day

For immediate-release, doses below 100 mg/day usually given as a single dose at bedtime; doses above 100 mg/day can be divided into two doses to enhance tolerability, with the larger dose administered at night, but can also be given as a single dose at bedtime

For controlled-release, initial 100 mg/day; increase by 50 mg/day each week until desired efficacy is reached; maximum generally 300 mg/day

Dosing Tips

50 mg and 100 mg tablets are scored, so to save costs, give 25 mg as half of 50 mg tablet, and give 50 mg as half of 100 mg tablet

To improve tolerability of immediate-release formulation, dosing can either be given once a day, usually all at night, or split either symmetrically or asymmetrically, usually with more of the dose given at night

Some patients take more than 300 mg/day Controlled-release capsules should not be chewed or crushed

If intolerable anxiety, insomnia, agitation, akathisia, or activation occur upon either dosing initiation or discontinuation, consider the possibility of activated bipolar disorder and switch to a mood stabilizer or an atypical antipsychotic

Overdose

Rare fatalities have been reported, both in combination with other drugs and alone; sedation, dizziness, vomiting, diarrhea, irregular heartbeat, seizures, coma, breathing difficulty

Safe

No

Long-Term Use

Habit Forming

How to Stop

Taper to avoid withdrawal effects (dizziness, nausea, stomach cramps, sweating, tingling, dysesthesias)

Many patients tolerate 50% dose reduction for 3 days, then another 50% reduction for 3 days, then discontinuation

If withdrawal symptoms emerge during discontinuation, raise dose to stop symptoms and then restart withdrawal much more slowly

Pharmacokinetics

Parent drug has 9– 28 hour half-life Inhibits CYP450 3A4

Inhibits CYP450 1A2

Inhibits CYP450 2C9/2C19

Drug Interactions

Tramadol increases the risk of seizures in patients taking an antidepressant

Can increase tricyclic antidepressant levels; use with caution with TCAs

Can cause a fatal “ serotonin syndrome†when combined with MAO inhibitors (MAOIs), so do not use with MAOIs or for at least 14 days after MAOIs are stopped

Do not start an MAOI for at least 5 half-lives (5 to 7 days for most drugs) after discontinuing fluvoxamine

May displace highly protein-bound drugs (e.g., warfarin)

Can rarely cause weakness, hyperreflexia, and incoordination when combined with sumatriptan or possibly with other triptans, requiring careful monitoring of patient

Possible increased risk of bleeding, especially when combined with anticoagulants (e.g., warfarin, NSAIDs)

NSAIDs may impair effectiveness of SSRIs

Via CYP450 1A2 inhibition, fluvoxamine may reduce clearance of theophylline and clozapine, thus raising their levels and requiring their dosing to be lowered

Fluvoxamine administered with either caffeine or theophylline can thus cause jitteriness, excessive stimulation, or rarely seizures, so concomitant use should proceed cautiously

Metabolism of fluvoxamine may be enhanced in smokers and thus its levels lowered, requiring higher dosing

Via CYP450 3A4 inhibition, fluvoxamine may reduce clearance of carbamazepine and benzodiazepines such as alprazolam and triazolam, and thus require dosage reduction

Via CYP450 3A4 inhibition, fluvoxamine could theoretically increase concentrations of certain cholesterol-lowering HMG CoA reductase inhibitors, especially simvastatin, atorvastatin, and lovastatin, but not pravastatin or fluvastatin, which would increase the risk of rhabdomyolysis; thus, coadministration of fluvoxamine with certain HMG CoA reductase inhibitors should proceed with caution

Via CYP450 3A4 inhibition, fluvoxamine could theoretically increase the concentrations of pimozide, and cause QTc prolongation and dangerous cardiac arrhythmias

Other Warnings/Precautions

Add or initiate other antidepressants with caution for up to 2 weeks after discontinuing fluvoxamine

Use with caution in patients with history of seizure

Use with caution in patients with bipolar disorder unless treated with concomitant mood-stabilizing agent

May cause photosensitivity

When treating children, carefully weigh the risks and benefits of pharmacological treatment against the risks and benefits of nontreatment with antidepressants and make sure to document this in the patientâ€TM s chart

Distribute the brochures provided by the FDA and the drug companies

Whenever possible, warn patients and their caregivers about the possibility of activating side effects, and advise them to report such symptoms immediately

Monitor patients for activation of suicidal ideation, especially children and adolescents

Do Not Use

If patient is taking an MAOI

If patient is taking thioridazine, pimozide, tizanidine, alosetron, or ramelteon

If there is a proven allergy to fluvoxamine

Special Populations Renal Impairment

Consider lower initial dose

Hepatic Impairment

Lower dose or give less frequently, perhaps by half; use slower titration

Cardiac Impairment

Preliminary research suggests that fluvoxamine is safe in these patients

Treating depression with SSRIs in patients with acute angina or following myocardial infarction may reduce cardiac events and improve survival as well as mood

Elderly

May require lower initial dose and slower titration

Reduction in the risk of suicidality with antidepressants compared to placebo in adults age 65 and older

Children and Adolescents

Immediate-release approved for ages 8– 17 for OCD

8– 17: initial 25 mg/day at bedtime; increase by 25 mg/day every 4– 7 days; maximum 200 mg/day; doses above 50 mg/day should be divided into 2 doses with the larger dose administered at bedtime

Preliminary evidence suggests efficacy for other anxiety disorders and depression in children and adolescents

Carefully weigh the risks and benefits of pharmacological treatment against the risks and benefits of nontreatment with antidepressants and make sure to document this in the patientâ€TM s chart

Monitor patients face-to-face regularly, particularly during the first several weeks of treatment

Use with caution, observing for activation of known or unknown bipolar disorder and/or suicidal ideation, and inform parents or guardians of this risk so they can help observe child or adolescent patients

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women

Not generally recommended for use during pregnancy, especially during first trimester

Nonetheless, continuous treatment during pregnancy may be necessary and has not been proven to be harmful to the fetus

At delivery there may be more bleeding in the mother and transient irritability or sedation in the newborn

Must weigh the risk of treatment (first trimester fetal development, third trimester newborn delivery) to the child against the risk of no treatment (recurrence of depression, maternal health, infant bonding) to the mother and child

For many patients this may mean continuing treatment during pregnancy

Exposure to SSRIs early in pregnancy may be associated with increased risk of septal heart defects (absolute risk is small)

SSRI use beyond the 20th week of pregnancy may be associated with increased risk of pulmonary hypertension in newborns, although this is not proven

Exposure to SSRIs late in pregnancy may be associated with increased risk of gestational hypertension and preeclampsia

Neonates exposed to SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding; reported symptoms are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome, and include respiratory

distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying

National Pregnancy Registry for Antidepressants: 1-866-961-2388,

https://womensmentalhealth.org/research/pregnancyregistry/antidepr essants

Breast Feeding

Some drug is found in motherâ€TM s breast milk

Trace amounts may be present in nursing children whose mothers are on fluvoxamine

If child becomes irritable or sedated, breast feeding or drug may need to be discontinued

Immediate postpartum period is a high-risk time for depression, especially in women who have had prior depressive episodes, so drug may need to be reinstituted late in the third trimester or shortly after childbirth to prevent a recurrence during the postpartum period

Must weigh benefits of breast feeding with risks and benefits of antidepressant treatment versus nontreatment to both the infant and the mother

For many patients this may mean continuing treatment during breast feeding

The Art Of Psychopharmacology Potential Advantages

Patients with mixed anxiety/depression

Generic is less expensive than brand name where available

Potential Disadvantages

Patients with irritable bowel or multiple gastrointestinal complaints Can require dose titration and twice daily dosing

Primary Target Symptoms

Depressed mood Anxiety

Pearls

âœ1⁄2 Often a preferred treatment of anxious depression as well as

major depressive disorder comorbid with anxiety disorders

Some withdrawal effects, especially gastrointestinal effects

May have lower incidence of sexual dysfunction than other SSRIs

Preliminary research suggests that fluvoxamine is efficacious in obsessive-compulsive symptoms in schizophrenia when combined with antipsychotics

Not FDA approved for depression, but used widely for depression in many countries

CR formulation may be better tolerated than immediate-release formulation, particularly with less sedation

SSRIs may be less effective in women over 50, especially if they are not taking estrogen

SSRIs may be useful for hot flushes in perimenopausal women

âœ1⁄2 Actions at sigma 1 receptors may explain in part fluvoxamineâ€TM s sometimes rapid onset effects in anxiety disorders and insomnia

âœ1⁄2 Actions at sigma 1 receptors may explain potential advantages of fluvoxamine for psychotic depression and delusional depression

âœ1⁄2 For treatment-resistant OCD, consider cautious combination of fluvoxamine and clomipramine by an expert

Normally, clomipramine (CMI), a potent serotonin reuptake blocker, at steady state is metabolized extensively to its active metabolite desmethyl-clomipramine (de-CMI), a potent noradrenergic reuptake blocker

Thus, at steady state, plasma drug activity is generally more noradrenergic (with higher de-CMI levels) than serotonergic (with lower parent CMI levels)

Addition of a CYP450 1A2 inhibitor, fluvoxamine, blocks this conversion and results in higher CMI levels than de-CMI levels

Thus, addition of the SSRI fluvoxamine to CMI in treatment- resistant OCD can powerfully enhance serotonergic activity, not only due to the inherent serotonergic activity of fluvoxamine, but also due to a favorable pharmacokinetic interaction inhibiting CYP450 1A2 and thus converting CMIâ€TM s metabolism to a more powerful serotonergic portfolio of parent drug

Suggested Reading

Cheer SM , Figgitt DP . Spotlight on fluvoxamine in anxiety disorders in children and adolescents . CNS Drugs 2002 ;16 :139– 44 .

Edwards JG , Anderson I . Systematic review and guide to selection of selective serotonin reuptake inhibitors . Drugs 1999 ;57 :507– 33 .

Figgitt DP , McClellan KJ . Fluvoxamine. An updated review of its use in the management of adults with anxiety disorders . Drugs 2000 ;60 :925– 54 .

Omori M , Watanabe N , Nakagawa A , et al. Fluvoxamine versus other anti-depressive agents for depression . Cochrane Database Syst Rev 2010 ;17 (3 ):CD006114 .

Pigott TA , Seay SM . A review of the efficacy of selective serotonin reuptake inhibitors in obsessive-compulsive disorder . J Clin Psychiatry 1999 ;60 :101– 6 .

Gabapentin

Therapeutics Brands

Neurontin

Horizant

see index for additional brand names

Generic?

Class

Neuroscience-based Nomenclature: glutamate, voltage-gated calcium channel blocker (Glu-CB)

Anticonvulsant, antineuralgic for chronic pain, alpha 2 delta ligand at voltage-sensitive calcium channels

Commonly Prescribed for

(bold for FDA approved)

Partial seizures with or without secondary generalization (adjunctive)

Postherpetic neuralgia

Yes (not for extended-release)

Restless leg syndrome (extended-release)

Neuropathic pain/chronic pain Anxiety (adjunctive)

Bipolar disorder (adjunctive)

How the Drug Works

Gabapentin is a leucine analog and is transported both into the blood from the gut and also across the blood– brain barrier into the brain from the blood by the system L transport system

âœ1⁄2 Binds to the alpha 2 delta subunit of voltage-sensitive calcium channels

This closes N and P/Q presynaptic calcium channels, diminishing excessive neuronal activity and neurotransmitter release

Although structurally related to gamma-aminobutyric acid (GABA), no known direct actions on GABA or its receptors

How Long Until It Works

Should reduce seizures by 2 weeks

Should also reduce pain in postherpetic neuralgia by 2 weeks; some patients respond earlier

May reduce pain in other neuropathic pain syndromes within a few weeks

If it is not reducing pain within 6– 8 weeks, it may require a dosage increase or it may not work at all

May reduce anxiety in a variety of disorders within a few weeks

Not yet clear if it has mood-stabilizing effects in bipolar disorder or antineuralgic actions in chronic neuropathic pain, but some patients may respond and if so, would be expected to show clinical effects starting by 2 weeks although it may take several weeks to months to optimize

If It Works

The goal of treatment is complete remission of symptoms (e.g., seizures)

The goal of treatment of chronic neuropathic pain is to reduce symptoms as much as possible, especially in combination with other treatments

Treatment of chronic neuropathic pain most often reduces but does not eliminate symptoms and is not a cure since symptoms usually recur after medicine stopped

Continue treatment until all symptoms are gone or until improvement is stable and then continue treating indefinitely as long as improvement persists

If It Doesnâ€TM t Work (for Neuropathic Pain or Bipolar Disorder)

âœ1⁄2 May only be effective in a subset of bipolar patients, in some patients who fail to respond to other mood stabilizers, or it may not work at all

Many patients have only a partial response where some symptoms are improved but others persist or continue to wax and wane without stabilization of pain or mood

Other patients may be nonresponders, sometimes called treatment- resistant or treatment-refractory

Consider increasing dose, switching to another agent, or adding an appropriate augmenting agent

Consider biofeedback or hypnosis for pain

Consider the presence of noncompliance and counsel patient

Switch to another agent with fewer side effects

Consider evaluation for another diagnosis or for a comorbid condition (e.g., medical illness, substance abuse, etc.)

Best Augmenting Combos for Partial Response or Treatment Resistance

âœ1⁄2 Gabapentin is itself an augmenting agent to numerous other anticonvulsants in treating epilepsy; and to lithium, atypical antipsychotics, and other anticonvulsants in the treatment of bipolar disorder

For postherpetic neuralgia, gabapentin can decrease concomitant opiate use

âœ1⁄2 For neuropathic pain, gabapentin can augment TCAs and SNRIs as well as tiagabine, other anticonvulsants and even opiates if done by experts while carefully monitoring in difficult cases

For anxiety, gabapentin is a second-line treatment to augment SSRIs, SNRIs, or benzodiazepines

Tests

False-positive readings with the Ames N-Multistix SG® dipstick test for urinary protein have been reported when gabapentin was administered with other anticonvulsants

Side Effects

How Drug Causes Side Effects

CNS side effects may be due to excessive blockade of voltage- sensitive calcium channels

Notable Side Effects âœ1⁄2 Sedation (dose-dependent), dizziness

âœ1⁄2 Ataxia (dose-dependent), fatigue, nystagmus, tremor Peripheral edema

Blurred vision

None for healthy individuals

Vomiting, dyspepsia, diarrhea, dry mouth, constipation, weight gain

Additional effects in children under age 12: hostility, emotional lability, hyperkinesia, thought disorder, weight gain

Life-Threatening or Dangerous Side Effects

Anaphylaxis and angioedema

Sudden unexplained deaths have occurred in epilepsy (unknown if related to gabapentin use)

Rare activation of suicidal ideation and behavior (suicidality)

Weight Gain

Occurs in significant minority

Sedation

Many experience and/or can be significant in amount Dose-related; can be problematic at high doses

Can wear off with time, but may not wear off at high doses

Wait Wait

What to Do About Side Effects

Wait

Take more of the dose at night to reduce daytime sedation Lower the dose

Switch to another agent

Best Augmenting Agents for Side Effects

Many side effects cannot be improved with an augmenting agent

Dosing And Use Usual Dosage Range

900– 1800 mg/day in 3 divided doses (immediate-release)

Dosage Forms

Capsule 100 mg, 300 mg, 400 mg

Tablet 100 mg, 300 mg, 400 mg, 600 mg, 800 mg Tablet extended-release 300 mg, 600 mg

Liquid 250 mg/5 mL – 470 mL bottle

How to Dose

Postherpetic neuralgia (immediate-release): 300 mg on day 1; on day 2 increase to 600 mg in 2 doses; on day 3 increase to 900 mg in 3 doses; maximum dose generally 1800 mg/day in 3 doses

Postherpetic neuralgia (extended-release): 600 mg in the morning on day 1; on day 4 increase to 600 mg twice daily

Restless leg syndrome (extended-release): 600 mg once daily at about 5 pm

Seizures (ages 12 and older): initial 900 mg/day in 3 doses; recommended dose generally 1800 mg/day in 3 doses; maximum dose generally 3600 mg/day; time between any 2 doses should usually not exceed 12 hours

Seizures (under age 13): see Children and Adolescents

Dosing Tips

Gabapentin should not be taken until 2 hours after administration of an antacid

If gabapentin is added to a second anticonvulsant, the titration period should be at least a week to improve tolerance to sedation

Some patients need to take immediate-release gabapentin only twice daily in order to experience adequate symptomatic relief for pain or anxiety

At the high end of the dosing range, tolerability may be enhanced by splitting immediate-release dose into more than 3 divided doses

Half-tablets not used within several days of breaking the scored tablet should be discarded

Do not break or chew extended-release tablets, as this could alter controlled-release properties

Extended-release tablets should be taken with food

For intolerable sedation, can give most of the dose at night and less during the day

To improve slow-wave sleep, may need to take gabapentin only at bedtime

Overdose

No fatalities; slurred speech, sedation, double vision, diarrhea

Safe

No

Long-Term Use

Habit Forming

How to Stop

Taper over a minimum of 1 week

Epilepsy patients may seize upon withdrawal, especially if withdrawal is abrupt

âœ1⁄2 Rapid discontinuation may increase the risk of relapse in bipolar disorder

Discontinuation symptoms uncommon

Pharmacokinetics

Gabapentin is not metabolized but excreted intact renally Not protein bound

Elimination half-life approximately 5– 7 hours

Drug Interactions

Antacids may reduce the bioavailability of gabapentin, so gabapentin should be administered approximately 2 hours before antacid medication

Naproxen may increase absorption of gabapentin

Morphine and hydrocodone may increase plasma AUC (area under the curve) values of gabapentin and thus gabapentin plasma levels over time

Other Warnings/Precautions

Depressive effects, including respiratory depression, may be increased by other CNS depressants (opioids, benzodiazepines, alcohol, MAOIs, other anticonvulsants, etc.)

Use lowest possible dose of gabapentin and monitor for symptoms of respiratory depression if patient is taking concomitant CNS depressant, has underlying respiratory disease, or is elderly

Dizziness and sedation could increase the chances of accidental injury (falls) in the elderly

Pancreatic acinar adenocarcinomas have developed in male rats that were given gabapentin, but clinical significance is unknown

Development of new tumors or worsening of tumors has occurred in humans taking gabapentin; it is unknown whether gabapentin affected the development or worsening of tumors

Whenever possible, warn patients and their caregivers about the possibility of activating side effects, and advise them to report such side effects immediately

Do Not Use

If there is a proven allergy to gabapentin or pregabalin

Special Populations Renal Impairment

Gabapentin is renally excreted, so the dose may need to be lowered

Immediate-Release

Creatinine Clearance (mL/min)

30– 59 16– 29 <16

Dosing

400– 1400 mg/day in 2 doses 200– 700 mg/day in 1 dose 100– 300 mg/day in 1 dose

Immediate-Release

Creatinine Clearance (mL/min)

<16 on hemodialysis

Extended-Release for

Creatinine Clearance (mL/min)

30– 59

15– 29

<15

<15 on hemodialysis

Extended-Release for

Creatinine Clearance (mL/min)

30– 59

Dosing

May need supplemental doses following dialysis

Restless Leg Syndrome Dosing

Initial 300 mg/day; increase to 600 mg/day if needed

300 mg/day

300 mg every other day Not recommended

Restless Leg Syndrome Dosing

Initial 300 mg in the morning; on day 4 increase to 300 mg twice daily; increase to 600 mg twice daily if needed

Extended-Release for Restless Leg Syndrome

Creatinine Clearance (mL/min)

15– 29

<15

<15 on hemodialysis

Dosing

Initial 300 mg in the morning on days 1 and 3; on day 4 increase to 300 mg in the morning; increase to 300 mg twice daily if needed

300 mg every other day in the morning; increase to 300 mg/day in the morning if needed

300 mg following dialysis; increase to 600 mg following dialysis if needed

Can be removed by hemodialysis; patients receiving hemodialysis may require supplemental doses of gabapentin

Use in renal impairment has not been studied in children under age 12

Hepatic Impairment

No available data but not metabolized by the liver and clinical experience suggests normal dosing

Cardiac Impairment

No specific recommendations

Elderly

Some patients may tolerate lower doses better

Elderly patients may be more susceptible to adverse effects, including peripheral edema and ataxia

Children and Adolescents

Approved for use starting at age 3 as adjunct treatment for partial seizures

Ages 5– 12: initial 10– 15 mg/kg per day in 3 doses; titrate over 3 days to 25– 35 mg/kg per day given in 3 doses; maximum dose generally 50 mg/kg per day; time between any 2 doses should usually not exceed 12 hours

Ages 3– 4: initial 10– 15 mg/kg per day in 3 doses; titrate over 3 days to 40 mg/kg per day; maximum dose generally 50 mg/kg per day; time between any 2 doses should usually not exceed 12 hours

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR

or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women

In animal studies, gabapentin was developmentally toxic (increased fetal skeletal and visceral abnormalities, and increased embryofetal mortality) when administered to pregnant animals at doses similar to or lower than those used clinically

Use in women of childbearing potential requires weighing potential benefits to the mother against the risks to the fetus

Antiepileptic Drug Pregnancy Registry: 1-888-233-2334,

http://www.aedpregnancyregistry.org

Taper drug if discontinuing

Seizures, even mild seizures, may cause harm to the embryo/fetus

âœ1⁄2 Lack of convincing efficacy for treatment of bipolar disorder or psychosis suggests risk/benefit ratio is in favor of discontinuing gabapentin during pregnancy for these indications

âœ1⁄2 For bipolar patients, given the risk of relapse in the postpartum period, mood-stabilizer treatment, especially with agents with better evidence of efficacy than gabapentin, should generally be restarted immediately after delivery if patient is unmedicated during pregnancy

âœ1⁄2 Atypical antipsychotics may be preferable to gabapentin if treatment of bipolar disorder is required during pregnancy

Bipolar symptoms may recur or worsen during pregnancy and some form of treatment may be necessary

Breast Feeding

Some drug is found in motherâ€TM s breast milk

âœ1⁄2 Recommended either to discontinue drug or bottle feed

If drug is continued while breast feeding, infant should be monitored for possible adverse effects

If infant becomes irritable or sedated, breast feeding or drug may need to be discontinued

âœ1⁄2 Bipolar disorder may recur during the postpartum period, particularly if there is a history of prior postpartum episodes of either depression or psychosis

âœ1⁄2 Relapse rates may be lower in women who receive prophylactic treatment for postpartum episodes of bipolar disorder

Atypical antipsychotics and anticonvulsants such as valproate may be safer and more effective than gabapentin during the postpartum period when treating a nursing mother with bipolar disorder

The Art Of Psychopharmacology

Potential Advantages

Chronic neuropathic pain

Has relatively mild side effect profile

Has few pharmacokinetic drug interactions Treatment-resistant bipolar disorder

Potential Disadvantages

Usually requires 3 times a day dosing

Poor documentation of efficacy for many off-label uses, especially bipolar disorder

Seizures Pain Anxiety

Primary Target Symptoms

Pearls

Gabapentin is generally well tolerated, with only mild adverse effects

Well studied and approved in epilepsy and postherpetic neuralgia âœ1⁄2 Most use is off label

âœ1⁄2 Off-label use for first-line treatment of neuropathic pain may be justified

âœ1⁄2 Off-label use for second-line treatment of anxiety may be justified

âœ1⁄2 Off-label use as an adjunct for bipolar disorder may not be justified

âœ1⁄2 Misperceptions about gabapentinâ€TM s efficacy in bipolar disorder have led to its use in more patients than other agents with proven efficacy, such as lamotrigine

âœ1⁄2 Off-label use as an adjunct for schizophrenia may not be justified May be useful for some patients in alcohol withdrawal

âœ1⁄2 One of the few agents that enhances slow-wave delta sleep, which may be helpful in chronic neuropathic pain syndromes

âœ1⁄2 May be a useful adjunct for fibromyalgia

Drug absorption and clinical efficacy may not necessarily be proportionately increased at high doses, and thus response to high doses may not be consistent

Suggested Reading

MacDonald KJ , Young LT . Newer antiepileptic drugs in bipolar disorder . CNS Drugs 2002 ;16 :549– 62 .

Marson AG , Kadir ZA , Hutton JL , Chadwick DW . Gabapentin for drug- resistant partial epilepsy . Cochrane Database Syst Rev 2000 ; (2):CD001415 .

Moore RA , Wiffen PJ , Derry S , McQuay HJ. Gabapentin for chronic neuropathic pain and fibromyalgia in adults . Cochrane Database Syst Rev

2011 ;16 (3 ):CD007938 .

Stahl SM . Anticonvulsants and the relief of chronic pain: pregabalin and gabapentin as alpha(2)delta ligands at voltage-gated calcium channels . J Clin Psychiatry 2004 ;65 :596 – 7 .

Stahl SM . Anticonvulsants as anxiolytics, part 2: pregabalin and gabapentin as alpha(2)delta ligands at voltage-gated calcium channels . J Clin Psychiatry 2004 ;65 :460 – 1 .

Galantamine

Yes

Generic?

Class

Razadyne

Razadyne ER

see index for additional brand names

Therapeutics Brands

Neuroscience-based Nomenclature: acetylcholine multimodal; enzyme inhibitor; receptor PAM (ACh-MM)

Cholinesterase inhibitor (acetylcholinesterase inhibitor); also an allosteric nicotinic cholinergic modulator; cognitive enhancer

Commonly Prescribed for

(bold for FDA approved)

Alzheimer disease (mild to moderate)

Memory disturbances in other dementias Memory disturbances in other conditions

Mild cognitive impairment

How the Drug Works

âœ1⁄2 Reversibly and competitively inhibits centrally active

acetylcholinesterase (AChE), making more acetylcholine available

Increased availability of acetylcholine compensates in part for degenerating cholinergic neurons in neocortex that regulate memory

âœ1⁄2 Modulates nicotinic receptors, which enhances actions of acetylcholine

Nicotinic modulation may also enhance the actions of other neurotransmitters by increasing the release of dopamine, norepinephrine, serotonin, GABA, and glutamate

Does not inhibit butyrylcholinesterase

May release growth factors or interfere with amyloid deposition

How Long Until It Works

May take up to 6 weeks before any improvement in baseline memory or behavior is evident

May take months before any stabilization in degenerative course is evident

If It Works

May improve symptoms and slow progression of disease, but does not reverse the degenerative process

If It Doesnâ€TM t Work

Consider adjusting dose, switching to a different cholinesterase inhibitor or adding an appropriate augmenting agent

Reconsider diagnosis and rule out other conditions such as depression or a dementia other than Alzheimer disease

Best Augmenting Combos for Partial Response or Treatment Resistance

âœ1⁄2 Atypical antipsychotics to reduce behavioral disturbances âœ1⁄2 Antidepressants if concomitant depression, apathy, or lack of

interest

âœ1⁄2 Memantine for moderate to severe Alzheimer disease

Divalproex, carbamazepine, or oxcarbazepine for behavioral disturbances

Not rational to combine with another cholinesterase inhibitor

Tests

Side Effects

How Drug Causes Side Effects

Peripheral inhibition of acetylcholinesterase can cause gastrointestinal side effects

None for healthy individuals

Central inhibition of acetylcholinesterase may contribute to nausea, vomiting, weight loss, and sleep disturbances

Notable Side Effects

âœ1⁄2 Nausea, diarrhea, vomiting, appetite loss, increased gastric acid

secretion, weight loss Headache, dizziness Fatigue, depression

Life-Threatening or Dangerous Side Effects

Rare seizures Rare syncope

Weight Gain

Reported but not expected

Some patients may experience weight loss

Sedation

What to Do About Side Effects

Reported but not expected

Wait

Wait

Wait

Use slower dose titration

Consider lowering dose, switching to a different agent, or adding an appropriate augmenting agent

Best Augmenting Agents for Side Effects

Many side effects cannot be improved with an augmenting agent

16– 24 mg/day

Dosing And Use Usual Dosage Range

Dosage Forms

Tablet 4 mg, 8 mg, 12 mg

Extended-release capsule 8 mg, 16 mg, 24 mg Liquid 4 mg/mL – 100 mL bottle

How to Dose

Immediate-release: initial 4 mg twice daily; after 4 weeks may increase dose to 8 mg twice daily; after 4 more weeks may increase to 12 mg twice daily

Extended-release: same titration schedule as immediate-release but dosed once a day in the morning, preferably with food

Dosing Tips

Gastrointestinal side effects may be reduced if drug is administered with food

Gastrointestinal side effects may also be reduced if dose is titrated slowly

Probably best to utilize highest tolerated dose within the usual dosing range

âœ1⁄2 When switching to another cholinesterase inhibitor, probably best to cross-titrate from one to the other to prevent precipitous decline in function if the patient washes out of one drug entirely

Overdose

Can be lethal; nausea, vomiting, excess salivation, sweating, hypotension, bradycardia, collapse, convulsions, muscle weakness (weakness of respiratory muscles can lead to death)

Long-Term Use

Drug may lose effectiveness in slowing degenerative course of Alzheimer disease after 6 months

Can be effective in some patients for several years

No

Taper not necessary

Habit Forming

How to Stop

Discontinuation may lead to notable deterioration in memory and behavior, which may not be restored when drug is restarted or another cholinesterase inhibitor is initiated

Pharmacokinetics

Terminal elimination half-life approximately 7 hours Metabolized by CYP450 2D6 and 3A4

Drug Interactions

Galantamine may increase the effects of anesthetics and should be discontinued prior to surgery

Inhibitors of CYP450 2D6 and CYP450 3A4 may inhibit galantamine metabolism and raise galantamine plasma levels

Galantamine may interact with anticholinergic agents and the combination may decrease the efficacy of both

Cimetidine may increase bioavailability of galantamine

May have synergistic effect if administered with cholinomimetics (e.g., bethanechol)

Bradycardia may occur if combined with beta blockers

Theoretically, could reduce the efficacy of levodopa in Parkinsonâ€TM s disease

Not rational to combine with another cholinesterase inhibitor

Other Warnings/Precautions

May exacerbate asthma or other pulmonary disease

Increased gastric acid secretion may increase the risk of ulcers

Bradycardia or heart block may occur in patients with or without cardiac impairment

Do Not Use

If there is a proven allergy to galantamine

Special Populations Renal Impairment

Should be used with caution

Not recommended for use in patients with severe renal impairment

Hepatic Impairment

Should be used with caution

Reduction of clearance may increase with the degree of hepatic impairment

Not recommended for use in patients with severe hepatic impairment

Cardiac Impairment

Should be used with caution

Syncopal episodes have been reported with the use of galantamine

Elderly

Clearance is reduced in elderly patients

Use of cholinesterase inhibitors may be associated with increased rates of syncope, bradycardia, pacemaker insertion, and hip fracture in older adults with dementia

Children and Adolescents

Safety and efficacy have not been established

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR

or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women

Animal studies do not show adverse effects

âœ1⁄2 Not recommended for use in pregnant women or in women of childbearing potential

Breast Feeding

Unknown if galantamine is secreted in human breast milk, but all psychotropics are assumed to be secreted in breast milk

âœ1⁄2 Recommended either to discontinue drug or bottle feed Galantamine is not recommended for use in nursing women

The Art Of Psychopharmacology Potential Advantages

Alzheimer disease with cerebrovascular disease

Theoretically, nicotinic modulation may provide added therapeutic benefits for memory and behavior in some Alzheimer patients

Theoretically, nicotinic modulation may also provide efficacy for cognitive disorders other than Alzheimer disease

Potential Disadvantages

Patients who have difficulty taking a medication twice daily

Primary Target Symptoms

Memory loss in Alzheimer disease Behavioral symptoms in Alzheimer disease Memory loss in other dementias

Pearls

Dramatic reversal of symptoms of Alzheimer disease is not generally seen with cholinesterase inhibitors

Can lead to therapeutic nihilism among prescribers and lack of an appropriate trial of a cholinesterase inhibitor

âœ1⁄2 Perhaps only 50% of Alzheimer patients are diagnosed, and only 50% of those diagnosed are treated, and only 50% of those treated are given a cholinesterase inhibitor, and then only for 200 days in a disease that lasts 7– 10 years

Must evaluate lack of efficacy and loss of efficacy over months, not weeks

âœ1⁄2 Treats behavioral and psychological symptoms of Alzheimer dementia as well as cognitive symptoms (i.e., especially apathy, disinhibition, delusions, anxiety, cooperation, pacing)

Patients who complain themselves of memory problems may have depression, whereas patients whose spouses or children complain of the patientâ€TM s memory problems may have Alzheimer disease

Treat the patient but ask the caregiver about efficacy What you see may depend upon how early you treat

The first symptoms of Alzheimer disease are generally mood changes; thus, Alzheimer disease may initially be diagnosed as depression

Women may experience cognitive symptoms in perimenopause as a result of hormonal changes that are not a sign of dementia or Alzheimer disease

Aggressively treat concomitant symptoms with augmentation (e.g., atypical antipsychotics for agitation, antidepressants for depression)

If treatment with antidepressants fails to improve apathy and depressed mood in the elderly, it is possible that this represents early Alzheimer disease and a cholinesterase inhibitor like galantamine may be helpful

What to expect from a cholinesterase inhibitor:

Patients do not generally improve dramatically although this can be observed in a significant minority of patients

Onset of behavioral problems and nursing home placement can be delayed

Functional outcomes, including activities of daily living, can be preserved

Caregiver burden and stress can be reduced

Delay in progression in Alzheimer disease is not evidence of disease-modifying actions of cholinesterase inhibition

Cholinesterase inhibitors like galantamine depend upon the presence of intact targets for acetylcholine for maximum effectiveness and thus may be most effective in the early stages of Alzheimer disease

The most prominent side effects of galantamine are gastrointestinal effects, which are usually mild and transient

For patients with intolerable side effects, generally allow a washout period with resolution of side effects prior to switching to another cholinesterase inhibitor

Weight loss can be a problem in Alzheimer patients with debilitation and muscle wasting

Women over 85, particularly with low body weights, may experience more adverse effects

Use with caution in underweight or frail patients

Cognitive improvement may be linked to substantial (>65%) inhibition of acetylcholinesterase

âœ1⁄2 Galantamine is a natural product present in daffodils and snowdrops

New extended-release formulation allows for once daily dosing

âœ1⁄2 Novel dual action uniquely combines acetylcholinesterase inhibition with allosteric nicotine modulation

âœ1⁄2 Novel dual action should theoretically enhance cholinergic actions but incremental clinical benefits have been difficult to demonstrate

âœ1⁄2 Actions at nicotinic receptors enhance not only the release of acetylcholine but also that of other neurotransmitters, which may boost attention and improve behaviors caused by deficiencies in those neurotransmitters in Alzheimer disease

Some Alzheimer patients who fail to respond to another cholinesterase inhibitor may respond when switched to galantamine

Some Alzheimer patients who fail to respond to galantamine may respond to another cholinesterase inhibitor

To prevent potential clinical deterioration, generally switch from long-term treatment with one cholinesterase inhibitor to another without a washout period

âœ1⁄2 Galantamine may slow the progression of mild cognitive impairment to Alzheimer disease

âœ1⁄2 May be useful for dementia with Lewy bodies (DLB, constituted by early loss of attentiveness and visual perception with possible hallucinations, Parkinson-like movement problems, fluctuating cognition such as daytime drowsiness and lethargy, staring into space for long periods, episodes of disorganized speech)

May decrease delusions, apathy, agitation, and hallucinations in dementia with Lewy bodies

âœ1⁄2 May be useful for vascular dementia (e.g., acute onset with slow stepwise progression that has plateaus, often with gait abnormalities, focal signs, imbalance, and urinary incontinence)

May be helpful for dementia in Downâ€TM s syndrome

Suggestions of utility in some cases of treatment-resistant bipolar disorder

Theoretically, may be useful for ADHD, but not yet proven

Theoretically, could be useful in any memory condition characterized by cholinergic deficiency (e.g., some cases of brain injury, cancer chemotherapy-induced cognitive changes, etc.)

Suggested Reading

Bentue-Ferrer D , Tribut O , Polard E , Allain H . Clinically significant drug interactions with cholinesterase inhibitors: a guide for neurologists . CNS Drugs 2003 ;17 :947– 63 .

Bonner LT , Peskind ER . Pharmacologic treatments of dementia . Med Clin North Am 2002 ;86 :657– 74 .

Coyle J , Kershaw P . Galantamine, a cholinesterase inhibitor that allosterically modulates nicotinic receptors: effects on the course of Alzheimerâ€TM s disease . Biol Psychiatry 2001 ;49 :289– 99 .

Jones RW . Have cholinergic therapies reached their clinical boundary in Alzheimerâ€TM s disease ? Int J Geriatr Psychiatry 2003 ;18 (Suppl 1):S7 – 13.

Olin J , Schneider L . Galantamine for Alzheimerâ€TM s disease . Cochrane Database Syst Rev 2002 ;(3):CD001747 .

Stahl SM . Cholinesterase inhibitors for Alzheimerâ€TM s disease . Hosp Pract (Off Ed) 1998 ;33 :131 – 6 .

Stahl SM . The new cholinesterase inhibitors for Alzheimerâ€TM s disease, part 1 . J Clin Psychiatry 2000 ;61 :710– 11 .

Stahl SM . The new cholinesterase inhibitors for Alzheimerâ€TM s disease, part 2 . J Clin Psychiatry 2000 ;61 :813– 14 .

Guanfacine

Yes

Generic?

Class

Intuniv

Tenex

see index for additional brand names

Therapeutics Brands

Neuroscience-based Nomenclature: norepinephrine receptor agonist (N-RA)

Centrally acting alpha 2A agonist; antihypertensive; nonstimulant for ADHD

Commonly Prescribed for

(bold for FDA approved)

Hypertension

Attention deficit hyperactivity disorder (ADHD) in children ages 6– 17 (Intuniv, adjunct and monotherapy)

Oppositional defiant disorder Conduct disorder

Pervasive developmental disorders Motor tics

Touretteâ€TM s syndrome

How the Drug Works

For ADHD, theoretically has central actions on postsynaptic alpha 2A receptors in the prefrontal cortex

Guanfacine is 15– 20 times more selective for alpha 2A receptors than for alpha 2B or alpha 2C receptors

The prefrontal cortex is thought to be responsible for modulation of working memory, attention, impulse, control, and planning

For hypertension, stimulates alpha 2A adrenergic receptors in the brain stem, reducing sympathetic outflow from the CNS and decreasing peripheral resistance, renal vascular resistance, heart rate, and blood pressure

How Long Until It Works

For ADHD, can take a few weeks to see maximum therapeutic benefits

Blood pressure may be lowered 30– 60 minutes after first dose; greatest reduction seen after 2– 4 hours

May take several weeks to control blood pressure adequately

If It Works

The goal of treatment of ADHD is reduction of symptoms of inattentiveness, motor hyperactivity, and/or impulsiveness that disrupt social, school, and/or occupational functioning

Continue treatment until all symptoms are under control or improvement is stable and then continue treatment indefinitely as long as improvement persists

Some studies of up to 2 years

Reevaluate the need for treatment periodically

Treatment for ADHD begun in childhood may need to be continued into adolescence and adulthood if continued benefit is documented

If It Doesnâ€TM t Work

Consider adjusting dose or switching to another agent Consider behavioral therapy

Consider the presence of noncompliance and counsel patient and parents

Consider evaluation for another diagnosis or for a comorbid condition (e.g., bipolar disorder, substance abuse, medical illness, etc.)

Best Augmenting Combos for Partial Response or Treatment Resistance

Best to attempt another monotherapy prior to augmenting for ADHD

Possibly combination with stimulants (with caution)

Combinations for ADHD should be for the expert, while monitoring the patient closely, and when other treatment options have failed

Chlorthalidone, thyazide-type diuretics, and furosemide for hypertension

Tests

Blood pressure should be checked regularly during treatment

Side Effects

How Drug Causes Side Effects

Excessive actions on alpha 2A receptors, nonselective actions on alpha 2B and alpha 2C receptors

Notable Side Effects

Sedation, dizziness

Dry mouth, constipation, abdominal pain Fatigue, weakness

Hypotension

Life-Threatening or Dangerous Side Effects

Sinus bradycardia, hypotension (dose-related)

Reported but not expected

Weight Gain

Sedation

Many experience and/or can be significant in amount Some patients may not tolerate it

Can abate with time

May be less sedation with extended-release formulation

What to Do About Side Effects

Wait

Adjust dose

If side effects persist, discontinue use

Best Augmenting Agents for Side Effects

Dose reduction or switching to another agent may be more effective since most side effects cannot be improved with an augmenting agent

Dosing And Use Usual Dosage Range

Immediate-release: 1– 2 mg/day Extended-release: 1– 4 mg/day

Dosage Forms

Immediate-release tablet 1 mg, 2 mg, 3 mg Extended-release: 1 mg, 2 mg, 3 mg, 4 mg

How to Dose

Immediate-release: initial 1 mg/day at bedtime; after 3– 4 weeks can increase to 2 mg/day

Extended-release: initial 1 mg/day; can increase by 1 mg/week; maximum dose 4 mg/day

Dosing Tips

Adverse effects are dose-related and usually transient

Doses greater than 2 mg/day are associated with increased side effects

If guanfacine is terminated abruptly, rebound hypertension may occur within 2– 4 days

For hypertension, dose can be raised to 2 mg/day if 1 mg/day is ineffective, but 2 mg may have no more efficacy than 1 mg

For extended-release formulation, do not administer with high-fat meals because this increases exposure

Extended-release tablets should not be crushed, chewed, or broken

Extended-release and immediate-release tablets have different pharmacokinetic properties, so do not substitute on a mg-per-mg basis

Consider dosing extended-release on a mg/kg basis (0.05 mg/kg to 0.12 mg/kg)

Overdose

Drowsiness, lethargy, bradycardia, hypotension

Long-Term Use

Shown to be safe and effective for treatment of hypertension Studies of up to 2 years in ADHD

No

Habit Forming

How to Stop

Taper to avoid rebound effects (nervousness, increased blood pressure)

Pharmacokinetics

Pharmacokinetic properties differ for immediate- and extended- release fomulations

Metabolized by CYP450 3A4

Drug Interactions

CYP450 3A inhibitors, such as nefazodone, fluoxetine, fluvoxamine, and ketoconazole, may decrease clearance of guanfacine and raise guanfacine levels significantly

CYP450 3A inducers may increase clearance of guanfacine and lower guanfacine levels significantly

Do not administer extended-release with high-fat meals, because this increases exposure

Combined use with valproate may increase plasma concentrations of valproate

Increased depressive effects when taken with other CNS depressants

Phenobarbital and phenytoin may reduce plasma concentrations of guanfacine

Other Warnings/Precautions

Excessive heat (e.g., saunas) may exacerbate some of the side effects, such as dizziness and drowsiness

Titrate slowly and monitor vital signs frequently in patients at risk for hypotension, heart block, bradycardia, syncope, cardiovascular

disease, vascular disease, cerebrovascular disease, or chronic renal failure

Do Not Use

If there is a proven allergy to guanfacine

Special Populations Renal Impairment

Patients should receive lower doses

Use with caution

Hepatic Impairment

Cardiac Impairment

Use with caution in patients with recent myocardial infarction, severe coronary insufficiency, cerebrovascular disease

Use with caution in patients at risk for hypotension, bradycardia, heart block, or syncope

Elderly

Elimination half-life may be longer in elderly patients Elderly patients may be more sensitive to sedative effects

Children and Adolescents

Safety and efficacy not established in children under age 6

Some reports of mania and aggressive behavior in ADHD patients taking guanfacine

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women Animal studies do not show adverse effects

Use in women of childbearing potential requires weighing potential benefits to the mother against potential risks to the fetus

Breast Feeding

Unknown if guanfacine is secreted in human breast milk, but all psychotropics are assumed to be secreted in breast milk

Recommended either to discontinue drug or bottle feed

The Art Of Psychopharmacology

Potential Advantages

No known abuse potential; not a controlled substance Not a stimulant

For oppositional behavior associated with ADHD Less sedation than clonidine

Potential Disadvantages

Not well studied in adults with ADHD

Primary Target Symptoms

Concentration

Motor hyperactivity

Oppositional and impulsive behavior High blood pressure

Pearls

The extended-release formulation often is much more tolerable than the immediate-release formulation, especially for patients sensitive to peak dose sedation of the immediate-release formulation

Guanfacine has been shown to be effective in both children and adults, and guanfacine extended-release is approved for ADHD in children ages 6– 17

Guanfacine can also be used to treat tic disorders, including Touretteâ€TM s syndrome

Although both guanfacine and clonidine are alpha 2 adrenergic agonists, guanfacine is relatively selective for alpha 2A receptors, whereas clonidine binds not only alpha 2A, 2B, and 2C receptors but also imidazoline receptors, causing more sedation, hypotension, and side effects than guanfacine

May be used as monotherapy or in combination with stimulants for the treatment of oppositional behavior in children with or without ADHD

Suggested Reading

Arnsten AF , Scahill L , Findling RL . alpha2-Adrenergic receptor agonists for the treatment of attention-deficit/hyperactivity disorder: emerging concepts from new data . J Child Adolesc Psychopharmacol 2007 ;17 (4 ):393 – 406 .

Biederman J , Melmed RD , Patel A , et al. Long-term, open-label extension study of guanfacine extended-release in children and adolescents with ADHD . CNS Spectr 2008 ;13 (12 ):1047 – 55.

Posey DJ , McDougal CJ . Guanfacine and guanfacine extended-release: treatment for ADHD and related disorders . CNS Drug Rev 2007 ;13 (4 ):465– 74 .

Sallee FR , Lyne A , Wigal T , McGough J . Long-term safety and efficacy of guanfacine extended-release in children and adolescents with attention- deficit/hyperactivity disorder . J Child Adolesc Psychopharmacol 2009 ;19 (3 ):215– 26 .

Sallee FR , McGough J , Wigal T , et al. Guanfacine extended-release in children and adolescents with attention-deficit/hyperactivity disorder: a placebo-controlled trial . J Am Acad Child Adolesc Psychiatry 2009 ;48 (2 ):155– 65 .

Spencer TJ , Greenbaum M , Ginsberg LD , Murphy WR . Safety and effectiveness of coadministration of guanfacine extended-release and psychostimulants in children and adolescents with attention- deficit/hyperactivity disorder . J Child Adolesc Psychopharmacol 2009 ;19 (5 ):501– 10 .

Haloperidol

Haldol

Therapeutics Brands

see index for additional brand names

Yes

Generic?

Class

Neuroscience-based Nomenclature: dopamine receptor antagonist (D-RAn)

Conventional antipsychotic (neuroleptic, butyrophenone, dopamine 2 antagonist)

Commonly Prescribed for

(bold for FDA approved)

Manifestations of psychotic disorders (oral, immediate-release injection)

Tics and vocal utterances in Touretteâ€TM s syndrome (oral, immediate-release injection)

Second-line treatment of severe behavior problems in children of combative, explosive hyperexcitability (oral)

Second-line short-term treatment of hyperactive children (oral)

Treatment of schizophrenic patients who require prolonged parenteral antipsychotic therapy (depot intramuscular decanoate)

Bipolar disorder

Behavioral disturbances in dementias Delirium (with lorazepam)

How the Drug Works

Blocks dopamine 2 receptors, reducing positive symptoms of psychosis and possibly combative, explosive, and hyperactive behaviors

Blocks dopamine 2 receptors in the nigrostriatal pathway, improving tics and other symptoms in Touretteâ€TM s syndrome

How Long Until It Works

Psychotic symptoms can improve within 1 week, but it may take several weeks for full effect on behavior

If It Works

Most often reduces positive symptoms in schizophrenia but does not eliminate them

Most schizophrenic patients do not have a total remission of symptoms but rather a reduction of symptoms by about a third

Continue treatment in schizophrenia until reaching a plateau of improvement

After reaching a satisfactory plateau, continue treatment for at least a year after first episode of psychosis in schizophrenia

For second and subsequent episodes of psychosis in schizophrenia, treatment may need to be indefinite

Reduces symptoms of acute psychotic mania but not proven as a mood stabilizer or as an effective maintenance treatment in bipolar disorder

After reducing acute psychotic symptoms in mania, switch to a mood stabilizer and/or an atypical antipsychotic for mood stabilization and maintenance

If It Doesnâ€TM t Work

Consider trying one of the first-line atypical antipsychotics Consider trying another conventional antipsychotic

If 2 or more antipsychotic monotherapies do not work, consider clozapine

Best Augmenting Combos for Partial Response or Treatment Resistance

Augmentation of conventional antipsychotics has not been systematically studied

Addition of a mood-stabilizing anticonvulsant such as valproate, carbamazepine, or lamotrigine may be helpful in both schizophrenia and bipolar mania

Augmentation with lithium in bipolar mania may be helpful Addition of a benzodiazepine, especially short-term for agitation

Tests

âœ1⁄2 Since conventional antipsychotics are frequently associated with weight gain, before starting treatment, weigh all patients and determine if the patient is already overweight (BMI 25.0– 29.9) or obese (BMI ≥ 30)

Before giving a drug that can cause weight gain to an overweight or obese patient, consider determining whether the patient already has pre-diabetes (fasting plasma glucose 100– 125 mg/dL), diabetes (fasting plasma glucose ≥ 126 mg/dL), or dyslipidemia (increased total cholesterol, LDL cholesterol, and triglycerides; decreased HDL cholesterol), and treat or refer such patients for treatment, including nutrition and weight management, physical activity counseling, smoking cessation, and medical management

âœ1⁄2 Monitor weight and BMI during treatment

âœ1⁄2 Consider monitoring fasting triglycerides monthly for several months in patients at high risk for metabolic complications and when

initiating or switching antipsychotics

âœ1⁄2 While giving a drug to a patient who has gained >5% of initial weight, consider evaluating for the presence of pre-diabetes, diabetes, or dyslipidemia, or consider switching to a different antipsychotic

Should check blood pressure in the elderly before starting and for the first few weeks of treatment

Monitoring elevated prolactin levels of dubious clinical benefit

Patients with low white blood cell count (WBC) or history of drug- induced leukopenia/neutropenia should have complete blood count (CBC) monitored frequently during the first few months and haloperidol should be discontinued at the first sign of decline of WBC in the absence of other causative factors

Patients should be monitored periodically for the development of abnormal movements of tardive dyskinesia, using neurological exam and the AIMS (Abnormal Involuntary Movement Scale)

Side Effects

How Drug Causes Side Effects

Acute blockade of dopamine 2 receptors in the striatum can cause drug-induced parkinsonism, dystonia, or akathisia

Chronic blockade of dopamine 2 receptors in the striatum can cause tardive dyskinesia

By blocking dopamine 2 receptors in the pituitary, it can cause elevations in prolactin

By blocking dopamine 2 receptors excessively in the mesocortical and mesolimbic dopamine pathways, especially at high doses, it can cause worsening of negative and cognitive symptoms (neuroleptic- induced deficit syndrome)

Blocking alpha 1 adrenergic receptors can cause dizziness, hypotension, and syncope

Mechanism of weight gain and any possible increased incidence of diabetes or dyslipidemia with conventional antipsychotics is unknown

Notable Side Effects âœ1⁄2 Neuroleptic-induced deficit syndrome

âœ1⁄2 Akathisia

âœ1⁄2 Drug-induced parkinsonism

âœ1⁄2 Tardive dyskinesia, tardive dystonia

âœ1⁄2 Risk of potentially irreversible involuntary dyskinetic movements may increase with cumulative dose and treatment duration

âœ1⁄2 Galactorrhea, amenorrhea

Dizziness, sedation

Dry mouth, constipation, urinary retention, blurred vision Decreased sweating

Hypotension, tachycardia, hypertension Weight gain

Life-Threatening or Dangerous Side Effects

Rare neuroleptic malignant syndrome (NMS) may cause hyperpyrexia, muscle rigidity, delirium, and autonomic instability with elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure

Rare seizures

Rare jaundice, agranulocytosis, leukopenia

As a class, antipsychotics are associated with an increased risk of death and cerebrovascular events in elderly patients with dementia; not approved for treatment of dementia-related psychosis

Occurs in significant minority

Sedation is usually transient

Weight Gain

Sedation

Wait Wait

What to Do About Side Effects

Wait

For drug-induced parkinsonism, add an anticholinergic agent

Beta blockers, benzodiazepines, or 5HT2A antagonists (e.g., mirtazapine, cyproheptadine) may reduce akathisia

Reduce the dose

For sedation, give at night

Switch to an atypical antipsychotic

Weight loss, exercise programs, and medical management for high BMIs, diabetes, dyslipidemia

Metformin may help prevent or reverse antipsychotic-induced weight gain

Best Augmenting Agents for Side Effects

Benztropine, trihexyphenidyl, or amantadine for drug-induced parkinsonism

Beta blockers, benzodiazepines, or 5HT2A antagonists (e.g., mirtazapine, cyproheptadine) for akathisia

Valbenazine or deutetrabenazine for tardive dyskinesia

Many side effects cannot be improved with an augmenting agent

Dosing And Use Usual Dosage Range

1– 40 mg/day orally

Immediate-release injection 2– 5 mg each dose

Decanoate injection 10– 20 times the previous daily dose of oral antipsychotic (see Haloperidol Decanoate section after Pearls for dosing and use)

Dosage Forms

Tablet 0.5 mg scored, 1 mg scored, 2 mg scored, 5 mg scored, 10 mg scored, 20 mg scored

Concentrate 2 mg/mL

Injection 5 mg/mL (immediate-release) Decanoate injection 50 mg/mL, 100 mg/mL

How to Dose

Oral: initial 1– 15 mg/day; can give once daily or in divided doses at the beginning of treatment during rapid dose escalation; increase as needed; can be dosed up to 100 mg/day; safety not established for doses over 100 mg/day

Immediate-release injection: initial dose 2– 5 mg; subsequent doses may be given as often as every hour; patient should be switched to oral administration as soon as possible

Dosing Tips – Oral

Haloperidol is frequently dosed too high

Some studies suggest that patients who respond well to low doses of haloperidol (e.g., approximately 2 mg/day) may have efficacy similar to atypical antipsychotics for both positive and negative symptoms of schizophrenia

Higher doses may actually induce or worsen negative symptoms of schizophrenia

Low doses, however, may not have beneficial actions for treatment- resistant cases or violence

Rather than raise the dose above normal dosing in acutely agitated patients requiring acute antipsychotic actions, consider short-term (one dose or more) augmentation with a benzodiazepine or another antipsychotic, especially intramuscularly

Rather than raise the dose above normal dosing in partial responders, consider augmentation with a mood-stabilizing anticonvulsant, such as valproate, topiramate, or lamotrigine

Children and elderly should generally be dosed at the lower end of the dosage spectrum

For treatment resistance, consider obtaining plasma drug levels to guide dosing above recommended levels

Treatment should be suspended if absolute neutrophil count falls below 1000/mm3

Overdose

Fatalities have been reported; drug-induced parkinsonism, hypotension, sedation, respiratory depression, shock-like state

Long-Term Use

Often used for long-term maintenance

Should periodically reevaluate long-term usefulness in individual patients, but treatment may need to continue for many years

No

Habit Forming

How to Stop

Slow down-titration of oral formulation (over 6– 8 weeks), especially when simultaneously beginning a new antipsychotic while switching (i.e., cross-titration)

Rapid oral discontinuation may lead to rebound psychosis and worsening of symptoms

If antiparkinson agents are being used, they should be continued for a few weeks after haloperidol is discontinued

Pharmacokinetics

Decanoate half-life approximately 3 weeks Oral half-life approximately 12– 38 hours

Drug Interactions

May decrease the effects of levodopa, dopamine agonists

May increase the effects of antihypertensive drugs except for guanethidine, whose antihypertensive actions haloperidol may antagonize

Additive effects may occur if used with CNS depressants; dose of other agent should be reduced

Some pressor agents (e.g., epinephrine) may interact with haloperidol to lower blood pressure

Haloperidol and anticholinergic agents together may increase intraocular pressure

Reduces effects of anticoagulants

Plasma levels of haloperidol may be lowered by rifampin

Some patients taking haloperidol and lithium have developed an encephalopathic syndrome similar to neuroleptic malignant syndrome

May enhance effects of antihypertensive drugs

Other Warnings/Precautions

If signs of neuroleptic malignant syndrome develop, treatment should be immediately discontinued

Use with caution in patients with respiratory disorders Avoid extreme heat exposure

If haloperidol is used to treat mania, patients may experience a rapid switch to depression

Patients with thyrotoxicosis may experience neurotoxicity

Use only with caution if at all in Parkisonâ€TM s disease or Lewy body dementia

Higher doses and IV administration may be associated with increased risk of QT prolongation and torsade de pointes; use particular caution if patient has a QT-prolonging condition, underlying cardiac abnormalities, hypothyroidism, familial long-QT syndrome, or is taking a drug known to prolong QT interval

Antipsychotics may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls; for patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment, and recurrently for patients on long-term antipsychotic therapy

As with any antipsychotic, use with caution in patients with history of seizures

Do Not Use

If patient is in a comatose state or has CNS depression If patient has Parkinsonâ€TM s disease

If there is a proven allergy to haloperidol

Use with caution

Use with caution

Special Populations Renal Impairment

Hepatic Impairment

Cardiac Impairment

Use with caution because of risk of orthostatic hypertension

Possible increased risk of QT prolongation or torsade de pointes at higher doses or with IV administration

Elderly

Lower doses should be used and patient should be monitored closely

Elderly patients may be more susceptible to respiratory side effects and hypotension

Although conventional antipsychotics are commonly used for behavioral disturbances in dementia, no agent has been approved for treatment of elderly patients with behavioral symptoms of dementia such as agitation

Elderly patients with dementia-related psychosis treated with antipsychotics are at an increased risk of death compared to placebo, and also have an increased risk of cerebrovascular events

Children and Adolescents

Safety and efficacy have not been established; not intended for use under age 3

Oral: initial 0.5 mg/day; target dose 0.05– 0.15 mg/kg per day for psychotic disorders; 0.05– 0.075 mg/kg per day for nonpsychotic disorders

Generally consider second-line after atypical antipsychotics

Pregnancy

Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

Controlled studies have not been conducted in pregnant women

There is a risk of abnormal muscle movements and withdrawal symptoms in newborns whose mothers took an antipsychotic during the third trimester; symptoms may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty feeding

Reports of drug-induced parkinsonism, jaundice, hyperreflexia, hyporeflexia in infants whose mothers took a conventional antipsychotic during pregnancy

Reports of limb deformity in infants whose mothers took haloperidol during pregnancy

Haloperidol should generally not be used during the first trimester Haloperidol should only be used during pregnancy if clearly needed

Psychotic symptoms may worsen during pregnancy and some form of treatment may be necessary

Atypical antipsychotics may be preferable to conventional antipsychotics or anticonvulsant mood stabilizers if treatment is required during pregnancy

Breast Feeding

Some drug is found in motherâ€TM s breast milk

âœ1⁄2 Recommended either to discontinue drug or bottle feed

The Art Of Psychopharmacology Potential Advantages

Intramuscular formulation for emergency use 4-week depot formulation for noncompliance

Low-dose responders may have comparable positive and negative symptom efficacy to atypical antipsychotics

Low-cost, effective treatment

For treatment-resistant cases with uncontrolled positive symptoms, aggression, and/or violence (at high doses, guided by plasma drug levels and tolerability)

Potential Disadvantages

Patients with tardive dyskinesia or who wish to avoid tardive dyskinesia and drug-induced parkinsonism

Vulnerable populations such as children or elderly Patients with notable cognitive or mood symptoms

Primary Target Symptoms

Positive symptoms of psychosis Violent or aggressive behavior

Pearls

Prior to the introduction of atypical antipsychotics, haloperidol was one of the most preferred antipsychotics

Haloperidol may still be a useful antipsychotic, especially at low doses for those patients who require management with a conventional antipsychotic or who cannot afford an atypical antipsychotic

Low doses may not induce negative symptoms, but high doses may

Not clearly effective for improving cognitive or affective symptoms of schizophrenia

May be effective for bipolar maintenance, but there may be more tardive dyskinesia when affective disorders are treated with a conventional antipsychotic long-term

Less sedating than many other conventional antipsychotics, especially “ low-potency†phenothiazines

Haloperidol is often used to treat delirium, generally in combination with lorazepam, with the haloperidol dose 2 times the loraze