STAHLÂ€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 .

STAHLÂ€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

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http://www.cambridge.org

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

Â© 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

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 â€“ 17.

Kranzler HR , Gage A . Acamprosate efficacy in alcohol-dependent patients: summary of results from three pivotal trials . Am J Addictions 2008 ; 17 :70 â€“ 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 â€“ 23 .

Agomelatine

Valdoxan

Therapeutics Brands

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 2â€“ 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.)

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

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

25â€“ 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

Habit Forming

No need to taper dose

How to Stop

Pharmacokinetics

Half-life 1â€“ 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 :628â€“ 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 â€“ 37.

Kennedy SH , Avedisova A , BelaÃ ̄di C , Picarel-Blanchot F , de Bodinat C. Sustained efficacy of agomelatine 10 mg, 25 mg, and 25â€“ 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 ):378â€“ 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 â€“ 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 ):487â€“ 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 ):574â€“ 87 .

Stahl SM . Mechanism of action of agomelatine: a novel antidepressant exploiting synergy between monoaminergic and melatonergic properties . CNS Spectr 2014 ;19 :207â€“ 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 ):616â€“ 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 ):151â€“ 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 â€“ after a few weeks, discontinue use or use on an â€œ as-neededâ€ 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 â€“ 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

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: 1â€“ 4 mg/day

Panic: alprazolam IR: 5â€“ 6 mg/day Panic: alprazolam XR: 3â€“ 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 0.75â€“ 1.5 mg/day divided into 3 doses; increase dose every 3â€“ 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 3â€“ 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 0.5â€“ 1 mg/day once daily in the morning; dose may be increased by 1 mg/day every 3â€“ 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 â€œ top-upâ€ 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; 3â€“ 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 12â€“ 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 (0.5â€“ 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 (0.5â€“ 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

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 2â€“ 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 â€œ clock-watchingâ€ 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 â€œ long-acting alprazolam- like anxiolytic,â€ then alprazolam XR can be considered â€œ an even longer-acting clonazepam-like anxiolyticâ€ 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 :463â€“ 73 .

Greenblatt DJ , Wright CE . Clinical pharmacokinetics of alprazolam. Therapeutic implications . Clin Pharmacokinet 1993 ; 24 :453â€“ 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 â€“ 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 â€“ 33 .

Speigel DA . Efficacy studies of alprazolam in panic disorder . Psychopharmacol Bull 1998 ; 34 :191â€“ 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 4â€“ 6 weeks to determine efficacy of drug, but in practice some patients require up to 16â€“ 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 5â€“ 15% of schizophrenic patients can experience an overall improvement of greater than 50â€“ 60%, especially when receiving stable treatment for more than a year

Such patients are considered super-responders or â€œ awakenersâ€ 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 25.0â€“ 29.9)

is obese (BMI â‰¥ 30)

has pre-diabetes (fasting plasma glucose 100â€“ 125 mg/dL) has diabetes (fasting plasma glucose â‰¥ 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

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: 400â€“ 800 mg/day in 2 doses Negative symptoms only: 50â€“ 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 400â€“ 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

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 3â€“ 7 days

Clinical experience has shown that asenapine, quetiapine, and olanzapine should be tapered off slowly over a period of 3â€“ 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 ;394:939â€“ 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 â€œ atypicalâ€ antipsychotic: a meta-analysis of randomized controlled trials . Am J Psychiatry 2002 ;159 (2 ):180â€“ 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 2â€“ 4 weeks

If it is not working within 6â€“ 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.)

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 25.0â€“ 29.9) or obese (BMI â‰¥ 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 100â€“ 125 mg/dL), diabetes (fasting plasma glucose â‰¥ 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

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

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

50â€“ 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 3â€“ 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

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 10â€“ 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

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

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 ):532â€“ 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 â€“ 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 2â€“ 4 weeks

If it is not working within 6â€“ 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.)

Best Augmenting Combos for Partial Response or Treatment Resistance

Lithium, buspirone, thyroid hormone

Tests

Baseline ECG is recommended for patients over age 50

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 100â€“ 125 mg/dL), diabetes (fasting plasma glucose â‰¥ 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

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

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

200â€“ 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 2â€“ 3 times/day; increase gradually to 100 mg 2â€“ 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

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)

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 â€“ may require lower than usual adult dose

Hepatic Impairment

Use with caution â€“ 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

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

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 25â€“ 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

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

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

Suggested Reading

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

Bull 2001 ; 57 :161â€“ 78 .

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

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

Jue SG , Dawson GW , Brogden RN . Amoxapine: a review of its pharmacology and efficacy in depressed states . Drugs 1982 ;24 :1 â€“ 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: 5â€“ 60 mg/day (divided doses for tablet, once daily morning dose for Spansule capsule)

ADHD: 5â€“ 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 3â€“ 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 2â€“ 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 10â€“ 12 hours

Drug Interactions

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

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 6â€“ 12: initial 5 mg/day; increase by 5 mg each week

ADHD: ages 3â€“ 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

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 5â€“ 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 â€“ 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 â€“ 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 â€“ viii , 1 â€“ 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 ):821â€“ 42 .

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

Wender PH , Wolf LE , Wasserstein J . Adults with ADHD. An overview . Ann NY Acad Sci 2001 ;931 :1 â€“ 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 6â€“ 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.)

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: 5â€“ 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 4â€“ 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 4â€“ 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 5â€“ 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 2.5â€“ 10 mg/day every 4â€“ 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 6â€“ 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 5â€“ 10 mg, 30â€“ 60 minutes before meals

Dosing Tips

Clinical duration of action often differs from pharmacokinetic half- life

âœ1⁄2 Immediate-release d,l-amphetamine has 3â€“ 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

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

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 2â€“ 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 6â€“ 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

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

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

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 3â€“ 5: initial 2.5 mg/day; can increase by 2.5 mg each week

Narcolepsy: ages 6â€“ 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

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