CLINICAL HANDBOOK OF Psychotropic Drugs - … Handbook of Psychotropic Drugs for Children and...

3DEAN ELBE · KALYNA Z. BEZCHLIBNYK-BUTLERADIL S. VIRANI · RIC M. PROCYSHYN (EDS.)

Online versi

on also availa

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CLINICAL HANDBOOK OF

Psychotropic Drugsfor Children and Adolescents 3rd edition

HOW TO USE THIS BOOKThe Clinical Handbook of Psychotropic Drugs uses color coding and icons for intuitivenavigation:– Blue sections contain general information on drugs / treatments and their avail-

ability.– Green sections cover drug action and dosing.– Red sections outline warnings and precautions.– Orange sections detail patient- and care-related information, such as nursing

considerations and patient advice.

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Onset and Duration of Action�

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Switching, Augmentation Strategies

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Further Reading

Clinical Handbook of Psychotropic Drugsfor Children and Adolescents

Dean Elbe, BSc (Pharm), PharmD, BCPP(A, B)

Kalyna Z. Bezchlibnyk-Butler, BScPhm, FCSHPAdil S. Virani, BSc (Pharm), PharmD, FCSHP(B)

Ric M. Procyshyn, BSc (Pharm), MSc, PharmD, PhD(C)

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

Tyler R. Black, BSc, MD, FRCPC(D) (Psychiatric Disorders in Children and Adolescents)Carla Dillon, BSc (Pharm), ACPR, PharmD(E) (Antipsychotics)Lynda Eccott, BSc, MScPharm(F) (Natural Health Products)Barry A. Martin, MD, FRCPC(G) (Electroconvulsive Therapy)

Roger S. McIntyre, MD, FRCPC(H) (Mood Stabilizers)Leslie Phillips, BSc (Pharm), PharmD(E) (Antipsychotics)

(A) Department of Child and Adolescent Mental Health, Children’s & Women’s Health Centre of British Columbia, Vancouver, BC, Canada(B) Lower Mainland Pharmacy Services and Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada

(C) British Columbia Mental Health & Addictions Research Insitute, Vancouver, BC, Canada; Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada(D) CAPE Unit, BC Children’s Hospital, and Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada

(E) School of Pharmacy, Memorial University of Newfoundland, St. John’s, NL, Canada(F) Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada

(G) Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, ON, Canada(H) Toronto Western Hospital, University Health Network, and Department of Psychiatry, University of Toronto, Toronto, ON, Canada

Library of Congress Cataloging-in-Publication Data

is available via the Library of Congress Marc Database under theLC Control Number 2014933647

National Library of Canada Cataloguing-in-Publication Data

Main entry under title:

Clinical handbook of psychotropic drugs for children and adolescents/ [edited by] Dean Elbe, BSc (Pharm), PharmD, BCPP, Kalyna Z.Bezchlibnyk-Butler, BScPhm, FCSHP, Adil S. Virani, BSc (Pharm), PharmD,FCSHP, Ric M. Procyshyn, BSc (Pharm), MSc, PharmD, PhD. – Third revised edition.Text runs parallel to spine.Revision of: Clinical handbook of psychotropic drugs for children andadolescents / Kalyna Z. Bezchlibnyk-Butler, Adil S. Virani, [eds.]. –2nd rev. ed. – Toronto : Hogrefe & Huber, c2007.Includes bibliographical references and index.Issued in print and electronic formats.

ISBN 978-0-88937-456-0 (pbk.).–ISBN 978-1-61676-456-2 (pdf)

1. Psychotropic drugs–Handbooks, manuals, etc. 2. Pediatricpsychopharmacology–Handbooks, manuals, etc. I. Elbe, Dean, editorII. Bezchlibnyk-Butler, Kalyna Z., 1947–, editor. III. Virani, Adil S., editorIV. Procyshyn, Ric M. (Ric Michael), 1961-, editorRM315.C56 2014 615’.788083 C2014-901234-9

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No part of this publication may be reproduced, stored in a retrieval system, ortransmitted, in any form or by any means, electronic, mechanical, photocopying,microšlming, recording, or otherwise, without written permission from the publisher.The authors and publisher have made every e−ort to ensure that drug selections anddosages suggested in this text are in accord with current recommendations andpractice at the time of publication. However, due to changing government regulations,continuing research, and changing information concerning drug therapy and reactions,the reader is urged to check the package insert for each drug for any change inindications and dosage, or for added precautions. The authors and publisher disclaimany responsibility for any consequences which may follow from the use of informationpresented in this book.

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3rd edition

ISBN 978-0-88937-456-0Hogrefe Publishing

INTRODUCTIONThe Clinical Handbook of Psychotropic Drugs for Children and Adolescents is intendedto be a user-friendly and practical resource guide on the use of psychotropic drugs inchildren and adolescents. Its content is derived from various forms of published literature(including randomized controlled trials, scientišc data such as pharmacokinetic trials,cohort trials, case series, and case reports) as well as from leading clinical experts. Weendeavor to continually update this handbook as the psychiatric literature evolves sowe can continue to provide evidence-based clinically relevant information that is easilyaccessed and utilized to aid with patient care decisions. New sections, periodically added,re¦ect changes in therapy and in current practice.

Many classes of psychotropic drugs are used to treat childhood and adolescent mentalillness on the basis of e³cacy in adults, despite not being currently approved for usein these populations. The lack of approval does not necessarily re¦ect lack of safety ore³cacy, but it does re¦ect a lack of controlled studies in these age groups. Many productmonographs include a statement stating their drug has not been adequately studied inchildren and the safety of the drug has not been established under a specišc age.

In the Product Availability section of each chapter, the Clinical Handbook includesmonograph statements regarding the recommendations for the use of each drug inchildren and adolescents. Approved indications for children and adolescents are stated,as are those for adults; also included are nonapproved indications for these drugs. Eachchapter includes data from open and double-blind studies, where available, regardingdoses, adverse e−ects, and other considerations in children and adolescents.

Because of a lack of comparative data in children and adolescents for most drug classes,Adverse Reaction tables and Drug Interaction charts re¦ect information that pertains toheterogeneous age groups (youth and adults).

Patient and Caregiver Information Sheets for most drug categories are provided asprintable pdf šles to facilitate education/counselling of patients receiving these medica-tions and their caregivers. For details, please see p. 354.

Most children and adolescents with a diagnosable psychiatric disorder require multi-modal interventions to address the symptoms of the disorder, the comorbid conditions,and the psychological, social, and developmental sequelae. Individual and family psy-choeducation are essential, and psychosocial interventions should be considered for mostpsychiatric disorders.

Until systematic double-blind studies of various psychotropic drugs have been con-ducted to determine the e³cacy, the pharmacokinetics, as well as the relative and

absolute risks of each drug in this population, physicians who choose to use specišcpsychotropic drugs in children and adolescents should review all available studies andmonitor their patients on a regular basis. Consideration should be given to obtaininginformed consent from the caregiver or youth (depending on the patient’s age) for usein unapproved indications.

Given that changes may occur in a medication’s indications, and di−erences are seenamong countries, specišc “indications” listed in this text as “approved” should be viewedin conjunction with product monographs approved in your jurisdiction of interest.

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

The purpose of this handbook is to provide quick access to relevant, practical, andimportant information clinicians should be aware of when considering pharmacologicaloptions available in the treatment of childhood and adolescent psychiatric disorders. Itprovides an overview of the plausible alternatives, dosing guidelines, as well as informa-tion on drug interactions and potential side e−ects. It is meant to be a resource to boththose in training and experienced clinicians.

For those who like the convenience of electronic resources, the Clinical Handbook ofPsychotropic Drugs for Children and Adolescents is also available as an online version thatprovides even quicker access to all the information in the handbook, with some addedextras: (1) An auto-completion powered search function, (2) browse features for genericnames, trade names, indications, and interacting agents, (3) column-selector enhance-ment of comparison charts (dosages, side e−ects, pharmacokinetics, interactions. . . ) thatallows you to choose which information is displayed, and (4) hundreds of additionalreferences. Further details on this can be found at http://www.hogrefe.com/chpd-online

Over the years, many readers have asked many interesting questions and provideduseful comments and suggestions regarding the content and format of the handbook.This input is critical to keeping this handbook current, accurate, and relevant to thereadership. We really appreciate the feedback. Please feel free to e-mail me at the addressbelow with your comments and questions.

Dean ElbeE-mail: [email protected]

The Clinical Handbook of Psychotropic Drugs for Children & Adolescents ONLINE is the full-text online version of the popular Clinical Handbook of Psychotropic Drugs for Children & Adolescents. It retains all the practical features for which the Clinical Handbook is re-nowned and makes the information even more easily accessible. As in the print edition, instantly recognizable icons and color coding allow you to find at a glance the informa-tion you seek. But the CHPD for Children & Adolescents ONLINE version offers much more. Unique features that allow even quicker access to the wealth of information include:

CLINICAL HANDBOOK OF PSYCHOTROPIC DRUGS FOR CHILDREN & ADOLESCENTS ONLINE

Also available:

Auto-completion powered search function

Browse features for

Generic Names Trade Names Indications Interacting Agents

Column-selector enhancement of comparison charts (dosages, side effects, pharmacokinet-ics, interactions, etc.) that allows you to choose which information is displayed.

Hundreds of additional references

Browse by generic names, trade names, indications, interacting agents

Column-selector enhancement of comparison charts

Auto-completion powered search function

TABLE OF CONTENTSPsychiatric Disorders in Children and Adolescents 2

Attention-Dešcit/Hyperactivity Disorder (ADHD) 2

Major Depressive Disorder (MDD) 3

Disruptive Mood Dysregulation Disorder (DMDD) 5

Bipolar Disorder (BD) 6

Schizophrenia 7

ANXIETY DISORDERS 8

Separation Anxiety Disorder 9

Generalized Anxiety Disorder (GAD) 10

Social Anxiety Disorder 10

Panic Disorder 11

Specišc Phobia 12

Obsessive-Compulsive Disorder (OCD) 13

TRAUMA- AND STRESSOR-RELATED DISORDERS 14

Posttraumatic Stress Disorder (PTSD) 14

TIC DISORDERS 15

Tourette’s Disorder 15

Autism Spectrum Disorder (ASD) 16

DISRUPTIVE, IMPULSE-CONTROL, AND CONDUCTDISORDERS 17

Conduct Disorder (CD) 17

Oppositional Dešant Disorder (ODD) 18

Drugs for ADHD 22

Psychostimulants 22

Atomoxetine 31

Comparison of Drugs for ADHD 34

α2 agonists 37

Augmentation Strategies in ADHD 41

Antidepressants 44

Selective Serotonin Reuptake Inhibitors (SSRI) 45

Norepinephrine Dopamine Reuptake Inhibitor (NDRI) 58

Serotonin Norepinephrine Reuptake Inhibitor (SNRI) 63

Serotonin-2 Antagonists/Reuptake Inhibitors (SARI) 69

Serotonin-1A Agonist/Serotonin Reuptake Inhibitor 74

Noradrenergic/Specišc SerotonergicAntidepressants (NaSSA) 76

Nonselective Cyclic Antidepressants 81

Monoamine Oxidase Inhibitors 89

Reversible Inhibitor of MAO-A (RIMA) 89

Irreversible Monoamine Oxidase (A&B) Inhibitors(MAOIs) 92

E−ects of Antidepressants on Neurotransmit-ters/Receptors 98

Pharmacological E−ects of Antidepressants onNeurotransmitters/Receptors 99

Frequency of Adverse Reactions to Antidepressantsat Therapeutic Doses 100

Antidepressant Doses and Pharmacokinetics 103

Switching Antidepressants 107

Antidepressant Augmentation Strategies 109

Electroconvulsive Therapy (ECT) 114

Antipsychotics 119

“Second-Generation” Antipsychotics/SGAs 126

“Third-Generation” Antipsychotic/TGA 152

“First-Generation” Antipsychotics/FGAs 161

E−ects of Antipsychotics on Neurotransmitters/Receptors 177

Pharmacological E−ects of Antipsychotics onNeurotransmitters/Receptors 178

Frequency (%) of Adverse Reactions toAntipsychotics at Therapeutic Doses 179

Antipsychotic Doses and Pharmacokinetics (Oraland Short-Acting Injections) 181

Comparison of Long-Acting IM Antipsychotics 190

Switching Antipsychotics 194

Antipsychotic Augmentation Strategies 195

Antipsychotic-Induced Extrapyramidal Side E−ects(EPSE) and Their Management 202

Extrapyramidal Side E−ects of Antipsychotics 202

Treatment Options for Extrapyramidal Side E−ects 206

E−ects on Extrapyramidal Symptoms 210

Comparison of Agents for Treating AcuteExtrapyramidal Side E−ects 211

Doses and Pharmacokinetics of Agents for TreatingAcute Extrapyramidal Side E−ects 213

Anxiolytic (Antianxiety) Agents 216

Benzodiazepines 216

Comparison of the Benzodiazepines 225

Buspirone 230

Hypnotics/Sedatives 234

Comparison of Hypnotics/Sedatives 240

Mood Stabilizers 247

Lithium 247

Anticonvulsants 255

Comparison of Anticonvulsants 270

Frequency of Adverse Reactions to Mood Stabilizersat Therapeutic Doses 279

Drugs/Substances of Abuse 282

Alcohol 285

Stimulants 289

Hallucinogens 294

Opioids 301

Inhalants/Aerosols 305

Sodium Oxybate (Gamma-Hydroxybutyrate – GHB) 306

Flunitrazepam (Rohypnol) 308

Nicotine/Tobacco 309

Treatment of Substance Use Disorders 313

Disulšram 313

Acamprosate 316

Naltrexone 318

Methadone 321

Buprenorphine 325

Pharmacotherapy for Nicotine/Tobacco UseDependence 329

Unapproved Treatments of Psychiatric Disorders 335

Adrenergic Agents 335

Cholinergic Agents 336

Dopaminergic Agents 337

GABA Agents/Anticonvulsants 338

Miscellaneous 339

NMDA Agents 339

Natural Health Products 341

Glossary 349

Drug Use in Pregnancy and E−ects on Breast Milk 353

Patient and Caregiver Information Sheets 354

Index of Drugs 355

Clinical Handbook of Psychotropic Drugs for Children and Adolescents, 3rd edition, © 2015 Hogrefe Publishing 2

PSYCHIATRIC DISORDERS IN CHILDREN AND ADOLESCENTSSignišcant psychiatric illnesses a−ect approximately 10–15% of North American children and adolescents. These consist of conditions such as mood and anxiety disorders, bipolardisorder, attention-dešcit/hyperactivity disorder (ADHD), schizophrenia, Tourette’s disorder, and autism spectrum disorder. Symptoms of these disorders are often serious andhave an enormous impact on the lives of the patients and their families. Many factors complicate the recognition, management, and treatment of psychiatric disorders in childrenand adolescents. These include a high variance in symptom presentation and interpretation, diagnostic di³culties, scarcity of resources, research limitations, environmentalin¦uences, societal attitudes, and medication issues. In a signišcant change, DSM-5 (released 2013)[1] removed the category of disorders usually šrst diagnosed in infancy,childhood, or adolescence. Where applicable, diagnostic considerations specišc to presentation of a disorder in infancy, childhood, or adolescence are included with each disorder.This chapter covers the following diagnoses:• Anxiety disorders

– Generalized anxiety disorder (GAD) (p. 10)– Panic disorder (p. 11)– Separation anxiety disorder (p. 9)– Social anxiety disorder (p. 10)– Specišc phobia (p. 12)

• Attention-dešcit/hyperactivity disorder (ADHD) (p. 2)• Autism spectrum disorder (ASD) (p. 16)• Bipolar disorder (BD) (p. 6)• Disruptive, impulse-control, and conduct disorders

– Conduct disorder (CD) (p. 17)– Oppositional dešant disorder (ODD) (p. 18)

• Disruptive Mood Dysregulation Disorder (DMDD) (p. 5)• Major Depressive Disorder (MDD) (p. 3)• Obsessive-compulsive disorder (OCD) (p. 13)• Posttraumatic stress disorder (PTSD) (p. 14)• Schizophrenia (p. 7)• Tourette’s disorder (p. 15)

Attention-Dešcit/Hyperactivity Disorder (ADHD)

ADHD is a heterogeneous behavioral disorder šrst evident in children before the age of 12

Prevalence • There is no evidence to suggest that ADHD prevalence is increasing when standardized diagnostic procedures are followed[2]

• 3–7% (4–12% in the USA)

Onset • Symptoms begin as early as age 3; several inattentive or hyperactive-impulsive symptoms must be present by age 12

• 3–6 times more common in male than female children (but may be underreported in females); some individuals with inattentive presentation maymask symptoms by being quiet

Risk Factors • Genetic link suggested• Complications during pregnancy or delivery• Adverse family environment

Comorbidity • Mood and anxiety disorders, bipolar disorder, Tourette’s disorder, conduct disorder, oppositional dešant disorder, learning disorders, substance-related disorders

• Rule out vision and learning dešcits, developmental delays, neurological abnormalities, endocrine disorders, sleep disorders, anxiety disorders

Presentation & Symptoms• Presentations include: (1) predominantly inattentive (2) predominantly hyperactive-impulsive (3) combined presentation – most common; presen-

tation may change over time• Inattentive symptoms: poor attention to detail, trouble holding attention, trouble listening, trouble following instructions, trouble organizing tasks,

avoids tasks requiring mental e−ort, often loses necessary items, easily distracted, often forgetful• Hyperactive-impulsive symptoms: šdgets, trouble staying seated, runs or climbs inappropriately, unable to participate quietly, always “on the go,”

talks excessively, blurts out answers, trouble waiting his/her turn, often intrudes on others

Diagnosis• Up to age 16: six or more inattentive or hyperactive-impulsive symptoms• Age 17 and up: šve or more inattentive or hyperactive-impulsive symptoms• Symptoms must cause impairment in social, academic, or occupational functioning

Course of Illness• Hyperactive-impulsive behaviors tend to diminish as the person ages; inattention and restlessness often continue• About 70% of children who are diagnosed with ADHD continue to have some symptoms in mid-adolescence and for about 40% this continues into

adulthood

Consequences of ADHD • Can result in poor academic performance, self-esteem, social and interpersonal relationships• High risk of injuries (4 times that of non-a−ected individuals) and 50% more likely to have a motor vehicle accident than non-a−ected individuals[3]

• If inadequately treated, these children and adolescents are at increased risk for abusing substances (50% vs. 30% in non-a−ected individuals) anddeveloping antisocial personality disorder

• Educational and employment di³culties, problems with driving and with sexual relationships• Risk of teen pregnancy is 50% (vs. 4% in non-a−ected individuals)• 20% risk of incarceration (vs. 1% in non-a−ected individuals)• Minor involuntary movements (tics) occur in 8–11% of school-age children with ADHD

Treatment • Treatment did not a−ect prognosis in a large longitudinal study (MTA)[4], so collaborative, multimodal approaches, including psychoeducation,pharmacotherapy (stimulants, atomoxetine, α2 agonists, selected antidepressants), and behavioral interventions are recommended and ongoingmonitoring is necessary

• See chapters on Drugs for ADHD (pp. 22–41) and Antidepressants (pp. 44–109)

Major Depressive Disorder (MDD)

Major depressive disorder is a mood disorder with signišcant physical and mental symptoms that causes signišcant impairment in a child’s functioning

Prevalence • Preschoolers: rare• Children: 1–2%; males = females

Clinical Handbook of Psychotropic Drugs for Children and Adolescents, 3rd edition, © 2015 Hogrefe Publishing Psychiatric Disorders inChildren and Adolescents

3


Comparison of Drugs for ADHD

Methylphenidate Dexmethylphenidate Dextroamphetamine/Amphetamine Salts/

Methamphetamine/Lisdexamfetamine

Atomoxetine

Pharmacology Selectively inhibits presynaptic transporters

(i.e., reuptake) for DA and NE – dependent on

normal neuronal activity

Increases levels of synaptic DA and NE

Selectively inhibits presynaptic

transporters (i.e., reuptake) for DA

and NE – dependent on normal

neuronal activity

Increases levels of synaptic DA and NE

Cause release of DA, NE, and 5-HT into the

synapse – occurs independently of normal

neuronal activity

Inhibit MAO enzymes (high doses)

Selectively blocks reuptake of NE; increases

NE and DA in frontal cortex

Dosing

ADHD Start with 2.5–5 mg bid and increase by

2.5–5 mg weekly

Usual dose: 10–60 mg/day or

0.25–1 mg/kg/day body weight (divided

doses); up to 3 mg/kg/day has been used in

children

Extended-release: 18–20 mg q a.m.; can in-

crease by 18–20 mg weekly to a maximum of

72 mg/day (some references support a maxi-

mum of 90 mg daily in adolescents)

Transdermal patch: Week 1, apply 27.5 mg

patch (for 9 h/day); increase dose in weekly

intervals as necessary

Over age 6: Start with 2.5 mg bid and

can increase weekly in 2.5–5 mg

increments to a maximum of

20 mg/day (divided dose, given at

least q 4 h)

Usual dose: 5–20 mg daily divided bid

When switching from

methylphenidate, the starting dose of

dexmethylphenidate should be half

that of methylphenidate

Dextroamphetamine: Age 3–5: Start with

2.5 mg and increase by 2.5 mg weekly. Over

age 6: Start with 5 mg and increase by 5 mg

weekly. Usual dose: Dextroamphetamine:

2.5–40 mg/day or 0.1–0.8 mg/kg (divided

doses); Spansules can be opened and

sprinkled on food

Adderall: 2.5–5 mg to start and increase by

2.5–5 mg every 3–7 days up to 30 mg/day

(given every 4–7 h). In adults up to 40 mg/day

(in divided doses)

Adderall XR: 10–30 mg q a.m.

Methamphetamine: Start with 5 mg daily bid

and increase by 5 mg/week. Usual dose:

20–25 mg/day – in divided doses; Gradumet

given once daily

Lisdexamfetamine: Children and adolescents:

start with 20–30 mg q a.m. and can increase

by 10–20 mg increments in 7-day intervals to a

maximum of 60 mg/day (Canada) or

70 mg/day (USA)

Dosing is based on body weight

Children: Up to 70 kg: Canadian labeling:

Initiate at 0.5 mg/kg/day, and increase after

a minimum of 7–14 days to 0.8 mg/kg/day

for 7–14 days; if clinical response is not

achieved, increase to a target dose of

1.2 mg/kg/day, given once daily or in

divided doses bid in the morning and late

afternoon. Do not exceed 1.4 mg/kg or

100 mg/day, whichever is less.

US labeling: Initiate at 0.5 mg/kg/day and

increase to 1.2 mg/kg/day after 3 days

(differs from Canadian labeling)

Over 70 kg: Canadian labeling: Initiate at

40 mg/day and increase after a minimum of

7–14 days to 60 mg/day for 7–14 days; if

clinical response is not achieved, increase to

a target dose of 80 mg/day, given once daily

or divided bid in the morning and later

afternoon. If response is inadequate after

2–4 weeks, the dose can be increased to a

maximum of 100 mg/day

US labeling: Initiate at 40 mg/day and

increase to 80 mg/day after minimum of

3 days. May increase to a maximum of

100 mg/day in 2–4 additional weeks

Adults: See dosing over 70 kg, above

Depression 10–30 mg/day – Dextroamphetamine: 5–60 mg/day –

Narcolepsy 10–60 mg/day (usual dose: 10 mg 2–3

times/day)

– Dextroamphetamine: 5–60 mg/day –

Augmentation Strategies in ADHD

Nonresponse in ADHD • Ascertain whether diagnosis is correct• Ascertain if patient is compliant with therapy (speak with caregivers, check with pharmacy for late rešlls)• Ensure dosage prescribed is therapeutic and attempt to have peak serum levels occur at those times of the day that symptoms are most prominent• Consider trying a stimulant from an alternate class (methylphenidate or amphetamine) if the šrst trial was ine−ective and the patient was adhering

to therapy recommendations

Factors Complicating Response • Concurrent medical or psychiatric condition, e.g., bipolar disorder, conduct disorder, learning disability• Concurrent prescription drugs may interfere with e³cacy, e.g., antipsychotics (see Drug Interactions pp. 29–30, 33, 40)• Metabolic inducers (e.g., carbamazepine) may decrease the plasma level of methylphenidate• High intake of acidifying agents (e.g., fruit juices, vitamin C) may decrease the e³cacy of amphetamine preparations• Substance use, including alcohol and marijuana, may make management di³cult; need to discontinue substance use to optimize treatment

outcomes• Side e−ects to medication• Psychosocial factors may a−ect response; nonpharmacological treatment approaches (e.g., behavior modišcation, psychotherapy, and education)

can increase the probability of response

Augmentation Strategies

Methylphenidate/

Dexmethylphenidate/

Dextroamphetamine + α2

agonist

• Additive e−ect on hyperactivity, aggression, mood lability, and sleep problems; studies indicate e³cacy in 50–80% of patients. Has been found help-ful in patients with concomitant tic disorders, conduct disorder or oppositional dešant disorder [monitor ECG, heart rate, and blood pressure withcombination]

• Kapvay (clonidine XR) and Intuniv (guanfacine XR) are approved for adjunctive use with stimulant medications

Psychostimulants +

Antidepressants

• Tricyclics (imipramine, nortriptyline, and desipramine) useful in refractory patients or those with concomitant enuresis or bulimia; they may reduceabnormal movements in patients with tic disorders. There is an increase in the incidence of adverse e−ects, including cardiovascular, GI, anticholin-ergic e−ects, and weight gain; use caution and limit quantities prescribed in patients at risk of overdose

• SSRIs or venlafaxine may be e−ective in adult patients with concomitant mood or anxiety disorders (e.g., PTSD)• Bupropion used to augment e−ects of psychostimulants and in patients with concomitant mood disorder, substance use disorder, or conduct

disorder. May cause dermatological reactions, exacerbate tics, and increase seizure risk

Psychostimulants +

Atomoxetine

• Use in patients who have partial relief of symptoms with maximally tolerated doses of stimulants alone. The combination may permit lowerstimulant doses and allows robust coverage as well as coverage early and late in the day and in the summer

• Monitor for increased blood pressure, tachycardia, and weight loss

Psychostimulants +

Antipsychotics

• Second-generation antipsychotics (low doses of risperidone, aripiprazole or quetiapine) may be useful in patients with comorbid symptoms ofdyscontrol, aggression, hyperactivity, and tics. Ensure appropriate metabolic monitoring of antipsychotic therapy completed and discontinue an-tipsychotic treatment if excessive BP, weight, cholesterol, triglyceride or glucose tolerance occur

• Low doses of haloperidol, risperidone, and pimozide have been used in patients with concurrent Tourette’s disorder

Psychostimulants + Mood

Stabilizers

• Combination used in patients with comorbid bipolar disorder, conduct disorder, impulsivity, and aggression; infrequent case reports in childreninclude the use of lithium, carbamazepine , and valproate – the possibility of drug interactions should be considered (see Drug Interactions pp. 29–30); limited likelihood of benešt

Psychostimulants + Buspirone • Open studies suggest buspirone may improve rage attacks, impulsivity, inattention, and disruptive behavior at doses of 15–30 mg daily

Clinical Handbook of Psychotropic Drugs for Children and Adolescents, 3rd edition, © 2015 Hogrefe Publishing Drugs for ADHD41


ANTIDEPRESSANTSClassification • Antidepressants can be classišed as follows:

Pharmacological Class Examples Page

Cyclic Antidepressants (A)

Selective Serotonin Reuptake Inhibitors (SSRI) Citalopram, fluoxetine, paroxetine, fluvoxamine, sertraline See p. 45

Norepinephrine Dopamine Reuptake Inhibitor (NDRI) Bupropion See p. 58

Selective Serotonin-Norepinephrine Reuptake Inhibitor (SNRI) Venlafaxine, duloxetine See p. 63

Serotonin-2 Antagonists/Serotonin Reuptake Inhibitors (SARI) Trazodone See p. 69

Serotonin-1A Agonist/Serotonin Reuptake Inhibitor Vilazodone See p. 74

Noradrenergic/Specific Serotonergic Agent (NaSSA) Mirtazapine See p. 76

Nonselective Cyclic Agents (Mixed Reuptake Inhibitor/Receptor Blockers) Desipramine, amitriptyline, nortriptyline, imipramine See p. 81

Monoamine Oxidase Inhibitors

Reversible MAO-A Inhibitor (RIMA) Moclobemide See p. 89

Irreversible MAO (A&B) Inhibitors (MAOIs) Phenelzine, tranylcypromine See p. 92

(A) Cyclic antidepressants are currently classified on the basis of their specificity on the reuptake of brain neurotransmitters. This specificity confers a pharmacologic profile on the drugs that determines their spectrum of activity and adverse effects (see table p. 98).

General Comments• Some antidepressants are associated with restlessness or psychomotor agitation prior to seeing any change in core symptoms of depression.

Antidepressants are also associated with a small (2–3%) risk of hostility or suicidal ideation and associated behaviors in children, adolescents, andyoung adults (aged up to 24 years). Risk for suicide should be closely assessed and monitored during the initial weeks of antidepressant therapyIn patients with major depression and a high risk of suicide, treatment selection should consider safety in overdose (i.e., consider using newerantidepressant agents rather than nonselective cyclic and MAOI antidepressants) and close monitoring

• Two recent studies examining previously published RCTs of ¦uoxetine and venlafaxine have shed some doubt on the validity of some of the blackbox warnings issued on antidepressants in 2004–2006 for risks of increasing suicidal ideation.[1, 2] Hence, there still appears to be some uncertainty,despite a well conducted meta-analysis and review by the FDA

• Use of antidepressants in children with bipolar disorder (with mixed features) reported to cause increased cycling (in 79%), increased aggression(71%), and increased psychotic symptoms (23%) when not using a mood stabilizer

• Though some randomized double-blind, controlled trials and systematic reviews suggest otherwise, on average, all antidepressants are equallye³cacious at reducing symptoms of depression. Overall e−ects of antidepressants are modest when the e−ects of publication bias are considered.Compared to placebo, the overall e−ect size of treatment is reported as being 0.31

[3]

• On the basis of some RCTs[4] and the TADS trial[5, 6] it has been suggested that ¦uoxetine may o−er a more favorable benešt-to-risk ratio in pediatricdepression, despite the fact that only some of the clinician-rated measures indicated a di−erence favoring ¦uoxetine

• A meta-analysis of “new generation” antidepressants found escitalopram and sertraline to have better e³cacy or acceptability for treating MDD inadults[7]

• Di−erent antidepressant classes may be combined in patients with a partial response or in refractory cases; however, consideration of, and addi-tional monitoring for, the potential interactions such as serotonin syndrome is necessary

• Prophylaxis of depression is most e−ective if the therapeutic dose is maintained; continued therapy with all classes of antidepressants has beenshown to signišcantly reduce risk of relapse

• Epidemiological studies of various designs have reported that antidepressant prescribing has declined following the 2004 increased suicidalitywarnings, however, other studies examining prescribing data from 1998 to 2007 suggest that prescription rates of antidepressants have notdecreased despite the warnings[8]

• The Treatment of Adolescent Suicide Attempters study, examined SSRI treatment, cognitive-behavioral therapy (CBT) plus suicide prevention, ora combination in 124 adolescents with moderate to severe depressive symptoms who had previously attempted suicide. After six months oftreatment, 22% taking an SSRI had a suicide-related event compared with 6.7% not on a SSRI[9]

• Tolerance (tachyphylaxis or “poop-out” syndrome) has been reported in 10–20% of patients on various antidepressants, despite adherence totherapy. Possible explanations include adaptations in the CNS, increase in disease severity or pathogenesis, loss of placebo e−ect, unrecognizedrapid-cycling, incorrect diagnosis, comorbid substance use, anxiety disorders, ADHD or eating disorders. [Check compliance with therapy; dosageadjustment may help; switching to an alternate antidepressant (p.107) or augmentation strategies (p. 109) have also been tried]

• A 2013 systematic review in depressed and anxious youths taking antidepressants demonstrated that the overall rate of activation-related orarousal adverse events of treated youths was 3–10 times higher than for those assigned to placebo.[10] Given the connection suggested betweenthe arousal adverse events and potential for suicidality, this šnding supports recommendations for close monitoring for arousal, agitation, and riskfor suicidality when youths are prescribed antidepressants

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

Selective Serotonin Reuptake Inhibitors (SSRI)

Product Availability∗

Chemical Class Generic Name Trade Name(A) Dosage Forms and Strengths Monograph Statement

Phthalane derivative Citalopram Celexa Tablets/capsules: 10 mg, 20 mg, 30 mg(C), 40 mg

Oral disintegrating tablets(B): 10 mg, 20 mg, 40 mg

Oral solution(B): 10 mg/5 mL

Safety and efficacy not established in children and

adolescents under age 18

Escitalopram Lexapro(B), Cipralex(C) Tablets: 5 mg(B), 10 mg, 15 mg(C), 20 mg

Oral solution: 5 mg/5 mL(B)

Approved in the USA for children age 12 and above

Cipralex Meltz(C) Orodispersible tablets: 10 mg, 20 mg Safety and efficacy not established in children and


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

Clinical Handbook of Psychotropic Drugs for Children and Adolescents, 3rd edition, © 2015 Hogrefe Publishing Antidepressants45


Selective Serotonin Reuptake Inhibitors (SSRI) (cont.)Chemical Class Generic Name Trade Name(A) Dosage Forms and Strengths Monograph Statement

Bicyclic Fluoxetine Prozac, Sarafem(B) Capsules: 10 mg, 20 mg, 40 mg(B)

Tablets(B): 10 mg, 15 mg, 20 mg, 60 mg

Oral solution: 20 mg/5 mL


Prozac Weekly(B) Delayed-release pellets 90 mg Safety and efficacy not established in pediatric

patients under age 7 in obsessive-compulsive

disorder and under age 8 in major depressive disorder

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

fluoxetine 50 mg with 6 mg or 12 mg olanzapine


(safety and efficacy for acute treatment of depressive

episodes in bipolar I disorder established in patients

age 10–17 in a single 8-week randomized,

placebo-controlled clinical trial)

Monocyclic Fluvoxamine Luvox Tablets: 25 mg(B), 50 mg, 100 mg Approved in the USA for children age 8 and above

Luvox CR Extended-release capsules(B): 100mg, 150mg

Phenylpiperidine Paroxetine hydrochloride Paxil Tablets: 10 mg, 20 mg, 30 mg, 40 mg

Oral suspension(B): 10 mg/5 mL

Safety and efficacy not established in children and


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

Paroxetine mesylate(B) Pexeva Tablets(B): 10 mg, 20 mg, 30 mg, 40 mg

Tetrahydronaphthylmethylamine Sertraline Zoloft Capsules(C)/tablets(B): 25 mg, 50 mg, 100 mg, 150mg(B), 200mg(B)

Oral solution: 20 mg/mL(B)


(A) Generic preparations may be available, (B) Not marketed in Canada, (C) Not marketed in the USA

Indications‡

( approved)

In children and adolescents:Depression (age 8 and above: ¦uoxetine – USA; age 12 and above: escitalopram - USA)Bipolar depression (age 10 and above: ¦uoxetine/olanzapine combination - USA)Obsessive-compulsive disorder (OCD) (USA: sertraline – age 6 and above, ¦uoxetine – age 7 and above, ¦uvoxamine – age 8 and above) USA)

• No SSRIs are approved for use in children and adolescents in Canada• SSRIs have been used in the treatment of depression, dysthymia, social anxiety disorder, anxiety, panic disorder, bulimia, OCD, Tourette’s disorder,

and ADHD; preliminary data suggest e³cacy in some children with autism spectrum disorder and selective mutism

In adults:Major depressive disorder (MDD) (all – Canada; citalopram, escitalopram, ¦uoxetine, paroxetine, sertraline – USA)MDD, recurrent: ProphylaxisBulimia nervosa (¦uoxetine, sertraline)Obsessive-compulsive disorder (OCD) (¦uvoxamine, ¦uoxetine, paroxetine, escitalopram (Canada only), sertraline)Panic disorder with or without agoraphobia (paroxetine, sertraline, ¦uoxetine)Social anxiety disorder (paroxetine, sertraline)Posttraumatic stress disorder (PTSD) (paroxetine, sertraline)

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

Antipsychotic Doses and Pharmacokinetics (Oral and Short-Acting Injections)

SECOND-GENERATION AGENTS (SGAs)

Drug CPE

(mg)

Suggested Doses for Psychosis in

Children and Adolescents

Bioavaila-

bility

Protein

Binding

Peak

Plasma

Level (h)

(Tmax)

Elimination Half-Life (h) Metabolizing

Enzymes(1)/

Transporters

(CYP450; other)

Enzyme In-

hibition(2)/

Transporters

(CYP450;

other)

% D2 Receptor

Occupancy(3)

(dose &

plasma level)(4)

% 5-HT2A

Occu-

pancy

(dose)

Benzisoxazole

Iloperidone

(Fanapt)(B)

N/A No pediatric studies.

Adults:

Oral: 1 mg bid to start and increase daily

for 7 days to a target dose of 6 mg bid

96% ∼95% 2–4 18(K)–33(D) (parent)

26(K)–37(D) and

23(K)–31(D) (active

metabolites)

2D6(p), 3A4(p) 3A4(m) ? ?

Paliperidone

(active metabolite

of risperidone;

Invega)

Adolescents: 3 mg once daily (preferably

in AM)

If needed, increase by 3 mg q 5 days to a

maximum of 12 mg/day

28% 74% (to

albumin

and

α1-AGP)

24 23

In mild, moderate, and

severe renal

impairment: 24, 40, and

51, respectively

2D6(w), 3A4(w),

P-gp

(Minimally

metabolized,

under 7%)

P-gp(w) (at

high doses

in vitro)

66% (6 mg)

70−80%

predicted for

4.5−9 mg

?

Risperidone

(Risperdal,

Risperdal M-tab)

2–2.5 0.25 mg bid to start and increase

gradually

Suggested daily dose ranges:

Children: 1–2 mg

Adolescents: 2.5–4 mg

70% 88–90%

(parent; to

albumin

and

α1-AGP)

77% (active

metabo-

lite)

Reduced in

hepatic

disease

1–1.5

(parent)

3(K)–17(D)

(active

metabo-

lite)

3(K)–20(D) (parent)

21(K)–30(D) (active

metabolite)

Increased by ∼60% in

moderate to severe

renal disease

2D6(p), 3A4(m),

P-gp

2D6, 3A4(w) 60–75%

(2–4 mg)

63–85%

(2–6 mg;

36–252

nmol/L)

60–90%

(1–4 mg)

Benzisothiasol

Lurasidone

(Latuda(B))

? No pediatric studies

Adults:

40 mg once daily to start

Maximum: 80 mg once daily

Doses above 80 mg/day do not appear

to provide additional benefit

9−19% over 99.8%

(to

albumin

and

α1-AGP)

1−3 18−37 (parent) 7.5−10

(active metabolite)

3A4(p) – 63−79%

(40−80 mg)

?

Clinical Handbook of Psychotropic Drugs for Children and Adolescents, 3rd edition, © 2015 Hogrefe Publishing Antipsychotics181


Antipsychotic Doses and Pharmacokinetics (Oral and Short-Acting Injections) (cont.)SECOND-GENERATION AGENTS (SGAs)

Drug CPE

(mg)

Suggested Doses for Psychosis in

Children and Adolescents

Bioavaila-

bility

Protein

Binding

Peak

Plasma

Level (h)

(Tmax)

Elimination Half-Life (h) Metabolizing

Enzymes(1)/

Transporters

(CYP450; other)

Enzyme In-

hibition(2)/

Transporters

(CYP450;

other)

% D2 Receptor

Occupancy(3)

(dose &

plasma level)(4)

% 5-HT2A

Occu-

pancy

(dose)

Benzothiazolyl-

piperazine

Ziprasidone

(Geodon(B),

Zeldox(C))

40–80 Children and adolescents: 10–20 mg bid

to start. If needed, increase ≥ q 2 days

to a maximum of 80 mg bid

Adults: 20–40 mg bid(E) to start. If

needed, increase ≥ q 2 days.

Doses above 80 mg bid generally not

recommended

Oral: 30%

(60% with

food)

over 99%

(to

albumin

and

α1-AGP)

Oral: 6–8

(Cmax

increased

32–72% in

mild renal

impair-

ment)

Oral: 4–10

dose-dependent (6.6

mean)

No change in renal

disease

Prolonged in hepatic

disease (mean in

hepatic disease = 7.1 vs.

4.8 in control group)

3A4(m), 1A2(w),

2D6, 3C18/19;

Aldehyde

oxidase(w)

2D6(w),

3A4(w)

45–75%

(40–80 mg)

80–90%

(40–

80 mg)

Ziprasidone

mesylate

No pediatric studies

Adults:

Short-acting IM: 10 mg q 2 h or 20 mg

q 4 h to a maximum of 40 mg/24 h for

up to 3 days

Short-

acting IM:

100%

Short-

acting IM:

∼60 min

Short-acting IM: 2–5 h

(Caution in renal

disease due to excipient

– cyclodextrin)

Dibenzodiazepine

Clozapine

(Clozaril, FazaClo

ODT(B))

200–

250?

(CPE

un-

clear)

12.5 mg once daily to bid on day 1, then

increase as tolerated by 12.5–25 mg

increments every 3–5 days, to a target

dose of 125–475 mg/day (in divided

doses)

Suggested daily dose ranges:

Children: 125–350 mg

Adolescents: 225–475 mg

Prescribing restrictions:

First 6 months: Max. 1-week prescription

Months 7–12: If approved, max. 2-week

prescription

1 year onward: If approved, max. 4-week

prescription

(other countries may have less stringent

regulations)

90–95%

(40–60%

after 1st

pass

metabo-

lism)

95–97%

(to

α1-AGP)

1–6 (mean

2.5)

6–33 (mean 12; parent)

11–105 (active

metabolite)

Reduced in smokers

(20–40% shorter)

1A2(p), 2D6(w),

3A4(m), 2C9(w),

2C19(m), 2E1(w);

FMO;

UGT1A4;

P-gp(w)

1A2(w),

2D6(w), 3A4,

2C9(w),

2C19, 2E1(w)

38–68%

(300–900 mg;

600–

2500 nmol/L)(G)

85–94%

(over

125 mg)

Frequency of Adverse Reactions to Mood Stabilizers at Therapeutic Doses

Reaction Lithium Carbamazepine Oxcarbazepine Valproate Gabapentin Lamotrigine Topiramate

CNS

Drowsiness, sedation > 10%(a) > 10% > 10% > 10% > 10% > 10% > 10%(b)

Headache > 2% > 2% > 30% > 10% > 2% > 10% > 10%

Cognitive blunting, memory impairment > 10% > 2% > 2% > 2% < 2% > 2% > 2%(b)

Weakness, fatigue > 30%(a) > 10% > 10% > 10% > 10% > 2% > 10%

Insomnia, agitation < 2% < 2% > 2% > 2% > 2% > 2% > 10%

Neurological

Incoordination < 2%(a) > 10% > 2% > 2% < 2% > 2% > 2%

Dizziness – > 10% > 2% > 10% > 10% > 30% > 10%(b)

Ataxia < 2%(a) > 10% > 10% > 2% > 10% > 10% > 2%(b)

Tremor > 30%(a) > 30% > 2% > 10% > 2% > 2% > 2%

Paresthesias – > 2% > 2% > 2% < 2% < 2% > 10%

Diplopia – > 10% > 10% > 10% > 2% > 10% > 2%

Anticholinergic

Blurred vision > 2%(a) > 2% > 2% > 2% < 2% > 10% > 2%

Cardiovascular

ECG changes(c) > 10% > 2% < 2% > 2% – < 2% –

Gastrointestinal

Nausea, vomiting > 30% > 10% > 10% > 10% > 2% > 10% > 2%

Diarrhea > 10%(a) > 2% > 2% > 10% – > 2% > 2%

Weight gain > 30% > 2% > 2% > 30% > 10%(b) < 2% –

Weight loss < 2% < 2% < 2% > 2% < 2% > 2% > 10%(b)

Endocrine

Hair loss, thinning > 10% > 2% < 2% > 10% – – < 2%

Menstrual disturbances > 10% > 30% < 2% > 30% – > 2% –

Polycystic ovary syndrome – > 10% – > 30% – – –

Hypothyroidism > 30% < 2% – < 2% – < 2% –

Polyuria, polydipsia > 30% > 2% < 2% – – – –

Skin reactions, Rash > 10%(d) > 10%(e) > 2% > 2% < 2% > 10%(e) < 2%

Sexual dysfunction > 2% < 2% – > 2% < 2% – –

Blood dyscrasias

Transient leukopenia < 2% > 10% < 2% < 2% < 2% < 2% < 2%

Leukocytosis > 30% < 2% < 2% < 2% – – –

Thrombocytopenia – > 2% – > 30%(b) – < 2% –

Hepatic

Transient enzyme elevation(f) – > 10% < 2% > 30%(b) < 2% < 2% –

(a) Higher incidence and more pronounced symptoms with higher serum lithium concentration; may indicate early toxicity – monitor level (b) Greater with higher doses; (c) ECG abnormalities usually without cardiac injury, including ST segment depression,

flattened T waves, and increased U wave amplitude; (d) Worsening of psoriasis reported; (e) May be first sign of impending blood dyscrasia; (f) Evaluate for hepatotoxicity if transaminases elevated > 3 times upper limit of normal

Clinical Handbook of Psychotropic Drugs for Children and Adolescents, 3rd edition, © 2015 Hogrefe Publishing Mood Stabilizers279

3CLINICAL HANDBOOK OF

Psychotropic Drugs

This book is designed to fill a need for a com-prehensive but compact and easy-to-use reference for all mental health professio nals dealing with children and adolescents. This new edition of the widely praised Clinical Handbook summarizes the latest information from the published literature (monograph statements, scientific data, controlled clinical trials, case reports) and clinical experience in compact and easy-to-use charts and bulleted lists for each class of psychotropic drugs used in children and adolescents.

The Clinical Handbook includes for each class of drugs:

Monograph statements on use in children and adolescents

Approved indications in children and adolescents

Off-label indications Findings from open and double-blind studies

Product availability, dosing, pharmacokinetics, adverse effects, precautions, interactions, and other considerations relevant to these age groups.

This 3rd completely revised and expanded edition of the highly acclaimed psychotropic drug reference for all health care professionals dealing with children and adolescents is now more user friendly than ever:

Updated information on psychiatric disorders in children and adolescents (including DSM-V changes)

Packed with unique comparison charts (dosages, side effects, pharmacokinetics, interactions…) that allow you to see at a glance which medication is the most suitable for each patient

Now in full color throughout and with instantly recognizable icons that allow you to find at a glance all the information you seek:

– General information on medications, availability, and indications

– Drug action, dosing, pharmacokinetics, and related areas

– Warnings and precautions

– Patient-related information, such as lab monitoring recommendations, nursing implications, and patient advice

Patient and Caregiver Information Sheets provided as printable pdf files

“A ‘must-have’ for those prescribing psychotropic medications in children and adolescents. It remains by far the most user-friendly and comprehensive handbook available for prescribers, teachers, students, and others working or interested in the field of child and adolescent psychopharmacology.”

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“If you see children who are placed on psychotropic medications, this books clearly falls into your ‘must-have’ category.”

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“Provides the busy clinician with all the information that is essential for those prescribing a psychotropic drug to a child or adolescent....Very ‘user friendly’... Highly recommended to all clinicians that specialize in treating children and adolescents.”

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“The main strength of this book is its ability to summarize a large amount of information and make it immediately available at one’s fingertips. The clinician needing facts and needing them fast will enjoy the handbook.”

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“Authoritatively and exhaustively compiles currently available infor-

mation in a user-friendly form. The aim of the Handbook is to be a source

of ‘fast facts’ for the busy clinician...an aim it achieves splendidly.”

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“Well-researched... An essential reference book [that] all professionals should have... Full of indispensable information and data in a sequenced and logical design.”

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“A useful guide for busy clinicians and one that puts pharmacotherapy

for child and adolescent psychiatry in context.”

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“Well organized... Excellent patient and caregiver information sheets...

Factual information is concisely displayed in tables that educators will

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From the reviews of the previous editions:

ISBN: 978-0-88937-456-0

9 780889 374560

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Now also available: The Clinical Handbook of Psychtropic Drugs for Children and Adolescents ONLINE. For details, see http://chpd.hogrefe.com/

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