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Pharmacotherapy of
Child and Adolescent
Psychiatric Disorders
EDITED BY

David R. Rosenberg MD
Miriam L. Hamburger Endowed Chair of Child Psychiatry and Professor & Chief of Child
Psychiatry and Psychology at Wayne State University and the Children’s Hospital of Michigan,
Detroit, MI, USA

Samuel Gershon MD
Emeritus Professor of Psychiatry, University of Pittsburgh, PA, USA

THIRD EDITION

FOREWORD BY NEAL RYAN MD

A John Wiley & Sons, Ltd., Publication

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This edition first published 2012 © 2012 by John Wiley & Sons, Ltd.
Wiley-Blackwell is an imprint of John Wiley & Sons, formed by the merger of Wiley’s global Scientific,
Technical and Medical business with Blackwell Publishing.
Registered office: John Wiley & Sons, Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK
Editorial offices: 9600 Garsington Road, Oxford, OX4 2DQ, UK
The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK
111 River Street, Hoboken, NJ 07030-5774, USA
For details of our global editorial offices, for customer services and for information about how to apply for
permission to reuse the copyright material in this book please see our website at
www.wiley.com/wiley-blackwell
The right of the author to be identified as the author of this work has been asserted in accordance with the
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All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted,
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Library of Congress Cataloging-in-Publication Data

Pharmacotherapy of child and adolescent psychiatric disorders / [edited by] David Rosenberg and
Samuel Gershon. – 3rd ed.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-0-470-97376-9 (cloth)
I. Rosenberg, David R. II. Gershon, Samuel.
[DNLM: 1. Psychotropic Drugs–therapeutic use. 2. Adolescent. 3. Child. 4. Mental Disorders–drug
therapy. 5. Psychotropic
Drugs–pharmacology. QV 77.2]
LC classification not assigned
618.92 8918–dc23
2011029295
A catalogue record for this book is available from the British Library.
This book is published in the following electronic formats: ePDF 9781119958321;
Wiley Online Library 9781119958338; ePub 9781119961000; Mobi 9781119961017
Set in 9.5/13pt Meridien by Aptara Inc., New Delhi, India
First Impression 2012
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To J, Isa, the Henster and Foo—the reasons I smile inside and out.

David R. Rosenberg
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Contents

List of Contributors, xv
Foreword, xix

Chapter 1 Historical Perspectives on Child and Adolescent

Psychopharmacology, 1
Samuel Gershon
References, 4

Chapter 2 Pharmacoepidemiology of Psychotropic

Medications in Youth, 7
Daniel J. Safer & Julie Magno Zito
Introduction, 7
Prevalence and trends for medications prescribed for ADHD, 8
Nonstimulant medications for ADHD, 11
Antidepressant medication, 11
Antipsychotic medication, 13
Alpha-agonists, 14
Anticonvulsant “mood stabilizers”, 15
Concomitant psychotropic medication, 15
Preschool psychotropic medication use, 17
International patterns of psychotropic medication for youth, 17
Conclusion, 18
References, 18

Chapter 3 Off-Label Prescribing of Drugs in Child and

Adolescent Psychiatry, 25
C. Lindsay DeVane
Introduction, 25
Extent of off-label prescribing, 27

vii
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viii Contents

Need for psychoactive drug treatments for children and

adolescents, 31
Legislation supporting pediatric drug development, 33
Recommendations to follow when considering off-label
prescribing, 35
References, 36

Chapter 4 The Use of Generic Drugs in Pediatric

Psychopharmacology, 39
Richard I. Shader & Christopher-Paul Milne
What is a generic drug?, 39
Why are we discussing generic drugs?, 39
Basic requirements for generic drugs, 40
The status of regulations regarding generic drugs and children, 41
Abbreviated new drug application (ANDA) requirements, 42
Pediatric assessments of adult drugs (history up to
current status), 43
Best Pharmaceuticals for Children Act, 44
Pediatric Research Equity Act, 45
Intersection of requirements for generics and pediatric
assessment, 46
Future directions, 48
Concluding thoughts, 49
References, 49

Chapter 5 Psychoactive Drug Use in Children: Basic Concepts

in Clinical Pharmacology, 51
David J. Edwards
Introduction, 51
Basic concepts in pharmacokinetics, 52
Dosing considerations for psychoactive drugs in children, 55
Summary, 60
References, 60

Chapter 6 Psychostimulants, 65
Steven R. Pliszka
Introduction, 65
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Contents ix

Epidemiology of stimulant use, 66

Structure and biochemical mechanism of action, 66
Neuroimaging studies of stimulant effects, 67
Studies of short-term efficacy, 72
Studies of long-term efficacy, 76
Clinical use, 79
Common side-effects, 84
Cardiovascular safety issues, 86
Growth suppression, 88
Substance use and diversion, 88
Comparison with nonstimulant treatment, 89
Treatment of comorbidity, 92
Pharmacogenetics, 93
Conclusions, 94
References, 94

Chapter 7 Tricyclic Antidepressants and Monoamine Oxidase

Inhibitors for the Treatment of Child and Adolescent
Psychiatric Disorders, 105
Charlotte M. Heleniak, Tejal Kaur, Kareem D. Ghalib & Moira A. Rynn
Tricyclic antidepressants (TCAs), 105
Drug interactions, contraindications, 116
Monoamine oxidase inhibitors (MAOIs), 117
General summary, 122
References, 123

Chapter 8 Selective Serotonin Reuptake Inhibitors

(SSRIs), 131
Dara Sakolsky & Boris Birmaher
Pharmacokinetics, 131
Initiation and titration, 133
Indications and efficacy, 134
Adverse effects, 146
Withdrawal, 149
References, 149
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x Contents

Chapter 9 Novel (Atypical) Antidepressants, 155

Heidi R. Bruty, Graham J. Emslie & Paul Croarkin
Novel (atypical) antidepressants, 155
General overview, 155
Bupropion, 157
Duloxetine, 162
Mirtazapine, 164
Trazodone, 166
Venlafaxine, 170
Desvenlafaxine, 173
Alternative treatments, 174
Summary, 175
References, 176

Chapter 10 Antipsychotic Agents, 181

Brieana M. Rowles, John L. Hertzer & Robert L. Findling
Introduction, 181
Chemical properties, 182
Typical antipsychotics, 183
Atypical antipsychotics, 186
Ethical issues: treatment of at-risk populations, 212
Conclusions, 213
References, 213

Chapter 11 Lithium, 221

Garrett M. Sparks & David A. Axelson
Introduction, 221
Pharmacology, 222
Potential mechanisms of action, 222
Evidence for the use of lithium in children and adolescents, 232
Dosing and drug monitoring, 239
Contraindications, precautions, and drug interactions, 242
Side-effects, 246
References, 250
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Contents xi

Chapter 12 Anticonvulsants Used in Child and Adolescent

Psychiatric Disorders, 261
Mani Pavuluri & Tushita Mayanil
Introduction, 261
Divalproex sodium, 261
Carbamazepine, 271
Oxcarbazepine, 275
Lamotrigine, 279
Gabapentin, 284
Topiramate, 285
Conclusion, 288
References, 288

Chapter 13 Anxiolytics, 301

Barbara J. Coffey & Amanda L. Zwilling
Chemical properties, 301
Indications, 305
Contraindications, 320
Adverse effects, 321
Overdose, 324
Abuse/dependence, 324
Drug interactions, 325
Available preparations and cost, 325
Initiation and maintenance of treatment, 325
Management of specific side-effects, 330
How to withdraw medication, 332
References, 332

Chapter 14 Adrenergic Agents in Child and Adolescent

Psychiatry, 341
Lawrence David Scahill
Clonidine and guanfacine, 341
Guanfacine, 349
Beta-blockers, 355
Acknowledgements, 361
References, 361
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xii Contents

Chapter 15 Atypical Psychopharmacologic Strategies, 365

Jess Shatkin & Aron Janssen
Opiate antagonists, 365
Memantine, 368
Riluzole, 369
Secretin, 371
Topiramate, 372
Herbal medications and dietary supplements, 373
Ginkgo (Ginkgo biloba), 375
Melatonin, 381
Omega-3 fatty acids, 383
St. John’s wort (Hypericum perforatum), 384
Valerian (Valeriana officinalis), 387
Conclusion, 388
References, 389

Chapter 16 Psychopharmacology in Preschool Children, 399

Mini Tandon & Joan Luby
Introduction, 399
Developmental considerations, 400
Rise in psychopharmacology use, 402
Psychotherapy before psychopharmacology, 403
When psychopharmacology may be considered as a first line:
pragmatic considerations, 404
Psychopharmacology in preschool disorders: administration and
monitoring, 404
Off-label prescribing: special considerations, 407
Use of psychotropics in specific disorders, 408
Summary, 415
References, 415

Chapter 17 Combination Pharmacotherapy for Psychiatric

Disorders in Children and Adolescents, 421
Gagan Joshi & Anna M. Georgiopoulos
Bipolar disorder, 422
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Contents xiii

Major depressive disorder, 429

Attention-deficit hyperactivity disorder, 431
Obsessive-compulsive disorder, 433
Tics and Tourette’s syndrome, 434
Pervasive developmental disorders, 434
Conclusion, 434
References, 435

Index, 439
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List of Contributors

David A. Axelson MD C. Lindsay DeVane PharmD

University of Pittsburgh School of Medicine Department of Psychiatry and Behavioral
Western Psychiatric Institute and Clinic Sciences
University of Pittsburgh Medical Center Medical University of South Carolina
3811 O’Hara St 173 Ashley Avenue
Pittsburgh, PA 15213 Children’s Research Institute, Room 405B
USA Charleston, SC 29425
USA
Boris Birmaher MD
University of Pittsburgh School of Medicine David J. Edwards PharmD
Western Psychiatric Institute and Clinic School of Pharmacy
University of Pittsburgh Medical Center University of Waterloo
Bellefield Towers, Room 605 200 University Avenue West
100 North Bellefield Avenue Waterloo
Pittsburgh, PA 15213 Ontario
USA Canada N2L 3G1

Heidi R. Bruty MD Graham J. Emslie MD

Department of Psychiatry Department of Psychiatry
University of Texas Southwestern University of Texas Southwestern Medical
Medical Center Center
5323 Harry Hines Blvd. 5323 Harry Hines Blvd.
Dallas, TX 75390-8589 Dallas, TX 75390-8589
USA USA

Robert L. Findling MD
Barbara J. Coffey MD, MS
Department of Psychiatry
New York University Langone School of
Case Western Reserve University
Medicine and Nathan Kline Institute for
10524 Euclid Avenue, Suite 1155A
Psychiatric Research
Cleveland, OH 44106
NYU Child Study Center
USA
577 First Avenue
New York, NY 10016 Anna M. Georgiopoulos MD
USA Department of Child and Adolescent
Psychiatry
Paul Croarkin DO
Massachusetts General Hospital
Department of Psychiatry
Yawkey 6900
University of Texas Southwestern
55 Fruit Street
Medical Center
Boston, MA 02114
5323 Harry Hines Blvd.
USA
Dallas, TX 75390-8589
USA

xv
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xvi List of Contributors

Samuel Gershon MD Joan Luby MD

University of Pittsburgh Washington University School of Medicine
Clinical Research Building Department of Psychiatry, Child Division
1120 N.W. 14th Street Early Emotional Development Program
Suite 1464 Campus Box 8134
Miami, FL 33136 660 S Euclid
USA St. Louis, MO 63110
USA
Kareem D. Ghalib MD
Department of Psychiatry Tushita Mayanil MD
Columbia University/New York State Pediatric Brain Research and Intervention
Psychiatric Institute Center
1051 Riverside Drive, Unit 74 University of Illinois at Chicago
New York, NY 10032 1747 West Roosevelt Street
USA Chicago, IL 60607
USA
Charlotte M. Heleniak BA
Department of Psychiatry Christopher-Paul Milne DVM,
Columbia University/New York State MPH, JD
Psychiatric Institute Center for the Study of Drug Development
1051 Riverside Drive, Unit 74 Department of Public Health and Community
New York, NY 10032 Medicine
USA Tufts University School of Medicine
75 Kneeland Street
John L. Hertzer MD Boston, MA 02111
Department of Psychiatry USA
Case Western Reserve University
10524 Euclid Avenue, Suite 1155A Mani Pavuluri MD, PhD
Cleveland, OH 44106 University of Illinois at Chicago
USA 1747 West Roosevelt Street
Chicago, IL 60607
Aron Janssen MD USA
NYU/Bellevue Department of Child and
Adolescent Psychiatry Steven R. Pliszka MD
577 1st Avenue Division of Child and Adolescent Psychiatry
New York, NY 10016 Department of Psychiatry
USA The University of Texas Health Center at
San Antonio
Gagan Joshi MD 7703 Floyd Curl Drive MC 7792
Department of Child and Adolescent San Antonio, TX 78229-3900
Psychiatry USA
Massachusetts General Hospital
Yawkey 6900 David R. Rosenberg MD
55 Fruit Street Department of Child Psychiatry and
Boston, MA 02114 Psychology
USA Wayne State University and the Children’s
Hospital of Michigan
Tejal Kaur MD 4201 Street Antoine Boulevard
Department of Psychiatry Detroit, MI 48201
Columbia University/New York State USA
Psychiatric Institute
1051 Riverside Drive, Unit 74
New York, NY 10032
USA
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List of Contributors xvii

Brieana M. Rowles MA Jess Shatkin MD

Department of Psychiatry New York University School of Medicine
Case Western Reserve University 577 First Avenue
10524 Euclid Avenue, Suite 1155A New York, NY 10016
Cleveland, OH 44106 USA
USA
Garrett M. Sparks MD
Moira A. Rynn MD Western Psychiatric Institute and Clinic
Department of Psychiatry University of Pittsburgh Medical Center
Columbia University/New York State 3811 O’Hara St
Psychiatric Institute Pittsburgh, PA 15213
1051 Riverside Drive, Unit 74 USA
New York, NY 10032
USA Mini Tandon DO
Washington University School of Medicine
Daniel J. Safer MD Department of Psychiatry, Child Division
Departments of Psychiatry and Pediatrics Early Emotional Development Program
Johns Hopkins University School of Medicine Campus Box 8134
6 Hadley Square North 660 S Euclid
Baltimore, MD 21218 St. Louis, MO 63110
USA USA

Dara Sakolsky MD, PhD Julie Magno Zito PhD

University of Pittsburgh School of Medicine Department of Pharmaceutical Health
Western Psychiatric Institute and Clinic Services Research and Department of
University of Pittsburgh Medical Center Psychiatry
Bellefield Towers, Room 515 School of Pharmacy and School of Medicine
100 North Bellefield Avenue University of Maryland, Baltimore
Pittsburgh, PA 15213 Baltimore, MD 21201
USA USA

Lawrence David Scahill MSN, PhD Amanda L. Zwilling BA

Yale Child Study Center Tics and Tourette’s Clinical and Research
230 S. Frontage Rd Program
New Haven, CT 06520 New York University Langone School of
USA Medicine
NYU Child Study Center
Richard I. Shader MD 577 First Avenue
The Center for the Study of Drug New York, NY 10016
Development USA
Tufts University School of Medicine,
Suite 1100
75 Kneeland Street
Boston, MA 02111
USA
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Foreword

It has been a decade since the publication of Pharmacotherapy for Child and
Adolescent Psychiatric Disorders, Second Edition, by David Rosenberg, Pablo
Davanzo and Samuel Gershon. New research over this decade has signifi-
cantly changed the pharmacological and psychotherapeutic approaches to
our most significant child psychiatric disorders. This new edition, there-
fore, has much that is new and important in our day-to-day clinical work.
Advanced psychopharmacology in children and adolescents is hampered
by the paucity of studies and the relatively limited information that each
separate study provides. Studies are expensive, research is difficult, and
children are more complex to study than adults. Therefore, most but not
all studies in youth address acute treatment in children with little comor-
bidity. Even in the most straightforward studies, we do not have the very
large sample sizes that would give us narrow confidence intervals and the
ability to ask meaningful questions about which subpopulations do best
with which treatments. We also have little data on the comparative effi-
cacy of treatments, even as first-line treatment of the acute disorder.
The questions that are more vexing and a larger part of our practice
are, however, questions about how to treat refractory disorders, how to
treat recurrent disorders, how to manage chronic medication use over
years, and the risks of potential rare but serious side-effects. Studying these
questions with adequate sample sizes is much harder and much more ex-
pensive. Guided by a few groundbreaking studies attempting to answer
this sort of question in youth over the past decade, we will, nevertheless,
frequently be forced to extrapolate from acute studies and from studies in
adults. Not perfect but, like in most of medicine, we choose between Scylla
and Charybdis. Most of us choose to extrapolate rather than nihilistically
refusing to offer potential treatment to the difficult comorbid refractory
youth that make up the majority of patients who come to us.
There has been remarkable progress in our field over the past decade.
Few areas have been as fertile and active as the study of bipolar disor-
der in youth. We now have well-specified studies examining where the
boundaries of this condition lie, testing the acute efficacy of a number of
treatments particularly atypical antipsychotics, and comparing efficacy
between different treatments. Research with antipsychotics in adults is

xix
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