FOURTH

EDITION

W
hen it comes to the use of psychotropic agents in pediatric pa-
tients, it is not merely a question of extrapolating data from adults
to children and adolescents; special consideration must be given
to the effects of the drug on developing bodies and brains.

Adolescent Psychopharmacology
That is what makes this fourth edition of the Clinical Manual of Child and

Clinical Manual of Child and

Clinical Manual of
Adolescent Psychopharmacology so essential. Updated to include a suc-
cinct yet thorough review of the most recent evidence-based information
and data-driven best treatment practices in child and adolescent psychia-
try, this new volume is organized by DSM-5-TR® diagnosis and offers an
exhaustive analysis of the use of drugs in nine disorder categories that
include depressive disorders, attention-deficit/hyperactivity disorder, au-
Child and Adolescent
Psychopharmacology
tism spectrum disorder, eating disorders, and early schizophrenia and psy-
chotic illnesses.

Each chapter includes comprehensive medication tables that allow easy

reference of dosing, side effects, and tips for management as well as key
points that summarize the most essential information for treating clinicians.

Whether they are clinical psychiatrists, medical students on psychiatry ro-

FOURTH EDITION
tation, advanced practice providers, or pediatricians, readers will benefit
from the depth of information in this indispensable desktop reference.

About the Editors

Molly McVoy, M.D., is an Associate Professor in Psychiatry in the Divi-
sion of Child and Adolescent Psychiatry Fellowship at University Hospitals/
Case Western Reserve University in Cleveland, Ohio.

Ekaterina Stepanova, M.D., Ph.D., is Chair of Child and Adolescent Psy-

chiatry at Virginia Commonwealth University in Richmond, Virginia.
McVoy
Robert L. Findling, M.D., M.B.A., is Chair of the Department of Psychia- Stepanova
try at Virginia Commonwealth University in Richmond, Virginia. Findling

Edited by
Molly McVoy, M.D.
Ekaterina Stepanova, M.D., Ph.D.
Robert L. Findling, M.D., M.B.A.
 Clinical Manual of
Child and Adolescent
Psychopharmacology
Fourth Edition
 Clinical Manual of
Child and Adolescent
Psychopharmacology
Fourth Edition

Edited by

Molly McVoy, M.D.

Ekaterina Stepanova, M.D., Ph.D.
Robert L. Findling, M.D., M.B.A.
Note: The authors have worked to ensure that all information in this book is accurate at the time
of publication and consistent with general psychiatric and medical standards, and that information
concerning drug dosages, schedules, and routes of administration is accurate at the time of
publication and consistent with standards set by the U.S. Food and Drug Administration and the
general medical community. As medical research and practice continue to advance, however,
therapeutic standards may change. Moreover, specific situations may require a specific therapeutic
response not included in this book. For these reasons and because human and mechanical errors
sometimes occur, we recommend that readers follow the advice of physicians directly involved in
their care or the care of a member of their family.
Books published by American Psychiatric Association Publishing represent the findings,
conclusions, and views of the individual authors and do not necessarily represent the policies and
opinions of American Psychiatric Association Publishing or the American Psychiatric Association.
If you wish to buy 50 or more copies of the same title, please go to www.appi.org/specialdiscounts
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ALL RIGHTS RESERVED
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Library of Congress Cataloging-in-Publication Data
Names: McVoy, Molly, editor. | Stepanova, Ekaterina (Psychiatrist), editor. | Findling, Robert L,
editor. | American Psychiatric Association Publishing, issuing body.
Title: Clinical manual of child and adolescent psychopharmacology / edited by Molly McVoy,
Ekaterina Stepanova, Robert L. Findling.
Description: Fourth edition. | Washington, DC : American Psychiatric Association Publishing,
[2024] | Includes bibliographical references and index.
Identifiers: LCCN 2023022897 (print) | LCCN 2023022898 (ebook) | ISBN 9781615374892
(paperback ; alk. paper) | ISBN 9781615374908 (ebook)
Subjects: MESH: Mental Disorders—drug therapy | Child | Psychopharmacology—methods |
Psychotropic Drugs—therapeutic use | Adolescent
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 Contents
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii
Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xix
Mina K. Dulcan, M.D.
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xxi
Molly McVoy, M.D., Ekaterina Stepanova, M.D., Ph.D., and
Robert L. Findling, M.D., M.B.A.

1 Developmental Aspects of Pediatric

Psychopharmacology. . . . . . . . . . . . . . . . . . . . . . . . 1
Chiara Davico, M.D., Daniele Marcotulli, M.D., Ph.D., and
Benedetto Vitiello, M.D.
Pharmacokinetics and Metabolism. . . . . . . . . . . . . . . . . . . . 2
Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Ethical Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Regulatory Aspects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

2 Attention-Deficit/Hyperactivity Disorder. . . . . . . . 33
Lauren Schumacher, M.D., and Laurence Greenhill, M.D.
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
Role of Nonstimulant Medication in the Treatment
of ADHD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Monitoring Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Choice of Medication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
3 Disruptive Behavior Disorders and
Aggression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
Ekaterina Stepanova, M.D, Ph.D., Solomon G. Zaraa, D.O., and
Peter S. Jensen, M.D.
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
Course and Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
Rationale and Justification for Psychopharmacological
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
Review of Treatment Studies . . . . . . . . . . . . . . . . . . . . . . 106
Safety Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
Practical Management Strategies . . . . . . . . . . . . . . . . . . . 128
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131

4 Anxiety Disorders . . . . . . . . . . . . . . . . . . . . . . . . . 147

Moira A. Rynn, M.D., Paula K. Yanes-Lukin, Ph.D., and
Pablo H. Goldberg, M.D.
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
Course and Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
Rationale and Justification for Psychopharmacological
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
Medications for Pediatric Anxiety Disorders: Review of
Treatment Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
Safety Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
Practical Management Strategies: Treatment
Approaches, Algorithms, and Guidelines . . . . . . . . . . . 184
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188

5 Major Depressive Disorder . . . . . . . . . . . . . . . . . 199

Boris Birmaher, M.D., and Manivel Rengasamy, M.D.
Assessment of Treatment Response . . . . . . . . . . . . . . . . 200
Treatment Phases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
Treatment of MDD With Selective Serotonin Reuptake
Inhibitors and Other Novel Antidepressants . . . . . . . . . 201
Treatment of Major Depressive Disorder Subtypes and
Bipolar Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216
 Treatment of Comorbid Conditions and Suicidality . . . . . . 223
Continuation Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224
Maintenance Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226

6 Bipolar Disorders . . . . . . . . . . . . . . . . . . . . . . . . . 245

Tiffany Thomas-Lakia, M.D., Baris Olten, M.D., and
Robert L. Findling, M.D., M.B.A.
Treatment of Acute Manic or Mixed States . . . . . . . . . . . . 246
Maintenance Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273
Treatment of Pediatric Bipolar Depression . . . . . . . . . . . . 274
Combination Pharmacotherapy . . . . . . . . . . . . . . . . . . . . 274
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276

7 Autism Spectrum Disorder . . . . . . . . . . . . . . . . . 283

Michelle L. Palumbo, M.D., Christopher J. Keary, M.D., and
Christopher J. McDougle, M.D.
Atypical Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . 285
Serotonin Reuptake Inhibitors. . . . . . . . . . . . . . . . . . . . . . 297
Psychostimulants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304
Other Drug Treatments for ADHD . . . . . . . . . . . . . . . . . . . 306
Mood Stabilizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310
Cholinesterase Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . 312
Glutamatergic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313
Other Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316
Safety Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320
Practical Management Strategies . . . . . . . . . . . . . . . . . . . 323

8 Tic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341

Lawrence Scahill, M.S.N., Ph.D., Sarah Lytle, M.D.,
Stephanie Pope, M.D., and Basim Mikhail, M.D.
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342
Diagnosis and Assessment . . . . . . . . . . . . . . . . . . . . . . . 344
Treatment of Tics in Children With Tourette’s Disorder . . . 346
Comorbid Illnesses With Tics or Tourette’s Disorder. . . . . 355
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365
 9 Early-Onset Schizophrenia and Psychotic
Illnesses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377
Ekaterina Stepanova, M.D., Ph.D., David I. Driver, M.D.,
Nitin Gogtay, M.D., and Judith L. Rapoport, M.D.
History and Classification of Psychosis in Children . . . . . 378
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379
Course and Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379
Rationale for Psychopharmacological Treatment . . . . . . . 380
Pharmacotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381
Treatment of Comorbid Conditions . . . . . . . . . . . . . . . . . . 402
Treatment of Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . 403
Early Intervention Studies. . . . . . . . . . . . . . . . . . . . . . . . . 415
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423

10 Eating Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . 441

Roxanne Demarest, P.A.-C., and Griffin Stout, M.D.
Anorexia Nervosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443
Bulimia Nervosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450
Binge-Eating Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . 455
Avoidant/Restrictive Food Intake Disorder . . . . . . . . . . . . 461
Pica. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 463
Rumination Disorder. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 466

Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479
 List of Tables
Table 1–1 Essential pharmacokinetics terminology. . . . . . . . . 3
Table 1–2 Selected compounds relevant to pediatric
pharmacotherapy that are metabolized by
cytochrome P450 (CYP) enzymes. . . . . . . . . . . . . . 5
Table 1–3 Pediatric indications approved by the FDA and
off-label use of selected psychotropic
medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Table 2–1 Stimulant medications used in the treatment
of ADHD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Table 2–2 Representative controlled studies of stimulant
medication for ADHD . . . . . . . . . . . . . . . . . . . . . . 46
Table 2–3 Nonstimulant medications approved by the
FDA for the treatment of ADHD . . . . . . . . . . . . . . . 76
Table 3–1 Selected agents prescribed for the treatment
of aggressive youth with disruptive behavior
disorders (DBDs) . . . . . . . . . . . . . . . . . . . . . . . . 109
Table 3–2 Common and serious side effects for various
classes of psychopharmacological agents . . . . 116
Table 4–1 Selected medications for pediatric anxiety
disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
Table 5–1 Definitions of treatment outcome . . . . . . . . . . . . 200
Table 5–2 Selected data on SSRIs and SNRIs in
pediatric MDD . . . . . . . . . . . . . . . . . . . . . . . . . . 203
Table 5–3 Dosages of antidepressants usually
administered to youth with MDD . . . . . . . . . . . . . 215
Table 6–1 FDA-recommended lithium dosing for bipolar I
disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248
Table 6–2 Management of common lithium side effects . . . 250
Table 6–3 Management of divalproex sodium–related
side effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258
Table 6–4 Management of aripiprazole side effects . . . . . . 263
Table 6–5 Management of olanzapine side effects . . . . . . . 265
Table 6–6 Management of quetiapine side effects . . . . . . . 267
Table 6–7 Management of risperidone side effects. . . . . . . 269
Table 6–8 Management of ziprasidone side effects . . . . . . 272
Table 7–1 Selected published double-blind, placebo-
controlled trials in ASD . . . . . . . . . . . . . . . . . . . . 286
Table 8–1 Dosing guidelines for antipsychotic drugs used
in the treatment of tics of moderate or greater
severity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348
Table 8–2 Randomized placebo-controlled trials (N>20)
focused on tic reduction using YGTSS Total
Tic score . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352
Table 8–3 Dosing guidelines for nonstimulant medications
used in the treatment of children with tics and
ADHD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360
Table 9–1 Select controlled trials of antipsychotics in
patients with COS or EOS . . . . . . . . . . . . . . . . . . 382
Table 9–2 Rates of extrapyramidal symptoms (EPS) in
select controlled studies of antipsychotics in
treatment of childhood-onset and/or early-onset
schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . 405
Table 9–3 Randomized trials of interventions for patients
at ultrahigh risk of developing psychosis . . . . . . 418
 List of Figures
Figure 7–1 A target symptom approach to the
pharmacotherapy of autism spectrum
disorder (ASD). . . . . . . . . . . . . . . . . . . . . . . . . . . 324
 Contributors

Boris Birmaher, M.D.

Distinguished Professor of Psychiatry, University of Pittsburgh Medical Cen-
ter, Pittsburgh, Pennsylvania

Chiara Davico, M.D.

Division of Child and Adolescent Neuropsychiatry, Department of Public
Health and Pediatrics, University of Turin, Turin, Italy

Roxanne Demarest, P.A.-C.

Physician Assistant, Nationwide Children’s Hospital, Columbus, Ohio

David I. Driver, M.D.

Child Psychiatry Branch, National Institute of Mental Health, National In-
stitutes of Health, Bethesda, Maryland

Mina K. Dulcan, M.D.

Pritzker Department of Psychiatry and Behavioral Health, Ann and Robert
H. Lurie Children’s Hospital of Chicago; Professor of Psychiatry and Behav-
ioral Sciences and Pediatrics, Northwestern University Feinberg School of
Medicine, Chicago, Illinois

Robert L. Findling, M.D., M.B.A.

Department of Psychiatry, Virginia Commonwealth University, Richmond,
Virginia

Nitin Gogtay, M.D.

Chief, Division of Research, and Deputy Medical Director, American Psychi-
atric Association, Washington. D.C.

xiii
xiv Clinical Manual of Child and Adolescent Psychopharmacology

Pablo H. Goldberg, M.D.

Associate Clinical Professor of Psychiatry, Columbia University Irving Medical
Center/NewYork-Presbyterian Morgan Stanley Children's Hospital, CUIMC/
Herbert Pardes Building of the New York State Psychiatric Institute, New York,
New York

Laurence Greenhill, M.D.

Professor of Psychiatry, Voluntary Faculty, University of California at San
Francisco, San Francisco, California

Peter S. Jensen, M.D.

Adjunct Professor, University of Arkansas for Medical Sciences, Little Rock,
Arkansas; Board Chair and Founder, The REACH Institute, New York, New
York

Christopher J. Keary, M.D.

Assistant Professor, Harvard Medical School, Boston, Massachusetts

Sarah Lytle, M.D.

Assistant Professor of Psychiatry, University Hospitals, Cleveland Medical
Center, Case Western Reserve University, Cleveland, Ohio

Daniele Marcotulli, M.D., Ph.D.

Division of Child and Adolescent Neuropsychiatry, Department of Public
Health and Pediatrics, University of Turin, Turin, Italy

Christopher J. McDougle, M.D.

Professor, Harvard Medical School, Boston, Massachusetts

Molly McVoy, M.D.

Associate Professor in Psychiatry, Division of Child and Adolescent Psychiatry
Fellowship, University Hospitals/Case Western Reserve University, Cleve-
land, Ohio

Basim Mikhail, M.D.

Consultant Psychiatrist, Al Minya, Egypt
 Contributors xv

Baris Olten, M.D.

Child and Adolescent Psychiatry Fellow, Akron Children’s Hospital, Akron,
Ohio

Michelle L. Palumbo, M.D.

Instructor, Harvard Medical School, Boston, Massachusetts

Stephanie Pope, M.D.

Assistant Professor, Case Western Reserve University School of Medicine,
Cleveland, Ohio

Judith L. Rapoport, M.D.

Child Psychiatry Branch, National Institute of Mental Health, National In-
stitutes of Health, Bethesda, Maryland

Manivel Rengasamy, Ph.D.

Assistant Professor, University of Pittsburgh, Pittsburgh, Pennsylvania

Moira A. Rynn, M.D.

Consulting Professor and Chair of the Department of Psychiatry and Behav-
ioral Sciences, Duke University School of Medicine, Durham, North Carolina

Lawrence Scahill, M.S.N., Ph.D.

Professor, Marcus Autism Center and Emory University, Atlanta, Georgia

Lauren Schumacher, M.D.

Assistant Clinical Professor, Division of Child and Adolescent Psychiatry, De-
partment of Psychiatry, University of California San Francisco, San Francisco,
California

Ekaterina Stepanova, M.D., Ph.D.

Chair, Child and Adolescent Psychiatry, Virginia Commonwealth University,
Richmond, Virginia
xvi Clinical Manual of Child and Adolescent Psychopharmacology

Griffin Stout, M.D.

Child and Adolescent Psychiatry Attending, Nationwide Children’s Hospital,
Columbus, Ohio

Tiffany Thomas-Lakia, M.D.

Child and Adolescent Psychiatrist, Akron Children’s Hospital, Akron, and Se-
nior Instructor, Case Western Reserve University School of Medicine, Cleve-
land, Ohio

Benedetto Vitiello, M.D.

Division of Child and Adolescent Neuropsychiatry, Department of Public
Health and Pediatrics, University of Turin, Turin, Italy; Department of Men-
tal Health, Johns Hopkins Bloomberg School of Public Health, Baltimore,
Maryland

Paula K. Yanes-Lukin, Ph.D.

Assistant Professor of Clinical Psychology in the Division of Child and Ado-
lescent Psychiatry at Columbia University Medical Center/New York State
Psychiatric Institute, New York, New York

Solomon G. Zaraa, D.O.

Director, Inpatient Psychiatric Services, University Hospitals Rainbow Babies
and Children’s Hospital; Assistant Professor, Psychiatry, Case Western Reserve
University School of Medicine, Cleveland, Ohio

Disclosures
The following contributors have indicated a financial interest in or other affilia-
tion with a commercial supporter, manufacturer of a commercial product, and/or
provider of a commercial service as listed below:

Boris Birmaher, M.D.

Salary: University of Pittsburgh, University of Pittsburgh Medical Center/
Western Psychiatric Institute and Clinic. Research funding: National Institute
of Mental Health. Royalties: Random House, Lippincott Williams & Wilkins,
Wolters Kluwer.
 Contributors xvii

Chiara Davico, M.D.

Consultant: Roche, Lundbeck Pharmaceuticals.

Robert L. Findling, M.D.

Research support, consultant, and/or honoraria: Acadia, Adamas, Aevi, Afecta,
Akili, Alkermes, Allergan, American Academy of Child and Adolescent Psychi-
atry, American Psychiatric Association Publishing, Arbor, Axsome, Daiichi-
Sankyo, Emelex, Gedeon Richter, Genentech, Idorsia, Intra-Cellular Therapies,
Kempharm, Luminopia, Lundbeck, MedAvante-ProPhase, Merck, MJH Life
Sciences, National Institutes of Health, Neurim, Otsuka, PaxMedica, PCORI,
Pfizer, Physicians Postgraduate Press, Q BioMed, Receptor Life Sciences, Roche,
Sage, Signant Health, Sunovion, Supernus Pharmaceuticals, Syneos, Syneurx,
Takeda, Teva, Tris, and Validus.

Laurence Greenhill, M.D.

Salary: Kaiser Permanente Medical Group. Honoraria and Travel Support: The
Klingenstein Third Generation Foundation Scientific Advisory Board.

Christopher J. Keary, M.D.

Advisory Board: Ovid Therapeutics, Biogen. Research funding: Ovid Thera-
peutics.

Daniele Marcotulli, M.D., Ph.D.

Consultant: Ethos, Ltd.

Christopher J. McDougle, M.D.

Consultant: Precidiag, Receptor Life Sciences, Sage Therapeutics, Acadia Phar-
maceuticals. Royalties: Oxford University Press, Springer Publishing.

Molly McVoy, M.D.

Research funding: The Hartwell Foundation, Allergan Pharmaceuticals, Na-
tional Institute of Mental Health, Case Western Reserve University. Salary:
Case Western Reserve University.

Michelle L. Palumbo, M.D.

Research funding: Otsuka Pharmaceutical Inc.
xviii Clinical Manual of Child and Adolescent Psychopharmacology

Moira A. Rynn, M.D.

Consultant: Allergan (DSMB), Abbvie (DSMB), Otsuka America Pharma-
ceutical, IngenioRx. Advisory Board: Allergan (DSMB), Abbvie (DSMB)

Ekaterina Stepanova, M.D., Ph.D.

Research support: Psychnostics, LLC and Supernus.

Benedetto Vitiello, M.D.

Consultant: Medice, Angelini, Menari Pharmaceuticals.

The following contributors stated that they had no competing interests during the
year preceding manuscript submission:

Roxanne Demarest, P.A.-C.; David I. Driver, M.D.; Nitin Gogtay, M.D.;

Pablo H. Goldberg, M.D.; Peter S. Jensen, M.D.; Sarah Lytle, M.D.; Baris
Olten, M.D.; Stephanie Pope, M.D.; Manivel Rengasamy, Ph.D.; Judith L.
Rapoport, M.D.; Lawrence Scahill, M.S.N., Ph.D.; Lauren Schumacher,
M.D.; Griffin Stout, M.D.; Tiffany Thomas-Lakia, M.D.; Paula K. Yanes-
Lukin, Ph.D.; Solomon G. Zaraa, D.O.
 Foreword

The most essential resource for anyone prescribing psychotropic medications

for children and adolescents is an up-to-date, efficient, accessible, and trust-
worthy reference book. We have that here in the fourth edition of the Clinical
Manual of Child and Adolescent Psychopharmacology. In the 5 years since the
publication of the third edition, there has been impressive growth in our knowl-
edge of using medications for emotions, cognition, and behavior in youth, and
it is all right here. Bob Findling, the senior editor, is both a pediatrician and a
child and adolescent psychiatrist, with broad and deep experience and expertise
in pediatric psychopharmacology research and clinical practice. He is joined in
this editorial effort by Drs. McVoy and Stepanova, and all are experienced child
and adolescent psychiatric clinicians and educators.
The chapters, organized by disorders and syndromes, retain the structure
of the previous edition, each written by acknowledged experts and thoroughly
updated in this new edition. Several new chapter coauthors have been added to
bring fresh perspectives. The clinical wisdom and experience of the authors
supplement the balanced presentation of the findings of research studies. Clin-
ical Pearls and summary tables in each chapter greatly enhance the value of this
book for busy clinicians who are seeking efficient guidance on evidence-based
treatments. How to select a medication and the practical management of side
effects are covered well, in addition to treatment recommendations that go be-
yond medications. I was delighted to discover that the references are in author-
date format rather than being numbered; this is a great help for readers like me
who want to know quickly who wrote what and when.

xix
xx Clinical Manual of Child and Adolescent Psychopharmacology

This book should be on the shelves (and in the hands) of trainees and cli-
nicians not only in child and adolescent psychiatry but also in pediatrics, be-
cause pediatric practitioners are increasingly expected to address patient mental
health issues, including psychopharmacology. Others who treat children, in-
cluding advanced practice nurses, physician assistants, and general psychia-
trists, will also benefit greatly. In addition, other mental health professionals
and those who direct programs serving children would benefit from the wis-
dom in this concise reference.

Mina K. Dulcan, M.D.

 Preface

The field of pediatric psychopharmacology is complex and constantly chang-

ing, with new studies being published regularly, leading to more and more
treatment options becoming available for the management of mental health
conditions. In light of the ever-increasing demand to deliver mental health
care, it can be difficult for busy providers to spend the additional time neces-
sary for navigating the vast variety of studies so they can stay current with
evidence-based treatment. For that specific reason, it remains our priority to
continue to provide clinicians with the most recent evidence-based informa-
tion and disseminate data-driven best treatment practices.
This fourth edition of the Clinical Manual of Child and Adolescent Psycho-
pharmacology is consistent with the structure of the previous edition, in which
each chapter describes treatment options for a particular diagnosis. All of the
chapters have been updated with the newest research in pediatric psychophar-
macology and not only provide a background for the medications discussed
but also focus on how to practically use these new data to inform treatment in
a clinical setting. Our goal was to make it easy for providers to find a compre-
hensive summary of evidence-based treatments. As in the previous editions,
leading clinician-scientists with extensive research and clinical experience con-
tributed to writing this book. One of the major changes from the previous edi-
tion is the addition of another editor, Ekaterina Stepanova, M.D., Ph.D., who
is an expert clinician and scientist in mood and disruptive behavior disorders.
She is a leader in the field, currently serving as director of child and adolescent
psychiatry at Virginia Commonwealth University School of Medicine.

xxi
xxii Clinical Manual of Child and Adolescent Psychopharmacology

Despite the constantly growing data in the field of child and adolescent
psychiatry, many providers continue to prescribe medications “off label.” Al-
though we acknowledge that there may be circumstances when this is neces-
sary, we encourage providers to look carefully at the most current evidence
available and to develop an appropriate treatment plan based on that evidence.
For that purpose, it is especially important to review the acute and longitudi-
nal trials as well as head-to-head comparisons of the medications. It is also vi-
tal to understand the methodology and the quality of these trials in order to
accurately interpret the results. In this edition, we have attempted not only to
provide comprehensive reviews of the evidence for treating mental health dis-
orders in children and adolescents but also to help readers understand the dif-
ference between methodological approaches among the various clinical trials.
We are living during exciting times when the knowledge of how to treat
psychiatric disorders in children and adolescents is expanding rapidly. Al-
though the growing research field helps bridge the gap in understanding the
treatment options, it can be daunting for providers to keep up with the pace of
change. It may be especially difficult to interpret trials that seem methodolog-
ically similar, yet yield different results. In this edition, we strive to help pro-
viders understand the best clinical practices and be able to interpret the results
of the clinical trials, all leading to providing better patient care.

Molly McVoy, M.D.

Ekaterina Stepanova, M.D., Ph.D.
Robert L. Findling, M.D., M.B.A.
 1
Developmental Aspects of
Pediatric Psychopharmacology
Chiara Davico, M.D.
Daniele Marcotulli, M.D., Ph.D.
Benedetto Vitiello, M.D.

P ediatric psychopharmacology is the science behind the therapeutic use of

psychotropic agents in youth. Clinicians prescribing psychotropics to children
and adolescents must be familiar with developmental psychopathology and
the interaction between medication and the developing organism, in addition
to the general principles of psychopharmacology. It is well recognized that
mere extrapolation to children of information acquired from adults is insuf-
ficient to guide rational pharmacotherapy. Differences in how the developing
organism affects the drug (pharmacokinetics), how the developing brain re-
acts to the drug (pharmacodynamics), and how psychopathology manifests
during development can have clinically important implications for both effi-

1
2 Clinical Manual of Child and Adolescent Psychopharmacology

cacy and safety. Over the years, progress in pediatric psychopharmacology re-
search has provided a foundation on which evidence-based pharmacotherapy
can be built. In addition, special ethical and legal considerations apply when
treating children for purposes of either clinical care or research.
In this chapter, we aim to describe the specific aspects of pediatric psycho-
pharmacology that make it a distinct discipline at the crossroads of child and
adolescent psychiatry, neurology, pediatrics, and pharmacology.

Pharmacokinetics and Metabolism

Pharmacokinetics determines the availability of a drug at the site of action and
thus directly influences the intensity and duration of the pharmacological ac-
tivity (Smits et al. 2022). The basic pharmacokinetic processes of absorption,
distribution, metabolism (biotransformation), and excretion are all influenced
by development (see Table 1–1 for essential terms). Because knowledge of a
drug’s pharmacokinetics is critical for identifying its therapeutic dosage range
and frequency of administration, pediatric pharmacokinetics studies should
precede and inform clinical trials aimed at testing the drug’s efficacy in children.
Children have smaller body sizes than adults but have a greater proportion
of liver and kidney parenchyma when adjustment for body weight is made.
Compared with adults, children also have relatively more body water, less fat,
and less plasma albumin to which drugs can bind. These structural character-
istics can result in a smaller volume of distribution for drugs, greater drug ex-
traction during the first pass through the liver following oral administration,
lower bioavailability, and faster metabolism and elimination. These differ-
ences mean that simply decreasing adult doses based on child weight may re-
sult in undertreatment. Adjusting by body surface area would control for both
weight and height, but this approach is usually reserved for drugs with a nar-
row therapeutic index, such as antineoplastics, and is seldom used in pediatric
psychopharmacology.
Adolescence is characterized by marked growth in body size and by redis-
tribution of body compartments. Differences between sexes become more
pronounced. In males, the percentage of total body water increases and that of
body fat decreases, whereas in females, the opposite occurs. These changes can
contribute to sex differences in pharmacokinetics. For example, higher serum
 Developmental Aspects of Pediatric Psychopharmacology 3

Table 1–1. Essential pharmacokinetics terminology

Term Definition

Absorption Process by which a drug is absorbed from the

site of administration into the systemic
circulation
Liver first-pass extraction Drug metabolism that occurs when a drug goes
through the liver soon after intestinal absorp-
tion, before reaching the systemic circulation
Bioavailability Proportion of administered drug that reaches
the systemic circulation
Area under the curve (AUC) Concentration of drug plasma as a function of
time
Metabolism (biotransformation) Phase I: cytochrome P450 (CYP)–mediated
oxidation; hydroxylation
Phase II: conjugation reactions
(glucuronidation, sulfation, acetylation)
Volume of distribution (Vd) Apparent volume in which the drug is distrib-
uted after absorption (Vd =dose absorbed/Cp)
Concentration in plasma (Cp) Drug quantity for unit of plasma
(Cp =dose absorbed/Vd)
Peak plasma concentration (Cmax) Highest plasma concentration
Time to Cmax (Tmax) Time it takes from drug administration to reach
Cmax
Clearance (plasma clearance [CL]) Volume of plasma completely cleared of the
drug in a unit of time; the cumulative result of
drug removal that occurs in the liver, kidney,
and other parts of the body (e.g., lungs, skin,
bile); CL=dose absorbed/AUC
Elimination half-life (t½) Time that it takes, after full drug absorption and
distribution in the body, for Cp to be reduced
by 50%; a function of CL and Vd
(t½ =0.693·Vd/CL)
Steady-state plasma concentration Stable Cp between doses that is achieved when
the rate of elimination equals the rate of
absorption; usually achieved after about four
half-lives during constant drug administration
4 Clinical Manual of Child and Adolescent Psychopharmacology

concentrations of risperidone have been found in males than in females (Ca-

large and Miller 2011). Faster metabolism in females may also account for this
difference.
Drug metabolism consists of biotransformations that turn the drug into
derivative products (metabolites) that are more polar and therefore more eas-
ily eliminated. Not all drugs undergo metabolism; lithium, for instance, is ex-
creted unchanged through the kidneys. Drug metabolism typically includes a
Phase I, during which medications undergo enzymatic oxidative or hydrolytic
transformations, and a Phase II, during which conjugates are formed between
the drug or its metabolites and glucuronic acid, sulfate, glutathione, or ace-
tate. The Phase I oxidative processes are mediated by cytochrome P450 (CYP)
microsomal enzymes, which are concentrated in the liver but present in small
quantities in other tissues as well.
The CYP system matures rapidly after birth (van Groen et al. 2021). For
instance, liver microsomes demonstrate only 1% of the adult CYP2D6 activ-
ity in the fetus, but this rate increases to about 20% of the adult activity by
1 month after birth. The immaturity of the CYP2D6 system at birth is one of
the possible explanations for the syndrome of irritability, tachypnea, tremors,
and increased muscle tone that has been observed in newborns of mothers tak-
ing selective serotonin reuptake inhibitors (SSRIs) (Chambers et al. 1996). An
alternative explanation is that the syndrome represents a withdrawal reaction
from the SSRI. In any case, the CYP metabolizing capacity is well developed
by age 3 years (van Groen et al. 2021). Because children have proportionally
greater liver parenchyma than adults, the weight-adjusted metabolic capacity is
greater in childhood. Nonetheless, the activity of some CYP systems appears to
be age dependent. For example, drugs metabolized by CYP1A2 tend to show a
higher concentration in children following administration of equal doses by
weight (Fekete et al. 2020).
The two most important CYP enzymes in pediatric psychopharmacology
are CYP3A4 and CYP2D6, which are involved in the metabolism of most
psychotropics, as summarized in Table 1–2. Genetic polymorphism has been
associated with CYP2D6. About 7%–10% of whites, 1%–8% of Blacks, and
1%–3% of East Asians are poor metabolizers. Poor metabolizers have higher
drug concentrations in plasma and other body tissues. For example, the mean
elimination half-life of atomoxetine is about 5 hours in children or adults who
are extensive metabolizers, but it is 22 hours in poor metabolizers (Sauer et al.
Table 1–2. Selected compounds relevant to pediatric pharmacotherapy that are metabolized by
cytochrome P450 (CYP) enzymes

Genetic

Developmental Aspects of Pediatric Psychopharmacology

CYP
enzyme polymorphism Substrates Inhibitors Inducers

CYP3A4 None Alprazolam Lurasidone Clarithromycin Carbamazepine

Aripiprazole Mirtazapine Erythromycin Dexamethasone
Brexpiprazole Nefazodone Fluoxetine Oxcarbazepine
Bupropion Pimozide Fluvoxamine Phenobarbital
Buspirone Quetiapine Grapefruit juice Phenytoin
Citalopram Ritonavir Indinavir Primidone
Erythromycin Saquinavir Ketoconazole Rifampin
Escitalopram Sertraline Nefazodone St. John’s wort (Hypericum
Esketamine Ziprasidone Ritonavir perforatum)
Ethinyl estradiol Zolpidem Topiramate
Indinavir

5
Table 1–2. Selected compounds relevant to pediatric pharmacotherapy that are metabolized by

6 Clinical Manual of Child and Adolescent Psychopharmacology

cytochrome P450 (CYP) enzymes (continued)

CYP Genetic
enzyme polymorphism Substrates Inhibitors Inducers

CYP2D6 Yes (poor metabolizers: Amitriptyline Imipramine Amitriptyline

7%–10% of whites, Aripiprazole Nortriptyline Bupropion
1%–8% of Blacks, and
Atomoxetine Olanzapine Clomipramine
1%–3% of East Asians;
ultrafast metabolizers: Brexpiprazole Paroxetine Desipramine
1%–3% of whites) Desipramine Perphenazine Fluoxetine
Dextromethorphan Risperidone Haloperidol
Fluoxetine Venlafaxine Imipramine
Haloperidol Viloxazine Lamotrigine
Nortriptyline
Paroxetine
Viloxazine
CYP1A2 None Agomelatine Fluvoxamine Ciprofloxacin Carbamazepine
Amitriptyline Olanzapine Erythromycin Modafinil
Caffeine Theophylline Fluvoxamine Tobacco smoke
Clozapine Viloxazine
Table 1–2. Selected compounds relevant to pediatric pharmacotherapy that are metabolized by
cytochrome P450 (CYP) enzymes (continued)

Genetic

Developmental Aspects of Pediatric Psychopharmacology

CYP
enzyme polymorphism Substrates Inhibitors Inducers

CYP2C9 Yes (poor metabolizers: Fluoxetine Ibuprofen Fluoxetine Carbamazepine

6%–12% of whites, 4% Fluvoxamine Naproxen Fluvoxamine Rifampin
of Blacks, and 3% of
Modafinil
East Asians)
Sertraline
CYP2C19 Yes (Poor metabolizers: Amitriptyline Diazepam Fluoxetine
1%–3% of whites, 1%– Citalopram Escitalopram Fluvoxamine
3% of Blacks, and 20%
Clomipramine Imipramine Modafinil
of East Asians)
CYP2B6 Yes (reported in white and Bupropion Clonazepam
Japanese populations) Esketamine Diazepam

7
8 Clinical Manual of Child and Adolescent Psychopharmacology

2005). The clearance of risperidone in children and adolescents is fourfold

greater in extensive CYP2D6 metabolizers than in poor metabolizers (Sherwin
et al. 2012). Being a poor metabolizer can have safety implications, as shown
by a case of death in a child with CYP2D6 genetic deficiency and unusually
high plasma levels of fluoxetine (Sallee et al. 2000). Assaying for genetic poly-
morphism is not a standard procedure in pediatric psychopharmacology, but
it can be considered for individual patients receiving long-term treatment
with drugs metabolized by CYP enzymes with genetic polymorphism (e.g.,
CYP2D6, CYP2C19) or drugs with a low therapeutic index (e.g., tricyclic an-
tidepressants [TCAs]); patients with treatment resistance or poor tolerability;
or in cases of polypharmacy.
Possible medication interactions and medication-food interactions must
be taken into account because some medications or foods can inhibit, induce,
or compete with specific CYP enzymes (see Table 1–2). For example, fluoxe-
tine, bupropion, and lamotrigine inhibit CYP2D6 activity and, when used
concomitantly with risperidone, can increase risperidone serum levels. Espe-
cially important are those genetic polymorphisms and medication interac-
tions that involve drugs with potential toxicities at high plasma concentration.
Poor metabolizer status or the concomitant administration of another medi-
cation that competes with or inhibits the metabolism of the first agent would
result in increased plasma concentrations. For example, toxic levels of TCAs
could develop in poor metabolizers of CYP2D6; concomitant administration
of fluvoxamine (an inhibitor of CYP3A4) and pimozide (metabolized by
CYP3A4) could lead to high levels of pimozide and QTc interval prolonga-
tion; and oral contraceptives can induce CYP enzymes and thus increase drug
metabolism and elimination.
The main route of drug elimination is through the kidneys, whereas bile,
lungs, and skin account for a much smaller portion of elimination. Absolute
clearance is usually lower in children than in adults, but weight-adjusted clear-
ance can be greater. Because of the faster elimination, a drug plasma half-life
can be shorter in children than in adults. Pharmacokinetics can be influenced
by the dose of medication and the duration of treatment, as shown with ser-
traline in adolescents (Axelson et al. 2002). After a single dose of sertraline
50 mg in adolescents, the mean half-life was about 27 hours, but at steady
state, after repeated administrations, the mean half-life decreased to about
15 hours. In addition, the steady-state half-life was found to be longer (about
 Developmental Aspects of Pediatric Psychopharmacology 9

20 hours) after administration of higher doses (100–150 mg). The clinical

implication is that lower dosages (50 mg/day) should be given in two divided
doses daily to ensure consistent treatment and prevent withdrawal, whereas
higher dosages can be given once daily.
The pharmacokinetics of a number of commonly prescribed medications,
such as escitalopram, aripiprazole, quetiapine, risperidone, lurasidone, and
lithium, was found to be similar in children as in adults (Findling et al. 2008,
2010, 2015; Rao 2007; Thyssen et al. 2010). However, considerable intersub-
ject variability was observed, suggesting that significant individual differences
in the time course of the pharmacological effects may occur clinically.
In the case of medications such as methylphenidate and amphetamines,
whose short half-lives result in a short duration of action and the consequent
need for multiple daily doses, a variety of extended-release formulations have
been developed. The first generation of extended-release methylphenidate con-
sisted of tablets with different coatings of immediate- and slower-release med-
ication. However, because of the large intersubject variability in absorption,
the onset of action may be delayed in the morning and/or the therapeutic effect
may attenuate in the afternoon. The second generation of biphasic extended-
release formulations provided an initial bolus of medication to be absorbed
immediately, followed by a second with more gradual release. The plasma phar-
macokinetics curve thus shows an acute initial peak at about 1.5 hours after dos-
ing, followed by a second peak about 3 hours later. The rationale behind these
biphasic release formulations lies in the observation that optimal clinical effect
occurs when the plasma level of methylphenidate is on the rise (Swanson et al.
2003). These extended-release preparations can be administered once daily in
the morning because they allow adequate control of ADHD symptoms for up
to 12 hours. Similarly, prolonged-release formulations of lithium (e.g., ex-
tended-release lithium carbonate and lithium sulfate) have been approved for
use in the pediatric population. Extended-release lithium formulations might
have more consistent serum lithium concentrations and fewer adverse events
and thus might improve adherence to therapy, but direct comparison studies
between regular and extended-release formulations are lacking.
Plasma levels are used as an indication (“surrogate marker”) of drug con-
centration at the site of action, which, in the case of psychotropics, is not easily
accessible. In fact, plasma drug levels are a rather incomplete reflection of the
drug concentration in the brain, as also suggested by the rather low correlation
10 Clinical Manual of Child and Adolescent Psychopharmacology

between plasma level and clinical effects that is observed for most, but not all,
drugs. Proton magnetic resonance spectroscopy has allowed the brain level of
several medications, such as lithium and fluoxetine, to be directly measured. A
direct correlation between serum and brain lithium levels was reported in both
children and adults; younger subjects, however, had a lower brain-to-serum ra-
tio, suggesting that they may need higher maintenance serum lithium concen-
trations than adults to achieve therapeutic lithium concentrations in the brain
(Moore et al. 2002).

Pharmacodynamics
Although the exact mechanism of action responsible for the therapeutic effects
of many psychotropics remains unknown, the basic biochemical activity of
these medications is generally considered to be similar across ages. For instance,
SSRIs block the reuptake of serotonin in both children and adults, and the an-
tidepressant effect of these agents was found to be associated with the degree of
inhibition of the serotonin transporter in platelets (Axelson et al. 2005). How-
ever, the possible effects of development on the intensity and specificity of this
pharmacological activity have not been systematically evaluated.
Most psychotropics act through neurotransmitters, such as dopamine, se-
rotonin, and norepinephrine, whose receptors undergo major changes during
development (Rho and Storey 2001). Receptor density tends to peak between
the ages of 3 and 6 years and then gradually declines to reach adult levels in
late adolescence (Chugani et al. 2001). Recent evidence suggests that typical
and fast-acting antidepressants act by binding the brain-derived neurotrophic
factor receptor TrkB, which not only is developmentally regulated but also has
a fundamental effect on neuronal survival and plasticity (Casarotto et al. 2021).
The impact of these developmental changes on drug activity and the possible
clinical implications have not been fully elucidated, but the observed differ-
ences between children and adults in the efficacy and safety of a number of psy-
chotropics support the notion that development has a significant influence on
the effects of psychotropic medications. For example, amphetamine-like stim-
ulants are more likely to induce euphoria in adults than in children, and anti-
psychotics are more likely to induce metabolic effects in children than in adults
(Correll et al. 2009).
 Developmental Aspects of Pediatric Psychopharmacology 11

Although not yet applicable to clinical care, brain imaging technology has
been used to assess medication effects on neural circuits. For example, in
youth with bipolar disorder, treatment with quetiapine was associated with
normalization of the functional connectivity between brain regions involved
in cognitive processing (Li et al. 2022).
Pharmacodynamics is expected to be significantly determined by genetic
factors, and pharmacogenetics holds much appeal and promise to explain in-
tersubject variability in drug effects and thus help clinicians personalize treat-
ment. Although the theoretical rationale for applying pharmacogenetics to
pediatric psychopharmacology is strong, the clinical data are still rather lim-
ited (Maruf et al. 2021; Rossow et al. 2020). Nonetheless, a number of guide-
lines about the clinical implementation of pharmacogenomic testing for
psychoactive drugs have been published (https://cpicpgx.org/publications),
and databases collecting up-to-date pharmacogenomic knowledge, including
information regarding psychoactive drugs used in the pediatric population,
are available online (www.pharmgkb.org/labelAnnotations).
Few pharmacogenomics-guided therapy prescription trials have been con-
ducted, and their results are mixed (Papastergiou et al. 2021; Vande Voort et
al. 2022). Thus, at this time, there is not sufficient evidence to recommend
the routine use of pharmacogenetics tests in pediatric psychopharmacology
(American Academy of Child and Adolescent Psychiatry 2020).
The only exception to the use of carbamazepine is in patients of Asian ethni-
city because of their greater risk of Stevens-Johnson rash in those with HLA-B
polymorphism HLA-B*1502, which is more common among Asian popula-
tions. Otherwise, genetic testing should be reserved for clinical situations in
which there is concern that the tolerability or efficacy of the medication will be
influenced by genetically determined functioning of metabolizing enzymes,
such as CYP2D6.
Of great interest is research on mechanism-targeted interventions. As neu-
roscience sheds light on the pathogenesis of a disorder, opportunities arise to
engage and modify specific biological targets in order to correct the pathoge-
netic mechanisms. This approach is already possible for conditions such as
fragile X syndrome, Rett syndrome, and Down syndrome, whose underlying
genetic and biochemical pathogenesis has been elucidated. This work can pro-
vide the model for a new generation of targeted interventions (Vitiello 2021).
12 Clinical Manual of Child and Adolescent Psychopharmacology

Efficacy
As in adults, efficacy in children is ascertained primarily through controlled
clinical trials. The theoretical framework of this methodology is the same
across ages, but there are important differences when it is applied to pediatric
samples. A distinctive characteristic is that the evidence for treatment effect
often comes from adult informants, such as parents and teachers, rather than
directly from the child. This is especially the case with young children or those
with neurodevelopmental disorders such as intellectual development disorder
(intellectual disability), autism spectrum disorder, or disruptive behavior dis-
orders. This particular feature of pediatric pharmacology makes drug evalua-
tions more complex and time-consuming for children than for adults, in both
research and practice settings. Clinicians must integrate information from a
variety of sources and arrive at a determination about therapeutic benefit.
Various rating instruments have been developed and validated for assess-
ing treatment effects. In the absence of biological markers of disease and treat-
ment effects, clinicians must rely on changes in clinical symptoms to gauge
response. Although symptom rating scales have been introduced primarily for
research purposes, with the goal of quantifying psychopathology at different
points in time, they can and should be applied to usual clinical practice be-
cause they help the clinician measure and document the patient’s condition
prospectively. Thus, rating scales that are sensitive to medication effects are
available in common child psychiatric disorders such as ADHD (e.g., Con-
ners 2008; DuPaul et al. 2016), depression (e.g., Poznanski and Mokros
1996), and anxiety (e.g., Research Units on Pediatric Psychopharmacology
Anxiety Study Group 2002). In some cases, scales originally developed for
adults have been applied to pediatric psychopharmacology, such as the clinical
trials of antipsychotics in early-onset schizophrenia that used the Positive and
Negative Syndrome Scale with success (Kay et al. 1987). Further research is
needed to develop measures of the core symptoms of autism that are sensitive
to possible treatment effects of medications.
Besides effects on symptoms, it is relevant to document the overall level of
functioning before and during treatment. Some scales of global functioning are
available, including the Children’s Global Assessment Scale for children and
adolescents ages 6–17 years—along with its adaptation to children with autism
spectrum disorder (Shaffer et al. 1983; Wagner et al. 2007)—and the Health
 Developmental Aspects of Pediatric Psychopharmacology 13

of the Nation Outcome Scales for Children and Adolescents, a clinician report
scale regarding general health and social functioning (Pirkis et al. 2005).
For some medications, continuity of efficacy from childhood to adult-
hood has been consistently found, such as for serotonin reuptake inhibitors
(e.g., SSRIs) in OCD, stimulants in ADHD, and clozapine in schizophrenia
(Kasoff et al. 2016). Remarkable differences have been observed for other
medications; most notably, none of the placebo-controlled trials of TCAs has
shown superiority of the active medication in children, and among the SSRIs,
only fluoxetine and escitalopram have been found to be better than placebo in
more than one study (Zhou et al. 2020). It is unclear whether the inability to
consistently demonstrate antidepressant efficacy in youth for all of the SSRIs
found to be effective in adults can be ascribed to some intrinsic difference in
pharmacological activity or, more likely, to methodological issues in the pedi-
atric clinical trials.
The increasing body of research in child and adolescent psychopharma-
cology has allowed evidence-based clinical practice guidelines and treatment
algorithms to be developed. Treatment algorithms consist of step-by-step in-
structions on how to treat individual patients based on their symptoms and
history of previous treatment. Algorithms are therefore more detailed and spe-
cific than general treatment guidelines or practice parameters. Practice guide-
lines and algorithms have been developed for ADHD, depression, bipolar
disorder, and other conditions (Cheung et al. 2018; National Institute for
Health and Care Excellence 2020; Penfold et al. 2022; Wolraich et al. 2019).
The magnitude of the treatment effect relative to a control is often ex-
pressed in standard deviation units using the effect size. Among the most com-
mon ways of computing an effect size is with Cohen’s d or Hedges’ g, either of
which shows the difference in outcome measure between the study groups di-
vided by the pooled standard deviation at the end of treatment (Rosenthal et
al. 2000). Compared with placebo, stimulant medications have a large effect
size (≥0.8) in decreasing symptoms of ADHD (Cortese et al. 2018). In the tri-
als that detected a statistically significant difference between an SSRI and pla-
cebo, the SSRI had a medium effect size (0.5–0.7) in major depression (March
et al. 2004) and in OCD (Pediatric OCD Treatment Study Team 2004).
Meta-analyses of all available pediatric clinical trials, however, have consistently
reported a small effect size for SSRIs in depression and a medium to large effect
size in OCD and anxiety disorders (Locher et al. 2017; Zhou et al. 2020).
14 Clinical Manual of Child and Adolescent Psychopharmacology

The effect size is a purely mathematical computation to quantify a differ-

ence between means and, as such, is at times used to quantify the difference
from pretreatment to posttreatment within the same treatment group. When
this is done, a large effect size often emerges because it includes the time effect.
In the absence of a control condition and because of the consequent inability to
distinguish treatment effect from time effect, the pre- to posttreatment effect
size has limited meaning and cannot be taken as an index of treatment effect.
In addition to the effect size, a useful index of magnitude of the therapeu-
tic benefit is the number needed to treat (NNT), which is the number of pa-
tients who need to be given the treatment for one more improved patient to be
added to the number of those on the control condition who are expected to
improve. For example, in the Treatment for Adolescents With Depression
Study (March et al. 2004), 61% of patients treated with fluoxetine had im-
proved by the end of the 12-week treatment, compared with 35% of those
who received placebo. The NNT was 4, which indicates that, on average, four
patients had to be treated for one patient to improve more than the placebo
condition. The smaller the NNT, the greater the relative efficacy of the treat-
ment. Clinical trials have shown that the NNTs of psychotropic medications,
although variable across studies, are often quite favorable and compare well
with those of other nonpsychiatric drugs used in pediatrics or general medi-
cine (Leucht et al. 2012).
Because most psychiatric conditions are chronic or recurrent, treatment is
often prolonged in time. Progress has been made in assessing the long-term ef-
fectiveness of pharmacotherapy in ADHD and some mood disorders (DelBello
et al. 2021; Maia et al. 2017), but more research is needed to evaluate the ef-
fectiveness of pharmacotherapy beyond 1 year of treatment. An especially im-
portant issue for pediatric psychopharmacology is whether early treatment
with successful control of symptoms translates distally into better “real-life”
functional outcomes, such as higher educational and occupational attainment.
This type of research poses considerable challenges from a methodological and
implementation perspective, given the practical difficulties of conducting
long-term randomized controlled trials and the limitations of uncontrolled ob-
servational studies for inferring causality. In this regard, analyses of population-
based databases have recently provided useful information—for example, by
documenting that pharmacotherapy of ADHD in childhood was associated
with greater likelihood of entering high school education (Jangmo et al. 2019).
 Developmental Aspects of Pediatric Psychopharmacology 15

Safety
Safety considerations are paramount in pediatric psychopharmacology. Phar-
macological treatment during a period in which the body undergoes marked
developmental changes may result in toxicities not seen in adults. For exam-
ple, prolonged administration of phenobarbital to young children to prevent
recurrence of febrile seizures impairs their cognitive development (Farwell et
al. 1990), and the risk of valproic acid–induced hepatotoxicity is much higher
for children younger than 2 years than later in life (Bryant and Dreifuss 1996).
A general concern is that administration of agents acting on the neuro-
transmitter systems during development may interfere with brain maturation
and result in unwanted long-lasting changes. Although some studies in animals
suggest lasting effects of early medication exposure (Ansorge et al. 2004), no
correlates of detectable adverse outcomes have emerged in humans. A high
level of suspicion is, however, warranted when treating children with medica-
tions, especially if treatment is prolonged in time. Different types of adverse ef-
fects can occur (Vitiello et al. 2003). Some, such as rash or dystonias, emerge
acutely upon initial brief drug exposure, whereas others, such as tardive dyski-
nesia or metabolic syndrome, are the result of chronic treatment. Some toxic-
ities, such as lithium-induced tremor, are related to drug dosage and/or plasma
concentrations; others, such as withdrawal dyskinesias, emerge after drug dis-
continuation. Some adverse effects may be anticipated based on the medica-
tion’s mechanism of action, but others, such as the increased suicidality seen
with antidepressant treatment, may be unexpected and even paradoxical.
As in assessing efficacy, the assessment of safety in pediatric psychopharma-
cology depends in large part on monitoring and reporting by parents and other
adults. From the clinician’s perspective, the identification of treatment adverse
effects depends on the level of detail and accuracy with which the relevant in-
formation is elicited and collected from the child and their caregivers (Green-
hill et al. 2004). Over the years, more information has become available on the
long-term safety of psychotropic medications in children. Although limited by
the fact that most of the studies have been observational in nature, the available
data provide some guidance to clinicians. The paragraphs that follow provide
examples of safety issues that pertain to commonly used psychotropics.
Chronic administration of methylphenidate and amphetamines to chil-
dren for the treatment of ADHD has been found to cause a dose-related delay
16 Clinical Manual of Child and Adolescent Psychopharmacology

in physical growth in both weight and height. After 14 months of treatment,

children treated with stimulant medication for ADHD had grown on average
1.2 cm less in height than peers treated with behavior therapy (MTA Cooper-
ative Group 2004). The deficit in height growth was found to persist in con-
tinuously medicated children despite caloric supplementation (Waxmonsky et
al. 2020). The mechanism underlying the interference of stimulants with skel-
etal growth is unclear, but it does not seem merely to be the result of a caloric
deficit.
Stimulants have adrenergic effects, and concern has been raised about ad-
verse cardiovascular outcomes, including sudden death (Gould et al. 2009).
However, a number of retrospective analyses have not found any association
between stimulant treatment and adverse cardiac events (Cooper et al. 2011).
Moreover, prospective analyses of children treated for up to 10 years did not
find an increased risk for hypertension, although stimulants have a detectable
effect on heart rate even with long-term use (Vitiello et al. 2012).
Because stimulant medications are drugs of potential abuse, concerns have
been raised about the possibility that treatment in childhood may sensitize the
brain and thus make substance abuse and dependence more likely in adoles-
cence and adulthood. The feasibility of mounting randomized, well-controlled
studies to address this issue is questionable, and researchers have relied on nat-
uralistically treated samples. Most of these studies have not found an increased
risk of substance abuse after treatment with stimulants (Biederman et al. 2008;
McCabe et al. 2016).
Differences in tolerability have been observed across age and type of devel-
opment. Preschoolers with ADHD have lower tolerability to methylphenidate
than older children (Childress et al. 2022; Wigal et al. 2006). Moreover, long-
lasting effects of methylphenidate on human striatal and thalamic blood flow
have been observed in children but not in adults, suggesting age-dependent
effects of the drug on brain circuitry (Schrantee et al. 2016). Children with
autism spectrum disorder or other pervasive developmental disorders with
ADHD symptoms are more sensitive to methylphenidate, as indicated by an
18% treatment discontinuation rate due to intolerable adverse events (most
commonly irritability) (Masi et al. 2022; Research Units on Pediatric Psycho-
pharmacology Autism Network 2005). Youth exposed to second-generation
antipsychotics are more prone to weight gain than adults (Correll et al. 2009).
 Developmental Aspects of Pediatric Psychopharmacology 17

Antidepressant treatment of children and adolescents has been associated

with a slight but statistically significant increased risk of suicidality (i.e., sui-
cidal ideation and suicide attempt), although not of suicide (Hammad et al.
2006). Subsequent analyses found strong evidence for suicide-related behavior
only for patients treated with venlafaxine (Zhou et al. 2020). However, close
monitoring of adolescents taking antidepressants is still warranted. A signifi-
cant association was found between age and emergence of suicidality during
antidepressant treatment, with an increased risk compared with placebo for pa-
tients younger than 25 years, a neutral effect for those ages 25–64 years, and a
protective effect for patients older than 64 (Stone et al. 2009). These data
demonstrate the interaction between development and pharmacological effect,
although the biological underpinnings of this interaction remain unknown.
Safety is a relative concept, and possible risks of pharmacotherapy must be
weighed against possible risks of untreated psychopathology. Decisions about
prescribing medications must also take into account the availability of effective
nonpharmacological interventions. Although it is generally found to be some-
what less effective at decreasing symptoms of ADHD or depression in children
and adolescents, psychotherapy can be considered in lieu of medication for pa-
tients with mild depression or in combination with medications for those with
more severe illness. Psychotherapy, used either sequentially (i.e., starting first
with psychotherapy, then adding medication if insufficient) or in combination
(i.e., starting both psychotherapy and medication concurrently), may reduce
the medication dosage needed to control symptoms. Consideration should be
given to using psychosocial interventions as first-line treatment, especially in
young children. In any case, carefully monitoring children receiving psycho-
tropics and documenting both positive and negative outcomes have emerged
as critically important components of rational pharmacotherapy.

Ethical Aspects
Children should be given as much explanation as they can reasonably under-
stand about their condition and possible therapeutic options, but they cannot
give legal consent for treatment, which is the responsibility of the parents. Par-
ents are also instrumental in implementing pharmacotherapy by ensuring ap-
propriate administration of prescribed medication and by reporting possible
18 Clinical Manual of Child and Adolescent Psychopharmacology

treatment-emergent adverse effects. Parental permission is required for child

participation in research, and such participation is subject to special regulations
over and above those required for adults (Office for Human Research Protec-
tions 2018).
Only scientifically sound research investigations that use valid methodol-
ogy and are posited to add new knowledge about important health issues can
be ethically acceptable (Vitiello 2003). Pediatric research can be divided into
two broad categories based on whether it presents the prospect of direct benefit
to the individual participant. Prospect of direct benefit refers to the fact that each
participant has the potential to derive a health benefit from participation. Gen-
eral acquisition of knowledge relevant to the child’s condition does not satisfy
the requirement of direct benefit. To be ethically acceptable, research with the
prospect of direct benefit must show a favorable balance between anticipated
benefits and foreseeable harms. A study that tests the efficacy of a treatment in-
tervention usually has potential for direct benefit to the research participants.
In this case, the main criterion for determining whether the study is ethically
acceptable is the risk-benefit ratio. The presence of a placebo arm in a random-
ized clinical trial is usually considered acceptable in child psychiatry conditions.
Placebo does not equal absence of treatment and has been associated with sub-
stantial improvement, especially in the case of mood and anxiety disorders.
Pharmacological research that does not offer a prospect of direct benefit in-
cludes pharmacokinetics and pharmacodynamics studies. To examine the ac-
ceptability of a study in this category, one must determine whether such a study
has the potential for generating essential knowledge relevant to the disorder or
condition of the participants. If the information that the study will acquire is
not relevant to the child’s disorder or condition (e.g., a pharmacokinetics study
in healthy children who are at no increased risk for the condition being targeted
by the treatment), then the research can be conducted only if it entails no more
than minimal risk. Minimal risk means that the “probability and magnitude of
harm or discomfort anticipated in the research are not greater in and of them-
selves than those ordinarily encountered in daily life risk for harm not greater
than ordinarily encountered in daily life or during the performance of routine
physical or psychological examinations or tests” (Office for Human Research
Protections 2018, 45 C.F.R, Subpart A, Section 46.102[j]). The prevailing in-
terpretation is that the daily life, examinations, and tests of a normal child are
 Developmental Aspects of Pediatric Psychopharmacology 19

to be used as reference, but a precise quantification of risk in ordinary daily life

is not easy and remains a matter of discussion (Wendler et al. 2005).
If the study aims to acquire information relevant to the child’s condition
(e.g., pharmacokinetics of a medication for ADHD being studied in children
with ADHD), then the research risk cannot be greater than a “minor increase
over minimal risk.” A minor increase over minimal risk can be considered accept-
able only if 1) it presents “experiences to the subjects that are commensurate
with those inherent in their actual or expected medical, dental, psychological,
social, or educational situations” (Office for Human Research Protections
2018, 45 C.F.R., Subpart D, Section 46.406[b]) and 2) the study has the po-
tential to generate new knowledge considered of “vital importance” for un-
derstanding or treating the child’s disorder or condition.
Research that is not otherwise approvable based on these criteria but offers
an opportunity to understand, prevent, or alleviate a serious problem affecting
the health or welfare of children can be referred to the U.S. Secretary of Health
and Human Services for further review under regulations at 45 C.F.R., Sub-
part D, Section 46.407 (Office for Human Research Protections 2018) and
21 C.F.R. 50.56 (U.S. Food and Drug Administration 2001). Studies in
which psychotropic medications may be given to children who are physically
and mentally healthy for the purpose of understanding the medication’s
mechanisms of action on the brain would fall into this category because a non-
therapeutic administration of a pharmacological compound would generally
be considered to pose more than minimal risk. For example, the protocol for
a brain MRI study of healthy children age 9 years or older receiving a single
oral dose of dextroamphetamine was referred in 2004 by the institutional re-
view board of the National Institute of Mental Health under regulations at
45 C.F.R. 46.407 (Couzin 2004). This study was reviewed and approved by
the Pediatric Ethics Subcommittee of the FDA Pediatric Advisory Committee
in September 2004. The reviewers determined that a single administration of
dextroamphetamine 10 mg to a child age 9 years or older entails more than
minimal risk because the potential adverse effects are more than those expected
in a routine visit to a doctor, but the risk is limited to a minor increase over
minimal risk. That being the case, and because the study had the potential to
generate important information on the effects of a medication commonly
used in children, the research was eventually approved.
20 Clinical Manual of Child and Adolescent Psychopharmacology

The process of informing parents and children about the aims, procedures,
and potential risks and benefits of research participation; the presence of alter-
native treatments; and the rights of research participants is critical for obtain-
ing their informed permission and assent. In general, children age 7 years or
older are able to provide assent, and this is often documented in writing with
an appropriate assent form. With proper communication and explanation by
researchers, parents can achieve a good understanding of both research proce-
dures and participant rights. By age 16, youth generally have a level of under-
standing similar to that of their parents (Vitiello et al. 2007).
Several public and private websites provide detailed information about
child participation in research and the process of determining whether a par-
ticular project is ethically acceptable (Office for Human Research Protections
2016).

Regulatory Aspects
A number of psychotropic medications currently have pediatric indications
approved by the FDA and other regulatory agencies, whereas others are used
off-label for indication or age (Table 1–3). The off-label use of a drug is not in
itself inappropriate, because it is often supported by considerable empirical
evidence and is consistent with treatment guidelines. However, patients and
their family need to be informed that a medication is being prescribed for an
off-label use so that they can make fully informed decisions.
Research in pediatric psychopharmacology has greatly expanded in the
past 20 years thanks to a number of publicly funded clinical research networks
and several seminal legislative and regulatory initiatives (Vitiello and Davico
2018). In particular, financial incentives have been provided to pharmaceuti-
cal companies for conducting pediatric research (Best Pharmaceuticals for
Children Act 2002). This legislation and its subsequent reauthorizations and
expansions have substantially changed the industry’s approach to pediatric
pharmacology, including also pediatric psychopharmacology. In parallel, leg-
islation was enacted giving the FDA the authority to request that the industry
conduct pediatric studies of a drug, even prior to its approval for adult use,
when there are reasons to expect that it may be used also in children (Pediatric
Research Equity Act 2003).
Table 1–3. Pediatric indications approved by the FDA and off-label use of selected psychotropic
medications

Developmental Aspects of Pediatric Psychopharmacology 21

Relative child Off-label use and child age,
Medication FDA-approved indication(s) age, years years

Agomelatine None MDD: ≥7

Amphetamines ADHD ≥3
Aripiprazole Schizophrenia ≥13 Aggression
Bipolar disorder ≥10 Tourette’s disorder
“Irritability” in autism 5–16
Asenapine Bipolar disorder ≥10 Schizophrenia
Atomoxetine ADHD ≥6 ADHD: <6
Brexpiprazole Schizophrenia ≥13
Bupropion None MDD: ≥6
ADHD: ≥6
Carbamazepine Epilepsy From infancy Mania, aggression
Citalopram None OCD, other anxiety disorders: ≥6
MDD: ≥6
Clomipramine OCD ≥10
Clonidine ADHD ≥6 Tourette’s disorder
Dexmethylphenidate ADHD ≥6 ADHD: <6
Table 1–3. Pediatric indications approved by the FDA and off-label use of selected psychotropic

22 Clinical Manual of Child and Adolescent Psychopharmacology

medications (continued)

Relative child Off-label use and child age,

Medication FDA-approved indication(s) age, years years

Duloxetine GAD ≥7 MDD: ≥6

Escitalopram MDD ≥12 MDD: 6–11
Fluoxetine MDD ≥8 MDD: <8
OCD ≥7 Other anxiety disorders: ≥6
Fluvoxamine OCD ≥7 Other anxiety disorders: ≥6
Guanfacine ADHD ≥6 Tourette’s disorder
Haloperidol Psychosis, Tourette’s disorder, hyperactivity, severe ≥3
behavioral problems, explosive hyperexcitability
Lamotrigine Epilepsy ≥2 Depression in bipolar disorder
Lisdexamfetamine ADHD ≥6 ADHD: <6
Lithium Bipolar disorder (acute and maintenance treatment) ≥7 Aggression, prevention of suicidal
behavior
Lurasidone Schizophrenia ≥13
Bipolar I depression ≥10
Methylphenidate ADHD ≥6 ADHD: <6
Olanzapine Schizophrenia ≥13 Aggression, Tourette’s disorder,
Bipolar disorder ≥10 anorexia nervosa
Table 1–3. Pediatric indications approved by the FDA and off-label use of selected psychotropic
medications (continued)

Developmental Aspects of Pediatric Psychopharmacology 23

Relative child Off-label use and child age,
Medication FDA-approved indication(s) age, years years

Oxcarbazepine Epilepsy ≥4 Mania, aggression

Paroxetine None OCD, other anxiety disorders: ≥6
MDD: ≥6
Pimozide Tourette’s disorder ≥12
Quetiapine Schizophrenia ≥13 Aggression
Bipolar disorder ≥10 Tourette’s disorder
Risperidone Schizophrenia ≥13 Aggression
Bipolar disorder ≥10 Tourette’s disorder
“Irritability” in autism 5–16
Sertraline OCD ≥6 OCD, anxiety disorders: ≥6
MDD: ≥6
Valproate Epilepsy From infancy Mania, aggression
Venlafaxine None MDD: ≥6
Viloxazine ADHD ≥6
Note. GAD=generalized anxiety disorder; MDD=major depressive disorder.
24 Clinical Manual of Child and Adolescent Psychopharmacology

Conclusion
Pediatric psychopharmacology is a relatively new field of clinical pharmacol-
ogy that has recently undergone a rapid expansion due to intense research ac-
tivity. It is also the object of frequent debate and, at times, controversy in the
media and the general public. The therapeutic value of several psychotropic
medications is now well documented for both the short and intermediate term.
Knowledge gaps remain, especially in the understanding of the long-term im-
pact of pharmacotherapy with respect to both efficacy and safety. Practicing
rational pharmacotherapy requires integration of knowledge at different lev-
els, including developmental psychopathology, pharmacology, and drug reg-
ulation and bioethics, and a considerable investment of time on the part of the
treating clinician and the child’s parents.

Clinical Pearls
• Simply decreasing adult medication dosages on the basis of
child weight can result in undertreatment because of faster drug
elimination in children.
• Assessing treatment effects and safety requires collection and
integration of data from different sources (i.e., child, parent,
teacher).
• Safety is paramount, and a high level of suspicion is warranted
when prescribing medication for children, especially at the be-
ginning of treatment and when multiple medications are pre-
scribed and taken concurrently.
• Younger children and children with neurodevelopmental disor-
ders, such as autism spectrum disorder and intellectual develop-
mental disorder (intellectual disability), tend to be more sensitive
to the adverse effects of medications.
• Children should have their condition explained to the extent that
they can understand, and whenever possible, their assent to
treatment should be obtained.
 Developmental Aspects of Pediatric Psychopharmacology 25

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 2
Attention-Deficit/
Hyperactivity Disorder
Lauren Schumacher, M.D.
Laurence Greenhill, M.D.

ADHD is a frequently occurring childhood-onset neurodevelopmental

disorder with prevalence estimates of 7.2%–9.4% (Danielson et al. 2018;
Thomas et al. 2015; Wolraich et al. 2019). ADHD costs the United States
between $143 billion and $266 billion per year due to lost productivity and
income, health care, and education (Doshi et al. 2012). ADHD is a chronic
disorder. Follow-up studies of children first diagnosed with ADHD in pri-
mary school suggest that 60%–80% will continue to meet the full DSM-IV-
TR criteria (American Psychiatric Association 2000) for ADHD throughout
their teenage years. The estimated point prevalence in adults is 4.4%, with
continued significant symptoms and impairment (Kessler et al. 2006; Swan-
son et al. 2017).

33
34 Clinical Manual of Child and Adolescent Psychopharmacology

Diagnosis
First described in the nineteenth century, ADHD is a heterogeneous disorder
characterized by a persistent, developmentally inappropriate pattern of gross
motor overactivity, inattention, and impulsivity that impairs academic, social,
and family function. DSM-5 (American Psychiatric Association 2013, 2022)
subdivides the disorder into three presentations: predominantly hyperactive/
impulsive, predominantly inattentive, and combined. The term presentation
describes the shifting symptom picture over development better than subtype
(Lahey and Willcutt 2010). Two-thirds of young children with ADHD have
symptoms that also meet criteria for other childhood psychiatric disorders, in-
cluding anxiety disorders, depression, oppositional defiant disorder (ODD),
conduct disorder (CD), mood disorders, learning disorders, sleep disorders,
and tic disorders (Molina et al. 2009; Reale et al. 2017). These comorbid psy-
chiatric conditions are thought to increase the impairment associated with
ADHD.
The DSM-5 age-at-onset criterion requires that the child present with
ADHD symptoms before 12 years of age. Symptom criteria require the per-
sistence of six or more symptoms of inattentiveness or hyperactivity/impul-
sivity for at least 6 months to a degree that is inconsistent with developmental
level and negatively impacts social and academic/occupational activities. Five
symptoms are required for adults age 17 years or older. DSM-5 also requires
that symptoms cause impairment in more than one setting and are not better
explained by a different disorder.

Diagnostic Procedures
Consensus guidelines for making the ADHD diagnosis have been published
by the American Academy of Pediatrics (AAP; Wolraich et al. 2019) and the
American Academy of Child and Adolescent Psychiatry (AACAP; Pliszka and
AACAP Work Group on Quality Issues 2007). Because ADHD is so preva-
lent, the AACAP recommends that screening for ADHD be part of any pa-
tient’s mental health assessment. Such screening can be accomplished by
having the practitioner ask questions about inattention, impulsivity, and hy-
peractivity and whether such symptoms cause impairment. If ADHD is sus-
pected, parents and teachers can fill out ADHD rating scales. A positive screen
on a rating scale, however, does not constitute a definitive ADHD diagnosis.
 Attention-Deficit/Hyperactivity Disorder 35

A medical history should be obtained by the clinician during the diagnos-

tic evaluation. Positive findings on this screening interview should be followed
by referral to a pediatrician for a physical examination. If the patient’s medical
examination and history are unremarkable, no additional laboratory or neu-
rological testing is required. Because neuropsychological testing has limited
sensitivity and/or specificity for ADHD, it is not a requirement for making
the ADHD diagnosis. However, neuropsychological testing may be helpful
when a comorbid learning disorder is suspected (Pliszka and AACAP Work
Group on Quality Issues 2007).
The child or adolescent should be interviewed to further assess for ADHD
symptoms and to help determine whether other psychiatric disorders are pres-
ent that would better explain the symptoms causing impairment. Although it
is helpful to interview a preschool- or school-age child with the parent present,
older children and adolescents should be interviewed alone because they are
more likely to discuss symptoms of substance use, suicidal ideation or behav-
ior, or depression when the parents are absent.
Most children with ADHD have at least one other major psychiatric dis-
order (Reale et al. 2017). Inquiries should be made about symptoms of ODD,
CD, depression, anxiety disorders, tic disorders, substance use disorders,
learning disorders, and mania. Parent-scored symptom checklists, such as the
Child Behavior Checklist (a component of the Achenbach System of Empir-
ically Based Assessment; Achenbach and Ruffle 2000), and rating scales, such
as the revised Swanson, Nolan, and Pelham rating scale (SNAP-IV; Swanson
1992) and the Vanderbilt ADHD Diagnostic Rating Scale (Wolraich et al.
2003), may pick up these symptoms. In addition, the clinician should obtain
information about the patient’s family history, prenatal history, developmen-
tal milestones, medical history, and detailed school history.

Diagnostic Controversy
ADHD diagnosis has been controversial because there are no confirmatory
laboratory tests. Although the diagnosis of ADHD remains a clinical one,
there are ongoing efforts to define the neurobiological correlates of the di-
agnosis through neuroimaging and peripheral biomarkers (Scassellati et al.
2012), among other modalities. However, this remains a relatively new area
of scientific research in terms of clinical application, and this literature
should be followed over time.
36 Clinical Manual of Child and Adolescent Psychopharmacology

The diagnosis of ADHD has been revised five times since 1970, with the
most recent criteria published in DSM-5 (Box 2–1). These revisions have
been made as new data have emerged. ADHD subtypes have been shown to
be unstable over time (Lahey and Willcutt 2010), and the DSM-IV criteria
(American Psychiatric Association 1994) underrepresented impulsivity.
ADHD criteria thresholds for adults requiring six symptom criteria also may
exclude those who are highly impaired but have fewer endorsed symptoms,
and children with onset between ages 7 and 12 years do not show different
outcomes (Kieling et al. 2010), suggesting that the requirement for having
ADHD by age 7 may be too low. The DSM-5 criteria revisions may have led
to an increased prevalence estimate of the disorder (McKeown et al. 2015;
Vande Voort et al. 2014).

Box 2–1. Attention-Deficit/Hyperactivity Disorder

A. A persistent pattern of inattention and/or hyperactivity-impulsivity that
interferes with functioning or development, as characterized by (1) and/
or (2):
1. Inattention: Six (or more) of the following symptoms have persisted
for at least 6 months to a degree that is inconsistent with develop-
mental level and that negatively impacts directly on social and aca-
demic/occupational activities:
Note: The symptoms are not solely a manifestation of oppositional
behavior, defiance, hostility, or failure to understand tasks or in-
structions. For older adolescents and adults (age 17 and older), at
least five symptoms are required.
a. Often fails to give close attention to details or makes careless
mistakes in schoolwork, at work, or during other activities (e.g.,
overlooks or misses details, work is inaccurate).
b. Often has difficulty sustaining attention in tasks or play activities
(e.g., has difficulty remaining focused during lectures, conversa-
tions, or lengthy reading).
c. Often does not seem to listen when spoken to directly (e.g.,
mind seems elsewhere, even in the absence of any obvious dis-
traction).
d. Often does not follow through on instructions and fails to finish
schoolwork, chores, or duties in the workplace (e.g., starts tasks
but quickly loses focus and is easily sidetracked).
 Attention-Deficit/Hyperactivity Disorder 37

e. Often has difficulty organizing tasks and activities (e.g., difficulty

managing sequential tasks; difficulty keeping materials and be-
longings in order; messy, disorganized work; has poor time
management; fails to meet deadlines).
f. Often avoids, dislikes, or is reluctant to engage in tasks that re-
quire sustained mental effort (e.g., schoolwork or homework; for
older adolescents and adults, preparing reports, completing
forms, reviewing lengthy papers).
g. Often loses things necessary for tasks or activities (e.g., school
materials, pencils, books, tools, wallets, keys, paperwork, eye-
glasses, mobile telephones).
h. Is often easily distracted by extraneous stimuli (for older adoles-
cents and adults, may include unrelated thoughts).
i. Is often forgetful in daily activities (e.g., doing chores, running
errands; for older adolescents and adults, returning calls, paying
bills, keeping appointments).
2. Hyperactivity and impulsivity: Six (or more) of the following
symptoms have persisted for at least 6 months to a degree that is
inconsistent with developmental level and that negatively impacts
directly on social and academic/occupational activities:
Note: The symptoms are not solely a manifestation of oppositional
behavior, defiance, hostility, or a failure to understand tasks or in-
structions. For older adolescents and adults (age 17 and older), at
least five symptoms are required.
a. Often fidgets with or taps hands or feet or squirms in seat.
b. Often leaves seat in situations when remaining seated is expect-
ed (e.g., leaves his or her place in the classroom, in the office or
other workplace, or in other situations that require remaining in
place).
c. Often runs about or climbs in situations where it is inappropriate.
(Note: In adolescents or adults, may be limited to feeling rest-
less.)
d. Often unable to play or engage in leisure activities quietly.
e. Is often “on the go,” acting as if “driven by a motor” (e.g., is un-
able to be or uncomfortable being still for extended time, as in
restaurants, meetings; may be experienced by others as being
restless or difficult to keep up with).
f. Often talks excessively.
g. Often blurts out an answer before a question has been complet-
ed (e.g., completes people’s sentences; cannot wait for turn in
conversation).
38 Clinical Manual of Child and Adolescent Psychopharmacology

h. Often has difficulty waiting his or her turn (e.g., while waiting in
line).
i. Often interrupts or intrudes on others (e.g., butts into conversa-
tions, games, or activities; may start using other people’s things
without asking or receiving permission; for adolescents and
adults, may intrude into or take over what others are doing).
B. Several inattentive or hyperactive-impulsive symptoms were present
prior to age 12 years.
C. Several inattentive or hyperactive-impulsive symptoms are present in
two or more settings (e.g., at home, school, or work; with friends or rel-
atives; in other activities).
D. There is clear evidence that the symptoms interfere with, or reduce the
quality of, social, academic, or occupational functioning.
E. The symptoms do not occur exclusively during the course of schizo-
phrenia or another psychotic disorder and are not better explained by
another mental disorder (e.g., mood disorder, anxiety disorder, disso-
ciative disorder, personality disorder, substance intoxication or with-
drawal).
Specify whether:
(F90.2) Combined presentation: If both Criterion A1 (inattention) and
Criterion A2 (hyperactivity-impulsivity) are met for the past 6 months.
(F90.0) Predominantly inattentive presentation: If Criterion A1 (inat-
tention) is met but Criterion A2 (hyperactivity-impulsivity) is not met for
the past 6 months.
(F90.1) Predominantly hyperactive/impulsive presentation: If Crite-
rion A2 (hyperactivity-impulsivity) is met and Criterion A1 (inattention)
is not met for the past 6 months.
Specify if:
In partial remission: When full criteria were previously met, fewer than
the full criteria have been met for the past 6 months, and the symptoms
still result in impairment in social, academic, or occupational function-
ing.
Specify current severity:
Mild: Few, if any, symptoms in excess of those required to make the
diagnosis are present, and symptoms result in no more than minor im-
pairments in social or occupational functioning.
Moderate: Symptoms or functional impairment between “mild” and “se-
vere” are present.
Severe: Many symptoms in excess of those required to make the diag-
nosis, or several symptoms that are particularly severe, are present, or
 Attention-Deficit/Hyperactivity Disorder 39

the symptoms result in marked impairment in social or occupational

functioning.

Source. Reprinted from American Psychiatric Association: Diagnostic and Statisti-

cal Manual of Mental Disorders, 5th Edition, Text Revision, Washington, DC, Ameri-
can Psychiatric Association, 2022. Copyright © 2022 American Psychiatric
Association. Used with permission.

Treatment
The AAP clinical practice guidelines recommend that treatment of ADHD
include use of FDA-approved medication, evidence-based behavioral inter-
ventions (e.g., parent training in behavior management), and educational in-
terventions for those age 6 years or older. For children younger than 6 years,
behavioral and educational interventions are the first-line treatment, with
methylphenidate as a second-line treatment option (Wolraich et al. 2019).
FDA-approved medications for ADHD include stimulant medications, selec-
tive norepinephrine reuptake inhibitors, and α2-adrenergic agonists. Bupro-
pion and modafinil are other medications used for ADHD, although they are
not FDA approved for this indication.
These recommendations are largely influenced by the National Institute
of Mental Health (NIMH)–sponsored Multimodal Treatment Study of Chil-
dren With ADHD (MTA). This parallel-design, double-blind, randomized
controlled trial (RCT) compared 579 children ages 7–10 years diagnosed with
combined-type ADHD who were randomly assigned to one of the following
four treatment strategies for 14 months: stimulant medication alone, behav-
ioral treatment alone, their combination, or community care (MTA Cooper-
ative Group 1999b, 1999a). Children treated with medication (alone or
combined) had significant improvements in inattention and hyperactivity
compared with behavioral treatment alone or community care. Although
there were no significant differences in the primary outcomes of core ADHD
symptoms between the combined and medication-alone groups, the com-
bined group required lower dosages of medication and had significant im-
provement in some secondary outcomes (social skills, oppositionality,
internalizing symptoms, parent-child relations, and reading achievement
scores). Details of pharmacological treatment of ADHD are discussed in later
sections.
40 Clinical Manual of Child and Adolescent Psychopharmacology

Psychosocial Treatments
In addition to medication, parent training in behavioral management, behav-
ioral classroom interventions, and school accommodations are recommended
as part of ADHD treatment (Wolraich et al. 2019). Behavioral interventions
use strategies to increase desired behaviors and decrease undesired behaviors.
For instance, parent training in behavioral management teaches parents meth-
ods to strengthen parent-child relationships and skills to manage problem be-
haviors. Behavioral classroom interventions employ strategies such as using a
daily report card to track and reward desired classroom behaviors. Other psy-
chosocial treatments studied for ADHD include cognitive training, which in-
volves repeated practice to develop a targeted skill such as working memory or
attention, and neurofeedback, which teaches patients to increase attention
through visualization of brain activity with electroencephalography. In a
meta-analysis of pharmacological and nonpharmacological treatments for
ADHD, behavioral therapy was superior to placebo but inferior to stimulants
(Catalá-López et al. 2017). Behavioral therapy in combination with stimu-
lants outperformed stimulants and nonstimulant medications alone. Neuro-
feedback and cognitive training did not separate from placebo.

Stimulant Medications
The FDA has approved numerous stimulant medications for the treatment of
ADHD. Fourteen racemic (d-,l-)-methylphenidate medications, two dex-
methylphenidate medications, four dextroamphetamine medications, eight
mixed amphetamine salts, and one lisdexamfetamine medication, some of
which are also available in generic formulations, have been approved for chil-
dren and adolescents ages 6 years or older. The duration of action and dosing
for these medications are described in Table 2–1. All dextroamphetamine and
methylphenidate preparations are structurally related to the catecholamines
(dopamine and norepinephrine). The term psychostimulant used for these
compounds refers to their ability to increase CNS activity in some but not all
brain regions. In neuroscience-based nomenclature, they are referred to as do-
pamine and norepinephrine reuptake inhibitors and releasers or norepineph-
rine-dopamine–releasing agents.
Table 2–1. Stimulant medications used in the treatment of ADHD

Pediatric dosage, mga Adult dosage, mg

Duration of
Medication action, hours Starting Typical Starting Typical

Dexmethylphenidate

Focalin (Novartis)b; generic available 5–6c 2.5 bid 2.5–10 bid 5 bid 5–10 bid
d
Focalin XR (Novartis) ; generic available 12; dual pulse 5 qAM 5–30 qAM 10 qAM 10–40 qAM

Attention-Deficit/Hyperactivity Disorder
d,l-Methylphenidate hydrochloride

Short-acting (immediate release)

Methylin Chewable Tablets 3–5 5 bid or tid 10–20 tid 10 bid or tid 10–20 tid
(Mallinckrodt); generic available

Methylin Oral Solution (Mallinckrodt) 3–5 5 bid or tid 10–20 tid 10 bid or tid 10–20 tid

Ritalin (Novartis); generic available 3–5 5 bid or tid 10–20 tid 10 bid or tid 10–20 tid

Intermediate-acting

Metadate ER (Upstate); generic available 3–8; single pulse 20 qAM 20–60 qAM 20 qAM 20–80 qAM

Long-acting

Adhansia XR (Adlon)d 8–16 25 qAM 25–70 qAM 25 qAM 25–85 qAM

Aptensio XR (Rhodes)d 12 10 qAM 10–60 qAM No adult data No adult data

41
Table 2–1. Stimulant medications used in the treatment of ADHD (continued)

42 Clinical Manual of Child and Adolescent Psychopharmacology

Pediatric dosage, mga Adult dosage, mg
Duration of
Medication action, hours Starting Typical Starting Typical

Long-acting (continued)

Concerta (Janssen)e; generic available 10–12; ascending 18 qAM 18–72 qAM 18 or 36 qAM 18–72 qAM
single pulse

Cotempla XR-ODT (Neos)f 12 17.3 qAM 8.6–51.8 qAM No adult data No adult data
f
Daytrana (Noven) 10–12; transdermal 10 (patch) 10–30 (patch) 10 (patch) 10–30 (patch)
single pulse qd×9 hours, qd×9 hours, qd×9 hours, qd×9 hours,
off 15 hours off 15 hours off 15 hours off 15 hours

Jornay PM (Ironshore)d 7–12 20 qAM 20–100 qPM 20 qAM 20–100 qAM

Metadate CD (UCB)d; generic available 8–10; dual pulse 20 qAM 20–60 qAM 20 qAM 20–80 qAM

QuilliChew ER (Pfizer) 12 20 qAM 20–60 qAM No adult data No adult data

Quillivant XR (Pfizer) 12 20 qAM 20–60 qAM No adult data No adult data

d
Ritalin LA (Novartis) ; generic available 8–10; dual pulse 10–20 qAM 10–60 qAM 10–20 qAM 10–80 qAM
Table 2–1. Stimulant medications used in the treatment of ADHD (continued)

Pediatric dosage, mga Adult dosage, mg

Duration of
Medication action, hours Starting Typical Starting Typical

d-Amphetamine

Short-acting

Dextroamphetamine genericg 4–6 5 qAM or bid 5–20 bid 5 bid 5–20 bid

Attention-Deficit/Hyperactivity Disorder
ProCentra solution (Independence) 6 5 qAM or bid 5–20 bid 5 bid 5–20 bid

Zenzedi (Arbor) 4–6 5 qAM or bid 5–20 bid 5 bid 5–20 bid

Long-acting

Dexedrine Spansule (Amedra); generic 8–12 5 qAM 10–40 qAM 5 qAM 10–40 qAM
available

Amphetamine mixed salts (d-and l-isomers)

Short-acting

Adderall (Teva)g; generic available 4–6 5 qAM or bid 5–20 bid 5 qAM or bid 5–20 bid

Long-acting

Adderall XR (Shire)d,g 10–12; dual pulse 5 qAM 5–30 qAM 5 qAM 5–60 qAM

Adzenys ER suspension (Neos) 10–12 6.3 qAM 6.3–18.8 qAM 12.5 qAM 12.5 qAM

43
Table 2–1. Stimulant medications used in the treatment of ADHD (continued)

44 Clinical Manual of Child and Adolescent Psychopharmacology

Pediatric dosage, mga Adult dosage, mg
Duration of
Medication action, hours Starting Typical Starting Typical

Long-acting (continued)

Adzenys XR-ODT (Neos) 10–12 6.3 qAM 6.3–18.8 qAM 12.5 qAM 12.5 qAM

Dyanavel XR suspension (Tris) 13 2.5–5 qAM 2.5–20 qAM 2.5–5 qAM 2.5–20 qAM

Evekeo (Arbor) 10 5 qAM or bid 5–40 qAM No adult data No adult data

Evekeo ODT (Arbor) 10 5 qAM or bid 5–40 qAM No adult data No adult data
d
Mydayis (Shire) 16 12.5 qAM 12.5–25 qAM 12.5 qAM 12.5–50 qAM

Lisdexamfetamine

Vyvanse (Shire)g capsule and chewable tab 13–14 30 qAM 30–70 qAM 30 qAM 30–70 qAM
a
Dosage for children age 6 years or older.
bFocalin
and Focalin XR should not be taken with antacids or other drugs that decrease gastric acidity.
cLimited data.
d
Contents of capsule can be sprinkled on small amount of applesauce or ice cream to disguise bitter taste and given immediately. Pharmacokinetics is
identical whether the beads are swallowed whole or sprinkled on food.
eSome generic formulations (manufactured by Mallinckrodt and Kudco) may not be therapeutically equivalent to the brand-name product. The generic

formulation that is manufactured by Janssen and marketed by Actavis is bioequivalent (www.fda.gov/drugs/drugsafety/ucm422568.htm).

fFDA approved only for use in children ages 6–17 years.
gDextroamphetamine, mixed amphetamine salts, lisdexamfetamine: Taking the drugs with ascorbic acid or fruit juice decreases their absorption, where-

as alkalinizing agents such as sodium bicarbonate increase their absorption.

 Attention-Deficit/Hyperactivity Disorder 45

The RCTs considered by the FDA in their approval process revealed that
stimulants are highly effective in reducing ADHD symptoms, with an effect
size of about 1 (Wolraich et al. 2019). As shown in Table 2–2, about 70% of
ADHD participants responded to stimulants, whereas less than 13% experi-
enced a response to placebo. Higher response rates can be achieved if individ-
uals whose symptoms do not respond to one medication then try a stimulant
of a different class. For instance, in the MTA study, 73% of participants re-
sponded to methylphenidate and another 10% responded to dextroamphet-
amine (MTA Cooperative Group 1999b). Symptoms return when stimulant
medications are stopped (Coghill et al. 2014). A meta-analysis of 62 methyl-
phenidate treatment RCTs of 3 months (or less) revealed large effect sizes
when ratings were made by teachers and moderate effect sizes when ratings
were made by parents (Schachter et al. 2001). A meta-analysis of 133 double-
blind RCTs of medication for ADHD in 10,068 children and adults found
that at 12 weeks, all medications examined (amphetamine, methylphenidate,
atomoxetine, clonidine, guanfacine, modafinil, and bupropion) were superior
to placebo in youth with regard to clinician-rated ADHD symptoms (Cortese
et al. 2018). Amphetamines had an effect size of 1.02 (95% CI, 1.19–0.85),
and methylphenidate had an effect size of 0.78 (95% CI, 0.93–0.62). Amphet-
amine was more efficacious than methylphenidate, guanfacine, atomoxetine,
and modafinil, whereas methylphenidate was more efficacious than atomox-
etine. A meta-analysis of 190 randomized trials including 52 different treat-
ments, both pharmacological and nonpharmacological, and 26,114 subjects
with ADHD found that stimulants, nonstimulants, and behavioral therapy
were significantly more efficacious than placebo (Catalá-López et al. 2017).
Stimulants outperformed nonstimulants and behavioral therapy. Methylphe-
nidate and amphetamine had similar efficacy. Combination treatment with
stimulants and behavioral therapy was superior to stimulants alone.
Compared with placebo, psychostimulants have a significantly greater abil-
ity to reduce externalizing ADHD symptoms such as overactivity (e.g., fidget-
iness, off-task behavior during direct observation), classroom-disruptive
behavior (e.g., constant requests of the teacher during direct observation), and
parent- and teacher-rated inattention. Both types of stimulants have been
shown to improve child behavior during parent-child interactions and prob-
lem-solving activities with peers. The behavior of children with ADHD has a
tendency to elicit negative, directive, and controlling behavior from their par-
Table 2–2. Representative controlled studies of stimulant medication for ADHD

46 Clinical Manual of Child and Adolescent Psychopharmacology

Age
range,
Study N years Design Drug (dosage*) Duration Response Comments

Castellanos et 20 6–13 Crossover MPH (45 mg bid), 9 weeks ADHD + TD Dosage-related tics at high
al. 1997 DEX (22.5 mg dosages
bid)

Childress et al. 107 6–12 Crossover R-AMPH (Evekeo; 2 weeks P<0.0001 for all time R-AMPH effective with
2015 10–40 mg/day); points 0.45–10 hours single daily dose 0.45–
PBO 10 hours following
administration; well
tolerated

Coghill et al. 157 6–17 Randomized LDX (30, 50, or 6 weeks Treatment failure: LDX LDX efficacy maintained
2014 withdrawal 70 mg/day); 15.8%, PBO: 67.5% over long-term periods
PBO

Douglas et al. 17 6–11 Crossover MPH (0.3, 0.6, 4 weeks 70% (behavior) No cognitive toxicity at
1995 0.9); PBO high dosages; linear dose-
response curves

Elia et al. 48 6–12 Crossover MPH (0.5, 0.8, 6 weeks MPH, 79%, DEX: 86% Response rate for two
1991 1.5); PBO; DEX stimulants: 96%
(0.25, 0.5, 0.75)
Table 2–2. Representative controlled studies of stimulant medication for ADHD (continued)

Age
range,
Study N years Design Drug (dosage*) Duration Response Comments

Fernández de 579 7–9 Parallel MPH (<0.8 tid) 14 weeks MPH 77%, DEX: 10%, Treatments targeting
la Cruz et (4 months) none 13% ADHD symptoms
al. 2015 helpful for improving
irritability in children
with ADHD; moreover,

Attention-Deficit/Hyperactivity Disorder
irritability did not
appear to influence
response to treatment

Findling et al. 269 13–17 Parallel, LDX (30, 50, 70 52 weeks Change from baseline TEAEs (≥5%) such as
2013 followed mg/day) (SD) ADHD-RS-IV upper respiratory tract
by open- –26.2 (P<0.001) infection (21.9%),
label decreased appetite
(21.1%), headache
(20.8%), decreased
weight (16.2%),
irritability (12.5%),
and insomnia (12.1%)

47
Table 2–2. Representative controlled studies of stimulant medication for ADHD (continued)

48 Clinical Manual of Child and Adolescent Psychopharmacology

Age
range,
Study N years Design Drug (dosage*) Duration Response Comments

Findling et al. 461 6–17 Parallel Stimulant + GXR 9 weeks Least-squares change vs. GXR added to stimulant
2014 (1–4 mg qAM PBO: GXR qAM + reduced oppositional
or qPM) + PBO stimulant –2.4, symptoms in subjects
(qAM or qPM); P=0.001; GXR qPM + whose symptoms had
stimulant + stimulant –2.2, suboptimal response to
PBO P=0.003 stimulant alone

Gadow et al. 34 6–12 Crossover MPH (0.1, 0.3, 8 weeks MPH 100% No nonresponders in terms
1995 (ADHD + 0.5); PBO of behavior; physician
tic) motor tic ratings showed
two minimal increases
while subjects were
taking drug; only effects
over 8 weeks of
treatment studied

Gillberg et al. 62 6–12 Parallel MAS (17 mg); 60 weeks 70%; 27%–40% No dropouts, but only
1997 PBO improved 25% of placebo group at
15-month assessment

Greenhill et 277 6–12 Parallel Long-acting MPH; 3 weeks 70% Mean total daily dosage
al. 2001 PBO 40 mg; FDA registration
Table 2–2. Representative controlled studies of stimulant medication for ADHD (continued)

Age
range,
Study N years Design Drug (dosage*) Duration Response Comments

Greenhill et 321 6–16 Parallel MPH-MR 3 weeks MPH-MR 64%, PBO Mean MPH-MR dosage
al. 2002 (Metadate ER; 27% 40.7 mg/day (1.28 mg/
20, 60 mg qd); kg/day)
PBO (tid)

Attention-Deficit/Hyperactivity Disorder
Greenhill et 97 6–17 Parallel d-MPH-ER 7 weeks d-MPH-ER 67.3%, PBO Mean d-MPH-ER
al. 2006a (Focalin LA; 5– 13.3% dosage 24 mg/day
30 mg qd); PBO

Greenhill et 165 3–5.5 Crossover IR MPH (1.25, 70 weeks 88%; ES=0.4–0.8 Optimal IR MPH dosage
al. 2006b 2.5, 5, 7.5 mg 14.22±8.1 mg/day (0.7±
tid); PBO (tid) 0.4 mg/kg/day); treat-
ment effect sizes less than
in school-age children

Klein et al. 84 6–15 Parallel MPH (1.0) 5 weeks MPH, 59%–78%, PBO MPH reduced CD
1997 9%–29% symptoms

49
Table 2–2. Representative controlled studies of stimulant medication for ADHD (continued)

50 Clinical Manual of Child and Adolescent Psychopharmacology

Age
range,
Study N years Design Drug (dosage*) Duration Response Comments

Levin et al. 126 18–60 Parallel MAS (60 mg, 13 weeks Abstinence in past Robust doses of MAS +
2015 80 mg); PBO 3 weeks: CBT effective for co-
with CBT 30.2% (80 mg) vs. occurring ADHD and
17.5% (60 mg) vs. cocaine use disorder,
7% (PBO) both improving ADHD
symptoms and reducing
cocaine use

Manor et al. 200 6–13 Parallel PS-Omega3 vs. 15 weeks + ADHD-Index PS-Omega3: reduced
2012 PBO 15-week (P=0.020); Global: ADHD symptoms in
extension restless/impulsive children; preliminary
phase (P=0.014); DSM-IV analysis suggested that
inattentive (P=0.027); this treatment may be
and DSM-IV total especially effective in a
score (P=0.044) subgroup of hyperactive-
markedly reduced in impulsive, emotionally
PS-Omega3 group vs. and behaviorally dysreg-
PBO group ulated ADHD children
Table 2–2. Representative controlled studies of stimulant medication for ADHD (continued)

Age
range,
Study N years Design Drug (dosage*) Duration Response Comments

McElroy et al. 260 18–55 Parallel LDX (30, 50, 14 weeks 50 mg (P=0.008) vs. 70 Efficacy demonstrated for
2015 70 mg) mg (P≤0.001) vs. 30 active drug groups
mg (NS) compared with placebo
group in decreased
binge-eating days, binge-

Attention-Deficit/Hyperactivity Disorder
eating cessation, and
global improvement

McGough et 97 6–17 Crossover MPH transdermal 2 weeks 79.8% MPH transdermal system
al. 2006 worn 9 hours/ well tolerated and
day (12.5, 18.75, significantly more
25, 37.5 cm2); efficacious than PBO;
PBO FDA registration trial

MTA 579 7–9 Parallel MPH (<0.8 tid) 14 weeks MPH 77%, DEX 0%, NIMH-sponsored
Cooperative (4 months) none: 13% multisite, multimodal
Group study supports stimulant
1999b medication use in
ADHD

Musten et al. 31 4–6 Crossover MPH (0.3, 0.5) 3 weeks MPH>PBO MPH: improvement in
1997 attention in preschoolers

51
Table 2–2. Representative controlled studies of stimulant medication for ADHD (continued)

52 Clinical Manual of Child and Adolescent Psychopharmacology

Age
range,
Study N years Design Drug (dosage*) Duration Response Comments

Newcorn et al. 333 6–12 Parallel GXR (1–4 mg 8 weeks GXR qAM = GXR qPM; Once-daily GXR mono-
2013 qAM, PBO both >PBO therapy effective whether
qPM); GXR administered in morning
(PBO qAM, 1– or evening
4 mg qPM); PBO

Philipsen et al. 419 18–58 Parallel MPH (average 12 months ES 0.5 for MPH vs. PBO Psychological interven-
2015 48.8 mg) tions resulted in better
outcomes during a 1-year
period when combined
with MPH vs. PBO

Rapport et al. 76 6–12 Crossover MPH (5, 10, 15, 5 weeks 94% (behavioral), 53% MPH normalized behavior
1994 20 mg); PBO (attention) more than academic
performance; higher
dosages better; linear
dose-response curve
Table 2–2. Representative controlled studies of stimulant medication for ADHD (continued)

Age
range,
Study N years Design Drug (dosage*) Duration Response Comments

Rommel et al. 232 16–20 NA Energy expenditure 4 years ES small (0.02) for Regular exercise in
2015 twin based on self- hyperactivity/ adolescents significantly
pairs reports of PA impulsivity (0.21); associated with reduced
frequency, inattention reduced ADHD symptom levels
intensity, and (0.19) in early adulthood

Attention-Deficit/Hyperactivity Disorder
duration

Scahill et al. 62 Mean Parallel Guanfacine XR 8 weeks Cohen’s d=1.57 ER guanfacine shown to be
2015 8.5 (1–4 mg/day) safe and effective for
vs. PBO reducing hyperactivity,
impulsiveness, and
distractibility in children
with ASD

Schachar et al. 91 6–12 Parallel MPH (33.5 mg); 52 weeks ES 0.7 SD 15% side effects: affective
1997 PBO symptoms, overfocusing
led to dropouts

Spencer et al. 23 18–60 Crossover MPH (1 mg/kg/ 7 weeks MPH 78%, PBO 4% MPH at 1 mg/kg/day led
1995 day) to improvement in adults
equivalent to that seen in
children

53
Table 2–2. Representative controlled studies of stimulant medication for ADHD (continued)

54 Clinical Manual of Child and Adolescent Psychopharmacology

Age
range,
Study N years Design Drug (dosage*) Duration Response Comments

Swanson et al. 29 7–14 Crossover MAS (5, 10, 15, 7 weeks 100% Adderall peak at 3 hours;
1998 20 mg); PBO, MPH at 1.5 hours
MPH

Tannock et al. 40 6–12 Crossover MPH (0.3, 0.6); 2 weeks 70% Activity level better in both
1995a ADHD + anxiety groups; working
memory not improved in
anxious children

Tannock et al. 28 6–12 Crossover MPH (0.3, 0.6, 2 weeks 70% Effects on behavior: dose-
1995b 0.9); PBO response curve linear but
effects on response
inhibition U-shaped;
suggests dosage adjust-
ment on objective
measures
Table 2–2. Representative controlled studies of stimulant medication for ADHD (continued)

Age
range,
Study N years Design Drug (dosage*) Duration Response Comments

Vitiello et al. 579 7–9 Parallel and MPH equivalents 14 months Heart rate in medication Risk of prehypertension or
2012 naturalistic 22.6–38.1 mg alone (84.2 bpm) and hypertension over
combined medication/ 10-year observation not
behavioral modifica- increased with stimulant
tion (84.6 bpm) groups use; suggests cardiovas-

Attention-Deficit/Hyperactivity Disorder
was higher vs. behav- cular safety requires
ioral modification–only monitoring, starting
group (79.1 bpm) at 14 with baseline health
months status before stimulants

Wigal et al. 132 6–17 Parallel d-MPH (2, 5, 10); 4 weeks d-MPH 67%, d,l-MPH Average d-MPH dosage
2004 d,l-MPH (5, 10, 49% (18.25 mg) as safe and
20); PBO effective as half of the
average d,l-MPH dose
(32.14 mg)

Wilens et al. 177 13–18 Parallel OROS MPH (18, 2 weeks OROS MPH 52%, PBO OROS MPH well
2006 36, 54, 72 mg 31% tolerated and effective in
qd); PBO adolescents at total daily
dosage of up to 72 mg;
FDA trial evidence for
adolescents 72 mg

55
Table 2–2. Representative controlled studies of stimulant medication for ADHD (continued)

56 Clinical Manual of Child and Adolescent Psychopharmacology

Age
range,
Study N years Design Drug (dosage*) Duration Response Comments

Wilens et al. 314 13–17 Parallel Guanfacine XR 13 weeks ES=0.52 GXR associated with
2015 (1–7 mg) vs. statistically significant
PBO improvements in
ADHD symptoms in
adolescents

Note. *Dosages are listed in milligrams/kilogram/dose and medication or PBO is given twice daily (bid) unless otherwise stated.
ADHD-RS-IV=ADHD Rating Scale–IV; ASD=autism spectrum disorder; bpm=beats per minute; CBT=cognitive-behavioral therapy; CD=conduct
disorder; DEX=dextroamphetamine; ER=extended release; ES=effect size; GXR=guanfacine extended release; IR=immediate release; LA=long-acting;
LDX=lisdexamfetamine; MAS=mixed amphetamine salts (Adderall); MPH=methylphenidate; MPH-MR=modified-release methylphenidate; NA=not
applicable; NIMH=National Institute of Mental Health; NS=nonsignificant; OROS=osmotic-release oral system; PA=physical activity; PBO= placebo;
PS=phosphatidylserine; R-AMPH=racemic-amphetamine; TD=Tourette’s disorder; TEAE=treatment-emergent adverse event; XR= extended release.
 Attention-Deficit/Hyperactivity Disorder 57

ents and peers. When these children are started on a regimen of stimulants,
their mother’s rate of disapproval, commands, and control diminishes to the
extent seen between mothers and their children who do not have ADHD. Hy-
peractive children with CD show reductions in aggressive behavior when
treated with stimulants, as observed in structured and unstructured school set-
tings. Stimulants also can reduce the display of covert antisocial behaviors
such as stealing and property destruction (Hinshaw et al. 1992). Although
there is some evidence that stimulants may improve neurocognitive impair-
ments associated with ADHD, findings are inconsistent (Wang et al. 2015).

Mechanism of Psychostimulant Action

Psychostimulants are thought to release catecholamines and to block their re-
uptake. Methylphenidate blocks dopamine and norepinephrine reuptake, in-
creasing concentrations in the synaptic cleft. The amphetamines both block
dopamine and norepinephrine reuptake and induce release of dopamine
(Hodgkins et al. 2012).

Neuroimaging
Early brain imaging studies reported psychostimulant effects on glucose metab-
olism. In PET and 18F-labeled PET studies carried out in adults with ADHD,
stimulant treatment was associated with increased brain glucose metabolism
in the striatal and frontal regions (Ernst and Zametkin 1995), but other stud-
ies (Matochik et al. 1994) have been unable to find a change in glucose me-
tabolism during acute and chronic stimulant treatment. A 2012 meta-analysis
of 55 studies revealed growing evidence of ADHD-related dysfunction in
multiple neuronal systems involved not only in higher-level cognitive functions
but also in sensorimotor processes, including the visual system, and in the de-
fault network. This finding extended our neurobiological models of ADHD
pathophysiology beyond those focused on prefrontal-striatal circuits (Cortese
et al. 2012) and led to a theory that ADHD resulted from a “breakthrough” of
resting-state default mode activity into active cognitive processes, disrupting
them (Sonuga-Barke and Castellanos 2007).
During treatment with 11C-labeled methylphenidate, the drug’s concen-
tration in the brain is maximal in the striatum, an area rich in dopamine ter-
minals where the dopamine transporter resides. Significant differences in the
pharmacokinetics of [11C]methylphenidate and [11C]cocaine (Volkow et al.
58 Clinical Manual of Child and Adolescent Psychopharmacology

1995) have been found in adults with cocaine addiction. Although both drugs
rapidly concentrate in the striatum, methylphenidate is cleared more slowly
than cocaine. This may explain why oral methylphenidate does not reinforce
as powerfully as does snorted or injected cocaine and does not lead to as much
self-administration as does cocaine.
On the other hand, therapeutic doses of oral methylphenidate have been
shown to significantly increase extracellular dopamine in the human brain. As
Volkow et al. (2001) noted, “DA [dopamine] decreases the background firing
rates and increases signal-to-noise in target neurons[;] we postulate that the
amplification of weak DA signals in subjects with ADHD by methylpheni-
date would enhance task-specific signaling, improving attention and decreas-
ing distractibility” (p. 1).
Functional MRI data have shown that psychostimulants can be effective
in suppressing activation in the default mode or task-negative neural circuit
(Peterson et al. 2009). This neural circuit becomes increasingly deactivated as
attentional demands increase. Failure to suppress or deactivate this circuit is
associated with attentional lapses (Weissman et al. 2006). Children with
ADHD show impaired suppression of the task-negative circuit during atten-
tionally demanding tasks; psychostimulants seem to normalize this suppres-
sion and improve task performance. Other functional MRI studies suggest
that psychostimulants may have direct effects on affective circuits, offering a
potential explanation for the palliative effect that psychostimulants can have
on emotional impulsivity in hyperactive children (Posner et al. 2011a, 2011b).
In an additional meta-analysis, Hart et al. (2014) found consistency across the
potential site of action of stimulants, demonstrating increased activation in
the bilateral inferior frontal cortex/insula during inhibition and time discrim-
ination, key areas of cognitive control.

Psychostimulant Treatment Studies

A variety of RCTs of ADHD medications, including those based on stimu-
lants (methylphenidate and amphetamine) and nonstimulants, have contrib-
uted to the rich evidence base for the efficacy and safety of these preparations
in the treatment of ADHD in youth, as shown by the sample of 35 ADHD
RCTs listed in Table 2–2. Details of the individual medications are given in
the sections that follow.
 Attention-Deficit/Hyperactivity Disorder 59

Methylphenidate, Short-Acting Preparations

Pharmacokinetics. Methylphenidate constitutes the active ingredient of the
majority of stimulant medications prescribed in the United States. With the
exception of the two dexmethylphenidate products (Focalin and Focalin XR;
methyl α-phenyl-2-piperidineacetate hydrochloride), methylphenidate is
used in its racemic form, which is composed of the d- and l-threo enantiomers.
The d-threo enantiomer is more pharmacologically active than the l-threo en-
antiomer.
Methylphenidate absorption into the systemic circulation is rapid after the
immediate-release (IR) tablet is swallowed, such that effects on behavior can be
seen within 30 minutes. The plasma concentration peaks by 90 minutes, with
a mean half-life of about 3 hours and a 3- to 5-hour duration of action.
If children take one methylphenidate dose just after breakfast, most will
require a second dose at lunch (which for young children must be given by the
school nurse) and a third dose just after school in the afternoon to prevent loss
of effectiveness as well as rebound crankiness and tearfulness. Long-duration
preparations of methylphenidate overcome the need for multiple daily doses,
and these preparations are now the mainstay of practice.

Metabolism and excretion. In humans, methylphenidate is metabolized ex-

trahepatically via de-esterification to α-phenylpiperidine acetic acid (or rital-
inic acid), an inactive metabolite. About 90% of radiolabeled methylphenidate
is recovered from the urine.

Dosage and administration. IR tablets may be utilized to augment long-

duration forms to provide a boost in the morning or to smooth withdrawal in
the late afternoon. Treatment may be initiated with either IR or long-duration
preparations. If one starts with a long-duration methylphenidate such as os-
motic-release oral system (OROS) methylphenidate (Concerta), it should be
initiated with the lowest option (18 mg) in the morning. The total daily dose
may be increased by adding additional 18-mg caplets at the morning admin-
istration, up to 54 mg for children (three caplets) and 72 mg (four caplets) for
adolescents and adults.

Efficacy: clinical trials. Multiple RCTs, in addition to more than a half-

century of clinical use, support methylphenidate’s safety and efficacy (Pliszka
60 Clinical Manual of Child and Adolescent Psychopharmacology

and AACAP Work Group on Quality Issues 2007). The MTA study used a
double-blind, placebo-controlled titration protocol to determine each child’s
optimal methylphenidate dosage, which was delivered in a three-times-daily
dosing schedule (Greenhill et al. 2001; MTA Cooperative Group 1999b).
School-age children with ADHD demonstrated a greater than 75% response
rate to methylphenidate. Both the medication alone and the combined med-
ication +behavioral treatment groups showed significant improvements in in-
attention and hyperactivity compared with behavioral treatment alone and
community care. The medication-alone group, on average, required higher
dosages of methylphenidate (37.7 mg/day) compared with the combined
group (31.2 mg/day) (MTA Cooperative Group 1999b).
The Preschool ADHD Treatment Study (PATS), carried out with a sim-
ilar titration trial and subsequent RCT methylphenidate optimization
scheme, was conducted with 165 preschoolers with ADHD by the same in-
vestigators as the MTA study (Greenhill et al. 2006a, 2006b, 2006c). The
mean best IR methylphenidate total daily dose varied by age, with preschool-
ers doing best at 14.4±0.75 mg/day (0.75 mg/kg/day) and school-age chil-
dren in the MTA doing best at 31.2±0.55 mg/day (0.95 mg/kg/day). IR effect
sizes were greater in school-age children (1.2 according to teachers and 0.8 ac-
cording to parents at 30 mg/day) than in preschoolers (0.8 according to teach-
ers and 0.5 according to parents at 14 mg/day), but optimal total daily doses
were higher in the former. The preschoolers also had higher rates of adverse ef-
fects. On the basis of these findings, the AAP clinical practice guidelines rec-
ommend parent training in behavioral management and behavioral classroom
interventions as first-line approaches for preschoolers and methylphenidate
treatment as a second line approach (Wolraich et al. 2019).
Follow-up studies with the preschool ADHD sample 3 and 6 years after
study completion revealed that 70.9% of the sample continued taking an in-
dicated ADHD medication for as long as 6 years after completing the PATS
protocol (Vitiello et al. 2015).

Medication interactions. Methylphenidate interacts with monoamine oxi-

dase inhibitors (e.g., isocarboxazid, phenelzine, selegiline, and tranylcypro-
mine), as well as antibiotics with similar activity (linezolid), leading to blood
pressure elevations and an increase in methylphenidate serum concentrations.
In addition, phenytoin, phenobarbital, tricyclic antidepressants, and warfarin
 Attention-Deficit/Hyperactivity Disorder 61

increase the serum concentrations of methylphenidate. The effects of centrally

acting antihypertensives (i.e., guanadrel, methyldopa, and clonidine) can be re-
duced by methylphenidate.

Methylphenidate, Long-Duration Preparations

Long-duration preparations deliver methylphenidate over the school day from
a single morning administration. This approach is a mainstay of clinical prac-
tice in the United States (Chou et al. 2012). Long-duration formulations dif-
fer in the number and shape of stimulant pulses that they release over time into
the blood circulation. Long-duration methylphenidate medications include
single-pulse formulations such as extended-release (ER) Metadate; the dual-
pulse beaded methylphenidate products such as Metadate CD, long-acting
(LA) Ritalin, Focalin XR, Aptensio XR, Quillivant XR, and QuilliChew ER;
and complex-release formulations, such as Concerta (OROS methylpheni-
date), that simulate a triple-pulse delivery system.
Single-pulse methylphenidate sustained-release preparations. Single-
pulse, sustained-release methylphenidate formulations (Methylin ER and
Metadate ER) are formulated in a wax-matrix preparation to prolong release.
They have a slower onset of action than IR methylphenidate, produce lower
serum concentrations, and have a 6- to 8-hour duration of action. Clinicians
regard these as less effective in practice than the newer long-duration prod-
ucts. Clinicians administer them twice daily or give them with an IR tablet in
the morning to compensate for the slow onset of action.
Dual-pulse, beaded methylphenidate preparations. Beaded methylpheni-
date products (Ritalin LA) are an ER formulation with a dual-pulse release
profile that use a proprietary SODAS (Spheroidal Oral Drug Absorption Sys-
tem) technology involving a mixture of IR and delayed-release (DR) beads.
These preparations help young children who have difficulty swallowing pills,
because the capsule can be opened and the tiny medication spheres can be
sprinkled into applesauce or yogurt.
Each dual-pulse capsule contains various proportions of IR methylpheni-
date beads and half as enteric-coated DR beads. For example, Ritalin LA’s 50%
proportion of each mimics the use of IR methylphenidate given in two doses,
4 hours apart. Given once daily, Ritalin LA exhibits a lower second-peak con-
centration, higher interpeak minimum concentrations, and less peak-to-peak
62 Clinical Manual of Child and Adolescent Psychopharmacology

trough fluctuation in serum concentration of methylphenidate than two ad-

ministrations of IR methylphenidate tablets given 4 hours apart. This effect
may be due to the earlier onset and more prolonged absorption of the DR
beads. The efficacy of Ritalin LA in ADHD treatment was established in one
controlled trial involving 134 children ages 6–14 years (Biederman et al. 2003).
Single-isomer dexmethylphenidate (Focalin, Focalin XR). D e x m e t h y l -
phenidate hydrochloride (Focalin and Focalin XR) is the d-threo enantiomer of
racemic methylphenidate. The drug’s plasma concentration increases rapidly af-
ter ingestion, reaching a maximum in the fasted state at about 1–1.5 hours post-
dose (Quinn et al. 2004). Plasma levels of dexmethylphenidate are comparable
with those achieved by a milligram dose of IR methylphenidate twice that of the
single enantiomer; that is, plasma levels of dexmethylphenidate 10 mg are
equivalent to methylphenidate 20 mg. This is thought to be related to the lack
of efficacy of the l-threo enantiomer, with racemic methylphenidate having half
the dose of d-threo methylphenidate compared with dexmethylphenidate.
Focalin XR is an ER form of dexmethylphenidate that uses the same pro-
prietary SODAS technology as Ritalin LA. Each Focalin XR capsule contains a
1:1 mixture of IR beads and DR beads. In a single dose, Focalin XR capsules in
strengths of 5 mg, 10 mg, and 20 mg provide the same amount of dexmethyl-
phenidate as Focalin at dosages of 2.5 mg, 5 mg, and 10 mg bid.
IR dexmethylphenidate (5 mg, 10 mg, or 20 mg total daily dose) was com-
pared with placebo in a multicenter, 4-week, parallel-group study of 132 pa-
tients (Keating and Figgitt 2002). Patients treated with dexmethylphenidate
showed a statistically significant improvement in SNAP-ADHD teacher-rated
symptom scores from baseline compared with patients who received placebo.
The long-duration preparation (Focalin XR) was demonstrated to be ef-
fective in a randomized, double-blind, placebo-controlled, parallel-group
study of 103 pediatric patients ages 6–17 years (Greenhill et al. 2006c). Using
the mean change from baseline scores on teacher-rated Conners’ ADHD/
DSM-IV Scales, the study reported a significantly greater decrease in ADHD
scores for youth taking active Focalin XR than for youth receiving placebo.
The drug’s effectiveness for adult ADHD was reported in a 5-week, random-
ized, double-blind, parallel-group, placebo-controlled study of 221 adults
ages 18–60 years whose signs and symptoms met DSM-IV criteria for ADHD
on the DSM-IV ADHD Rating Scale (ADHD-RS) (Spencer et al. 2007b).
 Attention-Deficit/Hyperactivity Disorder 63

Signs and symptoms of ADHD were far fewer for adults taking daily doses of
20 mg, 30 mg, and 40 mg than for those randomly assigned to placebo.
OROS methylphenidate (Concerta). The OROS methylphenidate caplet
uses an osmotic delivery system to produce ADHD symptom reduction for
up to 12 hours (Swanson et al. 2004). IR methylphenidate is applied to the
outside of the OROS caplet to provide immediate drug benefits in the first
2 hours after it is swallowed. Its long-duration component is delivered by an
osmotic pump (OROS) that gradually releases the drug from an internal res-
ervoir over a 12-hour period, producing a slightly ascending methylphenidate
serum concentration curve. Taken once daily, it mimics the serum concentra-
tions produced by taking IR methylphenidate three times daily, but with less
variation (Modi et al. 2000). Long-duration preparations containing the
beaded dual-pulse technology show a greater release concentration in the
morning than does OROS, but they do not last as long in the afternoon
(Swanson et al. 2004).
Two double-blind, placebo-controlled RCTs have tested the efficacy and
safety of OROS methylphenidate compared with IR methylphenidate for
children with ADHD (Swanson et al. 2003). Another multisite trial showed
efficacy for Concerta over placebo in adolescents when the upper limit of the
dosage range of Concerta was extended to 72 mg/day (Wilens et al. 2006). In
addition, OROS methylphenidate was demonstrated in a small study (N=6)
to have a longer duration of effect in reducing ADHD-induced driving im-
pairments in the evening than IR methylphenidate given three times daily
(Cox et al. 2004). A 2012 study demonstrated increased efficacy (66.1%), su-
perior satisfaction, and equivalent safety for OROS methylphenidate com-
pared with IR methylphenidate in a tolerable forced-titration scheme from IR
methylphenidate to OROS methylphenidate (Chou et al. 2012), reinforcing
the value of the OROS preparation.
Multilayer bead technology (Aptensio XR). In May 2015, the FDA ap-
proved a new formulation of an ER methylphenidate known as Aptensio XR.
The capsules contain multilayer beads designed to provide both a rapid onset
and a long duration of action. This formulation of methylphenidate has been
available in Canada as Biphentin since 2006. The recommended starting dos-
age in patients older than 6 years is 10 mg every morning with or without food.
The dosage can be increased in weekly increments of 10 mg up to a maximum
64 Clinical Manual of Child and Adolescent Psychopharmacology

of 60 mg taken once daily. The capsules may be swallowed whole or, alterna-
tively, opened, sprinkled on applesauce, and taken immediately. In a random-
ized, double-blind, placebo-controlled trial, 221 patients had significantly
lower DSM-IV ADHD-RS scores with Aptensio XR versus placebo in the
double-blind phase as well as an 11-week open-label phase (Wigal et al. 2015).
No studies are available comparing Aptensio XR directly with other LA meth-
ylphenidate formulations, and this lack of comparison studies limits any con-
clusion about clinical advantage over existing preparations at this time.

More Palatable Methylphenidate Preparations

Methylin Chewable Tablets and Methylin Oral Solution are two forms of a
short-duration branded methylphenidate generic formulated for young chil-
dren who have difficulty swallowing pills or capsules. Methylin Chewable Tab-
lets show peak plasma methylphenidate concentrations in 1–2 hours, with a
mean peak concentration of 10 ng/mL after a 20-mg chewable tablet is taken.
High-fat meals delay the peak by 1 hour (1.5 hours fasted, and 2.4 hours fed),
which is similar to that seen with an IR methylphenidate tablet. Methylin
Chewable Tablets are available in doses of 2.5 mg, 5 mg, and 10 mg. Methylin
Oral Solution is available in 5 mg/mL and 10 mg/mL strengths. No large-scale
clinical trials published that used Methylin Chewable Tablets or Methylin Oral
Solution have been published.
In January 2013, the first ER liquid methylphenidate preparation, Quilli-
vant XR, was released. It is available as a liquid (25 mg/5 mL suspension), which
must be reconstituted before administration, and has a duration of action of
12 hours. In one randomized, double-blind, placebo-controlled crossover
study of 45 children ages 6–12 years, Quillivant significantly reduced ADHD
symptoms compared with placebo (Cortese et al. 2017). The same manufac-
turer also produces a chewable version of Quillivant called QuilliChew. Quil-
liChew significantly improved ADHD symptoms compared with placebo in
one randomized, double-blind, placebo-controlled study of 90 children ages
6–12 years (Cortese et al. 2017).

Transdermal Methylphenidate Preparations

Methylphenidate is available in a transdermal patch (Daytrana). It is steadily
absorbed through the skin, with no noticeable reduction in ADHD symptoms
for the first 2 hours. This delivery method bypasses the first-pass effect, so
 Attention-Deficit/Hyperactivity Disorder 65

blood levels of l-methylphenidate are higher than those obtained from the oral
route. Steady dosing with the patch results in higher peak methylphenidate lev-
els than does equivalent doses of OROS methylphenidate, suggesting increased
absorption. Duration of action for a 9-hour wear period is about 11.5 hours. A
double-blind, placebo-controlled crossover study conducted in a laboratory
classroom showed significantly lower ADHD symptom scores and higher
mathematics test scores for participants receiving the active versus placebo
patch for postdose hours 2–9 (McGough et al. 2006). Transdermal methyl-
phenidate appears to be as effective as other long-duration preparations, but
adverse effects, including anorexia, insomnia, and tics, occur more frequently
with the patch, and mild skin reactions are common. There has been a single
report of possible Stevens-Johnson syndrome occurring in a child treated with
the transdermal patch.

Amphetamines
Pharmacokinetics. As with methylphenidate, amphetamines are manufac-
tured in the single dextro isomer (e.g., dextroamphetamine [Dexedrine] and
lisdexamfetamine [Vyvanse]) or in a racemic version, with mixtures of d- and
l-amphetamine (e.g., Adderall, Adderall XR, and Evekeo). The efficacy of
these amphetamine products matches that of methylphenidate products in
controlling overactivity, inattention, and impulsivity in patients with ADHD.
Some children who experience severe adverse events associated with taking
methylphenidate may achieve response without such problems when taking
amphetamine products. Absorption of amphetamines is rapid, and the plasma
levels of the drug peak 3 hours after oral administration. All of the amphet-
amines are metabolized hepatically. Urine acidification increases urinary out-
put of amphetamines (Greenhill et al. 2002). Taking the medication with
ascorbic acid or fruit juice decreases absorption, whereas taking it with alka-
linizing agents such as sodium bicarbonate increases it (Vitiello 2007).
Effects of dextroamphetamine can be seen within 1 hour of ingestion, and
the duration of action is up to 5 hours, which is somewhat longer than that of
methylphenidate. Nevertheless, at least twice-daily administration is needed to
extend the IR preparation treatment throughout the school day.
Racemic Adderall and Adderall XR. Adderall uses a mixture of the various
salts of amphetamine. Adderall XR is a dual-pulse capsule preparation that in-
66 Clinical Manual of Child and Adolescent Psychopharmacology

cludes both IR and ER beads. These mixed amphetamine salts have not been
shown to offer any advantage over similarly designed long-duration methyl-
phenidate products, but some patients’ symptoms may respond better to one
and not to another.
Lisdexamfetamine dimesylate (Vyvanse) is the first formulation of amphet-
amine available for the treatment of ADHD in a prodrug formulation intended
for a single, long-duration, daily-dose regimen. The preparation is inactive par-
enterally because the d-amphetamine molecule is covalently bonded to L-lysine,
an essential amino acid. The pharmacologically active d-amphetamine is re-
leased after digestion when the covalent bond is cleaved. This bond is an am-
ide bond, which means that a proteolytic enzyme or enzymes in the digestive
tract or in red blood cells release the amphetamine. Prodrugs were originally
employed to reduce a medication’s potential for abuse, diversion, or overdose
toxicity (Jasinski and Krishnan 2009).
Two double-blind, placebo-controlled RCTs involving a total of 342 chil-
dren with ADHD found that those receiving lisdexamfetamine at dosages of
30–50 mg for 3 or 4 weeks showed more improvement in DSM-IV ADHD-
RS scores than those receiving placebo. The first study—a Phase II, double-
blind, placebo-controlled, randomized crossover trial involving 52 children
with ADHD (Biederman et al. 2007a)—showed significant reductions of
ADHD behaviors with lisdexamfetamine compared with placebo according to
trained but observer-blind ratings across eight hourly sessions of a 12-hour day.
The second study—a multisite, Phase III RCT of 290 children with ADHD
ages 6–12 years, with a parallel design (Biederman et al. 2007b)—showed sig-
nificant decreases in ADHD behaviors reported by parents for morning, af-
ternoon, and early evening on the Conners’ Parent Rating Scale.
Maintenance of efficacy with lisdexamfetamine has been demonstrated.
In a Phase III extension randomized-withdrawal, placebo-controlled study,
157 children ages 6–17 years with ADHD who completed the 26-week open-
label trial period were randomly assigned to either their optimized dosage of
lisdexamfetamine dimesylate (30 mg/day, 50 mg/day, or 70 mg/day) or pla-
cebo for a 6-week withdrawal period (Coghill et al. 2014). Significantly fewer
patients who continued taking the stimulant compared with those receiving
placebo met the criteria for treatment failure, which was defined as an at least
50% increase in DSM-IV ADHD-RS total score and at least a two-point in-
crease in Clinical Global Impression–Severity score.
 Attention-Deficit/Hyperactivity Disorder 67

More palatable preparations. Multiple amphetamine options are available

for those who cannot swallow pills. Vyvanse can be dissolved in juice or water; it
is also available as a chewable tablet. Orally disintegrating tablets are available as
Evekeo ODT and Adzenys XR-ODT. Adzenys ER, Dyanavel XR, and ProCen-
tra are liquids. Additionally, Adderall XR and Mydayis capsules can be opened
and sprinkled on a small amount of food such as applesauce.

Adverse Events and Effects

The most common adverse effects associated with stimulants include delay in
sleep onset, appetite loss, weight decrease, headache, and abdominal pain. In-
frequent adverse events include tics, nausea, dry throat, dizziness, tachycardia,
and palpitations. Rare but serious adverse events include angina, tactile and vi-
sual hallucinations, urticaria, fever, arthralgia, exfoliative dermatitis, erythema
multiforme, and thrombocytopenic purpura. Also rare are priapism, peripheral
vasculopathy, visual disturbance, insect phobias, leukopenia, anemia, eosino-
philia, transient depression, hair loss, and reports of sudden unexpected death.
One case of neuroleptic malignant syndrome has been reported in an individ-
ual treated with a combination of methylphenidate and venlafaxine.

Standard Warnings
All stimulant products carry a black box warning in the package insert that the
product should be used with care in patients with a history of drug depen-
dence or alcoholism. In addition, there is a warning about the extremely rare
adverse event of sudden death that may be associated with preexisting cardiac
abnormalities or other serious heart problems. For adults, the warning extends
to stroke and myocardial infarction.
The package insert text warns adults that they should be cautious about tak-
ing stimulants if they have preexisting hypertension, heart failure, recent myo-
cardial infarction, or ventricular arrhythmia. Patients with preexisting psychotic
and bipolar psychiatric illness are cautioned against taking stimulants because of
the psychotomimetic properties of these agents at high doses. Additionally,
there is a warning about stimulants’ ability to slow growth rates and lower the
convulsive threshold in children. However, in ADHD patients without epi-
lepsy, stimulant treatment did not increase the incidence of seizures compared
with placebo, and even in those with well-controlled epilepsy, methylphenidate
was effective for ADHD and had a low seizure risk (Cortese et al. 2013).
68 Clinical Manual of Child and Adolescent Psychopharmacology

These concerns arose from an FDA review of the cardiovascular and psy-
chiatric adverse events associated with approved stimulant medications. On
June 30, 2005, FDA began this review by examining the passive surveillance
reports associated with OROS methylphenidate (Concerta; U.S. Food and
Drug Administration 2017). The review uncovered 135 adverse events, in-
cluding 36 psychiatric and 20 cardiovascular events. In particular, the reports
included 12 instances of tactile and visual hallucinations (classified under “psy-
chosis”) during OROS methylphenidate use. These OROS methylphenidate
adverse event reports are rare, representing 135 of 1.3 million cases. Patients
with active psychosis, mania, substance abuse disorders, and/or eating disor-
ders should not be treated with stimulants until their symptoms stabilize.
More worrisome were the reports of 20 cases of sudden unexpected death
(14 children and 6 adults) and 12 cases of stroke in patients taking mixed am-
phetamine salts (Adderall XR). This led to Health Canada suspending the
sales of Adderall XR (Center for Drug Evaluation and Research 2011). Five
patients who died had preexisting structural heart defects. The rest had “fam-
ily histories of ventricular tachycardia, association of death with heat exhaus-
tion, fatty liver, heart attack, and Type 1 diabetes.”
Pliszka and AACAP Work Group on Quality Issues (2007) noted that the
rate of sudden, unexpected death is estimated to be 0.5 per 100,000 patient-
years in patients taking mixed amphetamine salts and 0.19 per 100,000 pa-
tient-years in patients taking methylphenidate, whereas the rate of sudden,
unexpected death in the general population has been estimated at 1.3–1.6 per
100,000 patient-years (Liberthson 1996), which is higher than the risk asso-
ciated with stimulant treatment. Even so, patients with preexisting heart dis-
ease should be referred to a cardiologist before stimulant treatment is initiated.
Some more recent studies (Cooper et al. 2011) have shown no significant dif-
ferences in risks of vascular events or symptoms with stimulant use. However,
a case-control study in the United States and a nationwide prospective cohort
study of children born in Denmark did show that, although rare, cardiovas-
cular events were about twice as likely in stimulant users as they were in those
who did not use stimulants (Dalsgaard et al. 2014; Gould et al. 2009).
In summary, serious unexpected cardiac or psychiatric adverse events asso-
ciated with taking stimulants are extremely rare. The rates are too low to prove
a causal association with stimulants in patients with no history of previous
heart disease. Routine electrocardiograms and echocardiograms are not indi-
 Attention-Deficit/Hyperactivity Disorder 69

cated prior to starting stimulant treatment in patients with unremarkable med-

ical histories and physical examinations. Physicians prescribing stimulants
should first ask the patient and their family for a history of structural heart dis-
ease and whether they have previously consulted with a cardiologist. Known
cardiac problems that raise concern about using stimulants include tetralogy of
Fallot, cardiac artery abnormalities, and obstructive subaortic stenosis. Clini-
cians should be alert if the patient has hypertension or complains of syncope,
arrhythmias, or chest pain because these may indicate hypertrophic cardiomy-
opathy, which has been associated with sudden, unexpected death.

Other Rare Adverse Events: Growth Slowdown

Growth slowdown is another infrequent psychostimulant adverse reaction
that has been controversial since it was first observed in a publication in 1972
(Safer et al. 1972). Myriad methodological difficulties prevent an easy inter-
pretation of studies showing growth slowdown. Few studies employ the opti-
mal controls, which include untreated children with ADHD, a psychiatric
control group, and an ADHD group receiving treatment with a class of med-
ications other than stimulants. Studies differ in the quality of compliance
measures used and whether the children were using the stimulants on week-
ends or during the summer.
Most recently, growth slowdown for height and weight was reported for
children with ADHD ages 7–10 years who were treated with methylpheni-
date at a mean dosage of 30 mg/kg/day in the MTA study (MTA Cooperative
Group 2004). School-age children grew 1.0 cm less and gained 2.5 kg less
than predicted from CDC growth charts. Similar effects were observed for
preschool children, who grew 1.5 cm less in height and gained 2.5 kg less
weight than predicted while being treated with methylphenidate at a mean
dosage of 14 mg/kg/day. Spencer et al. (1996) detected similar differential
growth for children with ADHD that could be associated with the disorder it-
self and not only with stimulant treatment.
Interestingly, a longitudinal study of BMI trajectories from electronic
health records of 163,820 children ages 3–18 years from January 2001 to Feb-
ruary 2012 found that age at first stimulant use and longer duration of stim-
ulant use were each associated with slower BMI growth earlier in childhood
but with a more rapid rebound to higher BMIs compared with control sub-
jects in late adolescence (Schwartz et al. 2014).
70 Clinical Manual of Child and Adolescent Psychopharmacology

The psychostimulant mechanism for any growth slowdown is unknown.

Exposure to oral methylphenidate in clinical doses in young monkeys led to a
6-month delay in the onset of puberty but no loss of weight or height (Mat-
tison et al. 2011). Early theories blamed the medication’s putative growth-
suppressant action on its effects on growth hormone or prolactin, but research
studies failed to confirm this effect. The most parsimonious explanation for
this drug effect is the medication’s suppression of appetite, leading to reduced
caloric intake. No study, however, has collected the standardized diet diaries
necessary to track calories consumed by children with ADHD who are taking
psychostimulants.
Data regarding long-term growth effects of stimulants are mixed. A pro-
spective adult follow-up study of 5,718 subjects found no association between
differences in height or significant changes in growth over a 2-year period of
treatment with stimulants (Harstad et al. 2014). During naturalistic follow-up
of participants in the MTA study at age 25 years, the subgroup that self-
selected to consistently take stimulants was significantly shorter than partici-
pants with ADHD who did not take stimulants (by 4.06 cm) and those who
inconsistently took stimulants (by 2.74 cm) (Greenhill et al. 2020). The con-
sistent and inconsistent subgroups initially had decreased weight compared
with the negligible subgroup. Weights converged during adolescence; by age
25 years, the consistent and inconsistent subgroups weighed more than the
negligible group.
Height and weight should be measured at 6-month intervals during stim-
ulant treatment and recorded on age-adjusted growth forms to determine the
presence of a drug-related reduction in height or weight velocity. If such a dec-
rement is discovered during maintenance therapy with psychostimulants, a re-
duction in dosage or change to another class of medication can be carried out,
as shown in reports of growth changes in the MTA study and the PATS (Bie-
derman et al. 2010; Faraone et al. 2008; Swanson et al. 2007).

Stimulants and Tics

Although FDA labels include a warning that stimulants may exacerbate tics,
this has not been supported by more recent studies. A meta-analysis of 22
studies involving 2,385 children found no difference in the risk of new-onset
or worsening tics in those receiving stimulant treatment versus those receiving
 Attention-Deficit/Hyperactivity Disorder 71

placebo. Type of stimulant, dosage, age, or duration of treatment did not

change the risk of tics (Cohen et al. 2015).

Stimulants and Anxiety

Stimulant side effects were originally thought to be exacerbated by the presence
of comorbid anxiety symptoms; this led to a warning against using methylphe-
nidate in youth with comorbid anxiety disorders. Other concerns were that anx-
iety disorders interfered with a stimulant’s ability to lower ADHD symptoms.
Tannock et al. (1995a) reported findings from a treatment study involving
40 children with ADHD, some with (n=18) and some without (n=22) comor-
bid anxiety symptoms, in a double-blind, randomized, crossover design with
three methylphenidate doses (0.3, 0.6, and 0.9 mg/kg). The two groups showed
equal decreases in motor activity, but the group with comorbid anxiety did more
poorly on a serial addition task and had a differential heart-rate response to
methylphenidate. DuPaul et al. (1994) found that 40 children with ADHD
and comorbid anxiety were less likely to achieve response to methylphenidate
and experienced more side effects for three methylphenidate dosages (5 mg,
10 mg, and 15 mg) and placebo than children with ADHD and no comorbid
anxiety. However, the study did not collect ratings for anxiety symptoms, so the
direct effect of methylphenidate on such symptoms was not recorded.
Subsequent studies failed to support these early impressions. One con-
trolled study (Gadow et al. 1995) that tested the effects of methylphenidate in
children with comorbid anxiety symptoms found equally good response for
those with and those without anxiety disorder. Results of a meta-analysis of
23 studies involving 2,959 children with ADHD found that risk of anxiety
was significantly reduced in participants receiving stimulants compared with
those receiving placebo, perhaps because of a secondary effect of improved
ADHD symptoms (Coughlin et al. 2015). It therefore appears appropriate to
conclude that stimulants may improve anxiety symptoms and that a comorbid
anxiety disorder does not predict a poor response to treatment.

Stimulant Medication Use in the

Treatment of ADHD in the United States
Outpatient visits for ADHD have been increasing since the early 1990s (Jen-
sen et al. 1999). Rates of ADHD diagnosis have likewise increased. The Na-
72 Clinical Manual of Child and Adolescent Psychopharmacology

tional Survey of Children’s Health found that American parents’ report of

their child ever being diagnosed with ADHD increased from 7.8% in 2003 to
11% in 2011 (Visser et al. 2014). In the 1990s, methylphenidate-based prod-
ucts dominated the types of prescriptions for ADHD for children (Vitiello
and Jensen 1997). However, since the early 2000s, amphetamine products
have shown a 40-fold increase in rates of prescriptions, surpassing methylphe-
nidate products, which increased 8-fold (Safer 2016). This has led to concerns
about potentially overmedicating patients for ADHD, but data on this are
mixed. An analysis of data from the Great Smoky Mountain Study found that
although 72% of children meeting DSM-III-R criteria (American Psychiatric
Association 1987) for ADHD received stimulants, an additional 22% of sub-
jects received stimulants even though they did not meet criteria for ADHD
(Angold et al. 2000). However, another epidemiologically based survey in the
United States found that only 12.5% of children diagnosed with ADHD re-
ceived adequate stimulant treatment (Jensen et al. 1999). More recently, an-
nual rates of stimulant prescribing in the United States have continued to rise,
from 5.6 per 100 persons in 2014 to 6.1 per 100 persons in 2019 (Board et al.
2020). Notably, this rise is due to increased rates of prescribing for adults, with
rates for those age 19 years or younger actually decreasing from 2014 to 2019.

Predicting Responses to Stimulant Medications

Predicting drug response in the a child with ADHD is difficult. Although pre-
treatment patient characteristics (young age, low rates of anxiety, low severity
of disorder, high IQ) may influence response to methylphenidate on global
rating scales (Buitelaar et al. 1995), most research shows that neurological,
physiological, or psychological measures of functioning are not reliable pre-
dictors of response to psychostimulants (Pelham and Milich 1991). In the
NIMH MTA study, participants with comorbid anxiety disorders experi-
enced a better response to behavioral treatments than the overall study popu-
lation, with behavioral treatment being superior to community care and no
longer inferior to medication or combined treatment. The frequency of phy-
sician visits mediated the benefits of stimulant treatment, with more frequent
visits associated with more effective medication treatment (MTA Cooperative
Group 1999a).
 Attention-Deficit/Hyperactivity Disorder 73

Determining How Much Improvement

Constitutes a Meaningful Clinical Response
Once a child’s symptoms respond to medication, there has been no universally
agreed-upon criterion for how much the symptoms must change before the
clinician stops increasing the dosage, and there is no standard for the outcome
measure. Some have advocated a 25% reduction of ADHD symptoms as a
threshold, whereas others suggest that the dosage should continue to be ad-
justed until the child’s behavior and classroom performance are normalized.
The concept of normalization has helped standardize the definition of a cat-
egorical responder across domains and studies. Studies now use classroom con-
trol subjects instead of just statistical significance to determine whether the
improvement from treatment is clinically meaningful. Further advances oc-
curred when investigators used statistically derived definitions of clinically
meaningful change during psychotherapeutic treatment (Jacobson and Truax
1991). Rapport et al. (1994) used this technique to calculate reliable change
and normalization on the Conners’ Abbreviated Teacher Rating Scale using na-
tional norms. The researchers determined that a child’s behavior would be con-
sidered normalized when their Conners’ Abbreviated Teacher Rating Scale score
fell closer to the mean of the general population (matched with children with-
out ADHD) than to the mean of the ADHD population. Using this technique
in a controlled trial of four methylphenidate doses in children with ADHD,
Rapport et al. (1994) found that methylphenidate normalized behavior and, to
a lesser extent, academic performance (94% and 53%, respectively). Similarly,
DuPaul and Rapport (1993) found that methylphenidate normalized behavior
for all children with ADHD who were treated, but only 75% of the children
showed normalized academic performance. In another study, DuPaul et al.
(1994) reported that normalization in behavior and academic performance oc-
curred less often when ADHD subjects had high levels of comorbid internal-
izing disorders. Swanson et al. (2001) applied this approach to the cumulative
distribution curves on the SNAP-IV parent and teacher behavior ratings at the
end of the MTA study. They found that 88% of children without ADHD, 68%
of children with ADHD treated with medication plus behavior therapy, and
56% of children with ADHD treated with medication alone achieved symp-
tom scores of 1 or less, which represented a normal response on those scales.
74 Clinical Manual of Child and Adolescent Psychopharmacology

Limitations of Stimulant Treatment for ADHD

Although there is good evidence showing stimulants are effective through
14 months of treatment, there is less evidence for longer-term efficacy. Fol-
lowing 14 months of randomized treatment, the MTA sample transitioned to
care in their communities. These data were reported in a series of publications
that describe responses of the MTA sample (n =515) versus 289 classroom
control subjects (the local normative comparative group) during an uncon-
trolled long-term follow-up period that extended to 16 years after the MTA’s
baseline (Swanson et al. 2017). By 22 months after the end of assigned treat-
ment, there were no longer significant differences in ADHD symptoms be-
tween the treatment groups. This lack of significant differences between the
original treatment groups continued in the 6- to 8-year follow-up report, with
the ADHD group presenting as having more ADHD symptoms and poorer
functioning than the control group (Molina et al. 2009). By 16 years after the
MTA’s baseline, when participants were age 25 years on average, the ADHD
group continued to have significantly more ADHD symptoms (Swanson et al.
2017) and poorer functioning (Hechtman et al. 2016) than the control group.
There were no significant differences in ADHD symptoms between three nat-
uralistic subgroups of consistent, inconsistent, or negligible stimulant treat-
ment during the follow-up period (Swanson et al. 2017). Although clear
conclusions cannot be drawn, these findings highlight the need for longer-
term RCTs to better understand the long-term efficacy of stimulants.
Other caveats have been expressed about using psychostimulants to treat
ADHD in children. Approximately 25% of children with ADHD are not
helped by the first psychostimulant given or experience side effects so bother-
some that meaningful dosage adjustments cannot be made (DuPaul and Bar-
kley 1990). Stimulants cannot be given too late in the day because delayed
sleep onset and insomnia may result, so they are less helpful for nighttime
homework and behavioral challenges. Second, indications for choosing a par-
ticular psychostimulant and the best methods for adjusting the dosage remain
unclear, and these factors may prove confusing to the clinician and family.
Some practitioners use the child’s weight as a guideline (dose-by-weight
method), and others titrate each child’s response through the approved dosage
range until clinical response occurs or side effects limit further dosage increases
(stepwise titration method). Studies have shown no consistent relationship be-
 Attention-Deficit/Hyperactivity Disorder 75

tween weight-adjusted methylphenidate doses and behavioral responses, call-

ing into question this practice. Third, the credibility of many treatment
studies is limited by methodological problems, including failure to control for
prior medication treatment and inappropriately short washout periods.
In addition, a few studies have reported problems with dissociation of
cognitive and behavioral responses to methylphenidate, showing an inverted-
U dose-response curve with an optimal cognitive response at 0.3 mg/kg and
an optimal behavioral response at 1.0 mg/kg. Parents worry about stigmati-
zation, dependence, growth delays, and blunted emotional responses in their
children from long-term exposure to stimulant treatment.

Role of Nonstimulant Medication

in the Treatment of ADHD
Because nonstimulants have a smaller effect size than stimulants for lowering
ADHD symptoms, they are not first-line medications for ADHD treatment
(Hirota et al. 2014; Newcorn et al. 2008). Nonstimulants may be used when
there is an unsatisfactory response to or significant adverse effects from two
different stimulants. In addition, some families have concerns about stimu-
lants being classified by the Drug Enforcement Administration as drugs of
abuse and controlled substances; nonstimulant options do not have this
problem. This approach has been supported by the Texas Children’s Medi-
cation Algorithm Project (TCMAP), which recommends that atomoxetine
be used when two different stimulants fail to be effective because of nonre-
sponse, unwanted side effects, or parental preference (Pliszka et al. 2006).
The α2 agonists guanfacine and clonidine are also good second-line options
(Table 2–3).

Atomoxetine and Viloxazine

Atomoxetine and viloxazine are selective norepinephrine reuptake inhibitors.
Atomoxetine was approved by the FDA in 2002 and was the first nonstimu-
lant and first adult treatment approved for ADHD (Rosack 2002). Per the
TCMAP, atomoxetine represents the first nonstimulant medication option af-
ter a patient has demonstrated partial response or nonresponse to two stimu-
lants (Pliszka et al. 2006).
Table 2–3. Nonstimulant medications approved by the FDA for the treatment of ADHD

76 Clinical Manual of Child and Adolescent Psychopharmacology

Pediatric dosagea Adult dosage
Duration of
Medication action, hours Starting Typical Starting Typical

α2 Agonists

Intuniv (Shire); guanfacine ER genericb,c 8–24 1 mg/day 1–7 mg/day 1 mg/day 1–6 mg/day
b
Kapvay (Concordia); clonidine ER generic 12 0.1 mg qPM 0.1–0.2 mg bid No adult data No adult data

Selective norepinephrine reuptake inhibitors

Strattera (Lilly); atomoxetine generic 24 0.5 mg/kg/day 1.2 mg/kg/day 20 mg bid or 80 mg/day
or divided bid 40 mg/day

Qelbree (Supernus); viloxazineb,d 12; dual pulse 6–11 years: 100–400 mg/day 200 mg/day 200–600 mg/day
100 mg/day

12–17 years:
200 mg/day
aDosage
for children age 6 years or older.
bFDA
approved only for use in children ages 6–17 years.
c
See Ota et al. 2021 for adult dosing information.
dContents of capsule can be sprinkled on small amount of applesauce or ice cream to disguise bitter taste and be given immediately. See Supernus 2021a

for additional information.

 Attention-Deficit/Hyperactivity Disorder 77

Atomoxetine
Atomoxetine is not a controlled substance. It is rapidly absorbed, and peak se-
rum concentrations occur in 1 hour without food and in 3 hours with food.
The drug undergoes hepatic metabolism with the cytochrome P450 2D6 iso-
zyme (CYP2D6) and is then glucuronidated and excreted in urine. Plasma
elimination half-life averages 5 hours for most patients. However, 5%–10% of
patients have a loss-of-function polymorphism for the allele that codes for
CYP2D6; for them, the half-life of atomoxetine can be as long as 24 hours. If
a patient is a known poor metabolizer, the FDA label recommends lower
doses; however, genetic testing is not needed prior to starting atomoxetine (de
Leon 2015).
Atomoxetine’s pharmacodynamics differs from its pharmacokinetics in
that the duration of action in reducing symptoms of ADHD is much longer
than the pharmacokinetic half-life. ADHD symptoms can be managed with
once-daily dosing. Atomoxetine also can be given in the evening, whereas
stimulants cannot. Atomoxetine is valued as a treatment for patients whose
symptoms have not responded to or who cannot tolerate stimulants or for
those who do not want treatment with a Schedule II medication (Abramowicz
2003).
Efficacy. Atomoxetine’s effect size in reducing symptoms of ADHD was
calculated to be 0.64, which indicates a medium effect size. This calculation
was borne out in a meta-analysis (Schwartz and Correll 2014) that examined
25 double-blind RCTs (N = 3,928). In practice, some clinicians have been
concerned by the low numbers of children with ADHD responding to atom-
oxetine.
Dosage and administration. Atomoxetine is available in capsule strengths
of 10 mg, 18 mg, 25 mg, 40 mg, 60 mg, 80 mg, and 100 mg. To limit adverse
events, youth weighing 70 kg or less should have the medication started at
0.5 mg/kg/day in divided doses, with the dosage increased after 1 week to a tar-
get of 1.2 mg/kg/day. The maximum total daily dose is 1.4 mg/kg or 100 mg,
whichever is less. Patients with hepatic dysfunction should take half the usual
dosage.
Drug interactions. Atomoxetine and monoamine oxidase inhibitors should
not be used together or within 2 weeks of each other. The initial dosage of ato-
78 Clinical Manual of Child and Adolescent Psychopharmacology

moxetine should not be increased rapidly if the patient is taking a potent

CYP2D6 inhibitor such as fluoxetine (Prozac).
Adverse events. Somnolence, nausea, decreased appetite, weight loss, vomit-
ing, and headache have occurred in children starting atomoxetine, particularly
when the dosage is increased from the initial to top levels within 3 days. Slow
metabolizers displayed higher rates of decreased appetite. Starting with twice-
daily dosing can minimize side effects (Greenhill et al. 2007).
The FDA has added two warnings to the atomoxetine package insert in-
structions. The first warning, added on December 17, 2004, was based on re-
ports of severe liver injury and jaundice in two patients (one adult and one
child). The FDA warned that atomoxetine should be discontinued in patients
who develop jaundice, have dark urine, or have laboratory evidence of liver in-
jury. A second warning, added in September 29, 2005, was based on the report
by Eli Lilly stating that 5 of 1,800 youth in atomoxetine trials spontaneously
reported suicidal ideation, whereas none of the youth randomly assigned to
placebo made such reports. The FDA required that atomoxetine’s label carry a
black box warning about its possible association with suicidality. It is notewor-
thy that both warnings are based on spontaneous reports, not systematically
elicited adverse events. A 2014 meta-analysis examined this warning further
and found that although there was one pediatric attempted suicide (N=3,883
pediatric patients), there were no completed suicides, and the risk compared
with placebo was not significant (Bangs et al. 2014). The meta-analysis con-
cluded that there was no evidence of increased risk for suicidal behavior in ato-
moxetine-treated pediatric or adult patients (Bangs et al. 2014). Treatment of
children with ADHD using the nonstimulant atomoxetine has also been as-
sociated with transient growth suppression (Spencer et al. 2007a).

Viloxazine
In 2021, viloxazine was approved by the FDA for the treatment of ADHD
based on four double-blind, placebo-controlled randomized, multicenter,
parallel trials including 1,354 patients ages 6–17 years (Johnson et al. 2020;
Nasser et al. 2021; Supernus 2021b). Treatment with viloxazine led to signif-
icant improvement in DSM-IV ADHD-RS scores (total, inattentive symp-
toms, and hyperactive symptoms) by 2 weeks, with more improvement by
6 weeks, and an effect size of about 0.6. The most common adverse reactions
 Attention-Deficit/Hyperactivity Disorder 79

included somnolence, decreased appetite, nausea, vomiting, insomnia, and ir-

ritability. Viloxazine also had a black box warning of possible association with
suicidality based on reports of suicidal thoughts in 0.9% of those taking vilox-
azine compared with 0.4% of those taking placebo (Supernus 2021b). No
completed suicides occurred in these studies.
Viloxazine is metabolized by CYP2D6 and is then glucuronidated and ex-
creted in urine. It is a strong CYP1A2 inhibitor and should not be adminis-
tered with CYP1A2 substrates such as duloxetine or with monoamine oxidase
inhibitors. Viloxazine is dosed once daily and reaches steady state after 2 days.
Children ages 6–11 years start with 100 mg/day, which can be increased by
100 mg/week to a maximum dosage of 400 mg/day, depending on response
and tolerability. Youth ages 12–17 years start with 200 mg/day and can in-
crease to a maximum dosage of 400 mg/day after 1 week (Table 2–3). Unlike
atomoxetine, which must be swallowed whole, viloxazine can be swallowed or
the capsule can be opened and the contents sprinkled on a teaspoonful of food
such as applesauce (Supernus 2021b).

Clonidine and Guanfacine

ER clonidine (Kapvay) and guanfacine (Intuniv) were FDA approved for the
treatment of ADHD in youth ages 6–17 years in 2009. These agents are ap-
proved both as a monotherapy and as an adjunct to stimulants. They are pre-
synaptic α2-adrenergic agonists and are also called norepinephrine receptor
agonists. Clonidine binds to α2A, α2B, and α2C receptors, whereas guanfacine
binds specifically to α2A receptors. These agents were originally developed for
the treatment of hypertension.

Efficacy
A meta-analysis of 12 pediatric studies (N=2,276) determined that α2 ago-
nists significantly reduced overall ADHD symptoms, inattention, hyperactiv-
ity/impulsivity, and oppositionality, with an overall effect size of 0.59 (Hirota
et al. 2014). However, no significant differences in efficacy between different
α2 agonists were found. Although clonidine ER and guanfacine ER were each
significantly superior to placebo, neither IR formulation separated from pla-
cebo. The α2 agonists also significantly improved ADHD symptoms com-
pared with placebo when added to ongoing psychostimulant treatment.
80 Clinical Manual of Child and Adolescent Psychopharmacology

Adverse Events
The α2 agonists are well tolerated overall, with rates of discontinuation due to
adverse effects comparable with placebo. Sedation is the most common side
effect. Less common side effects include headache, dizziness, nausea, and hy-
potension (Hirota et al. 2014). Rare adverse effects include hallucinations
with guanfacine. There is one case report of sudden death in a patient taking
clonidine and methylphenidate, but it is not clear that the medication caused
the death. Many clinicians feel that side effects such as sedation and hypoten-
sion are less common with guanfacine than with clonidine, although head-to-
head trials of these medications in children with ADHD are absent. These
agents are not associated with significant changes in body weight, making
them a good choice for patients who struggle with the appetite suppression or
weight-loss effects of stimulants.

Dosage and Administration

The starting dosage for clonidine ER is 0.1 mg at bedtime. It can be increased
by 0.1 mg/week based on response and tolerability up to 0.4 mg/day, with the
dosage divided twice daily (Table 2–3). Guanfacine ER is started at 1 mg/day
and can be increased by 1 mg/week based on response and tolerability up to a
maximum of 4 mg/day for children ages 6–12 years and 7 mg/day for adoles-
cents ages 13–17 years. Guanfacine is primarily metabolized by CYP3A4.
Dosage adjustments are recommended when administering guanfacine with
CYP3A4 inhibitors or inducers. Clonidine is mostly metabolized by CYP2D6.
These agents should be tapered gradually (clonidine by 0.1 mg and guanfa-
cine by 1 mg every 3–7 days) because rebound hypertension following abrupt
discontinuation has been reported.

Bupropion
Bupropion is an atypical antidepressant with noradrenergic activity and has
been reported effective for some ADHD symptoms in placebo-controlled tri-
als. It is FDA approved for the treatment of depression in adults but not for
ADHD. A systematic review of bupropion use in children with ADHD found
six clinical trials (Ng et al. 2017) showing that bupropion reduced ADHD
symptoms. Three of the trials compared bupropion with methylphenidate
and found no significant differences between the medications. However, in
 Attention-Deficit/Hyperactivity Disorder 81

the largest trial, although bupropion was superior to placebo, effect sizes were
smaller than for stimulants (Conners et al. 1996; Ng 2017). In contrast, a
2018 meta-analysis of 133 double-blind RCTs of medication for ADHD in
youth and adults, including three bupropion trials in children, found that bu-
propion was superior to placebo, with a large effect size of 0.96 in clinician-
rated overall ADHD symptoms in youth, which was comparable with stimu-
lants (Cortese et al. 2018). Bupropion is a third-line treatment for ADHD
and should be considered for individuals with poor symptom responses to
stimulants, α2 agonists, and atomoxetine. It is also reasonable to consider bu-
propion for adolescents with ADHD and depression who may benefit from its
effects on both disorders.

Modafinil
Modafinil is a dopamine reuptake inhibitor that is FDA approved for the
treatment of narcolepsy in adults. The meta-analysis by Cortese et al. (2018)
of ADHD medications included seven trials of modafinil in children; the re-
searchers found that modafinil was superior to placebo, with a medium effect
size of 0.62 for clinician-rated overall ADHD symptoms. One study com-
pared modafinil with methylphenidate and showed no significant difference
between the two treatments on parent and teacher ADHD rating scales
(Amiri et al. 2008). In trials of modafinil for ADHD, 8 of 933 youth treated
with modafinil stopped the drug due to concerns for rash, including one case
of possible Stevens-Johnson syndrome (Rugino 2007). As a result, the FDA
advisory committee did not recommend approval of modafinil for ADHD in
children and adolescents and requested additional studies to better under-
stand the potential risk.

Monitoring Treatment
The AACAP practice parameter for ADHD (Pliszka and AACAP Work
Group on Quality Issues 2007) recommends that patients be monitored for
treatment-emergent side effects during psychopharmacological intervention
for ADHD. The effectiveness of regular monthly visits and dosage adjust-
ments based on tolerability and lingering ADHD symptoms was shown in the
MTA study (MTA Cooperative Group 1999a, 1999b). Those children as-
82 Clinical Manual of Child and Adolescent Psychopharmacology

signed to medication management based on the NIMH protocol had signifi-

cantly lower ADHD symptom scores than those followed by community
providers, even though 67% of this group also received medication. When
compared, children in the medication treatment arm had five times the rate of
appointments, more often had dosage adjustments based on teacher feedback,
and had higher mean methylphenidate total daily dosages than those in the
community control group.
Monitoring can be done through direct patient-provider visits, by phone
calls with the patient and family, or even by electronic messaging. Teacher input
should be sought at least once a semester for patients with ADHD attending
primary, middle, or high school. Monitoring should follow a predetermined
plan that is worked out with the patient and, if the patient is a child, with the
parents. Generally, the schedule of monitoring visits is weekly during the ini-
tial dosage-adjustment phase, then monthly for the first few months of main-
tenance. After that, the visits can be regularly scheduled but less frequent.
During the monitoring visit, the clinician should collect information on the
exact dosage used and the schedule according to which the stimulants were ad-
ministered, including times of day and skipped doses. The clinician should
ask about possible side effects. The family and clinician should then decide
whether the patient should continue taking the stimulant at the same dosage
or the dosage should be changed. The patient should leave the visit with a pre-
scription, a plan for administration, possibly a schedule for intervisit phone or
message contact, and the next appointment date.
The practitioner and family should agree on the frequency of stimulant
treatment during the day and the week. One choice is between the daily ad-
ministration of stimulant medications or treatment only for school days, with
the patient not taking the drug on weekends and holidays, versus daily ad-
ministration. Those patients with more impairing ADHD symptoms will
benefit from treatment with stimulants daily. Nonstimulants should be con-
sistently taken daily. Patients should have their need for continued treatment
with stimulant medication verified once per year through a brief period of
medication discontinuation. The discontinuation period should be planned
for a part of the school year when testing is not in progress.
Strategies for maintaining adherence to treatment are a key monitoring
component. These include the option to adjust stimulant dosages to reduce
treatment-emergent adverse events. When a treatment-emergent adverse
 Attention-Deficit/Hyperactivity Disorder 83

event occurs, the practitioner would do well to assess the impairment induced
by the event. Some adverse events may not interfere with the child’s health or
cause significant interruption of routine. If the adverse event worsens, then
dosage reduction is indicated. If the dosage reduction alleviates the adverse
event but leads to worsening of the ADHD symptoms, the clinician may want
to consider switching the patient to another stimulant or augmenting with an
α2 agonist.
The AACAP practice parameter (Pliszka and AACAP Work Group on
Quality Issues 2007) suggests that adjunctive pharmacotherapy can be used to
address a troublesome adverse event during stimulant treatment. Patients with
stimulant-induced delay of sleep onset may benefit from the addition of an-
tihistamines, clonidine, or a bedtime dose (3 mg) of melatonin (Tjon Pian Gi
et al. 2003).

Choice of Medication
An international consensus statement (Kutcher et al. 2004), the AACAP
practice parameter for ADHD, the TCMAP (Pliszka et al. 2006), and the
AAP clinical practice guideline (Wolraich et al. 2019) all recommend stimu-
lant medications as the first line of treatment for school-age children with
ADHD. Direct comparisons of methylphenidate and atomoxetine in a dou-
ble-blind, randomized, multisite trial (Newcorn et al. 2008) have shown a de-
cided benefit for methylphenidate and confirm the meta-analysis by Faraone
et al. (2003) that suggested methylphenidate had a larger effect size (0.91)
than atomoxetine (0.62). Although no direct comparisons of stimulants and
α-agonists have been published, multiple meta-analyses indicate a larger effect
size for stimulants than clonidine or guanfacine (Catalá-López et al. 2017;
Cortese et al. 2018).
According to the AACAP practice parameter (Pliszka and AACAP Work
Group on Quality Issues 2007), treatment should commence with either an
amphetamine-based or methylphenidate-based stimulant in a long-duration
formulation. The specific medication used can be chosen based on its rapidity
of onset, duration of action, and effectiveness for the specific patient in treat-
ment. Short-acting stimulants can be used at first for small children or pre-
schoolers if there is no long-acting preparation available in a low-enough
dosage. Dual-pulse methylphenidate and amphetamine products (see Table
84 Clinical Manual of Child and Adolescent Psychopharmacology

2–1) have strong effects in the morning and early afternoon, but these effects
wear off by late afternoon. These medications work best for children who have
academic problems at the beginning and middle of the school day, for those
whose appetite is strongly suppressed, or for those whose sleep onset is delayed
during stimulant treatment. Because transdermal stimulants are reported to
have a higher-than-average number of adverse events, orally administered
stimulants should be tried first. Atomoxetine or an α2 agonist should be em-
ployed if the full-dosage-range trials of both a long-duration methylphenidate
and a long-duration amphetamine formulation fail, if the family does not
want treatment with a controlled substance, or if the patient has a relative con-
traindication for stimulants (e.g., an untreated eating disorder, mania, or a
stimulant use disorder). Although pharmacogenetic tests for genetic markers
that may affect the pharmacokinetics or pharmacodynamics of stimulants
have been developed, evidence of their clinical utility to support their regular
use in clinical practice is insufficient (Wolraich et al. 2019).
The AACAP practice parameter for ADHD (Pliszka and AACAP Work
Group on Quality Issues 2007) wisely points out that none of the extant prac-
tice guidelines should be interpreted as justification for requiring that a pa-
tient experience treatment failure (or adverse events) with one agent before
allowing the trial of another.

Conclusion
Psychostimulant medications are a mainstay in the treatment of ADHD based
on their proven efficacy during controlled studies. Although the long-term re-
sponse of children with ADHD to psychostimulants has not been examined
in an RCT much longer than 24 months, reports suggest that children expe-
rience a relapse when their medication is withdrawn, and their symptoms re-
spond when it is restarted. The MTA open, uncontrolled follow-up study
(MTA Cooperative Group 2004), with reports at 3 years, 6 years, 9 years, and
16 years, has suggested that treatments in the community involve either psy-
chotherapy or low-dose stimulant medication. The results include a low re-
sponse rate in terms of ADHD symptom reduction, with only 10% of
patients continuing medication treatment after 10 years. More research is
needed on the barriers to maintaining effective stimulant treatment among
adolescents and young adults.
 Attention-Deficit/Hyperactivity Disorder 85

The initial effects of psychostimulants are rapid, dramatic, and normaliz-

ing, especially during the first 2 years of treatment. The risk of long-term side
effects remains low, and no substantial impairments have emerged to lessen
the remarkable therapeutic benefit-risk ratio of these medications. More ex-
pensive and demanding treatments, including behavior modification and cog-
nitive-behavioral therapies, have only equaled psychostimulant treatment at
best. The combination of behavioral and medication therapies is more effec-
tive than medication alone in reducing symptoms associated with ADHD
(MTA Cooperative Group 1999a). For those whose symptoms do not re-
spond well to stimulants, other FDA-approved pharmacological treatments
include atomoxetine, viloxazine, clonidine ER, or guanfacine ER.
Psychostimulant treatment research has continued support from the phar-
maceutical industry. However, there is ample opportunity for more studies of
nonstimulant medications. Not all patients experience a response to psycho-
stimulants, and this is particularly true in patients with comorbid psychiatric
disorders. More psychopharmacological studies with patients with ADHD
and comorbid disorders to examine differential responses to new medications
are needed. In addition, continued research on the underlying mechanisms of
ADHD, as well as its diagnosis, pharmacogenetics, and treatment combina-
tions, will further refine approaches to treating ADHD over time.

Clinical Pearls
• ADHD is characterized by a persistent, developmentally inap-
propriate pattern of gross motor overactivity, inattention, and im-
pulsivity that impairs academic, social, and family functioning.
Symptoms must start in childhood and have a chronic course.
• Two-thirds of young children with ADHD also meet criteria for other
childhood psychiatric disorders, including anxiety, depressive,
oppositional defiant, conduct, learning, and mood disorders.
• Because of its high prevalence, screening for ADHD should be
included in routine mental health assessments. This can be ac-
complished by asking questions about inattention, impulsivity,
and hyperactivity and about whether such symptoms cause im-
pairment.
86 Clinical Manual of Child and Adolescent Psychopharmacology

• ADHD symptoms are rapidly reduced by treatment with stimu-

lant medications. Medication treatment can begin with either an
amphetamine or a methylphenidate stimulant in a long-duration
formulation chosen based on its rapidity of onset, duration of ac-
tion, and effectiveness in the specific patient under treatment.
• Immediate-release stimulant preparations can be used at first
for small children and/or preschoolers if there is no long-acting
preparation available in a low-enough dose.
• Optimizing each child’s dosing based on the child’s response
has become the standard method of initiating treatment (step-
wise titration method).
• Stimulants come in numerous forms, including capsule (which
can be swallowed or sprinkled), chewable, liquid, oral dissolv-
able tablet, and transdermal patch formulations.
• Short- and long-duration stimulants result in the same adverse
effects, including delay in sleep onset, appetite loss, weight loss,
headache, abdominal pain, and potential growth slowdown.
Several clinical conditions can be worsened by stimulant treat-
ment, including florid psychosis, mania, stimulant abuse, and
eating disorders.
• Stimulants carry a warning about sudden death that may be as-
sociated with preexisting cardiac abnormalities or other serious
heart problems. Clinicians should ask the patient and family
about a history of structural heart disease and be alert if the pa-
tient has hypertension or complains of syncope, arrhythmias, or
chest pain. Routine electrocardiograms and echocardiograms
are not indicated prior to starting treatment in patients with an
unremarkable medical history and physical examination.
• If a patient’s symptoms fail to respond to trials of two stimulants,
second-line options include atomoxetine, viloxazine, extended-
release guanfacine, and extended-release clonidine.
 Attention-Deficit/Hyperactivity Disorder 87

• Optimal treatment involves initial titration to optimize the dosage,

followed by regular appointments. Patients should be monitored
for treatment-emergent side effects. Teacher input should be
sought at least once a semester.

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 3
Disruptive Behavior Disorders
and Aggression
Ekaterina Stepanova, M.D, Ph.D.
Solomon G. Zaraa, D.O.
Peter S. Jensen, M.D.

D isruptive behavior disorders (DBDs), which include disruptive, impulse-

control, and conduct disorders (American Psychiatric Association 2022), are
associated with increased risk of psychopathology later in life, substance
abuse, and incarceration (Bambauer and Connor 2005; Kazdin 1995; Trem-
blay et al. 2004). Aggressive behaviors that frequently occur in youth with
DBDs are one of the most common reasons children and their families seek
mental health services (Connor 2002). Such behaviors can manifest in the con-
text of oppositional defiant disorder (ODD), conduct disorder (CD), and in-
termittent explosive disorder (IED). However, symptoms of aggression are seen
in youth with diagnoses other than DBDs. Aggression can be present in chil-

101
102 Clinical Manual of Child and Adolescent Psychopharmacology

dren with ADHD, mood disorders, PTSD, autism spectrum disorder (ASD),
and other psychiatric illnesses. Although aggression co-occurs with several
psychiatric conditions, it is a distinct construct. For example, aggression with
impulsivity and reactivity can be distinguished from attention problems, rule-
breaking behaviors, and mood disorders (Young et al. 2020; Youngstrom et al.
2023). Given the public health importance of aggression, it is helpful to un-
derstand the nosology of aggressive behaviors as it relates to DBDs.
Different classifications of aggression have been described in the litera-
ture. Most commonly, aggression is divided into two subtypes: proactive and
reactive (Connor 2002; Dodge and Coie 1987). Proactive aggression (PA), also
referred to as instrumental or deliberate, often occurs without provocation.
Reactive aggression, on the other hand, often happens in response to a trigger.
It is also called impulsive aggression (IA), or “hot” or “hostile” aggression (Vi-
tiello and Stoff 1997).
These two forms of aggression and their relationship to the DBDs are yet
to be fully understood. This conceptual gap has been largely a result of the
limited number of clinical trials studying aggression in youth. In addition,
many clinical trials are not evaluating aggression in this way. It is often diffi-
cult to separate aggression into reactive/impulsive and proactive because many
youth exhibit both. Nevertheless, the type of aggression may affect the prog-
nosis and treatment response. For example, PA is more likely to be associated
with callous and unemotional traits (Kimonis et al. 2006) and may have
poorer long-term outcomes compared with IA (Fontaine et al. 2011; Pardini
and Fite 2010; Pardini and Loeber 2008). However, one trial of youth with
DBDs and aggressive behavior reported that callous and unemotional traits
and PA improved when optimized ADHD treatment was provided (Blader et
al. 2013). Conversely, Malone et al. (1998) found preferential response to
lithium in youth with IA but not in those with PA. Many trials, however, do
not discriminate between PA and IA; therefore, potential clinical benefits of
management of different forms of aggression have not yet been fully addressed
(Pappadopulos et al. 2006). Some investigators have suggested that the re-
sponse to pharmacological intervention differs based on the aggression sub-
type (Gillberg and Hellgren 1986; Malone et al. 1998; Padhy et al. 2011;
Steiner et al. 2011). As we discuss further in this chapter, youth with CD and
IA may greatly benefit from pharmacotherapy (Connor et al. 2004; Jensen et
al. 2007; Steiner et al. 2003b; Vitiello and Stoff 1997; Vitiello et al. 1990).
 Disruptive Behavior Disorders and Aggression 103

Similarly, IA in children with ADHD may also respond to medication man-

agement (Jensen et al. 2007). However, data are limited as to whether psycho-
pharmacological agents ameliorate symptoms of PA in CD (Jensen et al.
2007). Therefore, future randomized controlled trials (RCTs) may benefit from
including a reliable measure of aggression that distinguishes between the aggres-
sive subtypes (Brown et al. 1996). In this chapter, we address what is currently
known about the treatment of DBDs and aggression.

Epidemiology
Oppositional Defiant Disorder and Aggression
Diagnosis of ODD requires the presence of a frequent and consistent pattern
of angry/irritable mood, argumentative/defiant behavior, or vindictiveness that
persists for at least 6 months (American Psychiatric Association 2022). For the
diagnostic criteria for ODD to be met, the patient must exhibit at least four of
the following behaviors: often losing their temper, being easily annoyed by oth-
ers, being angry or resentful, arguing with adults, refusing to comply with au-
thority figures, deliberately doing things to annoy other people, blaming others
for their mistakes or behavior, and being spiteful or vindictive. Although none
of the symptoms required for the diagnosis of ODD describes aggressive be-
haviors, many youth with ODD also exhibit IA. Symptoms of ODD can be
conceptualized as falling into three dimensions: irritable, headstrong, and/or
hurtful (Stringaris and Goodman 2009). Approximately 1%–11% of children
in the United States have a pattern of behaviors that meets the ODD criteria
(Canino et al. 2010). Prevalence is even higher in children who are also diag-
nosed with ADHD, up to 19% (Mitchison and Njardvik 2019).
ODD appears to precede the development of CD but is only marginally
predictive of PA (Lahey et al. 1998; Rowe et al. 2010). Whereas most youth
with ODD do not subsequently develop CD, the spiteful/vindictive symptoms
that fall into the hurtful dimension of ODD carry the most risk for develop-
ment of CD (Stringaris and Goodman 2009). On the other hand, many fea-
tures of ODD may be indicative of verbal forms of IA, such as losing one’s
temper, being easily annoyed by others, arguing with adults, and being angry
or resentful. However, the relationship between different subtypes of ODD
and IA should be explored in future research.
104 Clinical Manual of Child and Adolescent Psychopharmacology

Conduct Disorder
CD occurs in 2%–9% of children and adolescents worldwide (Costello et al.
2005; INSERM Collective Expertise Centre 2005). The definition of CD has
transformed drastically over the past several decades. Earlier descriptions of
childhood-onset CD characterized explosive and aggressive children, suggest-
ing a significant role of impulsivity underlying the aggressive behaviors (Camp-
bell et al. 1984). However, with each consecutive iteration of CD in DSM, the
role of PA was emphasized more and more, along with a stronger emphasis on
the callous-unemotional traits (DSM-III, American Psychiatric Association
1987; DSM-IV, American Psychiatric Association 1994). CD is currently de-
fined as a repetitive and persistent pattern of behavior in which the rights of
others and/or major societal norms or rules are violated (American Psychiatric
Association 2022). These behaviors fall into four main categories: aggression
toward people and animals, destruction of property, deceitfulness or theft, and
serious violations of rules. As with ODD, it is possible that the features of this
behavior disorder may correspond to either IA or PA. Emerging evidence sug-
gests that PA, rather than IA, is a significant predictor of CD (Fite et al. 2009;
Pardini and Fite 2010; Stringaris and Goodman 2009; Vitaro et al. 1998), but
this area needs further study.

Intermittent Explosive Disorder

IED is another diagnosis that may describe youth with aggressive and disrup-
tive behaviors. The current definition of IED includes individuals with recur-
rent behavioral outbursts representing failure to control aggressive impulses
(American Psychiatric Association 2022). The symptoms of IED are verbal
and physical aggression. Physical aggression can involve property damage or
physical injury to people and animals. Compared with past iterations, DSM-5
specifies more frequent presence of aggressive behaviors, up to three times a
week. However, it is still unclear whether IED appropriately describes youth
with aggression who have multiple outbursts on an almost daily basis. Addi-
tionally, the research available to date shows that the age at onset of IED is
around adolescence, despite the DSM criterion of starting at age 6 years (Coc-
caro et al. 2005; Galbraith et al. 2018). More data are needed to clarify these
important distinctions.
 Disruptive Behavior Disorders and Aggression 105

Differential Diagnosis
In addition to ODD, CD, and IED, aggressive behaviors occur in the context
of other disorders, such as ADHD, mood disorders, psychotic disorders, anx-
iety, PTSD, ASD, and others (Burke et al. 2010; Jensen et al. 2007). There-
fore, aggression co-occurs with many diagnoses. In particular, IA is a distinct
construct and is not specific to any particular disorder (Jensen et al. 2007;
Young et al. 2020; Youngstrom et al. 2023). Whether IA represents a separate
diagnosis remains to be determined.

Course and Outcome

The occurrence of a DBD in youth may lead to the subsequent development
of other mental disorders. For example, ODD may precede a CD diagnosis
(Burke et al. 2010; Pardini et al. 2010). Loeber et al. (1993) found that youth
who were diagnosed with ODD had a 43% chance of eventually developing
CD. However, the emergence of CD does not necessarily mitigate or super-
sede a diagnosis of ODD; in fact, it is more common for ODD symptoms to
persist even after full CD symptoms emerge. Furthermore, studies indicate
that a number of youth with CD may also develop antisocial personality dis-
order in adulthood (Loeber et al. 2002, 2003, 2009). The diagnosis of ODD
confers an increased risk of emotional disorders in adulthood, including anx-
iety, depression, substance abuse, impulse-control problems, and antisocial
behavior (Burke et al. 2014; Kim-Cohen et al. 2003; Nock et al. 2007; Rowe
et al. 2010). Individuals with IED have psychosocial impairments and worse
quality of life, as well as legal problems (Rynar and Coccaro 2018). However,
no studies have evaluated children with IED prospectively, and little is known
about their prognosis.
In general, the prognosis for DBDs is especially poor if the youth’s symp-
toms fail to respond to behavioral interventions, which are often considered
the first line of treatment for behavior disorders and symptoms of aggression.
A significant predictor of nonresponse is the presence of PA, compared with
IA (Malone et al. 1998; Masi et al. 2011). However, the response to treatment
also may depend on the underlying disorder. For example, in children with
ADHD and a combination of IA and PA, the presence of baseline PA did not
106 Clinical Manual of Child and Adolescent Psychopharmacology

reduce the effectiveness of stimulant therapy on aggressive behavior (Blader et

al. 2013).
Because of the limitations of current psychotherapeutic interventions,
however, a growing body of literature has focused on the outcomes of psycho-
pharmacological treatment of aggressive symptoms in youth with DBDs
(Connor et al. 1999, 2002, 2019; dosReis et al. 2003; Pappadopulos et al.
2003; Schur et al. 2003; Steiner et al. 2003b), which our focus in this chapter.

Rationale and Justification for

Psychopharmacological Treatment
The first line of treatment for DBDs is evidence-based psychotherapeutic in-
terventions, such as parent management training, family therapy, and others.
However, when those interventions are not sufficiently effective, providers
may consider pharmacological options. As with treating any illness, pharma-
cotherapy should target the underlying diagnosis. Unfortunately, treating dis-
ruptive behaviors is more complicated than that, largely due to the fact that
youth with aggressive or disruptive behaviors often do not fit a single diagnos-
tic category. As discussed previously, aggression frequently co-occurs with
multiple diagnoses. To identify potential medications that could help children
with disruptive behaviors, many clinical trials were designed to target aggres-
sion as a symptom rather than as a particular diagnosis. What makes it even
more complicated for clinicians is that comorbid diagnoses differ greatly
among different studies and may include ADHD, CD, ODD or a combina-
tion of DBDs. Nevertheless, the research available to date offers some insight
into effective pharmacotherapy of aggressive behaviors in youth.

Review of Treatment Studies

Atypical Antipsychotics
Risperidone
Risperidone is currently the most extensively studied medication in the treat-
ment of aggression in youth (Loy et al. 2017), with RCTs testing short- and
long-term benefits of this agent. These studies include larger-scale, multisite
trials and small-scale RCTs.
 Disruptive Behavior Disorders and Aggression 107

Short-term efficacy. One of the largest studies of risperidone in this popu-

lation is the National Institute of Mental Health (NIMH)–funded Treatment
of Severe Child Aggression (TOSCA) study, which included 168 children ages
6–12 years with ADHD and co-occurring DBDs (Farmer et al. 2011). Chil-
dren initially received a 3-week open titration of a stimulant. Those who did
not show an adequate clinical response were randomly assigned to two groups.
Both groups received parent training and stimulant treatment. Of these, one
group received risperidone in addition to the stimulant and parent training,
while the other group received placebo instead of risperidone for 9 weeks. Par-
ticipants in the risperidone group showed lower aggression scores (measured
with the Nisonger Child Behavior Rating Form [NCBRF]), compared with
those in the placebo group (Aman et al. 2014). No serious adverse events were
reported in the study. Prolactin elevation was noted in the augmented group,
whereas trouble falling asleep was more common in the placebo group.
Post hoc analysis also suggests that children with more severe ADHD and
callous and unemotional symptoms demonstrate a more robust and faster
treatment response, regardless of the treatment received (Farmer et al. 2015).
Several other trials suggest that children receiving a stimulant and risperidone
whose parents also received parent training reported a greater reduction in
symptom-related impairment, aggression, ADHD, and ODD severity com-
pared with children who were given a stimulant and a placebo whose parents
also received parent training (Aman et al. 2014; Gadow et al. 2014).
Two industry-sponsored, multisite RCTs were conducted to test the effi-
cacy of risperidone in the treatment of aggressive symptoms and/or DBDs in
youth with low to normal or subaverage intelligence. The first RCT evaluated
118 children (ages 5–12) with subaverage intelligence and a primary diagnosis
of DBD, including ODD, CD, or DBD not otherwise specified (Aman et al.
2002). Compared with subjects receiving placebo, those receiving risperidone
experienced a significant reduction in aggressive symptoms as measured by the
Conduct Problem subscale of the NCBRF. The second study achieved com-
parable results in a similarly designed RCT (Snyder et al. 2002).
Several smaller trials have yielded comparable results. For example, Find-
ling et al. (2000) demonstrated significant reductions in aggressive behaviors
as measured by the Rating of Aggression Against People and/or Property Scale
in a sample of 20 youth with CD (ages 5–15) who were receiving outpatient
treatment. Similar reductions were noted in an RCT that specifically targeted
108 Clinical Manual of Child and Adolescent Psychopharmacology

symptoms of severe aggression during a 6-week trial of 38 inpatient adoles-

cents with subaverage intelligence and DBDs (Buitelaar et al. 2001). Their ag-
gressive symptoms were measured by the Clinical Global Impression (CGI)
Severity of Illness subscale and the Aberrant Behavior Checklist (ABC). More-
over, during the 2-week washout trial following the 6 weeks of treatment, the
risperidone group experienced a statistically significant worsening of aggres-
sive behaviors as measured by the CGI Severity of Illness subscale, the ABC,
and the Overt Aggression Scale (OAS)–Modified.
The efficacy of risperidone in the treatment of aggressive symptoms was
also documented in an 8-week, double-blind RCT of 101 youth with autism
(McCracken et al. 2002). Risperidone treatment was associated with signifi-
cant reductions in aggression as indicated by scores on the ABC and the CGI
within 4 weeks of receiving treatment. Additionally, a significant treatment-
by-time interaction effect indicated that the risperidone group continued to
improve through weeks 4–8, whereas the placebo group deteriorated. Cur-
rently, risperidone is one of the two antipsychotics that are FDA approved for
the management of irritability associated with ASD (autistic disorder).
Although the aforementioned trials offer some guidance in the acute man-
agement of aggressive behaviors, they do not evaluate comorbidity, treatment
in various settings, effects of childhood adversity, and other factors. In addi-
tion, these trials offer information on short-term outcomes and adverse
events. Longer-term studies are discussed later in this chapter. Despite these
limitations, available data suggest that risperidone appears to be effective in
the short-term treatment of aggressive symptoms and/or behavior disorders in
youth. For specific dosage information pertaining to the effective use of risper-
idone in the treatment of aggression in youth, see Table 3–1.
Long-term and maintenance efficacy. In addition to evidence of the short-
term efficacy of risperidone for symptoms of aggression and DBDs, emerging
evidence suggests risperidone may be beneficial for the long-term mainte-
nance of treatment gains. In one study of long-term efficacy (Reyes et al.
2006a), 335 youth ages 5–17 whose symptoms had responded to open-label
risperidone treatment over 12 weeks were then blindly and randomly assigned
to an additional 6 months of either a continuation of risperidone or placebo.
The NCBRF was used to assess both PA and IA. On average, symptom recur-
rence was slower in the risperidone group. Significant aggressive symptoms re-
 Disruptive Behavior Disorders and Aggression 109

Table 3–1. Selected agents prescribed for the treatment of

aggressive youth with disruptive behavior disorders
(DBDs)

Dosing for FDA

Class Generic (trade) DBDsa,b dosinga,c

Antipsychotics, Aripiprazole (Abilify) 2.5–30 2–30

atypical Clozapine (Clozaril) 150–600 NA
Olanzapine (Zyprexa) 2.5–20 2.5–10
Paliperidone (Invega) 3–12 3–12
Quetiapine (Seroquel) 100–600 400–600
Risperidone (Risperdal) 0.25–1.5 0.5–6
Ziprasidone (Geodon) 40–160 NA
Antipsychotics, Haloperidol (Haldol) 1–16 0.5–15
typical Thioridazine (Mellaril) 1.75 mg/kg/ 0.5–3 mg/
day kg/day
Stimulants Dexmethylphenidate (Focalin, 5–30
Focalin XR)
Dextroamphetamine (Dexedrine, 2.5–40
ProCentra, Zenzedi)
Lisdexamfetamine (Vyvanse) 20–70
Methylphenidate (Ritalin, Ritalin 5–60 5–60
LA, Metadate, Metadate CD,
Methylin, Quillivant XR)
Methylphenidate (Concerta) 18–72
Methylphenidate transdermal 10–30 mg/
(Daytrana) 9 hours
Mixed amphetamine salts 2.5–40
(Adderall, Adderall XR, Evekeo)
Norepinephrine Atomoxetine (Strattera) 40–100
reuptake
inhibitor
110 Clinical Manual of Child and Adolescent Psychopharmacology

Table 3–1. Selected agents prescribed for the treatment of

aggressive youth with disruptive behavior disorders
(DBDs) (continued)

Dosing for FDA

Class Generic (trade) DBDsa,b dosinga,c

Mood stabilizers Carbamazepine (Tegretol) 600–800 10–20 mg/

kg/dayd
Lithium, lithium carbonate 1,800 mean 10–30 mg/
(Eskalith, Lithobid) kg/daye
Valproic acid (Depakene, 250–1,500 15–60 mg/
Depakote, Depakote ER, kg/dayf
Depakote Sprinkle Capsules)
α2-Agonists Clonidine (Catapres, Kapvay) 0.1–0.2 0.1–0.4
Guanfacine (Tenex, Intuniv) 1–4 1–4
β-Blockers Nadolol (Corgard) 30–220 20–200
Note. See Jensen et al. (2004) and Martin et al. (2003) for additional information.
aDosages are mg/day unless otherwise noted.
b
Dosing is based on randomized controlled trials of DBDs.
cFDA-approved dosing for other indications in youth.
dCarbamazepine dosages optimally adjusted based on blood levels, 4–14 μg/L.
e
Lithium doses optimally adjusted based on blood levels, 0.6–1.1 mEq/L.
fValproic acid doses optimally adjusted based on blood levels, 50–125 μg/L.

occurred after 119 days in 25% of patients in the risperidone group and in
47.1% of patients in the placebo group. Notably, the results indicated that
more than half of the placebo group did not experience a recurrence of symp-
toms. Therefore, psychopharmacological discontinuation may be a plausible
option for some youth with resolved symptoms of aggression or DBD. Reyes
et al. (2006a) also reported significant treatment gains in hyperactive, com-
pliant, and adaptive social behaviors in the risperidone group compared with
the placebo group. After the completion of this yearlong study, an additional
1-year open-label expansion study was conducted involving 48 responders,
and maintenance of the original treatment gains was again demonstrated
(Reyes et al. 2006b). Overall, these studies suggest that risperidone may be ef-
ficacious in the treatment of DBDs or aggression in children for a cumulative
period up to 2 years.
 Disruptive Behavior Disorders and Aggression 111

The TOSCA postacute efficacy and maintenance studies showed similar

results. In a 12-week postacute trial, the augmented group’s symptoms re-
mained improved (Findling et al. 2017); at a 12-month follow-up, the groups
did not separate on primary outcome measures, but the augmented group had
lower illness severity scores (Gadow et al. 2016). Of note, more than half of
the participants in both groups failed to adhere to the prescribed regimen at
12 months, which could affect the overall results of the study.
Similar results are also supported by other yearlong, open-label trials as-
sessing the sustained safety and efficacy of risperidone in youth of subaverage
intelligence with symptoms of aggression and other disruptive behaviors
(Aman et al. 2004; Croonenberghs et al. 2005; Turgay et al. 2002). In general,
across these extension studies of initial RCTs, youth maintained treatment
gains reported in the initial waves of the study (see subsection “Short-Term
Efficacy” for risperidone). Of particular interest within the aggressive subtype
literature, a highly significant decrease was seen in scores on the secondary
outcome measure (the Vineland Adaptive Behavior Scales) used to assess
physical aggression and emotional outbursts (Turgay et al. 2002). Therefore,
preliminary evidence appears to indicate the utility of risperidone in the treat-
ment of IA.
Furthermore, risperidone showed effectiveness in the long-term treatment
of aggressive youth with a primary diagnosis of ASD or other pervasive devel-
opmental disorders. In the Research Units on Pediatric Psychopharmacology
(RUPP) follow-up study, two-thirds of patients maintained behavioral im-
provements for 6 months following the initial risperidone treatment, after be-
ing reassigned to either risperidone or placebo (Research Units on Pediatric
Psychopharmacology Autism Network 2005). Symptoms did not relapse in
37.5% of youth who had taken risperidone in the original study, even while
they were taking placebo in the follow-up. Furthermore, youth with different
subtypes of aggression reported comparable benefits with risperidone treat-
ment (Carroll et al. 2014). Similarly, Troost et al. (2005) studied 36 children
ages 5–17 with ASD who had symptoms of severe aggression or self-injurious
behavior. These youth initially received an 8-week, open-label trial of risper-
idone. Those whose symptoms responded continued treatment for another
16 weeks, and then a double-blind discontinuation (n=24) was carried out,
consisting of either 3 weeks of tapering and 5 weeks of placebo or continued
use of risperidone. Only 25% of patients who continued risperidone experi-
112 Clinical Manual of Child and Adolescent Psychopharmacology

enced relapse, compared with 66.67% of youth who were switched to pla-
cebo. Thus, both studies suggest that continuing treatment with risperidone
was more efficacious than placebo in preventing relapse. Findings from both
studies also imply that at least a subset of initially treated children may not ex-
perience relapse when their risperidone is switched to placebo, suggesting that
consideration of medication discontinuation may be appropriate for some
children who have done well for a substantial period of time.
Overall, there is increasing evidence to suggest that risperidone may be ef-
ficacious in the long-term treatment of aggressive symptoms and/or behavior
disorders in youth.

Paliperidone
There are low-evidence data on the use of paliperidone in treating aggressive
behaviors in youth. An 8-week open-label study of youth and young adults
with ASD (autistic disorder) reported that paliperidone was well tolerated and
associated with improvement of irritability symptoms (Stigler et al. 2012). In
another open-label study, paliperidone was noted to reduce aggressive behav-
iors in youth with developmental disorders or ADHD whose symptoms had
inadequate response to risperidone (Fernández-Mayoralas et al. 2012). Fur-
ther evaluation of paliperidone in the treatment of DBDs is warranted.

Olanzapine
Several small studies of olanzapine appear promising in the treatment of ag-
gressive disorders in children and adolescents (see Table 3–1 for dosage infor-
mation). In a study by Stephens et al. (2004), 10 children with Tourette’s
disorder and aggression were treated in single-blind fashion (after a 2-week
placebo run-in) with olanzapine over 8 weeks. The study participants demon-
strated significant reductions in both aggressive symptoms and tic severity, as
assessed with standard rating scales. In one open-label trial of olanzapine in
children, adolescents, and adults with pervasive developmental disorders, sig-
nificant behavioral improvement was documented within the first several
weeks of treatment (Potenza et al. 1999). Similarly, a case report by Horrigan
et al. (1997) concluded that olanzapine was associated with decreased aggres-
sion toward people and property and fewer explosive outbursts in youth. A
10-week open-label study reported reduced ADHD and aggression symptoms
with the combination of olanzapine and atomoxetine given to youth with
 Disruptive Behavior Disorders and Aggression 113

ADHD and comorbid DBDs (Holzer et al. 2013). Although these reports
suggest that olanzapine may have a role in treating aggression and DBDs, firm
conclusions about its potential efficacy cannot be reached without further
studies.

Quetiapine
A 7-week RCT of quetiapine involving 19 adolescents with CD showed ben-
efit in the treatment of aggressive behaviors in CD (Connor et al. 2008). Find-
ings from an 8-week open-label trial involving 16 youth with CD suggested
that quetiapine may be effective in the treatment of aggression in that popula-
tion (Findling et al. 2006). In the 26-week open-label extension of that trial,
the benefit of quetiapine was found to be sustained, and medications were well
tolerated (Findling et al. 2007). One open-label trial of quetiapine and meth-
ylphenidate found a reduction in aggression and ADHD symptoms in youth
with severe aggression whose symptoms did not respond to methylphenidate
monotherapy (Kronenberger et al. 2007). An open-label trial of low-dose que-
tiapine in youth with ASD reported decreased severity of aggressive behavior
(Golubchik et al. 2011). Quetiapine had similar efficacy compared with
risperidone in reducing aggression in adolescents with bipolar II disorder and
comorbid CD in a 12-week, open-label, flexible-dose trial (Masi et al. 2015).
At this time, further research on quetiapine in the treatment of aggression and
DBDs is needed (see Table 3–1 for dosage information).

Aripiprazole
Aripiprazole is FDA-approved for the management of irritability associated
with ASD in children, based on two short-term RCTs that support its efficacy
(Marcus et al. 2009; Owen et al. 2009). Findings from a 52-week open-label
study of aripiprazole in youth with ASD support the medication’s efficacy in
long-term reduction of irritable symptoms (Marcus et al. 2011). However, one
RCT reported no statistical significance between aripiprazole and placebo in
preventing relapse of irritable symptoms in youth with ASD during a 16-week
period of maintenance therapy (Findling et al. 2014b). In an open-label study
of youth with CD, aripiprazole was well tolerated and was associated with im-
provements in aggressive behaviors. The authors also found that lower starting
dosages of aripiprazole improved tolerability and reduced side effects in youth
(Findling et al. 2009). Another open-label study of children and adolescents
114 Clinical Manual of Child and Adolescent Psychopharmacology

with ADHD and CD reported that aripiprazole reduced symptoms of both

disorders (Ercan et al. 2012). Further evaluation of aripiprazole in the treat-
ment of DBDs is warranted (see Table 3–1 for dosage information).

Clozapine
To date, no RCTs have evaluated the efficacy of clozapine in the treatment of
aggressive symptoms in children or adults. However, several case studies have
suggested that clozapine is an effective treatment for aggression in adults
(Rabinowitz et al. 1996; Volavka and Citrome 1999). Significant reductions
in physical and verbal aggression were seen in 75 adults with schizophrenia
over 6 months of clozapine treatment (Rabinowitz et al. 1996). Few studies
have evaluated clozapine’s effectiveness in the treatment of aggression in youth
(Chalasani et al. 2001; Kranzler et al. 2005). In a chart review of six children
and adolescents with schizophrenia spectrum disorders treated with cloza-
pine, violent episodes reduced significantly and global function improved sig-
nificantly (Chalasani et al. 2001). Similarly, an open-label study by Kranzler
et al. (2005) indicated that clozapine yielded significant pre-to-post benefits
in patients with treatment-refractory schizophrenia and aggression. An open,
naturalistic, observational study reported that treatment with clozapine led to
reductions in aggression over a 26-week period in youth with CD (Teixeira et
al. 2013). Finally, findings from a retrospective cohort study of patients with
ASD and severe DBDs suggest that clozapine may decrease aggressiveness in
patients whose symptoms are treatment resistant (Beherec et al. 2011). None-
theless, additional research is needed to assess the efficacy of clozapine in the
treatment of aggression and DBDs in youth (see Table 3–1 for dosage infor-
mation).

Other Atypical Antipsychotics

Available data have not demonstrated efficacy of ziprasidone in the manage-
ment of aggressive symptoms in youth with DBDs. One RCT of low-dose
ziprasidone in youth with DBDs found no significant difference between the
treatment and placebo groups (Fleischhaker et al. 2011). Therefore, addi-
tional research is needed to further assess the comparative efficacy of other
atypical antipsychotics. This research may be especially beneficial in treatment
planning for youth with DBDs and/or aggression in light of the reported ef-
ficacy of the other atypical antipsychotics (principally risperidone) that have
 Disruptive Behavior Disorders and Aggression 115

been extensively studied. Moreover, it would be of great clinical relevance for

assessing the different side effect profiles of the various atypical antipsychotics
to meet the need for a wider array of safe and effective therapeutic agents in
the management of aggressive symptoms and DBDs in youth (see Table 3–1
for dosage information).

Risks and Benefits of Atypical Antipsychotics

Overall, atypical antipsychotics have demonstrated efficacy in reducing ag-
gressive behaviors in youth. To date, risperidone and aripiprazole have the
most evidence to support their use in the treatment of aggression.
Similar to many other medications, atypical antipsychotics are associated
with mild to moderate side effects, including extrapyramidal symptoms, som-
nolence, headache, increases in prolactin levels, gynecomastia, and weight
gain (Aman et al. 2004; Peuskens et al. 2014; Rosenbloom 2010; Snyder et al.
2002). Of particular importance to pediatric care providers, youth treated
with these agents appear to experience significantly greater weight gain than
adults using atypical antipsychotics, even at low dosages (Sikich et al. 2004).
Less commonly reported problems in youth may include type 2 diabetes and
cardiac rhythm abnormalities, but more studies may be needed to address
concerns about these possible side effects (Schur et al. 2003). Data on a ret-
rospective cohort of more than 9,000 children and adolescents suggest a sig-
nificant increase in the incidence of diabetes mellitus in those treated with
atypical antipsychotics (Andrade et al. 2011). In children and adolescents,
long-term risks typically associated with atypical antipsychotic use also in-
clude withdrawal symptoms, tardive dyskinesia, parkinsonism, and neurolep-
tic malignant syndrome. Table 3–2 provides additional information on the
potential side effects of atypical antipsychotics.
Because atypical antipsychotics are associated with an array of serious side
effects, the FDA has required that these medications carry warning labels to
specifically indicate their potential risk for increased weight gain and disrup-
tion of metabolic functioning (Stigler et al. 2004; U.S. Food and Drug Ad-
ministration 2005). Given the concerns about side effects and the increasing
rates at which atypical antipsychotics are being prescribed to youth with
symptoms of aggression (Olfson et al. 2006), additional studies are necessary
to examine the safety of these agents in the treatment of aggression in this pop-
ulation.
Table 3–2. Common and serious side effects for various classes of psychopharmacological

116 Clinical Manual of Child and Adolescent Psychopharmacology

agents

Class Common side effects Serious or uncommon side effects

Atypical antipsychotics Insomnia, agitation, extrapyramidal symptoms, Hypotension, severe syncope (rare), severe
headache, anxiety, rhinitis, constipation, nausea/ tardive dyskinesia, neuroleptic malignant
vomiting, dyspepsia, dizziness, dyslipidemia, syndrome, hyperglycemia, severe diabetes
tachycardia, somnolence, increased dream activity, dry mellitus, seizures (rare), priapism (rare), stroke,
mouth, diarrhea, weight gain, visual disturbance, sexual transient ischemic attack
dysfunction, hyperprolactinemia, gynecomastia,
menstrual irregularities
Typical antipsychotics Extrapyramidal symptoms, tardive dyskinesia, akathisia, Neuroleptic malignant syndrome, pneumonia,
dystonia, insomnia, anxiety, drowsiness, lethargy, arrhythmia, hypotension, hypertension,
weight changes, anticholinergic effects, gynecomastia, seizures, jaundice, hyperpyrexia, heat stroke
breast tenderness, galactorrhea, menstrual irregularities,
injection-site reaction (depot), elevated prolactin levels
Stimulants Nervousness, insomnia, abdominal pain, nausea, Growth suppression (long term), seizures,
anorexia, motor tics, headache, palpitations, dizziness, dependence, abuse, arrhythmia, leukopenia
blurred vision, tachycardia, weight loss, fever, (rare), thrombocytopenic purpura (rare), toxic
depression, transient drowsiness, dyskinesia, angina, psychosis (rare), Tourette’s disorder (rare),
rash, urticaria, blood pressure changes exfoliative dermatitis (rare), erythema
multiforme (rare), neuroleptic malignant
syndrome (rare), cerebral arteritis (rare),
hepatotoxicity (rare)
Table 3–2. Common and serious side effects for various classes of psychopharmacological
agents (continued)

Class Common side effects Serious or uncommon side effects

Norepinephrine Nausea, vomiting, fatigue, decreased appetite, abdominal Suicidal ideation (rare), severe hepatic injury
reuptake inhibitor pain, somnolence, insomnia, constipation, dry mouth, (rare), sudden death (rare), stroke (rare),

Disruptive Behavior Disorders and Aggression 117

dizziness, sexual dysfunction, urinary hesitancy myocardial infarction (rare), dysphoria (rare),
irritability (rare), severe mood lability (rare),
hallucinations (rare), mania (rare), aggressive
behavior
Mood stabilizers Enuresis, fatigue, ataxia, increased thirst, nausea, Disruption in hepatic, hematological, and
vomiting, urinary frequency, gastrointestinal upset, metabolic functioning
sleepiness, weight gain
α2 Agonists Drowsiness and dizziness, dry mouth, irritability, Syncope (rare), hypotension (rare)
dysphoria, rebound hypertension, abdominal pain,
headache, agitation
β-Blockers Sedation, mild hypotension, lowered heart rate, Hypoglycemia (in patients with diabetes),
bronchoconstriction, dizziness, sleep disruption growth-hormone regulation issues
Note. Side effects for specific medications may vary within classes; specific details of differences among specific agents can be found elsewhere (Connor
et al. 2001; Pappadopulos et al. 2003; Weiner 1996).
Source. Center for the Advancement of Children’s Mental Health, Office of Mental Health: “10 Tips: Navigating Child and Adolescent Inpatient and
Residential Services in New York State.” Unpublished document.
118 Clinical Manual of Child and Adolescent Psychopharmacology

Typical Antipsychotics
Haloperidol
Prior to the emergence of atypical antipsychotics, conventional antipsychotics
were considered first-line agents in the treatment of aggression and DBDs in
youth (see Campbell et al. 1999). Haloperidol may be an effective means to
treat aggression; for example, during a double-blind study of inpatient youth
(ages 5.2–12.9) with treatment-resistant CD, a significant reduction in aggres-
sive symptoms was seen in those given haloperidol compared with those given
placebo (Campbell et al. 1984). However, a double-blind, placebo-controlled
study of haloperidol in the treatment of aggression in adolescents with subav-
erage intelligence found that the treatment led to only moderate behavioral
improvements (Aman et al. 1989). See Table 3–1 for dosage information.

Other Typical Antipsychotics

Several early studies of thioridazine suggest its efficacy in managing aggressive
symptoms in youth. For example, an RCT of thioridazine in children with
subaverage intelligence showed modest clinical improvements in symptoms of
aggression (Aman et al. 1991), with thioridazine leading to a reduction in hy-
peractivity and conduct problems. A meta-analysis of three RCTs of antipsy-
chotics suggested a lower effect size for thioridazine (0.35) versus haloperidol
(0.8) in the management of aggression in youth. Chlorpromazine was associ-
ated with reduction in aggressive symptoms in youth with CD; however, this
agent was difficult to tolerate due to sedation (Campbell et al. 1972).

Risks and Benefits of Typical Antipsychotics

Early studies suggested that low dosages of typical antipsychotics were effec-
tive for managing aggressive behaviors in youth. However, typical antipsy-
chotics can be associated with adverse events (see Table 3–2), including an
increased occurrence of extrapyramidal symptoms and tardive dyskinesia
(Connor et al. 2001; McConville and Sorter 2004). Therefore, the risks and
benefits of treatment with this drug class in a given patient should be evalu-
ated before initiating therapy. It is often wise to consider the patient’s personal
and family history of medication response, current medical comorbidities (di-
abetes, cardiac and neurological problems), weight, psychiatric diagnoses, and
other factors when making a decision to start medications treatment.
 Disruptive Behavior Disorders and Aggression 119

Stimulants
Methylphenidate
Short-term efficacy. To date, a growing number of short-term RCTs have
provided evidence for the efficacy of methylphenidate and other stimulants in
the treatment of aggression and DBDs in youth. In fact, treatment with meth-
ylphenidate was shown to improve emotional impulsivity and self-regulation
in about half of youth with ADHD (Connor et al. 2002). The effect size of
stimulants in the management of symptoms in aggressive youth is medium to
large, ranging from 0.69 to 0.84 (Faraone et al. 2020). Moreover, the use of
methylphenidate and other stimulants to treat aggression appears to have a
substantial treatment effect that is independent from effects on core ADHD
symptoms in youth with ADHD and aggressive behavior. For example, an
RCT testing the efficacy of methylphenidate in 84 children with CD with or
without ADHD found significant reductions in core behaviors associated
with CD, independent of the effects on the children’s ADHD symptoms
(Klein et al. 1997). Another RCT of methylphenidate in 31 children with
ADHD and comorbid tic disorder found improvement of oppositional be-
havior and peer aggression (Gadow et al. 2008).
Long-term and maintenance efficacy. Several reports from the NIMH’s
Multimodal Treatment of ADHD (MTA) study have explored longer-term
treatment for youth experiencing comorbid IA and ADHD. For example, the
MTA study’s 14-month follow-up indicated that stimulants (principally
methylphenidate) not only alleviated the core symptoms of ADHD but also
reduced the secondary symptoms of ODD and aggression (MTA Cooperative
Group 1999) as rated on the revised Swanson, Nolan, and Pelham rating scale
(SNAP-IV; Swanson et al. 2001). However, symptoms of aggression and op-
positionality that are present along with internalizing disorders such as depres-
sion or anxiety may improve most with psychopharmacological treatment
used in combination with a behavioral intervention (Jensen et al. 2001). De-
spite promising results with stimulants in treating aggressive behaviors in
some youth, about 44% of children with aggression remain aggressive after a
stimulant trial (Jensen et al. 2007). Overall, the evidence suggests that meth-
ylphenidate may be efficacious in treating aggressive symptoms associated
with DBDs and ADHD.
120 Clinical Manual of Child and Adolescent Psychopharmacology

Other Stimulants
Although methylphenidate is the most common stimulant used in RCTs for
the treatment of ADHD and co-occurring aggressive symptoms, some evi-
dence suggests that other stimulants may also be efficacious (see also Chapter 2,
“Attention-Deficit/Hyperactivity Disorder”). One open-label study of lis-
dexamfetamine found improvement of ADHD symptoms and emotional
control functioning as rated on the Behavior Rating Inventory of Executive
Function (BRIEF; Katic et al. 2013). Given the small number of studies cur-
rently available for evaluation, however, more research on stimulants other
than methylphenidate is required to determine whether they are comparable
with methylphenidate for the treatment of aggression (see Table 3–1 for dos-
age information).

Benefits of Stimulants
Stimulants are recommended as a first-line treatment for youth with comorbid
ADHD and aggression (Pappadopulos et al. 2006). The rationale for stimu-
lant use in the management of aggressive symptoms of ADHD or behavior
disorder is based on the number of controlled trials demonstrating its efficacy
and its large overall effect size (Connor et al. 2002; Pappadopulos et al. 2006).
In contrast to earlier concerns regarding stimulant usage, MTA data also sug-
gest that stimulant use is effective in treating ADHD, even among youth who
present with co-occurring symptoms of mania and aggression (Galanter et al.
2003). Youth with comorbid ADHD and aggression may be more likely than
nonaggressive youth to experience an insufficient response to stimulant
monotherapy and may require more rigorous dosing for symptom remission
(Blader et al. 2010). Stimulant treatment also appears to yield improvements
in global functioning and social interaction (Bukstein and Kolko 1998; MTA
Cooperative Group 1999; Swanson et al. 2001).

Risks of Stimulants
Despite their efficacy, stimulants are associated with several adverse effects, in-
cluding insomnia, reduced appetite, stomachache, headache, and dizziness. In
addition, the FDA has recommended that stimulants be labeled with a black
box warning indicating their potential for adverse cardiac effects in children
(U.S. Food and Drug Administration 2022). Please refer to Chapter 2 for fur-
ther details on the risks of stimulant medications.
 Disruptive Behavior Disorders and Aggression 121

Mood Stabilizers
Lithium
Most existing literature on the efficacy of mood stabilizers in the treatment of
aggression in children and adolescents has focused on the use of lithium in pa-
tients with CD. Overall, these results suggest that lithium is associated with a
reduction in aggressive behavior (Campbell et al. 1992, 1995; Malone et al.
2000). For example, in one RCT, inpatient youth with a primary diagnosis of
CD received either lithium or placebo (Campbell et al. 1995). Lithium was as-
sociated with a reduction in aggressive behaviors across a number of standard-
ized measures, including the Children’s Psychiatric Symptom Rating Scale
(CPRS). An RCT comparing lithium and placebo in 40 children with CD
demonstrated improvements in aggressive behaviors, as measured by the OAS,
for those who received lithium (Malone et al. 2000).
Overall, lithium has been shown to reduce temper outbursts in severely
aggressive, inpatient children and adolescents with CD (Campbell et al. 1984,
1995; Carlson et al. 1992; Malone et al. 2000). This evidence implies that
lithium may have an important role in the treatment of IA in youth. However,
the necessity of frequent monitoring and blood draws associated with this
treatment may render it a second-line choice after pharmacological agents
such as the atypical antipsychotics (Pappadopulos et al. 2003) (see Table 3–1
for dosage information).

Divalproex
Some evidence indicates that divalproex is effective in reducing aggressive
symptoms and DBDs in youth. For example, in one RCT, improvement in
impulse control was observed in incarcerated male youth who were treated
with high doses of divalproex; moreover, global improvements among the pa-
tients, as measured by the CGI scale (Steiner et al. 2003a), were also noted.
Similarly, another trial found that divalproex was associated with a reduction
in aggressive symptoms in youth with CD (Donovan et al. 2000, 2003). Ev-
idence also suggests that divalproex may be especially beneficial for treating
children and adolescents who present with severe IA (Donovan et al. 1997) as
well as for treating IA symptoms in those with pervasive developmental dis-
orders (Hollander et al. 2001). Another RCT found that when administered
adjunctive treatment with a stimulant and divalproex, 30 youth with ADHD
122 Clinical Manual of Child and Adolescent Psychopharmacology

and chronic aggression refractory to stimulant monotherapy had higher rates

of remission of aggressive behavior compared with placebo (Blader et al.
2009).
An RCT involving 58 male subjects with severe CD in the juvenile justice
system found significantly higher response to divalproex among male youth
with IA than among those with PA (Padhy et al. 2011). Another RCT directly
compared adjunct divalproex, risperidone, and placebo when added to opti-
mized stimulant therapy in children ages 6–12 years (Blader et al. 2021). Both
the divalproex and risperidone groups demonstrated significant reductions in
aggressive behavior when compared with placebo, although the participants
given risperidone gained more weight. Therefore, evidence suggests that di-
valproex may be efficacious in treating youth with an array of psychiatric dis-
orders, including CD, ADHD, and bipolar disorder, whose behavior includes
severe IA (see Table 3–1 for dosage information).

Carbamazepine
The use of carbamazepine and other mood stabilizers/anticonvulsants in the
treatment of aggressive disorders has increased twofold over the past decade
and a half (Hunkeler et al. 2005). Data on the efficacy of carbamazepine in the
management of aggression in youth are limited and mixed. Preliminary re-
search indicates that carbamazepine may lead to decreases in aggressiveness
and explosiveness, with a moderate effect size (Evans et al. 1987; Kafantaris et
al. 1992; Pappadopulos et al. 2006). On the other hand, countervailing evi-
dence suggests that carbamazepine does not differ from placebo in reducing
aggression (Cueva et al. 1996). Thus, the results are inconclusive with regard
to the efficacy of carbamazepine (see Table 3–1 for dosage information).

Benefits of Mood Stabilizers

In general, some mood stabilizers appear to be beneficial in the treatment of
aggression in youth with behavior disorders. A mood stabilizer such as lithium
may be a suitable alternative to atypical antipsychotics or stimulants. Overall,
the current evidence largely supports the efficacy of lithium and divalproex in
the treatment of IA in youth with CD. However, because many of the symp-
toms of CD correspond to PA, more research is needed to determine whether
either subtype of aggression responds differentially to mood stabilizers.
 Disruptive Behavior Disorders and Aggression 123

Risks of Mood Stabilizers

To date, studies pertaining to mood stabilizers in the treatment of aggression
in youth have been limited in that they have measured only short-term treat-
ment outcomes. Therefore, certain adverse effects may not become evident
during the limited duration of these studies but may appear in trials spanning
longer periods. Additional research is needed to measure the risks, benefits,
and efficacy of mood stabilizers in aggressive youth in an array of settings (e.g.,
outpatient and emergency care).
Mood stabilizers are associated with a variety of adverse side effects (see Ta-
ble 3–2). Common side effects of lithium include enuresis, fatigue, ataxia, in-
creased thirst, nausea, vomiting, urinary frequency, and weight gain (Bassarath
2003; Malone et al. 2000). Moreover, frequent blood draws for dosage mon-
itoring are required; thus, lithium may be less suitable for children who have
difficulty tolerating blood draws (Malone et al. 2000). Side effects associated
with divalproex include gastrointestinal upset and sleepiness (Steiner et al.
2003b). Carbamazepine may carry the greatest risk for adverse side effects
among the mood stabilizers and has been linked to disruption in hepatic, he-
matological, and metabolic functioning (Cummings and Miller 2004). In
2008, the FDA found that patients treated with anticonvulsants had nearly
twice the risk of suicidal ideation or behavior compared with those given pla-
cebo and therefore mandated warning labeling for anticonvulsant medica-
tions (U.S. Food and Drug Administration 2008).

Other Agents
α2 Agonists
Clonidine. Some evidence supports the use of α2 agonists in the treatment of
aggressive symptoms and DBDs among children and adolescents. Specifically,
clonidine has demonstrated efficacy in the treatment of aggression in youth,
according to a meta-analysis of 11 double-blind RCTs (Connor et al. 1999).
Hazell and Stuart (2003) reported gains in a 6-week randomized, double-
blind, placebo-controlled trial of a combined clonidine-plus-stimulant treat-
ment. Specifically, conduct problems were improved in youth with ADHD
and comorbid ODD or CD. Further research on clonidine in the treatment of
aggression and DBDs is needed (see Table 3–1 for dosage information).
124 Clinical Manual of Child and Adolescent Psychopharmacology

Guanfacine. Guanfacine demonstrated efficacy in the treatment of aggres-

sive symptoms in an 8-week RCT involving 34 youth ages 7–15 with ADHD
and a tic disorder (Scahill et al. 2001). A 9-week RCT of extended-release
guanfacine in 217 youth with ADHD and oppositional symptoms resulted in
a significant reduction in both oppositional and ADHD symptoms (Connor
et al. 2010). Furthermore, one RCT (Findling et al. 2014a) involving youth
with ADHD whose symptoms responded suboptimally to stimulant mono-
therapy demonstrated reductions in oppositional symptoms after the partici-
pants received extended-release guanfacine. Thus, it appears that guanfacine
may be beneficial in the treatment of oppositional symptoms in youth with
comorbid ADHD; however, further research is needed to provide conclusive
support for the use of this agent in the treatment of DBDs in this population
(see Table 3–1 for dosage information).

Risks and benefits of α2 agonists. Overall, α2 agonists have shown prom-

ise when added to stimulants in the treatment of aggression in children with
ADHD. Additional research is needed to compare the efficacy of α2 agonists
with that of other psychotropic agents in the treatment of aggressive symp-
toms in youth with behavior disorders.
The α2 agonists are associated with several adverse side effects, including
drowsiness, dizziness, headache, abdominal pain, and changes in blood pres-
sure and heart rate (Cantwell et al. 1997; Connor et al. 2010). Earlier reports
warned against the risk of syncopal episodes, whereas more recent studies did
not find a high risk of serious adverse events. Nevertheless, caution should be
executed in administering α2 agonists to youth, and their vital signs should be
frequently checked. (See Table 3–2 for additional details on the potential ad-
verse effects associated with α2 agonists.)

β-Blockers
Current literature on the efficacy of β-blockers in the treatment of aggression
in youth is sparse. Connor et al. (1997) reported treatment gains for more than
80% of children and adults with developmental disabilities who were pre-
scribed β-blockers to manage symptoms of aggression (see Table 3–1 for dos-
age information). To date, no RCTs on the use of β-blockers in the treatment
of youth have been conducted. Therefore, firm conclusions about the efficacy
of these agents cannot be drawn. Some of the adverse effects associated with β-
 Disruptive Behavior Disorders and Aggression 125

blockers include sedation, mild hypotension, lowered heart rate, bronchocon-

striction, hypoglycemia (in patients with diabetes), dizziness, sleep disruption,
and potential growth-hormone regulation disturbances (see Table 3–2) (Rid-
dle et al. 1999). Further research is needed on the benefits and risks associated
with using β-blockers to treat youth with aggressive symptoms.

Norepinephrine Reuptake Inhibitors

Atomoxetine. In an RCT evaluating atomoxetine treatment of comorbid
ADHD and ODD, Newcorn et al. (2005) found that atomoxetine improves
ADHD and ODD symptoms and suggested that higher dosages may be
needed to treat youth who meet criteria for both conditions. However, a meta-
analysis of aggression in RCTs of atomoxetine found that the risk of aggressive
or hostile events in patients taking atomoxetine was not statistically significant
from that in those given placebo (Polzer et al. 2007). Despite the fact that ato-
moxetine did not improve aggressive symptoms, it may be beneficial in the
treatment of ODD, as seen in a randomized, placebo-controlled, double-
blind study of 180 youth with ADHD and comorbid ODD (Dittmann et al.
2011). The group receiving atomoxetine had significant reductions in symp-
toms of ADHD and ODD after 9 weeks of treatment. A meta-analysis of
25 RCTs reported that atomoxetine had a medium effect size of 0.33 in treat-
ing ODD symptoms in youth with ADHD (Schwartz and Correll 2014). Fi-
nally, an RCT of 97 patients with ADHD and ASD reported significant
improvement in ADHD symptoms but no difference from placebo in oppo-
sitional subscale measures (Harfterkamp et al. 2012). Further research on the
long-term benefits and risks associated with using atomoxetine to treat youth
with DBDs is needed.
Risks of norepinephrine reuptake inhibitors. Children and adolescents
who take atomoxetine may experience dry mouth, fatigue, irritability, nausea,
appetite change, constipation, dizziness, sweating, dysuria, urinary retention
or hesitancy, priapism, increased obsessive behaviors, weight changes, palpi-
tations, suicidal ideation, hepatic injury, increased heart rate, and increased
blood pressure. Six cases of drug-induced liver injury were reported between
2005 and 2008 (U.S. Food and Drug Administration 2009). The FDA has
mandated a black box warning for atomoxetine because of increased risk of
suicidal ideation in children and adolescents (Gephart 2005).
126 Clinical Manual of Child and Adolescent Psychopharmacology

Safety Issues
Monitoring
Antipsychotics
Height and weight should be thoroughly monitored during treatment with an-
tipsychotic agents. If weight gain is identified in a patient taking these agents,
the physician should implement a diet and exercise plan. Vital signs, with par-
ticular attention to cardiac function, should also be routinely assessed in pa-
tients taking antipsychotics (Schur et al. 2003). If cardiac symptoms emerge,
the physician should consider consulting with a cardiology specialist.
In youth taking typical or atypical antipsychotics, physicians should care-
fully monitor for extrapyramidal symptoms such as akathisia, akinesia, tremor,
dystonia, and emergent tardive dyskinesia (Connor et al. 2001; McConville
and Sorter 2004). Furthermore, youth should be routinely screened for ab-
normalities in liver function and lipid production, particularly in the presence
of weight gain. Monitoring of glucose metabolism is important, given that
certain agents may be linked to juvenile diabetes (Clark and Burge 2003). Fur-
thermore, prolactin levels should be monitored if endocrine abnormalities are
suspected (Wudarsky et al. 1999). Patients should be monitored for rare but
life-threatening side effects, including neuroleptic malignant syndrome, sei-
zures, and heat stroke. Finally, one cohort study of 153 youth with DBDs, To-
urette’s disorder, and ASD reported that combining stimulant treatment with
atypical antipsychotics did not significantly reduce the risk for weight gain
and metabolic changes caused by atypical antipsychotics (Penzner et al. 2009).

Stimulants
Children and adolescents who are prescribed stimulants should be routinely
monitored for adverse symptoms, including insomnia, reduced appetite,
stomachache, headache, and dizziness (Lisska and Rivkees 2003; MTA Co-
operative Group 1999). Stimulant use has been linked to long-term adverse ef-
fects, including height and weight suppression; therefore, it is important for
vital signs, height and weight, and abnormalities in metabolic function to be
thoroughly monitored throughout the course of treatment. If the stimulant is
being taken concurrently with another psychopharmacological agent, such as
clonidine, additional caution is recommended (Fenichel and Lipicky 1994).
 Disruptive Behavior Disorders and Aggression 127

Mood Stabilizers
Certain mood-stabilizing agents such as lithium require frequent blood draws
for dosage monitoring and therefore may be less suitable in the treatment of
children who have difficulty tolerating blood draws (Bassarath 2003; Malone
et al. 2000). In addition, common side effects associated with mood stabilizers
include enuresis, fatigue, ataxia, increased thirst, nausea, vomiting, and uri-
nary frequency. Therefore, careful monitoring of these symptoms is required.
Moreover, because weight gain is associated with the use of mood stabilizers,
height and weight should be monitored during the treatment course. Impor-
tantly, because carbamazepine has been linked to serious adverse effects, in-
cluding hepatotoxic, hematological, and metabolic reactions, comprehensive
assessment of these systems is important (Cummings and Miller 2004).

α2 Agonists
Careful thought is needed before prescribing α2 agonists to youth with aggres-
sion. Concerns about the safety of these agents have been raised following re-
ports of harmful and potentially life-threatening side effects in several children
treated with clonidine (Cantwell et al. 1997). Careful monitoring of vital signs
and educating patients and families about the risks of rebound hypertension
with abrupt discontinuation of α2 agonists should minimize safety concerns.
Moreover, clonidine can produce drowsiness and dizziness, and patients
should be routinely monitored for these symptoms (Hazell and Stuart 2003).

Preventing Adverse Effects

Conservative dosing procedures may prevent the possible occurrence of ad-
verse effects in youth taking psychopharmacological agents. The general rule
of thumb is to “start low, go slow, and taper slowly” (Pappadopulos et al.
2003). Potential side effects should be monitored on a systematic basis with
rating scales or structured assessment methods (Pappadopulos et al. 2003). It
is best to avoid polypharmacy whenever possible to prevent adverse effects.
Youth who remain aggressive may require medication changes rather than the
addition of other agents. In addition, if aggressive symptoms remit for a sig-
nificant period of time, providers may consider initiating a slow taper of med-
ications. If the treatment response is maintained during the taper, it may be
possible to eventually discontinue the medications.
128 Clinical Manual of Child and Adolescent Psychopharmacology

Interventions to Address Adverse Effects

of Psychotropic Agents
The side effects of pharmacological interventions range in severity from life-
threatening, irreversible, and acutely distressing to merely uncomfortable. In
Table 3–2, we separate the potential side effects of various psychotropic agents
into two categories: common and uncommon but serious. As a general rule of
thumb, if the side effect is considered serious, the medication must be discon-
tinued. In some cases, consultation with a specialist is appropriate to address
adverse events. Once the serious adverse event is resolved, a different psycho-
pharmacological intervention may be a suitable next step.

Practical Management Strategies

Treatment Guidelines
As discussed earlier, several studies suggest the efficacy of some psychophar-
macological agents for the treatment of aggression associated with DBDs.
However, these trials have limitations that make it difficult for clinicians to
choose specific medications for their patients. Some of the problems discussed
earlier in this chapter involve the different inclusion diagnoses used to enroll
participants into the studies. In addition, several versions of DSM have been
published since the first trials of aggression were conducted; therefore, it is of-
ten difficult to compare the results of those studies. For example, as discussed
previously, the criteria for the CD changed dramatically over the past 20 years,
and the results of the earlier studies on CD may not be comparable with more
recent studies on CD. In addition, very few trials have offered head-to-head
comparisons of the medications used; therefore, the possibility of comparing
their efficacy is lacking.
Practice parameters offer some insight to help clinicians make decisions
on evidence-based psychopharmacology. Unfortunately, the American Acad-
emy of Child and Adolescent Psychiatry practice parameters are outdated and
therefore are not discussed in this chapter (see www.jaacap.org). However,
specific clinical guidelines have been developed by other sources for the man-
agement and treatment of maladaptive aggression in youth (Knapp et al.
2012; Pappadopulos et al. 2003; Scotto Rosato et al. 2012). Jensen et al.
(2004) created Treatment Recommendations for the Use of Antipsychotic
 Disruptive Behavior Disorders and Aggression 129

Medications for Aggressive Youth using evidence and consensus-based meth-

odologies. The Centers for Education and Research on (Mental Health) Ther-
apeutics (CERT) Treatment of Maladaptive Aggression in Youth (T-MAY) was
created to identify specific practice guidelines for outpatient management of
youth with severe and persistent behavioral issues (Pappadopulos et al. 2011).
These guidelines suggest starting treatment with family engagement, perform-
ing a full assessment, and establishing a diagnosis. Further recommendations
include engaging in family skills training, targeting underlying psychiatric dis-
orders with evidence-based guidelines, avoiding polypharmacy, and monitor-
ing for treatment response and side effects (Scotto Rosato et al. 2012).
The T-MAY recommendations can be briefly summarized as follows. Pa-
tients and families should be engaged during an initial evaluation (preferably
using a standardized assessment tool) before starting psychosocial treatment to
manage aggressive symptoms. The provider should obtain collateral informa-
tion, provide psychoeducation, and monitor aggressive symptoms with the
child and their parents in order to develop an appropriate plan and establish
community supports. If at any time the patient presents with significant aggres-
sion risk factors, they should be referred to a mental health clinician (or to the
emergency department) for acute management. Typically, an evidence-based
psychosocial intervention is a first-line method of treatment in an aggressive
youth. If psychotherapy is not successful in reducing the aggressive behaviors,
evidence-based psychopharmacological treatment of the underlying condition
may be warranted. If the youth’s symptoms fail to improve with the agent best
suited for their primary disorder, adding an atypical antipsychotic is recom-
mended. Regardless of the psychopharmacological approach, it is wise to use a
conservative dosing strategy. During the course of treatment, the physician
should routinely and systematically assess the youth for potential adverse ef-
fects and ensure an adequate trial of the agent before modifying the treatment
plan. (For additional information about the T-MAY and the CERT guidelines,
see Knapp et al. 2012; Pappadopulos et al. 2003; Scotto Rosato et al. 2012.)

Role of Nonmedication Interventions

Regardless of whether a psychopharmacological intervention is ultimately
used, psychoeducation is a critical component of the successful treatment of
aggressive disorders in youth. Psychoeducation enables the patient and family
to understand and identify triggers for aggressive behaviors as well as to figure
130 Clinical Manual of Child and Adolescent Psychopharmacology

out which coping skills and other interventions are most successful. Moreover,
it helps them learn about plausible treatment options, including psychophar-
macological treatments and behavioral interventions.
As noted in the T-MAY guidelines, empirically supported behavioral in-
terventions should typically constitute the first-line treatment approach for
aggressive youth (Knapp et al. 2012; Scotto Rosato et al. 2012). Evidence-
based psychosocial interventions for aggression in youth include cognitive-
behavioral therapy for aggressive disorders and parent management training.
These evidence-based treatments work to increase positive time that the youth
and family members spend together, help set rules and consequences, and pro-
vide training on problem-solving and social skills. Other psychosocial inter-
ventions have been considered for addressing DBDs (Waddell et al. 2018);
however, a review of behavioral interventions is beyond the scope of this chap-
ter. It is important to note that moderate to severe aggressive symptoms in
youth typically require a combination of psychoeducation, cognitive and be-
havioral management strategies, and pharmacological agents.

Involvement of Others
It is often necessary to involve community supports to help the child and fam-
ily deal with aggressive behaviors. These may include teachers, youth leaders,
sports coaches, and other important adults in the child’s life. Parents often ben-
efit from attending support groups themselves. Many such groups are offered
online and thus are accessible even to people living in remote areas. Organiza-
tions offering such groups include the National Alliance on Mental Illness
(www.nami.org), Children and Adults with Attention-Deficit/Hyperactivity
Disorder (www.chadd.org), the Depression and Bipolar Support Alliance
(www.dbsalliance.org), the National Federation of Families for Children’s
Mental Health (www.ffcmh.org), and Mental Health America (formerly the
National Mental Health Association; www.mentalhealthamerica.net).
It is important to provide evidence-based psychotherapeutic support for
children and families. Various psychosocial interventions have been developed
for treating aggression and related conduct problems, including parent man-
agement training (Brestan and Eyberg 1998; Burke et al. 2002; Kazdin et al.
1989, 1992), parent-child interaction therapy (Schuhmann et al. 1998), some
school and community-based programs (Farmer et al. 2004), and some indi-
 Disruptive Behavior Disorders and Aggression 131

vidual cognitive-behavioral treatments, including anger management training

and problem-solving skills training (Brestan and Eyberg 1998; Lochman and
Curry 1986; Lochman and Lampron 1988).

Conclusion
Several medications have shown promise in RCTs in addressing aggressive be-
haviors. However, further studies are needed to establish the short- and long-
term efficacy, safety, and tolerability of psychotropic agents in managing the
symptoms of aggression and DBDs in youth. More data comparing the effi-
cacy of various agents are needed.
Additional research in systematically assessing and treating symptoms of
PA and IA in youth is also needed. Because these two forms of aggression may
have different etiological pathways, they may respond differently to various
forms of treatment. Thus far, some, albeit limited, evidence suggests that cer-
tain psychopharmacological agents may be best suited to manage IA in youth.
Moreover, the development of a standardized measure of aggression subtypes
would assist in the goal of understanding and subsequently successfully treat-
ing the subtypes of aggression.

Clinical Pearls
• Carefully consider using and following the currently available
evidence- and consensus-based guidelines to achieve the best
possible outcomes.
• Treat the underlying condition first.
• Whenever possible, avoid polypharmacy. Consider adjusting
the dosage of the current medication until either the maximum
allowed dosage is reached or side effects develop.
• Always start low, go slow, and taper slowly.
• Assess and address compliance and adherence.
• Encourage youth and their parents to actively participate in psy-
chosocial interventions.
132 Clinical Manual of Child and Adolescent Psychopharmacology

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 4
Anxiety Disorders
Moira A. Rynn, M.D.
Paula K. Yanes-Lukin, Ph.D.
Pablo H. Goldberg, M.D.

A nxiety disorders begin in childhood and often evolve well into adulthood,
resulting in lifelong impairment in multiple areas, such as school achievement,
work, relationships, and health. Anxiety disorders are insidious in nature; if not
identified and treated, they can lead to a person experiencing chronic symptoms,
typically with a waxing and waning course, and often without relief. This lack
of acknowledgment—and, consequently, treatment—is partly due to patient and
clinician belief that symptoms of anxiety are an expected part of normal life. A
bias exists among health care providers that having an anxiety disorder is not as
serious as having other psychiatric disorders, such as major depressive disorder
(MDD). In fact, an analysis of the data from the National Comorbidity Survey–
Adolescent Supplement (NCS-A) found that among adolescents with psychiat-
ric disorders, those with any anxiety disorder or a specific phobia were the least

147
148 Clinical Manual of Child and Adolescent Psychopharmacology

likely to receive treatment within a 12-month period (Costello et al. 2014), and
anxiety was estimated to be the most prevalent mental health disorder world-
wide at 6.5% (Polanczyk et al. 2015).
The evolution of anxiety disorders as a diagnostic entity is reflected in the
diagnostic definitions given in editions of DSM revisions. Initially, the anxiety
disorders were all classified as psychoneurotic disorders (reactions) in DSM-I
(American Psychiatric Association 1952) and as neuroses in DSM-II (American
Psychiatric Association 1968). It was not until DSM-III (American Psychiatric
Association 1980) that the anxiety disorders diagnosis began to take shape, with
delineated criteria for both adults and children, and separation anxiety disorder
was specified and included. In DSM-IV and DSM-IV-TR (American Psychi-
atric Association 1994, 2000), most of the childhood anxiety disorders were
subsumed under the adult definitions for generalized anxiety disorder (GAD),
OCD, PTSD, social anxiety disorder (social phobia), and panic disorder (Rick-
els and Rynn 2001). For example, children who in the past may have been di-
agnosed with overanxious disorder in childhood would now receive the
diagnosis of GAD on the basis of contemporary psychiatric nosology. This trend
continued in DSM-5 (American Psychiatric Association 2013, 2022). The
chapter on disorders usually first diagnosed in infancy, childhood, or adoles-
cence that separated childhood-related disorders was eliminated in DSM-5,
and previously childhood-specific disorders (e.g., separation anxiety disorder)
can now be diagnosed in adulthood. OCD and PTSD are presented in differ-
ent chapters in DSM-5; however, they are still related to the anxiety disorders.
The exception to this trend is the inclusion of a new subtype of PTSD in DSM-
5 for preschool-age children 6 years or younger, which adapts the criteria in or-
der to be developmentally sensitive and appropriate.

Epidemiology
Anxiety disorders such as GAD (earlier known as overanxious disorder) and
social anxiety disorder are among the most common diagnoses reported in ep-
idemiological studies of child and adolescent populations (Feehan et al. 1994;
Lewinsohn et al. 1993; McGee et al. 1990). Beesdo et al. (2009) found that the
lifetime prevalence rate of a child or adolescent having symptoms that meet cri-
teria for any anxiety disorder is about 15%–20%. In community epidemiolog-
 Anxiety Disorders 149

ical studies, the prevalence rates for overanxious disorder ranged from 2.9% to
4.6%, and the rates for separation anxiety disorder ranged from 2.4% to 4.1%
(Anderson et al. 1987; Bowen et al. 1990; Costello 1989). In one general pe-
diatric clinical sample, 8%–10% of patients had symptoms that met the criteria
for any anxiety disorder (Costello et al. 1988; Egger and Angold 2006). The
NCS-A, which used a DSM-IV in-person survey of 10,123 adolescents (ages
13–18) in the United States, found that anxiety disorders were the most com-
mon, at 31.9% (Merikangas et al. 2010b).
In addition, social avoidance that interferes with functioning and is man-
ifested in worry, isolation, hypersensitivity, sadness, and self-consciousness has
been reported in 10%–20% of school-age children (Orvaschel and Weissman
1986). Prevalence rates for internalizing disorders are also greater in clinical
samples, with 14% of patients being diagnosed with an anxiety disorder (Keller
et al. 1992).
For specific anxiety disorders, the reported prevalence rates are variable
(for a review, see Costello et al. 2005). GAD/overanxious disorder is the most
common, and separation anxiety disorder is the second most common. The
prevalence rate of PTSD is 5% for adolescents (Merikangas et al. 2010a) but
is thought to be rare for children, at less than 0.5% (Copeland et al. 2007).
The prevalence of OCD is 1%–2%, and the prevalence of panic disorder ap-
proaches 1% in population studies (Geller et al. 1998; Rasmussen and Eisen
1992). However, these reported rates vary depending on whether the level of
functional impairment is included in the definition. A child with some im-
paired functioning may not exhibit every symptom to satisfy the full diagnos-
tic criteria and, unfortunately, may not be recommended for treatment.
Prevalence rates among young males and females do not differ significantly,
but a difference in rates becomes noticeable in adolescence, as females become
two to three times more likely to experience an anxiety disorder (Costello et al.
2003; Rockhill et al. 2010).

Course and Outcome

Children with anxiety disorders often experience low self-esteem and social
isolation, which fosters inadequate social skills (Strauss 1988). These children
also report higher rates of physical symptoms, such as headaches, stomach-
150 Clinical Manual of Child and Adolescent Psychopharmacology

aches, and irritable bowel syndrome (Livingston et al. 1988). These symp-
toms can then increase visits to the pediatrician, leading to an increase in
medical costs. Furthermore, there is concern that the presence of anxiety dis-
orders early in childhood provides a pathway for the development of subse-
quent mood and substance abuse disorders (Weissman et al. 1999). Pine and
Grun (1998) reported that children with a history of long-term anxiety dis-
order exhibited increased rates of other psychiatric disorders, psychiatric hos-
pitalizations, and suicide attempts as adults.
Anxiety disorders and symptoms are not simply transitory but persist over
time (Beidel et al. 1996; Cantwell and Baker 1989; Keller et al. 1992). Dadds
et al. (1997) performed a school-based prevention study in which untreated
anxious children were identified by self-report or teachers’ ratings as having
features of an anxiety disorder but not meeting the full diagnostic criteria. The
results revealed that 54% of the children developed a full anxiety disorder over
the remaining 6 months of the study. Children with GAD/overanxious disor-
der were also found to be at a higher risk for concurrent additional anxiety dis-
orders (Last et al. 1987a). A prospective 3- to 4-year follow-up study by Last et
al. (1996) showed that children with anxiety disorders, although free from
their initial anxiety diagnosis at follow-up, were more likely than control sub-
jects to develop new psychiatric disorders, usually a different anxiety disorder,
over the time course.
There also appears to be an association between childhood disorders and
the presence of adult anxiety disorders. A large number of adults who receive
an anxiety diagnosis report childhood histories of separation anxiety or over-
anxious disorders (Aronson and Logue 1987; Last et al. 1987b, 1987c). One
of the few prospective studies to assess anxious children’s adjustment to early
adulthood found that those with anxiety, especially those with comorbid de-
pression, were less likely than control subjects with no history of psychiatric
illness to be living independently, working, or attending school (Last et al.
1997). In an outpatient setting, approximately 30% of children with an anx-
iety disorder have comorbid depression (for a review, see Brady and Kendall
1992).
The Great Smoky Mountains Study, a longitudinal study examining the
development of emotional and behavioral disorders and the need for mental
health treatment in North Carolina, has also provided valuable data regarding
outcome predictions (Costello et al. 1996). Bittner et al. (2007) reported that
 Anxiety Disorders 151

within this sample, childhood separation anxiety was associated with subse-
quent separation anxiety in adolescence; childhood overanxious disorder was
associated with the development of overanxious disorder, panic attacks, depres-
sion, and conduct disorder in adolescence; GAD was associated with conduct
disorder; and social anxiety in childhood was related to social anxiety, overanx-
ious disorder, and ADHD in adolescence. Furthermore, the presence of co-
morbid anxiety and depression increased the chance of high-risk behaviors
such as substance use and suicidality (Federman et al. 1997; Foley et al. 2006).
In addition, there is some evidence that as many as 41% of children or ad-
olescents who experience MDD had or have an anxiety disorder that preceded
their depression (Brady and Kendall 1992; Kovacs et al. 1989). The presence
of an anxiety disorder was found to predict a worse prognosis for the depression
and, at times, had an effect on the length of, or recovery from, the depressive
episode. Furthermore, after treatment of and recovery from depression, the
anxiety disorder usually persisted (Kovacs et al. 1989). Similar results have
been found for bipolar disorder; 42% of adults diagnosed with bipolar disorder
reported having a childhood anxiety disorder (separation anxiety and overanx-
ious disorder) compared with 5% of adults without a diagnosis of bipolar dis-
order (Henin et al. 2007). Early treatment intervention for anxiety disorders
may prevent and alter the course of developing depression and other psychiat-
ric disorders, leading to an improved opportunity for a successful adulthood.

Rationale and Justification for

Psychopharmacological Treatment
Strong evidence suggests that antidepressants, particularly the selective sero-
tonin reuptake inhibitor (SSRI) class of medications, are safe and efficacious for
treating childhood anxiety disorders. In addition to medication treatment, there
is an extensive literature supporting the use of cognitive-behavioral therapy
(CBT) for the treatment of these disorders as well. The American Academy of
Child and Adolescent Psychiatry (AACAP) practice parameter for OCD rec-
ommends, when possible, to treat first with CBT for patients with symptoms
of mild to moderate severity and to use a combination of CBT plus an SSRI
for patients with more severe symptoms (American Academy of Child and
Adolescent Psychiatry 2012; Walter et al. 2020). For anxiety disorders, the
AACAP practice parameter recommends considering an SSRI+CBT combi-
152 Clinical Manual of Child and Adolescent Psychopharmacology

nation first for moderate to severe cases, given that remission rates were found
to be greater for children receiving combination treatment than for those re-
ceiving monotherapy with either approach (Walter et al. 2020). This is sup-
ported by the results from the largest anxiety clinical trial to date, the Child/
Adolescent Anxiety Multimodal Study (CAMS), which supported the effec-
tiveness of combined treatment of CBT with medication (Walkup et al.
2008). Unfortunately, one of the challenges of recommending CBT for pa-
tients is its limited availability in many communities. This may necessitate the
use of medication treatment as the first-line approach with supportive therapy.
Another issue concerning the use of medication treatment is a consider-
ation of the risk-benefit profile. The available safety data from completed ran-
domized controlled trials (RCTs) demonstrate that the adverse effect profiles
of SSRIs in children resemble those in adults and that, overall, these medica-
tions are safe and well tolerated. However, the FDA has required a boxed warn-
ing on all antidepressants, as well as on medications for adjunctive treatment of
MDD (e.g., aripiprazole), because of concern for a potentially increased risk of
suicidal ideation or behaviors for children taking these medications (U.S.
Food and Drug Administration 2005). In contrast to the pediatric depression
RCTs, most pediatric anxiety studies did not show evidence of increased sui-
cidal thinking or behaviors for children given medications compared with
those given placebo.

Medications for Pediatric Anxiety Disorders:

Review of Treatment Studies
Selective Serotonin Reuptake Inhibitors
To date, the most widely studied pharmacological treatments for pediatric
anxiety disorders are SSRIs (Table 4–1), which include fluvoxamine (Luvox),
sertraline (Zoloft), fluoxetine (Prozac), citalopram (Celexa), escitalopram
(Lexapro), and paroxetine (Paxil), among others. Although SSRIs are charac-
terized as antidepressants, they are unique in that they specifically inhibit the
reuptake of the neurotransmitter serotonin, therefore resulting in increased
amounts of serotonin in the synapses of the brain. Decreased serotonin levels
are attributed to various disorders, including depression (Roy et al. 1989) and
anxiety disorders (Nutt and Lawson 1992; Pigott 1996; Tancer 1993). Exten-
Table 4–1. Selected medications for pediatric anxiety disorders

Dosing Main Side effects /

Drug Total daily dosage schedule indications Recommended action

Antidepressants
Tricyclic antidepressants
Tertiary amines
Clomipramine 2–5 mg/kg qd or bid OCD, school Anticholinergic effects (e.g.,
refusal dizziness, drowsiness, dry
mouth)
Imipramine 2–5 mg/kg qd or bid GAD, PD Requires ECG monitoring
Secondary amines
Desipramine 2–5 mg/kg qd or bid OCD Potential for cardiac toxicity
Selective serotonin reuptake inhibitors GI side effects, weight gain and

Anxiety Disorders 153

loss, sweating, dry mouth,
headache, irritability, insom-
nia, fatigue, hypersomnia,
restlessness, increased hyper-
activity, tremor, increased
risk for self-injury and SIBs,
mania, withdrawal effects,
sexual side effects
Table 4–1. Selected medications for pediatric anxiety disorders (continued)

154 Clinical Manual of Child and Adolescent Psychopharmacology

Dosing Main Side effects /
Drug Total daily dosage schedule indications Recommended action

Selective serotonin reuptake inhibitors (continued)

Citalopram 20–40 mg qAM SOC Due to risk of QTc
prolongation, dosage should
Children ages Initial 2.5–10 mg qd; titrate every 1–
not be increased above total
7–11 years 2 weeks to target of 10–20 mg/day
of 40 mg
Children/adolescents Initial 10 mg qd; titrate every 1–
age ≥12 years 2 weeks to target of 20–40 mg/day
Escitalopram
Children/adolescents Initial range 5–10 mg qd; may be qd Due to risk of QTc prolong-
age ≥12 years increased to 20 mg after at least ation, dosage should not be
3 weeks increased above total of
40 mg
Fluoxetine 10–60 mg qAM OCD, GAD,
SAD, SOC
Fluvoxamine 50–300 mg qAM OCD, GAD,
SAD, SOC
Paroxetine 10–40 mg qAM SAD, SOC
Sertraline 25–200 mg qAM PD
Table 4–1. Selected medications for pediatric anxiety disorders (continued)

Dosing Main Side effects /

Drug Total daily dosage schedule indications Recommended action

Serotonin-norepinephrine reuptake inhibitors

Atomoxetine Starting at 40 mg/day, may increase qd or bid ADHD and may Monitor for mania and
after 3 days to 80 mg/day; single reduce comor- serotonin syndrome
daily dose qAM or two divided bid anxiety
doses, one qAM and one qPM. symptoms
Depending on clinical response,
may increase to 100 mg/day after
another 2–4 weeks
Venlafaxine XR 37.5–225 mg qd GAD, SAD, GI side effects, headache,
SOC weight loss, fatigue, insom-
nia, irritability, hypersomnia
Monitor blood pressure

Anxiety Disorders 155

Duloxetine 30–120 mg qd GAD GI side effects, oropharyngeal
pain, dizziness, cough, and
palpitations
Table 4–1. Selected medications for pediatric anxiety disorders (continued)

156 Clinical Manual of Child and Adolescent Psychopharmacology

Dosing Main Side effects /
Drug Total daily dosage schedule indications Recommended action

Benzodiazepines
Long-acting
Clonazepam* 0.25–2 mg qd, bid, GAD, PD Sedation, drowsiness,
tid decreased alertness,
disinhibition; taper
Short- to intermediate-acting
Alprazolam* 0.25–4 mg prn, qd, GAD, PD Sedation, drowsiness,
bid, tid decreased alertness,
disinhibition; taper
Lorazepam* 0.25–6 mg prn, qd, GAD, PD Sedation, drowsiness,
bid, tid decreased alertness,
disinhibition; taper
Nonbenzodiazepines
Buspirone 0.2–0.6 mg/kg bid or tid OCD, GAD, Light-headedness, dizziness,
SOC nausea, sedation
Note. ECG=electrocardiogram; GAD=generalized anxiety disorder; GI=gastrointestinal; PD=panic disorder; SAD=separation
anxiety disorder; SIB=self-injurious behavior; SOC=social anxiety disorder.
*Adjunct treatment.
 Anxiety Disorders 157

sive empirical literature supports the efficacy of SSRIs in treating adult anxiety
disorders (Katzelnick et al. 1995; Liebowitz et al. 2002; Pohl et al. 1998; Pol-
lack et al. 2001).

Acute Treatment
The use of SSRIs and other, newer antidepressants in the U.S. population
younger than age 18 years increased significantly from 1.3% in 2005 to 1.6%
in 2012 (Bachmann et al. 2016), with the SSRI class of antidepressants being
the most common. Owing to the evidence presented in the current literature
and their relatively minimal side effects, SSRIs are presently considered the first-
line pharmacotherapy choice for childhood anxiety disorders. The field began
with numerous promising open-label and limited sample studies (Birmaher et
al. 1994; Compton et al. 2001), which paved the way for the subsequent RCTs
discussed in the following sections and, taken together, demonstrated the most
compelling evidence for the acute treatment of anxiety disorders with SSRIs.
Fluoxetine (Prozac). To date, several well-designed fluoxetine studies for the
treatment of pediatric anxiety disorders have been published. Black and Uhde
(1994) conducted a double-blind, placebo-controlled trial to examine the ef-
ficacy of fluoxetine in treating children (ages 5–16) with the primary diagnosis
of selective mutism. Sixteen children were given a placebo run-in for 2 weeks
(Phase I). Nonresponders were then randomly assigned to either placebo (n=9)
or to fluoxetine (n=6; mean maximum dosage, 21.4 mg/day; range, 12–27 mg/
day) for another 12 weeks (Phase II).
By the end of the trial, although the participants in the fluoxetine group
showed improvement over time on all parent, patient, and clinician ratings, an
analysis of variance (ANOVA) indicated few significant results (Black and
Uhde 1994). The fluoxetine group, compared with the placebo group, had sig-
nificantly greater improvement in one symptom—mutism—as reflected by a
change in ratings on two of the nine parent scales, the mutism Clinical Global
Impression (CGI) Scale (P<0.0003) and global CGI (P<0.04), and on one
teacher rating, the Conners’ Anxiety Scale (P<0.02). The proportion of chil-
dren rated as treatment responders based on their parent’s rating of mutism
change (P<0.03) and global change (P<0.03) was also significantly greater in
the fluoxetine group. Side effects were minimal and did not differ significantly
between treatment groups.
158 Clinical Manual of Child and Adolescent Psychopharmacology

Several reasons may account for the lack of significant results in the study
by Black and Uhde (1994). The sample size was relatively small, and the
length of the trial may not have been long enough to show the effects of flu-
oxetine, given that treatment response did not increase markedly until weeks
8–12. In addition, the investigators noted that timing may have affected treat-
ment response. Clinical response in an earlier case report (Black and Uhde
1992), in which treatment began before the start of the school year, was more
striking than in their 1994 study, which was carried out in the last half of the
school year, when children with selective mutism may have already known
what to expect from their teachers and peers and were less motivated to im-
prove.
In a later, double-blind, placebo-controlled trial, Geller et al. (2001) stud-
ied response to fluoxetine in children and adolescents diagnosed with OCD.
Participants were randomly assigned to fluoxetine (n=71; mean total dosage,
24.6 mg/day) or placebo (n=32) for 13 weeks. The fluoxetine was initiated at
10 mg/day for the first 2 weeks and then increased to 20 mg/day. If subjects’
symptoms were unresponsive after 4 weeks of treatment, as indicated by no
change or worsening on the CGI Severity of Illness subscale (CGI-S), the
medication dosage could be titrated to 40 mg/day and again to 60 mg/day at
week 7.
In an intent-to-treat analysis, Geller et al. (2001) found that participants
randomly assigned to fluoxetine showed a greater reduction in OCD severity
on the primary efficacy measure, the total Children’s Yale-Brown Obsessive
Compulsive Scale (CY-BOCS) score (P=0.026). The reduction trended toward
significance at week 5 (P=0.086) and reached significance thereafter (P<0.05).
Almost half of the youth (49%) in the fluoxetine group were considered re-
sponders (defined as a ≥40% reduction in symptoms on the CY-BOCS) com-
pared with 25% in the placebo group (P=0.030, Mantel-Haenszel exact test).
In addition, significantly more participants in the fluoxetine group were rated
as being “much improved” or “very much improved” on the CGI Improve-
ment subscale (CGI-I) (55% vs. 18.8% placebo; P<0.001). Patient and par-
ent improvement ratings also reflected this trend (P<0.001). Fluoxetine was
well tolerated in this trial, with no adverse effects occurring significantly more
often in the fluoxetine group than in the placebo group.
Although the results of this study do support the efficacy of fluoxetine in
treating children and adolescents with OCD, these findings have are some no-
 Anxiety Disorders 159

table limitations. The investigators indicated that the week in which treatment
differences became significant occurred slightly later in this trial than in similar
trials using different SSRIs. Also, the study design did not allow for a compar-
ison of efficacy between fixed doses of fluoxetine, so it is difficult to determine
whether the higher dosage caused treatment effects or whether participants
would have improved at a later point in the study while taking the fluoxetine at
a lower dosage. These results are supported by a similar crossover trial (Riddle
et al. 1992).
Birmaher et al. (2003) completed a fluoxetine treatment study involving
children and adolescents diagnosed with separation anxiety disorder, social
phobia, and/or GAD. Seventy-four individuals (ages 7–17) were randomly as-
signed to placebo or fluoxetine (maximum dose, 20 mg/day) for a period of
12 weeks. The investigators found that at treatment end, the fluoxetine group
showed significantly more improvement in CGI-I scores, the primary outcome
variable (61% vs. 35% placebo; χ2 =4.93). Fluoxetine-treated subjects diag-
nosed with social phobia seemed to have the best outcome, with significantly
improved scores on the CGI-I (χ2 =12.13) and the Children’s Global Assess-
ment Scale (CGAS; χ2 =6.01) compared with those receiving placebo. Side ef-
fects in this study were minimal for the most part but included occasional
headaches, drowsiness, abdominal pain, nausea, and agitation. The investiga-
tors noted that approximately half of the subjects remained symptomatic by
the end of the trial, and they suggested that some subjects may have required a
higher dosage or may have fared better with concurrent psychotherapy.

Sertraline (Zoloft). RCTs using sertraline as treatment have focused on pe-

diatric populations diagnosed with OCD, GAD, and PTSD. In a double-blind,
placebo-controlled trial, March et al. (1998) tested the efficacy of sertraline for
children (n=107, ages 6–12) and adolescents (n=80, ages 13–17) with OCD.
Subjects were randomly assigned to placebo (n=95) or sertraline (n=92) for
12 weeks, with the dosage starting at 25 mg/day for children and 50 mg/day
for adolescents. The dosage was then titrated upward (in a forced design) by
50 mg/week to a maximum of 200 mg/day (mean total dosage, 167 mg/day).
Efficacy analyses revealed that by the end of week 2, subjects treated with sertra-
line showed significantly greater improvement on the primary outcome vari-
able—CY-BOCS (P=0.005) and National Institute of Mental Health Global
Obsessive-Compulsive Scale (NIMH-GOCS; P=0.002) scores—compared
160 Clinical Manual of Child and Adolescent Psychopharmacology

with those given placebo. In addition, 53% of the sertraline group was consid-
ered responders compared with 37% of the placebo group (P=0.03), as indi-
cated by their CY-BOCS scores. The results were similar on the NIMH-GOCS
(42% vs. 26%; P=0.02). Side effects reported in the trial by March et al. (1998)
were generally mild to moderate, with sertraline-treated subjects reporting sig-
nificantly more incidences of insomnia, nausea, agitation, and tremor (P<0.05).
The results of this study indicate that sertraline is efficacious in treating children
and adolescents with OCD in the short term. As with other studies, some sub-
jects continued to exhibit symptoms at the end of the trial, which may indi-
cate the need for concurrent psychotherapy.
Rynn et al. (2001) conducted a double-blind, placebo-controlled trial to as-
sess the efficacy of a lower daily dosage of sertraline (50 mg/day) in youth diag-
nosed with GAD (N=22, ages 5–17). An analysis of covariance (ANCOVA) on
the primary outcome variables revealed that significant treatment differences
were apparent by week 4 and continued until the end of the study. At the end of
week 9, subjects receiving sertraline were rated as endorsing fewer symptoms on
all Hamilton Anxiety Scale scores than subjects receiving placebo, including
Total (F=15.3; P<0.001), Psychic Factor (F=22.6; P<0.001), and Somatic
Factor (F =8.91; P < 0.01); measuring less severity on the CGI-S (F= 30.5;
P < 0.001); and showing greater improvement in CGI-I scores (F = 14.9;
P<0.001). At treatment end point, 90% of sertraline-treated subjects were
considered to have improved symptoms based on CGI-I scores (1=very much
improved or 2=much improved), as opposed to 10% of subjects given placebo
(P<0.001, Fisher exact test). Yet only 18% of subjects in the improved ser-
traline group were rated as markedly improved, which represents a small re-
mission rate. Side effects did not differ significantly between the sertraline and
placebo groups. This trial suggests that sertraline 50 mg/day may be an effec-
tive, safe dosage for short-term use in young patients diagnosed with GAD, re-
ducing both psychic and somatic symptoms of anxiety with mild side effects.
However, given the low rate of markedly improved ratings, these findings sug-
gest that a higher dosage may be needed to achieve remission.
Evidence of the efficacy of SSRIs and other medications in treating PTSD
in children and adolescents is limited. Robb et al. (2010) conducted one of the
few existing RCTs on the treatment of pediatric PTSD, comparing sertraline
(50–200 mg/day) with placebo (N=131, ages 6–17) over 10 weeks. The study
failed to find any significant effects for sertraline and, in fact, provided evidence
 Anxiety Disorders 161

for the superiority of placebo on some of the secondary outcome measures, al-
though sertraline has demonstrated efficacy in treating PTSD in adults.

Fluvoxamine (Luvox). In a multisite, randomized, placebo-controlled trial,

Riddle et al. (2001) studied the effects of fluvoxamine in pediatric OCD. Fol-
lowing a 1- to 2-week, single-blind screening period, eligible patients (N=120,
ages 8–17) were randomly assigned to placebo or fluvoxamine (maximum
dosage, 200 mg/day) for 10 weeks. The investigators found that fluvoxamine
was significantly more effective than placebo in ameliorating OCD symptoms
on all measures. A two-way ANOVA on the CY-BOCS total score revealed
significant treatment effects at weeks 1, 2, 3, 4, 6, and 10. At the end of the
study, 42% of subjects given fluvoxamine were defined as treatment respond-
ers, with a 25% reduction of symptoms based on CY-BOCS scores since base-
line, versus 25% of those given placebo (P=0.065, Cochran-Mantel-Haenszel
test). Responder analysis on the CGI-I also revealed that significantly more
subjects treated with fluvoxamine had a meaningful response to treatment
(“much” or “very much” improved) at the end of 10 weeks (29.8% vs. 17.5%
placebo; P=0.078, Cochran-Mantel-Haenszel test). Adverse effects that were
significantly more prevalent in the fluvoxamine group included asthenia (fa-
tigue, loss of energy, or weakness) and insomnia.
Riddle et al. (2001) demonstrated that fluvoxamine is both fast acting and
effective as a short-term pediatric OCD treatment. A limitation of the study is
that most subjects did not have comorbid diagnoses—a sample that is less typ-
ical of the OCD population, in which psychiatric comorbidity is high.
In another large-scale study, the Research Units on Pediatric Psychophar-
macology (RUPP) Anxiety Study Group (2001) assessed the efficacy of flu-
voxamine treatment in children and adolescents (N=128, ages 6–17) whose
signs and symptoms met criteria for social phobia, separation anxiety disorder,
or GAD. Subjects were randomly assigned to fluvoxamine (n=63) or placebo
(n=65) for 8 weeks. The fluvoxamine dosage was titrated upward 50 mg/week
to a maximum of 300 mg/day for adolescents and 250 mg/day for children
(age 12 years or younger). From an intent-to-treat analysis, the investigators
found that participants receiving fluvoxamine had a greater reduction in anxiety
symptoms and higher rates of clinical response than did those given placebo.
Treatment differences on one primary outcome variable, the Pediatric Anxiety
Rating Scale (PARS), reached significance by week 3 and increased through
162 Clinical Manual of Child and Adolescent Psychopharmacology

week 6. By the end of the study, the fluvoxamine group had significantly lower
PARS scores, indicating mild symptoms of anxiety (P<0.001). The CGI-I score,
which defines meaningful clinical response to treatment as scores of 3 (im-
proved), 2 (much improved), or 1 (free of symptoms), revealed that at study end
point, significantly more subjects treated with fluvoxamine received scores less
than 4 (76% vs. 29% placebo; P <0.001). They also reported significantly
more abdominal discomfort (P=0.02) and showed a trend for increased motor
activity (P=0.06).
Following the acute trial, the RUPP group investigated possible modera-
tors and mediators of pharmacological treatment in children and adolescents
with anxiety disorders (RUPP Anxiety Study Group 2002; Walkup et al.
2003). Although no significant moderators were found, analyses revealed that
subjects presenting with social phobia (P<0.05) and a greater severity of base-
line illness (P < 0.001) were less likely to improve, regardless of treatment
group.
Paroxetine (Paxil). In a placebo-controlled multicenter trial, Wagner et al.
(2004) evaluated the effects of treatment with paroxetine in children and ad-
olescents (N=319, ages 8–17) diagnosed with social anxiety disorder. Partic-
ipants were randomly assigned to either paroxetine (n=163; mean dosage,
24.8 mg/day) or placebo (n=156) for a 16-week trial.
Results at week 16 demonstrated that 77.6% of paroxetine-treated sub-
jects were defined as treatment responders, having a score of “improved” or
“much improved” on the CGI-I, compared with 38.3% of subjects given pla-
cebo (P<0.001). This trend appeared even within the first 4 weeks of treat-
ment. Adverse effects were rated from mild to moderate in severity, with
insomnia (P= 0.02), decreased appetite (P= 0.11), and vomiting (P= 0.07)
considered treatment emergent. Because paroxetine treatment exhibited a
greater response rate than placebo, and treatment differences reached signifi-
cance on all five secondary outcome variables, Wagner et al. (2004) supported
the use of paroxetine in treating pediatric social anxiety disorder. Another in-
teresting finding is that the children and adolescents in this study (77.6%)
demonstrated a greater response to treatment than did socially anxious adults
treated with paroxetine (55%; Stein et al. 1998). The investigators acknowl-
edged that commonly occurring comorbid disorders such as MDD were iden-
tified as exclusions and that their findings, therefore, cannot be generalized to
 Anxiety Disorders 163

a broader population. Similar findings were presented in another large-scale,

multisite trial (Geller et al. 2004).

Citalopram (Celexa) and escitalopram (Lexapro). Limited data are avail-

able examining the effectiveness of citalopram and escitalopram, which is the
pharmacologically active S-enantiomer of citalopram. Escitalopram received
FDA approval for the treatment of adolescent depression (ages 12–17) (Wagner
et al. 2006). Strawn et al. (2020) conducted an 8-week randomized placebo-
controlled double-blind study in adolescents (n = 51; ages 12–17) with the
primary diagnosis of GAD in which they examined the efficacy and safety of
escitalopram with a dosage titration based on response to the maximum of
20 mg/day. The study found that escitalopram led to significant clinical im-
provement compared with placebo as measured by the primary outcome mea-
sure, the PARS (P<0.001). Additionally, this study examined the impact of
phenotype variations of CYP2C19, which leads to individual differences in
pharmacokinetics that may impact treatment effectiveness.
In an open-label study evaluating the treatment impact of escitalopram
for children and adolescents (age 10–17 years) diagnosed with primary social
phobia, Isolan et al. (2007) showed that 65% of the sample (13 of 20) expe-
rienced greater improvement at the end of 12 weeks of treatment with a max-
imum dose of 20 mg/day. In another open-label study of citalopram
treatment for children and adolescents (ages 9–18) diagnosed with primary
OCD, participants received flexible dosing for 10 weeks; results suggested
that this treatment was effective and safe (Thomsen 1997). As reported on
ClinicalTrials.gov, in September 2021 the pharmaceutical company Allergan
Inc. completed a randomized, double-blind, flexible-dose study of escitalo-
pram (10–20 mg) versus placebo for the efficacy and safety in children and ad-
olescents (n=256, ages 7–17) with the primary diagnosis of GAD. At this time,
the results have not been posted (ClinicalTrials.gov identifier NCT03924323).

Meta-Analytic Data
A meta-analysis of pediatric OCD trials conducted by Geller et al. (2003) re-
vealed a highly significant pooled effect for each SSRI and clomipramine versus
placebo (P<0.001). There were no significant pooled mean differences be-
tween one SSRI and another, indicating that no one SSRI was more efficacious
than another in treating pediatric OCD. There was, however, a significant
164 Clinical Manual of Child and Adolescent Psychopharmacology

pooled mean difference favoring clomipramine over the SSRIs (P=0.002, χ2

test), indicating that clomipramine was more effective in reducing OCD
symptoms across studies.
Although this analysis showed clomipramine as superior to the SSRIs,
Geller et al. (2003) did not recommend using clomipramine as a first-line
pharmacological agent because of its side effect profile and association with
cardiac toxicity. In less severe cases, the investigators suggest that SSRIs should
be the first-choice medication, specifying that the choice of individual SSRI
should be based more on adverse effect profiles and pharmacokinetic proper-
ties such as half-life than on efficacy.
The meta-analysis for non-OCD anxiety studies involved nine studies
(N=1,673) and six medications (SSRIs/serotonin-norepinephrine reuptake in-
hibitors [SNRIs]) (Strawn et al. 2015b). The medications studied showed effi-
cacy of moderate magnitude (Cohen’s d=0.62, 95% CI 0.34–0.89; P=0.009).
Regarding adverse events, activation appeared more likely with antidepressant
treatment (OR 1.86, 95% CI 0.98–3.53; P=0.054). However, the study inves-
tigators found no increased risk for nausea/abdominal symptoms (P=0.262),
discontinuation due to an adverse event (P=0.132), or presence of suicidality
(OR 1.3, 95% CI 0.53–3.2; P=0.514).

Risks of SSRIs
Currently, the FDA has approved only fluoxetine, sertraline, and fluvoxamine
for the treatment of pediatric OCD. The consensus is that, in most cases, the
benefits of SSRIs outweigh their risks. However, the use of psychopharmaceu-
ticals, including SSRIs, for anxiety disorders in children and adolescents is not
without risk. SSRI-related side effects include nausea, diarrhea, gastrointestinal
distress, headaches, lack of energy, sexual dysfunction, sweating, dry mouth,
restlessness, initial insomnia, sleepiness, increased hyperactivity, vivid dreams,
and tremor. These problems are usually short-lived and dose related and tend to
resolve with time. Potentially more serious side effects include the development
of hypomania, mania, serotonin syndrome, seizures, and abnormal bleeding
(AACAP anxiety practice parameter; Walter et al. 2020). However, discontin-
uation symptoms are possible with some SSRIs, such as paroxetine, sertraline,
and fluvoxamine, which have increasingly been associated with a withdrawal
syndrome on discontinuation (Leonard et al. 1997; Rosenbaum et al. 1998).
Withdrawal symptoms do not generally occur with fluoxetine because of its
 Anxiety Disorders 165

long half-life, and there is somewhat less concern with sertraline because of the
presence of its one weak metabolite. Some trials (Geller et al. 2001; Riddle et
al. 2001) have also reported cases of participants who showed abnormal vital
signs—an unsurprising finding, given that the medication has been associated
with changes in weight and decreases in blood pressure. As with any medica-
tion, there is always a risk of allergic reaction.
In addition to these issues, the FDA issued an advisory to physicians that
the use of antidepressants may lead to suicidal thinking/suicide attempts in
youth (U.S. Food and Drug Administration 2005). This warning highlights
the need for close observation for signs of worsening symptoms and the emer-
gence of suicidality in children treated with these medications.

Long-Term Treatment
Benefits. Following their acute trial (described in the “Fluvoxamine [Lu-
vox]” section), the RUPP group conducted a 6-month, open-label extension
study (Walkup et al. 2002) to examine the effects of continuing treatment with
fluvoxamine or with a second SSRI in the remaining subjects. The study design
was such that active treatment responders from the acute trial continued with
fluvoxamine (group I, n=35), active nonresponders switched to fluoxetine
(group II, n=14), and placebo nonresponders began fluvoxamine (group III,
n=48), with dosage schedules that varied according to treatment group.
This study was not controlled; therefore, data analyses are suggestive and
pertain more to clinical functioning (Walkup et al. 2002). Using the CGI-I as
a primary outcome measure, the investigators found that 94% of subjects who
continued receiving open-label fluvoxamine (mean final dosage, 131 mg/day)
were considered responders (scores ≤ 3 on the CGI-I) after 24 weeks and
maintained response. After 24 weeks, 71% of subjects to whom fluoxetine was
administered (mean final dosage, 24 mg/day) met the criteria for response. Fi-
nally, 56% of placebo nonresponders who began receiving open-label fluvox-
amine (135 mg/day) were considered responders at week 24. Side effects were
mild and generally transient. Data from this extension study suggest that re-
lapse rates for anxious children maintained on SSRI treatment are low and
that extended SSRI treatment is generally safe.
In addition to the RUPP extension study, data from long-term OCD trials
can provide some indication of the efficacy and safety of maintenance treatment
with SSRIs. Following a 12-week double-blind study (March et al. 1998),
166 Clinical Manual of Child and Adolescent Psychopharmacology

Cook et al. (2001) conducted a 52-week sertraline extension trial for subjects
who completed the acute phase. Dosages for subjects (N=137, ages 6–18) were
titrated to and maintained at the level at which satisfactory clinical response was
exhibited (not to exceed 200 mg/day). Data analysis was performed according
to age, with a mean dosage of 108 mg/day for children (n=72) and 132 mg/day
for adolescents (n=65). Response rates, with response defined as a greater than
25% decrease in baseline CY-BOCS score and a CGI-I score of 1 or 2 at trial
end point, were 67% for the combined age groups, 72% for children, and 61%
for adolescents. Significant improvements over the course of treatment were ev-
ident on all outcome measures (P<0.05). By the end of the study, 85% of active
treatment responders who completed the full 52 weeks maintained responder
status compared with 43% of nonresponders. Side effects were common, with
an incidence of 77% among all subjects, and included headache, insomnia,
nausea, diarrhea, somnolence, abdominal pain, hyperkinesia, nervousness, dys-
pepsia, and vomiting.
These results provide support for long-term sertraline treatment in youth
with OCD. The most striking feature of the analyses is that of participants who
did not respond to sertraline in the acute phase, 43% were considered respond-
ers by the end of the extension trial. Although side effects generally improved as
treatment continued, the percentage of participants withdrawing because of
adverse events (12%) seems somewhat high in comparison with other trials.
A smaller trial assessing the long-term effects of citalopram concurrent with
CBT on adolescents with OCD (Thomsen et al. 2001) revealed similar results.
Following a 10-week open-label trial (N=23) of citalopram (maximum dosage,
40 mg/day) (Thomsen 1997), subjects given citalopram (N=30, ages 13–18)
continued in an open trial (mean dosage, 46.5 mg/day; range, 20–80 mg/day)
for a 6-month to 2-year period. Although 28 of the subjects continued taking
citalopram for a year, only 14 completed the 2-year study. Analyzing the data
from baseline to the 2-year end point, investigators found that the decrease in
Yale-Brown Obsessive Compulsive Scale (Y-BOCS)/CY-BOCS scores was
statistically significant for each time period (baseline to 10 weeks, 10 weeks to
6 months, 6 months to 1 year, and baseline to 2 years; P<0.001), except for
the time from the 1-year end point to the 2-year end point. This finding indi-
cated that subjects maintaining citalopram treatment for 4.5 months following
the acute trial continued to exhibit a reduction of symptoms on the Y-BOCS/
CY-BOCS, with an even greater reduction over the next 6 months, but that
 Anxiety Disorders 167

symptom reduction did not continue in the second year of treatment. Side ef-
fects, similar to those reported in other SSRI trials, were generally mild and
decreased with continued treatment. Only sexual dysfunction and sedation
were reported as persistent, causing two subjects to drop out of the trial.
In addition to these trials, review articles provide guidance on the long-
term SSRI use in children and adolescents. In his review of acute-anxiety tri-
als and adult and animal studies, Pine (2002) argued that children who have
shown satisfactory response to SSRI treatment should be given a medication-
free trial instead of having long-term treatment maintained, and they should
be promptly returned to medication if their symptoms relapse. Longitudinal
data suggest that mood and anxiety disorders evident in childhood carry a sig-
nificant risk for mood and anxiety disorders later in life. If left untreated,
these disorders may have considerable harmful effects on development, with
possible long-term implications. Pine (2002) stated that this finding must be
weighed against potential risks in using SSRI medication long term. Evidence
from animal studies also provides an interesting dilemma. Although sero-
tonin plays a role in neural plasticity, and long-term SSRI use may adversely
affect cellular processes that involve serotonin, stress and impairing anxiety
symptoms in early life can also greatly impact brain development. Currently,
the AACAP anxiety practice parameter recommendation regarding treatment
length is to continue the antidepressant treatment at the best tolerated dosage
for 12 months, beginning at remission, and then carefully monitor for any re-
turn of symptoms over the following several months (Walter et al. 2020).

Risks of long-term treatment. Side effects reported in long-term studies

were similar to those reported in acute trials, which included gastrointestinal
disturbance, headache, and insomnia. These effects were often mild in nature
and decreased with continued treatment. Overall, adverse effects did not typ-
ically lead to study withdrawal, and most trials reported relatively low dropout
rates. However, there were reports of hyperkinesia (Cook et al. 2001) that was
severe enough to warrant study withdrawal, as well as persistent complaints of
sexual dysfunction and sedation (Thomsen et al. 2001) in some long-term
studies. Reports have also documented a decrease in growth rate among youth
treated with various SSRIs over a period ranging from 6 months to 5 years
(dosage, 20–100 mg/day) (Weintrob et al. 2002).
168 Clinical Manual of Child and Adolescent Psychopharmacology

Serotonin-Norepinephrine Reuptake Inhibitors

Pharmacological treatments tend to focus on several neurotransmitter systems
believed to form the biological foundation of anxiety disorders, such as sero-
tonin and GABA. Another class of medications that shows promise in the
treatment of pediatric anxiety disorders is the SNRIs, which target both the
serotonergic and noradrenergic systems. The SNRI venlafaxine XR (extended
release) has been shown to be effective in adult GAD at total daily doses between
75 and 225 mg in several large, double-blind, placebo-controlled trials (Da-
vidson et al. 1999; Gelenberg et al. 2000; Rickels et al. 2000). As has been the
case with SSRI use, children with anxiety disorders appear to respond to venla-
faxine XR in the same manner as adults (Rynn et al. 2004). Duloxetine, an-
other SNRI considered effective for adult MDD and possibly for adult GAD
(Rynn et al. 2007), was also shown to be effective for youth with GAD at total
daily doses between 30 mg and 120 mg (Strawn et al. 2015a). Duloxetine has
been FDA approved for pediatric GAD.

Acute Treatment
Benefits. Rynn et al. (2007) reported on the results of a pooled analysis of
two combined multisite, 8-week studies examining the efficacy and safety of
venlafaxine XR (n=154) compared with placebo (n=159) in the treatment of
childhood GAD (ages 6–17; P<0.001). Exclusions included concurrent psy-
chiatric disorders such as MDD, social anxiety disorder, and separation anxiety
disorder. Dosing for venlafaxine XR began with 37.5 mg/day, and the total
daily dose was increased on the basis of body weight (37.5–112.5 mg for chil-
dren weighing 25–39 kg; minimum dosage range of 75–150 mg for those
weighing 40–49 kg; and a maximum dosage of 225 mg for those weighing
≥50 kg). In an analysis of the two studies, one showed statistically significant
improvement favoring venlafaxine XR on both primary (P<0.001) and second-
ary (P<0.01) outcome measures. The other study showed significant improve-
ment for venlafaxine XR on some secondary outcome measures but not on the
primary measure (P=0.06). Pooled analysis indicated a greater mean decrease
on the primary outcome for venlafaxine XR versus placebo (–17.4 vs. –12.7;
P<0.001). Response rates, with response defined as a CGI-I score less than 3,
were also significantly greater for venlafaxine XR (69% vs. 48%; P=0.004).
 Anxiety Disorders 169

Tourian et al. (2004) found similar results when comparing venlafaxine

XR (n=137) and placebo (n=148) in children and adolescents (ages 8–17)
with social anxiety disorder (P<0.001) over 16 weeks. Subjects with scores of
50 or more on the Social Anxiety Scale (SAS), 4 or more in the CGI-S, and no
concurrent psychiatric disorder were eligible. Results showed that baseline-to-
end point improvement in total SAS scores was significantly higher for the
venlafaxine XR group compared with the placebo group (22.5 vs. 14.9 points,
adjusted change; P<0.001).
Examining the treatment effects of duloxetine on pediatric GAD, Strawn et
al. (2015a) conducted a randomized, double-blind, placebo-controlled study in
which children and adolescents (ages 7–17) were assigned to either duloxetine
(n=135) or placebo (n=137) over 10 weeks. Duloxetine dosing was flexible, be-
ginning at 30 mg once daily for 2 weeks before titration and continuing up to
120 mg based on tolerability and response. The results suggested a significant
treatment effect of duloxetine compared with placebo on the main outcome
measure—severity of GAD based on PARS score (mean change, 9.7 vs. 7.1;
P< 0.001)—as well as greater symptom response and functional remission
(P<0.05).
Risks of SNRIs. In the study by Rynn et al. (2007), the incidence of asthe-
nia, pain, anorexia, and somnolence in subjects treated with venlafaxine XR
was twice that (≥5%) in the placebo group. Only the development of anorexia
differed significantly between treatment groups (13% for venlafaxine XR vs.
3% for placebo); also, two medication-treated subjects displayed suicidal ide-
ation and behavior, leading to their removal from the study. In addition, there
were statistically significant mean increases from baseline cholesterol serum
levels for children treated with venlafaxine XR and statistically significant
mean changes from baseline in subjects’ vital signs, with a difference in pulse
rate of approximately 4 beats per minute (bpm) and a difference in blood pres-
sure (supine diastolic and systolic) of approximately 2 mm Hg for children
treated with venlafaxine XR. The group treated with venlafaxine XR had a
height increase of 0.3 cm from baseline (P < 0.05) compared with 1.0 cm
(P<0.001) in children given placebo (difference between groups: P=0.041).
In the study by Tourian et al. (2004), the most common adverse effects
among venlafaxine XR–treated patients were influenza, anorexia, asthenia,
170 Clinical Manual of Child and Adolescent Psychopharmacology

weight loss, nausea, and pharyngitis. Three adolescents in the medication

group also displayed suicidal ideation, as opposed to none in the placebo arm.
As found in the GAD study, patients treated with venlafaxine XR experienced
significant mean weight loss compared with the placebo group (P<0.001); in
several cases (n=8), the weight loss was considered clinically significant.
In the study of duloxetine by Strawn et al. (2015a), children and adoles-
cents who were randomly assigned to the duloxetine group were more likely to
experience nausea, vomiting, decreased appetite, oropharyngeal pain, dizziness,
cough, and palpitations those randomly assigned to placebo (P<0.05). The
proportion of patients who experienced at least one adverse event was signifi-
cantly greater for the duloxetine group (106 of 135 [78.5%] vs. 90 of 137
[65.7%]; P=0.022). The investigators also found significant differences in
mean change in pulse (increase of 6.5 bpm in the duloxetine group compared
with 2.0 bpm in the placebo group) and weight loss of 0.1 kg in the duloxetine
group compared with weight gain of 1.1 kg in the placebo group (P<0.01).

Long-Term Treatment
In the Strawn et al. (2015a) study of duloxetine for pediatric GAD, following
the 10-week acute trial, participants in both the duloxetine and placebo groups
were treated with open-label duloxetine for an additional 18 weeks. All partic-
ipants demonstrated mean score improvement in PARS severity for GAD at
28 weeks (3.96 for participants initially randomly assigned to duloxetine vs.
4.68 for participants initially randomly assigned to placebo). The probability
of achieving remission based on PARS severity for GAD was roughly the same
for both groups at week 28 (84% for those initially randomly assigned to du-
loxetine vs. 87% for those initially randomly assigned to placebo).
Two adult studies (Allgulander et al. 2001; Gelenberg et al. 2000) were
conducted to assess response to 6 months of treatment with venlafaxine XR
compared with placebo. The results indicated no decrease in the efficacy of
venlafaxine XR over the 6-month treatment period. Although neither adult
study was designed to assess relapse rates following treatment discontinuation
as a function of long-term treatment, both suggested that patients with GAD
may benefit from at least 6 months of continuous treatment. Presently, very
limited data exist evaluating the long-term use of this class of compound for
pediatric anxiety disorders.
 Anxiety Disorders 171

Benzodiazepines
Benzodiazepines have been used as effective anxiolytics and sedatives in adults
since they first appeared in clinical practice in the early 1960s, before their
mechanism of action was understood. It was not until almost two decades later
that researchers discovered specific benzodiazepine receptors on the neurons of
the brain and began to understand how benzodiazepines produce their varying
effects. Following this discovery, they posited that benzodiazepines function
by activating GABA, an inhibitory neurotransmitter, which slows the response
of neural activity in the brain and produces an overall sedating effect.
Although the exact chemical process by which benzodiazepines produce
anxiolytic effects is yet to be completely determined, their effect is strongly
linked to the relationship between benzodiazepines and the GABAergic sys-
tem. Bernstein et al. (1993) hypothesized that because abnormalities in nor-
epinephrine and GABA levels in the brain are thought to underlie anxiety
disorders, correcting these levels with agents such as benzodiazepines should
lead to a reduction of anxiety symptoms.
Benzodiazepines vary widely in terms of what are considered to be their ef-
fective daily dose and half-life, which represents how fast the drug is metabo-
lized by the body. According to the cited literature, some benzodiazepines, such
as clonazepam, can be effective in adults at a total daily dose of 0.5–3.0 mg; oth-
ers, such as lorazepam, are effective at a dose of 1–6 mg/day (Witek et al. 2005).
Clonazepam also has a much longer half-life than lorazepam (18–50 hours
compared with 10–20 hours), indicating that clonazepam remains in the body
for a longer period of time. This means that clonazepam is long-acting, and al-
though it may be useful in relieving long-term anxiety, it may also lengthen
the incidence for side effects.
Justification for using benzodiazepines in clinical practice for the treat-
ment of anxious children is provided by adult studies on GAD and panic dis-
order. In a large, multisite, placebo-controlled study, Ballenger et al. (1988)
examined the effects of alprazolam on 481 adults diagnosed with panic disorder
in an 8-week trial. According to the end-point analysis, subjects in the alpra-
zolam group were judged to have significantly higher physician- and patient-
rated global improvement scores (P<0.0001) and fewer phobic (P<0.0001)
and anxiety (P<0.0001) symptoms on the Overall Phobia Rating Scale and
172 Clinical Manual of Child and Adolescent Psychopharmacology

clinician-rated Hamilton Anxiety Scale, respectively, and they reported sig-

nificantly fewer panic attacks.
Benzodiazepines have also been effective in treating adults with GAD.
Rickels et al. (1983) found that anxious adults (N=151) randomly assigned to
alprazolam or diazepam greatly improved compared with those assigned to pla-
cebo during the 4-week trial. More patients dropped out of the placebo group;
subjects in the medication groups had significantly more improvement on pa-
tient and physician ratings as early as 1 week into the study (mean alprazolam
dosage 1.2 mg/day; mean diazepam dosage 20 mg/day). Significance between
active treatment and placebo was also apparent on many of the ratings scales at
end-point analysis, indicating that effects were maintained throughout the
trial. Alprazolam is the only benzodiazepine approved by the FDA for the treat-
ment of GAD.

Acute Treatment
Benefits. Unlike the substantial literature available about treatment with
SSRIs, relatively few structured investigations assessing the efficacy of benzo-
diazepines for pediatric anxiety disorders have been published.
In one of the earliest RCTs measuring the efficacy of benzodiazepines in
children with anxiety disorders, Bernstein et al. (1990) examined the effect of
alprazolam and imipramine for the treatment of young school refusers. En-
couraged by the positive results of an open-label trial, in which 67% of patients
randomly assigned to alprazolam showed marked or moderate improvement
and 55% returned to school, the investigators created a double-blind crossover
study. Subjects were randomly assigned to alprazolam, imipramine, or placebo
for 8 weeks, and then the medication was tapered for 1–2 weeks and discon-
tinued. The investigators discovered that the treatments produced statistically
significant differences at week 8 on the Anxiety Rating for Children measure,
with subjects randomly assigned to alprazolam (maximum dosage, 3 mg/day)
showing the most improvement. However, these results failed to reach signifi-
cance once the baseline scores were factored in as covariates in the ANCOVA.
Simeon et al. (1992) conducted an RCT following the results of their
open study (Simeon and Ferguson 1987). As in the Bernstein et al. (1990)
trial, the follow-up, placebo-controlled, double-blind study failed to corrobo-
rate the earlier findings. Subjects (N=30) were children with presentations
meeting DSM-III criteria for anxiety and avoidance who were given placebo for
 Anxiety Disorders 173

1 week and then randomly assigned to alprazolam or placebo for 4 weeks (mean
maximum dosage 1.57 mg/day; range, 0.5–3.5 mg/day). The medication was
tapered for 2 additional weeks and then replaced with placebo. Subjects either
received the replacement placebo or continued receiving the original placebo,
respectively. Although their evaluations, administered after the double-blind
trial (day 28), seemed to indicate symptom improvement among the children
given alprazolam, Simeon and colleagues found that differences in clinical
global ratings were not statistically significant.
Following the Simeon et al. (1992) trial, Graae et al. (1994) performed a
double-blind, crossover pilot study involving children with similar anxiety di-
agnoses (N=15). All but one of the children were diagnosed with separation
anxiety disorder according to DSM-III criteria, and all but two presented with
comorbid anxiety disorders. In this study, unlike in the Simeon et al. (1992)
study, subjects were immediately randomly assigned to either clonazepam
(maximum dosage, 2 mg/day) or placebo for a 4-week, double-blind trial. Al-
though at the end of the study, half the children no longer had symptoms that
met the criteria for an anxiety disorder, treatment-effect comparisons did not
reach significant levels. No significant treatment differences were found related
to the frequency and severity of anxiety symptoms identified by the other mea-
sures, the Diagnostic Interview Schedule for Children and the Children’s Man-
ifest Anxiety Scale. The authors did not support using clonazepam at the dosing
schedule of 2 mg/day in children and adolescents with anxiety disorders.

Risks of benzodiazepines. Side effects for most benzodiazepines have been

reported as infrequent and mild, although they vary in severity across studies.
The most common side effects were dry mouth and drowsiness. Simeon et al.
(1992) also reported that sedation and disinhibition, manifested by aggressiv-
ity, irritability, and incoordination, were common. In addition, 71% of partic-
ipants in the Bernstein et al. (1990) trial presented with abdominal pain,
dizziness, and headaches.
Graae et al. (1994), in their study, reported the most severe side effects.
Disinhibition, irritability, and oppositionality were notable in their sample; in
three cases, these side effects were severe enough to cause the subjects to drop
out of the study during Phase I. Benzodiazepines can lead to dependence with
chronic use, usually defined as longer than 8 weeks of treatment (Nishino et al.
1995). Although none of the reviewed studies indicated withdrawal symptoms
174 Clinical Manual of Child and Adolescent Psychopharmacology

during the tapering period, it would be wise to monitor children closely during
this period and to not administer benzodiazepines on a long-term basis. Al-
though the review findings indicate that benzodiazepine treatment offers some
benefits for anxious children and adolescents, there have not been enough well-
designed clinical trials with large sample sizes to clearly evaluate the safety and
efficacy of this class of compounds.

Long-Term Treatment
Because of concern that dependence will develop as a result of long-term treat-
ment with benzodiazepines, many of the published RCTs have been acute
studies, and no long-term studies have evaluated treatment for anxious chil-
dren and adolescents. However, many long-term studies have used benzodi-
azepines in adults diagnosed with anxiety disorders, especially panic disorder,
because the chronic nature of panic disorder tends to require longer treatment
duration. For example, in a large, placebo-controlled study, Schweizer et al.
(1993) studied the treatment effect of long-term alprazolam (mean dosage,
5.7 mg/day) and imipramine (mean dosage, 175 mg/day) use in adults with
panic disorder, with or without agoraphobia (N=106, ages 18–65). Following
an acute trial, participants who experienced symptom improvement were ran-
domly assigned to alprazolam (n=27), imipramine (n=13), or placebo (n=11)
for 6 months of maintenance treatment. Monthly assessments included mea-
sures of panic attack frequency and severity, generalized anxiety, and phobias.
The results indicated that following maintenance treatment, panic attack
frequency declined for all patients except one in the placebo group. At week
32, only 9% of the alprazolam group, 0% of the imipramine group, and 22%
of the placebo group still reported experiencing minor symptom attacks. Sub-
jects receiving maintenance treatment with alprazolam who showed tolerance
to adverse events such as sedation, a common side effect for benzodiazepines,
had a decrease in incidence from 49% during the acute trial to 7%.
Although this study had a high attrition rate from the acute trial to the
maintenance phase, with significantly more subjects remaining in the alpra-
zolam group, the results are striking. Alprazolam-treated patients showed sig-
nificantly more difficulty than imipramine- or placebo-treated subjects in
discontinuing medication. In addition, the investigators noted that after 1-
year follow-up, patients who had originally been treated with imipramine or
placebo did just as well on clinical measures as those who had been treated
 Anxiety Disorders 175

with alprazolam but without exhibiting any of the physical dependence or

withdrawal symptoms. This finding indicates that the sustained treatment ef-
fects of long-term therapy with benzodiazepines might not be worth the risk,
especially in the pediatric population.

Tricyclic Antidepressants
Tricyclic antidepressants (TCAs), named for their three-ring structure, are
known for their mood-elevating effects. For this reason, they have been used as
a front-line pharmacological treatment for adults with depression and anxiety
since the mid-1960s (Potter et al. 1995). Precursors to the safer SSRIs, TCAs
bind to presynaptic transporter proteins in the brain and inhibit the reuptake
of norepinephrine and serotonin in the presynaptic terminal. Although all
TCAs are equally effective in inhibiting both norepinephrine and serotonin,
some are more preferential to one or the other, causing them to be referred to
as “noradrenergic” or “serotonergic,” respectively (Meyer and Quenzer 2005).
TCAs may be helpful for long-term treatment of anxiety because inhibition of
norepinephrine and serotonin extends the duration of the transmitter action
at the synapse and changes both the presynaptic and postsynaptic receptors.
This adaptation over time may increase the potential for clinical improvement,
but it also extends the potential for side effects. In terms of half-life, most TCAs
remain in the body for approximately 24 hours, allowing for once-daily dosing
(Potter et al. 1995). In adults, TCAs are used for the treatment of MDD, anx-
iety disorders (GAD, panic disorder, OCD), and pain syndromes.

Acute Treatment
Benefits. Although some RCTs (Bernstein et al. 2000; Gittelman-Klein and
Klein 1971) indicated significant treatment differences between TCAs and
placebo, a number of studies were unable to replicate and support these find-
ings (Berney et al. 1981; Bernstein et al. 1990; Klein et al. 1992). Addition-
ally, investigators have reported serious side effects in children taking TCAs,
suggesting that the risk involved may outweigh the potential benefits.
Gittelman-Klein and Klein (1971) performed the first RCT evaluating
the effect of TCAs on children with school phobia. In a double-blind, pla-
cebo-controlled study, they randomly assigned children with school phobia
(N=35) to either imipramine or placebo (mean dosage, 152 mg/day; range,
176 Clinical Manual of Child and Adolescent Psychopharmacology

100–200 mg/day) for 6 weeks. Assessments included measures of global im-

provement on a seven-point scale, school attendance, and psychiatric ratings of
symptoms. At the end of the 6-week trial, the investigators found that imipra-
mine was significantly more effective than placebo in increasing school atten-
dance, and greater improvement on all other measures was indicated. Of
children given medication, 81% returned to school, as opposed to 47% of those
given placebo (P<0.05), a significantly greater frequency of improvement in
the imipramine group.
Berney et al. (1981) followed the Gittelman-Klein and Klein (1971) study
with a 12-week trial assessing the efficacy of clomipramine in child and ado-
lescent school refusers (N=46). Subjects were randomly selected to receive clo-
mipramine or placebo, prescribed according to age (40 mg/day for ages 9–10;
50 mg/day for ages 11–12; 75 mg/day for ages 13–14). Although the investi-
gators discovered a significant shift toward improvement on global scores
within both the placebo and the medication groups, they found that this sig-
nificance disappeared when the groups were compared in an ANCOVA. By the
end of the study, more than one-third of the sample still had serious difficulty
returning to school.
In a double-blind, placebo-controlled study comparing the use of alpra-
zolam and imipramine in treating children and adolescents who refused to at-
tend school (N=24), Bernstein et al. (1990) found similar effects. An ANOVA
showed that subjects randomly assigned to imipramine (n=9; mean total daily
dose, 164.29 mg) for the full 8 weeks showed significantly less improvement
in Anxiety Rating for Children scores compared with those in the alprazolam
group (n=7; mean total daily dose, 1.82 mg) but demonstrated significantly
more improvement than those given placebo (n=7; P=0.03). However, these
results were no longer significant after ANCOVAs were performed.
Following this trial, Klein et al. (1992) conducted another RCT comparing
imipramine and placebo in children with separation anxiety disorder (N=20).
If subjects’ symptoms did not respond to a 4-week behavioral treatment, they
were randomly assigned to placebo or imipramine (mean dosage, 153 mg/day;
range, 75–275 mg/day) for a 6-week trial. By the end of the study, the results
were not significant on any of the ratings, which included parent and child self-
reports, teacher and psychiatrist ratings, and global improvement scores. Al-
though half of the subjects reported improved symptoms, these results do not
appear to support the use of TCAs as a monotherapy for pediatric anxiety dis-
 Anxiety Disorders 177

orders. The targeted sample had pure separation anxiety without comorbid
depression, not school phobia, yet the medication did not prove to be any more
effective than placebo. Also, children in the imipramine group reported some
severe side effects and were still receiving psychotherapy as an adjunctive treat-
ment.
Studies assessing the efficacy of the serotonergic TCA clomipramine in
children with OCD also give some insight into the overall efficacy of TCAs for
anxiety disorders. In a 10-week, double-blind crossover trial (N=48), Leonard
et al. (1989) compared two TCAs: clomipramine, which has been shown to be
effective in children with OCD, and desipramine, which is less potent in inhib-
iting serotonin reuptake (Ross and Renyi 1975). Following a 2-week, single-
blind placebo phase to assess efficacy, subjects were randomly assigned to either
clomipramine or desipramine for the first 5 weeks (Phase A), with their med-
ication switched to the alternate medication for another 5 weeks (Phase B).
Doses were on a fixed schedule, with a target total daily dose of 3 mg/kg, and
were based on weight (mean dosage for clomipramine, 150 mg/day; for de-
sipramine, 153 mg/day; range, 50–250 mg/day). An ANCOVA showed that
clomipramine, but not desipramine, produced a significant decrease in all ob-
sessive-compulsive rating (NIMH-GOCS; P=0.0002) and depression ratings
(Hamilton Rating Scale for Depression, P=0.006; NIMH depression scales,
P=0.0001) and an increase in a measure of global functioning (P=0.001).
Drug order was also shown to have a significant effect. Of the subjects who
were switched from clomipramine in Phase A to desipramine in Phase B, 64%
showed signs of relapse, defined as at least a 1-point decline on the NIMH-
GOCS by the fifth week of Phase B. This would indicate that desipramine did
not produce the same positive clinical effects as clomipramine and could not
sustain those effects following clomipramine treatment. DeVeaugh-Geiss et al.
(1992) found similar results in their 8-week multisite study assessing clomipra-
mine use in children and adolescents with OCD (N=60). Subjects were ran-
domly assigned to clomipramine (maximum dosage by body weight: 25–30 kg,
75 mg/day; 31–45 kg, 100 mg/day; 46–60 kg, 150 mg/day; and > 60 kg,
200 mg/day) or to continue with placebo. Those in the clomipramine group
had a 37% mean reduction of symptoms on the Y-BOCS compared with 8%
in those receiving placebo and had a 34% mean reduction on the NIMH-
GOCS compared with 6% for the placebo group. Both findings were signif-
icant after an ANCOVA was performed (P<0.05).
178 Clinical Manual of Child and Adolescent Psychopharmacology

Risks of TCAs. Side effects for TCAs ranged in severity across studies. Git-
telman-Klein and Klein (1971) found that most side effects disappeared with-
out requiring a dosage change. The most common were drowsiness, dizziness,
dry mouth, and constipation. Similarly, Berney et al. (1981) argued that al-
though side effects were reported, they were usually not severe. No subject in
the Bernstein et al. (1990) study had side effects that were rated higher than
mild, the most common being headache, dizziness, dry mouth, abdominal
pain, and nausea.
Klein et al. (1992) reported the most severe cases, with the most frequent
side effects being irritability or angry outbursts and dry mouth. Children in
the imipramine group experienced considerably more side effects than those
in the placebo group (χ2 =5.05; P<0.03), with all complaints lasting at least
3 days, and two-thirds of those reported being in the moderate to severe
range. This is troubling because the mean daily dosage in this trial was similar
to that administered by Gittelman-Klein and Klein (1971), although their
sample was significantly smaller. Side effects in studies using clomipramine
and desipramine to treat children with OCD were similar. Leonard et al.
(1989) reported dry mouth, tiredness, and dizziness as the most common ad-
verse effects. However, participants who received clomipramine experienced
more tremor and other side effects, such as chest pain, hot flashes, heartburn,
rash, and acne.
Beyond these side effects, some case studies have reported sudden, unex-
plained death in children taking TCA medications (Biederman 1991; Riddle
et al. 1993; Varley and McClellan 1997). In many of the reported cases, the
children were being treated with desipramine at varying but therapeutic or
even subtherapeutic levels for attention-deficit disorder or ADHD. Monitor-
ing seems to have been inconsistent among the cases, but the cause of death was
usually linked to adverse cardiac events. Because of the possibility of cardiac
toxicity in young children, clinicians are advised to monitor the effects of TCA
levels on their subjects very closely and to follow serial electrocardiograms
(ECGs) over the course of treatment to ensure that plasma levels are not above
the therapeutic threshold.
Overall, there does not yet appear to be enough evidence to support the
frequent use of TCAs as a monotherapy for children and adolescents with anx-
iety disorders, with the exception of OCD and clomipramine treatment.
 Anxiety Disorders 179

Long-Term Treatment
Although long-term studies with small sample sizes assessing the efficacy of
TCAs in children with pure anxiety disorders are very limited, evidence from
long-term OCD trials provides some indication of effects. Following their
short-term, placebo-controlled trial, DeVeaugh-Geiss et al. (1992) continued
with an open-label extension study for 1 year. They found that efficacy was
maintained in subjects who elected to participate and completed the whole year
(n=25). By the end of the year, the mean Y-BOCS score was 9.5, compared with
23 at the beginning of the extension. The investigators reported that clomip-
ramine was still well tolerated.
Leonard et al. (1991) also performed an 8-month trial similar in design to
their previous short-term crossover trial. Children and adolescents from the pre-
vious trial receiving maintenance clomipramine treatment (N=26) entered into
the study and continued to receive clomipramine (mean dosage, 143 mg/day)
for 3 months. At month 4, subjects were randomly assigned to desipramine
substitution (mean dosage, 123 mg/day) or to continue with clomipramine for
2 months. For the final 3-month phase, all subjects continued to receive clo-
mipramine treatment. For subjects completing the entire trial (N=20), results
revealed that during the months of the substitution, those randomly assigned
to desipramine showed greater impairment across ratings than those continu-
ing with clomipramine. These results were only significant, however, on the
NIMH-GOCS scale once the investigators controlled for the error rate. This
study would seem to indicate that efficacy was maintained in subjects receiv-
ing long-term TCA treatment, given that few subjects in the clomipramine
group experienced symptom relapse. However, even those subjects receiving
clomipramine for the full 8 months still experienced OCD symptoms, which
varied in severity over time. Thus, long-term clomipramine treatment for
children and adolescents with OCD seems to be effective in decreasing symp-
toms but does not completely eliminate troubling symptoms.

Buspirone
Two randomized, placebo-controlled trials have examined the efficacy of bus-
pirone in pediatric patients with GAD. In these studies, patients ages 6–17
(N=559) received 15–60 mg of buspirone daily (Bristol-Myers Squibb 2010).
There were no unexpected safety findings associated with buspirone. The stud-
180 Clinical Manual of Child and Adolescent Psychopharmacology

ies did not find significant differences in patients’ GAD symptoms between
buspirone and placebo. However, pharmacokinetic studies of buspirone have
shown that plasma exposure to buspirone—and to its active metabolite, 1-(2-
pyrimidinyl)-piperazine—is equivalent or greater in pediatric patients com-
pared with adults. Much of the other available information on this agent stems
from case reports, case series, and open-label trials. Although individual case re-
ports seem to indicate some usefulness of buspirone in relieving anxiety symp-
toms, they also do not provide evidence of its efficacy (Alessi and Bos 1991;
Balon 1994; Kranzler 1988).
Two controlled trials and one open-label study have assessed the efficacy
of buspirone in treating pediatric anxiety disorders. The two controlled trials
(one flexibly dosed and one fixed dose), which were sponsored by Bristol-
Myers Squibb, examined the efficacy of buspirone versus placebo for the treat-
ment of GAD in the pediatric population. Both studies found no separation
between buspirone and placebo. Adverse events occurred more frequently in
the patients receiving the active treatment (Strawn et al. 2018). In a small
open-label study, Pfeffer et al. (1997) investigated the treatment effects of bus-
pirone in child psychiatric inpatients ages 5–12 (N=25) who exhibited symp-
toms of anxiety and moderate aggression. Subjects who received high scores
on the Revised Children’s Manifest Anxiety Scale (RCMAS) and the Measure
of Aggression, Violence, and Rage in Children (MAVRIC) were eligible to re-
ceive buspirone treatment. The total daily dosage was titrated up 5–10 mg ev-
ery 3 days (maximum dosage, 50 mg) for 3 weeks (Phase II), after which the
medication was kept at the optimum dosage for a 6-week maintenance period
(Phase III). The results indicated that by the end of the 9-week trial, subjects
had a significant reduction in symptoms on the Social Anxiety factor of the
RCMAS (P<0.04) but not on the total RCMAS score. There was also a signif-
icant reduction in overall aggression, as measured by the MAVRIC (P<0.02),
and in the number of seclusions and daily physical restraints used (P<0.01).
Some children (n=6) had to discontinue use of buspirone because of severe
side effects, including agitation, increased aggressivity, euphoric symptoms,
increased impulsivity, and out-of-control behavior.
Although the results of this study are limited by its open-label design, they
do demonstrate some efficacy in treating pediatric social anxiety disorder with
buspirone. The 19 participants who completed the trial tolerated buspirone
(mean dosage, 28 mg/day) well, reporting few side effects other than head-
 Anxiety Disorders 181

ache. However, as the investigators noted, it is troubling that almost 25% of

the sample had to discontinue treatment because of interfering adverse events.
A later case series (Thomsen and Mikkelsen 1999) also seemed to support
the addition of buspirone to SSRI treatment in adolescents diagnosed with
OCD (N=6, ages 15–19). If patients did not show improvement following
previous SSRI treatment or an SSRI+CBT combination, they were treated with
buspirone (mean dosage, 20 mg/day). Although cases varied in severity, the
investigators reported that buspirone in combination with continuing SSRI
treatment showed a positive reduction effect on obsessive-compulsive symp-
toms, especially anxiety and distress. In addition, dramatic clinical improve-
ment, as measured by the Y-BOCS, was seen in three of the six cases. Buspirone
was well tolerated, inasmuch as no patients reported severe side effects or had to
discontinue combined treatment.

Other Potential Compounds

Guanfacine
Guanfacine is another medication that has also been used to treat anxiety dis-
orders in pediatric populations. Guanfacine and other α2 agonists, such as clon-
idine, were initially developed to manage hypertension. Guanfacine XR, which
is sometimes prescribed to address impulsive or disruptive behavior, is FDA ap-
proved for the treatment of ADHD in patients ages 6–17 years. Guanfacine is
less sedating than clonidine and yet should be carefully managed in relation to
cardiovascular side effects (e.g., hypotension, bradycardia); guanfacine XR is a
longer-acting and potentially more tolerable formulation.
Evidence for the use of guanfacine in the treatment of pediatric anxiety
disorders is limited. In an RCT, Strawn et al. (2016) examined the safety and
tolerability of guanfacine XR in children and adolescents ages 6–17 with
GAD, separation anxiety disorder, or social anxiety disorder. In the trial, pa-
tients (N=83) received flexibly dosed guanfacine XR (1–6 mg/day) or placebo
for a period of 12 weeks. The medication was well tolerated, but the study
lacked the power to detect treatment-related differences in efficacy between
guanfacine XR and placebo.
An open-label study by Connor et al. (2013) found support for the use of
guanfacine XR in treating PTSD in pediatric patients ages 6–18 (N=17). Par-
ticipants in the study were prescribed 1–4 mg/day. Of the 13 patients who
182 Clinical Manual of Child and Adolescent Psychopharmacology

completed the 8-week open-label trial, 70.6% were rated as having very much
improved or much improved symptoms on the CGI-I. Specifically, guanfa-
cine XR may be effective in decreasing PTSD Cluster B (reexperiencing),
Cluster C (avoidant), and Cluster D (overarousal) symptoms.

Atomoxetine
Atomoxetine is a highly selective SNRI and currently is FDA approved for the
treatment of pediatric ADHD. However, a study completed by Geller et al.
(2007) evaluated the treatment effectiveness of atomoxetine for children and
adolescents diagnosed with both ADHD and an anxiety disorder such as
GAD, social phobia, or separation anxiety disorder. In their double-blind,
placebo-controlled 12-week trial, a total of 176 participants (ages 8–17) were
randomly assigned to treatment, and dosing was based on weight, not to ex-
ceed a dosage of 120 mg/day. On both of the primary outcome measures (At-
tention-Deficit/Hyperactivity Disorder Rating Scale IV–Parent Version and
the PARS), total scores in the treatment groups improved significantly at the
end of the study as compared with the placebo group, with P values of 0.001
and 0.011, respectively. The only statistically significant adverse event in the
atomoxetine group compared with the placebo group was decreased appetite.

Safety Issues
Monitoring
Prior to initiating medication treatment, it is important to review the family’s
medical and psychiatric history as well as the patient’s laboratory results and
previous medical evaluations. When prescribing a medication, the clinician
should document the child’s baseline weight, height, and vital signs and then
monitor them over time, as well as consult with the child’s primary care phy-
sician in order to obtain additional medical information (e.g., concomitant
medication history, last physical examination) and to establish a collaborative
treatment relationship. Informed consent and assent should be obtained from
the parent and child following a full explanation of the risks and benefits of the
selected medication treatment. It is helpful to identify for the child and parent
a list of the most impairing anxiety symptoms to track over time, with the ex-
pectation that the medication will lead to improvement in these symptoms.
 Anxiety Disorders 183

No laboratory tests are required for the use of SSRIs. SSRIs are well tol-
erated by children and adolescents, and the pediatric side effect profile is sim-
ilar to that seen in adult clinical studies. The main side effects of concern are
gastrointestinal discomfort, drowsiness, headache, insomnia, nervousness, hy-
perkinesia, and hostility (Waslick 2006). There are reports of withdrawal
symptoms accompanying the discontinuation of SSRIs; patients may experi-
ence gastric distress, headache, dizziness, irritability, and agitation (Labellarte
et al. 1998). Given this possibility, it is recommended that these medications
not be abruptly discontinued.
Recent acute-treatment studies showed that children receiving venlafaxine
XR had statistically significant changes in blood pressure, heart rate, weight,
height, and total cholesterol. From these results, it is unclear what impact
long-term exposure to this medication would have on these clinical parame-
ters. When using this agent, clinicians should monitor vital signs, weight, and
height and conduct a periodic laboratory assessment of cholesterol with acute
and long-term treatment.
TCA use in children has the potential for cardiac risk. When a TCA is pre-
scribed, the child’s baseline vital signs, including sitting and standing blood
pressure with pulse, and a baseline ECG should be obtained. Once the clinician
has titrated the medication to the therapeutic dosage, another ECG should be
performed when the serum level of the medication has been reached. This pro-
cess should be repeated with each dosage adjustment and with periodic moni-
toring for long-term use. Another concern with this class of medication is the
risk of lethal overdose.
In 2004, the FDA issued a directive to add a black box warning for all an-
tidepressant medications after examining the outcome of all pediatric pla-
cebo-controlled trials of antidepressant medications and finding an increased
incidence of suicidal thoughts and behaviors in the medication group (4%)
compared with the placebo group (2%) (Leslie et al. 2005; U.S. Food and
Drug Administration 2005). More recently, a meta-analysis by Bridge et al.
(2007), which involved a larger number of pediatric clinical trials, showed—
in terms of suicidality and behaviors—a number needed to harm (NNH) of
143 for all conditions and specifically an NNH of 140 for non-OCD anxiety
disorders and an NNH of 200 for OCD. Clinicians should review this infor-
mation with the parents and stress the need to contact them if the child expe-
riences changes in behaviors, sleep patterns, and activity levels.
184 Clinical Manual of Child and Adolescent Psychopharmacology

Prevention and Intervention of Adverse Effects

The best prevention and intervention for the management of medication ad-
verse effects is educating the parent and child about what to expect in terms of
adverse effects and how the clinician plans to manage these if they occur. As
part of this education, it must be stressed that although there may be mild side
effects initially, most will usually resolve in the first several weeks of treatment.
The clinician should also document the child’s baseline physical symptoms
and levels of severity prior to starting medication and review these with the
child and family at treatment initiation and at each medication visit to assess
changes in severity or identify the development of a new symptom. Children
with anxiety disorders have somatic symptoms that may be confused with ad-
verse medication effects. Documenting the presence of somatic symptoms at
baseline will assist in delineating the development of new adverse events or the
worsening of previous symptoms.
For all medications, treatment should be initiated at a low dosage for the
first 7 days, with the dosage slowly increased over subsequent weeks, depend-
ing on the child’s clinical response and tolerability of the medication. Unfor-
tunately, there is a dearth of information about dosing guidelines for these
medications in treating specific anxiety disorders. Once a clinically efficacious
dosage is achieved, it should be maintained for 8–12 weeks and later reevalu-
ated to gauge successful treatment of the primary anxiety target symptoms
and tolerability of the medication.

Practical Management Strategies: Treatment

Approaches, Algorithms, and Guidelines
Psychotherapy
Several clinical trials have clearly demonstrated that 10- to 16-week cognitive-
behavioral treatments (with in vivo exposure) lead to a significant reduction in
anxiety symptoms in children (Barrett et al. 1996; Kendall et al. 1997). Given
this information, it is reasonable for clinicians to initially recommend treat-
ment with CBT. However, some families may find it difficult to obtain CBT
treatment because of the limited availability of pediatric therapists proficient
in this modality. If CBT is tried initially, it should be noted that a significant
percentage of children remain symptomatic following CBT treatment. An-
 Anxiety Disorders 185

other consideration is the presence of comorbid diagnoses, such as MDD, and

the severity of illness, for which the prudent approach would be to treat with
a combination of CBT and an SSRI.

Medication
In general, medication is often considered for treating pediatric anxiety disor-
ders either when a psychosocial intervention trial has failed or when anxiety
symptoms are considered to be in the moderate to severe range, leading to
functional impairment such as poor school performance, school refusal, in-
somnia, and the development of comorbid diagnoses (e.g., MDD).

Combination Treatment
The scientific evidence demonstrates that both CBT and medications (SSRIs)
are efficacious treatments, and recent research has been focused on the effects
of combining these two treatments at onset. For example, Bernstein et al.
(2000) investigated the efficacy of imipramine plus CBT in treating adoles-
cents with school phobia (N=47) who were diagnosed with comorbid anxiety
and MDD in an 8-week trial. Subjects were randomly assigned to imipramine
(mean total daily dose, 182.3 mg) or placebo, in combination with CBT. The
results of this study indicated that school attendance improved significantly
only in the imipramine+CBT group (z=4.36; P<0.001) and that that group
improved at a faster rate than did the placebo+CBT group (3.6% vs. 0.9%;
z=2.39; P=0.017), even when comparisons were made with baseline. Anxiety
and depression symptoms on various measures decreased significantly for
both imipramine and placebo groups, with only one measure—the Children’s
Depression Rating Scale, Revised—favoring imipramine (z=2.08; P=0.037).
Additionally, remission on clinical measures significantly favored imipramine
+ CBT only on the school attendance variable (χ2 =7.38; P=0.007).
Bernstein et al. (2000) provided data on the use of TCAs in combination
with CBT for youth with a combination of anxiety and depression symptoms
who refuse to attend school. As with many previous studies, a comorbidity
factor precludes recommending TCAs for pure anxiety disorders; neverthe-
less, school attendance did improve significantly.
Another study (Neziroglu et al. 2000) investigated the possible additional
benefits of treating children and adolescents ages 10–17 with OCD (N=10)
using a combination of fluvoxamine and behavior therapy compared with us-
186 Clinical Manual of Child and Adolescent Psychopharmacology

ing fluvoxamine alone. Subjects were eligible if they had previously failed a trial
of behavior therapy lasting at least 10 sessions by not complying either inside or
outside of treatment sessions. Following randomization, all subjects received
10 weeks of fluvoxamine (maximum dosage, 200 mg/day) until week 5, when
5 of the subjects were assigned to receive 20 sessions of behavior therapy. Re-
sults showed that 8 of the 10 total subjects had improved scores on the primary
outcome variable, the CY-BOCS, following the initial 10 weeks of fluvoxamine
treatment. At week 43, 3 of the 5 subjects in the fluvoxamine +behavior therapy
group had significantly improved CY-BOCS scores, and 2 subjects remained
stable; 1 of the 5 subjects in the fluvoxamine-only group experienced significant
symptom improvement, 2 remained stable, and 2 deteriorated significantly.
At week 52, the pattern was similar; by 2-year follow-up, subjects in both treat-
ment groups all continued to report improved symptoms or remained stable.
The Pediatric OCD Treatment Study (POTS) Team (2004) later con-
ducted a multisite, placebo-controlled, double-blind study assessing the effi-
cacy of sertraline, CBT, and their combination for children and adolescents
ages 7–17 diagnosed with OCD (N=122). During Phase I, subjects were ran-
domly assigned to sertraline (target dosage, 200 mg/day), CBT, combination
therapy, or placebo for 12 weeks. Results from intent-to-treat random regres-
sion analyses revealed that all active treatments were significantly more effec-
tive than placebo, based on change in CY-BOCS score (CBT: P = 0.003;
sertraline: P=0.007; combination: P=0.001), and that combined treatment
was superior to CBT alone (P=0.008) and to sertraline alone (P=0.006). The
results for the CBT-alone and sertraline-alone groups did not differ signifi-
cantly from each other. Furthermore, the rate of clinical remission, defined as
a CY-BOCS score of 10 or less in the combined treatment group, differed sig-
nificantly from that of the sertraline-only (P = 0.03) and placebo groups
(P<0.001) but did not differ significantly from that of the CBT-only group.
Side effects included decreased appetite, diarrhea, enuresis, motor activity,
nausea, and stomachache. Despite these reports, there were no serious adverse
events or reports of suicidality. The POTS showed that sertraline, CBT, and
their combination are effective treatments for pediatric OCD. However, be-
cause the combination and CBT-only groups showed both a higher reduction
of symptoms on the CY-BOCS and a higher rate of clinical remission, the in-
vestigators recommended combination treatment or CBT alone as first-line
treatment approaches.
 Anxiety Disorders 187

Beidel et al. (2007) conducted a study comparing fluoxetine, pill placebo,

and Social Effectiveness Therapy for Children (SET-C), a behavioral therapy
combining group sessions and individualized exposure sessions for treating
social phobia in children and adolescents. Their findings indicate that both
SET-C and fluoxetine were more effective than placebo in reducing the symp-
toms of social phobia, with 79% of the SET-C group and 36.4% of the fluox-
etine group having a significant improvement in CGI-I scores versus 6.3% of
the placebo group.
The largest NIMH-funded anxiety multisite study examining combina-
tion treatment to date, the CAMS, provided strong evidence in favor of com-
bining CBT and an SSRI when treating non-OCD pediatric anxiety disorders.
The trial compared the outcomes of children ages 7–17 (N=488) with pri-
mary diagnoses of GAD, separation anxiety disorder, and social anxiety dis-
order who were randomly assigned to CBT alone, CBT in combination with
sertraline (up to 200 mg/day), or sertraline alone versus placebo for 12 weeks
(Walkup et al. 2008). The results showed that 80.7% of the children who were
assigned to the combination treatment group experienced symptom improve-
ment (P<0.001) compared with the 59.7% assigned to CBT (P<0.001) and
the 54.9% assigned to sertraline (P<0.001), as measured by the CGI-I scale
(Walkup et al. 2008). All of the active treatments were statistically superior to
placebo (P<0.001), which led to only 23.7% improvement in participants.
There were no significant differences in the frequency of adverse events in the
sertraline versus the placebo groups, although there were fewer reports of phys-
ical symptoms with the CBT group compared with the sertraline group. A sec-
ondary analysis examining adverse events from the CAMS (Rynn et al. 2015)
found that the rate of psychiatric adverse events was higher in children younger
than 12 years across all study arms, leading to the recommendation for addi-
tional adverse monitoring when medication treatment is initiated in this
younger population.
These findings demonstrate that both pharmacological treatment and
psychotherapy are effective in treating pediatric anxiety disorders but that
their combination is the most effective approach.
188 Clinical Manual of Child and Adolescent Psychopharmacology

Conclusion
Empirical evidence supports the use of pharmacological and psychotherapy
(specifically CBT) treatments for pediatric anxiety disorders. The data suggest
that several classes of medications can be used safely and lead to an efficacious
outcome and that the SSRIs should be considered first-line treatment. For pe-
diatric OCD, evidence supports using a combination treatment approach,
but CBT alone should be considered first. Additional long-term medication
studies are warranted to examine both safety and treatment outcomes.

Clinical Pearls
• Before initiating medication treatment, develop a list of target
anxiety symptoms to be tracked during treatment in order to de-
termine response.
• Carefully assess for comorbid diagnoses and the severity of the
anxiety symptoms. Greater severity may indicate the need for
combination treatment with medication and cognitive-behavioral
therapy.
• To prevent early termination from a medication trial, spend an
adequate amount of time educating the child and their guardian
on what to expect from medication treatment and about poten-
tial adverse events.
• Maintaining a suboptimal dosage of medication will frustrate the
child and family, leading to treatment nonadherence and a pre-
maturely failed treatment trial.
• As their symptoms respond positively to treatment, the child’s
behavior may change, which may be interpreted by the parent
as a possible adverse event. For example, a child who is ordi-
narily compliant may begin to challenge their guardian. How-
ever, if the behavior change is unusual and is thought to be a
significant change from baseline, a careful assessment should
be made to evaluate whether the medication is the cause.
 Anxiety Disorders 189

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 5
Major Depressive Disorder
Boris Birmaher, M.D.
Manivel Rengasamy, M.D.

Pediatric major depressive disorder (MDD) is a familial recurrent illness as-

sociated with poor psychosocial functioning; academic, substance abuse, anx-
iety, and psychosocial difficulties; and an increased risk of suicide and suicide
attempts (Birmaher et al. 1996b, 2002; Lewinsohn et al. 1999; Pine et al.
1998). The prevalence of MDD in children and adolescents is approximately
2% and 6%, respectively (Birmaher et al. 1996b). Because pediatric MDD is
continuous into adulthood, early identification and prompt treatment at its
early stages are critical.
Our primary aim in this chapter is to review the current pharmacological
treatments for children and adolescents with MDD. Although psychotherapy
interventions, including cognitive-behavioral therapy (CBT)—either alone
(Brent et al. 1997) or in combination with antidepressants (Brent et al. 2009;
Kennard et al. 2014; March et al. 2004)—and interpersonal psychotherapy
(Mufson et al. 2004), are also found to be efficacious for the acute treatment

199
200 Clinical Manual of Child and Adolescent Psychopharmacology

Table 5–1. Definitions of treatment outcome

Response No symptoms or a significant reduction in depressive symptoms for at

least 2 weeks
Remission A period of at least 2 weeks and less than 2 months with no or very few
depressive symptoms
Recovery Absence of symptoms of major depressive disorder for 2 months or
more (e.g., can have no more than two symptoms to be considered
in recovery)
Relapse A major depressive episode during the period of remission
Recurrence A new major depressive episode during the period of recovery

of pediatric MDD, particularly for adolescents, treatment using only these in-
terventions is not reviewed in this chapter.
Five terms—response, remission, recovery, relapse, and recurrence—are use-
ful for understanding treatment outcomes. Their current definitions (Birma-
her et al. 2000; Emslie et al. 1997, 2002, 2008) are presented in Table 5–1.

Assessment of Treatment Response

Understanding the research definition of treatment response can aid clinicians
in interpreting the research-based evidence for the effectiveness of each antide-
pressant in day-to-day practice. Treatment response has traditionally been de-
termined by the absence of MDD criteria (e.g., no more than one DSM
symptom) or, more frequently, by a significant reduction in symptom severity
(usually 50%). However, when the latter criterion is used, patients (deemed re-
sponders) may still have considerable residual depressive symptoms. Therefore,
an absolute final score of 9 or lower on the Beck Depression Inventory (Beck
1967), 7 or less on the 17-item Hamilton Rating Scale for Depression (Ham-
ilton 1960), o r28 or lower on the Children’s Depression Rating Scale–Revised
(CDRS-R; Poznanski et al. 1985), together with persistent improvement in
the patient’s functioning for at least 2 weeks, may better reflect a satisfactory
response. Overall improvement has also been measured with the Clinical
Global Impression–Improvement (CGI-I; Guy 1976) subscale, with scores of
1 and 2 indicating “very much” and “much improvement,” respectively. Func-
 Major Depressive Disorder 201

tional improvement can be measured using several rating scales, such as the
Global Assessment Scale (American Psychiatric Association 1994) or the
Children’s Global Assessment Scale (Shaffer et al. 1983).

Treatment Phases
Treatment of MDD is divided into three phases: acute, continuation, and
maintenance (American Academy of Child and Adolescent Psychiatry 1998;
American Psychiatric Association 2010). The main goal during the acute phase
is to achieve response and, more importantly, remission of the depressive
symptoms. This phase usually lasts 6–12 weeks. The continuation phase usu-
ally lasts 4–12 months, during which remission is consolidated to prevent re-
lapses. The maintenance phase lasts 1 year or longer, and its main objective is
the prevention of depression recurrences. Almost all studies of children and
adolescents have evaluated treatments during the acute phase, and few have
been continuation studies (Clarke et al. 2005; Emslie et al. 2008; Goodyer et
al. 2007; Kennard et al. 2014). No maintenance treatment studies have been
reported to date. Therefore, recommendations regarding maintenance treat-
ments are extrapolated from the adult research literature. However, caution is
warranted because youth may respond differently to interventions that thus
far have been tested only on adults with MDD (Birmaher et al. 1996a).

Treatment of MDD With Selective Serotonin

Reuptake Inhibitors and Other Novel
Antidepressants
Psychoeducation and Supportive Therapy
The optimal pharmacological management of MDD in children and adoles-
cents should involve educative and supportive psychotherapy. In fact, at least
for youth with mild to moderate depression, supportive management and ed-
ucation may be sufficient to ameliorate the symptoms of depression (Goodyer
et al. 2007; Mufson et al. 2004; Renaud et al. 1998). Education of the patient
and family about the illness, nature of treatment, and prognosis is critical to
engagement in treatment and enhancement of compliance (Brent et al. 1993).
202 Clinical Manual of Child and Adolescent Psychopharmacology

During and after the depression remission, psychosocial scars or complications

(e.g., family conflict, poor self-esteem and social skills, academic difficulties,
problems with peers) must be addressed with psychotherapy (Birmaher et al.
2000; Kovacs and Goldston 1991; Puig-Antich et al. 1985; Rao et al. 1995;
Stein et al. 2000; Strober et al. 1993).
Parents of depressed youth may also be experiencing depression and other
psychiatric disorders (Klein et al. 2001), and this depression may lead to ad-
verse outcomes in their children. In fact, successful treatment of the parents
may ameliorate or even prevent the development of psychopathology in their
children (Birmaher 2011; Pilowsky et al. 2014). Thus, to treat the child suc-
cessfully, the clinician should assess the parents and refer them for their own
treatment.

Acute Phase
Studies on the acute treatment of children and adolescents with MDD have fo-
cused on the effects of tricyclic antidepressants (TCAs), selective serotonin re-
uptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors
(SNRIs; e.g., venlafaxine, duloxetine). Agomelatine also demonstrated modest
efficacy for the treatment of pediatric MDD in one randomized controlled trial
(RCT) (Arango et al. 2021). Preliminary open-label studies or RCTs have sug-
gested that bupropion (Kim et al. 2012) and the monoamine oxidase inhibi-
tors (MAOIs) can be used safely in children and adolescents (Ryan et al.
1988b), although noncompliance with the dietary requirements may present
a significant problem for these patients. Other antidepressants, including the
heterocyclics (e.g., amoxapine), intranasal esketamine, and intravenous ket-
amine, have been found to be efficacious for the treatment of depressed adults
(American Psychiatric Association 2010), but they have not been well studied
for the treatment of MDD in children and adolescents (e.g., only one existing
small open-label trial exists for ketamine; Zheng et al. 2020). Large failed/neg-
ative trials have been noted for specific SSRIs (paroxetine, vilazodone, vorti-
oxetine) and specific SNRIs (duloxetine, desvenlafaxine). The TCAs have not
been found to be better than placebo (Hazell et al. 2002) and are associated
with significant side effects and a high risk for lethality in the event of an over-
dose. Therefore, we mainly describe the use of SSRIs and SNRIs for youth
with MDD. Table 5–2 summarizes data on RCTs examining SSRIs in pedi-
atric depression.
Table 5–2. Selected data on SSRIs and SNRIs in pediatric MDD

Randomized controlled trials

Dosage, FDA
Medication Study mg/day Outcome and sample sizea approval

Citalopram Wagner et al. 2004 20–40 Citalopram>placebo (n=174) No

von Knorring et al. 2006 10–40 Did not separate from placebo (n=233)
Desvenlafaxine Atkinson et al. 2018 20–50 (weight- Did not separate from placebo (n=363) No
based)
Weihs et al. 2018 25–50 (weight- Did not separate from placebo (n=227);
based) fluoxetine also did not separate from placebo

Major Depressive Disorder

Duloxetine Atkinson et al. 2014 30–120 Did not separate from placebo in adolescents No
(n=220); also no separation between fluoxetine
(20–40 mg/day) and placebo
Emslie et al. 2014 30–60 Did not separate from placebo in children No
(n=346); also no separation between fluoxetine
(20 mg/day) and placebo
Escitalopram Wagner et al. 2006 10–20 Did not separate from placebo in general Yes; MDD ages
population; escitalopram>placebo in 12–17 years
adolescents (n=261)

203
Emslie et al. 2009 10–20 Escitalopram>placebo (n=311)
Table 5–2. Selected data on SSRIs and SNRIs in pediatric MDD (continued)

204 Clinical Manual of Child and Adolescent Psychopharmacology

Randomized controlled trials

Dosage, FDA
Medication Study mg/day Outcome and sample sizea approval

Fluoxetine Simeon et al. 1990 20–60 Did not separate from placebo (n=32) Yes; MDD ages
8–18 years
Emslie et al. 1997 20 Fluoxetine > placebo (n=96)
Emslie et al. 2002 20 Fluoxetine > placebo (n=219)
March et al. 2004 10–40 Fluoxetine > placebo (n=221)
Paroxetine Keller et al. 2001 20–40 Paroxetine > placebo (n=180) No
Berard et al. 2006 20–40 Did not separate from placebo (n=275)
Emslie et al. 2006 10–50 Did not separate from placebo (n=206)
Sertraline Wagner et al. 2003b 50–200 Sertraline > placebo (n=364) No
Donnelly et al. 2006 50–200 Did not separate from placebo in children;
sertraline > placebo in adolescents (n=199)
Vilazodone Durgam et al. 2018 15–30 Did not separate from placebo (n=529) No
Table 5–2. Selected data on SSRIs and SNRIs in pediatric MDD (continued)

Randomized controlled trials

Dosage, FDA
Medication Study mg/day Outcome and sample sizea approval

Venlafaxinec Mandoki et al. 1997 Children: 37.5 Did not separate from placebo in adolescents No
Adolescents: 75 (n=33, very low dosages)
Emslie et al. 2007b 37.5–225 Did not separate from placebo overall (n=334);
(weight-based) venlafaxine > placebo in adolescents (n=197)
Vortioxetine Findling et al. 2022 10–20 Did not separate from placebo at either 10 mg No
(n=147) or 20 mg (n=161) dosages; fluoxetine
20 mg (n=153) separated from placebo

Major Depressive Disorder

(n=154)
Note. MDD=major depressive disorder; SNRI=serotonin-norepinephrine reuptake inhibitor; SSRI=selective serotonin reuptake inhibitor.
a
Sample size refers to combined sample size of participants receiving antidepressant described and placebo unless otherwise specified.
bData pooled from two controlled trials.
c
An unpublished study was also negative, but a reanalysis showed that venlafaxine was only positive for adolescents (cited by Bridge et al. 2009).

205
206 Clinical Manual of Child and Adolescent Psychopharmacology

Using CGI-I scores of 2 (“much improved” to “very much improved”) as

indicating a positive outcome, in general, RCTs using the SSRIs have shown
that children and adolescents with MDD had significantly better symptom re-
sponse to acute treatment with these antidepressants (50%–60%) than to pla-
cebo (30%–50%) (Bridge et al. 2009). Of these SSRIs, fluoxetine showed the
largest effect sizes, in part because of a low placebo response rate. In contrast,
other antidepressants showed small effect sizes (e.g., sertraline, citalopram, es-
citalopram) or no effects (e.g., duloxetine, paroxetine), particularly when the
studies were done in large multicenter studies (see Table 5–2). Moreover, de-
spite the significant rates of response with some antidepressants, a smaller pro-
portion of patients (30%–40%) achieved full remission (usually defined as a
score of 28 or less on the CDRS-R) (Emslie et al. 1997, 2008; March et al.
2004; Wagner et al. 2004).
A possible explanation for the low rate of remission is that optimal phar-
macological treatment may involve a higher dosage or a longer duration of
treatment or that the ideal treatment for some individuals may involve a com-
bination of pharmacological and psychosocial interventions, as suggested by
the Treatment for Adolescents with Depression Study (TADS; March et al.
2004). However, in the TADS, although the rate of remission was higher with
combination treatment (37% for the combination vs. 23% for medication
alone), particularly for less severely depressed subjects, it was not optimal.
Moreover, other studies did not show an advantage to adding CBT to regular
SSRI treatment (Clarke et al. 2005; Goodyer et al. 2007).
As noted earlier, several published or unpublished industry-sponsored stud-
ies with SSRIs and SNRIs found small or no differences between active medi-
cation and placebo (for review, see Atkinson et al. 2014; Bridge et al. 2009;
Emslie et al. 2014; Mandoki et al. 1997; Mann et al. 2006). Overall, partici-
pants responded to SSRIs (46%–63%), but the placebo response was also high
(about 50%). The placebo response was associated with less depressive severity
at intake and a large number of centers involved in the trial (Bridge et al.
2009).
Except in a large fluoxetine study in which no age differences were found
(Emslie et al. 1997), younger subjects overall have higher placebo responses
than older adolescents. Mild to moderate depressive symptoms may have re-
sponded to supportive management offered in these studies. Also, other meth-
odological issues may have been responsible for the lack of difference between
 Major Depressive Disorder 207

medication and placebo. (For a review of the limitations of pharmacological

RCTs, see Cheung et al. 2005.)
A clinically meaningful way to understand the effect of treatment is through
the concept of the number needed to treat (NNT), which refers to the number
of patients who must be treated to observe one response that is attributable to
active treatment and not placebo. Across all of the published and unpublished
SSRI RCTs, patients with depression treated with SSRIs had relatively good
response rates (50%–70% clinically improved), but the placebo response rates
were also high (30%–60%), resulting in an overall NNT of 9 (Bridge et al.
2009; Cheung et al. 2005). Fluoxetine was the first medication to receive FDA
approval for the treatment of pediatric depression, and studies show a larger
difference between fluoxetine and placebo than other antidepressants, with an
overall NNT of 4. It is not clear whether this difference is attributable to actual
differences in the medication’s effect, to other related properties of the medi-
cation (long half-life may lessen the impact of poor adherence to treatment), or
to better design and performance of the fluoxetine studies, which may have in-
cluded more severely depressed patients. Interestingly, in contrast to MDD, for
pediatric anxiety the NNT is 3, even in large multicenter studies, which is
mainly accounted for by lower placebo response in the anxiety studies.
In addition to fluoxetine, which was approved for youth ages 8–18 years
with depression, escitalopram has been approved to treat MDD in adolescents
ages 12–17. Data from several trials of escitalopram, in addition to safety data
from studies of citalopram, led to FDA approval of escitalopram. In the trials
of escitalopram, differences in response between children younger than 12
and adolescents led to the 12–17 age range associated with FDA approval
(Emslie et al. 2009; Wagner et al. 2004, 2006).
Few RCTs have evaluated the effects of other classes of antidepressants for
the treatment of depressed youth. Two unpublished, industry-sponsored RCTs
with mirtazapine (pooled N=250) were negative (cited by Bridge et al. 2009;
Mann et al. 2006). Although bupropion is being used clinically for the treat-
ment of youth with MDD, no placebo-controlled RCTs have been conducted,
although a few smaller open-label studies (Ns<25) and a larger chart review
(N=127) suggest its potential efficacy (Kim et al. 2012). A recent large multi-
center RCT compared a flexible dose of selegiline transdermal system (an
MAOI) and placebo in a sample of adolescents with moderate to severe MDD
(n=308) (DelBello et al. 2014). Results showed that the selegiline transdermal
208 Clinical Manual of Child and Adolescent Psychopharmacology

system was safe and well tolerated; both groups had a decline from baseline in
depressive symptoms over the length of the study, without statistical superi-
ority by either group. One study showed better response in most measure-
ments between nefazodone and placebo for adolescents with MDD (Bridge et
al. 2007), but a second study including depressed children and adolescents
was negative (Cheung et al. 2005). Although the generic form of this medi-
cation is still available, nefazodone is largely not used in the United States,
with several brand-name forms withdrawn previously because of a rare but se-
rious side effect—liver damage resulting in hepatic failure.
Several medications available in Europe but not in the United States may
also be beneficial for youth with MDD. In a recent placebo-controlled RCT
(Arango et al. 2021), youth receiving agomelatine (n=94) dosed at 25 mg/day
demonstrated greater improvement in depressive symptoms than youth receiv-
ing placebo (n=99). Open-label trials of mianserin (a tetracyclic antidepres-
sant; n=110), reboxetine (n=14), and tianeptine (n=60) suggest that further
research may be useful for understanding the benefit of these antidepressants
for children and youth (Dugas et al. 1985; Graovac 2009; Toren et al. 2019).

Side Effects
Overall, SSRIs, SNRIs, and other novel antidepressants have been well toler-
ated by both children and adolescents, with only a few short-term side effects
commonly reported. It appears that the side effects of SSRIs and SNRIs are
similar and dose dependent and may subside with time (Cheung et al. 2005;
Emslie et al. 1999; Leonard et al. 1997; Safer and Zito 2006). The most com-
mon side effects include gastrointestinal symptoms, restlessness, diaphoresis,
headache, akathisia, changes in appetite (increase or decrease), sleep changes
(e.g., vivid dreams, nightmares, impaired sleep), and impaired sexual func-
tioning. Approximately 3%–8% of children and adolescents taking antide-
pressants may show increased impulsivity, agitation, irritability, silliness, and
behavioral activation (Hammad et al. 2006; Martin et al. 2004; Wilens et al.
1998). These symptoms must be differentiated from the mania or hypomania
that may appear in children and adolescents with bipolar disorder or in those
predisposed to develop bipolar disorder (Wilens et al. 1998).
More rarely, the use of antidepressants has been associated with serotonin
syndrome (Boyer and Shannon 2005) (see “Interactions With Other Medica-
tions” later in this section), with increased suicidal behaviors (see “Suicidal Be-
 Major Depressive Disorder 209

haviors” later), and with bruising (Lake et al. 2000). Citalopram was found to
be associated with arrhythmias and prolonged QTc interval, particularly at
dosages higher than 40 mg/day (www.fda.gov), but this finding has been
questioned. Because of the risk of bruising, patients treated with SSRIs and
SNRIs who will undergo surgery should inform their physicians, and they may
wish to discontinue treatment during the preoperative period. Venlafaxine and
perhaps other SNRIs may elevate blood pressure and cause tachycardia (e.g.,
typically <5 mm Hg for systolic blood pressure/diastolic blood pressure and
<10 beats per minute), but not all studies have indicated this effect (Brent et
al. 2009; Findling et al. 2014). Mirtazapine, a serotonin and α2-adrenergic re-
ceptor blocker, may increase appetite, weight, and somnolence. Trazodone, a
serotonin-2A (5-HT2A) receptor blocker and weak serotonin reuptake inhib-
itor, and mirtazapine are mainly used as adjunctive and transient treatments
for insomnia. Trazodone must be used with caution in males because it can in-
duce priapism. Serzone, the branded form of nefazodone, a 5-HT2A receptor
blocker and weak serotonin reuptake inhibitor, was taken off the market by
major manufacturers because it may induce liver problems.
The long-term side effects of antidepressants have not been systematically
evaluated. Bupropion has been associated with headache, tremor, and seizure.
Risk of seizures can be minimized by titrating the dosage slowly and avoiding
high dosages (no more than 450 mg/day). It seems that bupropion cannot be
used for patients with eating disorders with potential electrolyte abnormalities
because of the high risk for seizures (American Psychiatric Association 2010).

Suicidal Behaviors
There are two ways to ascertain side effects. The first relies on spontaneous re-
porting of side effects by patients or their families (i.e., adverse events). The sec-
ond uses side effects questionnaires. Compared with pediatric patients given
placebo, those taking antidepressants appear to have a small but statistically sig-
nificant increase in spontaneous self-harm behavior and suicidal ideation (sui-
cide-related events [SREs]). In an FDA-sponsored meta-analysis conducted in
collaboration with Columbia University (Hammad et al. 2006) that included
24 RCTs (16 studies of MDD, 4 of OCD, 2 of generalized anxiety disorder, 1 of
social anxiety disorder, and 1 of ADHD) comparing several antidepressants
with placebo, the overall risk ratio for SREs was 1.95 (95% CI, 1.28–2.98). For
only MDD studies, the overall risk ratio was 1.66 (95% CI, 1.02–2.68). Only
210 Clinical Manual of Child and Adolescent Psychopharmacology

the TADS showed a significant difference between active treatment and pla-
cebo; among the antidepressants, only venlafaxine showed a statistically signif-
icant association with suicidality (March et al. 2004). In general, these results
translate to 2 emergent or worsened SREs for every 100 youth treated with one
of the antidepressants included in the FDA meta-analysis. The study authors
reported very few suicide attempts and no completions.
In contrast to the SRE analyses, evaluation of the suicidality ascertained
through rating scales in 17 studies did not show significant onset or worsening
of suicidality (RR 0.92–0.93) (Hammad et al. 2006). It is not clear why the
FDA meta-analysis had increased rates of spontaneously reported SREs for
subjects taking medication versus placebo but no differences in suicidality on
regularly assessed clinical measures. It is possible that in a subgroup of patients
treated with antidepressants, particularly those already agitated or suicidal,
treatment causes a disinhibition that leads to worsening of ideation or a
greater tendency to make suicidal threats. Because suicidal ideation usually
leads to removal of the subject from the study and a change in treatment, anal-
yses that look at the slope of suicidal ideation will not find an effect (although
the TADS found greater reduction of suicidal ideation in the fluoxetine+CBT
arm, which was not found in the fluoxetine-only or CBT-only arm). In addi-
tion, as measured on rating scales, suicidal ideation is highly correlated with
the severity of depression, which is more likely to decline in those given the
study drug than in those given placebo.
These results must be viewed in the context of the FDA study’s limitations,
which include use of the metric of relative risk (limited to trials with at least one
event), inability to generalize the results to populations not included in RCTs,
short-term data, failure to include all available RCTs, and multiple compari-
sons (Hammad et al. 2006). As stated by the FDA (Hammad et al. 2006), the
implications and clinical significance of these findings are uncertain, given that
with the increase in SSRI use, rates of adolescent suicide have declined dramat-
ically (Olfson et al. 2003). Moreover, pharmacoepidemiological studies, which
are correlative rather than causal, support a positive relationship between SSRI
use and the reduction in the rate of adolescent and young adult suicides (Gib-
bons et al. 2005; Olfson et al. 2003; Valuck et al. 2004). Finally, one study
showed increased suicide attempts only immediately before the SSRIs were ad-
ministered (Simon et al. 2006), and later studies in several countries showed
 Major Depressive Disorder 211

that after the FDA’s black box warning for SSRIs was implemented, a surge
occurred in the number of suicides (e.g., Katz et al. 2008; Libby et al. 2009).
A thorough meta-analysis extended the FDA analyses by including all of
the existing published and unpublished antidepressant studies (13 of MDD,
6 of OCD, and 6 of anxiety disorders) (Bridge et al. 2009). This meta-analysis
found comparable overall findings when similar statistical methods (relative
risk) were used rather than the methods used in the FDA study (Bridge et al.
2009)—namely, a significantly increased relative risk for spontaneously re-
ported suicidality only for subjects with MDD. However, in pooled random-
effects analyses of risk differences, which make possible an analysis of all existing
RCTs, a nonsignificant risk difference (drug minus placebo) was found for
MDD (0.8%; 95% CI –0.2% to 1.8%) and other disorders. The overall num-
ber needed to harm (NNH; i.e., number of subjects needed to treat in order to
observe one adverse event that can be attributed to the active treatment) for
MDD was 125 (Bridge et al. 2009). As stated earlier in the “Acute Phase” dis-
cussion, the overall NNT for antidepressants in pediatric depression is 9.
Thus, nearly 14 times more depressed patients will respond favorably to antide-
pressants than will spontaneously report suicidality (although one must keep
in mind the limitations of meta-analyses). The benefit-risk ratio was larger for
the SSRIs (10) than for non-SSRI antidepressants (5).
In conclusion, SREs appear to be more common with antidepressant treat-
ment than with placebo. Nevertheless, given the greater number of patients who
benefit from antidepressant treatment (particularly the SSRIs) than who expe-
rience these SREs, as well as the decline in overall suicidal ideation on rating
scales, the risk-benefit ratio for SSRI use in pediatric depression appears to be fa-
vorable, with careful monitoring. Additional work is required to determine
whether the risk-benefit ratio is indeed less favorable for children than for ado-
lescents. Also, it remains to be clarified whether certain factors are related to in-
creased risk for suicidality (Apter et al. 2006; Brent 2004; Hammad et al.
2006; Safer and Zito 2006), such as gender or biological sex, subject or family
history of suicidality, disorder type (the effects of disorder type appear to be
more obvious in depressed youth), severity of depressive symptoms at intake,
medication dosages, medication half-life (in terms of efficacy), type of anti-
depressants administered, treatment duration, poor adherence to treatment,
withdrawal side effects (due to noncompliance or short medication half-life),
212 Clinical Manual of Child and Adolescent Psychopharmacology

susceptibility to side effects (e.g., slow metabolizers or variations in genetic

polymorphisms), and/or induction of agitation, activation, or hypomania.

Pharmacokinetic Studies
Aside from fluoxetine, which has a half-life of 24–72 hours in children (whereas
norfluoxetine, the active metabolite of fluoxetine, has an a half-life of 7 days),
the half-lives of most of the SSRIs (including paroxetine, sertraline, citalopram,
and sustained-release bupropion) are between 14 and 16 hours (Axelson et al.
2000a, 2000b; Clein and Riddle 1995; Daviss et al. 2005; Findling et al.
1999, 2000, 2006). One study suggested that sertraline at a dosage of 200 mg/
day can be prescribed once daily (Alderman et al. 1998). The results of previ-
ously mentioned studies suggest that SSRIs, particularly when prescribed at
lower dosages, may need to be given twice daily. However, since this may be im-
practical, and adherence to treatment, which usually is low, may be worse with
twice-daily regimens, it is recommended to first administer the SSRI once daily
and to carefully evaluate the child for withdrawal side effects. If withdrawal side
effects occur, twice-daily dosing is necessary. Otherwise, children and adoles-
cents may experience withdrawal side effects during the evening, and these
symptoms can be confused with lack of response or medication side effects.
More pharmacokinetic studies conducted on the other antidepressants (i.e.,
SNRIs, atypical antidepressants) are necessary, because it appears that youth me-
tabolize these medications faster than adult populations do.

Interactions With Other Medications

Careful attention to possible medication interactions is recommended, given
that the antidepressants and their metabolites are metabolized in different de-
grees by the hepatic cytochrome P450 (CYP) enzymes. Of the five major CYP
enzymes mediating known oxidative drug metabolism, CYP3A3/4 and
CYP2D6 are responsible for approximately 50% and 30%, respectively. Except
for citalopram/escitalopram and sertraline, the currently available SSRIs are
mainly metabolized by CYP3A3/4 and/or CYP2D6 enzymes. One notable in-
teraction is fluvoxamine and fluoxetine’s inhibition of CYP2D6 (which also
metabolizes aripiprazole and several TCAs). Bupropion is mainly metabolized
by the CYP2B6 enzyme, but it also inhibits the enzyme CYP2D6. Venlafaxine
is metabolized by the CYP2D6 enzyme. Substantial inhibition of these en-
zymes converts a normal metabolizer into a slow metabolizer, with regard to
 Major Depressive Disorder 213

this specific pathway. Therefore, clinicians should be aware that toxicity could
result in patients who are also taking other medications metabolized by the CYP
system, including the TCAs, neuroleptics, antipsychotics, antiarrhythmics, an-
tihypertensives, theophylline, atomoxetine, benzodiazepines, carbamazepine,
and warfarin. It is impossible to memorize all interactions, but, fortunately, sev-
eral websites and mobile applications provide up-to-date information about
medication metabolism and interaction, including Medscape (https://
reference.medscape.com), Epocrates (https://online.epocrates.com), Microme-
dex (www.micromedexsolutions.com), and UpToDate (www.uptodate.com).
Interactions of antidepressants with other serotonergic medications, par-
ticularly MAOIs, may induce the serotonin syndrome, which is marked by ag-
itation, confusion, and hyperthermia (Boyer and Shannon 2005). MAOIs
should not be given within 5 weeks of stopping fluoxetine and at least 2 weeks
of stopping other SSRIs due to the possibility of inducing this syndrome.
Some antidepressants also have a high rate of protein binding, which can
lead to increased therapeutic or toxic effects when taken with other protein-
bound medications.

Discontinuation
Sudden or rapid cessation, especially for antidepressants with shorter half-lives
(e.g., paroxetine and SNRIs), may induce withdrawal symptoms that can
mimic a relapse or recurrence of a depressive episode (e.g., tiredness, irritabil-
ity). Furthermore, rapid discontinuation of antidepressants may induce re-
lapses or recurrences of depression. Therefore, if these medications must be
discontinued, they should be tapered progressively.

Summary and Recommendations for Acute Treatment

Given that 30%–60% of children and adolescents with MDD respond to pla-
cebo (Bridge et al. 2009; Cheung et al. 2005; Mann et al. 2006) or very brief
or supportive psychotherapy treatments (Goodyer et al. 2007; Mufson et al.
2004; Renaud et al. 1998), it is reasonable, when treating a patient with a mild
depression or mild psychosocial impairment, to offer psychoeducation, sup-
port, and case management related to possible environmental stressors in the
family and school. If the symptoms of mild depression worsen or the child has
not responded after 4–6 weeks of supportive therapy, more specific forms of
psychotherapy or antidepressants are warranted.
214 Clinical Manual of Child and Adolescent Psychopharmacology

In contrast, youth who present with chronic or recurrent depression, mod-

erate to severe psychosocial impairment, comorbid disorder, suicidal ideation,
or a significant family history of depression will initially require more specific
types of psychotherapies or antidepressants.
Independent of the treatment administered, the patient and their family
will require education about the nature and treatment of depression, support,
and management of daily problems. Problems at school, academic issues,
school refusal, abuse of drugs, exposure to negative events (e.g., abuse, conflict
with parents), and peer issues must be addressed. For example, family discord
is associated with slower recovery and a greater chance of recurrence (Birma-
her et al. 2000), and ongoing disappointments have been associated with
chronic depression (Goodyer et al. 1998). Therefore, addressing family discord
and improving the patient’s coping skills are likely to improve outcomes with
either psychosocial or psychopharmacological treatment. Moreover, a high in-
cidence of parental mental health problems indicates the need for evaluation
and appropriate referral of the parents and siblings of depressed youth, partic-
ularly because several studies have demonstrated that a mother’s depression is
associated with an increased risk for psychopathology in her children (Birma-
her 2011). Finally, a high degree of comorbidity also emphasizes the impor-
tance of a multimodal pharmacological and psychosocial treatment approach
(Hughes et al. 1999). For example, a child with MDD and ADHD may not
experience symptom response to treatment with an SSRI alone and may re-
quire either combined treatment with a stimulant plus an SSRI or an alterna-
tive medication such as a TCA, bupropion, or venlafaxine (Daviss et al. 2001;
Pliszka 2000).
Currently, SSRIs are the antidepressants of choice to treat children and ad-
olescents with MDD. Fluoxetine has the most consistent data showing sepa-
ration from placebo, but in clinical practice, other antidepressants may also be
useful. Other important factors to consider when selecting the appropriate an-
tidepressants include prior response to a specific antidepressant, patient and
family preference, costs, safety or tolerably of side effects for the individual pa-
tient, pharmacological properties of the antidepressants (e.g., potential inter-
actions with other medications, metabolism, half-life), and co-occurring
psychiatric and medical illnesses (American Academy of Child and Adolescent
Psychiatry 1998; American Psychiatric Association 2002). Patients should be
treated with adequate dosages for at least 6 weeks before the clinician declares
 Major Depressive Disorder 215

Table 5–3. Dosages of antidepressants usually administered to

youth with MDD

Starting
dosage, Dosage
Medication group Medication mg/daya range, mg/day

SSRIs Citalopram 10 20–60b

Escitalopram 10 10–40
Fluoxetine 10 20–80
Fluvoxamine 25 50–150
Paroxetine 10 20–60
Sertraline 25 50–300
SSRI/serotonin modulators Vilazodone 10 10–40
Vortioxetine 5 5–20
SNRIs Desvenlafaxine 25 50–100
Duloxetine 20 60–120
Venlafaxine XR 37.5 75–375
Others Bupropion SR 100 150–450
Bupropion XL 150 150–450
Mirtazapine 7.5 7.5–30
Note. MDD=major depressive disorder; SNRI=serotonin-norepinephrine reuptake inhibi-
tor; SR=sustained release; SSRI=selective serotonin reuptake inhibitor; XL=extended release;
XR=extended release.
a
For children, consider using lower dosages.
bFor citalopram dosages above 40 mg, an electrocardiogram should be done both prior to and

following dosage increase, given concerns of QT prolongation.

a lack of response to treatment (the treatment of nonresponders is described in

subsection “Treatment-Resistant Depression” later in this chapter).
The dosages of SSRIs and SNRIs prescribed for children and adolescents
usually are similar to those used for adult patients (American Psychiatric As-
sociation 2010; Birmaher et al. 2007; Leonard et al. 1997) (Table 5–3), except
that lower initial dosages, particularly for children, are used to avoid un-
wanted effects. Fewer studies have examined side effects in children. To avoid
216 Clinical Manual of Child and Adolescent Psychopharmacology

side effects and improve treatment adherence, clinicians should start the medi-
cation at a low dosage and increase the dosage slowly as indicated and tolerated.
During the acute phase of treatment, patients should be treated with adequate
and tolerable dosages for at least 4–6 weeks. Clinical response should be as-
sessed at 4- to 6-week intervals, and the dosage can be increased if a complete
response has not been obtained. If only a partial response has been achieved at
the point of assessment, the physician may consider strategies described in the
subsection “Treatment-Resistant Depression” later in this chapter. At each step,
adequate time should be allowed for clinical response, and frequent, early dos-
age adjustments should be avoided.
Given the small but significant association between antidepressants and
worsening or emergent spontaneous SREs, all patients receiving these medi-
cations for suicidal and other symptoms should be carefully monitored, par-
ticularly during the first weeks of treatment. The FDA recommends that
patients be seen every week for the first 4 weeks and biweekly thereafter. If
weekly face-to-face appointments cannot be scheduled, evaluations should be
carried out briefly by phone. However, there are currently no data available to
suggest that the face-to-face monitoring schedule proposed by the FDA or
telephone calls have any impact on the risk of suicide. Although monitoring is
important for all patients, it should be more carefully done for patients who
have a history of suicidal ideation or suicide attempts or who show behavior
associated with an increased risk for suicide (e.g., prior suicidality, impulsivity,
substance abuse, history of sexual abuse, psychosis, mixed manic/hypomanic
episodes) (Gould et al. 1996; Shaffer and Craft 1999); patients who have be-
come agitated, disinhibited, or irritable while taking an antidepressant; and
those with family history of bipolar disorder or suicide.

Treatment of Major Depressive Disorder

Subtypes and Bipolar Depression
Bipolar Depression
Many children and adolescents seeking treatment for depression are usually ex-
periencing their first depressive episode. Because the symptoms of unipolar and
bipolar depression are similar, it is difficult to decide whether a patient needs
only an antidepressant or treatment with other medications or psychothera-
 Major Depressive Disorder 217

pies. Some symptoms, such as psychosis, greater mood lability, pharmacologi-

cally induced mania/hypomania, and family history of bipolar disorder, may
alert the clinician to the risk that the child could develop a manic or hypomanic
episode (Diler et al. 2017). Also, the presence of subthreshold manic or hypo-
manic episodes (currently called “major depressive disorder, with mixed fea-
tures” in DSM-5 [American Psychiatric Association 2022] if there are at least
three manic symptoms but not enough for mania/hypomania) may indicate
the existence of bipolar disorder.
Lurasidone and the olanzapine-fluoxetine combination were more effica-
cious than placebo for youth with bipolar depression in RCTs, whereas studies
suggest potential benefits with quetiapine, risperidone, and ziprasidone (cited
by DelBello et al. 2017; Rengasamy and Birmaher 2019). In adults, RCTs
have found positive effects with lithium carbonate, valproate, and some of the
second-generation antipsychotics, such as quetiapine and lurasidone, either
alone or in combination with mood stabilizers for treatment of bipolar de-
pression. Similarly, for MDD with mixed features, adult studies have found
that second-generation antipsychotics (e.g. lurasidone or ziprasidone) may be
efficacious (Kennedy et al. 2016). Lamotrigine as monotherapy or as an ad-
junctive treatment appears to be efficacious in preventing relapses or recur-
rences of depression, and a meta-analysis showed modest effects for the acute
treatment of bipolar depression in adults (Geddes et al. 2009). SSRIs and bu-
propion combined with mood stabilizers may be beneficial for the treatment
of bipolar depression in adults (American Psychiatric Association 2002; Gijs-
man et al. 2004; Hirschfeld 2007). Moreover, one RCT found that mono-
therapy with fluoxetine was better than placebo for the management of
depressed adult patients with bipolar II disorder and did not induce signifi-
cant increases in manic switches (Amsterdam et al. 1998). However, antide-
pressants must be used cautiously because they may induce a switch to mania/
hypomania.
Children and adolescents do not always respond to medications in the same
way as adults, and they may be more prone to switch to mania with antidepres-
sant treatment. In particular, youth who have subthreshold manic symptoms or
a family history of bipolar disorder may be at the greatest risk for conversion to
mania with antidepressant use (Baumer et al. 2006; Goldsmith et al. 2011).
Therefore, these recommendations must be followed with caution until re-
sults from controlled studies of children and adolescents are made available.
218 Clinical Manual of Child and Adolescent Psychopharmacology

Psychotic Depression
No controlled studies of psychotic depression in children and adolescents have
been done. Because only 20%–40% of adults respond to antidepressant mono-
therapy (American Psychiatric Association 2010), recommended treatment
often consists of antidepressants combined with an antipsychotic. In clinical
practice, the antipsychotic is usually tapered after remission of the depression.
However, at least in adults, the second-generation antipsychotic medications
are beneficial as monotherapy for depression, raising a question about the need
to discontinue them unless they are inducing significant side effects (e.g., met-
abolic or neurological side effects). Electroconvulsive therapy (ECT) is partic-
ularly effective for the psychotic subtype of depression in adults (American
Psychiatric Association 2010) and may be useful for depressed adolescents as
well (Ghaziuddin et al. 2004). Treatment with antidepressants in psychotic de-
pressed children should be conducted with caution because the presence of
psychosis is a marker for possible development of bipolar disorder (Geller et al.
1994; Strober and Carlson 1982).

Seasonal Affective Disorder

Studies in adults have shown that SSRIs and bright-light therapy are beneficial
for the treatment of subjects with recurrent seasonal affective disorder. One
small RCT (n=28) suggested that bright-light therapy is efficacious for the
treatment of children and adolescents with seasonal affective disorder (Swedo
et al. 1997), but no studies with antidepressants have been conducted in this
younger population.

Treatment-Resistant Depression
As in adults (American Psychiatric Association 2010), up to 60% of youth
with MDD experience a partial treatment response (moderate response on the
CGI-I; presence of significant symptoms of MDD but not the full syndrome),
and 20%–30% may have no response at all (Birmaher et al. 2000; Brent et al.
2009; Emslie et al. 2008; March et al. 2004). Patients with a partial response
have a significantly higher rate of relapse during the first 6 months following
therapy and have significantly more psychosocial, occupational, and medical
problems (American Psychiatric Association 2010). Moreover, among chil-
dren, chronic depression does not usually remit spontaneously and is not re-
 Major Depressive Disorder 219

sponsive to placebo (American Academy of Child and Adolescent Psychiatry

1998; American Psychiatric Association 2010), indicating the need for more
aggressive treatments for patients with these conditions.
The first step in treatment for patients with treatment-resistant depression
is to establish the nonresponse. Several definitions of nonresponse have been
used, including the presence of a significant number of depressive symptoms,
symptom improvement of less than 50% as measured by rating scales (e.g., the
CDRS-R), and no change or worsening per CGI scores. After establishing
that the patient’s symptoms have not responded, the clinician must learn why.
The most common reasons for treatment failure are inappropriate diagnoses,
inappropriate or inadequate drug/psychosocial therapy dosage or length of
trial, treatment noncompliance, pharmacokinetic/pharmacodynamic factors,
comorbidity with other psychiatric disorders (e.g., persistent depressive disor-
der, anxiety, ADHD, covert substance abuse, personality disorders) or medical
illnesses (e.g., hypothyroidism), presence of subthreshold manic/hypomanic
symptoms, psychosocial issues and stressors (e.g., abuse, conflicts), and per-
sistent or intolerable side effects (American Psychiatric Association 2010;
Brent et al. 1998, 2009; Hughes et al. 1999). Other factors associated with
nonresponse include severe depression, long depression, suicidality, lack of re-
sponse or mild response after 2–4 weeks of treatment, hopelessness, and in-
adequate treatment by the therapist (e.g., poor-quality CBT) or a poor “fit”
between patient/family and therapist. Carefully evaluating for subtle symp-
toms of hypomania is important to determine whether bipolar disorder may
be the reason that the patient’s symptoms are not responding to treatment or
are even worsening with antidepressant treatment.
The Treatment of SSRI-Resistant Depression in Adolescents (TORDIA)
study (Brent et al. 2008) is the only RCT of youth with treatment-refractory
depression. This study of a large sample of adolescents with MDD indicated
that the combination of CBT and an antidepressant was more efficacious than
the antidepressant alone (54.8% vs. 40.5%). No differences were found
among the antidepressants used in the study (fluoxetine, citalopram, venla-
faxine). The expected variables were associated with poor response (e.g., more
severe depression, comorbid disorder, abuse). Follow-up assessments showed
continuous remission, with approximately 60% of patients achieving remis-
sion by 72 weeks. About 25% of those who had achieved remission later ex-
perienced relapse (Emslie et al. 2010; Vitiello et al. 2011).
220 Clinical Manual of Child and Adolescent Psychopharmacology

Once treatment noncompliance has been ruled out, the following strate-
gies, based on the TORDIA study and the adult research literature, have been
recommended:

1. Optimize initial treatments. Although few studies have evaluated the effi-
cacy of this strategy, initial treatment can be maximized by increasing the
length of the trial or the dosage.
a. Extend the initial medication trial. For patients who experience at least a
partial response after receiving a therapeutic dose of an antidepressant
for 6 weeks, the first and simplest strategy is to extend the treatment for
another 2–4 weeks if the patient’s clinical and functional status allows
(American Psychiatric Association 2010; Thase and Rush 1997).
b. Increase the dosage. This strategy can be utilized for partial responders.
Dosages can be increased to the maximum dosages unless the patient
develops side effects (American Psychiatric Association 2010; Heili-
genstein et al. 2006).
2. Switch strategies. For patients whose symptoms do not respond to a specific
antidepressant medication or who cannot tolerate its side effects, another
antidepressant of the same class or a different class (e.g., venlafaxine for a pa-
tient who did not respond to a SSRI) can be tried. The few adult studies
published to date suggest that, because of the probable heterogeneity in de-
pression mechanisms, the more efficacious approach is to switch antidepres-
sant classes rather than stay within the same class. Also, severe depression
appears to respond better to antidepressants with both serotonergic and ad-
renergic properties (e.g., venlafaxine) (Poirier and Boyer 1999). MAOIs
have been found beneficial for patients whose symptoms have not re-
sponded to other medications (American Psychiatric Association 2010;
Thase and Rush 1997), but their use in children and adolescents is compli-
cated because of the dietary restrictions. An open study suggested that
symptoms of depression in adolescents that had not responded to TCAs did
respond to MAOIs (Ryan et al. 1988b). However, the adolescents’ symp-
toms may not have responded to TCAs because this group of medications is
not efficacious for the treatment of pediatric MDD (Birmaher et al. 1996a).
3. Augment or combine strategies. The TORDIA study (Brent et al. 2009)
provided evidence that the combination of an antidepressant and CBT is
 Major Depressive Disorder 221

efficacious for adolescents with treatment-resistant MDD. However, phar-

macological augmentation has not been well studied in youth. In adults,
the most common augmentation or combination strategies include adding
atypical antipsychotics (aripiprazole, quetiapine, or lurasidone), atypical
antidepressants (bupropion or mirtazapine), lithium carbonate at thera-
peutic levels for a period of 4 weeks, or L-triiodothyronine (25–50 μg/day).
Esketamine (intranasal form) and brexpiprazole were recently FDA ap-
proved for augmentation of MDD in adults. Less common augmentation
strategies include adding a stimulant or omega-3 fatty acids or combining
an SSRI with a TCA (American Psychiatric Association 2010; Bauer et al.
2000). In adults, the combination of lithium and antidepressants has
yielded response rates of 50%–65% in studies that administered lithium at
therapeutic levels for at least 4 weeks (e.g., American Psychiatric Associa-
tion 2010; Thase and Rush 1997). The interval before response to lithium
augmentation has been reported to be from several days to 3 weeks. After
this period, the chance to observe improvement with lithium decreases.
In adolescents with MDD, an open-label study showed significant im-
provement of refractory depressive symptoms after augmentation of TCA
treatment with lithium (Ryan et al. 1988a). Another open-label study,
however, did not replicate this finding (Strober et al. 1992). Observational
studies suggest that augmentation using quetiapine and aripiprazole may
be beneficial for overall functioning or for reducing self-injury (Bildik et
al. 2012; Pathak et al. 2005).
Case reports have suggested that adding stimulant medications or
combining an SSRI with a TCA may also be effective (American Psychi-
atric Association 2010), but these combinations must be used with cau-
tion because of the possibility of interactions (as with, e.g., SSRIs and
TCAs). In adolescents and adults, the combination of antidepressants and
psychotherapy (CBT, interpersonal psychotherapy) for patients with se-
vere or treatment-resistant depression has also been found useful (Keller et
al. 2000; March et al. 2004).
4. Consider ECT. ECT is one of the most efficacious treatments for adults
with nonresistant MDD (70% response) and resistant MDD (50% re-
sponse) (American Psychiatric Association 2010; Ghaziuddin et al. 2004).
However, because of its invasiveness, ECT remains the treatment of
choice only for the most severe, incapacitating forms of resistant depres-
222 Clinical Manual of Child and Adolescent Psychopharmacology

sion. No controlled studies have been conducted in adolescents, although

retrospective chart reviews suggest similar response rates (e.g., 58%) and
that ECT is safe in adolescents (cited in Cullen et al. 2019). Approxi-
mately 60% of adult patients who are treated successfully with ECT tend
to experience relapse after 6 months (American Psychiatric Association
2010). Therefore, they require maintenance treatment with antidepres-
sants and sometimes maintenance ECT. However, maintenance ECT has
never been reported in adolescents.
5. Try other biological treatments. Other innovative treatments, such as intra-
venous ketamine, intravenous clomipramine, transcranial magnetic stim-
ulation (TMS), transcranial direct current stimulation (tDCS), and vagal
nerve stimulation (VNS), have been used for the treatment of adults with
depression that has not responded to standard treatment (American Psy-
chiatric Association 2010). Promisingly, intravenous ketamine/esketamine
has demonstrated significantly greater reduction in depressive symptoms
compared with placebo in several adult RCTs, with effects lasting from sev-
eral hours up to 1 week after ketamine administration (Marcantoni et al.
2020). Ketamine, although generally well tolerated, requires postinfusion
medical monitoring for 2–4 hours. Several ongoing RCTs are investigat-
ing ketamine for the treatment of MDD in youth, with one open-label
trial (n=13) suggesting efficacy and tolerability (cited in Kim et al. 2021).
In adolescents, intravenous clomipramine has been shown to be efficacious
for patients whose symptoms have failed to respond to other antidepressant
treatment (Sallee et al. 1997). In addition, preliminary open-label/natural-
istic studies suggest that TMS may be safe and effective, although no stud-
ies exist examining tDCS or VNS in depressed youth (cited by Cullen et al.
2019). Activity-based interventions (e.g., aerobic exercise or yoga) may
also be beneficial for some depressed youth (James-Palmer et al. 2020;
Wegner et al. 2020). Although some supplements (e.g., vitamin D and N-
acetylcysteine) may be safe and have some preliminary evidence suggesting
potential benefit as an augmentation treatment for MDD in youth, cau-
tion should be taken in using over-the-counter herbs or supplements be-
cause the quality of such compounds may vary, and some supplements may
have adverse effects (e.g., psychosis with kratom) or may interact with an-
tidepressant treatments (e.g., St. John’s wort).
 Major Depressive Disorder 223

All of the strategies described require implementation in a systematic fash-

ion (for reviews, see American Academy of Child and Adolescent Psychiatry
1998; American Psychiatric Association 2010; Thase and Rush 1997). Com-
paring these strategies with other treatments of medical disorders can be useful
to help patients and their families understand the medication plan and to im-
prove compliance with and tolerance of treatment. The example of hyperten-
sion is appropriate: diuretics may be used alone or combined with other
antihypertensives in different trials, according to response. Psychoeducation
for the patient and family is also required to avoid the development of hope-
lessness in the patient and family as well as in the clinician.

Treatment of Comorbid Conditions

and Suicidality
Comorbid disorders may influence the onset, maintenance, and recurrence of
depression (Birmaher et al. 1996a, 1996b; Emslie et al. 2010). Thus, in addi-
tion to treating the depressive symptoms, clinicians should treat the comorbid
conditions that often accompany depressive disorders (Hughes et al. 1999).
For example, depressed adolescents with comorbid ADHD respond less
well to treatment than do those with depression alone (Hamilton and Bridge
1999). For patients with depression and ADHD—especially those for whom
the ADHD seems to be the primary problem—and because the stimulants exert
their effect quickly, it is recommended that the ADHD be treated first. There-
after, if the depressive symptoms continue after the ADHD is stabilized, an
SSRI should be added (Hughes et al. 1999; Pliszka 2000). This strategy, how-
ever, has not been validated. An open study using bupropion suggested that
this medication can be efficacious in treating both MDD and ADHD (Daviss
et al. 2001), although the effect of bupropion on ADHD is not as impressive
as that obtained by treatment with stimulants (Conners et al. 1996). It has
been suggested that atomoxetine may help both ADHD and depression, but
this medication is a weak antidepressant and has notably weaker effects com-
pared with stimulants in the treatment of ADHD.
The treatment of comorbid anxiety, which more often precedes depression
than vice versa, is essential both because it contributes to improvement and be-
cause the anxiety, if left untreated, may predispose the individual to future de-
224 Clinical Manual of Child and Adolescent Psychopharmacology

pressive episodes (Hayward et al. 2000; Kovacs et al. 1989). Fortunately,

similar pharmacotherapy and psychotherapy treatments found useful for the
treatment of MDD have also been found beneficial for the treatment of youth
with anxiety disorders (e.g., CBT, SSRIs) (Birmaher et al. 2003; Kendall 1994;
Research Unit on Pediatric Psychopharmacology Anxiety Study Group 2001).
Other comorbid conditions, such as OCD, conduct disorder, eating dis-
orders, and PTSD, have also been found to affect treatment response. These
comorbid conditions must be addressed in order for the treatment of de-
pressed youth to be successful (Birmaher et al. 1996b; Brent et al. 1998;
Goodyer et al. 1997).
Suicidal ideation and behavior are common symptoms accompanying
major depression and are more likely to occur in the face of comorbid disrup-
tive disorders, mixed manic/hypomanic symptoms, substance abuse, physical
or sexual abuse, impulsive behaviors, prior suicide attempts, and family his-
tory of suicidal behavior (e.g., Gould et al. 1996). Assessing suicidality, secur-
ing any lethal agents (e.g., medications, firearms), and developing safety plans
with the patient and family are essential components of the management of
the suicidal depressed patient. Patients who cannot formulate a safety plan (or
have low confidence in their ability to use such a plan) and those at higher fu-
ture risk of acting on suicidal thoughts (e.g., those with ongoing suicidal ide-
ation with intent, a plan, or a recent suicide attempt) may require inpatient
hospitalization. Treatment of the underlying depression may be necessary but
not sufficient to prevent recurrent attempts. Other contributors to suicidality,
such as sexual abuse, drug and alcohol use, ADHD, conduct problems, im-
pulsivity and aggression, personality disorders, and family discord, must be as-
sessed and targeted (Brent et al. 1999).
An important consideration is that in the TADS, the combination of
CBT and fluoxetine was associated with lower risk for suicidality (March et al.
2004). However, not all studies have found the protective effect of CBT (e.g.,
TORDIA; Goodyer et al. 2007; Spirito et al. 2011).

Continuation Therapy
Naturalistic longitudinal studies and open follow-up studies following acute
RCTs have shown that the rate of MDD relapse is very high (e.g., 25%–48%
within 1 year) (Birmaher et al. 2002; Kennard et al. 2009a, 2009b, 2014; Vi-
 Major Depressive Disorder 225

tiello et al. 2011). An RCT of fluoxetine discontinuation showed that, com-

pared with a switch to placebo, continuing fluoxetine was associated with a
much lower rate of relapse (22% vs. 48%) (Emslie et al. 2008). Similar results
have been reported in adults with MDD (American Psychiatric Association
2010). Therefore, until further research results are available, clinicians should
offer all patients continuation treatment for 6–12 months after complete
symptom remission to consolidate the response and prevent relapse of symp-
toms. During this phase, patients should be seen biweekly or monthly depend-
ing on the their clinical status, functioning, support systems, environmental
stressors, motivation for treatment, and other psychiatric or medical disorders.
Patients and their families should be taught to recognize early signs of relapse.
One study openly administered fluoxetine for 6 weeks to a large sample of
children and adolescents with MDD (Kennard et al. 2014). Responders were
offered to continue fluoxetine alone or fluoxetine+relapse-prevention CBT
for an additional 6 months. Relapse-prevention CBT was effective in reducing
the risk of relapse compared with fluoxetine alone (9% vs. 27%) but not in ac-
celerating time to remission.
During the continuation phase, antidepressants must be maintained at
the same dosage used to attain remission of acute symptoms, provided that the
medication causes no significant side effects or dosage-related negative effects
on the patient’s compliance (American Psychiatric Association 2010). At the
end of the continuation phase, if a decision is made to discontinue the anti-
depressant, the medication should be tapered gradually (e.g., over a period of
6 weeks) to avoid withdrawal effects (e.g., sleep disturbance, irritability, gas-
trointestinal symptoms) that may lead the clinician to misinterpret the need
for continued medication treatment. In addition, clinical practice has sug-
gested that rapid discontinuation of antidepressants may precipitate a relapse
or recurrence of depression. Ideally, treatment discontinuation should occur
while children and adolescents are on extended vacation, rather than during
the school year.
If relapse occurs, the clinician should first determine whether the patient
has been compliant with treatment. If the patient has not been compliant, the
antidepressant medication should be resumed. If the patient has been compli-
ant and their symptoms had been previously responding to the medication
(without significant side effects), the clinician should consider the presence of
ongoing stressors (e.g., conflict, abuse), comorbid psychiatric disorders (e.g.,
226 Clinical Manual of Child and Adolescent Psychopharmacology

anxiety disorder; ADHD, predominantly inattentive or combined presenta-

tion; substance abuse; persistent depressive disorder; subthreshold manic/hypo-
manic symptoms or undetected bipolar II disorder; or eating disorder), and
medical illnesses. Depending on the circumstances, an increase in the medica-
tion dosage, a change to another medication, augmentation strategies, or psy-
chotherapy may be indicated. For patients receiving only psychotherapy, the
clinician should consider adding medications or using new psychotherapeutic
strategies.

Maintenance Therapy
After the patient has been asymptomatic for approximately 6–12 months (con-
tinuation phase), the clinician must decide whether the patient should receive
maintenance therapy, which therapy to use, and for how long. The main goal
of the maintenance phase is to prevent recurrences. This phase may last from
1 year to much longer and is typically conducted with a visit frequency of every
1–3 months depending on the patient’s clinical status, functioning, support
systems, environmental stressors, motivation for treatment, and other psychi-
atric or medical disorders.

Determining Who Should Receive Maintenance Therapy

The recommendation for maintenance therapy depends on several factors,
such as severity of the initial depressive episode (e.g., suicidality, psychosis,
functional impairment), number and severity of prior depressive episodes,
chronicity, comorbid disorders, family psychopathology, presence of support,
patient and family willingness to adhere to the treatment program, and con-
traindications to treatment.
Factors associated with increased risk for recurrence in naturalistic studies
and open follow-ups after acute RCTs of depressed children and adolescents
may serve as a guide for the clinician in deciding who needs maintenance treat-
ment. These factors include a history of prior depressive episodes, female sex,
late onset, suicidality, “double” depression, subsyndromal depressive symptoms,
poor functioning, comorbid disorders, personality disorders, exposure to nega-
tive events (e.g., abuse, conflicts), and family history of recurrence (two or more
family members with a history of MDD recurrence) (Birmaher et al. 1996a,
 Major Depressive Disorder 227

1996b; Goodyer et al. 1998; Kennard et al. 2009a, 2009b; Klein et al. 2001;
Vitiello et al. 2011; Wagner et al. 2004).
No maintenance RCTs in depressed children and adolescents have been
reported to date. Among depressed adults, those who have had only a single
uncomplicated episode of depression, mild episodes, or lengthy intervals be-
tween episodes (e.g., 5 years) probably should not start maintenance treat-
ment (American Psychiatric Association 2010), whereas those who have had
three or more depressive episodes (especially if they occur in a short period of
time and have deleterious consequences), chronic depressions, and severe de-
pressions should receive maintenance treatment.
Controversy exists about using maintenance treatment to treat patients who
have had two previous episodes. Overall, maintenance treatment has been rec-
ommended for adult depressed patients who have had two depressive episodes
and who meet one or more of the following criteria (American Psychiatric As-
sociation 2002; Depression Guideline Panel 1993): 1) the family has a history
of bipolar disorder or recurrent depression, 2) the first depressive episode oc-
curred before age 20 years, and 3) both episodes were severe or life-threatening
and occurred during the previous 3 years. Given that depression in youth has
a similar clinical presentation, sequelae, and natural course as in adults, these
guidelines should probably also be applied for children and adolescents who
have experienced two previous major depressive episodes.

Deciding Which Treatment to Use

For practical reasons, unless there is any contraindication (e.g., medication side
effects), the treatment that was efficacious in the induction of remission of the
acute episode should be continued for maintenance therapy. However, patients
whose symptoms are being maintained with medications should also be offered
psychotherapy to help them cope with the psychosocial scars induced by the
depression. Furthermore, many depressed youth live in environments charged
with stressful situations, and their parents usually have psychiatric disorders;
therefore, multimodal treatments are ideal.
When selecting a medication for maintenance therapy, the clinician
should consider the side effect profile and the way the side effects may affect
the patient’s compliance. For example, dry mouth, weight gain, increased
sweating, sexual dysfunction, and polyuria (if the patient is taking lithium)
228 Clinical Manual of Child and Adolescent Psychopharmacology

may be very troublesome and may induce discontinuation of treatment. In

addition, in children and adolescents, the long-term consequences of using
antidepressant medications (e.g., chronic inhibition of serotonin reuptake by
an SSRI) are unknown.
Other factors—such as a patient’s embarrassment with friends, uneasiness
about the idea of having their mind “controlled by a medication,” view of treat-
ment with medications as a sign of “weakness,” and uncertainty about the risk
of relapse in spite of doing well while taking medications—should all be ad-
dressed with both the patient and parents.

Determining How Long the

Maintenance Phase Should Last
Adult patients with second episodes who fulfill the criteria for maintenance
therapy noted earlier in this section should be maintained for several years (up
to 5 years in adult studies) with the same antidepressant dosage used to achieve
clinical remission during the acute treatment phase. However, patients with
three or more episodes and patients with second episodes associated with psy-
chosis, severe impairment, and severe suicidality that proved very difficult to
treat should be considered for longer periods of treatment or even lifelong
treatment.
TCAs, SSRIs, and lithium have been found to be efficacious for the pre-
vention of depressive recurrences in adult patients (American Psychiatric As-
sociation 2010). However, given the apparent lack of efficacy of TCAs in
youth, as well as the advantages of SSRIs and their efficacy in the acute treat-
ment of MDD, the SSRIs are considered first-line medications in mainte-
nance therapy in this population. Antidepressant medication, unless it is not
tolerated, should be continued at the full dosage used to exert the initial ther-
apeutic effect.
For most children and adolescents, multimodal therapies are recom-
mended. In addition to antidepressant medications, psychosocial maintenance
strategies should be implemented to help the patient’s inner and interpersonal
conflicts, improve their coping and social skills, help them deal with the psy-
chosocial and personal scars left by the depression, and improve their academic
and social functioning. The reduction of family stress, promotion of a support-
 Major Depressive Disorder 229

ive environment, and effective treatment of parents and siblings with psychi-
atric disorders may also help diminish the risk for recurrence.

Disruptive Mood Dysregulation Disorder

DSM-5 (American Psychiatric Association 2013) added a new disorder to the
mood disorders category, disruptive mood dysregulation disorder (DMDD).
This disorder is characterized by frequent, severe, recurrent temper outbursts
and chronically irritable and/or angry mood, both of which must have been
present for at least 1 year and must not be accounted for by other mood disor-
ders. DMDD was mainly included in DSM-5 to reduce the misdiagnosis of bi-
polar disorder in children with chronic irritability and temper outbursts without
the episodicity that characterizes bipolar disorder (Axelson 2013). However,
the high degree of overlap with symptoms of depression and oppositional de-
fiant disorder (ODD) and similar course and outcome of youth with ODD
has raised questions as to whether DMDD represents a distinct disorder or is
simply a more severe form of ODD or bipolar disorder (Axelson et al. 2012;
Copeland et al. 2014; Leibenluft 2011; Rowe et al. 2010; Stringaris et al.
2009). It could also be asked whether it was premature to include DMDD in
DSM-5 because of the scarce literature available, the fact that irritable mood
and temper outbursts are ubiquitous across psychiatric disorders, its high co-
morbidity with other disorders, and the low reliability of the diagnosis.
Few pharmacological studies have examined treatments for DMDD or se-
vere mood dysregulation (SMD) (Leibenluft 2011), a syndrome from which
DMDD was derived. However, in contrast to DMDD, SMD also includes
some symptoms of ADHD, mania, and depression. A recent RCT of youth
with SMD/DMDD (n=53) found greater response (defined by improvement
in irritability) to treatment with a combination of citalopram and methylphe-
nidate compared with placebo and methylphenidate (Towbin et al. 2020).
Other smaller studies (Ns<35) of youth with SMD/DMDD suggest reduc-
tions in irritability with risperidone and methylphenidate but not with lith-
ium (cited by Benarous et al. 2017). Until the diagnosis of DMDD is clear,
clinicians should be careful when assessing children with chronic irritability
and temper tantrums and should search for the presence of underlying disor-
ders for which there are known treatments, rather rush to DMDD.
230 Clinical Manual of Child and Adolescent Psychopharmacology

Clinical Pearls
• Inform patients and families that the treatment of major depres-
sive disorder (MDD) includes three phases: acute, continuation,
and maintenance.
• Remember that the goal of treatment is not only to achieve re-
sponse but also to achieve remission and good psychosocial
functioning.
• Offer education and support to depressed youth and their fami-
lies during all phases of treatment. Some mildly depressed youth
may respond well to short-term management with education and
support.
• Depending on the severity and chronicity of the youth’s depres-
sion and other factors, use antidepressants (selective serotonin
reuptake inhibitors [SSRIs] as first line) and/or psychotherapy
(cognitive-behavioral therapy [CBT] and interpersonal psycho-
therapy) during the acute phase.
• Question youth and families about side effects because chil-
dren and adolescents treated with SSRIs may uncommonly ex-
hibit onset or worsening of suicidal ideation and, more rarely,
suicide attempts.
• After successful acute treatment, offer all youth continuation treat-
ment with the same dosage of antidepressants and psychother-
apy (e.g., CBT) for 6–12 months to prevent relapses.
• After the continuation phase, provide maintenance treatment
with antidepressants and/or psychotherapy for 1 year or longer
to prevent recurrences, especially for depressed youth with se-
vere depressions or frequent recurrences. For some, treatment
may last years. In these cases, intermittent trials without medi-
cations are warranted to observe whether the patient needs fur-
ther treatment.
 Major Depressive Disorder 231

• Manage comorbid disorders (with evidence-based treatments

for each of these conditions), ongoing conflicts, and family psy-
chopathology to help patients achieve remission.
• In managing resistant depressions, consider factors associated
with poor response to treatment, such as severe depression, long
depressions, poor treatment adherence, misdiagnoses, ongoing
negative life events (e.g., abuse), presence of comorbid disor-
ders (e.g., subthreshold manic/hypomanic symptoms, anxiety,
ADHD, eating disorders), and poor adherence to treatment.
• Until the disruptive mood dysregulation disorder (DMDD) diag-
nosis is clarified, look for and treat the underlying disorders in
children with DMDD.

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 6
Bipolar Disorders
Tiffany Thomas-Lakia, M.D.
Baris Olten, M.D.
Robert L. Findling, M.D., M.B.A.

R esearch over the past 20 years has helped better define the phenomenol-
ogy and course of bipolar disorder in children and adolescents. Pediatric bi-
polar disorder (PBD) has been shown to have a chronic course with high rates
of subsyndromal and syndromal episodes, as well as little interepisode recovery,
and therefore can lead to substantive psychosocial dysfunction (Biederman et
al. 2004; Birmaher et al. 2009; Findling et al. 2001; Geller et al. 2004). For
these reasons, effective treatments are needed for youth with PBD. The purpose
of this chapter is to present a rational, practical, and common-sense approach to
the pharmacotherapeutic management of bipolar disorder in children and ad-
olescents.
Pharmacotherapy guidelines and practice parameters for treating PBD
have been published (Kowatch et al. 2005; McClellan et al. 2007), with more

245
246 Clinical Manual of Child and Adolescent Psychopharmacology

recent studies in children and adolescents providing clinicians with additional

valuable information on the treatment of PBD. Briefly, the use of lithium or
one of several atypical antipsychotics as monotherapy is suggested in the initial
treatment of manic or mixed bipolar presentations in outpatients without psy-
chosis. Partial response to monotherapy with a given agent should be addressed
by adding another drug from a different class of compounds to the preexisting
pharmacological regimen. A rational approach to patients whose symptoms do
not respond at all to a given agent might be to treat the youth with a medica-
tion from a different drug class.
In this chapter, we review medications that have been studied in the treat-
ment of pediatric bipolar illness and summarize the extant evidence for the
treatment of acute manic or mixed states, maintenance therapy, bipolar de-
pression, and combination pharmacotherapy.

Treatment of Acute Manic or Mixed States

Lithium
Our focus in this section is on lithium monotherapy for the treatment of
manic/mixed states. The use of lithium in bipolar depression and as part of
combination therapy is described further in the sections “Treatment of Pedi-
atric Bipolar Depression” and “Combination Pharmacotherapy.”
Lithium was the first medication approved by the FDA for use in treating
bipolar disorder in children and adolescents ages 12 years or older. In 2006, the
Collaborative Lithium Trials (CoLT) group began definitive testing of lithium
in juvenile mania under the auspices of a National Institute of Child Health
and Human Development contract. These innovative studies provided data to
inform the labeling of lithium for children and adolescents with bipolar disor-
der. The CoLT trials provided definitive data on 1) evidence-based dosing
strategies for lithium, 2) pharmacokinetic and biodisposition of lithium in pe-
diatric patients, 3) acute efficacy of lithium in pediatric bipolar illness, 4) long-
term effectiveness of lithium treatment, and 5) short- and long-term safety of
lithium (Findling et al. 2008, 2013c). Based on this extensive work, lithium is
now an FDA-approved treatment for acute manic and mixed episodes and a
maintenance treatment for patients age 7 years or older with bipolar I disorder.
 Bipolar Disorders 247

Supporting Studies in Youth

The published literature on lithium provides evidence to suggest that lithium
is both effective and reasonably well tolerated in the treatment of PBD. Under
the auspices of CoLT, Findling et al. (2015c) performed an 8-week random-
ized, double-blind, placebo-controlled study of youth ages 7–17 years and
found lithium to be superior to placebo in reducing manic symptoms. Other
trials have found lithium combined with divalproex or antipsychotics to be
useful as well (Findling et al. 2003; Kafantaris et al. 2003). However, in head-
to-head studies comparing lithium with divalproex or risperidone in youth,
both divalproex and risperidone demonstrated superiority over lithium for
acute mania (Geller et al. 2012; Kowatch et al. 2007).
In summary, although lithium can be a complicated medication to use,
and perhaps has a more modest acute response than antipsychotics in the
treatment of mania, compelling evidence supports its effectiveness.

Formulations
Lithium is available in tablet, liquid, and long-acting formulations. Lithium
carbonate is perhaps the most widely used formulation and comes in generic
tablets at strengths of 150 mg, 300 mg, and 600 mg. Lithobid, a sustained-
release preparation in film-coated dissolving tablets, is available in 300-mg
strength. A generic version of extended-release lithium carbonate is also avail-
able in 300- and 450-mg strengths. Lithium citrate is an oral solution of lith-
ium with a concentration of 300 mg/tsp (8 mEq/5 mL).

Preliminary Evaluation
Prior to initiating any medication regimen, clinicians should give thoughtful
consideration to the target symptoms and their severity, anticipated barriers
to medication adherence, and their patient’s ability to swallow pills. Before
lithium treatment is initiated, a careful medical history should be obtained.
Particular attention should be paid to reviewing organ systems known to be
affected by lithium administration, including the renal, endocrine, neurolog-
ical, and cardiovascular systems. Given that lithium is known to be a terato-
gen, increasing the likelihood of Ebstein’s anomaly, especially during the first
trimester of pregnancy, a pregnancy test should be completed for females of
childbearing potential prior to initiating treatment.
248 Clinical Manual of Child and Adolescent Psychopharmacology

Table 6–1. FDA-recommended lithium dosing for bipolar I disorder

Adult and pediatric

patients weighing Pediatric patients
Patient group >30 kg weighing 20–30 kg

Formulation Tablets Tablets

Starting dosage, mg 300 tid 300 bid

Dosage titration, mg 300 every 3 days 300 weekly

Acute goal
Serum level, mEq/L 0.8–1.2 0.8–1.2

Usual dosage, mg 600 bid to tid 600–1,500 in divided

doses daily
Maintenance goal
Serum level, mEq/L 0.8–1.0 0.8–1.0

Usual dosage, mg 300–600 bid to tid 600–1,200 in divided

doses daily

Discussion with females of childbearing potential should also be consid-

ered both before and throughout treatment to assess whether these patients are
sexually active or intend to become pregnant. Baseline laboratory work, includ-
ing blood urea nitrogen (BUN)/creatinine, electrolytes, and thyrotropin (thy-
roid-stimulating hormone [TSH]), should be obtained to evaluate for the
possibility of any preexisting renal impairment, electrolyte imbalances, or hy-
pothyroidism that may lead the clinician to eschew prescribing lithium to the
patient. We also recommend obtaining a pretreatment electrocardiogram
(ECG) for each patient to rule out any cardiac conduction abnormalities.

Medication Dosing
We advise that the FDA-recommended dosing guidelines be followed for the
administration of immediate-release lithium in children and adolescents with
bipolar I disorder (Table 6–1).
Findling et al. (2010) investigated the first-dose pharmacokinetics of oral
lithium carbonate in children and adolescents ages 7–17 years after adminis-
tration of immediate-release capsules of 600 mg or 900 mg. Lithium plasma
 Bipolar Disorders 249

concentrations were followed over 48–72 hours in 39 subjects. Lithium clear-

ances did not vary systematically with age, dose, sex, or creatinine clearances.
Allometrically scaled clearance and volume of distribution from the popula-
tion analysis were within the range reported in adults. Single-dose profiles of
lithium in these young patients did show marked variability. This finding in-
dicates that ongoing serum monitoring is needed during continued lithium
therapy. Serum levels at the higher end of this therapeutic range appear to be
associated with better symptom amelioration but also with greater side effects.
The FDA recommends obtaining serum lithium concentration assays
3 days after medication initiation. For immediate-release formulations, the
level should be drawn 12 hours after the last dose and regularly until the patient
is stabilized. For sustained-release formulations, a trough level should be ob-
tained prior to the next dose. When the lithium dosage is stable, we recom-
mend that screening laboratory work be repeated. Subsequently, lithium levels,
calcium levels, TSH, and renal function (BUN/creatinine or creatinine clear-
ance) should be evaluated every 2–3 months or more frequently if necessary.
In addition to regular monitoring of serum lithium levels, the FDA rec-
ommends that levels be reassessed any time there is a change in dosage, an ad-
dition or change in dosage of a concurrent medication, or a marked change in
strenuous physical activity or in the event of a concomitant disease or illness.

Side Effects
Adverse effects from lithium are common and involve the CNS and the renal,
dermatological, endocrine, and gastrointestinal systems (Table 6–2). While
side effects during lithium treatment are common, they generally do not lead
to lithium discontinuation. It appears that gastrointestinal symptoms (e.g.,
stomachache, nausea, vomiting, and diarrhea) are the most common side effects
noted. Often, gastrointestinal side effects can be addressed by recommending
that the patient take lithium with food, dividing the doses more frequently
throughout the course of the day, or administering lithium in the liquid citrate
formulation. Persistent nausea, vomiting, and diarrhea (as well as other side
effects noted later) may all signal the presence of lithium toxicity; for this rea-
son, careful inquiry and reassessment of serum lithium levels should be con-
sidered for patients presenting with these concerns. If the lithium level is
indeed high, lithium doses may be stopped for 24 hours while the level is re-
checked and reinitiation at a lower dosage is considered.
250 Clinical Manual of Child and Adolescent Psychopharmacology

Table 6–2. Management of common lithium side effects

System Side effect Suggested intervention

Gastrointestinal Nausea, emesis, diarrhea Reduce dosage or split dose.

Take with food.
Change to citrate formulation.
CNS Tremor, ataxia, slowed Reduce dosage or split dose.
mentation
Renal Polyuria, changes in renal Allow for bathroom breaks.
function Monitor kidney function every
3 months.
Dermatological Acne, rash Educate patient/family about side
effects.
Endocrine Weight gain, thyroid Educate patient/family about
abnormalities. appropriate diet and exercise.
Monitor thyroid function every
3–6 months.

Other side effects appear to be less common. CNS side effects reported in-
clude tremor, ataxia, and slowed mentation. Tremor is usually mild and can be
aided by dosage reduction. Although propranolol has been described as a treat-
ment for lithium-related tremor in adults, this management strategy is not one
we generally recommend for youth. Renal side effects include polyuria, poly-
dipsia, and possible morphological changes to the kidney after long-term use.
Unfortunately, insufficient data are available regarding the long-term renal ef-
fects of lithium in young patients. Dermatologically, an acne-like rash can be a
troubling side effect for adolescents, and patients should be educated concern-
ing this possibility. Rash and hair loss have been infrequently described in re-
lation to lithium therapy. Last, endocrine side effects can include weight gain
and hypothyroidism.

Drug Interactions and Cautions

Lithium is excreted by the kidney. Thus, medication interactions may occur as
a result of modification of renal excretion by other agents. Concomitant use of
other medications or substances may either increase or decrease lithium levels.
 Bipolar Disorders 251

For example, nonsteroidal anti-inflammatory drugs (NSAIDs) can increase

lithium levels by reducing renal excretion. Although the use of NSAIDs is not
necessarily contraindicated for patients prescribed lithium, care should be
given if NSAIDs are taken during lithium therapy, with particular attention to
symptoms of lithium toxicity. Thiazide diuretics, although not commonly
used in young people, may substantively increase lithium levels; theophylline
and caffeine may decrease lithium levels by enhancing renal excretion. Be-
cause sodium chloride can also affect the renal excretion of lithium, excessive
intake of salty snack foods or salt-repleting sports drinks can lower the lithium
level. These medication interactions, dietary considerations, and adequate hy-
dration, especially during summer months and during vigorous physical ac-
tivities, should be discussed with the patient.
In summary, lithium use in PBD is supported by the literature and at pres-
ent is one of the FDA-approved treatments for PBD. Although the use of lith-
ium has substantive burdens in terms of monitoring and its side effect profile,
its potential for significant benefit allows it to remain a potential agent in the
treatment of PBD.

Anticonvulsants
Although anticonvulsants appear to be widely used in the treatment of PBD,
no anticonvulsants have been FDA-approved for treating acute mania or as a
maintenance therapy for bipolar disorder in children and adolescents. In
adults, divalproex sodium, lamotrigine, and extended-release carbamazepine
are approved for bipolar disorder. Carbamazepine, oxcarbazepine, divalproex
sodium, lamotrigine, and topiramate have all been investigated in youth with
bipolar illness. Other, newer agents such as zonisamide, levetiracetam, and ti-
agabine have not yet received rigorous testing in youth with bipolar disorder.

Carbamazepine
Carbamazepine was the first anticonvulsant extensively studied as a potential
treatment for bipolar disorder in adults. However, carbamazepine is not com-
monly used in the treatment of bipolar disorder in children and adolescents.
This is most likely attributable to a paucity of clinical trial data for carbamaz-
epine use in youth, compared with lithium or divalproex sodium. Another
possible contributing factor is that challenges associated with the administra-
tion of carbamazepine might complicate its use, including the possibility of
252 Clinical Manual of Child and Adolescent Psychopharmacology

medication interactions, concerns regarding aplastic anemia and agranulocy-

tosis, and metabolic autoinduction.
Supporting studies in youth. The limited data that exist on the use of car-
bamazepine in PBD suggest that it may be useful in the treatment of children
and adolescents. In an open-label trial comparing carbamazepine, lithium,
and divalproex sodium, 5 of 13 participants (ages 6–18 years) with bipolar I
or bipolar II disorder achieved a 50% reduction in manic symptoms within
6 weeks of initiating carbamazepine therapy (Kowatch et al. 2003). One pro-
spective, 8-week, open-label trial investigated the use of extended-release car-
bamazepine monotherapy in 27 youth (ages 6–12 years) with bipolar disorder.
Extended-release carbamazepine was initiated at 200 mg/day, and the dosage
was increased by 100 mg in the first 2 weeks and by 200 mg weekly thereafter
per clinician judgment based on tolerability and response. The maximum
dosage used in the study was 1,200 mg/day (not to exceed 35 mg/kg body
weight or serum concentrations >12 μg/mL). In this trial, extended-release
carbamazepine was found to have modest antimanic effects and a somewhat
better antidepressive and antipsychotic response. Although the medication
was well tolerated in this trial, high dropout rates occurred, predominantly
due to lack of response (Joshi et al. 2010). Another open-label trial of ex-
tended-release carbamazepine studied a total of 60 children (ages 10–12) and
97 adolescents (ages 13–17) with bipolar I disorder who were experiencing
acute or manic episodes (Findling et al. 2014). The investigators concluded
that extended-release carbamazepine may be an effective treatment but that
more definitive studies are needed (Findling and Ginsberg 2014).
Formulations. Carbamazepine is available in several forms. Generic carba-
mazepine is available as 100-mg tablets and chewable tablets, 200-mg tablets,
and an 100-mg/5-mL oral solution. These formulations are generally dosed
three or four times daily. An extended-release form of carbamazepine (Carba-
trol) is also available in capsule form in strengths of 100 mg, 200 mg, and
300 mg, which allows twice-daily dosing. The contents of a Carbatrol capsule
may be sprinkled over food, such as applesauce. This form is similar to the ex-
tended-release formulation (Equetro), which is available in sprinkle capsules
in strengths of 100 mg, 200 mg, and 300 mg. The tablet version of extended-
release carbamazepine, Tegretol-XR, is available in strengths of 100 mg,
200 mg, and 400 mg.
 Bipolar Disorders 253

Preliminary evaluation. A thorough medical history should be obtained be-

fore carbamazepine is prescribed. Particular attention should be paid to any
history of hepatic dysfunction, hematological abnormalities, cardiac conduc-
tion problems, or immunological concerns. Laboratory work should include a
complete blood count (CBC) with differential and platelets, electrolytes,
BUN/creatinine, transaminases, and a urine pregnancy test, if applicable.
Careful discussion about the teratogenic potential of carbamazepine should oc-
cur with all patients of childbearing potential, both before initiating treatment
and throughout maintenance therapy. In addition, carbamazepine-induced
Stevens-Johnson syndrome/toxic epidermal necrolysis is strongly associated
with the HLA-B*1502 allele, which is highly prevalent in populations with
ancestry across broad areas of Asia. Patients with ancestry in genetically at-risk
populations should be screened for the presence of the HLA-B*1502 allele
prior to beginning treatment with carbamazepine, and the drug should be
avoided in those testing positive. Because carbamazepine can autoinduce its me-
tabolism, blood levels should be monitored carefully and dosage adjustments
made accordingly (Kudriakova et al. 1992). In addition, carbamazepine can
significantly affect the metabolism of numerous other medications, so a use of
concomitant medications should be fully assessed.
Medication dosing. Carbamazepine use in the child and adolescent popula-
tion has been extensively studied in the pediatric neurology literature, and the
following recommendations are based on those studies. In children younger
than 6 years, carbamazepine should be initiated at 10–20 mg/kg/day bid or tid,
and the dosage should be titrated at weekly intervals until symptom resolution
or until dosage-limiting side effects develop. The maximum daily dosage in
this age group is 35 mg/kg/day. As noted in the earlier section “Formulations,”
the carbamazepine oral solution should be administered in a three- or four-
times-daily dosing regimen to minimize any side effects from the higher peak
serum levels seen with this formulation. In children ages 6–12 years, carbamaz-
epine may be initiated at a dosage of 100 mg bid and the dosage increased
weekly by 100 mg, with the total daily dose not to exceed 1 g. For those older
than 12 years, carbamazepine can be initiated at a dosage of 200 mg bid and
the total daily dose titrated by 200 mg weekly. Adequate serum levels in indi-
viduals older than 12 years are generally achieved at dosages similar to those
used in adults (800–1,200 mg/day). Of note, in the open-label study to com-
254 Clinical Manual of Child and Adolescent Psychopharmacology

pare carbamazepine, lithium, and divalproex sodium in children and adoles-

cents with bipolar disorder, all of the subjects in the carbamazepine arm had
the drug initiated at a dosage of 15 mg/kg/day (Kowatch et al. 2000). Joshi et
al. (2010) studied extended-release carbamazepine in an open-label trial men-
tioned previously (see the earlier subsection “Supporting Studies in Youth”). In
this study, extended-release carbamazepine was initiated at 200 mg/day, and
the dosage was increased by 100 mg in the first 2 weeks and 200 mg weekly
thereafter. The maximum dosage used in the study was 1,200 mg/day (not to
exceed 35 mg/kg body weight or serum concentrations >12 μg/mL).
We have generally found that initiating carbamazepine at a dosage of ap-
proximately 15 mg/kg/day is reasonably well tolerated. The therapeutic serum
level range is 4–12 μg/mL, with 7–10 μg/mL being a common maintenance
drug level. Because autoinduction may occur during carbamazepine therapy,
dosages initially found to be therapeutic may subsequently be inadequate. For
this reason, careful laboratory and symptom monitoring is indicated. We rec-
ommend that drug levels, CBC with differential and platelets, and liver en-
zyme measurements be completed at least every other week during the first
2 months of treatment, then at least every 3 months thereafter.
Side effects. Common side effects of carbamazepine affect both the gastro-
intestinal system and the CNS. Nausea and sedation are commonly experi-
enced and can often be minimized with gradual titration of treatment and
divided dosing. Blurred vision and ataxia also may be noted.
Hematological, dermatological, and hepatic side effects seem to be less
common. Mild leukopenia and thrombocytopenia may occur in some individ-
uals. Rarely, some patients develop aplastic anemia or agranulocytosis. Tran-
sient skin rashes may occur. Stevens-Johnson syndrome may occur very rarely
with carbamazepine use; this risk increases in individuals with the HLA-
B*1502 allele, and at-risk populations should be tested before initiating treat-
ment, as described earlier (see “Preliminary Evaluation”). Transaminase levels
may become mildly elevated with carbamazepine administration. Hyponatre-
mia has been reported in some patients in addition to abnormal renal function.
Weight gain does not appear to be a substantive problem with this medication.
Drug interactions and cautions. Carbamazepine is metabolized through the
cytochrome P450 (CYP) 3A3 and CYP3A4 systems and therefore has the po-
tential to interact with many commonly used medications. A partial listing of
 Bipolar Disorders 255

drugs that can increase carbamazepine levels includes fluoxetine, fluvoxamine,

valproate, tricyclic antidepressants, prednisolone, and macrolide antibiotics
(erythromycin). Use of carbamazepine may decrease blood levels of oral contra-
ceptives (and possibly cause contraceptive failure), benzodiazepines, theophyl-
line, sertraline, and neuroleptics, among other medications. Carbamazepine has
been associated with fetal abnormalities when used by pregnant females during
the first trimester.
In summary, data on carbamazepine’s effectiveness in treating pediatric
mania are limited. No randomized, double-blind trials currently exist to sup-
port its routine use. In addition, the numerous risks related to carbamazepine
use and its extensive interactions with other concomitant medications suggest
that it should be considered a second-line or adjunctive agent in treating PBD
until further studies are performed. At this time, we do not recommend car-
bamazepine as a first-line agent for the treatment of PBD.

Divalproex Sodium
Divalproex sodium received FDA approval for treatment of mania in adults in
1994. It appears that valproate, unlike carbamazepine, is commonly prescribed
to children and adolescents with bipolar disorder.

Supporting studies in youth. Acute treatment of manic, hypomanic, and

mixed mania symptoms in youth has been evaluated in open-label trials of up
to 8 weeks in duration (Papatheodorou et al. 1995; Scheffer et al. 2005; Wag-
ner et al. 2002). These studies suggest that divalproex may be effective in the
treatment of bipolar disorder in young patients. Headache, gastrointestinal
complaints, and sedation were commonly observed side effects in these reports.
Findling et al. (2005) evaluated the longer-term use of divalproex sodium
in PBD. Their study reported on an 18-month, double-blind, maintenance
comparison of lithium and divalproex sodium in youth ages 5–18 years with
bipolar disorder. Divalproex was initiated in divided doses, and the dosage was
gradually increased to a target of 20 mg/kg/day. In this trial, lithium and dival-
proex treatment appeared to have similar effectiveness as maintenance treat-
ments. Gastrointestinal complaints, tremor, and headache were commonly
reported side effects.
The National Institute of Mental Health (NIMH) funded a double-blind
comparison study of lithium, divalproex, and placebo over an 8-week period.
256 Clinical Manual of Child and Adolescent Psychopharmacology

In that trial, divalproex was found to be superior to placebo (Kowatch et al.

2007). However, in a randomized, double-blind, industry-sponsored study of
extended-release divalproex use in youth with bipolar disorder (N=150), no
statistically significant improvement in acute manic symptoms was found for
those given divalproex versus those given placebo (Wagner et al. 2009). An ex-
planation for the discrepant results between these two studies may be related to
between-site variability. The NIMH-supported study was conducted at sub-
stantially fewer sites than the industry-sponsored trial; therefore, intersite vari-
ability may have contributed to the results of the industry-supported trial.
Furthermore, combination pharmacotherapy studies have suggested that dival-
proex may be beneficial when coadministered with lithium, quetiapine, or
risperidone (Findling et al. 2003; Kowatch et al. 2003).
Formulations. Standard valproic acid without enteric coating is available as
Depakene in 250-mg capsules and as a 250-mg/5-mL elixir. Enteric-coated val-
proic acid (divalproex sodium) is available as Depakote in 125-mg, 250-mg, and
500-mg tablets. Depakote Sprinkle Capsules are available in 125-mg strength.
The beaded contents of the capsules can be sprinkled over applesauce for chil-
dren who have difficulty swallowing pills. Extended-release Depakote is avail-
able in 250- and 500-mg tablets, and once-daily dosing may be possible with
this form.
Preliminary evaluation. A detailed medical history is recommended prior
to beginning treatment with valproate. Particular attention should be paid to
any history of hepatic or hematological dysfunction. Concomitant medica-
tions that are hepatically metabolized should also be reviewed. The terato-
genic potential for neural tube defects has been well established with valproate
therapy, and urine pregnancy testing and documentation of education regard-
ing this possibility is suggested for patients of childbearing potential. Con-
cerns regarding polycystic ovary syndrome (PCOS) have prompted some
clinicians to document patients’ pretreatment menstrual patterns in order to
facilitate the identification of any changes in menses that might occur during
valproate therapy. Baseline laboratory work should include a CBC with dif-
ferential and platelets as well as an assessment of liver function (e.g., transam-
inases, bilirubin). Because treatment with divalproex may lead to weight gain,
monitoring of weight and height prior to and during treatment is also recom-
mended.
 Bipolar Disorders 257

Medication dosing. Enteric-coated preparations are generally preferred

over generic valproic acid for the treatment of pediatric patients with bipolar
illness, given that enteric-coated formulations are associated with a reduced
risk for gastrointestinal side effects such as dyspepsia and abdominal pain. For
outpatients, we generally recommend initiating divalproex sodium at a dosage
of approximately 10–15 mg/kg/day in divided doses. Then, based on the re-
sults of serum levels and on clinical response, dosage increases in 250-mg to
500-mg increments may be considered. Serum levels of valproic acid should
be obtained shortly after treatment initiation, during dosage titration periods,
or as clinically indicated. Valproic acid levels should be drawn 12 hours after
the last dose (trough level), and in clinical practice it is generally collected be-
fore the first morning dose. Adequate serum levels have been reported in the
50- to 125-μg/mL range, and the total daily dose should not exceed 60 mg/kg.
After dosage stabilization, liver function tests, CBC with differential and
platelets, and serum levels should be obtained at least every 6 months or
whenever clinical symptoms change.

Side effects. Side effects that have been associated with divalproex pharma-
cotherapy in the pediatric bipolar population have included weight gain as
well as gastrointestinal, CNS, hematological, and hepatic events (Table 6–3).
CNS effects that have been reported include cognitive dulling, headache,
tremor, and somnolence. Although the enteric-coated preparations can min-
imize gastrointestinal symptoms, patients taking these formulations have re-
ported nausea, stomach pain, diarrhea, and emesis. Rare cases of hepatic
failure and potentially fatal pancreatitis have also been observed. Specifically,
cases of fatal valproate-induced acute liver failure have been reported in pa-
tients with mitochondrial disease caused by mutations of the mitochondrial
DNA polymerase gamma gene POLG. Hence, valproate is contraindicated in
patients with mitochondrial disorders caused by POLG mutations and in chil-
dren younger than 2 years who are suspected of having a mitochondrial dis-
order, as stated in the boxed warning for the drug. We routinely advise
patients to notify their physician about new-onset symptoms of nausea, leth-
argy, jaundice, or anorexia. Thrombocytopenia also may occur, so patients
should be monitored for bleeding or easy bruising.
The issue surrounding PCOS has received substantive interest. PCOS is a
syndrome of hyperandrogenism (menstrual irregularities, hirsutism, acne, and
258 Clinical Manual of Child and Adolescent Psychopharmacology

Table 6–3. Management of divalproex sodium–related side effects

System Side effect Suggested intervention

Gastrointestinal Nausea, emesis, stomach Take with food.

pain, diarrhea Switch to Depakote formulation.
Consider checking serum level for
toxicity.
CNS Tremor, headache, sedation, Reduce dosage or split dose.
cognitive dulling
Hematological Leukopenia, Consider hematology
thrombocytopenia consultation.
Consider medication
discontinuation.
Hepatic Elevated transaminases/ Consider rechecking laboratory
pancreatic enzymes values.
Consider medication
discontinuation.
Endocrine Menstrual irregularities, Consider referral to an
hyperandrogenism endocrinologist.
Consider switching mood-
stabilizing agents.
General Weight gain Educate patient/family about
appropriate diet and exercise.
Consider nutrition consultation.

alopecia). Small studies have failed to consistently show a relationship between

PCOS and valproate use among patients without seizure disorders (H. Joffe et
al. 2003; R.T. Joffe et al. 2003). However, Qin et al. (2006) identified a func-
tional single nucleotide polymorphism, –71G, that may contribute to the cre-
ation of excessive testosterone production. Furthermore, valproate has been
shown to potentiate this gene’s expression in ovarian cells (Nelson-DeGrave et
al. 2004; Wood et al. 2005). In sum, valproate treatment may play a role in the
potentiation of PCOS in certain patients, so careful monitoring may be indi-
cated until a clearer picture of the association between valproate administra-
tion and PCOS is available.
 Bipolar Disorders 259

Drug interactions and cautions. Like many other psychotropic agents, val-
proate is metabolized in the liver. Because of the possibility of medication in-
teractions, care should be used when valproate is prescribed with concomitant
agents. Commonly used drugs that can increase valproate levels include eryth-
romycin, fluoxetine, aspirin, and ibuprofen. Similarly, carbamazepine may de-
crease valproate levels during concomitant use.
Valproate can lead to substantive increases in lamotrigine levels when both
agents are used together, which may result in serious dermatological reactions.
Therefore, dosing of lamotrigine should be modified when prescribed con-
comitantly with valproate.

Other Anticonvulsants
Evidence for the use of other, newer anticonvulsants in the acute treatment of
PBD is sparse. For this reason, we generally do not prescribe these compounds
to patients unless other agents with more extensive empirical support fail to
provide adequate therapeutic benefit.
Lamotrigine is indicated for the maintenance treatment of adults with bi-
polar disorder, although its acute management of mood episodes in adults is not
well established. Findling et al. (2015a) aimed to compare the efficacy of ad-
junctive lamotrigine versus placebo in children ages 10–17 years with bipolar I
disorder who were receiving conventional bipolar disorder treatment. In this
randomized withdrawal trial, patients with bipolar I disorder of at least mod-
erate severity received lamotrigine during an open-label phase (up to 18 weeks).
Patients who maintained a stable lamotrigine dosage for 2 weeks or longer and
met specific clinical improvement criteria were randomly assigned to double-
blind lamotrigine or to placebo for up to 36 weeks. Data from the open-label
phase indicated that most patients experienced benefit in mood symptoms with
lamotrigine treatment. However, data analysis of the randomized double-blind
phase failed to detect a benefit of adjunctive lamotrigine. Data analysis also in-
dicated that lamotrigine may be effective in a subset of older adolescents.
One methodologically stringent, double-blind, placebo-controlled clinical
trial by Delbello et al. (2005) examined the use of topiramate in children ages
6–17 years with bipolar I disorder. Topiramate appeared to trend toward hav-
ing some therapeutic efficacy, but the trial was ended before the entire planned
sample was ascertained because results of concurrent adult mania studies failed
to demonstrate efficacy for the compound. Definitive conclusions about the
260 Clinical Manual of Child and Adolescent Psychopharmacology

short-term efficacy of topiramate cannot be made on the basis of this pediatric

trial because of its limited sample size and therefore reduced statistical power to
detect a difference between medication and placebo.
Similar to what had been suggested previously in adults (Benedetti et al.
2004; Hummel et al. 2002), oxcarbazepine was described in two separate case
reports as possibly being beneficial in the treatment of PBD (Davanzo et al.
2004; Teitelbaum 2001). However, in a large, multisite, randomized, double-
blind, placebo-controlled study in children and adolescents, treatment with
oxcarbazepine was found not to be superior to treatment with placebo (Wag-
ner et al. 2006).
Although some published reports have considered zonisamide, levetirac-
etam, and tiagabine in the adult literature, these studies were not placebo-
controlled and generally lacked methodological rigor. At present, we do not
prescribe these three agents to youth for management of PBD given the lack
of data to support their use.

Atypical Antipsychotics
At present, the atypical antipsychotic agents that are available to clinicians in
the United States include aripiprazole, asenapine, clozapine, lurasidone, olan-
zapine, paliperidone (the active metabolite of risperidone), quetiapine, risper-
idone, and ziprasidone. In addition, brexpiprazole, cariprazine, iloperidone,
and lumateperone have been marketed in the United States but remain un-
studied in children and adolescents currently experiencing manic or mixed ep-
isodes. We do not yet have a head-to-head randomized trial comparing the
efficacy of different atypical antipsychotics in children and adolescents, but ef-
ficacy appears to be comparable across separate trials (Correll et al. 2010). Re-
searchers in pediatric bipolar illness continue to explore the usefulness of
atypical antipsychotics as a monotherapy and as an adjunctive therapy in this
often difficult-to-treat population.

General Evaluation and Monitoring

Before any atypical antipsychotic medication is prescribed, care must be taken
to obtain an accurate psychiatric, medical, and family history. Particular atten-
tion should be paid to the patient’s medical and family history and a physical
examination that considers weight/obesity, endocrine, and cardiovascular sys-
tem issues as well as neurological status and movement disorders. When pre-
 Bipolar Disorders 261

scribing any psychotropic medication to children and adolescents, clinicians

should review its potential for short- and long-term side effects with both the
patient and their guardian. In addition to considerations pertaining to this en-
tire class of medications, some issues are specific to individual agents; these are
reviewed in the respective discussions of each agent later in the chapter.
One of the key aspects that confers atypicality to this drug class is its re-
duced propensity to cause extrapyramidal side effects (EPS) compared with
the older, typical antipsychotics. However, neurological side effects such as
dystonia, parkinsonism, and tardive dyskinesia have been reported with these
agents. The potential for these risks should be reviewed with patients and their
guardians. We also recommend paying extra attention to the assessment of
EPS prior to and during the course of treatment with this group of drugs. Tar-
dive dyskinesia is a possibly irreversible side effect of atypical antipsychotics,
and we recommend carefully evaluating and monitoring patients for this pos-
sibility. A commonly used instrument to facilitate this process is the Abnormal
Involuntary Movement Scale (National Institute of Mental Health 1985).
The potential for metabolic/endocrine and cardiovascular complications
in patients taking atypical antipsychotics has been greatly discussed. The
American Academy of Child and Adolescent Psychiatry has developed prac-
tice parameters to assist clinicians with suggested monitoring strategies when
using atypical antipsychotic medications in children and adolescents (Find-
ling et al. 2011). Preliminary data suggest that metformin might decrease the
weight gain associated with atypical antipsychotics in this population; how-
ever, additional high-quality evidence is needed (Ellul et al. 2018).
Avoiding medication interactions with atypical antipsychotics generally
involves avoiding specific concomitant therapies. Because atypical antipsy-
chotic medications can be sedating, caution should be used when combining
them with other CNS depressants. Medications that affect cardiac conduction
by lengthening the QT interval should be used cautiously and with regular
cardiac monitoring. Concomitant use of medications affecting hepatic metab-
olism can reduce (e.g., carbamazepine) or increase (e.g., fluvoxamine, atom-
oxetine) blood levels of certain atypical antipsychotics.

Aripiprazole (Abilify)
Aripiprazole is currently FDA approved for the acute and maintenance treat-
ment of manic and mixed episodes associated with bipolar I disorder in pa-
262 Clinical Manual of Child and Adolescent Psychopharmacology

tients ages 10–17 years. Of the atypical antipsychotics, aripiprazole is distinct

because it acts as a partial dopamine agonist.
Supporting studies. One randomized, double-blind, placebo-controlled
study of 296 patients ages 10–17 years with bipolar I disorder showed that ar-
ipiprazole, at dosages of 10 mg/day and 30 mg/day, was superior to placebo in
the acute treatment of manic and mixed episodes (Findling et al. 2009). A
meta-analysis of the efficacy and safety of aripiprazole across pediatric bipolar
disorder trials and observational studies revealed that this agent was effective,
and its safety profile was comparable with that of other medications, with sig-
nificantly lower risk of hyperprolactinemia (Meduri et al. 2016).

Formulations. Aripiprazole is available in both tablet and liquid formula-

tions. Tablets are available in strengths of 2 mg, 5 mg, 10 mg, 15 mg, 20 mg,
and 30 mg. The liquid preparation is available as a 1-mg/mL elixir. An orally
disintegrating tablet formulation is available in strengths of 10 mg, 15 mg,
20 mg, and 30 mg. Aripiprazole is also available in an injectable form that has
not yet been studied in children.
Medication dosing. Given its long half-life, aripiprazole is routinely pre-
scribed in once-daily dosing. The FDA recommends a starting dosage of
2 mg/day in pediatric patients (ages 10–17), with titration to 5 mg/day after
2 days and a target dosage of 10 mg/day after 2 additional days. We do not
recommend exceeding the FDA-approved maximum dosage of 30 mg/day.

Side effects. Common side effects reported with aripiprazole in youth in-
clude sedation, motoric activation, nausea, and emesis (Table 6–4). Studies in
adults suggest that aripiprazole may have a reduced propensity for inducing
weight gain compared with some of the other atypical agents; however, it does
appear to be associated with weight gain in youth. Clinically significant ECG
changes do not appear to be common with aripiprazole. In addition, because
of aripiprazole’s distinct partial dopamine agonism, prolactin levels seem to
decrease during therapy with this medication.

Asenapine (Saphris)
Asenapine has been approved by the FDA for the acute treatment of manic
or mixed episodes associated with bipolar disorder in children and adolescents
ages 10–17 years. This approval was based on a 3-week randomized controlled
 Bipolar Disorders 263

Table 6–4. Management of aripiprazole side effects

System Side effect Suggested intervention

Gastrointestinal Nausea, emesis Take with food.

Titrate more slowly.
Reduce dosage.
CNS Headache, sedation, Reduce or split dosage.
activation, akathisia Change time of daily administration.
General Weight gain Educate patient and family about
appropriate diet and exercise.
Consider nutrition consultation.
Switch to another treatment.

trial (RCT) involving 403 children and adolescents who were assigned to either
placebo or to one of three fixed doses of asenapine (2.5 mg, 5 mg, or 10 mg)
twice daily. The patients assigned asenapine all showed statistically significant
improvement in symptoms. The most common side effect reported was seda-
tion (>30% with asenapine vs. 6% with placebo). Other, more common side
effects in this study included dizziness, nausea, increased appetite, weight
gain, strange taste sensation, and numbing of the mouth. The latter two side
effects are likely related to the sublingual formulation of asenapine. Overall,
asenapine was generally well tolerated in this study population (Findling et al.
2015b).

Clozapine (Clozaril)
Whereas the other atypical antipsychotics are considered first-line agents,
clozapine is generally reserved for patients whose symptoms fail to respond to
other forms of therapy, and it appears to be used only rarely in pediatric pa-
tients with bipolar illness because of its associated risk for potentially fatal
agranulocytosis. Also, clozapine can lower the seizure threshold and lead to
both electroencephalographic changes and overt seizures in youth who take
this medication.
Some evidence suggests that clozapine may be of benefit to adolescents with
treatment-resistant bipolar illness (Masi et al. 2002). Unfortunately, no pro-
spective RCTs of clozapine have been reported in this population.
264 Clinical Manual of Child and Adolescent Psychopharmacology

Olanzapine (Zyprexa, Zydis)

Olanzapine is FDA approved for the acute treatment of manic or mixed epi-
sodes associated with bipolar I disorder in youth ages 13–17 years. Weight gain
and endocrine abnormalities (e.g., diabetes, dyslipidemias) associated with
olanzapine therapy have received attention in adults and are of important
clinical concern for children and adolescents, who may be at greater risk for
antipsychotic-related weight gain.
Supporting studies. In a 3-week double-blind, placebo-controlled, ran-
domized trial (Tohen et al. 2007), adolescent patients (ages 13–17 years) with
mania were randomly assigned to olanzapine (n = 107) at dosages ranging
from 2.5 mg/day to 20 mg/day or to placebo (n=54). The investigators found
that, compared with placebo, treatment with olanzapine was associated with
greater reduction in manic symptoms. Patients given olanzapine gained more
weight (3.7 kg) than those given placebo (0.3 kg). Furthermore, the olanzap-
ine-treated group showed significantly greater changes in levels of prolactin,
fasting glucose, fasting total cholesterol, uric acid, and the hepatic enzymes as-
partate transaminase and alanine transaminase. Post hoc analysis of this study
revealed that early response to olanzapine at week 1 in acute pediatric manic
or mixed episodes was strongly associated with ultimate response and remis-
sion at week 3 (Xiao et al. 2017). These results suggest that the benefits of
olanzapine for the treatment of PBD should be considered within the context
of its safety profile. This may lead clinicians to consider this medication only
after other atypical antipsychotics have been tried first.
Formulations. Olanzapine is available in tablets, in an intramuscular prepa-
ration (short- and long-acting), and in the dissolving formulation Zydis. Tablets
are available in strengths of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, and 20 mg.
Zydis orally disintegrating tablets, available in strengths of 5 mg, 10 mg, 15 mg,
and 20 mg, may be useful for children who are unable to swallow tablets. The
short-acting injectable form of olanzapine is generally reserved for management
of emergencies and potentially dangerous situations, whereas the long-acting in-
tramuscular injection (Zyprexa Relprevv) is available for maintenance therapy.
Preliminary evaluation. Given that olanzapine therapy may be associated
with weight gain and endocrine dysfunction, care should be exercised to es-
tablish any history of endocrine dysfunction or obesity in both the child or ad-
 Bipolar Disorders 265

Table 6–5. Management of olanzapine side effects

System Side effect Suggested intervention

Endocrine Glucose intolerance Monitor fasting glucose and hemoglobin

A1C at least annually.
Consider nutrition consultation.
Prolactin elevation Monitor for changes in menses,
galactorrhea, or gynecomastia.
CNS Headache, sedation Reduce dosage or split dose.
Administer dose at bedtime.
General Weight gain Educate patient/family about appropriate
diet and exercise.
Consider nutrition consultation.
Switch to another atypical antipsychotic.
Consider adding metformin or topiramate.

olescent and their biological family prior to therapy. Discussions with patients
and their families should include both short- and long-term risks noted in pe-
diatric trials. We also suggest that the patient and family actively participate in
monitoring of side effects.
Medication dosing. The FDA-approved dosing guidelines recommend
that oral olanzapine be initiated at dosages of 2.5 mg/day or 5 mg/day, with a
target dosage of 10 mg/day. Dosing adjustments in increments of 2.5 mg or
5 mg are recommended. Dosages greater than 20 mg/day have not been clin-
ically evaluated in the pediatric population.
Side effects. Side effects associated with olanzapine include glucose intoler-
ance, prolactin elevation, headache, sedation, and weight gain (Table 6–5).
Weight gain has been noted in published pediatric bipolar trials. Although se-
dation is commonly reported with olanzapine use, gastrointestinal problems
appear to be relatively uncommon. Unfortunately, methodologically stringent
long-term studies of olanzapine in this patient population are lacking. There-
fore, the magnitude of weight gain associated with long-term olanzapine ther-
apy in the pediatric population has yet to be adequately characterized.
266 Clinical Manual of Child and Adolescent Psychopharmacology

Quetiapine (Seroquel)
Quetiapine is FDA approved for the acute treatment of manic episodes in pe-
diatric patients ages 10–17 years with bipolar I disorder.
Supporting studies. In one prospective study, 50 patients ages 12–18 years
with mania were randomly assigned to treatment with either quetiapine (at dos-
ages ranging from 400 mg/day to 600 mg/day) or divalproex (at dosages nec-
essary to achieve serum levels of 80–120 μg/mL) for up to 4 weeks (Delbello et
al. 2006). The authors found both medications to be equally effective in ame-
liorating manic symptoms, and both were reasonably well tolerated. Another
randomized, placebo-controlled trial of 277 patients ages 10–17 years found
that quetiapine at dosages of 400 mg/day and 600 mg/day was more effective
than placebo in treating acute manic symptoms in PBD (Pathak et al. 2013).
Other studies have evaluated the usefulness of quetiapine as an adjunctive
treatment in PBD. These clinical trials are discussed in the “Combination
Pharmacotherapy” section later in this chapter.
Formulations. Quetiapine is available in 25-, 50-, 100-, 200-, 300-, and
400-mg strengths. A long-acting formulation of quetiapine (Seroquel XR) is
available in 50-, 150-, 200-, 300-, and 400-mg strengths.
Medication dosing. For adolescents, the FDA recommends that the total
daily dose for the initial 5 days of therapy be 50 mg (day 1), 100 mg (day 2),
200 mg (day 3), 300 mg (day 4), and 400 mg (day 5). After day 5, the dosage
should be adjusted within the recommended range of 400–600 mg/day on the
basis of response and tolerability. Dosage adjustments should be in increments
no greater than 100 mg/day. No additional benefit has been shown in pre-
scribing more than 600 mg/day for adolescents. The dosing schedule for im-
mediate-release formulations should be divided twice or three times daily as
necessary.
Side effects/preliminary evaluation. The management of the common side
effects of quetiapine is described in Table 6–6. The adult research literature
notes blood pressure elevation, sedation, and orthostatic hypotension as com-
mon adverse effects with quetiapine treatment. Although we have observed
weight gain with quetiapine in our clinical practice, it appears to be less than
that noted with olanzapine and clozapine treatment. The risk of EPS may be
relatively modest with quetiapine compared with the other atypical agents.
 Bipolar Disorders 267

Table 6–6. Management of quetiapine side effects

System Side effect Suggested intervention

Cardiovascular Elevated blood pressure Monitor blood pressure closely;

(both systolic and adjust dosage as necessary to
diastolic) minimize blood pressure changes.
CNS Sedation, orthostasis Reduce or split dosage to three times
daily, with the larger dose at night.
Caution patient to be careful when
getting out of bed and standing up.
Visual Cataracts Educate patient about possible
changes in eyesight.
Recommend regular
ophthalmological evaluation.
General Weight gain Educate patient about appropriate
diet and exercise.
Consider nutrition consultation.
Consider switching to another
agent.

Cataract formation has been noted in laboratory animals administered

quetiapine. Although a relationship between quetiapine use and cataract for-
mation has not been established in humans, clinicians may want to consider
recommending ophthalmological examinations for patients prescribed this
medication, in addition to the other evaluations that should be considered be-
fore beginning atypical antipsychotic therapy (see “General Evaluation and
Monitoring” earlier in this chapter).

Risperidone (Risperdal)
Risperidone was the first atypical antipsychotic to receive FDA approval for
the treatment of acute mania or mixed episodes associated with bipolar I dis-
order in youth ages 10–17 years.
Supporting studies. Haas et al. (2009) conducted a randomized study of
risperidone versus placebo in the acute treatment of manic or mixed episodes
in 169 patients ages 10–17 years. Risperidone was found to be superior to pla-
268 Clinical Manual of Child and Adolescent Psychopharmacology

cebo and was relatively well tolerated at dosages as low as 0.5–2.5 mg/day.
Geller et al. (2012) compared risperidone with valproic acid or lithium in an
8-week RCT assessing their comparative efficacy in pediatric bipolar manic or
mixed episodes. The study demonstrated that risperidone was more effica-
cious than valproic acid and lithium for the initial treatment of a manic epi-
sode but had potentially serious metabolic side effects.

Formulations. Risperidone is available in tablet, liquid, disintegrating tablet,

and long-acting injectable forms. The tablets and oral disintegrating tablets are
available in 0.25-, 0.5-, 1-, 2-, 3-, and 4-mg strengths. The concentration of
the liquid formulation is 1 mg/mL. Data are limited on the use of injectable
Risperdal Consta and long-acting oral paliperidone (Invega) in youth.

Preliminary evaluation. As recommended before any atypical antipsychotic

initiation, clinicians should obtain an accurate psychiatric, medical, and fam-
ily history (see “General Evaluation and Monitoring” earlier in this chapter).
Risperidone, compared with other atypical antipsychotics, appears to have a
greater propensity to increase prolactin concentrations. In our experience,
prolactin-related side effects are not often problematic. Therefore, we gener-
ally do not monitor prolactin concentrations over time. However, we do rec-
ommend that a pretreatment prolactin level be obtained for youth prior to
initiating risperidone. Then, if side effects that might be attributable to pro-
lactin (e.g., irregular menses/amenorrhea, galactorrhea, breast enlargement)
develop de novo and a prolactin measurement is subsequently obtained, the
clinician has a baseline level for comparison.
Medication dosing. The FDA-recommended starting dosage of risperidone
in youth with bipolar disorder is 0.5 mg/day, administered as a single daily
dose in either the morning or evening. Dose adjustments, if indicated, should
occur at intervals of not less than 24 hours, in increments of 0.5 mg/day or
1 mg/day (administered daily or divided twice daily), as tolerated, to a recom-
mended dosage of 2.5 mg/day. Although efficacy at dosages between 0.5 mg/
day and 6 mg/day has been demonstrated in studies of pediatric patients with
bipolar mania, no additional benefit was seen for dosages higher than 2.5 mg/
day, and these higher dosages were associated with more adverse events. Dos-
ages greater than 6 mg/day have not been studied. In our experience, dosage-
limiting side effects during risperidone titration are sedation and EPS.
 Bipolar Disorders 269

Table 6–7. Management of risperidone side effects

System Side effect Suggested intervention

CNS Sedation, headache Reduce the total dosage.

Administer more of the daily dose at night.
Endocrine Glucose intolerance, Monitor fasting glucose.
prolactin elevation Monitor for changes in menses,
galactorrhea, or gynecomastia.
General Weight gain Educate patient/family about appropriate
diet and exercise.
Consider switching to another agent.

For younger children, we generally suggest starting at 0.25 mg/day, with ti-
tration every 2–3 days, to a total dosage that does not exceed 2 mg/day. This to-
tal daily dosage is typically administered in two relatively equal doses. For older
children and adolescents (typically weighing >40 kg), we generally consider a
similar dosing strategy that employs 0.5-mg dosing increments and a total dos-
age that does not exceed 4 mg/day.
Side effects. The most commonly reported side effects during risperidone
treatment include weight gain, headache, and sedation (Table 6–7). A more
rapid rate of dosage titration, as well as higher final total daily dosages, seems to
increase the risk of EPS during pediatric risperidone therapy. As noted (see ear-
lier subsection “Preliminary Evaluation”), rates of hyperprolactinemia seem
higher with risperidone than with other atypical antipsychotics.

Ziprasidone (Geodon)
Ziprasidone is FDA approved as monotherapy for schizophrenia and for acute
treatment of manic or mixed episodes associated with bipolar I disorder in
adults. The European Medicines Agency (EMA) has approved ziprasidone as
an acute treatment for pediatric mania in patients ages 10–17 years. To date,
the FDA has not yet approved ziprasidone for any pediatric indication.
Supporting studies. One randomized, placebo-controlled trial of 237 pa-
tients ages 10–17 years with a manic or mixed episode associated with bipolar I
disorder found that ziprasidone at dosages of 40–160 mg/day was effective for
270 Clinical Manual of Child and Adolescent Psychopharmacology

the treatment of bipolar disorder and was generally well tolerated, with a neu-
tral metabolic profile (Findling et al. 2013a).
More recently, Findling et al. (2022) investigated the acute efficacy, safety,
and tolerability of flexibly dosed ziprasidone in youth with bipolar I disorder.
In a 4-week double-blind study, participants ages 10–17 years were randomly
assigned to ziprasidone (20–80 mg bid) or placebo. Some were then enrolled in
a 26-week open-label extension study. Based on the results of the double-blind
phase, the authors concluded that ziprasidone was effective for youth with bi-
polar I disorder in a manic episode. Overall, ziprasidone was safe and well tol-
erated, with no meaningful effects on weight or metabolic parameters.
Formulations. Ziprasidone is available in capsules and as an intramuscular
injection. The capsule form is available in 20-mg, 40-mg, 60-mg, and 80-mg
strengths. The injectable form is reserved for acute agitation; although its use
has been described in case reports (Hazaray et al. 2004; Staller 2004), this for-
mulation has not been examined in methodologically stringent research in the
pediatric population.
Preliminary evaluation. The evaluation prior to initiating ziprasidone ther-
apy is similar to that mentioned earlier for the other atypical antipsychotics (see
“General Evaluation and Monitoring”). Particular attention should be paid to
any individual or family history of cardiac conduction problems or symptoms
associated with cardiac disease (e.g., syncope, arrhythmias, or family history of
sudden cardiac death). The EMA reports that ziprasidone was associated with
a mild to moderate dose-related prolongation of the QT interval in pediatric
bipolar clinical trials, similar to that seen in the adult population. Ziprasidone
should not be given together with medicinal products known to prolong the
QT interval, and caution is advised regarding its use in patients with significant
bradycardia. Electrolyte disturbances such as hypokalemia and hypomagnese-
mia increase the risk for malignant arrhythmias and should be corrected before
treatment with ziprasidone is started. If patients with stable cardiac disease are
treated, an ECG should be considered before treatment is started. In clinical
practice, we recommend that ECGs be obtained prior to and during the course
of ziprasidone therapy (see subsection “Side Effects”).
Medication dosing. The EMA’s recommended dosage of ziprasidone in the
acute treatment of pediatric (ages 10–17 years) bipolar mania is a single 20-mg
 Bipolar Disorders 271

dose on day 1. The drug should subsequently be administered in two divided

doses daily and titrated over 1–2 weeks to a target range of 120–160 mg/day
for patients weighing 45 kg or more or 60–80 mg/day for those weighing less
than 45 kg. Subsequent dosing should be adjusted based on clinical status,
within the weight-based ranges of 80–160 mg/day or 40–80 mg/day, respec-
tively. The EMA warns against exceeding the weight-based maximum dose
(160 mg/day or 80 mg/day) because ziprasidone’s safety profile at these dos-
ages has not been confirmed, and it is associated with dose-related QT interval
prolongation.
In addition, because taking ziprasidone with food increases its bioavail-
ability, we generally recommend that patients take ziprasidone with food con-
sistently in order to achieve predictable drug exposure.

Side effects. Sedation, akathisia, and elevated heart rates have been noted
when ziprasidone is prescribed to youth (Barnett 2004) (Table 6–8). Unlike
with many other atypical agents, substantive weight increases and dyslipidemias
do not appear to be associated with ziprasidone therapy in adults. Ziprasidone
does have a generally modest effect on intracardiac conduction in adults, but the
risks associated with this effect appear to be modest (Daniel 2003). Although
concerns have been raised (Blair et al. 2005), the effects of ziprasidone on car-
diac electrophysiology have not yet been fully characterized in children or ad-
olescents. In the absence of definitive information regarding the magnitude of
QTc prolongation that may occur in youth, no definitive recommendations
about ECG monitoring in those treated with ziprasidone can be made. How-
ever, in our practice, in addition to a baseline ECG, we generally suggest that
an ECG be repeated after every 40- to 60-mg/day increase in dosage.
Ziprasidone-associated mania has also been described (Keating et al.
2005). The mechanism for this action and frequency of this occurrence in
young people remain empirical questions for which further research is needed.

Lurasidone (Latuda)
Lurasidone is not currently approved by the FDA for the treatment of mixed
or manic states in PBD but is approved for the treatment of pediatric patients
(ages 10–17) with bipolar I disorder experiencing an acute depressive episode.
Lurasidone is available in 20-, 40-, 60-, and 80-mg tablets. The FDA rec-
ommends initiating lurasidone at a dosage of 20 mg given once daily as mono-
272 Clinical Manual of Child and Adolescent Psychopharmacology

Table 6–8. Management of ziprasidone side effects

System Side effect Suggested intervention

CNS Sedation, akathisia, Reduce the daily dosage.

extrapyramidal side
Administer the total daily dosage
effects
three times daily rather than in
twice-daily divided doses.
Administer a larger proportion of
the total daily dose at bedtime.
Cardiovascular QTc prolongation, Monitor for any syncopal events
elevated heart rates or dizziness.
Consider medication dosage
decrease or discontinuation.
Consider electrocardiographic
monitoring at baseline and
during upward dosage
titration.
Consider electrocardiographic
monitoring when optimal
dosage is achieved, then
periodically or if symptoms
change.

therapy. Initial dosage titration is not required. The dosage may be increased
after 1 week based on clinical response. Lurasidone has been shown to be ef-
fective in a dosage range of 20–80 mg/day as monotherapy.
In a 6-week randomized, double-blind, placebo-controlled trial, lurasidone
showed significant efficacy in the treatment of pediatric bipolar depression in
patients ages 10–17 within the dosage range of 20–80 mg/day (DelBello et al.
2017). It was well tolerated, with no significant metabolic side effects. Patients
who completed the acute phase were enrolled in a 2-year, open-label extension
phase. The study results demonstrated that lurasidone was generally well tol-
erated and effective for up to 2 years, with low rates of discontinuation due to
adverse events (DelBello et al. 2021).
Further information on lurasidone can be found in Chapter 5 (“Major
Depressive Disorder”).
 Bipolar Disorders 273

Maintenance Therapy
Bipolar illness is a chronic, long-term condition. However, many pharmaco-
therapy studies in the pediatric bipolar literature have lasted no longer than
8 weeks. Limited studies are available to provide physicians with long-term ef-
ficacy and safety information. Although the pediatric neurology literature
provides some insights into the long-term safety of several of the anticonvul-
sants, data are limited regarding the long-term effectiveness and use of these
medications in children and adolescents with bipolar illness.
Maintenance therapy with lithium has been investigated. The CoLT group
studied the long-term effect of lithium following acute treatment of mania. The
average length of treatment after stabilization was 14.9 weeks. Investigators
found that lithium is safe and effective at maintaining remission for patients
whose symptoms initially responded to lithium for the treatment of mania.
However, patients who only partially responded to lithium during acute treat-
ment did not demonstrate substantial improvement during the long-term
phase, despite the ability to receive adjunctive medications (Findling et al.
2013c). The CoLT trials provided further evidence in support of lithium for
the maintenance treatment of pediatric bipolar I disorder. In this double-blind,
placebo-controlled discontinuation study, participants ages 7–17 experiencing
a manic or mixed episode received 24 weeks of lithium treatment in one of the
prior CoLT trials (CoLT 1 or CoLT 2). Those who responded clinically to lith-
ium were randomly assigned to continue lithium or cross-titrated to placebo
for up to 28 weeks. The results of this study indicated that lithium mainte-
nance treatment was generally safe and well tolerated (Findling et al. 2019).
One 18-month study evaluating the effectiveness of lithium monotherapy
versus divalproex monotherapy in PBD found lithium to be as useful as dival-
proex monotherapy, and both drugs were generally well tolerated (Findling et
al. 2005). Evidence indicated that lithium was superior to placebo in mainte-
nance treatment of PBD, and lithium and divalproex seemed to perform sim-
ilarly, which implies that divalproex might also be superior to placebo for
maintenance treatment. Further research is necessary to answer this question.
The superiority of aripiprazole in maintenance therapy has also been
demonstrated. Findling et al. (2013b) conducted a 30-week randomized,
double-blind, placebo-controlled study involving youth ages 10–17 with bipo-
lar I disorder with manic or mixed episodes, with or without psychosis. By
274 Clinical Manual of Child and Adolescent Psychopharmacology

study completion, the participants randomly assigned to either aripiprazole

10 mg/day or 30 mg/day showed statistically significant improvement in
manic symptoms versus placebo. The medication was generally well tolerated,
although a high attrition rate was noted in all treatment arms.
In another study, following mood stability with up to 16 weeks of open-
label aripiprazole treatment, patients ages 4–9 years with bipolar disorder were
randomly assigned in a double-blind manner to either continue aripiprazole
or switch to a placebo for up to 72 weeks. The study results indicated that pa-
tients given aripiprazole had lower rates of symptom relapse compared with
those given placebo (Findling et al. 2012).
Maintenance therapy with quetiapine was investigated in an open-label
study (Duffy et al. 2009). Following mood stabilization and discontinuation
of other psychotropic medications, 13 of 18 youth maintained mood stability
for 40 weeks on quetiapine monotherapy. No patients in the study withdrew
because of lack of tolerability.
Nearly all maintenance studies in youth have focused on manic symp-
toms. Findling et al. (2015a) studied the efficacy of adjunctive lamotrigine for
manic, depressed, and mixed states. In a randomized, double-blind, placebo-
controlled withdrawal study, youth ages 10–17 assigned to lamotrigine experi-
enced delayed time to onset of bipolar events compared with those assigned to
placebo, although the results were not statistically significant. In subgroup anal-
ysis, however, results were statistically significant for adolescents ages 13–17.
Although more evidence is emerging, additional studies are needed to ad-
dress the long-term effectiveness and safety of maintenance medication op-
tions in the pediatric bipolar population.

Treatment of Pediatric Bipolar Depression

Treatment of pediatric bipolar depression is covered in Chapter 5. Please refer
to the section in that chapter titled “Treatment of Major Depressive Disorder
Subtypes and Bipolar Depression.”

Combination Pharmacotherapy
Much of the recent treatment research into PBD suggests that lithium, mood
stabilizers, or atypical antipsychotics may be effective as drug monotherapy in
 Bipolar Disorders 275

treating this illness. Increasing evidence suggests that combination pharma-

cotherapy, consisting of more than one agent, also might be appropriate for
some patients, including inpatients, youth with psychosis, and patients who
experience only a partial symptom response to one class of medications.
The combination of lithium with divalproex sodium has demonstrated
effectiveness in treating pediatric mania (Findling et al. 2003). Other data
suggest that lithium in combination with other antipsychotics may also be a
rational therapeutic strategy (Kafantaris et al. 2001). Similarly, adjunctive ad-
ministration of quetiapine with divalproex has been found to be an effective
approach in adolescent mania (Delbello et al. 2002).
One of the goals of the CoLT studies was to investigate monotherapy with
lithium versus combination therapy. Most patients (25 of 41) were prescribed
multiple psychotropics; 13 patients were concomitantly prescribed divalproex
and/or an antipsychotic for refractory mania. Researchers found that for pa-
tients with refractory mania, the addition of other psychotropics provided lit-
tle to no improvement in symptoms (Findling et al. 2013c).
Clinicians may infer from these data that many, but not all, patients will
require more than one psychotropic agent. Unfortunately, at present, it is not
possible to identify prior to treatment initiation which patients will or will not
experience a response to drug monotherapy. Traditionally, monotherapy with
a mood stabilizer was the preferred initial treatment for patients with less severe
mania and mania without psychosis. However, a recent meta-analysis found
that second-generation antipsychotics were more efficacious in the treatment
of mania, albeit more likely to cause side effects (Correll et al. 2010). Clearly,
more research is needed in this area.
Because psychiatric comorbidity is the rule (not the exception) in PBD,
clinicians should pay careful attention to discerning whether other psychiatric
conditions are present when they are faced with a young patient with bipolar-
ity. Unfortunately, very few data are available about how to treat psychiatric
comorbidities in PBD.
The best evidence available regarding psychiatric comorbidities in PBD
pertains to the treatment of comorbid ADHD. Scheffer et al. (2005) demon-
strated that the addition of mixed amphetamine salts was effective in treating
ADHD symptoms following mood stabilization with divalproex monother-
apy. Similarly, in youth who had achieved a stable mood with lithium and/or
divalproex sodium, those treated with stimulants did not have an increased
276 Clinical Manual of Child and Adolescent Psychopharmacology

risk of relapse compared with those who were not treated with a psychostim-
ulant (Findling et al. 2005).
Another study investigated the short-term efficacy of methylphenidate in
16 youth with bipolar disorder and ADHD who were euthymic when taking at
least one mood stabilizer but continued to experience clinically significant
ADHD symptoms. Participants received 1 week each of placebo, methylphe-
nidate 5 mg bid, methylphenidate 10 mg bid, and methylphenidate 15 mg bid
in a crossover design. Findings demonstrated that treatment with methylphe-
nidate was superior to placebo in treating ADHD symptoms, and its adminis-
tration was not associated with mood destabilization (Findling et al. 2007).
In patients who have not achieved mood stability, Vitiello et al. (2012)
found that patients with comorbid ADHD were more likely to respond to
risperidone versus lithium compared with peers without ADHD. The authors
suggested this difference may be due to risperidone improving hyperactivity/
impulsivity, although caution should be used in interpreting these findings.

Conclusion
Quite a bit of progress has occurred since the start of this century in the phar-
macological treatment of PBD. Clinicians are now better able to recognize
and more effectively treat this condition. Continued research into the phe-
nomenology, longitudinal course, genetics, and therapeutics of this spectrum
of illnesses will eventually provide insights into the pathophysiology of PBD.
Those insights, in turn, should contribute to the development of a broader,
evidence-based foundation for the identification and management of PBD.
As research into those domains continues and as a better appreciation and un-
derstanding of the development and course of the illness develops, it is possi-
ble that these avenues of research may eventually lead to useful preventive
strategies for this chronic, debilitating illness.

Clinical Pearls
• Be sure the diagnosis is correct. Because pediatric bipolar dis-
order can be difficult to diagnose, it is important to be sure the
right patients are receiving the correct interventions.
 Bipolar Disorders 277

• Select a medication regimen that is based on scientific data

from pediatric populations.
• Use the right dosage of medication. Some medicines require
therapeutic drug concentration monitoring. In addition, many
agents will be less effective if underdosed or may be less safe if
prescribed at too high a dosage.
• Continue the medication trial for an adequate period of time.
Some drugs do not provide noteworthy salutary effects until af-
ter several weeks of treatment at an appropriate dosage.
• Be aware of any psychiatric comorbidities that might contribute
to what seemingly is “treatment nonresponse.”
• Carefully assess for side effects because the medications used
in the treatment of pediatric bipolarity may be associated with
substantive risks.
• Remove agents that might be exacerbating the illness. Some
medications can worsen the course of illness in some patients.

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 7
Autism Spectrum Disorder
Michelle L. Palumbo, M.D.
Christopher J. Keary, M.D.
Christopher J. McDougle, M.D.

I n 1943, Leo Kanner presented 11 case histories illustrating a syndrome in

which the “pathognomonic, fundamental disorder is the children’s inability
to relate themselves in the ordinary way to people and situations from the
beginning of life” (Kanner 1943, p. 242). He described several common char-
acteristics, such as an autistic aloneness, impaired language development, ste-
reotypies, literalness, and a need for sameness. In this compelling article,
Kanner illustrated the clinical entity known today as autism spectrum disor-
der (ASD).

We want to thank the Nancy Lurie Marks Family Foundation for their support of this
work. We also thank Drs. Kimberly A. Stigler and Craig A. Erickson for their contri-
butions to a previous version of this chapter.

283
284 Clinical Manual of Child and Adolescent Psychopharmacology

Thirty-seven years later, the publication of DSM-III (American Psychiat-

ric Association 1980) heralded the inclusion of infantile autism among its for-
mal diagnoses. Many of Kanner’s initial findings were reflected in the criteria
in DSM-III as well as in subsequent revisions. DSM-IV (American Psychiatric
Association 1994) recharacterized the disorder under the larger umbrella term
of pervasive developmental disorders (PDDs), including autistic disorder (au-
tism), Asperger’s disorder, Rett’s disorder, childhood disintegrative disorder,
and pervasive developmental disorder not otherwise specified (PDD-NOS).
Similar to Kanner’s observations, these criteria emphasized severe impair-
ments in social interaction and communication as well as restricted interests
and activities as being core features. More recently, DSM-5 (American Psy-
chiatric Association 2013) collapsed autistic disorder, Asperger’s disorder, and
PDD-NOS into one term, autism spectrum disorder, in an attempt to simplify
diagnosis while still capturing the heterogeneity of the disorder. In this vein,
designations of mild, moderate, and severe can be assigned and impairments
in verbal communication are no longer a requirement for diagnosis.
Recent estimates have calculated the prevalence of intellectual develop-
mental disorder (intellectual disability) in children with ASD at 31% and
40%, respectively (Van Naarden Braun et al. 2015; Wingate et al. 2014).
These estimates, which are lower than rates of co-occurring intellectual dis-
ability seen in the mid-1990s, may reflect the increasing prevalence of ASD
among children with average, above-average, or borderline intellectual ability
compared with that of children with intellectual disability (Van Naarden
Braun et al. 2015).
In this chapter, we focus on the pharmacotherapy of ASD. The therapeu-
tic approach to the management of ASD is multimodal. Treatments must take
into account the global cognitive functioning of the individual, highlighting
the importance of educational interventions. In addition, many people with
ASD have delays in language development, thus making speech therapy es-
sential to improving outcomes. Occupational therapy, social skills training,
and physical therapy are also frequently necessary. Educating caregivers in be-
havioral management techniques can be very useful and may decrease the use
of pharmacotherapy in this population.
In addition to nonpharmacological approaches, medication is often re-
quired to treat co-occurring psychiatric diagnoses or behavioral concerns.
 Autism Spectrum Disorder 285

Such treatments can significantly improve the patient’s ability to benefit from
behavioral and educational interventions. Yet no medication carries expert
consensus as a treatment for the core symptoms of ASD. To date, risperidone
and aripiprazole are the only drugs with an FDA approval specifically for use
in populations with ASD in the treatment of irritability. Although no other
medications have obtained FDA approval for specific use in patients with
ASD, various drugs are used to treat interfering associated target symptoms in
this population. In this chapter, we present current evidence regarding the
pharmacotherapy of ASD (Table 7–1), review the adverse effects of the med-
ications used, and outline practical management strategies.

Atypical Antipsychotics
Research into the pharmacotherapy of ASD began in the 1960s with the typical
antipsychotics. Because of significant adverse effects associated with the low-
potency antipsychotics (e.g., chlorpromazine, thioridazine), the high-potency
antipsychotic haloperidol was systematically investigated in numerous well-
designed studies (Anderson et al. 1989; Campbell et al. 1978; Cohen et al.
1980). However, haloperidol’s potent dopamine D2 receptor antagonism fre-
quently led to acute dystonic reactions as well as drug-induced and withdrawal-
related dyskinesias (Campbell et al. 1997). Currently, the typical antipsychotics
as a whole are reserved for patients with severe treatment-resistant symptoms.
Concerns regarding the typical antipsychotics directed researchers toward
the development of the atypical antipsychotics. These drugs, with their profile
of potent antagonism at serotonin and dopamine receptors, have a purported
decreased risk of acute extrapyramidal symptoms (EPS) and tardive dyskinesia.

Clozapine
Clozapine is an antagonist at the serotonin 5-HT2A, 5-HT2C, and 5-HT3 re-
ceptors and the dopamine D1, D2, D3, and D4 receptors (Baldessarini and
Frankenburg 1991). Four case reports and one small retrospective study have
been published on the use of clozapine for irritability in ASD (defined as severe
tantrums, aggression, and self-injury) (Beherec et al. 2011; Chen et al. 2001;
Gobbi and Pulvirenti 2001; Lambrey et al. 2010; Zuddas et al. 1996). Over-
all, the lack of research on clozapine in patients with ASD is largely due to the
Table 7–1. Selected published double-blind, placebo-controlled trials in ASD

286 Clinical Manual of Child and Adolescent Psychopharmacology

Subjects
Age,
Drug Study N years Design Results Target symptom

Antipsychotics
Aripiprazole Marcus et al. 2009 218 6–17 8 weeks, parallel Aripiprazole > placebo (29/52 Irritability
groups responders [56%])
Owen et al. 2009 98 6–17 8 weeks, parallel Aripiprazole > placebo (24/46 Irritability
groups responders [52%])
Findling et al. 2014 85 6–17 16 weeks, parallel Aripiprazole = placebo Irritability
groups (extension (measuring rate of relapse)
study)
Haloperidol Anderson et al. 1989 45 2–7 12 weeks, crossover Haloperidol > placebo Hyperactivity,
irritability
Lurasidone Loebel et al. 2016 150 6–17 6 weeks parallel Lurasidone 20 mg/day = Irritability
groups lurasidone 60 mg/day =
placebo
Risperidone McDougle et al. 1998b 31 18–43 12 weeks, parallel Risperidone > placebo (8/14 Repetitive and
groups responders [57%]) aggressive behavior
McCracken et al. 2002 101 5–17 8 weeks, parallel Risperidone > placebo (34/49 Irritability
groups responders [69%])
Shea et al. 2004 79 5–12 8 weeks, parallel Risperidone > placebo (35/40 Irritability
groups responders [87%])
Table 7–1. Selected published double-blind, placebo-controlled trials in ASD (continued)

Subjects
Age,
Drug Study N years Design Results Target symptom

Risperidone Kent et al. 2013 96 5–17 6 weeks, parallel High-dose risperidone > Irritability
(continued) groups placebo; low-dose
risperidone = placebo
Serotonin reuptake inhibitors
Citalopram King et al. 2009 149 5–17 12 weeks, parallel Citalopram = placebo Repetitive behavior
groups
Clomipramine Gordon et al. 1993 24 6–23 10 weeks, crossover Clomipramine > placebo; Anger and obsessive-
clomipramine > compulsive behavior

Autism Spectrum Disorder

desipramine (19/28
responders [68%])
Remington et al. 2001 36 10–36 7 weeks, crossover Clomipramine > placebo Irritability, stereotypy
Fluoxetine Hollander et al. 2005 39 5–16 20 weeks, crossover Fluoxetine > placebo Repetitive behaviors
Hollander et al. 2012 37 18–60 12 weeks, parallel Fluoxetine > placebo Compulsive behavior
groups
Reddihough et al. 2019 109 7.5–18 16 weeks, parallel Fluoxetine = placebo Repetitive behavior
groups
Herscu et al. 2020 158 5–17 14 weeks, parallel Fluoxetine = placebo Repetitive behavior
groups

287
Table 7–1. Selected published double-blind, placebo-controlled trials in ASD (continued)

288 Clinical Manual of Child and Adolescent Psychopharmacology

Subjects
Age,
Drug Study N years Design Results Target symptom

Fluvoxamine McDougle et al. 1996a 30 18–53 12 weeks, parallel Fluvoxamine > placebo (8/15 Repetitive behavior
groups responders [53%])
McDougle et al. 2000 34 5–18 12 weeks, parallel Fluvoxamine = placebo Repetitive behavior
groups
Sugie et al. 2005 18 3–8 12 weeks, parallel Fluvoxamine > placebo Global improvement
groups

α2-Adrenergic agonists
Clonidine Jaselskis et al. 1992 8 5–13 14 weeks, crossover Clonidine > placebo by Inattention,
teacher and parent ratings impulsivity,
but not clinician ratings (6/ hyperactivity
8 responders [75%]
Clonidine Fankhauser et al. 1992 9 5–33 10 weeks, crossover Clonidine > placebo (6/9 Social relationships,
(transdermal) responders) [67%]) affectual and sensory
responses
Guanfacine ER Scahill et al. 2015 62 5–14 8 weeks, parallel Guanfacine ER > placebo Hyperactivity
groups (15/30 responders [50%])
Table 7–1. Selected published double-blind, placebo-controlled trials in ASD (continued)

Subjects
Age,
Drug Study N years Design Results Target symptom

Psychostimulants
Methylphenidate Quintana et al. 1995 10 7–11 4 weeks, crossover Methylphenidate > placebo Hyperactivity
Handen et al. 2000 13 5–11 3 weeks, crossover Methylphenidate > placebo Hyperactivity
(8/13 responders [62%])
Research Units on Pe- 72 5–14 4 weeks, crossover Methylphenidate > placebo Hyperactivity
diatric Psychophar- (35/72 responders [49%])
macology Autism
Network 2005a

Autism Spectrum Disorder

Selective norepinephrine reuptake inhibitors
Atomoxetine Harfterkamp et al. 97 6–17 8 weeks, parallel Atomoxetine > placebo (9/43 ADHD symptoms
2012 groups responders [20.9%])
Atomoxetine± Handen et al. 2015 128 5–14 10 weeks, parallel Atomoxetine = atomoxetine + ADHD symptoms
parent groups parent training > placebo
training
Note. ASD=autism spectrum disorder; ER=extended release.

289
290 Clinical Manual of Child and Adolescent Psychopharmacology

drug’s adverse effect profile. Its propensity to lower the seizure threshold is
troubling, particularly in a patient population that is predisposed to develop
seizures. In addition, individuals with cognitive limitations and an impaired
ability to communicate would have difficulty conveying information regard-
ing symptoms associated with agranulocytosis and tolerating frequent veni-
puncture.

Risperidone
Risperidone is FDA approved for the treatment of irritability in children and
adolescents ages 5–16 years with ASD. Risperidone has negligible affinities for
muscarinic receptors and high affinities for serotonin 5-HT1D, 5-HT2A, and
5-HT2C receptors; dopamine D2, D3, and D4 receptors; α1-adrenergic recep-
tors; and H1-histaminic receptors (Leysen et al. 1988). Several open-label
studies have demonstrated that risperidone effectively targets core and related
symptoms of ASD (Findling et al. 1997; Masi et al. 2001a; McDougle et al.
1997; Nicolson et al. 1998). The efficacy of risperidone was considered in a
12-week, double-blind, placebo-controlled study of irritability and repetitive
behaviors in adults with autism (n=17) or PDD-NOS (n=14) (McDougle et
al. 1998b). Of 14 subjects randomly assigned to risperidone (mean dosage
2.9 mg/day), 8 (57%) were deemed responders as measured by the Clinical
Global Impression–Improvement (CGI-I) subscale versus none in the placebo
group. The most common adverse effect was transient somnolence. Weight
gain was reported in only two of the subjects in the risperidone group.
The first double-blind, placebo-controlled study of risperidone in youth
with autism was conducted by the Research Units on Pediatric Psychophar-
macology (RUPP) Autism Network (McCracken et al. 2002). In this 8-week
study, 101 children and adolescents (mean age, 8.8 years) with target symp-
toms of tantrums, aggression, or self-injurious behavior were treated with
risperidone or placebo. Risperidone treatment at a mean dosage of 1.8 mg/
day (range, 0.5–3.5 mg/day) was found to reduce Aberrant Behavior Check-
list (ABC) Irritability subscale scores by 56.9% compared with a 14.1% re-
duction with placebo. Overall, 69% of risperidone-treated subjects were
judged responders compared with only 12% of those given placebo. Adverse
effects of risperidone compared with placebo included weight gain (mean,
2.7 kg vs. 0.8 kg), increased appetite, sedation, dizziness, and sialorrhea. Fur-
 Autism Spectrum Disorder 291

ther analyses revealed the medication to be significantly more effective than

placebo for reducing interfering stereotypic and repetitive behaviors (Mc-
Dougle et al. 2005).
The RUPP Autism Network subsequently published the results of a
risperidone open-label extension study. This 16-week study involved 63 of the
subjects whose symptoms responded to risperidone in the 8-week trial. The
mean risperidone dosage remained stable. Subjects in this study continued to
gain weight (mean, 5.1 kg over 24 weeks). Overall, only 8% discontinued the
drug because of loss of efficacy; one subject discontinued the drug because of
adverse effects (constipation). At the end of this phase, 32 subjects considered
responders were then randomly assigned either to continued risperidone or to
gradual substitution with placebo over a duration of 4 weeks. A statistically
significant difference in relapse rate was reported, with 10 of the 16 subjects
(62.5%) switched to placebo experiencing relapse versus 2 of the 16 (12.5%)
who continued risperidone (Research Units on Pediatric Psychopharmacol-
ogy Autism Network 2005b). A follow-up trial an average of 21 months later
reported that 84 of these subjects continued taking risperidone with ongoing
therapeutic benefit but also with persistent elevated appetite, weight gain, and
enuresis (Aman et al. 2015).
In a second double-blind, placebo-controlled study of risperidone for the
treatment of irritability in children and adolescents with PDDs, Shea et al.
(2004) randomly assigned 79 youth ages 5–12 years to risperidone at a mean
dosage of 1.2 mg/day or placebo over a duration of 8 weeks. Overall, 87% of
risperidone-treated subjects had improved CGI-I scores compared with 40%
of those given placebo. In addition, there was a 64% reduction in ABC Irri-
tability subscale scores for children given risperidone versus a 31% reduction
for those given placebo. Regarding adverse effects, weight gain was more com-
mon in the risperidone group than in the placebo group (2.7 kg vs. 1.0 kg), as
were increased sedation, heart rate, and systolic blood pressure.
A 6-week, double-blind, placebo-controlled study of risperidone in chil-
dren and adolescents ages 5–17 years with ASD examined the efficacy and
side effect profile of risperidone dosages less than 0.25 mg/day (Kent et al.
2013). The findings replicated the efficacy of higher dosages (1.25 mg/day
and 1.75 mg/day) in the treatment of irritability; however, the investigators
did not find efficacy at dosages below 0.25 mg/day.
292 Clinical Manual of Child and Adolescent Psychopharmacology

Olanzapine
Olanzapine has high affinity for the dopamine D1, D2, and D4 receptors;
serotonin 5-HT2A, 5-HT2C, and 5-HT3 receptors; α1-adrenergic receptors;
H1-histaminic receptors; and muscarinic receptors (Bymaster et al. 1996).
Olanzapine is reported to be beneficial in the treatment of irritability in ASD
according to case reports, open-label trials, and a small double-blind, placebo-
controlled trial (Hollander et al. 2006b; Malone et al. 2001; Potenza et al.
1999). However, significant weight gain and its possible associated metabolic
sequelae have restricted its use in this population. A small 8-week, double-
blind, placebo-controlled trial evaluated olanzapine in 11 youth ages 6–
14 years with PDD (Hollander et al. 2006b). At a mean dosage of 10 mg/day
(range, 7.5–12.5 mg/day), 3 of 6 subjects (50%) in the olanzapine group were
considered responders based on the CGI-I scale measure of global functioning
compared with 1 of 5 subjects (20%) in the placebo group. Olanzapine was as-
sociated with sedation and increased appetite as well as considerable weight
gain compared with placebo (3.4 kg±2.2 kg vs. 0.68 kg±0.68 kg).

Quetiapine
Quetiapine has affinity for the dopamine D1 and D2 receptors, the serotonin
5-HT2A and 5-HT1A receptors, and the histaminic H1 receptors (Arnt and
Skarsfeldt 1998). It has been studied in an uncontrolled fashion, with mixed
findings. A retrospective review of quetiapine was conducted with data for
patients in an outpatient autism clinic (Corson et al. 2004). Twenty patients
ages 5–28 years (mean, 12.1 years) were included in the study and received
quetiapine (mean dosage, 248.7 mg/day; range, 25–600 mg/day) over a mean
duration of 59.8 weeks (range, 4–180 weeks). Of the 20 patients, 8 (40%)
were considered responders to quetiapine based on results on the CGI-I scale
anchored to irritability and hyperactivity. Adverse effects were reported in
50% of the patients, and 15% subsequently discontinued quetiapine.
Three notable open-label trials have been conducted with varying results.
The first, a 16-week trial, involved six subjects (mean age, 10.9 years) (Martin
et al. 1999). Two participants who completed the trial were considered re-
sponders. Three withdrew because of sedation and lack of effectiveness, and
one dropped out after a possible seizure. Overall, no statistically significant im-
provement was reported. Findling et al. (2004) conducted a 12-week open-
 Autism Spectrum Disorder 293

label study of quetiapine (mean dosage, 292 mg/day; range, 100–400 mg/day)
in nine youth ages 12–17 years (mean, 14.6±2.3 years) with autism. Two pa-
tients (22%) experienced a response to treatment, as assessed with the CGI-I
anchored to global functioning. The most common adverse effects included
sedation, weight gain, and increased agitation. Golubchik et al. (2011) con-
ducted an 8-week open-label trial of low-dosage quetiapine (mean, 122 mg/
day) in 11 high-functioning adolescents ages 13–17 with ASD. Although only
a trend toward improvement in the CGI Severity subscale score was found, sig-
nificant reductions in aggression and sleep disturbances were reported. More-
over, tolerability was favorable compared with previous studies, with improved
rates of study completion and no significant change in body weight.

Ziprasidone
Ziprasidone is a potent antagonist at the dopamine D1 and D2 receptors and
the serotonin 5-HT2A and 5-HT2C receptors (Tandon et al. 1997). It is also a
5-HT1A receptor agonist that inhibits serotonin and norepinephrine reuptake.
In a case series of ziprasidone that included 12 youth ages 8–20 years (mean,
11.6 ±4.4 years) with autism (n=9) or PDD-NOS (n=3), 6 patients (50%)
experienced a response to ziprasidone at a mean dosage of 59.2 mg/day (range,
20–120 mg/day) over a duration of at least 6 weeks (McDougle et al. 2002).
Treatment resulted in improvement, as assessed with the CGI-I, in symptoms
of aggression, agitation, and irritability. The most common adverse effect was
transient sedation. The mean weight change was –2.6 kg (range, –16.1 kg to
+2.7 kg). No cardiovascular adverse effects were reported. Malone et al. (2007)
conducted a 6-week open-label study of ziprasidone for irritability in 12 youth
(mean age, 14.5 years; range, 12–18 years) with autism. Nine subjects (75%)
were judged treatment responders as assessed with the CGI-I. Ziprasidone
was associated with mild to moderate sedation, and dystonic reactions oc-
curred in two subjects. The authors reported that the medication was weight
neutral. Although the mean QTc interval seen on electrocardiograms (ECGs)
increased by 14.7 msec, the clinical significance of this finding was unclear.

Aripiprazole
Aripiprazole is FDA approved for the treatment of irritability in youth ages 6–
17 years with ASD. The drug is a partial dopamine D2 and serotonin 5-HT1A
294 Clinical Manual of Child and Adolescent Psychopharmacology

agonist and a serotonin 5-HT2A antagonist (Burris et al. 2002). A 14-week,

prospective, open-label study of aripiprazole for irritability was conducted in
25 children and adolescents with PDD-NOS and Asperger’s disorder (mean
age, 8.6 years; range, 5–17 years) (Stigler et al. 2009). Of the 25 study partic-
ipants, 22 (88%) were considered responders to aripiprazole at a mean dosage
of 7.8 mg/day (range, 2.5–15 mg/day), as assessed with the CGI-I and the ABC
Irritability subscale. Aripiprazole was well tolerated, with tiredness and weight
gain among the more commonly recorded adverse effects.
Two larger-scale controlled studies of aripiprazole were subsequently con-
ducted in children and adolescents with autism and associated irritability.
Marcus et al. (2009) conducted an 8-week double-blind, placebo-controlled,
fixed-dose study in 218 youth ages 6–17 years. Subjects were randomly assigned
to placebo or to aripiprazole (5 mg/day, 10 mg/day, or 15 mg/day). Improve-
ment in irritability was seen on the ABC Irritability subscale at all dosages. Ad-
verse effects included sedation, weight gain, and EPS, among others. Owen et
al. (2009) conducted an 8-week, double-blind, placebo-controlled trial of flex-
ibly dosed aripiprazole (2–15 mg/day) in 98 youth ages 6–17 years with autism.
They reported significant improvement in irritability, as demonstrated with
the CGI-I and the ABC Irritability subscale. Weight gain, drooling, tremor,
vomiting, and sedation were among the adverse effects recorded, with post hoc
analysis revealing higher mean increases in weight and rates of somnolence, se-
dation, and fatigue in antipsychotic-naive subjects (Mankoski et al. 2013).
The long-term safety and tolerability of aripiprazole (range, 2–15 mg/day)
for irritability in children and adolescents ages 6–17 years with autism was ex-
amined in a 52-week open-label, flexibly dosed study (Marcus et al. 2011b).
In addition to de novo subjects, patients from the aforementioned studies by
Marcus et al. (2009) and Owen et al. (2009) were eligible to enroll. Of the
300 participants, 199 (66%) completed 52 weeks of treatment. Common ad-
verse effects included weight gain, vomiting, and increased appetite, among
others. Efficacy, a secondary objective after safety and tolerability, was evalu-
ated using the CGI-I and the ABC Irritability subscale (Marcus et al. 2011a).
Concomitant psychotropic agents were permitted during the study (except
α2-adrenergic agonists, carbamazepine, oxcarbazepine, and other antipsy-
chotics). At end point, most subjects had a CGI-I score of “much improved”
or “very much improved.” The authors concluded that aripiprazole reduced
symptoms of irritability associated with autism in youth ages 6–17 years.
 Autism Spectrum Disorder 295

A separate blind, placebo-controlled study examined the efficacy of long-

term aripiprazole usage compared with placebo among children and adolescents
with autism whose symptoms had responded to short-term aripiprazole treat-
ment (Findling et al. 2014). An initial 157 subjects completed 13–26 weeks of
single-blinded aripiprazole treatment. Eighty-five subjects whose symptoms
responded to treatment, as defined by a change in ABC Irritability subscale and
CGI-I scores, were randomly assigned to blinded allocation to placebo or to on-
going aripiprazole treatment for 16 additional weeks (mean dosage at study
completion, 9.7 mg/day). No statistically significant differences in Kaplan-
Meier relapse rates were found between aripiprazole and placebo; however, a
post hoc analysis demonstrated a number needed to treat of 6 to prevent one
additional relapse, which the authors concluded signified that some patients
could benefit from maintenance treatment. The most significant common
long-term adverse events were upper respiratory tract infection (10.3%), con-
stipation (5.1%), and movement disorder (5.1%).
A more recent double-blind, placebo-controlled trial sought to compare
the efficacy and tolerability of risperidone and aripiprazole in children and ad-
olescents ages 6–17 years with ASD and significant irritability (DeVane et al.
2019). By the end of a 10-week, double-blind treatment phase, there was a
nonsignificant trend toward superiority for risperidone as measured using the
ABC Irritability subscale, and there were no differences in CGI-I scores. Effi-
cacy results between the two treatment arms were similar after an additional 12-
week open-label extension. Both groups demonstrated significant reductions in
ABC Irritability subscale and CGI-I scores compared with baseline. Mean
weight gain in the aripiprazole treatment arm was significantly less than that in
the risperidone group at 10 weeks (1.38 kg vs. 3.31 kg), but the difference be-
tween groups became nonsignificant for the 31 participants who completed the
12-week extension.

Paliperidone
Paliperidone (9-hydroxy-risperidone) is FDA approved for the treatment of
schizophrenia in adolescents ages 12–17 years. Stigler et al. (2012) evaluated
the effectiveness and tolerability of paliperidone for irritability in autism. In
this 8-week, prospective, open-label study, 21 of 25 subjects (84%) with autism
(mean age, 15.3 years; range, 12–21 years) were considered responders to pal-
iperidone (mean dosage, 7.1 mg/day; range, 3–12 mg/day), based on CGI-I
296 Clinical Manual of Child and Adolescent Psychopharmacology

and ABC Irritability subscale scores. Mean serum prolactin increased from
5.3 ng/mL (baseline) to 41.4 ng/mL (end point); however, no signs or symp-
toms associated with hyperprolactinemia were observed or reported. Weight
gain, sedation, and EPS were among the adverse effects reported.

Lurasidone
Lurasidone antagonizes dopamine D2 and serotonin 5-HT2A receptor systems
with high affinity and is FDA approved for the treatment of schizophrenia and
bipolar I depression in adults. Loebel et al. (2016) evaluated the effectiveness
and tolerability of lurasidone for irritability in ASD in a 6-week, double-
blind, placebo-controlled study of outpatients ages 6–17 years with ASD. The
study had three treatment arms: placebo (n = 51), lurasidone 20 mg/day
(n=50), and lurasidone 60 mg/day (n=49). By 6 weeks, there were no differ-
ences between either the 20-mg/day or 60-mg/day groups versus placebo on
the primary outcome measures of ABC Irritability subscale or CGI-I scores.
Vomiting and somnolence were the most common side effects. Subjects in the
60-mg/day treatment arm showed greater rates of weight gain compared with
placebo, but those in the 20-mg/day arm did not.

Metformin
Metformin hydrochloride is a biguanide medication that increases insulin
sensitivity and decreases intestinal glucose absorption and hepatic glucose
production. It is approved for the treatment of type 2 diabetes and has been
found to stop or reverse weight gain associated with antipsychotic medications
(Zheng et al. 2015). Anagnostou et al. (2016) published a 16-week, double-
blind, placebo-controlled study to evaluate the tolerability and efficacy of
metformin for weight gain rate reduction in 60 subjects ages 6–17 years with
ASD. Metformin was titrated up to 500 mg bid for children ages 6–9 years
and 850 mg bid for those ages 10–17 years. For subjects with weight gain as-
sociated with starting an atypical antipsychotic, metformin reduced rates of
BMI increase (z score) and weight gain compared with placebo. A small per-
centage of subjects (11%) taking metformin experienced a decrease in BMI of
8%–9%. A difference between treatment and placebo arms was not apparent
until after 8 weeks of treatment. Gastrointestinal adverse events were the most
common, and five subjects in the treatment arm discontinued due to adverse
 Autism Spectrum Disorder 297

events (agitation, n = 4; sedation, n = 1). A 16-week, open-label follow-up

study of the same participants found that improvements in the rate of weight
gain seen in the treatment arm were maintained but without additional de-
creases in BMI or weight (Handen et al. 2017).

Serotonin Reuptake Inhibitors

Research into the pathophysiology of ASD identified some abnormalities in
serotonergic system function. Schain and Freedman (1961) first reported on
elevated whole-blood levels of serotonin in children with autism compared with
control children. Additional reports have pointed to the possibility of abnormal
maturational processes of the serotonergic system in youth with autism, as ex-
hibited by a lack of age-related decline in blood levels of serotonin as seen in
typically developing subjects (Anderson et al. 1987; Leboyer et al. 1999).
Research into the genetic basis of a potential serotonergic abnormality in
autism has yielded mixed results. Some studies have noted nominally signifi-
cant excess transmission of alleles of the serotonin transporter gene, whereas
other studies have reported no excess transmission (Conroy et al. 2004).
Other evidence suggesting the potential utility of medications affecting
serotonin in patients with ASD comes from findings of an exacerbation of be-
havioral symptoms in medication-free adults with autism experiencing acute
dietary depletion of the serotonin precursor tryptophan (McDougle et al.
1996b).

Clomipramine
Clomipramine is a tricyclic antidepressant that potently inhibits serotonin
reuptake and affects norepinephrine and dopamine reuptake (Greist et al.
1995). Clomipramine is FDA approved for the treatment of OCD in youth
ages 10–17 years.
One open-label and two controlled studies have evaluated clomipramine in
patients with ASD. In a 12-week open-label trial of clomipramine (mean dos-
age, 139.4 ±50.4 mg/day) in 35 adults with PDDs, 18 of the 33 participants
(55%) who completed the trial were judged, based on their CGI-I scores, to
have a treatment response (Brodkin et al. 1997). Improvement in aggression,
self-injurious behavior, repetitive phenomena, and social relatedness was re-
298 Clinical Manual of Child and Adolescent Psychopharmacology

corded. Thirteen patients (39%) experienced significant adverse effects, in-

cluding seizures (n=3), weight gain, constipation, sedation, and agitation.
In another study, clomipramine (mean dosage, 152±56 mg/day) was shown
to be superior to the relatively selective norepinephrine reuptake inhibitor
desipramine (mean dosage, 127±52 mg/day) and to placebo in a 10-week, ran-
domized crossover study of 24 children with autism (mean age, 9.6 years)
(Gordon et al. 1993). Improvement with clomipramine was associated with
decreased anger and obsessive-compulsive symptoms. Adverse effects included
tachycardia, QTc interval prolongation, and a grand mal seizure in one subject.
Similar tolerability issues were noted by Remington et al. (2001) in their report
on a 7-week, double-blind, placebo-controlled trial of clomipramine (mean
dosage, 128 mg/day), haloperidol (mean dosage, 1.3 mg/day), and placebo in
36 patients ages 10–36 years with autism. Among patients who completed this
trial, clomipramine and haloperidol were similarly effective in reducing irrita-
bility and stereotypy. However, significantly fewer individuals receiving clo-
mipramine versus haloperidol were able to complete the trial (37.5% vs.
69.7%). Reasons for leaving the trial that were associated with clomipramine
included lack of efficacy and the emergence of adverse effects, among which se-
dation and tremor were most prevalent. Because of tolerability issues, the use of
clomipramine in patients with ASD remains limited.

Fluvoxamine
Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) FDA-approved
for use in children and adolescents ages 8–17 years with OCD. In a double-
blind, placebo-controlled study, fluvoxamine (mean dosage, 276.7 mg/day)
reduced repetitive and maladaptive behavior in 8 of 15 adults with autism
(53%) randomly assigned to the active drug (McDougle et al. 1996a). In these
adults, fluvoxamine was generally well tolerated, with adverse effects includ-
ing sedation and nausea. A double-blind, placebo-controlled study did not
find fluvoxamine (mean dosage, 107 mg/day) effective for repetitive behavior
in 34 children and adolescents with PDDs (McDougle et al. 2000). In these
younger patients, fluvoxamine was poorly tolerated, with 14 patients experienc-
ing adverse effects, including hyperactivity, insomnia, aggression, and agitation.
In an open-label report of 18 youth (mean age, 11.3 ±3.6 years) with PDDs
treated with low-dosage fluvoxamine (1.5 mg/kg/day) for 10 weeks, the drug
 Autism Spectrum Disorder 299

was similarly not associated with a significant treatment response (Martin et al.
2003). In a 12-week, double-blind, placebo-controlled crossover study of flu-
voxamine in 18 children with autism, Sugie et al. (2005) noted that 10 patients
(55%) had at least a mild treatment response, with 5 (28%) showing an excellent
drug response in terms of global improvement on the CGI-I scale. In this report,
fluvoxamine was generally well tolerated. Three children (17%) had to exit the
study due to behavioral activation. Overall, although findings are mixed, flu-
voxamine appears to be better tolerated in adults than in youth with ASD.

Fluoxetine
Fluoxetine is an SSRI that is FDA-approved in children and adolescents for
the treatment of OCD (ages 7–17 years) and major depressive disorder (ages
8–17 years). Two open-label trials and three small, placebo-controlled crossover
trials suggested fluoxetine may be effective for repetitive symptoms in patients
with autism (Buchsbaum et al. 2001; DeLong et al. 2002; Fatemi et al. 1998;
Hollander et al. 2005, 2012). Hollander et al. (2005) performed a 20-week,
placebo-controlled, crossover study of fluoxetine (mean dosage, 9.9 mg/day;
range 2.4–20 mg/day) in 39 children (mean age, 8.2 years) with PDDs. They
found that the medication performed significantly better than placebo in re-
ducing repetitive behaviors. No improvement in measures of speech or social in-
teraction was noted, and adverse effects were not significantly different between
fluoxetine and placebo. Moreover, Hollander et al. (2012) performed a trial of
fluoxetine among mostly higher-functioning adults with ASD (mean age,
34.3 years) in a 12-week, placebo-controlled study design. Similarly, subjects
receiving the active drug (mean dosage, 64.76 mg/day) showed statistically
significant reductions in compulsive behavior as measured by the Yale-Brown
Obsessive Compulsive Scale (Y-BOCS) and general improvement in repeti-
tive symptoms as measured with the CGI.
In contrast, the Study of Fluoxetine in Autism (SOFIA) study—a large-
scale, 14-week, double-blind, placebo-controlled study in 158 children and
adolescents ages 5–17 years with autism—determined that fluoxetine (dos-
age, 2–18 mg/day) was no more effective than placebo for repetitive behavior
(Herscu et al. 2020). Subjects with ASD in this larger study had, on average,
lower intellectual and adaptive functioning than those in the earlier Hollander
et al. (2012) trial. A 16-week, double-blind, placebo-controlled study (Reddi-
300 Clinical Manual of Child and Adolescent Psychopharmacology

hough et al. 2019) included 146 youth ages 7.5–18 years with ASD and ex-
amined fluoxetine for the treatment of repetitive behavior. Although the study
used higher dosages (20–30 mg) and included higher-functioning subjects
(only 30% with intellectual disability), the results were equivocal. At study
end point, the difference in change in Children’s Yale-Brown Obsessive Com-
pulsive Scale (CY-BOCS) PDD scores (3.72-point decrease in the fluoxetine
group vs. 2.53-point decrease in placebo group) became nonsignificant after
controlling for group differences. Moreover, there was no difference in CGI-I
scores between the treatment and placebo groups. In summary, results with
fluoxetine bear similarities to those with fluvoxamine, supporting a stronger
research basis for the use of SSRIs in adults with ASD than for youth with the
disorder.

Sertraline
To date, only open-label trials have described the use of the SSRI sertraline in
the treatment of ASD. Sertraline is approved for the treatment of OCD in chil-
dren ages 6–17 years. In a 12-week open-label study of 42 adults with PDDs,
McDougle et al. (1998a) found that sertraline (mean dosage, 122 mg/day) was
effective for reducing aggression and repetitive behavior. Participants with au-
tism and PDD-NOS showed significantly more improvement than did those
with Asperger’s disorder. The authors attributed this response to the possibility
that subjects with Asperger’s disorder had been less symptomatic at baseline.
Three patients (7%) dropped out of the study because of worsening agitation
and anxiety. An open-label trial of sertraline (25–50 mg/day for 2–8 weeks)
was conducted in nine children ages 6–12 years with autism (Steingard et al.
1997). Eight children (88%) showed improvement during the trial, manifest-
ing reduced irritability, anxiety, and need for sameness.

Paroxetine
The SSRI paroxetine has been the subject of a few uncontrolled reports in ASD.
Case reports have noted decreased irritable behavior associated with paroxetine
use in a 15-year-old boy with autism (Snead et al. 1994) and a 7-year-old boy
with autism (Posey et al. 1999). In a heterogeneous sample, 15 adults with in-
tellectual disability with or without a concomitant diagnosis of PDD received
16 weeks of open-label treatment with paroxetine (20–50 mg/day) (Davanzo
 Autism Spectrum Disorder 301

et al. 1998). The drug was associated with reduced aggression after 1 month
but not at the 4-month follow-up.

Citalopram
A 12-week, double-blind, placebo-controlled study of citalopram (mean dos-
age, 16.5±6.5 mg/day) for repetitive behavior was conducted in 149 children
and adolescents (mean age, 9.4 years; range, 5–17 years) with PDDs (King et al.
2009). In contrast to the positive preliminary findings of the retrospective stud-
ies, this large-scale controlled study found citalopram to be ineffective for repet-
itive behaviors. In addition, citalopram was more likely to be associated with
adverse effects, including increased energy level, impulsiveness, hyperactivity,
decreased concentration, stereotypy, and insomnia, among others.

Escitalopram
Escitalopram, the S-enantiomer of citalopram, is approved for the treatment of
major depressive disorder in adolescents ages 12–17 years. A 10-week open-
label study of escitalopram (mean dosage, 11.1 mg/day) in 28 youth (mean age,
10.4 years) with PDDs found that 17 (61%) were treatment responders, with
response defined as a 50% reduction in parent-rated ABC Irritability subscale
scores (Owley et al. 2005). A wide variety of dose response was noted, with
some participants unable to tolerate the medication at 10 mg/day and others
showing positive response at the lowest dosage of 2.5 mg/day.

Other Medications With Serotonergic Effects

Mirtazapine
Mirtazapine, a drug with both serotonergic and noradrenergic properties, was
evaluated in an open-label trial in patients with ASD (Posey et al. 2001).
Twenty-six subjects with ASD were given mirtazapine (range, 7.5–45 mg/day)
over a mean duration of 150 days. Nine patients (35%) were considered treat-
ment responders, as measured with the CGI-I, with reduced aggression, self-
injury, irritability, hyperactivity, anxiety, insomnia, and depression. No effect
on social relatedness or communication impairment was noted. Adverse effects
were considered mild and included increased appetite, irritability, and seda-
tion. A retrospective study investigated the effectiveness of mirtazapine (mean
dosage, 21.6 mg/day; range, 15–30 mg/day) for inappropriate sexual behavior
302 Clinical Manual of Child and Adolescent Psychopharmacology

(e.g., excessive masturbation) in 10 youth ages 5–16 years with autistic disor-
der (Coskun et al. 2009). Eight of the 10 patients were deemed by their CGI-I
scores as having “much improved” or “very much improved” in the symptom
of excessive masturbation. Increased appetite, weight gain, and sedation were
among the most frequently reported adverse effects.
A recent 10-week, double-blind, placebo-controlled pilot trial examined
mirtazapine for the treatment of anxiety in youth ages 5–17 years with ASD
(McDougle et al. 2022). Thirty subjects were randomly assigned to mirtazapine
(mean dosage, 41.8±5.2 mg) or placebo in a 2:1 ratio, with the CGI-I measur-
ing anxiety and the Pediatric Anxiety Rating Scale (PARS) as primary outcome
measures. A nonsignificant trend toward superiority of mirtazapine compared
with placebo was observed with the PARS (effect size, 0.63). For 47% of par-
ticipants assigned to mirtazapine, symptoms were considered much improved
(CGI-I=2) or very much improved (CGI-I=1) compared with 20% of those
assigned to placebo. No subjects withdrew due to adverse effects. Although
the most common side effects with mirtazapine were sedation/drowsiness, ap-
petite increase, and irritability, no statistically significant difference was found
in the frequency of adverse effects between the placebo and the active drug.
Although the results were not statistically significant, the authors concluded
that mirtazapine showed favorable tolerability and efficacy, which warrant
conducting a controlled trial of mirtazapine for anxiety in a larger population
of subjects with ASD.

Venlafaxine
Venlafaxine is a dual serotonin and norepinephrine reuptake inhibitor. Low-
dose venlafaxine (18.75 mg/day) was associated with decreased hyperactivity
and irritability in two adolescents and one young adult with autistic disorder
over 6 months of treatment (Carminati et al. 2006). A retrospective review of
10 children, adolescents, and young adults with ASD treated with venlafaxine
(6.25–50 mg/day) found that 6 (60%) were responders, as defined by the
CGI-I (Hollander et al. 2000). The medication was reportedly well tolerated,
and improvement in repetitive behaviors, socialization, communication, and
inattention was noted. One case report noted increased aggressive behavior
when venlafaxine (37.5 mg increased to 75 mg/day) was added to the treat-
ment regimen of an adolescent female with autistic disorder who was also tak-
ing a stable dosage of olanzapine (10 mg/day) (Marshall et al. 2003).
 Autism Spectrum Disorder 303

Buspirone
Buspirone is a serotonin 5-HT1A receptor partial agonist with FDA approval
for the treatment of generalized anxiety disorder in adults. Several case reports
and small open-label studies have reported on the effectiveness of buspirone in
patients with ASD. Larger open-label studies have generated conflicting re-
sults. An open-label study of buspirone (30–60 mg/day for 28–413 days)
found it to be ineffective in treating target symptoms, including aggression
and self-injury, in a sample of 26 adults with intellectual disability, which in-
cluded 9 patients with ASD (King and Davanzo 1996). In another open-label
study, however, 22 children and adolescents with ASD were treated with bus-
pirone (15–45 mg/day) for 6–8 weeks (Buitelaar et al. 1998). Nine patients
(41%) showed significant improvement as measured with the CGI-I, address-
ing target symptoms of anxiety and irritability. During a continuation phase
for treatment responders, one child developed an orofacial-lingual dyskinesia
after 10 months of treatment that remitted following drug discontinuation.
In an 8-week, randomized, double-blind, placebo-controlled trial of bus-
pirone in combination with risperidone in children and adolescents ages 4–
17 years with autistic disorder, investigators found that buspirone added to
risperidone was more effective than risperidone alone in the treatment of
ASD-related irritability (Ghanizadeh and Ayoobzadehshirazi 2015). Con-
comitant medications were allowed as long as they were stable for the study
duration. A total of 40 subjects participated in the study, and the target dos-
ages of risperidone were 2 mg/day for subjects weighing less than 40 kg and
3 mg/day for those weighing more than 40 kg. The target dosages of buspi-
rone were 10 mg/day for subjects weighing less than 40 kg and 20 mg/day for
those weighing more than 40 kg. Both medications reached the target dosage
by week 2 and could be modified afterward based on efficacy and side effects;
dosages could not exceed the targets set. A positive response was defined as a
25% or greater decrease in ABC Irritability subscale score. The results showed
that 81.2% of subjects in the buspirone group were classified as responders
compared with 44.4% in the placebo group. The mean risperidone dosage be-
tween groups was not statistically different. Side effects were most common in
the buspirone group and included increased appetite, drowsiness, and fatigue.
Both appetite increase and decrease and dry mouth were reported in the pla-
cebo group (Ghanizadeh and Ayoobzadehshirazi 2015).
304 Clinical Manual of Child and Adolescent Psychopharmacology

A larger double-blind, placebo-controlled study of low-dose buspirone in

young children with ASD examined the drug’s effect in reducing core symp-
toms of autism (Chugani et al. 2016). The 166-subject trial was conducted in
children ages 2–6 years with ASD over 48 weeks of treatment, with the Au-
tism Diagnostic Observation Schedule (ADOS) as the primary outcome mea-
sure. No significant differences were seen in total ADOS score between the
placebo and treatment arms, and there were no significant differences in ad-
verse events between the placebo group and the 2.5-mg-bid and 5-mg-bid
groups. A decrease in the ADOS restricted repetitive behaviors subcategory
was seen in the 2.5-mg-bid group compared with the placebo and the 5-mg-
bid groups. However, the authors acknowledged limitations in the use of the
ADOS as an outcome measure for autism severity. Further trials exploring the
use of buspirone for repetitive behaviors in ASD are required.

Psychostimulants
Psychostimulants are considered first-line agents for the treatment of hyper-
activity and inattention in patients diagnosed with ADHD (Greenhill et al.
2002b). Whereas some preliminary research concluded that stimulants were
generally ineffective and associated with adverse effects in patients with autis-
tic disorder (Aman 1982; Campbell 1975; Stigler et al. 2004a), other trials
have suggested that they may be effective in this population. Methylphenidate is
FDA-approved for the treatment of ADHD in children and adolescents ages 6–
17 years. A double-blind, crossover study (2-week treatment phases) of methyl-
phenidate (10 mg or 20 mg bid) was conducted in 10 children ages 7–11 years
with autistic disorder (Quintana et al. 1995). Overall, a modest benefit of
methylphenidate treatment over placebo was found. Adverse effects included
insomnia, irritability, and decreased appetite. Another double-blind, placebo-
controlled crossover study of methylphenidate (0.3 mg/kg/day and 0.6 mg/kg/
day) found a 50% reduction in the Conners’ Hyperactivity Index scores in 8 of
13 children (62%) ages 5–11 years with autistic disorder (Handen et al. 2000).
Adverse effects, which were more common with the 0.6-mg/kg/day dosage,
included social withdrawal and irritability.
The RUPP Autism Network completed the largest controlled trial of a psy-
chostimulant in patients with ASD to date. This study involved 72 youth ages
5–14 years with target symptoms of moderate to severe hyperactivity. Subjects
 Autism Spectrum Disorder 305

entered a 1-week test-dosage phase in which placebo and three doses (low, me-
dium, and high) of methylphenidate were administered. The 66 subjects who
tolerated the test-dosage phase received 1 week each of placebo and methyl-
phenidate at three different dosages in random order during a 4-week, double-
blind, crossover phase. Those whose symptoms responded to methylphenidate
then entered an 8-week open-label phase. Overall, 35 of 72 enrolled subjects
(49%) experienced a response to methylphenidate. Discontinuation of study
medication due to adverse effects occurred in 13 of 72 subjects (18%) (Research
Units on Pediatric Psychopharmacology Autism Network 2005a). These re-
sults are consistent with the findings of a smaller study of methylphenidate in
13 youth with ASD (Di Martino et al. 2004) in which five participants devel-
oped increased hyperactivity, stereotypy, dysphoria, or tics within 1 hour of a
single test dose (0.4 mg/kg) and were unable to tolerate the medication. Symp-
toms in six of the remaining eight subjects responded to the methylphenidate,
resulting in an overall response rate of 46%.
In contrast with these findings, data from the National Institute of Mental
Health Multimodal Treatment of ADHD (MTA) study showed that 69% of
typically developing youth with ADHD experienced a response to methylphe-
nidate treatment, with only 1.4% discontinuing due to adverse effects (Green-
hill et al. 2002a). Methylphenidate is less effective and is associated with more
frequent adverse effects in youth with ASD and ADHD than in typically devel-
oping youth with ADHD. A within-subjects crossover, double-blind, placebo-
controlled study of three different dosages (low, 0.21 mg/kg; medium, 0.35 mg/
kg; and high, 0.48 mg/kg) of extended-release methylphenidate was published
in 2013 (Pearson et al. 2013). The specific extended-release formulation used
mimicked twice-daily dosing, with a morning dose of extended-release methyl-
phenidate that was combined with a dose of immediate-release methylpheni-
date in the afternoon. This study included 24 school-age children (mean age,
8.8±1.7 years; mean IQ, 85±16.8) with ASD. In the double-blind phase, sub-
jects were given 1 week at each dosage level, including placebo. Decreases in hy-
peractivity and impulsivity based on parent and teacher measures were found
at both the high and medium dosage levels. Teachers were able to detect a small
difference with the lower dosage. Reduction in oppositional behavior and im-
provement in social skills were also found on parent measures. The side effect
profile of the long-acting stimulant preparation was similar to the immediate-
release formulation, with trouble sleeping and appetite changes being the pre-
306 Clinical Manual of Child and Adolescent Psychopharmacology

dominant side effects. Of note, no significant increase in irritability, repetitive

behavior, or repetitive language was observed in this study. In a follow-up study
completed with the same cohort, extended-release methylphenidate demon-
strated improvements in cognitive performance, specifically in the areas of sus-
tained attention, impulsivity/inhibition, and selective attention (Pearson et al.
2020).
Kim et al. (2017) completed a 6-week pilot study with 27 children ages 5–
15 years with ASD and ADHD to examine the dose-effect response to long-
acting liquid methylphenidate. Initially, participants were randomly assigned
to one of three dosage groups: very low (5–10 mg/day), low (5–20 mg/day), and
moderate (5–40 mg/day). Because the maximum tolerated dosage was 20 mg/
day in all but two participants in the moderate-dosage group, that and the low-
dosage group were combined and renamed the medium-dosage group. The
ADHD Rating Scale was administered by a blinded clinician, and the scores
showed a significant linear downward trend in both dosage groups. By the end
of week 6, the CGI-I score was “much improved” or “very much improved” in
83% of the medium-dosage group compared with 33% of the low-dosage
group. The medium-dosage group also displayed improvement in all five sub-
scales of the ABC, a secondary measure. No serious adverse events were re-
ported in this study. In the medium-dosage group, aggression, irritability, and
end-of-the-day rebound decreased from baseline.

Other Drug Treatments for ADHD

Clonidine
Clonidine is an α2-adrenergic agonist, and its extended-release formulation
(clonidine ER) has been FDA approved for the treatment of ADHD in chil-
dren and adolescents ages 6–17 years. Clonidine has been evaluated in two
small controlled trials involving youth with autism/autistic disorder. A double-
blind, placebo-controlled, crossover trial (6-week treatment periods) of clon-
idine (4–10 μg/kg/day) was conducted in eight young males with autism (mean
age, 8.1 years) with symptoms of inattention, impulsivity, and hyperactivity
(Jaselskis et al. 1992). The drug was associated with decreased hyperactivity
and irritability on teacher and parent ratings, but no treatment-associated dif-
ferences on clinician ratings were found. Adverse effects of clonidine included
 Autism Spectrum Disorder 307

hypotension, sedation, and irritability. Transdermal clonidine (5 μg/kg/day)

was evaluated in a double-blind, placebo-controlled, crossover study (4-week
treatment phases) involving nine males ages 5–33 years with autistic disorder
(Fankhauser et al. 1992). Significant improvement in hyperactivity and anx-
iety was recorded. The most commonly reported adverse effects were sedation
and fatigue. To date, no studies of effectiveness of clonidine ER specifically in
individuals with ASD have been published.

Guanfacine
Guanfacine is an α2-adrenergic agonist, and its extended-release formulation
(guanfacine ER) is FDA-approved for the treatment of ADHD in youth ages
6–17 years. Preliminary research suggested that guanfacine may be well toler-
ated and beneficial for hyperactivity symptoms in children and adolescents
with ASD (Posey et al. 2004b). A prospective, open-label trial was conducted
in 25 youth (mean age, 9 years; range, 5–14 years) with autism and hyperac-
tivity whose symptoms had previously not responded to methylphenidate
(Scahill et al. 2006). In this study, 48% of patients showed improvement in
hyperactivity at total daily doses of 1–3 mg. Decreased frustration tolerance
and tearfulness led three patients to discontinue the study. A small double-
blind, placebo-controlled trial of guanfacine was completed in 11 children with
hyperactivity and intellectual disability and/or autism (Handen et al. 2008).
Forty-five percent of participants had a significant reduction in hyperactivity.
The most common adverse effects included increased irritability and drowsi-
ness. To date, one case report of guanfacine ER in patients with autism/ASD has
been published (Blankenship et al. 2011). The authors found improvement in
inattention, hyperactivity, and impulsivity in two patients (ages 4 and 9 years)
at total daily dosages of 2–3 mg. Adverse effects included sedation and reduced
blood pressure. An 8-week, randomized, double-blind, placebo-controlled trial
of guanfacine ER was conducted in 62 youth (mean age, 8.5±2.5 years) with
ASD (Scahill et al. 2015). Subjects were classified as positive responders if
their CGI-I score was “much improved” or “very much improved.” Fifty percent
of participants in the guanfacine ER group were classified as responders com-
pared with 9.4% of the placebo group. The guanfacine ER group also exhibited
significant improvement compared with the placebo group on the ABC Hyper-
activity subscale. The maximum dosage of guanfacine ER was 3 mg/day for par-
308 Clinical Manual of Child and Adolescent Psychopharmacology

ticipants weighing less than 25 kg and 4 mg/day for those weighing more than
25 kg. The dosage schedule was not fixed, and dosages could be adjusted to
manage side effects. With the exception of stable doses of antiepileptic medica-
tions, no other medications were allowed in this study. Sedation, fatigue, and
decreased appetite were the most common side effects. Blood pressure was
lower than baseline in the guanfacine ER group for approximately 4 weeks and
returned to nearly baseline values by week 8. No clinically significant ECG
changes were observed in this study.

Atomoxetine
The selective norepinephrine reuptake inhibitor atomoxetine is approved for
the treatment of youth ages 6–17 years with ADHD. Results of two open-label
studies suggested that the drug may decrease symptoms of motor hyperactiv-
ity and inattention in less severely affected children and adolescents with
ASD (Posey et al. 2006; Troost et al. 2006). In the study by Posey et al. (2006),
16 youth ages 6–14 years with autism received atomoxetine at a mean dosage
of 1.2 mg/kg/day. Of these 16 subjects, 12 (75%) were deemed responders.
The medication was well tolerated, aside from two patients who discontinued
due to irritability. A 10-week open-label study of atomoxetine (mean dosage,
1.2 mg/kg/day) was conducted in 12 youth with ASD (Troost et al. 2006). Al-
though treatment led to a 44% reduction in ADHD symptoms, five subjects
(42%) discontinued the study due to adverse effects such as irritability, nausea,
and anxiety. A placebo-controlled, crossover pilot study of atomoxetine was
completed in 16 youth ages 5–15 years with autism and hyperactivity (Arnold
et al. 2006). Of the 16 participants, 9 (56%) demonstrated a significant reduc-
tion in symptoms of hyperactivity. One patient was rehospitalized for recurrent
irritability on the drug. Upper gastrointestinal symptoms and fatigue were the
most frequently reported adverse effects. A randomized 8-week, double-blind,
placebo-controlled study of atomoxetine for ADHD symptoms in children
with ASD demonstrated a moderate improvement in ADHD symptoms. There
were a total of 97 subjects in the study, with an age range of 6–17 years. All had
an IQ of at least 60. Dosages were titrated up over a 3-week period to atom-
oxetine 1.2 mg/kg/day or placebo. After 8 weeks of treatment, ADHD Rating
Scale total and subscale scores improved significantly in the atomoxetine group,
and the mean Conners’ Teacher Rating Scale hyperactivity score decreased sig-
nificantly. No serious adverse events were reported, and nausea, decreased ap-
 Autism Spectrum Disorder 309

petite, headache, and fatigue were the most common side effects. One subject
in the atomoxetine group discontinued the trial secondary to fatigue.
As has been seen with other medication trials for ADHD symptoms in
subjects with ASD, lower rates of response to treatment were observed com-
pared with similar trials in more typically developing subjects with ADHD
alone. The studies of typically developing children with ADHD found no dif-
ference between improvement in hyperactivity and improvement in inatten-
tion with atomoxetine, whereas the study of children with ASD and ADHD
found greater improvement in hyperactivity over inattention (Harfterkamp et
al. 2012). No beneficial effect was observed in social interaction. There were,
however, some signs of beneficial effects of atomoxetine in regard to inappro-
priate speech, fear of change, and stereotypies. Eighty-eight subjects (42 in the
atomoxetine group and 46 who initially received placebo) were followed for
an additional 20 weeks in an open-label extension phase (Harfterkamp et al.
2014). No drug-related serious adverse events occurred during this phase. Sub-
jects in this phase demonstrated continued improvement in ADHD symptoms
as well as subsiding adverse effects (Harfterkamp et al. 2014).
Combining non-drug interventions with psychopharmacology is a com-
mon question of interest in many psychiatric disorders, including ADHD. In a
10-week, randomized, double-blind placebo-controlled study, adding parent
training to atomoxetine did not result in a statistically significant improvement
in response rate versus drug alone. The study had 128 subjects ages 5–14 years;
99 completed the study. Responders were characterized by a CGI-I score of 2
or less and a decrease in Swanson, Nolan, and Pelham (SNAP) Teacher and
Parent Rating Scale score of 30 or more. The results showed that 45.2% of sub-
jects in the atomoxetine group were classified as responders compared with
46.9% in the combined treatment group. This difference was not statistically
significant. Although adding parent training to atomoxetine did not result in a
significant difference compared with atomoxetine alone, parent training alone
was significantly better than placebo. Atomoxetine was well tolerated; however,
complaints of abdominal pain and decreased appetite were significantly higher
in the atomoxetine group (Handen et al. 2015). At the end of a 24-week open-
label extension of this study, 68% of responders originally in the atomoxetine
group continued to meet response criteria. Subjects who participated in the
open-label trial were more likely to be considered responders with a combina-
tion of parent therapy and atomoxetine (Smith et al. 2016). At 1.5 years, most
310 Clinical Manual of Child and Adolescent Psychopharmacology

of the subjects retained their 34-week improvement; only 34% were still taking
atomoxetine, 27% were taking stimulants, and 25% were taking no medica-
tion (Arnold et al. 2018).

Mood Stabilizers
Valproic Acid
The mood stabilizer and antiepileptic drug valproic acid (divalproex sodium)
has been investigated in open-label and double-blind, placebo-controlled
studies in individuals with autism (Hellings et al. 2005; Hollander et al. 2001,
2006a, 2010).
An 8-week, double-blind, placebo-controlled study of valproic acid
(mean blood level, 77.8 μg/mL at 8 weeks) was conducted in 30 youth ages 6–
20 years with autism and significant aggressive behavior (Hellings et al.
2005). In this trial, treatment was not associated with significant improve-
ment in irritability as measured by the ABC Irritability subscale or in global
symptoms as measured with the CGI-I. One participant developed a rash,
which remitted following drug discontinuation, and two others developed el-
evated serum ammonia. In an 8-week, double-blind, placebo-controlled trial
of valproic acid in 13 youth with autism and interfering repetitive behaviors,
treatment was associated with a significant reduction in repetitive phenomena
as measured with the CY-BOCS (Hollander et al. 2006a). Overall, the med-
ication was well tolerated. A 12-week, double-blind, placebo-controlled study
of valproic acid was completed in 27 youth ages 5–15 years with ASD and ir-
ritability (Hollander et al. 2010). The authors reported that 62.5% of the val-
proic acid group experienced a response to treatment versus 9% of the placebo
group (mean blood level, 89.8 μg/mL for responders vs. 64.3 μg/mL for non-
responders). Irritability, insomnia, headache, and weight gain were among the
adverse effects reported.

Lithium
Lithium is a mood stabilizer that is FDA-approved for the treatment of bipolar
disorder in youth ages 12–17 years. Three case reports have described the use of
lithium in patients with ASD. Two reports have noted reduced manic-like
symptoms in individuals with ASD and a family history of bipolar disorder
 Autism Spectrum Disorder 311

(Kerbeshian et al. 1987; Steingard and Biederman 1987). A single report of

lithium augmentation of fluvoxamine in an adult with autistic disorder noted
improvement in symptoms of aggression and irritability after 2 weeks of treat-
ment, as measured with the CGI-I (Epperson et al. 1994). A retrospective
chart review was conducted in 30 psychiatrically hospitalized subjects with ASD
who were prescribed lithium for mood disorder and/or irritability (Siegel et al.
2014). The mean age of this sample was 13.6 years, and 53.3% of the subjects
had a full-scale IQ of less than 70. Overall, 43% of participants demonstrated
improvement based on a CGI-I score of 1 or 2. A greater effect was noted
when at least two pretreatment mood symptoms were present, especially mania
and euphoria/elevated mood. The mean lithium blood level was 0.70 mEq/L.
Improved status on the CGI-I did not correlate with lithium blood levels.
Most study participants were also taking other psychotropic medications, and
all had a history of exposure to atypical antipsychotics. The average length of
treatment was 29.7 days. A high rate of side effects (47%) was reported, with the
most common being vomiting (13%), tremor (10%), fatigue (10%), irritabil-
ity (7%), and enuresis (7%) (Siegel et al. 2014).

Lamotrigine
Lamotrigine is an anticonvulsant and mood stabilizer that attenuates some
forms of glutamate release via inhibition of sodium, calcium, and potassium
channels. The use of lamotrigine (mean dosage, 4.5 mg/kg/day) over a mean
duration of 14 months was described in 13 children ages 3–13 years with autism
and intractable epilepsy (Uvebrant and Bauzienè 1994). Eight subjects (62%)
showed a decrease in autism symptoms. Adverse effects included sleep distur-
bance and rash. In a 4-week, double-blind, placebo-controlled trial of lamotrig-
ine (5 mg/kg/day) in 14 children ages 3–11 years with autistic disorder, Belsito
et al. (2001) reported no treatment-associated benefit as measured by the ABC,
Childhood Autism Rating Scale, and Pre-Linguistic Autism Diagnostic Ob-
servation Scale. Insomnia and hyperactivity were the most common side ef-
fects reported.

Levetiracetam
Levetiracetam is an anticonvulsant with inhibitory and neuroprotective prop-
erties. A 10-week, double-blind, placebo-controlled trial of the drug (mean
312 Clinical Manual of Child and Adolescent Psychopharmacology

dosage, 862.5 mg/day; range, 500–1,250 mg/day) was conducted in 20 youth

ages 5–17 years with ASD (Wasserman et al. 2006). No significant difference
was found between levetiracetam and placebo on global measures of autism or
on measures of irritability, affective instability, and repetitive behavior. Over-
all, the drug was well tolerated, with mild agitation, aggression, and hyperac-
tivity among the adverse effects reported.

Cholinesterase Inhibitors
Donepezil
The cholinesterase inhibitor donepezil has been evaluated in two open-label
reports in patients with ASD. Improved speech was noted in 25 young males
(mean age, 6.6 years) given donepezil (2.5 mg/day or 5 mg/day) over 12 weeks
of open-label treatment (Chez et al. 2000). No improvement in social relat-
edness was noted. Adverse effects included aggression, irritability, sedation,
and sleep disturbance. In a retrospective review of open-label donepezil add-
on treatment (mean dosage, 9.4±1.8 mg/day), Hardan and Handen (2002)
reported that four of eight patients (50%) ages 7–19 years with autistic disor-
der who were taking other psychotropic medications experienced a positive re-
sponse to treatment as measured with the CGI-I. In addition, scores decreased
on the Hyperactivity and Irritability subscales of the ABC. In this study, do-
nepezil was generally well tolerated, with one patient developing nausea and
vomiting and one patient reporting mild irritability. Handen et al. (2011) in-
vestigated the efficacy and tolerability of donepezil on executive functioning
in 34 patients ages 8–17 years with autism. The study involved a 10-week, dou-
ble-blind, placebo-controlled trial of donepezil (5 mg/day and 10 mg/day),
followed by a 10-week open-label trial for placebo nonresponders. No signif-
icant differences were found between donepezil and placebo on measures of
executive functioning. Mild adverse effects associated with the drug included
diarrhea, headache, and fatigue.

Rivastigmine
The cholinesterase inhibitor rivastigmine was evaluated in a 12-week open-
label trial in 32 participants with autistic disorder (Chez et al. 2004). Im-
 Autism Spectrum Disorder 313

provement with treatment was noted in expressive speech and overall autistic
behavior using standardized measures.

Galantamine
Galantamine is a cholinesterase inhibitor and nicotinic receptor modulator. A
12-week open-label trial (mean dosage, 18.4 mg/day; range, 12–24 mg/day)
was conducted in 13 youth ages 4–17 years with autistic disorder (Nicolson et
al. 2006). The medication was well tolerated and considered beneficial for re-
ducing symptoms of aggression, behavioral dyscontrol, and inattention. A 10-
week, randomized, double-blind, placebo-controlled, parallel-groups study of
galantamine in combination with risperidone in 40 children ages 4–12 years
with ASD was published in 2014 (Ghaleiha et al. 2014). Compared with pla-
cebo, the group that received galantamine demonstrated improvement in the
ABC Irritability and Lethargy/Social Withdrawal subscale scores. No signifi-
cant differences in side effects between groups were reported (Ghaleiha et al.
2014).

Glutamatergic Agents
Amantadine
Amantadine, a compound used to treat influenza, herpes zoster, and Parkinson’s
disease, has known noncompetitive N-methyl-D-aspartate (NMDA) antago-
nist activity (Kornhuber et al. 1994). In one 4-week, double-blind, placebo-
controlled trial in 39 youth ages 5–19 years with autistic disorder, amantadine
(final dosage, 5 mg/kg/day) was associated with improved clinician ratings in
the domains of hyperactivity and inappropriate speech on the ABC (King et al.
2001). No significant treatment-associated improvements were noted on par-
ent ratings. The medication was reportedly well tolerated. A double-blind,
placebo-controlled study using amantadine in conjunction with risperidone
in 40 children ages 4–12 years with ASD demonstrated a beneficial effect in
terms of hyperactivity and irritability as well as overall general improvement
with amantadine (100–150 mg bid) compared with placebo. No significant
differences in adverse effects between groups were seen (Mohammadi et al.
2013).
314 Clinical Manual of Child and Adolescent Psychopharmacology

Memantine
Memantine is an uncompetitive NMDA antagonist used in the treatment of
Alzheimer’s disease. Initial open-label studies suggested improvement in social
behavior and other core symptoms of autism (Chez et al. 2007) as well as in ir-
ritability, hyperactivity, and memory (Owley et al. 2006). Despite these prom-
ising findings, larger double-blind, placebo-controlled trials examining the
extended-release formulation (memantine ER) for social impairment in ASD
have failed to show differences from placebo (Aman et al. 2017; Hardan et al.
2019). These trials have used the Social Responsiveness Scale (SRS) as a pri-
mary outcome measure and employed multiple trial designs, including a 12-
week randomized, placebo-controlled, open-label extension and a randomized
treatment withdrawal. More than 1,000 youth ages 6–12 years with ASD par-
ticipated in the trials. Secondary measures including the ABC for children and
the CGI-I also failed to show significant differences between the placebo and
treatment groups. High placebo responses on the SRS were noted. Within the
12-week trial and the 48-week open-label extension, irritability was the most
common treatment-emergent adverse effect (6.7% in the treatment group vs.
3.3% in the placebo group).

D-Cycloserine

D-Cycloserine is an antibiotic traditionally used to treat tuberculosis. It is also

an NMDA partial agonist shown to reduce the negative symptoms associated
with schizophrenia (Goff et al. 1999). Ten medication-free patients with autis-
tic disorder (mean age, 10±7.7 years) participated in an 8-week trial that began
with a 2-week placebo lead-in phase followed by 2 weeks at each of three dos-
ages: 0.7 mg/kg/day, 1.4 mg/kg/day, and 2.8 mg/kg/day (Posey et al. 2004a).
D-Cycloserine was associated with improvement on the CGI-I and the Social
Withdrawal subscale of the ABC. Four participants (40%) were considered
responders based on CGI-I ratings of “much improved.” Two patients (20%)
had to drop out of the study due to development of a transient motor tic and
increased echolalia, respectively. In a 10-week randomized, double-blind trial
conducted by Urbano et al. (2014, 2015), 20 adolescents with ASD were ran-
domly assigned to D-cycloserine, either 50 mg/day or 50 mg/week. Mean ages
of participants were 17.9 years (SD 2.51) and 17.3 years (SD 2.83) for the daily-
dose and weekly-dose groups, respectively. The groups received D-cycloserine
 Autism Spectrum Disorder 315

for 8 weeks and were followed up for 2 weeks afterward for a total of 10 weeks.
Participants were not required to stop all other psychiatric medications; how-
ever, those medications had to be maintained at their current dosage for the
duration of the trial. A 37% decrease in the ABC Stereotypy subscale score
was found (Urbano et al. 2014). Significant improvement was also seen on
both the SRS and the ABC Social Withdrawal/Lethargy subscale (Urbano et
al. 2015). There was no significant difference related to whether the dose was
given on a daily or weekly basis.

N-Acetylcysteine
N-Acetylcysteine (NAC) is a prodrug of cysteine used as a treatment for acet-
aminophen overdose–induced liver injury. It acts to inhibit the vesicular release
of glutamate through a complex mechanism mediated via the cellular uptake of
cystine, a byproduct of oxidized cysteine. This mechanism reduces glutamater-
gic neurotransmission, which is proposed to address the excitatory-inhibitory
imbalances in glutamate, as well as oxidative stress, that are hypothesized to un-
derlie some forms of ASD. A randomized, double-blind, controlled pilot trial
of oral NAC was conducted by Hardan et al. (2012) to examine its effect in re-
ducing irritability in children ages 3.2–10.7 years with autism. Thirty-three
participants were randomly assigned 1:1 to 12 weeks of NAC and uptitrated
to 900 mg tid or to placebo, with the ABC Irritability subscale as the primary
outcome measure. NAC treatment significantly improved irritability com-
pared with placebo (F=6.80; P<0.001; d=0.96), whereas secondary measures of
core symptoms of ASD showed no differences. In contrast, a more recent ran-
domized, double-blind, placebo-controlled trial of 31 youth ages 4–12 years
with ASD failed to find a difference between placebo and NAC over 12 weeks
on measures of irritability using the ABC Irritability subscale (Wink et al.
2016). This more recent study used the CGI-I anchored to core social impair-
ment as the primary outcome, with the SRS, ABC, and Vineland Adaptive
Behavioral Scales, Second Edition, as secondary outcome measures. No sig-
nificant differences between the placebo and NAC groups were observed on
any of the outcome measures. The average daily dose of NAC at the conclu-
sion of the trial was 56.2±9.7 mg/kg. Although efficacy results of NAC use in
ASD have been mixed, both trials suggested good tolerability. Gastrointestinal
side effects (nausea, vomiting, and diarrhea) were most common in the 2012
316 Clinical Manual of Child and Adolescent Psychopharmacology

trial, whereas upper respiratory symptoms, headache, and stomachache were

most common in the 2016 trial.

Other Compounds
β-Adrenergic Antagonists
β-Adrenergic blockers block norepinephrine receptors, thus limiting norepi-
nephrine neurotransmission. Eight hospitalized adults with autistic disorder
were described as having improved speech and socialization following open-
label treatment with propranolol or nadolol (mean dosage, 225 mg/day over
14.2 months) (Ratey et al. 1987). All patients showed a marked decrease in
aggression. Six patients (75%) demonstrated improvement in social skills, and
four (50%) developed improved speech during treatment. Seven patients were
taking concomitant antipsychotics, with five able to decrease and one able to
discontinue the antipsychotic during the trial. The investigators thought the
improvement noted was due to decreased hyperarousal. A 13-year-old male
patient with severe ASD and impairing hypersexual behaviors that occurred
across settings and were unresponsive to behavioral interventions was given
propranolol 10 mg bid (0.3 mg/kg/day) to target the hypersexual behaviors
(Deepmala and Agrawal 2014). Improvement was noticed as early as 2 weeks
after starting treatment. His hypersexual behaviors subsequently increased
when the medication was discontinued due to an unfilled prescription, and
they improved when it was resumed. Of note, this patient was taking risperi-
done (1.5 mg bid) concomitantly. At the time of the case report, he had been
taking propranolol for 1 year at the same dosage with no adverse effects.

Naltrexone
The opiate receptor antagonist naltrexone has been evaluated in four con-
trolled studies in patients with autism. This research was stimulated by findings
of elevated endorphin levels in the blood (Weizman et al. 1984) and cerebro-
spinal fluid (Gillberg et al. 1985; Ross et al. 1987) of individuals with autism.
Although the initial reports were promising, subsequent larger, double-blind,
placebo-controlled studies did not demonstrate significant efficacy regarding
core or associated symptoms of autism (Campbell et al. 1993; Feldman et al.
1999; Leboyer et al. 1992; Willemsen-Swinkels et al. 1995). Overall, most of
 Autism Spectrum Disorder 317

the evidence points toward naltrexone as ineffective in improving ASD symp-

toms or self-injurious behavior and as potentially having a modest effect in the
treatment of hyperactivity.

Secretin
The gastrointestinal peptide secretin stimulates secretion of water and bicar-
bonate from the pancreas and supports the activity of cholecystokinin, which,
in turn, further activates pancreatic secretion. Extensive study of this compound
in autism occurred following an initial report of successful open-label treat-
ment in three patients who experienced improvement in maladaptive behavior
and core ASD symptoms (Horvath et al. 1998). After initial reports of secretin’s
success were described in the mainstream media, its use spread to the point
that more than 500,000 doses had been administered to patients with autism
by 1999 (Kamińska et al. 2002). Fifteen double-blind, placebo-controlled tri-
als have now evaluated the use of secretin in patients with ASD, and none of
the reports concluded that the drug was effective (Sturmey 2005). These re-
ports included single-dose and multiple-dose trials of human or porcine se-
cretin. Although secretin represents one of the most studied compounds in
patients with ASD, no evidence yet supports its use in this diagnostic group.

Oxytocin
Oxytocin is a neuropeptide synthesized in the hypothalamus that acts periph-
erally in the body in the induction of milk letdown and the facilitation of uterine
contractions. Treatment roles for oxytocin in humans include the management
of postpartum hemorrhage and the induction of labor. It is also involved in so-
cial behavior and is thought to play a role in mother-child and adult-adult in-
terpersonal bonds as well as in social memory and recognition (for review, see
Preti et al. 2014). Many initial studies among primarily high-functioning sub-
jects with autism that assessed emotional recognition found improvement at-
tributable to oxytocin administration (Anagnostou et al. 2012; Domes et al.
2014; Guastella et al. 2010; Hollander et al. 2007; Watanabe et al. 2014), but
this was not the case in all studies (Dadds et al. 2014). Some studies using
functional MRI measures found changes in activation in response to oxytocin
in areas of the brain hypothesized to mediate social behavior (Domes et al.
2014; Watanabe et al. 2014). Results have been more mixed for oxytocin’s ef-
318 Clinical Manual of Child and Adolescent Psychopharmacology

fect on restricted repetitive behaviors or eye gaze, and two studies (Anagnos-
tou et al. 2012; Dadds et al. 2014) failed to find differences in global measures
of clinical improvement in response to oxytocin.
Two more recent, large, placebo-controlled, double-blind trials in youth
with ASD have, unfortunately, failed to find benefit with oxytocin for social
behavior compared with placebo. The first study (Sikich et al. 2021) was con-
ducted in 290 children and adolescents ages 3–17 years with ASD and included
subjects with and without intellectual disability. The trial was 24 weeks long
and failed to find a difference between intranasal oxytocin and placebo groups
using the ABC modified Social Withdrawal subscale as the primary outcome
measure. The second study (Yamasue et al. 2020) was conducted in 106 adults
ages 18–48 years with ASD without intellectual disability. The study failed to
find improvement on the primary outcome measure, the social reciprocity score
on ADOS module 4. In the pediatric study by Sikich et al. (2021), adverse
events included increased appetite, increased energy, restlessness, weight loss,
increased thirst, inattention, and myalgia. Three subjects withdrew due to irri-
tability. One participant in the adult trial by Yamasue et al. (2020) experienced
temporary gynecomastia.

Folinic Acid
Folate (vitamin B9) is a water-soluble vitamin essential for neurodevelopment.
Deficiencies in folate and metabolism may be linked to ASD (Frye et al.
2020). Past evidence for folic acid and its related derivatives has been limited
to case series and case reports. More recently, three randomized, double-blind
placebo-controlled trials have been published.
Frye et al. (2018) published a 12-week randomized, double-blind, placebo-
controlled trial of high-dose folinic acid (2 mg/kg/day; maximum, 50 mg/
day) in 48 children and adolescents ages 3–14 years with nonsyndromic ASD
with language impairment (preverbal, fewer than 25 functional words). They
reported a medium to large effect size (Cohen’s d=0.70) on verbal communi-
cation in participants receiving folinic acid compared with those receiving pla-
cebo. The investigators also studied biomarkers for altered folate metabolism,
including the folate receptor autoantibody and a glutathione redox ratio. The
presence of folate receptor autoantibody was associated with an even larger
effect size (Cohen’s d=0.91). No serious adverse events were reported in the
 Autism Spectrum Disorder 319

folinic acid group. The difference in adverse events between groups was not
significant.
Renard et al. (2020) published findings of a 12-week randomized, placebo-
controlled study of folinic acid in 19 children ages 3–12 years with ASD. Par-
ticipants receiving folinic acid did not demonstrate a statistically significant
improvement in ADOS scores, the primary outcome measure. However, there
was a significant difference in scores on the ADOS Communication and So-
cial Interaction subscales compared with placebo. No serious adverse events
were reported in this study.
Looking at folinic acid as an adjunct treatment to risperidone, Batebi et al.
(2021) completed a 10-week randomized, double-blind, placebo-controlled
study in 55 youth ages 4–12 years with ASD. Both groups received risperi-
done concurrently. In this trial, no other concomitant medications were al-
lowed. There was a significant effect in time×treatment on the Inappropriate
Speech subscale of the ABC, the primary outcome measure (P=0.044). Ap-
petite stimulation and diarrhea were the most common side effects reported in
the treatment group. The difference in side effects was not statistically signif-
icant between groups.

Cannabinoids
The cannabis plant contains more than 100 cannabinoids, the most common
being Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is
considered the psychoactive part of the cannabis plant. CBD has become a
compound of interest for various psychiatric disorders, including psychotic dis-
orders, anxiety disorders, substance use disorders, insomnia, PTSD, ADHD,
mood disorders, and ASD. Despite its popularity, evidence for its use is limited.
A few small, nonrandomized studies of CBD have suggested positive behav-
ioral effects in individuals with ASD (Aran et al. 2019; Bar-Lev Schleider et al.
2019; Bilge and Ekici 2021; Fleury-Teixeira et al. 2019), but only one ran-
domized, double-blind placebo-controlled trial of CBD in ASD has been pub-
lished (Aran et al. 2021). In this study, 150 participants ages 5–21 years with
ASD received either a 20:1 CBD/THC compound, pure cannabinoids, or pla-
cebo for 12 weeks, followed by a 4-week washout and crossover for an addi-
tional 12 weeks. The primary outcome measures for this study included the
Home Situations Questionnaire–Autism Spectrum Disorder (HSQ-ASD)
320 Clinical Manual of Child and Adolescent Psychopharmacology

and the CGI-I based on disruptive behavior. The difference in the HSQ-ASD
between groups was not statistically significant. A CGI-I rating of much im-
proved or very much improved was found in 49% of patients treated with
whole-plant CBD compared with 21% of those given placebo. Subjects treated
with whole-plant CBD demonstrated an improvement of 14.9 points on the
SRS-2, a secondary outcome measure, which was statistically significant com-
pared with the control group (P=0.009). The most common adverse events
during the study were sleepiness and decreased appetite. No serious adverse
events occurred during the trial (Aran et al. 2021).

Safety Issues
In this portion of the chapter, we focus on adverse effects reported for selected
classes of medications that are used in the pharmacotherapy of ASD. This is
not meant to be an extensive review of all adverse effects for all drugs previ-
ously discussed but, rather, to highlight major adverse effects of several com-
monly used classes of drugs that should be brought to the reader’s attention.
When selecting a medication, the clinician must educate the patient and care-
givers about its potential adverse effects.

Atypical Antipsychotics
Atypical antipsychotics are associated with a risk of several adverse events that
warrant monitoring. Although they purportedly have a decreased risk of EPS
and tardive dyskinesia in comparison with the typical antipsychotics, these
events have been reported in individuals with ASD taking atypical agents (Cor-
rell et al. 2011; Kidd 2018; Malone et al. 2002; Zuddas et al. 2000). Hyper-
prolactinemia is another adverse effect that may occur during treatment with
an atypical antipsychotic. With the exception of aripiprazole, which can de-
crease prolactin, all other atypical antipsychotics can cause elevations in prolac-
tin levels. Studies of risperidone and paliperidone found significant elevation in
prolactin levels in patients with ASD, despite the fact that no participants
showed clinical signs of hyperprolactinemia (Gagliano et al. 2004; Masi et al.
2001b, 2003; Stigler et al. 2012). Chronic hyperprolactinemia can lead to dis-
ordered growth, sexual dysfunction, and osteoporosis (Saito et al. 2004).
 Autism Spectrum Disorder 321

In children and adolescents, olanzapine is associated with a considerable

risk of weight gain, whereas quetiapine, risperidone, aripiprazole, and paliper-
idone are associated with a moderate risk (De Hert et al. 2011; Stigler et al.
2012). In contrast, published data in youth suggest that ziprasidone may be
associated with a decreased risk of weight gain. The association between weight
gain and atypical antipsychotic use in patients with ASD is of significant con-
cern. Evidence has implicated this class of drugs in the onset or exacerbation
of diabetes and hyperlipidemia (De Hert et al. 2011; Stigler et al. 2004b).
Regular monitoring of patient weight, as well as fasting glucose, hemoglobin
A1C, and lipids, is highly recommended. In addition, selection of a particular
antipsychotic may warrant monitoring of liver functions, blood count, and
ECG depending on the choice of agent and additional clinical history.

Selective Serotonin Reuptake Inhibitors

In 2004, the FDA required SSRI manufacturers to include a black box warn-
ing describing the potential for increased suicidality in children and adoles-
cents taking these medications, especially in the first few months of treatment.
With this in mind, regular assessment for suicidality must be part of the treat-
ment plan for patients with ASD taking any of these agents. Prepubertal pa-
tients with ASD who are taking SSRIs also may be at increased risk of
behavioral activation and irritability during treatment compared with postpu-
bertal patients (McDougle et al. 2000). Given these concerns, clinicians
should consider initially prescribing low dosages of SSRIs for patients and
slowly titrating toward an effective dosage.

Psychostimulants
Psychostimulants may be less well tolerated in youth with ASD than in typi-
cally developing children with ADHD (Research Units on Pediatric Psycho-
pharmacology Autism Network 2005a). Adverse effects that warrant close
monitoring include increased irritability, agitation, hyperactivity, decreased
appetite, weight loss, insomnia, exacerbation/development of tics, and psy-
chosis (rarely). In addition, this drug class rarely may be associated with car-
diovascular adverse events, which places individuals with preexisting heart
conditions at higher risk. A baseline medical history and physical examination
322 Clinical Manual of Child and Adolescent Psychopharmacology

are recommended to identify at-risk individuals with structural cardiac abnor-

malities or other cardiovascular symptoms (Correll et al. 2011).

α2-Adrenergic Agonists
α2-Adrenergic agonists are typically well tolerated, aside from possible adverse
effects of sedation and hypotension. Depressive symptoms may worsen or be
induced as well. A baseline ECG prior to beginning this class of drugs should
be considered, particularly in patients with a significant history of cardiovas-
cular problems. Constipation can also occur with this particular class of med-
ications.

Atomoxetine
In 2005, the FDA required manufacturers of atomoxetine to include a black
box warning regarding potential increased suicidal ideation in children and
adolescents treated with this drug. Because of this risk, regular assessment for
suicidality in patients prescribed atomoxetine is warranted. In addition, rare
cases of hepatic dysfunction associated with atomoxetine use warrant ongoing
assessment for signs and symptoms of liver failure in ASD patients taking this
medication (Bangs et al. 2008; Erdogan et al. 2011).

Mood Stabilizers
Among the mood stabilizers, the anticonvulsant valproic acid is frequently used
to treat persons with ASD. Drug levels should be monitored on a regular basis
to ensure that they remain in the therapeutic range. Patients should be regularly
assessed for symptoms of valproic acid toxicity, including nausea, vomiting,
ataxia, tremor, dizziness, headache, confusion, and somnolence. Hepatotoxicity
is a possible serious adverse effect associated with the drug, warranting periodic
liver function tests (Dreifuss et al. 1987). Pancreatitis is another rare but po-
tentially life-threatening complication. In addition, due to the risk of thrombo-
cytopenia, a blood count including platelets should be obtained for all patients
receiving this medication.
Risks from taking another mood stabilizer, lithium, include impaired re-
nal and thyroid function, thus warranting regular monitoring (Scahill et al.
2001). In addition, baseline ECGs are recommended. Lithium levels must be
monitored on a regular basis during treatment. Toxic levels of lithium are often
 Autism Spectrum Disorder 323

close to the therapeutic range (0.6–1.2 μg/mL), thus making it essential to

monitor for signs and symptoms of lithium toxicity during treatment. Signs of
toxicity include lethargy, nausea, vomiting, diarrhea, tremor, weakness, and sei-
zures.

Practical Management Strategies

A multimodal approach to the management of ASD is essential. This often in-
corporates speech therapy, occupational therapy, physical therapy, educational
interventions, and social skills training. Ongoing collaboration with the pa-
tient’s educational team at school can ease transitions, decrease maladaptive
behaviors, and optimize learning in the classroom setting. In addition, behav-
ior therapy may be of particular importance because it may decrease the need
for pharmacotherapy in patients with ASD. Even with the use of such inter-
ventions, however, medication is often required to decrease the serious behav-
ioral problems commonly observed in youth with ASD.
The pharmacotherapy of ASD is currently based on a target symptom ap-
proach. As described in this chapter, a variety of medications may impact spe-
cific target symptom domains in this population. The algorithm shown in
Figure 7–1 provides an overview of drug treatment strategies for three symptom
domains commonly encountered in ASD: irritability (tantrums, aggression,
self-injury), motor hyperactivity and inattention, and interfering repetitive
phenomena.

Clinical Pearls
• Use a multimodal therapeutic approach to the management of
autism spectrum disorder (ASD).
• Prescribe medication to reduce maladaptive behaviors, allowing
youth with ASD to maximize benefit from therapy and educational
services.
• Base pharmacotherapy of ASD on a target symptom approach.
Three major target symptom domains in ASD are irritability (tan-
trums, aggression, self-injury), hyperactivity/inattention, and in-
terfering repetitive interests/activities.
 Target symptom domain

324 Clinical Manual of Child and Adolescent Psychopharmacology

Irritability Hyperactivity and inattention Repetitive interests and activities

Prepubertal Postpubertal Prepubertal Postpubertal

Mild Severe

2-Adrenergic Atypical antipsychotic Atypical antipsychotic 2-Adrenergic agonist Trial of atypical SSRI
agonist antipsychotic

NR/PR; D/C NR/PR; D/C atypical NR/PR; D/C atypical

NR/PR; D/C NR/PR; D/C SSRI;
2-adrenergic agonist; antipsychotic; antipsychotic;
trial of second 2-adrenergic agonist; trial of atypical
trial of atypical trial of second
atypical antipsychotic atypical antipsychotic trial of atomoxetine antipsychotic
antipsychotic

NR/PR; D/C second NR/PR; D/C second NR/PR; D/C

atypical antipsychotic; atypical antipsychotic; atomoxetine;
trial of typical trial of typical trial of low-dose
antipsychotic antipsychotic stimulant

NR/PR; D/C NR/PR; D/C NR/PR; D/C stimulant;

typical antipsychotic; typical antipsychotic; trial of atypical
trial of mood stabilizer trial of mood stabilizer antipsychotic

Figure 7–1. A target symptom approach to the pharmacotherapy of autism spectrum disorder (ASD).
This algorithm provides an overview of drug treatment strategies for three symptom domains commonly encountered in ASD: irritability
(tantrums, aggression, self-injury), motor hyperactivity and inattention, and interfering repetitive phenomena. For repetitive behaviors,
behavioral therapy is recommended as the first-line treatment. There is better evidence to support a trial of an SSRI prior to an atypical
antipsychotic for postpubertal patients than for prepubertal patients.
D/C=discontinue; NR/PR=nonresponse/partial response; SSRI=selective serotonin reuptake inhibitor.
 Autism Spectrum Disorder 325

• Try prescribing an α2-adrenergic agonist for youth with mild ag-

gression or self-injury or an atypical antipsychotic for individuals
with more severe symptoms.
• Consider risperidone and aripiprazole for the treatment of irrita-
bility in youth with ASD because these medications are FDA ap-
proved.
• Keep in mind that prepubertal versus postpubertal patients with
ASD may be at increased risk of behavioral activation and irri-
tability during selective serotonin reuptake inhibitor (SSRI) treat-
ment for interfering repetitive phenomena.
• Remember that stimulants appear less well tolerated and less
effective in youth with ASD compared with typically developing
children with ADHD.
• Consider a trial of guanfacine prior to atomoxetine or a stimulant
for symptoms of hyperactivity and inattention in ASD.
• Given the increased challenges with the safety and tolerability
of SSRIs in prepubertal children with ASD, consider a trial of
buspirone before using an SSRI or serotonin-norepinephrine re-
uptake inhibitor.

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 8
Tic Disorders
Lawrence Scahill, M.S.N., Ph.D.
Sarah Lytle, M.D.
Stephanie Pope, M.D.
Basim Mikhail, M.D.

Tic disorders, including Tourette’s disorder, are movement disorders that be-
gin in childhood and are defined by the presence of enduring motor tics, pho-
nic tics, or both. The tics of Tourette’s disorder show an extraordinary range
from mild to severe across patients and a fluctuating course within patients
(Lin et al. 2002; Roessner et al. 2011). In addition to the association with tics,
Tourette’s disorder is frequently connected with hyperactivity, impulsiveness,
distractibility, obsessive-compulsive symptoms, and anxiety (Jankovic 2009).
Therefore, the assessment and treatment of children and adolescents with
Tourette’s disorder correctly includes consideration of these multiple sources
of impairment. Indeed, although the referral question may be about tics, the
presence of ADHD, OCD, or an anxiety disorder may be more pressing than

341
342 Clinical Manual of Child and Adolescent Psychopharmacology

the tic symptoms. In assessment and treatment planning, clinicians must take
into account, in addition to the sources of impairment, the domains of func-
tioning that may be adversely affected.
We begin with a brief review of the epidemiology of tic disorders to under-
score their public health importance, followed by a review of the diagnosis and
treatment of children with tic disorders. Our major focus in this chapter is the
pharmacological treatment of children with tic disorders. Because of the com-
mon co-occurrence of OCD and ADHD in individuals with tic disorders, we
also examine the treatment of these disorders in the pediatric population. Be-
havioral treatments for Tourette’s disorder, which are beyond the scope of this
chapter, can also play an key role in treatment, as reported in a meta-analysis by
McGuire et al. (2014). Although there is growing interest in deep brain stim-
ulation and repetitive transcranial magnetic stimulation, these approaches are
not discussed (for a review of surgical approaches to the treatment of refrac-
tory Tourette’s disorder, see Deeb and Malaty 2020 and Schrock et al. 2015).

Epidemiology
Transient tics are relatively common, affecting up to 20% of school-age chil-
dren (Scahill et al. 2014). Tic disorders are defined in DSM-5 (American Psy-
chiatric Association 2022) by the duration and types of tics present. DSM-5
also stipulates that the tics must begin before the child reaches 18 years of age.
In practice, tics usually begin in early school age, between the ages of 5 and 7.
Historically, Tourette’s disorder has been considered a rare and uniformly
severe condition. However, prior estimates of its prevalence were frequently
based on counts of clinically ascertained cases. This method resulted in a sys-
tematic undercount because it failed to include cases that had not come to
clinical attention—perhaps milder cases or cases with poor access to care. To
correct this problem, later studies surveyed community samples, which has re-
sulted in higher estimates of prevalence.
In a previous study, the CDC conducted a national telephone survey of
nearly 64,000 households with children ages 6–17 years (Centers for Disease
Control and Prevention 2009). A lifetime diagnosis of Tourette’s disorder was
reported in 3 per 1,000 children, for an estimated total count of 148,000 cases
nationwide, with a male-to-female ratio of 3:1. Because most cases were de-
scribed as mild according to the parents, missing mild cases are not likely to pro-
 Tic Disorders 343

vide a complete explanation. The survey also reported a rate of 3.9 per 1,000 in
non-Hispanic white children compared with 1.6 per 1,000 for Hispanic chil-
dren and 1.5 per 1,000 for Black children, suggesting that race and ethnicity
may affect rates of identified cases. With regard to comorbidities, 64% of the
children with Tourette’s disorder also had a diagnosis of ADHD, 43% had a his-
tory of disruptive behavior, and 40% had a history of anxiety problems.
Another challenge to determining the prevalence of tics over time has been
the changing criteria with evolving DSM editions. This can be seen in com-
paring the determined prevalence rates between the Isle of Wight study (Rutter
et al. 1970) and a study from Costello et al. (1996). In the time between these
two studies, the introduction of DSM-III (American Psychiatric Association
1980) specified and broadened the diagnostic criteria. Specifically, in the Isle
of Wight study, Rutter et al. (1970) evaluated a sample of 3,000 children ages
10–12 years. In that sample, 4.4% of the children were identified as having tics,
but no cases of Tourette’s disorder were identified. In contrast, using DSM-
III-R criteria (American Psychiatric Association 1987), Costello et al. (1996)
reported a prevalence of 4.2% for all tic disorders combined (transient tic dis-
order, chronic tic disorder, and Tourette’s disorder) in a similar age group of
children who were participants in the Great Smoky Mountains Study. The
differences in diagnostic classification across these two studies appear to be at-
tributable to differences in definitions rather than true differences in the prev-
alence of tic disorders.
Several reviews have also examined prevalence rates. Knight et al. (2012)
completed a systematic review and meta-analysis looking at this question.
They reported a prevalence of Tourette’s disorder in children of 0.77% overall.
When comparing the prevalence of Tourette’s disorder between boys and girls,
the researchers found a rate of 1.06% versus 0.25%, respectively. Transient tic
disorder prevalence for children was much higher at 2.99%.
In a critical review of the literature including 11 published surveys, Scahill
et al. (2014) found that transient tics are relatively common, affecting up to
20% of school-age children, with a male-to-female ratio between 2:1 and
3.5:1. Meanwhile, the prevalence of Tourette’s disorder has been estimated
from a lower bound of 2.6 per 1,000 to an upper bound of 38 per 1,000. This
level of imprecision is not ideal for judging public health importance and ser-
vice need, and this same review proposed a narrower range of 3–8 cases per
1,000. Indeed, five studies reviewed reported 4–6 cases per 1,000.
344 Clinical Manual of Child and Adolescent Psychopharmacology

Other literature assessing this question includes a review of prevalence

studies that also considered participant location, race, comorbid illness, and
study methodology. The authors concluded that prevalence is within the
range of 0.3%–5.7% (Robertson 2015). Another review in that same year re-
ported a prevalence of 0.3%–0.9% (Scharf et al. 2015) but suggested that
study limitations likely led to lower estimates than what is most likely true.

Diagnosis and Assessment

Any assessment of a child suspected of having a tic disorder begins with a
review of tic symptoms and exploration of associated problems, such as inat-
tention, hyperactivity, and obsessive-compulsive symptoms. Pertinent infor-
mation about tic symptoms includes the age at onset and course of symptoms,
current severity of motor and phonic tics, presence of premonitory sensations
and capacity for tic suppression, overall burden caused by the tics, and treat-
ment approaches implemented to date.
Tics tend to be rapid movements or brief vocalizations that are performed
in a stereotyped manner. Tics also tend to occur in brief or extended clusters,
followed by a period of relative quiescence. In mild cases, the bouts of tics are
brief, with relatively long tic-free periods (an hour to several hours), and may
go unnoticed by casual observers. By contrast, individuals with moderate or
marked severity may have bouts of forceful tics consisting of multiple move-
ments and vocalizations with only brief tic-free periods. Frequent and forceful
movements or vocalizations may be easily noticeable across settings and may
interfere with everyday activities.
Many patients with Tourette’s disorder describe a warning or urge prior to
the performance of a tic. This may be described as a vague feeling of tension or
a physical feeling occurring in a specific body region. In fact, the body region
involved may be the same muscle group inherent in tic expression (Leckman
et al. 1993; Woods et al. 2005). Patients with Tourette’s disorder also describe
an ability to suppress their tics—at least momentarily. The relationship be-
tween premonitory sensations and tic suppression is intriguing but not com-
pletely understood.
Young children, usually between ages 7 and 10 years, may not sponta-
neously report either of these phenomena. However, by age 10 years, most chil-
dren with Tourette’s disorder describe both the warning before some of their
 Tic Disorders 345

tics and at least a fleeting capacity to suppress them. Children and adults often
report that the act of suppressing a tic intensifies the urge to perform it. This ac-
centuation pushes the urge to a crescendo and ultimately makes the tic irresist-
ible (Leckman et al. 1993). Although many patients describe the capacity to
suppress tics, at least momentarily, few can explain how this is accomplished.
The effort to suppress tics may reflect the individual’s gradual awareness that
the tics can have social consequences. In other words, as children with Tou-
rette’s disorder begin to understand the social consequences of tics, they in-
crease their vigilance about the tics and recruit conscious effort to suppress
them. This increased vigilance may promote the evolution of premonitory sen-
sations as the child becomes more aware of the earliest signs of tic behavior.
This conceptualization has not been specifically tested and remains speculative.
The differential diagnosis of Tourette’s disorder and tic disorders is based
on the type of tics present (motor or vocal) and the duration of symptoms
(American Psychiatric Association 2022). Provisional tic disorder is defined
by the presence of motor and/or vocal tics for less than a year. The diagnosis of
persistent (chronic) motor or vocal tic disorder is made when the child has
motor or vocal tics (but not both) for longer than a year. Tourette’s disorder is
defined by the presence of both motor and phonic tics for more than a year.
Diagnosis of Tourette’s disorder does not require that both motor and phonic
tics be present at the same time but does require that both be present during
the course of illness (and may wax and wane). Other key elements in these di-
agnoses include onset before age 18 years and exclusion of other causes for the
tics, such as medication or other medical conditions. For example, a child who
only showed tics while being treated with a psychostimulant would not be di-
agnosed with Tourette’s disorder.
Another important aspect to consider when assessing for tics is the phe-
nomenon of a seemingly abrupt upsurge, such as was seen with a possible as-
sociation to “Tik Tok tics” in 2020 and 2021 (Olvera et al. 2021). This
sudden increase in tics was also noted by the CDC, which examined data from
the National Syndromic Surveillance Program and found that visits to emer-
gency departments for a variety of mental health issues increased following the
National Emergency Declaration for COVID-19 in March 2020. Among the
increased mental health concerns was an increase in tics and tic-like behavior,
particularly among females ages 12–17 years. This was atypical, given the
known prevalence of tics presenting at a younger age and usually in males
346 Clinical Manual of Child and Adolescent Psychopharmacology

(Radhakrishnan et al. 2022). Thus, when evaluating patients with new-onset

tics, clinicians should ask about online and social media activities, assess time-
lines in terms of onset of symptoms, and evaluate thoroughly for other causes
of tic-like symptoms.
Several tic symptom checklists and clinician interviews are available for
the assessment of tic severity. Two commonly used instruments are the Tic
Symptom Self-Report (Allen et al. 2005; Scahill et al. 1997) and the Yale
Global Tic Severity Scale (YGTSS; Leckman et al. 1989). In addition, a thor-
ough developmental, family, and social history can help distinguish Tourette’s
disorder from other medical or psychiatric conditions and guide treatment de-
cisions.

Treatment of Tics in Children

With Tourette’s Disorder
The first-line treatment for tics in children with Tourette’s disorder is educa-
tion, particularly the following points:

1. Tourette’s disorder is not a progressive condition.

2. In most cases, tics are mild to moderate in severity.
3. Treating tics may not improve symptoms of ADHD or other disruptive
behavior.
4. Tics have a fluctuating course, even when the individual is taking a tic-
suppressing medication.
5. Most children with Tourette’s disorder will show a decline in tics by early
adulthood (Bloch et al. 2006b).

Understandably, parents and children may overfocus on the child’s tics.

The clinician’s role is to help refocus them on the child’s most pressing prob-
lems and to keep the parents mindful of the child’s overall development. This
discussion may extend to teachers and other school personnel as well. For ex-
ample, children may attempt to suppress tics, which can affect their focus.
Children with tics may also be subject to bullying. When tics interfere with a
child’s functioning, including social sequelae or self-esteem, pharmacotherapy
may be considered.
 Tic Disorders 347

Antipsychotics
The FDA-approved medications for Tourette’s disorder are haloperidol for
children ages 3–12 years, pimozide for adolescents ages 12 years or older, and
aripiprazole for individuals ages 7–17 years. Other antipsychotics have been
studied and are discussed here as well.
Early randomized trials demonstrated that the potent dopamine D2 recep-
tor antagonists haloperidol and pimozide were superior to placebo for sup-
pressing tics in adults with Tourette’s disorder (Ross and Moldofsky 1978;
Shapiro and Shapiro 1984). Two randomized controlled trials (RCTs) com-
pared pimozide with haloperidol; one study found better results with haloper-
idol in adults (Shapiro et al. 1989), whereas the other study, which involved
youth, found no difference (Sallee et al. 1997). However, the latter trial indi-
cated that haloperidol had more severe side effects than pimozide at equivalent
dosages (Sallee et al. 1997). Compared with current practice, earlier studies
used high dosages of these medications (up to 20 mg/day for haloperidol and
up to 48 mg/day for pimozide). In contemporary clinical practice, the trend is
clearly toward the use of lower dosages, such as 1–4 mg/day for haloperidol and
2–6 mg/day for pimozide (Roessner et al. 2011; Scahill et al. 2006).
Fluphenazine has also been studied. In an open-label trial with subjects
that included children and adults, fluphenazine was effective for 17 of 21 pa-
tients at dosages ranging from 2 mg/day to 15 mg/day given in two divided
doses. Most of the subjects who had previous experience with haloperidol pre-
ferred fluphenazine (Goetz et al. 1984). Another study reviewed charts of chil-
dren and adults treated with fluphenazine (dosage range, 0.5–1.2 mg/day) for
Tourette’s disorder over a 26-year period, with many of the participants taking
fluphenazine for months. Of the 268 participants, 211 showed marked im-
provement (Wijemanne et al. 2014).
The atypical antipsychotic medications currently available in the United
States include aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine,
iloperidone, lumateperone, lurasidone, olanzapine, paliperidone, quetiapine,
risperidone, and ziprasidone, which have serotonin-blocking effects and vari-
able D2-blocking properties (Table 8–1).
As mentioned earlier, aripiprazole is FDA-approved for the treatment of
Tourette’s disorder. A number of open-label studies provided preliminary ev-
idence for its safety and efficacy. (Cui et al. 2010; Lyon et al. 2009; Wang et al.
348 Clinical Manual of Child and Adolescent Psychopharmacology

Table 8–1. Dosing guidelines for antipsychotic drugs used in the

treatment of tics of moderate or greater severity

Placebo-
Starting dosage, Usual dosage controlled
Medicationa mg/day range, mg/day trial?

Aripiprazole 2–5 5–10 Yesb

Asenapine NR No
Brexpiprazole NR No
Cariprazine NR No
Fluphenazine 0.5–1.0 1.5–10 No
Haloperidol 0.25–0.5 1–4 Yesb
Iloperidone NR No
Lumateperone NR No
Lurasidone NR No
Olanzapine 2.5–5.0 2.5–12.5 No
Paliperidone 3 3–6 No
Pimozide 0.5–1.0 2–6 Yesb
Quetiapine 25–50 75–150 No
Risperidone 0.25–0.5 1–3 Yesb
Ziprasidone 5–10 10–40 Yesc
Note. NR=no reports in Tourette’s disorder.
a
Clozapine is not listed because of its complexity of use and failure to show efficacy.
b
Superior to placebo in more than one study.
cSuperior to placebo in one study.

2016). A 10-week multicenter, double-blind, randomized, placebo-controlled

trial of 61 youth ages 6–18 years with Tourette’s disorder reported a significant
reduction in tics on the YGTSS (P=0.0196) in participants given aripiprazole
compared with those who given placebo, and the drug was well tolerated (Yoo
et al. 2013). A multicenter, randomized, double-blind, placebo-controlled
trial of aripiprazole in 133 children and adolescents ages 7–17 years with Tou-
rette’s disorder reported that aripiprazole was a safe and efficacious treatment
for the disorder in this age group (Sallee et al. 2017). Dosing guidelines suggest
 Tic Disorders 349

a starting dosage of 2 mg/day, with recommended and maximum dosages of

5 mg/day and 10 mg/day, respectively, for patients who weigh less than 50 kg,
and recommended and maximum dosages of 10 mg/day and 20 mg/day, re-
spectively, for those who weigh 50 kg or more.
Aripiprazole was also studied in head-to-head trials with other medica-
tions. In an open-label study comparing aripiprazole and haloperidol, 48 youth
ages 6–15 years with tics were treated with either aripiprazole 5–20 mg/day or
haloperidol 0.75–4.5 mg/day for 8 weeks. Both medications were similarly ef-
ficacious in reducing tic symptoms. Improvement was noted in the first follow-
up visit at week 2 and was sustained during the rest of the 8-week trial (Yoo et
al. 2011). A double-blind trial compared risperidone and aripiprazole for chil-
dren with tics. This study included 60 children, with a duration of 8 weeks.
Participants in both groups were found to have at least 35% reduction in their
Total Tic Severity Scale score. There was no significant difference between the
groups (Ghanizadeh and Haghighi 2014).
A number of meta-analyses also have concluded that aripiprazole is a gen-
erally tolerable and effective treatment for children with tics (Cox et al. 2016;
Wang et al. 2017; Yang et al. 2015, 2019; W. Zheng et al. 2016).
Risperidone has also been well studied. It was found to be superior to pla-
cebo for tic reduction in two trials (Dion et al. 2002; Scahill et al. 2003b) and
in other studies was found to be equally as effective as pimozide (Bruggeman et
al. 2001; Gilbert et al. 2004), clonidine (Gaffney et al. 2002), and aripiprazole
(Ghanizadeh and Haghighi 2014). Ziprasidone was well tolerated and found
to be superior to placebo in a randomized trial of 28 children with Tourette’s
disorder (Sallee et al. 2000). Two open-label trials of olanzapine in a total of
30 adult patients offer some encouraging results for the treatment of tics
(Budman et al. 2001; Stamenkovic et al. 2000). One small study of 10 chil-
dren ages 7–13 years with Tourette’s disorder and aggression had statistically
significantly lowered YGTSS scores (Stephens et al. 2004). To date, only two
small case series are available for quetiapine (Mukaddes and Abali 2003).
Clozapine was no better than placebo for the treatment of tics (Caine et al.
1979). When considered in light of the effectiveness of haloperidol and pi-
mozide, the failure of clozapine suggests that dopamine D2 blockade is an im-
portant mechanism in tic suppression. One small case series is available for
extended-release paliperidone (Yamamuro et al. 2014). No studies for indi-
350 Clinical Manual of Child and Adolescent Psychopharmacology

viduals with tic disorders have been completed for the other antipsychotic
medications.
The appeal of the atypical antipsychotics is their demonstrated lower
probability for neurological side effects such as dystonia, dyskinesia, tremor,
and parkinsonism. Atypical antipsychotics are less likely to cause tardive dys-
kinesia in the long term and have a lower likelihood of neurological side effects
in the short term (Findling and McNamara 2004). One study examined mo-
tor side effects in 80 children treated with antipsychotics (mostly atypical) ver-
sus treatment without antipsychotics for 6 months or longer. Nine percent of
the subjects who were given antipsychotics exhibited hyperkinesia compared
with none of those who were not given antipsychotics. Of note, a higher per-
centage of African American youth (15%) exhibited hyperkinesia compared
with European American youth (4%) (Wonodi et al. 2007). A systematic re-
view of the literature including 10 studies with a total of 783 children and ad-
olescents given mainly risperidone (n = 737; mean dosage, 1.58 mg/day),
quetiapine (n= 27), and olanzapine (n=19) reported an annualized tardive
dyskinesia rate of 0.38% (Correll and Kane 2007). A meta-analysis of 41 stud-
ies including 2,114 youth reported a mean extrapyramidal symptom rate of
17.1% for aripiprazole (Bernagie et al. 2016).
Other adverse effects of clozapine include increased appetite, weight gain,
and the potential for metabolic abnormalities (Meyer and Koro 2004). Based
on reports from non–Tourette’s disorder clinical populations, clozapine appears
to be associated with the highest risk of weight gain, followed (in order) by olan-
zapine, quetiapine, risperidone, and ziprasidone (Allison and Casey 2001). A
systematic review and pooled analysis of youth treated for pediatric bipolar
disorder also found an association between atypical antipsychotics and weight
gain. A large retrospective study of 3.7 million patients taking an antipsy-
chotic (of whom 82,754 were prescribed an atypical antipsychotic) between
1998 and 2004 found a higher association with diabetes, which was higher
still in younger patients (Hammerman et al. 2008). Other adverse events re-
ported in children and adolescents include social phobia, constipation, drool-
ing, sedation, and cognitive blunting (Aman et al. 2005; Scahill et al. 2003b).
Clinical concerns have also been raised about alterations in cardiac conduc-
tion times, such as QTc prolongation. This issue is not new, given that similar
concerns have been expressed about pimozide. Although the occurrence of
QTc prolongation is presumed to be rare in the dosage ranges used in the treat-
 Tic Disorders 351

ment of tics, clinicians should obtain electrocardiograms (ECGs) for patients

before starting treatment with pimozide, during the dosage-adjustment phase,
and annually during ongoing treatment (Scahill et al. 2006). Pimozide also
appears to interact with medications that inhibit CYP3A4, such as clarithro-
mycin (Desta et al. 1999). In a study comparing aripiprazole and pimozide, the
group given pimozide showed decreases in blood pressure and increases in QTc,
whereas those given aripiprazole showed increases in blood pressure but no sig-
nificant change in QTc (Gulisano et al. 2011). Of the atypical antipsychotics,
ziprasidone appears to increase QTc to a mild degree. In a series of 20 children
with various psychiatric conditions, a modest increase in QTc occurred during
treatment with ziprasidone (Blair et al. 2005). Unlike pimozide, however, zi-
prasidone does not seem to be vulnerable to drug interactions because it does
not rely on a single hepatic pathway. The package insert for ziprasidone men-
tions that it is contraindicated in patients with a known history of QTc pro-
longation. Until more data are available to inform practice, guidelines similar
to those used for pimozide have been recommended (Scahill et al. 2006).
Medications for tic disorders studied in RCTs are listed in Table 8–2.

Non-Antipsychotic Medications
Over the past decade, various non-antipsychotic medications have been tried for
the treatment of tics, including baclofen, botulinum toxin, clonidine, D-serine,
ecopipam, guanfacine, intravenous immunoglobulin, levetiracetam, mecamyl-
amine, metoclopramide, N-acetylcysteine, nicotine, omega-3 fatty acids, on-
dansetron, pergolide, pramipexole, riluzole, tetrabenazine, topiramate, valproic
acid, and 5-Ling granule (an herbal medicine). Most have not been well studied;
the medications that have been studied in RCTs with more than 20 subjects
with tics are listed in Table 8–2.
Following encouraging results in three open studies (Jankovic 1994;
Kwak et al. 2000; Marras et al. 2001), Porta et al. (2004) conducted a placebo-
controlled trial of botulinum toxin in Tourette’s disorder. The authors reported
about a 40% difference between active drug and placebo. Treatment with bot-
ulinum toxin involves direct injection into the selected muscle of the motor tic,
or the laryngeal folds in the case of a vocal tic (Porta et al. 2004). In open-label
studies, the botulinum toxin injections appeared to reduce both the premon-
itory sensations at the injection site and the actual tic. Adverse effects included
transient soreness at the injection site, weakness of the injected muscle, and
Table 8–2. Randomized placebo-controlled trials (N>20) focused on tic reduction using YGTSS Total Tic

352 Clinical Manual of Child and Adolescent Psychopharmacology

scorea

Duration, Treatment Active >

Study Drug N weeks effectb placebo? Dropouts, N

Sallee et al. 2000 Ziprasidone 28 8 6.9 Yes 2

Cummings et al. 2002 Guanfacine 24 4 5.6 No NR
Scahill et al. 2003bb Risperidone 34 8 6.0 Yes 2
c
Nicolson et al. 2005 Metoclopramide 28 8 5.9 Yes 4
Toren et al. 2005 Ondansetron 30 3 2.0 No 3
Jankovic et al. 2010 Topiramate 29 10 8.5 Yes 16
Yoo et al. 2013 Aripiprazole 61 10 5.4 Yes 1
Sallee et al. 2017 Aripiprazole 13 8 6.26 Yes 14
Note. Trials with mecamylamine, botulinum toxin, and tetrahydrocannabinol were not included in the table. Trials did not use YGTSS Total Tic
score. Levetiracetam was not included because report did not include results for the first arm of the crossover trial.
NR=not reported; YGTSS=Yale Global Tic Severity Scale.
a
Several other trials (e.g., atomoxetine, guanfacine, selegiline) evaluated tic outcomes on the YGTSS but were primarily focused on ADHD.
bChange in active drug vs. change in placebo.
cFour subjects dropped out; three additional subjects were excluded for protocol violations.
 Tic Disorders 353

loss of voice volume if the vocal cords were the target of treatment. Because
benefit is generally confined to the injected muscle group, botulinum toxin
should only be considered in cases with a prominent tic or interfering tics.
The dosage and frequency of repeat injections have not been standardized.
More study is needed to answer these critical issues, particularly in youth.
Levetiracetam has been examined in open trials and three RCTs. An open-
label trial included 60 youth ages 6–18 years with tics or Tourette’s disorder.
All 60 patients had improvement in tics (YGTSS score, –17.2, P=0.05; mean
total tic score, –5.0, P=0.03) over the course of 1 year (Awaad et al. 2005). Four
years later, the same authors published a randomized, placebo-controlled trial of
levetiracetam for pediatric tics that included 24 children ages 6–18 years with
Tourette’s disorder. Of the 12 patients in the levetiracetam group, 10 noted
improvements in Clinical Global Impression (CGI) scores compared with
1 of 12 patients in the placebo group. (Awaad et al. 2009).
Another RCT compared active levetiracetam with placebo (N=22) (Smith-
Hicks et al. 2007), whereas yet another (N=22) compared it with clonidine
and included adults up to age 27 years (Hedderick et al. 2009). Both trials
used a crossover design and did not provide interpretable information on the
first arm of the trial, thereby making it difficult to compare these results with
those of other trials. Nonetheless, the results of these trials do not support the
use of levetiracetam in children with Tourette’s disorder.
Ondansetron is a selective serotonin 5-HT3 receptor antagonist that was de-
veloped as an antiemetic. A placebo-controlled trial provided encouraging al-
though inconclusive results (Toren et al. 2005). In this study, 30 subjects ages
14–46 years were randomly assigned to ondansetron 24 mg/day (8 mg tid) or
placebo for the 3-week trial. On one measure of tic severity, a significant dif-
ference was found between the active drug and placebo, but no difference was
found between groups in the more frequently used YGTSS Total Tic score.
Ondansetron was well tolerated, but the study had significant limitations. This
drug is not currently recommended for the treatment of tics in youth.
Topiramate is an anticonvulsant that is also used to treat migraine. Its mech-
anism of action is not completely understood, but it appears to enhance GABA-
mediated inhibition at GABAA receptors. It may also have glutamate-blocking
properties. Jankovic et al. (2010) enrolled 29 children and adults in a 10-week,
placebo-controlled trial. Topiramate was started at 25 mg/day and increased
slowly in 25-mg increments to an average dosage of 118 mg/day. The medica-
354 Clinical Manual of Child and Adolescent Psychopharmacology

tion is typically administered on a twice-daily schedule. As shown in Table 8–2,

the treatment effect on the YGTSS Total Tic score was the largest over any
other listed medication, including risperidone (the only studied medication
showing superiority to placebo in more than one trial [Dion et al. 2002; Sca-
hill et al. 2003b]). However, the attrition rate in the topiramate trial was con-
siderably larger than in the other trials presented in the table. The statistical
analysis followed the intent-to-treat convention with last observation carried
forward. Attrition was greater in the placebo group, suggesting that higher
YGTSS scores were carried forward to end point in the placebo group. Thus,
although these results are encouraging, the relatively large treatment effect of
topiramate may be misleading.
A recent meta-analysis of articles compared topiramate with other medica-
tions for children with Tourette’s disorder, using risk ratios to report efficacy and
safety. In the 15 studies, which included 1,070 individuals ages 2–17 years,
topiramate was found to be more effective than the control medication (Yu et
al. 2020). However, current evidence is insufficient to support the use of topi-
ramate because high-quality, placebo-controlled trials are needed. Reports on
the risk of birth defects following fetal exposure to topiramate and the risk, al-
beit apparently low, of metabolic acidosis warrant discussion of the risk-benefit
ratio of this drug in the treatment of Tourette’s disorder. A survey of some
800,000 live births in Denmark over a 12-year period identified 1,532 infants
exposed to newer anticonvulsants, including topiramate (Mølgaard-Nielsen
and Hviid 2011). The authors reported a slight but not significant increase in
the risk of birth defects in infants exposed to topiramate (4.6%) compared
with unexposed infants (2.4%). In a large study of insurance claims between
2002 and 2019, the frequency of oral clefts in children exposed in utero was
0.23% for topiramate and 0.17% for other antiepileptic medications
(RR 1.39) (Green et al. 2012).
An 8-week study of 603 youth ages 5–18 years investigated 5-Ling granule
versus tiapride versus placebo (Y. Zheng et al. 2016). The investigators found
that both the 5-Ling granule and tiapride significantly reduced YGTSS scores.
Participants treated with 5-Ling granule also showed less fatigue, sleep distur-
bance, and dizziness compared with the tiapride group.
In an open study of 10 children treated with metoclopramide, many of
whom had comorbid conditions such as ADHD, all experienced improve-
ment in tics based on YGTSS scores. On average, these participants saw an
 Tic Disorders 355

improvement of 55% in YGTSS scores (Acosta and Castellanos 2004). In an

8-week RCT, 27 children ages 7–18 years were given metoclopramide or pla-
cebo for tics. The medication group (average dosage,32.9±5.1 mg/day) was
found to have a nearly 39% reduction in YGTSS scores versus 13% in the pla-
cebo group (P=0.001) (Nicolson et al. 2005). Side effects did not significantly
differ between groups. Future studies are needed to confirm the efficacy and
safety of metoclopramide in treating Tourette’s disorder.

Summary of Pharmacotherapy for Tics

For children and adolescents with mild tics, medications aimed at reducing
their tics may not be necessary. For children who have tics that are frequent and
forceful and that interfere with activities of daily living, medication is likely in-
dicated. Effective pharmacological treatment typically reduces the frequency
and intensity of tics, but it does not eliminate them. The antipsychotic medi-
cations haloperidol, pimozide, and aripiprazole appear to be the most effective.
Risperidone, ziprasidone, and fluphenazine have also demonstrated some ben-
efit. Although it is considered effective, haloperidol has fallen out of use due to
concerns about its short- and long-term adverse effects. Pimozide is effective
and generally well tolerated at low dosages but requires cardiac monitoring and
is vulnerable to medication interactions. Aripiprazole and risperidone are the
best studied of the newer atypical antipsychotics and are superior to placebo.
Despite a lower risk of neurological side effects with these agents, weight gain
remains an important clinical concern. Ziprasidone also appears to be effective,
but supportive data are limited to one RCT. Botulinum toxin may be consid-
ered for patients with a single interfering tic. However, treatment guidelines on
the dosage and frequency of injection remain somewhat uncertain.

Comorbid Illnesses With Tics

or Tourette’s Disorder
Epidemiology of Comorbid Illnesses
Tourette’s disorder has a high association with comorbid OCD and ADHD,
and they are thought to be of closely related and interconnected pathophysi-
ology (Bloch et al. 2006b; Coffey et al. 1998; Denckla 2006; Lewin et al.
2010; Peterson et al. 2001; Sukhodolsky et al. 2003). In DSM-5 (American
356 Clinical Manual of Child and Adolescent Psychopharmacology

Psychiatric Association 2022), OCD includes a specifier for “tic-related” if a

patient “has a current or past history of a tic disorder.” One study examined
OCD, ADHD, and other comorbidities with a larger sample size. In this mul-
tisite trial, 1,374 participants ages 6 years or older with Tourette’s disorder
were assessed. Of all the participants, 85.7% had at least one comorbidity di-
agnosis and 57.7% had two or more comorbid diagnoses. The most common
comorbidities were ADHD (54.3%) and OCD (50.0%), with 72.1% of pa-
tients having either ADHD or OCD. Most interestingly, of these participants,
29.5% had Tourette’s disorder with OCD and ADHD, 22.4% had Tourette’s
disorder with ADHD, 20.2% had Tourette’s disorder with OCD, and only
27.9% had Tourette’s disorder without ADHD or OCD. Other comorbidi-
ties included mood disorders (29.8%), anxiety disorders (36.1%), disruptive
behavior disorders (28.7%), elimination disorders (16.2%), and low rates of
psychotic and substance use disorders (most likely related to the young age of
the participants) (Hirschtritt et al. 2015).
The evaluation and treatment of comorbid psychiatric illnesses is an im-
portant component of the successful management of a tic disorder. The man-
agement of OCD and ADHD comorbid with tic disorders is covered in
further detail in the discussion that follows.

Pharmacotherapy of OCD With Tics

or Tourette’s Disorder
Diagnosis and Assessment of OCD With Tics or Tourette’s Disorder
OCD is characterized in DSM-5 by recurrent and persistent thoughts, urges,
or images (obsessions) that are difficult to dislodge and/or repetitive behaviors
or mental acts that the person feels driven to perform (compulsions). Many pa-
tients report that attempts to resist the performance of compulsions increases
anxiety as well as the urge to perform the compulsion. According to DSM-5,
the obsessions or compulsions must be time-consuming (taking up at least
1 hour per day) or cause clinically significant distress or impairment. Adoles-
cents and adults with OCD acknowledge that their obsessions or compulsions
are excessive. This realization may not be present in younger children.
In the assessment of children with tic disorders and OCD, it may be diffi-
cult to distinguish between tics and compulsive behaviors. For example, some
children may describe a recurring concern that “something bad will happen” if
 Tic Disorders 357

a specific touching ritual is not completed. Another child may perform a sim-
ilar-appearing ritual but will describe a need or an urge to carry out the behav-
ior in response to an urge that is not related to a fear. This description often
sounds similar to satisfying the premonitory sensations preceding a tic. Chil-
dren with these behaviors who are driven by a sensation or urge will often de-
scribe a need to “get it right” or achieve a sense of completion. In a series of 80
children and adolescents, investigators observed differences in the OCD symp-
tom picture according to the presence or absence of chronic tics (Scahill et al.
2003a). Children with OCD without tics tended to perform rituals to prevent
harm. By contrast, children with chronic tics and OCD appeared to carry out
repetitive behaviors to achieve a sense of completion rather than for harm re-
duction. These findings suggest that assessment should consider the events and
situations associated with the ritualized behaviors and what seems to drive
them—harm reduction or a need to achieve completion.

Pharmacotherapy
Selective serotonin reuptake inhibitors (SSRIs) are often effective in treating
OCD, but unfortunately most RCTs of SSRIs in children and adolescents with
OCD have excluded subjects with Tourette’s disorder, making it unclear how
these results translate to naturalistic clinical samples (Geller et al. 2003b). In
addition, some evidence in children and adults suggests that tic-related OCD
may be a distinct subtype of OCD (Leckman et al. 1994; Scahill et al. 2003a).
OCD with comorbidities responds differently to medications. In a post hoc
study of a previously reported 32-week multisite, efficacy study of paroxetine
in 335 youth with OCD that included those with comorbidities, comorbid
disorders included generalized anxiety disorder (20%), ADHD (19%), specific
phobia (16%), tic disorder (15%), separation anxiety disorder (10%), dysthy-
mia (8%), oppositional defiant disorder (8%), and major depressive disorder
(6%). The response rate to paroxetine for all participants was 71% and was
significantly lower in those with comorbid ADHD (56%), tic disorder (53%),
and oppositional defiant disorder (39%) (Geller et al. 2003a).
Another study used the data sample from the Pediatric OCD Treatment
Study (POTS) published in 2004. Of the 112 participants, 17 had comorbid
tics. When this group of 17 patients was analyzed separately, their treatment re-
sponse was higher for cognitive-behavioral therapy (CBT)+sertraline combi-
nation treatment than for CBT alone. Sertraline was not found to be more
358 Clinical Manual of Child and Adolescent Psychopharmacology

effective than placebo in the comorbid group. These results differed from the
original POTS, which reported that OCD without tics responded better to the
CBT + sertraline combination than to either CBT or sertraline alone (Pediatric
OCD Treatment Study Team 2004).
These results suggest that SSRIs may not be as effective in the treatment of
children and adolescents with OCD and comorbid tics compared with those
with OCD who do not have comorbid tics. Others have suggested using aug-
mentation strategies. One study that looked at augmenting an SSRI included
youth ages 7–18 years with OCD who had not responded to SSRI monother-
apy. The 69 nonresponders were randomly assigned to continue treatment with
adjunctive risperidone or aripiprazole for 12 weeks, and 68.1% saw an improve-
ment in their tics with the addition of the antipsychotic (Masi et al. 2013).
The adult research literature includes studies examining OCD in adult pa-
tients with or without tics. For example, one retrospective study showed that pa-
tients with comorbid tic disorder responded to the addition of haloperidol,
whereas none of those with and without comorbid tics in the placebo group had
improvement in OCD symptoms (McDougle et al. 1994). A systematic review
examined augmentation strategies for treating adults with OCD with or with-
out tics. The results indicated that antipsychotics, specifically risperidone and
haloperidol, are appropriate augmentation for SSRI nonresponders because
one-third of those whose symptoms did not respond to SSRI monotherapy im-
proved with an adjunctive antipsychotic medication. This was particularly true
for those with comorbid tic disorder (Bloch et al. 2006a). In addition, an open-
label study of aripiprazole in 16 youth ages 8–17 years with Tourette’s disorder
or chronic tic disorder, in which 12 had comorbid OCD, demonstrated statis-
tically significant improvements in Child’s Yale-Brown Obsessive Compulsive
Scale obsessions (P<0.002), compulsions (P<0.003), and total (P<0.0003)
scores (Murphy et al. 2009).

Pharmacotherapy of ADHD With Tics

or Tourette’s Disorder
Stimulants
Stimulants are the first-line agents for the treatment of ADHD (MTA Coop-
erative Group 1999; see also Chapter 2, “Attention-Deficit/Hyperactivity Dis-
order”). Because of the lack of efficacy or adverse effects, trials of stimulants fail
 Tic Disorders 359

in 10%–20% of children with ADHD (Elia et al. 1991; MTA Cooperative

Group 1999). Case reports over the past three decades suggest that stimulants
may induce the emergence of tics or an increase in preexisting tics in children
with ADHD (Erenberg et al. 1985; Golden 1974; Lipkin et al. 1994; Lowe et
al. 1982; Riddle et al. 1995; Varley et al. 2001). Two placebo-controlled trials
that excluded children with tic disorders (Barkley et al. 1990; Borcherding et
al. 1990) also reported the emergence of tics in a small percentage of children
treated with stimulants.
However, meta-analyses have examined this purported association. One
study examined the risk of developing de novo tics or of exacerbating existing
tics with psychostimulant treatment of ADHD in children (Cohen et al. 2015).
This meta-analysis included 22 double-blind, randomized, placebo-controlled
trials. The authors found that de novo tics and exacerbation of tics were re-
ported in both the psychostimulant and the placebo groups (5.7% vs. 6.5%).
The risk of de novo tics or exacerbation of tics between psychostimulant and
placebo was similar, with a relative risk of 0.99. Dosage, length of treatment,
and type of psychostimulant did not alter the risk of de novo tics or tic exac-
erbation (Cohen et al. 2015). These and other analyses have concluded that
evidence from RCTs does not support an association between the use of psy-
chostimulants and worsening preexisting tics (Bloch et al. 2009; Pringsheim
and Steeves 2011), as discussed later in this chapter.
Two naturalistic studies also provide information on the longer-term ef-
fects of stimulants in youth with Tourette’s disorder (Gadow et al. 1999; Law
and Schachar 1999). Although most children in these longer-term studies did
not show an increase in tics, acute exacerbations did occur in a few partici-
pants, resulting in either discontinuation of the stimulant or the addition of a
tic-suppressing medication. Taken together, these findings suggest that stimu-
lants should be considered in the treatment of children with ADHD and tics
(Bloch et al. 2009).

Nonstimulants
Various nonstimulant medications have been used in the treatment of children
with ADHD, including the selective norepinephrine reuptake inhibitors atom-
oxetine and desipramine, the antidepressant bupropion, modafinil, and sele-
giline as well as the α2-adrenergic agonists clonidine and guanfacine. Table 8–3
shows the starting dosages and usual maintenance dosages of nonstimulant
360 Clinical Manual of Child and Adolescent Psychopharmacology

Table 8–3. Dosing guidelines for nonstimulant medications used

in the treatment of children with tics and ADHD

Placebo-controlled
trial?

Starting Usual dosage ADHD +

Medicationa dosage, mg range, mg/day ADHDb ticsc

Atomoxetine 18–25 36–100 Yes Yes

Bupropion 25–50 75–150 Yes No
Clonidine 0.025–0.05 0.2–0.3 Yes Yes
Clonidine ER 0.1 0.2–0.3 Yes No
Guanfacine 0.25–0.5 2–3 No Yes
Guanfacine ER 1 2–4 Yes No
Modafinil 50–100 200–400 Yes No
Pindolol 5–10 15–40 Yes No
Selegiline 5 5–10 No Yes
Note. ER=extended release.
a
Desipramine is not listed, having fallen out of use due to concerns about QTc prolongation.
bChildren with ADHD without a tic disorder.
c
Children with ADHD plus a chronic tic disorder.

medications that have been evaluated in the treatment of ADHD (see Chapter 2
for descriptions of other nonstimulants used in the treatment of ADHD).
Four nonstimulant drugs are now FDA-approved for the treatment of
children with ADHD: guanfacine ER (extended release), clonidine ER, ato-
moxetine, and viloxazine ER. Viloxazine ER was FDA-approved for the treat-
ment of ADHD in children and adolescents in 2021, but there are currently
no studies of this medication in individuals with tic disorders.
Three RCTs comparing atomoxetine with placebo in children with ADHD
showed greater efficacy for atomoxetine (Kelsey et al. 2004; Michelson et al.
2001, 2002). An 18-week, placebo-controlled study conducted by Allen et al.
(2005) evaluated the efficacy and safety of atomoxetine in 148 children (mean
age, 11.2 years) with ADHD and a chronic tic disorder. Atomoxetine resulted
in a 28% improvement on a clinician-rated measure of ADHD symptoms com-
 Tic Disorders 361

pared with 14% for placebo. This level of improvement in ADHD symptoms is
similar to but slightly lower than that seen with guanfacine, clonidine, and de-
sipramine in this population. Treatment with atomoxetine also showed a reduc-
tion in tic severity compared with placebo, although this association was not
statistically significant. Atomoxetine treatment was associated with a greater re-
duction in tic severity at end point relative to placebo, approaching significance
(YGTSS total score, –5.5±6.9 vs. –3.0±8.7; P=0.063). The adverse effects in
this study were also similar to those in other reports for atomoxetine in children
with ADHD. Nausea, vomiting, decreased appetite, and weight loss were sig-
nificantly more frequent in the atomoxetine group than the placebo group. In-
somnia, which has been reported in other pediatric ADHD studies, was no
different from placebo in this study.
The α2-adrenergic agonists clonidine and guanfacine are also used to treat
children with ADHD and co-occurring tic disorders, and further information
can be found Chapter 2. Indeed, this class of medications is perhaps the most
commonly used for the treatment of tics and ADHD in tic disorder clinics
(Freeman et al. 2000). The use of clonidine in children with tic disorders has
been evaluated mainly in small studies (e.g., Hunt et al. 1985). The random-
ized, placebo-controlled trial of desipramine by Singer et al. (1995) involving
34 children also included a clonidine arm in the crossover design. In that
study, clonidine was deemed to be no better than placebo.
In a randomized, placebo-controlled trial, Scahill et al. (2001) evaluated
34 children ages 7–14 years with ADHD and a chronic tic disorder treated with
guanfacine. After 8 weeks of treatment with dosages ranging from 1.5 mg/day
to 3.0 mg/day given in three divided doses, the guanfacine group showed 37%
improvement on the teacher-rated ADHD Rating Scale, compared with 8%
for the placebo group. Sedation led to discontinuation by only one subject.
Other adverse effects included a slight drop in mean blood pressure and pulse
and mid-sleep awakening in a few subjects. The three-times-daily dosing may
have been protective against hypotensive effects by minimizing the fluctuation
of the medication level across the day. For example, in a case series of 200 chil-
dren from a Tourette’s disorder clinic who were treated with guanfacine, four
participants had syncopal episodes (King et al. 2006). In this case series, guan-
facine was administered in a single bedtime dose. A review by Scahill et al.
(2006) indicated that cardiac monitoring with routine ECGs is not necessary
when treating children with clonidine or guanfacine. Clearly, the patient’s blood
362 Clinical Manual of Child and Adolescent Psychopharmacology

pressure and pulse should be monitored during dosage adjustment and during
the maintenance phase.
An extended-release formulation of guanfacine was approved for the treat-
ment of ADHD in 2009. This approval was supported by two large-scale trials
that compared multiple fixed doses of guanfacine ER with placebo and estab-
lished its short-term efficacy and safety in children with ADHD (Biederman et
al. 2008; Sallee et al. 2009). However, a multisite, 8-week, randomized, double-
blind, placebo-controlled trial found that guanfacine ER did not have a large
effect on tic severity in youth with chronic tic disorders (Murphy et al. 2017).
The tricyclic antidepressant desipramine has also been used in the treat-
ment of ADHD. Placebo-controlled trials in the 1980s and 1990s showed that
it was effective for the treatment of ADHD in children without co-occurring tic
disorders (Biederman et al. 1989) and in children with ADHD and tic disor-
ders (Singer et al. 1995). Spencer et al. (2002) conducted a 6-week placebo-
controlled study in 41 children with ADHD and a chronic tic disorder. At total
dosages averaging 3.4 mg/kg/day given in two divided doses, desipramine was
superior to placebo on an ADHD symptom rating scale, improving by 42%,
compared with little change in the placebo group. Tics improved by 30% on
average in the desipramine group, compared with no change in the placebo
group. Adverse effects included decreased appetite, insomnia, and dry mouth.
The investigators detected a significant increase in pulse and blood pressure in
the desipramine group but no abnormalities on ECG. Despite these overall
positive results, desipramine is falling out of use due to concerns about pro-
longed cardiac conduction times and reports of sudden death.
Selegiline is a selective monoamine oxidase inhibitor that directly en-
hances dopamine function in the brain. In addition, it is metabolized to an
amphetamine compound in the brain, which may further enhance central cat-
echolamine function. To date, there have been two controlled studies of sele-
giline in children with ADHD. In the first study, Mohammadi et al. (2004)
compared selegiline with methylphenidate in a double-blind, randomized
trial involving 40 children ages 6–15 years with ADHD without co-occurring
tics. Following 60 days of treatment at a maximum total dosage of methyl-
phenidate 40 mg/day or selegiline 10 mg/day (both dispensed in two divided
doses), there was a 54% decrease in the teacher rating for children receiving
methylphenidate and a 50% improvement for those receiving selegiline. Re-
sults on parent ratings were slightly more favorable for both medications.
 Tic Disorders 363

Headache and decreased appetite were more frequent in the methylphenidate

group; otherwise, both medications were well tolerated.
In the second study, Feigin et al. (1996) studied selegiline in 24 children
with Tourette’s disorder and ADHD using a double-blind, crossover design.
Subjects were randomly assigned either to selegiline followed by placebo or to
placebo followed by selegiline. Despite the 6-week washout between phases,
the study design poses serious problems to the interpretation of the results. First,
more than one-third of the sample dropped out of the study. Second, there was
a clear order effect, in that the participants who received selegiline first showed
benefit compared with those assigned to placebo. By contrast, the participants
who received selegiline second actually showed a mean worsening of ADHD
symptoms. Overall, selegiline was no better than placebo. However, a secondary
analysis showed a significant effect for selegiline in the first phase, although
the medication had no apparent impact on tics. Selegiline appears to be well
tolerated. At low dosages, it requires no dietary restrictions, and medication
interaction is not a major concern. However, given the inconsistent results to
date, more study is needed to demonstrate its efficacy for ADHD symptoms.

Comparison Studies of Stimulants and Nonstimulants

In the 16-week Treatment of ADHD in Children with Tic disorders (TACT)
trial conducted by the Tourette’s Syndrome Study Group (2002), 136 children
with ADHD and a tic disorder were randomly assigned to placebo, clonidine
alone, methylphenidate alone, or clonidine plus methylphenidate. Although
the effects were modest, tics declined in all active treatment groups. Approx-
imately one-quarter of the participants in the methylphenidate-only group
showed an increase in tics, which was only slightly higher than the rate seen in
the placebo group. Monotherapy with either clonidine or methylphenidate
was effective in reducing teacher-rated ADHD symptoms, but the magnitude
was small (38% and 36%, respectively, with no correction for placebo) com-
pared with the level of improvement documented for methylphenidate in the
multisite Multimodal Treatment of ADHD (MTA) study (56% for the med-
ication-only group) (MTA Cooperative Group 1999). In contrast, partici-
pants who were randomly assigned to clonidine plus methylphenidate showed
a 57% improvement on ADHD outcomes. The dosage of methylphenidate in
the TACT study was relatively low compared with that given in the MTA
study (25.7 mg/day in two divided doses vs. 31–38 mg/day in three divided
364 Clinical Manual of Child and Adolescent Psychopharmacology

doses). The more conservative approach used in the TACT study may explain
the lower level of improvement observed in the methylphenidate group. The
level of improvement for monotherapy with clonidine in this study is consistent
with the results of another study that employed the same design in children
with ADHD uncomplicated by tic disorders (Palumbo et al. 2008). Taken to-
gether, the results of the TACT trial indicate that methylphenidate can be used
safely in youth with Tourette’s disorder. Given the conservative dosing for
methylphenidate used in that study, clinicians may decide against taking the
more aggressive approach described in the MTA study; although the more con-
servative approach may be associated with a lower magnitude of effect, it may
also be associated with a lower likelihood of adverse effects, including tics.
In more support of the safety of stimulants in treating ADHD with tics, a
meta-analysis by Bloch et al. (2009) included nine RCTs that examined the use
of stimulants and nonstimulants for children with ADHD and comorbid tics.
The study medications in these studies included dextroamphetamine, methyl-
phenidate, clonidine, guanfacine, desipramine, atomoxetine, and deprenyl. The
authors concluded that methylphenidate was the most effective medication
for treating ADHD and did not worsen tics, whereas clonidine and guanfacine
were the most effective in treating both tics and ADHD.
In another meta-analysis, Pringsheim and Steeves (2011) included eight
RCTs of stimulants and nonstimulants for children with tics and ADHD.
They found that tics improved in children treated with guanfacine, desipra-
mine, methylphenidate, clonidine, and the combination of methylphenidate
and clonidine.
One small 12-week, open-label study of aripiprazole in 28 children and
adolescents ages 8–16 years with Tourette’s disorder and comorbid ADHD
demonstrated a significant improvement in tics based on YGTSS scores and
DSM-IV ADHD Rating Scale scores (Masi et al. 2012).

Summary of Pharmacotherapy of ADHD With Tics or Tourette’s Disorder

Stimulants are an appropriate option for the treatment of ADHD in individ-
uals with comorbid tics. The exacerbation of tics or appearance of de novo tics
should be considered a potential side effect, although evidence has not shown
that stimulants worsen tics. Meanwhile, atomoxetine and the α2-adrenergic ag-
onists are also rational choices for the treatment of ADHD in children with
chronic tic disorders, especially if an adequate stimulant trial has been unsuc-
 Tic Disorders 365

cessful. Further data on viloxazine are needed. The α2-adrenergic agonists may
also be used in combination with stimulants. For families who decline treatment
with a stimulant, the α2-adrenergic agonists may be a rational alternative.

Conclusion
The proper diagnosis and assessment of children and adolescents with tic disor-
ders is important to ensure accurate treatment recommendations. Although the
first-line treatment for tic disorders is education, medications may be warranted
for individuals with frequent, forceful, and interfering tics. Habit reversal train-
ing can also be effective in the treatment of tic disorders. Atypical antipsychot-
ics, including aripiprazole and risperidone, have demonstrated effectiveness in
reducing tics and have a better safety profile than older typical antipsychotics.
Tics are also often comorbid with OCD and ADHD. SSRIs typically do not
lead to improvement in tics; therefore, children and adolescents with comorbid
OCD and tic disorders may require treatment with both an SSRI and an aug-
menting agent for the tic disorder. Youth with comorbid ADHD and tic disor-
der may be treated with stimulant medications because newer evidence suggests
that stimulants do not worsen tics. Atomoxetine and the α2-adrenergic agonists
may also be used to treat ADHD in youth with tic disorders.

Clinical Pearls
• Advise patients and their families that Tourette’s disorder is fre-
quently associated with ADHD, obsessive-compulsive symp-
toms, and anxiety.
• Consider education to be the first-line treatment for tics in chil-
dren with Tourette’s disorder.
• Remember that pharmacotherapy specifically targeted at re-
ducing tics may not be needed for children and adolescents
with mild tics.
• Consider psychostimulants, particularly methylphenidate, as a
treatment option for children with ADHD and tics.
366 Clinical Manual of Child and Adolescent Psychopharmacology

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 9
Early-Onset Schizophrenia
and Psychotic Illnesses
Ekaterina Stepanova, M.D., Ph.D.
David I. Driver, M.D.
Nitin Gogtay, M.D.
Judith L. Rapoport, M.D.

C hildhood-onset schizophrenia (COS) or very early-onset schizophrenia is de-

fined as the onset of psychotic symptoms before age 13 (Rapoport et al. 2012).
Clinically, COS resembles the adult form in its positive and negative symptoms.
Neurobiologically, it shares many of the same neuroanatomical anomalies, ge-
netic risks, and neuropsychological deficits as adult-onset schizophrenia (for
review, see Driver et al. 2020). The prevalence of COS is very low (Kleinhaus
et al. 2011). In a National Institute of Mental Health (NIMH) study, the prev-
alence was less than 0.04% (Driver et al. 2020). Given the timing and nature
of the onset, COS is associated with a particularly severe disruption of cogni-

377
378 Clinical Manual of Child and Adolescent Psychopharmacology

tive and social development, and the burden to the family can be devastating.
The term early-onset schizophrenia (EOS) has been used to describe onset be-
fore age 18 years (American Academy of Child and Adolescent Psychiatry
2001). It is estimated that about 10% of patients with schizophrenia have on-
set before age 18 (Rabinowitz et al. 2006). Although many studies considered
in this chapter include patients with symptom onset during adolescence, we
emphasize studies of patients with COS (onset before age 13).

History and Classification of

Psychosis in Children
Although the existence of childhood schizophrenia was recognized early in the
twentieth century (Kraepelin 1919), the term psychosis was used broadly in
children, and a spectrum of behavioral disorders and autism were also grouped
under the category of childhood schizophrenia (Volkmar 1996). The land-
mark studies by Kolvin first established the clinical distinction between au-
tism and other psychotic disorders of childhood (Kolvin 1971). Today, high
rates of initial misdiagnosis remain because of symptom overlap, primarily in
the context of the presence of hallucinations and delusions in nonpsychotic
pediatric patients (Kelleher et al. 2012).
The prevalence of hallucinations in nonpsychotic youth is around 12%
(Maijer et al. 2018). Negative life events and trauma leading to anxiety and
stress have been suggested as the causes of hallucinations in preschool-age chil-
dren, and the prognosis of these phenomena is usually benign. However, psy-
chotic phenomena in school-age children may be more persistent and are
associated with a significant increase in the prevalence and severity of illness
(David and Rapoport 2012; David et al. 2011; Polanczyk et al. 2010). Ac-
cording to data from a large birth cohort, self-reported psychotic symptoms at
age 11 predicted a high risk (OR 16.4) of schizophreniform diagnoses by age
26 (Poulton et al. 2000).
A heterogeneous but sizable group of children referred to as the NIMH
Childhood-Onset Schizophrenia Study since 1991 show transient psychotic
symptoms and multiple developmental abnormalities that cannot be ade-
quately characterized by existing DSM-5 categories (American Psychiatric As-
sociation 2022; Gordon et al. 1994). Therefore, the term multidimensionally
 Early-Onset Schizophrenia and Psychotic Illnesses 379

impaired has been used to capture the mix of stress-related transient episodes of
psychosis, emotional instability, impaired interpersonal skills, and informa-
tion-processing deficits exhibited by these children (Frazier et al. 1994; Kumra
et al. 1998). Along with children with COS, children who are multidimension-
ally impaired have been followed up longitudinally, and they have provided a
medication-matched contrast for various clinical and neuroimaging studies.
In this chapter, we highlight studies that focused on COS because of the
unique psychiatric vantage point provided by this diagnostic subset (Rapoport
et al. 2005a, 2005b).

Epidemiology
Due to the rarity of COS, large-scale epidemiological studies are not feasible.
A study of hospital admissions of 312 psychotic youth over a 13-year period in
Denmark found only four patients who were younger than 13 years at the
time of symptom onset (Thomsen 1996). The NIMH study indicated that
most children younger than 13 who are given a diagnosis of schizophrenia do
not actually meet the criteria for schizophrenia (Driver et al. 2020; Rapoport
and Gogtay 2011). After more than 3,500 screenings, only 217 children have
been offered admission to our study (Driver et al. 2020). Of those, only
134 patients have received a diagnosis of COS.

Course and Outcome

Long-term follow-up of EOS cases indicates chronic illness and impairment.
Hollis (2000) found that, compared with subjects with nonschizophrenic psy-
choses, a large cohort diagnosed with EOS (mean age at onset, 14 years) had
significantly worse outcomes at a mean follow-up of 11 years. A follow-up at
42 years found that earlier age at onset among 44 patients retrospectively
meeting diagnostic criteria for COS was associated with poorer clinical out-
come and higher levels of disability (Eggers and Bunk 1997). Greenstein et al.
(2006) reported on a prospective follow-up study over a mean of 5 years with
32 children in a NIMH cohort and noted that, despite optimal pharmaco-
therapy, high levels of disability and residual psychotic symptoms were evi-
dent. Data from these studies suggest a particularly disabling course of illness.
380 Clinical Manual of Child and Adolescent Psychopharmacology

Although early age at onset was suggested to predict poorer outcomes

(Remschmidt and Theisen 2012), a large longitudinal register-based study in
Denmark did not support poorer long-term outcomes of EOS compared with
adult onset (Vernal et al. 2020). Another study evaluated 10-year outcomes of
youth with EOS and found that age at onset of psychotic symptoms was not
associated with outcomes at follow-up (Xu et al. 2020). Interestingly, predic-
tors of improved functioning in this cohort were an extroverted and suspi-
cious personality as well as a high level of education.
Another factor that plays a large role in the course and outcome of EOS is
treatment resistance, usually defined as a failure of symptoms to respond to at
least two trials of antipsychotic medications (Keepers et al. 2020; Lehman et
al. 2004). A large study examined predictors of treatment resistance in ado-
lescents and young adults (Chan et al. 2021). The investigators showed that
about 15% of patients with schizophrenia spectrum disorders developed treat-
ment resistance. Predictors of treatment resistance were longer duration of the
first episode, younger age at onset, poor premorbid functioning, and higher
dose of antipsychotics.

Rationale for Psychopharmacological Treatment

Treatment of EOS is mostly focused on psychopharmacological intervention.
Nevertheless, the role of psychological interventions should not be neglected,
especially very early in the course of illness (Kendall et al. 2013; McClellan et
al. 2013; Stafford et al. 2013).
The main treatment for schizophrenia is antipsychotic medications (Mc-
Clellan et al. 2013). Most classifications of antipsychotics divide them into
first-generation antipsychotics (FGAs; typical) and second-generation anti-
psychotics (SGAs; atypical). The FGAs are all high-affinity antagonists of do-
pamine D2 receptors, a property that remains the most plausible explanation
for their therapeutic effects. D2 receptor antagonism also explains, in part, one
of the other key features of FGAs: the high rate of movement-related side ef-
fects, particularly extrapyramidal side effects (EPS) and tardive dyskinesia (see
“Extrapyramidal Side Effects” later in the chapter). SGAs differ pharmacolog-
ically from FGAs in their affinity for both D2 and other neuroreceptors
(Burstein et al. 2005). They are also thought to be associated with lower rates
 Early-Onset Schizophrenia and Psychotic Illnesses 381

of EPS, tardive dyskinesia, and hyperprolactinemia, although they vary con-

siderably in their side effect profiles (Abi-Dargham and Laruelle 2005; Miy-
amoto et al. 2005).
In clinical practice, SGAs have been more frequently prescribed. In a re-
view of practices in the United States, SGA prescriptions increased by nearly
500% between 1995 and 2000 and accounted for most of the antipsychotic
prescriptions among children and adolescents (Patel et al. 2002). The ratio of
use for SGA to FGA antipsychotics is greater for children (2.7:1) and adoles-
cents (3.8:1) than for adults (1.6:1) (Sikich et al. 2004). Similar trends are
seen in European countries; however, psychotic disorders account for a mi-
nority of diagnoses in youth receiving antipsychotics (Varimo et al. 2020).

Pharmacotherapy
In evaluating the efficacy of antipsychotics in patients with COS, we focus on
double-blind studies. In addition, we include summaries of the larger prospec-
tive open trials of SGAs that reflect current practices, and we share our experi-
ence with newer medications. It should be stressed here that antipsychotics are
used for a wide range of disorders, and information about the use of both FGA
and SGA formulations is presented throughout this manual.

First-Generation (Typical) Antipsychotics

Efficacy of First-Generation Antipsychotics Versus Placebo in EOS
Early studies of EOS used a placebo comparison to address the important
question of whether antipsychotics had any treatment efficacy (Pool et al.
1976; Spencer et al. 1992) (Table 9–1). In one of the earliest such studies,
Pool et al. (1976) conducted a double-blind, placebo-controlled trial compar-
ing haloperidol (mean dosage, 9.8 mg/day), loxapine (mean dosage, 87.5 mg/
day), and placebo in 75 hospitalized adolescents. All three groups showed sig-
nificant improvement, as assessed with the Clinical Global Impression (CGI)
scale, although patients rated as severely or very severely ill at baseline showed
a trend toward greater improvement with the active treatments (88% for lox-
apine and 72% for haloperidol) than with placebo (38%).
The trial by Pool et al. (1976) had several limitations. First, the criteria for
the diagnosis of schizophrenia rested on clinical consensus, and it is unclear
Table 9–1. Select controlled trials of antipsychotics in patients with COS or EOS

382 Clinical Manual of Child and Adolescent Psychopharmacology

Mean
Mean age,
Study Medication dosage N years Design Criteria Result

First-generation (typical) antipsychotics

Engelhardt et al. 1973 Fluphenazine 10 mg/day 15 10 Randomized, DB CGI much or very 93% (14/15)
much improved
Haloperidol 10 mg/day 15 10 Randomized, DB CGI much or very 87% (13/15)
much improved
Pool et al. 1976 Loxapine 87.5 mg/day 26 15 Randomized, DB CGI much or very 88% (23/26)
much improved
Haloperidol 9.8 mg/day 25 15 Randomized, DB CGI much or very 72% (18/25)
much improved
Placebo NA 24 15 Randomized, DB CGI much or very 38% (9/24)
much improved
Paprocki and Versiani Loxapine 70 mg/day 25 16 Randomized, DB CGI much or very 64% (16/25)
1977 much improved
Haloperidol 8 mg/day 25 16 Randomized, DB CGI much or very 60% (15/25)
much improved
Table 9–1. Select controlled trials of antipsychotics in patients with COS or EOS (continued)

Mean
Mean age,
Study Medication dosage N years Design Criteria Result

Early-Onset Schizophrenia and Psychotic Illnesses

Realmuto et al. 1984 Thiothixene 0.26 mg/kg/ 13 15 Randomized, DB CGI much or very 54% (7/13)
day much improved
Thioridazine 2.57 mg/kg/ 8 15 Randomized, DB CGI much or very 63% (5/8)
day much improved
Spencer et al. 1992 Haloperidol 8.8 mg/day 12 9 Randomized, DB Marked improvement 75% (9/12)
crossover on clinical judgment
Placebo NA 12 9 Randomized, DB Marked improvement 0% (0/12)
crossover on clinical judgment
Second-generation (atypical) antipsychotics
Xiong 2004 Risperidone 2.6 mg/day 30 13.07 Randomized, DB Responder stratified as 80% (24/30)
remission, large responders
improvement, or
minor improvement
based on BPRS
Chlorpromazine 285.8 mg/day 30 93 Randomized, DB Responder stratified as 82% (26/30)
remission, large responders
improvement, or
minor improvement
based on BPRS

383
Table 9–1. Select controlled trials of antipsychotics in patients with COS or EOS (continued)

384 Clinical Manual of Child and Adolescent Psychopharmacology

Mean
Mean age,
Study Medication dosage N years Design Criteria Result

McClellan et al. 2007; Olanzapine 11.4 mg/day 35 8–19 Randomized, DB ≥20% improvement 34%
Sikich et al. 2008 parallel groups, of PANSS score and
multisite CGI score≤2
Risperidone 2.8 mg/day 41 8–19 Randomized, DB ≥20% improvement 46%
parallel groups, of PANSS score and
multisite CGI score ≤2
Molindone 59.9 mg/day 40 8–19 Randomized, DB ≥20% improvement 50%
(+1 mg/day parallel groups, of PANSS score and
benztropine) multisite CGI score ≤2
Kumra et al. 2008a Olanzapine 26.2 mg/day 21a 15.6 Randomized, DB Decrease ≥30% in 33% (7/21)
parallel groups, BPRS from baseline
multisite and CGI score ≤2
Clozapine 403.1 mg/day 18a 15.6 Randomized, DB Decrease ≥30% in 66% (12/18)
parallel groups, BPRS from baseline
multisite and CGI score ≤2
Table 9–1. Select controlled trials of antipsychotics in patients with COS or EOS (continued)

Mean
Mean age,
Study Medication dosage N years Design Criteria Result

Early-Onset Schizophrenia and Psychotic Illnesses

Jensen et al. 2008 Risperidone 3.4 mg/day 10b 15.6 Randomized, OL Decrease ≥40% of 70% (7/10)
PANSS total score
and PANSS positive/
negative subscale
scores
Olanzapine 14.0 mg/day 10b 15.3 Randomized, OL Decrease ≥40% of 50% (5/10)
PANSS total score
and PANSS positive/
negative subscale
scores
Quetiapine 611 mg/day 10b 14.8 Randomized, OL Decrease ≥40% of 30% (3/10)
PANSS total score
and PANSS positive/
negative subscale
scores
Findling et al. 2012 Quetiapine 800 mg/day 74 15.4 Randomized, DB, Decrease ≥30% in 36.5% (27/
(high) parallel groups, PANSS 75)
multisite
Quetiapine 400 mg/day 73 15.4 Randomized, DB, Decrease ≥30% in 38.4% (28/
(low) parallel groups, PANSS 73)

385
multisite
Table 9–1. Select controlled trials of antipsychotics in patients with COS or EOS (continued)

386 Clinical Manual of Child and Adolescent Psychopharmacology

Mean
Mean age,
Study Medication dosage N years Design Criteria Result

Findling et al. 2012 Placebo NA 73 15.4 Randomized, DB, Decrease ≥ 30% in 26.0% (19/
(continued) parallel groups, PANSS 73)
multisite
Findling et al. 2015 Asenapine 5 mg/day bid 104 15.3 Randomized, DB, Decrease ≥ 20% in 50% (52/104)
(high) parallel groups, PANSS total score
multisite and PANSS positive/
negative subscale
scores
Asenapine (low) 2.5 mg/day 96 15.3 Randomized, DB, Decrease ≥ 20% in 49% (47/96)
bid parallel groups, PANSS total score
multisite and PANSS positive/
negative subscale
scores
Placebo NA 100 15.3 Randomized, DB, Decrease ≥ 20% in 36% (36/100)
parallel groups, PANSS total score
multisite and PANSS positive/
negative subscale
scores
Table 9–1. Select controlled trials of antipsychotics in patients with COS or EOS (continued)

Mean
Mean age,
Study Medication dosage N years Design Criteria Result

Early-Onset Schizophrenia and Psychotic Illnesses

Savitz et al. 2015a Paliperidone ER 6.75 mg/day 112 15.3 Randomized, DB, Maintained clinical 52% (58/112)
parallel groups, stabilityc and ≥20% stable,
multisite improvement on 76.8% (86/
PANSS 112) PANSS
Aripiprazole 11.56 mg/day 114 15.3 Randomized, DB Maintained clinical 60% (47/114)
parallel groups, stabilityc and ≥20% stable,
multisite improvement on 81.6% (93/
PANSS 114) PANSS
Correll et al. 2017 Aripiprazole 10–30 mg/day 146 15.3 Randomized, DB, Time to symptom Longer time to
PC, withdrawal, exacerbation exacerbation
multicenter (HR 0.46)
Pagsberg et al. 2017a Quetiapine ER 600 mg/day 55 15.8 DB, randomized, PANSS positive score –5.05
multicenter change
Aripiprazole 20 mg/day 58 15.7 DB, randomized, PANSS positive score –6.21
multicenter change
Goldman et al. 2017 Lurasidone 40 mg/day 108 15.5 DB, randomized, PANSS positive score –18.6
PC change
80 mg/day 106 15.3 DB, randomized, PANSS positive score –18.3
PC change

387
Table 9–1. Select controlled trials of antipsychotics in patients with COS or EOS (continued)

388 Clinical Manual of Child and Adolescent Psychopharmacology

Mean
Mean age,
Study Medication dosage N years Design Criteria Result

Goldman et al. 2017 Placebo NA 112 15.3 DB, randomized, PANSS positive score –10.5
(continued) PC change

Note. BPRS=Brief Psychiatric Rating Scale; CGI=Clinical Global Impression Scale; COS=childhood-onset schizophrenia; DB=double-blind;
EOS=early-onset schizophrenia; HR=hazard ratio; NA=not applicable; OL=open-label; PANSS=Positive and Negative Syndrome Scale; PC= placebo-
controlled.
a
This study was done with patients with treatment-refractory EOS.
bThese populations included EOS and EOS spectrum disorders.
c
Clinical stability is defined as >20% improvement from baseline PANSS, <4 on CGI by day 56, and no hospitalizations.
 Early-Onset Schizophrenia and Psychotic Illnesses 389

whether all of the subjects would meet contemporary DSM-5 criteria for
schizophrenia. The exact age at onset of first symptoms was not given; subse-
quently, it may have been variable. Finally, the degree of treatment resistance
was not provided. Despite these caveats, this remains a landmark study estab-
lishing the efficacy of FGAs in EOS. Additional trials of FGAs in EOS are
summarized in Table 9–1, alongside the landmark atypical trial of the Treat-
ment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS) study (Mc-
Clellan et al. 2007; Sikich et al. 2008). In a double-blind, placebo-controlled
crossover study, Spencer et al. (1992) randomly assigned 12 children meeting
DSM-III-R (American Psychiatric Association 1987) criteria for schizophre-
nia to either haloperidol for 4 weeks followed by placebo for 4 weeks or pla-
cebo for 4 weeks followed by haloperidol for 4 weeks. The exact details of
prior antipsychotics response were not given. On the primary outcome mea-
sure (CGI) and ratings of positive psychotic symptoms, the haloperidol group
alone showed significant improvement (decrease from a baseline score of 5.15
to 2.99; P<0.001), with no significant change in the placebo group. The au-
thors noted that a relatively small dosage of haloperidol, with a range of 0.5–
3.5 mg/day, was optimal.

Comparison of Efficacy of First-Generation Antipsychotics

Several studies have directly compared the efficacy of two FGAs in the absence
of a placebo arm, including double-blind comparisons of fluphenazine and
haloperidol (Engelhardt et al. 1973), thiothixene and thioridazine (Realmuto
et al. 1984), and loxapine and haloperidol (Paprocki and Versiani 1977) (see
Table 9–1). All studies reported high rates of response (based on the CGI),
ranging from 54% to more than 90%, and the antipsychotics did not differ
significantly from each other on nearly all outcome measures. However, these
earlier studies all suffered from the same limitations: the criteria used to define
schizophrenia were unclear, and changes in specific psychotic symptoms were
not reported.
Indeed, given current prescribing practices, most comparisons of FGAs
are of historical interest. However, the results of the NIMH Clinical Antipsy-
chotic Trials of Intervention Effectiveness (CATIE) project, which demon-
strated equal efficacy for the FGA perphenazine and four SGAs in adults with
chronic schizophrenia, may renew interest in the use of FGAs for psychosis
(Lieberman et al. 2005). Xiong (2004) extended this finding in a comparison
390 Clinical Manual of Child and Adolescent Psychopharmacology

of risperidone (response rate 80%) and chlorpromazine (response rate 82%).

The TEOSS study (described in detail later in this chapter) found similar re-
sponse rates between molindone and risperidone (Sikich et al. 2008).

Second-Generation (Atypical) Antipsychotics

Mechanisms of Action
The advent of SGAs appeared to herald an era of treatment for schizophrenia,
with the possibility of more efficacious agents and more favorable side effect
profiles (Kane et al. 1988). Several reviews have considered the issue of what
makes an SGA atypical (e.g., Kapur and Remington 2001). Most agree on
lowered risk of EPS and hyperprolactinemia, with some also reporting that
SGAs are more effective in ameliorating the negative symptoms of schizophre-
nia, although this differential effect is likely to be small (effect size on the order
of 0.1 [Cohen’s d]).
In terms of pharmacological properties, most SGAs have a higher affinity
for serotonin receptors, specifically the 5-HT2A family, and, to a lesser extent,
the dopamine D4 receptor. However, neither property is necessary for atypi-
cality. For example, amisulpride is a relatively pure D2/D3 antagonist lacking
serotonin receptor antagonism, and several FGAs, including haloperidol, have
high affinity for D4 receptors. More recently, it has been proposed that SGAs
may have a faster rate of dissociation from the D2 receptor, allowing the drug
to be more responsive to endogenous dopamine. This, in turn, allows an an-
tipsychotic effect while avoiding EPS and prolactin elevation. Amato et al.
(2011) discussed dynamic dopamine and serotonin responses in both treat-
ment action and failure. Their work highlighted specific changes in dopamin-
ergic response and their reversal as a possible fundamental underpinning for
the action and failure of antipsychotics, respectively.

Efficacy of Second-Generation Antipsychotics

Several SGAs are currently FDA approved for the treatment of schizophrenia
in youth ages 13–17, including olanzapine, risperidone, aripiprazole, lurasi-
done, and quetiapine. In addition, paliperidone has been approved by the
FDA for the treatment of adolescents as young as 12 with schizophrenia.
Most second-generation antipsychotics (aripiprazole, paliperidone, risperi-
done, quetiapine, olanzapine), with the exclusion of ziprasidone, show com-
 Early-Onset Schizophrenia and Psychotic Illnesses 391

parable efficacy based on Positive and Negative Syndrome Scale (PANSS)

total symptom change (meta-analysis; Pagsberg et al. 2017b). Another meta-
analysis suggested that only three antipsychotics (molindone, olanzapine, and
risperidone) were associated with a statistically significant reduction in total
PANSS score (Harvey et al. 2016). In the same study, only haloperidol, olan-
zapine, and risperidone showed significant change in positive PANSS scores,
whereas none of the interventions was significant in improving negative
PANSS scores. In this chapter, we look at SGAs individually to highlight un-
derstanding of their differences and respective strengths.
Risperidone. Among the SGAs, risperidone is prescribed more frequently
than other antipsychotic medications for the treatment of EOS (Vernal et al.
2015). A 6-week open-label study of risperidone (mean dosage, 3.14 mg/day)
in 11 treatment-naive adolescents who met DSM-IV (American Psychiatric
Association 1994) criteria for schizophrenia reported significant improve-
ments in ratings on the CGI and the Brief Psychiatric Rating Scale (BPRS)
and positive, but not negative symptoms, rated on the PANSS (Zalsman et al.
2003). Another study reported a categorical response rate of 60% (response
defined with the CGI) among 10 adolescents (Armenteros et al. 1997). The
dosages of risperidone in this study were higher (mean, 6.6 mg/day), perhaps
reflecting the inclusion of a large proportion of subjects with a history of treat-
ment resistance.
In a 6-week, randomized, double-blind, placebo-controlled study, 160 ad-
olescents ages 13–17 years with schizophrenia were given placebo, risperidone
1–3 mg/day, or risperidone 4–6 mg/day (Haas et al. 2009b). Both risperidone
groups had significantly improved PANSS scores compared with the placebo
group (P<0.001). Adverse effects were present at higher rates in both risper-
idone groups (75% and 76%) than in the placebo group (54%), with the
higher-dosage group demonstrating increased rates of dizziness, hypertonia,
and EPS than the lower-dosage group. Haas et al. (2009a) also published a
study of adolescents with schizophrenia who were randomly assigned 1:1 to
risperidone either 1.5–6.0 mg/day (n=125) or 0.15–0.6 mg/day (n=132). Al-
though treatment was well tolerated overall, patients given the higher dosage
experienced adverse events at a rate of 74%, whereas those given the lower
dosage experienced adverse events at a rate of 65%. In consideration of the low
overall incidence of EPS and lack of hyperprolactinemia, the authors recom-
392 Clinical Manual of Child and Adolescent Psychopharmacology

mended a dosage of risperidone 1–3 mg/day for adolescents with schizophre-

nia (Haas et al. 2009b).

Olanzapine. In some of the earliest work in COS, data from an open-label

NIMH study suggested only modest improvement with olanzapine, with 17%
improvement on the BPRS but only a 1% improvement in positive symptoms
and no significant change in CGI Improvement subscale scores (Kumra et al.
1998). These modest gains are thought to reflect the treatment-refractory na-
ture of the illness in most of the NIMH cohort.
In 12-week open-label olanzapine study involving a group of nine chil-
dren with treatment-refractory schizophrenia, Mozes et al. (2003) found an
overall response of significant improvement on all outcome measures. Studies
that include a treatment-naive population or those involving youth with min-
imal prior exposure to antipsychotics show more robust effects. For example,
among patients in an outpatient study, Findling et al. (2003) found responses
in both negative and positive symptoms. Similarly, Ross et al. (2003) reported
37% full response and 32% partial response rates with olanzapine for school-
age children with schizophrenia. Notably, this significant improvement was
observed only at the 1-year mark, and there was evidence of an increasing
amelioration of negative symptoms with time. This serves to emphasize the
need for longer-term studies. The more recent literature echoes similar find-
ings, although some researchers recommend considering olanzapine as a sec-
ond-line agent for EOS because of its heightened risks for significant weight
gain and lipid dysregulation (Deniau et al. 2008).
Shaw et al. (2006) performed an 8-week, double-blind randomized con-
trolled trial (RCT) of olanzapine versus clozapine with a 2-year open-label
follow-up in a large sample of children ages 7–16 years who met unmodified
DSM-IV criteria for schizophrenia and whose schizophrenia was resistant to
treatment. Compared with clozapine (see section “Use of Clozapine in Treat-
ing Childhood-Onset Schizophrenia”), olanzapine demonstrated a less con-
sistent profile of clinical improvement. Although the results of this study do
not definitively demonstrate the superiority of clozapine over olanzapine in
treatment-refractory COS, the study suggests that in an independent, dichot-
omous comparison of the two antipsychotics, clozapine has a more favorable
clinical response profile and is better balanced against associated adverse
events.
 Early-Onset Schizophrenia and Psychotic Illnesses 393

In another randomized, single-blind, 6-month study conducted in 50 ad-

olescents with early-onset psychosis, no changes were observed in patients’
cognitive performance, and there was no evidence of differential efficacy of
olanzapine or quetiapine on cognitive improvement (Robles et al. 2011).
More recent work has continued to highlight the complex relationship be-
tween olanzapine’s potential for clinical response and its adverse side effects.
One multisite, international, randomized (2:1), double-blind controlled trial
assessed 117 adolescents with schizophrenia receiving flexible dosages of olan-
zapine 2.5–20.0 mg/day (n=72; mean age, 16.1 years) or placebo (n=35; mean
age, 16.3 years) for up to 6 weeks (Kryzhanovskaya et al. 2009b). Participants
given olanzapine showed significantly greater improvement in a comprehen-
sive battery of measures: PANSS total (P= 0.005) and positive (P = 0.002)
scores, BPRS total score (P=0.003), and CGI Severity of Illness subscale score
(P=0.004). They also gained more weight (4.3 kg vs. 0.1 kg; P<0.001) and
had higher mean prolactin and triglyceride levels compared with participants
given placebo (Kryzhanovskaya et al. 2009b).
From a pooled analysis of olanzapine safety in adolescent schizophrenia
populations and a comparison of these data with those of adults treated with
olanzapine, Kryzhanovskaya et al. (2009a) reviewed the data from the acute
phase of multiple olanzapine trials with a mean daily dose of 10.6 mg (expo-
sure =48,946 patient-days). Among the adolescents (N=454) in this study,
2 (0.4%) attempted suicide and 13 (2.9%) experienced suicidal ideation. The
most common adverse events were increased appetite (17.4%), increased
weight (31.7%), and somnolence (19.8%). The adolescents gained signifi-
cantly more weight than did the adults (7.4 kg vs. 3.2 kg; P<0.001). Specif-
ically, within the placebo-controlled database, adolescents demonstrated
significantly greater increases in prolactin levels (11.4 μg/L; P<0.001) from
baseline to study end point (47.4% had high levels), and the overall magni-
tude of prolactin and weight increases was greater in adolescents than in adults
(Kryzhanovskaya et al. 2009a).
In a continuation of the TEOSS study (see McClellan et al. 2007 and Si-
kich et al. 2008 rows in Table 9–1 and the discussion in “Efficacy of First-
Generation Antipsychotics Versus Placebo in Early-Onset Schizophrenia”),
participants ages 8–19 years with schizophrenia who had improved during an
8-week, randomized, double-blind acute trial of olanzapine, risperidone, or
molindone (plus benztropine) were eligible to continue taking the same med-
394 Clinical Manual of Child and Adolescent Psychopharmacology

ication for up to 44 additional weeks under double-blind conditions. No par-

ticular agent was found to demonstrate superior efficacy; instead, patients
taking any of the three medications exhibited typical weight gain and other
metabolic side effects (Findling et al. 2010b; Sikich et al. 2008).
Aripiprazole. Aripiprazole has a unique receptor profile, with partial ago-
nist action at the D2 and 5-HT1A receptors. According to Normala and Ha-
midin (2009), it has unique properties of fewer metabolic complications and
EPS than are commonly observed with other SGAs used to treat children and
adolescents with EOS.
One study evaluated the safety and pharmacokinetics of various dosages
of aripiprazole in patients ages 10–17 years (Findling et al. 2008a). Patients re-
ceived aripiprazole for up to 12 days by forced titration to achieve dosages of
20 mg/day, 25 mg/day, or 30 mg/day and then received the maximum dosage
for 14 more days. Aripiprazole proved generally well tolerated; although all
patients experienced at least one adverse side effect, none met criteria for a se-
rious classification. The pharmacokinetics of aripiprazole administration in
youth appeared linear across the dosage range and was comparable with pre-
vious pharmacokinetics observations in adults.
Another study by Findling et al. (2008b) enrolled youth ages 13–17 years
with schizophrenia in a 6-week, multicenter, double-blind RCT comparing ar-
ipiprazole (10 mg/day and 30 mg/day) with placebo. Subjects given either ari-
piprazole dosage showed statistically significant improvement in PANSS total
scores and improvement in PANSS Hostility factor scores compared with those
given placebo. Although the medication was well tolerated overall, EPS, somno-
lence, and tremors emerged at twice the rate for placebo. However, both the ar-
ipiprazole 10-mg/day and 30-mg/day dosages proved to have superior efficacy to
placebo in treating acute schizophrenia in this young population. The 30-mg/day
dosage showed significant contrasts to placebo by week 3, whereas changes in the
10-mg/day dosage did not appear until week 6 (Findling et al. 2008b).
Aripiprazole’s effectiveness in the treatment of EOS was evaluated in a mul-
ticenter, double-blind, placebo-controlled, randomized withdrawal trial of ad-
olescents ages 13–17 years (Correll et al. 2017). In this study, participants’
symptoms were stabilized on aripiprazole 10–30 mg/day for up to 21 weeks.
Subsequently, they were randomly assigned either to continue the active med-
ication or to placebo for 52 weeks. Those receiving aripiprazole had longer
 Early-Onset Schizophrenia and Psychotic Illnesses 395

time to exacerbation of psychotic symptoms and had lower rates of discontin-

uation compared with the placebo group.
In light of this research, aripiprazole has been suggested as a possible initial
choice for the treatment of schizophrenia, with a better risk-benefit ratio than
risperidone (Goeb et al. 2010), or as an augmentation option with alternative
treatments such as repetitive transcranial magnetic stimulation (Normala and
Hamidin 2009).
A head-to-head comparison of aripiprazole, olanzapine, and risperidone
for the treatment of first-episode schizophrenia was conducted in a random-
ized open trial in China (Cheng et al. 2019). More people receiving risperi-
done had a reduction of 50% or greater in PANSS total score than did those
receiving aripiprazole. However, all medications showed similar efficacy in re-
ducing PANSS scores by 30% or more. Olanzapine was associated with the
largest weight gain but with fewer neurological side effects.
Quetiapine. Quetiapine has a higher affinity for 5-HT2A receptors relative
to D2 receptors and affinity for α1-adrenergic and dopamine D1 receptors but
relatively little muscarinic action. Three open-label studies suggest that que-
tiapine has some efficacy in the treatment of a variety of psychotic disorders in
children, including EOS (Findling et al. 2012; McConville et al. 2003; Shaw
et al. 2001).
In a double-blind, randomized, fixed-dose study compared quetiapine
200 mg/day versus 400 mg/day in 141 drug-naive acutely ill patients ages
15–25 years with first-episode psychosis, both dosages were safe and well tol-
erated, although global and social functioning improved more in the 200-mg
group than in the 400-mg group (Berger et al. 2008). The 200-mg group also
had improvement on the Anhedonia-Asociality subscale of the Scale for the
Assessment of Negative Symptoms, whereas the 400-mg group worsened
slightly. The second phase of the study (a single-blind, naturalistic, flexible-
dose, 8-week period) highlighted that, regardless of the initial dosage, the abil-
ity to flexibly modify the dosage resulted in similar quetiapine levels (average,
268 mg/day for both high- and low-dosage groups) after 12 weeks. The au-
thors recommended conservative quetiapine dosing, beginning with 250–
300 mg/day, for previously untreated patients with new-onset psychosis.
A head-to-head comparison of aripiprazole and extended-release quetia-
pine was described in a double-blind, multicenter, randomized trial in Den-
396 Clinical Manual of Child and Adolescent Psychopharmacology

mark (Pagsberg et al. 2017a). In this study, youth ages 12–17 years diagnosed
with psychotic disorder received treatment with either quetiapine 600 mg/day
or aripiprazole 20 mg/day (both were titrated starting from smaller dosages)
for 12 weeks. PANSS positive scores decreased from baseline but did not differ
between the two groups. Treatment with quetiapine was associated with
weight gain, whereas treatment with aripiprazole was associated with akathisia.
Ziprasidone and paliperidone. Ziprasidone has a complex pharmacology,
acting as an agonist at 5-HT1A receptors and an antagonist at 5-HT1D and
5-HT2C receptors—properties that may confer antidepressant effects. Pub-
lished studies on the use of ziprasidone in patients with COS remain scarce,
although its efficacy in open-label studies of youth with a variety of disorders
has been reported (Barnett 2003). One industry-supported, double-blind,
placebo-controlled, flexible-dose study failed to show any difference in efficacy
between treatment with ziprasidone and placebo in 283 adolescents (Findling
et al. 2010a).
Paliperidone is now approved for use in patients with schizophrenia as
young as age 12 years, following recent additions to the literature of double-
blind trials in adolescents. In a 6-week, double-blind, parallel-group study of
201 youth ages 12–17 years, three weight-based fixed doses of extended-release
paliperidone were compared with placebo. Only the medium (3–6 mg) treat-
ment resulted in a statistically significant improvement, and the authors con-
cluded that this meant there was no need for weight-based dosing (Singh et al.
2011). Interestingly, Savitz et al. (2015a) compared extended-release paliper-
idone and aripiprazole in randomized, double-blind, parallel groups and
found no difference between groups.
Long-term tolerability was assessed in 220 adolescents with schizophrenia
in a large, 2-year, open-label study (Savitz et al. 2015b). The mean decrease in
PANSS total scores was –19.1. Paliperidone was generally well tolerated. The
most frequent side effects included somnolence, weight gain, headache, in-
somnia, akathisia, and tremor.
Amisulpride. Publications have discussed amisulpride as a possible alterna-
tive antipsychotic medication to treat adolescent schizophrenia (Varol Tas and
Guvenir 2009), although the drug is not approved in the United States. De-
spite claims that amisulpride is associated with fewer EPS, case reports of in-
duced tardive dyskinesia have surfaced in adult and adolescent patients. These
 Early-Onset Schizophrenia and Psychotic Illnesses 397

findings have encouraged other analyses, and some results suggest that a com-
bination of amisulpride and multiple other medications, especially antidepres-
sants, may synergistically raise rates of tardive dyskinesia (Goyal and Sinha
2010). Other work suggests that amisulpride does not provide any efficacy ad-
vantage over other SGAs, but a possible reduction in weight gain risk is indi-
cated (Martin et al. 2002; Rummel et al. 2003). Currently, the use of
amisulpride in the treatment of COS has been found to be limited in scope;
with the limited available research, no definitive conclusions can be drawn
(Komossa et al. 2009).

Asenapine and lurasidone. Interest has arisen regarding the use of asena-
pine in adolescent patients. Findling et al. (2015) conducted a randomized,
double-blind, parallel-group comparison of high- and low-dose asenapine
versus placebo in a group of 300 adolescents. Although they noted a trend to-
ward improvement both of the asenapine groups at day 56, this trend did not
achieve statistical significance. Although there is no evidence that asenapine’s
efficacy is superior to that of currently available agents, its favorable weight
and metabolic profiles are of clinical interest (Citrome 2009).
One study evaluated the efficacy and safety of lurasidone in adolescents
ages 13–17 years with schizophrenia (Goldman et al. 2017). This 6-week, ran-
domized placebo-controlled trial showed statistically significant reductions in
PANSS scores compared with placebo at dosages of 40 mg/day (PANSS score
change –18.6) or 80 mg/day (change –18.3). The most common side effects in
this study were nausea, somnolence, akathisia, vomiting, and sedation.

Efficacy of Second-Generation Antipsychotics

Versus First-Generation Antipsychotics in
Childhood-Onset Schizophrenia
A direct comparison between two SGAs, olanzapine and risperidone, and the
most commonly prescribed FGA, haloperidol, was made in a double-blind,
parallel-treatment study (Sikich et al. 2004). The 8-week study included
75 children and adolescents with psychotic symptoms. All three treatments
were associated with significant reductions in BPRS for Children total scores,
which fell to 50% of the baseline score in the risperidone group, 44% of the
baseline score in the olanzapine group, and 67% of the baseline score in the hal-
operidol group. The categorical response rates, like most outcome measures, did
398 Clinical Manual of Child and Adolescent Psychopharmacology

not differ significantly, but there was a trend toward better response rates with
the SGAs: 74% (14 of 19) with risperidone, 88% (14 of 16) with olanzapine,
and 53% (8 of 15) with haloperidol. However, there are important limitations
to the generalizability of these findings. The trials included a diagnostically het-
erogeneous group, and only half of the subjects had a diagnosis of schizophrenia.
A large proportion of the participants were receiving other psychotropic med-
ications; however, no differences in response rates were found across treatment
groups for those treated exclusively with an antipsychotic. These latter findings
are congruent with an 8-week, open-label, nonrandomized comparison of
olanzapine, risperidone, and haloperidol in 43 adolescents in which all three of
the agents were found to be equally efficacious (Gothelf et al. 2003), as well as
with a randomized, double-blind comparison of risperidone and chlorpro-
mazine in 60 adolescents that found equal efficacy (Xiong 2004).
Kennedy et al. (2007) examined the Cochrane Schizophrenia Group Trials
Register in 2006–2007 for antipsychotic effects in COS. Use of FGAs or SGAs
emerged as the only significant distinction criterion in treatment groups. Al-
though Kennedy et al. (2007) noted that any benefit from SGA use was offset
by an increase in adverse effects, Halloran et al. (2010) found that SGAs were
the common primary treatment choice for children with severe psychosis or
multiple psychiatric diagnoses.
Sikich, McClellan, and colleagues conducted the TEOSS study (McClel-
lan et al. 2007; Sikich et al. 2008), which was undertaken in an effort to bring
clarity to the debate regarding the increased efficacy of SGAs. This double-
blind multisite trial randomly assigned children with EOS and schizoaffective
disorder to risperidone (0.5–6 mg/day), olanzapine (2.5–20 mg/day), or mo-
lindone (10–140 mg/day plus benztropine 1 mg/day) for 8 weeks. Results
from the 116 pediatric patients receiving treatment indicated that there was
no significant difference in response rate between treatment groups (see Table
9–1). The study also showed that risperidone and olanzapine were implicated
in the risk of weight gain, with olanzapine causing greater changes than risper-
idone. Additionally, olanzapine was associated with an increased risk of raising
total cholesterol and lipoprotein levels. The patients receiving molindone had
higher rates of self-reported akathisia (a dysphoric sensation of restlessness as-
sociated with an intense need for movement).
In follow-up work from the TEOSS study, Findling et al. (2010b) found
that patients who had shown improvement during the 8-week randomized
 Early-Onset Schizophrenia and Psychotic Illnesses 399

trial continued taking the same medication (for up to 44 weeks under double-
blind conditions). These data confirmed their earlier suppositions that no one
medication had significantly improved efficacy compared with the others. In
addition, although the olanzapine and risperidone groups experienced greater
weight gain during the acute trial, maintenance treatment showed no signif-
icant differences, with increased weight gain and side effects seen in all groups.
From these findings, the researchers questioned recent trends of nearly exclu-
sive SGA use for schizophrenia treatment in youth, while pointing out the
considerable metabolic complications resulting from their administration.

Age-Specific Pharmacotherapy Considerations

Factors such as age at onset, diagnosis subtype, premorbid adjustment, and
cognitive functioning have a meaningful impact on treatment-response tra-
jectories (Levine and Rabinowitz 2010). Vahia et al. (2010) observed nuances
in treatment variations for patients with early- or late-onset schizophrenia.
The EOS group differed from the late-onset group on all measures of psycho-
pathology and cognitive functioning. Despite similarities on measures of de-
pression severity, education, and negative symptoms, patients with EOS
included more males, experienced more severe symptoms, and required higher
antipsychotic dosages. The differences between the subgroups remained sig-
nificant after adjustments for biological sex, age, illness duration, and negative
symptom severity, highlighting treatment differences influenced by age at on-
set of psychosis. Similarly, in a study from Japan, Uchida et al. (2008) found
age to be a vital factor in determining the appropriate antipsychotic dosages
for patients with schizophrenia spectrum disorders, noting that dosage in-
creases progressed with patient age through the third decade, and then they
reached a plateau for two decades before decreasing.

Use of Clozapine in Treating

Childhood-Onset Schizophrenia
Clozapine has emerged as the gold-standard antipsychotic for patients with
treatment-refractory schizophrenia (Kane et al. 1988). Most but not all meta-
analyses suggest clozapine is more efficacious than FGAs and possibly most
SGAs in the short term in adults (Davis et al. 2003; Geddes et al. 2000;
Kumra et al. 2008b; Leucht et al. 2003; Moncrieff 2003). Unfortunately, the
data for youth are much more limited. However, one systematic review found
400 Clinical Manual of Child and Adolescent Psychopharmacology

that clozapine led to an average improvement of 69% on the BPRS in youth

(Schneider et al. 2014). One study found that in 120 youth available for follow-
up in a COS cohort, 72.5% remained adherent to long-term clozapine therapy,
a rate likely reflective of the highly effective nature of clozapine as treatment
(Kasoff et al. 2016). Unfortunately, despite the evidence in favor of clozapine,
the benefits must be weighed carefully against its risks, often limiting its use.
Clinical trials of clozapine for COS have all incorporated the criteria of
treatment resistance, which is a convention for current routine clinical use.
Thus, no data are available on the efficacy of clozapine as a first-line agent for
COS (unlike in adult schizophrenia; see Lieberman et al. 2003). A striking re-
sult is that all open trials found clear efficacy for clozapine in children with
treatment-resistant COS. Frazier et al. (1994) found that 9 of 11 adolescents
from the NIMH cohort showed a greater than 33% reduction in BPRS rat-
ings. Turetz et al. (1997) demonstrated a reduction of approximately 50% on
all measures and also noted that the response occurred relatively early in treat-
ment, between weeks 2 and 8, and was sustained at a 4-month follow-up. No-
tably, data show that about 25%–70% of patients with treatment-resistant
schizophrenia do not achieve response with clozapine (Chan et al. 2021; Sis-
kind et al. 2017). However, long-term follow-up suggests that patients with
treatment-resistant schizophrenia who were given clozapine had lower mor-
tality rates compared with patients whose schizophrenia was not treatment re-
sistant (Chan et al. 2021).
Clozapine has been compared with both SGAs and FGAs. In the first
study, Kumra et al. (1996) compared haloperidol, probably the most widely
used FGA at the time of the study (1990–1996), with clozapine. They ran-
domly assigned 21 children to haloperidol or clozapine for 6 weeks. Clozapine
was markedly superior on all components of the BPRS and ratings of clinical
improvement—a striking finding, given the small sample and the severity of
illness at baseline. The mean dosage of haloperidol was 16.8 mg/day, which is
at the upper end of the contemporary treatment range. Such relatively high
dosages have been implicated in an excess of side effects that mimic the neg-
ative symptoms of schizophrenia and lead to an underestimation of antipsy-
chotic efficacy (Geddes et al. 2000). However, given the history of previous
resistance to antipsychotics among the patients in this study, high dosages
would have been expected and were guided by clinical judgment.
 Early-Onset Schizophrenia and Psychotic Illnesses 401

Shaw et al. (2006) compared the efficacy and safety of olanzapine with
that of clozapine. In an 8-week, double-blind RCT with a 2-year follow-up,
25 patients with COS were randomly assigned to treatment with clozapine
(n=12) or olanzapine (n=13). In this study, clozapine was associated with a
significant reduction in all outcome measures, with olanzapine showing a
rather less impressive improvement. A direct comparison of treatment efficacy
showed generally no significant difference between the groups, but a signifi-
cant advantage for clozapine did emerge in the alleviation of negative symp-
toms of schizophrenia (producing a 45% greater reduction in Scale for the
Assessment of Negative Symptoms ratings; P=0.04; effect size, 0.89). The size
of the differential effect on negative symptoms is therefore large and in
marked contrast to studies of adults with schizophrenia, which report no sig-
nificant difference between olanzapine and clozapine in treating negative
symptoms, despite a larger sample size and power to detect smaller effects
(Bitter et al. 2004; Tollefson et al. 2001; Volavka et al. 2002). The improve-
ment in negative symptoms is unlikely to have been an epiphenomenon of
improvement in mood or EPS, given the lack of correlation between change in
these indices and change in negative symptoms.
Data on the effectiveness and tolerability of antipsychotics in the longer
term are of importance. However, with some significant exceptions (Findling
et al. 2004; Ross et al. 2003), such data are scarce in the pediatric literature. In
the NIMH trial, Shaw et al. (2006) reported that by the 2-year stage, 15 of
18 patients were being treated with clozapine; olanzapine produced a moder-
ately sustained treatment response for only 2 patients. Thus, clozapine ap-
pears to be a highly efficacious choice in a treatment-resistant population.
Considerable interest has been shown in determining what attributes afford
clozapine its efficacy. A study of 54 patients with COS determined that out-
come at 2 years (using the Children’s Global Assessment Scale) was associated
with less severe illness at baseline and a greater initial clinical response to clo-
zapine during the first 6 weeks of treatment (Shaw et al. 2006), as reported in
studies of adults with schizophrenia (Pickar et al. 1994; Sporn et al. 2007). In-
triguingly, the ratio of one of the metabolites of clozapine, N-desmethylclozap-
ine (NDMC), to clozapine was the only variable that was significantly
associated with response at 6 weeks. This result replicated a finding in an adult-
onset schizophrenia study that indicated that a greater NDMC-to-clozapine
402 Clinical Manual of Child and Adolescent Psychopharmacology

ratio, but not the concentrations of clozapine and NDMC themselves, is asso-
ciated with better response (Weiner et al. 2004).
About the time the first edition of this manual was being prepared, Find-
ling et al. (2007) discussed evidence in support of the FDA’s eventual allowance
for clozapine use in children and adolescents, based on controlled treatment
trial data showing clozapine to be more effective for pediatric patients with
treatment-refractory COS or other refractory EOS-spectrum disorders than
at least two FGA medications, haloperidol and olanzapine (Kumra et al.
2008b; Shaw and Rapoport 2006). In addition, a 12-week controlled com-
parison of clozapine versus high-dose olanzapine (up to 30 mg/day) in youth
ages 10–18 years with treatment-refractory schizophrenia supported clozapine
as the agent of choice (Kumra et al. 2008a). Significantly more participants
given clozapine met the response criteria (66%) than those given olanzapine
(33%), and clozapine proved superior in the reduction (from baseline to end
point of their analysis) of negative symptoms as well as psychosis cluster
scores.
The course of COS is difficult, but the high overall response rates found
among patients treated with clozapine are encouraging. Although not cur-
rently seen consistently in the NIMH COS study (Driver et al. 2020), a find-
ing reported by some studies (e.g., Sholevar et al. 2000) is significantly greater
improvement with clozapine in younger subjects. However, although clozapine
is now better established for treatment-resistant schizophrenia, its use in pedi-
atric populations continues to be rare, mainly due to lingering community
concern about its potential adverse effects (Gogtay and Rapoport 2008).

Treatment of Comorbid Conditions

Patients with COS have a very high rate of comorbid conditions (Driver et
al. 2013b; Nicolson et al. 2000). Among 76 children from the NIMH cohort,
the most frequent comorbid diagnosis at screening was depression (54%), fol-
lowed by OCD (21%) and generalized anxiety disorder (15%) (Gochman et
al. 2011). A particularly challenging comorbid condition is ADHD (present
in 15% of the NIMH sample). Psychiatrists have often been reluctant to treat
these symptoms with stimulants for fear of worsening psychosis. However,
Tossell et al. (2004) found that a case series of five children showed a signifi-
 Early-Onset Schizophrenia and Psychotic Illnesses 403

cant improvement in Brief Conners’ Teacher Rating Scale scores of inattentive

symptoms with stimulant treatment following stabilization with an antipsy-
chotic, without any initial worsening of psychosis. This reflects a more general
principle of comorbidity treatment in children with psychosis: treatment of a
coexisting condition should not be overlooked and should be modeled on the
evidence for each disorder following the stabilization of psychosis.

Treatment of Side Effects

The available data from short-term studies suggest that youth might be more
sensitive than adults to developing antipsychotic-related adverse side effects
(e.g., EPS, prolactin elevation, weight gain) (Kumra et al. 2008b). Because the
chronic course of COS necessitates long-term treatment, a thorough consid-
eration of side effects and differential profile is vital in the treatment of pedi-
atric and adolescent populations.

Extrapyramidal Side Effects

EPS are among the most troublesome and distressing unwanted sequelae of
treatment with antipsychotic medications. Pathophysiologically, the blockade
of nigrostriatal dopaminergic tracts mimics the neurochemical deficits seen in
Parkinson’s disease and exhibits a similar clinical profile. The mechanisms un-
derlying tardive dyskinesias are less clear but may stem from the development
of supersensitivity to dopamine resulting from chronic blockade. As men-
tioned in the subsection “Mechanisms of Action,” SGAs have a high sero-
tonin-to-dopamine receptor blockade ratio in the brain. The serotonergic
blockade leads to increased dopamine release, which may partially offset the
postsynaptic dopaminergic blockade, resulting in fewer EPS (Glazer 2000).
Abnormal movements that arise in the first few hours or days of treatment
are typically acute dystonic reactions, which may manifest as spasms of the
orofacial or oculogyric muscles. Adverse effects typically arising after a pro-
longed period of use include akathisia and pseudoparkinsonism (a form of
dyskinetic movement distinguished from parkinsonism by the presence of ap-
raxic slowness and gait, essential tremor, paratonic rigidity, and frontal ataxia).
Several rating scales have been developed to assess abnormal movements, in-
cluding the Abnormal Involuntary Movement Scale (Guy 1976), the Barnes
404 Clinical Manual of Child and Adolescent Psychopharmacology

Akathisia Rating Scale (Barnes 1989), and the Simpson-Angus Rating Scale
(Simpson and Angus 1970).
A comparison of rates of EPS across various studies suggests that FGAs are
associated with high levels of EPS (26%–73%) in patients with COS (Table
9–2). These rates are higher than those typically reported in patients with
adult-onset schizophrenia (32%–55%; Bobes et al. 2003; Novick et al. 2010).
By contrast, five open-label studies of olanzapine and quetiapine, involv-
ing patients with varying treatment histories and a range of ages at illness on-
set, found no significant change in ratings of EPS from baseline (Findling et
al. 2003; McConville et al. 2003; Mozes et al. 2003; Ross et al. 2003; Shaw et
al. 2001). One randomized, double-blind comparison of extended-release
paliperidone and aripiprazole noted a low incidence of, and no statistically sig-
nificant difference on, the occurrence of EPS (Savitz et al. 2015a).
Three open-label studies of risperidone suggest that this SGA is associated
with EPS, akathisia, and acute dystonic reactions, especially at higher dosages
(Armenteros et al. 1997; Grcevich et al. 1996; Zalsman et al. 2003). However,
some studies comparing FGAs and SGAs did not see more severe EPS in pa-
tients treated with risperidone compared with other treatment groups (Find-
ling et al. 2010b; Sikich et al. 2004).
The management of EPS in children follows the principles derived from
adult populations. Strategies such as dosage reduction—with awareness that
this reduction may be associated with a temporary increase in abnormal
movements—and switching while using anticholinergics to provide immedi-
ate relief are commonly used. For tardive dyskinesia, two controlled studies in
adults suggest that switching to clozapine may be the best overall option,
given its ability to treat both the psychosis and the EPS, although the risks and
intensive monitoring make this a less attractive option. Other agents carrying
a low risk of adverse effects, such as vitamin E (Attard and Taylor 2012; Lieb-
erman et al. 1991), can be used as part of an augmentation strategy.

Akathisia
Akathisia has been described mostly in association with typical neuroleptics
but also with olanzapine and risperidone (at rates of about 13%) and cloza-
pine (at rates of about 7%) (Chengappa et al. 1994; Leucht et al. 1999). In the
NIMH cohort, 2 of 40 children treated with clozapine developed akathisia,
Table 9–2. Rates of extrapyramidal symptoms (EPS) in select controlled studies of antipsychotics in
treatment of childhood-onset and/or early-onset schizophrenia

Mean
dosage,

Early-Onset Schizophrenia and Psychotic Illnesses

Study Medication mg/day Measures Results

First-generation (typical) antipsychotics

Engelhardt et al. 1973 Fluphenazine 10.4 Clinical 8/15 EPS, 1/15 acute dystonia, 0/15 akathisia
Haloperidol 10.4 4/15 EPS, 0/15 acute dystonia, 1/15 akathisia
Pool et al. 1976 Loxapine 87.5 Clinical, EPS defined as muscular 19/26 EPS
rigidity of parkinsonian type
Haloperidol 9.8 18/25 EPS
Placebo NA 1/24 EPS
Spencer et al. 1992 Haloperidol 8.8 AIMS 3/12 parkinsonian, 2/12 orofacial dyskinesia,
2/12 acute dystonia
Placebo NA No symptoms (0/12)
First-generation and second-generation (atypical) antipsychotics
Kumra et al. 1996 Haloperidol 16 AIMS/SAS No significant difference from baseline
Clozapine 176 No significant difference from baseline
Gothelf et al. 2003 Olanzapine 12.9 AIMS/UKU 3/19 EPS, 0/19 dystonia, 0/19 akathisia
Risperidone 3.3 4/17 EPS, 1/17 dystonia, 1/17 akathisia

405
Haloperidol 8.3 4/7 EPS, 2/7 dystonia, 3/7 akathisia
Table 9–2. Rates of extrapyramidal symptoms (EPS) in select controlled studies of antipsychotics in

406 Clinical Manual of Child and Adolescent Psychopharmacology

treatment of childhood-onset and/or early-onset schizophrenia (continued)

Mean
dosage,
Study Medication mg/day Measures Results

Sikich et al. 2004 Olanzapine 12.3 AIMS, SAS No significant difference from baseline, 56%
given anticholinergics, no acute dystonia, 2/16
akathisia
Risperidone 4 No significant difference from baseline, 53%
given anticholinergics, no acute dystonia, no
akathisia
Haloperidol 5 Mean SAS significantly higher at end point than
baseline, mean SAS score change significantly
higher than olanzapine or risperidone groups,
67% receiving anticholinergics, 2/15 acute
dystonia, 2/15 akathisia
Shaw et al. 2006 Olanzapine 18.1 AIMS, BARS, SAS No significant difference from baseline
Clozapine 327 No significant difference from baseline
Findling et al. 2010ba Risperidone 1.4 NRS, BARS, AIMS 5% (1/21); no significant difference in mean
changes between groups, no patient in any
group had tardive dyskinesia
Olanzapine 9.6 8% (1/13); no significant difference in mean
changes between groups, no patient in any
group had tardive dyskinesia
Table 9–2. Rates of extrapyramidal symptoms (EPS) in select controlled studies of antipsychotics in
treatment of childhood-onset and/or early-onset schizophrenia (continued)

Mean
dosage,

Early-Onset Schizophrenia and Psychotic Illnesses

Study Medication mg/day Measures Results

Findling et al. 2010ba Molindone 76.5 (+1 35% (7/20) experienced pacing or restlessness;
(continued) benztropine no significant difference in mean changes
for molindone between groups, no patient in any group had
group) tardive dyskinesia
Findling et al. 2012 Quetiapine 800 AIMS, BARS, SAS 13.5% mild to moderate EPS events
(high)
Quetiapine (low) 400 12.4% mild to moderate EPS events
Placebo NA 5.3% mild to moderate EPS events; no
significant difference in baseline to final
between groups
Findling et al. 2015b Asenapine (high) 5 (bid) Clinical, narrow EPSc 10.4% (11/106) EPS, 6.6% (7/114) akathisia
Asenapine (low) 2.5 (bid) 5.1% (5/98) EPS, 4.1% (4/98) akathisia
Placebo NA 3.9% (4/102) EPS, 1% (1/102) akathisia
Savitz et al. 2015a Paliperidone ER 6.75 AIMS, BARS, SAS 11.5% (13/113) akathisia, 6.2% (7/113) muscle
rigidity
Aripiprazole 11.56 7.9% (9/114) akathisia, 2.6% (3/114) muscle
rigidity

407
Table 9–2. Rates of extrapyramidal symptoms (EPS) in select controlled studies of antipsychotics in

408 Clinical Manual of Child and Adolescent Psychopharmacology

treatment of childhood-onset and/or early-onset schizophrenia (continued)

Mean
dosage,
Study Medication mg/day Measures Results

Correll et al. 2017 Aripiprazole 10–30 AIMS, BARS, SAS 6.1% (6/98) EPS, 3.1% (3/98) akathisia, 2%
(2/98) muscle rigidity
Pagsberg et al. 2017a Quetiapine ER 600 AIMS, SAS 32% (15/47) akathisia
Aripiprazole 20 27% (13/48) akathisia
Note. AIMS=Abnormal Involuntary Movement Scale; BARS=Barnes Akathisia Rating Scale; ER=extended release; NRS=Neurological Rating Scale;
SAS=Simpson-Angus Rating Scale; UKU=Udvalg for Kliniske Undersøgelser Side Effect Rating Scale.
aThis is an extension trial of the Sikich et al. (2008) and McClellan et al. (2007) studies. These data are from week 52; earlier data were to week 8.
b
Reported data are only from the double-blind portion of the trial (first 8 weeks).
c
EPS included akathisia, dyskinesia, dystonia, and Parkinson’s-like events.
 Early-Onset Schizophrenia and Psychotic Illnesses 409

which was misinterpreted as a worsening of psychotic symptoms in one case

and led to a temporary increase in clozapine dosage and a concomitant wors-
ening of symptoms (Gogtay et al. 2002). However, when the diagnosis was
made, propranolol was initiated and ameliorated symptoms greatly, allowing
continued treatment with clozapine. Other useful agents include benzodiaz-
epines and perhaps anticholinergics.

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a rare but potentially life-threatening
complication of antipsychotics, typically arises in the early stages of treatment
and has been attributed to the effects of dopamine blockade. Classic signs and
symptoms of NMS include severe muscle rigidity or marked EPS; autonomic
instability, including a high or sometimes fluctuating temperature and blood
pressure; delirium; and laboratory findings of elevated creatine kinase and leu-
kocytosis. SGAs are thought to have a lower incidence of and produce perhaps
a milder form of NMS (Caroff et al. 2000). However, some dramatic case
studies illustrate the potential for this side effect in adolescents who are only
briefly exposed to even SGAs (Hanft et al. 2004). Treatment of NMS relies on
prompt transfer to a medical setting, withdrawal of the neuroleptic, intensive
supportive care, and, if indicated, treatment with dantrolene and/or bro-
mocriptine. Psychotic exacerbations during this period of abrupt antipsychotic
withdrawal have sometimes been treated successfully with electroconvulsive
therapy.

Sedation
High rates of fatigue or sedation have been consistently reported in associa-
tion with nearly all antipsychotics in patients with COS. Rates for haloperidol
range from a low of 25% in a NIMH double-blind study (Shaw et al. 2006) to
50% and 66% in two earlier trials of the medication (Pool et al. 1976; Spencer
et al. 1992). Other FGAs have been associated with even higher rates of seda-
tion (Pool et al. 1976; Spencer et al. 1992).
SGAs are well known to produce the side effect of sedation, and rates
higher than 50% have been reported for ziprasidone and clozapine, with risper-
idone occupying an intermediate position (31%) and olanzapine (20%) and
quetiapine (20%) having lower, but still high, rates (for review, see Cheng-
410 Clinical Manual of Child and Adolescent Psychopharmacology

Shannon et al. 2004). Interestingly, one study linked initial sedation when
taking olanzapine with a better clinical response at 8 weeks, suggesting the
need for perseverance with fatigue and sedation occurring early in treatment
(Sholevar et al. 2000). The management of sedation is empirical and requires
rigorous assessment to exclude underlying psychopathology, maintenance
treatment with as low a dosage as possible, encouragement of activity sched-
uling, and constant motivation.

Weight Gain
Weight gain, reported in association with antipsychotics since their initial use,
has become a focus of more interest given the increased awareness of morbidity
and mortality accompanying obesity (Deckelbaum and Williams 2001). In
their study of 50 children with psychotic symptoms, Sikich et al. (2004) found
a weight gain of 7.1 kg over an 8-week period for children given olanzapine—
a value greater than the gains of 4.9 kg and 3.5 kg reported for risperidone and
haloperidol, respectively. In a double-blind comparison of clozapine and olan-
zapine, a similar weight gain of just under 4 kg over an 8-week period was as-
sociated with both agents, corresponding to an increase of 1.5 units in BMI
(Shaw et al. 2006), with the most extreme weight gains occurring with cloza-
pine. The TEOSS study reported average weight gain of 0.74 kg for molin-
done, 4.13 kg for risperidone, and 7.29 kg for olanzapine (Taylor et al. 2018).
In that study, age, sex, socioeconomic status, baseline weight, and symptoms
did not moderate weight changes.
Among the SGAs other than clozapine, open-label studies report the
greatest weight gain with olanzapine (see Fedorowicz and Fombonne 2005). A
systematic review of antipsychotic use in children, regardless of diagnoses,
found weight gains of 4% with ziprasidone, 7% with clozapine, 17% with
risperidone, and 22% with olanzapine and quetiapine (Cheng-Shannon et al.
2004). In another study, a significant link was found between early-onset di-
agnoses and the subsequent increase in BMI after 6 months of risperidone use
(Goeb et al. 2010). We caution that there may be subtle biological sex and age
confounds in such BMI conclusions, because the general dearth of pediatric
studies does not allow for definitive conclusions (Goeb et al. 2010).
Actively avoiding the use of SGAs solely on the basis of weight gain con-
cerns is debated in the literature. A recent study of EOS showed that although
SGAs caused a significantly larger (P=0.04) gain in baseline weight compared
 Early-Onset Schizophrenia and Psychotic Illnesses 411

with FGAs, this difference was not seen 6 weeks later (Hrdlicka et al. 2009).
The results suggest that pediatric populations may demonstrate much more
variability in weight responses than do adult patients. Because medication non-
compliance may follow excessive weight gain, this should be a particular con-
cern for physicians as they consider social withdrawal and stigma consequences
(Goeb et al. 2010).
Similar weight gain concerns occur in adult studies, which should further
encourage clinicians to explore this side effect holistically. A recent study of
400 patients recruited in the 52-week Comparison of Atypicals in First Epi-
sode of Psychosis trial evaluated olanzapine, quetiapine, and risperidone (Patel
et al. 2009). The investigators found that 31% of patients were overweight
and 18% were obese at baseline (Patel et al. 2009). In addition, 4.3% of pa-
tients met criteria for metabolic syndrome.
Mechanistically, the relative affinities of the SGAs for histamine H1 recep-
tors appear to be the most robust correlate of these clinical findings, although
interactions with serotonergic and dopaminergic receptors are also likely to
play a role (Wirshing et al. 1999). Elevated levels of leptin, a hormone secreted
by adipocytes that partly regulates body weight, are also greater among the an-
tipsychotics most closely linked with weight gain (Herrán et al. 2001).
The management of this side effect has typically relied on behavioral pro-
grams, which unfortunately have mixed evidence of success (Faulkner et al.
2003). One long-term trial of behavior counseling in adolescents receiving
olanzapine did not show differences between intense behavior intervention
and standard weight counseling (Detke et al. 2016). Pharmacological inter-
ventions are also unproven; some case reports suggest that amantadine, topi-
ramate, and various anorectic agents attenuate antipsychotic-induced weight
gain (Generali and Cada 2014; Reekie et al. 2015). Metformin has been in-
vestigated as a possible effective and safe therapy option to manage weight
gain (Klein et al. 2006). Although literature on controlled trials still remains
scarce (Canitano 2005; Gracious et al. 2002), a recent meta-analysis found
significant weight loss in youth receiving metformin along with SGAs (Ellul et
al. 2018). Adolescents taking antipsychotics and metformin lost an average of
3.23 kg after 16 weeks of treatment.
Studies focused on weight gain from antipsychotic treatment remain
scarce. The use of antipsychotics is increasing, despite adverse side effects,
with an increase in the use of SGA medications for off-label purposes (Har-
412 Clinical Manual of Child and Adolescent Psychopharmacology

tung et al. 2008). The risk for weight gain, as well as metabolic side effects,
should be weighed carefully when contemplating the use of any antipsychotic
and should be monitored closely.

Glycemic Control
The link between impaired glycemic control and SGAs is well established in
both children and adults. Sikich et al. (2004) found that olanzapine, but not
risperidone or haloperidol, was associated with a trend toward increased fast-
ing blood glucose. During direct comparison of clozapine and olanzapine (see
“Use of Clozapine in Treating Childhood-Onset Schizophrenia”), little evi-
dence was found for marked hyperglycemia, although comprehensive data
were available only for the 8-week phase. The link with impaired glucose con-
trol could arise through hyperinsulinemia and the impaired sensitivity to in-
sulin found with SGA use (Sowell et al. 2002). Antipsychotics may also have
direct toxic effects on the pancreas. A final link between antipsychotics and
type 2 diabetes mellitus could be through obesity and weight gain associated
with both. Despite the lack of an association between antipsychotic use and
impaired glycemic control in our cohort (Driver et al. 2020), given the limited
evidence, regular blood monitoring is judicious (Jin et al. 2004).

Hyperlipidemia
Sikich et al. (2004) noted a deleterious increase in low-density lipoprotein and
a decrease in high-density lipoprotein in patients randomly assigned to olan-
zapine but not those assigned to risperidone or haloperidol. In the NIMH co-
hort, high levels of hypercholesterolemia and hypertriglyceridemia were seen
in 6 of 15 patients followed up for a 2-year period while receiving open-label
clozapine (Shaw et al. 2006). Although all cases were detected early and man-
aged through diet and lipid-lowering agents, the high rates underscore the
need for regular monitoring (Melkersson et al. 2004).

Hyperprolactinemia
An increase in prolactin secondary to antipsychotics reflects the D2 receptor
blockade in the tuberoinfundibular pathway that releases the tonic inhibition
from dopamine upon pituitary lactotrophs, leading to increased prolactin (for
review, see Pappagallo and Silva 2004). As a result, elevated prolactin levels are
 Early-Onset Schizophrenia and Psychotic Illnesses 413

typically produced by the antipsychotics with greatest D2 affinity (Saito et al.

2004). The sequelae of hyperprolactinemia range from sexual dysfunction,
menstrual irregularities, and lactation to decreased bone density and possible
cardiovascular disease. Wudarsky et al. (1999) found increased prolactin levels
in 36 children with early-onset psychosis after 6 weeks of treatment with ei-
ther haloperidol or olanzapine but not with clozapine. The association may be
modulated by biological sex; in the NIMH cohort, a correlation between
olanzapine and prolactin levels was found among females only (Alfaro et al.
2002). In this study, all but one child remained asymptomatic; the female
with the highest prolactin levels developed transient galactorrhea.
The most effective treatment for symptomatic hyperprolactinemia is to
either reduce the dosage of the antipsychotic (Masi et al. 2001) or switch to an
agent that is possibly less associated with the complication (Shaw et al. 2001).
Dopamine agonists reinstitute the dopaminergic inhibition of prolactin re-
lease, and cabergoline has been used with success in male children with risper-
idone-induced hyperprolactinemia (Cohen and Biederman 2001), although
bromocriptine has a more established role. Whether asymptomatic hyperpro-
lactinemia requires intervention is more controversial, given evidence for the
normalization of prolactin levels at 1-year follow-up in disruptive children be-
ing treated with risperidone (Findling et al. 2004).

Cardiovascular and Autonomic Side Effects

Several antipsychotics alter repolarization of cardiac muscle, as reflected in a
prolonged QT interval. In turn, this change may act as a risk factor for more
serious arrhythmias, such as torsades de pointes. In a double-blind study com-
paring clozapine and olanzapine (see subsection “Use of Clozapine in Treating
Childhood-Onset Schizophrenia”), there were higher rates of supine tachycar-
dia, but no serious arrhythmias, among patients treated with clozapine. How-
ever, seven patients in the clozapine arm became hypertensive during the trial,
compared with only one patient treated with olanzapine.
Cardiometabolic effects of SGAs are of concern to the clinician but have
not been sufficiently studied in pediatric and adolescent patients who were pre-
viously unexposed to antipsychotic medication. Correll et al. (2009) showed
that first-time use of SGAs was associated with significant cardiometabolic
risk. Biases regarding baseline weights and race and ethnicity were limitations
to this study (Correll et al. 2009; Mangurian et al. 2010).
414 Clinical Manual of Child and Adolescent Psychopharmacology

Side Effects Particularly Associated With Clozapine

The association between clozapine and neutropenia is well established. In a re-
view of data on more than 1,100 patients treated with clozapine, the risk of
agranulocytosis was greater in patients younger than 21 years than in those
21–40 years (Alvir et al. 1993). However, Cheng-Shannon et al. (2004) re-
ported two cases of agranulocytosis occurring among 243 children and ado-
lescents treated with clozapine, giving a rate more in line with that seen in the
adult population. Because of this connection, clozapine requires intensive
blood monitoring.
The high rates of neutropenia and agranulocytosis in children are particu-
larly unfortunate given the severity of COS, for which clozapine is often the
only effective treatment. As a result, there is considerable interest in developing
strategies to maximize the opportunity for children to be treated with clozapine
following initial withdrawal due to the development of neutropenia. Sporn et
al. (2003) described the management of two cases of clozapine-induced neu-
tropenia in which the addition of lithium carbonate was associated with a sus-
tained elevation of the white blood cell count, allowing a successful rechallenge
with clozapine. A common strategy is to ensure that blood is drawn after a 2-
hour period of wakefulness/movement as well as in the afternoon, capitalizing
on the diurnal variation in neutrophil levels (McKee et al. 2011). Another rel-
atively new development is the FDA’s modification of the monitoring param-
eters for neutropenia associated with clozapine use, introducing both the
ability to consider benign ethnic neutropenia and the use of clinical judgment.
Epileptiform abnormalities are not uncommon in the electroencephalo-
grams of children and adolescents taking clozapine. Clozapine also has the po-
tential to reduce seizure threshold, and seizures occur in approximately 2% of
children taking the medication. Most patients can continue clozapine along
with an adjunctive anticonvulsant, and prophylactic anticonvulsants are jus-
tified when patients are given high dosages of clozapine. We recommend ga-
bapentin as an anticonvulsant for clozapine-induced seizures, chosen because
of its relatively benign side effect profile and its lack of significant medication
interactions (Usiskin et al. 2000).
Hypersalivation is a distressingly common side effect of clozapine that has
been reported only rarely with the use of other antipsychotics. Proposed mech-
anisms include the action of clozapine at the muscarinic M4 receptor, blockade
 Early-Onset Schizophrenia and Psychotic Illnesses 415

of α2-adrenoceptors, or distortion of the swallowing reflex. Treatment options

include using chewing gum, reducing the dosage of clozapine, or using phar-
macological agents such as anticholinergics, α2-adrenergic agonists, or, in ex-
treme cases, botulinum toxin (Kahl et al. 2004). Some studies suggest that the
addition of other antipsychotics, such as amisulpride, at low dosages may be
efficacious, although a double-blind study found that pirenzepine, one of the
most promising agents (based on results of open-label studies), was no more
effective than placebo (Bai et al. 2001).
Fever, unrelated to neutropenia, agranulocytosis, or NMS, is a rare side ef-
fect of clozapine, with only one report of its occurrence in a child. In the adult
literature, the incidence ranges from 2% to 55%. In both populations, the
consensus is that continuing therapy and providing supportive care are rec-
ommended (Driver et al. 2013a).

Early Intervention Studies

Most of the existing literature focuses on improving treatment when a patient
is already involved with psychiatric services. However, there are several other
windows for intervention. From childhood, adults who develop schizophrenia
have subtle motor and cognitive abnormalities similar to the constellation of
deficits found in children who are at high risk of developing psychosis by vir-
tue of having a parent with schizophrenia (Cornblatt 2002). Many other stud-
ies—most notably, Age, Beginning, and Course, the large epidemiological
study on the course of psychosis—have established the existence of a prodro-
mal phase lasting 2–5 years (Beiser et al. 1993; Häfner et al. 1998). During
this time, an individual experiences a marked decline in overall functioning,
and mental state is characterized by abnormalities of thought, perception, and
action. Nearer the onset of established psychosis, many patients have fully de-
veloped positive psychotic symptoms, but these are transient, intermittent,
and self-terminating. Finally, several studies have demonstrated that typically
a long period of delay occurs between the onset of definite psychotic symp-
toms and the onset of treatment.
Research into interventions during the period between the development
of a DSM-IV-TR (American Psychiatric Association 2000) psychotic disorder
and the beginning of treatment was fueled by evidence that a longer duration
of untreated psychosis is linked to poorer clinical outcome in many, but not
416 Clinical Manual of Child and Adolescent Psychopharmacology

all, studies (for review, see Ruhrmann et al. 2005). Additionally, there are con-
cerns that untreated psychosis is not only intensely distressing for the patient
but also possibly neurotoxic (Lieberman et al. 1997; Pantelis et al. 2003).
Another, more ambitious strategy attempts to identify people who are in a
prepsychotic or prodromal phase and to intervene during this stage. Consid-
ering that the median age at onset of schizophrenia is 19 years, most subjects
in the prodromal phase are adolescents, making the rise of preventive inter-
ventions of particular relevance to the psychiatrist working with youth.
The feasibility of such preventive intervention relies on the ability to accu-
rately identify individuals at high risk of psychosis. The current dominant ap-
proach defines patients at ultrahigh risk of developing psychosis in the near
future by combining the traditional definition of genetic high risk (having a
first-degree relative with a psychotic disorder) with early symptomatic and
functional changes. McGorry et al. (2003) led the field in developing criteria
that suggest ultrahigh risk for the development of psychosis: genetic high risk
and/or schizotypal personality disorder as well as a rapid, recent decline in global
function. Other groups at ultrahigh risk are those with clusters of attenuated
positive symptoms (including unusual thought content/delusional ideation,
suspiciousness/persecutory ideas, grandiosity) and brief, limited, or intermittent
psychotic symptoms. Overall, approximately 40% of patients meeting these cri-
teria will transition to psychosis (not just schizophrenia) within 12 months, with
psychosis defined as the presence of positive psychotic symptoms for longer than
1 week (Yung et al. 2003).
An alternative approach emphasizes so-called basic symptoms, which are
subtle, self-experienced neuropsychological deficits such as thought pressure,
perseverative thinking, derealization, and slight perceptual aberrations. In one
study using this approach, the Cologne Early Recognition Study investigators
correctly predicted a transition to schizophrenia (not only psychosis) in 78%
of cases within 4 years (Klosterkötter et al. 2001), and their work has partly
formed the basis of ongoing prevention studies in Germany.
One of the first studies on early intervention at the prodromal stage was
conducted in the United Kingdom (Falloon 1992). In this study, all patients
who were in the prodromal phase, as defined by DSM-III criteria (American
Psychiatric Association 1980), were given psychoeducation, and some patients
additionally received low-dose antipsychotics. The authors reported a 10-fold
decrease in the incidence of schizophrenia in the region compared with a pre-
 Early-Onset Schizophrenia and Psychotic Illnesses 417

vious period, although the study was uncontrolled, and it is unclear which
components of the intervention were efficacious.
In the first RCT, McGorry et al. (2003) found that significantly fewer pa-
tients who were treated with a mix of low-dose risperidone and psychotherapy
progressed to first-episode psychosis by the end of the 6-month trial period
compared with a group who received nonspecific “needs-based” interventions
(9.7% vs. 35.7%, respectively; P<0.05). This and other RCTs are summarized
in Table 9–3. The significant difference between the groups was not sustained
at a 6-month follow-up after the active intervention, however, because of an in-
crease in the number of patients in the specific-intervention group who became
psychotic. A post hoc analysis suggested that, overall, subjects in the specific-
intervention group who received low-dose risperidone had the lowest rates of
transition to psychosis, although the numbers were small. Given the design of
the study, it is difficult to determine the specific contribution of risperidone to
the findings.
In the Prevention Through Risk Identification, Management, and Edu-
cation trial comparing olanzapine with placebo, Woods et al. (2003) found
that although olanzapine treatment reduced the rate of transition to psychosis
by 50% (from 35% to 16%), the reduction was not statistically significant.
Detailed reporting on the data 8 weeks after initial randomization suggested
more improvement in psychopathology associated with olanzapine treatment,
given at a mean dosage of 10 mg/day over the period (with a significant in-
teraction of groups with scores on the PANSS and the Scale of Prodromal
Symptoms in a linear, mixed-model regression). However, these results must
be taken with caution. A larger, double-blind, placebo-controlled study of
1.4 g/day of omega-3 acids in young people at ultra-high risk for psychosis
failed to detect significant difference between the intervention and placebo
groups in rates of transition to psychosis (Nelson et al. 2018).
A descriptive, interim analysis of a German intervention trial comparing
amisulpride with placebo indicates beneficial effects with amisulpride not
only on attenuated positive symptoms but also on negative and depressive
symptoms and global functioning (Ruhrmann et al. 2003). Whether these
promising initial results will be sustained by future work with additional data
is unclear.
Issues of intervention are contentious. There are several ethical and prag-
matic issues related to using psychotropic drugs during the prepsychotic or
Table 9–3. Randomized trials of interventions for patients at ultrahigh risk of developing

418 Clinical Manual of Child and Adolescent Psychopharmacology

psychosis

Study Interventions N Outcome measures Results Comments

McGorry et al. NBI vs. SPI 59 Development of definite 10/28 NBI vs. 3/31 SPI Lower rate of development of
2003 (risperidone 1.3 mg/ psychotic symptoms developed psychosis at psychosis in patients fully
day + CBT) 6 months; difference not adherent to risperidone
sustained at 12 months (2/17 adherent, 7/17 not)
Woods et al. 2003 Olanzapine (average 60 Development of psychosis 5/31 olanzapine vs. 10/29 Significant group difference
8 mg/day) vs. PBO (based on SOPS) PBO developed psychosis found at 8 weeks using linear
at 8 weeks mixed-models analyses
Morrison et al. TAU vs. CT 58 Development of definite 4/23 TAU vs. 2/35 CT 96% reduction in odds of
2004 psychotic symptoms (based developed psychosis at making a transition to
on PANSS) 12 months psychosis in CT group*
Amminger and ω-3 PUFA (1.2 g/day) 81 Development of definite 2/41 PUFA vs. 11/40 PBO Study in process of being
McGorry 2012; vs. PBO psychotic symptoms (based developed psychosis at replicated on a larger scale by
Amminger et al. on PANSS) 12 months (12-week Markulev et al. 2015
2010 treatment period)
van der Gaag et CBT+TAU vs. TAU 201 Development of psychosis 10/98 CBT + TAU vs. Average age 22.9 years (range,
al. 2012 (defined by CAARMS and 22/103 TAU developed 14–35); CBT specifically
verified by SCAN) psychosis at 18 months focused on normalization
(6-month treatment and awareness of cognitive
period) biases
Table 9–3. Randomized trials of interventions for patients at ultrahigh risk of developing
psychosis (continued)

Study Interventions N Outcome measures Results Comments

Early-Onset Schizophrenia and Psychotic Illnesses 419

Zarafonitis et al. IPI vs. SC 128 Transition to psychosis 12 months: 3.2% IPI vs. Treatment for 12 months with
2012 16.9% SC follow-up at 24 months
24 months: 6.3% IPI vs.
20% SC
McGorry et al. CT+risperidone vs. 115 Transition to psychosis CT+risperidone: 10.7% All three groups improved but
2013 CT+PBO vs. (assessed with CAARMS) no significant differences
CT+PBO: 9.6%
ST+PBO
ST+PBO: 21.8%
Miklowitz et al. 18 sessions FFT vs. 102 Development of psychotic 1/55 of FFT vs. 5/47 PE PE focused on symptom pre-
2014 3 sessions PE conversion (change in 1+ developed psychosis vention, whereas FFT fo-
SOPS positive symptoms cused on early signs, stress
for a score of 6) management, communica-
tion, and problem-solving;
PE was shorter, and neither
group had 100% adherence
Table 9–3. Randomized trials of interventions for patients at ultrahigh risk of developing

420 Clinical Manual of Child and Adolescent Psychopharmacology

psychosis (continued)

Study Interventions N Outcome measures Results Comments

Flach et al. 2015 CBT + MSM vs. 288 Looked at CAARMS at On average, receiving all four CBT specifically included
MSM several points in the study of the necessary CBT formulation and homework,
components, symptom and not everyone randomly
severity reduced by assigned to CBT+MSM
20 points received all four necessary
components of the CBT;
significance of results
depends on defining
treatment effects for patients
who received CBT with none
of the four necessary
components

Note. CAARMS=Comprehensive Assessment of At-Risk Mental States; CBT=cognitive-behavioral therapy; CT=cognitive therapy; FFT=family-
focused therapy; IPI=integrated psychological intervention; MSM=medication self-management; NBI=needs-based intervention; PANSS=Positive
and Negative Syndrome Scale; PBO=placebo; PE=psychoeducation; PUFA=polyunsaturated fatty acid; SC=supportive counseling; SCAN= Sched-
ules for Clinical Assessment in Neuropsychiatry; SOPS=Scale of Prodromal Symptoms; SPI=specific preventive intervention; ST=supportive therapy;
TAU=treatment as usual.
*After adjustment for potential moderating variables.
 Early-Onset Schizophrenia and Psychotic Illnesses 421

prodromal phase. The evidence base for psychotropic use is relatively scant.
This is of particular concern because the best current criteria carry a high rate
of false positives, which means that many patients will be exposed to medica-
tions without any clear evidence that they would have developed psychosis if
left untreated.
The use of nonpharmacological interventions alone for patients in the
prepsychotic and prodromal phrases has also proven to be a promising ave-
nue (Flach et al. 2015; McGorry et al. 2013; van der Gaag et al. 2012). Mor-
rison et al. (2004) found that 5.7% of patients receiving cognitive therapy
developed psychosis over a 1-year period compared with 17.4% receiving
treatment as usual. In addition to research on therapy and management styles,
there is ongoing interest and controversy about the use of preventive omega-3
treatment, after one study showed results similar to those of antipsychotics or
antidepressants: significantly fewer patients (0.05% vs. 27%; n=81) devel-
oped psychosis at 1 year following 3 months of omega-3 treatment (Am-
minger et al. 2010; Mischoulon and Freeman 2013; Mossaheb et al. 2013).
Although promising, this result has not been replicated at this time, and a
larger (n=304) replication study is ongoing (Markulev et al. 2015).
Moreover, whether antipsychotics are necessarily the only, or the best,
pharmacological intervention remains unclear. In the Hillside Recognition
and Prevention Program, adolescents first were identified as being at risk of
developing psychosis based on specific combinations of neurocognitive defi-
cits and then were treated (Cornblatt 2002). Unlike other studies, the youth
did not have to display any attenuated positive symptoms. The 54 adolescents
in this group were treated on an unrandomized, open-label basis with either
antipsychotics or antidepressants (SSRIs). Interestingly, the antidepressants,
often given in combination with mood stabilizers, were as effective as the an-
tipsychotics in promoting clinical improvement.
One review agreed that randomized clinical trials may suggest a positive
effect upon the completion of treatment (Masi and Liboni 2011). However,
without significantly stronger results in the literature, continuing concerns
about side effects and nonadherence preclude any validation to standardize
prodromal intervention in a typical clinical setting (de Koning et al. 2009).
In theory, long-acting injectable antipsychotics (LAIs) could offer a solu-
tion for treating psychosis in children and adolescents who are noncompliant.
This suggestion is extrapolated from data on the use of LAIs in adults with
422 Clinical Manual of Child and Adolescent Psychopharmacology

psychotic disorders, which show the benefit of LAIs in the prevention of hos-
pitalization and relapse compared with oral antipsychotics (Kishimoto et al.
2018, 2021). One meta-analysis provided the best evidence data for a 3-
month formulation of paliperidone and aripiprazole for relapse prevention in
adult participants compared with placebo (Ostuzzi et al. 2021). Unfortu-
nately, the use of LAIs in youth has not been empirically studied, and the lit-
erature is limited to a few case reports within a broader diagnostic cohort. The
use of LAIs in the pediatric population is summarized in a review by Lytle et
al. (2017). Nevertheless, the 2013 practice parameters of the American Acad-
emy of Child and Adolescent Psychiatry recommend that LAIs could be of
value in adolescent patients with schizophrenia who show chronic psychotic
symptoms in combination with poor medication compliance (McClellan et
al. 2013).
Fàbrega et al. (2015) reported the use of LAI paliperidone palmitate in
two adolescent patients. One patient received 50 mg per 28 days to treat EOS
and showed significant improvement on the PANSS and the Global Assess-
ment of Functioning (GAF) Scale after his initial dose. He sustained these
improvements after 1 year of continued treatment and had no adverse effects.
The other patient also received 50 mg per 28 days for psychotic disorder not
otherwise specified. He had an oculogyric crisis but continued treatment
with the addition of biperiden. Although the patient showed improvement
on the PANSS and the GAF, he experienced drowsiness, concentration prob-
lems, and asthenia, causing him to refuse treatment (Fàbrega et al. 2015). In
a case report, Kowalski et al. (2011) described the use of LAI paliperidone
palmitate in an autistic 5-year-old with severe irritability and aggression that
prevented daily medication use. After 3 months of treatment at 39 mg/
0.25 mL/month, the patient’s symptoms were rated as very much improved
using the CGI Improvement subscale. The injections were well tolerated, and
the only reported adverse effect was an increase in appetite.
These case reports suggest that although child and adolescent patients
might benefit from LAI use, responses to treatment and the emergence of po-
tentially harmful side effects are not fully understood. Given the lack of evi-
dence, further research in pediatric populations is needed before LAIs can be
recommended as a standard treatment course.
 Early-Onset Schizophrenia and Psychotic Illnesses 423

Conclusion
Considering the current body of evidence available to guide the child psychi-
atrist through this controversial field, further work to develop our under-
standing of primary and secondary prevention is key. Current reviews of the
literature advocate judicious pharmacotherapy in combination with nonphar-
macological intervention to greatly improve outcomes (Masi and Liboni
2011). Low pharmacological effect sizes, variable remission rates, and an over-
all high incidence of adverse effects, mainly metabolic, highlight the impor-
tance of future efficacy, effectiveness, and efficiency research incorporating
randomized, placebo-controlled studies and long-term, naturalistic follow-up
of large patient samples.

Clinical Pearls
• Childhood-onset schizophrenia (COS) is similar to the adult form
of the disorder but is much more rare, usually more severe, and
more challenging to treat.
• A good treatment plan includes multidisciplinary evaluations
and treatment modalities because COS is associated with nu-
merous deficits.
• Carefully consider the risks and benefits when choosing be-
tween first-generation (typical) and second-generation (atypi-
cal) antipsychotics.
• Consider a trial of clozapine as a third-line option because it re-
mains the only antipsychotic, typical or atypical, with clear, su-
perior efficacy for treatment-resistant forms of psychosis.
• All antipsychotics are associated with adverse side effects, in-
cluding extrapyramidal symptoms and metabolic complica-
tions. Prudent monitoring is key, regardless of the agent used.
• It remains unclear whether treatment during the prepsychotic or
prodromal phase is effective; this continues to be an area of fo-
cused research.
424 Clinical Manual of Child and Adolescent Psychopharmacology

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 10
Eating Disorders
Roxanne Demarest, P.A.-C.
Griffin Stout, M.D.

Eating disorders are a complex and multifaceted group of diagnoses that

have high rates of morbidity and mortality, and they are often difficult to treat.
Eating disorders are prevalent among adolescents, and onset often occurs from
adolescence to young adulthood. Treatment options for eating disorders are
limited, often requiring the patient’s acceptance of the diagnosis to make a
change and do what is feared most: gain weight and adjust their dietary intake.
The treatments that are most studied include psychosocial therapies, including
family-based therapy (FBT), cognitive-behavioral therapy (CBT), and adoles-
cent-focused therapy (Herpertz-Dahlmann 2017). There is limited research
on psychopharmacological treatment of eating disorders, especially in child-
hood and adolescence. Clinicians should use medications cautiously because
of the lack of strong evidence and because no medications have been FDA-ap-
proved for treating eating disorder symptoms in youth. Medications, if used,
should be accompanied by multimodal treatment (e.g., nutrition, psychoso-

441
442 Clinical Manual of Child and Adolescent Psychopharmacology

cial, medical) (Reinblatt et al. 2008). Owing to the dearth of data, the World
Federation of Societies of Biological Psychiatry (WFSBP) instituted a task
force that systematically reviewed psychopharmacological treatments of eat-
ing disorders from 1977 to 2010 (Aigner et al. 2011), which is frequently re-
ferred to in this chapter along with the American Psychiatric Association
(APA), American Academy of Child and Adolescent Psychiatry (AACAP),
and National Institute for Health and Care Excellence (NICE) guidelines.
In this chapter, we discuss the current evidence base for psychopharmaco-
logical treatment of eating disorders. Published randomized controlled trials
(RCTs) of medications conducted specifically with children and adolescents
are very limited (Golden and Attia 2011); therefore, we also discuss the results
of adult studies so that the background evidence can be understood. However,
it is difficult to extrapolate evidence from the adult data for many reasons, in-
cluding differing pharmacodynamics and pharmacokinetics, lack of FDA ap-
proval of medication treatments for youth, and the varying developmental
needs of youth versus adults (Gowers et al. 2010).
Eating disorders are characterized in DSM-5 (American Psychiatric Asso-
ciation 2022) as a persistent disturbance of eating that alters consumption or
absorption of food and leads to impairment of physical or psychosocial func-
tioning. This is an expanded view from DSM-IV-TR (American Psychiatric
Association 2000), which focused on anorexia nervosa (AN), bulimia nervosa
(BN), and eating disorder not otherwise specified (EDNOS). The Eating Dis-
orders Work Group made criteria clearer and more inclusive across the life
span and the sexes, accounting for developmental changes in childhood and
adolescence. They combined the two separate feeding and eating disorders of
infancy or early childhood and eating disorders sections in DSM-IV-TR and
created the “Feeding and Eating Disorders” chapter, which now includes pica,
rumination disorder, avoidant/restrictive food intake disorder (ARFID), AN,
BN, and binge-eating disorder (BED). Other changes include elimination of
amenorrhea as a required criterion for AN because males and premenarchal fe-
males cannot meet this criterion, expansion of the frequency requirement of
compensatory behaviors for BN, and the addition of BED. Using DSM-IV
(American Psychiatric Association 1994) criteria, more than 50% of children
and adolescents with eating disorders were diagnosed with EDNOS (Fisher et
al. 2014). With the new DSM-5 criteria, discussed for each diagnosis, the goal
 Eating Disorders 443

is making more specific diagnoses in children and adolescents and therefore

employing more focused and appropriate treatment.

Anorexia Nervosa
Diagnosis
AN is a serious illness involving the persistent restriction of food intake, fear of
gaining weight, and behavior that interferes with weight gain (Box 10–1). The
severity of AN is determined by the patient’s current BMI; extreme AN is di-
agnosed in individuals with a BMI below 15 (calculated as height in kilograms
divided by meters squared). Developmentally, this leads to a body weight that
is below what is appropriate based on the person’s age, sex, physical health, and
developmental trajectory, which can lead to life-threatening medical condi-
tions. Medically, starvation can affect most major organ systems and can cause
amenorrhea, bradycardia, QTc prolongation, loss of bone mineral density, loss
of hair, blood count abnormalities, and so on (Moore and Bokor 2022). The
malnourished brain often displays symptoms of worsened mood, depression,
irritability, and obsession with food. Some patients with AN have extreme
guilt when they eat, leading to behaviors such as binge eating and subsequent
purging and excessive exercising. The suicide risk is high for those with AN,
with rates of completed suicide of 12 per 100,000 per year (American Psychi-
atric Association 2013). The mortality rate is approximately 5.6% per decade
from either medical complications or suicide (Moore and Bokor 2022). It is
important to highlight how debilitating and deadly this diagnosis can be.

Box 10–1. Anorexia Nervosa

A. Restriction of energy intake relative to requirements, leading to a sig-
nificantly low body weight in the context of age, sex, developmental tra-
jectory, and physical health. Significantly low weight is defined as a
weight that is less than minimally normal or, for children and adoles-
cents, less than that minimally expected.
B. Intense fear of gaining weight or of becoming fat, or persistent behavior
that interferes with weight gain, even though at a significantly low weight.
C. Disturbance in the way in which one’s body weight or shape is experi-
enced, undue influence of body weight or shape on self-evaluation, or
444 Clinical Manual of Child and Adolescent Psychopharmacology

persistent lack of recognition of the seriousness of the current low body

weight.
Coding note: The ICD-10-CM code depends on the subtype (see be-
low).
Specify whether:
F50.01 Restricting type: During the last 3 months, the individual has not
engaged in recurrent episodes of binge-eating or purging behavior (i.e.,
self-induced vomiting or the misuse of laxatives, diuretics, or enemas).
This subtype describes presentations in which weight loss is accom-
plished primarily through dieting, fasting, and/or excessive exercise.
F50.02 Binge-eating/purging type: During the last 3 months, the indi-
vidual has engaged in recurrent episodes of binge-eating or purging be-
havior (i.e., self-induced vomiting or the misuse of laxatives, diuretics,
or enemas).
Specify if:
In partial remission: After full criteria for anorexia nervosa were previ-
ously met, Criterion A (low body weight) has not been met for a sus-
tained period, but either Criterion B (intense fear of gaining weight or
becoming fat or behavior that interferes with weight gain) or Criterion C
(disturbances in self-perception of weight and shape) is still met.
In full remission: After full criteria for anorexia nervosa were previous-
ly met, none of the criteria have been met for a sustained period of time.
Specify current severity:
The minimum level of severity is based, for adults, on current body mass
index (BMI) (see below) or, for children and adolescents, on BMI percentile.
The ranges below are derived from World Health Organization categories
for thinness in adults; for children and adolescents, corresponding BMI per-
centiles should be used. The level of severity may be increased to reflect
clinical symptoms, the degree of functional disability, and the need for su-
pervision.
Mild: BMI ≥17 kg/m2.
Moderate: BMI 16–16.99 kg/m2.
Severe: BMI 15–15.99 kg/m2.
Extreme: BMI <15 kg/m2.

Source. Reprinted from American Psychiatric Association: Diagnostic and Statisti-

cal Manual of Mental Disorders, 5th Edition, Text Revision. Washington, DC, American
Psychiatric Association, 2022. Copyright © 2022 American Psychiatric Association.
Used with permission.
 Eating Disorders 445

Epidemiology
AN commonly begins during adolescence or young adulthood (Moore and
Bokor 2022), and the average prevalence is 0.5%–1.5% in young females.
The female-to-male ratio for AN is estimated to be 10:1 (Lock 2019; Lock et
al. 2015). Data regarding its racial and ethnic distribution are sparse; however,
AN can occur in all racial, socioeconomic, and gender groups (Lock 2019;
Lock et al. 2015).

Treatment
In the past decade, no significant strides have been made in effective treatment
for AN, and no new psychopharmacological treatments have been identified
for adolescents (Lock 2019). According to a 2020 meta-analysis, no evidence
has been published for the use of any psychotropic medication for weight re-
covery, anxiety, or depression in acute-phase AN (Cassioli et al. 2020). High-
quality evidence supporting specific pharmacological interventions for AN at
any age is very limited (Frank and Shott 2016). Thus, medication should not
be used as the sole or primary treatment (National Collaborating Centre for
Mental Health 2004; Treasure and Schmidt 2003). Often, depressive and ob-
sessive-compulsive symptoms can resolve with weight restoration alone. Med-
ications that may have a negative cardiac effect, especially QTc prolongation,
orthostatic hypotension, or cardiac arrhythmias (Pacher and Kecskemeti
2004), should be used with caution in those with AN because of the cardiac
complications associated with the starvation state. The primary goal of initial
treatment is to restore weight through nutritional rehabilitation. FBT is the
most well-studied therapeutic treatment, with repeated positive results in
youth.
Psychotropic medications for AN are greatly needed, especially in adoles-
cents. Research studies in this field are difficult due to high dropout and re-
fusal rates as well as the minority of patients who accept a treatment that will
lead to weight gain or who have the resources to participate in an intensive
treatment (Halmi 2008). This may affect the outcome of studies because the
individuals who are most willing to take part in a study already have some mo-
tivation to recover.
446 Clinical Manual of Child and Adolescent Psychopharmacology

Nutritional Rehabilitation
Treatment for any eating disorder requires a multidisciplinary team including
a medical physician, therapist, dietitian, and, if necessary, a psychiatrist. Indi-
viduals struggling with AN are at higher risk for medical and psychiatric co-
morbidities; therefore, involving other disciplines is key. Weight restoration is
of utmost importance because many symptoms may resolve once weight is re-
stored. Outpatient treatment is recommended, with a weight restoration goal
of 0.5–1 kg/week, which may require consuming an additional 3,500–7,000
calories per week. Hospitalization may be necessary and is most frequently
recommended when there is vital sign instability, including bradycardia, or-
thostatic hypotension, QTc prolongation, electrolyte abnormalities, or sui-
cidality (National Collaborating Centre for Mental Health 2004).

Family-Based Therapy
FBT, or Maudsley family therapy, is one of the most effective treatments for
youth with AN. The philosophy of FBT is that the parent’s involvement is es-
sential in the treatment because the adolescent is unable to make good deci-
sions about food due to their eating disorder cognitions. FBT has three main
phases: 1) weight restoration, 2) transition of control of eating back to the ad-
olescent, and 3) resolution of typical adolescent issues and termination (Lock
and LeGrange 2013).
Studies of FBT involve varying ages of adolescents up to young adults;
therefore, it is difficult to separate the evidence pertaining to adults from that
pertaining to youth. Some RCTs have supported the efficacy of FBT for AN
in adolescents. Patients increased their BMI, improved their scores on eating
disorder assessments, and overall experienced improved psychopathological
symptoms (Lock 2015). FBT has been recommended as the initial treatment
of choice for adolescents with AN (Carr 2000; Eisler et al. 2005; Wilson and
Fairburn 1998; Yager et al. 2014). Individual therapy can be offered for pa-
tients in places where FBT is not feasible. Adolescent-focused therapy is an-
other evidence-based treatment option for AN when FBT is not appropriate;
this approach encourages the patient to work individually on eating and
weight gain with their therapist (Lock 2019). CBT for eating disorders (CBT-
E) is often used in individual therapy for eating disorders, and multiple studies
have shown efficacy of CBT-E for adolescents with AN (Dalle Grave et al.
2019, 2020; Lock et al. 2015).
 Eating Disorders 447

Atypical Antipsychotics
Initially, there was significant interest in antipsychotics for helping those with
AN for many reasons. Antipsychotics block both serotonergic and dopamin-
ergic pathways and have been shown to improve anxiety, agitation, depres-
sion, and obsessions in patients with psychosis. Individuals with AN often
have significant fixed and near-delusionary thoughts about body image and a
distorted self-image. Weight gain is also one of the most commonly noted side
effects of atypical antipsychotics, which could medically benefit patients but
worsen their emotional distress.
Adult studies. The WFSBP found that olanzapine had grade-B evidence
(i.e., “limited positive evidence from controlled studies”) for weight gain, and
other atypical antipsychotics received a grade C (i.e., “evidence from uncon-
trolled studies or case reports/expert opinion”) (Aigner et al. 2011). Olanza-
pine is the most studied antipsychotic in patients with AN and shows modest
efficacy, with more rapid weight gain and improvement in disordered
thoughts/obsessions versus placebo. It has also been shown to improve depres-
sion, anxiety, OCD, and aggression (Aigner et al. 2011; Flament et al. 2012;
Mitchell et al. 2013). RCTs of olanzapine include a trial of 34 adults with AN
that indicated improvement in obsessive thoughts and weight gain (Bissada et
al. 2008). However, a more recent study found no benefit of olanzapine for
psychological symptoms (Attia et al. 2019). With atypical antipsychotics,
concerns have been raised about increasing fasting glucose and insulin levels
in olanzapine treatment groups as well as increased thyroid-stimulating hor-
mone and prolactin in those with AN (Swenne and Rosling 2011).
Among other antipsychotics, risperidone, quetiapine, amisulpride, and
aripiprazole have case studies and small trials that show modest efficacy in im-
proving core AN depression and anxiety symptoms (Aigner et al. 2011; Fla-
ment et al. 2012; Marzola et al. 2015). Evidence is unclear regarding weight
gain in this population while taking antipsychotics (Aigner et al. 2011; Fla-
ment et al. 2012; McKnight and Park 2010). In systematic reviews and meta-
analyses, minimal evidence has been found for the benefit of antipsychotics
(Kishi et al. 2012; Lebow et al. 2013). Typical antipsychotics (e.g., pimozide,
sulpiride, haloperidol, chlorpromazine) have been studied; however, they
were found to be not efficacious and to have a high side effect burden (Aigner
et al. 2011; Flament et al. 2012; Mitchell et al. 2013).
448 Clinical Manual of Child and Adolescent Psychopharmacology

Youth studies. Although studies in children and adolescents are limited,

olanzapine and quetiapine have been used safely in these populations (Boachie
et al. 2003; Mehler et al. 2001; Mehler-Wex et al. 2008). The handful of
open-label and case studies of olanzapine for AN in youth have had mixed re-
sults. One open-label study demonstrated an improvement in BMI (Leggero
et al. 2010). Some case reports have shown improved anxiety and agitation be-
fore and after meals at a dosage of 2.5 mg/day (Boachie et al. 2003), and de-
creased body concerns, anxiety, and sleep disturbances at dosages of 1.255–
7.5 mg/day (Dennis et al. 2006). However, an RCT conducted by Kafantaris
et al. (2011) found no benefit in weight gain or psychological functioning to
adding olanzapine to intensive behavioral treatment for adolescent females
with restricting-type AN.
Case reports of the benefits and safety of risperidone (Fisman et al. 1996;
Mehler-Wex et al. 2008; Newman-Toker 2000) are also very limited. In a re-
cent RCT pilot trial of risperidone (dosage up to 2.5 mg/day for 4 weeks)
given to 40 hospitalized adolescents, no advantage was seen in psychological
measures, including the Eating Disorder Inventory–2, the Color-A-Person
Body Dissatisfaction Test, and the Multidimensional Anxiety Scale for Chil-
dren, or in weight gain with the treatment arm versus placebo (Hagman et al.
2011). Hyperprolactinemia with risperidone remains a concern because this is
a previously associated medical complication of AN (Strike et al. 2012).
In general, side effects with atypical antipsychotics in individuals with
eating disorders were similar to side effects in those without eating disorders
(Swenne and Rosling 2011). Overall, these medications exhibit insufficient
evidence to support their use in the treatment of AN, but they may be helpful
for comorbid conditions. Although the evidence remains limited, providers
commonly use atypical antipsychotics off-label clinically, most frequently
olanzapine (Beykloo et al. 2019).

Antidepressants
In a literature review of case studies, RCTs, and open-label studies in adoles-
cents and adults with AN, Marvanova and Gramith (2018) showed that an-
tidepressants do not benefit AN pathology but may improve symptoms of
comorbid anxiety and depression.
 Eating Disorders 449

Adult studies. Antidepressants have limited proven efficacy in studies of in-

dividuals with AN. In a Cochrane review of four RCTs, it was determined that
information was of limited quality, and none of the evidence supported the
use of antidepressants for weight gain or eating disorder pathology (Claudino
et al. 2006). There are many theories about why antidepressants are not helpful
for those with AN. Flament et al. (2012) found that patients who are severely
underweight may not experience a response to antidepressants. Malnourished
patients have depleted levels of tryptophan due to nutritional deficiencies and
therefore have lower peripheral serotonin levels and profound depletion of cen-
tral serotonin due to weight loss, which can limit the antidepressant’s efficacy
(Brewerton 2012; Kaye 2008). Therefore, guidelines do not advocate for the
use of antidepressants in patients with AN without premorbid anxiety or de-
pressive illnesses (National Collaborating Centre for Mental Health 2004).
Two studies of fluoxetine have attempted to determine any benefit regard-
ing relapse prevention in adults. Kaye et al. (2001) found improvement in
weight gain and a reduction in eating disorder symptoms as well as depres-
sion/anxiety symptoms. However, Walsh et al. (2006) found no difference be-
tween fluoxetine and placebo in time to relapse, BMI, or symptoms of
depression 1 year after weight restoration in a large, well-designed multisite
study. One preliminary study showed that antidepressants used in conjunc-
tion with transcranial magnetic stimulation (TMS) may improve eating dis-
order symptoms more than TMS alone (Dalton et al. 2021).
Tricyclic antidepressants (TCAs) were among the first antidepressants to
be studied; however, no evidence of weight gain in patients was found, and
side effects were significant. Of primary concern are cardiac arrhythmias and
toxicity in overdose (Flament et al. 2012; Mitchell et al. 2013). Monoamine
oxidase inhibitors are also not recommended because of safety concerns (Mar-
vanova and Gramith 2018).

Youth studies. For children and adolescents with AN, several studies have
shown no significant benefit with antidepressant treatment on underlying AN
pathology (Attia et al. 1998; Holtkamp et al. 2005; Kaye et al. 2001). In one
case report, a 16-year-old with AN and depression showed clinical improve-
ment with mirtazapine (Jaafar et al. 2007). Ebeling et al. (2003) studied youth
450 Clinical Manual of Child and Adolescent Psychopharmacology

in recovery who had weight restored and who showed a reduction in eating-
related anxiety when treated with fluoxetine and short-acting benzodiaze-
pines. Antidepressants may negatively influence bone marrow density in ad-
olescents with AN (DiVasta et al. 2017).
Overall, antidepressants can be used to treat comorbid disorders in youth
with AN. Gowers et al. (2010) found that clinically selective serotonin re-
uptake inhibitors (SSRIs) are used to treat comorbid depression and obsessive-
compulsive symptoms in patients with AN.

Other Agents
Low levels of zinc have been thought to contribute to reduced dietary intake.
It has also been hypothesized that zinc deficiency worsens anorexia symptoms
because it affects the areas of the brain involved in food seeking, serotonin me-
tabolism, and weight regulation (Birmingham et al. 1994). The use of zinc
supplementation has been supported by the APA and been given a grade B in
the WFSBP guidelines (Aigner et al. 2011; American Psychiatric Association
2006); however, these effects were less beneficial in children and adolescents
(Lask et al. 1993). Oxytocin may play a role in the AN disease process due to
altered social-emotional functioning (Giel et al. 2018). Results of the benefits
of oxytocin are mixed at this time, and more research is needed. In a study by
Halmi et al. (1986), cyproheptadine was shown to have promise for improve-
ment in weight gain and reduced depressive symptoms in patients who were
not purging; however, there is insufficient evidence for the routine use of an-
tihistamines for weight gain with AN (Aigner et al. 2011). Cannabinoids have
not been found to be effective and were shown to have frequent side effects
(Contreras et al. 2017; Rosager et al. 2021). Studies on benzodiazepines, lith-
ium, naltrexone, Δ-9-tetrahydrocannabinol, and D-cycloserine are limited;
therefore, their use cannot be recommended (Aigner et al. 2011; Flament et
al. 2012).

Bulimia Nervosa
Diagnosis
BN is a complex illness involving periods of binge eating along with maladap-
tive, compensatory behaviors to prevent weight gain and address poor body
 Eating Disorders 451

image. Severity is based on the frequency of these behaviors (American Psychi-

atric Association 2022). Being of significantly low body weight is not a crite-
rion for a BN diagnosis (Box 10–2) as it is for AN (see Box 10–1) (American
Psychiatric Association 2022). Compensatory behaviors can include vomiting,
laxative and diuretic abuse, other medication misuse, fasting, and excessive ex-
ercise (Gorrell and Le Grange 2019). The numerous medical complications of
BN include electrolyte imbalances, cardiac arrhythmias, parotid gland en-
largement, and, rarely, esophageal tears. Individuals who abuse laxatives are
susceptible to an array of gastrointestinal symptoms and disorders (Castillo
and Weiselberg 2017).

Box 10–2. Bulimia Nervosa

A. Recurrent episodes of binge eating. An episode of binge eating is char-
acterized by both of the following:
1. Eating, in a discrete period of time (e.g., within any 2-hour period),
an amount of food that is definitely larger than what most individuals
would eat in a similar period of time under similar circumstances.
2. A sense of lack of control over eating during the episode (e.g., a feeling
that one cannot stop eating or control what or how much one is eating).
B. Recurrent inappropriate compensatory behaviors in order to prevent
weight gain, such as self-induced vomiting; misuse of laxatives, diuret-
ics, or other medications; fasting; or excessive exercise.
C. The binge eating and inappropriate compensatory behaviors both oc-
cur, on average, at least once a week for 3 months.
D. Self-evaluation is unduly influenced by body shape and weight.
E. The disturbance does not occur exclusively during episodes of anorexia
nervosa.
Specify if:
In partial remission: After full criteria for bulimia nervosa were previ-
ously met, some, but not all, of the criteria have been met for a sus-
tained period of time.
In full remission: After full criteria for bulimia nervosa were previously
met, none of the criteria have been met for a sustained period of time.
Specify current severity:
The minimum level of severity is based on the frequency of inappropriate
compensatory behaviors (see below). The level of severity may be increased
to reflect other symptoms and the degree of functional disability.
452 Clinical Manual of Child and Adolescent Psychopharmacology

Mild: An average of 1–3 episodes of inappropriate compensatory be-

haviors per week.
Moderate: An average of 4–7 episodes of inappropriate compensatory
behaviors per week.
Severe: An average of 8–13 episodes of inappropriate compensatory
behaviors per week.
Extreme: An average of 14 or more episodes of inappropriate compen-
satory behaviors per week.

Source. Reprinted from American Psychiatric Association: Diagnostic and Statisti-

cal Manual of Mental Disorders, 5th Edition, Text Revision, Washington, DC, American
Psychiatric Association, 2022. Copyright © 2022 American Psychiatric Association.
Used with permission.

Epidemiology
The median age at onset of BN is 16–17 years. The lifetime prevalence is be-
tween 0.9% and 3%, with a female-to-male ratio of 10:1 to 3:1. Rates of BN
are highest in the Hispanic/Latino population, second highest in the Black
population, and lowest in the white population, in contrast with AN, for
which the 12-month and lifetime prevalence is consistent among ethnic
groups (Castillo and Weiselberg 2017; Lock et al. 2015; Marques et al. 2011).

Treatment
Per AACAP practice parameters (Lock et al. 2015), CBT is the recommended
treatment for BN in adolescents; however, FBT has also been shown to be an
evidence-based treatment for this population (Gorrell and Le Grange 2019).
Current clinical guidelines for treating BN in youth do not recommend psy-
chiatric medication due to the limited amount of published positive studies
(Gorrell and Le Grange 2019). As discussed later in this section (see “Medi-
cation Treatment”), fluoxetine (60 mg/day) has an FDA indication for treat-
ment of purging and binge-eating urges in adults (Sohel et al. 2022).

Psychological Treatment
CBT and FBT have been shown to be effective treatments for adolescents with
BN (Gorrell and Le Grange 2019; Lock et al. 2015). CBT focuses first on nor-
malizing eating patterns. Once this is accomplished, the patient’s beliefs, fears,
and cognitive distortions are challenged via behavioral experiments (Lock et
 Eating Disorders 453

al. 2015). Two RCTs of FBT for BN versus supportive psychotherapy and
CBT for adolescents have demonstrated statistical and clinical improvements
with FBT in binge eating and purging that were maintained up to 12 months
posttreatment (Gorrell and Le Grange 2019).
CBT-E for eating disorders is recommended if FBT is not indicated (Gor-
rell and Le Grange 2019). There is emerging evidence that CBT can be effec-
tive for older adults and older adolescents with BN, and multiple subtypes of
CBT are currently being studied (Atwood and Friedman 2019; Gorrell and Le
Grange 2019). In one subtype, CBT-E, stage 1 includes psychoeducation and
preparing the patient for change, weekly weighing, and regular eating (three
meals and two or three snacks per day). Stage 2 is a brief check-in with prog-
ress, involving either praise for positive movement or refocusing if there is a
lack of change. Stage 3 focuses on cognitions associated with eating disorders,
including body image, dietary rules, perfectionism, and low self-esteem. Fi-
nally, stage 4 includes relapse prevention and termination of therapy (Murphy
et al. 2010). A meta-analysis by Wade (2019) showed that CBT-E outper-
formed other psychological treatment comparisons, including interpersonal
therapy (IPT) and psychoanalytic therapy. This meta-analysis also showed that
CBT-E can be effective when used as guided self-help. IPT is a second-line
therapeutic option for the treatment of BN in adults (Hagan and Walsh 2021).

Medication Treatment
Antidepressants. New evidence for medication efficacy in BN has been lim-
ited. Therapy continues to be the recommended first-line treatment, and very
few RCTs for BN in adolescents exist (Hagan and Walsh 2021).
Adult studies. The most well-studied antidepressant is fluoxetine, which has
an FDA indication for the acute and maintenance treatment of binge eating and
self-induced vomiting behaviors in adults with moderate to severe BN. Its use
consistently has been shown to improve BN psychopathology and to help with
relapse prevention (Goldstein et al. 1999; Gorrell and Le Grange 2019; McEl-
roy et al. 2019). Fluoxetine is supported as the first-line medication treatment
for adults with BN at a dosage of 60 mg/day over 8–16 weeks (Aigner et al.
2011; Bacaltchuk and Hay 2003; Flament et al. 2012). In a trial of 387 adults
with BN, fluoxetine medication response, as measured by at least a 60% de-
crease in binge eating or vomiting, was predictable at 3 weeks; however, 8 weeks
454 Clinical Manual of Child and Adolescent Psychopharmacology

were required to see a full response (Sysko et al. 2010; Walsh et al. 2006). The
positive effects of antidepressants in bingeing/purging symptoms are indepen-
dent of their positive effects on mood (Goldstein et al. 1995; Shapiro et al.
2007; Walsh et al. 1984). In one study, citalopram showed a positive effect for
reducing depressive feelings in adults with BN (Leombruni et al. 2006).
Bupropion is contraindicated in patients with BN due to its increased risk
of seizures (McElroy et al. 2019). In a 1988 study, 4 of 55 patients with no
previous history of seizures who received bupropion experienced grand mal
seizures. The study was discontinued because of the perceived danger to pa-
tients (Horne et al. 1988).
In their review, the WFSBP looked at 36 RCTs of medications for the
treatment of BN. Looking for an overall decrease in bulimic behaviors, Aigner
et al. (2011) gave grade A to fluoxetine, with a good risk-benefit ratio. TCAs
and topiramate were also given grade A, but with a moderate risk-benefit ratio
(Aigner et al. 2011).

Youth studies. One uncontrolled, open trial suggested that antidepressants

may be helpful for adolescents with BN. Kotler et al. (2003) studied 10 adoles-
cents ages 12–18 years who received fluoxetine 60 mg/day along with support-
ive psychotherapy for 8 weeks. Weekly binge-and-purge episodes decreased to
zero and “almost none,” respectively, as rated by the youth. Although TCAs have
shown efficacy, their use is discouraged in children and adolescents due to con-
cerns about their side effect profile and toxicity in overdose (Aigner et al. 2011;
Flament et al. 2012; Mitchell et al. 2013).

Other Agents
Topiramate has shown efficacy in adults at reducing core BN symptoms,
bingeing, and purging. However, topiramate has frequent side effects that im-
pact tolerability (Aigner et al. 2011; Hedges et al. 2003; Hoopes et al. 2003;
Nickel et al. 2005). One RCT of extended-release phentermine-topiramate
that included four adults with BN found this medication to be well tolerated
and more effective at reducing binge eating than placebo (Safer et al. 2020).
Case studies in adults treated with aripiprazole and methylphenidate have
shown positive effects for treatment-resistant BN; however, their use is not sup-
ported because of the potential risk of seizures (Aigner et al. 2011). Currently,
no studies have shown efficacy for lisdexamfetamine in BN, although it has
 Eating Disorders 455

been shown to be safe in adults with BN (Keshen et al. 2021). In an open-label

trial that included seven adults with BN, a reduction in objective and subjec-
tive binge episodes was seen when polaprezinc was added to antidepressant
treatment (Sakae et al. 2020). In a double-blind, placebo-controlled crossover
study in Korea, a single dose of intranasal oxytocin in college-age women with
BN led to enhanced emotional sensitivity and decreased caloric intake over
24 hours (Kim et al. 2015).

Binge-Eating Disorder
Diagnosis
BED is a serious illness associated with significant stigma (Hollett and Carter
2021; Phelan et al. 2015). Symptoms can be debilitating; however, patients
often do not seek treatment due to shame. They also rarely self-disclose binge
behaviors; therefore, physicians should screen for BED (Maguen et al. 2018).
Embarrassment related to the binge episode is a diagnostic criterion of BED,
so providers must gather information sensitively and with compassion. BED
was first defined in DSM-5 (Box 10–3; American Psychiatric Association
2013) and the primary symptoms include eating an objectively large amount
of food (more than what most would eat) and the sense that one has lost con-
trol of their eating.

Box 10–3. Binge-Eating Disorder

A. Recurrent episodes of binge eating. An episode of binge eating is char-
acterized by both of the following:
1. Eating, in a discrete period of time (e.g., within any 2-hour period),
an amount of food that is definitely larger than what most people
would eat in a similar period of time under similar circumstances.
2. A sense of lack of control over eating during the episode (e.g., a
feeling that one cannot stop eating or control what or how much one
is eating).
B. The binge-eating episodes are associated with three (or more) of the
following:
1. Eating much more rapidly than normal.
2. Eating until feeling uncomfortably full.
456 Clinical Manual of Child and Adolescent Psychopharmacology

3. Eating large amounts of food when not feeling physically hungry.

4. Eating alone because of feeling embarrassed by how much one is
eating.
5. Feeling disgusted with oneself, depressed, or very guilty afterward.
C. Marked distress regarding binge eating is present.
D. The binge eating occurs, on average, at least once a week for 3 months.
E. The binge eating is not associated with the recurrent use of inappro-
priate compensatory behavior as in bulimia nervosa and does not
occur exclusively during the course of bulimia nervosa or anorexia
nervosa.
Specify if:
In partial remission: After full criteria for binge-eating disorder were
previously met, binge eating occurs at an average frequency of less
than one episode per week for a sustained period of time.
In full remission: After full criteria for binge-eating disorder were pre-
viously met, none of the criteria have been met for a sustained period
of time.
Specify current severity:
The minimum level of severity is based on the frequency of episodes of
binge eating (see below). The level of severity may be increased to reflect
other symptoms and the degree of functional disability.
Mild: 1–3 binge-eating episodes per week.
Moderate: 4–7 binge-eating episodes per week.
Severe: 8–13 binge-eating episodes per week.
Extreme: 14 or more binge-eating episodes per week.

Source. Reprinted from American Psychiatric Association: Diagnostic and Statisti-

cal Manual of Mental Disorders, 5th Edition, Text Revision, Washington, DC, American
Psychiatric Association, 2022. Copyright © 2022 American Psychiatric Association.
Used with permission.

Although research for treatments of BED often uses weight loss and BMI
as a primary outcome measure, it is crucial to recognize that weight is not a cri-
terion of BED. There are significant concerns with using weight and BMI as
a measure. The measure of BMI is not an effective tool in measuring adiposity,
and near the start of the obesity epidemic, the National Institutes of Health re-
classified the BMI categories, thus classifying millions of Americans as “over-
weight” overnight. The medical community often recommends that patients
be within normal weight; however, a meta-analysis showed that individuals in
 Eating Disorders 457

the overweight category (BMI 25–30) had significantly lower mortality com-
pared with all other categories, including those with normal weight. Individu-
als with grade 1 obesity did not have higher mortality compared with
individuals with normal weight (Flegal et al. 2013). There are significant con-
cerns about misclassifying a patient’s cardiac health based on their BMI. Tomi-
yama et al. (2016) found that more than half of patients in the overweight
BMI category were metabolically healthy, and 30% of those in the normal-
weight category were metabolically unhealthy. Therefore, clinicians should
exercise caution when using BMI as a measure of overall health and not as-
sume that a lower BMI means improved health.
In children and adolescents, BED may be even more difficult to diagnose
because children may struggle with describing the subjective feeling of loss of
control. Also, the amount of food a growing youth eats may vary depending
on multiple factors, including pubertal development, growth trajectory, activ-
ity, and others (Tanofsky-Kraff et al. 2007).

Epidemiology
BED is the most prevalent eating disorder, with a lifetime prevalence of 2.6%
in the United States (Guerdjikova et al. 2017; Kessler et al. 2013). Data from
the World Health Organization Mental Survey Study show a lifetime prevalence
of 1.4% across 14 countries (Yilmaz et al. 2015). The male-to-female ratio
(4:6) is higher for BED than for other eating disorders based on the current lit-
erature (Bohon 2019). BED has been found to be a highly heritable illness, with
studies suggesting 41%–57% heritability, independent of obesity (Yilmaz et al.
2015). The prevalence of BED in children and adolescents is estimated to be
between 1% and 3% (Smink et al. 2014).

Clinical Presentation
A common clinical presentation of a patient with BED is a person of higher
weight who has attempted to lose weight several times in the past and has of-
ten been told by medical professionals that they need to lose weight to im-
prove their health. In an attempt to do so, they often underfuel their bodies
during the day, intentionally restricting their dietary intake for as long as they
can. Toward the end of the day, their hunger and physical drive for food often
overpowers their “willpower,” and they participate in one or multiple binges in
458 Clinical Manual of Child and Adolescent Psychopharmacology

secrecy. They experience significant shame and remorse around their loss of
control and their perception of “failing” their diet. They promise to stick with
their diet the next day, and the cycle repeats. Dietary restraint has been con-
sistently shown to be the most direct cause of binge eating (Lowe et al. 2011).
A 5-year longitudinal study of adolescents found that dieting and unhealthful
weight control predicted obesity and eating disorders for both males and fe-
males (Neumark-Sztainer et al. 2011). A prospective study of adolescent girls
showed that elevated dieting, pressure to be thin, modeling of eating distur-
bances, appearance overvaluation, body dissatisfaction, depressive symptoms,
emotional eating, body mass, and low self-esteem predicted binge-eating on-
set with 92% accuracy (Stice et al. 2002).
Patients with BED often have comorbid psychiatric illness. For example,
a previous study reported that 79% of those with BED have at least one other
psychiatric disorder (most frequently anxiety, PTSD, or alcohol abuse or de-
pendence) (Kessler et al. 2013). Binges are often triggered by a negative affect.
Neuropathway changes in dopaminergic reward processing and poor inhibi-
tory control have also been proposed as potential avenues for treatment, tar-
geting the dopamine pathway (Dingemans et al. 2017; Goracci et al. 2015).

Treatment
Similar to other eating disorders, a multidisciplinary team is crucial to helping
patients achieve full recovery from BED. Nutritional rehabilitation focusing
on consistent, adequate fueling is necessary for full recovery. One potential lim-
itation of current research is weight loss as a common outcome. Although in-
dividuals with BED often have larger bodies, it is important to consider
whether long-term weight loss is an appropriate measure. Questions have been
raised as to whether long-term weight loss, beyond 5 years, is achievable (An-
derson et al. 2001; Melby et al. 2017; Sumithran et al. 2013). This may be
hindering current research, and treatments may already exist that are effective
in decreasing binge-eating behaviors but not in decreasing weight, especially in
long-term studies (Mann et al. 2007). Therefore, it could be beneficial for fu-
ture research to focus more on behaviors rather than explicit weight loss. The
Women’s Health Initiative studied more than 20,000 women with behavioral
weight loss and moderately decreasing intake; at 8-year follow-up, partici-
 Eating Disorders 459

pants demonstrated no change in weight, and their waist circumference actu-

ally increased (Howard et al. 2006).

Therapy
CBT and self-help programs have been shown to be helpful for those with BED.
A meta-analysis of nearly 8,000 patients across 114 studies looked at outcomes
over 12 months, and the authors found that CBT and self-help psychotherapy
showed improvements in binge-eating episodes and abstinence and in overall
psychopathology (Hilbert et al. 2014, 2020). CBT is the best-established ther-
apeutic treatment and, per NICE guidelines, has been identified as grade A.
CBT and IPT have shown improvements with eating disorder psychopathology
through 24 and 48 months (Hilbert et al. 2012; Wilson et al. 2010). Behav-
ioral weight loss has also been studied in females; however, despite participants
maintaining a reduced calorie/fat intake, no change in weight was recorded
(Howard et al. 2006).

Psychopharmacology
There has been increasing research on the neurobiological targets, including
reward center and dopaminergic systems, to address BED behaviors. Studies
of BED in adolescents and children are limited; therefore, the focus of the fol-
lowing discussion is on adult studies.

Stimulants
Lisdexamfetamine dimesylate (LDX) is the only FDA-approved medication
for adults with moderate to severe BED. The drug received approval after one
large Phase-II RCT and two Phase-III RCTs (McElroy et al. 2015). LDX was
found to separate from placebo at a dosage of 50–70 mg/day in measures of
decreasing binge-eating symptoms and obsessive-compulsive features of binge
eating (Citrome 2015). Side effects reported included decreased appetite, in-
somnia, dry mouth, and headache (McElroy et al. 2015). Citrome (2015)
completed a meta-analysis and determined that the number needed to treat to
remission was 4, and the number needed to harm was 44. Overall, these find-
ings indicate that LDX is safe; studies showed low dropout and adverse effects.
Given that LDX is a stimulant, clinicians should keep in mind the general
460 Clinical Manual of Child and Adolescent Psychopharmacology

safety considerations with this controlled medication, including its potential

for misuse and precipitation of mania. Currently, no studies of LDX for BED
have been performed in children and adolescents.

Antiepileptics
Topiramate has been tested in three RCTs and was shown to be significantly
superior to placebo in decreasing binge-eating episodes (Claudino et al. 2007;
McElroy et al. 2003, 2007). It was also found to have clinically significant
benefit as augmentation in patients with BED whose symptoms had not re-
sponded to CBT alone (Claudino et al. 2007). However, topiramate has been
shown to have significant adverse events, most notably cognitive dulling and
difficulty with word finding. Previous studies had high dropout rates, with 68%
discontinuing topiramate due to adverse events (Claudino et al. 2007; McElroy
et al. 2003, 2007). Zonisamide was shown in one RCT to decrease binge eat-
ing (McElroy et al. 2006). In an open-label study, zonisamide was also found to
decrease eating disorder behaviors and depression when it was added to CBT at
24 weeks and 12 months (Ricca et al. 2009). Lamotrigine was not found to
separate from placebo (Guerdjikova et al. 2009). Therefore, although some
antiepileptics have shown some early promise, adverse effects are noted more
frequently for these agents than for other medications.

Antidepressants
SSRIs have been the most frequently studied medications for BED in adults.
They have not consistently shown to decrease binge-eating episodes either in-
dependently or in combination with CBT or behavioral weight loss. There have
been open-label studies of fluoxetine, desipramine, and fluvoxamine (Agras et
al. 1994; Ricca et al. 2001). Imipramine and fluoxetine have been studied in
several double-blind RCTs, and results have been inconclusive (Devlin et al.
2005, 2007; Grilo et al. 2005, 2012; Laederach-Hofmann et al. 1999). These
studies have demonstrated some benefits for depressive symptoms with fluox-
etine, but otherwise no significant improvements in eating disorder symptoms
or weight loss were observed, compared with CBT or behavioral weight loss.
One positive study looked at patients with comorbid depression and BED.
Participants receiving duloxetine showed improvements in binge-eating epi-
sodes and depression symptoms after 12 weeks, compared with those receiving
placebo (Guerdjikova et al. 2012).
 Eating Disorders 461

Avoidant/Restrictive Food Intake Disorder

Diagnosis and Epidemiology
ARFID is an expansion of the DSM-IV diagnosis of feeding disorders of in-
fancy or early childhood. ARFID involves the restriction of food, leading to a
failure to meet appropriate nutritional requirements, weight loss, and nutri-
tional deficiencies that require enteral feedings and affect psychosocial func-
tioning (Box 10–4). A key feature that differentiates ARFID from other eating
disorder diagnoses is the lack of body image disturbance. ARFID etiology is
heterogeneous, including fear of food contamination, fear of choking, lack of
interest in food, or sensory concerns (Zimmerman and Fisher 2017). Further
research is needed into this heterogeneous etiology to best understand and
guide treatment.

Box 10–4. Avoidant/Restrictive Food Intake Disorder

A. An eating or feeding disturbance (e.g., apparent lack of interest in eat-
ing or food; avoidance based on the sensory characteristics of food;
concern about aversive consequences of eating) associated with one
(or more) of the following:
1. Significant weight loss (or failure to achieve expected weight gain or
faltering growth in children).
2. Significant nutritional deficiency.
3. Dependence on enteral feeding or oral nutritional supplements.
4. Marked interference with psychosocial functioning.
B. The disturbance is not better explained by lack of available food or by
an associated culturally sanctioned practice.
C. The eating disturbance does not occur exclusively during the course of
anorexia nervosa or bulimia nervosa, and there is no evidence of a dis-
turbance in the way in which one’s body weight or shape is experienced.
D. The eating disturbance is not attributable to a concurrent medical condition
or not better explained by another mental disorder. When the eating distur-
bance occurs in the context of another condition or disorder, the severity of
the eating disturbance exceeds that routinely associated with the condition
or disorder and warrants additional clinical attention.
462 Clinical Manual of Child and Adolescent Psychopharmacology

Specify if:
In remission: After full criteria for avoidant/restrictive food intake disor-
der were previously met, the criteria have not been met for a sustained
period of time.

Source. Reprinted from American Psychiatric Association: Diagnostic and Statisti-

cal Manual of Mental Disorders, 5th Edition, Text Revision, Washington, DC, American
Psychiatric Association, 2022. Copyright © 2022 American Psychiatric Association.
Used with permission.

ARFID can be diagnosed across the age spectrum but is more frequently
diagnosed in childhood. The average age of youth diagnosed with ARFID is
11–14 years, and it is most common in females; however, the male-to-female ra-
tio is higher for ARFID than for AN or BN (Mammel and Ornstein 2017;
Zimmerman and Fisher 2017). Prevalence of ARFID has varied across studies
from less than 1% to 15.5% (Bourne et al. 2020). Patients are more likely to
have comorbid medical and psychiatric conditions. The most common comor-
bid psychiatric illnesses are anxiety disorders, but mood disorders, autism spec-
trum disorder, ADHD, and learning disorders or cognitive impairment can also
be present. Medically, the most common comorbid conditions are malnutri-
tion, bradycardia, QT prolongation, and electrolyte abnormalities (Katzman et
al. 2019).

Treatment
Currently, no empirically validated treatments are available for patients with
ARFID, in part due to the heterogeneous etiology of the diagnosis. In treat-
ment, the underlying origin of the food restriction must be addressed. As with
other eating disorders, it is important to treat the malnutrition and medical
complications by increasing the variety or amount of food. Because of the se-
verity of malnutrition that can occur, clinicians should monitor vital signs, or-
der laboratory tests to check for electrolyte imbalances, consider a dual x-ray
absorptiometry bone density scan, and assess for cardiac effects. ARFID has
been successfully treated in outpatient, day-program, and inpatient settings. An
interdisciplinary approach that includes medical care, behavioral health, and
nutrition can be beneficial. In cases involving sensory issues, occupational ther-
apy also can be helpful. Case studies of CBT and FBT for ARFID have shown
promising results; however, more rigorous studies are needed (Bourne et al.
 Eating Disorders 463

2020; Mammel and Ornstein 2017). Monitoring and treating any underlying
comorbid psychiatric illnesses, specifically anxiety, neurocognitive, or depres-
sive disorders, is recommended. Medications that have been studied to target
anxiety and appetite in ARFID, including olanzapine, mirtazapine, and bus-
pirone, have had mixed results. A small, double-blind, placebo-controlled
study was performed with D-cycloserine, and preliminary findings suggest that
this may be an effective adjunct to behavioral intervention (Bourne et al.
2020). Considerably more research is needed to substantiate the use of med-
ications for treating ARFID.

Pica
Diagnosis and Epidemiology
Pica is defined as the eating of nonnutritive, nonfood substances that are not
developmentally appropriate or related to cultural practices (Box 10–5). Pica is
generally seen in individuals diagnosed with autism spectrum disorder, intel-
lectual developmental disorder (intellectual disability), schizophrenia, or
OCD and, more rarely, during pregnancy. It is necessary to assess whether the
oral intake is developmentally appropriate; therefore, pica is not diagnosed in
children younger than age 2 years, for whom teething and oral exploration
have not yet ceased (Bohon 2015). The patient’s and family’s cultural beliefs
should also be assessed; some cultures support eating nonnutritive substances
because they are believed to have some value. Pica tends to be initially recog-
nized and identified by primary care practitioners, gastroenterologists, or den-
tists. The eating of nonnutritive substances can lead to damaging metabolic
abnormalities, parasitic infections, gastrointestinal complications (from ob-
struction to perforations), iron deficiency, or lead poisoning as well as damage
to the teeth (Leung and Hon 2019; Liu et al. 2015). Thus, early identification
and intervention are important.

Box 10–5. Pica

A. Persistent eating of nonnutritive, nonfood substances over a period of at
least 1 month.
B. The eating of nonnutritive, nonfood substances is inappropriate to the
developmental level of the individual.
464 Clinical Manual of Child and Adolescent Psychopharmacology

C. The eating behavior is not part of a culturally supported or socially nor-

mative practice.
D. If the eating behavior occurs in the context of another mental disorder
(e.g., intellectual developmental disorder [intellectual disability], autism
spectrum disorder, schizophrenia) or medical condition (including preg-
nancy), it is sufficiently severe to warrant additional clinical attention.
Coding note: The ICD-10-CM codes for pica are (F98.3) in children and
(F50.89) in adults.
Specify if:
In remission: After full criteria for pica were previously met, the criteria
have not been met for a sustained period of time.

Source. Reprinted from American Psychiatric Association: Diagnostic and Statisti-

cal Manual of Mental Disorders, 5th Edition, Text Revision, Washington, DC, American
Psychiatric Association, 2022. Copyright © 2022 American Psychiatric Association.
Used with permission.

Pica can be associated with ARFID, especially in patients with strong sen-
sory avoidance issues, and can be comorbid with AN. However, if the goal of
ingesting nonfood items is to decrease appetite and thus weight, then the di-
agnosis is purely AN. Pica may be comorbid with factitious disorder if the
nonfood is ingested to induce symptoms of illness. Pica may also be associated
with nonsuicidal self-injury, in which the individual may swallow objects such
as utensils or pens in order to self-harm (Bohon 2015).
Overall, the prevalence of pica is unclear due to the different populations
studied, cultural and regional differences, and underreporting. It also can of-
ten be overlooked by physicians. Pica occurs worldwide, and prevalence stud-
ies in German, Swiss, and Australian children have shown prevalence rates
between 10% and 22.4%. The prevalence of pica has been found to be highest
in Africa and higher in children from lower-income backgrounds as well as in
refugees and immigrants (Leung and Hon 2019).

Treatment
Individuals with a diagnosis of pica for whom it is cognitively appropriate
should seek a therapist to explore the reasoning behind the eating of nonnu-
tritive substances because attention to emotional stressors and needs are of
high importance to recovery (Leung and Hon 2019). In the case of a child
 Eating Disorders 465

with autism spectrum disorder or an intellectual disability, environmental re-

strictions, including increasing supervision and removing objects that may be
eaten from the environment, are necessary. Iron deficiency, lead poisoning, or
gastrointestinal obstruction should be treated if present (Leung and Hon
2019). Currently, no evidence exists for medication management in the treat-
ment of pica.

Rumination Disorder
Diagnosis and Epidemiology
Rumination disorder is characterized by the regurgitation of food that has oc-
curred for at least 1 month (Box 10–6). Generally, the food is regurgitated,
then rechewed and reswallowed or spit out. In rumination disorder, intense
fear of weight gain is not present as with other eating disorders. However, ru-
mination symptoms can be comorbid with other eating disorders (Murray et
al. 2019). Rumination can be used as a self-soothing mechanism, similar to
head banging in those with neurocognitive disorders (American Psychiatric
Association 2022). Rumination behaviors can cause shame and embarrass-
ment; thus, many individuals are secretive and do not report symptoms, mak-
ing identification of the disorder difficult. Medically, patients may experience
weight loss, malnutrition, gastrointestinal issues, and dental problems. Before
diagnosing rumination disorder, clinicians should rule out any gastrointesti-
nal or medical issues, including gastroesophageal reflux or pyloric stenosis.
Rumination disorder is diagnosed exclusively via clinical history (Murray et al.
2019). The causes of rumination behaviors are not fully clear; however, high
anxiety or a stressful/neglectful environment may be contributing factors. Ha-
bitual abdominal wall contraction through a conditioned response to stimuli
is the most widely recognized primary etiology (Murray et al. 2019).

Box 10–6. Rumination Disorder

A. Repeated regurgitation of food over a period of at least 1 month. Regur-
gitated food may be re-chewed, re-swallowed, or spit out.
B. The repeated regurgitation is not attributable to an associated gastroin-
testinal or other medical condition (e.g., gastroesophageal reflux, pylor-
ic stenosis).
466 Clinical Manual of Child and Adolescent Psychopharmacology

C. The eating disturbance does not occur exclusively during the course of
anorexia nervosa, bulimia nervosa, binge-eating disorder, or avoidant/
restrictive food intake disorder.
D. If the symptoms occur in the context of another mental disorder (e.g.,
intellectual developmental disorder [intellectual disability] or another
neurodevelopmental disorder), they are sufficiently severe to warrant
additional clinical attention.
Specify if:
In remission: After full criteria for rumination disorder were previously
met, the criteria have not been met for a sustained period of time.

Source. Reprinted from American Psychiatric Association: Diagnostic and Statisti-

cal Manual of Mental Disorders, 5th Edition, Text Revision, Washington, DC, American
Psychiatric Association, 2022. Copyright © 2022 American Psychiatric Association.
Used with permission.

Rumination disorder is more prevalent in individuals with intellectual dis-

abilities, and there is a higher incidence among those with anxiety disorders.
Rumination can occur in infancy, childhood, adolescence, or adulthood;
however, it is most commonly present around ages 3–12 months. There is no
clear sex bias (American Psychiatric Association 2022).

Treatment
The first-line treatment for rumination disorder is diaphragmatic breathing
(Kusnik and Vaqar 2022). This is an easy-to-learn treatment that can be im-
plemented in the outpatient setting and has substantial evidence for efficacy
(Robles et al. 2020). Diaphragmatic breathing is the most effective behavioral
intervention that has been studied, most likely because it operates as a com-
peting response to habitual abdominal wall contractions. Baclofen, TCAs,
and various gastrointestinal medications have been studied in this disorder;
however, no significant evidence of benefit has been found for any medica-
tion, and more research is needed (Murray et al. 2019).

Conclusion
Although eating disorders are prevalent, with a high rate of morbidity and mor-
tality, evidence and research around their treatment are limited, especially for
children and adolescents. The current standard of treatment is a combination
 Eating Disorders 467

of therapy, dietary interventions, and psychopharmacological management of

comorbid psychiatric illnesses. Due to the dearth of current research, few treat-
ment options are available; however, with future studies, eating disorders may
be better understood, thus prompting better treatments and outcomes.

Clinical Pearls
• Treatment of children and adolescents with eating disorders re-
quires a multidisciplinary team including a therapist, dietitian,
and medical and psychiatric practitioners.
• Anorexia nervosa (AN) has the second highest mortality rate of
any psychiatric illness due to its medical complications and in-
creased rate of suicide.
• Nutritional rehabilitation is the best treatment for numerous psy-
chiatric symptoms related to AN.
• Olanzapine has the most evidence for the treatment of AN symp-
toms.
• Initial treatment for bulimia nervosa should include cognitive-
behavioral therapy (CBT); individuals whose symptoms do not
respond to CBT may benefit from the addition of fluoxetine.
• Initial treatment for binge-eating disorder should focus on nutri-
tional rehabilitation and behavioral therapies, including CBT
and interpersonal therapy.
• A key feature of avoidant/restrictive food intake disorder is the
lack of an abnormal body image.
• Pica is the eating of nonfood substances that are inappropriate
to a person’s developmental age and that are not culturally ap-
propriate for that person.
• Rumination syndrome is the repeated regurgitation of food, and
workup should include ruling out any organic gastrointestinal
causes.
468 Clinical Manual of Child and Adolescent Psychopharmacology

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 Index

Page numbers printed in boldface type refer to tables or figures.

Aberrant Behavior Checklist (ABC), antipsychotics for tic disorders in, 347
108, 290, 294, 295, 301, 306, aripiprazole for schizophrenia in,
307, 311, 312, 313, 314, 315, 394–395
318, 319 BED and, 458
Abnormal Involuntary Movement bupropion for ADHD in, 81
Scale, 261, 403 buspirone for OCD in, 181
Absorption, and pharmacokinetics, 3 CBT for eating disorders in, 453
Activities of daily living, and tic clozapine for treatment-resistant
disorders, 355 schizophrenia in, 400
Activity-based interventions, for combination treatment for school
treatment-resistant depression, 222 phobia in, 185
ADHD. See Attention-deficit/ D-cycloserine for ASD in, 314
hyperactivity disorder developmental issues in
ADHD Rating Scale, 306, 308, 361 pharmacokinetics and, 2, 4
Adherence to treatment, and ADHD, electroconvulsive therapy for
82–83. See also Compliance depression in, 218
Adolescents, and adolescence. See also FBT for eating disorders in, 446,
Age; Age at onset 452
antidepressants for eating disorders interpersonal psychotherapy for
in, 448, 450, 454 MDD in, 199–200
antidepressants and risk of lamotrigine for bipolar disorder in,
suicidality in, 17 259, 274
antipsychotics for aggressive lurasidone for schizophrenia in,
behavior in, 108, 113, 118 394–395
antipsychotics for eating disorders neuroleptic malignant syndrome
in, 44 and, 409

479
480 Clinical Manual of Child and Adolescent Psychopharmacology

Adolescents, and adolescence clozapine and, 414–415

(continued) divalproex sodium and, 257–258
olanzapine for schizophrenia in, guanfacine and, 80, 124
393, 398 lithium and, 249–250
paliperidone for schizophrenia in, methylphenidate and, 65
296, 390, 396 mirtazapine and, 302
prevalence of anxiety disorders in, 149 mood stabilizers and, 123, 322–323
prevalence of eating disorders in, 441 norepinephrine reuptake inhibitors
quetiapine for ASD in, 293 and, 125
risperidone for schizophrenia in, olanzapine and, 265, 393
391–392, 398 quetiapine and, 266–267
SSRIs for MDD in, 207–208, 211, risperidone and, 268, 269
301 SSRIs and, 164, 167, 208–209
venlafaxine for ASD in, 302 sertraline and, 166, 186
weight gain as side effect of stimulants and, 67–71, 120, 126,
antipsychotics, 411 321–322
Adults. See also Age TCAs and, 175, 178
bulimia nervosa in, 454–455 venlafaxine and, 169–170
clozapine for aggression in, 114 viloxazine and, 78–79
continuation of pediatric MDD ziprasidone and, 271, 272
into, 199 Age. See also Adolescents; Adults; Age at
persistence of childhood anxiety onset; Infants; Preschool children;
disorders in, 147, 150 School-age children
prevalence of ADHD in, 33 diagnosis of ARFID and, 462
SNRIs for anxiety disorders in, 170 diagnosis of pica and, 463
Adverse effects, of medications. See also dosage of carbamazepine and, 253
Cardiac side effects; Central emergence of suicidality during anti-
nervous system; Endocrine side depressant treatment and, 17
effects; Extrapyramidal side effects; pharmacotherapy for schizophrenia
Gastrointestinal side effects; and, 399
Growth; Hypertension; Sudden Age, Beginning, and Course study, 415
death; Tardive dyskinesia; Weight Age at onset
gain of ADHD, 34
aripiprazole and, 262, 263 of IED, 104
atomoxetine and, 78 of schizophrenia, 378, 379–380, 416
buspirone and, 180, 181, 303 of tic disorders, 342, 345
carbamazepine and, 254 Aggression
clomipramine and, 298 atypical antipsychotics and, 106–115
clonidine and, 80 classifications of, 102
 Index 481

conduct disorder and, 104 Amphetamines. See also

as distinct construct, 101–102 Methylphenidate
evidence-based psychotherapy for, 106 ADHD and, 43–44, 45, 65–67
IED and, 104 DBDs and aggression, 109
ODD and, 103 dose-related delay in growth and,
practical management strategies for, 15–16
128–131 FDA-approved indication of, 21
Agomelatine, 21, 202, 208 increase in prescriptions for, 72
Agranulocytosis, and clozapine, 414 Anorexia nervosa. See also Eating
Akathisia, and antipsychotics for disorders
schizophrenia, 403, 404, 409 antidepressants and, 448–450
Allergan Inc., 163 atypical antipsychotics and, 447–448
α-Adrenergic agonists. See also cannabinoids and, 450
Clonidine; Guanfacine diagnosis of, 443, 443–444
ADHD and, 76, 79–80 epidemiology of, 445
ASD and, 288, 322 FBT for, 445, 446
common and serious side effects of, nutritional rehabilitation for, 446
117, 127 oxytocin and, 450
comorbidity of ADHD with tic pica comorbid with, 464
disorders, 364–365 SNRIs and, 169
DBDs and aggression, 110, 123–124, zinc supplementation for, 450
127 Anticonvulsants. See also Topiramate
Alprazolam, and anxiety disorders, 156, adverse effects of, 123, 354
171, 172, 173, 174, 176 BED and, 460
Amantadine, 313, 411 bipolar disorders and, 251–260
American Academy of Child and Antidepressants. See also Selective
Adolescent Psychiatry (AACAP), serotonin reuptake inhibitors;
34, 68, 81, 83, 84, 128, 151, 167, Tricyclic antidepressants
261, 422, 442, 452 anorexia nervosa and, 448–450
American Academy of Pediatrics (AAP), anxiety disorders and, 153–155
34, 39, 60, 83 BED and, 460
American Psychiatric Association bulimia nervosa and, 453–454
(APA), 442, 450. See also DSM-5 discontinuation of, 213
Amisulpride dosages of for children with MDD,
anorexia nervosa and, 447 215
clozapine and, 415 risk of suicidality and, 17, 152, 165,
dopamine receptors and mechanism 183, 211, 321
of action, 390 Antihistamines, and anorexia nervosa,
schizophrenia and, 396–397, 417 450
482 Clinical Manual of Child and Adolescent Psychopharmacology

Antipsychotics. See also Atypical anti- SNRIs and, 155, 168–170

psychotics; Haloperidol; Pimozide SSRIs and, 152, 154, 157–167
ASD and, 285, 286–287 TCAs for, 153, 175–179
common and serious side effects of, Anxiety Rating for Children, 172, 176
116, 118, 126 Area under the curve (AUC), and
DBDs and aggression, 109, 118 pharmacokinetics, 3
long-acting injectable forms of, ARFID. See Avoidant/restrictive food
421–422 intake disorder
psychotic depression and, 218 Aripiprazole
schizophrenia and, 381, 382–383, anorexia nervosa and, 447
389–390, 397–399, 403–415 ASD and, 285, 286, 293–295, 320
Tourette’s disorder and, 347–351 bipolar disorders and, 261–262,
Antisocial behaviors, and ADHD, 57 273–274
Anxiety bulimia nervosa and, 454
depression and comorbid, 223–224 DBDs and aggression, 109, 113–114
side effects of stimulants and, 71 FDA-approved and off-label use of, 21
Anxiety disorders. See also General management of side effects of, 263,
anxiety disorder; Obsessive- 404
compulsive disorder; MDD in adolescents and, 221
Posttraumatic stress disorder; schizophrenia and, 387, 394–395,
Separation anxiety disorder; Social 396, 407, 408, 422
anxiety disorder tic disorders and, 347–349, 350,
atomoxetine for, 182 351, 352, 355, 358
benzodiazepines for, 156, 171–175 ASD. See Autism spectrum disorder
buspirone for, 179–181 Asenapine
course and outcome of, 149–151 bipolar disorder and, 262–263
epidemiology of, 148–149 dosage of, 348
evidence for psychopharmacological extrapyramidal symptoms and, 407
treatment of, 151–152 FDA-approved and off-label use of, 21
guanfacine for, 181–182 schizophrenia and, 386, 397
lifelong impact of, 147 Asperger’s disorder, 294, 300
practical management strategies for, Atomoxetine
184–187 ADHD and, 75, 76, 77–78,
revisions of DSM and, 148 112–113, 223, 308–310
safety issues in anxiety disorders and, 155, 182
psychopharmacological ASD and, 289, 308–310
treatment of, 182–184 DBDs and aggression, 109, 125
selected medications for pediatric, depression and, 223
153–156 FDA-approved and off-label use of, 21
 Index 483

metabolism and elimination half-life anorexia nervosa and, 447–448

of, 4 ASD and, 285, 290–296, 320–321
tic disorders comorbid with ADHD bipolar disorders and, 260–272
and, 360, 361, 364–365 DBD and aggression, 106–115
Attention-deficit/hyperactivity disorder schizophrenia and, 383–387,
(ADHD) 390–402
aripiprazole for, 114 tic disorders and, 347, 350
atomoxetine for, 112–113, 125, Augmentation, pharmacological
308, 309 of fluvoxamine with lithium, 311
bipolar disorders and treatment of tic disorders comorbid with OCD
comorbid, 275–276 and, 358
choice of medications for, 83–84 treatment-resistant depression and,
diagnosis of, 34–36 220–221
drug treatments for ASD comorbid Autism Diagnostic Observation
with, 306–310 Schedule (ADOS), 304, 318, 319
DSM-5 criteria for, 36–39 Autism spectrum disorder (ASD)
extended-release formulations of aripiprazole and, 113, 286
methylphenidate and, 9 atypical antipsychotics and, 285,
guanfacine and oppositional 290–296, 320–321
symptoms in, 124 β-adrenergic antagonists and, 316
monitoring of treatment for, 81–83 cannabinoids and, 319–320
nonstimulant medication for cholinesterase inhibitors and,
treatment of, 75–81 312–313
olanzapine combined with drug treatments for ADHD
atomoxetine and, 112–113 comorbid with, 306–310
prevalence and impact of, 33 DSM editions and diagnosis of, 284
psychosocial interventions for, 40 folinic acid and, 318–319
recommendations on treatment of, 39 glutamatergic agents and, 313–316
schizophrenia comorbid with, 402 Kanner’s description of, 283
stimulant medications for, 40–75, mood stabilizers and, 310–312,
120 322–323
tic disorders comorbid with, 355– multimodal therapeutic approach to
356, 358–365 pharmacotherapy for, 284,
Atypical antipsychotics. See also 323
Aripiprazole; Olanzapine; naltrexone and, 316–317
Paliperidone; Risperidone; oxytocin and, 317–318
Ziprasidone paliperidone and irritability in, 112
adverse effects of, 115, 116–117, practical management strategies for,
126, 320, 350, 448 323
484 Clinical Manual of Child and Adolescent Psychopharmacology

Autism spectrum disorder (ASD) Biotransformation, and drug

(continued) metabolism, 3, 4
psychostimulants and, 304–306, 321 Bipolar depression, 216–217
risperidone for aggressive behavior Bipolar disorders
in, 108, 111 anticonvulsants and, 251–260
safety issues in pharmacotherapy for, atypical antipsychotics and, 260–272
320–323 childhood anxiety disorders and, 151
secretin and, 317 combination pharmacotherapy for,
SSRIs and, 297–304, 321 274–276
Avoidant/restrictive food intake DMDD and, 229
disorder (ARFID), 461–463, 464 divalproex sodium and, 122, 255–259
lithium and, 246–251
Baclofen, 466 maintenance therapy for, 273–274
Barnes Akathisia Rating Scale, 403–404 quetiapine for aggression in
Beck Depression Inventory, 200 adolescents with, 113
BED. See Binge-eating disorder treatment-resistant depression and,
Behavior. See Aggression; Antisocial 219
behavior; Repetitive behaviors Black box warnings. See also Food and
Behavioral interventions. See also Drug Administration
Activity-based interventions; antidepressants and, 17, 152, 165,
Cognitive-behavioral therapy; 183, 211, 321
Psychosocial interventions atomoxetine and, 78, 125, 322
for aggression, 130 stimulants and, 67, 120
for ADHD, 40, 45 viloxazine and, 79
for ASD, 323 Blood draws, for dosage monitoring of
for BED, 458–459 lithium, 123, 127
weight gain as side effect of Botulinum toxin, and Tourette’s
antipsychotics and, 411 disorder, 351, 353, 355
Behavior Rating Inventory of Executive Brexpiprazole, 21, 221, 260, 348
Function (BRIEF), 120 Brief Conners’ Teacher Rating Scale,
Benzodiazepines, 156, 171–175, 450 403
Benztropine, 398 Brief Psychiatric Rating Scale (BPRS),
β-Blockers 391, 392, 393, 397, 400
ASD and, 316 Bright-light therapy, for seasonal
common and serious side effects of, affective disorder, 218
117 Bristol-Myers Squibb, 180
DBDs and aggression, 110, 124–125 Bromocriptine, 413
Binge-eating disorder (BED), 455–460 Bulimia nervosa, 450–455. See also
Bioavailability, and pharmacokinetics, 3 Eating disorders
 Index 485

Bupropion Central nervous system (CNS), and

ADHD and, 80–81 adverse effects
bipolar depression and, 217 of aripiprazole, 263
bulimia nervosa and, 454 of divalproex sodium, 257, 258
dosage of, 215 of lithium, 250
MDD and, 202, 207, 209, 223 of olanzapine, 265
off-label use of, 21 of quetiapine, 267
tic disorders comorbid with ADHD of risperidone, 269
and, 360 of ziprasidone, 272
Buspirone, 156, 179–181, 303–304 Checklists, for tic symptoms, 346
Chewable tablets, of methylphenidate,
Cabergoline, 413 64
Caffeine, and lithium levels, 251 Child/Adolescent Anxiety Multimodel
Cannabinoids Study (CAMS), 152, 187
anorexia nervosa and, 450 Child Behavior Checklist, 35
ASD and, 319–320 Childhood Autism Rating Scale, 311
Carbamazepine Childhood-onset schizophrenia (COS),
adverse effects of, 123, 127 377–378. See also Schizophrenia
Asian ethnicity as exception to use Childhood-Onset Schizophrenia Study
of, 11 (NIMH), 378, 402
bipolar disorder and, 251–255 Children. See Adolescents; Age; Age at
DBDs and aggression, 110, 122 onset; Development; Infants;
FDA-approved and off-label use of, Preschool children; School-age
21 children; specific disorders; specific
Cardiac adverse effects medications
of antipsychotics for schizophrenia, Children and Adults with Attention-
413 Deficit/Hyperactivity Disorder,
of quetiapine, 267 130
of stimulants, 68, 120 Children’s Depression Rating Scale–
of ziprasidone, 270, 272 Revised (CDRS-R), 185, 200
Cariprazine, 260, 348 Children’s Global Assessment Scale
Cataract formation, and quetiapine, (CGAS), 12, 159
267 Children’s Manifest Anxiety Scale, 173
CBT. See Cognitive-behavioral Children’s Psychiatric Symptom Rating
therapy Scale (CPRS), 121
Centers for Disease Control and Children’s Yale-Brown Obsessive Scale
Prevention (CDC), 345 (CY-BOCS), 158, 159, 160, 161,
Center for Education and Research on 186, 300, 310
Therapeutics (CERT), 129 Chlorpromazine, 118, 390, 398
486 Clinical Manual of Child and Adolescent Psychopharmacology

Cholinesterase inhibitors, and ASD, Clozapine

312–313. See also Donepezil; adverse effects of, 414–415
Galantamine; Rivastigmine bipolar disorders and, 263
Citalopram DBDs and aggression, 109, 114
anxiety disorders and, 154, 163, schizophrenia and, 384, 392, 399–402,
166–167 404, 405, 406, 409, 410, 413
ASD and, 287, 301 tic disorders and, 349, 350
bulimia nervosa and, 454 Cocaine, 58
DMDD and, 229 Cochrane Schizophrenia Group Trials
dosage of, 215 Register, 398
off-label use of, 21 Cognitive-behavioral therapy (CBT)
pediatric MDD and, 203, 209 anxiety disorders and, 151–152,
Clearance, and pharmacokinetics, 3 184–187
Clinical Antipsychotic Trials of eating disorders and, 446, 452–453,
Intervention Effectiveness 459, 462
(CATIE) project, 389 fluoxetine for pediatric depression
Clinical Global Impression (CGI) and, 210
scales, 66, 108, 157, 158, 159, relapse of MDD and, 225
161, 162, 187, 206, 290, 291, tic disorders comorbid with OCD
293, 294, 295, 299, 306, 307, and, 357–358
310, 311, 314, 315, 320, 353, 393 Cognitive therapy, and development of
Clinical response, to stimulants, 73 psychosis, 421
Clomipramine Cognitive training, and ADHD, 40
anxiety disorders and, 153, 164, Collaborative Lithium Trials (CoLT),
176, 177, 179 246, 247, 273, 275
ASD and, 287, 297–298 Cologne Early Recognition Study, 416
FDA approval of, 21 Color-A-Person Body Dissatisfaction
MDD in adolescents and, 222 Test, 448
Clonazepam, 156, 171, 173 Columbia University, 209
Clonidine Combination pharmacotherapy
ADHD and, 76, 79–80 for anxiety disorders, 185–187
ASD and, 285, 288, 290 for bipolar disorders, 274–276
comorbid ADHD and ASD, Community supports, and treatment of
306–307 aggressive behaviors, 130
comorbid ADHD and tic disorders, Comorbid psychiatric conditions
360, 361, 363–364 ADHD and, 34, 214, 275–276, 305,
DBDs and aggression, 110, 123–124, 306–310, 355–356, 358–365,
127 402
FDA-approved and off-label use of, 21 anorexia nervosa and, 450
 Index 487

ARFID and, 462, 463 DBD. See Disruptive behavior disorder

ASD and, 305, 306–307 D-Cycloserine, 314–315, 450, 463
BED and, 458 Dependence, and benzodiazepines,
bipolar disorders and, 275–276 173–174. See also Substance abuse
MDD and, 214, 223–224 Depression. See also Bipolar depression;
schizophrenia and, 402–403 Major depressive disorder
Tourette’s disorder and tic disorders, anxiety disorders in children and,
343, 355–365 151
Compliance, with treatment. See also BED and comorbid, 460
Adherence treatment-resistant forms of,
long-acting injectable antipsychotics 218–223
and, 422 Depression and Bipolar Support
MDD and, 225–226 Alliance, 130
Compulsions, and OCD, 356 Dermatological side effects, of lithium,
Concentration in plasma, and 250
pharmacokinetics, 3 Desipramine
Conduct disorder (CD) ADHD and co-occurring tic
diagnosis of, 104, 128 disorders, 362
divalproex and, 122 anxiety disorders and, 153, 177, 178
lithium and, 121 ASD and, 298
methylphenidate and, 119 Desvenlafaxine, 203, 215
ODD and, 105 Development. See also Growth
quetiapine and, 113 efficacy of medications and, 12–14
stimulants and, 57 ethical aspects of
Conners’ Abbreviated Teacher Rating psychopharmacology and,
Scale, 73 17–20
Conners’ Anxiety Scale, 157 FDA-approved and off-label use of
Conners’ ADHD/DSM-IV Scales, 62 selected medications for
Conners’ Hyperactivity Index, 304 children, 21–23
Conners’ Parent Rating Scale, 66 influence of on pharmacokinetics
Conners’ Teacher Rating Scale, 308 and metabolism, 2–10
Continuation therapy, and MDD, pharmacodynamics and, 10–11
224–226 regulatory issues in
COVID-19, and increase in tics and tic- psychopharmacology and, 20
like behavior, 345 safety considerations and, 15–17
Culture, and pica, 463 Dexmethylphenidate, 21, 41, 109
Cyproheptadine, 450 Dextroamphetamine, 43, 109
Cytochrome P450 (CYP450) enzymes, Diabetes, and antipsychotics, 115, 126,
3, 4, 5–7, 212–213 350, 412
488 Clinical Manual of Child and Adolescent Psychopharmacology

Diagnosis. See also Differential evidence-based psychotherapy for,

diagnosis; DSM-5; Misdiagnosis 106
of ADHD, 34–39 practical management strategies for,
of anorexia nervosa, 443, 443–444 128–131
of ARFID, 461–462 Disruptive mood dysregulation disorder
of BED, 455–457 (DMDD), 229
of bulimia nervosa, 450–452 Diuretics, and hypertension, 223
of conduct disorder, 104 Divalproex sodium. See also Valproic
of IED, 104 acid
of ODD, 103 bipolar disorders and, 247,
of pica, 463 255–259, 266, 273, 275
of rumination disorder, 465–466 DBDs and aggression, 121–122
of tic disorders, 344–346 DMDD. See Disruptive mood
Diagnostic Interview Schedule for dysregulation disorder
Children, 173 Donepezil, 312
Diaphragmatic breathing, and Dopamine system
rumination disorder, 466 atypical antipsychotics and, 390
Diazepam, 172 psychostimulants and, 57, 58
Diet. See also Food Dosages
BED and, 458 of antidepressants for MDD,
lithium and, 251 215–216
nutritional rehabilitation for of antipsychotics for tic disorders,
anorexia nervosa, 446 348
Differential diagnosis of aripiprazole, 262
of DBDs, 105 of atomoxetine, 77, 360
of Tourette’s disorder and tic of carbamazepine, 253–254
disorders, 345 of clonidine and guanfacine, 80,
Discontinuation, of medications 360
ADHD and, 82 of divalproex sodium, 257
pediatric MDD and, 213, 225 of lithium for bipolar disorder,
SSRIs and, 164, 183 248–249
Disruptive behavior disorder (DBD). of lurasidone, 272
See also Conduct disorder; of methylphenidate, 59
Intermittent explosive disorder; of nonstimulant medications for
Oppositional defiant disorder comorbid tic disorders and
atypical antipsychotics for, 106–115 ADHD, 360
course and outcome of, 105–106 of olanzapine, 265
differential diagnosis of, 105 prevention of adverse effects and,
epidemiology of, 103–104 127, 184
 Index 489

of quetiapine, 266 Eating disorders. See also Anorexia

of risperidone, 268–269 nervosa; Avoidant/restrictive food
treatment-resistant depression and, intake disorder; Binge-eating
220 disorder; Bulimia nervosa; Pica;
of viloxazine, 79 Rumination disorder
of ziprasidone, 270–271 caution on use of medications for,
Drug Enforcement Administration, 75 441–442
DSM-IV ADHD Rating Scale characterization of in DSM-5,
(ADHD-RS), 62 442–443
DSM-5 nutritional rehabilitation and,
anorexia nervosa in, 443–444 446
anxiety disorders in, 148 Efficacy
ADHD in, 34, 36–39 of atomoxetine for ADHD, 77
ARFID in, 461–462 of clonidine and guanfacine, 79
ASD in, 284 developmental issues and, 12–14
BED in, 455–456 of methylphenidate for ADHD,
bulimia nervosa and, 451–452 59–60
DMDD and, 229 of risperidone for DBDs and
eating disorders in, 442–443 aggression, 107–108,
IED and, 104 110–112
MDD with mixed features in, 217 Electrocardiograms, and ziprasidone,
OCD in, 356 270, 271
pica in, 463–464 Electroconvulsive therapy (ECT), and
rumination disorder in, 465–466 depression, 218, 221–222
tic disorders in, 342 Elimination half-life, and
Dual-pulse, beaded methylphenidate pharmacokinetics, 3
preparations, 61–62 Endocrine side effects
Duloxetine of divalproex sodium, 258
anxiety disorders and, 155, 168, of lithium, 250
169, 170 of risperidone, 269
BED and, 460 Epidemiology
dosage of, 215 of anorexia nervosa, 445
FDA-approved and off-label use of, 22 of anxiety disorders, 148–149
MDD and, 203 of BED, 457
of bulimia nervosa, 452
Early-onset schizophrenia (EOS), 378 of DBDs, 103–104
Eating Disorder Inventory–2, 448 of schizophrenia, 379
Eating disorder not otherwise specified of tic disorders, 342–344
(EDNOS), 442 Epocrates, 213
490 Clinical Manual of Child and Adolescent Psychopharmacology

Escitalopram, 22 bulimia nervosa and, 453–454

anxiety disorders and, 154, 163 CYP450 enzymes and metabolism
ASD and, 301 of, 8
dosage of, 215 dosage of, 215
FDA-approved and off-label use of, 22 FDA-approved and off-label use of, 22
MDD and, 203, 207 MDD and, 204, 206, 207, 210,
Esketamine, 221 214, 225
Ethics Fluphenazine
developmental issues in pediatric dosage of, 348
psychopharmacology and, extrapyramidal symptoms of, 405
17–20 schizophrenia and, 382, 389
psychotropic drugs during Tourette’s disorder and, 347
prepsychotic/prodromal phase Fluvoxamine
of schizophrenia and, 417, 421 anxiety disorders and, 154,
European Medicine Agency (EMA), 161–162, 185–186
269, 270, 271 ASD and, 288, 298–299, 311
Extended-release formulations dosage of, 215
of carbamazepine, 252 lithium augmentation of, 311
of guanfacine, 362 medication interactions and, 8
intersubject variability in FDA-approved and off-label use of, 22
pharmacokinetics and, 9 Folinic acid, 318–319
of lithium, 9, 247 Food, CYP450 enzymes and interac-
of methylphenidate, 305–306 tions of medications with, 8. See
of valproic acid, 256 also Diet
Extrapyramidal side effects (EPS), of Food and Drug Administration (FDA).
antipsychotics for schizophrenia, See also Black box warnings
261, 380–381, 403–404, 405–408 anticonvulsants and, 123
approval of medications for pediatric
Factitious disorder, 464 use, 20, 21–23
Family-based therapy (FBT), for eating atomoxetine and, 78
disorders, 445, 446, 452, 453, 462 atypical antipsychotics and, 115
Fever, and clozapine, 415 clozapine and, 402
5-Ling granule, 354 fluoxetine and, 207
Fluoxetine stimulants and, 40, 45, 68, 120
anorexia nervosa and, 449, 450
anxiety disorders and, 154, 157 GABAergic system, and
ASD and, 287, 299–300 benzodiazepines, 171
BED and, 460 Gabapentin, 414
bipolar depression and, 217 Galantamine, 313
 Index 491

Gastrointestinal side effects Guanfacine

of divalproex sodium, 257, 258 anxiety disorders and, 181–182
of lithium, 249, 250 ADHD and, 79–80
Gender ASD and, 288, 307–308
anorexia nervosa and, 445 DBDs and aggression, 110, 124
antipsychotics and prolactin levels, FDA-approved and off-label use of, 22
413 tic disorders and, 352, 360, 361–362
ARFID and, 462 Half-life
developmental issues in of benzodiazepines, 171
pharmacokinetics and, 2, 4 of SSRIs, 212
prevalence of anxiety disorders by, Hallucinations, prevalence of in
149 nonpsychotic children, 378
General anxiety disorder (GAD) Haloperidol
benzodiazepines and, 172 ASD and, 285, 286, 298
citalopram and escitalopram for, 163 DBDs and aggression, 109, 118
duloxetine and, 170 FDA-approved and off-label use of, 22
fluoxetine and, 159 schizophrenia and, 382, 383, 389,
prevalence of, 149 398, 400, 405, 406, 409
sertraline and, 160 tic disorders and, 347, 348, 349,
Genetics 355, 358
ASD and, 297 Hamilton Anxiety Scale, 160, 172
BED and, 457 Hamilton Rating Scale for Depression,
carbamazepine and, 253 200
CYP450 and drug metabolism, 4, 8 Health Canada, 68
psychosis and, 416 Health of the Nation Outcome Scales for
Global Assessment of Functioning Children and Adolescents, 12–13
(GAF) Scale, 422 Heart disease, and adverse effects of
Glutamatergic agents, and ASD, stimulants, 68–69. See also Cardiac
313–316. See also Amantadine; adverse effects
D-cycloserine; Memantine; Hematological and hepatic side effects,
N-acetylcysteine of divalproex sodium, 258
Glycemic control, and atypical Herbal medications or supplements,
antipsychotics, 412 and treatment-resistant depression
Great Smoky Mountains Study, 72, and, 222
150–151, 343 Hillside Recognition and Prevention
Growth. See also Development Program, 421
SSRIs and decrease in rate of, 167 Home Situations Questionnaire-Autism
stimulants and delay in, 15–16, Spectrum Disorder (HSQ-ASD),
69–70 319, 320
492 Clinical Manual of Child and Adolescent Psychopharmacology

Hospitalization, and anorexia nervosa, Lamotrigine

446 ASD and, 311
Hyperkinesia, and SSRIs, 167 BED and, 460
Hyperlipidemia, and antipsychotics, bipolar depression and, 217
412 FDA-approved and off-label use of, 22
Hyperprolactinemia, and maintenance treatment of bipolar
antipsychotics, 320, 412–413, 448 disorder and, 259, 274
Hypersalivation, and clozapine, valproate and, 259
414–415 Leptin, and weight gain, 411
Hypertension Levetiracetam, 260, 311–312, 353
α-agonists and, 127 Lisdexamfetamine
diuretics for, 223 ADHD and, 44, 66
quetiapine and, 267 BED and, 459–460
Hypomania, and bipolar depression, 217 bulimia nervosa and, 454–455
DBDs and aggression, 109, 120
IED. See Intermittent explosive disorder FDA-approved and off-label use of, 22
Iloperidone, 260, 348 Lithium
Imipramine adverse effects of, 123, 322–323
anxiety disorders and, 153, 172, anorexia nervosa and, 450
174, 175–176, 178, 185 ASD and, 310–311
BED and, 460 bipolar disorder and, 246–251
Immediate-release (IR) form combined with antidepressants for
of lithium, 249 treatment-resistant depression,
of methylphenidate, 59, 62 221
Impulsive aggression (IA), 102 combined with divalproex sodium
Infants, topiramate and birth defects in, for mania, 275
354. See also Pregnancy correlation between serum and brain
Intellectual developmental disorder, levels of, 10
284 DBDs and aggression, 110, 121,
Intersubject variability, in 122, 127
pharmacokinetics, 9 extended-release formulations of, 9,
Intermittent explosive disorder (IED), 247
104, 105 FDA-approved and off-label use of,
Interpersonal therapy, for eating 22
disorders, 453, 459 maintenance therapy for bipolar
Isle of Wight study, 343 disorders and, 273
maintenance therapy for MDD and,
Kanner, Leo, 283 228
Ketamine, 202, 222 Liver failure, and divalproex, 257
 Index 493

Long-acting injectable antipsychotics Mania

(LAIs), 421–422 bipolar depression and, 217
Long-duration preparations, of ziprasidone-associated, 271
methylphenidate, 61–64 MDD. See Major depressive disorder
Long-term treatment Measurement of Aggression, Violence,
benzodiazepines and, 174–175 and Rage in Children (MAVRIC),
TCAs and, 179 180
Lorazepam, and anxiety disorders, 156, Mechanism-targeted interventions, and
171 pharmacogenetics, 11
Loxapine, 382, 389, 405 Medical complications. See also
Lumateperone, 260, 348 Diabetes; Heart disease;
Lurasidone Hypertension; Physical symptoms
ASD and, 286, 296 of anorexia nervosa, 443
bipolar depression and, 217 of bulimia nervosa, 451
bipolar disorders and, 271–272 Medical history
FDA-approved and off-label use of, ADHD and, 35
22 atypical antipsychotics and,
schizophrenia and, 387, 397 260–261
tic disorders and, 348 bipolar disorder and, 247
carbamazepine and, 253
Maintenance therapy divalproex sodium and, 256
benzodiazepines and, 174 olanzapine and, 264–265
bipolar disorders and, 273–274 risperidone and, 268
MDD and, 226–229 Medication interactions
Major depressive disorder (MDD). See atomoxetine and, 77–78
also Depression atypical antipsychotics and, 261
assessment of treatment response in, carbamazepine and, 254–255
200–201 CYP450 enzymes and, 8, 212–213
continuation therapy and, lithium and, 250–251
224–226 methylphenidate and, 60–61
definitions of treatment outcome SSRIs and, 212–213
for, 200 valproate and, 259
maintenance therapy for, 226–229 Medscape, 213
phases of treatment for, 201 Memantine, 314
prevalence of, 199 Mental Health America, 130
SSRIs and, 201–216 Metabolism
treatment of subtypes, 216–223 influence of development on
Management, practical strategies of for pharmacokinetics, 2–10
ASD, 323 methylphenidate and, 59
494 Clinical Manual of Child and Adolescent Psychopharmacology

Metformin, 261, 296–297, 411 ASD and, 310–312, 322–323

Methylphenidate common and serious side effects of,
ADHD and, 41–42, 45, 59–65, 73, 117, 127
276, 362–364 DBDs and aggression, 110, 121–123
ASD and, 289, 304 Mortality rate, and anorexia nervosa,
bipolar disorder and, 276 443. See also Sudden death;
bulimia nervosa and, 454 Suicide and suicidal ideation
DBDs and aggression, 109, 119 Multidimensional Anxiety Scale for
DMDD and, 229 Children, 448
dosage of, 59 Multidimensionally impaired, and
dose-related delay in growth and, schizophrenia, 378–379
15–16 Multilayer bead technology, and
extended-release formulations of, 9 methylphenidate, 63–64
FDA-approved and off-label use of, 22 Multimodal therapies
tic disorders and, 363–364 for maintenance treatment of
Metoclopramide, 352, 354–355 MDD, 228–229
Mianserin, 208 practical management strategies for
Micromedex, 213, 215 ASD and, 284, 323
Minimal risk, and pharmacological Multimodal Treatment Study of
research, 18–19 Children With ADHD (MTA),
Mirtazapine, 207, 209, 301–302, 39, 45, 60, 69, 72, 73, 74, 81,
449 119, 120, 305, 363, 364
Misdiagnosis, of psychosis in children,
378 N-Acetylcysteine (NAC), 315–316
Mitochondrial disorder, and valproate, Nadolol, 110, 316
257 Naltrexone, 316–317, 450
Modafinil, 81, 360 National Alliance on Mental Illness, 130
Molindone, 384, 398, 407 National Comorbidity Survey–
Monitoring, of treatment Adolescent Supplement (NCS-A),
ADHD and, 81–83 147, 149
anxiety disorders and, 182–183 National Federation of Families for
DBDs and aggression, 126–127 Children’s Mental Health, 130
serum lithium levels and, 249 National Institute of Child Health and
suicidal ideation and, 216 Human Development, 246
Monoamine oxidase inhibitors National Institute for Health and Care
(MAOIs), 202, 213, 449 Excellence (NICE), 442
Mood stabilizers. See also Lamotrigine; National Institute of Mental Health
Levetiracetam; Lithium; Valproic (NIMH), 39, 159, 160, 255–256,
acid 377
 Index 495

National Institutes of Health, 456 prevalence of, 149

National Survey of Children’s Health, sertraline and, 159–160, 166, 186
71–72 tic disorders comorbid with, 355–358
National Syndrome Surveillance ODD. See Oppositional defiant
Program, 345 disorder
N-desmethylclozapine (NDMC), 401 Off-label use, of psychotropic
Nefazodone, 208, 209 medications, 20, 21–23
Neuroimaging, and psychostimulants, Olanzapine
57–58 anorexia nervosa and, 447, 448
Neuroleptic malignant syndrome ASD and, 292, 321
(NMS), 409 bipolar disorders and, 264–265
Neuropsychological testing, and combined with fluoxetine for
ADHD, 35 bipolar depression, 217
Neutropenia, and clozapine, 414 DBDs and aggression, 109, 112–
Nisonger Child Behavior Rating Form 113
(NCBRF), 107, 108 extrapyramidal side effects of, 404
Nonresponse, treatment-resistant FDA-approved and off-label use of, 22
depression and definitions of, 219 psychosis and, 417, 418
Nonsteroidal anti-inflammatory drugs schizophrenia and, 384, 385, 392–
(NSAIDs), and lithium, 251 394, 398, 401, 402, 405, 406,
Norepinephrine receptor agonists. See 409, 410, 411, 412
Clonidine; Guanfacine tic disorders and, 348, 349, 350
Norepinephrine reuptake inhibitors, 57, Omega-3, 421
117, 125 Ondansetron, 352, 353
Normalization, and clinical response to Oppositional defiant disorder (ODD),
stimulants, 73 103, 105, 229
Number needed to harm (NNH), 211 Oral contraceptives, and medication
Number needed to treat (NNT), 14, 207 interactions, 8, 255
Nutritional rehabilitation, for eating Oral solution
disorders, 446, 456 of carbamazepine, 253
of methylphenidate, 64
Obsessive-compulsive disorder (OCD) Osmotic-release oral system (OROS)
buspirone and, 181 methylphenidate, 59, 63
citalopram and escitalopram for, Overall Phobia Rating Scale, 171
163, 166–167 Overanxious disorder, 149
clomipramine and, 164, 177 Overt Aggression Scale (OAS)–
desipramine and, 177 Modified, 108
fluoxetine and, 158 Oxcarbazepine, 23, 260
fluvoxamine and, 161 Oxytocin, 317–318, 450, 455
496 Clinical Manual of Child and Adolescent Psychopharmacology

Palatability, of stimulants, 64, 67 hyperactivity disorder; Autism

Paliperidone spectrum disorder; Bipolar
ASD and, 295–296, 320 disorders; Development;
DBDs and aggression, 109, 112 Disruptive behavior disorders;
extrapyramidal side effects of, 404 Eating disorders; Major depressive
schizophrenia and, 387, 390, 396, disorder; Preschool children;
407, 422 Schizophrenia; School-age
tic disorders and, 348, 349 children; Tic disorders
Panic disorder, 149, 171–172, 174 Pervasive developmental disorders
Parents. See also Family-based therapy; (PDDs), 284, 294
Psychoeducation Pharmacodynamics, and development
atomoxetine and training for, 309 of children and adolescents, 10–11
of children with depression, 202, Pharmacogenetics, 11
214 Pharmacokinetics
ethical issues in pharmacological development of children and
research and, 18, 20 adolescents, 2–10
schizophrenia in and development of psychostimulants for treatment of
psychosis in child, 415 ADHD and, 59, 65–67
Parkinson’s disease, 403 Phase I and Phase II, of drug
Paroxetine metabolism, 3, 4
anxiety disorders and, 154, 162–163 Phenobarbital, 15
ASD and, 300–301 Physical symptoms, of anxiety disorders
dosage of, 215 in children, 149–150
FDA-approved and off-label use of, 23 Pica, 463–465
MDD and, 204 Pimozide
tic disorders comorbid with OCD CYP450 enzymes and medication
and, 357 interactions, 8
Patch, and methylphenidate, 64–65 FDA-approved and off-label use of,
Peak plasma concentration, and 23
pharmacokinetics, 3 tic disorders and, 347, 348, 351,
Pediatric Anxiety Rating Scale (PARS), 355
161–162, 163, 169, 170, 302 Pindolol, 360
Pediatric bipolar disorder (PBD). See Pirenzepine, 415
Bipolar disorder Polaprezinc, 455
Pediatric OCD Treatment Study Polycystic ovary syndrome (PCOS),
(POTS), 186, 357–358 256, 257–258
Pediatric psychopharmacology. See Positive and Negative Syndrome Scale
Adolescents; Aggression; Anxiety (PANSS), 12, 391, 393, 394, 396,
disorders; Attention-deficit/ 397, 422
 Index 497

Posttraumatic stress disorder (PTSD) Psychoneurotic disorders, 148

guanfacine and, 181–182 Psychosis
prevalence of in children, 149 early intervention studies of
sertraline and, 160–161 schizophrenia and, 415–422
Practice guidelines history and classification of in
for ADHD, 83–84 children, 378–379
for DBDs and aggression, 128–131 parent with schizophrenia and
Pregnancy development of in child, 415
divalproex sodium and, 256 Psychosocial interventions. See also
lithium and, 247–248 Behavioral interventions
topiramate and, 354 for ADHD, 40
Pre-Linguistic Autism Diagnostic for aggressive behavior, 129, 130
Observation Scale, 311 Psychostimulants, use of term, 40
Preschool ADHD Treatment Study Psychotherapy. See also Cognitive-
(PATS), 60 behavioral therapy; Interpersonal
Preschool children therapy; Multimodal therapies
choice of medications for ADHD in, for anxiety disorders, 184–185
83 for DBDs and aggression, 106, 129
hallucinations in and psychosis, 378 for eating disorders, 453
interviews to assess ADHD in, 35 for MDD, 202
methylphenidate for ADHD in, 16, safety issues in psychopharmacology
60 and, 17
methylphenidate and growth Psychotic depression, 218
slowdown in, 69 PTSD. See Posttraumatic stress disorder
PTSD subtype for, 148
Prevalence. See Epidemiology QT interval, and atypical
Prevention Through Risk antipsychotics, 270, 350–351, 413
Identification, Management, and Quetiapine
Education trial, 417 anorexia nervosa and, 447, 448
Proactive aggression (PA), 102 ASD and, 292–293
Prolactin concentrations, and atypical bipolar disorders and, 266–267,
antipsychotics, 268, 320, 412–413 274, 275
Propranolol, 250, 316, 409 DBDs and aggression, 109, 113
Pseudoparkinsonism, and extrapyramidal side effects of, 404
extrapyramidal side effects, 403 FDA-approved and off-label use of, 23
Psychoeducation MDD in adolescents and, 221
aggressive behavior and, 129–130 schizophrenia and, 385, 387, 395–
MDD and, 201–202, 214, 223 396, 407, 408, 409
Tourette’s disorder and, 346 tic disorders and, 348
498 Clinical Manual of Child and Adolescent Psychopharmacology

Race psychosis and, 417, 418, 419

bulimia nervosa and, 452 schizophrenia and, 383, 384, 385,
carbamazepine and, 11 390, 391–392, 398, 405, 406,
CYP450 and drug metabolism, 4 410
prevalence of tic disorders and, 343 tic disorders and, 348, 349, 350,
Rating of Aggression Against People 352, 355, 358
and/or Property Scale, 107 Rituals, and OCD, 357
Rating scales Rivastigmine, 312–313
assessment of tic severity and, 346 Rumination disorder, 465–466
evaluation of efficacy and, 12–13
evaluation of suicidality and, 210 Safety. See also Black box warnings;
Reactive aggression, 102 Monitoring; Suicide and suicidal
Reboxetine, 208 ideation
Relapse development issues in pediatric
of ASD, 295 psychopharmacology and,
of MDD, 225–226 15–17
of schizophrenia, 422 psychopharmacology for anxiety
Renal side effects, of lithium, 250 disorders and, 182–184
Repetitive behaviors, and OCD, 357 psychopharmacology for ASD and,
Research Units on Pediatric 320–323
Psychopharmacology (RUPP) psychopharmacology for DBDs and
Study, 111, 161–162, 165, 290– aggression, 126–128
291, 304–305 suicidality and plans for, 224
Revised Children’s Manifest Anxiety Scale for the Assessment of Negative
Scale (RCMAS), 180 Symptoms, 395, 401
Risperidone Schizophrenia
acute mania and, 247 atypical antipsychotics and,
anorexia nervosa and, 447, 448 390–402
ASD and, 285, 286–287, 290–291, clozapine for aggression in
295, 303, 319, 320 treatment-refractory, 114
bipolar disorders and, 267–269 course and outcome of, 379–380
CYP450 enzymes and clearance of, 8 early intervention studies on,
DBDs and aggression, 106–108, 415–422
109, 110–112, 122 efficacy of first-generation anti-
DMDD and, 229 psychotics for, 381, 382–388,
extrapyramidal side effects of, 404 389–390
FDA-approved and off-label use of, 23 epidemiology of, 379
influence of gender on metabolism rationale for pharmacological
of, 4 treatment of, 380–381
 Index 499

treatment of comorbid conditions MDD and, 201–216, 228

in, 402–403 monitoring of, 183
treatment of medication side effects tic disorders comorbid with OCD
and, 403–415 and, 357
Schizotypal personality disorder, 416 Selegiline, 207–208, 360, 362–363
School. See School refusal; Teachers Self-help programs, and BED, 459
School-age children. See also Age; Age at Self-injury, and pica, 464
onset Separation anxiety disorder, 149, 159,
interviews to assess ADHD in, 35 176–177
methylphenidate for ADHD in, 60, Serotonergic system
83 atypical antipsychotics and, 390
methylphenidate for ASD in, 305 autism and, 297
methylphenidate and growth Serotonin-norepinephrine reuptake
slowdown in, 69 inhibitors (SNRIs). See also
prevalence of social avoidance in, 149 Atomoxetine
prevalence of transient tics in, 342, anxiety disorders and, 155, 168–170
343 ASD and, 289
psychotic symptoms in, 378 dosages of, 76, 215–216
School refusal, and school phobia, 172, MDD and, 203–205, 206, 208
175–176, 185 Serotonin syndrome, 208, 213
Screening, for ADHD, 34 Sertraline
Seasonal affective disorder, 218 anxiety disorders and, 154, 159–161,
Second-generation antipsychotics. See 166, 186, 187
Atypical antipsychotics ASD and, 300
Secretin, 317 dosage of, 215
Sedation, and antipsychotics for elimination half-life of, 8–9
schizophrenia, 409–410 FDA-approved and off-label use of, 23
Seizures pediatric MDD and, 204, 212
bupropion and, 209, 454 tic disorders comorbid with OCD
clozapine and, 290, 414 and, 357–358
Selective mutism, 157–158 Severe mood dysregulation (SMD), 229
Selective serotonin reuptake inhibitors Simpson-Angus Rating Scale, 404
(SSRIs) Single-isomer dexmethylphenidate,
anorexia nervosa and, 450 62–63
anxiety disorders and, 151–152, Single-pulse methylphenidate sustained-
154, 157–167, 181 release preparations, 61
ASD and, 287–288, 297–304, 321 Sleep, stimulant-induced delay of, 83
continuity of efficacy from SNRIs. See Serotonin-norepinephrine
childhood to adulthood, 13 reuptake inhibitors
500 Clinical Manual of Child and Adolescent Psychopharmacology

Social anxiety disorder, 162, 169, Suicide and suicidal ideation

180–181 anorexia nervosa and risk of, 443
Social Anxiety Scale (SAS), 169 anticonvulsants and, 123
Social avoidance, prevalence of in antidepressants and, 17, 152, 165,
school-age children, 149 183, 209–212, 216, 321
Social Effectiveness Therapy for atomoxetine and, 78, 125, 322
Children (SET-C), 187 olanzapine and, 393
Social phobia, 159, 163, 187 SNRIs and, 169, 170
Social Responsiveness Scale (SRS), 314, treatment of MDD and, 223–224
315 viloxazine and, 79
Spheroidal Oral Drug Absorption Support groups, for parents of children
System (SODAS), 61, 62 with aggressive behavior, 130
SSRIs. See Selective serotonin reuptake Supportive therapy, for MDD,
inhibitors 201–202
Standard warnings, and stimulants, Sustained-release formulation, of
67–69 lithium, 249
Steady-state plasma concentration, and Swanson, Nolan, and Pelham rating
pharmacokinetics, 3 scale (SNAP-IV), 35, 73, 119, 309
Stevens-Johnson syndrome, and
carbamazepine, 253, 254 Tardive dyskinesia, and atypical anti-
Stimulants. See also Methylphenidate psychotics, 261, 350, 380–381,
ADHD and, 40–75, 358–359, 396–397, 403, 404
363–364 Target symptom approach, to
adverse effects of, 67–71, 116, 126 pharmacotherapy for ASD, 323
ASD and, 289, 304–306, 321–322 TCAs. See Tricyclic antidepressants
BED and, 459–460 Teachers, and monitoring of treatment
DBDs and aggression, 109, 119–120 for ADHD, 82
safety issues and, 16, 126 Texas Children’s Medication Algorithm
tic disorders and, 358–359, 363–364 Project (TCMAP), 75, 83
Stroke, and stimulants, 68 Theophylline, and lithium levels, 251
Study of Fluoxetine in Autism (SOFIA) Thiazide diuretics, and lithium levels,
study, 299–300 251
Substance abuse, stimulants and risk of, Thioridazine, 109, 118, 389
16. See also Dependence Thiothixene, 383, 389
Subtypes, of ADHD, 34 Tiagabine, 260
Sudden death Tianeptine, 208
clonidine and, 80 Tiapride, 354
stimulants and, 68 Tic(s), and adverse effects of stimulants,
TCAs and, 178 70–71
 Index 501

Tic disorders. See also Tourette’s disorder Treatment of Early Onset Schizophre-
comorbid illnesses with, 355–365 nia Spectrum Disorders (TEOSS)
definition of, 341 study, 389, 390, 393–394, 398
diagnosis and assessment of, 344–346 Treatment of Maladaptive Aggression in
dosages of antipsychotics for, 348 Youth (T-MAY), 129, 130
epidemiology of, 342–344 Treatment outcome, definition of in
Tic Symptom Self-Report, 346 context of MDD, 200
Time effect, and research on efficacy, 14 Treatment Recommendations for the
Tolerability, age-related for Use of Antipsychotic Medications
methylphenidate, 16 for Aggressive Youth, 128–129
Topiramate Treatment resistance
antipsychotic-induced weight gain depression and, 218–223
and, 411 schizophrenia and, 400
BED and, 460 Treatment response, assessment of for
bipolar disorder and, 259–260 MDD, 200–201
bulimia nervosa and, 454 Treatment of Severe Child Aggression
tic disorders and, 352, 353–354 (TOSCA) study, 107, 111
Total Tic Severity Scale, 349 Treatment of SSRI-Resistant
Tourette’s disorder Depression in Adolescents
assessment and treatment of, 341–342 (TORDIA), 219–222
comorbidities in, 343, 355–365 Tricyclic antidepressants (TCAs)
olanzapine for aggression and, 112 anorexia nervosa and, 449
premonitory sensations and tic anxiety disorders and, 153, 175–179,
suppression, 344–345 183
prevalence of, 342 bulimia nervosa and, 454
treatment of, 346–355 MDD and, 202, 228
Tourette’s Syndrome Study Group, 363 medication interactions and, 8
Toxicity, of lithium, 249, 322–323 rumination disorder and, 466
Transcranial magnetic stimulation
(TMS), and anorexia nervosa, 449 U.S. Secretary of Health and Human
Transdermal preparations, of Services, 19
methylphenidate, 64–65 UpToDate (website), 213
Trazodone, 209
Treatment for Adolescents With Valproate, 23
Depression Study (TADS), 14, Valproic acid. See also Divalproex sodium
206, 210, 224 ASD and, 310, 322
Treatment of ADHD in Children with DBDs and aggression, 110
Tic disorders (TACT), 363–364 formulations of, 256
Treatment algorithms, 13 hepatotoxicity in younger children, 15
502 Clinical Manual of Child and Adolescent Psychopharmacology

Vanderbilt ADHD Diagnostic Rating divalproex sodium and, 256, 257, 258
Scale, 35 metformin and, 296
Venlafaxine mood stabilizers and, 127
anxiety disorders and, 155, 168– olanzapine and, 292
169, 183 Weight loss
ASD and, 302 treatment of BED and, 458–459
dosage of, 215 venlafaxine and, 170
FDA-approved and off-label use of, 23 Withdrawal, and discontinuation of
MDD and, 205, 209 SSRIs, 183
suicide-related behavior and, 17 Women’s Health Initiative, 458–459
Very early onset schizophrenia, 377 World Federation of Societies of
Vilazodone, 204, 215 Biological Psychiatry (WFSBP),
Viloxazine 442, 447, 450, 454
ADHD and, 75, 76, 78–79, 360 World Health Organization Mental
FDA-approved and off-label use of, 23 Survey Study, 457
Vineland Adaptive Behavioral Scales,
111, 315 Yale-Brown Obsessive Compulsive
Visual adverse effects, of quetiapine, 267 Scale (Y-BOCS), 166, 179, 181,
Volume of distribution, and 299, 358
pharmacokinetics, 3 Yale Global Tic Severity Scale
Vortioxetine, 205, 215 (YGTSS), 346, 348, 349, 352,
353, 354, 355
Websites
medication interactions and, 213 Zinc, and anorexia nervosa, 450
participation of children in research Ziprasidone
and, 20 ASD and, 293, 321
pharmacogenetics and, 11 bipolar disorders and, 269–271, 272
support groups for parents of DBDs and aggression, 109, 114
children with aggressive schizophrenia and, 396, 409, 410
behavior, 130 tic disorders and, 348, 349, 351,
Weight gain, and adverse effects of 352, 355
medications Zonisamide, 260, 460
antipsychotics and, 115, 126, 261,
265, 267, 269, 321, 350, 393,
410–412, 447
 FOURTH
EDITION

W
hen it comes to the use of psychotropic agents in pediatric pa-
tients, it is not merely a question of extrapolating data from adults
to children and adolescents; special consideration must be given
to the effects of the drug on developing bodies and brains.

Adolescent Psychopharmacology
That is what makes this fourth edition of the Clinical Manual of Child and

Clinical Manual of Child and

Clinical Manual of
Adolescent Psychopharmacology so essential. Updated to include a suc-
cinct yet thorough review of the most recent evidence-based information
and data-driven best treatment practices in child and adolescent psychia-
try, this new volume is organized by DSM-5-TR® diagnosis and offers an
exhaustive analysis of the use of drugs in nine disorder categories that
include depressive disorders, attention-deficit/hyperactivity disorder, au-
Child and Adolescent
Psychopharmacology
tism spectrum disorder, eating disorders, and early schizophrenia and psy-
chotic illnesses.

Each chapter includes comprehensive medication tables that allow easy

reference of dosing, side effects, and tips for management as well as key
points that summarize the most essential information for treating clinicians.

Whether they are clinical psychiatrists, medical students on psychiatry ro-

FOURTH EDITION
tation, advanced practice providers, or pediatricians, readers will benefit
from the depth of information in this indispensable desktop reference.

About the Editors

Molly McVoy, M.D., is an Associate Professor in Psychiatry in the Divi-
sion of Child and Adolescent Psychiatry Fellowship at University Hospitals/
Case Western Reserve University in Cleveland, Ohio.

Ekaterina Stepanova, M.D., Ph.D., is Chair of Child and Adolescent Psy-

chiatry at Virginia Commonwealth University in Richmond, Virginia.
McVoy
Robert L. Findling, M.D., M.B.A., is Chair of the Department of Psychia- Stepanova
try at Virginia Commonwealth University in Richmond, Virginia. Findling

Edited by
Molly McVoy, M.D.
Ekaterina Stepanova, M.D., Ph.D.
Robert L. Findling, M.D., M.B.A.