Practical Child and Adolescent Psychopharmacology

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Author: Stan Kutcher

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Practical child and adolescent psychopharmacology The ﬁeld of child and adolescent psychopharmacology is rapidly growing, but psychopharmacologic treatments for children cannot be straightforwardly extrapolated from adult studies, which presents clinicians with assessment and prescribing challenges. In this important book, a team of expert clinicians synthesizes the most recent research ﬁndings about drug treatment of a broad range of psychiatric disorders in children, including attention-deﬁcit hyperactivity disorder, obsessive–compulsive disorder, major depression, schizophrenia, bipolar mania, aggression in pervasive developmental disorder, Tourette’s syndrome, and substance abuse. They examine the issues of tolerability and efﬁcacy, and inappropriate over-use, within a social and developmental context. For each disorder, pharmacotherapy is discussed in the wider context of neurobiology, etiology, diagnosis, and treatment. This will be essential reading for all mental health professionals to inform practice and improve patient outcomes. Stan Kutcher is Professor and Head of the Department of Psychiatry at Dalhousie University, and Chief of Service, Department of Psychiatry and Mental Health Services at the Queen Elizabeth II Health Sciences Center, and Associate Dean of International Medical Development and Research at Dalhousie University, Halifax, Nova Scotia.

Cambridge Child and Adolescent Psychiatry

Child and adolescent psychiatry is an important and growing area of clinical psychiatry. The last decade has seen a rapid expansion of scientiﬁc knowledge in this ﬁeld and has provided a new understanding of the underlying pathology of mental disorders in these age groups. This series is aimed at practitioners and researchers both in child and adolescent mental health services and developmental and clinical neuroscience. Focusing on psychopathology, it highlights those topics where the growth of knowledge has had the greatest impact on clinical practice and on the treatment and understanding of mental illness. Individual volumes beneﬁt both from the international expertise of their contributors and a coherence generated through a uniform style and structure for the series. Each volume provides ﬁrstly an historical overview and a clear descriptive account of the psychopathology of a speciﬁc disorder or group of related disorders. These features then form the basis for a thorough critical review of the etiology, natural history, management, prevention and impact on later adult adjustment. Whilst each volume is therefore complete in its own right, volumes also relate to each other to create a ﬂexible and collectable series that should appeal to students as well as experienced scientists and practitioners. Editorial board Series editor Professor Ian M. Goodyer University of Cambridge Associate editors Professor Donald J. Cohen Yale Child Study Center

Dr Robert N. Goodman Institute of Psychiatry, London

Professor Barry Nurcombe The University of Queensland

Professor Dr Helmut Remschmidt Klinikum der Philipps-Universita¨t, Germany

Professor Dr Herman van Engeland Academisch Ziekenhuis Utrecht

Dr Fred R. Volkmar Yale Child Study Center

Already published in this series: Psychotherapy with Children and Adolescents edited by Helmut Remschmidt 0 521 77558 2 pb Speciﬁc Learning Disabilities and Difﬁculties in Children and Adolescents edited by Alan and Nadeen Kaufman 0 521 65840 3 pb The Depressed Child and Adolescent second edition edited by Ian M. Goodyer 0 521 79426 9 pb Schizophrenia in Children and Adolescents edited by Helmut Remschmidt 0 521 79428 5 pb Anxiety Disorders in Children and Adolescents: Research, Assessment and Intervention edited by Wendy Silverman and Philip Treffers 0 521 78966 4 pb Conduct Disorders in Childhood and Adolescence edited by Jonathan Hill and Barbara Maughan 0 521 78639 8 pb Autism and Pervasive Developmental Disorders edited by Fred R. Volkmar 0 521 55386 5 hb Cognitive Behaviour Therapy for Children and Families by Philip Graham 0 521 57252 5 hb 0 521 57626 1 pb Hyperactivity Disorders of Childhood edited by Seija Sandberg 0 521 43250 2 hb

Practical child and adolescent psychopharmacology Edited by

Stan Kutcher Dalhousie University, Halifax, Nova Scotia, Canada

   Cambridge, New York, Melbourne, Madrid, Cape Town, Singapore, São Paulo Cambridge University Press The Edinburgh Building, Cambridge  , United Kingdom Published in the United States by Cambridge University Press, New York www.cambridge.org Information on this title: www.cambridge.org/9780521655422 © Cambridge University Press 2002 This book is in copyright. Subject to statutory exception and to the provision of relevant collective licensing agreements, no reproduction of any part may take place without the written permission of Cambridge University Press. First published in print format 2002 ISBN-13 ISBN-10

978-0-511-06643-6 eBook (NetLibrary) 0-511-06643-0 eBook (NetLibrary)

ISBN-13 978-0-521-65542-2 paperback ISBN-10 0-521-65542-0 paperback

Cambridge University Press has no responsibility for the persistence or accuracy of s for external or third-party internet websites referred to in this book, and does not guarantee that any content on such websites is, or will remain, accurate or appropriate. Every effort has been made in preparing this book to provide accurate and up-to-date information which is in accord with accepted standards and practice at the time of publication. Nevertheless, the authors, editors and publishers can make no warranties that the information contained herein is totally free from error, not least because clinical standards are constantly changing through research and regulation. The authors, editors and publisher therefore disclaim all liability for direct or consequential damages resulting from the use of material contained in this book. Readers are strongly advised to pay careful attention to information provided by the manufacturer of any drugs or equipment that they plan to use.

Dedicated to my wife and to my mother – both of whom have put up with me for many years

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Contents List of contributors Preface and acknowledgements 1

Child and adolescent psychopharmacology at the turn of the millennium

ix xiii 1

Charles W. Popper

2

Developmental psychopharmacology

38

Normand Carrey, Paul Mendella, Frank P. MacMaster, and Stan Kutcher

3

Clinical aspects of child and adolescent psychopharmacology

70

Gabrielle A. Carlson

4

Depression

91

Neal D. Ryan

5

Bipolar mood disorders: diagnosis, etiology, and treatment

106

Vivek Kusumakar, Lorraine Lazier, Frank P. MacMaster, and Darcy Santor

6

Schizophrenia and related psychoses

134

Keith Marriage

7

Obsessive–compulsive disorder

159

Douglas A. Beer, Mai Karitani, Henrietta L. Leonard, John S. March, and Susan E. Swedo

8

Anxiety disorders

187

E. Jane Garland

9

Attention-deﬁcit/hyperactivity disorder

230

Thomas Spencer, Joseph Biederman, and Timothy Wilens

10

Pervasive development disorder

265

Sandra N. Fisman

11

Aggressive behavior

305

Deborah Lynn and Bryan H. King

12

Adolescent substance use disorder K.A. Hussain Mirza

vii

328

viii

13

Contents

Tic disorders and Tourette’s syndrome

382

John T. Walkup

14

Eating disorders and related disturbances

410

Lisa A. Kotler, Michael J. Devlin, and B. Timothy Walsh

15

Medical psychiatric conditions

431

Daniel S. Pine, Elizabeth Cohen, and Yana Brayman

Index

455

Contributors

Douglas A. Beer Department of Psychiatry and Human Behavior Brown University Butler Hospital 345 Blackstone Boulevard Providence, RI 02906 USA [email protected] Joseph Biederman Pediatric Psychopharmacology Unit Massachusetts General Hospital WACC 75 15 Parkman Street Boston, MA 02114 USA Yana Brayman New York Psychiatric Institute 1051 Riverside Drive New York, NY 10032 USA Gabrielle A. Carlson Child and Adolescent Psychiatry State University of New York at Stony Brook Stony Brook, NY 11794-8790 USA [email protected]

ix

Normand Carrey Maritime Psychiatry IWK Health Centre 5850 University Avenue Halifax, NS B3J 3G9 Canada [email protected] Elizabeth Cohen New York Psychiatric Institute 1051 Riverside Drive New York, NY 10032 USA Michael J. Devlin Department of Clinical Psychopharmacology Columbia University New York State Psychiatric Institute 1051 Riverside Drive-Unit 98 New York, NY 10032 USA Sandra N. Fisman Children’s Hospital of Western Ontario PO Box 5375 Stn Ctr CSC London, ON N6A 4G5 Canada sﬁ[email protected] E. Jane Garland Outpatient Psychiatry 4480 Oak Street Vancouver, BC V6H 3V4 Canada [email protected]

x

List of contributors

Mai Karitani Rhode Island Hospital 593 Eddy Street Providence, RI 02903 USA Bryan H. King Dartmouth Medical School Dartmouth Hitchcock Medical Center One Medical Center Drive Lebanon, NH 03756 USA [email protected] Lisa Kotler Department of Child and Adolescent Psychiatry Columbia University/New York State Psychiatric Institute 1051 Riverside Drive-Unit 74 New York, NY 10032 USA [email protected] Vivek Kusumakar Division of Child and Adolescent Psychiatry IWK Grace Health Centre 5850 University Avenue Halifax, NS B3J 3G9 Canada [email protected] Stan Kutcher Department of Psychiatry Queen Elizabeth II Health Sciences Center Lane Building, Suite 4082 5909 Jubilee Road Halifax, NS B3H 2E2 Canada [email protected] Lorraine Lazier Valley Regional Hospital Western Regional Health Board Kentville, NS Canada

Henrietta L. Leonard Rhode Island Hospital Department of Child Psychiatry 593 Eddy Street Providence, RI 02903-4923 USA Deborah Lynn Department of Child Adolescent Psychiatry UCLA Neuropsychiatric Institute 760 Westwood Plaza Los Angeles, CA 90024 USA [email protected] Frank Petrie MacMaster Mood Disorders Group Dalhousie University Halifax, NS Canada John S. March Duke Child and Family Study Center Duke University Medical Center Box 3527 Durham, NC 27710 USA Keith J. Marriage British Columbia Children’s Hospital WC1-4480 Oak Street Vancouver, BC V6H 3V4 Canada Paul Mendella Dalhousie University Department of Psychology Halifax, NS Canada

xi

List of contributors

K.A. Hussein Mirza University Department of Child and Adolescent Psychiatry Institute of Psychiatry Kings College Denmark Hill London SE5 8AF UK [email protected] Daniel S. Pine Development and Affective Neuroscience Section NIMH Intramural Research Program Building 10, Room 4N-222 MSC-1381 Bethesda, MD 20817 USA [email protected] Charles W. Popper McLean Hospital 115 Mill Street Belmont, MA 02178-9106 USA [email protected] Neal Ryan Western Psychiatric Institute and Clinic 3811 O’Hara Street Pittsburgh, PA 15213-2593 USA [email protected] Darcy Santor Adolescent Inter-Personal Therapy Program Dalhousie University Halifax, NS B3J 3G9 Canada

Thomas J. Spencer Pediatric Psychopharmacology Unit Massachusetts General Hospital WACC 725 15 Parkman Street Boston, MA 02114 USA [email protected] Susan E. Swedo Chief, Pediatrics & Developmental Neuropsychiatry Branch National Institute of Mental Health 9000 Rockville Pike Building 10 Bethesda, MD 20892 USA John T. Walkup Johns Hopkins Hospital CMSC 343 600 N. Wolfe Street Baltimore, MD 21287 USA [email protected] B. Timothy Walsh Department of Clinical Psychopharmacology Columbia University/New York State Psychiatric Institute 1051 Riverside Drive-Unit 98 New York, NY 10032 USA Timothy Wilens Pediatric Substance Abuse Pediatric Psychopharmacology Unit Massachusetts General Hospital WACC 725 15 Parkman Street, Boston, MA 02114 USA

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Preface

The ﬁeld of child and adolescent psychopharmacology is rapidly growing and every clinician, physician, and other health provider alike must be informed of new directions and applications in the use of medications as they pertain to the treatment of psychiatric disorders in children and adolescents. To date, considerable research has been conducted which can properly direct the use of a variety of psychotropic compounds in a number of child and adolescent psychiatric disorders. In particular, well-established and effective pharmacologic treatments are available for attention-deﬁcit hyperactivity disorder, obsessive–compulsive disorder, and Tourette’s syndrome. Less well-established but nonetheless frequently applied pharmacotherapies are used to treat a variety of psychiatric illness (such as major depression, schizophrenia, bipolar mania) or speciﬁc symptoms which may occur independently or as a component of a particular psychiatric diagnosis – such as aggression in pervasive developmental disorder. Evidence and experience to date clearly indicates that psychopharmacologic treatments for children and teenagers cannot be extrapolated from studies conducted in adult patients. Young people have a different central nervous system development, exhibit different cognitive, behavioral, and affective ‘‘norms’’ and are exposed to different environmental inﬂuences. All of these factors can inﬂuence the response to pharmacologic treatments – efﬁcacy as well as tolerability. Thus, the study and practice of pharmacologic treatments of child and adolescent psychiatric disorders must become a special and signiﬁcant area in its own right. These treatments, while demanding proper scientiﬁc evaluation, also do not occur within a social vacuum. In many cases, popular sentiments often guided by inadequate knowledge or misinformation about the risks and beneﬁts of the use of psychotropic compounds in children and adolescents can affect the prescription and use of these medications in young people. In some cases, this may lead to inappropriate over-use. In other cases, this may lead to the withholding of potentially effective interventions. In order to avoid both of these unacceptable outcomes, the clinician must be well informed about both xiii

xiv

Preface

the science and the pragmatics of the use of medications in the treatment of child and adolescent psychiatric disorders. This book provides the practicing clinician with important information about the use of medications in treating psychiatric conditions found in young people. It is set in a social and developmental context as the chapters by Popper and Carrey outline. The clinical pragmatics are well summarized by Carlson. The remaining chapters deal with speciﬁc psychiatric disorders of children and adolescents and include chapters dedicated to the use of psychotropics in substance abuse and in medical conditions – two areas not well understood by many clinicians. Overall, this volume attempts to provide practical evidencebased information within an understandable clinical context. Acknowledgements I would like to thank all the contributing authors to this text. As is evident, each chapter has been written by an expert in the ﬁeld and the addition of extra writing in the already ‘‘too busy’’ lives of academics is a burden that is not often appreciated by the reader. Christina Rice and Maria Scott provided valuable organizational support. My colleagues and patients taught me enough about the ﬁeld to enable me to edit the various contributions with some degree of understanding and knowledge. My wife, as always, provided ongoing support. The positive reﬂections on this book are due to the expertise of the chapter authors and the publisher. The limitations are my responsibility. Stan Kutcher

1 Child and adolescent psychopharmacology at the turn of the millennium Charles W. Popper McLean Hospital, Belmont, Massachusetts, USA

Child and adolescent psychopharmacology is a leading edge of pediatric psychiatry and is rapidly growing. It has not always been this way. Child and adolescent psychopharmacology essentially began in 1937, when Bradley reported that some children with behavior disorders showed a seemingly paradoxical improvement during treatment with racemic amphetamine (Benzedrine“), which he had exploratorily used to treat 30 mostly preadolescent children in a residential treatment facility (Bradley, 1937). For over 60 years, psychostimulant treatment has basically remained unchanged. The characteristics of stimulant-responsive children have been studied and reﬁned over the decades, and (what is currently called) attention-deﬁcit/hyperactivity disorder (ADHD) has become the psychiatric model or prototype disorder for the medication treatment of children. The prototype treatment: psychostimulants for ADHD Throughout its existence, psychostimulant treatment has also been the prototype treatment used to express uneasiness about children receiving psychiatric medications. Although fully established scientiﬁcally, at least as much as antibiotic treatment, psychostimulant treatment is still controversial in some quarters. Concerns include trepidation about the inappropriate management of children in schools and homes, chemical control of children’s minds and behaviors, poisoning of children’s bodies, excessive dosing of medication, overmedicalization of child care, departure from the psychoanalytic or child guidance model, inadequate emphasis on the psychosocial themes, inappropriate attempts to ﬁnd surrogates for adequate stafﬁng and supervision, and social and psychological stigmatization. Despite such misgivings, Bradley’s approach has evolved into the widespread use of various psychostimulants to treat children with ADHD. 1

2

C.W. Popper

Psychostimulant treatment is no longer viewed as paradoxical, although there are many paradoxical aspects of this treatment. ADHD is one of the most thoroughly studied psychiatric disorders, but its pathophysiology is only roughly understood in terms of neuroanatomic chemistry. Psychostimulants appear to remain effective for years and even decades, but psychostimulants have only recently been demonstrated to sustain improvement over a period of 14–15 months (Arnold et al., 1997; Gillberg et al., 1997; The MTA Cooperative Group, 1999a,b), and longer-term treatment has still not been investigated in a controlled manner. Although ADHD is the most robust of syndromes in child and adolescent psychiatry, most children with ADHD are now recognized to have additional concurrent biopsychiatric disorders. Even with successful drug treatment, stimulant monotherapy is often not sufﬁcient for optimal outcome. For many individuals, psychostimulants need to be combined with additional psychopharmacologic agents in order to have clinically adequate effects. The strategy of treating psychopathology with combinations of psychiatric drugs can be used to ‘‘tickle’’ multiple neuronal systems that underlie different clinical presentations. Yet, as treatment of ADHD becomes more complex, the psychostimulants remain the central element. For many, and probably most, children with ADHD, concurrent educational interventions are needed to remediate the delayed acquisition of learned skills, including social skills, responsiveness to limits, behavioral self-discipline, persistence in effortful activities, self-correcting behavior, study skills, and enjoyment of calmness and quiet pleasures. Although educational interventions combined with psychostimulants are often helpful, the multimodal combination of psychosocial intervention with psychostimulants may not be more advantageous than psychostimulant drugs alone for treating the core symptoms of ADHD (inattention and impulsivity/ hyperactivity). Several studies have indicated that multimodal psychopharmacologic–psychosocial treatment, at least under some circumstances, is not (or only slightly) more effective than stimulant monotherapy for treating the core symptoms of ADHD, but may be more effective for treating features often associated with ADHD, such as academic underperformance, impaired social skills, oppositionality, and aggressivity (Gittelman Klein et al., 1976; Carlson et al., 1992, Ialongo et al., 1993, Pelham et al., 1993; MTA 1999a,b). It is possible that combination treatment might be more effective if inadequate stimulant doses or ineffective psychosocial treatments are used; however, it offers little more than stimulant monotherapy under conditions of optimal or appropriate treatment. Speculatively, though, further reﬁnement

3

Child and adolescent psychopharmacology

of the psychosocial treatments might produce a more potent combination. Over 150 double-blind placebo-controlled studies have demonstrated the efﬁcacy of psychostimulants for both the cognitive and behavioral symptoms of ADHD (Spencer et al., 1996). In addition to psychostimulants, at least 13 different investigative groups over the last 35 years have conducted doubleblind placebo-controlled studies demonstrating the clinical efﬁcacy of tricyclic antidepressants (TCAs) such as imipramine, desipramine, and amitriptyline for treating ADHD (Krakowski, 1965; Winsberg et al., 1972; Rapoport et al., 1974; Waizer et al., 1974; Kupietz and Balka, 1976; Yepes et al., 1977; Yellin et al., 1978; Werry et al., 1980; Garﬁnkel et al., 1983; Donnelly et al., 1986; Gualtieri and Evans, 1988; Biederman et al., 1989a,b; Gualtieri et al., 1991; Singer et al., 1995). Although TCAs are relatively useful in treating impulsivity and hyperactivity, they are less helpful for cognitive features of the disorder. More than 60 years following their introduction, psychostimulants remain the treatment of choice for ADHD, partially because of their solid effectiveness in treating the behavioral symptoms and especially because of their unmatched effectiveness in ameliorating the cognitive symptoms. In some ways, child and adolescent psychopharmacology has never again reached the peak attainment of its original treatment. No subsequent medication has equaled the psychostimulants for relative diagnostic speciﬁcity, target symptom speciﬁcity, strength of response, sustained effectiveness over time, the large proportion of patients who respond therapeutically, or the huge number of patients who have beneﬁted from its use. Evolution of child and adolescent psychopharmacology The 1930s marked the beginning of modern child psychopharmacology, a time when few validated psychosocial or drug treatments were available even for adults. Not one of the present-day pharmacotherapies for psychiatric disorders was described in the ﬁrst textbook of child psychiatry (Kanner, 1935), which advised against using ‘‘toxics and sedatives’’ to control children’s behavior. Two years later, the original papers on amphetamine treatment of behavior disorders of children (Bradley, 1937) were published. In the same year (in fact, in the same issue of the American Journal of Psychiatry), the ﬁnding that this drug treatment also improved cognitive functioning in the children and adolescents was reported independently by Molitch and colleagues (Molitch and Eccles, 1937; Molitch and Sullivan, 1937). Two years later, paradoxical phenobarbitalinduced excitation was described in children with behavioral disorders (Cutts and Jasper, 1939).

4

C.W. Popper

In the 1940s, psychostimulants were examined more extensively in children by Bradley and independently by Lauretta Bender (Bradley and Bowen, 1940; Bradley and Green, 1940; Bradley, 1941; Bradley and Bowen, 1941; Bender and Cottington, 1942). By the end of the decade, Bradley had treated 350 preadolescent children with psychostimulants (Bradley, 1950), essentially conﬁrming the earlier ﬁndings and spelling out the major features of this treatment. The anticonvulsant phenytoin was reported to help some children with behavior disorders (Brown and Solomon, 1942; Lindsley and Henry, 1942; Walker and Kirkpatrick, 1947). Studies in the 1940s were largely focused on hyperactive children with brain damage, cerebral dysfunction, and developmental disorders. In the 1950s, the biologic revolution in psychiatry began with the initial appearance of antipsychotic and antidepressant agents and a growth spurt of psychopharmacologic research in adults. Chlorpromazine was initially synthesized in 1950 and was reported to have antipsychotic properties in adults in 1952. The ﬁrst anecdotal description of its use in children was published in 1953 (Heuyer et al., 1953) regarding six children and adolescents (ages 5–14) with psychosis and agitation treated with chlorpromazine in doses up to 2 mg/kg. There were seven additional reports on chlorpromazine for youths in 1955, including a placebo-controlled study of 195 hospitalized children with mixed diagnoses who were treated with doses of 30–100 mg (Freedman et al., 1955). A partial-blind placebo-crossover study was reported the following year (Hunt et al., 1956). Also during the 1950s, the treatment of childhood behavior disorders with diphenhydramine (Effron and Freedman, 1953; Freedman et al., 1955) and meprobamate (Litchﬁeld, 1957; Kraft et al., 1959) was ﬁrst described, and monoamine oxidase inhibitors (MAOIs) were reported to increase awareness and language production in children with autistic disorder (Freedman, 1958). Reserpine was found to be effective in reducing symptoms of irritable and hypertonic infants (Talbot, 1955). The ﬁrst review article in the ﬁeld was published by Freedman et al., 1955. The ﬁrst National Institute of Mental Health (NIMH) grant in child psychopharmacology was awarded in 1958 to Leon Eisenberg, largely because of his careful methodology, to examine perphenazine treatment of hyperactive children (Eisenberg et al., 1961). The 1960s were a time of large-scale expansion of treatment and research in pedipsychopharmacology. TCAs were ﬁrst reported to be useful in treating enuresis (MacLean, 1960; Poussaint and Ditman, 1965), ADHD (Krakowski, 1965; Rapoport, 1965), and, seemingly, childhood depression (Lucas et al., 1965; Frommer, 1972). MAOIs were described for treating depressive (Frommer, 1967) and phobic disorders (Kelly et al., 1970) in children. Barbara Fish began to

5

Child and adolescent psychopharmacology

report on various neuroleptics and diphenhydramine, including comparison studies, in hospitalized children with autistic disorder (Fish, 1960a,b). Neuroleptics were ﬁrst described to treat children with Tourette’s disorder (Chalas and Brauer, 1963; Chapel et al., 1964; Lucas, 1964). Chlordiazepoxide was used clinically (Skynner, 1961) and studied in 130 children (2–17 years old) with mixed diagnoses who were treated with doses of 30–130 mg daily (Kraft et al., 1965). Annell ﬁrst reported on lithium treatment in a series of children (Annell, 1969a,b), although a single case report had been published previously (Van Krevelen and Van Voorst, 1959). These adventurous times also included some forays by Lauretta Bender into LSD (lysergic acid diethylamide) treatment of children with autistic disorder. Conducted with an intent to ‘‘break through the autistic defenses of severely [disturbed] children,’’ LSD was reported to heighten mood, increase alertness and awareness of reality, improve eye contact and interpersonal responsiveness, and reduce stereotypies, headbanging, and self-injurious behavior without causing psychotic reactions or signiﬁcant adverse effects (Bender et al., 1962; Bender 1966). Keith Conners, Gabrielle Weiss, and John Werry were leaders in bringing pedipsychopharmacology research on ADHD to a higher plane of methodologic rigor and moving it into the scientiﬁc age. Despite the accelerating pace of child psychopharmacologic research, practitioners in the 1960s remained cautious and, in retrospect, overprotective. Medication treatments were viewed as palliative, and clinicians raised concerns over the potential for medication treatments to disrupt psychoanalytically oriented psychotherapies, interfere with a child’s developing sense of selfcontrol and responsibility, foster psychologic and physical dependence on medications, promote or induce drug abuse, expose small vulnerable beings to dangerous medications, and lead to over-reliance on medications to the exclusion of other coping strategies and interventions. These unfounded fears were part of more general doubts about biologic formulations by physicians and simplistic thinking by patients (Robinowitz and Wiener, 1990). In the 1970s, there was another quantum jump in the quantity and quality of psychopharmacotherapy research in youth. Howard Abikoff, Michael Aman, Eugene Arnold, Russell Barkley, Magda Campbell, Dennis Cantwell, Gabrielle Carlson, David Engelhardt, Kenneth Gadow, Laurence Greenhill, Rachel (Gittelman) Klein, William Pelham, Judith Rapoport, Daniel Safer, Robert Sprague, James Swanson, and Paul Wender began their careers and wide-ranging contributions to the ﬁeld. Imipramine was reported to appear effective in treating children with school phobia and separation anxiety (Gittelman-Klein and Klein, 1971, 1973). Carbamazepine was ﬁrst used to treat nonepileptic children with

6

C.W. Popper

behavior disorders (Puente, 1976; Remschmidt, 1976), and propranolol was introduced for treating children with brain damage or neurologic abnormalities (Schreier, 1979; Williams et al., 1982). Anecdotal reports on the use of antidepressants and lithium in children were occasionally published, but there was little systematic progress on treating mood disorders in youth, and many clinicians maintained doubt about whether mood disorders even existed in children. The NIMH in the United States held a consensus conference in 1977 which concluded that depression does in fact appear in children, but it could not agree on a deﬁnition, and a minority statement dissented with the conclusion that childhood depression exists (Schulterbrandt and Raskin, 1977). Moreover, the budding use of antidepressants was dampened by the report of a fatality (Saraf et al., 1974) in a 6-year-old child being treated with imipramine 15 mg/kg daily, a markedly excessive dose by today’s standards and administered prior to the now routine use of electrocardiography (Saraf et al., 1978) to monitor cardiac conduction. The year 1978 turned out to be a landmark in child and adolescent psychiatry and psychopharmacology. Kim Puig-Antich and colleagues issued an initial report suggesting that a substantial number of children with major depressive disorder, deﬁned by Diagnostic and Statistical Manual of Mental Disorders, Second Edition (American Psychiatric Association, 1975) criteria formulated for adults, improved clinically when treated with imipramine (Puig-Antich et al., 1978). Puig-Antich also noted that these children often had concurrent separation anxiety disorder and that both syndromes appeared to improve with imipramine treatment, echoing the earlier ﬁndings of Rachel and Donald Klein, who used a more rigorous design in examining separation anxiety (GittelmanKlein and Klein, 1971, 1973). Puig-Antich’s study was historically pivotal in launching the ongoing surge in the use of psychopharmacologic agents in children, by bringing attention to the potential treatability of childhood depression. Ironically, this ﬁnding did not hold up to replication (Puig-Antich et al., 1987) and was not supported by many subsequent controlled trials with various TCAs ( Jensen and Elliott, 1992). Toward the end of the decade, clonidine was ﬁrst introduced for treating Tourette’s disorder (Cohen et al., 1979, 1980). At the start of the 1980s, the general use of these treatments was still quite limited, largely because psychostimulants remained the only child psychopharmacotherapy with well-demonstrated efﬁcacy. Most residency training programs in child psychiatry taught about psychostimulants but not other medications. Many programs discouraged the use of any psychiatric medications in children, partly due to the dearth of scientiﬁc knowledge and partly due

7

Child and adolescent psychopharmacology

to unscientiﬁc reasoning and historical tradition, but certainly not out of a lack of well-controlled demonstrations of psychostimulant efﬁcacy. Antipsychotic agents were becoming less stigmatized and were generally used for psychotic disorders and some cases of severe impulsivity. TCAs were employed sparingly, but, over the course of the decade, clinicians gradually became comfortable in using TCA treatments, predominantly for major depression and separation anxiety disorder, as psychopharmacologic research on these disorders expanded. Lithium therapy remained uncommon. At mid-decade, a major thirdparty carrier in the United States was still refusing to pay for lithium treatment, even for hospitalized children, on the grounds that it was too experimental. By the end of the decade, though, a child with bipolar disorder was featured on the videotaped section of the national board examinations in child psychiatry in the United States. Clonidine, which quickly became a common treatment for Tourette’s syndrome, began to be used to treat ADHD (Hunt et al., 1985), but the psychostimulants remained by far the most predominantly prescribed psychiatric medication for children. In parallel with the expansion of psychopharmacologic research in children and adolescents, the clinical use of these treatments became increasingly prevalent during the mid-1980s. By the end of the decade, these treatments had spread far beyond the conﬁnes of university clinics, but their widespread use was not based on solid scientiﬁc documentation of their safety or efﬁcacy. The extensive use of child psychopharmacologic treatments without adequate documentation in the medical literature became commonplace. In the 1990s, child and adolescent psychopharmacologic treatment entered everyday psychiatric practice. Its speedy expansion led drug treatment, alongside and integrated with psychosocial interventions, to become the prevailing approach in child psychiatry by the mid-1990s. The use of psychostimulants in youth more than doubled between 1990 and 1995 (Safer et al., 1996; Zito et al., 1998). The shift from TCAs toward speciﬁc serotonin reuptake inhibitors (SSRIs) for treating children (Ambrosini et al., 1995) proceeded contemporaneously with their swift deployment in adults and, concurrently, the accumulation of studies on TCAs showed their ineffectiveness in treating childhood depression. The newly introduced SSRIs rapidly became the most commonly used child psychopharmacologic treatment, the ﬁrst time that another medication had surpassed the psychostimulants in prevalence of use. Despite two initially negative studies of SSRI treatment in childhood depression (Simeon et al., 1990; Mandoki et al., 1997), a large-scale study of ﬂuoxetine became the ﬁrst demonstration of the value of SSRIs for treating children with major depressive episodes (Emslie et al., 1997, 1998). Toward the end of the decade,

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the ﬁrst and only randomized double-blind, placebo-controlled trial of lithium in treating bipolar disorder in youth yielded a positive outcome (Geller et al., 1998a). This study also showed that lithium reduced the associated substancerelated disorders that appeared during bipolar episodes in those adolescents. In addition, the efﬁcacy of lithium was ﬁrst demonstrated for treating major depressive disorder in preadolescents who had a family history of bipolar disorder (Geller et al., 1998b). Other mood stabilizers (Ryan et al., 1999), atypical antipsychotics (Toren et al., 1998), and novel antidepressants became routine treatments during the 1990s, despite a relatively small amount of research in youth. Even at present, and despite the widespread use of psychiatric medications in youth, few child psychopharmacologic treatments have been rigorously demonstrated to have efﬁcacy in formal well-designed and well-controlled studies, efﬁciency in large populations treated in naturalistic clinical settings, or safety in short-term or long-term use. Changing prescribing philosophies Lifting the taboo

The long-standing taboo on psychopharmacologic ‘‘experimentation’’ in children, which had dominated the clinical practice of child and adolescent psychiatry, all but disappeared in the late 1980s. The taboo had long been used to justify reliance on psychodynamic treatments, which then viewed medications primarily in terms of hazards. Only in recent years did psychopharmacologic research come to be viewed as presenting important beneﬁts to youth and not merely risks. It was increasingly recognized that studies in adults were not adequate for extrapolation to children and that the systematic avoidance of innovative treatments for youths was depriving them of important opportunities. Most crucially, clinicians became aware that the current generation of children and adolescents were still missing out on the beneﬁts of the biologic revolution. With the continuing expansion of empirical psychopharmacologic treatment of youth in the 1990s, a type of caution previously exercised by most child and adolescent psychiatrists began to break down and was gradually abandoned. Traditionally, newly developed medications were not generally used for treating children with psychiatric disorders until there was a clear ‘‘track record’’ of their safety and clinical effectiveness in adults, a process that typically required at least several years (Popper, 1987b). This protective strategy began to wear thin with the introduction of the SSRIs, because they offered a clear improve-

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ment in effectiveness, tolerability, and adverse effects over the previously available antidepressants. With the SSRIs, for the ﬁrst time, it took only about 1–2 years after the initial commercial introduction of a new drug class in the United States for it to begin to be used in signiﬁcant numbers in American youths (and, once again, prior to documentation of pediatric efﬁcacy). Concurrently, in the early 1990s, atypical neuroleptics were introduced in the United States and were almost immediately employed for treating children with Tourette’s syndrome, autistic disorder, and psychotic disorders. In addition, there was a shift in approach from ‘‘least restrictive’’ and ‘‘lowest effective dose’’ treatments to ‘‘most effective’’ treatment. The change in level of ‘‘caution’’ reﬂected the increasing comfort and decreasing rigidity of clinicians employing pedipsychopharmacologic methods. Confronting clinical uncertainty

The scientiﬁc and clinical unknowns in child psychopharmacology remain quite broad. There is little available detail on the biochemical development of the brain (especially in humans), drug disposition in children, developmental changes in the responses of target sites of drug action, or developmental differences in drug neurotoxicity (Popper, 1987a). Ethical and legal implications of child psychopharmacologic treatments, the integration of drug and psychosocial child therapies, and the psychotherapeutic implications of these treatments remain poorly understood. However, for better and for worse, current clinical attitudes no longer regard this lack of knowledge as a major obstacle to the use of these medication treatments in children. Instead, it has been customary to view this paucity of information as a challenge requiring child and adolescent psychiatrists to update the ﬁeld while practicing it. In this situation, clinicians are attuned to watch carefully for potential adverse effects and complications. Exercising such caution in the face of uncertainty, they may be less likely to consider the possibility that some unknown drug effects may be therapeutic. We know from preclinical investigations that psychopharmacologic agents can cause beneﬁcial as well as untoward inﬂuences on the central nervous system during development. For example, a medication treatment for acute symptoms might speculatively also delay or reverse brain degeneration associated with a psychiatric disorder. We must realize that potentially serious adverse effects will surely continue to be uncovered in children, but we should also expect currently unknown beneﬁcial drug effects to emerge. The promise of new ﬁndings on drug effects, both good and bad, remains an essential part of this ﬁeld. Despite the scientiﬁc unknowns and ethical dilemmas (and impasses), parents and practitioners appear willing

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to take chances – because they judge that the risks of child psychiatric disorders themselves appear, in general, to exceed the risks of the child psychopharmacologic treatments (Popper, 1987b).

The rise of therapeutic empiricism

The case for delaying the use of these treatments until their safety and efﬁcacy are formally demonstrated is logically strong, but compellingly impractical. Such studies would take years or decades to produce results, and the seemingly logical ‘‘conservative’’ approach would prevent the current generation of youths from receiving the new and generally improved modern methods of psychiatric treatment. Empirical treatments have, then, proceeded in concert with studies of efﬁcacy and tolerability, and eventually a selection of ‘‘older’’ treatments can be based on scientiﬁc grounds. In psychiatry now, and in pediatrics, research empiricism supplements and augments therapeutic empiricism in clinical practice in developing old drugs for new uses. In contrast, new drugs for initial applications cannot be introduced until they have scientiﬁcally demonstrable safety and (in at least some indications) demonstrable value. The preoccupation of child psychiatry with psychoanalysis has given way to a more eclectic and empirical clinical methodology. The former tension between the biologic and psychodynamic conceptualizations, for many years viewed as a substantive division in theoretical understanding and choice in treatment selection, has essentially dissolved. This resolution has allowed these approaches to become coupled and integrated in clinicians’ work. Uniﬁed biologic and psychosocial treatment has now become the ‘‘standard of care’’ for most if not all psychiatric disorders of youth. Speciﬁc questions about how to balance these treatments are being worked out empirically in clinical practice and research. Therapeutic empiricism (Popper, 1990) has become the watchword by which clinicians decide when to treat and when to delay the use of medication and psychosocial treatments. At the turn of the millennium, clinical knowledge and know-how in pedipsychopharmacology is surprisingly widespread among everyday practitioners. There is increasingly broad, deep, large-scale, and well-funded research in child psychopharmacology, which is now a focus of substantive government effort and ﬁnancial support. The general discussion and sophisticated questions at national and local conferences demonstrate how extensively child and adolescent psychopharmacology is practiced and understood by large numbers of psychiatrists.

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New trends Excessive use

Public fears of rampant overmedication of children are quite understandable and hardly unjustiﬁed. In 1970, the Washington Post erroneously reported that 5–10% of public school students in Omaha were being treated with stimulants (Maynard, 1970), a revelation that was generally viewed as scandalous. More recently, a careful study examining about 30 000 students in two cities found an 8–10% prevalence of drug treatment for ADHD, with the highest rate, among white boys in ﬁfth grade, at 18–20% (LeFever et al., 1999). Such high rates do not imply generalized overtreatment. It is well known that the use of child psychopharmacologic treatments varies drastically among nations, regional divisions, cities, medical schools, clinics, and individual physicians (Gadow, 1997). In fact, the under-use as well as over-use of psychiatric medications remains a prominent current problem – if over-use means treatment of children who do not have the relevant disorder or need medication, and if under-use means failure to treat youths whose disorders are best treated with medications. Numerous studies have indicated that concerns about massive overmedication are unfounded; even at present, undertreatment appears to be more of a problem than overtreatment ( Jensen et al., 1999). Debates about overtreatment and undertreatment, both in individuals and in populations, highlight the perennial uncertainty and endless process of revision throughout medicine, so practitioners in child and adolescent psychopharmacology can anticipate this to be an ongoing source of tension for decades to come. Money-oriented medicine

Some nations have learned to administer health care in a relatively altruistic and cost-effective manner, but the system of health care in the United States has become dominated by ﬁnancial rather than medical management. Financially managed medicine is a direct result of the historical inability of physicians to control prices or provide for the needs of the whole population. Caps on costs, often at the expense of quality, have inﬂuenced all aspects of medicine, including psychopharmacotherapy, psychosocial treatment, and psychomanagement, with equally injurious effects. Evidence-based medicine, a force emerging from the combined efforts of third-party commercialism and scientiﬁc academicism, emphasizes science as the basis for sound or improved practice (Evidence-Based Medicine Working Group, 1992). However, overly rigid use of evidence-based medicine could present a threat to the valuable beneﬁts yielded by therapeutic empiricism for

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psychiatric and general medical treatment. Given the major gaps in the evidence base, especially in child psychiatry, many common clinical decisions must be made on the basis of less rigorous evidence, including qualitative data (Graham, 2000) and clinical practice surveys (Hickie et al., 1999). The risks of evidence-based psychiatry are particularly striking when combined with overly zealous ﬁnancial management (Berk and Janet, 1999). It is commonly believed that ﬁnancially based medicine, unless repaired, will lead to ‘‘bargains’’ that weaken and eventually bankrupt the system of care. Third-party managers, questioning the value of the initial psychiatric comprehensive evaluation, have managed to fund clinical evaluations that are shorter than is medically necessary. A thorough child psychiatric/psychopharmacologic evaluation may take 4–7 hours, yet managed care in the United States pays for and expects physicians to make treatment decisions after one hour or less of psychiatric assessment. Shorter evaluations may be hypothetically more cost-effective, but longer evaluations are almost certainly more likely to identify multiple diagnoses, anticipate problems, and avoid setbacks. Evidence-based medicine applies mainly to the needs of the ‘‘‘average’ randomized patient’’ (Feinstein and Horwitz, 1997), leaving others out. In any case, there is little evidence supporting the value of strict evidence-based medicine vs. therapeutic empiricism. Even when there are differences in treatment outcome, they may not be clinically signiﬁcant. The relative usefulness of these two approaches will be decided empirically, with luck by an equitable balance of medical and administrative research. Changing training programs

Psychopharmacology in residency training programs went from being a luxury frill in 1985 to a staple component in 10 years. Most residents in child psychiatry in the United States are now ﬁnishing their training with substantial experience in psychopharmacologic techniques, supplementing other clinical skills. Even for the most biologically oriented trainees, it quickly becomes clear in actual practice that prescribers must talk to children, engage their cooperation in treatment, promote their self-observation and awareness of treatment effects, educate them and their families about psychiatric disorders and interventions, and be prepared to respond effectively to a wide range of potential psychosocial barriers to treatment. Despite the increasing reliance on diagnosis, the gradual de-emphasis of developmental principles in treatment, the decreasing reliance on one-to-one psychodynamic therapies, and the ﬂoating of responsibility for individual child psychiatric patients among multiple types of therapists, most residents in child

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and adolescent psychiatry continue to be trained in psychopharmacology in a manner that promotes a multifaceted approach to treatment. Academic child and adolescent psychopharmacology

Academic medicine continues to provide critical leadership in training and research, and has maintained a superlative record of creating and adapting to new developments in concepts and treatments, but some features of the traditional disdain toward the clinical observations made by nonuniversity practitioners and individual clinicians’ observations have lingered. Nonetheless, in child and adolescent psychopharmacology, as in other ﬁelds of medicine, clinical knowledge grows largely by nonacademic mechanisms. In the United States, pedipsychopharmacology is a model medical ﬁeld whose information explosion has been largely fueled by the empirical observations made by clinicians and whose new ﬁndings are rapidly expressed in the daily practice of clinicians throughout the country. Academic research in child and adolescent psychopharmacology consists mainly of controlled clinical trials of medications already in general use, early phase testing of drugs recently marketed or soon to be marketed, neurochemical investigations of children with deﬁned biopsychiatric disorders, and studies in developmental neurobiology. For the most part, ideas for new applications of ‘‘old’’ medications are generated by clinicians in the ﬁeld. The pace of child psychopharmacologic innovation and academic research is continuing to intensify. The rapid growth of investigation is reﬂected in the numbers of double-blind placebo-controlled studies, long-term and follow-up research designs, multisite studies, well-organized research departments, specialized research units in pediatric psychopharmacology (RUPPs), young and established contributors, larger case series, original research articles, and medical journals publishing articles on child psychopharmacology. Over forty books whose titles indicate a major focus on child and adolescent psychopharmacology have appeared in English over the last ﬁve decades, including textbooks, monographs, trade books, periodicals (except medical journals), and ‘‘book-like’’ special issues of medical journals. Unsurprisingly, the number of such publications has been accelerating: one book in the 1950s, one in the 1960s, 13 in the 1970s, 15 in the 1980s, 23 in the 1990s, and two so far in the 00s (Fisher, 1959; Freed, 1962; Blanco, 1972; National Institute of Mental Health, 1973; Conners, 1974; Gittelman-Klein, 1975; Spiel, 1976; Bosco and Robin, 1977; White, 1977; Wiener, 1977; Mendlewicz and van Praag, 1978; Werry, 1978; Cohen, 1979; Food and Drug Administration, 1979; Gadow, 1979; Klein et al., 1980; Gadow and Gadow, 1981; Raskin et al., 1981; Scruggs et al.,

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1982; Nissen et al., 1984; Campbell et al., 1985; Rapoport et al., 1985; Wiener, 1985; Gadow, 1986a,b; Krasnegor et al., 1986; Popper, 1987; Voss, 1987; Aman and Singh, 1988; Gadow and Poling, 1988; Rothenberger, 1990; Weizman and Weizman, 1990; Green, 1991; Greenhill and Osman, 1991; Shaffer, 1992; Van Hasselt and Hersen, 1993; Werry and Aman, 1993; Rosenberg et al., 1994; Green, 1995; Richardson and Haugland, 1995; Riddle, 1995; Theesen, 1995; Wiener, 1995; Kutcher, 1997; Reiss and Aman, 1997; Rosenberg et al., 1997; Findling and Blumer, 1998; Roemmelt, 1998; Walsh, 1998; Wilens, 1998; Dulcan and Benton, 1999; Greenhill and Osman, 1999; Werry and Aman, 1999; Nutt, 2000; Kutcher, 2001). About 100–150 papers are now published annually on child and adolescent psychopharmacologic treatment, in addition to about another 50-75 studies on other biodevelopmental aspects of pediatric psychiatry. About 80% of these articles are published in two peer-reviewed journals. The Journal of Child and Adolescent Psychopharmacology, which turned 10 years old in 2000, is the ﬁrst medical journal to focus speciﬁcally on pharmacologic and biologic aspects of child and adolescent psychiatry. The Journal of the American Academy of Child and Adolescent Psychiatry, the long-established central journal in the ﬁeld, is now publishing about 20% of its articles on clinical psychopharmacology. The Child and Adolescent Psychopharmacology Newsletter, founded and edited by Stanley Kutcher since 1997, has become a widely read update and review (Kutcher, 1997). The Brown University Child and Adolescent Psychopharmacology Update, edited by Henrietta Leonard, has been published since 1999 (Leonard, 1999). In addition, a child and adolescent psychopharmacology discussion group (listserv) on the Internet has over 225 subscribers on its mailing list; it can be accessed through [email protected] JOHNS.EDU or its moderator ([email protected]). Beyond quantitative expansion, the quality of funded research has been keeping pace with the expansion of the ﬁeld. Controlled studies increasingly examine carefully speciﬁed populations with systematically assessed diagnoses, explicit clinical inclusion and exclusion criteria, speciﬁed comorbidity, multiple observers and observation techniques, a range of clinical outcome measures, and advanced methods of statistical analyses. Efﬁcacy and effectiveness

Clinicians as well as researchers are becoming more familiar with the limitations of double-blind placebo-controlled studies. The relevance of these studies has been called into question by the ﬁndings that some drugs that appear efﬁcacious in controlled studies do not render a useful clinical effect in actual

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‘‘naturalistic’’ treatments and, similarly, that some drugs observed to have value in the hands of clinicians working with real-world patients appear ineffective in controlled studies. The difference between drug ‘‘efﬁcacy’’, as deﬁned in rigorously controlled studies, and drug ‘‘effectiveness,’’ as deﬁned in large-scale naturalistic studies, is emerging as an important distinction in understanding the clinical properties of medications. To a degree, this distinction breaks down in newer and more sophisticated studies that examine formulaic algorithm-based treatments in large populations of children. In general, both drug efﬁcacy and naturalistic effectiveness studies are needed to evaluate fully the clinical promise and valid scope of a drug treatment. Drug–placebo comparisons are essential for the work of the United States Food and Drug Administration (FDA), whose role is to determine whether commercially marketed drugs are safe and efﬁcacious. In contrast, clinical decision-making is often promoted more directly by drug comparison studies (comparing drug against drug), which identify how different drugs or treatments compare in clinical efﬁcacy. Both clinical practitioners and clinical researchers in child and adolescent psychopharmacology contribute essential information that strengthens available treatment. This is not a ﬁeld where the academics have a hegemony over the production of clinically important ﬁndings. Both clinicians and researchers are ahead of each other in certain respects, and both spur the successes of the other. Combined medication treatments

Simplicity and clarity remain important features of optimal care, but the effectiveness of psychopharmacologic monotherapies is quite limited in many cases. The use of multiple concurrent psychiatric medications, though formerly denigrated as ‘‘polypharmacy,’’ has appropriately become a common practice and even a routine part of the ‘‘standard of care.’’ The multipronged approach to inﬂuencing different brain neurotransmitter systems goes well beyond the former ‘‘one disease/one treatment’’ model, which is often simplistic in medicine, weakly applicable to most psychiatric disorders, and almost irrelevant to child psychiatric disorders. However, multiple concurrent drug treatments have rarely been studied with regard to safety or therapeutic effect, with methylphenidate/desipramine being the only such combination to have received systematic investigation in children (Rapport et al., 1993; Pataki et al., 1993; Carlson et al., 1995). In addition to the increased likelihood of adverse effects with two or more pharmacotherapies, medical regimens consisting of three or more drugs can give rise to multiple

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C.W. Popper

concurrent drug interactions, generating at times genuinely unpredictable effects (Fisman et al., 1996). When rigorously conducted, however, multiple concurrent drug treatments can add signiﬁcantly to the sophistication and effectiveness of child psychopharmacologic treatment. Setbacks The march of progress has not been without setbacks. It was fully predictable that these innovative treatments would be the source of signiﬁcant problems themselves, including some serious ones. Limited beneﬁts

The widely held, empirically based belief in the 1980s that TCAs can effectively treat major depression in youth has been tempered by the ﬁndings of controlled research. Double-blind placebo-controlled studies have repeatedly shown no generalized clinical efﬁcacy of TCAs in childhood depression ( Jensen and Elliott, 1992; Birmaher et al., 1996; Findling et al., 1999; Ambrosini, 2000), even in the recent studies with current methodology (Kye et al., 1996; Birmaher et al., 1998; Klein et al., 1998). Estimates of the pooled effect size of 0.35 standard deviations (95% conﬁdence interval of 0.16–0.86) and the pooled odds ratio of 1.08 (95% conﬁdence interval of 0.53–2.17) indicate no signiﬁcant clinical value is likely to be uncovered by further controlled trials (Hazell et al., 1995). However, TCAs appear to be decisive in certain youths with depressive disorders, as demonstrated in the responses of individual patients to dose changes as well as to drug discontinuations and restarts. Even some researchers who demonstrated a lack of clinical efﬁcacy of TCAs in controlled trials continue to use the drugs in their own clinical practices. Despite the spate of negative studies which formally demonstrate that they do not work signiﬁcantly better than placebo, TCAs remain possible secondary and supplementary agents for treating depression in youth. The SSRIs do not have the potential to replace the role of the TCAs in treating enuresis (bedwetting), ADHD, or SSRI-induced frontal release, which includes frontal disinhibition (King et al., 1991; Riddle et al., 1991a) and frontal apathy (Hoehn-Saric et al., 1990; Walkup, 1994; Popper, 1995a). It remains unclear whether TCAs are less effective in treating depression in youths than in adults for developmental pharmacodynamic reasons or perhaps other reasons, including the possibility that the usefulness of TCAs in major depression was historically overvalued in adults. In a similar, but less conspicuous reversal, naltrexone treatment of autistic

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disorder was another example of overly optimistic estimates of therapeutic drug effects that were later determined to be unfounded or at least overrated. Adverse effects in youth

Certain adverse drug effects in children and adolescents were not anticipated by studies of adults, including the classic example of psychostimulant-induced growth slowing. In a similar manner, valproate-induced polycystic ovary disease appears to be a problem mainly of young women (Isoja¨rvi et al., 1993), resulting from the hormonal consequences of weight gain (Isoja¨rvi et al., 1996, 1998). Lamotrigine is known to be more of a dermatologic risk to children than to adults (Li et al., 1996; Messenheimer, 1998), both with respect to Stevens Johnson syndrome (1/1000 in adults, 1/200 in children) and rash of any type associated with hospitalization (3/1000 in adults, 1/100 in children). The induction of frontal apathy and disinhibition by SSRIs may be more common in youths than adults (Popper, 1995a). TCAs appear more likely to induce increased blood pressure (Kuekes, 1992) and perhaps sinus tachycardia (Leonard et al., 1995) in youths than adults. In addition, there are suggestive data that akathisia may be more prevalent in youths than adults treated with conventional neuroleptics (Keepers et al., 1983). Extrapyramidal symptoms (Mandoki, 1995) and perhaps obsessive–compulsive symptoms may be more common in youths than adults treated with atypical neuroleptics. Nefazodoneinduced hepatic failure might, speculatively, be more common in youths (Aranda et al., 1999). The list of age-related adverse drug effects will enlarge, and the search for other untoward developmental–pharmacodynamic changes will become a staple of this ﬁeld. Sudden death

Beyond the traditional concerns about the risks of TCA overdose (Frommer et al., 1987), the appearance of sudden medically unexplained deaths in children and adolescents treated with desipramine have raised major concerns with considerable justiﬁcation. Although the initial three cases (Abramowicz, 1990) identiﬁed by the FDA were generally viewed as inconclusive (Elliott et al., 1990; Popper and Elliott, 1990; Biederman, 1991; Elliott and Popper, 1991; Riddle et al., 1991b), three subsequent cases (plus another that could be equally attributed to concurrent neuroleptic treatment) convinced most clinicians that desipramine should be used sparingly in children (Riddle et al., 1993; Zimnitzky and Popper, 1994; Varley and McClellan, 1997), especially for nonlethal disorders such as ADHD and enuresis (Popper and Zimnitzky, 1995). Sudden deaths attributable to desipramine exceed the risks of other TCAs (Biederman

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et al., 1995), but the risks might be comparable in magnitude in both children and adults (Popper, 1994). Although baseline screening and ongoing medical monitoring, including electrocardiography, might be able to prevent some of the deaths due to long Q-T syndrome, even invasive angiography would not necessarily prevent other sudden deaths associated with other cardiac abnormalities (Popper and Zimnitzky, 1995). These rare catastrophes were particularly worrisome because of the previously extensive use of desipramine, whose value in treating childhood depression is now known to be small. Serious questions have also been raised about the combined use of clonidine and methylphenidate (Fenichel, 1995). Although the three initially reported cases were readily attributable to other medical factors (Popper, 1995b), new cases might generate greater concern. The only subsequently reported death on this drug combination involved a 10-year-old boy with a history of several incidents of syncope prior to starting the medication combination (Cantwell et al., 1997). The child went swimming, felt faint, rested for 45 minutes, swam again for another 45 minutes until he felt faint again, and then had a seizure. At autopsy, he was found to have a congenital cardiac abnormality of the left coronary artery. The history of syncope prior to starting the blood pressurelowering medication and the continuing exertion despite hypotensive symptoms that day may have, in retrospect, been a signiﬁcant risk to a child with potential cardiac vulnerability. In all four cases of methylphenidate–clonidine death, other medical factors presented risks that probably exceeded an unproven risk hypothesized to be associated with the drug combination. The risks associated with psychopharmacologic treatment cannot be stated with certainty, because unknown risks and dangers are likely to be described in the future. Serious overestimation of effectiveness and underestimation of the dangers of these treatments can be expected for years to come, so it is critical to temper enthusiasm or satisfaction in prescribing these treatments with a respectful doubt about the ultimately determined effects of each treatment. Rising expectations While the standards of care are changing, the expectations of care are changing as well. Heightened public understanding of psychiatric disorders and treatments, increasing acceptance of child psychopharmacology, the swelling of newly introduced drugs and drug classes, the unmasking of blindly antipsychiatry and antimedication forces in society, and the new focus in medicine on ‘‘quality of life’’ (in addition to symptom amelioration) have led to a much higher visibility of psychopharmacologic treatments and a sense of promise in

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child psychiatry. Child psychopharmacology and child psychiatry are now mainstream medicine, and they carry all the attendant hopes, unrealistic expectations, and disappointments. Rush to use

New psychiatric drugs are employed more quickly for clinical treatment of children than in the past. Although it has previously taken years of postmarketing experience before new psychiatric medications were put to use for children, the erosion of this protective delay is certain to bring a comeuppance. Indeed, at this point, a new corner is being turned: new psychiatric drugs are coming into clinical use more rapidly than they can be effectively investigated. New drugs are replacing old drugs while the postmarketing studies on old drugs are not yet completed, and this is especially so for the new psychiatric drugs used in children and adolescents. SSRIs became predominant in child and adolescent psychiatry when TCAs were still being evaluated for the treatment of mood and anxiety disorders. Atypical neuroleptics replaced conventional antipsychotic medications for treating a variety of child psychiatric disorders approximately as quickly as for adult disorders. Anticonvulsant mood stabilizers are now routinely used to treat children with bipolar disorder, starting even before the ﬁrst adequately controlled prospective study had been conducted of lithium treatment of bipolar disorder in children or adolescents. The potential for rapid drug obsolescence, resulting from the fast expansion of pharmacologic alternatives, might conceivably herald an age when new drugs are quickly replaced before they can be adequately examined and understood. This shift has already begun, and it certainly challenges the traditional manner in which clinical decision-making about medications is made. Whether this shift will pose mainly advantages or disadvantages remains to be seen and will itself require ongoing study. In addition to exposing patients to potentially serious risks, a decreasing reliance on completed formal drug studies might come to make clinical decisions increasingly subject to the subtle effects of pharmaceutical advertising. The role of industry and technology

Major pharmaceutical houses are now quite interested in child and adolescent psychopharmacology, perhaps the clearest and most convincing sign of the ‘‘coming of age’’ of this ﬁeld, and pharmaceutical manufacturers have for years been reaping beneﬁts from off-label treatments in child psychopharmacology.

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Even though the FDA asserts that approved labeling is speciﬁcally intended to regulate pharmaceutical advertising (Food and Drug Administration, 1982), many physicians have regarded them as guides and used them inappropriately as restraints on their prescribing practices. With the FDA now placing more emphasis on the pediatric use of medications in clinical practice and drug trials in children prior to marketing (Food and Drug Administration, 1992), new conduits are being established for new drugs to receive drug package insert labeling for child psychiatric treatment (Laughren, 1996). In the 1997 FDA Modernization Act (Food and Drug Administration, 1997), the US Congress gave clearance for the FDA to grant time extensions on exclusivity patents of already marketed drugs to pharmaceutical houses that conduct clinical research in children. These governmental actions have further spurred the industry to devote resources to research on children (Walkup et al., 1998), which in turn is leading to more advertising of psychiatric drugs for use in children. Medication advertisement

The approaches by pharmaceutical companies to the marketing of medications are generally expected to inﬂuence physicians’ prescribing, alter market share, and enhance company revenues. Although largely educational in nature, these approaches still raise concern. Direct-to-consumer advertising on television and magazine pages carries potential advantages (Pines, 1998) and disadvantages (Tsao, 1997; Schommer et al., 1998) for the public, evokes disapproval from most physicians (Lipsky and Taylor, 1997), and poses nettlesome issues for the FDA (Baylor Henry and Drezin, 1998). The detailing techniques of company representatives who promote drugs to physicians include marketing methods whose mechanisms and effects are not well understood by physicians (Roughead et al., 1998). Pharmaceutical advertising in medical journals might appear to be more reliable because of the careful surveillance by the FDA in the United States and similar regulatory agents in other nations (Lexchin, 1997). Nonetheless, certain drug advertisements in medical journals are misleading at best. In some instances, the phrasing and ﬁgures in drug advertisements are meaningless or perplexing. More insidious factors in commercial medical advertising include the widespread use of subtle communications pitched to the so-called ‘‘cognitive unconscious’’ and the impact of obvious emotional appeals. (Franz Ingelﬁnger used to talk about the New England Journal of Medicine receiving an advertisement for an endocrinologic drug that contained the silhouette of a physician looking down, with a banner saying, ‘‘How would you feel, Doctor, if your genitals began to shrink?’’) Drug advertisements in medical journals are

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unquestionably more colorful and eye-catching than the rest of the contents. Numerous studies have shown that physicians believe that decision-making by other physicians is swayed by medical advertising, but, interestingly, most physicians believe that they themselves are not at all inﬂuenced by drug advertisements. This fascinating ﬁnding attests to the power of advertising, the strength of denial, and naivety of the target physician audience. An additional problem is probably uncommon, but vexing at any occurrence. Continuing medical education materials and drug company ‘‘throwaway’’ promotional publications are quietly edited by pharmaceutical companies or their ‘‘arm’s length’’ contracted agencies, at times encouraging crucial changes in wording, content, and emphasis that may include potentially signiﬁcant clinical omissions. Sponsored medical lectures are given at times by physicians who have received implicit or explicit directives from company representatives about what to discuss and what to avoid. Pharmaceutical manufacturers provide unique and essential scientiﬁc support for drug research. Certain breakthroughs and types of drug development can come only from the enormous wealth of industry. The relatively smallscale approach of academic medicine and government-funded research cannot provide the necessary resources. Pharmaceutical houses provide the only hope for supra-large-scale research required for the development of new drug products. A balance between the competing and complementary interests of industry, academia, and public need has, for example, resulted in the discovery of increasingly neurotransmitter-speciﬁc agents. Innovative treatments

Major drug breakthroughs are, of course, still to come. We still need neuroleptics that cause no (rather than less) tardive dyskinesia and do not induce neuroleptic malignant syndrome. SSRIs are limited by the emergence of frontal release, and none of the antidepressants is free of mania-inducing properties. Pharmacologic research is not the only source of innovative biologic treatments in child and adolescent psychiatry. Light therapies have recently been shown to be potentially successful in treating youths with bipolar disorder (Papatheodorou and Kutcher, 1995) and seasonal affective disorder (Swedo et al., 1997). These therapies might, speculatively, open the way toward psychiatric treatments based on stimulation of other sensory modalities. Electroconvulsive treatment, initially described in children in the early 1980s (Carr et al., 1983; Black et al., 1985; Guttmacher and Cretella, 1988), is now undergoing systematic study in adolescents and children (Cizadlo and Wheaton, 1995; Kutcher and Robertson, 1995; Ghaziuddin et al., 1996; Hill

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et al., 1997). Transcranial magnetic stimulation, a technological improvement on electroconvulsive therapy, has been used to study children with Rett’s syndrome, ADHD, and benign childhood epilepsy, and also to examine the ontogeny of neuronal connections in normal children (Ucle´s et al., 1996; Heinen et al., 1997; Nezu et al., 1997; Heinen et al., 1998). Gene therapy is just beginning in child psychiatric disorders, with the ﬁrst attempt being directed at Wolfram syndrome (Owen 1998, Swift et al., 1998). Wolfram gene carriers (including heterozygotes) are psychiatrically hospitalized 26 times more frequently than noncarriers. Wolfram syndrome is a primary (progressive) neurogenerative autosomal recessive disorder, ﬁrst evident in early childhood, which is characterized by generalized brain atrophy, optic atrophy, deafness, juvenile-onset diabetes insipidus, diabetes mellitus, and psychiatric symptoms including behavioral and personality problems, loss of memory function, and frontal release (apathy and disinhibition). A gene has been implicated at chromosome 4p16.1 – particularly, exon 8. The gene, designated as wolframin or WFS1 (Hardy et al., 1999; Ohtsuki et al., 2000), codes for a transmembrane protein expressed in the brain and pancreas, where it appears to promote cell survival (islet beta-cells). Interestingly, a susceptibility gene for bipolar disorder has also been reported at chromosome 4p16 in several linkage studies, but ﬁve recent reports have found no association of bipolar disorder with the wolframin gene (Inoue et al., 1998; Furlong et al., 1999; Evans et al., 2000; Middle et al., 2000; Ohtsuki et al., 2000). An additional locus at chromosome 4q22–24 has been suggested (El Shanti et al., 2000), and the disorder has also been proposed to be a mitochondrial DNA disease involving genome deletions (Barrett and Bundey, 1997). Based on the work with the wolframin gene, studies of gene therapy for Wolfram syndrome are progressing. Antibiotic therapy, plasmapheresis, and intravenous immunoglobulins are being found helpful in alleviating psychiatric symptoms in some youths with obsessive–compulsive disorder and Tourette’s syndrome (Matarazzo, 1992; Swedo, 1994; Swedo et al., 1998); anorexia nervosa (Sokol and Gray, 1997), and other disorders in children. These immunologic treatments are based on the neuroimmunological cross-reactivity of antistreptococcal antibodies with central dopaminergic neurons. Nutrition-based medicine is beginning to become assimilated into child psychiatry, based on the recent wave of rigorously designed studies of natural substances and herbals in adults (Stoll et al., 1999a,b) and preliminary ﬁndings in children (Horrigan et al., 1998). The treatment of ADHD with fatty acids has been a particular focus of research (Colquhoun and Bunday, 1981; Aman et al.,

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1987; Burgess et al., 2000). Lower serum levels of omega-3 and omega-6 fatty acids have been reported in children with ADHD (Mitchell et al., 1987; Arnold et al., 1994; Stevens et al., 1995, 1996), with the reductions in fatty acid levels possibly correlating to symptom severity. Double-blind, placebo-controlled studies in youth have suggested some effect of omega-6 gamma-linolenic acid in treating ADHD (Arnold et al., 1989; T Duvner, unpublished data) and of omega-3 docosahexanoic acid in treating aggressive behavior (Hamazaki et al., 1996). In a particularly intriguing recent open-label study (Kaplan et al., 2000), a mixture of 36 minerals and vitamins (modiﬁed from a supplement commonly administered to treat aggressive/violent behavior in livestock!) was found to be effective for treating bipolar disorder in adults. Initial results in the doubleblind, placebo-controlled trials have robustly supported this ﬁnding (effect size 0.8), but data collection is continuing (Kaplan et al., Nutraceutical treatment of mental disorders: a randomized, placebo-controlled clinical trial in adults with bipolar disorder – funded by the Alberta (Canada) Science and Research Authority, 2000–2002). Open trials of the same supplement were found to rapidly reduce symptom ratings of bipolar disorder in children as well (Bonnie Kaplan, personal communication). The results of my limited use of this supplement in bipolar children have been, simply put, startling and unprecedented. These observations have made me re-think my traditional bias against consideration of nutritional supplementation as a potential treatment of major psychiatric disorders. Tolerability, safety, efﬁcacy, effect size and duration, pharmacokinetics, and drug interactions of all the nutritional treatments will need to be determined, alongside the continuing experimentation with natural substances by the public at large. The turn of the millennium

Technologic advances are not likely to make us wiser, but we can expect to become more knowledgeable and effective in our clinical practices. Just as it may be hard to imagine that child psychopharmacology consisted mainly of psychostimulants and barbiturates 50 years ago, that antidepressants and lithium were scarcely used in youths 15 years ago, or that traditional neuroleptics were still in wide use in children just a few years ago, it will not be long before we will look back on 20th-century psychopharmacology as curious, primitive, and vaguely amusing. Hopefully, we will also be able to look back on these times with a sense of satisfaction about what we were able to accomplish using the knowledge and

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tools available, while perhaps feeling regretful for the currently unknown, perhaps serious or even devastating, toxic effects of our current drug treatments. Possibly in the more distant future, we may wish to disown medication treatments of brain disorders entirely. We may come to regard the era of psychopharmacology as a time when we had nothing better to offer than our old nonspeciﬁc chemicals. We should welcome such progress. In the meantime, for the generation or generations of children, adolescents, and adults who are still best treated by psychopharmacologic methods, this book will provide essential knowledge, techniques, and sustenance. Knowing that our clinical reach is limited, we have much to learn.

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direct-to-consumer advertising. J Fam Pract 45:495–9. Litchﬁeld HR (1957). Clinical evaluation of meprobamate in disturbed and prepsychotic children. Ann NY Acad Sci 67:828–31. Lucas AP, Lockett HJ, Grimm F (1965). Amitriptyline in childhood depression. Dis Nerv Sys 28:105–13. Lucas AR (1964). Gilles de la Tourette’s disease in children: treatment with phenothiazine drugs. Am J Psychiatry 121:606–8. MacLean REG (1960). Imipramine hydrochloride (Tofranil) and enuresis. Am J Psychiatry 117:551. Mandoki M (1995). Risperidone treatment of children and adolescents: increased risk of extrapyramidal side effects? J Child Adolesc Psychopharmacol 5:49–67. Mandoki MW, Tapia MR, Tapia MA, Sumner GS, Parker JL (1997). Venlafaxine in the treatment of children and adolescents with major depression. Psychopharmacol Bull 33:149–54. Matarazzo EB (1992). Tourette’s syndrome treated with ACTH and prednisone: reports of two cases. J Child Adolesc Psychopharmacol 2:215–26. Maynard R (1970). Omaha pupils given ‘‘behavior’’ drugs. Washington Post, June 29. Mendlewicz J, van Praag HM (Eds.) (1978). Childhood Psychopharmacology: Current Concepts, Symposium on Childhood Psychopharmacology, Amsterdam, October 1977. New York: S Karger AG. Messenheimer JA (1998). Rash in adult and pediatric patients treated with lamotrigine. Can J Neurol Sci 25:S14–18. Middle F, Jones I, McCandless F et al. (2000). Bipolar disorder and variation at a common polymorphism (A1832G) within exon 8 of the Wolfram gene. Am J Med Genet 96:154–7. Mitchell EA, Aman MG, Turbott SH, Manku M (1987). Clinical characteristics and serum essential fatty acid levels in hyperactive children. Clin Pediatr 26:406–11. Molitch M, Eccles AK (1937). The effect of benzedrine sulfate on the intelligence scores of children. Am J Psychiatry 94:587–90. Molitch M, Sullivan JP (1937). The effect of benzedrine sulfate on children taking the New Stanford Achievement Test. Am J Orthopsychiatry 7:519–22. MTA Cooperative Group (1999a). A 14-month randomized clinical trial of treatment strategies for attention-deﬁcit/hyperactivity disorder. The MTA Cooperative Group Multimodal Treatment Study of Children with ADHD. Arch Gen Psychiatry 56:1073–86. MTA Cooperative Group (1999b). Moderators and mediators of treatment response for children with attention-deﬁcit/hyperactivity disorder: the Multimodal Treatment Study of children with attention-deﬁcit/hyperactivity disorder. Arch Gen Psychiatry 56:1088–96. National Institute of Mental Health, Department of Health, Education, and Welfare, United States (1973). Special Issue on Pharmacotherapy of Children. Psychopharmacol Bull 9:1–241. Nezu A, Kimura S, Ohtsuki N, Tanaka M (1997). Transcranial magnetic stimulation in benign childhood epilepsy with centro-temporal spikes. Brain Dev 19:134–7. Nissen G, Eggers C, Martinius J (1984). Kinder- und Jugendpsychiatrische Pharmakotherapie in Klinik und Praxis. Berlin: Springer-Verlag. Nutt D (2000). Child and Adolescent Psychopharmacology. London: Martin Dunitz. Ohtsuki T, Ishiguro H, Yoshikawa T, Arinami T (2000). WFS1 gene mutation search in

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depressive patients: detection of ﬁve missense polymorphisms but no association with depression or bipolar affective disorder. J Affect Disord 58:11–17. Owen MJ (1998). Psychiatric disorders in Wolfram syndrome heterozygotes. Mol Psychiatry 3:12–13. Papatheodorou G, Kutcher S (1995). The effect of adjunctive light therapy on ameliorating breakthrough depressive symptoms in adolescent-onset bipolar disorder. J Psychiatry Neurosci 20:226–32. Pataki CD, Carlson GA, Kelly KL, Rapport MD, Biancaniello TM (1993). Side effects of methylphenidate and desipramine alone and in combination in children. J Am Acad Child Adolesc Psychiatry 32:1065–72. Pelham WE, Carlson C, Sams SE, Vallano G, Dixon MJ, Hoza B (1993). Separate and combined effects of methylphenidate and behavior modiﬁcation on boys with attention deﬁcit-hyperactivity disorder in the classroom. J Consult Clin Psychol 61:506–15. Pines WL (1998). Direct-to-consumer promotion: an industry perspective. Clin Ther 20(Suppl C):C96–103. Popper C (1995a). Balancing knowledge and judgment: a clinician looks at new developments in child and adolescent psychopharmacology. Special Issue: Pediatric Psychopharmacology II, ed. MA Riddle. Child Adolesc Psychiatr Clin North Amer 4:483–513. Popper C (Ed.) (1987a). Psychiatric Pharmacosciences of Children and Adolescents. Washington, DC American Psychiatric Press. Popper CW (1995b). Combining methylphenidate and clonidine: pharmacologic questions and news reports about sudden death. J Child Adolesc Psychopharmacol 5:157–66. Popper CW (1994). Desipramine deaths may be adrenergic (abstract). New Research Program and Abstracts, Annual Meeting of the American Psychiatric Association, p. 182. Popper CW (1990). Therapeutic empiricism and therapeutic basics. J Child Adolesc Psychopharmacol 1:3–5. Popper CW (1987b). Medical unknowns and ethical consent: prescribing psychotropic medication for children in the face of uncertainty. In Psychiatric Pharmacosciences of Children and Adolescents, ed. CW Popper. Washington, DC: American Psychiatric Press, pp. 127–61. Popper CW, Zimnitzky B (1995). Sudden death putatively related to desipramine treatment in youth: a ﬁfth case and a review of speculative mechanisms. J Child Adolesc Psychopharmacol 5:283–300. Popper CW, Elliott GR (1990). Sudden death and tricyclic antidepressants: clinical considerations for children. J Child Adolesc Psychopharmacol 1:125–32. Poussaint AF, Ditman KS (1965). A controlled study of imipramine (Tofranil) in the treatment of childhood enuresis. J Pediatr 67:283–90. Puente RM (1976). The use of carbamazepine in the treatment of behavioral disorders in children. In Epileptic Seizures – Behavior – Pain, ed. W Birkmayer. Berne: Hans Huber, pp. 243– 52. Puig-Antich J, Blau S, Marx N, Greenhill LL, Chambers W (1978). Prepubertal major depressive disorder: a pilot study. J Am Acad Child Psychiatry 17:695–707. Puig-Antich J, Perel JM, Lupatkin W et al. (1987). Imipramine in prepubertal major depressive

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2 Developmental psychopharmacology Normand Carrey, Paul Mendella, Frank MacMaster, and Stan Kutcher Maritime Psychiatry, IWK Health Centre, Halifax, Canada

Introduction Developmental psychopharmacology takes place within the context of developmental neurobiology. Normal maturation of the brain is characterized by complex anatomic, molecular, and organizational changes which are required to prepare the individual for optimal adaptive behavior (Chugani et al., 1996). The practicing clinician should strive to understand evolving psychopathology and psychopharmacologic treatments within this context as both may affect central nervous system (CNS) developmental processes. Advances in our understanding of brain development in experiments derived from both animals and humans have started to shed some light on certain underlying principles which could serve as the rational basis for developmental psychopharmacology. In this chapter, we will review brieﬂy the normal development of the CNS, developmental aspects of neurotransmitters and receptors, developmental neuroimaging, and experimental studies involving psychotropic compounds in young animals.

Microdevelopment Models and concepts

It is well recognized that various neuroanatomic regions and neurotransmitter systems develop at different rates and mature at different times (Teicher and Baldessarini, 1987). Neural development can be traced through four overlapping processes: cell birth (neurogenesis), cell migration, formation of connectivity (including elaboration of processes, synapse formation, cell death, and axonal regression), and myelination (Insel, 1995). In many areas of the immature brain, more neurons and neurites are produced than in the mature brain. Signiﬁcant numbers of neurons die prenatally whereas neurite elimination goes on at least until late childhood or early adolescence (Huttenlocher, 1979; Rakic et al., 1986), with myelination extending across the life cycle (Benes, 1998; 38

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Yakovlev and Lecours, 1967). Although there are variations across mammalian species as to the exact timing of these events, all species follow the basic pattern of overshoot (overproduction) followed by widespread pruning of both neurons and cell processes (Insel, 1995). Much of this ‘‘pruning’’ occurs during that period of development corresponding to early childhood. In adolescence, further pruning occurs as well as other organizational changes of a qualitatively different nature. For example, Andersen et al. (1997) have noted that D1 and D2 receptors in the male rat striatum are at their highest levels at day 40 (corresponding to puberty), with receptors pruned to adult levels subsequently. Plasticity and sensitive periods

The complementary concepts of brain plasticity and sensitive periods are two important frameworks which inform our understanding of many aspects of brain development. Plasticity is conceptualized as the brain’s ability to shape itself in response to environmental or chemical input during the sensitive period (the period during which experience can alter neural representation before so-called hard wiring occurs) and also as the ability to compensate for cortical damage by ipsilateral or contralateral reconnections. An example of experience-dependent plasticity in development is the study by Hubel et al. (1977) demonstrating that monocular deprivation leads to lasting changes in ocular dominance columns in the cortex. Similarly, levels of neurotransmitters can be developmentally programmed to alter during sensitive periods, as shown by transiently elevated levels of N-methyl-D-aspartate (NMDA) receptors in the visual cortex of kittens during the period critical for experiencedependent modiﬁcation of the cortex (Bode-Greuel and Singer, 1989). Thus, the model that emerges is that of a complex relationship between preordained changes in brain function interacting with particular environmental stimuli during speciﬁc periods of neural development. In most species studied to date, immature animals have been found to be able to sustain damage to large areas of the cerebral cortex and show remarkably little functional deﬁcit (Chugani et al., 1996). This has been attributed to the reorganizational potential of the developing brain and is known as the Kennard effect. As a general rule, mammalian brains (because of bilateral interhemispheric connections) can re-establish connections between intact cortical areas and subcortical structures to compensate for loss of function secondary to damaged or destroyed cortical areas. Small neocortical lesions are associated with recovery mediated by intact ipsilateral brain areas, whereas larger lesions trigger compensatory changes in the contralateral hemisphere. The degree of compensation depends on: the age of the organism (the more

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immature an organism is, the greater are the chances for compensation); the size and location of the lesion; and the sensitive period for the speciﬁc neural pathway in which the lesion occurred. For example, there can be near complete recovery of language function in infants whereas motor and visual functions do not recover as well with lesions of comparable size occurring at a comparable age. Different brain areas can reconﬁgure themselves to compensate for lost function – such as the caudate assuming the delayed response of the lesioned dorsolateral prefrontal cortex following bilateral frontal cortical lesions in neonatal monkeys (Kling and Tucker, 1967). Interestingly, at least in adults, certain medications such as the amphetamines promote recovery in reorganization after some types of brain injury (Crisostomo et al., 1988) whereas neuroleptics and antihypertensives may not. Apoptosis

Many of the intracellular events in neurons are genetically programmed to unfold as part of the developmental sequence. This has been demonstrated in studies of the nematode Caenorhabditis elegans which have demonstrated that a certain family of genes is associated with programmed cell death whereas another family of genes is associated with cellular survival (Sulston, 1976). This process of cell death or survival can be subsumed under the conceptual framework identiﬁed as ‘‘apoptosis.’’ Apoptosis is a normal part of cell development where cells may self-destruct (commit suicide) by orderly self-disassembly, avoiding an inﬂammatory reaction (Barnes and Mackenzie, 1999). Jacobsen et al. (1997) have identiﬁed ﬁve overlapping functions of apoptosis in animals. These are: development of functionally necessary structures; deleting functionally unnecessary structures; controlling cell numbers; eliminating abnormal or harmful cells; and producing differentiated cells without organelles. Cell homeostasis depends in part on inhibitory mechanisms responsible for stopping or delaying apoptosis such as the protein NF-kB, a protein capable of activating the transcription of speciﬁc genes as part of the molecular and cellular response to noxious stimuli. An example of normal apoptosis in the CNS is the controlled harvesting of 50% of the original complement of alpha-motor neurons occurring in the process of modeling skeletal muscle motor end units. Disturbance of the processes which regulate apoptosis is now being investigated as one of the central mechanisms in several disease processes occurring in both CNS and nonCNS disorders. These include atherosclerotic heart disease, cancer, tuberculosis, Alzheimer’s disease, diabetes, HIV-AIDS, and,

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possibly, schizophrenia. Cell-damaging effects of some toxins and drugs such as ethanol and barbiturates which lead to hepatic dysfunction may be due to their effect on the intracellular mechanisms which regulate apoptosis. In amyotrophic lateral sclerosis, disordered apoptosis may be induced by the effect of free radicals, intracellular calcium entry, and excitatory amino acids such as glutamate and N-methyl-D-aspartate. Apoptosis of the dopaminergic neurons in the nigrostriatal pathways results in Parkinson’s disease. MPP (1-methylphenyl-pyridium), an agent used to induce Parkinson’s in experimental animals, and reserpine, which causes Parkinson’s by depleting dopamine, both induce apoptosis. Thus, factors which inﬂuence cellular survival or cell death through apoptosis contribute to brain developmental plasticity both in health and in disease. Following from this understanding of apoptosis, a variety of clinical or pathoetiologic mechanisms can be developed or understood. For example, the ﬁrst human gene capable of inhibiting apoptosis was identiﬁed by Mackenzie and Korneluk in 1995 (Barnes and Mackenzie, 1999). Called NAIP (neuronal apoptosis inhibitory protein), this compound may have potential clinical applications. Microinjections of NAIP-expressing adenovirus introduced into the rat hippocampus protects populations of sensitive neurons from ischemia-induced cell death (Xu et al., 1997). From a pathoetiologic perspective, disordered apoptosis may be part of the mechanism by which extreme environmental stress such as child abuse leads to elevated corticosteroid levels, hippocampal granule cell death, and cognitive dysfunction. In the future, NAIP analogs may be used to mitigate the effects of in utero exposure to ethanol and cocaine or to offset the adverse effects of dopamine antagonists used in the treatment of childhood schizophrenia or Tourette’s syndrome. Cellular migration and growth

Many aspects of cell migration, axon outgrowth, and neural pathway formation are also under genetic control (Morilak et al., 1995). In the cortex, neurons are helped to their ﬁnal destinations by an interactive scaffolding structure of radial glial cells which extend their processes to both pial and ventricular surfaces. It has been suggested that migration along these glial cells forms the developmental basis for the vertical, columnar organization of functional cortical modules in the brain. Genetic mouse mutants have been developed which show separate defects in the ability of CNS neurons to attach or detach from this radial glia scaffold (Caviness and Rakic, 1978; Hatten, 1990). In patients with dyslexia, autism, schizophrenia, and fetal alcohol syndrome, the

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presence of ectopic cells and migratory arrests in postmortem tissue suggest that abnormal migration may be of pathoetiologic signiﬁcance (Nowakowski, 1991). Thus, neural programming errors can result in disturbances in normal cell growth and connectivity. Axon outgrowth and pathway formation toward the ﬁnal genetically predetermined destination are guided along by complex interactions between cellsurface proteins, extracellular matrix proteins, and attractant and repellant factors secreted by target regions in the brain (Dodd and Jesell, 1988; TessierLavigne et al., 1988). In Drosophila, axonal pathﬁnding defects have been demonstrated to arise from defects in the genes coding for the cell-adhesion proteins neuroglian and the fascilins-1, -2, and -3 (Bieber et al., 1989; Harrelson and Goodman, 1988; Snow et al., 1989; Zinn et al., 1988). The process of establishing and maintaining patterns of cell survival, cell growth, and cell connectivity is also inﬂuenced by nerve growth factors. These ‘‘target-derived neurotrophic growth factors’’ are secreted by the innervated targets of nerve ﬁbers and are speciﬁc to neuron populations and receptors. These trophic factors are then taken up into the nerve terminal by receptors and transported retrogradely to the cell body where they may affect cell growth and differentiation. Neurons, in turn, may affect their targets anterogradely by the release of neurotransmitters and neuropeptides which seek to establish the appropriate connection points. Failure to establish connection successfully may result in cell death or inappropriate pruning. At the current time, insufﬁcient study of these processes has occurred and the particular effects of speciﬁc tropic factors on pathoetiology or treatment of particular psychiatric disorders have not been determined. The relative contributions of intrinsic, genetically ordered processes and the effects of environmental stimuli on the outcomes of cell migration and connectivity are at this time unknown. For the clinician, however, an appreciation of the complexity of these developments and their potential for enhancing understanding of treatment and disease is necessary. Neurotransmitters

At the more microscopic level, neural development is orchestrated by a cascade of events affecting the brain’s intracellular signaling system. This involves a variety of neurotransmitters, receptors, second messengers (such as inositol, cGMP, and calcium), nerve growth factors, and neuropeptides. Many of these neural elements play a role during early CNS development that is very different than their function in the mature brain. For example, it is known that neurotransmitters and receptors are expressed at their highest levels in the immature

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brain and in anatomic regions different than in the mature brain, even in the absence of fully functional synapses. It is important to understand their changing role as this may affect the expression of psychopathology or the response to psychopharmacologic interventions. Monoamine-secreting neurons (serotonin, noradrenaline, and dopamine) are detectable by embryonic day 13 in rats and catecholamines appear as early as gestational week 5 in humans (Zecevic and Verney, 1995). These cells distribute afferents to the cerebral cortex where their processes may play an important but time-limited role by providing an orientation target to other axons arriving later on in cortical development ( Jones, 1991). In the cortex, the serotonin (5-HT) ﬁbers are the ﬁrst afferent ﬁbers to arrive, but the last to fully establish their innervation pattern (Lidow and Molliver, 1982). Thus, different monoamine neurons may exhibit different and unique patterns of programmed development. Species-speciﬁc patterns also exist, such as the more extensive innervation of the cerebral cortex by dopaminergic terminals in primates compared with rodents (Gaspar et al., 1989). The ﬁnal outcome is that monoaminergic brainstem cells contain processes that innervate extensive areas of the brain either by synaptic contact or secretion of neurotransmitter substances into the neuropil – thus demonstrating that monoaminergic neurotransmitters have structural and functional, as well as trophic, roles in CNS development. Serotonin levels in the postnatal cortex of the young mouse are roughly twice the adult concentrations (Hohman et al., 1988). Chugani et al. (1997) examined serotonin synthesis rates, using alpha-methyl-l-tryptophan, in a pediatric population and found that from age 3 months to 3 years children demonstrated levels that were 200% higher than those found in adults. These levels remained high until age 5, when they began the decline leading toward adult levels. Conversely, depletion of serotonin from birth to postnatal days 10–20 in rats has been demonstrated to result in a permanent decrease in synaptic density and learning deﬁcits persisting into adulthood (Mazer et al., 1997). This has led some researchers to hypothesize that serotonin in the developing brain acts as a developmental signal (Lauder et al., 1983; Whitaker-Azmitia et al., 1996). It has been proposed by these investigators that serotonin autoregulates its own development and that changes in 5-HT levels during development alter the ﬁnal morphology of the 5-HT system (via inhibition of outgrowth of 5-HT terminals). Prenatal depletion of 5-HT with p-chlorophenylalanine, an irreversible inhibitor of tryptophan hydroxylase, delays the onset of neurogenesis in 5-HT target regions by delaying the onset of differentiation of raphe serotonergic neurons (Lauder and Krebs, 1976), while serotonin stimulation with 5-methoxytryptamine produces dose-dependent effects on

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neurite outgrowth (Shemer et al., 1991). Development of mesencephalic dopamine neurons (targets of raphe serotonergic axons) are also delayed. 5-HT can thus be conceptualized as playing a dual role in development: autoregulation of the serotonergic neurons and development of target tissues for neurons containing other monoamine neurotransmitters. Serotonin may have effects on other neurotransmitter systems. Ascending serotonergic systems from the median and dorsal raphe innervate areas of the brain rich in dopamine neurons (Pineyro and Blier, 1999) where they regulate the ﬁring rate and release of dopamine. In human subjects from 21 to 49 years of age, Wang et al. (1995) demonstrated a correlation between frontal 5-HT-2 decline and number of striatal dopamine D2 receptors. Liu and Lauder (1992) have shown that serotonin, through regional effects on either raphe glia or mesencephalic glia, will promote nerve growth factors affecting the maturity of serotonergic neurons or tyrosine hydroxylase neurons, respectively. Alternatively, D1 receptors have been shown to be inhibitory to growth cone motility in serotonergic terminals; if rat pups are treated prenatally with a D1 agonist, as adults they have greatly reduced serotonin-uptake sites (Whitaker-Azmitia et al., 1990). If the dopamine system is depleted in the neonate, through 6hydroxydopamine lesions in the caudate, then overgrowth of 5-HT terminals occurs (Breese et al., 1984). Interestingly, in these animals as adults, the effect of dopamine is increased whereas the effect of serotonin is decreased suggesting adaptive changes secondary to the changes in neurotransmitter level ( Jackson et al., 1988). Receptors

(1)

(2)

Neuroreceptors evolve different developmental functions as the organism matures and there is regional as well as receptor subtype speciﬁcity whose functional properties change across maturational time. Whitaker-Azmitia (1991) hypothesizes that receptors can be conceptualized as ﬁtting into two categories or roles: Programmable receptors – these are thought to need appropriate amounts of stimulation to develop their functions. The D2 receptor is an example of this and an over- or understimulated receptor may be functionally impaired permanently. For example, in adults, chronic neuroleptic administration generally results in an increase in D2 receptors, but neonates deprived of dopamine stimulation do not show this effect (Duncan et al., 1987; Saleh and Kostrzewa 1988). Receptors that affect development – these are mostly transiently expressed receptors since they play a speciﬁc developmental role, possibly through

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coupling with second messenger systems. The dopamine D2 receptor, absent in the frontal cortex in adult rats, is transiently expressed in the immature brain (Noisin and Thomas, 1988). Insel (1995) offers the following insights about the role of transient receptors in development: (a) receptor binding may develop independently of innervation; (b) the pattern of binding is diverse with speciﬁc brain regions showing intense binding transiently in the ﬁrst to third week postnatally; and (c) the expression of binding precedes receptor–effector (second messenger) coupling. Serotonergic receptors in rats attain peak levels in fetal or early postnatal life and then decrease to adult levels (Whitaker-Azmitia, 1991). For some receptor subtypes, the highest number of receptors occurs during brain development at a time when properly functioning synapses are not present. Additionally, structurally similar receptors may be involved in different developmentally important functions; for example, in the serotonergic neuron, the 5-HT-1C receptor may regulate cell division, whereas 5-HT-1A receptors may regulate cell differentiation (Whitaker-Azmitia, 1991). The 5-HT-1A receptor subtype has been thought to play a critical role in both neuronal and glial cell growth through trophic effects on nerve growth factors. Whitaker-Azmitia and Azmitia (1994) have shown that astroglial cells promote immature neuronal growth through the secretion of S-100, a nerve growth factor, but the effect is mediated through 5-HT-1A receptors on brain astroglial cells. As the serotonergic neuron matures, the level of S-100 decreases – as does the number of 5-HT-1A receptors found on astroglia. Drugs which act as agonists to the 5-HT-1A receptor, such as 8-OH-DPAT, promote astroglial cell maturity. In the developing rat, 5-HT-2 receptor levels have been shown to increase dramatically between embryonic day 17 (E17) and postnatal day 13 (P13), and then to decline until P27 to then stabilize at adult levels. These ontogenetic variations in 5-HT-2 receptor levels have been accompanied by similar changes in 5-HT-2 mRNA (Roth et al., 1991). This developmental pattern of 5-HT-2 receptors corresponds to the pattern of innervation of the cortex, peaking at postnatal day 14 (D’Amato et al., 1987) and pruned back to adult levels around postnatal day 27. In other studies using positron emission tomography (PET) scanning of human subjects aged 21–49 years, Wang et al. (1995) have shown that 5-HT-2 receptors decrease with age in frontal cortex and striatum. This decrease over time was relatively speciﬁc as it was not found to occur at a similar rate in the occipital cortex. Gross-Isseroff et al. (1990) conﬁrmed these ﬁndings in postmortem autoradiographic analyses of 12 healthy brains which showed sharp decreases in prefrontal and hippocampal 5-HT-2 receptors over the second and

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third decade. These receptor numbers reached a minimum around age 50, but began to increase again in the sixth and seventh decade, showing the dynamic nature of receptor changes over the entire lifespan and raising implications for medication treatment including both efﬁcacy and adverse effects. A similar developmentally sensitive role for dopamine and the dopamine receptor has also been documented. The level of hyperactivity and its persistence into adulthood is correlated positively with the degree of dopamine depletion as induced by 6-hydroxydopamine in neonate rodents (Miller et al., 1981). However, contrary to high levels of 5-HT in mouse neocortex neonatally, dopamine levels in rat forebrain slowly rise to adult levels by postnatal day 45 (Rodriguez et al., 1994). Mesencephalic levels of dopamine, however, reach adult levels prenatally, reﬂecting dopamine turnover in cells, whereas postnatal forebrain dopamine reﬂects axonal growth and synaptogenesis (Santana et al., 1992). The highest numbers of both dopamine 1 and dopamine 2 receptors occur in the immature brain in rats, baboons, and humans (Whitaker-Azmitia, 1991). The D1 receptor has been localized on growth cones which are located on the tip of the growing nerve terminal, suggesting a role in inﬂuencing neuronal differentiation and maturation (Lockerbie et al., 1988). D2 receptors are transiently expressed in the frontal cortex of the immature rat but are absent in the adult brain (Noisin and Thomas, 1988). However, if dopaminergic receptors are deprived of stimulation then permanent changes in binding or compensatory receptor expression may occur in adults, such as demonstrated when neonates are lesioned with 6-hydroxydopamine (Duncan et al., 1987). Profound depletion of forebrain dopamine by 6-hydroxydopamine in neonatal rats was associated with an 82% loss of D1 receptors, but administration of a D1 agonist abolished this effect (Gelbard et al., 1990). Gelbard and coworkers speculate that D1 receptor density may be regulated by reciprocal processes during normal development, but may fail to develop in the absence of an adequate level of stimulation. In human studies, D1 receptor density decreased 48% between childhood and adulthood (Seeman et al., 1987) and then continued to decrease throughout the life span from 20 to 72 years, in both the striatum and frontal cortex (Iyo and Yamasaki, 1993). The D2 receptor has also been shown to depend on the input of a dopamine terminal for development (Broaddus and Bennett, 1990). As a result of D2 agonist and antagonist actions, it has been shown that stimulation of D2 receptors results in increased length and branching of neurites in a subset of frontal cortical neurons (Todd, 1992). Stimulation of 5-HT-1A receptors in the same culture system resulted in a decrease in neurite branch growth. Most

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cortical cells express 5-HT-1A receptors, whereas only a small percentage have D2 receptors. Accordingly, the same neurotransmitter may elicit different morphogenic responses in different cells depending on the receptor subtype the cell expresses and the second messenger system to which the receptor couples. In human subjects, striatal D2 receptors fell by 59% between childhood and adulthood (Seeman et al., 1987). Additionally, it has been shown that between 21 and 49 years of age striatal D2 receptors also decrease signiﬁcantly with age (Iyo and Yamasaki, 1993; Wang et al., 1995). Sex effects are evident in these processes as the decrease is greater for males than for females: 43% vs. 25% (Wong et al., 1984). There are also animal data to indicate that the period of adolescence may show a unique developmental proﬁle that differentiates this portion of the lifespan from either childhood or adulthood. These ﬁndings have suggested that, in the adolescent years, changes may occur in speciﬁc brain regions, may be preferentially directed toward speciﬁc receptor types, and may be sex sensitive. For example, Andersen et al. (1997) investigated D1 and D2 receptors in male and female rats at ages 25, 35, 40, 60, 80, 100, and 120 postnatal days in both the striatum and nucleus accumbens. Both D1 and D2 receptors were increased in striatum for males during the periadolescent period, but were pruned back as the animal matured. In the nucleus accumbens, D1 receptors dramatically increased at the onset of puberty and this increase was sustained into adulthood. In females, D1 and D2 receptors in striatum and nucleus accumbens also increased in periadolescence, although the increase was notably less than that found in males. Possibly, as a consequence of this smaller change in receptor numbers, the investigators noted that there was practically no pruning of receptors as the animals matured. The authors speculate that these receptor changes are, if not necessary, then at least permissible factors in the expression of various disorders which exhibit psychiatric symptomatology prepubertally (such as in attention-deﬁcit/hyperactivity disorder [ADHD]/ and Tourette’s syndrome) that tend to wane after adolescence, especially in males. Amino acids and neuropeptides

The amino acid neurotransmitters GABA (gamma-aminobutyric acid) and glutamate are thought to play important roles in development because of their ubiquitous and time-sensitive distribution throughout the brain. They have been observed in two telencephalic neuron populations that demonstrate early maturation, and Cameron et al., (1998) hypothesize that their function is to direct the development of later maturing neuronal populations. That both of these neuron populations appear only transiently supports the hypothesis of a

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speciﬁc developmental role in the formation of CNS structures for these two neurotransmitters. It has been further proposed that glutamate plays a role in neuron cell migration and survival, but other studies suggest a role for glutamate in controlling cell proliferation. According to Lo Turco and colleagues (1995), when nonNMDA receptors are stimulated, there is a signiﬁcant decrease in proliferation (up to 60%) of cortical progenitor cells in rat cortical explants. Blockade of NMDA receptors by antagonists in the ﬁrst week postnatally results in increased proliferation of granule cells in the rat dentate gyrus (Gould et al., 1994). The rat dentate gyrus, which continues to produce granule cells throughout life, apparently retains its sensitivity to NMDA antagonists in adulthood. Similarly, GABA has a multifaceted and complex role in neurodevelopment. The GABA receptor changes its role from being excitatory during childhood to becoming inhibitory during adulthood. This may help to explain the clinical observation of the increased disinhibitory effect of benzodiazepines in children. Similarly to glutamate, GABA can decrease proliferation of cortical progenitors (LoTurco et al., 1995) during a speciﬁc developmental time window. There is evidence to suggest that the GABAa receptor may exert its effect by modulating a growth factor, bFGF (ﬁbroblast growth factor; reviewed in Cameron et al., 1998), but the clinical signiﬁcance of this is not known. Similarly to the role of glutamate and GABA in development, endogenous opioid peptides inhibit CNS cell proliferation. This process is thought to be routed through a receptor only expressed during early development, the zeta receptor (Zagon and McLaughlin, 1991). Naltrexone treatment increases the total number of neurons generated postnatally in the dentate gyrus and the subventricular zone (Zagon and McLaughlin, 1986). Neuropeptides work in concert with other neurotransmitters to regulate neurogenesis. Neuropeptides and their receptors are expressed at their highest level in the immature brain as shown for substance P, oxytocin, and neurotensin which can be as high as 2000 times the adult value (Insel, 1995). Many of these peptides are expressed early on in the developing brain in regions undergoing proliferation, but some continue to be expressed postnatally and may persist into adulthood. For example, FGF or the FGF family, consisting of at least 15 members, acting through tyrosine kinase receptors, are expressed early in development and persist into adulthood in the granule layer of the hippocampal dentate gyrus and the subventricular zone lining the lateral ventricles of the forebrain (Cameron et al., 1998). A similar pattern of persistence into adulthood in regions undergoing neurogenesis has been found for

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other peptide growth factors including epidermal growth factor, transforming growth factor-alpha and beta-2, insulin-like growth factor-1, and plateletderived growth factor (Cameron et al., 1998). The thyroid hormone T3 has also been implicated in regulating neurogenesis pre- and postnatally and into adulthood. In summary, then, a complex array of neuropeptides interacts with neurotransmitters to regulate neurogenesis. Although our understanding of their expression, interrelationships, and function is incomplete, it seems that many of these growth factors continue to function into adulthood and continue to modulate areas of the brain responsible for adaptive functioning such as the dentate gyrus of the hippocampus. Coupling

An important aspect of neurodevelopmental signaling is the coupling of neurotransmitters and receptors to second messenger systems. While later in development a cell’s survival may depend on establishing functional synapses, earlier in development transiently expressed receptors, through their coupling with second messengers, may play a role in directing development (WhitakerAzmitia, 1991). The activity level of phospholipase C, the enzyme responsible for the production of inositol phosphates, is much greater in the immature compared with the mature rat brain. Cell proliferation may be regulated through receptors that stimulate phosphotidylinositol hydrolysis whereas cellular differentiation may be regulated by receptors that stimulate adenylyl cyclase. However, not all systems operate in this manner, as it has been found that the developmental patterns of various G proteins are independent of their coupling to receptors (Insel et al., 1988). Macrodevelopment Recent advances in neuroimaging techniques have conﬁrmed existing data on microscopic neuroanatomic growth patterns in cell processes and synapses. Hashimoto et al. (1995) used magnetic resonance (MR) spectroscopy to study 47 children ranging in age from 1 month to 18 years. Their ﬁndings demonstrated a rapid increase in the NAA/Cho (N-acetyl aspartate/choline) ratio occurring over the period from 1 month to 2–3 years in the right parietal area, after which time it increased more slowly. The increase in the right frontal area was evident until 4 years, but was slower than the right parietal area, indicating the slower maturational curve of the frontal cortex. These ﬁndings were consistent with the MR ﬁndings of Barkovich et al. (1988) and the postmortem ﬁndings of Yakovlev and Lecours (1967). van der Knaap et al. (1990) found a

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similar increase in NAA/Cr (N-acetyl aspartate/creatine) and NAA/Cho and a decrease in Cho/Cr. The most powerful changes were seen by age 3, but were still evident at age 16. More recently, Pouwels et al. (1999) found an increase in NAA in gray matter while white matter remained constant during infancy and childhood. As this increase in NAA was concurrent with an increase of taurine, which plays a role in synapse formation, it was hypothesized that NAA might not just mark the presence of neurons, but the presence of functioning neurons. Additionally, these investigators found that N-acetyl-aspartyl-glutamate increased in the thalamus and white matter, while glutamate itself decreased in white matter. Creatine, choline, myo-inositol, and glutamate were found to be fairly constant during development. All of these substances are implicated in the metabolism of neural cell membrane synthesis or membrane breakdown. The ratio of creatine to phosphocreatine in these studies, however, showed longitudinal consistency and remained a constant 2:1 regardless of developmental state. Minshew and Pettegrew (1996) found a reduction of phosphomonoesters and an increase in phosphocreatine in a population ranging from adolescence to young adulthood. It was posited that this indicated a reduction in the synthesis of neural cell membranes and an increase in their breakdown. The increased phosphocreatine was hypothesized to be the result of a decrease in utilization of high-energy phosphates (thus, an increase in the metabolic pool), presumably a reﬂection of a reduction in synapse number, which is a change consistent with maturation. Chugani et al. (1987) studied local cerebral metabolic rates for glucose utilization (ICMRGlc) with PET in 29 children between the ages of 5 days and 15.1 years. In infants less than 5 weeks old, ICMRGlc was highest in sensorimotor cortex, thalamus, brainstem, and cerebellar vermis. By 3 months, ICMRGlc had increased in parietal, occipital, and temporal cortices, the basal ganglia, and the cerebellar cortex. Interestingly, frontal and dorsolateral occipital cortices displayed later maturational rises onsetting at 6–8 months. The anatomic distribution was similar to adult patterns by 1 year of age, but adult values were not reached until 2 years of age. ICMRGlc values then surpassed adult values by 3–4 years of age and were maintained until 9 years of age where they declined again to adult values by the end of the second decade. Overall, the cerebral cortex underwent the highest proportional increase in ICMRGlc over its adult mature rates when compared with other portions of the brain, but the frontal and dorsolateral occipital cortices matured more slowly than other cortical areas. Chugani et al. interpreted these ﬁndings as evidence that, in general, a rise in

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metabolic rate of a particular part of the brain is highly correlated with that part of the brain’s effect on the animal. Given this argument, their data show that over the lifespan different brain regions may ‘‘phase in’’ or ‘‘phase out’’ in terms of their relative contribution to the control of a variety of functions. Chugani et al. further speculated that the cause of the increase then decrease of metabolic rates in developing brain structures is a reﬂection of the protracted process of overproduction followed by pruning of synapses and dendritic processes. For example, at age 7, when the child’s brain is almost identical in size and weight to that of the adult, the average synaptic density in the frontal cortex is 1.4 times the adult value. Over the teenage years, loss of density occurs which leads to the establishment of ‘‘adult’’ levels. These ﬁndings support earlier postmortem ﬁndings by Huttenlocher (1990) who found the highest synaptic density in the ﬁrst 3 years of life, followed by a gradual decline over the course of childhood and adolescence. Similar patterns of results have been identiﬁed by other investigators using other methods of CNS evaluation. In a study of magnetic resonance imaging (MRI) scanning of 121 normal children between 4 and 18 years of age, Giedd et al. (1997) found that males had mean cerebral volumes 9% larger than females, but that females had relatively larger basal ganglia. There were sex differences in maturational rates, with males showing greater increases in lateral ventricular volumes especially after age 11. There was a decrease in left globus pallidus volume and increased amygdala volume with age for males, whereas hippocampal volumes increased for females, ﬁndings that indicate the possible organizational dimorphic roles of sex steroids. Giedd et al. (1999b) further examined corpus callosal development in 139 healthy children. These investigators found that corpus callosal area increased with age, especially in the posterior CNS regions between the ages of 5–18 years. No sex differences in corpus callosum development were noted. Perhaps the most interesting ﬁnding from these studies was the large variability in brain structure sizes in this normal, carefully evaluated population. Pfefferbaum et al. (1994) studied cerebral volumes (using MRI) in children and adults. A 300 ml increase in intracranial volume was noted from 3 months to 10 years. Gray matter peaked at 4 years of age and dropped after this. White matter increased past age 20 years. Cerebral spinal ﬂuid (CSF) volumes remained constant throughout the age range. When adjusted for head size, the older probands in the sample demonstrated a reduction in gray matter (0.7 ml/year) while white matter remained constant for ﬁve decades. More recently, Sowell et al. (1999) found decreases with age in the striatal and prefrontal areas in children and adolescents. The changes were most apparent in the

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putamen and globus pallidus. The frontal lobe differences arose from changes in gray matter. In another study, Giedd et al. (1999a) found a sharp increase in brain gray matter occurring during the adolescent years, with females peaking approximately 1 year earlier than males. Klingberg et al. (1999) utilized the new technology of diffusion tensor imaging (DTI) to examine the in vivo development of white matter tracts in children and adults. DTI can be used to measure the anisotropy of a sample – anisotropy is the movement of water along tissues. With increased myelin, one would expect an increase in anisotropy as the water moves along the myelin sheath rather than against it. In this study, the anisotropy in frontal white matter was lower in children relative to adults, indicating less myelin in the children. Right frontal lobe coherence (the orientation of myelin sheaths) was less than that of the left frontal lobe in children and adults. These ﬁndings further demonstrate that myelination occurs over the lifespan. In MRI studies of ADHD, three groups of investigators have reported a smaller right prefrontal cortex in probands compared with controls, (Castellanos et al., 1994; Filipek et al., 1997; Hynd et al., 1990), but these same investigators found contradictory results regarding either loss or reversal of normal asymmetry in caudate volumes in the ADHD group. It is not clear, therefore, if these ﬁndings are evidence of abnormalities or simply exaggerated phenotypic variants of normal developmental patterns. While much work remains to be done before MRI can be considered to be a useful clinical tool, MRI ﬁndings as currently available can perhaps be correlated to clinical characteristics (such as severity or comorbidity) or used to help guide treatment interventions. Another application of MRI would be to monitor for potential brain changes accompanying chronic pharmacologic interventions. For example, Frazier et al. (1996) found that children with a diagnosis of schizophrenia and who were treated with typical neuroleptics had an increase in basal ganglia volume which decreased 2 years later when these same patients were treated with clozapine. Similar effects were noted by Keshavan et al. (1994) and Chakos et al. (1995) with ﬁrst-episode schizophrenics. Rosenberg et al. (1998) reported a reduction in striatal glutamate after 12 weeks of paroxetine treatment in children with pediatric obsessive–compulsive disorder (OCD). Structural changes were also noted in the nucleus accumbens (Bailey et al., 1998) and thalamus (Gilbert et al., 2000) with paroxetine treatment. At this time, the clinical meaning of these ﬁndings has not been clariﬁed and the relationship of these changes to outcome or adverse effects of treatment still needs to be established.

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Effects of stress, early experience, and hippocampal neurogenesis An exciting area for the neurodevelopmentalist is the convergence of clinical and basic science in studying the effects of early environmental stress on developing CNS neurotransmitters, hormones, and anatomic structures. For the sake of this discussion, we will limit ourselves to the role of the impact of early stress on the hormones (cortisol, adrenocorticotrophic hormone [ACTH] and corticotrophin-releasing factor [CRF]) of the limbic–hypothalamic–pituitary–adrenal axis (or LHPA axis). The neurophysiologic adaptation or maladaptation to stress following a critical period of development may be modiﬁed by psychopharmacologic treatments with immediate and subsequent long-term effects on psychopathology and level of functioning. In general, adults who have experienced severe and longstanding early adverse childhood experiences are more susceptible to experience mood and anxiety symptoms in later adult life (McCauley et al., 1997). Certain investigators have postulated that changes in CRF may mediate the association between stressful experiences and the later development of mood and anxiety disorders (Heim and Nemeroff, 1999). CRF immunoreactivity has been measured in the brainstem, implicating this hormone’s role in modulating monoamines and their projections to the forebrain. An interesting limbic connection is between CRF neurons in the amygdala and noradrenergic neurons of the locus ceruleus (van Bockstaele et al., 1996). Acute and chronic stress increase CRF concentrations in many brain areas including the amygdala and the locus ceruleus. Some types of stress activate the LHPA axis, where neurotransmitters stimulate the synthesis and release of CRF which then stimulates corticotrophs to produce ACTH, which, in turn, stimulates the synthesis and release of glucocorticoids from the adrenal cortex. While few human studies exist to elucidate the relationships between the effects of signiﬁcant early stress and LHPA dysfunction, DeBellis et al. (1994) found that sexually abused girls exhibited blunted ACTH responses to a CRF challenge. Animal studies have documented that separation of young rat pups from their mothers may make them susceptible to increased ACTH and corticosterone responses to a variety of stressors in adult life (Plotsky and Meaney, 1993). Interestingly, Plotsky et al. (in press) found that the excessive stress response of the LHPA axis is reversed by treating the maternally separated rats with the antidepressants paroxetine and reboxetine. Fluoxetine treatment decreases CSF CRF concentrations in recovering depressed patients (DeBellis et al., 1993). Finally, Gould and Tanapat (1999) have put forth several interesting propositions based on their experimental animal work about the effects of early stress

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on hindering hippocampal neurogenesis. The granule cells of the dentate gyrus undergo rapid development beginning in gestation and continuing postnatally, but new granule cell production has been documented in adulthood as well. Adrenal steroid levels decrease and remain low for the ﬁrst 2 postnatal weeks in the rat (the hyporesponsive period) which coincides with maximal granule cell production in the dentate gyrus, but, subsequently, as the adrenal steroid levels increase, granule cell production slows to the rate observed in adults. In animals exposed to chronic stress, there is persistent inhibition of granule cell production with resulting changes in the structure of the dentate gyrus. The researchers propose that the elevated levels of glucocorticoids activate excitatory NMDA receptors in the entorhinal cortex which suppress granule cell formation in the hippocampus via the perforant path. Investigators have hypothesized that stressful experiences during development may have a long-term effect on the hippocampus by directly altering its structure and functioning (particularly learning and memory). Cognitive impairments in children who have been sexually and physically abused have indeed been documented (Carrey et al., 1995). It is not yet clear if some psychotropics, such as antidepressants which impact on the serotonin system, have a protective effect on susceptible developing brain regions by dampening an over-reactive LHPA axis resulting from child abuse. Additionally, it is not known if some psychosocial interventions such as family therapy may affect the child’s environment in such a manner as to modify the stress effects of that environment on hippocampal development. Genetic evidence for some psychiatric developmental disorders and pediatric pharmacogenetics Although it is beyond the scope of this chapter to review all the genetic ﬁndings emerging now in molecular genetic psychiatry, identiﬁcation of a few genetic mechanisms has implications for advancing our understanding of these disorders and guiding the future development of psychopharmacologic interventions. Two areas of research that are of immediate application in the child and adolescent age group are the theory of genetic anticipation and the identiﬁcation of candidate genes in ADHD. The concept of anticipation in genetics is dependent on the action of trinucleotide repeats over generations. Triplets or trinucleotides consist of 3 nucleotides consecutively repeated either within genes or in the large stretches of DNA that lie between genes. Many of the trinucleotide repeats are the same length in all individuals, but other repeats are of variable length. These repeats,

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even the variable or polymorphic areas, are transmitted unchanged from one generation to the next. However, some repeats may change in length when passed on and, when this occurs, gene expression is disrupted. This is referred to as a dynamic or expansion mutation. One group of diseases is characterized by a number of repeats above which (40) the expansion causes the disease, as in neurodegenerative diseases such as Huntington’s chorea. The excessively long stretches of glutamine residues encoded by the CAG repeat are apparently neurotoxic to a particular set of cortical or subcortical neurons. The second group of triplet repeat diseases consists of skeletal developmental disorders which result from one or two additional triplets which result in abnormal conformational changes to produce an abnormal protein product. A third group of disorders results from repeat expansions outside the protein-coding region, such as in fragile X syndrome. The discovery of triplet repeat disorders helped to explain the phenomenon of anticipation – where certain diseases have an earlier age of onset and/or a more severe phenotype – since repeat mutations are unstable and tend to get longer with each successive generation. An anticipation pattern of inheritance has been used to explain the earlier age of onset and increased severity in bipolar disorder and schizophrenia (Margolis and Ross, 1999). These earlier onset disorders may be more difﬁcult to treat with the usual psychopharmacologic agents compared with adult onset disorders. Pharmacologic interventions in the future could target the development of small molecules capable of upregulating or downregulating the expression of faulty genes. A more recent approach to pharmacogenetics has been to assess responders vs. nonresponders to a speciﬁc pharmacologic intervention and test candidate genes that might distinguish the two groups. This approach has been used for lithium in bipolar patients (Grof et al., 1994), and ﬂuvoxamine for mood disorder for the 5-HT transporter gene (Smeraldi et al., 1998), and, more recently, ritalin response in ADHD for the dopamine transporter gene or DAT1 (Winsberg and Comings, 1999). These latter authors found that ritalin nonresponders were more frequently homozygous for the ‘‘10 copy of the DAT1 gene’’ (86%) compared with the responders (31%), although overall, in their sample of 30, only 53% of the total group were responders, lower than the 75–80% response rate found in other studies. In an accompanying editorial, Cook (1999) pointed out the difﬁculty in interpreting these results since this approach utilized response as a categorical clinical variable, whereas ADHD and its response to treatment are multidimensional. Cook also mentioned that, although the symptoms of hyperactivity and impulsivity are highly heritable, the mode of transmission is likely to be polygenic as other studies have found

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positive associations for the dopamine receptor genes (D4 and D5) and the dopamine beta hydroxylase gene. He also cautioned that other variables such as family environment, comorbidity, and access to health care may add to the complexity of interpreting these early results. Developmental psychopharmacology Finally, in terms of developmental neuropharmacology, it has now been reasonably well established that the nervous system shows different responses depending on the age of the organism and the level of plasticity. For unclear reasons, certain drugs are extremely toxic, others that would be predicted to be toxic have no effect, and others have enduring organizational effects or developmental phase-speciﬁc effects. Therefore, medications may have different effects if received in utero, in the neonatal period, prepubertally, peripubertally, in adulthood, or in old age. For example, cocaine and ethanol produce speciﬁc developmental syndromes when the fetus is exposed in utero. Concerning ethanol, as early as gestational day 15 (G15), there is a demonstrated toxic effect on raphe (serotonergic) neurons in cell cultures. At G19, it has been found that cortical neurons are impaired, possibly due to a 5-HT-1A deﬁcit. 5-HT-1A receptors in the brainstem of rat pups exposed in utero to alcohol are increased at postnatal day 5, as this may represent a developmental delay in expression of these receptors. Cultured rhombencephalon astrocytes exposed to ethanol secrete fewer growth factors; these teratogenic effects may be prevented by pretreating with buspirone pregnant mother rats who are fed ethanol (reviewed in Whitaker-Azmitia et al., 1996). In the immature brain, the 5-HT system appears to be particularly vulnerable to the teratogenic effects of cocaine (Akbari et al., 1992). There are fewer 5-HT-1A receptors in cortical astrocytes exposed to cocaine. Concomitant decrease in S-100b protein, a nerve growth factor, leads to cortical thinning. These abnormalities may, in turn, lead to abnormal pharmacologic responses to other drugs later on in development. On the other hand, certain excitotoxins such as quinolinate, which cause degeneration in the adult rat hippocampus, have no effect when injected during the ﬁrst 2 postnatal weeks (Keilhoff et al., 1990). In the adult brain, receptor blockade usually leads to homeostatic compensatory upregulation whereas receptor stimulation has the opposite effect. Exposure to agonists and antagonists prenatally or perinatally can give paradoxical and long-term effects. Early blockade of a neurotransmitter system can lead to permanent downregulation, whereas early stimulation results in upregulation

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that can persist into adulthood. This has been demonstrated with morphine, neuroleptics, antidepressants, substance P, vasopressin, benzodiazepines, and corticotropin releasing hormone (Insel, 1995). Recently, investigators have shown that treatment of neonate rats with ﬂuoxetine has resulted in an increase of paroxetine binding consistent with outgrowth of serotonergic projections in the frontal cortices persisting into adulthood (Wegerer et al., 1999). Insel (1995) proposes that exposure to an agonist during the neonatal period induces enduring functional increases in receptor responsiveness or a type of ‘‘chemical imprinting.’’ Whether the effects of agonists or antagonists confer an advantage or disadvantage to certain neuron populations during the developmental trajectory, especially neurons with terminals in areas of high pruning or neurons with extensive terminal ﬁelds, is not known at the current time. The developmental speciﬁcity of a drug response is the result of multiple interacting factors including the status of receptors and their effectors, metabolic enzymes, and the role of the blood–brain barrier. The motor response to clonidine, an alpha-2 adrenergic agonist, is an example of a developmentally determined drug response. From day 1 to day 14 postnatally, clonidine increases locomotor activity whereas, afterwards, it suppresses locomotor activity. Hartley and Seeman (1983) speculate that this effect is due to the late maturation of alpha-2 receptors in motor pathways. Teicher and Baldessarini (1987) have interpreted the observation that acute administration of imipramine to the adult rat produces sedation, whereas this is not shown until 4 weeks of age in the younger rat, as due to the delayed development of a serotonin-mediated inhibitory response. Similarly, McCracken and Poland (1995) found that in prepubertal rats the prolactin response to a serotonin agonist was not enhanced by pretreatment with amitryptiline whereas in adult rats the prolactin response was enhanced. They suggested that immature organisms may lack the full capacity to upregulate a 5-HT receptor-coupled response. These ontologic differences in the development of monoamine systems may help to explain the documented differences in clinical response in antidepressant–placebo studies in children and teenagers compared with adults. It seems logical to conclude that a drug effect may be beneﬁcial at one developmental stage, but may either have no effect or adverse effects at another developmental period. For example, periadolescent rats appear to be more sensitive to the behavioral (cataleptic) effects of catecholamine antagonists such as haloperidol while at the same time displaying hyposensitivity to dopamine agonists (Spear and Brake, 1983). This parallels the human clinical situation which demonstrates adolescents’ increased sensitivity to dystonic reactions and parkinsonism. In clinical studies, the incidence of drug-induced

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dystonias and bradykinetic reactions diminishes strikingly with maturation from ages 10–19 years to adulthood (Keepers et al., 1983) whereas neurolepticinduced akathisia is less common in children. Richardson et al. (1991) found a prevalence of parkinsonism of 34% and tardive dyskinesia of 12% in a mixed sample of inpatient children and adolescents, with only 18% of the sample having been given a diagnosis of psychosis or bipolar disorder. The incidence of drug-related dyskinesias ranges from 12% to 34% (Campbell et al., 1997) and neuroleptic-withdrawal dyskinesias are more common in children and can be as high as 51% (Campbell et al., 1988). Children may be at higher risk for developing neuroleptic malignant syndrome; in children less than 6 years of age, almost all cases here occurred after ingestion of a single dose of neuroleptic (Latz and McCracken, 1992). Spear and Brake hypothesize that the lagging of certain neurotransmitter systems or the immaturity of feedback loops responsible for neuronal homeostasis such as the various autoreceptors may explain why, clinically, younger children and adolescents may be more prone to some medication side effects which are either exaggerated or paradoxical drug reactions. The psychostimulants appear to be safe medications when appropriately prescribed (Tosyali and Greenhill, 1998), but there are concerns about their ability to induce dysphoric affect in the very young. There is evidence to suggest that global developmental disturbances may alter the child’s response to pharmacotherapy. For example, Handen et al. (1999) found that, while methylphenidate was effective in reducing ADHD symptoms in a group of developmentally delayed children, ﬁve out of 11 children had signiﬁcant adverse effects of severe social withdrawal, increased crying, and irritability, especially at the 0.6 mg/kg dosage. Children under 3 years old who have the diagnosis of ADHD are frequently prescribed psychotropics. Rappley et al. (1999) in a review of Medicaid health records from Michigan over a 15-month period identiﬁed 223 children with the diagnosis of ADHD of whom 57% were prescribed psychotropics with the most common medications prescribed being methylphenidate and clonidine. From the developmental perspective, it is not known whether the stimulants acquire their euphorigenic effects and addictive properties as the brain matures because of the confounding variable of route of administration (oral vs. intranasal or intravenous route). In an article with the provocative title ‘‘Is Methylphenidate like Cocaine’’, Volkow and colleagues (1995) investigated with PET scanning the pharmacokinetics of methylphenidate injected intravenously into eight healthy male subjects. The ﬁndings were compared with a previous PET study where subjects had PET scans taken after intravenous cocaine was administered. Cocaine and methylphenidate had

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similar afﬁnities, similar rates of uptakes for blocking the dopamine transporter, and a similar subjective experience of the ‘‘high’’, but the rate of clearance was much slower for methylphenidate. The authors concluded that it is the rate of clearance of the drug from the brain which may limit its frequent selfadministration. While this offers a theoretical rationale as to why methylphenidate is not abused more compared with its widespread availability, the clinician should maintain a high index of suspicion with older adolescents or adults suspected of drug abuse. Antidepressant mechanisms of action in children and adolescents are different than those in adults, presumably reﬂecting underlying developmental differences in neurotransmitter and receptor maturation. Tricyclic antidepressants (TCAs) have not been shown to be any more efﬁcacious than placebo in controlled trials (Ryan, 1990), whereas only two placebo-controlled trials involving a selective serotonin reuptake inhibitor (SSRI) (ﬂuoxetine and paroxetine) showed the medication to be superior to inactive drug (Emslie et al., 1997; Keller et al., in press). While the SSRIs as a category are considered to be safer and better tolerated than TCAs, the whole gamut of side effects present in adults can also become manifest in children – including movement disorders and drug-induced mania (DeVane and Sallee, 1996; Leonard et al., 1997). A side effect which appears to be more common in children, especially if the initiation dose is too high, is activation or agitation, which can be seen in as many as 50% of those children who are improperly prescribed excessive initial doses of an SSRI (Riddle et al., 1992). High dosages of the SSRIs may in effect override release-inhibiting autoreceptors and stimulate postsynaptic receptors to produce activation. These ﬁndings serve to remind clinicians of the importance of using age-appropriate medication dosing strategies and not applying dosing models used in adults to children or adolescents. Conclusions and future directions From the above survey, the following considerations will be put forth cautiously while we await more deﬁnitive neurodevelopmental research. While ongoing research is establishing the timetables of neurodevelopment for certain species (rodents and other primates), the processes of neural growth in humans extend over many years, making it difﬁcult to study and, in particular, difﬁcult to determine experimentally sensitive periods for the growth of different neuronal processes and regional brain differences. What has to date been established is that brain organization continues for many years postnatally, with an intense period of activity occurring during the ﬁrst 3 years of life

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followed by decreased growth in the next few decades. However, growth is only one of a number of important processes that affect CNS functioning. Over the course of development, such phenomena as cell death, changes in receptor functioning, and ongoing organizational reﬁnements all provide substantial contributions to how the brain functions. Additionally, such changes occur within different brain regions over different points of developmental time. For example, the cerebral cortices are slower to mature and, among these, the frontal lobes show an even slower development. Certain brain areas retain plasticity throughout life – such as the hippocampus, presumably as a reﬂection of its role in adaptive functioning – while others (such as the motor cortex) demonstrate less of an ability to do so. Superimposed on these genetically determined patterns of development, a variety of stressors (ranging from toxic substances to severe life experiences) internal to or external to the organism may affect neural organization. While animal and some human data show the negative effects of in utero exposure to some drugs or other maternally ingested substances, no overall conclusions as to the effect of speciﬁc compounds can be made ‘‘a priori’’ in the absence of data obtained from carefully constructed experiments. For example, according to longitudinal research, few if any signiﬁcant negative long-term effects on cognition, behavior, or functioning have been observed in those individuals who were exposed to SSRIs in utero. Maternal alcohol abuse, however, may result in fetal alcohol syndrome with signiﬁcant long-term cognitive, behavioral, and functional disturbances to the child. There may be lifespan-speciﬁc effects of medications known to affect CNS functioning and these may be dose related. For example, some anticonvulsants such as phenobarbital may have effects on children’s IQ after 2 years of treatment, an effect that lasts 6 months after the drug is stopped (Farwell et al., 1990). Such effects have not, however, been demonstrated for all anticonvulsants and the long-term effects of these disturbances are not well established. Benzodiazepines may exhibit disinhibitory effects in many children, but at a lower frequency in adults. Lithium may have a neuroprotective effect on the CNS at lower doses, but may be neurotoxic at abnormal or supratherapeutic levels or in combination with some antipsychotics. A further complication of this information is that these phenomena may be expressed in greater or lesser extent or not at all depending on the individual exposed. Antipsychotic medications, when given at an early age in animals, may have enduring effects on receptor changes later on in adulthood. When haloperidol is administered pre- and neonatally to rats, there is decreased D2 binding in the striatum and a decreased response to apomorphine – changes that persist

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until adulthood (Hill and Engblom, 1984; Rosengarten and Friedhoff, 1979). The atypical neuroleptics when given prophylactically may confer protection against relapse. Early evidence from ongoing research by McGorry and colleagues (2000) suggests that low-dose ‘‘novel’’ antipsychotic medications when given to populations at high risk for psychosis may have a neuroprotective effect. These changes may occur in the cerebral cortex and, while these may be positive in terms of treating an ongoing psychotic illness, effects of the same compound may be different in another brain region, such as the striatum. For example, some ‘‘typical’’ neuroleptics when used in young persons may cause an increase in volume of the basal ganglia. This may not occur with the use of the ‘‘atypical’’ compounds. It has now been established that there is a high prevalence of parkinsonian symptoms in young people associated with the use of ‘‘typical’’ antipsychotics. However, the newer ‘‘novel’’ antipsychotic medications may be less likely to cause such effects which may be due to differential effects of ‘‘novel’’ and ‘‘traditional’’ antipsychotic medications in the striatum. Additionally, it is also well established that psychotic illnesses such as schizophrenia are associated with movement disorders that are present prior to the use of any antipsychotic medications, perhaps due to abnormal functioning of the cortico–cerebellar–thalamic–cortical circuit. These data serve to illustrate the complexity of the issue and caution against simplistic pronouncements regarding the long-term positive or negative effects on neurodevelopment of these and, by extension, any medications in young people. Antidepressants such as the TCAs and the SSRIs may have neuroprotective effects, not only by downregulating receptors in mood disorders but also by decreasing elevated corticosteroid levels associated with stress. Their excessive usage in the child population may, however, kindle an activation or hypomanic response in predisposed individuals although at rates lower than those noted in adults. NMDA antagonists seem to have neuroprotective effects in animals. Stimulants, which have not undergone extensive preclinical study despite their widespread use, appear to be safe in both long- and short-term use, but may induce dysphorias in younger children and may have abuse potential in some, but not most, teenagers, particularly as part of multiple substance abuse. Knowledge of neurodevelopment from animal studies may have implications both for our understanding of the pathoetiology of child and adolescent psychiatric disorders and the possible salutary or deleterious effects of psychotropics on brain development. For example, Andersen et al. (1997) have shown that D1 and D2 receptors are overproduced and pruned to a greater extent in the striatum of male compared with female rats. DA receptors reach their peak

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at day 40, then decrease dramatically by day 60, the period of time corresponding to puberty in the rat. From this observation, Andersen et al. have speculated that the onset of symptoms and gender disparity that occur in ADHD and Tourette’s syndrome may stem from developmental receptor density changes. At the same time, generalizations from a single species must be interpreted with caution because of the much more extensive dopaminergic terminal ﬁelds in the primate cortex compared with the rodent cortex. We are only now starting to understand the multilevel inﬂuences of acute and long-term effect of drugs on neuron cell factors. Since most of the treatments in child psychiatry are of a long-term nature (ADHD, depression, OCD), pharmacotherapy has the potential to alter signal transduction pathways including altered levels of and altered types of proteins expressed in target neurons (Nestler and Duman, 1995). At least three mechanisms have been identiﬁed, including regulation of gene transcription, regulation of RNA translation/turnover, and regulation of protein turnover, as potential sites of action for drug effects. As such, drug treatments may interact at the neuronal level with psychopathologic inﬂuences and environmental factors to produce positive or negative loops leading to CNS recalibration, long-term neuroprotection, or negative effects. As child and adolescent psychiatrists are consulted to treat more severe cases at earlier ages, it is imperative that they possess not only an in-depth knowledge of psychopharmacology, neurosciences, genetics, developmental psychology, and environmental systems, but also demonstrate the conceptual rigor necessary to integrate these sources of knowledge in order to tailor treatments to individual patients, families, and clinical settings. The intuitive logic of prescribing to children psychotropic drugs known to be effective in adults, without knowledge of their relationship to neurodevelopment, should be tempered by careful clinical research, arising not from ‘‘top down’’ strategies but rather from ‘‘bottom up’’ strategies in which the development of psychopharmacologic interventions is informed by an understanding of the ontology of the central nervous system.

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3 Clinical aspects of child and adolescent psychopharmacology Gabrielle A. Carlson State University of New York, Stony Brook, USA

Introduction When his car stopped running, a man had his car towed to the mechanic. The mechanic opened the hood, contemplated the interior for a minute or two, took out his wrench, and tightened a bolt. When he turned on the ignition, the car miraculously started. The bill was for $95.98. The man asked how the bill was ﬁgured, given how little effort was involved. The mechanic said it cost 98 cents to turn the bolt and $95 to know which bolt to turn. Similarly, psychopharmacologic treatment is not simply writing prescriptions; it is knowing how and when to do so. Knowing ‘‘when to do so’’ is at the core of a psychiatric assessment. Making the correct diagnosis is akin to solving a murder-mystery. Just as one needs to have a considerable amount of information about the murder and its victim in order to discover who did it, there needs to be considerable understanding of the problem in order to give it a diagnosis. In both situations, it is necessary to be active in obtaining information. The more complicated the case, the more information sources must be contacted. One must sort through a considerable body of evidence, not all of which carries equal weight. There may be several suspects or other diagnoses that must be eliminated. There may be accomplices (comorbidity). In the end, one may only have circumstantial evidence (information from other informants) rather than incontrovertible fact (a reliably completed interview from the patient, validated by other information sources). Finally, in both situations, it is important to understand the context in which the crime/illness occurred. This analogy is particularly apt for child/adolescent psychiatry. The cases of children referred for psychiatric evaluation are becoming more complex not only because the intertwining of family, psychosocial, and individual pathology is becoming more complex, but also because the health care system is increasingly deﬁning child psychiatrists as the professionals who are referred the most diagnostically complicated, treatment refractory children. In addition, while 70

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the rest of medicine relies increasingly on procedures, tests, and the like to deﬁne diagnosis, psychiatry must still live by its wits. Success is determined by one’s ability to obtain the trust of the informants in order to obtain reliable information, to be a good observer, to have knowledge of psychopathology, knowledge of the diagnostic tools available, an ability to integrate a complicated body of information, and plain, old fashioned thought. One can develop screening tools, symptom lists, decision trees, algorithms, and manuals, but the point at which those are all that is needed to make a diagnosis is the point at which the discipline of psychiatry and child psychiatry deﬁnes its extinction. The framework of diagnosis in itself is not universally agreed upon. It implies that a deviation from normal (however that is deﬁned) has occurred which is of sufﬁcient magnitude to produce functional impairment. It implies a recognizable pattern of deviation. It is hoped that, by recognizing the pattern, the clinician will be able to advise the patient about what is accounting for the complaints for which help is sought, how the problems should best be treated, what is likely to occur if the problems are not treated, and what the likely outcome will be when treatment is applied. There are two basic schemata by which diagnosis is conceptualized: dimensional and categorical. Dimensions describe symptom clusters and behavior. Pathology is operationally deﬁned by a set of rating scales which address the dimension at issue. There is the assumption of normal distribution of the dimension within the population and, at a certain point, ‘‘pathology’’ is said to occur. IQ is the most obvious example. At a certain point (2 standard deviations below or above the ‘‘norm’’), mental retardation (at the low end) and giftedness (at the high end) are said to occur. In psychiatry, many dimensions are measured with rating scales e.g., anxiety, depression, hyperactivity, impulsivity, inattention, aggressiveness, extroversion, introversion, and emotional lability. Rating scales have the advantage of being easy to complete, of providing a level of severity, and, in general, of quantifying the level of impairment. Since, at our level of ignorance, we are frequently treating symptoms, not entire illnesses, there is a deﬁnite place for well-normed, systematic rating scales in a psychiatric evaluation. In most clinical situations, they are used as a reliable method of quantifying observations originally made during a series of interviews. Categoric diagnosis is how we conceptualize illness. A disorder is assumed to be a single entity with a characteristic group of signs and symptoms, an onset (history), course, and conclusion. It presumably has a cause and, until an etiology or conﬁrmatory test is found, it presumably can be distinguished from another disorder by its history, symptoms, course, and treatment response. One ﬁnal concept needs emphasis. Symptoms and disorders happen in

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individuals. The individual’s genetic make-up and life circumstances color which symptoms predominate, or the manner in which they manifest. They may also signiﬁcantly impact on the course of illness and treatment response. They certainly inﬂuence attitude toward illness, doctor, and treatment. To reiterate then, giving medication is the easy part. The hard part is to determine what should be given, to whom, when, for what reasons, how, and for how long. Information gathering Evaluating disturbed children remains a relatively labor-intensive task. However, it can be made considerably more efﬁcient by obtaining as much information in advance, and as precisely as possible (Table 3.1). In the best of circumstances, that means obtaining biographic information, standardized rating scales from parents and teachers which evaluate symptoms and functioning, and having in advance any other assessments that have already been completed (e.g., IQ testing and written consultations from other mental health professionals). Sometimes, report cards dating back to kindergarten are important in ascertaining the child’s early behavior, educational attainments, or attendance. Such detailed assessments are more easily completed in an ofﬁce or clinic setting. However, even in an emergency room, it is possible to have parents and/or older child or teenager complete a comprehensive rating scale like the Child Symptom Inventory (Gadow and Sprafkin, 1995), the Child Behavior Checklist (Achenbach, 1991), or the Connors Parent Rating Scale (Conners, 1989). The formermost has the advantage of being DSM based and can be used as a semi-structured interview (Grayson and Carlson, 1991). The latter two have the advantage of having been normed on many children, giving informative cut-off scores for severity of multiple dimensions. The point is that, even before the clinician says hello to the family, the ‘‘wheels’’ should be turning regarding what information to elicit and what should be observed. In our clinic, we also ask children over the age of 10 (provided they have a fourth grade reading level) to complete rating scales addressing their overall behavior, and areas of depression and anxiety. If the history suggests other problems, speciﬁc rating scales are given. Kutcher’s text, Child and Adolescent Psychopharmacology (Kutcher, 1997) has a wonderful appendix with many forms or examples of forms used for this purpose. If we are conducting the evaluation on one day, children are asked to complete a variety of evaluation tools while we concurrently obtain collateral information from parents. If two separate appointments are used, parents are asked to have the child complete the

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Table 3.1. Systematic evaluation of children and adolescents Step 1:

Step 2:

Step 3:

Step 4a:

Step 4b:

Step 5:

Step 6:

Step 7:

Parents and teacher complete the Stony Brook Child Symptom Inventory (CSI; Gadow and Sprafkin, 1995), and a standardized behavior rating scale such as the Achenbach CBCL (Achenbach, 1991) and teacher report form (TRF) (Edelbrock and Achenbach, 1987) or Conners Parent/Teacher Rating Scales (Conners, 1989). Clinician reviews checklists and scales prior to meeting with patient/family assessing: (a) Diagnostic domains endorsed on the CSI; (b) Whether total symptom scores and relevant factor scores on the standardized rating scales are signiﬁcant; and (c) Areas of agreement and disagreement between informants. Parents and child/adolescent are interviewed initially together to ascertain reasons for evaluation, set gound rules for the assessment, and provide an understanding of the presenting problem. Level of child cooperation and cognitive ability brieﬂy assessed. If youth is competent and agreeable, he/she completes self-rating scales covering depression, anxiety, and the Adolescent Symptom Inventory (Gadow and Sprafkin, 1995) while parents are separately interviewed. A Sentence Completion Test is useful to judge the young person’s written language, handwriting, and spontaneous thoughts. Parents are interviewed either clinically, using the CSI to pursue signiﬁcant areas further, or with a semistructured interview (such as the K-SADS) with time organized to concentrate on areas of clinical signiﬁcance. After parents are interviewed, the child/adolescent is interviewed. Rating scales are visually inspected for signiﬁcant responses (which are discussed) and scored. Mental status exam is completed including neurodevelopmental screen as relevant. If there are discrepancies between parent and child, they are resolved at the subsequent informing session during which diagnosis and treatment recommendations are made and agreed upon. Rating scales are then used as baselines for subsequent treatment monitoring.

evaluation instruments at home. In the case of children between the ages of 6–10 where attention-deﬁcit/hyperactivity/disorder (ADHD) is one of the differential diagnoses, we conduct a Restricted Academic Playroom observation where the child’s off-task behavior, time out of seat, and ability to inhibit certain responses are observed (Roberts, 1990). We also observe for tics. If there are concerns about development and/or academic performance, a speciﬁc developmental examination assessing motor, language, memory, and visual– spatial difﬁculties is done (Levine, 1998).

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The decision about whether to complete the evaluation all at once, or seeing parents one day and child the next, should be based on what kind of information one is looking for, not how the insurance company or other third-party payer reimburses. If in advance of face to face assessment one has obtained demographic information and some idea of the symptoms/behaviors causing problems, one can organize this rationally. For instance, if one has a single parent with a hyperactive 5 year old, it might be better to schedule two separate visits because there will be no supervision for the child while the parent is being interviewed. However, if there is a question of a diagnosis where ‘‘relatedness’’ is of primary concern, it will be important to have a period of time where the parent(s) and child are seen together. Similarly, if parents are dealing with a teenager who will be upset at having parents talk to the doctor while he/she waits in the waiting room completing forms, it makes more sense to interview parents on a different day. History taking, in some jurisdictions, seems, unfortunately, to have become the province of social workers, and the child/adolescent psychiatrist is given the task of ‘‘doing the mental status.’’ This is an old division of labor, reinforced in the United States by managed care companies because social work time is considered ‘‘cheaper.’’ It has been exacerbated by research protocols where there is the need to have the child interviewer ‘‘blind’’ to parent information for a variety of experimental or statistical reasons. However, in a clinical setting, ‘‘blindness’’ is not a virtue – it is a handicap. Simultaneous interviewing is also conducted for logistic reasons. If both parties are seen simultaneously by two people, the family can leave more quickly and child supervision is not a problem. However, in such a scenario, professional time needs to be spent integrating the two sets of data, and, if information obtained has varied as to the informant, statisticians and myriads of other well-meaning professionals can engage in obsessive wrangling about who to believe. Using the same person to conduct both segments, or to gather enough history to put the mental status in a diagnostic framework, allows the person who evaluates the child to have a clear history in mind at the time he/she is seeing/interviewing the child. If there are discrepancies in information, these can be immediately resolved with the pertinent issues clariﬁed. The problem of conﬁdentiality is confronted at the outset by meeting everyone together and saying to the child, ‘‘I am going to be spending the next hour getting information about you from your parents. Then I am going to talk to you about what has been going on in your life.’’ Ground rules regarding conﬁdentiality should be deﬁned at the outset of the assessment. If an issue arises in either interview that potentially raises concern about conﬁdentiality

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(e.g., one parent is having an affair; a relative committed suicide; divorce is being contemplated; the child is using drugs or alcohol, is sexually active, is engaged in antisocial behavior, has made suicide attempts, or is thinking about suicide), the advisability for continued secrecy can be discussed with the person being interviewed. Ironically, the one party who thinks the information is a secret is often unaware that the other person knows about it already or is highly suspicious. In the United States, the imposition of managed care into child/adolescent evaluations and treatment is considered by many to be having a detrimental effect on the diagnostic process. If one clinician is paid to spend only 30 minutes with a child to obtain information, that is likely to be the time spent. However, those directives must change and those who need to change it are the clinicians on whom treatment responsibility falls in the end. Even with a complete database (and it has taken a good deal of time on the part of the clerical staff to make sure this is the case – and that time is not free), it is not possible to do a thorough, comprehensive psychiatric evaluation of a child, arrive at a diagnosis, consider a treatment plan, and provide feedback to parents, in less than 60 minutes, even in simple cases. This is partly because the purpose of assessment is not only to discover if pertinent diagnoses are present – it is also necessary to ensure that others are absent. For instance, even though ADHD in many cases is a relatively easy disorder to diagnose, ascertaining the presence of mild pervasive developmental disorders, anxiety disorders, and depression is not quickly conducted. Similarly, children with co-occurring learning and language disorders, especially those that have not been diagnosed by others prior to the psychiatric evaluation, need more time in order for a clinician to conduct those assessments properly or to ensure that they are done. Distinguishing a language disorder from a thought disorder is germane to the diagnosis of psychosis; knowing whether a child has a receptive language disorder is germane to how easily he/she will understand what you tell him/her; whether the child has an expressive language disorder is germane to how much you can trust the ‘‘output’’ the child gives you. These issues are not quickly evaluated and most often require the careful elicitation of information from a variety of sources including the child, parent, or signiﬁcant third party. Rating scales and structured interviews can be used during this process, but cannot be relied on in the absence of a clinical assessment. Where psychiatric evaluations of children are limited by structured interviews rather than enhanced by them is one of the great travesties of psychiatric diagnosis. Complicated cases take longer than simple ones, just as heart transplants take longer than uncomplicated appendectomies. This process is summarized in Table 3.1.

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Additionally, diagnosis may become relatively clear within the ﬁrst portion of the assessment. However, getting the parent/child to have enough conﬁdence in your conclusion so that they will, ﬁnally, follow through with treatment takes much longer even when the diagnosis is straightforward. This is especially true when psychopharmacologic treatment is recommended. Although some parents are comfortable with the ‘‘medical model’’, and are hoping for a ‘‘magic bullet’’ that will provide symptom removal, many are not. Parents often appear to be much more likely to take the recommendations of someone they hear on talk shows pushing unproved treatment on their child than they are to follow recommendations of qualiﬁed doctors to treat their hyperactive, impulsive, and inattentive child with a proven and well-tolerated medication such as methylphenidate. Structured and unstructured interviews

The diagnostician’s job is ﬁrst to connect the symptoms/problems with which the patient presents with the possible disorders that might be responsible for the symptoms/problems. The next step is to narrow the possibilities down to the ‘‘correct’’ one(s). Sometimes, the connection is easy to make. A parent will say his/her child is sleeping all the time and seems depressed, or the child will not sit still and is constantly in trouble for not ﬁnishing school work. Connecting these symptoms with a differential diagnosis that includes depression or ADHD is relatively straightforward. However, sometimes the symptoms are less easy to connect with a diagnosis. For instance, ‘‘my son spends all his time on the internet with white supremacist chat groups’’, or ‘‘my daughter has always made up tall stories. I got a call from the teacher saying she was sorry I had broken my leg. I didn’t know what she was talking about. I was ﬁne.’’ A single, speciﬁc diagnosis does not leap to mind from these identiﬁed concerns. On the other hand, a symptom or behavior can be cited as problematic and can connect with many different diagnoses. For instance, ‘‘my son/daughter cannot tolerate change of any sort’’ (e.g., obsessive–compulsive disorder; pervasive developmental disorder; some cases of ADHD; intermittent explosive disorder), or ‘‘my son/daughter has always been aggressive but, since s/he has become a teenager, it is much worse’’ (e.g., oppositional deﬁant disorder; mania; depression; ADHD). One of the reasons it is necessary to have a good understanding of psychopathology is to know what questions to ask next. However, for people with less knowledge, one of the innovations that have developed from research studies has been the availability of structured interviews. Although people trained at university centers engaged in research often

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know what ‘‘structured interviews’’ are, many people in clinical practice are aware only of acronyms like ‘‘Kiddie-SADS’’ (Schedule for Affective Disorders and Schizophrenia–Childhood Version; Orvaschel et al., 1982; Kaufman et al., 1994), ‘‘DICA’’ (Diagnostic Interview for Children and Adolescents; Reich et al., 1991), and ‘‘DISC’’ (Diagnostic Interview Schedule for Children; National Institute of Mental Health, 1992). However, structured interviews are merely the setting forth of the diagnostic criteria developed by the American Psychiatric Institute’s Diagnostic committees (DSM III–IV; American Psychiatric Association 1980, 1987, 1994) in a systematic manner and a language that is supposed to be understood by lay people. By consistently going through every question, it is often possible to stumble on the diagnosis/diagnoses by sheer thoroughness. If the interviewer follows the rules, he/she is ‘‘forced’’ to ask all the questions, not merely the ones thought to be relevant. For the child or adolescent, if one has had the foresight to obtain completed rating scales before the interview, the answers themselves should be read and discussed. Questions about suicidal behavior should be asked even if the question seems like it is from ‘‘left ﬁeld.’’ Similarly, homicidal ideation should be asked about. If the diagnosis is clear or it is considered by the clinician that medication will be of use in treatment, it is useful to get the parent’s and child’s perspective on its use early on in the course of the assessment. Children often reﬂect their parents’ biases. In teenagers, their viewpoint is often colored by the perspective of their peers. A hopeful comment is ‘‘my best friend takes ‘Zoloft’.’’ On the other hand, one cringes at ‘‘all the dorks go down to the nurse to get their ﬁx.’’ Unfortunately, the latter is a frequent quote from youths about their peers taking stimulants.

(1) (2) (3)

(4)

(5)

The parental interview The parental interview should cover the following: Chief complaint/presenting problem/reason for referral. When did the problem start, what has perpetuated it, and what has made it better? What was your child like as a baby/toddler/preschooler-school aged child, followed by a brief review of questions addressing cognitive development, anxious behaviors, sociability with adults and peers, activity level and impulse control, and physical/medical history. Psychiatric review of symptoms either from a structured interview or the Child Symptom Inventory starting with the diagnoses that one thinks are most probable based on the information to that point. What treatments have been tried? In addition to asking what medications have

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been used in the past, obtain information about doses, duration of treatment, response to treatment of various behaviors in question, and side effects. It is not just a question of cure vs. no cure, but what the degree of response was of a particular symptom or symptom cluster. Interview with the child By the time the child is interviewed (Table 3.2), the clinician should have some hypotheses about what disorders might be accounting for the problem. During the interview, where the child is being asked about him/herself, fun things, friends, school, parents, what he/she thinks the problems are, and psychiatric symptom review/structured interview questions, the clinician is also observing the following to address the disorders under consideration: Appearance Separation from parents Relationship with familiar/unfamiliar people Activity level/impulse control Cognitive ability (including approach to tasks like copying, writing, reading) Language Thought process Thought content Mood/affect Neurologic status (handedness, ﬁne and gross motor control, speciﬁc tasks if there is some sign or history of difﬁculty). In my experience as a specialty board examiner and a supervisor, the biggest gap in the young clinician’s diagnostic ability is the understanding of what one is supposed to be doing with the child/adolescent during the mental status examination. The mental status examination is often recited from memory with no idea of why one should or should not do ‘‘serial 7s’’ or a ‘‘draw-aperson.’’ Most surprising is the active avoidance of the obvious such as following up on leads provided by the patient or increasing the scope of the examination when a particular problem area has been identiﬁed. Table 3.1 outlines the evaluation process and Table 3.2 summarizes signiﬁcant areas of the mental status that should be assessed for the major diagnostic categories. Baseline assessment for psychopharmacologic treatment

Over and above the information needed for diagnostic purposes, it is necessary to delineate which symptoms/behaviors are causing difﬁculty, which will then be the target of treatment. The more these behaviors can be operationalized in

Overly familiar with examiner

Relationship with examiner/parents Activity level

Possibly sullen and uncooperative

May have difﬁculty

Unremarkable

Unremarkable

Poverty of speech; poverty of content of speech; blocking; latency of response; ‘‘pseudo-intellectual’’ Words often slower than mind is thinking; Unremarkable Evasive; vague; irrelevant; illogical; verbally impulsive circumstantial; tangential; neologisms Nonspeciﬁc Often complains; power struggles Hallucinations; delusions; paranoid ideation Silly; inappropriate; unchanging facial Appropriate; often quite cheerful and Depends on how cooperative; may be playful euthymic; may be irritable, manipulative, expression; poor eye contact; fails to smile evasive or laugh when prompted; lack of vocal inﬂection (ﬂat affect); suspicious; can appear ‘‘depressed’’ Recognition of inattention, hyperactivity, Distinguish impulsive/affective aggression Psychotic symptoms; depression; anxiety; physical symptoms easy boredom; anxiety, depression; from predatory aggression; distinguish from mania/depression/anxiety/PDD psychosis; grandiosity ‘‘Soft neurologic signs’’ Not relevant to primary diagnosis ‘‘Soft neurologic signs’’

Depends on if there is a comorbid learning disability; distractible (visual/auditory) Often problems with written language; in speaking, blurts out answers; interrupts

Disheveled; unkempt; bizarre; confused–perplexed May or may not have trouble depending on how withdrawn and disinterested May vary from disinterested to inappropriate; guarded; evasive May be overactive or underactive; inactivity is both lack of energy and lack of interest May be inattentive; vague

Schizophrenia

* Any of these disorders can co-occur with a learning disability which needs separate evaluation. ODD = oppositional deﬁant disorder; OLD = obsessive–compulsive disorder; PDD = pervasive developmental disorder. The above observations are not always present but should be looked for systematically.

Neuro status*

Symptom review

Mood/affect

Thought content

Thought process

Language*

Cognitive ability/attention*

Disinhibited; goes with strangers

Separation

Unremarkable

ODD/OCD

Physical restlessness; ﬁdgety – out of seat; Unremarkable touches everything

Unremarkable to disorganized

Appearance

ADHD

Table 3.2. Mental status chart—a

Uncaring/oblivious; if PDD NOS, may be catastrophically anxious No eye contact; oblivious to examiner; withdraws from interaction attempt Very over- or underactive; whirls, ﬂaps, hits self, rocks, toe-walks; aimless/disorganized Depends on how retarded; social/language much lower than motor abilities

Separation

Cognitive ability/attention

Relationship with examiner/ parents Activity

Depends on level of mental retardation if present

Appearance

PDD

Table 3.2. Mental status chart – b

Distractible; may seem smarter than is

Increased; may be purposeful but may not be; impulsive

Disinhibited; overly familiar; silly

Possibly disheveled; sometimes dressed outlandishly or sexually provocatively Age appropriate

Mania

May seem dull, distracted, indecisive

Not relevant to primary diagnosis

Won’t be able to separate; may have to do it gradually Very shy, slow to warm up; unassertive with examiner; clingy with parents Unremarkable to tense, ﬁdgety

Age appropriate unless also has separation anxiety Lack of spontaneity; reponds but does not initiate Fewer spontaneous movements; long latencies; sluggish

Hypervigilant; tense

No smile; little facial expression; looks dejected

Depression

Anxiety disorders, separation anxiety disorder, social phobia etc.

Symptom review Neuro status

Mood/affect

Thought content

Thought process

Speech/ language

Cries, laughs, smiles without external stimuli; unpredicable outbursts; no facial expression Not applicable with child Neurodevelopmental signs; clumsy; odd sensory responses – sniffs, rubs, stares, covers ears, studies small details

May be absent; echolalic; poor voice modulation; pronoun reversal; odd words/jargon; sticks to certain topics; poor pragmatic language Concrete; in PDD NOS may be pedantic; poverty of content Doesn’t use toys appropriately; agitated by change

Rule out substance intoxication Not relevant to primary diagnosis

Irritable; labile; silly; giddy; clowning, playful; elated

Flight of ideas; disjointed thoughts; distracted responses Grandiose; paranoid; silly; check psychotic

Rapid/pressured speech which can appear disjointed; overproductive

Check for somatic symptoms and panic Not relevant to primary diagnosis

Grumpy/irritable; sad, blah, bored

Check for somatic symptoms Not relevant to primary diagnosis

Unremarkable

May be pressured; nervous laugh

Reﬂective of worry + fears; somatic complaints; check fears, phobias, panic; compulsions/ obsessions Hyperaroused; overcompliant

Self depreciatory; morbid; check psychotic symptoms; check suicidal/ homicidal

Limited; possibly slowed

Slowed speech; underproductive; response latency; quiet voice; mumbling

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Table 3.3. Behavioral variables sometimes amenable to pharmacotherapy Mental retardation self-abusive behavior – rarely aggression/hyperactivity – sometimes Autism/PDD self-abusive behavior – rarely aggression/hyperactivity – sometimes ‘‘withdrawn’’ behavior – sometimes Attention deﬁcit/hyperactivity disorder inattention/distractibility – often hyperactivity/impulsivity – often aggression – sometimes Conduct disorder aggression (impulsive) – sometimes Anxiety disorders separation anxiety – sometimes panic attacks – often obsessions / rarely compulsions / sometimes Depressive disorders depressed mood – sometimes irritability – sometimes vegetative symptoms – often psychomotor retardation – often Psychosis/ schizophrenia ‘‘positive symptoms’’ – often ‘‘negative symptoms’’ – sometimes Mania hyperactivity – often volatility/irritability – sometimes psychosis – often

terms of intensity, frequency, and duration, the easier it will be to measure the impact of medication treatment. Table 3.3 lists behaviors that are frequently the object of treatment and this author’s experience with their responsiveness to psychopharmacologic treatment. In addition to rating the potential targets of treatment, it is also wise to obtain a baseline measure of potential side effects (which often merge with

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disorder anyway). If you do not know a child’s bedtime, or how picky their eating is, or how often they get headaches, or whether they occasionally are still enuretic, it will be easy to attribute symptoms in these areas to medication side effects. Psychoeducational aspects There are two groups of children a psychopharmacologist is likely to see – those in need of medication but who have not yet begun treatment, and those referred already on a regimen that is not working adequately. Those who have not yet begun treatment need to understand the disorder being treated (i.e., its signs and symptoms), treatments available for the disorder, what happens if it is not treated, and why the clinician is suggesting the course of treatment he/she is suggesting. This needs to be put into plain English. If an informed consent is necessary, parent and older child need to be able to say back in their own words what their understanding is of the problem and its treatment. Harold Koplewicz, MD, has helped to simplify this task for many disorders with his book Its Nobody’s Fault (Koplewicz, 1996). He not only provides information about the medications likely to be used, he also describes in a language that ordinary people will understand how the various disorders present. For parents who consider medication treatment as the court of last resort, it may be sensible to recommend a trial of psychologic treatment with a time period built in such that a continuation of problems after x number of weeks warrants a reconsideration of medication. I like to recommend no more than 8–12 weeks. Often, psychotherapists themselves will request adjunctive medication to enhance the psychotherapeutic process. Fortunately, most people have progressed past the ‘‘either/or’’ philosophy of medication and psychologic treatment. When a child is referred having been partially treated, it is necessary to ﬁnd out what kinds of treatments have been tried. Frequently, parents will say ‘‘we’ve tried everything.’’ It turns out that two stimulants have been used, at too low a dose and for too short a time. It is therefore necessary to have a careful accounting of what has been tried, and what results have accrued. This must also include the adverse effects experienced, the attitude of the child/ parent to the treatment, and the degree of adherence to previous treatments. One can then plan with the family whether it is appropriate to stop all medication and determine whether the medications used have simply not helped or if they have, in fact, worsened various problems. A ﬂow sheet like that in Table 3.4 can be of use.

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Table 3.4. Medication ﬂow chart

Medication + dose

Response (CGI score)

Methylphenidate/Ritalin

−3−2−1 0+1+2+3

dextroamphetamine/Dexedrine

−3−2−1 0+1+2+3

Other stimulants

−3−2−1 0+1+2+3

imipramine/Tofranil

−3−2−1 0+1+2+3

Other TCAs

−3 – 2−1 0+1+2+3

clonidine/Catapres

−3−2−1 0+1+2+3

guanfacine/Tenex

−3−2−1 0+1+2+3

Lithium

−3−2−1 0+1+2+3

valproate/Depakote

−3−2−1 0+1+2+3

carbamazepine/Tegretol

−3−2−1 0+1+2+3

clorpromazine/Thorazine

−3−2−1 0+1+2+3

thioridazine/Mellaril

−3 – 2−1 0+1+2+3

haloperidol/Haldol

−3−2−1 0+1+2+3

Other neuroleptics

−3−2−1 0+1+2+3

respiradone/Risperidal

−3−2−1 0+1+2+3

olanzepine/Zyprexa

−3−2−1 0+1+2+3

clozapine/Clozaril

−3−2−1 0+1+2+3

Other atypical neuroleptics

−3−2−1 0+1+2+3

ﬂuoxetine/Prozac

−3 – 2−1 0+1+2+3

paroxetine/Paxil

−3−2−1 0+1+2+3

sertraline/Zoloft

−3−2−1 0+1+2+3

clomipramine/Anafranil

−3−2−1 0+1+2+3

Other antidepressants

−3−2−1 0+1+2+3

Combinations

−3−2−1 0+1+2+3 −3−2−1 0+1+2+3 −3 – 2−1 0+1+2+3 −3−2−1 0+1+2+3

Side effects/reason for discontinuation

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Deciding which medication to use As can be seen in Table 3.5, there are several considerations to deciding what medication(s) should be tried and in what order. Targets of treatment and measures needed to quantify change have already been discussed. It is important to target psychosocial functioning separately from change in psychopathology. Although the two are related, it has become clear that symptoms remit long before change takes place in psychosocial functioning. In cases where the child had previously been a good student, or had decent peer relationships, remission of symptoms might enable a return to the previous level of functioning. If those areas had always been problematic, remission of symptoms enables focus to be put into these deﬁcits, but one should not assume that they will automatically improve. They may require additional, speciﬁc psychosocial interventions. Other parts of the decision tree regarding medication selection include the amount of information available on the safety and efﬁcacy of any speciﬁc medication in young people. Until recently, such data were rare. In fact, systematic data are still rare in children under the age of 12 for anything but stimulants and a few antipsychotic medications. Fortunately, in the United States, the Food and Drug Administration has mandated that this situation be rectiﬁed. A good psychopharmacologist will update his/her knowledge base periodically as information becomes available. This information is important to share with parents. A chart like that in Table 3.4 for major psychiatric disorders is one approach to organizing the information. The age of the child in question may impact on medication response. There is some evidence to suggest that preschool children, while responding to stimulant treatment, have higher rates of side effects than older children (Musten et al., 1997; Greenhill, 1998). This is also true for lithium in young children (Hagino et al., 1995). Children with early-onset schizophrenia respond less well to typical antipsychotic medication (Kumra et al., 1996). Whether these observations are the result of an earlier onset of disorder and, by implication, more severe disorder or whether there is something about the developing brain that leads to different medication responses is unknown (Vitiello, 1998). Clinically, however, it is wise to prepare oneself and the family for the fact that young children may be more complicated to treat with medication. Other issues that complicate treatment include the presence of multiple disorders, which is the rule rather than the exception for children requiring medication treatment. Some comorbidities respond to the same approach.

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Table 3.5. What to consider in initiating pharmacologic treatment for major depressive disorder Givens: 1. Accurate diagnosis 2. Adequate psychoeducation/patient preparation How to decide what medication to use: 1. What is the target of treatment? (e.g., major depressive episode) depressed mood – sometimes responds irritability – sometimes responds sleep/appetite symptoms – often respond low energy – often responds 2. How do you measure it? Children’s Depression Rating Scale (Poznanski et al., 1984): Hamilton is used but does not rate teen-appropriate behaviors Self-rating scales: (a) Childrens Depression Inventory (Kovacs, 1992); (b) Beck Depression Inventory (Beck, 1967); Depression Self Rating Scale (Birleson, 1981); (c) Visual analog scale for target symptoms; (d) Clinical Global Improvement Scale. Measure psychosocial function separately 3. What is known of therapeutic efﬁcacy? Drug

Trial status

ﬂuoxetine paroxetine sertraline ﬂuvoxamine bupropion nefazadone

double-blind study – published double-blind study ﬁnished, abstract published 75% effective in many open studies; double-blind study; complete? double-blind study in OCD; not depression studied only in ADHD small, open study double-blind study planned small open trial – no better than placebo no information of any sort double-blind study planned

venlafaxine mirtazepine

4. What medications are best tolerated? 5. What has been tried already? 6. Concurrent other issues: Young child vs. older child vs. adolescent Comorbidity – medical and psychiatric Baseline labs should include: CBC; liver function tests; pregnancy test for sexually active females; EKG; thyroid-stimulating hormone

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Table 3.5. (cont.) Environmental variables: A. Is the family receptive or hostile? If hostile, why? B. Does the family somaticize or deny? C. Is the drug being thought of as a ‘‘magic bullet’’ or facilitator? D. Will the drug be used at school? Home? Both? E. What is the effect of structure vs. no structure? F. Is there someone competent to administer and follow the medication? 7. Cost and availability.

Anxiety and depression, for instance, may respond to serotonin-speciﬁc reuptake inhibitors. Combined depression and ADHD may respond to a medication with dopamine and noradrenergic effects. An aggressive, manic young person may respond to medications which treat both aggression and mania. However, a child with tics and attention deﬁcit, or with hyperactivity and anxiety, or with depression and psychosis may need more than one medication. Children with medical conditions which impair liver metabolism or renal clearance will need closer monitoring and possibly different medications than healthy children. Another common-sense consideration to decide which medication to select has to do with where and when medication will be used. Having someone competent to administer and follow the medication becomes more important as the type of medication becomes more complicated. One of the most useless contributions to child treatment is an inpatient admission where the discharge plan describes a regimen of administering four medications at ﬁve precise time points during the day, and returning a child to a single mother with two jobs, several children, and a 3-month follow-up at the local mental health clinic – this is a house of cards that will collapse on discharge. How long to treat

A ﬁnal consideration in any kind of treatment is how long to continue it. Unfortunately, there are no child-speciﬁc studies to guide the clinician. Since the most serious psychiatric disorders in children are fairly chronic, it is safe to assume that medication treatment should not cease with the onset of response. Families are often concerned about the ‘‘will s/he need medicine for the rest of his/her life’’ question. That question should be anticipated in discussing the diagnosis and natural history of the disorder. Beyond that, it makes more sense to worry about how long treatment needs to be once remission of symptoms is achieved. The more protracted this period is, the more reluctant one should be to discontinue treatment prematurely. Treatment should be at least as long as

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the condition has existed and as long as symptoms continue. When the period of stability has allowed not only for symptomatic relief but also persistent psychosocial gains, it may be worth beginning to discuss medication discontinuation. Even then, discontinuation should be done with gradual cessation of medication, with parent and child knowledgeable about withdrawal symptoms and return of target symptoms, and with adequate supports in place. In other words, do not discontinue medication right before a child goes to overnight camp in the summer. In some disorders, such as schizophrenia, medication discontinuation may not be indicated. Summary Psychopharmacologic treatment of children has come a long way in the past 10 years. It still has a long way to go, however. The nagging concern we all have about the long-term effects of medication on the developing brain cannot be dismissed. What puts the concern in perspective is that the conditions we are treating are not trivial. With the rare exception of a parent with Munchausen By Proxy, almost no parent brings a child to a child/adolescent psychiatrist for no reason. The disorders are generally signiﬁcantly impairing and, at least in this day and age, have often been addressed by another professional ﬁrst with less ‘‘invasive’’ treatments. Additionally, the potential neuroprotective effects of medication on the developing brain should not be discounted. By making a careful diagnosis, it is possible to circumvent useless medication trials as well as giving the family conﬁdence that the clinician is not merely ‘‘pill pushing.’’ By informing the family about the therapeutic efﬁcacy and liabilities of medication, one can have a collaborative relationship rather than an adversarial one. Understanding the natural history of the disorders in question will inform the clinician about how long to continue treatment. Finally, it is important to remind oneself that illnesses, be they ‘‘medical’’ or ‘‘mental’’, are at the minimum inconvenient and, at the maximum, frightening and disabling. The medications we use, singly or in combination, have some empirical data to back them up, but not as much as we would like. A rule of thumb worth considering is – if I had a child or sibling with this disorder, would I allow him to be treated with this regimen? It has been my experience that families respond more to the honest answer to that question than to all of the data we can quote.

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REFE R EN C ES Achenbach TM (1991). Manual for the Child Behavior Checklist. Burlington: University of Vermont. Achenbach TM, Edelbrock C (1987). Manual for the Youth Self-Report and Proﬁle. Burlington: University of Vermont. American Psychiatric Association. (1980). Diagnostic and Statistical Manual of Mental Disorders, 3rd edn. Washington, DC: American Psychiatric Association. American Psychiatric Association. (1987). Diagnostic and Statistical Manual of Mental Disorders, 3rd edn (revised). Washington, DC: American Psychiatric Association. American Psychiatric Association. (1994). Diagnostic and Statistical Manual of Mental Disorders, 4th edn. Washington, DC: American Psychiatric Association. Beck AT (1967). Measurement of Depression: The Depression Inventory. Philadelphia, PA: University of Pennsylvania Press, Chapter 12. Birleson P (1981). The validity of depressive disorder in childhood and the development of a self-rating scale: a research report. J Child Psychol Psychiatry 22:73–86. Conners CK (1989). The Conners Rating Scales: Instruments for the Assessment of Child Psychopathology. Toronto, Ont: Multi-Health Systems. Edelbrock C, Achenbach TM (1987). Manual for the Teacher. Burlington: University of Vermont. Gadow KD, Sprafkin K (1995). Adolescent Supplement to the Child Symptom Inventor(ies) Manual, 3rd edn. New York: Dx Checkmate. Grayson P, Carlson GA (1991). The utility of a DSMIIIR-based checklist in screening child psychiatric patients. J Am Acad Child Adolesc Psychiatry 30:669–73. Greenhill LI (1998). The use of psychotropic medication in preschoolers: indications, safety, and efﬁcacy. Can J Psychiatry 43:576–81. Hagino OR, Weller EB, Weller RRA, Washing D, Fristad MA, Kontras SB (1995). Untoward effects of lithium treatment in children aged four through six years. J Am Acad Child Adolesc Psychiatry 34:1584–90. Kaufman J, Birmaher B, Brent D, Rau U, Ryan N (1994). Schedule for Affective Disorders – Schizophrenia for School-aged Children (6–18 years) Kiddie SADS – Lifetime Version (K-SADS-PL). Pittsburgh, PA: Western Psychiatric Institute of Psychiatry, Division of Child and Adolescent Psychiatry. Koplewicz HS (1996). It’s Nobody’s Fault: New Hope and Help for Difﬁcult Children and Their Parents. Toronto, Ont: Times Books/Random House. Kovacs M (1992). Children’s Depression Inventory – Manual. Toronto, Ont: Multi-Health Systems. Kumra S, Frazier JA, Jacobsen LK et al. (1996). Childhood onset schizophrenia: a double-blind comparison. Arch Gen Psychiatry 53:1090–7. Kutcher SP (1997). Child and Adolescent Psychopharmacology. Philadelphia, PA: WB Saunders. Levine MD (1998). Developmental Variation and Learning Disorders. Cambridge, Mass and Toronto: Educators Publishing Service. Musten LM, Firestone P, Pisterman S, Bennett S, Mercer J (1997). Effects of methylphenidate on preschool children with ADHD; cognitive and behavioral functions. J Am Acad Child Adolesc

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Psychiatry 36:1407–15. National Institute of Mental Health (1992). Diagnostic Interview Schedule for Children (NIMH DISC-C, P), Version 2.3. Orvaschel H, Puig-Antich J, Chambers W et al. (1982). Retrospective assessment of prepubertal major depression with Kiddie-SADS-E. J Am Acad Child Adolesc Psychiatry 21:392–7. Poznanski EO, Grossman JA, Buchsbaum Y, Banegus M, Freeman L, Gibbons R (1984). Preliminary studies of the reliability and validity of the children’s depression rating scale. J Am Acad Child Psychiatry 23:191–7. Reich W, Shayka JJ, Taibleson C (1991). Diagnostic Interview for Children and Adolescents (Parent and Child) DSMIIIR-version. St. Louis: Washington University Division of Child Psychiatry. Roberts MA (1990). A behavioral observation method for differentiating hyperactive and aggressive boys. J Abnorm Child Psychol 18:131–42. Vitiello B (1998). Pediatric psychopharmacology and the interaction between drugs and the developing brain. Can J Psychiatry 43:582–4.

4 Depression Neal D. Ryan Western Psychiatric Institute, Pittsburgh, Pennsylvania, USA

Child and adolescent depression: overview

Does child and adolescent depression exist?

Perhaps surprisingly, this was a contentious question as recently as 15 years ago. One inﬂuential line of thought argued that children did not have the cognitive development necessary to become depressed and, while they might have transient dysphoria, did not have long-duration, adult-like depressions. In fact, today’s best available estimates suggest that perhaps 2% of prepubertal children and 4% of adolescents may suffer depression at any one time (Fleming and Offord, 1990). Before puberty, there appears to be an approximately equal sex ratio, with an adult-type pattern of more depression in girls than boys beginning in adolescence. What is the naturalistic course? Is the course severe enough that treatment is warranted?

Obviously, if the naturalistic course is brief enough or mild enough, treatment with its costs and potential side effects may be unwarranted. The data suggest that child and adolescent depression is a persistent and recurring disorder. The natural course of clinic-referred depression appears to last 6–9 months on average with a signiﬁcant minority lasting years (Kovacs et al., 1984a,b; Ryan et al., 1987). Most children and adolescents who suffer a single episode get future recurrent episodes and grow up to be adults with depression (Harrington et al., 1990, 1993; Kovacs et al., 1984 a,b; Weissman et al., 1999). Estimates from various studies suggest that about 20–40% of children and adolescents who have a ﬁrst episode of major depression will turn out to be bipolar (Birmaher et al., 1996b). The phenomenon of ‘‘kindling’’ has been hypothesized to occur in adult unipolar depression – each episode of depression is thought to lower the threshold for future episodes so that prior depressions make future depressions more likely in the same individual. There are not yet strong data as to whether or not this occurs with child or adolescent depression, but it is, at least, a 91

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potential hazard. In adults, there appears to be more depression now than in prior decades (a secular increase) (Hagnell et al., 1982; Klerman et al., 1985) and the author and others have shown that there also appears to be more child and adolescent depression now than in the past (Kovacs and Gatsonis, 1994; Lewinsohn et al., 1993; Ryan et al., 1992). There is a high rate of attempted and completed suicide with child and adolescent depression, seen especially as these subjects are followed over time (Harrington et al., 1994; Rao et al., 1993; Ryan et al., 1987). During and after the acute episode, children and adolescents suffer impairment in their psychosocial functioning seen in school and with friends and family (Puig-Antich et al., 1985a,b). Even after recovery of the clinical episode, depressed youths have more other adverse health consequences and higher rates of smoking (Rohde et al., 1994). Who is at risk for child depression?

Child depression is strongly familial with depressed children having more depressed adult relatives and young depressed adults having more depression in their children than would be expected by chance (Puig-Antich et al., 1989; Weissman et al., 1984a,b; Williamson et al., 1995c). There are no available twin studies to help distinguish between family genetic transmission and family environmental transmission in children, but, in adults, depression appears to be both genetic (almost certainly involving several or many genes) and from nonshared environmental factors, with a relatively small contribution from shared family environment. Childhood adverse life events appear to play a role in the onset of depression both in childhood and subsequently (Kessler and Magee, 1993; Williamson et al., 1995a,b, 1996). In summary, depressive disorders in childhood and adolescence are protracted, recurrent illnesses which persist into adulthood. They are associated with suffering, functional impairment, and suicide both during the episode and afterwards. Current episodes may increase the hazard for future episodes. This is a morbid disorder strongly deserving of our best efforts at treatment. Child and adolescent depression: diagnosis

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To understand how to diagnose depression in children and adolescents we will address two questions: How does the clinical picture of depression change between childhood and adulthood? How does one adapt interviewing techniques for children?

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Depression

Surprisingly enough, the answer to the ﬁrst question appears to be that there is a relatively constant picture of the clinical syndrome of depression through development and into adulthood. In one large study by Ryan and colleagues (Ryan et al., 1987), a large sample of children and adolescents presenting to a research clinic were evaluated with the Schedule for Affective Disorders and Schizophrenia for School-Aged Children (K-SADS) semistructured diagnostic interview. The frequencies of both the symptoms required for diagnosis and other depressive symptoms were examined to see how they varied with age and maturation. Of over 30 depression-related symptoms examined, two-thirds did not show age-related differences in their severity or frequency and only a third showed some differences. For example, there was no maturational effect on depressed mood, guilt, negative self-image, fatigue, concentration problems, anger, irritability, insomnia, or suicidal ideation. Prepubertal children showed a greater frequency of anxiety, somatic complaints, phobias, and depressed appearance, while adolescents showed more hopelessness and helplessness, anhedonia, hypersomnia, and lethality of suicide attempt. While there were differences between the age groups in the frequency of these particular symptoms, the differences overall were not very large. The frequency of all these symptoms also was similar to that reported in adult studies (Carlson and Kashani, 1988). At ﬁrst, one might think that this is simply tautological – these symptoms were used to diagnose the children as depressed, so, of course, they had the same frequency of these symptoms. However, this is not the case because the associated depressive symptoms which were not used in the diagnosis also showed stability with age and, obviously, some of the symptoms used to make the diagnosis could still vary with age and yet the diagnosis still be met. In the same group of almost 200 children and adolescents, it appeared that the symptom factors (using principle component analysis) strongly paralleled those seen in adult depression with an overall endogenous factor, a factor for negative cognitions, and a factor for anxiety, among others. How then do we need to adapt our interview to elicit these symptoms? In the development of the K-SADS-P and its successor the K-SADS-PL, which is available at http://www.wpic.pitt.edu/ksads, the author and colleagues have suggested that the following are key to interviewing the child and adolescent who may have a depression successfully (Kaufman et al., 1997; Puig-Antich and Chambers, 1986): Obtain information from all sources of information particularly including the parent and child, but also including the school, prior medical and psychiatric charts, etc. Interview the parent without the child present and interview the parent before

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the child. The information that the parent conveys helps you to structure the interview with the child and helps you efﬁciently and completely to elicit symptoms from the child. If you interview the child ﬁrst, there are whole periods of time that you do not know to ask about while, if you have the information of the parent, you can successfully get the child to tell you about these impaired or symptomatic intervals. Interview the child, if at all possible, without the parent or parents present who tend to inhibit the child’s full and frank discussion of symptoms. Ask the parent and child together to help you clarify large discrepancies and use your best clinical judgment on those items where the parent and child reports differ. For example, while in general the parents are likely to be better reporters of behavior and the child perhaps a better reporter of internal affect states, this varies from family to family. Use child-speciﬁc terms and use multiple terms for the same phenomena or affect state in case the child has not generalized the meaning of one term. For example, one child, when asked if he was ‘‘depressed’’, said no but then I went on to ask if he was ‘‘sad’’ (again he answered no) and then ‘‘blue’’ to which he responded in the afﬁrmative. When asked to clarify, this 8-year-old boy said that he felt sad when his grandparent had died and now he felt a bad feeling, but it was a different one, so it was not ‘‘sad’’ but ‘‘blue.’’ It is frequently useful to develop a time-line using parent data and then to add data that the child provides. In general, start with an unstructured introductory interview during which you concentrate on what the child and family ﬁnds most problematic (the chief complaint). After the family and child understand that you are out to help them with what they identify as important, they will put up with the long stream of questions one needs to ask to elicit all the positive and negative symptoms. Especially with younger children, questions about time intervals have to be worded in a way that makes sense to the child. For example, intervals of weeks or months may be linked to external events in the year (e.g., the beginning of school, the child’s birthday, a particular holiday), while time intervals for an individual day may be linked to events within the day (e.g., ‘‘Does your depression last from breakfast time until lunch time?’’) rather than asking the child for the number of hours that she is blue every day. These are general guidelines which, overall, appear to be useful. However, the astute clinician will tailor the interview to the child and family, being sensitive to their language abilities, their cultural background, their degree of fatigue, especially as the evaluation goes on, etc. Overall reliability on the K-SADS and other instruments (Kaufman et al.,

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1997) suggests that using methods such as this, the diagnosis of depression in children and adolescents could be made as reliably as these diagnoses are made in adults. Hypothesized central nervous system mechanisms Multiple central nervous system (CNS) mechanisms have been associated with depression in adults including the serotonin and noradrenaline neurotransmitter systems, the HPA axis and other stress-related endocrine systems, intracellular messengers and neurotrophic factors, and speciﬁc neurocircuitry (e.g., prefrontal cortical circuits) (Drevets et al., 1997, 1998). Early studies focused on monoamines after noting that drugs such as reserpine, which depleted monoamines, induced depression in many individuals and noting that most of the antidepressants discovered by trial-and-error affected monoaminergic