Methodological Issues and Controversies in Clinical Trials with Child and Adolescent Patients with Bipolar Disorder : Report of a Consensus

OBJECTIVE To achieve consensus among researchers, pharmaceutical industry representatives, federal regulatory agency staff, and family advocates on a template for clinical trials of acute mania/bipolar disorder in children and adolescents. METHOD The American Academy of Child and Adolescent Psychiatry, in collaboration with Best Practice, convened a group of experts from the key stakeholder communities (including adult psychiatrists with expertise in bipolar disorder) and assigned them to workgroups to examine core methodological issues surrounding the design of clinical trials and, ultimately, to generate a consensus statement encompassing: (1) inclusion/exclusion criteria, (2) investigator training needs and site selection, (3) assessment and outcome measures, (4) protocol design and ethical issues unique to trials involving children/adolescents, and (5) regulatory agency perspectives on these deliberations. RESULTS Conference participants reached agreement on 18 broad methodological questions. Key points of consensus were to assign priority to placebo-controlled studies of acute manic episodes in children and adolescents aged 10-17 years, who may or may not be hospitalized, and who may or may not suffer from common comorbid psychiatric disorders; to require that specialist diagnostic "gatekeepers" screen youths' eligibility to participate in trials; to monitor interviewer and rater competency over the course of the trial using agreed upon standards; and to develop new tools for assessment, including scales to measure aggression/rage and cognitive function, while using the best available instruments (e.g., Young Mania Rating Scale) in the interim. CONCLUSIONS Methodologically rigorous, large-scale clinical trials of treatment of acute mania are urgently needed to provide information regarding the safety and efficacy, in youth, of diverse agents with potential mood-stabilizing properties.

[1]  S. Kay,et al.  The positive and negative syndrome scale (PANSS) for schizophrenia. , 1987, Schizophrenia bulletin.

[2]  M Davies,et al.  The NIMH Diagnostic Interview Schedule for Children Version 2.3 (DISC-2.3): description, acceptability, prevalence rates, and performance in the MECA Study. Methods for the Epidemiology of Child and Adolescent Mental Disorders Study. , 1996, Journal of the American Academy of Child and Adolescent Psychiatry.

[3]  Wolters Kluwer.  Effect Size of Lithium , Divalproex Sodium , and Carbamazepine in Children and Adolescents With Bipolar Disorder , 2022 .

[4]  P. Bech,et al.  The Bech‐Rafaelsen Mania Scale and the Hamilton Depression Scale , 1979, Acta psychiatrica Scandinavica.

[5]  D. Korn,et al.  The changing landscape for clinical research. , 1999, Academic medicine : journal of the Association of American Medical Colleges.

[6]  R. Perry,et al.  Behavioral efficacy of haloperidol and lithium carbonate. A comparison in hospitalized aggressive children with conduct disorder. , 1984, Archives of general psychiatry.

[7]  T. Laughren.  The scientific and ethical basis for placebo-controlled trials in depression and schizophrenia: an FDA perspective , 2001, European Psychiatry.

[8]  Juvenile mania versus ADHD. , 1999, Journal of the American Academy of Child and Adolescent Psychiatry.

[9]  I. Blackburn,et al.  A new scale for measuring mania , 1977, Psychological Medicine.

[10]  M. Hamilton.  A RATING SCALE FOR DEPRESSION , 1960, Journal of neurology, neurosurgery, and psychiatry.

[11]  W. Reich,et al.  Development of a Structured Psychiatric Interview for Children: Agreement Between Child and Parent on Individual Symptoms , 1982, Journal of abnormal child psychology.

[12]  B. Carroll,et al.  Use of the Children's Depression Rating Scale in an inpatient psychiatric population. , 1983, The Journal of clinical psychiatry.

[13]  N. Ryan,et al.  Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL): initial reliability and validity data. , 1997, Journal of the American Academy of Child and Adolescent Psychiatry.

[14]  C. McDougle,et al.  Risperidone in children with autism and serious behavioral problems. , 2002, The New England journal of medicine.

[15]  D. Kupfer,et al.  National Depressive and Manic-Depressive Association consensus statement on the use of placebo in clinical trials of mood disorders. , 2002, Archives of general psychiatry.

[16]  J. Calabrese,et al.  Efficacy of divalproex vs lithium and placebo in the treatment of mania. The Depakote Mania Study Group. , 1994, JAMA.

[17]  D. Murphy,et al.  Assessing clinical characteristics of the manic state. , 1971, The American journal of psychiatry.

[18]  G. Carlson,et al.  Mania and ADHD: comorbidity or confusion. , 1998, Journal of affective disorders.

[19]  H. Akiskal,et al.  Predictors of treatment nonresponse in bipolar children and adolescents with manic or mixed episodes. , 2004, Journal of child and adolescent psychopharmacology.

[20]  D. Klein,et al.  Resolved: mania is mistaken for ADHD in prepubertal children. , 1998, Journal of the American Academy of Child and Adolescent Psychiatry.

[21]  M. Fristad,et al.  Defining and identifying early onset bipolar spectrum disorder , 2004, Current psychiatry reports.

[22]  R. C. Young,et al.  A Rating Scale for Mania: Reliability, Validity and Sensitivity , 1978, British Journal of Psychiatry.

[23]  J. Endicott,et al.  A diagnostic interview: the schedule for affective disorders and schizophrenia. , 1978, Archives of general psychiatry.

[24]  M. Åsberg,et al.  A New Depression Scale Designed to be Sensitive to Change , 1979, British Journal of Psychiatry.

[25]  M. Davies,et al.  The assessment of affective disorders in children and adolescents by semistructured interview. Test-retest reliability of the schedule for affective disorders and schizophrenia for school-age children, present episode version. , 1985, Archives of general psychiatry.

[26]  J. Wernicke,et al.  Atomoxetine in the treatment of children and adolescents with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled, dose-response study. , 2001, Pediatrics.

[27]  M. Åsberg,et al.  A COMPREHENSIVE PSYCHOPATHOLOGICAL RATING SCALE , 1978, Acta psychiatrica Scandinavica. Supplementum.

[28]  David Korn,et al.  The changing landscape for clinical research [published erratum appears in Acad Med 1999 Sep;74(9):950] , 1999 .

[29]  B. Herjanic,et al.  Differentiating psychiatrically disturbed children on the basis of a structured interview , 1977, Journal of abnormal child psychology.

[30]  A. Rush,et al.  A double-blind, randomized, placebo-controlled trial of fluoxetine in children and adolescents with depression. , 1997, Archives of general psychiatry.

[31]  C. Bradshaw,et al.  The Manchester Nurse Rating Scales for the daily simultaneous assessment of depressive and manic ward behaviours. , 1988, Journal of affective disorders.

[32]  G. Emslie,et al.  A revised anchored version of the BPRS-C for childhood psychiatric disorders. , 2001, Journal of child and adolescent psychopharmacology.

[33]  D. Hedeker,et al.  The clinician-administered rating scale for mania (CARS-M): Development, reliability, and validity , 1994, Biological Psychiatry.

[34]  G. Carlson,et al.  Bipolar disorder in youth: An update , 2003 .

[35]  W. Marchand,et al.  Quetiapine adjunctive and monotherapy for pediatric bipolar disorder: a retrospective chart review. , 2004, Journal of child and adolescent psychopharmacology.

[36]  L. Freeman,et al.  Children's Depression Rating Scale - Revised (September 1984) , 1985 .

[37]  Philip D. Harvey,et al.  Development of neuropharmacologically based behavioral assessments of impulsive aggressive behavior. , 1991, The Journal of neuropsychiatry and clinical neurosciences.