title: Clinical significance of treatment effects with aripiprazole versus placebo in a study of manic or mixed episodes associated with pediatric bipolar I disorder.
abstract: OBJECTIVE
  Published studies in adult and pediatric bipolar disorder have used different definitions of treatment response. This analysis aimed to compare different definitions of response in a large sample of children and adolescents.
  
  
  METHODS
  Anexploratory analysis of a 4-week, multicenter, placebo-controlled study assessed patients (n=296; ages, 10-17 years) with an acute manic/mixed episode associated with BIPOLAR I disorder who were randomized to aripiprazole (10 or 30 mg/day) or placebo. The primary efficacy endpoint was mean change from baseline to week 4 in young mania rating scale (YMRS) total score. Additional assessments included: clinical global impressions-bipolar disorder (CGI-BP) Overall and mania scales, child global assessment scale (CGAS), and parent and subject general behavior inventory. Response was compared across seven operational definitions. Cohen's κ and Spearman's correlation tested relationships between various response definitions or changes in outcome measures and clinically meaningful improvement (defined as a CGI-BP overall improvement score of 1 or 2).
  
  
  RESULTS
  Response rates varied depending upon the operational definition, but were highest for 95% reliable change (statistical method used to determine individual change from previous assessment) and ≥33% reduction in YMRS total score. Response rate definitions with the highest validity in terms of predicting clinically meaningful improvement were: ≥50% reduction on YMRS (κ=0.64), a composite definition of response (YMRS <12.5, children's depression rating scale-revised (CDRS-R) ≤40, and CGAS ≥51; κ=0.59), and 95% reliable change on the CGAS or 33% reduction on YMRS (κ=0.56). Parent ratings of symptoms were generally better at detecting symptom improvement than were subject ratings (κ=∼0.4-0.5 vs. ∼0.2 when compared with CGI-BP overall improvement score).
  
  
  CONCLUSIONS
  Clinically meaningful definitions of response in acute treatment of a manic/mixed episode in pediatric subjects include a 50% change in YMRS and a composite measure of response. Parent-reported measures of symptom improvement appear reliable for assessing symptom change.
authors.affiliation: Department of Psychology, University of North Carolina, Chapel Hill, North Carolina 27599, USA. eay@unc.edu
authors.forename: Eric
authors.initials: E
authors.lastname: Youngstrom
authors.forename: Joan
authors.initials: J
authors.lastname: Zhao
authors.forename: Raymond
authors.initials: R
authors.lastname: Mankoski
authors.forename: Robert A
authors.initials: RA
authors.lastname: Forbes
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Marcus
authors.forename: William
authors.initials: W
authors.lastname: Carson
authors.forename: Robert
authors.initials: R
authors.lastname: McQuade
authors.forename: Robert L
authors.initials: RL
authors.lastname: Findling
mesh_terms: D000293:Adolescent; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D000068180:Aripiprazole; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000503:physiopathology; D002648:Child; D005260:Female; D006801:Humans; D008297:Male; D010290:Parents; D010879:Piperazines / Q000627:therapeutic use*; D011569:Psychiatric Status Rating Scales; D015363:Quinolones / Q000627:therapeutic use*; D015203:Reproducibility of Results; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric; D016896:Treatment Outcome
chemical_list: D014150:Antipsychotic Agents; D010879:Piperazines; D015363:Quinolones; D000068180:Aripiprazole