Clinical significance of treatment effects with aripiprazole versus placebo in a study of manic or mixed episodes associated with pediatric bipolar i disorder

摘要

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.