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.

Trial registration: ClinicalTrials.gov NCT00110461.

FIG. 1.

Jacobsen and Truax definitions of response (Jacobson and Truax 1991). A (Jacobson and Truax definition A): reliable change plus moving more than two standard deviations (SDs) Away from the impaired range of functioning; B (Jacobson and Truax definition B): reliable change plus moving Back within two SDs of the impaired, that is, in the normal functioning mean; C (Jacobson and Truax definition C): reliable change plus moving Closer to the normal functioning than to the impaired range of functioning.

FIG. 2.

YMRS response rates using different definitions of response and composite response (COMP*). *A composite of scores achieved on the YMRS (<12.5), CDRS-R (≤40), and CGAS (≥51) (Findling et al. 2003). COMP, composite response; CDRS-R, Children's Depression Rating Scale-Revised; CGAS, Children's Global Assessment Scale; JTA, Jacobson and Truax efinition A; JTB, Jacobson and Truax definition B; JTC, Jacobson and Truax definition C; RC, reliable change; YMRS, Young Mania Rating Scale.

FIG. 3.

Spearman correlation coefficients (absolute values) for changes in outcome measures compared with changes in CGI-BP Overall Improvement score (aripiprazole [10 and 30 mg/day] and placebo combined). CDRS-R, Children's Depression Rating Scale-Revised; CGAS, Children's Global Assessment Scale; CGI-BPD, Clinical Global Impressions–Bipolar Disorder Depression severity score; CGI-BPM, Clinical Global Impressions–Bipolar Disorder Mania severity score; P-GBI-M10/S-GBI-M10, parent/subject 10-item version of General Behavior Inventory Mania; P-GBI-D10/S-GBI-D10, parent/subject 10-item version of General Behavior Inventory Depression, YMRS, Young Mania Rating Scale.