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 j 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 (j = 0.64), a composite definition of response (YMRS < 12.5, Children's Depression Rating ScaleRevised (CDRS-R) £ 40, and CGAS ‡ 51; j = 0.59), and 95% reliable change on the CGAS or 33% reduction on YMRS (j = 0.56). Parent ratings of symptoms were generally better at detecting symptom improvement than were subject ratings (j = *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.

The International Society for Bipolar Disorders Task Force report on pediatric bipolar disorder: Knowledge to date and directions for future research

“…102,112 Some checklists have also shown sensitivity to treatment effects in masked randomized controlled trials (RCTs), with effect sizes equal to those based on direct interview of the youth and primary caregiver. 113,114 Checklists can improve diagnostic decision making in a range of clinical settings, as well as measuring treatment response. 90,100–102 …”

Voluntary wheel running ameliorates symptoms of MK-801-induced schizophrenia in mice

“…Numerous different neuroleptic drugs have been developed and proven to be partially effective in alleviating the behavioral symptoms of schizophrenia. Abilify (aripiprazole) is used to treat certain mental and mood disorders, including bipolar disorder and schizophrenia (13). This antipsychotic medication acts to improve mood swings, promote self-assurance, reduce anxiety and encourage participation in activities of everyday life (14).…”

Structural invariance of General Behavior Inventory (GBI) scores in Black and White young adults.

“…In particular, the GBI has been shown to have strong sensitivity and specificity (Miller et al, 2009) as well as convergent validity with many other measures (e.g., structured interviews, fMRI findings; e.g., Bebko et al, 2014). The GBI is best used as a diagnostic aid to identify individuals who may benefit from more in-depth structured interviews in both clinical and research settings, although it also has shown significant prognostic value predicting future conversion to bipolar disorder (e.g., Alloy et al, 2012) and also has shown good sensitivity to treatment effects (Findling et al, 2003; Youngstrom, Zhao et al 2013). The GBI has been studied extensively in both clinical- and community-based samples, and the majority of research on the GBI has focused on young adult populations (e.g., Depue, Krauss, Spoont, & Arbisi, 1989; Klein, Dickstein, Taylor, & Harding, 1989).…”