Efficacy and safety of low- and high-dose cariprazine in acute and mixed mania associated with bipolar I disorder: a double-blind, placebo-controlled study.

OBJECTIVE: This phase 3 trial evaluated the efficacy, safety, and tolerability of low- and high-dose cariprazine in patients meeting DSM-IV-TR criteria for acute manic or mixed episodes associated with bipolar I disorder.

METHOD: This multicenter, randomized, double-blind, placebo-controlled, parallel-group, fixed/flexible-dose study was conducted from February 2010 to December 2011. Patients were randomly assigned to placebo, cariprazine 3-6 mg/d, or cariprazine 6-12 mg/d for 3 weeks of double-blind treatment. Primary and secondary efficacy parameters were change from baseline to week 3 in Young Mania Rating Scale (YMRS) total score and Clinical Global Impressions-Severity of Illness (CGI-S) score, respectively. Post hoc analysis examined change from baseline to week 3 in YMRS single items.

RESULTS: A total of 497 patients were randomized; 74% completed the study. The least squares mean difference (LSMD) for change from baseline to week 3 in YMRS total score was statistically significant in favor of both cariprazine groups versus placebo (LSMD [95% CI]: 3-6 mg/d, -6.1 [-8.4 to -3.8]; 6-12 mg/d, -5.9 [-8.2, -3.6]; P < .001 [both]). Both cariprazine treatment groups showed statistically significant superiority to placebo on all 11 YMRS single items (all comparisons, P < .05). Change from baseline in CGI-S scores was statistically significantly greater in both cariprazine groups compared with placebo (LSMD [95% CI]: 3-6 mg/d, -0.6 [-0.9 to -0.4]; 6-12 mg/d, -0.6 [-0.9 to -0.3]; P < .001 [both]). The most common (≥ 5% and twice the rate of placebo) treatment-related adverse events for cariprazine were akathisia (both groups) and nausea, constipation, and tremor (6-12 mg/d only).

CONCLUSIONS: Results of this study demonstrated that both low- and high-dose cariprazine were more effective than placebo in the treatment of acute manic or mixed episodes associated with bipolar I disorder. Cariprazine was generally well tolerated, although the incidence of akathisia was greater with cariprazine than with placebo.

TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01058668.