Cariprazine for Bipolar I Depression: A Randomized Double-Blind Placebo-Controlled Trial

Depressive episodes in bipolar I disorder (BP-1) are associated with increased disability, morbidity, and suicide, and have fewer evidence-based treatment options compared to manic episodes. Cariprazine is an atypical antipsychotic approved for treatment of adults with schizophrenia and manic or mixed episodes associated with BP-1. In previous phase 2a/3 trials, cariprazine lowered depressive symptoms in patients with BP-1 in a depressive episode.This was a 6-week, randomized, double-blind, placebo-controlled, parallel-group phase 3 trial of cariprazine in adults with BP-I (DSM-5 criteria) and current depressive episode ≥4 weeks and ≤12 months (NCT02670538). Patients were randomized 1:1:1 to cariprazine 1.5 mg/day[d] (n=168), 3.0 mg/d (n=158), or placebo (n=167). Primary and secondary efficacy parameters were change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total and Clinical Global Impressions – Severity (CGI-S) scores, respectively. Least-squares mean difference (LSMD) was estimated using a mixed model for repeated measures. AEs, laboratory results, vital signs, and suicide risk were monitored.Cariprazine 1.5 mg/d improved depressive symptoms significantly compared to placebo, MADRS LSMD=-2.5 (P=.0417) and CGI-S LSMD=-0.3 (P=.0417). Cariprazine 3.0 mg/d numerically improved MADRS total scores and CGI-S scores versus placebo. Common treatment-emergent AEs (≥5% in either cariprazine group and twice that of placebo) were akathisia, restlessness, nausea, and fatigue. At week 6, mean metabolic changes were generally comparable among groups and mean weight increases were ≤0.5 kg for both cariprazine groups.Cariprazine 1.5 mg/d significantly reduced depressive symptoms in adults with BP-1, and cariprazine 1.5 and 3.0 mg/d were generally well tolerated.