Efficacy and safety of cariprazine in bipolar I depression: A double-blind, placebo-controlled phase 3 study.

OBJECTIVE: To assess the efficacy, safety, and tolerability of cariprazine in the treatment of the depressed phase of bipolar I disorder in adults (NCT02670538). METHODS: In this phase 3 double-blind placebo-controlled study, adult patients with bipolar I disorder according to the Diagnostic and Statistical Manual - 5th Edition criteria and a current depressive episode were randomized to placebo (n = 167), cariprazine 1.5 mg/day (n = 168) or cariprazine 3.0 mg/day (n = 158). Efficacy parameters were changes in the Montgomery-Åsberg Depression Rating Scale (MADRS) total scores (primary) and Clinical Global Impressions - Severity (CGI-S) scores (secondary) from baseline to Week 6 compared to placebo. A mixed-model for repeated measures was used to estimate the least-squares mean differences (LSMD); P-values were adjusted for multiplicity. Adverse events (AEs), laboratory results, vital signs, and suicide risk were monitored. RESULTS: Cariprazine 1.5 mg/day significantly reduced depressive symptoms on the primary (MADRS LSMD = -2.5; adjusted P = .0417) and secondary (CGI-S LSMD = -0.3; adjusted P = .0417) efficacy parameters vs placebo; differences were not statistically significant for cariprazine 3.0 mg/day. Common treatment-emergent AEs (≥5% in either cariprazine group and at least twice the incidence of placebo) were akathisia, restlessness, nausea, and fatigue. Mean metabolic parameter changes were low and generally comparable among groups; mean weight increases were ≤0.5 kg for all groups. CONCLUSIONS: Cariprazine 1.5 mg/day significantly reduced depressive symptoms in adults with bipolar I depression compared to placebo, but differences were not significant for cariprazine 3.0 mg/day. The safety and tolerability profiles were similar to previous studies of cariprazine.

Long-term safety and tolerability of cariprazine as adjunctive therapy in major depressive disorder.

Lack of treatment response is a critical problem in major depressive disorder (MDD). Cariprazine is a D3-preferring dopamine D3/D2 receptor partial agonist and 5-HT1A partial agonist. This phase 3, multicenter, open-label, long-term (26-week), flexible-dose (1.5-4.5 mg/day) study assessed the long-term safety and tolerability of cariprazine used adjunctively with antidepressant therapy in adult patients with MDD who had either completed a lead-in study (n=311) or had been newly recruited (n=131). A higher percentage of continuing patients (66.2%) than new patients (35.9%) completed the study. The most common reason for discontinuation was adverse events (AEs; 13.9%); 79% of patients experienced a treatment-emergent AE [most common: akathisia (15.9%,) headache (11.6%)]. Serious AEs occurred in 2% of patients; two deaths occurred (one traffic accident, one completed suicide, both considered unrelated to treatment). The mean changes in clinical laboratory, cardiovascular, and ophthalmologic parameters were generally not clinically relevant. The mean (SD) changes from the open-label baseline in Montgomery-Åsberg Depression Rating Scale total score and Clinical Global Impression-Severity score at week 26 were -7.3 (9.5) and -1.0 (1.2), respectively. By week 26, 53.3% of patients were in remission (Montgomery-Åsberg Depression Rating Scale total score≤10). The results suggest that cariprazine was generally safe and well tolerated as adjunctive therapy to treat MDD.