OBJECTIVES: Cariprazine, an orally active and potent dopamine D3 and D2 receptor 
partial agonist with preferential binding to D3 receptors, is being developed 
for the treatment of schizophrenia and bipolar mania. This Phase II trial 
evaluated the efficacy, safety, and tolerability of cariprazine versus placebo 
in the treatment of acute manic or mixed episodes associated with bipolar I 
disorder.
METHODS: This was a multinational, randomized, double-blind, placebo-controlled, 
flexible-dose study of cariprazine 3-12 mg/day in patients with acute manic or 
mixed episodes associated with bipolar I disorder. Following washout, patients 
received three weeks of double-blind treatment. The primary and secondary 
efficacy parameters were change from baseline to Week 3 in Young Mania Rating 
Scale (YMRS) and Clinical Global Impressions-Severity (CGI-S) scores, 
respectively. Post-hoc analysis evaluated changes on YMRS single items.
RESULTS: In each group, 118 patients received double-blind treatment; 61.9% of 
placebo and 63.6% of cariprazine patients completed the study. The overall mean 
daily dose of cariprazine was 8.8 mg/day. At Week 3, cariprazine significantly 
reduced YMRS and CGI-S scores versus placebo, with least square mean differences 
of -6.1 (p < 0.001) and -0.6 (p < 0.001), respectively. On each YMRS item, 
change from baseline to Week 3 was significantly greater for cariprazine versus 
placebo (all, p < 0.05). A significantly greater percentage of cariprazine 
patients than placebo patients met YMRS response (48% versus 25%; p < 0.001) and 
remission (42% versus 23%; p = 0.002) criteria at Week 3. Adverse events (AEs) 
led to discontinuation of 12 (10%) placebo and 17 (14%) cariprazine patients. 
The most common AEs (> 10% for cariprazine) were extrapyramidal disorder, 
headache, akathisia, constipation, nausea, and dyspepsia. Changes in metabolic 
parameters were similar between groups, with the exception of fasting glucose; 
increases in glucose were significantly greater for cariprazine versus placebo 
(p < 0.05). Based on Barnes Akathisia Rating Scale and Simpson-Angus Scale 
scores, more cariprazine than placebo patients experienced treatment-emergent 
akathisia (cariprazine: 22%; placebo: 6%) or extrapyramidal symptoms 
(parkinsonism) (cariprazine: 16%; placebo: 1%).
CONCLUSION: Cariprazine demonstrated superior efficacy versus placebo and was 
generally well tolerated in patients experiencing acute manic or mixed episodes 
associated with bipolar I disorder.