The efficacy and tolerability of cariprazine in acute mania associated with bipolar I disorder: a phase II trial

Abstract

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.

Efficacy and Safety of Adjunctive Cariprazine in Inadequate Responders to Antidepressants

“…The types and frequency of TEAEs in this study were generally similar to cariprazine monotherapy in bipolar mania. 38,39 As seen with adjunctive antipsychotics in other MDD studies, TEAEs of potential concern (eg, akathisia, metabolic changes, weight gain) were found in the present study, with cariprazine results being generally comparable to published findings with other antipsychotics. For example, the reported incidence of akathisia with cariprazine 2-4.5 mg/d (22%) was similar to that reported for adjunctive aripiprazole treatment (25%).…”

Efficacy and Safety of Low- and High-Dose Cariprazine in Acute and Mixed Mania Associated With Bipolar I Disorder

“…8 The current phase 3 trial evaluated the efficacy, safety, and tolerability of low-and high-dose cariprazine in patients with acute manic or mixed episodes associated with bipolar I disorder.…”

Global improvement with cariprazine in the treatment of bipolar I disorder and schizophrenia: A pooled post hoc analysis

“…RGH‐MD‐31 (NCT00488618)7 and RGH‐MD‐32 (NCT01058096)8 were flexible‐dose studies with cariprazine 3‐12 mg/d; RGH‐MD‐33 (NCT01058668)6 was a fixed/flexible‐dose study with 2 cariprazine treatment arms (3‐6 mg/d or 6‐12 mg/d).…”

“…Detailed methods of the included studies have been previously published 6, 7, 8, 9, 10, 11. Briefly, each study had a washout period of up to 1 week, followed by 3 weeks (bipolar mania studies) or 6 weeks (schizophrenia studies) of double‐blind treatment and a 2‐week safety follow‐up period.…”

“…Cariprazine has demonstrated efficacy in three 3‐week randomised, double‐blind, placebo‐controlled studies in bipolar mania6, 7, 8 and three 6‐week randomised, double‐blind, placebo‐ and active‐controlled studies in schizophrenia 9, 10, 11. In each of these studies, a significant difference vs placebo was seen in change from baseline on the primary efficacy measure (YMRS total score in the bipolar mania studies and PANSS total score in the schizophrenia studies); the CGI‐S was the secondary efficacy measure in each study.…”