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

Abstract

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 J Clin Psychiatry 2015;76(3):284-292

Cariprazine in Bipolar Disorders

“…A limitation of these comparisons across studies is of course that their populations may be quite diverse in terms of demographics and inclusion and exclusion criteria. In addition, the NNT of 5 for remission in this study 1 compares favorably to a pooled NNT of 8 for all atypical agents estimated by another meta-analysis conducted by Tamayo et al 9 Furthermore, Citrome 10 recently reported effect size metrics of different atypical antipsychotics compared to cariprazine with NNT values versus placebo for response and remission. The NNTs for response of 5 in this trial and 7 in a phase 2 study 3 are similar to those observed with other compounds including lithium (NNT = 4), divalproex extended release (NNT = 7), carbamazepine extended release (NNT = 4), olanzapine (NNT = 5), risperidone (NNT = 4), quetiapine extended release (NNT = 6), ziprasidone (NNT = 7), aripiprazole (NNT = 5), and asenapine (NNT = 8).…”

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.…”

Current drug treatments targeting dopamine D3 receptor

“…The recently published results of a randomized, double-blind, placebocontrolled study suggests that adjunctive cariprazine 2-4.5 mg/d is effective and generally well tolerated in adults with major depressive disorder who had inadequate responses to standard antidepressants (Durgam et al, 2016a). Positive results have been also obtained from phase II and III clinical trials for bipolar mania (Calabrese et al, 2015;Durgam et al, 2016b;Sachs A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT et al, 2015) leading to approval by the FDA of cariprazine also for the treatment of manic or mixed episodes associated with bipolar disorder (McCormack, 2015). Table S3 reports clinical trials currently running or recently completed regarding cariprazine in different CNS diseases.…”