title: The efficacy and tolerability of cariprazine in acute mania associated with bipolar I disorder: a phase II trial.
abstract: OBJECTIVE
  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%).
  
  
  CONCLUSIONS
  Cariprazine demonstrated superior efficacy versus placebo and was generally well tolerated in patients experiencing acute manic or mixed episodes associated with bipolar I disorder.
authors: Clinical Development, Forest Research Institute, Jersey City, NJ.
authors: Suresh
authors: S
authors: Durgam
authors: Anju
authors: A
authors: Starace
authors: Dayong
authors: D
authors: Li
authors: Raffaele
authors: R
authors: Migliore
authors: Adam
authors: A
authors: Ruth
authors: György
authors: G
authors: Németh
authors: István
authors: I
authors: Laszlovszky
mesh_terms: D000328:Adult; D017109:Akathisia, Drug-Induced / Q000175:diagnosis / Q000209:etiology; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects; D001480:Basal Ganglia Diseases / Q000139:chemically induced / Q000175:diagnosis; D001714:Bipolar Disorder / Q000175:diagnosis / Q000188:drug therapy / Q000523:psychology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects; D011569:Psychiatric Status Rating Scales; D016896:Treatment Outcome
chemical_list: D014150:Antipsychotic Agents; D010879:Piperazines; C533287:cariprazine
keywords: antipsychotic agents; bipolar disorder; cariprazine; dopamine D3 receptors; dopamine agents; schizophrenia