title: Efficacy and safety of low- and high-dose cariprazine in acute and mixed mania associated with bipolar I disorder: a double-blind, placebo-controlled study.
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.
  
  
  METHODS
  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.
  
  
  BACKGROUND
  ClinicalTrials.gov identifier: NCT01058668.
authors.affiliation: 10524 Euclid Ave, Room 12-135, Cleveland, OH 44106 joseph.calabrese@uhhospitals.org.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Calabrese
authors.forename: Paul E
authors.initials: PE
authors.lastname: Keck
authors.forename: Anju
authors.initials: A
authors.lastname: Starace
authors.forename: Kaifeng
authors.initials: K
authors.lastname: Lu
authors.forename: Adam
authors.initials: A
authors.lastname: Ruth
authors.forename: István
authors.initials: I
authors.lastname: Laszlovszky
authors.forename: György
authors.initials: G
authors.lastname: Németh
authors.forename: Suresh
authors.initials: S
authors.lastname: Durgam
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D017109:Akathisia, Drug-Induced / Q000209:etiology; D001714:Bipolar Disorder / Q000188:drug therapy*; D018491:Dopamine Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D010919:Placebos / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D012074:Remission Induction; D012720:Severity of Illness Index; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D018491:Dopamine Agonists; D010879:Piperazines; D010919:Placebos; C533287:cariprazine