title: Tolerability and Safety Profile of Cariprazine in Treating Psychotic Disorders, Bipolar Disorder and Major Depressive Disorder: A Systematic Review with Meta-Analysis of Randomized Controlled Trials.
abstract: Cariprazine is a novel antipsychotic agent recently approved for treating schizophrenia and bipolar mania in the USA. The sample sizes of published randomized controlled trials (RCTs) of the drug are small; previous meta-analyses included few RCTs and did not specifically investigate the tolerability/safety profile of cariprazine.
  
  
  
  Our objective was to conduct a meta-analysis of published RCTs to systematically review the tolerability and safety of cariprazine versus placebo.
  
  
  
  We searched the clinical trial registers (the metaRegister of controlled trials, ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform) and electronic databases (PubMed, Embase, PsycINFO and Cochrane library) up to June 2016 to identify phase II/III RCTs of cariprazine in patients with schizophrenia, bipolar disorder or major depressive disorder. We conducted a meta-analysis to investigate outcomes, including risks of discontinuation due to adverse events (AEs), extrapyramidal side effects (EPS) or related events, metabolic syndrome and cardiovascular-related events.
  
  
  
  We included nine RCTs, with a total of 4324 subjects. The risk of discontinuation due to AEs for cariprazine was similar to that for placebo (risk ratio [RR] 1.13, 95 % confidence interval [CI] 0.77-1.66). Cariprazine was associated with higher risks of EPS-related events than was placebo, including risk of akathisia (RR 3.92, 95 % CI 2.83-5.43), tremor (RR 2.41, 95 % CI 1.53-3.79) and restlessness (RR 2.17, 95 % CI 1.38-3.40). The cariprazine treatment group was more likely to have clinically significant weight gain (RR 1.68, 95 % CI 1.12-2.52). No statistically significant differences in results were found in other metabolic parameters or cardiovascular-related events.
  
  
  
  There was a statistically significant higher risk of EPS-related AEs and a slight increase in mean body weight with cariprazine. There were no statistically significant effects on prolactin level or cardiovascular parameters. EPSs were the main short-term adverse reactions reported in the limited number of patients studied. Further clinical and post-marketing pharmacovigilance studies are needed to investigate the long-term safety of cariprazine.
authors.affiliation: Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, Centre for Safe Medication Practice and Research, The University of Hong Kong, 2/F Laboratory Block FMB, 21 Sassoon Road, Hong Kong SAR, China.
authors.forename: Kim S J
authors.initials: KS
authors.lastname: Lao
authors.affiliation: Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, Centre for Safe Medication Practice and Research, The University of Hong Kong, 2/F Laboratory Block FMB, 21 Sassoon Road, Hong Kong SAR, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, Centre for Safe Medication Practice and Research, The University of Hong Kong, 2/F Laboratory Block FMB, 21 Sassoon Road, Hong Kong SAR, China.|Research Department of Practice and Policy, UCL, School of Pharmacy, London, UK.
authors.forename: Ian C K
authors.initials: IC
authors.lastname: Wong
authors.affiliation: Research Department of Practice and Policy, UCL, School of Pharmacy, London, UK.|East London NHS Foundation Trust, Bedfordshire, London, UK.|Institute of Psychiatry, Psychology and Neuroscience, London, UK.
authors.forename: Frank M C
authors.initials: FM
authors.lastname: Besag
authors.affiliation: Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, Centre for Safe Medication Practice and Research, The University of Hong Kong, 2/F Laboratory Block FMB, 21 Sassoon Road, Hong Kong SAR, China. ewchan@hku.hk.
authors.forename: Esther W
authors.initials: EW
authors.lastname: Chan
mesh_terms: D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000627:therapeutic use*; D001714:Bipolar Disorder / Q000188:drug therapy*; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D003865:Major Depressive Disorder / Q000188:drug therapy*; D006801:Humans; D010879:Piperazines / Q000009:adverse effects* / Q000627:therapeutic use*; D011618:Psychotic Disorders / Q000188:drug therapy*; D012559:Schizophrenia
chemical_list: D014150:Antipsychotic Agents; D010879:Piperazines; C533287:cariprazine