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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

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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, 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.

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The authors thank Ms Lisa Wong, Dr Anthony Wai Yee Tam and Dr Shweta Anand for editing and proof-reading.

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Correspondence to Esther W. Chan.

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Conflicts of Interest

KSJL, YH, ICKW, FMCB and EWC declare no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous 3 years; and no other relationships or activities that could appear to have influenced the submitted study.

Author Contributions

KSJL, ICKW and EWC had the original idea for this study and contributed to the development of the idea and study design. KSJL and YH independently conducted a systematic review and reviewed the literature for relevance. KSJL and YH undertook the analysis. KSJL, YH, ICKW and EWC contributed to interpretation of the analysis. KSJL and YH wrote the first draft of the paper. KSJL, YH, ICKW and EWC critically reviewed the results and the manuscript. FMCB reviewed the data and presentation of the paper and provided clinical input. ICKW and EWC provided oversight to all aspects of this project. KSJL and EWC are the guarantors. All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

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K. S. J. Lao and Y. He contributed equally to this work.

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Lao, K.S.J., He, Y., Wong, I.C.K. et al. 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. CNS Drugs 30, 1043–1054 (2016).

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