The results of this study support the efficacy and safety of cariprazine in patients with acute exacerbation of schizophrenia.

Objectives 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%). Conclusion Cariprazine demonstrated superior efficacy versus placebo and was generally well tolerated in patients experiencing acute manic or mixed episodes associated with bipolar I disorder.

ClinicalTrials.gov identifier: NCT01104766.

Objective. Cariprazine, a dopamine D 3 /D 2 partial agonist atypical antipsychotic with preferential binding to D 3 receptors, is approved for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder. The efficacy and safety of cariprazine was established in three randomized, double-blind, placebocontrolled, 6-week trials in patients with acute exacerbation of schizophrenia. This 53-week study evaluated the longterm safety and tolerability of cariprazine in patients with schizophrenia.Methods. This was a multicenter, open-label, flexible-dose study of cariprazine 3-9 mg/d in adults with schizophrenia. Participants included new patients and patients who had completed one of two phase III lead-in studies (NCT01104766, NCT01104779). Eligible patients entered a no-drug screening period of up to 1 week followed by 48 weeks of flexibly dosed, open-label cariprazine treatment (3-9 mg/d) and 4 weeks of safety follow-up.Results. A total of 586 patients received open-label cariprazine treatment, 39% of whom completed the study. No unexpected safety issues or deaths were reported. The most common (≥10%) adverse events (AEs) observed were akathisia (16%), headache (13%), insomnia (13%), and weight gain (10%). Serious AEs occurred in 59 (10.1%) patients, and 73 (12.5%) patients discontinued the study due to AEs during open-label treatment. Mean changes in metabolic, hepatic, and cardiovascular parameters were not considered clinically relevant. Mean body weight increased by 1.5 kg during the study, prolactin levels decreased slightly, and measures of efficacy remained stable.Conclusions. Long-term cariprazine treatment at doses up to 9 mg/d appeared to be generally safe and well tolerated in patients with schizophrenia. Clinical Implications' Cariprazine was generally safe and well tolerated in patients with schizophrenia when flexibly dosed at 3-9 mg/d for up to 48 weeks of treatment.' The most common treatment-emergent adverse events (TEAEs) were akathisia, headache, insomnia, and weight gain. Most were mild or moderate in intensity and rarely resulted in discontinuation.' Mean changes in metabolic, cardiovascular, and laboratory parameters were generally small and not clinically significant. Prolactin levels decreased over the course of 48 weeks of treatment.' There were no unexpected safety issues or deaths in patients exposed to long-term cariprazine treatment in this study.' This study provides further evidence supporting the safety and tolerability of cariprazine for the long-term treatment of schizophrenia.

RationaleCariprazine, a dopamine D3/D2 receptor partial agonist antipsychotic, demonstrated efficacy and tolerability in 6-week, randomized, placebo-controlled schizophrenia trials. Schizophrenia is a chronic disorder that requires continuous treatment; therefore, the long-term safety and tolerability profile of antipsychotic agents is an important factor in guiding clinician decisions.ObjectiveThis single-arm, open-label extension study evaluated the long-term safety and tolerability of cariprazine in patients with schizophrenia.MethodsPatients enrolled in this study completed a 6-week, randomized, placebo- and active-controlled study and had responded (Clinical Global Impressions-Severity [CGI-S] ≤3; ≥20 % reduction in Positive and Negative Syndrome Scale [PANSS] total score) to treatment at the end of the lead-in study. Patients (N = 93) received flexibly dosed, open-label cariprazine (1.5–4.5 mg/day) for up to 48 weeks.ResultsApproximately 50 % (46/93) of patients completed the 48 weeks of open-label treatment. The most common adverse events (AEs) were akathisia (14 %), insomnia (14 %), and weight increased (12 %). Serious AEs (SAEs) occurred in 13 % of patients; 11 % discontinued due to AEs. Mean changes in metabolic parameters were generally small and not clinically relevant. Mean body weight increased by 1.9 kg from the start of the lead-in study to the end of the extension study. There were no discontinuations associated with change in metabolic parameters or body weight. Long-term cariprazine treatment was not associated with prolactin elevation or clinically significant changes in cardiovascular parameters.ConclusionsIn this 48-week, single-arm trial, open-label cariprazine (1.5–4.5 mg/day) treatment was generally safe and well tolerated with no new safety concerns associated with long-term treatment.Electronic supplementary materialThe online version of this article (doi:10.1007/s00213-016-4450-3) contains supplementary material, which is available to authorized users.