Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial.

BACKGROUND: Although predominant negative symptoms of schizophrenia can be severe enough to cause persistent impairment, effective treatment options are lacking. We aimed to assess the new generation antipsychotic cariprazine in adult patients with predominant negative symptoms. METHODS: In this randomised, double-blind, phase 3b trial, we enrolled adults aged 18-65 years with long-term (>2 year), stable schizophrenia and predominant negative symptoms (>6 months) at 66 study centres (mainly hospitals and university clinics, with a small number of private practices) in 11 European countries. Patients were randomly assigned (1:1) by an interactive web response system to 26 weeks of monotherapy with fixed-dose oral cariprazine (3 mg, 4·5 mg [target dose], or 6 mg per day) or risperidone (3 mg, 4 mg [target dose], or 6 mg per day); previous medication was discontinued over 2 weeks. The primary outcome was change from baseline to week 26 or end of treatment on the Positive and Negative Syndrome Scale factor score for negative symptoms (PANSS-FSNS) analysed in a modified intention-to-treat population of patients who had follow-up assessments within 5 days after last receipt of study drugs with a mixed-effects model for repeated measures. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with EudraCT, number 2012-005485-36. FINDINGS: Between May 27, 2013, and Nov 17, 2014, 533 patients were screened and 461 (86%) patients were randomised to treatment (230 for cariprazine and 231 for risperidone); 460 were included in the safety population (one patient discontinued before study drug intake). 227 (99%) of 230 patients in the cariprazine group and 229 (99%) of 230 patients in the risperidone group were included in the modified intention-to-treat population (178 [77%] in each group completed 26 weeks of treatment). Mean daily doses were 4·2 mg (SD 0·6) for cariprazine and 3·8 mg (0·4) for risperidone. Treatment-emergent adverse events (eg, insomnia, akathisia, worsening of schizophrenia, headache, anxiety) were reported in 123 (54%) patients treated with cariprazine and 131 (57%) patients treated with risperidone. Use of cariprazine led to a greater least squares mean change in PANSS-FSNS from baseline to week 26 than did risperidone (-8·90 points for cariprazine vs -7·44 points for risperidone; least squares mean difference -1·46, 95% CI -2·39 to -0·53; p=0·0022; effect size 0·31). One patient in the risperidone group died of a cause regarded as unrelated to treatment. INTERPRETATION: Our results support the efficacy of cariprazine in the treatment of predominant negative symptoms of schizophrenia. FUNDING: Gedeon Richter Plc.

Tolerability of cariprazine in the treatment of acute bipolar I mania: A pooled post hoc analysis of 3 phase II/III studies.

BACKGROUND: Atypical antipsychotics have broad-spectrum efficacy against core symptoms of acute mania/mixed states in bipolar disorder; however, they are associated with clinically significant adverse effects (AEs). METHODS: This post hoc analysis evaluated the safety and tolerability of the atypical antipsychotic cariprazine in the treatment of adult patients with acute manic/mixed episodes of bipolar I disorder. Data were taken from three 3-week randomized, double-blind, placebo-controlled, flexible-dose trials of cariprazine 3-12mg/d. Patient subgroups categorized by modal daily dose (3-6mg/d; 9-12mg/d) were used to assess dose response. RESULTS: The pooled safety population comprised 1065 patients (placebo=442; cariprazine 3-6mg/d=263; cariprazine 9-12mg/d=360). More cariprazine- than placebo-treated patients reported double-blind treatment-emergent AEs; the overall AE incidence was similar among cariprazine-dose groups. AEs reported in ≥5% of cariprazine patients overall with at least twice the incidence of placebo were akathisia, extrapyramidal symptoms, restlessness, and vomiting. The incidence of SAEs was low and similar between the placebo- and cariprazine-treatment groups. Metabolic parameter changes were small and generally similar between cariprazine and placebo groups; mean increases in fasting glucose levels were greater with cariprazine (3-6mg/d=6.6mg/dL; 9-12mg/d=7.2mg/dL) than placebo (1.7mg/dL). Mean weight change was 0.54kg and 0.17kg for cariprazine and placebo, respectively; weight increase ≥7% was <3% in all treatment groups. Cariprazine was not associated with clinically meaningful changes in electrocardiogram parameters. LIMITATIONS: Post hoc analysis, flexible-dose design, short trial duration. CONCLUSION: Cariprazine was generally safe and well-tolerated in patients with manic/mixed episodes associated with bipolar I disorder.

Safety and tolerability of cariprazine in patients with acute exacerbation of schizophrenia: a pooled analysis of four phase II/III randomized, double-blind, placebo-controlled studies.

Cariprazine, a potent dopamine D3 and D2 receptor partial agonist antipsychotic with preferential binding to D3 receptors, is Food and Drug Administration approved for treating schizophrenia and manic or mixed episodes of bipolar I disorder. A post-hoc safety/tolerability analysis of data from the four acute trials in the cariprazine schizophrenia clinical development program (NCT00404573; NCT00694707; NCT01104766; NCT01104779) was carried out using the overall safety population (all patients who received ≥1 dose of study drug) and modal daily dose subgroups (1.5-3, 4.5-6, and 9-12 mg/day). These exploratory findings were summarized using descriptive statistics. Cariprazine was generally well tolerated. The incidence of treatment-emergent adverse events versus placebo was similar for cariprazine 1.5-3 mg/day and higher for cariprazine 4.5-6 and 9-12 mg/day; a dose-response relationship was observed for akathisia, extrapyramidal symptoms, and diastolic blood pressure. The mean changes in metabolic parameters were generally similar in cariprazine-treated and placebo-treated patients. There was no prolactin level increase or QTc value greater than 500 ms; small increases in mean body weight (∼1to2 kg) versus placebo were observed. Within the Food and Drug Administration-approved dose range (1.5-6 mg/day), cariprazine was generally safe and well tolerated in patients with schizophrenia.

Effect of cariprazine across the symptoms of mania in bipolar I disorder: Analyses of pooled data from phase II/III trials.

Bipolar I disorder is a chronic disorder characterized by episodic recurrences of mania, depression, and mixed affective states interspersed with periods of full or partial remission; subsyndromal residual symptoms between episodes are common and disabling. Cariprazine, an atypical antipsychotic, is a potent dopamine D3 and D2 receptor partial agonist with preferential binding to D3 receptors. Post-hoc analyses of pooled data from 3 positive trials were conducted to evaluate the effect of cariprazine 3-12 mg/d on the symptoms of mania in inpatients (18-65 years) with bipolar I disorder and a current manic episode. Analyses were based on the pooled intent-to-treat (ITT) population (placebo=429; cariprazine=608). Mean change from baseline to the end of treatment on individual Young Mania Rating Scale (YMRS) items was analysed using a mixed-effects model for repeated measures (MMRM); categorical symptom severity shifts were analysed using logistic regression. Statistically significant improvement in mean change was seen for cariprazine versus placebo on all 11 YMRS items (p<0.0001); significantly more cariprazine- versus placebo-treated patients had mild/no symptoms at the end of treatment on 11 YMRS items (p<0.0001) and concurrently on the 4 YMRS core symptoms (irritability, speech, content, and disruptive-aggressive behaviour) (p<0.0001). Significantly more cariprazine- versus placebo-treated patients shifted from a Moderate/Worse or Marked/Worse Symptoms categories to Mild/No Symptoms on all 11 (p<0.0001) and 9 of 11 YMRS items (p<0.05), respectively. Results suggest that cariprazine treatment improved mania across YMRS symptoms; a significant percentage of cariprazine- versus placebo-treated patients had mild/no symptoms at the end of treatment.