The novel atypical antipsychotic drug cariprazine is effective for the treatment of acute mania associated with bipolar I disorder, according to findings from a randomized, placebo-controlled phase III study.
In 158 patients randomized to receive 3 weeks of double-blind treatment with the orally active dopamine D3-preferring D3/D2 receptor partial agonist, the mean improvement on the Young Mania Rating Scale (YMRS), based on a mixed-effects model of repeated measures, was significantly greater than the mean improvement in 151 patients randomized to receive placebo, Anjana Bose, Ph.D. and her colleagues reported in a poster at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.
Cariprazine demonstrated fast onset of action, with a statistically greater improvement vs. placebo seen by day 4 of treatment and at every visit thereafter.
Significantly more patients in the active treatment group met the YMRS criteria for response (59% vs. 44% taking placebo achieved at least a 50% score reduction from baseline) and remission (52% vs. 35% achieved a total score of 12 or less) at 3 weeks, she said.
The mean improvement on the Clinical Global Impressions-Severity scale also was significantly greater in the treatment group at week 3, as was the reduction in Positive and Negative Syndrome Scale (PANSS) score, according to Dr. Bose of Forest Research Institute, Jersey City, N.J.
Of note, cariprazine demonstrated fast onset of action, with a statistically greater improvement vs. placebo seen by day 4 of treatment and at every visit thereafter, she said.
Patients in the 6-week multicenter study were adults aged 18-65 years with acute mania associated with bipolar I disorder (as defined by the DSM-IV-TR) and a YMRS score of 20 or higher. The mean YMRS scores at baseline were similar at 32.3 (treatment group) and 32.1 (placebo).
Patients were hospitalized for a 4- to 7-day wash-out period and for at least the first 14 days of the 3-week treatment period. Those randomized to the treatment group received between 3 and 12 mg of cariprazine daily during those 3 weeks; treatment was initiated at a dose of 1.5 mg/day and increased in increments of 3 mg to a maximum of 12 mg/day by day 7, based on patient response and tolerability. The mean dose given was 7.5 mg/day.
Treatment was followed by a 2-week safety follow-up period.
A similar proportion of patients in the treatment and placebo groups (69% and 68%, respectively) completed the study; 10% of treatment-group patients and 7% of placebo-group patients discontinued treatment because of adverse effects. Treatment-emergent adverse events occurred in 80% and 63% of the patients in each group, respectively, and included worsening of mania in two treatment-group patients and five placebo-group patients and akathisia in five treatment-group patients.
The most common adverse events were akathisia, extrapyramidal disorder, tremor, dyspepsia, and vomiting. Extrapyramidal symptom–related adverse events occurred in 46% of the treatment and 12% of the placebo-group patients, Dr. Bose reported.
“Cariprazine is an orally active atypical antipsychotic candidate in clinical development for the treatment of schizophrenia and bipolar disorder. It has been hypothesized that a compound that exhibits high potency for both D3 and D2 receptors may have treatment advantages compared with currently available atypical antipsychotics,” she wrote.
In this study, treatment was associated with a higher incidence of akathisia and extrapyramidal symptoms, but it was not associated with a mean increase in weight or metabolic parameters or with prolactin increase or QTc prolongation, she noted.
The drug was safe and generally well tolerated. The findings of this phase III study support those from an earlier phase II study in which cariprazine also was shown to be safe, well tolerated, and significantly superior to placebo for improvement of acute manic or mixed episodes, she concluded.
Dr. Bose is an employee of Forest Research Institute, a scientific subsidiary of Forest Laboratories, the maker of cariprazine and the sponsor of this study.