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Adjunctive Cariprazine for Major Depressive Disorder

The second-generation antipsychotic agent (SGA) cariprazine, a dopamine D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist, was effective for reducing depressive symptoms in a trial of adults with major depressive disorder and inadequate response to antidepressants alone.

Based on a primary outcome of change from baseline to week 6 in total score on the Montgomery-Åsberg Depression Rating Scale (MADRS), participants on cariprazine 1.5 or 2.0 mg/day or placebo produced these results: “The [modified intent-to-treat] population comprised 751 patients (placebo: N = 249; cariprazine 1.5 mg/day: N = 250; cariprazine 3.0 mg/day: N = 252). At week 6, the mean reduction from baseline in MADRS total score was significantly greater with cariprazine 1.5 mg/day than with placebo (−14.1 vs. −11.5) but not with cariprazine 3.0 mg/day (−13.1). Significant differences between the cariprazine 1.5 mg/day and placebo groups were also observed at weeks 2 and 4. Meeting the MADRS response criteria was significantly more likely among patients receiving cariprazine 1.5 mg/day than placebo (44.0% vs. 34.9%); remission rates were not significantly different among groups. Common treatment-emergent adverse events (≥5% in either cariprazine group and twice the placebo rate) were akathisia and nausea.”

Editorial: “As is still the case with other SGAs when prescribed as adjuncts to antidepressants, the field requires better data on longer-term treatment outcomes to determine the optimal duration of therapy to achieve the desired efficacy,” writes an editorialist. “We also need more comprehensive safety data during longer-term therapy so that the risks of weight gain, other metabolic complications, and tardive dyskinesia can be more accurately gauged. Meanwhile, potential clinical characteristics that might differentiate cariprazine from other SGAs include a relatively novel mechanism of action, a low risk of significant weight gain, and a low rate of daytime sedation. Of course, cost-effectiveness will also be a concern, as branded formulations of SGAs are substantially more expensive than generically available alternatives. Therefore, a skeptic with an eye focused on pharmacy expenditures might ask, ‘Do we really need another SGA approved for this indication?’ I believe the answer is ‘yes’ in part because individual differences in drug response make it useful to have more than one option within classes or subclasses of medications. Furthermore, assessments of cost-effectiveness are ephemeral as the time period for market exclusivity is relatively short-lived. Although data from head-to-head randomized controlled trials are ultimately needed to make more precise comparative judgments of benefits, risks, and cost-effectiveness, FDA approval of cariprazine for adjunctive treatment of MDD is a welcome step in treatment development.”

Source: American Journal of Psychiatry