REVIEW OF: Sachs GS et al, Am J Psychiatry2023;180(3):241–251

STUDY TYPE: Randomized double-blind placebo-controlled trial

When a patient with depression does not respond to an antidepressant alone, adding a second-generation antipsychotic is a well-known evidence-based strategy. Cariprazine (Vraylar), a dopamine D2 and D3 and serotonin 5-HT1A receptor partial agonist, is the latest option for such combination therapy. In December 2022, the FDA approved the drug as an adjunct to antidepressants for the treatment of major depressive disorder (MDD), and this AbbVie-funded Phase 3 trial was one of the key studies leading to that approval.

In this six-week double-blind study with participating sites in seven countries, 751 adults with MDD and inadequate response to antidepressant monotherapy were randomized in thirds to adjunctive cariprazine 1.5 mg/day, cariprazine 3 mg/day, and placebo groups. Participants had historically tried three or fewer antidepressants, but most had tried only one. No participants were using other psychiatric medications for affective symptoms during the trial period, and no one had attempted other options for treatment-resistant depression such as esketamine or ECT. Change in baseline was measured by the Montgomery-Åsberg Depression Rating Scale (MADRS). 

The 250 individuals in the cariprazine 1.5 mg/day group fared best, seeing a statistically significant mean 14.1-point drop in MADRS scores compared to a mean 11.5-point drop among the 249 individuals in the placebo group. The cariprazine 3 mg/day group saw a mean 13.1-point drop that was not statistically significant when compared to placebo. Overall, remission of depression did not significantly differ between the three groups. Both cariprazine groups had double the rates of akathisia and nausea compared to placebo but were otherwise well tolerated.

CARLAT TAKE

Cariprazine joins similar second-generation antipsychotics as an option for MDD when antidepressants alone are ineffective, but improvements seem to be modest. Considering that cariprazine’s side effect profile offers no clear advantages over generic aripiprazole, the outsized cost of this brand-name option might preclude its place as a first choice.