The clinical decision to augment with an atypical antipsychotic is supported by data from the VA Augmentation and Switching Treatments for Improving Depression of VAST-D clinical trial. Response rates were significantly higher for patients who augmented ongoing antidepressant therapy with an atypical antipsychotic than for patients who switched to a different antidepressant or combined antidepressants.
Adjunctive Treatment with Cariprazine
Compared to other antipsychotics, the atypical antipsychotic cariprazine (marketed as Vraylar) exhibits a greater affinity for and higher occupancy of dopamine D3 receptors. D3 receptors are highly expressed in brain regions involved in cognitive function, motivation, and reward-related behaviors. Thus, it has been hypothesized that, with greater occupancy of D3 receptors, cariprazine may positively affect cognition and mood. In addition, cariprazine acts on other receptors involved in mood regulation, most notably acting as a partial agonist at the 5-HT1A serotonin receptor.
A recent study published in the American Journal of Psychiatry from Mass General researchers including Gary Sachs, MD and Maurizio Fava, MD reports on the efficacy of cariprazine as adjunctive therapy for patients with major depressive disorder and inadequate response to at least one antidepressant.
In this double-blind placebo-controlled study, adults with MDD who had experienced an inadequate response to antidepressants alone were randomized in a 1:1:1 ratio to placebo, cariprazine at 1.5 mg/day, or cariprazine at 3.0 mg/day for six weeks. Depressive symptoms were measured using the Montgomery-Åsberg Depression Rating Scale (MADRS).
Analyzable data was collected from a total of 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 in depressive symptoms (MADRS total scores) was significantly greater in individuals receiving cariprazine at 1.5 mg/day than in individuals receiving placebo (−14.1 vs. −11.5). The difference between response to cariprazine 1.5 mg/day and placebo was also evident at weeks 2 and 4. However, the difference between cariprazine at 3.0 mg/day and placebo was not statistically significant at week 6 (−13.1 vs. -11.5).
Response (defined as reduction of ≥50% in MADRS total score) was more likely to occur among patients receiving cariprazine 1.5 mg/day than placebo (44.0% vs. 34.9%). However, remission rates did not differ significantly across the three groups.
Adjunctive treatment with cariprazine was generally well-tolerated. Common treatment-emergent adverse events (≥ 5% in either cariprazine group and twice the placebo rate) were akathisia and nausea.
Antidepressant Augmentation with Cariprazine
The current study indicates that adjunctive treatment with cariprazine at 1.5 mg/day has demonstrated efficacy in reducing depressive symptoms in adults with MDD and inadequate response to antidepressants alone. Cariprazine was generally well tolerated, with a safety profile that was consistent with previous clinical trials.
In this study, augmentation with cariprazine at the higher dose of 3 mg/day did not differ from placebo. Other studies, however, including a previously reported phase 2 study (Durgam et al, 2016) evaluating flexible dosing of cariprazine in adults with MDD with an inadequate response to antidepressant, found a greater reduction in depressive symptoms in those treated with doses of cariprazine ranging from 2.0 to 4.5 mg/day, with a mean effective daily dosage of 3.0 mg/day. Based on these findings, it is recommended that augmentation with cariprazine should be initiated at 1.5 mg/day; an increase to 3.0 mg/day may be considered in those who do not respond to the lower dose and who have minimal side effects.
The current study from Sachs and colleagues and previous studies indicate that cariprazine may be an efficacious and tolerable strategy for the treatment of depression in patients who have not responded to antidepressant monotherapy. For patients, adjunctive therapy with an atypical antipsychotic is typically easier to implement than switching to another antidepressant, as there is no need to taper one medication while starting another. In addition, when adjunctive treatment with an atypical is effective, we typically begin to see improvement within a few weeks.
Read More
Fava M, Durgam S, Earley W, Lu K, Hayes R, Laszlovszky I, Németh G. Efficacy of adjunctive low-dose cariprazine in major depressive disorder: a randomized, double-blind, placebo-controlled trial. Int Clin Psychopharmacol. 2018 Nov;33(6):312-321.
Durgam S, Earley W, Guo H, Li D, Németh G, Laszlovszky I, Fava M, Montgomery SA. Efficacy and safety of adjunctive cariprazine in inadequate responders to antidepressants: a randomized, double-blind, placebo-controlled study in adult patients with major depressive disorder. J Clin Psychiatry 2016; 77: 371–378.
