Efficacy of adjunctive low-dose cariprazine in major depressive disorder: a randomized, double-blind, placebo-controlled trial

Abstract

This 19-week, double-blind, placebo-controlled, randomized phase 2 study evaluated the efficacy, safety, and tolerability of adjunctive cariprazine (0.1-0.3 and 1.0-2.0 mg/day) as an antidepressant treatment for adults with treatment-resistant major depressive disorder (MDD) (NCT00854100). The primary endpoint was change in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score and the secondary was change in the Clinical Global Impression-Intensity score. Additional efficacy parameters were also assessed. A total of 231 patients were randomized. None of the predefined parameters reached significance for either cariprazine doses, but higher doses yielded numerically greater mean changes in MADRS and Clinical Global Impression-Intensity scores, and MADRS response and remission rates, compared with placebo. No differences were seen on any measures between cariprazine 0.1-0.3 mg/day and placebo. Cariprazine was relatively well tolerated, and common treatment-emergent adverse events (incidence ≥5% and twice the placebo group rate) in both dosage groups included headache, arthralgia, restlessness, fatigue, increased appetite, insomnia, dry mouth, and constipation. In conclusion, both cariprazine doses were relatively well tolerated; although differences were not statistically significant, patients treated with cariprazine 1.0-2.0 mg/day had greater mean decreases in measures of depression symptoms compared with placebo, which is consistent with another adjunctive cariprazine MDD study, and thus warrants further investigation.

Figures

Fig. 1

Patient disposition. ADT, antidepressant therapy; AE, adverse event; ITT, intent-to-treat; LTFU, lost to follow-up; WOC, withdrawal of consent. aOverall, 403 patients completed the prospective ADT treatment phase; of these patients, 231 patients did not respond to ADT and were randomized to the double-blind treatment group (double-blind safety population), and 172 patients did respond to ADT and continued receiving ADT treatment and placebo; one death occurred (suicide by intentional overdose) in the prospective ADT treatment period. bOne randomized patient withdrew consent before receiving the investigational product.

Fig. 2

(a) MADRS total score changes from baseline by study visit, and (b) MADRS response and remission rates. (a) Primary endpoint, MADRS total scorea. (b) MADRS response and remission at week 16. Six patients were enrolled twice in the study. Only data from the first enrollment phase are included. aMean changes from baseline by study visit in MADRS total score (ITT population), LS mean (SE), LSMD versus placebo, and P values are based on an MMRM model with treatment group, pooled study center, visit, and treatment group-by-visit interaction as fixed effects, and the baseline value and baseline-by-visit interaction as the covariates. bResponse and remission at week 16 (LOCF), analyses of response and remission (LOCF) rates were performed using a logistic regression model, with treatment group and the corresponding baseline values as the explanatory variables. ITT, intent-to-treat; LOCF, last observation carried forward; LS, least squares; MADRS, Montgomery–Åsberg Depression Rating Scale; MMRM, mixed-effects model for repeated measures.