Levomilnacipran SR in the Treatment of Major Depressive Disorder: An Analysis of Efficacy and Safety Data From 2 Phase III Studies

Objective: Levomilnacipran (1S, 2R-milnacipran) is a potent and selective serotonin and norepinephrine reuptake inhibitor (SNRI) with approximately 2-fold greater potency in vitro for norepinephrine than serotonin reuptake inhibition. Data from Phase III trials (Study 1:NCT00969709; Study 2:NCT00969150) were analyzed to evaluate the efficacy and safety of levomilnacipran sustained release (SR). Methods: Data from 2 multicenter, randomized, placebo-controlled 8-week double-blind studies were pooled; statistical advantage on the primary efficacy was seen only in Study 1. Studies enrolled patients with major depressive disorder (MDD), MADRS score ≥30, and current major depressive episode ≥8 weeks (Study 1) or ≥4 weeks (Study 2) who were randomized to once-daily fixed-dose levomilnacipran 40, 80, or 120 mg/day (Study 1), flex-dose levomilnacipran 40-120 mg/day (Study 2), or placebo. Efficacy parameters included MADRS and SDS total score change from baseline to end of Week 8. Safety and tolerability included AEs, vital signs and C-SSRS scores. Results: Baseline characteristics were similar for pooled placebo (n=358) and levomilnacipran (n=712) population. Significant improvement was seen for levomilnacipran versus placebo on MADRS (LSMD=-2.73; P=.0009) and SDS (LSMD=-1.44; P=.0190). Of placebo and levomilnacipran patients, respectively, 63.1% and 78.8% reported TEAEs and 2.0% and 9.1% discontinued due to AEs. The most common (≥10%) TEAEs (placebo vs levomilnacipran) were headache (12% vs 17%), nausea (3% vs 16%), and dry mouth (8% vs 10%). Conclusion: In this pooled analysis, levomilnacipran-treated patients showed statistically significant and clinically meaningful improvement in depressive symptoms and functional impairment. Higher placebo response in Study 2 may explain different individual study outcomes.