Efficacy and Safety of Levomilnacipran Sustained Release 40 mg, 80 mg, or 120 mg in Major Depressive Disorder: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study

Objective:This phase 3, randomized, double-blind, placebo-controlled study evaluated the efficacy and tolerability of fixed-dose levomilnacipran sustained release (SR) compared with placebo in patients with major depressive disorder (MDD); the study was conducted from September 2009-May 2011. Method: Outpatients met DSM-IV-TR criteria for MDD with an ongoing major depressive episode >= 8 weeks' duration. After a 1-week placebo lead-in, patients were randomly assigned to receive placebo (n = 179) or levomilnacipran SR 40 mg (n = 181), 80 mg (n = 181), or 120 mg (n = 183) once daily for 8 weeks of double-blind treatment, followed by a 2-week double-blind down-taper. The primary efficacy parameter was change from baseline on the clinician-rated Montgomery-Asberg Depression Rating Scale (MADRS) total score. The prespecified secondary efficacy parameter was change from baseline in Sheehan Disability Scale (SDS) total score. Additional efficacy measures included the 17-item Hamilton Depression Rating Scale (HDRS17) and Clinical Global Impressions-Severity of Illness (CGI-S) and -Improvement (CGI-I). Safety and tolerability were also evaluated. Results:The least squares mean difference (LSMD) for change from baseline in MADRS total score was significantly superior to placebo for all dose groups: -3.23 (P=.0186), -3.99 (P=.0038), and -4.86 (P=.0005) for levomilnacipran SR 40, 80, and 120 mg, respectively. The LSMD was significantly different for levomilnacipran SR 80 mg and 120 mg versus placebo on the SDS (-2.51 and -2.57, respectively, P < .05 for both doses), HDRS17 (-2.09 and -2.34, respectively, P < .05 for both doses), CGI-S (-0.43 [P<.01] and -0.35 [P<.05], respectively), and CGI-I (-0.34 and -0.32, respectively, P<.05 for both doses) assessments. The most common treatment-emergent adverse events (>= 10% of any treatment group) were headache, nausea, constipation, dry mouth, increased heart rate, and hyperhidrosis. Conclusions: Levomilnacipran SR demonstrated significant improvement in depressive symptoms and functioning relative to placebo. In this study, levomilnacipran SR was generally well tolerated. Trial Registration: ClinicalTrials.gov identifier: NCT00969709 J Clin Psychiatry 2013;74(3):242-248 (C) Copyright 2013 Physicians Postgraduate Press, Inc.