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Original Research

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

Gregory M. Asnis, MD; Anjana Bose, PhD; Carl P. Gommoll, MS; Changzheng Chen, PhD; and William M. Greenberg, MD

Published: March 15, 2013

Article Abstract

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: identifier: NCT00969709

J Clin Psychiatry 2013;74(3):242-248

Submitted: September 28, 2012; accepted January 28, 2013 (doi:10.4088/JCP.12m08197).

Corresponding author: Gregory M. Asnis, MD, Albert Einstein College of Medicine, Montefiore Medical Center, 111 East 210th St, Bronx, NY 10467 (

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