Efficacy and Safety of Levomilnacipran Sustained Release in Moderate to Severe Major Depressive Disorder: A Randomized, Double-Blind, Placebo-Controlled, Proof-of-Concept Study

Objective: To investigate the efficacy and safety of levomilnacipran sustained release (SR), an antidepressant candidate in late-stage development, in major depressive disorder (MDD).

Method: Between December 2006 and October 2007, a 10-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter, flexible-dose trial assessed once-daily levomilnacipran SR (75 mg or 100 mg) in outpatients (18-70 years) meeting DSM-IV criteria for a major depressive episode (duration ≥ 1 month) with a 17-item Hamilton Depression Rating Scale (HDRS17) score > 22 and Sheehan Disability Scale (SDS) score ≥ 10. Levomilnacipran SR dose was increased to 100 mg/d over 12 days. The primary efficacy measure was Montgomery Asberg Depression Rating Scale (MADRS) score change from baseline to week 10; secondary efficacy measures were the HDRS17, SDS, Clinical Global Impressions-Improvement scale, and MADRS response (≥ 50% decrease from baseline) and remission (score ≤ 10). Safety was evaluated according to adverse events, laboratory investigations, and vital signs/physical findings.

Results: Efficacy analyses included 276 levomilnacipran SR-treated patients and 277 placebo-treated patients. Levomilnacipran SR was significantly superior to placebo on MADRS total score change from baseline to week 10 (least squares mean difference [LSMD] = −4.2 [95% CI, −5.7 to −2.6]; P < .0001). Statistical significance in favor of levomilnacipran SR was demonstrated on change from baseline to week 10 in HDRS17 total score (LSMD = −3.4 [95% CI, −4.7 to −2.2]; P < .0001) and SDS total score (LSMD = −3.4 [95% CI, −4.6 to −2.2]; P < .0001) and subscales. Significantly more levomilnacipran SR patients versus placebo patients achieved MADRS response (59.1% vs 42.2%; P < .0001) and remission (46.4% vs 26.0%; P < .0001). Levomilnacipran SR was generally safe and well tolerated; more levomilnacipran SR patients (9.4%) versus placebo patients (6.5%) discontinued due to adverse events, but more placebo patients versus levomilnacipran SR patients discontinued overall (24.9% vs 20.2%).

Conclusions: Levomilnacipran SR demonstrated robust efficacy on all measures and was generally well tolerated.

Trial Registration: EudraCT number: 2006-002404-34

J Clin Psychiatry 2013;74(4):363-369

© Copyright 2013 Physicians Postgraduate Press, Inc.

Submitted: August 29, 2012; accepted February 1, 2013 (doi:10.4088/JCP.12m08141).

Corresponding author: Stuart A. Montgomery, MD, PO Box 8751, London W13 8WH, UK ([email protected]).