title: Efficacy and safety of levomilnacipran sustained release in moderate to severe major depressive disorder: a randomized, double-blind, placebo-controlled, proof-of-concept study.
abstract: OBJECTIVE
  To investigate the efficacy and safety of levomilnacipran sustained release (SR), an antidepressant candidate in late-stage development, in major depressive disorder (MDD).
  
  
  METHODS
  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.
  
  
  BACKGROUND
  EudraCT number: 2006-002404-34
authors: Imperial College School of Medicine, University of London, London, United Kingdom. stuart@samontgomery.co.uk
authors: Stuart A
authors: SA
authors: Montgomery
authors: Lucilla
authors: L
authors: Mansuy
authors: Adam
authors: A
authors: Ruth
authors: Anjana
authors: A
authors: Bose
authors: Hua
authors: H
authors: Li
authors: Dayong
authors: D
authors: Li
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000928:Antidepressive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D003521:Cyclopropanes / Q000008:administration & dosage* / Q000009:adverse effects; D003865:Major Depressive Disorder / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000078764:Milnacipran; D012720:Severity of Illness Index; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000928:Antidepressive Agents; D003521:Cyclopropanes; D000078764:Milnacipran