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

J Clin Psychiatry. 2013 Mar;74(3):242-8. doi: 10.4088/JCP.12m08197.

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 (HDRS(17)) 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), HDRS(17) (-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.

Publication types

  • Clinical Trial, Phase III
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cyclopropanes* / administration & dosage
  • Cyclopropanes* / adverse effects
  • Cyclopropanes* / chemistry
  • Delayed-Action Preparations / administration & dosage
  • Delayed-Action Preparations / adverse effects
  • Delayed-Action Preparations / chemistry
  • Depressive Disorder, Major / diagnosis
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / psychology
  • Diagnostic and Statistical Manual of Mental Disorders
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Monitoring
  • Female
  • Humans
  • Male
  • Middle Aged
  • Milnacipran
  • Psychiatric Status Rating Scales
  • Serotonin Uptake Inhibitors / administration & dosage
  • Serotonin Uptake Inhibitors / adverse effects
  • Serotonin Uptake Inhibitors / chemistry
  • Stereoisomerism
  • Treatment Outcome

Substances

  • Cyclopropanes
  • Delayed-Action Preparations
  • Serotonin Uptake Inhibitors
  • Milnacipran

Associated data

  • ClinicalTrials.gov/NCT00969709