title: A phase III, double-blind, placebo-controlled, flexible-dose study of levomilnacipran extended-release in patients with major depressive disorder.
abstract: Levomilnacipran (1S, 2R-milnacipran) is a potent and selective serotonin and norepinephrine reuptake inhibitor; an extended-release (ER) formulation allows for once-daily dosing. This phase III study (NCT01034462) evaluated the efficacy, the safety, and the tolerability of 40 to 120 mg/d of levomilnacipran ER versus placebo in the treatment of patients (18-80 y) with major depressive disorder. This multicenter, randomized, double-blind, placebo-controlled, parallel-group, flexible-dose study comprised a 1-week single-blind, placebo run-in period; an 8-week double-blind treatment; and a 2-week double-blind down-taper period. The primary efficacy parameter was total score change from baseline to week 8 on the Montgomery-Åsberg Depression Rating Scale (MADRS); the secondary efficacy was the Sheehan Disability Scale. Analysis was performed using the mixed-effects model for repeated measures on a modified intent-to-treat population. A total of 434 patients received at least 1 dose of double-blind treatment (safety population); 429 patients also had 1 or more postbaseline MADRS assessments (modified intent-to-treat population). The least squares mean differences and 95% confidence interval were statistically significant in favor of levomilnacipran ER versus placebo for the MADRS total score (-3.095 [-5.256, -0.935]; P = 0.0051) and the SDS total score (-2.632 [-4.193, -1.070]; P = 0.0010) change from baseline to week 8. Adverse events were reported in 61.8% of the placebo patients and in 81.6% of the levomilnacipran ER patients. Frequently reported adverse events (≥ 5% in levomilnacipran ER and twice the rate of placebo) were nausea, dizziness, constipation, tachycardia, urinary hesitation, hyperhidrosis, insomnia, vomiting, hypertension, and ejaculation disorder. In conclusion, there was a statistically significant difference in the score change from baseline to week 8 between levomilnacipran ER and placebo on several depression rating scales, reflecting symptomatic and functional improvement; treatment was generally well tolerated.
authors.affiliation: From the *Atlanta Institute of Medicine & Research, Atlanta, GA; †Forest Research Institute, Jersey City, NJ, at time of study; and ‡University of South Florida College of Medicine, Tampa, FL.
authors.forename: Angelo
authors.initials: A
authors.lastname: Sambunaris
authors.forename: Anjana
authors.initials: A
authors.lastname: Bose
authors.forename: Carl P
authors.initials: CP
authors.lastname: Gommoll
authors.forename: Changzheng
authors.initials: C
authors.lastname: Chen
authors.forename: William M
authors.initials: WM
authors.lastname: Greenberg
authors.forename: David V
authors.initials: DV
authors.lastname: Sheehan
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D000328:Adult; D000928:Antidepressive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D002626:Chemistry, Pharmaceutical; D003521:Cyclopropanes / Q000008:administration & dosage* / Q000009:adverse effects; D003692:Delayed-Action Preparations; D003865:Major Depressive Disorder / Q000175:diagnosis / Q000188:drug therapy* / Q000523:psychology; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D016018:Least-Squares Analysis; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D000078764:Milnacipran; D011569:Psychiatric Status Rating Scales; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000928:Antidepressive Agents; D003521:Cyclopropanes; D003692:Delayed-Action Preparations; D000078764:Milnacipran; D017367:Selective Serotonin Reuptake Inhibitors