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 treatmentemergent 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. September 28, 2012; accepted January 28, 2013 (doi:10.4088/JCP.12m08197 T he complex nature of major depressive disorder (MDD) suggests that recovery may be most appropriately judged by multiple factors. Even when patients achieve symptom improvement, impaired social and occupational functioning may persist and interfere with well-being. As such, it has been suggested that return to wellness in patients with MDD may be better defined by evaluating a combination of symptoms, functional status, and pathophysiologic changes. Submitted:1 The development of effective and safe new medications that address all aspects of MDD treatment is essential.Levomilnacipran (1S, 2R-milnacipran) is a potent and selective serotonin-norepinephrine reuptake inhibitor (SNRI) in late-stage clinical development for treatment of MDD in adults. A sustained release (SR) formulation of levomilnacipran was developed to al...

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.

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