Efficacy and Safety of Levomilnacipran Sustained Release 40 mg, 80 mg, or 120 mg in Major Depressive Disorder

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 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...

The effect of vortioxetine on overall patient functioning in patients with major depressive disorder

“…The SDS is a validated measure of functional impairment that has demonstrated sensitivity to impairment and the effects of treatment across a wide range of disorders, including MDD (Sheehan & Sheehan, 2008). The SDS has been used to assess functional improvement in association with improvements in depressive symptoms for duloxetine (Mancini et al., 2012; Oakes et al., 2012; Sheehan et al., 2011; Wise et al., 2008), desvenlafaxine (Dunlop et al., 2011; Guico‐Pabia et al., 2012; Soares et al., 2009), paroxetine (Wise et al., 2008), bupropion (Hewett et al., 2010; Soczynska et al., 2014), escitalopram (Romera et al., 2012; Soczynska et al., 2014), venlafaxine (Fann et al., 2015; Hewett et al., 2010), levomilnacipran (Asnis et al., 2013; Sambunaris, Bose, et al., 2014), and agomelatine (Montgomery, Nielsen, et al., 2014; Zajecka et al., 2010) with results that have been variable with respect to clinical significance; however, many of these antidepressants showed significant differences versus placebo in the change from baseline versus placebo in the SDS total score when patients were stratified by baseline depressive symptom severity. A recent pooled analysis showed that treatment with duloxetine ( n  = 1,029) and SSRIs ( n  = 835) resulted in significantly greater improvements in the SDS total score (∆ −1.9, p  <   .001; ∆ −1.7, p  <   .01, respectively) compared to placebo ( n  = 329).…”

Levomilnacipran for major depressive disorder: a systematic review of the efficacy and safety profile for this newly approved antidepressant - what is the number needed to treat, number needed to harm and likelihood to be helped or harmed?

“…Of these, two were original clinical trial reports for short-term randomised controlled efficacy studies (12,13). Available posters include reports for three other short-term randomised controlled efficacy studies (14)(15)(16), an openlabel 48-week extension study (17), and a randomised controlled study of relapse prevention (18).…”

“…Examining the effects on functional outcomes in the fixed-dose study testing levomilnacipran 40, 80 and 120 mg/day (23), levomilnacipran 80 and 120 mg significantly improved SDS scores and the largest and most robust treatment effects were in the levomilnacipran 120 mg group. For functional remission, significant treatment advantage was found in patients with severe MDD (baseline MAD-RS score at least 35) who received the highest dosage of levomilnacipran (120 mg/day), with remission rates of 28% vs. 12%, resulting in a NNT of 7 (95% CI [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19].…”

“…Safety and tolerability data were pooled from the five short-term placebo-controlled randomised trials (12)(13)(14)(15)(16) and an integrated analysis made available (21). Safety evaluations included AEs, clinical laboratory tests, vital signs, ECGs and the Columbia-Suicide Severity Rating Scale (C-SSRS) for the studies that included US subjects (13)(14)(15)(16).…”

“…Safety evaluations included AEs, clinical laboratory tests, vital signs, ECGs and the Columbia-Suicide Severity Rating Scale (C-SSRS) for the studies that included US subjects (13)(14)(15)(16).…”