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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...

Objective: This study evaluated the efficacy, safety, and tolerability of aripiprazole lauroxil, a novel long-acting injectable atypical antipsychotic, for the treatment of schizophrenia.

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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Objective:To investigate the efficacy and safety of levomilnacipran sustained release (SR), an antidepressant candidate in late-stage development, in major depressive disorder (MDD).Method: Between December 2006 and October 2007, a 10-week, randomized, double-blind, placebocontrolled, 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 (HDRS 17 ) 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 HDRS 17 , 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 HDRS 17 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% Submitted: August 29, 2012; accepted February 1, 2013 (doi:10.4088/JCP.12m08141 Major depressive disorder (MDD) is a common, potentially dangerous, and disabling disorder. It has a chronic recurrent course and is recognized as the most common cause of disability during the course of a working life.1 Effective treatment of MDD is a public health priority.Levomilnacipran (1S, 2R-milnacipran), a potent and selective serotonin-norepinephrine reuptake inhibitor (SNRI) with greater potency for inhibition of norepinephrine (NE) relative to serotonin (5-HT) reuptake, is in clinical development for the treatment of adult MDD. In animal models of depression, it shows a potent antidepressantlike effect 2 suggesting that it may offer therapeutic effects similar to older tricyclic antidepressants without the accompanying safety and tolerability issues. The sustained release (SR) formulation was developed to allow for once-daily dosing.Potency for inhibition of 5-HT reuptake...

These findings suggest that escitalopram is better tolerated and at least as effective as the serotonin-norepinephrine reuptake inhibitor duloxetine in the treatment of major depressive disorder.

Background: Current guidelines for antidepressant use recommend 4 to 6 months of continuation treatment to prevent relapse of depression following symptom resolution. This study evaluates the efficacy and safety of continuation escitalopram treatment. Method: Outpatients diagnosed with DSM-IV major depressive disorder (male or female, aged 18 to 81 years) who had completed 8 weeks of randomized double-blind treatment with escitalopram, citalopram, or placebo entered an 8-week flexible-dose, open-label phase in which all patients received escitalopram (10-20 mg/day). This study was initiated November 3, 1999, and completed April 5, 2001. Patients who met responder criteria (score of ≤ 12 on the Montgomery-Asberg Depression Rating Scale [MADRS]) were randomly assigned in a 2:1 ratio to escitalopram (at the dose each patient was receiving at the end of the open-label phase) or placebo for 36 weeks of double-blind treatment. The primary efficacy variable was time to depression relapse (defined as MADRS score ≥ 22 or discontinuation due to an insufficient therapeutic response) from the start of the double-blind treatment phase. Results: A total of 502 patients received openlabel escitalopram treatment and had at least 1 MADRS assessment. A total of 274 evaluable subjects entered the double-blind treatment phase; 93 received placebo and 181 received escitalopram. Time to depression relapse was significantly longer (p = .013) and the cumulative rate of relapse was significantly lower in patients who received escitalopram (26% escitalopram vs. 40% placebo; hazard ratio = 0.56; p = .01). Escitalopram-treated subjects had significantly lower depression ratings than those of placebotreated patients. Escitalopram continuation treatment was safe and well tolerated. Discontinuation rates due to adverse events were 7% for the placebo group and 4% for the escitalopram-treated group. Conclusion: Continuation treatment with escitalopram is effective in preventing relapse into an episode of major depressive disorder.