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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In this study, cariprazine 3-12mg/day was effective and generally well tolerated in the treatment of manic and mixed episodes associated with bipolar I disorder.

ObjectiveLevomilnacipran ER is a potent and selective serotonin and norepinephrine reuptake inhibitor (SNRI) approved for the treatment of major depressive disorder (MDD). Efficacy and safety have been evaluated in five Phase II/III studies, four of which met the pre-specified primary efficacy outcome. Results of the negative trial (ClinicalTrials.gov NCT00969150) are reported here.MethodsA Phase III randomized, double-blind, placebo-controlled trial comparing flexible-dose levomilnacipran ER 40–120 mg/day with placebo was conducted in outpatients with MDD. Patients met the DSM-IV-TR criteria for MDD, had a current episode of depression of at least 4 weeks’ duration, and a Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥30. The study comprised a 1-week, single-blind, placebo lead-in, 8-week double-blind treatment, and a 2-week down-taper. The primary and secondary efficacy measures were change from baseline to Week 8 in MADRS and Sheehan Disability Scale (SDS) total scores, respectively, analyzed using a mixed-effects model for repeated measures approach. Safety outcomes included adverse events (AEs), laboratory and vital sign measures, the Columbia-Suicide Severity Rating Scale, and the Arizona Sexual Experiences Scale (ASEX).ResultsThree hundred and fifty-five patients received the study drug and had ≥1 post-baseline MADRS total score assessment (ITT Population); 81.9% of placebo and 77.1% of levomilnacipran ER patients completed the study. For levomilnacipran ER vs placebo, MADRS (−15.7 vs −14.2) and SDS (−8.8 vs −8.2) total score improvements, and rates of MADRS response (38.5% vs 34.8%) and remission (25.3% vs 23.8%) were numerically greater but differences were not statistically significant. Levomilnacipran ER was generally well tolerated. More levomilnacipran ER patients vs placebo reported AEs; the most common AEs for levomilnacipran ER were nausea (17%) and headache (16%). Mean changes in most safety measures were small and similar between groups. There were no meaningful differences in total ASEX scores between groups.LimitationsShort duration of treatment, inclusion and exclusion criteria, and lack of an active comparator.ConclusionNumerical improvements for levomilnacipran ER vs placebo were detected in this study, but the differences were not statistically significant; levomilnacipran ER was generally well tolerated.

BackgroundLevomilnacipran (1S, 2R-milnacipran) is a potent and selective serotonin (5-HT) and norepinephrine (noradrenaline) reuptake inhibitor approved for the treatment of major depressive disorder in adults.ObjectiveThe objective of this study was to evaluate the longer-term safety and tolerability of levomilnacipran extended-release (ER).MethodsPatients who completed double-blind treatment/down-taper in one of three lead-in levomilnacipran ER studies were eligible for this 48-week open-label extension. Safety evaluations included assessment of treatment-emergent adverse events (TEAEs), physical examinations, laboratory and vital sign measures, and suicidality, summarized using descriptive statistics for the safety population.ResultsThe completion rate was 47 %; median treatment duration was 280 days. The most frequent reasons for discontinuation were withdrawal of consent (14 %) and adverse events (AEs; 13 %). TEAEs were reported by 712 (86 %) patients; most were mild/moderate and occurred early in treatment. The most common TEAEs were headache (22 %) and nausea (16 %); 36 (4 %) patients had ≥1 serious AEs. No clinically meaningful changes occurred in mean liver enzyme, metabolic, hematologic, urinalysis, or serum values; potentially clinically significant high AST or ALT values (≥3 × upper limit of normal) occurred in five patients. Vital sign changes occurred early and remained relatively stable. Mean increases for pulse rate (9.1 beats per minute [bpm]), and supine systolic (3.9 mmHg) and diastolic (3.3 mmHg) blood pressure were noted. The increase in the mean QT interval corrected using the Bazett formula (10.9 ms) was consistent with heart rate increase (12.8 bpm); there was no meaningful change in mean QT interval corrected using the Fridericia formula (−1.3 ms). Other than tachycardia and heart rate increases, ECG-related TEAEs were low (<0.5 %).ConclusionNo new or inconsistent safety/tolerability findings were discovered during longer-term evaluation.

RationaleCariprazine, a dopamine D3/D2 receptor partial agonist antipsychotic, demonstrated efficacy and tolerability in 6-week, randomized, placebo-controlled schizophrenia trials. Schizophrenia is a chronic disorder that requires continuous treatment; therefore, the long-term safety and tolerability profile of antipsychotic agents is an important factor in guiding clinician decisions.ObjectiveThis single-arm, open-label extension study evaluated the long-term safety and tolerability of cariprazine in patients with schizophrenia.MethodsPatients enrolled in this study completed a 6-week, randomized, placebo- and active-controlled study and had responded (Clinical Global Impressions-Severity [CGI-S] ≤3; ≥20 % reduction in Positive and Negative Syndrome Scale [PANSS] total score) to treatment at the end of the lead-in study. Patients (N = 93) received flexibly dosed, open-label cariprazine (1.5–4.5 mg/day) for up to 48 weeks.ResultsApproximately 50 % (46/93) of patients completed the 48 weeks of open-label treatment. The most common adverse events (AEs) were akathisia (14 %), insomnia (14 %), and weight increased (12 %). Serious AEs (SAEs) occurred in 13 % of patients; 11 % discontinued due to AEs. Mean changes in metabolic parameters were generally small and not clinically relevant. Mean body weight increased by 1.9 kg from the start of the lead-in study to the end of the extension study. There were no discontinuations associated with change in metabolic parameters or body weight. Long-term cariprazine treatment was not associated with prolactin elevation or clinically significant changes in cardiovascular parameters.ConclusionsIn this 48-week, single-arm trial, open-label cariprazine (1.5–4.5 mg/day) treatment was generally safe and well tolerated with no new safety concerns associated with long-term treatment.Electronic supplementary materialThe online version of this article (doi:10.1007/s00213-016-4450-3) contains supplementary material, which is available to authorized users.