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?

Abstract

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?L. Citrome SUMMA RYObjective: To describe the efficacy and safety of levomilnacipran (extendedrelease capsules) for the treatment of major depressive disorder (MDD). Data sources: The pivotal registration trials were accessed by querying http://www. ncbi.nlm.nih.gov/pubmed/, http://www.clinicaltrialsregister.eu and http://www.clinicaltrials.gov for the search terms 'levomilnacipran' and 'F2695', and by obtaining posters presented at congresses. Product labelling provided additional information. Study selection: All available clinical reports of studies were identified. Data extraction: Descriptions of the principal results and calculation of number needed to treat (NNT) and number needed to harm (NNH) for relevant dichotomous outcomes were extracted from the available study reports and other sources of information. Data synthesis: Levomilnacipran (1S, 2R-milnacipran) is a potent and selective serotonin-norepinephrine reuptake inhibitor with greater potency for inhibition of norepinephrine relative to serotonin reuptake. Approval for the treatment of MDD was based on a clinical development program that included one 10-week Phase II and four 8-week Phase III randomised placebo-controlled clinical trials in outpatients with MDD where levomilnacipran was titrated to target doses ranging from 40 to 120 mg taken once daily. Four of the five trials demonstrated efficacy as measured by the Montgomery Asberg Depression Rating Scale, with a NNT for response vs. placebo of 9 (95% CI 7-15), and for remission, 14 (95% CI 10-28). Levomilnacipran also demonstrated superiority over placebo as measured by improvement in the Sheehan Disability Scale functional impairment total score. NNH vs. placebo for discontinuation because an adverse event (AE) across all five trials was 19 (95% CI 14-28). The most commonly encountered AEs (incidence ≥ 5% and at least twice the rate of placebo) as identified in product labelling were nausea, hyperhidrosis, constipation, heart rate increased, erectile dysfunction in men, vomiting, tachycardia and palpitations, with NNH values vs. placebo of 10 (95% CI 8-12), 15 (95% CI 12-19), 17 (95% CI 13-24), 21 (95% CI 17-29), 20 (95% CI 14-36), 25 (95% CI 20-37), 25 (95% CI 19-40) and 30 (95% CI 22-49), respectively. Levomilnacipran was not associated with clinically relevant weight change in the short-term trials or in a 48-week open-label extension trial. Mean changes from baseline in systolic blood pressure (BP), diastolic BP and heart rate were +3.0 mmHg, +3.2 mm Hg and +7.4 bpm for levomilnacipran, and À0.4 mmHg, no change and À0.3 bpm for placebo, respectively. Categorical shift in BP from normal or prehypertension at baseline to stage 1 or stage 2 hypertension at end of study was 10.4% for levomilnacipran vs. 7.1% for placebo, for a NNH of 31 (95% CI 18-94). Conclu...

Orexin/Hypocretin Based Pharmacotherapies for the Treatment of Addiction: DORA or SORA?

“…A survey of 50 substance abuse treatment providers has shown that a 50 % increase in the abstinence rate (from 25 to 38 %) would be considered clinically significant, but a new therapy would have to halve the number of drinking days and drinks per drinking day to interest providers in adopting it [205]. A relapse risk difference of at least 10 % also appears in line with patterns of FDA approval for pharmacotherapies for psychiatric disorders, such as bipolar disorder or depression, where the number needed to treat for one person to benefit (NNT) 1 for approved drugs are typically less than 10 [206][207][208] and acamprosate was thought that have an NNT of 9.09 [209]. Certainly, individual studies in preclinical animal models are able to achieve such effect sizes but translational researchers might be more willing to bet on a DORA to deliver large enough effects [183] in the clinic where the patients have not been bred under controlled conditions.…”

The Combination of Levomilnacipran, Cognitive Behavior Therapy and Christian Based Self –Help Group in the Treatment of Bulimia Nervosa: A Case Report

“…Levomilnacipran increases systolic and diastolic blood pressure by a median of 4 mmHg and 2.5 mmHg, respectively [21], and 3% of patients (95% confidence interval, 1% to 6%) with normal blood pressure or prehypertension will develop hypertension [23]. It is advisable not to use it in patients with poorly controlled hypertension [22].…”

“…It is advisable not to use it in patients with poorly controlled hypertension [22]. Although, it does not cause clinically significant changes in basic laboratory tests or QT prolongation [21,[23][24][25][26]. Levomilnacipran should not be used with other serotonergic agents, such as MAOIs, triptans, tramadol, and other antidepressants to minimize the risk of serotonin syndrome [22].…”

Effects of 50 and 100 mg desvenlafaxine versus placebo on sexual function in patients with major depressive disorder

“…Duloxetine is associated with significantly lower rates of SD compared with SSRIs (paroxetine, escitalopram), although differences from placebo have been reported (Delgado et al, 2005;Clayton et al, 2007). Ejaculation disorder and erectile dysfunction are reported as common adverse events in levomilnacipran clinical trials (Asnis et al, 2013;Mago et al, 2013;Bakish et al, 2014;Sambunaris et al, 2014;Shiovitz et al, 2014), but none of the levomilnacipran studies published to date have included statistical analysis of data from a validated sexual functioning instrument (Citrome, 2013). On the basis of the current results, desvenlafaxine appears to have low potential for SD overall, but head-to-head trials will be needed to determine how it compares with other antidepressant drugs (e.g.…”