Vortioxetine 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?

Summary Objective To describe the efficacy and safety of levomilnacipran (extended-release 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 −0.4 mmHg, no change and −0.3 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). Conclusions Levomilnacipran represents another option for the treatment of MDD. Levomilnacipran appears to have a favourable weight-gain profile. Additional controlled data regarding long-term efficacy and comparative effectiveness will help characterise this new agent.