BACKGROUND: Vortioxetine is the first mixed serotonin agonist and antagonist 
antidepressant approved in the US. We sought to evaluate all published and 
unpublished data available to determine the efficacy and harms of vortioxetine 
in adults with major depressive disorder.
METHODS: We used a predefined search strategy of MEDLINE, the Cochrane Central 
Register of Controlled Trials, ClinicalTrials.gov, and Drugs@FDA to identify 
studies evaluating vortioxetine in the acute treatment of major depressive 
disorder. Only randomized controlled trials (RCTs) that provided results on 
relevant clinical efficacy and safety outcomes were included. Study quality was 
assessed and results were pooled using mixed effect meta-analyses where 
applicable.
RESULTS: We identified 11 RCTs with 6,145 participants meeting inclusion 
criteria (eight were published and three were unpublished). The trials did not 
exceed 8 weeks in duration. The response rate with vortioxetine was 
significantly higher for 1-mg (relative risk (RR) = 1.91; 95% confidence 
interval (CI) 1.36 to 2.69), 5-mg (RR = 1.33; 95% CI 1.10 to 1.61), 10-mg 
(RR = 1.42; 95% CI 1.21 to 1.67), and 20-mg doses (RR = 1.58; 95% CI 1.19 to 
2.08) compared to placebo. Remission rates were significantly higher for the 
10-mg group (RR = 1.45; 95% CI 1.18 to 1.77) and the 20-mg group (RR = 1.68; 95% 
CI 1.19 to 2.37) compared to placebo. Meta-regression of dose on the log odds 
ratio of response was not statistically significant (β = 0.01; P = 0.46). 
Vortioxetine response rates were lower than active serotonin and norepinephrine 
reuptake inhibitor (SNRI) comparators for the 5-mg (RR = 0.88; 95% CI 0.80 to 
0.98), 15-mg (RR = 0.78; 95% CI 0.68 to 0.90), and 20-mg (RR = 0.82; 95% CI 0.72 
to 0.94) doses. The most common adverse events were nausea and vomiting which 
increased in frequency with higher doses.
CONCLUSIONS: Vortioxetine was significantly more effective than placebo for 
acute treatment of major depressive disorder (MDD). Although treatment effect 
estimates varied substantially between studies, a dose effect was not observed. 
Vortioxetine does not appear to be more effective, and is potentially less 
effective, than an SNRI.
SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42013006198 .