OBJECTIVES: Vortioxetine, a novel antidepressant exhibiting a multimodal mechanism of action, was approved for the treatment of adults with major depressive disorder (MDD). This extension study of a recently published meta-analysis (Llorca et al. Curr Med Res Opin 2014;30(12):2589-606) compares the efficacy and tolerability of vortioxetine with seven commonly used antidepressants marketed in the US. METHODS: Indirect comparisons using meta-regression, an extension of random-effects meta-analysis, were performed using data from 54 double-blind, placebo-controlled Phase 3 pivotal studies identified in a systematic review (N= 18,312 patients). To ensure study comparability, only experimental drug and placebo arms were included in primary analyses. Study-level standardized effect sizes were regressed on active treatment to compare efficacy and tolerability of vortioxetine with branded (levomilnacipran, vilazodone, desvenlafaxine) and generic (duloxetine, escitalopram, sertraline, venlafaxine) antidepressants. Efficacy was defined as change from baseline on the Montgomery-Asberg Depression Scale or Hamilton Depression Rating Scale after 2 months (6-12 weeks) of treatment. Tolerability was defined as the withdrawal rate due to any adverse event. RESULTS: Standardized mean differences for vortioxetine compared with the selected antidepressants (negative estimates favor vortioxetine) were: duloxetine, 0.10 (95% confidence interval [CI]: -0.12, 0.32); escitalopram, -0.04 (95% CI:  -0.32, 0.24); sertraline, -0.02 (95% CI: -0.39, 0.34); venlafaxine, 0.14 (95% CI: -0.11, 0.39); levomilnacipran, -0.05 (95% CI: -0.28, 0.19); vilazodone, -0.23 (95% CI: -0.53, 0.06); and desvenlafaxine, 0.04 (95% CI: -0.16, 0.23).  Significantly lower withdrawal rates were observed for vortioxetine versus sertraline, venlafaxine, and desvenlafaxine (all P<0.05). No statistically significant difference in withdrawal rates was observed between vortioxetine and duloxetine, escitalopram, levomilnacipran, or vilazodone. CONCLUSIONS: These findings show that vortioxetine offers a comparable combination of efficacy and tolerability in MDD to other antidepressants marketed in the US.