OBJECTIVES: To assess relative efficacy and tolerability of vortioxetine versus other antidepressants in patients with major depressive disorder (MDD) who experience inadequate response after treatment with selective serotonin reuptake inhibitors (SSRIs) or serotonin–norepinephrine reuptake inhibitors (SNRIs). METHODS: A systematic literature review identified 27 switch studies, three of which (REVIVE, Kasper 2013 and STAR*D) contributed to the relevant network for quantitative assessment, based on remission rate and withdrawal rate due to adverse events (AEs). Switch treatments compared to vortioxetine in the analysis were agomelatine, sertraline, venlafaxine XR and bupropion SR, commonly used in clinical practice. Simple adjusted indirect comparisons using Bucher’s method were also conducted, in line with guidelines from EUnetHTA. RESULTS: Direct analysis of remission rates based on the REVIVE study showed vortioxetine had a significantly higher remission rate (relative difference: -11.0% [95% CI: -19.4; -2.6]) than agomelatine. Indirect comparisons revealed that vortioxetine had numerically higher remission rates than sertraline (relative difference: -14.4%, [95% CI: -29.9; 1.1]), venlafaxine (relative difference: -7.20%, [95% CI: -24.3; 9.9]), and bupropion (relative difference: -10.70%, [95% CI: -27.8; 6.4]). Rate of withdrawals due to AE was numerically lower with vortioxetine than agomelatine (relative difference: 3.6%, [95% CI: -1.1; 8.3]). Indirect comparison showed that withdrawal rates due to AE were significantly lower for vortioxetine than sertraline (relative difference: 12.1%, [95% CI: 3.1; 21.1]), venlafaxine (relative difference: 12.3%, [95% CI: 0.8; 23.8]), and bupropion (relative difference: 18.3%, [95% CI: 6.4; 30.1]).  CONCLUSIONS: The evidence supporting treatment strategies for patients with MDD with inadequate response to SSRI or SNRI is limited. This study demonstrates that remission rates for vortioxetine are numerically higher than other antidepressants widely used in clinical practice. Vortioxetine is a well-tolerated treatment, showing statistically lower withdrawal rates due to AE in patients with MDD with an inadequate response to prior SSRI or SNRI monotherapy.