OBJECTIVES: The primary objective was to estimate incremental cost-effectiveness of vortioxetine, a serotonin modulator and simulator (SMS) versus desvenlafaxine, a serotonin-norepinephrine reuptake inhibitor (SNRI), as potential first line medications for treatment of mild or moderate major depression. The clinical benefit of a SMS may be in faster onset and shorter time to remission. Evidence suggests vortioxetine causes fewer adverse drug events (ADEs) than desvenlafaxine, which has implications for discontinuation of therapy. METHODS: A decision tree was constructed to model the cost effectiveness of these two agents from the societal perspective. Parameters were obtained from published clinical trial data, a meta-analysis using indirect treatment comparison, observational studies, preference elicitation studies, and cost estimates from Average Wholesale Prices for medications and claims analyses for cost of medical care. The model assumed that patients achieved remission. The time horizon was 48 weeks and included opportunities to switch medication therapy at 8 weeks and relapse at 24 weeks. Incremental cost-effectiveness ratios (ICERs) were calculated using the number of discontinuations averted, relapses averted, and quality adjusted life years (QALYs) gained as outcomes. One-way sensitivity analyses were conducted. RESULTS: The ICER was $77,800 per QALY gained, $59,500 per relapse averted, and $58,500 per averted discontinuation due to ADEs. The parameter that was least robust was a utility value of maintenance therapy for vortioxetine or desvenlafaxine applied to weeks 8-48 (0.80, range: 0.78-0.82; 0.76, range 0.74-0.78, respectively). Time to remission was varied from 6-10 weeks. A shorter time to remission for vortioxetine provided modest improvements in the ICER while a longer time to remission increased cost over the point estimate of $77,800 per QALY gained ($69,000-$88,900 per QALY gained, respectively). CONCLUSIONS: Model results suggest that there is value in investing in vortioxetine over desvenlafaxine. A potentially faster time to remission for vortioxetine would result in increased value.