Background and Objectives To assess whether the association among depression, vascular disease, and mortality differs in people with multiple sclerosis (MS) compared with age-, sex-, and general practice–matched controls.

Methods We conducted a population-based retrospective matched cohort study between January 1, 1987, and September 30, 2018, that included people with MS and matched controls without MS from England, stratified by depression status. We used time-varying Cox proportional hazard regression models to test the association among MS, depression, and time to incident vascular disease and mortality. Analyses were also stratified by sex.

Results We identified 12,251 people with MS and 72,572 matched controls. At baseline, 21% of people with MS and 9% of controls had depression. Compared with matched controls without depression, people with MS had an increased risk of incident vascular disease regardless of whether they had comorbid depression. The 10-year hazard of all-cause mortality was 1.75-fold greater in controls with depression (95% confidence interval [CI] 1.59–1.91), 3.88-fold greater in people with MS without depression (95% CI 3.66–4.10), and 5.43-fold greater in people with MS and depression (95% CI 4.88–5.96). Overall, the interaction between MS status and depression was synergistic, with 14% of the observed effect attributable to the interaction. Sex-stratified analyses confirmed differences in hazard ratios.

Discussion Depression is associated with increased risks of incident vascular disease and mortality in people with MS, and the effects of depression and MS on all-cause mortality are synergistic. Further studies should evaluate whether effectively treating depression is associated with a reduced risk of vascular disease and mortality.