Abstract
BACKGROUND: MDD is a leading cause of disability worldwide, yet its associations with mortality and hospitalization remain unclear. We aimed to quantify the risks of cause-specific mortality and hospitalization associated with a lifetime history of MDD, while accounting for potential reverse causality and residual confounding. METHODS: We conducted a retrospective cohort study using data from 113,196 UK Biobank participants (62,822 women and 50,374 men), aged 40–69 years at recruitment, who were assessed between 2008 and 2010. Participants with pre-existing physical health conditions or mental or behavioural disorders other than MDD were excluded. Cause-specific Cox proportional hazards models estimated associations between MDD and mortality and hospitalization due to suicide, cerebrovascular and cardiac disease, respiratory diseases, and cancer. Models were sequentially adjusted for age, behavioural (smoking behaviour, alcohol use, body mass index, level of physical activity) and social (family status, education level, socioeconomic status, family history of MDD) factors. We focused on reductions in the log of the hazard ratios to assess potential residual confounding. RESULTS: MDD was associated with significantly increased risks of suicide mortality (HR = 8.52, 95% CI 3.31–21.94 in women; 3.56, 1.86–6.84 in men) and hospitalization from suicide attempts (HR = 1.94, 95% CI 1.45–2.61 in women; 3.20, 2.19–4.68 in men). In women, MDD also conferred increased risks of cerebrovascular mortality (HR = 1.92, 95% CI 1.25–2.94) and hospitalization (HR = 1.30, 95% CI 1.13–1.50). In contrast, no significant associations were observed between MDD and cerebrovascular outcomes in men. There were sex-specific differences in the associations between MDD and select cancers, notably breast, stomach, and leukemia. Associations with cardiac disease mortality were not significant after full covariate adjustment. CONCLUSIONS: Participants with MDD had elevated risks of mortality and hospitalization due to suicide and certain physical health conditions, with more prominent effects observed in women. These associations remained after adjusting for confounders, highlighting the independent and sex-specific effects of MDD on both psychiatric and physical health. Further investigation into the mechanisms driving these associations is warranted. CLINICAL TRIAL NUMBER: Not applicable. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12888-026-07939-9.