Premenopausal Depression and Risk of Cardiovascular Disease After Menopause: A Large Real-world Cohort Study

Objective: While depression has been linked to adverse cardiometabolic profiles in postmenopausal women, its temporal relationship with cardiovascular disease (CVD) when occurring before menopause remains unclear. This study examined whether depression diagnosed prior to menopause was associated with incident CVD after menopause. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network. Postmenopausal women were assigned to two cohorts: cohort 1 included women with depression diagnosed before menopause and without preexisting CVD, premature menopause, or conventional CVD risk factors (smoking, diabetes mellitus, hypertension, dyslipidemia, overweight/obesity, or family history of ischemic heart disease); cohort 2 included comparable women without premenopausal depression. Propensity score matching balanced baseline characteristics, including age at menopause, current age, and ethnicity. Risk differences and risk ratios (RRs) with 95% confidence intervals(CIs) were calculated to compare incident CVD (myocardial infarction, coronary heart disease, stroke, heart failure, or cardiovascular death). Time-to-event outcomes were assessed using Kaplan–Meier curves and log-rank testing, and hazard ratios (HRs) were estimated using Cox proportional hazards regression. Results: Initial queries identified 90,638 women in cohort 1 and 1,237,202 in cohort 2. After matching, 88,884 women remained in each cohort, with a mean (SD) age of 57.6(11.4) years. Follow-up varies according to database entry time, with maximum follow-up of 20 years. Women with premenopausal depression had a higher incidence of postmenopausal CVD than those without depression (4.0% vs. 3.3%; RR,1.23; 95% CI, 1.17–1.29; p<.001), corresponding to an absolute risk difference of 0.7% (95% CI, 0.6%–0.9%). Because the proportional hazards assumption was not satisfied, the Cox hazard ratio was interpreted as a secondary average time-to-event summary rather than as the primary effect estimate. The estimated hazard ratio for incident CVD was 1.21 (95% CI, 1.15–1.27; log-rank p<.001), representing an average association across the follow-up period rather than a constant hazard over time. Conclusion: Women with premenopausal depression had a higher cumulative incidence of postmenopausal cardiovascular disease than matched women without depression, suggesting that premenopausal depression may represent a marker of increased cardiovascular vulnerability in midlife women.