The longitudinal and reversible causal link between depressive symptoms and cardiovascular disease among middle-aged and older adults: findings from three national cohorts.

BACKGROUND: Although the association between depressive symptoms and cardiovascular disease (CVD) has been extensively studied, evidence for a long-term causal relationship remains sparse. This research employed advanced causal inference techniques to evaluate this longitudinal effect and its potential reversibility.

METHOD: We analyzed data from 37,668 participants across three prospective cohorts: CHARLS (China), HRS (USA), and KLoSA (South Korea). Applying the Longitudinal Targeted Maximum Likelihood Estimation (LTMLE) method across five time points, we assessed the causal effect of depression (defined by CES-D scale cutoffs) on self-reported physician-diagnosed CVD. Subgroup analyses were conducted by gender and age. Multiple sensitivity analyses were conducted to validate the robustness of the findings.

RESULTS: Across all cohorts, the risk of CVD significantly increased with longer follow-up durations under persistent depressive symptoms. For example, in CHARLS, the adjusted odds ratio (OR) increased from 1.570 (95% CI: 1.398-1.798) at Year 2 to 2.097 (95% CI: 1.659-2.651) by Year 9. Further analysis of different exposure sequences of depressive symptoms revealed that the risk of CVD increased gradually with a greater cumulative number of waves with depressive symptoms, whereas it decreased correspondingly with more waves without depressive symptoms, demonstrating a pattern consistent with reversible association.

CONCLUSIONS: This multi-cohort study provides evidence for a longitudinal causal relationship between depressive symptoms and CVD, showing temporal cumulative effect and a risk pattern consistent with reversible association. These results highlight the need to integrate mental health care into CVD prevention.