What is the clinical evidence from this study?

Study design: Cohort. Population: Cardiovascular disease (n=37668). Intervention: Depressive symptoms vs. Absence of or fewer waves with depressive symptoms. Primary outcome: Self-reported physician-diagnosed CVD (OR 2.097, 95% CI 1.659-2.651).

March 13, 2026Open Access

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

Key Result

Persistent depressive symptoms significantly increased the risk of cardiovascular disease over 9 years (OR 2.097; 95% CI 1.659-2.651 in the CHARLS cohort), demonstrating a reversible cumulative effect.

Study Design

Type

Cohort (n=37,668)

Multicenter

Yes

Structured PICO

Do persistent depressive symptoms increase the risk of cardiovascular disease in middle-aged and older adults?

Population

37,668 middle-aged and older adults from three prospective cohorts in China, the USA, and South Korea followed for up to 9 years to assess the longitudinal effect of depressive symptoms on CVD risk.

Exposure

Persistent depressive symptoms (defined by CES-D scale cutoffs)

Comparator

Absence of depressive symptoms or fewer waves with depressive symptoms

Outcome

Self-reported physician-diagnosed cardiovascular disease (CVD)hard clinical

Persistent depressive symptoms have a cumulative and reversible causal effect on the risk of developing cardiovascular disease, highlighting the importance of integrating mental health care into CVD prevention.

Main Result

Odds Ratio: 2.097 (95% CI 1.659–2.651)

Abstract

• The study for the first time applied the Longitudinal Targeted Maximum Likelihood Estimation (LTMLE) method, using data from three large prospective cohorts in China, the United States, and South Korea, to provide multi-country evidence for the longitudinal causal relationship between depressive symptoms and cardiovascular disease (CVD). • The research found that the impact of depressive symptoms on CVD risk exhibits a distinct temporal cumulative effect; the longer depressive symptoms persist, the higher an individual's risk of developing CVD. • The study revealed that the influence of depressive symptoms on CVD risk demonstrates a pattern consistent with reversible association: 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. 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. 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. 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. 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.