Abstract
Depression is prevalent in cardiovascular-kidney-metabolic (CKM) syndrome, but its complex association with mortality remains incompletely characterized. This prospective cohort study utilized National Health and Nutrition Examination Survey data (2007-2016), including 27,673 adults with CKM syndrome (median follow-up 93.5 months). Associations between patient health questionnaire-9 (PHQ-9) scores and all-cause/cardiovascular mortality were analyzed using multivariable Cox regression, threshold models, subgroup, and mediation analyses. Among 2468 all-cause and 745 cardiovascular deaths, deceased individuals were significantly older, more frequently male, and more often non-Hispanic White. Higher CKM stage (stages 3-4: 63.9% of deaths vs 7.8% survivors), clinical parameters, and lower socioeconomic status predicted mortality (all P < .001). PHQ-9 demonstrated a non-linear, J-shaped association with mortality. Per 1-point PHQ-9 increase, fully adjusted all-cause mortality risk rose 1% (hazard ratio (HR) = 1.01, 95% confidence interval (CI): 1.00-1.02, P = .030). Cardiovascular mortality association was non-significant after full adjustment (HR = 1.02, 95% CI: 1.00-1.04, P = .076). A significant inflection point occurred at PHQ-9 = 11. Below 11, each point increase significantly elevated all-cause (HR = 1.03, 95% CI: 1.01-1.04, P = .0001) and cardiovascular mortality risk (HR = 1.05, 95% CI: 1.02-1.08, P = .0004). Above 11, associations were non-significant. The PHQ-9-mortality association was significantly stronger in participants ≤ 60 years (P-interaction = .001), with moderate/high chronic kidney disease risk (P-interaction = .029), and with metabolic syndrome (P-interaction = .024). Physical activity, poverty income ratio, and marital status were found to significantly account for a portion (12.76-14.80%) of the association between PHQ-9 scores and all-cause mortality (all P < .0001). Depressive symptoms demonstrate threshold-specific mortality risks in CKM syndrome. Socioeconomic factors (income, marital status) and physical activity significantly attenuate depression-associated mortality risk, partly mediating the association.