Association of CTI and its obesity-related derivatives with incident depression among middle-aged and older adults across CKM stages 0-4: a nationwide prospective cohort study and external clinical validation

Background Cardiovascular-kidney-metabolic (CKM) syndrome integrates metabolic, renal, and cardiovascular risks. While C-reactive protein-triglycerides-glucose (CTI)-related indices are associated with future depression risk, their link to incident depression in populations across CKM stages 0–4 remains unestablished. Methods This prospective cohort included 3,130 depression-free participants across CKM stages 0–4 from the China Health and Retirement Longitudinal Study. Four machine learning algorithms determined the core covariates for multivariable adjustments. Receiver operating characteristic (ROC) curves, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) assessed the predictive performance of CTI-related indices. Multivariable Cox models, restricted cubic splines, and K-means clustering evaluated associations of the optimal indicator’s baseline, cumulative, and trajectory exposures with incident depression. An independent clinical cohort (n=350) provided directional replication. Results Over a 9-year median follow-up, 1,275 participants developed depression. The CTI-Chinese visceral adiposity index (CTI-CVAI) achieved the highest AUC (0.705), providing incremental predictive value (NRI = 0.126, IDI = 0.005; P 0.001). The fully adjusted model revealed a decreased depression risk with higher baseline CTI-CVAI (HR per 1-SD=0.91, 95% CI: 0.85-0.96). A linear dose-response relationship was observed for both baseline and cumulative CTI-CVAI. Furthermore, individuals in the high-increasing trajectory group (HR = 0.81, 95% CI: 0.69-0.97) and the highest cumulative exposure tertile (HR = 0.87, 95% CI: 0.76-0.97) exhibited significantly lower depression risks. This inverse association was primarily prominent in participants aged 60 years ( P for interaction=0.032). The external validation cohort replicated the moderate discriminatory power (AUC = 0.691) and the independent inverse association of CTI-CVAI with incident depressive symptoms (OR per 1-SD=0.92, P 0.001). Conclusions CTI-CVAI is an independent predictor with moderate discrimination for incident depression in populations across CKM stages 0-4. These findings support its potential as a candidate marker, suggesting moderate cardiometabolic and nutritional reserves may be associated with better mental health in middle-aged and older adults across CKM stages 0-4.