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.
Zhang R, Yang B, et al. • Frontiers in endocrinology • 2026
CTI-CVAI (C-reactive protein-triglycerides-glucose index combined with Chinese visceral adiposity index) is an independent predictor with moderate discrimination for incident depression in populations across CKM stages 0-4, with higher CTI-CVAI associated with lower depression risk.
Key Findings
Results
CTI-CVAI achieved the highest predictive performance among CTI-related indices for incident depression, with an AUC of 0.705.
ROC curve analysis compared multiple CTI-related indices for discriminatory ability.
CTI-CVAI provided incremental predictive value over the base model with NRI = 0.126 and IDI = 0.005 (P < 0.001).
External clinical validation cohort (n=350) replicated moderate discriminatory power with AUC = 0.691.
Four machine learning algorithms were used to determine core covariates for multivariable adjustments.
Results
Higher baseline CTI-CVAI was independently associated with decreased risk of incident depression in the fully adjusted model.
HR per 1-SD increase in baseline CTI-CVAI = 0.91 (95% CI: 0.85–0.96).
A linear dose-response relationship was observed for baseline CTI-CVAI using restricted cubic splines.
The external validation cohort replicated the independent inverse association with OR per 1-SD = 0.92 (P < 0.001).
The study included 3,130 depression-free participants at baseline across CKM stages 0–4.
Results
Over a 9-year median follow-up, 1,275 out of 3,130 participants developed depression.
The cohort was drawn from the China Health and Retirement Longitudinal Study.
Participants were middle-aged and older adults spanning CKM stages 0–4.
The incidence rate represents a substantial proportion (approximately 40.7%) of the depression-free baseline sample.
Multivariable Cox proportional hazards models were used to assess associations.
Results
Individuals in the high-increasing CTI-CVAI trajectory group had significantly lower depression risk compared to other trajectory groups.
HR for high-increasing trajectory group = 0.81 (95% CI: 0.69–0.97).
K-means clustering was used to identify CTI-CVAI trajectory groups over time.
Trajectory analysis captured longitudinal exposure patterns beyond single baseline measurements.
Results
Participants in the highest cumulative CTI-CVAI exposure tertile exhibited significantly lower depression risk.
A linear dose-response relationship was observed for cumulative CTI-CVAI exposure.
Cumulative exposure analysis accounted for sustained cardiometabolic and nutritional status over time.
Results
The inverse association between CTI-CVAI and incident depression was primarily prominent in participants aged under 60 years.
P for interaction by age group = 0.032.
Subgroup analysis stratified participants at the threshold of 60 years.
The age-specific interaction suggests differential metabolic-mental health relationships across age strata in middle-aged and older adults.
Discussion
The authors interpreted higher CTI-CVAI as potentially reflecting moderate cardiometabolic and nutritional reserves associated with better mental health outcomes.
The authors noted that 'moderate cardiometabolic and nutritional reserves may be associated with better mental health in middle-aged and older adults across CKM stages 0–4.'
CTI-CVAI combines C-reactive protein, triglycerides, glucose, and visceral adiposity components.
The findings were framed as supporting CTI-CVAI's 'potential as a candidate marker' for depression risk stratification.
The authors cautioned that the inverse association does not imply that high obesity or inflammation is protective, but rather reflects the composite index's nutritional and metabolic dimensions.
What This Means
This research suggests that a composite blood and body composition marker called CTI-CVAI — which combines measures of inflammation (C-reactive protein), blood fats (triglycerides), blood sugar (glucose), and abdominal fat (visceral adiposity) — can modestly predict which middle-aged and older adults are more likely to develop depression over time. In a large Chinese cohort of over 3,000 adults followed for about 9 years, roughly 40% developed depression. Counterintuitively, people with higher CTI-CVAI scores at baseline, and those whose scores increased or remained high over time, were actually less likely to develop depression. This inverse relationship was confirmed in an independent group of 350 patients.
The finding that higher CTI-CVAI was linked to lower depression risk may seem surprising given that its components (inflammation, blood sugar, visceral fat) are typically associated with poor health. The researchers suggest this pattern may reflect the role of nutritional and metabolic reserves — meaning that in older adults, having some metabolic 'buffer' may support better mental health, particularly in those under 60. The study used machine learning to identify the most relevant risk factors and multiple statistical approaches to confirm the robustness of the association.
This research suggests that CTI-CVAI could serve as a useful screening marker to identify people across all stages of cardiovascular-kidney-metabolic (CKM) syndrome who may be at higher risk for depression, potentially helping clinicians prioritize mental health monitoring in their patients. The moderate predictive accuracy (AUC around 0.70) means the marker is informative but not definitive on its own, and further research is needed to understand the biological mechanisms and whether this relationship holds in other populations.
Zhang R, Yang B, Pan N, An Y, Yu Q. (2026). 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.. Frontiers in endocrinology. https://doi.org/10.3389/fendo.2026.1849662