To explore the association of cardiovascular-kidney-metabolic (CKM) health with the risk of depression and anxiety and to investigate the joint association of CKM health and social connection with depression and anxiety.

This prospective cohort study included 344 956 participants from the UK Biobank. CKM syndrome was identified as a medical condition with the presence of metabolic risk factors, cardiovascular disease, and chronic kidney disease, and was classified into five stages (stage 0–4) in this study. Loneliness and social isolation status were determined by self-reported questionnaires. Cox proportional hazards models were applied for analyses.

Compared with participants in stage 0, the HRs for depression were 1.17 (95% CI 1.10–1.25), 1.40 (95% CI 1.33–1.48), and 2.14 (95% CI 1.98–2.31) for participants in stage 1, 2–3, and 4, respectively. Similarly, participants in stage 2–3 (HR = 1.20, 95% CI 1.14–1.26) and stage 4 (HR = 1.63, 95% CI 1.51–1.75) had greater risks of incident anxiety. We found additive interactions between loneliness and CKM health on the risk of depression and anxiety. Participants simultaneously reported being lonely and in stage 4 had the greatest risk of depression (HR = 4.44, 95% CI 3.89–5.07) and anxiety (HR = 2.58, 95% CI 2.21–3.01) compared with those without loneliness and in stage 0. We also observed an additive interaction between social isolation and CKM health on the risk of depression.

Our findings suggest the importance of comprehensive interventions to improve CKM health and social connection to reduce the disease burden of depression and anxiety.