Cardiorespiratory fitness and risk of depression and anxiety: A prospective cohort study with proteomic profiling in the UK Biobank

Background
Cardiorespiratory fitness may protect against mental disorders, but prospective evidence using objective fitness measures and mechanistic insights is limited.
Methods
In this prospective cohort of 46,062 UK Biobank participants free of depression or anxiety at baseline, VO2max was objectively estimated via standardized submaximal exercise testing. Incident depression and anxiety were ascertained via linked health records using ICD-10 codes. Cox proportional hazards models produced hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for sociodemographic, lifestyle, and clinical covariates. Restricted cubic splines assessed dose–response relationships. Proteomics were performed in a subset (n = 3245) to identify candidate biomarkers.
Results
Over a median 12.6-year follow-up, 2190 depression and 2483 anxiety cases occurred. Versus the lowest VO2max quartile, the highest quartile was associated with a 24% lower depression risk (HR 0.76, 95% CI 0.64–0.91) and a 17% lower anxiety risk (HR 0.83, 95% CI 0.71–0.98) in fully adjusted models. Per 1-SD higher VO2max, HRs were 0.90 (95% CI 0.84–0.96) for depression and 0.94 (95% CI 0.88–1.00) for anxiety. Dose–response analysis showed a linear relation for depression and a nonlinear pattern for anxiety. Associations were stronger among individuals with lower biological age. Proteomic analysis identified seven differentially expressed plasma proteins, including downregulated leptin and FABP4 and upregulated SPINT3 and INSL3; several proteins independently associated with mental health outcomes.
Conclusions
Higher objectively estimated cardiorespiratory fitness is associated with reduced incidence of depression and anxiety in dose-dependent patterns. Identified proteomic signatures implicate metabolic and neuroprotective pathways as potential mechanisms.