Recent stressful life events, immunometabolic markers, and risk of schizophrenia: A prospective cohort study

Although recent stressful life events (SLEs) have been implicated as a risk factor for schizophrenia, prospective evidence and the underlying immunometabolic mechanisms remain unclear. This study investigated the association between recent SLEs and schizophrenia risk and explored the potential mediating role of immunometabolic markers.

Data were drawn from the UK Biobank prospective cohort. Cox proportional hazards models, linear mixed-effects models, and mediation analyses were applied.

We included 493,294 participants (mean [SD] age, 56.55 [8.09] years; 45.56% male) free of schizophrenia at baseline, among whom 492 schizophrenia cases were identified over a median follow-up of 13.91 years. Exposure to any recent SLEs was associated with a 49% higher risk of schizophrenia, with evidence of a dose-response relationship (e.g. highest SLE score group: HR, 7.15, 95% CI: 5.74-9.11). Among individual SLE types, 'serious illness, injury, or assault to yourself' and 'financial difficulties' showed the strongest associations with schizophrenia risk. Recent SLEs were associated with alterations in multiple immunometabolic markers, several of which were also significantly associated with schizophrenia risk. Mediation analyses indicated that specific immunometabolic markers (e.g. C-reactive protein and degree of unsaturation) partially mediated the association between recent SLEs and subsequent schizophrenia risk, with proportion mediated estimates of 9.0% and 11.7%, respectively.

In this cohort of predominantly middle-aged and older adults, recent SLEs were associated with increased subsequent schizophrenia risk. Immunometabolic pathways may partially underlie this association, supporting further investigation of integrated psychosocial and biological approaches to schizophrenia risk stratification.