Adiposity and the first-onset of diagnosed mental illnesses: a population-based cohort study of 10 million UK adults

Background: Whether both high and low BMI are risk factors for mental illnesses is unclear, especially serious mental illnesses. Experimental evidence suggests that metabolic pathways might mediate the association, but this is uncertain. To examine associations between BMI and the first-onset of diagnosed mental illnesses with assessment for mediating effects of cardiometabolic disorders. Methods: Using the UK Clinical Practice Research Datalink (2000–2022), individuals ≥ 18 years with a recorded BMI assessment were included. Diagnosed mental illnesses were ascertained via clinical diagnoses, referrals to mental health services, or psychotropic prescriptions. Restricted cubic splines and Cox proportional hazard models estimated associations between BMI and incident mental illnesses. Mediation analyses assessed the mediating role of cardiometabolic disorders and biomarkers. Results: The study population included 10,465,562 adults (mean BMI 26.8 kg/m², standard deviation 5.5). Compared to those with a healthy BMI (18.5–25.0 kg/m²), individuals with severe obesity (≥ 40 kg/m²) had higher risks for depression (HR 1.32; 95% CI 1.31–1.33), anxiety (1.12; 1.10–1.13), bulimia nervosa (1.38; 1.20–1.58), other unspecified eating disorders (OUD) (2.04; 1.91–2.17), bipolar disorder (1.44; 1.36–1.54), schizophrenia (2.02; 1.91–2.15) and other psychoses (1.40; 1.28–1.53), but a lower risk for anorexia nervosa (0.45; 0.42–0.49). Individuals with underweight (< 18.5 kg/m²) were at increased risks of depression (1.28; 1.27–1.29), anxiety (1.26; 1.24–1.27), anorexia nervosa (3.88; 3.77–4.01), bulimia nervosa (1.52; 1.37–1.68), OUD (4.50; 4.33–4.67), schizophrenia (1.46; 1.35–1.56), and other psychoses (1.22; 1.10–1.35), with no association with bipolar disorder. Associations were stronger in women, younger adults, and Asian populations. Cardiometabolic diseases did not mediate associations, but LDL, triglycerides, HbA1c demonstrated partial mediation (indirect effect: 0.2%-15%). Conclusions: Individuals with severe obesity and underweight had increased risk of common and serious mental illnesses, especially in women, younger individuals, and Asian populations. Associations were not mediated by cardiometabolic diseases but partially by biomarkers.