Psychotropic medication use, lifestyle, genetic risk for high BMI and the incidence of cardiovascular disease

Psychotropic medication use, unhealthy lifestyle behavior and polygenic risk for high BMI (PGS-BMI) may contribute to weight gain and thereby increase cardiovascular disease (CVD) risk in people with mental illness. Using a sample of UK Biobank participants, we examined associations of psychotropic use, lifestyle and PGS-BMI with two coprimary outcomes, BMI and incident CVD, using regression, interaction and mediation models. Among 496,662 participants (mean (s.d.) age = 56.5 (8.1) yr, 54.3% female), psychotropic medication use was positively associated with BMI relative to no use (β = 0.053, R² = 0.019). This association was more pronounced for multiple psychotropic use than psychotropic monotherapy (9.12% and 5.08% BMI increases, respectively). Unhealthy lifestyle was associated with increased CVD risk among participants with psychotropic use (HR = 1.69, 95% CI = 1.59-1.80). Among users of psychotropics we found consistently positive and linear associations of increasing PGS-BMI and increasingly unhealthy lifestyle with higher BMI and CVD incidence, with highest CVD risks detected in people with high PGS-BMI and unhealthy lifestyle (HR relative to those not using psychotropics, with low PGS-BMI and healthy lifestyle, 3.33, 95% CI = 2.36-4.70). Among participants with a psychiatric diagnosis, CVD risk was not increased in those using psychotropics relative to those not using psychotropics (HR = 0.98, 95% CI = 0.92–1.05). These results suggest that, among psychotropic medication users, those with both a high PGS-BMI and unhealthy lifestyle had the highest BMI and CVD risk, whereas those with both a low PGS-BMI and healthy lifestyle had the lowest risk. Notably, the association between psychotropic medication use and CVD risk was modified by psychiatric diagnosis: among people with a psychiatric diagnosis, psychotropic medication use was not associated with increased CVD risk.