Abstract
Depression and anxiety are common mental disorders with substantial public health burden, yet the relative contributions of potentially modifiable physiological, psychosocial, and female-specific reproductive factors to their development remain incompletely understood, particularly across sex and age groups. We aimed to examine the associations of these factors with incident depression and anxiety in women and men and to estimate their population attributable fractions (PAFs). This prospective cohort study included 87,648 participants from the UK Biobank (44,383 women and 43,265 men) recruited between 2006 and 2010 and followed for a median of 13.7 years. Incident depression and anxiety were defined as the first recorded ICD-10 diagnosis or new-onset symptom positivity during follow-up among participants free of the respective condition at baseline. Sex-stratified Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), and individual and combined PAFs were calculated separately in women and men. During follow-up, 5.65% of women and 4.21% of men developed depression, while 6.02% and 3.60% developed anxiety, respectively. Psychosocial factors contributed the largest population burden in both sexes. Neuroticism symptoms had the largest PAFs for depression (women: HR 2.61, 95% CI: 2.36, 2.88; PAF 48.61%, 95% CI: 44.71%, 52.68%; men: HR 3.50, 95% CI: 3.07, 3.98; PAF 59.93%, 95% CI: 55.41%, 64.13%) and anxiety (women: HR 2.82, 95% CI: 2.56, 3.11; PAF 51.75%, 95% CI: 47.93%, 55.68%; men: HR 2.94, 95% CI: 2.58, 3.36; PAF 53.80%, 95% CI: 48.89%, 58.62%). The additive combined PAF of psychosocial factors was 61.17% in women and 66.90% in men for depression, and 59.98% and 56.80% for anxiety. Among physiological factors, obesity contributed the largest PAF for depression in both sexes, while chronic inflammation was associated with both outcomes in both sexes. In women, reproductive factors provided additional contributions, with hormone replacement therapy showing the largest PAFs for depression (HR 1.48, 95% CI: 1.34, 1.62; PAF 13.43%, 95% CI: 10.15%, 16.84%) and anxiety (HR 1.32, 95% CI: 1.20, 1.44; PAF 9.43%, 95% CI: 6.38%, 12.80%). Age-stratified analyses showed that psychosocial contributions remained substantial across age groups, whereas physiological and reproductive contributions were more pronounced in later life. When all factors were considered jointly, the overall additive combined PAFs were 67.54% in women and 69.71% in men for depression, and 61.23% and 57.82% for anxiety. These findings support sex-informed and life course-oriented prevention strategies for depression and anxiety.