ORIGINAL INVESTIGATION Bidirectional Association Between Depression and

the diabetes-depression relation is bidirectional, few studies have addressed this hypothesis in a prospective setting. Methods: A total of 65 381 women aged 50 to 75 years in 1996 were observed until 2006. Clinical depression was defined as having diagnosed depression or using an-tidepressants, and depressed mood was defined as hav-ing clinical depression or severe depressive symptoms, ie, a 5-item Mental Health Index (MHI-5) score of 52 or less. Self-reported type 2 diabetes mellitus was con-firmed by means of a supplementary questionnaire vali-dated by medical record review. Results:During 10 years of follow-up (531 097 person-years), 2844 incident cases of type 2 diabetesmellituswere documented. Compared with referents (MHI-5 score of 86-100) who had the best depressive symptom scores, participants with increased severity of symptoms (MHI-5 scores of 76-85 or 53-75, or depressed mood) showed a monotonic elevated risk of developing type 2 diabetes (P for trend=.002 in the multivariable-adjusted model). The relative risk for individuals with depressedmoodwas 1.17 (95 % confidence interval [CI], 1.05-1.30) after ad-justment for various covariates, and participants using antidepressants were at a particularly higher relative risk (1.25; 95%CI, 1.10-1.41). In a parallel analysis, 7415 cases of incident clinical depressionwere documented (474722 person-years). Comparedwith nondiabetic subjects, those with diabetes had a relative risk (95 % CI) of developing clinical depression after controlling for all covariates of 1.29 (1.18-1.40), and it was 1.25 (1.09-1.42), 1.24 (1.09-1.41), and 1.53 (1.26-1.85) in diabetic subjects without medications, with oral hypoglycemic agents, andwith in-sulin therapy, respectively. These associations re-mained significant after adjustment for diabetes-related comorbidities. Conclusion:Our results provide compelling evidence that the diabetes-depression association is bidirectional