Among adults with type 2 diabetes, we found that individuals with depression were at increased risk of clinically significant subsequent micro- and- macrovascular complications, relative to individuals without depression at baseline. Over a 5-year period, patients with major depression and diabetes had a 36% higher risk of developing advanced microvascular complications, such as ESRD or blindness, and a 25% higher risk of developing advanced macrovascular complications, such as myocardial infarction or stroke, compared with diabetic patients without depression. The strength of the association between depression and risk of adverse events generally increased with adjustment for demographic variables but decreased with adjustment for clinical characteristics. Adjustment for differences in health habits and glycemic control also reduced the association between depression and macrovascular complications but did not change the association between depression and microvascular complications.
We observed similar patterns in estimated associations between minor depression and microvascular and macrovascular complications, though the estimated increase in risk associated with minor depression was less than estimated increases associated with major depression. Associations between minor depression and macrovascular complications were not statistically significant.
Biological, psychological, or behavioral responses to stressors facing patients with diabetes and comorbid depression may all play important roles in the development of adverse diabetes outcomes (9
). Interestingly, our data showed that health habits such as physical inactivity and dietary factors (BMI) increased the risk for macrovascular complications such as myocardial infarction and stroke but had little effect on the association of depression and development of microvascular complications such as blindness and ESRD. Results from a recent study (23
) demonstrated that physical inactivity played a significant role in the association of depressive symptoms and subsequent cardiovascular events among patients with coronary heart disease. However, more research is needed to clarify the role of health risk behaviors (smoking, physical activity, and diet) on development of microvascular complications.
Activation of the hypothalamic-pituitary-adrenal axis (increased cortisol secretion), the sympathetic nervous system (increased catecholamine release), proinflammatory and procoagulation responses (increased levels of cytokines or platelet/endothelial cell adhesion molecule-1) associated with depression may provide a unifying pathophysiologic explanation for disease progression found in patients with type 2 diabetes in this study. Depression has consistently been linked to hypothalamic-pituitary-adrenal axis dysregulation, sympathetic nervous system activation, and proinflammatory and procoagulation markers among patients with coexisting cardiovascular disorders (8
). Perhaps these neuroendocrine and inflammatory responses accompanying depression also play similar roles in the progression of microvascular and macrovascular complications among patients with type 2 diabetes. Evidence that depression is associated with more negative appraisals of insulin therapy could also contribute to higher A1C levels and increased risk for complications (24
). Depressed patients would be less willing to start insulin therapy than nondepressed diabetic patients, thus delaying benefits from insulin treatment.
Limitations of this study include that depression was only measured at one point in time. However, depression runs a chronic or recurrent course among patients with coexisting diabetes. Approximately 75% of patients with depression and diabetes (recruited from same cohort) had a lifetime history of chronic depression lasting >2 years. Moreover, >80% of this cohort who met criteria for major depression at the 5-year follow-up also had major or minor depression at baseline (22
). Data on the number of prior depressive episodes were not collected to permit ascertainment of whether recurrent depression versus an initial depressive episode would have greater impact on adverse outcomes. The study was completed in one geographic region of the U.S., possibly limiting generalizability. Strengths of this study include prospective follow-up of a large sample of primary care patients with type 2 diabetes; structured assessment of depression; use of physician diagnoses, automated laboratory, pharmacy data, and chart review to confirm diagnosis; and the ability to control for important clinical covariates (e.g., prior adverse events medical comorbidity, glycemic control) and diabetes self-care activities (e.g., smoking and exercise). Finally, the focus on severe and documented adverse diabetes outcomes adds to the clinical significance and public health importance of these findings.
Major depression is associated with a 25% increased risk of advanced macrovascular complications and a 36% increased risk of microvascular complications among patients with type 2 diabetes. Given the rapidly increasing rates of type 2 diabetes, this increased risk has important clinical and public health implications. This work demonstrates a need for further research to test interventions that may reduce risks of diabetes complications among patients with comorbid depression and to explore explanatory biological mechanisms.