Depression in diabetes: the chicken or the egg?

The association of depression with diabetes was first noted in the scientific literature more than 300 years ago when Willis made the surprising remark that diabetes was the result of sadness or prolonged sorrow (1). After that time, investigators have studied this comorbidity in patients with either diabetes or depression as the primary disorder and focused on the prevalence of depression in patients with either type of diabetes, the relationship of depression with measures of diabetes severity (insulin resistance (IR), hyperglycemia, and complications), the risk of developing Type 2 diabetes in depressed patients, and the effect of depression on diabetes-related mortality. Data from two of these principal lines of investigation have led scientists to conclude that a) the prevalence of depression is increased significantly in persons with diabetes (Type 1 or Type 2) compared with those without diabetes (2,3) and b) depression appears to increase significantly the likelihood of developing Type 2 diabetes (4). The latter effect is independent of other conventional risk measures and presumably results from direct effects of depression on glucose dysregulation preceding the ultimate diagnosis of diabetes (5,6). Both conclusions are supported by meta-analyses (3,4). One such analysis (4), an aggregate of data from nine longitudinal studies having follow-up periods of 3 to 16 years, concluded that depressed adults have a 37% increased risk of developing Type 2 diabetes. Outcomes from these lines of investigation are very important to patients with or at risk for diabetes in that they may position depression as a potentially modifiable factor influencing the onset and course of the medical illness. In this issue of Psychosomatic Medicine, Knol et al. further contribute to this story with a cross-sectional study examining the rate of increased depression symptoms in patients selfreporting the diagnosis of diabetes (7). The authors also examine this rate in subsets with increased fasting blood sugar levels that did not meet the criteria for diabetes and that did, but subjects in the latter subset were unaware that they had the disorder. Only patients who carried the diagnosis of diabetes had greater risk of increased depression symptoms (in the unadjusted comparisons), but the significance of this observation was lost when all potential confounders, including other medical comorbidities, were included. Because the confidence interval crossed one with the final adjustment, the authors were led to conclude that the association of depression symptoms with diagnosed diabetes in the univariate analysis was related to the burden of medical illnesses in these patients and not to diabetes specifically. They were unable to demonstrate that acute depression symptoms were linked directly to either diabetes (diagnosed or undiagnosed) or prediabetes—findings that would speak against both conclusions from existing lines of investigation. Why are these outcomes at odds with prior work? The present study assessed depression with a self-report measure of current symptom severity, not an interview-determined Diagnostic and Statistical Manual of Mental Disorders diagnosis, and with antidepressant use as a surrogate. These methods have limited predictive value for major depression and interfere with the correct segregation of subjects (8). In a meta-analysis of 24 studies that showed the association of depression with hyperglycemia (9), effect sizes were larger when standardized interviews and diagnostic criteria rather than self-report questionnaires were used to assess depression (0.28 versus 0.15). But even those previous studies that relied on depression symptoms alone demonstrated a two-fold increase in the depression rate in subjects with diabetes compared with the control group (3). Is it possible that the bulk of this association is not attributable to diabetes per se but is created spuriously from the burden of additional medical illnesses often seen in diabetic patients? Speaking to this, Gavard et al. (2) found in a critical review that few studies considered comorbid medical illness when evaluating the prevalence of depression in diabetes, and, when they did, the rates of other medical conditions were higher in the diabetic subjects. Multivariable adjustment for comorbid illness had not been performed, but three studies compared the rates of depression in diabetic patients with those in medically ill control groups (10–12)—another way of approaching this question. Weyerer et al. (10) found an increased rate of structured interview-ascertained major depression in a Type 2 diabetes sample, although it did not reach statistical significance (27.3% versus 20.3%). Two other studies (11,12) found significantly greater increases in depression symptom scale scores in diabetic subjects than in medically ill controls. Subsequently, using a large sample from a health maintenance organization, Nichols and Brown (13) found a higher rate of diagnosed depression in a sample with Type 2 diabetes than in a control group after adjusting for the presence of cardiovascular disease. Although it is very likely that experiencing other medical illnesses contributes to depression and partially explains previous conclusions (3,14), this factor appears insufficient to negate the association when specifically examined. Possibly the use of current depression symptoms, reliance on self-reported diagnoses, and low participation rate (of those invited, 50% declined) interfered with DOI: 10.1097/PSY.0b013e318060cc2d