This meta-analysis of 16 longitudinal studies shows a positive association between depression and subsequent mortality rates in people with diabetes. Compared to those without depression, depressed individuals had a 46% increased risk for all-cause mortality. Although based on only 5 studies, our results also show a 39% increased risk for cardiovascular mortality associated with the presence of depression in diabetes.
Previous meta-analyses have also found positive associations between depression and mortality rates in the general population (RR
1.81, 95% CI 1.58–2.07) 
and in patients with established heart disease (OR
2.38, 1.76–3.22 and OR
2.59, 1.77–3.77 for all-cause and cardiac mortality, respectively) 
. The triad of depression, diabetes and cardiovascular disease is closely interrelated. Premature cardiovascular disease is the most common cause of morbidity and mortality in people with diabetes 
and co-morbid depression appears to increase the risk of developing vascular conditions in this group 
. However, depression is also common in people with established cardiovascular disease 
. Rather than being a (in)direct causal factor, depression in diabetes may be secondary to having cardiovascular complications. It may owe its association with mortality to the increased risk of new cardiovascular events in people with established cardiovascular conditions 
. We took this issue into account by including the risk estimates that were adjusted for existing vascular disease, and still found an almost 1.5-fold increased risk of mortality in depressed people with diabetes. Further prospective studies are needed to examine whether depression exerts a negative influence on mortality through the development of new vascular complications. These studies may also explore whether people with comorbid diabetes and depression face increased mortality risks beyond cardiovascular deaths, as suggested by recent results from the Pathways Epidemiologic Follow-up Study 
There are several potential behavioral or physiological mechanisms that could explain the increase of mortality for people with diabetes and depression. Depression is correlated with a decline in health-maintenance behaviors (e.g. physical activity, smoking, diet) in general 
, which is also true for people with diabetes 
. In addition, depression is associated with several biological alterations; activation of the hypothalamic-pituitary-adrenal axis and proinflammatory cytokines, sympathic nervous system dysregulation, decrease in heart rate variability and cardiac fibrillation threshold, which can contribute to an increased risk of cardiovascular mortality, but also mortality of other causes 
In line with previous studies examining post-myocardial infarction depression 
or depression in community samples 
, we did not observe a difference in mortality risk between studies assessing depression using a self-report questionnaire versus a clinical psychiatric interview. Only a minority of 30–40% of people with diabetes with an increased level of depressive symptoms suffers from clinically relevant depressive disorder 
. However, both major depression and self-reported depressive symptoms appear to be chronic/recurrent conditions in people with diabetes 
, and both are associated with the development of diabetes complications 
. Furthermore, depressive symptoms have been shown to predict the development of major depression 
The results need to be considered in relation to the study limitations. One important limitation in carrying out a meta-analysis is the inevitability to combine data from studies that are not equally designed. This meta-analysis included studies with differing study design and characteristics, and the results demonstrated significant heterogeneity. After conducting subgroup-analyses on follow-up length, age, method of depression assessment, method of diabetes assessment, number of participants and the percentage of females included, heterogeneity remained. However, after excluding the three articles presenting odds ratios (converted to risk ratios) the heterogeneity decreased substantially. This may be due to the fact that odds ratios and hazard ratios are different risk estimates, even after converting odds to risk ratios and combining them with relative risks 
In addition, the included studies often reported multiple hazard ratios, each adjusted for different covariates. To reveal the independent effect of depression on mortality we selected the hazard ratio that was most closely adjusted for both demographic and micro- and macrovascular complications. Unfortunately, these estimates sometimes also include adjustment variables through which depression may influence mortality rates, e.g. smoking, physical activity, HbA1c. By correcting for these potential mediators the hazard ratio can be an underestimation of the real effect of depression on mortality in people with diabetes. With respect to type of diabetes of study participants, five articles did not specify this information. Moreover, only one article reported on individuals with type 1 diabetes, and two articles reported on a combined study population of people with both type 1 and type 2 diabetes. Because type 2 diabetes is the most prevalent form of diabetes, cohort studies with patients with type 1 diabetes are scarce. Finally, we found an indication for publication bias: negative or insignificant result are often not submitted for publication by authors, or rejected by reviewers and editors. This form of bias generally results in an overestimation of the effect.
Despite these limitations several strengths should also be acknowledged. First, our meta-analysis comprises both all-cause and cardiovascular mortality. In addition, the independent effect of depression on mortality was assessed by adjusting for both demographic variables and micro- and macrovascular complications where possible.
It is still unclear whether adequate depression recognition and subsequent depression treatment can help to decrease mortality rates. Bogner et al. 
have conducted the Prevention of Suicide in Primary Care Elderly: Collaborative Trial (PROSPECT) study that examined a care-management intervention for older primary care patients with depression. The study had a median follow-up of more than 4 year. The authors reported that depressed patients with diabetes in the intervention category were less likely to have died during the 5-year follow-up interval than depressed diabetic patients in usual care after accounting for baseline differences among patients (adjusted hazard ratio 0.49 [95% CI 0.24–0.98]). However, the statistical methods used by Bogner et al. 
were criticized, as they may have resulted in model overfitting 
. Screening for depression in clinical practice may be a helpful first step, and should be embedded in collaborative care approaches 
. Effective intervention strategies include cognitive behavioral therapy and treatment with antidepressant medication 
. Given the close association of depression with suboptimal self-care behaviors 
, interventions that target behavioral mechanisms directly (e.g. coping skills training) may be of value as well.
In conclusion, the results of this meta-analysis suggest that depression is associated with a 1.5-fold increased risk of all-cause mortality in people with diabetes. Although based on only five studies, similar results were found for cardiovascular mortality. In consideration of the study limitations and strengths, we believe that a 1.5-fold increased risk of all-cause (and cardiovascular) mortality in people with diabetes is not an over- or underestimation, but could be an accurate risk estimation.
Future studies are encouraged to explore whether the association between depression and mortality is similar for people with type 1 and type 2 diabetes, and to address the behavioral or physiological pathways that may explain this association.