Introduction
It is now commonly accepted that depressive symptoms and major depressive disorder (MDD) are twice as prevalent in individuals with type 2 diabetes [
1,
2]. Moreover, psychological morbidity in people with diabetes poses huge challenges for clinical practice. In a recent WHO study, the greatest decrements in self-reported health were observed in those with both depression and diabetes, more so than in those with depression and other chronic conditions such as angina, arthritis or asthma [
3].
Depression has been found to be associated with lower quality of life [
4], poorer diabetes self-care [
5], impaired glycaemic control [
6], and an increased risk of developing diabetes-related complications [
7]. Given the higher healthcare expenditure [
8] and increased mortality [
9,
10] associated with depression, it is therefore not surprising that clinical guidelines now recommend that all patients with diabetes undergo regular screening for depression [
11,
12].
It remains unclear, however, whether the presence of diabetes increases risk for depression, or whether depression increases risk for diabetes. The early studies in this area used mainly cross-sectional study designs, which preclude any causal inferences as to the direction of this relationship, thus making any recommendations for practice problematic [
1,
2]. More recently, the temporal relationship between depression and diabetes has been the focus of a number of longitudinal prospective population-based studies. Three systematic reviews and meta-analyses [
13‐
15] found that depression was associated with an increased risk of incident diabetes. The reverse, that diabetes may be a risk factor for depression, has been the focus of one earlier systematic review and meta-analysis, which included seven studies [
15]. It was found that people with type 2 diabetes had a modest increased risk of developing depression. However, the authors did not distinguish between studies that used a diagnosis of a depressive disorder and those that measured depressive symptoms using self-report measures. This distinction is important, because high levels of depressive symptoms as measured through self-report questionnaires were found to be more reflective of general emotional and diabetes-specific distress than of clinical depression [
16,
17]. Therefore, this report examines the relationship between diabetes and depression by conducting a meta-analysis of longitudinal studies published on this subject in the peer-reviewed literature. Moreover, we examined separately studies that included a diagnosis of a depressive disorder and those using self-report measures of depression.
Results
The MEDLINE search identified 385 articles, of which 10 [
21‐
30] met our inclusion criteria and were subsequently included in the systematic review and meta-analysis (ESM Fig.
1). The search in EMBASE (total number of studies = 381) identified one additional study [
31] meeting the selection criteria, but no further studies were identified through the search in PsycInfo (total number of studies = 17). Thus, a total of 19 studies were retrieved for detailed evaluation, of which 11 studies were selected for inclusion in the meta-analysis. The extracted data of the 11 studies included are presented in ESM Table
2. It should be noted that two studies [
23,
24] reported HRs rather than ORs.
Discussion
The results of this systematic review and meta-analysis of 11 studies involving 172,521 participants, including 48,808 people with type 2 diabetes, show that overall people with type 2 diabetes have a 24% increased risk of incident depression compared with people without diabetes. The risk found in the current study including four more studies is slightly higher than the one found in an earlier meta-analysis (OR 1.15, 95% CI 1.02–1.30) [
15]. When studies that used questionnaires to define depression were separated from those using diagnostic criteria, the odds of incident depressive symptoms were somewhat lower (OR 1.21) than the risk of developing incident depressive disorder (OR 1.29). Interestingly, this difference was accentuated when a study that included incident diabetes rather than prevalent diabetes [
24] was excluded from the analysis; the increased chance of people with diabetes developing a depressive disorder was almost 50%. Although the difference in incidence rates between diagnostic studies and questionnaire studies was significant, the meta-regression analysis showed that this effect may have been confounded by higher ORs in more recent published studies.
Relative to the earlier meta-analysis [
15], heterogeneity was larger in the present meta-analysis. This is primarily a function of the fact that later studies, those not included in the earlier analysis, reported higher levels of increased risk for persons with diabetes. We have no definitive explanation for the apparent increase in incident depression in more recent studies, although it is possible that both people with diabetes and healthcare professionals have become increasingly aware of symptoms of depression in diabetes, which may have led to higher scores at follow-up measurements.
The results of this study should be interpreted cautiously with regard to whether diabetes is a risk for incident depression in the strictest sense, i.e. the initial episode of depression. With the exception of Brown et al. [
24], who excluded participants with depressive episodes within 3 years before the onset of the study, none of the other studies in this meta-analysis excluded people who had had depression at some point during a lengthy period before the onset of the study. Because recurrence of depressive disorder is high, especially among people with diabetes [
32], the increased incidence of depressive episodes may be due, in part, to diabetes or stressors related to diabetes triggering depression more frequently in people with vulnerability for depression, i.e., people with a history of depression.
It is possible that the incident depression was associated with the development of diabetes-related complications. For example, the Brown et al. [
24] study only included people with incident diabetes, and the likelihood of diabetes-related complications is likely to be lower in this sample. Interestingly, in this study the risk of developing depression was increased in people with cerebrovascular disease and peripheral arterial disease but not in those with coronary artery disease. de Jonge et al. [
26] found that the longitudinal association of diabetes and depression was reduced after controlling for other chronic somatic diseases and was no longer significant. These findings are consistent with the results of two large cross-sectional studies [
33,
34] showing that the prevalence of depressive disorder was higher in diabetes patients with diabetes-related complications, especially cardiovascular disease, than in those without complications.
The increased
incidence rate for depression in people with type 2 diabetes found in the current meta-analysis (OR 1.19– 1.47) contrasts with a two-fold increase in the
prevalence rate of depression (OR 2.0) found in a previous meta-analysis [
1]. This is likely to be a result of two distinct processes. First, because prevalence is a function of not only incidence but also duration, the prevalence of a chronic condition such as depression is higher than one might expect based on the incidence rate alone. This line of reasoning is supported by earlier reports that, among people with diabetes, episodes of MDD last longer and are more recurrent [
32,
35]. Our finding that the risk in diabetes of developing depressive disorder is greater than that of developing depressive symptoms is consistent with this. In addition, because depression is a risk factor for the development of diabetes [
13], relatively more people with diabetes would have a history of depression and as such an increased risk of developing a further episode.
This study has several limitations. First, measures of depression varied among studies. We were able to examine several aspects of this variation, finding that few factors were associated with study-specific levels of diabetes risk. However, there was substantial variation among studies using a particular form of depression measurement. Among the studies that used diagnostic criteria for the assessment of depression, two relied on the clinical judgement of general practitioners to establish a diagnosis while the other two used formal diagnostic interview schedules with trained researchers. Among studies using self-report questionnaires to assess depressive symptoms, different questionnaires and different cut-off values were used to define cases of depression. Because self-reported depressive symptoms in people with diabetes have been found to be indicative of general emotional and diabetes-specific distress rather than depressive disorder [
16], the questionnaire studies, especially those with lower cut-off values, may have resulted in an over-estimation of the incidence rate of clinically significant levels of depression in people with diabetes. In addition, some studies also included antidepressant medication use as a stand-alone proxy measure of depression [
24,
28,
29,
31]. However, because antidepressant medication is prescribed for other problems, such as neuropathic pain [
36,
37] or sedation, this also may have artificially increased the incidence rate, particularly among people with diabetes. Finally, a number of studies [
21,
27] used different measures or cut-off values at baseline than at follow-up, which may have led to misclassification of cases of depression at baseline and therefore affected the incidence rates for depression.
Another limitation is that the majority of the studies analysed here limited the assessment of incident depression to a single follow-up at a distinct time point, and none assessed the onset and offset of depressive episodes; thus these studies provide no insight into the temporal dynamics of the episodes.
Finally, the relatively small number of studies available for analysis limited our ability to examine the independent contribution of multiple methodological factors in accounting for the between-study variation in diabetes-related risk for depression.
Acknowledgements
The authors would like to thank A. Kokoszka (Department of Psychiatry, Medical University Warsaw, Poland), N. Hermanns (Forschungsinstitut Diabetes-Akademie & Diabetes Klinik Bad Mergentheim, Germany) and J. Assies (Department of Psychiatry, Academic Medical Centre, University of Amsterdam, the Netherlands) for their comments and suggestions on an earlier version of the manuscript.