The results of the present meta-analysis clearly show that people who have impaired glucose metabolism or undiagnosed type 2 diabetes are not at increased risk for depression compared with people in the general population or people with normal glucose metabolism. When compared with people with known type 2 diabetes, individuals with impaired glucose metabolism or unknown diabetes have significantly lower risk of having depressive symptoms. This result could be regarded as support for the “psychological burden hypothesis” (31
), which states that the burden of knowing that you have diabetes and having a chronic illness to manage, or complications to cope with contributes to higher levels of depression. By definition, people with IGM and undiagnosed diabetes have both higher levels of blood glucose than people with normal glucose metabolism or people in the general population. Results of the present meta-analysis indicate that higher blood glucose levels per se in the prediabetic or early diabetes stages are not associated with an increased level of depressive symptoms.
One explanation for the lower risk of depression in UDD compared with PDD might relate to differences in the number of complications between people with UDD and people with PDD. Although diabetes complications can occur in people with undiagnosed diabetes, these are more likely to be found in people with longstanding diabetes (32
). The results of the current meta-analysis would then concur with a large cross-sectional population-based study that showed that, compared with healthy control subjects, diabetes alone did not increase the chances of depressive symptoms but having diabetes and diabetes complications did (34
). However, a recent study showed that the risk of depressive disorder is increased in the 2 years after diagnosis of type 2 diabetes in the absence of diabetes complications (35
). In another study, it was found that diabetes distress did not become associated with depressive symptoms until after 1 year of living with diabetes (36
). In yet another study, people who were prescribed a more intensive treatment developed more depressive symptoms in the first 3 years after detection of type 2 diabetes than individuals on less intensive treatment (37
). These studies suggest that factors other than diabetes complications (e.g., fear of complications, burden of treatment) may increase the risk of depressive symptoms. However, because none of the studies included in the meta-analysis assessed diabetes complications, it was not possible to refute or support this argument. Future studies into depression and undiagnosed diabetes should assess diabetes complications in these groups.
There are several limitations to this study. First, the number of people with undiagnosed diabetes in the included investigations was quite small despite the fact that many were large-scale population-based studies. Second, the meta-analysis draws on observational cohort studies, and it is appropriate to analyze adjusted rather than unadjusted effect estimates. However, because only half of the studies provided adjusted effect estimates and controlled for important demographic confounders, we used the unadjusted ORs in our analyses. However, when calculating pooled ORs based on the studies that did provide ORs controlled for demographics, the outcome did not change. Given these results and the low heterogeneity, we are confident that the results in the current study are reliable. Third, although in all studies oral glucose tolerance tests were used to establish participants’ glucose metabolism classification, it is possible that unmeasured differences in blood glucose level between the previously diagnosed and undiagnosed diabetes groups may explain their differences in depression. Because these data were not routinely available in the published reports, we contacted authors of the more recent articles to obtain these data and used them to calculate weighted pooled mean blood glucose levels for each group. Whereas blood glucose levels did not differ between NGM (mean 5.1, 95% CI 3.9–6.3) and IGM (5.8, 4.6–7.0) and between UDD (8.8, 7.6–10.0) and PDD (8.3, 7.1–9.5), differences between the diabetes groups (UDD and PDD) and individuals without diabetes (NGM and IGM) were significant. These results suggest that despite differences in depression between those with versus those without diabetes, blood glucose levels did not differ within these broader categories. Fourth, the possibility of reporting bias cannot be ruled out. There was weak evidence of reporting bias for the comparison of undiagnosed diabetes versus normal glucose metabolism, but the number of studies here, as for other comparisons, was too low for strong inference.
The relatively low level of heterogeneity observed in most comparisons (I-squared ranging from 0 to 27%) was not amenable to productive exploration using meta-regression; this was because it is recommended that at least 10 studies per study level variable explored are required if spurious associations are to be avoided, and a complete set of data for this number of studies was unfortunately not available for study level variables of interest (e.g., age, sex, fasting plasma glucose).
Fifth, the studies in this meta-analysis used cross-sectional data and therefore do not provide evidence regarding the time frame in which depression develops after the diagnosis of type 2 diabetes. A recent study reported that antidepressant medication use showed a temporary peak during the year of diagnosis of type 2 diabetes, suggesting that the risk of depressive symptoms is increased soon after diagnosis and recedes thereafter in the absence of another incident risk factor (38
Finally, only one of the included studies (27
) used diagnostic criteria to determine depression status. In this study, the prevalence of depression was particularly increased in people with previously diagnosed diabetes (compared with NGM) and in people with undiagnosed diabetes, although for the latter, this failed to reach significance. IGM was not significantly associated with the increased prevalence of major depressive disorder. These findings suggest that diabetes, but not IGM, is associated with increased prevalence of major depressive disorder. However, the numbers in this study were small, and further research is needed.
Overall, the results of this meta-analysis show that the risk of depression is not directly related to elevated blood glucose levels. One conclusion, in line with the results of the current meta-analysis, is that the burden of diabetes and its complications are the main determinants of depressive symptoms in individuals with diabetes (16
). Future research should examine the constituents of this burden.