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Both depression and diabetes have been associated with an increased risk of all-cause and cardiovascular diseases (CVD) mortality. However, data evaluating the joint effects of these two conditions on mortality are sparse.
To evaluate the individual and joint effects of depression and diabetes on all-cause and CVD mortality in a prospective cohort study.
A total of 78282 female participants in the Nurses' Health Study aged 54-79 years at baseline in 2000 were followed until 2006. Depression was defined as having self-reported diagnosed depression, treatment with antidepressant medications, or a score indicating severe depressive symptomatology, i.e., a five-item Mental Health Index score ≤52. Self-reported type 2 diabetes was confirmed using a supplementary questionnaire.
All-cause and CVD-specific mortality.
During 6 years of follow-up (433066 person-years), 4654 deaths were documented, including 979 deaths from CVD. Compared to participants without either condition, the age-adjusted relative risks (95% confidence interval, CI) for all-cause mortality were 1.76 (1.64-1.89) for women with depression only, 1.71 (1.54-1.89) for individuals with diabetes only, and 3.11 (2.70-3.58) for those with both conditions. The corresponding age-adjusted relative risks of CVD mortality were 1.81 (1.54-2.13), 2.67 (2.20-3.23), and 5.38 (4.19-6.91), respectively. These associations were attenuated after multivariate adjustment for other demographic variables, body mass index, smoking status, alcohol intake, physical activity, and major comorbidities (including hypertension, hypercholesterolemia, heart diseases, stroke and cancer) but remained significant, with the highest relative risks for all-cause and CVD mortality found in those with both conditions (2.07 [95% CI, 1.79-2.40] and 2.72 [95% CI, 2.09-3.54], respectively). Furthermore, the combination of depression with a long duration of diabetes (i.e., >10 years) or insulin therapy was associated with particularly higher risk of CVD mortality after multivariate adjustment (relative risk=3.22 and 4.90, respectively).
Depression and diabetes are associated with significantly increased risk of all-cause and CVD mortality. The coexistence of both conditions identifies particularly high-risk women.
Depression is highly prevalent in the U.S. population, affecting approximately 6.7% (14.8 million) American adults in a given year.1 Strong evidence from epidemiological studies suggests that depression is associated with a significantly increased risk of coronary heart disease2 and all-cause mortality.3 Diabetes is also highly prevalent and over 10% (23.5 million) of U.S. adults have this disorder.4 It is also well known that diabetes and its related complications are leading causes of mortality globally.5
Epidemiological studies have consistently documented an increased prevalence of depression in diabetic patients. It is estimated that clinical significant depressive symptoms affects about 20% to 25% of individuals with diabetes, nearly twice as many as those without diabetes.6 The coexistence of diabetes and depression is known to be associated with poor glycemic control,7 an increased risk of diabetes complications,8 poor adherence to diabetes management.9 A growing body of evidence suggests that the combination of diabetes and depression could substantially increase the risk of mortality.10-17 However, previous investigations have been limited by small sample size,10,13,15 short-term follow-up,14-16 evaluation only in diabetics (with no comparison group of non-diabetics),13-15,17 and the utilization of a self-reported questionnaire-based depressive symptoms as the exposure (with no information on depression diagnosis and medication use).11-13,17 In addition, few studies have been conducted among women, in whom depression is more prevalent than that in men.18 Therefore, using data from the Nurses' Health Study, we aimed to examine the individual and joint impacts of depression and type 2 diabetes on all-cause and CVD mortality among middle-aged and elderly women during a 6-year follow-up.
The Nurses' Health Study cohort was established in 1976 when 121700 female registered nurses aged 30–55 years residing in 11 U.S. states responded to a mailed questionnaire regarding their medical history and health practices. The cohort has been followed every two years with mailed questionnaires that updated exposure information and inquired about newly diagnosed medical illnesses. Details have been published elsewhere.2,19 Till 2006, the follow-up rate was more than 94%. The study protocol was approved by the institutional review boards of the Brigham and Women's Hospital and Harvard School of Public Health.
We used 2000 questionnaire cycle as baseline since self-reported diagnosed depression were addressed in this year (n=94791). Participants with a history of gestational diabetes (n=339), type 1 diabetes (n=310), secondary diabetes (n=360), no information on depressive symptoms, depression diagnosis or antidepressant use (n=12041), with unknown diabetes diagnose date or uncertainty of the diagnosis (n=3361), missing values for covariates (n=98) at baseline were excluded. Therefore, 78282 participants were included in this analysis.
Self-reported symptoms of depression, use of antidepressant medication and doctor diagnosed depression were used as measures of depression. Depressive symptoms were assessed in 1992, 1996 and 2000 with the five-item Mental Health Index (MHI-5) subscale of the Short-Form 36 Health Status Survey designed to capture psychological distress versus well-being.20-22 The participants were asked how much of the time over the past month (all, most, good bit, some, little, or none) they 1) felt nervous, 2) felt so down that nothing could cheer them up, 3) felt calm and peaceful, 4) felt down and blue, or 5) felt happy. The scale was scored from 0 to 100, with lower scores indicating more severe depressive symptomatology (SDS). The MHI-5 has been shown to have high sensitivity and specificity for major depression, with an area under the receiver-operating characteristic curve of 0.88 to 0.91 for the detection of major depressive disorder (MDD).23 In accordance with our prior study using this scale, the MHI-5 score was considered a dichotomous indicator of the presence (MHI-5 score ≤52) or absence (MHI-5 score >52) of SDS.19
Participants were first asked to report regular antidepressant medication use in 1996 and history of physician-diagnosed depression in 2000, hence this year was utilized as the baseline for this study. The information on antidepressant medication and physician-diagnosed depression was updated biennially. Therefore, depression was defined as having diagnosed depression, treatment with antidepressant medications, suffering from SDS, or any of these conditions.
A supplementary questionnaire regarding symptoms, diagnostic tests, and hypoglycemic therapy was mailed to women who indicated on any biennial questionnaire that they had been diagnosed as having diabetes. Several repeated mailings were sent to non-respondents, and these were followed by telephone interviews. A case of diabetes was considered confirmed if at least one of the following was reported on the supplementary questionnaire according to the National Diabetes Data Group criteria:24 (1) one or more classic symptoms (excessive thirst, polyuria, weight loss, hunger) plus fasting plasma glucose levels of at least 7.8 mmol/L (140 mg/dL ) or random plasma glucose levels of at least 11.1 mmol/L (200 mg/dL); (2) at least two elevated plasma glucose concentrations on different occasions (fasting levels of at least 7.8 mmol/L, random plasma glucose levels of at least 11.1 mmol/L, and/or concentrations of at least 11.1 mmol/L after two hours or more shown by oral glucose tolerance testing) in the absence of symptoms; or (3) treatment with hypoglycemic medication (insulin or oral hypoglycemic agent). For cases of type 2 diabetes identified after June 1996, the cut-off point was lowered to 7.0 mmol/L (126 mg/dL ) for fasting plasma glucose concentrations according to the American Diabetes Association criteria.25 The self-reported type 2 diabetes diagnosis through supplemental questionnaire confirmation has been demonstrated to be highly accurate in a validation study conducted in a subsample of NHS participants, which consisted of comparisons with medical record review by an endocrinologist.26 In addition, another validation study assessing the prevalence of undiagnosed diabetes suggested a very low rate of false-negative results.27
The main outcome measures were all-cause and CVD-specific mortality that occurred after the return of the 2000 questionnaire but before June 1, 2006. The ascertainment of death has been documented in previous studies.2,28 Briefly, deaths were identified by reports from next of kin, postal authorities, or by searching National Death Index, and at least 98% of deaths were identified.29 We obtained copies of death certificates and medical records and determined causes of death (classified according to the categories of the International Classification of Diseases, Eighth Revision [ICD-8]). Fatal CVD was confirmed by hospital records or autopsy or if CVD was listed as the cause of death on the death certificate and evidence of previous CVD was available. Probable fatal CVD cases were designated where CVD was the underlying cause on the death certificate, but no medical records were available. We also included sudden deaths (5.4% of CVD death). Deaths owing to all CVD causes included ICD-8 codes 390 through 459 and 795.28
Demographic, lifestyle behavior, and comorbidity information were collected using the standardized questionnaires mailed to the nurses biennially. Marital status (having spouse or not), ethnicity (white/others), family history (in the first-degree relatives) of diabetes (yes/no) and cancer (yes/no), parental history of myocardial infarction (MI, yes/no) were obtained. Body mass index (BMI) was calculated from self-reported weight and height and categorized as <23, 23.0-24.9, 25.0-29.9, 30.0-34.9, ≥35 kg/m2. Physical activity level based on the individual's engagement in usual recreational activity was grouped as <3, 3.0-8.9, 9.0-17.9, 18.0-26.9, ≥27 Metabolic Equivalent-hours per week (MET-hrs/wk). Smoking was grouped as never, former, or current smoker, and alcohol drinking status was categorized as 0, 0.1-4.9, ≥5.0 grams of alcohol per day. Most of the women were postmenopausal or in the perimenopausal period, and information on hormone replacement therapy was queried and participants were categorized as never, former or current users. Current aspirin and multivitamin use was also asked and grouped as yes or no. In addition, respondents were asked to report previously diagnosed medical conditions, including hypertension, elevated cholesterol, heart disease, stroke and cancer.
Participants were classified into four groups: 1) without diabetes and depression, set as the reference group; 2) with depression but no diabetes; 3) with diabetes but no depression; 4) with both diabetes and depression. Means or proportions of covariates across the four groups were computed using the baseline information. For these comparisons, we used Mantel-Haenszel chi-square tests for categorical variables and Analysis of Variance for continuous variables. Person-year for each participant was calculated from the date the 2000 questionnaire was returned to the date of death from any cause, or June 2006, or the date of return of their last questionnaire, whichever came first. Time-dependent Cox proportional hazards models were used to estimate age- and multivariate-adjusted relative risks (RRs) of mortality for each group compared with the reference group. The basic model utilized the updated depression and diabetes status and included age (continuous), marital status, family history of diabetes and cancer, parental history of MI. Multivariate model included the terms in the basic model and several major lifestyle variables: BMI, physical activity level, smoking and drinking status, hormone replacement therapy use, current aspirin and multivitamin use. Major comorbidities (updated status of hypertension, elevated cholesterol, heart disease, stroke and cancer) were included in another multivariate model to explore whether the effects of diabetes and depression were independent of these comorbidities, which were more likely to be mediators. All the covariates except family history of diabetes and cancer, parental history of MI were updated every two years.
A series of stratified analyses were conducted by age, BMI, smoking status, alcohol intake status, physical activity level, postmenopausal hormone use, prior hypertension, hypercholesterolemia, heart disease, stroke, and cancer, all using updated information. Several complementary analyses were conducted to assess the robustness of the depression definition. The first analysis used only SDS to define depression and utilized the information from 1992 to 2006; the second one defined depression based on antidepressant medication use and utilized the information from 1996 to 2006, and the third analysis used only self-reported diagnosed depression from 2000 to 2006. We also conducted subgroup analysis according to duration or treatment of diabetes. The associations of different stages of depression (only SDS, only diagnosed depression, using antidepressant medication) and their combination with diabetes on mortality risk were further examined.
All reported P values were 2-sided, and statistical analyses were performed with SAS statistical software version 9.1 (SAS Institute Inc., Cary, North Carolina).
During the 6-year follow-up of these 78282 middle-aged and elderly women (433066 person-years), 4654 (5.9%) deaths were documented, with CVD mortality accounting for 21.0% (n=979) of all deaths. Generally, participants with both diabetes and depression had lower MHI scores and physical activity levels, had higher BMIs, and were less likely to have spouses at baseline compared with the other three groups (Table 1). In addition, they had higher rates of other comorbidities, including histories of hypertension, heart disease, stroke or cancer at baseline (Table 1). The prevalence of depression in diabetic participants (20.5%) was higher than that in the non-diabetic individuals (15.1%).
Compared with the reference group who did not have diabetes or depression, the age-adjusted RR for all-cause mortality was over three-fold higher in those with both conditions (RR, 3.11; 95% confidence interval [CI], 2.70-3.58) (Table 2). Multivariate adjustment did not substantially modify the results, with RRs of 1.53 (95% CI, 1.42-1.64) for those with depression, 1.52 (95% CI, 1.36-1.69) for those with diabetes, and 2.46 (95% CI, 2.12-2.84) for those with both diabetes and depression. Similar results were found with regard to CVD-specific mortality. Compared to the reference group, depression and diabetes alone showed a significant increased risk of CVD mortality, with multivariate-adjusted RRs of 1.56 (95% CI, 1.33-1.84) and 2.15 (95% CI, 1.76-2.64), respectively. The RR for individuals with both conditions was 3.89 (95% CI, 3.00-5.05, P for interaction=0.492).
All the associations were substantially attenuated after controlling for some major comorbidities (updated status of hypertension, hypercholesterolemia, heart disease, stroke, and cancer), but remained significant. Compared to the reference group who were free of either condition, the RRs of total and CVD mortality for individuals with both conditions dropped to 2.07 (95% CI, 1.79-2.40), and 2.72 (2.09-3.54). However, adjustment for major comorbidities might be over-adjustment to some extent, since both depression and diabetes are strong risk factors for those comorbidities, particularly CVD.30-31
In subgroup analyses (Table 3), the excess risk of CVD mortality associated with diabetes alone, depression alone, or both conditions was significant in most stratified subgroups. The magnitudes of the RRs varied across different stratifications, while the pattern was comparable with the highest RRs found in those with both conditions.
The results from the complementary analyses (using different definition of depression and time periods) were consistent with the main analysis (Table 4).
As expected, the risk of CVD mortality increased monotonically with increased duration of clinical diabetes. Compared with nondiabetic persons, the multivariate-adjusted RRs of CVD death across categories of diabetes duration (<5, 5-10, >10 years) were 0.95 (95% CI, 0.66-1.37), 1.75 (95% CI, 1.30-2.37), and 2.40 (95% CI, 1.94-2.97), respectively (data not shown). In the same multivariate model, the RR of CVD mortality for women with depression was 1.54 (95% CI, 1.29-1.83) compared to those without (data not shown). As shown in Figure 1a, among each stratum of duration of diabetes, presence of depression implied a significantly higher risk compared to those without depression. The combination of depression and a long duration of diabetes (i.e., >10 years) was associated with a RR of 3.22 (95% CI, 2.29-4.52) compared to those without either diabetes or depression.
The multivariate RRs of CVD death across categories of diabetes treatment (no treatment, oral diabetes medication use, insulin therapy) were 1.12 (95% CI, 0.78-1.52), 1.58 (95% CI, 1.26-1.99), and 3.11 (95% CI, 2.41-4.01), respectively (data not shown). The combination of depression and insulin therapy was associated with an approximate 4.90-fold (95% CI, 3.35-7.15) increased risk of CVD death compared to those free of diabetes and depression (Figure 1b).
The increased risk of CVD mortality was evident in each stage of depression. Compared to participants without depression, the multivariate-adjusted RRs of CVD death in each category of depression (only SDS, only diagnosed depression without treatment, antidepressant medication use) were 1.73 (95% CI, 1.28-2.33), 1.27 (95% CI, 0.97-1.67), and 1.42 (95% CI, 1.19-1.69), respectively (data not shown). Participants with both SDS and diabetes had a highest RR of 4.54 (95% CI, 2.60-7.92) on CVD death compared to those free of two conditions (Figure 1c).
In this large prospective cohort of women, we confirmed that diabetes and depression were both significant risk factors for all-cause and CVD mortality, while the coexistence of both conditions was associated with a much higher risk. We also observed a strong monotonic relation between diabetes severity (diabetes duration or type of treatment) and CVD mortality, with the highest risk among women with the combination of higher diabetes severity and comorbid depression.
Compared to individuals without diabetes, the risk of death in diabetic women was increased by 35% in the current study. This is slightly lower but consistent with several previous publications where a 1.5- to 2-fold increased risk of death was reported.32-35 However, it is slightly lower than our previous report in this cohort where 2.5-fold increased risk of all-cause mortality was observed for diabetic women during 20 years of follow-up (1976-1996).28 The discrepancy might be due to shorter duration of follow-up, secular trends in treatment for diabetes and cardiovascular disease, and age differences in the present study. We also confirmed that diabetes was a leading cause of CVD mortality with a multivariate adjusted relative risk of 1.67. This is consistent with most previous publications summarized in two meta-analyses.36-37 Additionally, we found that the risk of all-cause and CVD death was about 40 percent higher in depressed women compared to individuals without depression, which is also consistent with findings of other investigators,3,38 and our prior publication in the same cohort where a 1.54-fold increased risk of fatal CHD associated with depression was observed.2
We further observed that the coexistence of diabetes and depression was associated with a much higher risk of all-cause mortality (RR=2.07). Egede and his colleagues11 also found similar results, with a 2.5-fold increased mortality risk for the combination of diabetes and depression compared to those without either condition. Black et al.10 observed a much higher risk for diabetes-depression combination with a RR of 4.94, which might be because of using a reference group free from diabetes and depressive symptoms (Center for Epidemiologic Study of Depression [CESD] score of zero instead of the commonly used cutoff point of 1639). It could also be due to differences in the study populations: Black et al.'s study comprised Mexican-Americans aged 65 years or older, whereas our study included primarily white women.
In our multivariate-adjusted model, we also found that the diabetes-depression combination was associated with a 2.7-fold increased risk of CVD mortality compared to those without either condition. This risk was much higher than that due to either diabetes (RR=1.67) or depression (RR=1.37) alone. Egede et al.11 observed similar risks of CHD mortality among participants with both conditions (RR=2.43) and those with diabetes only (RR=2.26). However, they used CESD score of 16 to categorize depression status, which might represent less severe depressive symptoms than clinical diagnosis. In our study, the formal interaction test was not statistically significant, suggesting that the joint effects of diabetes and depression on CVD mortality are likely to be additive. Nevertheless, the relative risk (RR=2.72) was still moderately higher than the additive risk (1.67×1.37=2.29). Depression affects about 20% to 25% of diabetic population,6 therefore, considering the size of the potential populations affected, the excess risk of all-cause and CVD death associated with depression among individuals with type 2 diabetes deserves additional attention.
The underlying mechanisms of the increased mortality risk associated with depression in diabetic patients remain to be elucidated. Numerous studies have found that depression and diabetes are highly correlated,40 and the association is bidirectional.41 It is generally suggested that depression is associated with poor glycemic control,7 an increased risk of diabetes complications,8 and poor adherence to diabetes management in the diabetic patients,9 and isolation from the social network.40 Diabetes and depression are linked to unhealthy behaviors (such as tobacco use, poor diet quality, sedentary lifestyle and inadequate exercise),43-44 and these behaviors are particularly prevalent in individuals with both conditions. With regard to CVD death, depression could trigger episodes of transient ischemia,45 increase hypothalamic-pituitary-adrenal axis activity and sympathetic tone, decrease heart rate variability, cardiac fibrillation threshold and alter thrombogenesis.46-47 Alterations in platelet serotonin receptors and increased catecholamine and serotonin levels associated with depression may also promote platelet clumping and subsequent thrombosis.48
Our study is one of few cohort studies that investigated the joint effect of diabetes and depression on all-cause and CVD-specific mortality among women. The large sample size and long duration of follow-up provide the opportunity to examine the association of diabetes and depression alone and in combination with risk of mortality. The follow-up rate of this well-established cohort was high (>94%) and more than 98% of the death were ascertained. Thus, our study results are unlikely to be biased by losses to follow-up. In addition, we have collected detailed information on disease assessments (diabetes, depression and related comorbidities) and other risk factors such as smoking, BMI, and physical activity through repeated assessments.
Several limitations of the study should be considered. First, the study sample was a homogeneous population and all the participants were registered nurses and more than 96% participants were white. They had a greater concern about their health and better understanding of health-related issues, which enhanced the reliability of our questionnaire assessment, but on the other hand, the results might not be generalized to other populations. Recruitment bias and survival bias of the cohort might also restrict the generalizability. In addition, the information of diagnosed diabetes and depression was based on self-report and the exact diagnosis date of depression was not available. This may lead to some misclassification of the exposure variables. However, our previous studies have found self-reporting of diabetes to be highly reliable,26-27 although undiagnosed diabetes was possible in this cohort. On the other hand, physician recognition rate of major depression is generally considered not high compared to the Structured Clinical Interview for DSM-IV,49 and the prevalence of untreated mental disorders is relatively high in US.50 Therefore, history of depression is likely to be underreported, which might have led to an overestimation of the risk in the depression-free population. Furthermore, we did not have information on medication adherence, glycemic control, diabetes complications and disability levels, restricting our ability to explore the underlying mechanisms.
The comorbidity of depression and diabetes is associated with a substantial increase in the risk of mortality, particularly death from CVD. Considering the size of the population that could be affected by these two prevalent disorders, further consideration is required to design strategies aimed to provide adequate psychological management and support among those suffering from longstanding chronic conditions such as diabetes.
We are indebted to the participants in the Nurses' Health Study for their continuing outstanding support and colleagues working in the Study for their valuable help.
Funding/Support: The study was supported by the National Institute of Health (NIH) grant DK58845. Dr Ascherio received a grant from the National Alliance for Research on Schizophrenia & Depression (Project ID: 5048070-01). Dr Lucas received a postdoctoral fellowship from the Fonds de recherche en santé du Québec (FRSQ). The funding sources did not involve in the data collection, data analysis, manuscript writing and publication.
Author Contributions: FBH, AA, KMR, JEM and WCW obtained funding and were investigators of the Nurses' Health Study. AP, ML, JEM, WCW, KMR, AA and FBH collected data and had the idea for the current analysis. AP, ML, QS, RVDM, OHF, AA and FBH provided statistical expertise. AP and ML analyzed the data. AP wrote the first draft of the manuscript. All authors contributed to the interpretation of the results and critical revision of the manuscript for important intellectual content and approved the final version of the manuscript.
Conflict of Interest: The authors have no conflict of interest to declare.
Data Access and Responsibility: Dr Frank Hu had full access to all of the data (including statistical reports and tables) in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis.