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Original Article |

Increased Mortality Risk in Women With Depression and Diabetes Mellitus FREE

An Pan, PhD; Michel Lucas, PhD; Qi Sun, MD, ScD; Rob M. van Dam, PhD; Oscar H. Franco, MD, ScD, PhD; Walter C. Willett, MD, DrPH; JoAnn E. Manson, MD, DrPH; Kathryn M. Rexrode, MD; Alberto Ascherio, MD, DrPH; Frank B. Hu, MD, PhD
[+] Author Affiliations

Author Affiliations: Departments of Nutrition (Drs Pan, Lucas, Sun, van Dam, Willett, Ascherio, and Hu) and Epidemiology (Drs Willett, Manson, Ascherio, and Hu), Harvard School of Public Health, and Channing Laboratory (Drs van Dam, Willett, Ascherio, and Hu) and Division of Preventive Medicine (Drs Rexrode and Manson), Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Departments of Epidemiology and Public Health and Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (Dr van Dam); Department of Public Health and Primary Care, University of Cambridge, Cambridge, England (Dr Franco); and Health Sciences Research Institute, University of Warwick, Coventry, England (Dr Franco).


Arch Gen Psychiatry. 2011;68(1):42-50. doi:10.1001/archgenpsychiatry.2010.176.
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Context  Depression and diabetes mellitus have been associated with an increased risk of all-cause and cardiovascular disease (CVD) mortality. However, data evaluating the joint effects of these 2 conditions on mortality are sparse.

Objectives  To evaluate the individual and joint effects of depression and diabetes on all-cause and CVD mortality rate.

Design  Prospective cohort study.

Setting  The 11 states of the Nurses' Health Study.

Participants  A total of 78 282 women who participated in the Nurses' Health Study aged 54 to 79 years at baseline in 2000 were followed up until 2006. Depression was defined as having self-reported diagnosed depression, treatment with antidepressant medications, or a score indicating severe depressive symptoms (ie, a 5-item Mental Health Index score ≤52). Self-reported type 2 diabetes was confirmed using a supplementary questionnaire.

Main Outcome Measures  All-cause and CVD-specific mortality rate.

Results  During 6 years of follow-up (433 066 person-years), 4654 deaths were documented, including 979 deaths from CVD. Compared with participants without either condition, the age-adjusted relative risks (RRs) (95% confidence interval) 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 women with both conditions. The corresponding age-adjusted RRs 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 RRs for all-cause and CVD mortality found in those with both conditions (2.07 [1.79-2.40] and 2.72 [2.09-3.54], respectively). Furthermore, the combination of depression with a long duration of diabetes mellitus (ie, >10 years) or insulin therapy was associated with a particularly higher risk of CVD mortality after multivariate adjustment (RRs, 3.22 and 4.90, respectively).

Conclusions  Depression and diabetes are associated with a significantly increased risk of all-cause and CVD mortality rate. The coexistence of these conditions identifies women at particularly high risk.

Figures in this Article

Depression is highly prevalent in the US population, affecting approximately 14.8 million US adults (6.7%) in a given year.1 Strong evidence from epidemiologic studies suggests that depression is associated with a significantly increased risk of coronary heart disease2 and all-cause mortality.3 Diabetes mellitus is also highly prevalent, and more than 23.5 million US adults (10%) have this disorder.4 It is also well known that diabetes and its related complications are leading causes of mortality globally.5

Epidemiologic studies have consistently documented an increased prevalence of depression in patients with diabetes. It is estimated that clinically significant depressive symptoms affect approximately 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 and 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.1017 However, previous investigations have been limited by small sample size,10,13,15 short-term follow-up,1416 evaluation only in patients with diabetes (with no comparison group of patients without diabetes),1315,17 and the use of self-reported, questionnaire-derived depressive symptoms as the exposure (with no information regarding depression diagnosis and medication use).1113,17 In addition, few studies have been conducted among women, in whom depression is more prevalent than in men.18 Therefore, using data from the Nurses' Health Study, we aimed to examine the individual and joint effects of depression and type 2 diabetes on all-cause and cardiovascular disease (CVD) mortality rate among middle-aged and elderly women during a 6-year follow-up.

STUDY POPULATION

The Nurses' Health Study cohort was established in 1976, when 121 700 female registered nurses aged 30 to 55 years residing in 11 states responded to a mailed questionnaire regarding their medical history and health practices. The cohort has been followed up every 2 years with mailed questionnaires that updated exposure information and inquired about newly diagnosed medical illnesses. Details have been published elsewhere.2,19 Until 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 the 2000 questionnaire cycle as the baseline because self-reported diagnosed depression was addressed in this year (n = 94 791). 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 = 12 041); unknown diabetes diagnosis date or uncertainty of the diagnosis (n = 3361); and missing values for covariates (n = 98) at baseline were excluded. Therefore, 78 282 participants (aged 54 to 79 years) were included in this analysis.

DEPRESSION MEASUREMENT

Self-reported symptoms of depression, use of antidepressant medication, and physician-diagnosed depression were used as measures of depression. Depressive symptoms were assessed in 1992, 1996, and 2000 with the 5-item Mental Health Index (MHI-5) subscale of the 36-Item Short-Form Health Survey designed to capture psychological distress vs well-being.2022 The participants were asked how much of the time during the past month (all, most, a good bit, some, little, or none) they felt (1) nervous, (2) so down that nothing could cheer them up, (3) calm and peaceful, (4) down and blue, or (5) happy. The scale was scored from 0 to 100, with lower scores indicating more severe depressive symptoms (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.23 In accordance with a prior study coauthored by 2 of us19 that used 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.

Participants were first asked to report regular antidepressant medication use in 1996 and history of physician-diagnosed depression in 2000; hence, 2000 was used as the baseline for this study. The information regarding antidepressant medication and physician-diagnosed depression was updated biennially. Therefore, depression was defined as having diagnosed depression, being treated with antidepressant medications, having SDS, or having any of these conditions.

ASSESSMENT OF DIABETES

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 nonrespondents, and these were followed up by telephone interviews. A case of diabetes was considered confirmed if at least 1 of the following was reported on the supplementary questionnaire according to the National Diabetes Data Group criteria24: (1) the presence of 1 or more classic symptoms (excessive thirst, polyuria, weight loss, and/or hunger) plus fasting plasma glucose levels of at least 140 mg/dL or random plasma glucose levels of at least 200 mg/dL (to convert glucose levels to millimoles per liter, multiply by 0.0555); (2) at least 2 elevated plasma glucose concentrations on different occasions (fasting levels of at least 140 mg/dL, random plasma glucose levels of at least 200 mg/dL, and/or concentrations of at least 200 mg/dL after 2 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 cutoff point was lowered to 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 Nurses' Health Study participants, which consisted of comparisons with medical record review by an endocrinologist (J.E.M.).26 In addition, another validation study27 assessing the prevalence of undiagnosed diabetes suggested a low rate of false-negative results.

DEATH ASCERTAINMENT

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 searching the 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, Revision 8 (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 when 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 of all CVD causes included ICD-8 codes 390 through 459 and 795.28

COVARIATES

Demographic, lifestyle behavior, and comorbidity information were collected using the standardized questionnaires mailed to the nurses biennially. Marital status (having a spouse or not), ethnicity (white or other), family history (in the first-degree relatives) of diabetes (yes or no) and cancer (yes or no), and parental history of myocardial infarction (yes or no) were obtained. Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared from self-reported weight and height and categorized as less than 23, 23.0 through 24.9, 25.0 through 29.9, 30.0 through 34.9, or 35 or higher. Physical activity level based on the individual's engagement in usual recreational activity was grouped as less than 3, 3.0 through 8.9, 9.0 through 17.9, 18.0 through 26.9, or 27 or more metabolic equivalent hours per week. Smoking was grouped as never, former, or current smoker, and alcohol drinking status was categorized as 0, 0.1 through 4.9, or 5.0 or more g/d of alcohol. Most of the women were postmenopausal or in the perimenopausal period; information regarding estrogen hormone therapy was queried, and participants were categorized as never, former, or current users. Information regarding current aspirin and multivitamin use was also requested and grouped as yes or no. In addition, respondents were asked to report previously diagnosed medical conditions, including hypertension, elevated cholesterol level, heart disease, stroke, and cancer.

STATISTICAL ANALYSIS

Participants were classified into 4 groups: (1) without diabetes or depression, set as the reference group; (2) with depression but no diabetes; (3) with diabetes but no depression; and (4) with diabetes and depression. Means or proportions of covariates across the 4 groups were computed using the baseline information. For these comparisons, we used Mantel-Haenszel χ2 tests for categorical variables and analysis of variance for continuous variables. Person-years for each participant were calculated from the date the 2000 questionnaire was returned to the date of death from any cause; June 1, 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 used the updated depression and diabetes status and included age (continuous), marital status, family history of diabetes and cancer, and parental history of myocardial infarction. The multivariate model included the terms in the basic model and several major lifestyle variables: BMI, physical activity level, smoking and drinking status, use of estrogen hormone therapy, current aspirin use, and current multivitamin use. Major comorbidities (updated status of hypertension, elevated cholesterol level, 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 and parental history of myocardial infarction were updated every 2 years.

A series of stratified analyses were conducted by age, BMI, smoking status, alcohol intake status, physical activity level, postmenopausal estrogen hormone use, and 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 used the information from 1992 to 2006, the second defined depression based on antidepressant medication use and used the information from 1996 to 2006, and the third 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, or using antidepressant medication) and the effect of 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 78 282 middle-aged and elderly women (433 066 person-years), 4654 deaths (6.0%) were documented, with CVD mortality accounting for 979 (21.0%) of all deaths. Generally, participants with diabetes and depression combined had lower MHI-5 scores and physical activity levels, had higher BMIs, and were less likely to have spouses at baseline compared with the other 3 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 participants with diabetes (20.5%) was higher than that in the individuals without diabetes (15.1%).

Table Graphic Jump LocationTable 1. Baseline Characteristics of 78 282 Women According to Diabetes Mellitus and Depression Status in the Nurses' Health Study in 2000a
ANALYSES ACCORDING TO UPDATED STATUS OF DIABETES AND DEPRESSION

Compared with the reference group who had neither diabetes nor depression, the age-adjusted RR for all-cause mortality was more than 3-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 only, 1.52 (95% CI, 1.36-1.69) for those with diabetes only, and 2.46 (95% CI, 2.12-2.84) for those with diabetes and depression. Similar results were found with regard to CVD-specific mortality rate. Compared with the reference group, depression only and diabetes only alone showed a significantly 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 = .49).

Table Graphic Jump LocationTable 2. Relative Risks (95% Confidence Intervals) of Death From All Causes and Cardiovascular Disease According to Diabetes Mellitus and Depression Status: the Nurses' Health Study, 2000-2006

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 with the reference group who had neither condition, the RRs of total and CVD mortality for individuals with both conditions decreased to 2.07 (95% CI, 1.79-2.40) and 2.72 (2.09-3.54). However, adjustment for major comorbidities might be overadjustment to some extent because 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 only, depression only, or both conditions was significant in most stratified subgroups. The magnitudes of the RRs varied across different stratifications, whereas 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 periods) were consistent with the main analysis (Table 4).

Table Graphic Jump LocationTable 3. Multivariate Relative Risks (95% Confidence Intervals) of Cardiovascular Disease Death According to Diabetes and Depression Status: Subgroup Analysisa
Table Graphic Jump LocationTable 4. Relative Risks (95% Confidence Intervals) of Cardiovascular Disease Mortality According to Different Definition of Depression and Diabetes Status
EFFECT OF DIABETES DURATION AND TREATMENT AND DEPRESSION ON CVD MORTALITY RATE

As expected, the risk of CVD mortality increased monotonically with increased duration of clinical diabetes. Compared with women without diabetes, the multivariate-adjusted RRs of CVD death across categories of diabetes duration (<5, 5-10, and >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 with those without (data not shown). Among each stratum of duration of diabetes, the presence of depression implied a significantly higher risk compared with those without depression (Figure, A). The combination of depression and a long duration of diabetes (ie, >10 years) was associated with a RR of 3.22 (95% CI, 2.29-4.52) compared with those with neither diabetes nor depression.

Place holder to copy figure label and caption
Figure.

Multivariate relative risks and 95% confidence intervals (error bars) of cardiovascular disease (CVD) mortality. A, Relative risk of CVD mortality according to diabetes duration stratified by depression. B, Relative risk of CVD mortality according to diabetes treatment stratified by depression. C, Relative risk of CVD mortality according to depression categories stratified by diabetes. Relative risks were adjusted for age (continuous), family history of diabetes and cancer, parental history of myocardial infarction, current marital status, ethnicity (white or other), body mass index (calculated as weight in kilograms divided by height in meters squared) categories (<23, 23.0-24.9, 25.0-29.9, 30.0-34.9, or ≥35; physical activity level (<3, 3-8.9, 9-17.9, 18-26.9, or ≥27 metabolic equivalent hours per week), alcohol consumption (none, 0.1-4.9 g/d, or ≥5.0 g/d), smoking status (never, past, or current), current multivitamin use (yes or no), current estrogen hormone use (never, past, or current), current aspirin use (yes or no), and major comorbidities, including hypertension, hypercholesterolemia, heart disease, stroke, and cancer.

Graphic Jump Location

The multivariate RRs of CVD death across categories of diabetes treatment (no treatment, oral diabetes medication use, and 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 with those with neither diabetes nor depression (Figure, B).

EFFECT OF DEPRESSION CATEGORIES AND DIABETES ON CVD MORTALITY RATE

The increased risk of CVD mortality was evident in each stage of depression. Compared with participants without depression, the multivariate-adjusted RRs of CVD death in each category of depression (SDS only, diagnosed depression without treatment only, and 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 SDS and diabetes combined had the highest RR of 4.54 (95% CI, 2.60-7.92) on death of CVD compared with those who had neither condition (Figure, C).

In this large prospective cohort of women, we confirmed that diabetes and depression were significant risk factors for all-cause and CVD mortality, whereas the coexistence of these 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 rate, with highest risk among women with higher diabetes severity and comorbid depression combined.

Compared with individuals without diabetes, the risk of death in women with diabetes was increased by 35.2% in the current study. This is slightly lower but consistent with several previous publications3235 in which a 1.5- to 2-fold increased risk of death was reported. However, it is slightly lower than a previous report coauthored by 3 of us28 in this cohort in which a 2.5-fold increased risk of all-cause mortality was observed for women with diabetes during 20 years of follow-up (1976-1996). The discrepancy might be because of 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 RR of 1.67. This finding is consistent with most previous publications summarized in 2 meta-analyses.36,37 In addition, we found that the risk of all-cause and CVD death was approximately 40% higher in women with depression compared with individuals without depression, which is consistent with findings of other investigators3,38 and a prior publication in the same cohort coauthored by 1 of us,2 in which a 1.54-fold increased risk of fatal coronary heart disease associated with depression was observed.

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 colleagues11 also found similar results, with a 2.5-fold increased mortality risk for the combination of diabetes and depression compared with those without either condition. Black et al10 observed a much higher risk of the diabetes-depression combination with an RR of 4.94, which might occur because of using a reference group with neither diabetes nor depressive symptoms (Center for Epidemiologic Study of Depression score of 0 instead of the commonly used cutoff point of 1639). It could also occur because of differences in the study populations. The study by Black et al comprised Mexican Americans 65 years or older, whereas our study included primarily white women.

In our multivariate-adjusted model, we also found that the diabetes-and-depression combination was associated with a 2.7-fold increased risk of CVD mortality compared with those who had neither condition. This risk was much higher than that owing to diabetes (RR, 1.67) or depression (RR, 1.37) only. Egede et al11 observed similar risks of coronary heart disease mortality among participants with both conditions (RR, 2.43) and those with diabetes only (RR, 2.26). However, they used a Center for Epidemiologic Study of Depression 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 rate are likely to be additive. Nevertheless, the RR (2.72) was still moderately higher than the additive risk (1.67 × 1.37 = 2.29). Depression affects approximately 20% to 25% of the diabetic population6; 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 patients with diabetes remain to be elucidated. Numerous studies have found that depression and diabetes are highly correlated40 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 poor adherence to diabetes management by patients,9 and isolation from the social network.42 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 nervous system tone, decrease heart rate variability and the 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

Ours is one of few cohort studies that investigated the joint effect of diabetes and depression on all-cause and CVD-specific mortality rate among women. The large sample size and long duration of follow-up provide the opportunity to examine the association of diabetes and depression by themselves and in combination with risk of mortality. The follow-up rate of this well-established cohort was high (>94.0%), and more than 98.0% of the deaths 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. The study sample was a homogeneous population, all the participants were registered nurses, and more than 97.6% of participants were white. They had greater concern about their health and better understanding of health-related issues, which enhanced the reliability of our questionnaire assessment; however, the results might not be generalizable to other populations. Recruitment bias and survival bias of the cohort might also restrict the generalizability. In addition, the information regarding 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, previous studies coauthored by 2 of us26,27 have found self-reporting of diabetes to be highly reliable, although undiagnosed diabetes was possible in this cohort. On the other hand, the physician recognition rate of major depression is not generally considered to be high compared with the Structured Clinical Interview for DSM-IV,49 and the prevalence of untreated mental disorders is relatively high in the United States.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 regarding 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 2 prevalent disorders, further consideration is required to design strategies aimed to provide adequate psychological management and support among those with longstanding chronic conditions, such as diabetes.

Correspondence: Frank B. Hu, MD, PhD, Department of Nutrition, Harvard School of Public Health, 655 Huntington Ave, Boston, MA 02115 (frank.hu@channing.harvard.edu).

Submitted for Publication: April 16, 2010; final revision received June 13, 2010; accepted August 10, 2010.

Author Contributions: Drs Pan, Lucas, Franco, Willett, Manson, Rexrode, Ascherio, and Hu had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Financial Disclosure: None reported.

Funding/Support: The study was supported by National Institutes of Health grant DK58845. Dr Ascherio received a grant from the National Alliance for Research on Schizophrenia & Depression (project 5048070-01). Dr Lucas received a postdoctoral fellowship from the Fonds de recherche en santé du Québec.

Role of the Sponsor: The funding sources were not involved in the data collection, data analysis, manuscript writing, and publication.

Additional Information: We thank the participants in the Nurses' Health Study for their continuing support and colleagues who worked on the study for their valuable help.

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Arroyo  CHu  FBRyan  LMKawachi  IColditz  GASpeizer  FEManson  J Depressive symptoms and risk of type 2 diabetes in women. Diabetes Care 2004;27 (1) 129- 133
PubMed
McHorney  CAWare  JE  JrLu  JFSherbourne  CD The MOS 36-Item Short-Form Health Survey (SF-36): III: tests of data quality, scaling assumptions, and reliability across diverse patient groups. Med Care 1994;32 (1) 40- 66
PubMed
McHorney  CAWare  JE  JrRaczek  AE The MOS 36-Item Short-Form Health Survey (SF-36): II: psychometric and clinical tests of validity in measuring physical and mental health constructs. Med Care 1993;31 (3) 247- 263
PubMed
Ware  JE  JrSherbourne  CD The MOS 36-Item Short-Form Health Survey (SF-36): I: conceptual framework and item selection. Med Care 1992;30 (6) 473- 483
PubMed
Berwick  DMMurphy  JMGoldman  PAWare  JE  JrBarsky  AJWeinstein  MC Performance of a five-item mental health screening test. Med Care 1991;29 (2) 169- 176
PubMed
National Diabetes Data Group, Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 1979;28 (12) 1039- 1057
PubMed
Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 1997;20 (7) 1183- 1197
PubMed
Manson  JERimm  EBStampfer  MJColditz  GAWillett  WCKrolewski  ASRosner  BHennekens  CHSpeizer  FE Physical activity and incidence of non-insulin-dependent diabetes mellitus in women. Lancet 1991;338 (8770) 774- 778
PubMed
Field  AECoakley  EHMust  ASpadano  JLLaird  NDietz  WHRimm  EColditz  GA Impact of overweight on the risk of developing common chronic diseases during a 10-year period. Arch Intern Med 2001;161 (13) 1581- 1586
PubMed
Hu  FBStampfer  MJSolomon  CGLiu  SWillett  WCSpeizer  FENathan  DMManson  JE The impact of diabetes mellitus on mortality from all causes and coronary heart disease in women: 20 years of follow-up. Arch Intern Med 2001;161 (14) 1717- 1723
PubMed
Rich-Edwards  JWCorsano  KAStampfer  MJ Test of the National Death Index and Equifax Nationwide Death Search. Am J Epidemiol 1994;140 (11) 1016- 1019
PubMed
Nicholson  AKuper  HHemingway  H Depression as an aetiologic and prognostic factor in coronary heart disease: a meta-analysis of 6362 events among 146 538 participants in 54 observational studies. Eur Heart J 2006;27 (23) 2763- 2774
PubMed
Lloyd-Jones  DAdams  RJBrown  TMCarnethon  MDai  SDe Simone  GFerguson  TBFord  EFurie  KGillespie  CGo  AGreenlund  KHaase  NHailpern  SHo  PMHoward  VKissela  BKittner  SLackland  DLisabeth  LMarelli  AMcDermott  MMMeigs  JMozaffarian  DMussolino  MNichol  GRoger  VLRosamond  WSacco  RSorlie  PRoger  VLStafford  RThom  TWasserthiel-Smoller  SWong  NDWylie- Rosett  JAmerican Heart Association Statistics Committee and Stroke Statistics Subcommittee, Heart disease and stroke statistics—2010 update: a report from the American Heart Association [corrected in Circulation. 2010;121(12):e260]. Circulation 2010;121 (7) e46- e215
PubMed10.1161/CIRCULATIONAHA.109.192667
Gu  KCowie  CCHarris  MI Mortality in adults with and without diabetes in a national cohort of the U.S. population, 1971-1993. Diabetes Care 1998;21 (7) 1138- 1145
PubMed
Lotufo  PAGaziano  JMChae  CUAjani  UAMoreno-John  GBuring  JEManson  JE Diabetes and all-cause and coronary heart disease mortality among US male physicians. Arch Intern Med 2001;161 (2) 242- 247
PubMed
Cho  ERimm  EBStampfer  MJWillett  WCHu  FB The impact of diabetes mellitus and prior myocardial infarction on mortality from all causes and from coronary heart disease in men. J Am Coll Cardiol 2002;40 (5) 954- 960
PubMed
Saydah  SHEberhardt  MSLoria  CMBrancati  FL Age and the burden of death attributable to diabetes in the United States. Am J Epidemiol 2002;156 (8) 714- 719
PubMed
Lee  WLCheung  AMCape  DZinman  B Impact of diabetes on coronary artery disease in women and men: a meta-analysis of prospective studies. Diabetes Care 2000;23 (7) 962- 968
PubMed
Huxley  RBarzi  FWoodward  M Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies. BMJ 2006;332 (7533) 73- 78
PubMed
Wassertheil-Smoller  SShumaker  SOckene  JTalavera  GAGreenland  PCochrane  BRobbins  JAragaki  ADunbar-Jacob  J Depression and cardiovascular sequelae in postmenopausal women: the Women's Health Initiative (WHI). Arch Intern Med 2004;164 (3) 289- 298
PubMed
Radloff  L The CES-D scale: a self-report depression scale for research in the general population. Appl Psychol Meas 1977;1 (3) 385- 401
Mezuk  BEaton  WWAlbrecht  SGolden  SH Depression and type 2 diabetes over the lifespan: a meta-analysis. Diabetes Care 2008;31 (12) 2383- 2390
PubMed
Golden  SHLazo  MCarnethon  MBertoni  AGSchreiner  PJDiez Roux  AVLee  HBLyketsos  C Examining a bidirectional association between depressive symptoms and diabetes. JAMA 2008;299 (23) 2751- 2759
PubMed
Alexopoulos  GS Depression in the elderly. Lancet 2005;365 (9475) 1961- 1970
PubMed
Strine  TWMokdad  AHDube  SRBalluz  LSGonzalez  OBerry  JTManderscheid  RKroenke  K The association of depression and anxiety with obesity and unhealthy behaviors among community-dwelling US adults. Gen Hosp Psychiatry 2008;30 (2) 127- 137
PubMed
Katon  WJRusso  JEHeckbert  SRLin  EHCiechanowski  PLudman  EYoung  BVon Korff  M The relationship between changes in depression symptoms and changes in health risk behaviors in patients with diabetes. Int J Geriatr Psychiatry 2010;25 (5) 466- 475
PubMed
Jiang  WBabyak  MKrantz  DSWaugh  RAColeman  REHanson  MMFrid  DJMcNulty  SMorris  JJO’Connor  CMBlumenthal  JA Mental stress–induced myocardial ischemia and cardiac events. JAMA 1996;275 (21) 1651- 1656
PubMed
Carney  RMFreedland  KERich  MWJaffe  AS Depression as a risk factor for cardiac events in established coronary heart disease: a review of possible mechanisms. Ann Behav Med 1995;17 (2) 142- 149
PubMed
Carney  RMSaunders  RDFreedland  KEStein  PRich  MWJaffe  AS Association of depression with reduced heart rate variability in coronary artery disease. Am J Cardiol 1995;76 (8) 562- 564
PubMed
Schins  AHonig  ACrijns  HBaur  LHamulyák  K Increased coronary events in depressed cardiovascular patients: 5-HT2A receptor as missing link? Psychosom Med 2003;65 (5) 729- 737
PubMed
Löwe  BSpitzer  RLGräfe  KKroenke  KQuenter  AZipfel  SBuchholz  CWitte  SHerzog  W Comparative validity of three screening questionnaires for DSM-IV depressive disorders and physicians' diagnoses. J Affect Disord 2004;78 (2) 131- 140
PubMed
Demyttenaere  KBruffaerts  RPosada-Villa  JGasquet  IKovess  VLepine  JPAngermeyer  MCBernert  Sde Girolamo  GMorosini  PPolidori  GKikkawa  TKawakami  NOno  YTakeshima  TUda  HKaram  EGFayyad  JAKaram  ANMneimneh  ZNMedina-Mora  MEBorges  GLara  Cde Graaf  ROrmel  JGureje  OShen  YHuang  YZhang  MAlonso  JHaro  JMVilagut  GBromet  EJGluzman  SWebb  CKessler  RCMerikangas  KRAnthony  JCVon Korff  MRWang  PSBrugha  TSAguilar-Gaxiola  SLee  SHeeringa  SPennell  BEZaslavsky  AMUstun  TBChatterji  SWHO World Mental Health Survey Consortium, Prevalence, severity, and unmet need for treatment of mental disorders in the World Health Organization World Mental Health Surveys. JAMA 2004;291 (21) 2581- 2590
PubMed

Figures

Place holder to copy figure label and caption
Figure.

Multivariate relative risks and 95% confidence intervals (error bars) of cardiovascular disease (CVD) mortality. A, Relative risk of CVD mortality according to diabetes duration stratified by depression. B, Relative risk of CVD mortality according to diabetes treatment stratified by depression. C, Relative risk of CVD mortality according to depression categories stratified by diabetes. Relative risks were adjusted for age (continuous), family history of diabetes and cancer, parental history of myocardial infarction, current marital status, ethnicity (white or other), body mass index (calculated as weight in kilograms divided by height in meters squared) categories (<23, 23.0-24.9, 25.0-29.9, 30.0-34.9, or ≥35; physical activity level (<3, 3-8.9, 9-17.9, 18-26.9, or ≥27 metabolic equivalent hours per week), alcohol consumption (none, 0.1-4.9 g/d, or ≥5.0 g/d), smoking status (never, past, or current), current multivitamin use (yes or no), current estrogen hormone use (never, past, or current), current aspirin use (yes or no), and major comorbidities, including hypertension, hypercholesterolemia, heart disease, stroke, and cancer.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Baseline Characteristics of 78 282 Women According to Diabetes Mellitus and Depression Status in the Nurses' Health Study in 2000a
Table Graphic Jump LocationTable 2. Relative Risks (95% Confidence Intervals) of Death From All Causes and Cardiovascular Disease According to Diabetes Mellitus and Depression Status: the Nurses' Health Study, 2000-2006
Table Graphic Jump LocationTable 3. Multivariate Relative Risks (95% Confidence Intervals) of Cardiovascular Disease Death According to Diabetes and Depression Status: Subgroup Analysisa
Table Graphic Jump LocationTable 4. Relative Risks (95% Confidence Intervals) of Cardiovascular Disease Mortality According to Different Definition of Depression and Diabetes Status

References

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Black  SAMarkides  KSRay  LA Depression predicts increased incidence of adverse health outcomes in older Mexican Americans with type 2 diabetes. Diabetes Care 2003;26 (10) 2822- 2828
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Egede  LENietert  PJZheng  D Depression and all-cause and coronary heart disease mortality among adults with and without diabetes. Diabetes Care 2005;28 (6) 1339- 1345
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Zhang  XNorris  SLGregg  EWCheng  YJBeckles  GKahn  HS Depressive symptoms and mortality among persons with and without diabetes. Am J Epidemiol 2005;161 (7) 652- 660
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Bruce  DGDavis  WAStarkstein  SEDavis  TM A prospective study of depression and mortality in patients with type 2 diabetes: the Fremantle Diabetes Study. Diabetologia 2005;48 (12) 2532- 2539
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Katon  WJRutter  CSimon  GLin  EHLudman  ECiechanowski  PKinder  LYoung  BVon Korff  M The association of comorbid depression with mortality in patients with type 2 diabetes. Diabetes Care 2005;28 (11) 2668- 2672
PubMed
Ismail  KWinkley  KStahl  DChalder  TEdmonds  M A cohort study of people with diabetes and their first foot ulcer: the role of depression on mortality. Diabetes Care 2007;30 (6) 1473- 1479
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Katon  WFan  MYUnützer  JTaylor  JPincus  HSchoenbaum  M Depression and diabetes: a potentially lethal combination. J Gen Intern Med 2008;23 (10) 1571- 1575
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Lin  EHHeckbert  SRRutter  CMKaton  WJCiechanowski  PLudman  EJOliver  MYoung  BAMcCulloch  DKVon Korff  M Depression and increased mortality in diabetes: unexpected causes of death. Ann Fam Med 2009;7 (5) 414- 421
PubMed
Belmaker  RHAgam  G Major depressive disorder. N Engl J Med 2008;358 (1) 55- 68
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Arroyo  CHu  FBRyan  LMKawachi  IColditz  GASpeizer  FEManson  J Depressive symptoms and risk of type 2 diabetes in women. Diabetes Care 2004;27 (1) 129- 133
PubMed
McHorney  CAWare  JE  JrLu  JFSherbourne  CD The MOS 36-Item Short-Form Health Survey (SF-36): III: tests of data quality, scaling assumptions, and reliability across diverse patient groups. Med Care 1994;32 (1) 40- 66
PubMed
McHorney  CAWare  JE  JrRaczek  AE The MOS 36-Item Short-Form Health Survey (SF-36): II: psychometric and clinical tests of validity in measuring physical and mental health constructs. Med Care 1993;31 (3) 247- 263
PubMed
Ware  JE  JrSherbourne  CD The MOS 36-Item Short-Form Health Survey (SF-36): I: conceptual framework and item selection. Med Care 1992;30 (6) 473- 483
PubMed
Berwick  DMMurphy  JMGoldman  PAWare  JE  JrBarsky  AJWeinstein  MC Performance of a five-item mental health screening test. Med Care 1991;29 (2) 169- 176
PubMed
National Diabetes Data Group, Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 1979;28 (12) 1039- 1057
PubMed
Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 1997;20 (7) 1183- 1197
PubMed
Manson  JERimm  EBStampfer  MJColditz  GAWillett  WCKrolewski  ASRosner  BHennekens  CHSpeizer  FE Physical activity and incidence of non-insulin-dependent diabetes mellitus in women. Lancet 1991;338 (8770) 774- 778
PubMed
Field  AECoakley  EHMust  ASpadano  JLLaird  NDietz  WHRimm  EColditz  GA Impact of overweight on the risk of developing common chronic diseases during a 10-year period. Arch Intern Med 2001;161 (13) 1581- 1586
PubMed
Hu  FBStampfer  MJSolomon  CGLiu  SWillett  WCSpeizer  FENathan  DMManson  JE The impact of diabetes mellitus on mortality from all causes and coronary heart disease in women: 20 years of follow-up. Arch Intern Med 2001;161 (14) 1717- 1723
PubMed
Rich-Edwards  JWCorsano  KAStampfer  MJ Test of the National Death Index and Equifax Nationwide Death Search. Am J Epidemiol 1994;140 (11) 1016- 1019
PubMed
Nicholson  AKuper  HHemingway  H Depression as an aetiologic and prognostic factor in coronary heart disease: a meta-analysis of 6362 events among 146 538 participants in 54 observational studies. Eur Heart J 2006;27 (23) 2763- 2774
PubMed
Lloyd-Jones  DAdams  RJBrown  TMCarnethon  MDai  SDe Simone  GFerguson  TBFord  EFurie  KGillespie  CGo  AGreenlund  KHaase  NHailpern  SHo  PMHoward  VKissela  BKittner  SLackland  DLisabeth  LMarelli  AMcDermott  MMMeigs  JMozaffarian  DMussolino  MNichol  GRoger  VLRosamond  WSacco  RSorlie  PRoger  VLStafford  RThom  TWasserthiel-Smoller  SWong  NDWylie- Rosett  JAmerican Heart Association Statistics Committee and Stroke Statistics Subcommittee, Heart disease and stroke statistics—2010 update: a report from the American Heart Association [corrected in Circulation. 2010;121(12):e260]. Circulation 2010;121 (7) e46- e215
PubMed10.1161/CIRCULATIONAHA.109.192667
Gu  KCowie  CCHarris  MI Mortality in adults with and without diabetes in a national cohort of the U.S. population, 1971-1993. Diabetes Care 1998;21 (7) 1138- 1145
PubMed
Lotufo  PAGaziano  JMChae  CUAjani  UAMoreno-John  GBuring  JEManson  JE Diabetes and all-cause and coronary heart disease mortality among US male physicians. Arch Intern Med 2001;161 (2) 242- 247
PubMed
Cho  ERimm  EBStampfer  MJWillett  WCHu  FB The impact of diabetes mellitus and prior myocardial infarction on mortality from all causes and from coronary heart disease in men. J Am Coll Cardiol 2002;40 (5) 954- 960
PubMed
Saydah  SHEberhardt  MSLoria  CMBrancati  FL Age and the burden of death attributable to diabetes in the United States. Am J Epidemiol 2002;156 (8) 714- 719
PubMed
Lee  WLCheung  AMCape  DZinman  B Impact of diabetes on coronary artery disease in women and men: a meta-analysis of prospective studies. Diabetes Care 2000;23 (7) 962- 968
PubMed
Huxley  RBarzi  FWoodward  M Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies. BMJ 2006;332 (7533) 73- 78
PubMed
Wassertheil-Smoller  SShumaker  SOckene  JTalavera  GAGreenland  PCochrane  BRobbins  JAragaki  ADunbar-Jacob  J Depression and cardiovascular sequelae in postmenopausal women: the Women's Health Initiative (WHI). Arch Intern Med 2004;164 (3) 289- 298
PubMed
Radloff  L The CES-D scale: a self-report depression scale for research in the general population. Appl Psychol Meas 1977;1 (3) 385- 401
Mezuk  BEaton  WWAlbrecht  SGolden  SH Depression and type 2 diabetes over the lifespan: a meta-analysis. Diabetes Care 2008;31 (12) 2383- 2390
PubMed
Golden  SHLazo  MCarnethon  MBertoni  AGSchreiner  PJDiez Roux  AVLee  HBLyketsos  C Examining a bidirectional association between depressive symptoms and diabetes. JAMA 2008;299 (23) 2751- 2759
PubMed
Alexopoulos  GS Depression in the elderly. Lancet 2005;365 (9475) 1961- 1970
PubMed
Strine  TWMokdad  AHDube  SRBalluz  LSGonzalez  OBerry  JTManderscheid  RKroenke  K The association of depression and anxiety with obesity and unhealthy behaviors among community-dwelling US adults. Gen Hosp Psychiatry 2008;30 (2) 127- 137
PubMed
Katon  WJRusso  JEHeckbert  SRLin  EHCiechanowski  PLudman  EYoung  BVon Korff  M The relationship between changes in depression symptoms and changes in health risk behaviors in patients with diabetes. Int J Geriatr Psychiatry 2010;25 (5) 466- 475
PubMed
Jiang  WBabyak  MKrantz  DSWaugh  RAColeman  REHanson  MMFrid  DJMcNulty  SMorris  JJO’Connor  CMBlumenthal  JA Mental stress–induced myocardial ischemia and cardiac events. JAMA 1996;275 (21) 1651- 1656
PubMed
Carney  RMFreedland  KERich  MWJaffe  AS Depression as a risk factor for cardiac events in established coronary heart disease: a review of possible mechanisms. Ann Behav Med 1995;17 (2) 142- 149
PubMed
Carney  RMSaunders  RDFreedland  KEStein  PRich  MWJaffe  AS Association of depression with reduced heart rate variability in coronary artery disease. Am J Cardiol 1995;76 (8) 562- 564
PubMed
Schins  AHonig  ACrijns  HBaur  LHamulyák  K Increased coronary events in depressed cardiovascular patients: 5-HT2A receptor as missing link? Psychosom Med 2003;65 (5) 729- 737
PubMed
Löwe  BSpitzer  RLGräfe  KKroenke  KQuenter  AZipfel  SBuchholz  CWitte  SHerzog  W Comparative validity of three screening questionnaires for DSM-IV depressive disorders and physicians' diagnoses. J Affect Disord 2004;78 (2) 131- 140
PubMed
Demyttenaere  KBruffaerts  RPosada-Villa  JGasquet  IKovess  VLepine  JPAngermeyer  MCBernert  Sde Girolamo  GMorosini  PPolidori  GKikkawa  TKawakami  NOno  YTakeshima  TUda  HKaram  EGFayyad  JAKaram  ANMneimneh  ZNMedina-Mora  MEBorges  GLara  Cde Graaf  ROrmel  JGureje  OShen  YHuang  YZhang  MAlonso  JHaro  JMVilagut  GBromet  EJGluzman  SWebb  CKessler  RCMerikangas  KRAnthony  JCVon Korff  MRWang  PSBrugha  TSAguilar-Gaxiola  SLee  SHeeringa  SPennell  BEZaslavsky  AMUstun  TBChatterji  SWHO World Mental Health Survey Consortium, Prevalence, severity, and unmet need for treatment of mental disorders in the World Health Organization World Mental Health Surveys. JAMA 2004;291 (21) 2581- 2590
PubMed

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