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Psychosomatic Medicine 65:376-383 (2003)
© 2003 American Psychosomatic Society

ORIGINAL ARTICLES

Depression and Coronary Heart Disease in Women With Diabetes

Ray E. Clouse, MD, Patrick J. Lustman, PhD, Kenneth E. Freedland, PhD, Linda S. Griffith, MSW, Janet B. McGill, MD and Robert M. Carney, PhD

From the Departments of Psychiatry (R.E.C., P.J.L., K.E.F., L.S.G., R.M.C.) and Medicine (R.E.C., J.B.McG), Washington University School of Medicine, and the Department of Veterans Affairs (P.J.L.), Medical Center, St. Louis, Missouri.

Address reprint requests to: Ray E. Clouse, MD, Professor of Medicine and Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8124, St. Louis, MO 63110. Email: rclouse{at}im.wustl.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
OBJECTIVE: The protective effects of female gender on the appearance and course of coronary heart disease (CHD) in nondiabetic subjects are diminished in the presence of diabetes. Depression predicts onset of and poor outcome from CHD in nondiabetic populations. We hypothesized that the doubled rates of depression in female diabetic patients could help explain the high prevalence of CHD in women with diabetes.

METHOD: Seventy-six female type 1 and type 2 diabetic patients with (N=16) or without (N=60) active major depression (DSM-III) at index evaluation underwent systematic annual investigation of diabetes and its complications for up to 10 years. Occurrences of CHD and other macrovascular complications were examined in relation to depression status using survival analysis statistics. A multivariate model incorporating other CHD risk factors (age, duration of diabetes, body mass index, glycosylated hemoglobin, and presence of hypertension, hyperlipidemia, or tobacco use) was used to determine independent effects of depression on outcome.

RESULTS: Development of CHD was significantly more rapid in the depressed subset (p<0.01 between 10-year curves), an effect that persisted after controlling for base-line differences in body mass index. Depression also was retained as an independent predictor of CHD in the multivariate model with an age-adjusted hazard ratio of 5.2 (95% CI: 1.4–18.9; p=.01). In contrast, depression did not predict the development of clinically apparent peripheral or cerebrovascular disease.

CONCLUSIONS: In this sample of diabetic women, major depression was an independent risk factor that accelerated the development of CHD. Depression recognition and management may improve outcomes from diabetes in this gender subgroup.

Key Words: depression, • coronary heart disease, • diabetes, • peripheral vascular disease, • cerebrovascular disease.

Abbreviations: CHD = coronary heart disease;; DSM-III = Diagnostic and Statistical Manual of Mental Disorders, Version 3;; DIS = Diagnostic Interview Schedule, Version 3.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
RESEARCH DESIGN AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Diabetes increases the risk of developing coronary heart disease (CHD), doubling it in some populations and rivaling the risk for serious cardiac events imposed by established CHD in nondiabetic patients (1). It is associated with more severe and diffuse coronary atherosclerosis, especially in women, that cannot be explained by the presence of other traditional risk factors (2). In fact, protective effects of female gender on the appearance and course of CHD in nondiabetic subjects largely are lost in the presence of diabetes (3–5). Diabetes also is independently associated with the risk of dying from CHD (2), a risk that is particularly high for females. For example, the rate of early death following acute myocardial infarction is greater in women, the difference between genders remains whether or not thrombolytic therapy is employed, and the hospital mortality rate following coronary angioplasty, atherectomy, or bypass surgery is increased in female groups (6).

A straightforward explanation for the malicious course of CHD in diabetic women presently is unavailable. Adherence to diet and exercise guidelines reduces the risk of CHD in women in general (7). Poor adherence would unfavorably influence metabolic control in diabetic women, and poor metabolic control also has been linked to greater mortality from CHD in females (8). Depression has been associated with both poor adherence to medical regimens and higher percentage of glycosylated hemoglobin in diabetic subjects (9, 10). Thus, depression in women with diabetes surfaces as a potential explanation for their increased susceptibility to and mortality from CHD.

Depression rates are doubled in the presence of diabetes and are considerably higher in diabetic women compared with diabetic men (11). In nondiabetic patients, depression precipitates manifestations of CHD, is associated with more symptoms of and limitations from CHD, and has been linked consistently to higher mortality following myocardial infarction (12–14). Prospective studies have shown that among community residents with no known history of CHD, those who are depressed are more likely to have a myocardial infarction or die from cardiac-related causes in the ensuing years than are comparable nondepressed controls (15–17). Consequently, it is plausible that depression is important in the presentation and course of CHD in diabetic women. Epidemiological data already are available to indicate that depressive symptoms independently predict incident manifestations of CHD in type 1 diabetic women over as little as 4 years of observation (18).

The present study examined the development of CHD manifestations in diabetic women who were undergoing annual assessment of diabetes and its complications, acknowledging the limitations imposed by the small sample size. Survival analyses were used to compare rates in the subset with major depression established by psychiatric interview at initial evaluation to the group not meeting conventional criteria for this diagnosis. The findings were then corrected for potential confounding factors to determine the independent effect of depression on the course of CHD in this group. The effects of depression on the appearance of other macrovascular complications (peripheral vascular disease, cerebrovascular disease) also were examined.


   RESEARCH DESIGN AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Subjects
Seventy-six female diabetic subjects underwent a psychiatric interview during an inpatient evaluation of diabetes and its complications. These subjects represent the female subset of a group of 114 subjects who had been recruited and interviewed in 1982 as part of a series of investigations sponsored by the National Institutes of Health to study the interrelationship of diabetes and psychiatric illness (19). Only females were studied because the focus of the present study was on the high rate of CHD in diabetic women; additionally, the number of depressed male subjects in the initial study was insufficient for study. The parent group was a sample of convenience that had been randomly selected from consecutive patients undergoing annual diabetes evaluations at the General Clinical Research Center of Washington University School of Medicine as part of a diabetes registry. Characteristics of this group have been reported previously (19). The only explicit criteria for inclusion in this series of investigations were that subjects be 21 years of age or older, consent to participate, and be able to answer questions and fill out forms.

For the 76 female subjects in the present report, mean age at the time of interview was 41.3±15.7 years and the duration of diabetes was 12.4±7.9 years. Thirty-four subjects (44.7%) had type 1 diabetes and 42 (55.3%) had type 2 diabetes, as classified at the time according to the National Diabetes Data Group criteria (20). The majority of the subjects were white [44 (57.9%); African American, 31 (40.8%); Asian, 1 (1.3%)] and were managed with insulin [56 (73.7%); oral hypoglycemic agents, 20 (26.3%)]. Investigation of psychiatric illness and its relationship to clinical characteristics in this study population was approved by the Human Studies Committee (IRB) of Washington University Medical Center.

Psychiatric Interview
Psychiatric diagnoses were determined with the National Institute of Mental Health Diagnostic Interview Schedule—version 3 (DIS) (21), a standardized interview that establishes diagnoses from specific criteria. At the time of this investigation, the operative criteria were those outlined in the Diagnostic and Statistical Manual of Mental Disorders, 3rd ed. (22). The DIS is a highly structured psychiatric interview with demonstrated reliability and validity relative to making psychiatric diagnoses (23). Likewise, the DIS is sensitive to psychiatric diagnoses in patients with diabetes, wherein some apparent symptoms of psychiatric disorder (eg, fatigue, difficulty concentrating) may result from metabolic derangements (eg, hyper- or hypoglycemia) (24).

The focus of this investigation was on patients meeting the DSM-III criteria for major depressive episode, hereafter referred to as depression in this report. The DIS allows for characterization and timing of depression over the course of the subject’s lifetime. Subjects who reported sufficient criteria-defining symptoms at any time in their past were considered to have lifetime histories of depression; the subset who were experiencing sufficient symptoms at the time of the interview were diagnosed as having current depression. The latter group was examined most closely for the effects of depression on CHD because the diagnosis was less dependent on symptom recall and these subjects were most likely to experience recurrent episodes of depression over the subsequent years of follow-up (25). Two thirds of the currently depressed subjects in the parent study who were available for reinterview 5 years later again met criteria for currently active depression, as described in a previously published report (25). In contrast, only 25% of available patients with remote histories of depression in the parent subject group were depressed 5 years later. Symptomatic affective disorder surfaced over 5 years in an even smaller fraction of subjects (<10%) whose index interview had indicated neither current nor previous depression (25).

Medical Evaluation
At each registry admission, subjects were systematically evaluated for medical illnesses, including atherosclerotic complications of diabetes (CHD, peripheral vascular disease, cerebrovascular disease). Demographic information (including age and duration of diabetes), tobacco use, presence of hypertension or hyperlipidemia, body mass index, and glycosylated hemoglobin were extracted from the index registry visit (at the time of the psychiatric interview) for analysis as predictors toward the development of atherosclerotic complications. Final diagnoses of atherosclerotic disorders incorporated available historical data, findings on physical examination, and laboratory, electrocardiographic, and additional test results obtained during the admission or in the interval between registry visits. Criteria required for a diagnosis of manifest CHD in this investigation were: documented myocardial infarction or ischemic electrocardiographic changes (including ischemic ST-T wave changes or new Q-waves) observed at rest or during an exercise treadmill test, the latter being performed for clinical indications. Although not used as a criterion for CHD, a history of typical angina also was recorded. Peripheral vascular disease was diagnosed with a history of claudication, pulseless lower extremity, or ischemic ulceration of a lower extremity. Cerebrovascular disease was considered present by transient ischemic attacks or cerebrovascular accident. The presence of a positive diagnostic test or intervention in the interval between evaluations also was considered indicative of the complication, although routine testing was not a standard component of the registry protocol. Interval onset of a complication was attributed to the date of the registry visit when first recorded, and complications occurring before the index evaluation (time of psychiatric interview) were attributed to the date of the index evaluation.

Telephone contact was established with the subject or a family member 10 years after the index evaluation for those participants that did not complete 10 years of registry evaluations. Clinical status of the subject and development of atherosclerotic complications were recorded to determine the effects of attrition or relevant fatal events on the analyses.

Statistical Methods
Grouped data are reported as mean±SD throughout. Differences in demographic and clinical characteristics between groups were determined using Fisher’s exact or two-tailed t tests as appropriate. Kaplan-Meir plots were created by censoring subjects at the last registry visit; log-rank analyses were used to compare curves. Cox proportional hazards regression analysis was employed to determine the independent effects of clinical variables on the time to the development of atherosclerotic complications, with all independent variables included in the model without stepwise or directional exclusion. The data were censored at 6 years for this analysis because of the small number of depressed subjects available for evaluation beyond this point. In each case, p<0.05 was required for statistical significance.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Sixteen subjects (21.1%) met the criteria for current major depression at the time of the diagnostic interview. Characteristics of the groups with and without current depression are shown in Table 1. Only the difference in body mass index was significant, the depressed subjects being more obese. The groups also were similar in percentage insulin-managed (depressed, 75%; nondepressed, 73%; p=.99) and degree of metabolic control as measured by glycosylated hemoglobin (Table 1). Of the sixty remaining subjects, 18 (23.7%) met the criteria for major depression at some point in the past but were not depressed at the time of interview (lifetime but not current depression). The other 42 subjects (55.3%) had no lifetime history of depression. For the entire subject group, the mean length of registry follow-up after the psychiatric interview was 6.1±4.9 years.


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  		TABLE 1. Clinical Characteristics in Relation to Depression Status at the Time of the Psychiatric Interview
 
CHD was detected in a total of 11 subjects (14.5%) at some point over a maximum of 10 years of observation. The distributions of events in subsets with and without current depression are shown in Table 2; all myocardial infarctions were accompanied by hospital admission. The number of recorded CHD events, although small, was greater (p<0.05) in the depressed group. Appearance of these events over time is shown in a Kaplan-Meir plot in Fig. 1. Depression significantly accelerated the presentation of CHD over the 10-year period (p<0.01). When the analysis controlled for initial differences in body mass index, the only significant difference in clinical characteristics between groups, the effect of depression on the appearance of CHD was retained (p<.05). The risk was specifically related to those with current depression at the time of interview, as manifestations of CHD appeared at a similar rate in patients with remote histories of a depressive episode as they did in those with no prior depression history (Fig. 2).


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  		TABLE 2. Recorded Coronary Heart Disease Events During the Observation Period in Relation to Depression Status at Initial Evaluation
 


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  		Fig. 1. Kaplan-Meir plots showing the development of clinically manifest coronary heart disease (CHD) in relation to depression status. Depressed subjects met criteria for major depression at the time of the index interview. The curves were significantly different across the 10 years (p < .01).

 


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  		Fig. 2. Occurrence of coronary heart disease using Kaplan-Meir analysis with further division by depression history. Currently depressed subjects met criteria at the time of the index evaluation, whereas those with remote histories reported symptoms of major depression in the past. The remainder never met psychiatric diagnostic criteria for major depressive episode. The curves for the latter two groups were not significantly different (p > .5).

 
Information derived from the follow-up interview 10 years after the initial evaluation did not suggest a bias related to attrition or unrecorded CHD in the nondepressed group. Only 6 subjects or their relatives (7.9%) could not be located for interview [2 depressed (12.5%), 4 nondepressed (6.7%); p=.60]. Deaths occurred in a similar proportion of subjects in each group [1 depressed (6.2%), 5 nondepressed (8.4%); p=.99]. Only 1 patient died from a cardiac event after discontinuing registry examinations. Manifestations of CHD already had been recorded in this nondepressed patient because of a documented myocardial infarction during the period of registry observation. Consequently, there was no evidence that the findings were significantly biased by censored events.

Because trends toward differences between depressed and nondepressed subjects in the rates of at least two other risk factors for CHD were found (Table 1), further analyses of these potential confounders were performed. Kaplan-Meir plots were truncated at 6 years (the mean follow-up period) for these and subsequent analyses because of the small number of depressed patients available for evaluation beyond this time. The effect of depression on the appearance of CHD was retained in this truncated analysis (p=.01). Of the potential risk factors for the development of manifest CHD listed in Table 1, age at time of interview (p=.0004) and presence of hypertension (p=.005) were significant in univariate analyses. However, when all of the potential risk factors and depression were entered into a multivariate model, only age (p=.01) and depression (p=.03) were retained for their independent effects on manifest CHD (Table 3). The hazard ratio associated with depression for the 6-year period, when adjusted for age, was 5.2 (95% CI: 1.4–18.9; p=.01).


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  		TABLE 3. Independent Contributions of Depression and Other Potential Risk Factors at Index Evaluation toward the Subsequent Development of CHDa
 
In contrast to CHD, manifestations of peripheral vascular and cerebrovascular diseases as defined for this study were not predicted by depression at index evaluation-although the total number of events was very small. Kaplan-Meir plots did not differ between depressed and nondepressed subjects for either of these macrovascular complications at 6 or 10 years (p>.3 for each; Fig. 3). When comparisons were controlled for age and differences in body mass index, the effects of depression were even less significant (p>=.5 for each).



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  		Fig. 3. Kaplan-Meir plots showing the occurrence of clinically manifest A, peripheral vascular disease (PVD) and B, cerebrovascular disease (CVD) in relation to depression status. Depressed subjects met criteria for major depression at the time of the index interview. Depressed subjects did not differ from nondepressed subject in either comparison (p > .3 for each).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGMENTS
 REFERENCES
 
This study found that active major depression at index evaluation imposed a significantly increased risk of clinically apparent CHD over as much as a decade of observation in women with type 1 and type 2 diabetes attending a diabetes registry. The increased risk was not present for patients with only remote histories of depressive episodes. Although the depressed subset was more obese, the effect of depression was independent of body mass index and all other measured traditional risk factors for CHD. A similar effect of depression on the appearance of other macrovascular complications (peripheral vascular and cerebrovascular diseases) could not be demonstrated, but the number of these events was very small in our subjects. This is the first study to use psychiatric diagnosis in determining the impact of depression on macrovascular complications in diabetes, and, despite the small sample and small number of cardiac events, the findings support suspicions that depression is an important independent risk factor for the development of CHD in diabetic women.

Depression has been linked to a variety of traditional risk factors for CHD in nondiabetic samples, including obesity, tobacco use, and physical inactivity. These factors are not solely responsible for the risk, however, as patients with major or even subclinical depression have increased cardiovascular morbidity and mortality after controlling for relevant demographic and disease variables (14, 17, 26–29). A recent analysis of more than 7,000 subjects enrolled in the first National Health and Nutrition Examination Survey (NHANES I) found adjusted relative risks of depression on incident CHD of 1.7 in both men and women over a decade of observation, although the effects of depression on CHD mortality were restricted to men (30). The analyses were controlled for possible confounding factors (including demographics, socioeconomic status, presence of diabetes or hypertension, tobacco use, alcohol use, physical activity level, and body mass index), and were among the first to demonstrate that depression affects CHD risk in women. Additional data confirm that depression increases the risk of recurrent cardiac events in women with existing CHD (31).

We cannot determine if depression accelerated atherogenesis underlying CHD or, instead, precipitated CHD symptoms or events, as angiographic information was not routinely available in our patients. Women are more likely to present with chest pain syndromes that are unrelated to serious CHD processes (32, 33), but we did not rely solely on pain reporting to determine CHD manifestations. All patients with typical angina also had electrocardiographic abnormalities, and the majority had a documented history of myocardial infarction. Depression is associated with enhanced sympathetic activity that in turn could lead to platelet activation and increased aggregation (34–36). Depression also is associated with reduced heart rate variability in CHD patients, a finding unrelated to CHD severity, that likely represents autonomic dysregulation (37). This dysregulation could enhance risk of fibrillation, CHD presentation, and death. A rapidly enlarging body of investigative work is exposing the multiple mechanisms by which depression and associated anxiety could influence the presentation and course of CHD (38). Hypertension did not remain an independent risk in our multivariate model that included depression, and epidemiological data are accumulating linking depression to subsequent onset of hypertension in young adults (39, 40).

Depression in the diabetic patient may have additional negative effects. The general clustering of behavioral risks for CHD associated with depression includes poor adherence to medical regimens (9). Compared with nondepressed patients, the odds are three times greater that depressed individuals will be noncompliant with treatment recommendations (9). Not surprisingly, depressed diabetic patients are noncompliant with home glucose monitoring (41) and typically have poorer metabolic control than nondepressed cohorts (10). Besides its behavioral influences, depression has recognized direct effects on glucose homeostasis. Depression, via hypercortisolism, may promote insulin resistance (42), an independent predictor of CHD in both diabetic and nondiabetic samples (43–45). The association of depression with obesity and physical inactivity, other CHD risk factors that reduce insulin sensitivity (46–50), demonstrates the potential for important interactions compounding deleterious effects of depression on CHD in diabetic patients. In addition to interactions of particular importance in diabetes, adverse interactions of depression with tobacco use, hyperlipidemia, and inflammatory markers toward development of CHD have been demonstrated in nondiabetic subject groups (17, 51). Reductions in CHD mortality in the US general population attributed to modification of traditional risk factors have been attenuated in diabetic patients, especially women, possibly because of these interactions (52).

The relationship between depression and diabetes complications has been established as reliable by meta-analysis, with small to moderate effect sizes for most recognized complications (retinopathy, nephropathy, neuropathy, sexual dysfunction, and collapsed macrovascular complications) (53). This approach does not determine causal directionality, however. The fact that lifetime depression antedates the diagnosis of type 2 diabetes by an average of 8.7 years argues against the suggestion that depression is simply the emotional response to the distress of diabetes (25). In an analysis of participants in the Pittsburgh Epidemiology of Diabetes Complications Study, the only other series of reports examining potential effects of depression on macrovascular complications of diabetes over time, Forrest et al. found that higher reporting of depression symptoms on the Beck Depression Inventory independently predicted development of CHD in type 1 diabetics over 6 years (54). The effect may have been most pronounced for women, as depression remained an independent predictor of CHD in this gender with type 1 diabetes when the analysis was truncated at 4 years (18). The authors also noted that depression did not predict development of lower extremity vascular disease (54). These findings, in conjunction with our present observations using psychiatric diagnosis, strongly support a causal role of depression in the presentation of CHD in diabetes, a role that is not conspicuously generalized to all macrovascular complications.

Depression is common in diabetic patients, particularly women. Rates are doubled over nondiabetic samples whether depression is measured using diagnostic criteria or increased depression symptoms on self-report scales (11). Despite the possibilities, differences in prevalence by type of diabetes are not conspicuous. As in nondiabetic patient groups, women are more often afflicted than men (OR 1.6), and the calculated prevalence of clinically significant depression in diabetic women is as high as 28.2% (11). Consequently, the potential for an important role of this risk factor and its management in CHD outcomes in diabetic women is remarkable. Recurrent depression is common in diabetes, the average patient experiencing more than 4 episodes in 5 years –even after successful treatment (25, 55). Short-term treatment with both antidepressant medications and psychotherapy is effective in many cases (56–58), but improvement in the poor metabolic control associated with depression is not rapid nor profound (56, 58). Even small reductions in glycosylated hemoglobin may decrease complication rates (59, 60), but projected benefits on CHD may be more related to remission of depression itself and reduction of associated platelet activation, for example, than on alterations in glycemia (54, 61, 62).

The strength of our conclusions is limited by the small number of subjects in this study, the clinically-based methods of determining macrovascular outcomes, and the fact that the analyses only considered risk factor status at the index evaluation. We cannot assume that these were stable or persistent risks over the follow-up period in all subjects. The findings may not be generalized safely to all diabetic populations, as this was a convenience sample extracted from a university-based diabetes registry. Multivariate analyses also are inherently unstable with small sample sizes and numbers of outcome events, and the findings require replication in studies with larger pools of depressed and nondepressed subjects. Nevertheless, we were able to corroborate the risk of criteria-defined major depression on CHD in diabetic women, a group with at least a six-fold increased mortality over 20 years compared with nondiabetic women free of CHD (4). Similar studies are needed in men, as depression, although less prevalent, also may impose a risk in this gender. Poor compliance with medical treatment, presence of complications at the time of diabetes recognition, and death from complications continue to interfere with progress for the diabetic community, despite great gains in understanding the importance of diabetic regulation on outcome. Increased efforts at early depression recognition (63, 64), improved understanding of the benefits of individual depression treatments (65), and formulation and implementation of successful depression management strategies that consider specific needs of the diabetic patient may significantly reduce adverse outcomes related to CHD in diabetic women.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
REFERENCES
 
This work was supported in part by grants from the U.S. National Institutes of Health [DK36452, DK53060, and DK59364 (Drs. Clouse, Lustman, and Freedland), 5 P60 DK20579 (Dr. McGill), and 1UO1HL58946 (Drs. Carney and Freedland)], as well as the Lewis and Jean Sachs Trust (Dr. Carney). The findings were presented in abstract form at the annual meeting of the American Psychosomatic Association, Monterey, California, March 2001.

Received for publication May 10, 2002.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 

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