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(Circulation. 2000;102:1773.)
© 2000 American Heart Association, Inc.

Clinical Investigation and Reports

Depressive Symptoms and Risks of Coronary Heart Disease and Mortality in Elderly Americans

Abraham A. Ariyo, MD, MPH; Mary Haan, MPH, PhD; Catherine M. Tangen, PhD; John C. Rutledge, MD; Mary Cushman, MD, MS; Adrian Dobs, MD, MHS; Curt D. Furberg, MD, PhD; for the Cardiovascular Health Study Collaborative Research Group

From the Divisions of Cardiovascular Medicine (A.A.A.) and Endocrine (A.D), Johns Hopkins University, Baltimore, Md; the Divisions of Cardiovascular Medicine (J.C.R), Epidemiology and Prevention (M.H.), University of California-Davis; the Department of Biostatistics (C.M.T.), University of Washington, Seattle, Wash; Department of Pathology (M.C.), University of Vermont, Burlington; and the Department of Public Health Sciences (C.D.F.), Wake Forest University, Winston-Salem, NC. Correspondence to Dr Abraham A. Ariyo, Cardiovascular Division, Johns Hopkins Hospital, 600 N Wolfe St, Carnegie 568, Baltimore, MD 21287.

	Abstract

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Background—Several epidemiological studies have associated depressive symptoms with cardiovascular disease. We investigated whether depressive symptoms constituted a risk for coronary heart disease (CHD) and total mortality among an apparently healthy elderly cohort.

Methods and Results—In a prospective cohort of 5888 elderly Americans (65 years) who were enrolled in the Cardiovascular Health Study, 4493 participants who were free of cardiovascular disease at baseline provided annual information on their depressive status, which was assessed using the Depression Scale of the Center for Epidemiological Studies. These 4493 subjects were followed for 6 years for the development of CHD and mortality. The cumulative mean depression score was assessed for each participant up to the time of event (maximum 6-year follow-up). Using time-dependent, proportional-hazards models, the unadjusted hazard ratio associated with every 5-unit increase in mean depression score for the development of CHD was 1.15 (P=0.006); the ratio for all-cause mortality was 1.29 (P<0.0001). In multivariate analyses adjusted for age, race, sex, education, diabetes, hypertension, cigarette smoking, total cholesterol, triglyceride level, congestive heart failure, and physical inactivity, the hazard ratio for CHD was 1.15 (P=0.006) and that for all-cause mortality was 1.16 (P=0.006). Among participants with the highest cumulative mean depression scores, the risk of CHD increased by 40% and risk of death by 60% compared with those who had the lowest mean scores.

Conclusions—Among elderly Americans, depressive symptoms constitute an independent risk factor for the development of CHD and total mortality.

Key Words: risk factors • epidemiology • coronary disease • mortality • depression

	Introduction

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Depressive symptoms occur in 19% to 30% of the elderly, but only 1% of those affected receive the necessary treatment.^{1 2} Several epidemiological studies^{3 4} have suggested that high depression scores may predispose an individual to an increased risk of developing cardiovascular disease (CVD). Although most,^{3 4 5 6 7 8 9 10 11} but not all^{12 13 14} prospective studies of middle-aged populations addressing this issue have reported positive associations, data regarding the relationship between depressive symptoms and cardiovascular risk in the elderly are sparse.

In this article, we report the results of a 6-year study that prospectively investigated the relationship between depressive symptoms and subsequent risk of coronary heart disease (CHD) and mortality in 4493 elderly Americans.

	Methods

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The Cardiovascular Health Study (CHS)¹⁵ is a multicenter study of cardiovascular risk factors in Americans aged 65 years and older. It was started in 1989 with an initial cohort of 5201 subjects. An additional ethnic minority cohort of 687 subjects was later recruited, which brought the total to 5888 subjects. The participants were recruited from random samples of the Medicare eligibility lists provided by the Health Care Financing Administration from the following 4 communities: Washington County, Md (Johns Hopkins University); Sacramento County, Calif (University of California-Davis); Forsyth County, NC (Wake Forest University); and Allegheny County, Pa (University of Pittsburgh). Participants were noninstitutionalized persons who signed the informed consent forms to participate in the study; persons were eligible for enrollment whether or not they had a history of CVD. The full details of the CHS recruitment process have been published elsewhere.¹⁶

In brief, participants were initially given a 90-minute home interview, during which a questionnaire was given and information was sought regarding their health, depressive status, and medications. All participants were given a 4- to 5-hour medical examination.

Our study cohort comprised 4493 subjects who were free of CVD; CVD included angina, CHD, myocardial infarction, angioplasty, coronary artery bypass surgery, congestive heart failure, or stroke at study entry. Baseline status was initially based on a self-report that was confirmed by clinical examination, a review of prior hospital records, or both. Depression was assessed at baseline and annually thereafter for an average of 6 years for the initial cohort and for 3 years for the minority cohort.

Ascertainment of Cardiovascular Events
The cardiovascular event of interest was CHD, which was defined as first occurrence of angina, myocardial infarction, angioplasty, coronary artery bypass grafting, or coronary death. All events were assessed semiannually. The surveillance and ascertainment of cardiovascular events in CHS have been described elsewhere.¹⁷ In brief, all morbid events after the baseline clinic visit were classified as incident events. Mortality was investigated on the basis of death code, which was graded according to the International Classification of Disease code.¹⁸ Information on death was obtained through reviews of obituaries, medical records, death certificates, and interviews of contacts and proxies. The CHS has nearly 100% ascertainment of mortality status.¹⁷ All provisional diagnoses of CHD and fatal events were reviewed and adjudicated at periodic meetings of the Morbidity and Mortality Subcommittee. This Subcommittee was comprised of an investigator from each center, the coordinating center, and the project office of the National Heart, Lung, and Blood institute. The events and deaths discussed in this article are those that were adjudicated from 1989 through June 1996.

Assessment of Depressive Status
We used the modified, shorter version of the Center for Epidemiological Studies’ Depression Scale,¹⁹ which is a questionnaire widely used as a screening tool to assess depression in the elderly, especially in primary care or outpatient settings (Table 1). The reliability of the modified version of this scale has been validated by other studies.^{20 21} It is a 10-item scale, with participants’ depression scores recorded as a continuous measure from 0 to 30. Traditionally, a score 8 is recognized as "at risk of clinical depression"; however, we used continuous depression scores in our analyses instead so as not to lose any information by categorization.

View this table: [in this window] [in a new window]   Table 1. Center for Epidemiological Studies— Depression Scale

Statistical Analysis
We used the nonparametric Wilcoxon-Mann-Whitney test for categorical covariates and the Spearman correlation for continuous covariates to assess the association between covariate measures and the baseline depression scores.

For a missing depression score for a given yearly visit, the last prior non-missing score was carried forward. Thus, depression scores for every visit were cumulatively averaged after missing depression values were replaced. Scores after an event did not contribute to the exposure measure. For individuals without an event, mean depression scores of all visits were calculated up to the last visit. Although depression was assessed annually, to reduce possible biases, depression scores were considered to take effect 6 months before the clinic visit (the halfway-point between visits). This approach is more representative of the exposure window for a given depressive state than having the depression score take effect on the clinic visit day. Participants with missing data ranged from 5% in year 1 to 13% in year 6. A missing value carry-forward method was used to replace these missing values.

The following variables were forced into the covariate-adjusted model: age at entry, race, sex, education, hypertension, diabetes, smoking status, total cholesterol levels, physical inactivity, triglycerides, marital status, and alcohol consumption. Time-dependent covariates for congestive heart failure, chronic obstructive pulmonary disease, and cancer diagnosis were constructed for all-cause mortality outcome. There was no indication of collinearity between the covariates and depressive symptoms or between the covariates themselves. Proportional hazards models were fit to the outcomes of time to angina, myocardial infarction, CHD, and death. All analyses were performed using the SAS system.²²

	Results

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Table 2 shows the distribution of depression scores among the cohort at baseline according to associated events. Few subjects had depression scores >15. Tables 3 and 4 depict the characteristics of the 4493 participants in this analysis. Age range at entry was 65 to 98 years, with a mean age of 72 years for women and 73 years for men. Depressive symptoms were not associated with age at study entry. White women and men composed 84% and 85% of the cohort, respectively. At study entry, nonwhites had higher depression scores than whites, and women had higher baseline depression scores than men (4.9 versus 3.7; P<0.001). Depression was more prevalent among the less educated, those with lower incomes, and those with a history of diabetes. Smokers had the highest depressive scores, with previous smokers having higher scores than persons who had never smoked. Married participants and those who lived with others had lower depression scores than those who were widowed, separated, or divorced. Those who had problems with the instrumental activities of daily living or lower social network scores had higher depression scores.

View this table: [in this window] [in a new window]   Table 2. Distribution of Depression Scores Among the Cohort

View this table: [in this window] [in a new window]   Table 3. Baseline Characteristics of the 4493 Participants

View this table: [in this window] [in a new window]   Table 4. Association of Covariates and Depression Score at Study Entry

Physical activity was inversely related to depression scores. Those with a higher body mass index had higher scores than those who had a lower body mass index. Among women, total cholesterol, HDL cholesterol, and factor VII levels were not associated with depression scores. However, LDL cholesterol levels were negatively correlated with depression, and fibrinogen was positively correlated with depression. In men, total cholesterol, LDL cholesterol, triglycerides, platelet count, and factor VII levels were not significantly associated with depressive scores. Of the 4493 study participants, 188 (143 women and 45 men) were on antidepressants. No differences existed in baseline characteristics of the few men on antidepressants and the rest of the cohort. However, women on antidepressants had higher platelet counts (P=0.001) and were more likely to smoke than those not on medication (P=0.001).

Cumulative Mean Depression Scores and Events
Table 5 depicts the hazard ratios (HRs) associated with each 5-unit increase in mean depression score before an event. In both univariate and multivariate analyses, every 5-unit increase in mean score was associated with a 15% increased risk of developing CHD (P=0.006). For mortality, 16% and 29% increased risks were observed in univariate and adjusted models, respectively.

View this table: [in this window] [in a new window]   Table 5. Relationship Between HRs Associated With Every 5-Unit Increase in Cumulative Mean Depression Score and Cardiovascular Events

We further explored the possibility of a sex interaction for each event of interest but found no evidence of such effect modification, indicating that the HR estimates shown in Table 5 hold equally for both sexes. However, some indication existed for a higher HR for new angina among women than among men (P=0.09). Analyses excluding those who were on antidepressants produced no change in results. The Figure further illustrates the increased risk of CHD and death with increasing levels of depressive scores. It shows a good correlation between the depression scores and vascular risks; for example, among the participants with some of the highest depression scores, the CHD risk increased by 40% and that of death by 60%.

View larger version (31K): [in this window] [in a new window]   Figure 1. Covariate-adjusted hazard ratios for having an event based on grouped 5-unit categories for average cumulative depression score estimated before the event of interest. Covariates were the same as those listed in Table 5.

Baseline Depression Scores and Events
Table 6 displays the HRs associated with 5-unit increases in baseline depression scores and cardiovascular events. Persons with higher baseline scores had a significantly higher risk of dying (P=0.004), although the risk for CHD was nonsignificant (P=0.162). However, after adjusting for demographic and cardiovascular risk factors, baseline depression was a significant predictor of CHD (P=0.032) and death (P=0.012).

View this table: [in this window] [in a new window]   Table 6. Relationship Between HRs Associated With Every 5-Unit Increase in the Baseline Depression Scores in the Cohort

	Discussion

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In this prospective study of elderly (65 years) Americans who were free of cardiovascular disease at baseline and who were followed for 6 years, we found that depressive symptoms constituted an independent risk factor for the development of CHD and total mortality. This risk increased with higher depression scores. Our study provides new evidence and adds to the growing body of data indicating that depressive status is a risk factor for CVD.

Our findings are consistent with those of other studies finding that depressive symptoms constitute a risk factor for CHD^{3 4 5 6 7} and mortality.^{4 5 6 7 8} However, our data differ from those in other studies because the present study focused exclusively on the elderly. It provides a large amount of prospective data on depressive symptoms as risk factors for CHD in older adults, as well as information on the vascular risk of depressive symptoms in women. We demonstrated the magnitude and incremental risks of CHD associated with increasing levels of depressive scores. These findings are particularly important for the elderly, in whom the applicability of some traditional risk factors has been challenged.^{23 24 25 26}

Cumulative mean assessment of depression scores was more predictive of vascular events than baseline scores. The fact that baseline depression scores did not adequately predict vascular events as cumulative mean scores may be due to the following. (1) A one-time assessment of depression at study entry could not capture the chronic depressive state of an individual as adequately as a 6-year follow-up. (2) A healthy cohort like ours may have produced lower initial depression scores; therefore, a longitudinal assessment of depression that is also more stable may do a better job of predicting vascular events.

It is conceivable that depressive symptoms could have occurred as a result of disease rather than being a precursor of CVD, because any life-threatening illness could potentially cause a depressive state and cloud the cause-and-effect relationship between depressive symptoms and the occurrence of cardiovascular events. However, because our study design excluded participants with prior cardiac disease, the prospective data collection of antecedent depression scores before cardiovascular events and the use of apparently healthy, noninstitutionalized elderly subjects argues against this notion. Second, the demonstration of an independent relationship between higher depression scores and increasing vascular risks in this apparently healthy elderly cohort strongly favors a relationship between depressive symptoms and cardiovascular events. Third, because the last clinic visit scores were carried forward for participants who missed clinics, our analyses would have probably underestimated the effects of depression, because sick individuals (more depressed) tend to stay at home. Finally, the results shown in Table 6, which used only baseline assessment of depression, validated the time-dependent analysis results and lent support to the argument that it is not changing disease assessment that is being captured in Table >5 but depressive status.

It is also possible that our findings may have occurred by chance. However, the prospective nature of this study, the large sample size, the duration of follow-up, the blinded ascertainment of events, and our analyses, which used cumulative mean depression scores, argue against chance as a primary explanation for the result. Second, although we evaluated depressive symptoms annually in our cohort, we used cumulative mean depression scores in our model, which measures chronic or persistent depressive state rather than an acute or a brief one-time episodic depressive mood. The "halfway point" (mid-visit) depression scores that were used in these analyses better assess the day-to-day depressive state rather than the office visit scores.

Women reportedly suffer more than men from the adverse vascular effects of a depressive state.²⁷ This may be due to the higher prevalence of depressive symptoms in women than in men. Nonetheless, we found that the HRs associated with 5-unit increases in depression scores were similar in men and women but, because women had higher scores to begin with, more vascular risks may have been expected for them.

The exact mechanism by which depressive symptoms may predispose some individuals to increased vascular risk is unknown; however, 3 plausible mechanisms have been proposed. (1) Depressive state is associated with poor physical activity, less exercise, more smoking, and a high likelihood of indulging in behavioral patterns that may increase vascular risk. (2) Depressive state as a mental stress increases autonomic sympathetic activation.^{28 29} This activation may result in increased levels of circulating platelets (with enhanced activation and aggregability), fibrinogen, and thromboxane A₂.³⁰ (3) Depressive state is related to lipid metabolism, such that the increased production of steroid and free fatty acids and a reduced glucose use ensues when depressed.^{13 31 32 33 34} This combined sympathoadrenal activation stimulates platelets via ₂-adrenoceptor activation^{13 33} and augments arterial thrombosis. Interestingly, we observed higher circulating platelet counts and a correlation between fibrinogen levels and depression scores among women on antidepressant medications but not among those not taking antidepressants. Thus, platelet activation and increased fibrinogen may be the major links between depression and CHD. Also, the effects of antidepressant medications on platelets, vascular events, and mortality in patients in depressive states remain unclear.

The increased mortality observed in our study is similar to that reported by other investigators.^{4 5 6 7 8} Deaths associated with depressive state have been attributed to the imbalance between the autonomic parasympathetic and sympathetic systems, with an overriding effect of the latter.³⁵ Animal and human studies have shown a correlation between increased sympathetic activity and induction of ventricular arrhythmias³⁶ that can lead to sudden death. The serotonergic system, a key player in the depressive mechanism, also plays an important role in the genesis of arrhythmias.³⁶ A depressive state is associated with social isolation, less functional capacity, and less exercise, and it may be a surrogate of other diseases. High suicide rates, violent deaths, and deaths from cancer and chronic diseases also compound the effects of depressive symptoms on excess mortality.

The first limitation of this study relates to mortality. Because the CHS was designed to assess cardiovascular risk factors, complete ascertainment of all possible risk factors for mortality is impossible; therefore, we cannot draw strong conclusions about depressive symptoms being a major risk factor for total mortality. Further, high depressive scores may be a surrogate measure for deteriorating health that could not be assessed in this study. However, we did control for known risk factors for CHD. Second, a close association exists between depressive state and chronic medical conditions. Although our cohort was free of disease at baseline, it is difficult to ascertain with certainty the presence or absence of subclinical disease in an elderly population. Third, antidepressant medications are also used for medical conditions other than clinical depression, and we could not ascertain the specific indications for their use in individual patients in our database.

Of the 31 millions Americans 65 years of age, 5 million have depressive symptoms, with a lifetime risk of major depressive disorder estimated at 7% to 12% for men and 20% to 25% for women.³⁷ Depressive disorder is second only to CVD in time lost from work and lost productivity, and it has been estimated to cost society $44 billion per year.³⁸ In a recent study,¹ elderly persons with depressive symptoms accrued 50% higher healthcare costs from more frequent use of medical services than nondepressed elderly people. Although available therapy improves symptoms and quality of life,³⁹ most physicians under-recognize depressive symptoms in elderly patients and, thus, the elderly are underdiagnosed and undertreated.³⁹ Increased awareness and early screening for depressive symptoms may help reduce the associated healthcare costs and human suffering associated with depressive symptoms.

	Acknowledgments

 
This study was supported by National Heart, Lung, and Blood Institute contracts N01-HC-850079-85086 and NO1-HC-15103. The authors thank the Publication and Presentation and Steering Committee members for their critical review of this manuscript. They further thank Ms Shirley Cable for her assistance in the preparation of the manuscript.

	Footnotes

 
Reprint requests to CHS Coordinating Center, Century Square, 1501 Fourth Ave, Suite 2105, Seattle, WA 98101.

Received February 17, 2000; revision received May 8, 2000; accepted May 11, 2000.

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				E. E. Freeman, B. L. Egleston, S. K. West, K. Bandeen-Roche, and G. Rubin Visual Acuity Change and Mortality in Older Adults Invest. Ophthalmol. Vis. Sci., November 1, 2005; 46(11): 4040 - 4045. [Abstract] [Full Text] [PDF]

				N. R. Benazon, M. M. Mamdani, and J. C. Coyne Trends in the Prescribing of Antidepressants Following Acute Myocardial Infarction, 1993-2002 Psychosom Med, November 1, 2005; 67(6): 916 - 920. [Abstract] [Full Text] [PDF]

				L. R. Wulsin, J. C. Evans, R. S. Vasan, J. M. Murabito, M. Kelly-Hayes, and E. J. Benjamin Depressive Symptoms, Coronary Heart Disease, and Overall Mortality in the Framingham Heart Study Psychosom Med, September 1, 2005; 67(5): 697 - 702. [Abstract] [Full Text] [PDF]

				A. Nicholson, R. Fuhrer, and M. Marmot Psychological Distress as a Predictor of CHD Events in Men: The Effect of Persistence and Components of Risk Psychosom Med, July 1, 2005; 67(4): 522 - 530. [Abstract] [Full Text] [PDF]

				L. D. Ried, M. J. Tueth, E. Handberg, S. Kupfer, C. J. Pepine, and the INVEST Study Group A Study of Antihypertensive Drugs and Depressive Symptoms (SADD-Sx) in Patients Treated With a Calcium Antagonist Versus an Atenolol Hypertension Treatment Strategy in the International Verapamil SR-Trandolapril Study (INVEST) Psychosom Med, May 1, 2005; 67(3): 398 - 406. [Abstract] [Full Text] [PDF]

				S. Alesci, P. E. Martinez, S. Kelkar, I. Ilias, D. S. Ronsaville, S. J. Listwak, A. R. Ayala, J. Licinio, H. K. Gold, M. A. Kling, et al. Major Depression Is Associated with Significant Diurnal Elevations in Plasma Interleukin-6 Levels, a Shift of Its Circadian Rhythm, and Loss of Physiological Complexity in Its Secretion: Clinical Implications J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2522 - 2530. [Abstract] [Full Text] [PDF]

				K. E. Joynt and C. M. O'Connor Lessons From SADHART, ENRICHD, and Other Trials Psychosom Med, May 1, 2005; 67(Supplement_1): S63 - S66. [Abstract] [Full Text] [PDF]

				F Rasul, S A Stansfeld, C L Hart, and G Davey Smith Psychological distress, physical illness, and risk of coronary heart disease J. Epidemiol. Community Health, February 1, 2005; 59(2): 140 - 145. [Abstract] [Full Text] [PDF]

				C. Marzari, S. Maggi, E. Manzato, C. Destro, M. Noale, D. Bianchi, N. Minicuci, G. Farchi, M. Baldereschi, A. Di Carlo, et al. Depressive Symptoms and Development of Coronary Heart Disease Events: The Italian Longitudinal Study on Aging J. Gerontol. A Biol. Sci. Med. Sci., January 1, 2005; 60(1): 85 - 92. [Abstract] [Full Text] [PDF]

				B. B. Gump, K. A. Matthews, L. E. Eberly, Y.-f. Chang, and for the MRFIT Research Group Depressive Symptoms and Mortality in Men: Results From the Multiple Risk Factor Intervention Trial Stroke, January 1, 2005; 36(1): 98 - 102. [Abstract] [Full Text] [PDF]

				S U Shah, A White, S White, and W A Littler Heart and mind: (1) relationship between cardiovascular and psychiatric conditions Postgrad. Med. J., December 1, 2004; 80(950): 683 - 689. [Abstract] [Full Text] [PDF]

				J. P. van Melle, P. de Jonge, T. A. Spijkerman, J. G. P. Tijssen, J. Ormel, D. J. van Veldhuisen, R. H. S. van den Brink, and M. P. van den Berg Prognostic Association of Depression Following Myocardial Infarction With Mortality and Cardiovascular Events: A Meta-analysis Psychosom Med, November 1, 2004; 66(6): 814 - 822. [Abstract] [Full Text] [PDF]

				E. C. Suarez C-Reactive Protein Is Associated With Psychological Risk Factors of Cardiovascular Disease in Apparently Healthy Adults Psychosom Med, September 1, 2004; 66(5): 684 - 691. [Abstract] [Full Text] [PDF]