Epidemiology of comorbid coronary artery disease and depression

Epidemiology of Comorbid Coronary Artery Disease and Depression Bruce Rudisch and Charles B. Nemeroff This article reviews the epidemiology of comorbid coronary artery disease and unipolar depression. Both major depression and subsyndromal depressive symptoms will be considered; unless otherwise specified, the term depression will be used to designate all depressive states, including major depressive disorder, minor depression, dysthymia, and other subsyndromal forms of depression. While 17% to 27% of patients with coronary artery disease have major depression, a significantly larger percentage has subsyndromal symptoms of depression. Patients with coronary artery disease and depression have a twofold to threefold increased risk of future cardiac events compared to patients without depression, independent of baseline cardiac dysfunction. The relative risk for the development of coronary artery disease conferred by depression in patients initially free of clinical cardiac disease is approximately 1.5, independent of other known risk factors for coronary disease. In the discussion, special attention will be paid to the interactions of both gender and age with depression and coronary artery disease risk. Scrutiny of the role of confounding risk factors is presented, such as global burden of comorbid medical illness and modification of traditional risk factors, which may, in part, mediate the effect of depression on coronary artery disease. Biol Psychiatry 2003;54:227–240 © 2003 Society of Biological Psychiatry Key Words: Depression, coronary artery disease, epidemiology, risk factor, comorbidity

Introduction

P

rior to the 1930s, it was known that the mortality of institutionalized psychiatric patients was in excess of mortality in the general population. This excess mortality had largely been attributed to the combined effects of infectious disease and the chronic debilitation associated with long-term institutionalization. Malzberg (1937) published a seminal report in the American Journal of Psychiatry highlighting these observations. He, however, paid particular attention From the Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia. Address reprint requests to Charles B. Nemeroff, M.D., Ph.D., Emory University School of Medicine, Department of Psychiatry and Behavioral Sciences, 4th Floor WMB 1639 Pierce Drive, Atlanta GA 30322. Received February 10, 2003; revised May 15, 2003; accepted June 3, 2003.

© 2003 Society of Biological Psychiatry

to patients with “involutional melancholia.” He demonstrated that their age-adjusted mortality rate was approximately 6 times that of the general population, with 40% of these deaths due to “diseases of the heart.” The bulk of the early work relating psychological states to heart disease centered largely on the type A personality construct (Glassman and Shapiro 1997). Multiple reviews of type A personality and its relationship to coronary artery disease (CAD) have resulted in mixed findings and subsequent refinement of the concept, with greater emphasis being placed on the angry and hostile components of the construct (Kubzansky and Kawachi 2000; Williams and Schneiderman 2002). More recently, the type D personality construct, characterized by a tendency toward negative emotion and inhibition of expression in social interactions, has received increasing attention as a risk factor for the development of CAD (Denollet and Van Heck 2001). The notion of a specific relationship between depression and heart disease resurfaced with the growth of psychosomatic medicine as an independent discipline, with an emphasis on the post-myocardial infarction (MI) patient. The most influential of the more recent studies was the Frasure-Smith et al (1993) report demonstrating the adverse effect of post-MI depression on subsequent cardiac mortality, independent of known predictors of mortality post-MI, such as diminished left ventricular ejection fraction. The question of whether depression serves as an independent risk factor for the development of CAD in disease-free individuals has also been debated in the literature since the early 1960s. Two meta-analyses were conducted in the late 1980s (Booth-Kewley and Friedman 1987; Matthews 1988) but neither established independent risk factor status for depression. Since that time, however, multiple prospective studies have emerged in which depression has indeed been shown to be an independent risk factor for the development of CAD.

Methodological Issues—Measurement of Exposure (Depression) and Outcomes (Cardiac Events and Cardiac Death) Measurement of depression in patients with cardiac disease, particularly patients who are post-MI, presents par0006-3223/03/$30.00 doi:10.1016/S0006-3223(03)00587-0

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ticular diagnostic challenges. Cardiac patients are more likely to complain of somatic symptoms of depression and to attribute their complaints to their medical illness (Lesperance and Frasure- Smith 2000). In addition, the various instruments used to measure depression, most of which are validated in nonmedically ill populations and not validated in the medically ill, may lead to markedly varying estimates of depression, depending on the degree to which they include somatic symptoms. The inclusion of somatic symptoms used to make a diagnosis of depression has been reported to lead to an almost twofold difference in estimates of prevalence of depression (Koenig et al 1997). While the elimination of somatic items provides greater specificity for the diagnosis of depression, this more exclusive approach leads to the noninclusion of patients with subsyndromal depression, an important group given the impact of even minimal symptoms of depression on cardiac mortality (Bush et al 2001). The construct validity of subsyndromal depressive states has been supported by multiple studies demonstrating the impact of subthreshold symptoms of depression on health care utilization and outcome to be intermediate between the impact of no depression and major depression (Johnson et al 1992; Judd et al 1996). There is some, though limited, evidence regarding subsyndromal depressive symptoms as a biological entity distinct from major depression (Lavretsky and Kumar 2002). Given the relatively high prevalence rate of subsyndromal depression compared with categorical diagnoses of major depression or dysthymia, the overall medical and socioeconomic burden of subsyndromal depressive symptoms is greater than that of cases explicitly defined as major depression or dysthymia by the DSM (Johnson et al 1992). The most frequent outcome of interest in studies of depression and CAD is cardiac events, generally defined as cardiac death, incident MI, or arrhythmic events. “Soft outcomes,” such as symptoms of cardiac illness, including chest pain and fatigue, may confound the relationship between depression and CAD, as these symptoms may not be independent of depression. Patients who are depressed have a higher incidence of noncardiac chest pain than nondepressed patients (Vazquez-Barquero et al 1985), and among patients who do have cardiac disease, depressed patients are more likely to report angina (Ladwig et al 1999).

The Association between Depression and Coronary Artery Disease High rates of depression in patients with cardiac disease have been documented since the late 1960s. Early studies focused on the “catastrophic reaction” of patients confined

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to coronary care units post-MI (Hackett et al 1968; Cassem and Hackett 1971) and viewed depression as a response to illness. A stereotyped post-MI course was described, which included an anxious response for the first 2 days post-MI, followed by a depressive response. The diagnosis of depression was not systematic in these studies, ranging from asking patients whether or not they were depressed (Hackett et al 1968) to considering whether or not an individual patient had been referred for a psychiatric consult which specified depression (Cassem and Hackett 1971). Not surprisingly, the prevalence of post-MI depression varied widely, between 10% and 87% (Cassem and Hackett 1971; Cay et al 1972; Hackett et al 1968; Verwoerdt and Dovenmuehle 1964). In addition to varying methods of diagnosis, other important differences, including number of days post-MI at which depression was measured, age of study participants, and exclusion/inclusion criteria, likely accounted for the varying rates of depression. Despite the inconsistencies noted above, studies using Research Diagnostic (RDC) or DSM Criteria have reported more consistent rates of major depression. Table 1 includes 11 studies published between 1987 and 2001 reporting rates of major depression to be between 17% and 27%. Schleifer et al (1989) performed one of the earliest studies to systematically diagnose depression in post-MI patients using the RDC. This study was composed of 283 patients interviewed 8 to 10 days post-MI, with 18% meeting criteria for major depression and 27% for minor depression. Forrester et al (1992) employed similar methods to Schleifer et al (1989), and using the Present State Examination, they derived a DSM-III diagnosis of major depression in 19% of 129 inpatients within 10 days post-MI. Studies using dimensional rating instruments have led to estimates that between 20% and 45% of patients post-MI will have some symptoms of depression (Silverstone 1990; Ladwig et al 1994; Frasure-Smith et al 1999; Lesperance et al 2000). Rates of depression in outpatients with coronary artery disease (Table 1) have been consistent with those found in post-MI patients. Carney et al (1987) studied 50 outpatients with angiographically proven CAD and found 9 (18%) to have major depression. Gonzalez et al (1996) analyzed a similar population and found major depression in 23% of 90 patients with CAD. Rates of depression in patients post-coronary artery bypass graft (CABG) have not been studied to the extent of post-MI patients, though their rates were found to be within the 16% to 23% range for major depression and 28% to 40% for depressive symptoms cited for other inpatient cardiology samples (Connerney et al 2001; Pirraglia et al 1999).

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Table 1. Clinical Samples—Depression and Coronary Artery Disease

Study

Diagnostic Method

Study Participants

Percentage with Major Depression

Depression Associated with Cardiac Status?

Impact of Depression Prognosis

Adjustments for 1) Cardiac Status 2) Overall Medical Comorbidity

Depression not associated with NYHA functional class or severity of stenosis Depression not associated with LVEF, presence of Q waves, prior MI Patients with depression more likely to have large infarcts Depressed patients more likely to be prescribed warfarin

Depression correlated with worse cardiac outcome

1) Extent of coronary disease, LVEF 2) None

No impact

Not reported

Not reported

Not reported

At 6 months hazard ratio for mortality 3.44

Same as above

At 18 months odds ratio for mortality for BDI ⱖ10 ⫽ 6.64 Not reported

1) Left ventricular function and prior MI 2) None Same as above

Carney et al 1987 and 1988

Modified DIS

Outpatients with CAD

17%

Schleifer et al 1989

SADS/RDC

Post-MI patients

18%

Forrester et al 1992

Present State Exam

Post-MI patients

19%

Frasure-Smith et al 1993

Modified DIS

Post-MI patients

16%

Frasure-Smith et al 1995

Same as above

Same sample as above

Same as above

Gonzalez et al 1996 Hance et al 1996

Modified DIS

Inpatients with CAD Outpatients with CAD

23%

Not reported

17%

Kaufman et al 1999

Modified DIS

Post-MI patients

27.2%

Patients with MDD do not have greater extent of coronary disease Not reported

Lesperance et al 2000

Modified DIS

Inpatients with unstable angina

15.1%

Connerney et al 2001

Modified DIS

Post-CABG patients

20%

Modified DIS

Not reported

Not reported Not reported

Depression not an 1) History of prior MI, independent current CHF, LVEF predictor of 2) Diabetes, stroke mortality Depression not For BDI ⱖ10, odds 1) EKG, history of associated with ratio for cardiac CABG or cardiac disease events or cardiac angioplasty, LVEF, severity death for BDI ⱖ10 extent of CAD, ⫽ 6.73 cardiac medicines 2) None Major depression not At 1 year, RR for 1) Functional class, associated with LVEF cardiac events 2.3 LVEF, complexity of or history of MI, surgical procedure depression associated 2) None with functional class

DIS, Diagnostic Interview Schedule; CAD, coronary artery disease; NYHA, New York Heart Association; LVEF, left ventricular ejection fraction; SADS, Schedule for Affective Disorders and Schizophrenia; MI, myocardial infarction; BDI, Beek Depression Inventory; MDD, major depressive disorder; CHF, congestive heart failure; EKG, electrocardiogram; CABG, coronary artery bypass graft; RR, relative risk; RDC, research diagnostic criteria.

Several variables have been found to be predictive of depression in patients with cardiac disease, including degree of functional impairment post-MI, overall medical burden (Gonzalez et al 1996; Ladwig et al 1992; Travella et al 1994; Charlson and Peterson 2002), prior history of MI (Cay et al 1972; Ladwig et al 1992; Lesperance et al 1996), family history of psychopathology (Gonzalez et al 1996), and low levels of perceived social support (Brummett et al 1998).

Course of Depression in Clinical Populations with Coronary Disease Depression post-MI is frequently persistent after hospitalization, as demonstrated in multiple longitudinal studies with follow-up extending to 2 years (Hance et al 1996; Schleifer et al 1989; Wells et al 1993). Schleifer et al (1989) followed post-MI patients over the course of 3 months, and of the patients initially diagnosed with major

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depression, 83% continued to have either major or minor depression. In contrast, only 36% of those initially diagnosed with minor depression had persistent symptoms of depression at 3-month follow up. From these results, it was concluded that post-MI patients with depression can be divided into two groups—those with transient depressive reactions likely to remit over the period of several months and those with syndromal depressive disorders with courses similar to major depression in otherwise healthy subjects. These findings are in agreement with Ladwig et al (1992) who observed that in a significant number of post-MI patients, depressive symptoms resolved quickly, indicative of an adjustment reaction rather than syndromal depression. A history of prior psychiatric morbidity (Lloyd and Cawley 1978) and lack of social support post-MI (Travella et al 1994) are predictive of persistent rather than transient depression post-MI.

Comments on Causality While the association between CAD and depression has often been explained by shared risk factors such as smoking and physical inactivity (Musselman et al 1998), there is evidence to suggest that these two entities exert direct effects on each other through bidirectional mechanisms of causality. That CAD causes depression has frequently been explained by the psychological effect of chronic illness on mood. There is ample reason to question this hypothesis, however, as the prevalence per se of depression does not correlate with degree of cardiac dysfunction. Alternatively, CAD may contribute to the development of depression through inflammation. Coronary artery disease is a chronic inflammatory process (Falk and Fuster 2001). One would expect, then, that prevalence rates of depression would correspond with cardiac disease severity. While rates of depression are not necessarily linked with severity of cardiac dysfunction, this conclusion has largely, though not exclusively, (Carney et al 1987; Hance et al 1996; Lesperance et al 2000) been drawn from studies that have measured cardiac dysfunction using indices which are distinct from cardiac inflammation, such as peak CK values, ejection fraction, or Killip Class (Cay et al 1972; Ladwig et al 1991, 1992; Lane et al 1991; Mayou et al 2000; Schleifer et al 1989). While inflammation may be a mechanism through which CAD leads to depression, it may also provide a mechanism through which depression leads to the development of CAD. The majority of studies herein reviewed address the role of depression in the development and expression of CAD. Studies of clinical populations have implicated depression in the expression of CAD, likely

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through arrhythmogenic and prothrombogenic mechanisms, as will be discussed. While studies of community samples purport to implicate depression in the etiology of the atherosclerotic process, these studies inevitably blur the distinction between the atherosclerotic process and cardiac events.

Impact of Depression on Prognosis of Patients with Preexisting Coronary Artery Disease Several studies in the early 1990s demonstrated the connection between symptoms of depression and worsened cardiac outcome (Ahern et al 1990; Frasure-Smith et al 1992; Ladwig et al 1991). Ahern et al (1990) analyzed data from the Cardiac Arrhythmia Pilot Study, which included 352 post-MI patients with significant ventricular arrhythmias measured by Holter monitor 6 to 60 days post-MI. Elevated Beck Depression Inventory (BDI) scores were predictive of either death or cardiac events over the course of the year after enrollment, even when other cardiac risk factors were controlled for. In a 5-year follow-up study of 229 male patients, those with high measures of psychological distress, including anxiety and depression as measured by the General Health Questionnaire, were significantly more likely to die of cardiac causes than those with lower measures of psychological distress (Frasure-Smith 1991). A subsequent study demonstrated that the majority of the mortality among this cohort was confined to those with non–Q-wave infarctions and that the mortality occurred primarily in the first of the 5 years post-MI (Frasure-Smith et al 1992). The seminal studies of Frasure-Smith et al (1993, 1995) replicated these findings in a cohort of patients with RDC-diagnosed major depression, in contrast to their earlier studies which included patients with mixed symptoms of anxiety and depression. In these two studies, 222 patients were followed over the course of 6 months and then 18 months. The most adjusted hazard ratio for mortality when patients with major depression were compared to nondepressed patients was 3.10 (95% confidence interval [CI], 1.9 – 4.3), roughly equivalent to the risk conferred by clinical factors known to portend worse prognosis in cardiac patients, such as diminished left ventricular function and past history of MI. When patients in the Frasure-Smith et al (1993) study were followed for an additional 12 months (Frasure-Smith et al 1995), baseline major depression remained a predictor of mortality at the end of 18 months; however, major depression at baseline in those surviving to 6 months did not predict mortality from 6 months until 18 months, though elevated BDI scores at baseline did predict mortality in this same group from 6 to 18

Epidemiology of Comorbid CAD and Depression

months. The authors suggested that elevated BDI scores at study entry predicted later, postdischarge episodes of depression in those patients who did not initially meet criteria for depression. Clearly, patients who are initially free of depression in the first few weeks post-MI are at persistent risk for new-onset depression over the year following MI (Travella et al 1994; Lesperance et al 1996). Additionally, subsyndromal symptoms of depression in and of themselves elevate an individual’s risk for future cardiac events (Bush et al 2001; Frasure-Smith et al 1999; Lesperance et al 2000). Of note, despite the previously mentioned findings that prevalence of depression is not necessarily correlated with degree of cardiac dysfunction, two recent reviews have been critical of the association between post-MI depression and mortality, given the possible confounding effect of disease severity (Carrol and Lane 2002; Mendes de Leon 1999). Although many positive studies have taken the confounding effects of disease severity into account through multivariate analysis, including the seminal studies of Frasure-Smith (1993, 1995) or by making adjustments for surrogate markers of disease severity such as fatigue and dyspnea (Irvine et al 1999), Carrol and Lane (2002) urged caution when using these multivariate techniques, given the possibility of underadjustment for confounding risk factors. Although the Frasure-Smith et al (1993, 1995) studies cited above were critical in demonstrating the relationship between depression and cardiac events post-MI, the majority of cardiac patients admitted to the hospital have unstable angina, not MI (Theroux and Ludon 1993). Lesperance et al (2000) studied 430 patients admitted to a hospital for unstable angina. He found 41.4% of these patients to have depression as measured by a BDI ⱖ10, and 15.1% when using the Diagnostic Interview Schedule (DIS) to identify those with major depression. Over the course of a year, depression was an independent predictor of cardiac events, with an odds ratio (OR) of 6.73 (95% confidence interval [CI], 2.43–18.64), demonstrating that the risk of depression in cardiac patients is not confined to the post-MI population, consistent with Carney et al (1988). Additionally, depressed patients with coronary artery disease are at greater risk of cardiac morbidity as measured by other outcomes, including future hospitalizations and health care expenditures (Allison et al 1995; Frasure-Smith et al 2000). As in unstable angina, the role of depression in coronary artery bypass graft patients has not been as well studied as in post-MI patients. In a study of 309 patients interviewed 4 to 10 days after surgery (Connerney et al 2001), 20% were found to fulfill DSM-IV criteria for major depressive disorder (MDD) using the DIS. These patients were followed for a year, and major depression was found to be

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an independent risk factor for coronary events equivalent to that of low left ventricular ejection fraction, with a relative risk (RR) of 2.3 (95% CI, 1.1– 4.56). The population of post-CABG patients deserves greater study, given the possibility of a distinct physiologic basis for depression in patients postcardiopulmonary bypass, as evidenced by the vulnerability of the brain to metabolic insult during this procedure (Jacobs et al 1998).

Mechanisms by which Depression Confers Increased Risk of Cardiac Events The finding that depression is a risk factor for ventricular arrhythmias in patients with coronary disease has been posited to underlie the association between depression and sudden cardiac death. In a study of 103 patients with coronary artery disease, 23.8% of depressed patients had episodes of ventricular tachycardia by 24-hour Holter monitor, compared with 3.7% of patients without depression (Carney et al 1993). In the Frasure-Smith et al (1995) study with 18-month follow-up described above, there was an interaction between depressive symptoms and premature ventricular complexes (PVCs); elevated BDI scores were a more powerful predictor of mortality in those who had ⱖ10 PVCs per hour than in those who did not. This is consistent with results of an earlier study (Frasure-Smith 1991) in which depressive symptoms had a greater impact on patients with a greater propensity for cardiac arrhythmias. This is also consistent with the recent finding that moderate to severe depression is a risk factor for diminished heart rate variability in stable cardiac patients (Stein et al 2000), a well-known risk factor for mortality in post-MI patients (Bigger et al 1992). An equally compelling literature suggests that platelet hyperreactivity leading to thrombus formation is the pathophysiological basis for increased cardiac events postMI, as well as for increased risk for development of CAD (Musselman et al 1996, 1998, 2000, 2002; Nemeroff and Musselman 2000). Elevated levels of cortisol and inflammatory cytokines such as tumor necrosis factor-alpha (TNF-␣), interleukin (IL)-1, and IL-6 have also been hypothesized to mediate the effects of depression on the development of CAD (Musselman et al 1998; Rozanski et al 1999).

Impact of Depression on Community Samples Largely Free of Clinical Coronary Artery Disease at Baseline From the early 1990s until the current time, multiple studies in community samples, for the most part initially free of diagnosed coronary disease, have been conducted. Table 2 includes 14 such studies. In the table, studies were

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Table 2. Development of Coronary Artery Disease in Community Samples with Depression

Study Ford et al 1998

Anda et al 1993

Ferketich et al 2000

1) Method of Diagnosis 2) Outcome Measure 3) Length of Follow-Up (Mean)

1) Age at Enrollment 2) Criteria for Eliminating Subjects with Baseline Cardiac Disease

1) Self-reported depression 2) MI 3) Median follow-up 37 years 1) General Well Being Schedule 2) Fatal and nonfatal CAD 3) Mean follow-up 12.4 years 1) CES-D 2) CHD death 3) Mean follow-up 8.3 years

1) Participants enrolled at graduation from medical school (average age 26) 2) None 1) 45–77 2) Eliminated those with angina by Rose Criteria and those with CAD manifestations within 2 years of enrollment 1) Mean age women 54, men 56 2) Elimination of individuals with physician-diagnosed CAD at baseline, elimination of those with CAD events within 2 years of enrollment 1) Age 40 –90 2) Elimination of individuals with known history of CAD or angina based on questionnaire 1) Age 65 and older 2) None

Sesso et al 1998

1) MMPI-2 D 2) Nonfatal MI and CHD death 3) Mean follow-up 7 years

Whooley and Browner 1998

1) Geriatric Depression Scale 2) CHD death 3) Mean follow-up 6 years

Ariyo et al 2000

1) CES-D 2) Any CHD event 3) Mean follow-up 6 years

Pennix et al 2001

1) CES-D, DIS 2) Cardiac Death 3) Mean follow-up 4.2 years

1) Age 65 and older 2) Elimination of individuals with a selfreported or documented history of CVD 1) 55 and older 2) Elimination of those with CAD by selfreport, by collateral history from general practitioner, use of cardiac medicines

designated as equivocal if the relative risk was elevated only for certain subgroups, if the confidence intervals for the relative risk included unity, or if the relative risk was elevated depending on the chronicity of depressive symptoms (one study demonstrated a relative risk for new onset but not chronic depression; a second study demonstrated an elevated relative risk for change in depressive symptoms rather than baseline depression). Depression was

Baseline Depression Associated With

1) Relative Risk of Outcome 2) Assessment of Riska

Adjustment for Overall Medical Burden

Not reported

1) 2.12 2) (⫹)

Diabetes, family history of MI, smoking, lipids, hypertension, exercise

Alcohol intake

1) 1.50 2) (⫹)

Self-rated health, cholesterol, BP, BMI, exercise, smoking

Smoking, DM, Sedentary, elevated BMI

1) .74 women, 2.34 men 2) (⫹/⫺)

Race, smoking, BP, diabetes, BMI, nonfatal CHD during follow-up, poverty

Smoking, family history of heart disease, alcohol consumption

1) 1.69 2) (⫹/⫺)

Alcohol, family history of CAD, smoking, BP, BMI

Smoking, poor selfreported health, higher medical comorbidity, worse functional status Smoking, DM, lower ADLs

1) 1.7 2) (⫹)

History of CVD, diabetes, BP, COPD, perceived health, cognitive function, smoking

1) Hazard ratio of 1.15 per 5 unit increase in CES-D 2) (⫹)

Diabetes, smoking, lipids, CHF, physical inactivity, COPD, cancer

Not reported

1) Minor depression 1.5, major depression 3.9 2) (⫹)

BMI, BP, self-reported comorbidity

found to be a risk factor predicting coronary disease in 8 of the 14 studies, independent of the known risk factors for CAD listed in the last column of the table. Five of the 14 studies were equivocal, while 1 was negative. Recently, 11 of the studies included in Table 2 were subjected to a meta-analysis (Rugulies 2002). These were all population based, prospective studies, starting with individuals initially free of coronary disease. The presence

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Table 2. (Continued) 1) Method of Diagnosis 2) Outcome Measure 3) Length of Follow-Up (Mean)

1) Age at Enrollment 2) Criteria for Eliminating Subjects with Baseline Cardiac Disease

Pennix et al 1998

1) CES-D 2) New CHD events 3) Mean follow-up 4 years

Barefoot and Schroll 1996

1) MMPI OBD scale 2) MI 3) Mean follow-up not reported, max followup 27 years

Depression associated with physical disability, history of stroke, or diabetes Smoking

Vogt et al 1994

1) Depression index modeled on DSM-III 2) Ischemic heart disease 3) Mean follow-up NR, max follow-up 15 years 1) DIS 2) MI 3) Mean follow-up not reported, max followup 12 years 1) CES-D 2) Nonfatal MI and CAD death 3) Mean follow-up not reported, max followup 9 years

1) 70 and older 2) Elimination of participants with CAD by self-report, discharge diagnosis, or Rose Criteria 1) 50 or 60 2) Elimination of subjects with probable ischemia based on Rose Criteria or EKG, elimination of somatic items for diagnosis of depression 1) 18 –75 2) Patients with documented history eliminated

Langer Index, 1) .94 which includes 2) (⫺) psychophysiological symptoms

Self-reported health status, smoking

1) 18 and older, 91% ⬎ 60 2) Elimination of individuals with selfreport of cardiac history 1) 65 and older 2) Eliminations of individuals with a history of physiciandiagnosed MI, but included those with angina 1) 60 and older 2) Elimination of participants with cardiac events within 6 months of enrollment, though all participants had hypertension and 61% had EKG abnormalities 1) 65 and older 2) Elimination of individuals with a known history of cardiac disease based on self-report

Smoking, alcohol abuse/dependence

1) Dysphoria 2.06 MDD 4.14 2) (⫹)

Diabetes, smoking, BP

Diabetes, exertional chest pain, mobility impairments

1) Women 1.67b Men .70b 2) (⫹/⫺)

Diabetes, smoking, BP

Not reported

1) No increase for baseline depression, RR 1.18 for 5-unit increase in CES-D 2) (⫹/⫺)

ADLs, history of CVD, diabetes, smoking

Not reported

1) 2.23 2) (⫹)

BP, smoking, alcohol intake prescription med use, self-rated health

Study

Pratt et al 1996

Mendes de Leon et al 1998

WassertheilSmoller et al 1996

1) CES-D 2) MI or stroke grouped 3) Mean follow-up not reported, max followup 5 years

Schwartz et al 1998

1) CES-D 2) MI 3) Mean follow-up not reported, max followup 3 years

Baseline Depression Associated With

1) Relative Risk of Outcome 2) Assessment of Riska

Adjustment for Overall Medical Burden

1) 1.47 for new onset depression, not elevated for chronically depressed 2) (⫹/⫺)

Smoking, alcohol, BMI, BP, history of stroke, diabetes, cancer, physical disability

1) 1.50 2 (⫹)

Smoking, lipids, blood pressure, sedentary work and leisure

CAD, coronary artery disease; MI, myocardial infarction; BP, blood pressure; BMI, body mass index; CES-D, Center for Epidemiological Studies/Depression Scale; CHD, congenital heart disease; DM, diabetes mellitus; MMPI-2, Minnesota Multiphasic Personality Inventory-2; MMPI-D, Minnesota Multiphasic Personality Inventory-Depression Scale; CVD, cardiovascular disease; COPD, chronic obstructive pulmonary disease; ADL, activities of daily living; CHF, congestive heart failure; DIS, Diagnostic Interview Schedule; OBD, obvious depression; EKG, electrocardiogram; NR, not reported; MDD, major depressive disorder; RDC, research diagnostic criteria. a (⫹) ⫽ elevated, (⫺) ⫽ not elevated, (⫹/⫺) ⫽ equivocal. b Taken from Rugulies 2002.

of depression was assessed by standardized clinical procedures, and severity of depressive mood was measured by a standardized rating instrument. The outcome included

fatal and nonfatal cardiac events. In these 11 studies, the number of patients per study ranged from 750 to 7894, the number of cases of heart disease per study ranged from 50

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to 463, and the mean time of follow-up per study ranged from 3 to 37 years. Taken as a group, the relative risk of developing heart disease in patients who were initially depression-free was 1.64 (95% CI, 1.29 –2.08; p ⬍ .001). Of note, these studies controlled for other known risk factors for CAD, which are listed in the last column of the table. Results from studies of community samples initially free of clinical CAD have been called on to demonstrate the role of depression in the development of CAD. It should be noted, however, that individuals initially free of clinical CAD are not necessarily free from coronary atherosclerosis, a process that generally evolves over decades (Ross 1993). Table 2 lists the studies in order of average length of follow-up before a cardiac event. In the majority of the studies, the average length of time between study enrollment and the first cardiac event was less than 10 years, making it likely that a significant proportion of the subjects who experienced cardiac events during the follow-up period had undetected, subclinical cardiac disease at baseline. As such, the outcomes in these studies are likely to be a reflection not only of the role of depression in the development of CAD but in the precipitation of cardiac events in those with pre-existing heart disease.

Is There a Dose Response Relationship between Depression and the Development of Coronary Disease? The demonstration of a dose-response curve significantly strengthens an argument for causality (Grimes and Schulz 2002). In studies of depression and cardiac disease, the severity of depression has been assessed by either treating mood as a continuous variable or by placing depression into two dose categories (major or minor depression). Other studies have addressed the issue by measuring depressive symptoms over time, though these studies are few, given the more intensive follow-up that this requires. In Table 2, seven studies demonstrated graded relative risks for cardiac events for increasing depression severity using the Center for Epidemiologic Studies-Depression (CES-D) scale (Wassertheil-Smoller et al 1996; Mendes de Leon et al 1998; Sesso et al 1998; Ferketich et al 2000), the Minnesota Multiphasic Personality Inventory (MMPI) (Sesso et al 1998; Barefoot and Schroll 1996), or the General Well-Being Schedule (Anda et al 1993). In two studies, elevated relative risks were found for major compared with minor depression (Pratt et al 1996; Pennix et al 2001). Additionally, in the meta-analysis described above, the author demonstrated that those studies including individuals with categorical diagnoses of depression showed a greater relative risk for cardiac disease than those with depressed symptoms as measured by dimen-

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sional rating instruments (2.69 vs. 1.49), providing further evidence for a dose-response relationship. The data on the cumulative exposure to depressive symptoms over time are less clear. Coryell et al (1999) followed a clinical population of 903 patients with an initial diagnosis of MDD, mania, or schizoaffective disorder for a mean time of 11 years. He followed these patients semiannually for 5 years, then annually for the remainder of the study. He divided the patients into thirds, based on the total number of weeks spent depressed. The highest third spent approximately 75% of their weeks depressed, the middle third 28%, and the lowest third 6%. He found that the risk of cardiovascular mortality did not differ in any of the three groups. From this, he concluded that it was not the pathophysiologic concomitants of depression that predispose to cardiovascular illness but simply that the presence of a depressive disorder increases the likelihood that an individual has shared risk factors for both depression and cardiovascular disease, such as smoking or a sedentary lifestyle. Two other studies have addressed the issue of how depressive symptoms over time affect the risk of coronary disease. In these studies, change in depressive symptoms (Wassertheil-Smoller et al 1996) or new onset depression (Pennix et al 1998) conferred increased risk of coronary events rather than chronic depressive symptoms. The authors hypothesized that cases of new onset depression may be caused by or represent early signs of impending cardiac events, such as fatigue or loss of energy (Pennix et al 1998). Alternatively, it may be that the pathophysiological concomitants of new onset depression pose increased risk for the expression of cardiac events compared with chronic or recurrent depression, though there is little data supporting the hypothesis that the pathophysiological concomitants of depression differ by the chronicity of the illness (Anisman et al 1999).

Adjustment for Confounding Risk Factors Perhaps the most obvious variable mediating the unadjusted association between depression and cardiac disease is that of cigarette smoking. Smoking is associated with depression in a dose-dependent manner, with higher scores on depression inventories predicting greater likelihood of smoking (Anda et al 1990). After adjusting for smoking, however, the association between depression and cardiac disease remained in the majority of studies reviewed. Nevertheless, there is evidence that smoking and depression interact (Anda et al 1993), with the effect of depression on cardiac morbidity and mortality greater in smokers than nonsmokers. The fact that depression is associated with lower rates of smoking cessation is well established (Anda et al 1990; Glassman et al 1990). Although the

Epidemiology of Comorbid CAD and Depression

majority of studies controlled for smoking status at baseline, they did not control for rates of smoking cessation, perhaps the more important variable to control for when assessing the role of depression in the development of CAD. Other traditional cardiovascular risk factors, such as hypertension, diabetes, and obesity, are associated with depression, though not to the same degree or with the same regularity as cigarette smoking (Talbot and Nouwen 2000; Rutledge and Hogan 2002; Roberts et al 2000). The majority of the studies of CAD and depression controlled for these variables at baseline, as shown in Table 2. Controlling for modification of these risk factors, however, given the propensity of depression to affect an individual’s adherence to medication regimens (Carney et al 1995) or exercise regimens (Blumenthal et al 1982), is equally important. This analysis was included in a follow-up study of 1190 Johns Hopkins medical students initially free of cardiac disease assessed over 40 years of follow-up (Ford et al 1998). Cardiovascular risk factors, such as hypertension, diabetes, lipid status, and change in smoking status were measured at multiple follow-up points and were treated as time-dependent covariates. With these adjustments, depression remained as an independent risk factor for the development of CAD.

Adjusting for Undetected Heart Disease and Chronic Disease Burden If a subject has CAD at baseline, they are more likely to be depressed, confounding the cause-effect relationship between depression and coronary disease. As can be seen in Table 2, several strategies have been used to circumvent this confound. Anda et al (1993), in their cohort of 2832 adults, addressed this issue by eliminating any subject with a cardiac event occurring within 2 years from enrollment in the study, reasoning that individuals with cardiac events soon after study entry are more likely to have had cardiac disease at baseline. Removing the first 2 years of follow-up made little difference in the effect size of depression as a predictor of coronary disease. An alternative strategy for dealing with the confound of baseline cardiac disease is to eliminate somatic components from the standardized scale used to measure depression, such as fatigue. Feelings of fatigue, as well as the syndrome of vital exhaustion, characterized by low energy, irritability, and demoralization, have been shown to be risk factors for impending cardiac events, though the syndrome of vital exhaustion includes potentially confounding somatic symptoms (Appels and Mulder 1988; Appels et al 1995). Studies in both community samples initially free of cardiac disease (Barefoot and Schroll 1996) and clinical samples with diagnosed cardiac disease

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(Irvine et al 1999) have demonstrated that depression persists as an independent risk factor, albeit with a smaller effect size, after adjusting for symptoms consistent with vital exhaustion, such as fatigue and low energy. A recent review of medical comorbidity and depression (Charlson and Peterson 2002) pointed out the importance of controlling for overall medical burden when assessing depression as a risk factor for CAD mortality. Simply stated, depressed patients are more likely to have other comorbid medical illnesses, and as such, they will have higher mortality. Although the majority of studies in Tables 1 and 2 do make adjustments for individual chronic illnesses, such as diabetes and hypertension as well as for self-rated health, an imperfect proxy for chronic disease burden (Molarius and Janson 2002), they did not adjust for overall comorbidity as determined by objective measures.

Other Psychiatric Symptoms Although the literature on anxiety disorders and CAD is not extensive and the results are inconclusive, several studies have suggested that anxiety may serve as an independent risk factor for the development of CAD, with the effects most pronounced for sudden cardiac death (Kawachi et al 1994; Kubzanski and Kawachi 2000). Two of the studies beginning with community samples initially free of heart disease attempted to control for symptoms of anxiety (Pratt et al 1996; Sesso et al 1998). Depression remained an independent risk factor for coronary events, albeit with diminished effect size in one of the studies (Sesso et al 1998). Similar to anxiety, hopelessness is related to but not identical with depression (Greene 1989). Two populationbased studies have identified hopelessness as a risk factor for cardiac morbidity and mortality (Anda et al 1993; Everson et al 1996). In the Kupio Ischemic Heart Disease study of 2428 men living in Finland, hopelessness was found to correlate with cardiovascular death, independent of other biological, behavioral, or socioeconomic factors predictive of mortality, despite adjusting for depression.

The Effects of Gender The finding that depression is more prevalent in women than men in community samples extends to clinical samples with CAD as well (Stern et al 1977; Carney et al 1987, 1993; Schleifer et al 1989; Forrester et al 1992; Frasure-Smith et al 1993; Lesperance et al 2000). There is evidence to indicate that women also experienced significantly more anxiety in the hospital post-MI and at 1-year follow-up (Stern et al 1977). The question of whether depression’s impact on the development and progression of CAD differs by gender is unresolved. In general, men and women do differ in their

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vulnerability to traditional risk factors for CAD. Smoking, for example, is less of a risk factor for CAD in women than in men, but diabetes, low levels of high-density lipoprotein (HDL), and elevated triglycerides are stronger risk factors in women than in men (Knopp 2002). Women tend to have a poorer prognosis than men post-MI and post-CABG (Wenger 1998). In addition, women are less likely to be referred to cardiac rehabilitation programs post-MI than men and less likely to attend these programs if they are referred (Abbey and Stewart 2000). Despite the documented differences between CAD in women and men, the question of whether depression’s impact on the development and progression of coronary disease differs in these two groups remains unresolved. In patients with coronary disease, depression portends a worse prognosis in subgroup analyses of both men and women, with no detectable differences in effect size between these two groups (Frasure-Smith et al 1999). Of note, however, testing for gender-depression interactions has been limited by sample size considerations (FrasureSmith et al 1993), because clinical studies tend to include fewer individuals than community studies, and clinical samples of cardiac patients consist predominately of men. In community samples, depression has been shown to be a risk factor for cardiac events, both in samples including only women (Whooley and Browner 1998) and only men (Ford et al 1998; Sesso et al 1998). Genderdepression interactions in community samples have been inconsistent. Two studies found depression to be a risk factor for coronary events in men but not in women (Hippisley-Cox et al 1998; Pennix et al 1998), and one found depression to be a risk factor in a subgroup of women but not men (Mendes de Leon 1998). A fourth study found that depression conferred an elevated risk of nonfatal coronary events in both men and women, but the risk of fatal coronary events was elevated only in men (Ferketich et al 2000).

Cardiac Disease and Depression in the Elderly The association between major depression and CAD may be stronger in younger than in older patients. Hance et al (1996) studied a population of 200 outpatients with CAD. Over the course of a year, younger patients were less likely to remit if depressed at study entry and more likely to progress to major depression if they had minor depression at study entry. This led the authors to hypothesize that CAD in younger patients is more disruptive than in older patients, who may be used to the impact of chronic disease, consistent with findings from other studies (Silverstone 1990; Vazquez-Barquero et al l985). Others reported that age had no impact on prevalence of depression (Frasure-Smith et al 1993; Forrester et al 1992; Lesperance et al 2000; Schleifer et al 1989).

Coronary artery disease also differs in the elderly; the traditional risk factors for elevated CAD mortality in middle age patients do not carry the same risk in older patients (Shepherd 2001). As such, one cannot assume that depression presents the same risk for the development of CAD in elderly patients, in whom controlling for comorbidity may be particularly important (Charlson and Peterson 2002; Mendes de Leon et al 1998). When physical function was adjusted for in the Mendes de Leon et al (1998) study of patients 65 years and older, the association between depressive symptoms and cardiac mortality was no longer significant. Depressive symptoms did remain a risk factor in this study in the subgroup of elderly women who had little physical impairment. Two other studies did find that depression continued to be a risk factor for CAD after adjustment for perceived health and self reported comorbidity (Pennix et al 1998; Whooley and Browner 1998).

Future Directions Pathologic evidence of subclinical cardiovascular disease is present decades before the development of symptoms (Ross 1993). New techniques, such as electron beam computed tomography, are enabling investigators to detect the precursors of CAD in asymptomatic patients much earlier than previously possible (Rich and McLaughlin 2002). Studies of the association between psychological variables and subclinical CAD have led to inconsistent results (Iribarren et al 2000; O’Malley et al 2000). The availability of the technology for detecting subclinical CAD should, however, provide further opportunity for the elucidation of the temporal relationship between depression and CAD, the sine qua non of causality in epidemiologic studies (Grimes and Schulz 2002). Depression and CAD interact in a bidirectional manner; depression is likely to contribute to the development of CAD and CAD likely contributes to the development of depression. A third model is also possible, in which both depression and CAD are clinical manifestations of the same underlying pathophysiological process. The most concrete illustration of this hypothesis is the case of vascular depression and CAD. The effect of atherosclerotic lesions in the brain, most notably the interruption of prefrontal circuitry, leads to vascular depression (Alexopoulus et al 1997), while similar lesions in the coronary arteries are what define CAD. Similarly, underlying chronic infection and inflammation may lead to depression as well as CAD (Danesh et al 1997; Licinio and Wong 1999). Evidence for this third model, in which both depression and CAD are clinical manifestations of the same underlying process, might be gleaned from studies of familial

Epidemiology of Comorbid CAD and Depression

comorbidity. Are nondepressed patients with CAD more likely than nondepressed patients without CAD to have a family history of depression, and are patients with depression but not CAD more likely to have a family history of CAD than patients without depression and CAD? Answers to the above questions might shed further light on the mechanisms through which CAD and depression interrelate. Molecular biological techniques might also provide further understanding of comorbidity, given the possibility that two clinically distinct disorders, such as depression and CAD, may share several genetic susceptibility loci (Kendell and Jablensky 2003). In conclusion, the epidemiologic evidence for a causal role of depression in the development and course of CAD is compelling. Additionally, a myriad of studies have demonstrated the biological plausibility of an etiologic role for depression in CAD, including studies documenting altered immune, platelet, and hypothalamic-pituitaryadrenal (HPA) axis dysfunction in depressed patients. Nonetheless, while risk factor epidemiology and studies demonstrating biological plausibility are important components for inferring causality, the highest level of evidence is conferred by randomized controlled interventions (Ketterer et al 2000). While the safety and efficacy of both psychopharmacologic (Glassman et al 2002; Nelson et al 1999) and psychotherapeutic interventions have been demonstrated in post-MI patients with depression, the Sertraline Antidepressant Heart Attack Randomized Trial (SADHART) and Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) trials failed to demonstrate that these interventions significantly reduce mortality in post-MI patients. While these results are disappointing, the two trials were methodologically limited in regard to the timing of the treatment of depression and included only specific subsets of cardiac patients (post-MI patients and patients with significant psychosocial burdens) (Kandzari et al 2002). As such, the hope remains that larger scale trials aimed at treating depression in CAD patients will lead to not only effective treatment of depression in this population but diminished morbidity and mortality. Aspects of this work were presented at the conference, “The Diagnosis and Treatment of Mood Disorders in the Medically Ill,” November 12–13, 2002 in Washington, DC. The conference was sponsored by the Depression and Bipolar Support Alliance through unrestricted educational grants provided by Abbott Laboratories, Bristol-Myers Squibb Company, Cyberonics, Inc., Eli Lilly and Company, Forest Laboratories, Inc., GlaxoSmithKline, Janssen Pharmaceutica Products, Organon Inc., Pfizer Inc, and Wyeth Pharmaceuticals.

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