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Depression and ischemic heart disease
Depression and ischemic heart disease Christopher M. O’Connor, MD,a Paul A. Gurbel, MD,b and Victor L. Serebruany, MD, PhDb Durham, NC, and Baltimore, Md
Major depression is a common comorbidity associated with ischemic heart disease (IHD). There is growing evidence that psychological stress in general and depression in particular predispose to cardiovascular disease. Persons who have mental stress during daily life are at twice the risk of myocardial ischemia, and patients with post–myocardial infarction depression have higher mortality rates than nondepressed controls. These data suggest a psychophysiologic mechanism underlying the vulnerability of depressed patients to IHD. Clinical studies have demonstrated that depression is associated with a much higher risk of both cardiovascular morbidity and mortality, which could be caused by platelet activation. Physicians should maintain a heightened level of clinical suspicion for depression and depressive disorders in persons with IHD, particularly those individuals who are recovering from an acute ischemic event, such as myocardial infarction. Furthermore, depression may complicate the recovery of IHD, but in most cases depression can be effectively treated with antidepressant agents. (Am Heart J 2000;140:S63-9.)
Two of the most commonly encountered health problems in the United States are depression and ischemic heart disease (IHD). More than 12 million persons in the United States have a history of myocardial infarction (MI) or angina pectoris or both.1 The lifetime prevalence of depression has been reported to be higher than 17% in a US national probability sample.2 With such a high prevalence, it is not surprising that depression and IHD are commonly comorbid. Individually, each imposes huge economic burdens on society. Every year approximately $44 billion is spent in the treatment of depression, including the cost of medications, hospitalization, absenteeism, lost productivity at work, and suicide.3 In 1995, costs incurred by Medicare hospitalizations for cardiovascular illness accounted for $24.6 billion,1 which did not include costs of absenteeism, lost productivity, postdischarge medical expenses, or costs incurred by other insurance companies or Medicaid. An even greater cost burden to society is probable when depression and IHD are comorbid. The association between depression and IHD has been studied in epidemiologic and observational studies. Elevated total and cardiovascular mortality rates were found among patients treated for major depression.4-13 The exact mechanisms underlying this relation and the benefits of depression treatment on cardiovascular morbidity and mortality have not yet been established. Whether depression increases the risk of cardiovascular disease or cardiovascular disease itself increases the incidence of depression is not clear. However, numer-
From aDuke University Medical Center, Durham, and bSinai Hospital of Baltimore. Reprint requests: Christopher M. O’Connor, MD, Duke University Medical Center, Cardiology Associates, Room 7401A, Box 3356, Durham, NC 27710. Copyright © 2000 by Mosby, Inc. 0002-8703/2000/$12.00 + 0 4/0/109979 doi:10.1067/mhj.2000.109979
ous studies have demonstrated that depression adversely affects the course and prognosis of cardiovascular disease.
Clinical course and diagnosis of depression Major depression is a highly prevalent and disabling mental illness that is underdiagnosed and undertreated. High rates of disability, chronicity, and relapse or recurrence are common. Major depression is associated with as much physical and social dysfunction as many other common medical illnesses, including hypertension, diabetes, and arthritis. In the Medical Outcomes Study, the impairment of daily functioning associated with depression was significantly greater than the disability associated with other chronic conditions such as gastrointestinal disease, arthritis, diabetes, hypertension, and pulmonary problems.14,15 The impact of depression on social functioning is as great as the impairment associated with cardiac conditions, such as advanced coronary artery disease and angina (Figure 1).15 In fact, depression in the presence of other medical illnesses is associated with additive effects on functioning. Social dysfunction is twice as high in persons with advanced coronary artery disease and depression as in persons with either condition alone. If left untreated, major depression can persist for months and may complicate recovery from cardiac events. The potential for relapse and recurrence remains even after successful antidepressant treatment, particularly in patients with a history of depression.16-18 There are no clinically useful laboratory or physical examinations available to diagnose depression. Definitive criteria for major depressive episodes are provided in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV)19 (Table I). Additionally, a number of structured psychiatric interviews or questionnaires may be used in screening for depression.20,21
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Figure 1
Table I. Diagnostic criteria for depression
Table available in print only
Mean physical and social functioning for patients with depression and chronic illness. A score of 100 = perfect functioning. Data from Wells KB, Stewart A, Hays R, et al. The functioning and well-being of depressed patients: results from the Medical Outcomes Study. JAMA 1989;262:914-9.
The Primary Care Evaluation of Medical Disorders is an easy-to-use questionnaire that screens for depression and other psychiatric disorders, including mood, anxiety, alcohol, eating, and somatoform disorders.
Depression and IHD: Increased morbidity and mortality rates Depression is a common comorbid condition in persons with IHD, and evidence strongly links the copresence of these disorders to an increase in morbidity and mortality rates. Depressive symptoms (ie, subsyndromal depression) after acute MI have been reported in approximately 60% of patients.22,23 The prevalence of major depression in patients after MI has been estimated to be as high as 20%.24-29 Even in patients who have not had an MI but have angiographically proven coronary artery disease, the prevalence of depression is approximately 18%.30 The first evidence suggesting that depression is related to increased cardiovascular death appeared in the scientific literature 6 decades ago.11 However, it was not until more than 40 years later that mortality rates in patients with major depression were studied. A 5-year Danish study of approximately 6000 individuals compared the causes of death in persons with a diagnosis of depression or manic depression with those of the general population. A 50% increase in deaths from cardiovascular causes was found among depressed persons as compared with the general Danish population.31 Subsequent studies have also found an excess of total mortality and cardiovascular mortality in persons
with depression.7,8,12,32-36 A study of 62 elderly persons with major depression found the mortality rate of depressed persons to be 2.6 times higher than that of the age-matched national mortality rate. Among the study group, 6 of the 8 deceased persons (75%) died as a result of cardiovascular disease and only 3 of the 54 living individuals had diagnoses of cardiovascular disease (P < .001). The association between risk of death and affective disorders in 1003 adults was also studied in a 16-year prospective population study.12 The investigators found that death caused by circulatory disease was significantly associated with affective disorders, including depression (P < .03). Depression has been identified as a trigger for both nonfatal and fatal MI. Studies that were controlled for traditional cardiovascular risk factors, including smoking, have substantiated the role of depression in the development of initial cardiac events.4,6,10,37-39 Data from a study of 2832 US adults found that persons with baseline symptoms of depression are at an approximately 50% greater risk of fatal IHD (relative risk 1.5; 95% confidence interval [CI], 1.0-2.3) than persons without baseline depressive symptoms (Figure 2).4 This was the first study to link the symptoms of depression to both the risks of developing and dying of IHD. In a community survey of more than 700 individuals, Barefoot and Schroll6 found that persons with high scores on a measure of depressive symptoms are at increased risk of MI (relative risk 1.71; P = .005) and death from all causes (relative risk 1.59; P < .001) compared with persons with lower scores. In another study of almost 1200 male medical students followed up for a median of 35 years, higher risks of IHD (relative risk 2.12; 95% CI, 1.24-3.63) and MI (relative risk 2.12; 95% CI, 1.11-4.06) were found in those men with depression compared with those without depression.38 In contrast, one study of more than 2500 individuals followed up for 15 years did not observe an association between depression and increased cardiovascular death or IHD.40
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Figure 2
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Figure 3
Image available in print only
Fatal and nonfatal IHD in persons with depressed and nondepressed affect. Adjusted relative risk: *1.5, †1.0, ‡1.6. Data from Anda R, Williamson D, Jones D, et al. Depressed affect, hopelessness, and the risk of ischemic heart disease in a cohort of US adults. Epidemiology 1993;4:285-94.
The occurrence of depressive symptoms after an ischemic event has also been examined to determine influence on morbidity and mortality rates. Carney et al9 were the first investigators to study persons with preexisting cardiovascular disease and assess for depression. Over a 1-year follow-up period of 52 patients with coronary heart disease, major depression was found to be the greatest predictor of cardiac complications, accounting for a more than doubled risk of developing an adverse cardiac complication (relative risk 2.2, P < .02). Subsequent controlled studies with larger study populations have provided convincing evidence for the increased cardiovascular risk found in persons who develop depression after an ischemic event.26,28,41-44 Depression and subsequent impact on 6-month survival after MI was studied by Frasure-Smith et al.26 A total of 222 patients who had had an acute MI were enrolled. Patients were interviewed between 5 and 15 days after MI with a modified version of the National Institute of Mental Health Diagnostic Interview Schedule to determine if criteria for depression were met. During a 6month follow-up period, a 4-fold increase in the risk of death for patients who were depressed was apparent (Figure 3). When the data were corrected for relevant covariates that determine outcome, including previous MI and Killip class, major depression continued to be a major independent predictor of an adverse outcome (adjusted hazard ratio 4.29; 95% CI, 3.14-5.44; P = .013). Frasure-Smith et al43 followed up this population for
Cumulative mortality rates for depressed and nondepressed persons after MI. Reproduced with permission from Frasure-Smith N, Lespérance F, Talajic M. Depression following myocardial infarction: impact on 6-month survival. JAMA 1993;270:1819-25. Copyright 1993 by American Medical Association.
Figure 4
Premature ventricular contractions (PVC) and 18-month cardiac mortality rate. Reproduced with permission from Frasure-Smith N, Lespérance F, Talajic M. Depression and 18-month prognosis after myocardial infarction. Circulation 1995;91:999-1005.
another year and reported the results at 18 months. The investigators found that depression was associated with an increased risk of dying and that mild and moderate forms of depression (Beck Depression Inventory [BDI] score ≥10) are associated with an increased risk of cardiac events or death. Importantly, it was shown that mortality rate was significantly higher in patients with premature ventricular contractions of 10 or more per hour who scored higher than 10 on the BDI compared with patients who scored below 10 on the BDI (odds ratio 29.1; 95% CI, 6.97-122.07; P < .00001). In
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Table II. Results of stress management and exercise training Type of event Death Nonfatal MI CABG PTCA Total
Exercise 1 (2.9) 0 (0) 1 (2.9) 5 (14.7) 7 (20.6)
Stress management 0 (0) 0 (0) 2 (6.1) 1 (3.0) 3 (9.1)
Usual care 0 (0) 3 (7.5) 4 (10.0) 5 (12.5) 12 (30.0)
Values are n (%). CABG, Coronary artery bypass graft; PTCA, percutaneous transluminal coronary angioplasty. O’Connor et al, unpublished.
patients with fewer than 10 premature ventricular contractions per hour, there was no difference in cardiovascular death between groups (Figure 4). There is a considerable and compelling body of evidence demonstrating that depression and comorbid IHD lead to an increased risk of death, regardless of which illness occurred first. The underlying pathophysiologic characteristics and the effects of antidepressant treatment on mortality rate are subjects of ongoing clinical investigation.
Potential mechanisms explaining increased mortality rate in depressed patients after MI Several mechanisms have been suggested that may increase the risk of death in depressed patients after MI. Arrhythmias were the predominant mode of death in the studies done by Frasure-Smith et al.26,43 Decreased vagal and increased sympathetic tone in depressed persons without any other medical illnesses may be a prognostic factor in the development of cardiac disease.45-49 In fact, the alteration in the ratio between sympathetic and parasympathetic tone may make depressed patients more susceptible to cardiac arrhythmias and sudden death by lowering the threshold for ventricular fibrillation.50,51 Among other postulated triggers are reduced heart rate variability, emotional distress, and abnormalities in platelet reactivity.4,10,37,45,52,53 Increased platelet aggregation may also contribute to the increase in mortality rate found in persons with comorbid depression and IHD. Direct evidence of a significant tendency for clotting diatheses and thrombosis in depressed individuals has been found in pilot studies (and is reviewed in greater detail in this supplement).53,54 It has been consistently observed that patients with major depression exhibited significant differences in the number of binding sites for various compounds, including imipramine,55 paroxetine,56 and inositol57 on the platelet surface than controls. Platelet monoamine oxidase activity is significantly elevated in depressed patients,58,59 especially in women.60 Reduced platelet
serotonin uptake61,62 and enhanced serotonin receptor expression63,64 were also observed in the depressed patients. Depression is also known to be associated with increased levels of intraplatelet Ca++ ion mobilization65,66 and diminished activity of forskolin-stimulated platelet adenylyl cyclase.67 Moreover, the newly discovered imidazoline platelet receptors (45 kDa and 35 kDa proteins) have been found to be upregulated in patients with major depression.68
Should all patients with heart disease and depression be treated? Concurrent depression increases the risk of poor outcome in patients with MI, unstable angina, and heart failure. Depressed patients after MI take longer to return to work and have greater stress and psychosocial impairment than those patients without depressive symptoms.23,69,70 Patients who are depressed after an MI are more likely to drop out of exercise programs than patients who are not depressed.71 Depressed smokers are 40% less likely to stop smoking than nondepressed smokers (relative risk 0.6).72 Furthermore, depressed patients with coronary artery disease are less likely to comply with low-dose aspirin therapy.73 Based on this, should all these patients be treated for their depression? Trials to assess the effects of psychosocial intervention on depression have found varying results. In a small cohort study,74 107 persons with coronary artery disease, exercise-induced ischemia, and mental stress–induced ischemia (confirmed by Holter monitor or radionuclide imaging) were randomly assigned to receive usual care, stress management, or exercise training. Of the study population, 10% were determined to be depressed. At follow-up (mean 38 months), patients in the stress management group had the lowest combined rate of death, nonfatal MI, and revascularization (9.1%). Patients in the exercise group and the usual care group had higher combined rates of death, nonfatal MI, and revascularization, 20.6% and 30.0%, respectively (Table II). In the Montreal Heart Attack Readjustment Trial (M-HART),75 patients who had had an MI were randomly assigned to an intervention program (n = 692) or to usual care (n = 684). The intervention program was composed of monthly telephone follow-up and home nurse counseling as needed for patients who had high levels of anxiety, as measured by the Spielberger State Anxiety Scale. The usual care group did not receive monthly telephone monitoring or visits from nurses. Instead, they received usual care from their physicians and completed follow-up interviews at 3 and 12 months. The primary end point was cardiac death, and secondary end points were all-cause mortality and fatal and nonfatal MI. Overall, total mortality rate was higher for patients in the intervention group (5.5%)
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Table III. Similarity between depression and hyperlipidemia risk factors Cholesterol
Depression
Effect on risk Effect of treatment on surrogate Effect of nonpharmacologic treatment on risk Effect of pharmacologic treatment on risk
Proportional relation Lowering LDL decreases risk of MI Diet/exercise: no mortality data Reduction in MI (statins)
Proportional relation Unknown Stress management, group counseling: no mortality data TCAs may increase risk; SSRIs: unknown
SSRIs, Selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants.
compared with the control group (3.9%), although the difference was not statistically significant. Rates of cardiac death in the intervention group (4.8%) were also higher but not significantly different than the control group (3.4%). However, in women, there was an almost 2-fold increase in the risk of dying in those who received nonpharmacologic therapy targeted toward the higher state of anxiety. The increase in deaths was predominantly caused by a 5-fold increase in sudden death caused by arrhythmias. Although this study did not assess individuals with comorbid depression, the results suggest that nonpharmacologic interventions do not reduce the risk of death; rather, they may increase the risk of death in a patient after MI. Available data are limited regarding the effects of antidepressant treatment on the outcome of persons with comorbid IHD and depression. Tricyclic antidepressants are known to have adverse cardiovascular effects, including slowed intraventricular conduction and orthostatic hypotension.76,77 It would not be beneficial to use these agents in a population already at an increased risk of cardiac morbidity and mortality. In small studies, the selective serotonin reuptake inhibitors have appeared to be safe and effective in persons with comorbid IHD and depression.78-80 Although promising, the results are somewhat limited because the studies were small, of short duration, and 2 were open-labeled. Large randomized, controlled trials are necessary to assess the effects of long-term antidepressant treatment on morbidity and mortality rates. The Enhancing Recovery in Coronary Heart Disease (ENRICHD) trial, sponsored by the National Heart, Lung, and Blood Institute, is currently under way. 81 Psychosocial and pharmacologic interventions in patients with IHD who have high levels of social isolation and/or depression are being evaluated in this multicenter mortality trial of 3000 patients. Results should be available within 1 year and will begin to provide answers to the question of whether psychosocial and/or pharmacologic therapy with selective serotonin reuptake inhibitors should be initiated in an individual with comorbid IHD and depression. At present, the routine use of psychosocial therapy in depressed persons with IHD is not warranted. Treatment of depression with pharmacologic agents
may be easily accomplished. However, the impact of antidepressant treatment on the risk of cardiovascular disease and death remains to be determined. The findings of ongoing pharmacologic treatment studies will be viewed with interest.
Conclusion Depression has been shown to worsen the prognosis of persons with IHD and may be viewed as a risk factor similar to hypercholesterolemia (Table III). As with cholesterol, the evidence for effect on risk appears to be proportional. The effect of treatment is defined for cholesterol (lowering low-density lipoproteins decreases the risk of MI). However, we do not know whether lowering the rates of depression actually results in improved survival or diminished cardiovascular risk. The impact of nonpharmacologic and pharmacologic treatment on risk is currently under investigation. Clinicians eagerly await the results of the ENRICHD study, which should help to ascertain whether psychosocial intervention for the treatment of depression is beneficial. Pharmacologic therapy for the treatment of depression is valuable, but the effect on outcome is as yet unknown.
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cyclase activity is lower in persons with major depression. Biol Psychiatry 1997;42:30-8. Garcia-Sevilla JA, Escriba PV, Busquets X, et al. Platelet imidazoline receptors and regulatory G proteins in patients with major depression. Neuroreport 1996;8:169-72. Lloyd GG, Cawley RH. Distress or illness? A study of psychological symptoms after myocardial infarction. Br J Psychiatry 1983;142: 120-5. Mayou R, Foster A, Williamson B. Psychosocial adjustment in patients 1 year after myocardial infarction. J Psychosom Res 1978;22:447-53. Blumenthal JA, Williams RS, Wallace AG, et al. Physiological and psychological variables predict compliance to prescribed exercise therapy in patients recovering from myocardial infarction. Psychosom Med 1982;44:519-29. Anda RF, Williamson DF, Escobedo LG, et al. Depression and the dynamics of smoking: a national perspective. JAMA 1990;264: 1541-5. Carney RM, Freedland KE, Eisen SA, et al. Major depression and medication adherence in elderly patients with coronary artery disease. Health Psychol 1995;14:88-90. Blumenthal JA, Jiang W, Babyak MA, et al. Stress management and exercise training in cardiac patients with myocardial ischemia. Effects on prognosis and evaluation of mechanisms. Arch Intern Med 1997;157:2213-23. Frasure-Smith N, Lespérance F, Prince RH, et al. Randomised trial of home-based psychosocial nursing intervention for patients recovering from myocardial infarction. Lancet 1997;350:473-9. Glassman AH. Cardiovascular effects of antidepressant drugs: updated. J Clin Psychiatry 1998;59(suppl 15):13-8. Glassman AH, Roose SP, Bigger JT Jr. The safety of tricyclic antidepressants in cardiac patients: risk-benefit reconsidered. JAMA 1993; 269:2673-5. Roose SP, Glassman AH, Attia E, et al. Cardiovascular effects of fluoxetine in depressed patients with heart disease. Am J Psychiatry 1998;155:660-5. Roose SP, Laghrissi-Thode F, Kennedy JS, et al. Comparison of paroxetine and nortriptyline in depressed patients with ischemic heart disease. JAMA 1998;279:287-91. Shapiro PA, Lespérance F, Frasure-Smith N, et al. An open-label preliminary trial of sertraline for treatment of major depression after acute myocardial infarction (the SADHAT Trial). Am Heart J 1999; 137:1100-6. The ENRICHD investigators. Enhancing recovery in coronary heart disease patients (ENRICHD): study design and methods. Am Heart J 2000;139:1-9.
Major depression is a common comorbidity associated with ischemic heart disease (IHD). There is growing evidence that psychological stress in general and depression in particular predispose to cardiovascular disease. Persons who have mental stress during daily life are at twice the risk of myocardial ischemia, and patients with post–myocardial infarction depression have higher mortality rates than nondepressed controls. These data suggest a psychophysiologic mechanism underlying the vulnerability of depressed patients to IHD. Clinical studies have demonstrated that depression is associated with a much higher risk of both cardiovascular morbidity and mortality, which could be caused by platelet activation. Physicians should maintain a heightened level of clinical suspicion for depression and depressive disorders in persons with IHD, particularly those individuals who are recovering from an acute ischemic event, such as myocardial infarction. Furthermore, depression may complicate the recovery of IHD, but in most cases depression can be effectively treated with antidepressant agents. (Am Heart J 2000;140:S63-9.)
Two of the most commonly encountered health problems in the United States are depression and ischemic heart disease (IHD). More than 12 million persons in the United States have a history of myocardial infarction (MI) or angina pectoris or both.1 The lifetime prevalence of depression has been reported to be higher than 17% in a US national probability sample.2 With such a high prevalence, it is not surprising that depression and IHD are commonly comorbid. Individually, each imposes huge economic burdens on society. Every year approximately $44 billion is spent in the treatment of depression, including the cost of medications, hospitalization, absenteeism, lost productivity at work, and suicide.3 In 1995, costs incurred by Medicare hospitalizations for cardiovascular illness accounted for $24.6 billion,1 which did not include costs of absenteeism, lost productivity, postdischarge medical expenses, or costs incurred by other insurance companies or Medicaid. An even greater cost burden to society is probable when depression and IHD are comorbid. The association between depression and IHD has been studied in epidemiologic and observational studies. Elevated total and cardiovascular mortality rates were found among patients treated for major depression.4-13 The exact mechanisms underlying this relation and the benefits of depression treatment on cardiovascular morbidity and mortality have not yet been established. Whether depression increases the risk of cardiovascular disease or cardiovascular disease itself increases the incidence of depression is not clear. However, numer-
From aDuke University Medical Center, Durham, and bSinai Hospital of Baltimore. Reprint requests: Christopher M. O’Connor, MD, Duke University Medical Center, Cardiology Associates, Room 7401A, Box 3356, Durham, NC 27710. Copyright © 2000 by Mosby, Inc. 0002-8703/2000/$12.00 + 0 4/0/109979 doi:10.1067/mhj.2000.109979
ous studies have demonstrated that depression adversely affects the course and prognosis of cardiovascular disease.
Clinical course and diagnosis of depression Major depression is a highly prevalent and disabling mental illness that is underdiagnosed and undertreated. High rates of disability, chronicity, and relapse or recurrence are common. Major depression is associated with as much physical and social dysfunction as many other common medical illnesses, including hypertension, diabetes, and arthritis. In the Medical Outcomes Study, the impairment of daily functioning associated with depression was significantly greater than the disability associated with other chronic conditions such as gastrointestinal disease, arthritis, diabetes, hypertension, and pulmonary problems.14,15 The impact of depression on social functioning is as great as the impairment associated with cardiac conditions, such as advanced coronary artery disease and angina (Figure 1).15 In fact, depression in the presence of other medical illnesses is associated with additive effects on functioning. Social dysfunction is twice as high in persons with advanced coronary artery disease and depression as in persons with either condition alone. If left untreated, major depression can persist for months and may complicate recovery from cardiac events. The potential for relapse and recurrence remains even after successful antidepressant treatment, particularly in patients with a history of depression.16-18 There are no clinically useful laboratory or physical examinations available to diagnose depression. Definitive criteria for major depressive episodes are provided in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV)19 (Table I). Additionally, a number of structured psychiatric interviews or questionnaires may be used in screening for depression.20,21
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Figure 1
Table I. Diagnostic criteria for depression
Table available in print only
Mean physical and social functioning for patients with depression and chronic illness. A score of 100 = perfect functioning. Data from Wells KB, Stewart A, Hays R, et al. The functioning and well-being of depressed patients: results from the Medical Outcomes Study. JAMA 1989;262:914-9.
The Primary Care Evaluation of Medical Disorders is an easy-to-use questionnaire that screens for depression and other psychiatric disorders, including mood, anxiety, alcohol, eating, and somatoform disorders.
Depression and IHD: Increased morbidity and mortality rates Depression is a common comorbid condition in persons with IHD, and evidence strongly links the copresence of these disorders to an increase in morbidity and mortality rates. Depressive symptoms (ie, subsyndromal depression) after acute MI have been reported in approximately 60% of patients.22,23 The prevalence of major depression in patients after MI has been estimated to be as high as 20%.24-29 Even in patients who have not had an MI but have angiographically proven coronary artery disease, the prevalence of depression is approximately 18%.30 The first evidence suggesting that depression is related to increased cardiovascular death appeared in the scientific literature 6 decades ago.11 However, it was not until more than 40 years later that mortality rates in patients with major depression were studied. A 5-year Danish study of approximately 6000 individuals compared the causes of death in persons with a diagnosis of depression or manic depression with those of the general population. A 50% increase in deaths from cardiovascular causes was found among depressed persons as compared with the general Danish population.31 Subsequent studies have also found an excess of total mortality and cardiovascular mortality in persons
with depression.7,8,12,32-36 A study of 62 elderly persons with major depression found the mortality rate of depressed persons to be 2.6 times higher than that of the age-matched national mortality rate. Among the study group, 6 of the 8 deceased persons (75%) died as a result of cardiovascular disease and only 3 of the 54 living individuals had diagnoses of cardiovascular disease (P < .001). The association between risk of death and affective disorders in 1003 adults was also studied in a 16-year prospective population study.12 The investigators found that death caused by circulatory disease was significantly associated with affective disorders, including depression (P < .03). Depression has been identified as a trigger for both nonfatal and fatal MI. Studies that were controlled for traditional cardiovascular risk factors, including smoking, have substantiated the role of depression in the development of initial cardiac events.4,6,10,37-39 Data from a study of 2832 US adults found that persons with baseline symptoms of depression are at an approximately 50% greater risk of fatal IHD (relative risk 1.5; 95% confidence interval [CI], 1.0-2.3) than persons without baseline depressive symptoms (Figure 2).4 This was the first study to link the symptoms of depression to both the risks of developing and dying of IHD. In a community survey of more than 700 individuals, Barefoot and Schroll6 found that persons with high scores on a measure of depressive symptoms are at increased risk of MI (relative risk 1.71; P = .005) and death from all causes (relative risk 1.59; P < .001) compared with persons with lower scores. In another study of almost 1200 male medical students followed up for a median of 35 years, higher risks of IHD (relative risk 2.12; 95% CI, 1.24-3.63) and MI (relative risk 2.12; 95% CI, 1.11-4.06) were found in those men with depression compared with those without depression.38 In contrast, one study of more than 2500 individuals followed up for 15 years did not observe an association between depression and increased cardiovascular death or IHD.40
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Figure 2
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Figure 3
Image available in print only
Fatal and nonfatal IHD in persons with depressed and nondepressed affect. Adjusted relative risk: *1.5, †1.0, ‡1.6. Data from Anda R, Williamson D, Jones D, et al. Depressed affect, hopelessness, and the risk of ischemic heart disease in a cohort of US adults. Epidemiology 1993;4:285-94.
The occurrence of depressive symptoms after an ischemic event has also been examined to determine influence on morbidity and mortality rates. Carney et al9 were the first investigators to study persons with preexisting cardiovascular disease and assess for depression. Over a 1-year follow-up period of 52 patients with coronary heart disease, major depression was found to be the greatest predictor of cardiac complications, accounting for a more than doubled risk of developing an adverse cardiac complication (relative risk 2.2, P < .02). Subsequent controlled studies with larger study populations have provided convincing evidence for the increased cardiovascular risk found in persons who develop depression after an ischemic event.26,28,41-44 Depression and subsequent impact on 6-month survival after MI was studied by Frasure-Smith et al.26 A total of 222 patients who had had an acute MI were enrolled. Patients were interviewed between 5 and 15 days after MI with a modified version of the National Institute of Mental Health Diagnostic Interview Schedule to determine if criteria for depression were met. During a 6month follow-up period, a 4-fold increase in the risk of death for patients who were depressed was apparent (Figure 3). When the data were corrected for relevant covariates that determine outcome, including previous MI and Killip class, major depression continued to be a major independent predictor of an adverse outcome (adjusted hazard ratio 4.29; 95% CI, 3.14-5.44; P = .013). Frasure-Smith et al43 followed up this population for
Cumulative mortality rates for depressed and nondepressed persons after MI. Reproduced with permission from Frasure-Smith N, Lespérance F, Talajic M. Depression following myocardial infarction: impact on 6-month survival. JAMA 1993;270:1819-25. Copyright 1993 by American Medical Association.
Figure 4
Premature ventricular contractions (PVC) and 18-month cardiac mortality rate. Reproduced with permission from Frasure-Smith N, Lespérance F, Talajic M. Depression and 18-month prognosis after myocardial infarction. Circulation 1995;91:999-1005.
another year and reported the results at 18 months. The investigators found that depression was associated with an increased risk of dying and that mild and moderate forms of depression (Beck Depression Inventory [BDI] score ≥10) are associated with an increased risk of cardiac events or death. Importantly, it was shown that mortality rate was significantly higher in patients with premature ventricular contractions of 10 or more per hour who scored higher than 10 on the BDI compared with patients who scored below 10 on the BDI (odds ratio 29.1; 95% CI, 6.97-122.07; P < .00001). In
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Table II. Results of stress management and exercise training Type of event Death Nonfatal MI CABG PTCA Total
Exercise 1 (2.9) 0 (0) 1 (2.9) 5 (14.7) 7 (20.6)
Stress management 0 (0) 0 (0) 2 (6.1) 1 (3.0) 3 (9.1)
Usual care 0 (0) 3 (7.5) 4 (10.0) 5 (12.5) 12 (30.0)
Values are n (%). CABG, Coronary artery bypass graft; PTCA, percutaneous transluminal coronary angioplasty. O’Connor et al, unpublished.
patients with fewer than 10 premature ventricular contractions per hour, there was no difference in cardiovascular death between groups (Figure 4). There is a considerable and compelling body of evidence demonstrating that depression and comorbid IHD lead to an increased risk of death, regardless of which illness occurred first. The underlying pathophysiologic characteristics and the effects of antidepressant treatment on mortality rate are subjects of ongoing clinical investigation.
Potential mechanisms explaining increased mortality rate in depressed patients after MI Several mechanisms have been suggested that may increase the risk of death in depressed patients after MI. Arrhythmias were the predominant mode of death in the studies done by Frasure-Smith et al.26,43 Decreased vagal and increased sympathetic tone in depressed persons without any other medical illnesses may be a prognostic factor in the development of cardiac disease.45-49 In fact, the alteration in the ratio between sympathetic and parasympathetic tone may make depressed patients more susceptible to cardiac arrhythmias and sudden death by lowering the threshold for ventricular fibrillation.50,51 Among other postulated triggers are reduced heart rate variability, emotional distress, and abnormalities in platelet reactivity.4,10,37,45,52,53 Increased platelet aggregation may also contribute to the increase in mortality rate found in persons with comorbid depression and IHD. Direct evidence of a significant tendency for clotting diatheses and thrombosis in depressed individuals has been found in pilot studies (and is reviewed in greater detail in this supplement).53,54 It has been consistently observed that patients with major depression exhibited significant differences in the number of binding sites for various compounds, including imipramine,55 paroxetine,56 and inositol57 on the platelet surface than controls. Platelet monoamine oxidase activity is significantly elevated in depressed patients,58,59 especially in women.60 Reduced platelet
serotonin uptake61,62 and enhanced serotonin receptor expression63,64 were also observed in the depressed patients. Depression is also known to be associated with increased levels of intraplatelet Ca++ ion mobilization65,66 and diminished activity of forskolin-stimulated platelet adenylyl cyclase.67 Moreover, the newly discovered imidazoline platelet receptors (45 kDa and 35 kDa proteins) have been found to be upregulated in patients with major depression.68
Should all patients with heart disease and depression be treated? Concurrent depression increases the risk of poor outcome in patients with MI, unstable angina, and heart failure. Depressed patients after MI take longer to return to work and have greater stress and psychosocial impairment than those patients without depressive symptoms.23,69,70 Patients who are depressed after an MI are more likely to drop out of exercise programs than patients who are not depressed.71 Depressed smokers are 40% less likely to stop smoking than nondepressed smokers (relative risk 0.6).72 Furthermore, depressed patients with coronary artery disease are less likely to comply with low-dose aspirin therapy.73 Based on this, should all these patients be treated for their depression? Trials to assess the effects of psychosocial intervention on depression have found varying results. In a small cohort study,74 107 persons with coronary artery disease, exercise-induced ischemia, and mental stress–induced ischemia (confirmed by Holter monitor or radionuclide imaging) were randomly assigned to receive usual care, stress management, or exercise training. Of the study population, 10% were determined to be depressed. At follow-up (mean 38 months), patients in the stress management group had the lowest combined rate of death, nonfatal MI, and revascularization (9.1%). Patients in the exercise group and the usual care group had higher combined rates of death, nonfatal MI, and revascularization, 20.6% and 30.0%, respectively (Table II). In the Montreal Heart Attack Readjustment Trial (M-HART),75 patients who had had an MI were randomly assigned to an intervention program (n = 692) or to usual care (n = 684). The intervention program was composed of monthly telephone follow-up and home nurse counseling as needed for patients who had high levels of anxiety, as measured by the Spielberger State Anxiety Scale. The usual care group did not receive monthly telephone monitoring or visits from nurses. Instead, they received usual care from their physicians and completed follow-up interviews at 3 and 12 months. The primary end point was cardiac death, and secondary end points were all-cause mortality and fatal and nonfatal MI. Overall, total mortality rate was higher for patients in the intervention group (5.5%)
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Table III. Similarity between depression and hyperlipidemia risk factors Cholesterol
Depression
Effect on risk Effect of treatment on surrogate Effect of nonpharmacologic treatment on risk Effect of pharmacologic treatment on risk
Proportional relation Lowering LDL decreases risk of MI Diet/exercise: no mortality data Reduction in MI (statins)
Proportional relation Unknown Stress management, group counseling: no mortality data TCAs may increase risk; SSRIs: unknown
SSRIs, Selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants.
compared with the control group (3.9%), although the difference was not statistically significant. Rates of cardiac death in the intervention group (4.8%) were also higher but not significantly different than the control group (3.4%). However, in women, there was an almost 2-fold increase in the risk of dying in those who received nonpharmacologic therapy targeted toward the higher state of anxiety. The increase in deaths was predominantly caused by a 5-fold increase in sudden death caused by arrhythmias. Although this study did not assess individuals with comorbid depression, the results suggest that nonpharmacologic interventions do not reduce the risk of death; rather, they may increase the risk of death in a patient after MI. Available data are limited regarding the effects of antidepressant treatment on the outcome of persons with comorbid IHD and depression. Tricyclic antidepressants are known to have adverse cardiovascular effects, including slowed intraventricular conduction and orthostatic hypotension.76,77 It would not be beneficial to use these agents in a population already at an increased risk of cardiac morbidity and mortality. In small studies, the selective serotonin reuptake inhibitors have appeared to be safe and effective in persons with comorbid IHD and depression.78-80 Although promising, the results are somewhat limited because the studies were small, of short duration, and 2 were open-labeled. Large randomized, controlled trials are necessary to assess the effects of long-term antidepressant treatment on morbidity and mortality rates. The Enhancing Recovery in Coronary Heart Disease (ENRICHD) trial, sponsored by the National Heart, Lung, and Blood Institute, is currently under way. 81 Psychosocial and pharmacologic interventions in patients with IHD who have high levels of social isolation and/or depression are being evaluated in this multicenter mortality trial of 3000 patients. Results should be available within 1 year and will begin to provide answers to the question of whether psychosocial and/or pharmacologic therapy with selective serotonin reuptake inhibitors should be initiated in an individual with comorbid IHD and depression. At present, the routine use of psychosocial therapy in depressed persons with IHD is not warranted. Treatment of depression with pharmacologic agents
may be easily accomplished. However, the impact of antidepressant treatment on the risk of cardiovascular disease and death remains to be determined. The findings of ongoing pharmacologic treatment studies will be viewed with interest.
Conclusion Depression has been shown to worsen the prognosis of persons with IHD and may be viewed as a risk factor similar to hypercholesterolemia (Table III). As with cholesterol, the evidence for effect on risk appears to be proportional. The effect of treatment is defined for cholesterol (lowering low-density lipoproteins decreases the risk of MI). However, we do not know whether lowering the rates of depression actually results in improved survival or diminished cardiovascular risk. The impact of nonpharmacologic and pharmacologic treatment on risk is currently under investigation. Clinicians eagerly await the results of the ENRICHD study, which should help to ascertain whether psychosocial intervention for the treatment of depression is beneficial. Pharmacologic therapy for the treatment of depression is valuable, but the effect on outcome is as yet unknown.
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