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Depression and coronary heart disease: Association and implications for treatment
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James A. Blumenthal, PhD

Depression refers to an emotional condition ranging from a transient negative mood state of sadness or mild dysphoria to a chronic and severe psychiatric illness. The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) identifies two depressive disorders: major depressive disorder (MDD) and dysthymic disorder.1 The essential feature of MDD is a clinical course characterized by one or more major depressive episode (whose diagnostic criteria are presented in Table 1) without a history of manic, mixed, or hypomanic episodes. The diagnosis requires the presence of a total of at least five symptoms over a period of at least 2 weeks, which must include either depressed mood or loss of interest or pleasure. Dysthymic disorder is marked by mild depressive symptoms that are more chronic in nature, lasting at least 2 years.1

Minor depressive disorder (mDD) is not an official DSM-IV diagnosis but is used for research purposes; it is similar to MDD in duration but requires that only two to four symptoms be present.

EPIDEMIOLOGY OF DEPRESSION

Depression is a widespread and often chronic condition. Lifetime prevalence estimates for MDD are approximately 15% to 20%;2,3 1-year prevalence estimates are 5% to 10%;2,4 and point prevalence estimates range from 4% to 7%.3,5 Moreover, MDD is characterized by high rates of relapse: 22% to 50% of patients suffer recurrent episodes within 6 months after recovery.6

Women are twice as likely as men to be diagnosed with MDD, with lifetime prevalence rates of 10% to 25% in women versus 5% to 12% in men.1

Although rates of depression do not appear to increase with age, MDD often goes undertreated in older adults3 and in cardiac patients.7

DIAGNOSING AND ASSESSING DEPRESSION

The gold standard for diagnosing MDD is a clinical interview. Commonly used instruments include the Diagnostic Interview Schedule8 and the Composite International Diagnostic Interview.9 The Structured Clinical Interview for DSM-IV Axis I Disorders10 and the Schedule for Affective Disorders and Schizophrenia11 are frequently used semistructured interviews.

The most common clinical instruments for assessing the severity of depressive symptoms are the Hamilton Rating Scale for Depression (HAM-D),12 which is a clinician-rated scale, and various psychometric questionnaires, including the Beck Depression Inventory (BDI)13,14 and the Center for Epidemiological Studies Depression Scale (CES-D).15

THE DEPRESSION–HEART DISEASE LINK

Depression as a primary risk factor

Reprinted from Rozanski A, et al. The epidemiology, pathophysiology, and management of psychosocial risk factors in cardiac practice: the emerging field of behavioral cardiology. J Am Coll Cardiol 2005; 45:637–651, © 2005, with permission from the ACC.
Figure 1. Risk ratios of traditional risk factors for coronary heart disease (CHD) observed in the Framingham study as compared with risk ratios of depressive symptoms and depressed mood as derived from the recent meta-analysis by Rugulies.17 The risk of CHD conferred by depressive symptoms is comparable to that conferred by traditional risk factors, and the presence of clinical depression appears to raise this risk. For traditional risk factors, risk ratios were calculated for cardiac death, myocardial infarction, coronary artery insufficiency, and angina. For depressed mood and clinical depression, risk ratios were calculated for cardiac disease and myocardial infarction.18
Evidence that depression is a primary risk factor for coronary heart disease (CHD) in healthy individuals has been reviewed previously.16 A recent meta-analysis of 11 prospective cohort studies of initially healthy individuals indicated that depression (either depressive mood or clinical MDD) conferred a relative risk of 1.64 for adverse cardiac events, including myocardial infarction (MI) and cardiac death; the presence of MDD was associated with the greatest risk (relative risk of 2.69).17Figure 1 shows that clinical depression is comparable to traditional risk factors for CHD, such as smoking and elevated blood lipid levels, as observed in the Framingham study.18

Depression as a secondary risk factor

Depression is an even stronger risk factor for cardiac events in patients with established CHD. Point estimates range from 14% to as high as 47%, with higher rates in patients with unstable angina and in patients awaiting coronary artery bypass graft (CABG) surgery; an additional 20% of patients exhibit elevated depressive symptoms or minor depression (mDD).19–25

Prospective studies have shown that depression increases the risk for death or nonfatal cardiac events approximately 2.5-fold in patients with CHD. For instance, Frasure-Smith et al followed 896 patients with a recent acute MI and found that the presence of depressive symptoms as indicated by an elevated BDI score was a significant predictor of cardiac mortality after controlling for multivariate predictors of mortality (odds ratio [OR] = 3.29 for women and 3.05 for men).26

Two recent meta-analyses confirmed the association between depression and adverse clinical outcomes in patients with CHD.27,28 For example, van Melle et al reported that post-MI depression was associated with a 2- to 2.5-fold increase in the risk of adverse health outcomes.28 In this analysis, depression’s effect on cardiac mortality and all-cause mortality was especially pronounced in older studies (before 1992) (OR = 3.2) compared with more recent studies (after 1992) (OR = 2.01).28

Duke University researchers have conducted several prospective studies in various cardiac populations.29–31 Barefoot et al assessed 1,250 patients with documented CHD using the Zung Self-Rating Depression Scale at the time of diagnostic coronary angiography and followed them for up to 19.4 years.29 Results showed that patients with moderate to severe depression were at 69% greater risk for cardiac death and 78% greater risk for all-cause death than were their nondepressed counterparts.

Reprinted from The Lancet (Blumenthal JA, et al. Depression as a risk factor for mortality after coronary artery bypass surgery. Lancet 2003; 362:604–609.), copyright 2003, with permission from Elsevier.
Figure 2. Kaplan-Meier survival curves for all-cause mortality among coronary surgery patients according to their presurgery (baseline) depressive symptoms as measured by the Center for Epidemiological Studies Depression Scale (CES-D). Compared with the absence of depressive symptoms, the presence of moderate to severe symptoms was associated with a hazard ratio of 2.4 (95% CI = 1.40 to 4.00; P = .001) for all-cause mortality. Mild symptoms were associated with no difference in risk relative to the absence of symptoms (hazard ratio = 1.08, 95% CI = 0.70 to 1.67; P = .723).30
In a prospective study of patients undergoing CABG surgery, we assessed the effect of depression on mortality in 817 patients followed for up to 12 years (mean, 5.2 years).30 Using the CES-D instrument, patients were categorized on the day before surgery as having either no depression (CES-D score < 16), mild depression (score of 16 to 26), or moderate to severe depression (score ≥ 27). We found that moderate to severe depression was independently associated with a twofold to threefold increase in the risk of death, even after controlling for age, gender, number of grafts, diabetes, smoking, left ventricular ejection fraction, and history of acute MI (Figure 2). Moreover, patients who exhibited persistent depression, with CES-D scores of 16 or greater at baseline and after 6 months, had more than a doubling in risk relative to patients who were never depressed.

We also recently reported results from a prospective study that followed 204 patients with heart failure over a median interval of 3 years.31 Clinically significant symptoms of depression (BDI score ≥ 10) were associated with a hazard ratio of 1.56 (95% CI, 1.07 to 2.29) for the combined end point of death or cardiovascular hospitalization. These observations included adjustment for plasma NT-proBNP level, ejection fraction, and other established risk factors, suggesting that heightened risk of adverse clinical outcomes associated with depressive symptoms is not simply a reflection of the severity of heart failure.

In summary, a number of observational studies have demonstrated that depression is associated with increased risk of morbidity and mortality both in healthy populations and in a variety of populations with established cardiac disease.

BIOBEHAVIORAL MECHANISMS LINKING DEPRESSION AND CHD

A number of biobehavioral mechanisms have been hypothesized to underlie the relationship between depression and CHD. Most evidence is derived from cross-sectional studies and suggests that depression is associated with traditional risk factors for CHD, such as hypertension, diabetes, and insulin resistance,32,33 as well as changes in platelet reactivity,34 dysregulation of the autonomic nervous system35 and hypothalamic-pituitary-adrenal axis,36 and alterations in the immune response/inflammation.37 Depression is also associated with behavioral factors that are in turn associated with CHD risk, such as reduced treatment adherence,38 smoking,39 and physical inactivity.40

 

 

STUDIES OF DEPRESSION TREATMENT IN CARDIAC PATIENTS

Successful treatments for depression in patients with CHD may have the potential to improve not only quality of life but also cardiovascular and physical health. Several treatments for depression exist for use in the general population, such as antidepressant medication or psychotherapy.41 However, only three studies have tested the efficacy of these treatments in patients with CHD: SADHART, ENRICHD, and CREATE.42–44

SADHART (Sertraline Antidepressant Heart Attack Randomized Trial) was a safety and efficacy evaluation of antidepressant medication in patients with MDD and a recent MI or unstable angina.42 It showed only modest differences in reductions in depressive symptoms between sertraline recipients and placebo recipients, and it lacked statistical power to examine the impact of treatment on hard clinical end points.

ENRICHD (Enhancing Recovery in Coronary Heart Disease Patients) assessed the effect of psychosocial treatment on survival among more than than 2,400 post-MI patients.43 Although this trial found that cognitive behavior therapy resulted in significant, albeit small, improvements in depressive symptoms compared with usual care, it failed to demonstrate that treating depression and low social support was associated with increased survival.

CREATE (Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy), a recent placebo-controlled trial, assessed the value of antidepressant medication and clinical management in patients with CHD.44 The study’s 284 patients, all of whom had CHD as well as MDD and a HAM-D score of 20 or greater, underwent two separate randomizations: (1) to 12 weeks of interpersonal therapy plus clinical management or 12 weeks of clinical management alone, and (2) to 12 weeks of citalopram therapy or matching placebo. There was no difference between interpersonal therapy and clinical management alone; however, citalopram was superior to placebo in reducing HAM-D scores and demonstrated better remission rates (35.9% with citalopram vs 22.5% with placebo). The same therapists who provided interpersonal therapy also performed the clinical management, so it could be argued that this was why additional interpersonal therapist time did not result in greater reductions in depressive symptoms than did clinical management alone. Furthermore, this study did not examine the effects of depression therapy on clinical outcomes.

EXERCISE AS A TREATMENT FOR DEPRESSION

There is growing evidence that exercise may be an effective treatment for depression.45 Most of the existing studies of exercise for depression have focused on aerobic exercise.

In the relatively large SMILE study (Standard Medical Intervention and Long-term Exercise),46 conducted at Duke University, 156 adult noncardiac patients with MDD were randomized to 4 months of treatment with supervised aerobic exercise, antidepressant medication (sertraline), or a combination of exercise and medication. Although antidepressant medication was associated with faster reductions in depression in the first 4 weeks of treatment among mildly depressed patients, exercise was as effective as antidepressant medication in treating depression by the end of the 16-week intervention for all participants.

Reprinted, with permission, from Babyak MA, et al. Exercise treatment for major depression: maintenance of therapeutic benefit at 10 months. Psychosom Med 2000; 62:633–638.
Figure 3. Clinical status at 10 months (6 months after end of treatment) among 83 patients who achieved remission from major depressive disorder following 4 months of treatment in the SMILE study,46 according to the three treatment groups. Compared with participants in the other treatment groups, those in the exercise group were more likely to remain fully or partially recovered and less likely to have relapsed.47
Six-month follow-up among patients from the SMILE study who had achieved remission revealed that those who had been randomized to exercise were less likely to have relapsed than those randomized to the medication or combination-therapy groups (Figure 3).47 Moreover, across the entire follow-up population, those patients who reportedly engaged in regular aerobic exercise during the 6-month follow-up period were only half as likely to have relapsed compared with those who did not engage in regular exercise.

Exercise generally is considered safe for most patients with stable CHD.48 Some studies of exercise treatments for patients with CHD have tracked depressive symptoms and thus have provided insight into the potential efficacy of exercise as a treatment for depression in this population. Although most of these studies have reported significant improvements in depression after completion of an exercise program, many have had important methodologic limitations, including absence of a control group. In one of the few controlled studies in this area, Stern et al49 randomized 106 men who had a recent acute MI and elevated depression, anxiety, or low fitness to 12 weeks of exercise training, group therapy, or usual care (control). At 1-year follow-up, subjects in both the exercise and counseling groups showed improvements in depression relative to controls.

EFFECT OF EXERCISE ON CARDIOVASCULAR RISK FACTORS AND OUTCOMES

Exercise is a particularly promising intervention for depression in patients with CHD because it has well-documented cardiovascular benefits. In addition to the well-established role of exercise interventions in primary prevention, such interventions have been shown to improve outcomes for patients with CHD.50

Jolliffe et al conducted a meta-analysis comparing exercise-only interventions, comprehensive rehabilitation (including educational and behavioral components such as dietary changes and stress reduction in addition to exercise), and usual care.51 Exercise-only interventions were associated with reductions in both all-cause and cardiac mortality relative to usual care. Comprehensive rehabilitation, on the other hand, was not associated with statistically significant reductions in all-cause mortality relative to usual care, but it was associated with a decreased risk for cardiac mortality, to a slightly lesser extent than exercise-only interventions.

Reprinted, with permission, from Blumenthal JA, et al. Exercise, depression, and mortality after myocardial infarction in the ENRICHD trial. Med Sci Sports Exerc 2004; 36:746–755.
Figure 4. Predicted survival functions for patients who did (n = 952) and did not (n = 1,096) exercise regularly during the 6 months following an index myocardial infarction in the ENRICHD trial. There were a total of 187 fatal events; the mortality rate was 5.7% among the exercisers compared with 12.0% among the nonexercisers.52
Recent data from the ENRICHD trial suggest that exercise may reduce rates of death and recurrent nonfatal infarction in post-MI patients with depression or low levels of social support.52 Self-reported data were used to categorize participants as exercising regularly or not exercising regularly. After adjustment for medical and demographic variables, regular excercise was found to be associated with a nearly 40% reduction in the risk of death and a nearly 30% reduction in the risk of recurrent nonfatal infarction. Figure 4 depicts the Kaplan-Meier survival curves for patients who did and did not exercise regularly.

The evidence that exercise affects depression, CHD risk factors, and CHD outcomes suggests that exercise is a particularly promising intervention for depression in this population.

UPBEAT trial promises further insight

A new Duke University study known as UPBEAT (Understanding Prognostic Benefits of Exercise and Antidepressant Treatment) is randomizing 200 patients with elevated depressive symptoms to exercise, antidepressant therapy (sertraline), or placebo for 4 months.53 A variety of “biomarkers” of risk are being assessed, including measures of heart rate variability, vascular function, inflammation, and platelet aggregation. Results of this 5-year trial should be available by 2011.

 

 

CONCLUSIONS

Although depression has emerged as an important risk factor for CHD, there is no consensus on the optimal way to treat depression in patients with CHD. Interventions that are guided by an understanding of the mechanisms linking depression to CHD may prove to be most effective in improving both depression and physical health outcomes.

Exercise targets many of the mechanisms by which depression may be associated with increased risk, including autonomic nervous system activity, hypothalamic-pituitary-adrenal axis function, platelet activation, vascular function, and inflammation. Moreover, a growing body of evidence suggests that exercise is an effective treatment for depression that may be comparable in effect to antidepressant medication, at least in select subgroups (eg, patients who are receptive to exercise as a treatment for depression). The value of exercise training—not only for improving quality of life, but also for improving “biomarkers” of risk and other relevant health outcomes—is the focus of our current research efforts.

References
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  27. Barth J, Schumacher M, Hermann-Lingen C. Depression as a risk factor for mortality in patients with coronary heart disease: a meta-analysis. Psychosom Med 2004; 66:802–813.
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  31. Sherwood A, Blumenthal JA, Trivedi R, et al. Relationship of depression to mortality and hospitalization in patients with heart failure. Arch Intern Med 2007; 167:367–373.
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  34. Musselman DL, Tomer A, Manatunga AK, et al. Exaggerated platelet reactivity in major depression. Am J Psychiatry 1996; 153:1313–1317.
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  36. Akil H, Haskett RF, Young EA, et al. Multiple HPA profiles in endogenous depression: effect of age and sex on cortisol and beta-endorphin. Biol Psychiatry 1993; 33:73–85.
  37. Kop WJ, Gottdiener JS, Tangen CM, et al. Inflammation and coagulation factors in persons > 65 years of age with symptoms of depression but without evidence of myocardial ischemia. Am J Cardiol 2002; 89:419–424.
  38. Carney RM, Freedland KE, Eisen SA, Rich MW, Jaffe AS. Major depression and medication adherence in elderly patients with coronary artery disease. Health Psychol 1995; 14:88–90.
  39. Lehto S, Koukkunen H, Hintikka J, Viinamaki H, Laakso M, Pyorala K. Depression after coronary heart disease events. Scand Cardiovasc J 2000; 34:580–583.
  40. Camacho TC, Roberts RE, Lazarus NB, Kaplan GA, Cohen RD. Physical activity and depression: evidence from the Alameda County Study. Am J Epidemiol 1991; 134:220–231.
  41. Depression Guideline Panel. Depression in Primary Care: Volume 2. Treatment of Depression, Clinical Practice Guideline, No. 5. Rockville, MD: Agency for Health Care Policy and Research, Public Health Service, US Dept of Health and Human Services; 1993.
  42. Glassman AH, O’Connor CM, Califf RM, et al. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA 2002; 288:701–709.
  43. Berkman LF, Blumenthal J, Burg M, et al. Effects of treating depression and low perceived social support on clinical events after myocardial infarction: the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) randomized trial. JAMA 2003; 289:3106–3116.
  44. Lesperance F, Frasure-Smith N, Koszycki D, et al. Effects of citalopram and interpersonal psychotherapy on depression in patients with coronary artery disease: the Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) trial. JAMA 2007; 297:367–379.
  45. Brosse AL, Sheets ES, Lett HS, Blumenthal JA. Exercise and the treatment of clinical depression in adults: recent findings and future directions. Sports Med 2002; 32:741–760.
  46. Blumenthal JA, Babyak MA, Moore KA, et al. Effects of exercise training on older patients with major depression. Arch Intern Med 1999; 159:2349–2356.
  47. Babyak M, Blumenthal JA, Herman S, et al. Exercise treatment for major depression: maintenance of therapeutic benefit at 10 months. Psychosom Med 2000; 62:633–638.
  48. Franklin BA, Bonzheim K, Gordon S, Timmis GC. Safety of medically supervised outpatient cardiac rehabilitation exercise therapy: a 16-year follow-up. Chest 1998; 114:902–906.
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James A. Blumenthal, PhD
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC

Correspondence: James A. Blumenthal, PhD, Box 3119, Duke Uni­versity Medical Center, Durham, NC 27710; [email protected]

This work was supported by grants MH49679 and HL080664 from the National Institutes of Health.

Dr. Blumenthal reported that he has no financial relationships that pose a potential conflict of interest with this article.

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Correspondence: James A. Blumenthal, PhD, Box 3119, Duke Uni­versity Medical Center, Durham, NC 27710; [email protected]

This work was supported by grants MH49679 and HL080664 from the National Institutes of Health.

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Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC

Correspondence: James A. Blumenthal, PhD, Box 3119, Duke Uni­versity Medical Center, Durham, NC 27710; [email protected]

This work was supported by grants MH49679 and HL080664 from the National Institutes of Health.

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Depression refers to an emotional condition ranging from a transient negative mood state of sadness or mild dysphoria to a chronic and severe psychiatric illness. The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) identifies two depressive disorders: major depressive disorder (MDD) and dysthymic disorder.1 The essential feature of MDD is a clinical course characterized by one or more major depressive episode (whose diagnostic criteria are presented in Table 1) without a history of manic, mixed, or hypomanic episodes. The diagnosis requires the presence of a total of at least five symptoms over a period of at least 2 weeks, which must include either depressed mood or loss of interest or pleasure. Dysthymic disorder is marked by mild depressive symptoms that are more chronic in nature, lasting at least 2 years.1

Minor depressive disorder (mDD) is not an official DSM-IV diagnosis but is used for research purposes; it is similar to MDD in duration but requires that only two to four symptoms be present.

EPIDEMIOLOGY OF DEPRESSION

Depression is a widespread and often chronic condition. Lifetime prevalence estimates for MDD are approximately 15% to 20%;2,3 1-year prevalence estimates are 5% to 10%;2,4 and point prevalence estimates range from 4% to 7%.3,5 Moreover, MDD is characterized by high rates of relapse: 22% to 50% of patients suffer recurrent episodes within 6 months after recovery.6

Women are twice as likely as men to be diagnosed with MDD, with lifetime prevalence rates of 10% to 25% in women versus 5% to 12% in men.1

Although rates of depression do not appear to increase with age, MDD often goes undertreated in older adults3 and in cardiac patients.7

DIAGNOSING AND ASSESSING DEPRESSION

The gold standard for diagnosing MDD is a clinical interview. Commonly used instruments include the Diagnostic Interview Schedule8 and the Composite International Diagnostic Interview.9 The Structured Clinical Interview for DSM-IV Axis I Disorders10 and the Schedule for Affective Disorders and Schizophrenia11 are frequently used semistructured interviews.

The most common clinical instruments for assessing the severity of depressive symptoms are the Hamilton Rating Scale for Depression (HAM-D),12 which is a clinician-rated scale, and various psychometric questionnaires, including the Beck Depression Inventory (BDI)13,14 and the Center for Epidemiological Studies Depression Scale (CES-D).15

THE DEPRESSION–HEART DISEASE LINK

Depression as a primary risk factor

Reprinted from Rozanski A, et al. The epidemiology, pathophysiology, and management of psychosocial risk factors in cardiac practice: the emerging field of behavioral cardiology. J Am Coll Cardiol 2005; 45:637–651, © 2005, with permission from the ACC.
Figure 1. Risk ratios of traditional risk factors for coronary heart disease (CHD) observed in the Framingham study as compared with risk ratios of depressive symptoms and depressed mood as derived from the recent meta-analysis by Rugulies.17 The risk of CHD conferred by depressive symptoms is comparable to that conferred by traditional risk factors, and the presence of clinical depression appears to raise this risk. For traditional risk factors, risk ratios were calculated for cardiac death, myocardial infarction, coronary artery insufficiency, and angina. For depressed mood and clinical depression, risk ratios were calculated for cardiac disease and myocardial infarction.18
Evidence that depression is a primary risk factor for coronary heart disease (CHD) in healthy individuals has been reviewed previously.16 A recent meta-analysis of 11 prospective cohort studies of initially healthy individuals indicated that depression (either depressive mood or clinical MDD) conferred a relative risk of 1.64 for adverse cardiac events, including myocardial infarction (MI) and cardiac death; the presence of MDD was associated with the greatest risk (relative risk of 2.69).17Figure 1 shows that clinical depression is comparable to traditional risk factors for CHD, such as smoking and elevated blood lipid levels, as observed in the Framingham study.18

Depression as a secondary risk factor

Depression is an even stronger risk factor for cardiac events in patients with established CHD. Point estimates range from 14% to as high as 47%, with higher rates in patients with unstable angina and in patients awaiting coronary artery bypass graft (CABG) surgery; an additional 20% of patients exhibit elevated depressive symptoms or minor depression (mDD).19–25

Prospective studies have shown that depression increases the risk for death or nonfatal cardiac events approximately 2.5-fold in patients with CHD. For instance, Frasure-Smith et al followed 896 patients with a recent acute MI and found that the presence of depressive symptoms as indicated by an elevated BDI score was a significant predictor of cardiac mortality after controlling for multivariate predictors of mortality (odds ratio [OR] = 3.29 for women and 3.05 for men).26

Two recent meta-analyses confirmed the association between depression and adverse clinical outcomes in patients with CHD.27,28 For example, van Melle et al reported that post-MI depression was associated with a 2- to 2.5-fold increase in the risk of adverse health outcomes.28 In this analysis, depression’s effect on cardiac mortality and all-cause mortality was especially pronounced in older studies (before 1992) (OR = 3.2) compared with more recent studies (after 1992) (OR = 2.01).28

Duke University researchers have conducted several prospective studies in various cardiac populations.29–31 Barefoot et al assessed 1,250 patients with documented CHD using the Zung Self-Rating Depression Scale at the time of diagnostic coronary angiography and followed them for up to 19.4 years.29 Results showed that patients with moderate to severe depression were at 69% greater risk for cardiac death and 78% greater risk for all-cause death than were their nondepressed counterparts.

Reprinted from The Lancet (Blumenthal JA, et al. Depression as a risk factor for mortality after coronary artery bypass surgery. Lancet 2003; 362:604–609.), copyright 2003, with permission from Elsevier.
Figure 2. Kaplan-Meier survival curves for all-cause mortality among coronary surgery patients according to their presurgery (baseline) depressive symptoms as measured by the Center for Epidemiological Studies Depression Scale (CES-D). Compared with the absence of depressive symptoms, the presence of moderate to severe symptoms was associated with a hazard ratio of 2.4 (95% CI = 1.40 to 4.00; P = .001) for all-cause mortality. Mild symptoms were associated with no difference in risk relative to the absence of symptoms (hazard ratio = 1.08, 95% CI = 0.70 to 1.67; P = .723).30
In a prospective study of patients undergoing CABG surgery, we assessed the effect of depression on mortality in 817 patients followed for up to 12 years (mean, 5.2 years).30 Using the CES-D instrument, patients were categorized on the day before surgery as having either no depression (CES-D score < 16), mild depression (score of 16 to 26), or moderate to severe depression (score ≥ 27). We found that moderate to severe depression was independently associated with a twofold to threefold increase in the risk of death, even after controlling for age, gender, number of grafts, diabetes, smoking, left ventricular ejection fraction, and history of acute MI (Figure 2). Moreover, patients who exhibited persistent depression, with CES-D scores of 16 or greater at baseline and after 6 months, had more than a doubling in risk relative to patients who were never depressed.

We also recently reported results from a prospective study that followed 204 patients with heart failure over a median interval of 3 years.31 Clinically significant symptoms of depression (BDI score ≥ 10) were associated with a hazard ratio of 1.56 (95% CI, 1.07 to 2.29) for the combined end point of death or cardiovascular hospitalization. These observations included adjustment for plasma NT-proBNP level, ejection fraction, and other established risk factors, suggesting that heightened risk of adverse clinical outcomes associated with depressive symptoms is not simply a reflection of the severity of heart failure.

In summary, a number of observational studies have demonstrated that depression is associated with increased risk of morbidity and mortality both in healthy populations and in a variety of populations with established cardiac disease.

BIOBEHAVIORAL MECHANISMS LINKING DEPRESSION AND CHD

A number of biobehavioral mechanisms have been hypothesized to underlie the relationship between depression and CHD. Most evidence is derived from cross-sectional studies and suggests that depression is associated with traditional risk factors for CHD, such as hypertension, diabetes, and insulin resistance,32,33 as well as changes in platelet reactivity,34 dysregulation of the autonomic nervous system35 and hypothalamic-pituitary-adrenal axis,36 and alterations in the immune response/inflammation.37 Depression is also associated with behavioral factors that are in turn associated with CHD risk, such as reduced treatment adherence,38 smoking,39 and physical inactivity.40

 

 

STUDIES OF DEPRESSION TREATMENT IN CARDIAC PATIENTS

Successful treatments for depression in patients with CHD may have the potential to improve not only quality of life but also cardiovascular and physical health. Several treatments for depression exist for use in the general population, such as antidepressant medication or psychotherapy.41 However, only three studies have tested the efficacy of these treatments in patients with CHD: SADHART, ENRICHD, and CREATE.42–44

SADHART (Sertraline Antidepressant Heart Attack Randomized Trial) was a safety and efficacy evaluation of antidepressant medication in patients with MDD and a recent MI or unstable angina.42 It showed only modest differences in reductions in depressive symptoms between sertraline recipients and placebo recipients, and it lacked statistical power to examine the impact of treatment on hard clinical end points.

ENRICHD (Enhancing Recovery in Coronary Heart Disease Patients) assessed the effect of psychosocial treatment on survival among more than than 2,400 post-MI patients.43 Although this trial found that cognitive behavior therapy resulted in significant, albeit small, improvements in depressive symptoms compared with usual care, it failed to demonstrate that treating depression and low social support was associated with increased survival.

CREATE (Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy), a recent placebo-controlled trial, assessed the value of antidepressant medication and clinical management in patients with CHD.44 The study’s 284 patients, all of whom had CHD as well as MDD and a HAM-D score of 20 or greater, underwent two separate randomizations: (1) to 12 weeks of interpersonal therapy plus clinical management or 12 weeks of clinical management alone, and (2) to 12 weeks of citalopram therapy or matching placebo. There was no difference between interpersonal therapy and clinical management alone; however, citalopram was superior to placebo in reducing HAM-D scores and demonstrated better remission rates (35.9% with citalopram vs 22.5% with placebo). The same therapists who provided interpersonal therapy also performed the clinical management, so it could be argued that this was why additional interpersonal therapist time did not result in greater reductions in depressive symptoms than did clinical management alone. Furthermore, this study did not examine the effects of depression therapy on clinical outcomes.

EXERCISE AS A TREATMENT FOR DEPRESSION

There is growing evidence that exercise may be an effective treatment for depression.45 Most of the existing studies of exercise for depression have focused on aerobic exercise.

In the relatively large SMILE study (Standard Medical Intervention and Long-term Exercise),46 conducted at Duke University, 156 adult noncardiac patients with MDD were randomized to 4 months of treatment with supervised aerobic exercise, antidepressant medication (sertraline), or a combination of exercise and medication. Although antidepressant medication was associated with faster reductions in depression in the first 4 weeks of treatment among mildly depressed patients, exercise was as effective as antidepressant medication in treating depression by the end of the 16-week intervention for all participants.

Reprinted, with permission, from Babyak MA, et al. Exercise treatment for major depression: maintenance of therapeutic benefit at 10 months. Psychosom Med 2000; 62:633–638.
Figure 3. Clinical status at 10 months (6 months after end of treatment) among 83 patients who achieved remission from major depressive disorder following 4 months of treatment in the SMILE study,46 according to the three treatment groups. Compared with participants in the other treatment groups, those in the exercise group were more likely to remain fully or partially recovered and less likely to have relapsed.47
Six-month follow-up among patients from the SMILE study who had achieved remission revealed that those who had been randomized to exercise were less likely to have relapsed than those randomized to the medication or combination-therapy groups (Figure 3).47 Moreover, across the entire follow-up population, those patients who reportedly engaged in regular aerobic exercise during the 6-month follow-up period were only half as likely to have relapsed compared with those who did not engage in regular exercise.

Exercise generally is considered safe for most patients with stable CHD.48 Some studies of exercise treatments for patients with CHD have tracked depressive symptoms and thus have provided insight into the potential efficacy of exercise as a treatment for depression in this population. Although most of these studies have reported significant improvements in depression after completion of an exercise program, many have had important methodologic limitations, including absence of a control group. In one of the few controlled studies in this area, Stern et al49 randomized 106 men who had a recent acute MI and elevated depression, anxiety, or low fitness to 12 weeks of exercise training, group therapy, or usual care (control). At 1-year follow-up, subjects in both the exercise and counseling groups showed improvements in depression relative to controls.

EFFECT OF EXERCISE ON CARDIOVASCULAR RISK FACTORS AND OUTCOMES

Exercise is a particularly promising intervention for depression in patients with CHD because it has well-documented cardiovascular benefits. In addition to the well-established role of exercise interventions in primary prevention, such interventions have been shown to improve outcomes for patients with CHD.50

Jolliffe et al conducted a meta-analysis comparing exercise-only interventions, comprehensive rehabilitation (including educational and behavioral components such as dietary changes and stress reduction in addition to exercise), and usual care.51 Exercise-only interventions were associated with reductions in both all-cause and cardiac mortality relative to usual care. Comprehensive rehabilitation, on the other hand, was not associated with statistically significant reductions in all-cause mortality relative to usual care, but it was associated with a decreased risk for cardiac mortality, to a slightly lesser extent than exercise-only interventions.

Reprinted, with permission, from Blumenthal JA, et al. Exercise, depression, and mortality after myocardial infarction in the ENRICHD trial. Med Sci Sports Exerc 2004; 36:746–755.
Figure 4. Predicted survival functions for patients who did (n = 952) and did not (n = 1,096) exercise regularly during the 6 months following an index myocardial infarction in the ENRICHD trial. There were a total of 187 fatal events; the mortality rate was 5.7% among the exercisers compared with 12.0% among the nonexercisers.52
Recent data from the ENRICHD trial suggest that exercise may reduce rates of death and recurrent nonfatal infarction in post-MI patients with depression or low levels of social support.52 Self-reported data were used to categorize participants as exercising regularly or not exercising regularly. After adjustment for medical and demographic variables, regular excercise was found to be associated with a nearly 40% reduction in the risk of death and a nearly 30% reduction in the risk of recurrent nonfatal infarction. Figure 4 depicts the Kaplan-Meier survival curves for patients who did and did not exercise regularly.

The evidence that exercise affects depression, CHD risk factors, and CHD outcomes suggests that exercise is a particularly promising intervention for depression in this population.

UPBEAT trial promises further insight

A new Duke University study known as UPBEAT (Understanding Prognostic Benefits of Exercise and Antidepressant Treatment) is randomizing 200 patients with elevated depressive symptoms to exercise, antidepressant therapy (sertraline), or placebo for 4 months.53 A variety of “biomarkers” of risk are being assessed, including measures of heart rate variability, vascular function, inflammation, and platelet aggregation. Results of this 5-year trial should be available by 2011.

 

 

CONCLUSIONS

Although depression has emerged as an important risk factor for CHD, there is no consensus on the optimal way to treat depression in patients with CHD. Interventions that are guided by an understanding of the mechanisms linking depression to CHD may prove to be most effective in improving both depression and physical health outcomes.

Exercise targets many of the mechanisms by which depression may be associated with increased risk, including autonomic nervous system activity, hypothalamic-pituitary-adrenal axis function, platelet activation, vascular function, and inflammation. Moreover, a growing body of evidence suggests that exercise is an effective treatment for depression that may be comparable in effect to antidepressant medication, at least in select subgroups (eg, patients who are receptive to exercise as a treatment for depression). The value of exercise training—not only for improving quality of life, but also for improving “biomarkers” of risk and other relevant health outcomes—is the focus of our current research efforts.

Depression refers to an emotional condition ranging from a transient negative mood state of sadness or mild dysphoria to a chronic and severe psychiatric illness. The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) identifies two depressive disorders: major depressive disorder (MDD) and dysthymic disorder.1 The essential feature of MDD is a clinical course characterized by one or more major depressive episode (whose diagnostic criteria are presented in Table 1) without a history of manic, mixed, or hypomanic episodes. The diagnosis requires the presence of a total of at least five symptoms over a period of at least 2 weeks, which must include either depressed mood or loss of interest or pleasure. Dysthymic disorder is marked by mild depressive symptoms that are more chronic in nature, lasting at least 2 years.1

Minor depressive disorder (mDD) is not an official DSM-IV diagnosis but is used for research purposes; it is similar to MDD in duration but requires that only two to four symptoms be present.

EPIDEMIOLOGY OF DEPRESSION

Depression is a widespread and often chronic condition. Lifetime prevalence estimates for MDD are approximately 15% to 20%;2,3 1-year prevalence estimates are 5% to 10%;2,4 and point prevalence estimates range from 4% to 7%.3,5 Moreover, MDD is characterized by high rates of relapse: 22% to 50% of patients suffer recurrent episodes within 6 months after recovery.6

Women are twice as likely as men to be diagnosed with MDD, with lifetime prevalence rates of 10% to 25% in women versus 5% to 12% in men.1

Although rates of depression do not appear to increase with age, MDD often goes undertreated in older adults3 and in cardiac patients.7

DIAGNOSING AND ASSESSING DEPRESSION

The gold standard for diagnosing MDD is a clinical interview. Commonly used instruments include the Diagnostic Interview Schedule8 and the Composite International Diagnostic Interview.9 The Structured Clinical Interview for DSM-IV Axis I Disorders10 and the Schedule for Affective Disorders and Schizophrenia11 are frequently used semistructured interviews.

The most common clinical instruments for assessing the severity of depressive symptoms are the Hamilton Rating Scale for Depression (HAM-D),12 which is a clinician-rated scale, and various psychometric questionnaires, including the Beck Depression Inventory (BDI)13,14 and the Center for Epidemiological Studies Depression Scale (CES-D).15

THE DEPRESSION–HEART DISEASE LINK

Depression as a primary risk factor

Reprinted from Rozanski A, et al. The epidemiology, pathophysiology, and management of psychosocial risk factors in cardiac practice: the emerging field of behavioral cardiology. J Am Coll Cardiol 2005; 45:637–651, © 2005, with permission from the ACC.
Figure 1. Risk ratios of traditional risk factors for coronary heart disease (CHD) observed in the Framingham study as compared with risk ratios of depressive symptoms and depressed mood as derived from the recent meta-analysis by Rugulies.17 The risk of CHD conferred by depressive symptoms is comparable to that conferred by traditional risk factors, and the presence of clinical depression appears to raise this risk. For traditional risk factors, risk ratios were calculated for cardiac death, myocardial infarction, coronary artery insufficiency, and angina. For depressed mood and clinical depression, risk ratios were calculated for cardiac disease and myocardial infarction.18
Evidence that depression is a primary risk factor for coronary heart disease (CHD) in healthy individuals has been reviewed previously.16 A recent meta-analysis of 11 prospective cohort studies of initially healthy individuals indicated that depression (either depressive mood or clinical MDD) conferred a relative risk of 1.64 for adverse cardiac events, including myocardial infarction (MI) and cardiac death; the presence of MDD was associated with the greatest risk (relative risk of 2.69).17Figure 1 shows that clinical depression is comparable to traditional risk factors for CHD, such as smoking and elevated blood lipid levels, as observed in the Framingham study.18

Depression as a secondary risk factor

Depression is an even stronger risk factor for cardiac events in patients with established CHD. Point estimates range from 14% to as high as 47%, with higher rates in patients with unstable angina and in patients awaiting coronary artery bypass graft (CABG) surgery; an additional 20% of patients exhibit elevated depressive symptoms or minor depression (mDD).19–25

Prospective studies have shown that depression increases the risk for death or nonfatal cardiac events approximately 2.5-fold in patients with CHD. For instance, Frasure-Smith et al followed 896 patients with a recent acute MI and found that the presence of depressive symptoms as indicated by an elevated BDI score was a significant predictor of cardiac mortality after controlling for multivariate predictors of mortality (odds ratio [OR] = 3.29 for women and 3.05 for men).26

Two recent meta-analyses confirmed the association between depression and adverse clinical outcomes in patients with CHD.27,28 For example, van Melle et al reported that post-MI depression was associated with a 2- to 2.5-fold increase in the risk of adverse health outcomes.28 In this analysis, depression’s effect on cardiac mortality and all-cause mortality was especially pronounced in older studies (before 1992) (OR = 3.2) compared with more recent studies (after 1992) (OR = 2.01).28

Duke University researchers have conducted several prospective studies in various cardiac populations.29–31 Barefoot et al assessed 1,250 patients with documented CHD using the Zung Self-Rating Depression Scale at the time of diagnostic coronary angiography and followed them for up to 19.4 years.29 Results showed that patients with moderate to severe depression were at 69% greater risk for cardiac death and 78% greater risk for all-cause death than were their nondepressed counterparts.

Reprinted from The Lancet (Blumenthal JA, et al. Depression as a risk factor for mortality after coronary artery bypass surgery. Lancet 2003; 362:604–609.), copyright 2003, with permission from Elsevier.
Figure 2. Kaplan-Meier survival curves for all-cause mortality among coronary surgery patients according to their presurgery (baseline) depressive symptoms as measured by the Center for Epidemiological Studies Depression Scale (CES-D). Compared with the absence of depressive symptoms, the presence of moderate to severe symptoms was associated with a hazard ratio of 2.4 (95% CI = 1.40 to 4.00; P = .001) for all-cause mortality. Mild symptoms were associated with no difference in risk relative to the absence of symptoms (hazard ratio = 1.08, 95% CI = 0.70 to 1.67; P = .723).30
In a prospective study of patients undergoing CABG surgery, we assessed the effect of depression on mortality in 817 patients followed for up to 12 years (mean, 5.2 years).30 Using the CES-D instrument, patients were categorized on the day before surgery as having either no depression (CES-D score < 16), mild depression (score of 16 to 26), or moderate to severe depression (score ≥ 27). We found that moderate to severe depression was independently associated with a twofold to threefold increase in the risk of death, even after controlling for age, gender, number of grafts, diabetes, smoking, left ventricular ejection fraction, and history of acute MI (Figure 2). Moreover, patients who exhibited persistent depression, with CES-D scores of 16 or greater at baseline and after 6 months, had more than a doubling in risk relative to patients who were never depressed.

We also recently reported results from a prospective study that followed 204 patients with heart failure over a median interval of 3 years.31 Clinically significant symptoms of depression (BDI score ≥ 10) were associated with a hazard ratio of 1.56 (95% CI, 1.07 to 2.29) for the combined end point of death or cardiovascular hospitalization. These observations included adjustment for plasma NT-proBNP level, ejection fraction, and other established risk factors, suggesting that heightened risk of adverse clinical outcomes associated with depressive symptoms is not simply a reflection of the severity of heart failure.

In summary, a number of observational studies have demonstrated that depression is associated with increased risk of morbidity and mortality both in healthy populations and in a variety of populations with established cardiac disease.

BIOBEHAVIORAL MECHANISMS LINKING DEPRESSION AND CHD

A number of biobehavioral mechanisms have been hypothesized to underlie the relationship between depression and CHD. Most evidence is derived from cross-sectional studies and suggests that depression is associated with traditional risk factors for CHD, such as hypertension, diabetes, and insulin resistance,32,33 as well as changes in platelet reactivity,34 dysregulation of the autonomic nervous system35 and hypothalamic-pituitary-adrenal axis,36 and alterations in the immune response/inflammation.37 Depression is also associated with behavioral factors that are in turn associated with CHD risk, such as reduced treatment adherence,38 smoking,39 and physical inactivity.40

 

 

STUDIES OF DEPRESSION TREATMENT IN CARDIAC PATIENTS

Successful treatments for depression in patients with CHD may have the potential to improve not only quality of life but also cardiovascular and physical health. Several treatments for depression exist for use in the general population, such as antidepressant medication or psychotherapy.41 However, only three studies have tested the efficacy of these treatments in patients with CHD: SADHART, ENRICHD, and CREATE.42–44

SADHART (Sertraline Antidepressant Heart Attack Randomized Trial) was a safety and efficacy evaluation of antidepressant medication in patients with MDD and a recent MI or unstable angina.42 It showed only modest differences in reductions in depressive symptoms between sertraline recipients and placebo recipients, and it lacked statistical power to examine the impact of treatment on hard clinical end points.

ENRICHD (Enhancing Recovery in Coronary Heart Disease Patients) assessed the effect of psychosocial treatment on survival among more than than 2,400 post-MI patients.43 Although this trial found that cognitive behavior therapy resulted in significant, albeit small, improvements in depressive symptoms compared with usual care, it failed to demonstrate that treating depression and low social support was associated with increased survival.

CREATE (Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy), a recent placebo-controlled trial, assessed the value of antidepressant medication and clinical management in patients with CHD.44 The study’s 284 patients, all of whom had CHD as well as MDD and a HAM-D score of 20 or greater, underwent two separate randomizations: (1) to 12 weeks of interpersonal therapy plus clinical management or 12 weeks of clinical management alone, and (2) to 12 weeks of citalopram therapy or matching placebo. There was no difference between interpersonal therapy and clinical management alone; however, citalopram was superior to placebo in reducing HAM-D scores and demonstrated better remission rates (35.9% with citalopram vs 22.5% with placebo). The same therapists who provided interpersonal therapy also performed the clinical management, so it could be argued that this was why additional interpersonal therapist time did not result in greater reductions in depressive symptoms than did clinical management alone. Furthermore, this study did not examine the effects of depression therapy on clinical outcomes.

EXERCISE AS A TREATMENT FOR DEPRESSION

There is growing evidence that exercise may be an effective treatment for depression.45 Most of the existing studies of exercise for depression have focused on aerobic exercise.

In the relatively large SMILE study (Standard Medical Intervention and Long-term Exercise),46 conducted at Duke University, 156 adult noncardiac patients with MDD were randomized to 4 months of treatment with supervised aerobic exercise, antidepressant medication (sertraline), or a combination of exercise and medication. Although antidepressant medication was associated with faster reductions in depression in the first 4 weeks of treatment among mildly depressed patients, exercise was as effective as antidepressant medication in treating depression by the end of the 16-week intervention for all participants.

Reprinted, with permission, from Babyak MA, et al. Exercise treatment for major depression: maintenance of therapeutic benefit at 10 months. Psychosom Med 2000; 62:633–638.
Figure 3. Clinical status at 10 months (6 months after end of treatment) among 83 patients who achieved remission from major depressive disorder following 4 months of treatment in the SMILE study,46 according to the three treatment groups. Compared with participants in the other treatment groups, those in the exercise group were more likely to remain fully or partially recovered and less likely to have relapsed.47
Six-month follow-up among patients from the SMILE study who had achieved remission revealed that those who had been randomized to exercise were less likely to have relapsed than those randomized to the medication or combination-therapy groups (Figure 3).47 Moreover, across the entire follow-up population, those patients who reportedly engaged in regular aerobic exercise during the 6-month follow-up period were only half as likely to have relapsed compared with those who did not engage in regular exercise.

Exercise generally is considered safe for most patients with stable CHD.48 Some studies of exercise treatments for patients with CHD have tracked depressive symptoms and thus have provided insight into the potential efficacy of exercise as a treatment for depression in this population. Although most of these studies have reported significant improvements in depression after completion of an exercise program, many have had important methodologic limitations, including absence of a control group. In one of the few controlled studies in this area, Stern et al49 randomized 106 men who had a recent acute MI and elevated depression, anxiety, or low fitness to 12 weeks of exercise training, group therapy, or usual care (control). At 1-year follow-up, subjects in both the exercise and counseling groups showed improvements in depression relative to controls.

EFFECT OF EXERCISE ON CARDIOVASCULAR RISK FACTORS AND OUTCOMES

Exercise is a particularly promising intervention for depression in patients with CHD because it has well-documented cardiovascular benefits. In addition to the well-established role of exercise interventions in primary prevention, such interventions have been shown to improve outcomes for patients with CHD.50

Jolliffe et al conducted a meta-analysis comparing exercise-only interventions, comprehensive rehabilitation (including educational and behavioral components such as dietary changes and stress reduction in addition to exercise), and usual care.51 Exercise-only interventions were associated with reductions in both all-cause and cardiac mortality relative to usual care. Comprehensive rehabilitation, on the other hand, was not associated with statistically significant reductions in all-cause mortality relative to usual care, but it was associated with a decreased risk for cardiac mortality, to a slightly lesser extent than exercise-only interventions.

Reprinted, with permission, from Blumenthal JA, et al. Exercise, depression, and mortality after myocardial infarction in the ENRICHD trial. Med Sci Sports Exerc 2004; 36:746–755.
Figure 4. Predicted survival functions for patients who did (n = 952) and did not (n = 1,096) exercise regularly during the 6 months following an index myocardial infarction in the ENRICHD trial. There were a total of 187 fatal events; the mortality rate was 5.7% among the exercisers compared with 12.0% among the nonexercisers.52
Recent data from the ENRICHD trial suggest that exercise may reduce rates of death and recurrent nonfatal infarction in post-MI patients with depression or low levels of social support.52 Self-reported data were used to categorize participants as exercising regularly or not exercising regularly. After adjustment for medical and demographic variables, regular excercise was found to be associated with a nearly 40% reduction in the risk of death and a nearly 30% reduction in the risk of recurrent nonfatal infarction. Figure 4 depicts the Kaplan-Meier survival curves for patients who did and did not exercise regularly.

The evidence that exercise affects depression, CHD risk factors, and CHD outcomes suggests that exercise is a particularly promising intervention for depression in this population.

UPBEAT trial promises further insight

A new Duke University study known as UPBEAT (Understanding Prognostic Benefits of Exercise and Antidepressant Treatment) is randomizing 200 patients with elevated depressive symptoms to exercise, antidepressant therapy (sertraline), or placebo for 4 months.53 A variety of “biomarkers” of risk are being assessed, including measures of heart rate variability, vascular function, inflammation, and platelet aggregation. Results of this 5-year trial should be available by 2011.

 

 

CONCLUSIONS

Although depression has emerged as an important risk factor for CHD, there is no consensus on the optimal way to treat depression in patients with CHD. Interventions that are guided by an understanding of the mechanisms linking depression to CHD may prove to be most effective in improving both depression and physical health outcomes.

Exercise targets many of the mechanisms by which depression may be associated with increased risk, including autonomic nervous system activity, hypothalamic-pituitary-adrenal axis function, platelet activation, vascular function, and inflammation. Moreover, a growing body of evidence suggests that exercise is an effective treatment for depression that may be comparable in effect to antidepressant medication, at least in select subgroups (eg, patients who are receptive to exercise as a treatment for depression). The value of exercise training—not only for improving quality of life, but also for improving “biomarkers” of risk and other relevant health outcomes—is the focus of our current research efforts.

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  34. Musselman DL, Tomer A, Manatunga AK, et al. Exaggerated platelet reactivity in major depression. Am J Psychiatry 1996; 153:1313–1317.
  35. Delgado PL, Moreno FA. Role of norepinephrine in depression. J Clin Psychiatry 2000; 61:5–12.
  36. Akil H, Haskett RF, Young EA, et al. Multiple HPA profiles in endogenous depression: effect of age and sex on cortisol and beta-endorphin. Biol Psychiatry 1993; 33:73–85.
  37. Kop WJ, Gottdiener JS, Tangen CM, et al. Inflammation and coagulation factors in persons > 65 years of age with symptoms of depression but without evidence of myocardial ischemia. Am J Cardiol 2002; 89:419–424.
  38. Carney RM, Freedland KE, Eisen SA, Rich MW, Jaffe AS. Major depression and medication adherence in elderly patients with coronary artery disease. Health Psychol 1995; 14:88–90.
  39. Lehto S, Koukkunen H, Hintikka J, Viinamaki H, Laakso M, Pyorala K. Depression after coronary heart disease events. Scand Cardiovasc J 2000; 34:580–583.
  40. Camacho TC, Roberts RE, Lazarus NB, Kaplan GA, Cohen RD. Physical activity and depression: evidence from the Alameda County Study. Am J Epidemiol 1991; 134:220–231.
  41. Depression Guideline Panel. Depression in Primary Care: Volume 2. Treatment of Depression, Clinical Practice Guideline, No. 5. Rockville, MD: Agency for Health Care Policy and Research, Public Health Service, US Dept of Health and Human Services; 1993.
  42. Glassman AH, O’Connor CM, Califf RM, et al. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA 2002; 288:701–709.
  43. Berkman LF, Blumenthal J, Burg M, et al. Effects of treating depression and low perceived social support on clinical events after myocardial infarction: the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) randomized trial. JAMA 2003; 289:3106–3116.
  44. Lesperance F, Frasure-Smith N, Koszycki D, et al. Effects of citalopram and interpersonal psychotherapy on depression in patients with coronary artery disease: the Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) trial. JAMA 2007; 297:367–379.
  45. Brosse AL, Sheets ES, Lett HS, Blumenthal JA. Exercise and the treatment of clinical depression in adults: recent findings and future directions. Sports Med 2002; 32:741–760.
  46. Blumenthal JA, Babyak MA, Moore KA, et al. Effects of exercise training on older patients with major depression. Arch Intern Med 1999; 159:2349–2356.
  47. Babyak M, Blumenthal JA, Herman S, et al. Exercise treatment for major depression: maintenance of therapeutic benefit at 10 months. Psychosom Med 2000; 62:633–638.
  48. Franklin BA, Bonzheim K, Gordon S, Timmis GC. Safety of medically supervised outpatient cardiac rehabilitation exercise therapy: a 16-year follow-up. Chest 1998; 114:902–906.
  49. Stern MJ, Gorman PA, Kaslow L. The group counseling v exercise therapy study. A controlled intervention with subjects following myocardial infarction. Arch Intern Med 1983; 143:1719–1725.
  50. Oldridge NB, Guyatt GH, Fischer ME, Rimm AA. Cardiac rehabilitation after myocardial infarction. Combined experience of randomized clinical trials. JAMA 1988; 260:945–950.
  51. Jolliffe JA, Rees K, Taylor RS, Thompson D, Oldridge N, Ebrahim S. Exercise-based rehabilitation for coronary heart disease. Cochrane Database Syst Rev 2001; (1):CD001800.
  52. Blumenthal JA, Babyak MA, Carney RM, et al. Exercise, depression, and mortality after myocardial infarction in the ENRICHD trial. Med Sci Sports Exerc 2004; 36:746–755.
  53. Blumenthal JA, Sherwood A, Rogers SD, et al. Understanding prognostic benefits of exercise and antidepressant therapy for persons with depression and heart disease: the UPBEAT study—rationale, design, and methodological issues. Clin Trials 2007; 4:548–559.
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  35. Delgado PL, Moreno FA. Role of norepinephrine in depression. J Clin Psychiatry 2000; 61:5–12.
  36. Akil H, Haskett RF, Young EA, et al. Multiple HPA profiles in endogenous depression: effect of age and sex on cortisol and beta-endorphin. Biol Psychiatry 1993; 33:73–85.
  37. Kop WJ, Gottdiener JS, Tangen CM, et al. Inflammation and coagulation factors in persons > 65 years of age with symptoms of depression but without evidence of myocardial ischemia. Am J Cardiol 2002; 89:419–424.
  38. Carney RM, Freedland KE, Eisen SA, Rich MW, Jaffe AS. Major depression and medication adherence in elderly patients with coronary artery disease. Health Psychol 1995; 14:88–90.
  39. Lehto S, Koukkunen H, Hintikka J, Viinamaki H, Laakso M, Pyorala K. Depression after coronary heart disease events. Scand Cardiovasc J 2000; 34:580–583.
  40. Camacho TC, Roberts RE, Lazarus NB, Kaplan GA, Cohen RD. Physical activity and depression: evidence from the Alameda County Study. Am J Epidemiol 1991; 134:220–231.
  41. Depression Guideline Panel. Depression in Primary Care: Volume 2. Treatment of Depression, Clinical Practice Guideline, No. 5. Rockville, MD: Agency for Health Care Policy and Research, Public Health Service, US Dept of Health and Human Services; 1993.
  42. Glassman AH, O’Connor CM, Califf RM, et al. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA 2002; 288:701–709.
  43. Berkman LF, Blumenthal J, Burg M, et al. Effects of treating depression and low perceived social support on clinical events after myocardial infarction: the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) randomized trial. JAMA 2003; 289:3106–3116.
  44. Lesperance F, Frasure-Smith N, Koszycki D, et al. Effects of citalopram and interpersonal psychotherapy on depression in patients with coronary artery disease: the Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) trial. JAMA 2007; 297:367–379.
  45. Brosse AL, Sheets ES, Lett HS, Blumenthal JA. Exercise and the treatment of clinical depression in adults: recent findings and future directions. Sports Med 2002; 32:741–760.
  46. Blumenthal JA, Babyak MA, Moore KA, et al. Effects of exercise training on older patients with major depression. Arch Intern Med 1999; 159:2349–2356.
  47. Babyak M, Blumenthal JA, Herman S, et al. Exercise treatment for major depression: maintenance of therapeutic benefit at 10 months. Psychosom Med 2000; 62:633–638.
  48. Franklin BA, Bonzheim K, Gordon S, Timmis GC. Safety of medically supervised outpatient cardiac rehabilitation exercise therapy: a 16-year follow-up. Chest 1998; 114:902–906.
  49. Stern MJ, Gorman PA, Kaslow L. The group counseling v exercise therapy study. A controlled intervention with subjects following myocardial infarction. Arch Intern Med 1983; 143:1719–1725.
  50. Oldridge NB, Guyatt GH, Fischer ME, Rimm AA. Cardiac rehabilitation after myocardial infarction. Combined experience of randomized clinical trials. JAMA 1988; 260:945–950.
  51. Jolliffe JA, Rees K, Taylor RS, Thompson D, Oldridge N, Ebrahim S. Exercise-based rehabilitation for coronary heart disease. Cochrane Database Syst Rev 2001; (1):CD001800.
  52. Blumenthal JA, Babyak MA, Carney RM, et al. Exercise, depression, and mortality after myocardial infarction in the ENRICHD trial. Med Sci Sports Exerc 2004; 36:746–755.
  53. Blumenthal JA, Sherwood A, Rogers SD, et al. Understanding prognostic benefits of exercise and antidepressant therapy for persons with depression and heart disease: the UPBEAT study—rationale, design, and methodological issues. Clin Trials 2007; 4:548–559.
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Depression and coronary heart disease: Association and implications for treatment
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