A randomized controlled trial of the effect of hostility reduction on cardiac autonomic regulation

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A randomized controlled trial of the effect of hostility reduction on cardiac autonomic regulation
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Richard P. Sloan, PhD
Peter A. Shapiro, MD
Ethan E. Gorenstein, PhD
Felice A. Tager, PhD
Catherine E. Monk, PhD
Paula S. McKinley, PhD
Michael M. Myers, PhD
Emilia Bagiella, PhD
Ivy Chen, MST
Richard Steinman, BA
J. Thomas Bigger, MD
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Richard P. Sloan, PhD
Department of Psychiatry, Columbia University, New York, NY

Peter A. Shapiro, MD
Department of Psychiatry, Columbia University, New York, NY

Ethan E. Gorenstein, PhD
Department of Psychiatry, Columbia University, New York, NY

Felice A. Tager, PhD
Department of Psychiatry, Columbia University, New York, NY

Catherine E. Monk, PhD
Department of Psychiatry, Columbia University, New York, NY

Paula S. McKinley, PhD
Department of Psychiatry, Columbia University, New York, NY

Michael M. Myers, PhD
Department of Psychiatry, Columbia University, New York, NY

Emilia Bagiella, PhD
Mailman School of Public Health, Columbia University, New York, NY

Ivy Chen, MST
Mailman School of Public Health, Columbia University, New York, NY

Richard Steinman, BA
Department of Medicine, Columbia University, New York, NY

J. Thomas Bigger, MD
Department of Medicine, Columbia University, New York, NY

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Richard P. Sloan, PhD
Peter A. Shapiro, MD
Ethan E. Gorenstein, PhD
Felice A. Tager, PhD
Catherine E. Monk, PhD
Paula S. McKinley, PhD
Michael M. Myers, PhD
Emilia Bagiella, PhD
Ivy Chen, MST
Richard Steinman, BA
J. Thomas Bigger, MD
Author(s)
Richard P. Sloan, PhD
Peter A. Shapiro, MD
Ethan E. Gorenstein, PhD
Felice A. Tager, PhD
Catherine E. Monk, PhD
Paula S. McKinley, PhD
Michael M. Myers, PhD
Emilia Bagiella, PhD
Ivy Chen, MST
Richard Steinman, BA
J. Thomas Bigger, MD
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Richard P. Sloan, PhD
Department of Psychiatry, Columbia University, New York, NY

Peter A. Shapiro, MD
Department of Psychiatry, Columbia University, New York, NY

Ethan E. Gorenstein, PhD
Department of Psychiatry, Columbia University, New York, NY

Felice A. Tager, PhD
Department of Psychiatry, Columbia University, New York, NY

Catherine E. Monk, PhD
Department of Psychiatry, Columbia University, New York, NY

Paula S. McKinley, PhD
Department of Psychiatry, Columbia University, New York, NY

Michael M. Myers, PhD
Department of Psychiatry, Columbia University, New York, NY

Emilia Bagiella, PhD
Mailman School of Public Health, Columbia University, New York, NY

Ivy Chen, MST
Mailman School of Public Health, Columbia University, New York, NY

Richard Steinman, BA
Department of Medicine, Columbia University, New York, NY

J. Thomas Bigger, MD
Department of Medicine, Columbia University, New York, NY

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Richard P. Sloan, PhD
Department of Psychiatry, Columbia University, New York, NY

Peter A. Shapiro, MD
Department of Psychiatry, Columbia University, New York, NY

Ethan E. Gorenstein, PhD
Department of Psychiatry, Columbia University, New York, NY

Felice A. Tager, PhD
Department of Psychiatry, Columbia University, New York, NY

Catherine E. Monk, PhD
Department of Psychiatry, Columbia University, New York, NY

Paula S. McKinley, PhD
Department of Psychiatry, Columbia University, New York, NY

Michael M. Myers, PhD
Department of Psychiatry, Columbia University, New York, NY

Emilia Bagiella, PhD
Mailman School of Public Health, Columbia University, New York, NY

Ivy Chen, MST
Mailman School of Public Health, Columbia University, New York, NY

Richard Steinman, BA
Department of Medicine, Columbia University, New York, NY

J. Thomas Bigger, MD
Department of Medicine, Columbia University, New York, NY

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A randomized controlled trial of the effect of hostility reduction on cardiac autonomic regulation
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Depression in coronary artery disease: Does treatment help?

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Depression in coronary artery disease: Does treatment help?
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Peter A. Shapiro, MD

Depression’s association with incident coronary artery disease (CAD) and recurrent cardiac events became established 10 to 20 years ago. Efforts in the past decade have focused on the specific effects of treating depression in patients with CAD—whether such treatment is beneficial and, if so, exactly how it exerts its benefits. This article briefly surveys the current evidence on these questions after reviewing how we got interested in depression in CAD in the first place.

THE EMERGENCE OF DEPRESSION AS A CARDIAC RISK FACTOR

The shift from a focus on Type A behavior

Not long ago, Type A behavior pattern was the psychosocial variable of greatest research interest as a contributor to CAD. Just 26 years ago, a National Institutes of Health consensus development conference anointed Type A behavior pattern as a CAD risk factor.1 Five years later, one of the landmark studies in psychosomatic medicine—the Recurrent Coronary Prevention Project—showed that Type A behavior modification, added to usual cardiac care in post–myocardial infarction (MI) patients, not only reduced patients’ Type A behavior but also reduced the rate of reinfarction and death.2

But that was the high-water mark for Type A behavior in CAD research. The focus soon shifted, especially after the publication of a 1987 review by Booth-Kewley and Friedman showing that larger and later studies found less and less impressive effects of Type A on cardiac outcomes.3 This same review pointed out the cumulative evidence indicating that depression might be the most important psychological factor associated with coronary disease.3

An explosion of research on depression in CAD

In the 10 years following the review by Booth-Kewley and Friedman, there was an explosion of study about depression in CAD.4 This resulted in what is fair to call a consensus on several key points about this relationship:

  • Depression is associated with an approximate 1.5-­fold to twofold increase in the risk for incident CAD.5–8
  • Depression is associated with about a threefold to fourfold increase in the risk of recurrent cardiac events and death in patients with CAD, including patients with a new diagnosis, those with acute coronary events, and those who have undergone revascularization procedures.9–13
  • Several biobehavioral mechanisms are plausible candidates as mediators of the mind-body relationship linking depression and coronary disease. These include abnormal platelet function, autonomic function, inflammatory processes, and nonadherence to therapy.4,14
  • Depression is extremely common in CAD, affecting about 15% to 20% of patients, and is a serious illness in its own right, even apart from its effects on cardiac outcomes.9–11,15–17

In light of these observations, the obvious research questions are whether treating depression in patients with CAD helps, and if so, what it helps with—the depression itself, the pathophysiology and outcomes of CAD, or both. These questions have been the increasing focus of the past 10 years.

DOES DEPRESSION THERAPY IN CAD PATIENTS IMPROVE DEPRESSION IN THESE PATIENTS?

The short answer to this question is an almost unqualified yes. Even setting aside the literature on tricyclic antidepressants (which is an old literature but impressive in its own right in its systematic working through of issues of efficacy and the delineation and management of adverse effects18–25), we have at least half a dozen studies showing that depression treatment helps to relieve depression in patients with CAD with reasonable safety and efficacy. Some are open-label, small-scale studies, while others are more rigorously designed and controlled, but the overall conclusion is unambiguous.26–34

Roose, Glassman, and colleagues were among the first to describe the effects of antidepressants other than tricyclics in cardiac patients.26–29 They demonstrated the safety profile of bupropion, but did not report on its efficacy.26 They demonstrated safety but found rather low efficacy of fluoxetine in doses up to 60 mg/day in markedly depressed inpatients, many of whom had a “melancholic” profile (early-morning waking, positive diurnal mood variation, guilt, anhedonia, poor appetite).27,28 In a randomized double-blind trial, these same researchers subsequently demonstrated paroxetine to be at least as effective as the tricyclic agent nortriptyline and to have excellent tolerability at doses up to 40 mg/day.29

Strik et al published an early study of the efficacy of depression treatment in 54 patients with major depression after a first MI.30 Fluoxetine demonstrated superiority over placebo with respect to the percentage of patients achieving a clinical response (48% vs 26%; P = .05) (clinical response was defined as a ≥ 50% reduction in the Hamilton Depression Rating Scale [HAM-D] score), but fluoxetine did not have a statistically significant effect on HAM-D symptom ratings except in the subset of patients with mild symptoms to start with. This is somewhat counterintuitive, and to be contrasted with the results of SADHART.

The Sertraline Antidepressant Heart Attack Randomized Trial (SADHART), conducted in depressed patients following MI or unstable angina, is well known.31,32 Patients with a recent acute coronary syndrome (acute MI in 74%; unstable angina in 26%) were randomized within 30 days of the coronary event to sertraline or placebo (following a 2-week placebo run-in period for all patients). Sertraline was associated with superior scores on the Clinical Global Impression Improvement Scale, particularly among patients with recurrent depression and more severe depression, but its effect on HAM-D scores was not significantly better than that of placebo. As opposed to the finding of Strik et al, the biggest difference in response was among patients with more severe depression symptoms rather than those with mild symptoms to begin with.

The Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) trial tested the hypothesis that psychosocial intervention aimed at depression and low levels of social support would improve cardiac prognosis in post-MI patients.33 In this large randomized study (N = 2,481), cognitive behavior therapy exerted a modestly significant effect in reducing symptoms of depression as compared with usual medical care. Most patients in the intervention arm underwent 6 to 10 sessions of individual and/or group therapy over 6 months, and their HAM-D scores improved by approximately 10 points from baseline to 6-month follow-up. However, patients in the usual-care arm also had substantial improvements (almost 9 points) in HAM-D scores at 6-month follow-up.

The Canadian Cardiac Randomized Evalution of Antidepressant and Psychotherapy Efficacy (CREATE) used a 2 x 2 factorial design to assess interpersonal psychotherapy and antidepressant therapy (citalopram) for depression in patients with stable CAD.34 Citalopram was more effective than placebo in reducing depression symptoms and in achieving response and remission. The mean decline in HAM-D scores was more than 3 points greater in citalopram recipients than in placebo recipients. Interpersonal psychotherapy was no more effective than clinical management.

In none of the studies reviewed above was the benefit of active treatment very powerful—response rates were between 50% and 60%, and remission rates were much lower.

 

 

DOES DEPRESSION THERAPY IN CAD PATIENTS IMPROVE CAD OUTCOMES?

In the ENRICHD trial, cognitive behavior therapy–based psychosocial intervention did not result in lower rates of recurrent MI or mortality compared with usual medical care, but the (nonrandomized) use of selective serotonin reuptake inhibitors (SSRIs) by some patients in the study was associated with a 42% reduction in the risk of death.33,35

Likewise, depression intervention had no significant effect on cardiac outcome in SADHART, although this 369-patient study was not powered to demonstrate such a benefit.31 Deaths were reduced by more than 50% with sertraline compared with placebo, but there were only 5 and 2 deaths in the placebo and sertraline groups, respectively. The point estimate for sertraline’s effect on major adverse cardiac events was a 23% reduction in events (ie, relative risk of 0.77), but the 95% confidence interval corresponding to this relative risk was 0.51 to 1.16, indicating a lack of statistical significance.

Still, this 23% reduction from SADHART was suggestive—certainly enough to interest the cardiologists associated with the study. Together with the ENRICHD trial findings and results from case-control studies indicating that SSRI therapy reduces the risk of incident MI,36,37 the SADHART findings have encouraged other investigators to suggest additional studies of the effects of antidepressant therapy on CAD outcomes.38,39

Notably, in both the ENRICHD trial40 and SADHART (unpublished data, manuscript in preparation), patients who recovered from depression (regardless of treatment assignment) had better long­term survival, and this was also true in a long-term longitudinal study of patients following coronary artery bypass graft (CABG) surgery.12 This suggests that interventions to promote recovery from depression should be useful in improving cardiac prognosis, but it does not prove it. It may be that patients whose depression improves are in some way healthier, regardless of their depression intervention.

As noted above, data from observational case-control studies of patients admitted to coronary care units suggest that SSRI therapy reduces incident MI.36,37 On the other hand, a study of mortality among patients undergoing CABG surgery revealed worse outcomes in those taking SSRIs than in those who were not.41 Because this study was observational and not randomized, its findings must be interpreted with caution. The effect observed could be due to an adverse effect of SSRI treatment, an adverse effect of depression, or some other mechanism.

DOES DEPRESSION THERAPY HAVE A BENEFICIAL EFFECT ON INTERMEDIARY MECHANISMS LINKING DEPRESSION TO CORONARY EVENTS?

The answer to this question depends on the specific mechanism being considered.

Platelet activation. In the case of platelet activation, the answer may be yes. In a randomized study of depressed patients with ischemic heart disease, paroxetine but not nortriptyline reduced elevated biomarkers of platelet activation.42 In a substudy of SADHART, blood levels of sertraline and desmethylsertraline were inversely correlated with platelelet activation.43 Moreover, serotonin reuptake inhibitors appear to reduce platelet activation in proportion to their affinity for the serotonin transporter.37,44

Heart rate variability. There is little evidence that depression therapy influences heart rate variability. In SADHART, for instance, sertraline and placebo did not differ in their effects on heart rate variability.31

Nonadherence to CAD therapy. It is clear that nonadherence to therapy is more common in depressed patients with cardiac disease than in their nondepressed counterparts45,46 and that poor adherence is associated with worse cardiac outcomes.47 But no study in depressed patients has yet demonstrated that depression treatment per se results in improved adherence. One study has demonstrated, however, that adherence tends to “travel with” depression over the course of treatment: as symptoms of depression declined, adherence improved.48

FUTURE DIRECTIONS

In the future, a more efficient way to improve cardiac outcomes associated with depression may be to target interventions directly at intermediary mechanisms rather than at depression itself. For example, if depression is robustly associated with a deleterious effect on platelet function that heightens the risk of thrombus formation, it might be helpful to optimize antiplatelet therapy in patients with depression, independent of the depression treatment. Similarly, anti-inflammatory treatments might have added benefit in those cardiac patients who are depressed, because these patients tend to have abnormally elevated inflammatory activity, which is associated with worse outcomes. These hypotheses would need to be specifically tested in randomized controlled trials, of course.

Because depression is associated with smoking, a recent study of a 3-month smoking cessation intervention in patients admitted to a coronary care unit provides an instructive example.49 At 2-year follow-up, significantly more patients had continuously abstained from smoking in the intervention group than in a usual-care control group (33% vs 9%, respectively), and significantly fewer patients had died in the intervention group compared with the control group (2.8% vs 12%, respectively).

Another desirable objective is the development of treatments that are more robust in their effects on depression for patients with CAD than the interventions tested so far. Higher rates of response and remission of depression would be highly desirable in their own right. Moreover, only with more potent interventions, whose effects separate more robustly from those seen with placebo or usual care, is it likely that depression treatments themselves could affect cardiac outcomes.

References
  1. Review Panel on Coronary-Prone Behavior and Coronary Heart Disease. Coronary-prone behavior and coronary heart disease: a critical review. Circulation 1981; 63:1199–1215.
  2. Friedman M, Thoresen CE, Gill JJ, et al. Alteration of type A behavior and its effect on cardiac recurrences in post myocardial infarction patients: summary results of the recurrent coronary prevention project. Am Heart J 1986; 112:653–665.
  3. Booth-Kewley S, Friedman HS. Psychological predictors of heart disease: a quantitative review. Psychol Bull 1987; 101:343–362.
  4. Glassman AH, Shapiro PA. Depression and the course of coronary artery disease. Am J Psychiatry 1998; 155:4–11.
  5. Ariyo AA, Haan M, Tangen CM, et al. Depressive symptoms and risks of coronary heart disease and mortality in elderly Americans. Circulation 2000; 102:1773–1779.
  6. Penninx BWJH, Beekman ATF, Honig A, et al. Depression and cardiac mortality. Results from a community-based longitudinal study. Arch Gen Psychiatry 2001; 58:221–227.
  7. Penninx BWJH, Geerlings SW, Deeg dJH, van Eijk JTM, van Tilburg W, Beekman ATF. Minor and major depression and the risk of death in older persons. Arch Gen Psychiatry 1999; 56:889–895.
  8. Rosengren A, Hawken S, Ôunpuu S, et al. Association of psychosocial risk factors with risk of acute myocardial infarction in 11 119 cases and 13 648 controls from 52 countries (the INTERHEART study): case-control study. Lancet 2004; 364:953–962.
  9. Frasure-Smith N, Lesperance F, Talajic M. Depression following myocardial infarction: impact on 6-month survival. JAMA 1993; 270:1819–1825.
  10. Frasure-Smith N, Lesperance F, Talajic M. Depression and 18­month prognosis following myocardial infarction. Circulation 1995; 91:999–1005.
  11. Connerney I, Shapiro PA, McLaughlin JS, Bagiella E, Sloan RP. Relation between depression after coronary artery bypass surgery and 12-month outcome: a prospective study. Lancet 2001; 358:1766–1771.
  12. Blumenthal JA, Lett HS, Babyak MA, et al. Depression as a risk factor for mortality after coronary artery bypass surgery. Lancet 2003; 362:604–609.
  13. Lesperance F, Frasure-Smith N, Talajic M, Bourassa MG. Five-year risk of cardiac mortality in relation to initial severity and one-year changes in depression symptoms after myocardial infarction. Circulation 2002; 105:1049–1053.
  14. Musselman DL, Evans DL, Nemeroff CB. The relationship of depression to cardiovascular disease. Arch Gen Psychiatry 1998; 55:580–592.
  15. Schleifer SJ, Macari-Hinson MM, Coyle DA, et al. The nature and course of depression following myocardial infarction. Arch Intern Med 1989; 149:1785–1789.
  16. Hance M, Carney RM, Freedland KE, Skala J. Depression in patients with coronary heart disease. Gen Hosp Psychiatry 1996; 18:61–65.
  17. Ruo B, Rumsfeld JS, Hlatky MA, Liu H, Browner WS, Whooley MA. Depressive symptoms and health-related quality of life: the Heart and Soul Study. JAMA 2003; 290:215–221.
  18. Giardina EG, Barnard T, Johnson L, Saroff AL, Bigger JT Jr, Louie M. The antiarrhythmic effect of nortriptyline in cardiac patients with premature ventricular depolarizations. J Am Coll Cardiol 1986; 7:1363–1369.
  19. Giardina EGV, Cooper TB, Suckow R, et al. Cardiovascular effects of doxepin in cardiac patients with ventricular arrhythmias. Clin Pharmacol Ther 1987; 42:20–27.
  20. Glassman AH, Rodriguez AI, Shapiro PA. The use of antidepressant drugs in patients with heart disease. J Clin Psychiatry 1998; 59(Suppl 10):16–21.
  21. Glassman AH, Roose SP, Bigger JT Jr. The safety of tricyclic antidepressants in cardiac patients. Risk-benefit reconsidered. JAMA 1993; 269:2673–2675.
  22. Roose SP, Glassman AH, Dalack GW. Depression, heart disease, and tricyclic antidepressants. J Clin Psychiatry 1989; 50(Suppl):12–16.
  23. Roose SP, Glassman AH, Giardina EGV, et al. Nortriptyline in depressed patients with left ventricular impairment. JAMA 1986; 256:3253–3257.
  24. Roose SP, Glassman AH, Giardina EGV, Walsh BT, Woodring S, Bigger JT. Tricyclic antidepressants in depressed patients with cardiac conduction disease. Arch Gen Psychiatry 1987; 44:273–275.
  25. Shapiro PA. Psychiatric aspects of cardiovascular disease. Psychiatr Clin North Am 1996; 19:613–629.
  26. Roose SP, Dalack GW, Glassman AH, Woodring S, Walsh BT, Giardina EGV. Cardiovascular effects of bupropion in depressed patients with heart disease. Am J Psychiatry 1991; 148:512–516.
  27. Roose SP, Glassman AH, Attia E, Woodring S. Comparative efficacy of selective serotonin reuptake inhibitors and tricyclics in the treatment of melancholia. Am J Psychiatry 1994; 151:1735–1739.
  28. Roose SP, Glassman AH, Attia E, Woodring S, Giardina EGV, Bigger JT. Cardiovascular effects of fluoxetine in depressed patients with heart disease. Am J Psychiatry 1998; 155:660–665.
  29. Roose SP, Laghrissi-Thode F, Kennedy JS, et al. Comparison of paroxetine and nortriptyline in depressed patients with ischemic heart disease. JAMA 1998; 279:287–291.
  30. Strik JJMH, Honig A, Lousberg R, et al. Efficacy and safety of fluoxetine in the treatment of patients with major depression after first myocardial infarction: findings from a double-blind, placebo-controlled trial. Psychosom Med 2000; 62:783–789.
  31. 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.
  32. Glassman AH, Bigger JT Jr, Gaffney M, Shapiro PA, Swenson JR. Onset of major depression associated with acute coronary syndromes. Relationship of onset, major depressive disorder history, and episode severity to sertraline benefit. Arch Gen Psychiatry 2006; 63:283–288.
  33. Writing Committee for the ENRICHD Investigators. 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.
  34. 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.
  35. Taylor CB, Youngblood ME, Catellier D, et al. Effects of antidepressant medication on morbidity and mortality in depressed patients after myocardial infarction. Arch Gen Psychiatry 2005; 62:792–798.
  36. Sauer WH, Berlin JA, Kimmel SE. Selective serotonin reuptake inhibitors and myocardial infarction. Circulation 2001; 104:1894–1898.
  37. Sauer WH, Berlin JA, Kimmel SE. Effect of antidepressants and their relative affinity for the serotonin transporter on the risk of myocardial infarction. Circulation 2003; 108:32–36.
  38. Glassman AH. Does treating post-myocardial infarction depression reduce medical mortality? Arch Gen Psychiatry 2005; 62:711–712.
  39. Davidson KW, Kupfer DJ, Bigger JT, et al. Assessment and treatment of depression in patients with cardiovascular disease: National Heart, Lung, and Blood Institute Working Group Report. Psychosom Med 2006; 68:645–650.
  40. Carney RM, Blumenthal JA, Freedland KE, et al. Depression and late mortality after myocardial infarction in the Enhancing Recovery in Coronary Heart Disease (ENRICHD) study. Psychosom Med 2004; 66:466–474.
  41. Xiong GL, Jiang W, Clare R, et al. Prognosis of patients taking selective serotonin reuptake inhibitors before coronary artery bypass grafting. Am J Cardiol 2006; 98:42–47.
  42. Pollock BG, Laghrissi-Thode F, Wagner WR. Evaluation of platelet activation in depressed patients with ischemic heart disease after paroxetine or nortriptyline treatment. J Clin Psychopharmacol 2000; 20:137–140.
  43. Serebruany VL, Glassman AH, Malinin AI, et al. Platelet/endothelial biomarkers in depressed patients treated with the selective serotonin reuptake inhibitor sertraline after acute coronary events: the Sertraline AntiDepressant Heart Attack Randomized Trial (SADHART) Platelet Substudy. Circulation 2003; 108:939–944.
  44. Shimbo D, Child J, Davidson K, et al. Exaggerated serotonin-mediated platelet reactivity as a possible link in depression and acute coronary syndromes. Am J Cardiol 2002; 89:331–333.
  45. Kronish IM, Rieckmann N, Halm EA, et al. Persistent depression affects adherence to secondary prevention behaviors after acute coronary syndromes. J Gen Intern Med 2006; 21:1178–1183.
  46. Ziegelstein RC, Fauerbach JA, Stevens SS, Romanelli J, Richter DP, Bush DE. Patients with depression are less likely to follow recommendations to reduce cardiac risk during recovery from a myocardial infarction. Arch Intern Med 2000; 160:1818–1823.
  47. Rasmussen JN, Chong A, Alter DA. Relationship between adherence to evidence-based pharmacotherapy and long-term mortality after acute myocardial infarction. JAMA 2007; 297:177–186.
  48. Rieckmann N, Gerin W, Kronish IM, et al. Course of depressive symptoms and medication adherence after acute coronary syndromes: an electronic medication monitoring study. J Am Coll Cardiol 2006; 48:2218–2222.
  49. Mohiuddin SM, Mooss AN, Hunter CB, Grollmes TL, Cloutier DA, Hilleman DE. Intensive smoking cessation intervention reduces mortality in high-risk smokers with cardiovascular disease. Chest 2007; 131:446–452.
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Correspondence: Peter A. Shapiro, MD, Department of Psychiatry, New York Presbyterian Hospital–Columbia University Medical Center, 622 W. 168 Street, Box 427, New York, NY 10032; [email protected]

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

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

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Depression’s association with incident coronary artery disease (CAD) and recurrent cardiac events became established 10 to 20 years ago. Efforts in the past decade have focused on the specific effects of treating depression in patients with CAD—whether such treatment is beneficial and, if so, exactly how it exerts its benefits. This article briefly surveys the current evidence on these questions after reviewing how we got interested in depression in CAD in the first place.

THE EMERGENCE OF DEPRESSION AS A CARDIAC RISK FACTOR

The shift from a focus on Type A behavior

Not long ago, Type A behavior pattern was the psychosocial variable of greatest research interest as a contributor to CAD. Just 26 years ago, a National Institutes of Health consensus development conference anointed Type A behavior pattern as a CAD risk factor.1 Five years later, one of the landmark studies in psychosomatic medicine—the Recurrent Coronary Prevention Project—showed that Type A behavior modification, added to usual cardiac care in post–myocardial infarction (MI) patients, not only reduced patients’ Type A behavior but also reduced the rate of reinfarction and death.2

But that was the high-water mark for Type A behavior in CAD research. The focus soon shifted, especially after the publication of a 1987 review by Booth-Kewley and Friedman showing that larger and later studies found less and less impressive effects of Type A on cardiac outcomes.3 This same review pointed out the cumulative evidence indicating that depression might be the most important psychological factor associated with coronary disease.3

An explosion of research on depression in CAD

In the 10 years following the review by Booth-Kewley and Friedman, there was an explosion of study about depression in CAD.4 This resulted in what is fair to call a consensus on several key points about this relationship:

  • Depression is associated with an approximate 1.5-­fold to twofold increase in the risk for incident CAD.5–8
  • Depression is associated with about a threefold to fourfold increase in the risk of recurrent cardiac events and death in patients with CAD, including patients with a new diagnosis, those with acute coronary events, and those who have undergone revascularization procedures.9–13
  • Several biobehavioral mechanisms are plausible candidates as mediators of the mind-body relationship linking depression and coronary disease. These include abnormal platelet function, autonomic function, inflammatory processes, and nonadherence to therapy.4,14
  • Depression is extremely common in CAD, affecting about 15% to 20% of patients, and is a serious illness in its own right, even apart from its effects on cardiac outcomes.9–11,15–17

In light of these observations, the obvious research questions are whether treating depression in patients with CAD helps, and if so, what it helps with—the depression itself, the pathophysiology and outcomes of CAD, or both. These questions have been the increasing focus of the past 10 years.

DOES DEPRESSION THERAPY IN CAD PATIENTS IMPROVE DEPRESSION IN THESE PATIENTS?

The short answer to this question is an almost unqualified yes. Even setting aside the literature on tricyclic antidepressants (which is an old literature but impressive in its own right in its systematic working through of issues of efficacy and the delineation and management of adverse effects18–25), we have at least half a dozen studies showing that depression treatment helps to relieve depression in patients with CAD with reasonable safety and efficacy. Some are open-label, small-scale studies, while others are more rigorously designed and controlled, but the overall conclusion is unambiguous.26–34

Roose, Glassman, and colleagues were among the first to describe the effects of antidepressants other than tricyclics in cardiac patients.26–29 They demonstrated the safety profile of bupropion, but did not report on its efficacy.26 They demonstrated safety but found rather low efficacy of fluoxetine in doses up to 60 mg/day in markedly depressed inpatients, many of whom had a “melancholic” profile (early-morning waking, positive diurnal mood variation, guilt, anhedonia, poor appetite).27,28 In a randomized double-blind trial, these same researchers subsequently demonstrated paroxetine to be at least as effective as the tricyclic agent nortriptyline and to have excellent tolerability at doses up to 40 mg/day.29

Strik et al published an early study of the efficacy of depression treatment in 54 patients with major depression after a first MI.30 Fluoxetine demonstrated superiority over placebo with respect to the percentage of patients achieving a clinical response (48% vs 26%; P = .05) (clinical response was defined as a ≥ 50% reduction in the Hamilton Depression Rating Scale [HAM-D] score), but fluoxetine did not have a statistically significant effect on HAM-D symptom ratings except in the subset of patients with mild symptoms to start with. This is somewhat counterintuitive, and to be contrasted with the results of SADHART.

The Sertraline Antidepressant Heart Attack Randomized Trial (SADHART), conducted in depressed patients following MI or unstable angina, is well known.31,32 Patients with a recent acute coronary syndrome (acute MI in 74%; unstable angina in 26%) were randomized within 30 days of the coronary event to sertraline or placebo (following a 2-week placebo run-in period for all patients). Sertraline was associated with superior scores on the Clinical Global Impression Improvement Scale, particularly among patients with recurrent depression and more severe depression, but its effect on HAM-D scores was not significantly better than that of placebo. As opposed to the finding of Strik et al, the biggest difference in response was among patients with more severe depression symptoms rather than those with mild symptoms to begin with.

The Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) trial tested the hypothesis that psychosocial intervention aimed at depression and low levels of social support would improve cardiac prognosis in post-MI patients.33 In this large randomized study (N = 2,481), cognitive behavior therapy exerted a modestly significant effect in reducing symptoms of depression as compared with usual medical care. Most patients in the intervention arm underwent 6 to 10 sessions of individual and/or group therapy over 6 months, and their HAM-D scores improved by approximately 10 points from baseline to 6-month follow-up. However, patients in the usual-care arm also had substantial improvements (almost 9 points) in HAM-D scores at 6-month follow-up.

The Canadian Cardiac Randomized Evalution of Antidepressant and Psychotherapy Efficacy (CREATE) used a 2 x 2 factorial design to assess interpersonal psychotherapy and antidepressant therapy (citalopram) for depression in patients with stable CAD.34 Citalopram was more effective than placebo in reducing depression symptoms and in achieving response and remission. The mean decline in HAM-D scores was more than 3 points greater in citalopram recipients than in placebo recipients. Interpersonal psychotherapy was no more effective than clinical management.

In none of the studies reviewed above was the benefit of active treatment very powerful—response rates were between 50% and 60%, and remission rates were much lower.

 

 

DOES DEPRESSION THERAPY IN CAD PATIENTS IMPROVE CAD OUTCOMES?

In the ENRICHD trial, cognitive behavior therapy–based psychosocial intervention did not result in lower rates of recurrent MI or mortality compared with usual medical care, but the (nonrandomized) use of selective serotonin reuptake inhibitors (SSRIs) by some patients in the study was associated with a 42% reduction in the risk of death.33,35

Likewise, depression intervention had no significant effect on cardiac outcome in SADHART, although this 369-patient study was not powered to demonstrate such a benefit.31 Deaths were reduced by more than 50% with sertraline compared with placebo, but there were only 5 and 2 deaths in the placebo and sertraline groups, respectively. The point estimate for sertraline’s effect on major adverse cardiac events was a 23% reduction in events (ie, relative risk of 0.77), but the 95% confidence interval corresponding to this relative risk was 0.51 to 1.16, indicating a lack of statistical significance.

Still, this 23% reduction from SADHART was suggestive—certainly enough to interest the cardiologists associated with the study. Together with the ENRICHD trial findings and results from case-control studies indicating that SSRI therapy reduces the risk of incident MI,36,37 the SADHART findings have encouraged other investigators to suggest additional studies of the effects of antidepressant therapy on CAD outcomes.38,39

Notably, in both the ENRICHD trial40 and SADHART (unpublished data, manuscript in preparation), patients who recovered from depression (regardless of treatment assignment) had better long­term survival, and this was also true in a long-term longitudinal study of patients following coronary artery bypass graft (CABG) surgery.12 This suggests that interventions to promote recovery from depression should be useful in improving cardiac prognosis, but it does not prove it. It may be that patients whose depression improves are in some way healthier, regardless of their depression intervention.

As noted above, data from observational case-control studies of patients admitted to coronary care units suggest that SSRI therapy reduces incident MI.36,37 On the other hand, a study of mortality among patients undergoing CABG surgery revealed worse outcomes in those taking SSRIs than in those who were not.41 Because this study was observational and not randomized, its findings must be interpreted with caution. The effect observed could be due to an adverse effect of SSRI treatment, an adverse effect of depression, or some other mechanism.

DOES DEPRESSION THERAPY HAVE A BENEFICIAL EFFECT ON INTERMEDIARY MECHANISMS LINKING DEPRESSION TO CORONARY EVENTS?

The answer to this question depends on the specific mechanism being considered.

Platelet activation. In the case of platelet activation, the answer may be yes. In a randomized study of depressed patients with ischemic heart disease, paroxetine but not nortriptyline reduced elevated biomarkers of platelet activation.42 In a substudy of SADHART, blood levels of sertraline and desmethylsertraline were inversely correlated with platelelet activation.43 Moreover, serotonin reuptake inhibitors appear to reduce platelet activation in proportion to their affinity for the serotonin transporter.37,44

Heart rate variability. There is little evidence that depression therapy influences heart rate variability. In SADHART, for instance, sertraline and placebo did not differ in their effects on heart rate variability.31

Nonadherence to CAD therapy. It is clear that nonadherence to therapy is more common in depressed patients with cardiac disease than in their nondepressed counterparts45,46 and that poor adherence is associated with worse cardiac outcomes.47 But no study in depressed patients has yet demonstrated that depression treatment per se results in improved adherence. One study has demonstrated, however, that adherence tends to “travel with” depression over the course of treatment: as symptoms of depression declined, adherence improved.48

FUTURE DIRECTIONS

In the future, a more efficient way to improve cardiac outcomes associated with depression may be to target interventions directly at intermediary mechanisms rather than at depression itself. For example, if depression is robustly associated with a deleterious effect on platelet function that heightens the risk of thrombus formation, it might be helpful to optimize antiplatelet therapy in patients with depression, independent of the depression treatment. Similarly, anti-inflammatory treatments might have added benefit in those cardiac patients who are depressed, because these patients tend to have abnormally elevated inflammatory activity, which is associated with worse outcomes. These hypotheses would need to be specifically tested in randomized controlled trials, of course.

Because depression is associated with smoking, a recent study of a 3-month smoking cessation intervention in patients admitted to a coronary care unit provides an instructive example.49 At 2-year follow-up, significantly more patients had continuously abstained from smoking in the intervention group than in a usual-care control group (33% vs 9%, respectively), and significantly fewer patients had died in the intervention group compared with the control group (2.8% vs 12%, respectively).

Another desirable objective is the development of treatments that are more robust in their effects on depression for patients with CAD than the interventions tested so far. Higher rates of response and remission of depression would be highly desirable in their own right. Moreover, only with more potent interventions, whose effects separate more robustly from those seen with placebo or usual care, is it likely that depression treatments themselves could affect cardiac outcomes.

Depression’s association with incident coronary artery disease (CAD) and recurrent cardiac events became established 10 to 20 years ago. Efforts in the past decade have focused on the specific effects of treating depression in patients with CAD—whether such treatment is beneficial and, if so, exactly how it exerts its benefits. This article briefly surveys the current evidence on these questions after reviewing how we got interested in depression in CAD in the first place.

THE EMERGENCE OF DEPRESSION AS A CARDIAC RISK FACTOR

The shift from a focus on Type A behavior

Not long ago, Type A behavior pattern was the psychosocial variable of greatest research interest as a contributor to CAD. Just 26 years ago, a National Institutes of Health consensus development conference anointed Type A behavior pattern as a CAD risk factor.1 Five years later, one of the landmark studies in psychosomatic medicine—the Recurrent Coronary Prevention Project—showed that Type A behavior modification, added to usual cardiac care in post–myocardial infarction (MI) patients, not only reduced patients’ Type A behavior but also reduced the rate of reinfarction and death.2

But that was the high-water mark for Type A behavior in CAD research. The focus soon shifted, especially after the publication of a 1987 review by Booth-Kewley and Friedman showing that larger and later studies found less and less impressive effects of Type A on cardiac outcomes.3 This same review pointed out the cumulative evidence indicating that depression might be the most important psychological factor associated with coronary disease.3

An explosion of research on depression in CAD

In the 10 years following the review by Booth-Kewley and Friedman, there was an explosion of study about depression in CAD.4 This resulted in what is fair to call a consensus on several key points about this relationship:

  • Depression is associated with an approximate 1.5-­fold to twofold increase in the risk for incident CAD.5–8
  • Depression is associated with about a threefold to fourfold increase in the risk of recurrent cardiac events and death in patients with CAD, including patients with a new diagnosis, those with acute coronary events, and those who have undergone revascularization procedures.9–13
  • Several biobehavioral mechanisms are plausible candidates as mediators of the mind-body relationship linking depression and coronary disease. These include abnormal platelet function, autonomic function, inflammatory processes, and nonadherence to therapy.4,14
  • Depression is extremely common in CAD, affecting about 15% to 20% of patients, and is a serious illness in its own right, even apart from its effects on cardiac outcomes.9–11,15–17

In light of these observations, the obvious research questions are whether treating depression in patients with CAD helps, and if so, what it helps with—the depression itself, the pathophysiology and outcomes of CAD, or both. These questions have been the increasing focus of the past 10 years.

DOES DEPRESSION THERAPY IN CAD PATIENTS IMPROVE DEPRESSION IN THESE PATIENTS?

The short answer to this question is an almost unqualified yes. Even setting aside the literature on tricyclic antidepressants (which is an old literature but impressive in its own right in its systematic working through of issues of efficacy and the delineation and management of adverse effects18–25), we have at least half a dozen studies showing that depression treatment helps to relieve depression in patients with CAD with reasonable safety and efficacy. Some are open-label, small-scale studies, while others are more rigorously designed and controlled, but the overall conclusion is unambiguous.26–34

Roose, Glassman, and colleagues were among the first to describe the effects of antidepressants other than tricyclics in cardiac patients.26–29 They demonstrated the safety profile of bupropion, but did not report on its efficacy.26 They demonstrated safety but found rather low efficacy of fluoxetine in doses up to 60 mg/day in markedly depressed inpatients, many of whom had a “melancholic” profile (early-morning waking, positive diurnal mood variation, guilt, anhedonia, poor appetite).27,28 In a randomized double-blind trial, these same researchers subsequently demonstrated paroxetine to be at least as effective as the tricyclic agent nortriptyline and to have excellent tolerability at doses up to 40 mg/day.29

Strik et al published an early study of the efficacy of depression treatment in 54 patients with major depression after a first MI.30 Fluoxetine demonstrated superiority over placebo with respect to the percentage of patients achieving a clinical response (48% vs 26%; P = .05) (clinical response was defined as a ≥ 50% reduction in the Hamilton Depression Rating Scale [HAM-D] score), but fluoxetine did not have a statistically significant effect on HAM-D symptom ratings except in the subset of patients with mild symptoms to start with. This is somewhat counterintuitive, and to be contrasted with the results of SADHART.

The Sertraline Antidepressant Heart Attack Randomized Trial (SADHART), conducted in depressed patients following MI or unstable angina, is well known.31,32 Patients with a recent acute coronary syndrome (acute MI in 74%; unstable angina in 26%) were randomized within 30 days of the coronary event to sertraline or placebo (following a 2-week placebo run-in period for all patients). Sertraline was associated with superior scores on the Clinical Global Impression Improvement Scale, particularly among patients with recurrent depression and more severe depression, but its effect on HAM-D scores was not significantly better than that of placebo. As opposed to the finding of Strik et al, the biggest difference in response was among patients with more severe depression symptoms rather than those with mild symptoms to begin with.

The Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) trial tested the hypothesis that psychosocial intervention aimed at depression and low levels of social support would improve cardiac prognosis in post-MI patients.33 In this large randomized study (N = 2,481), cognitive behavior therapy exerted a modestly significant effect in reducing symptoms of depression as compared with usual medical care. Most patients in the intervention arm underwent 6 to 10 sessions of individual and/or group therapy over 6 months, and their HAM-D scores improved by approximately 10 points from baseline to 6-month follow-up. However, patients in the usual-care arm also had substantial improvements (almost 9 points) in HAM-D scores at 6-month follow-up.

The Canadian Cardiac Randomized Evalution of Antidepressant and Psychotherapy Efficacy (CREATE) used a 2 x 2 factorial design to assess interpersonal psychotherapy and antidepressant therapy (citalopram) for depression in patients with stable CAD.34 Citalopram was more effective than placebo in reducing depression symptoms and in achieving response and remission. The mean decline in HAM-D scores was more than 3 points greater in citalopram recipients than in placebo recipients. Interpersonal psychotherapy was no more effective than clinical management.

In none of the studies reviewed above was the benefit of active treatment very powerful—response rates were between 50% and 60%, and remission rates were much lower.

 

 

DOES DEPRESSION THERAPY IN CAD PATIENTS IMPROVE CAD OUTCOMES?

In the ENRICHD trial, cognitive behavior therapy–based psychosocial intervention did not result in lower rates of recurrent MI or mortality compared with usual medical care, but the (nonrandomized) use of selective serotonin reuptake inhibitors (SSRIs) by some patients in the study was associated with a 42% reduction in the risk of death.33,35

Likewise, depression intervention had no significant effect on cardiac outcome in SADHART, although this 369-patient study was not powered to demonstrate such a benefit.31 Deaths were reduced by more than 50% with sertraline compared with placebo, but there were only 5 and 2 deaths in the placebo and sertraline groups, respectively. The point estimate for sertraline’s effect on major adverse cardiac events was a 23% reduction in events (ie, relative risk of 0.77), but the 95% confidence interval corresponding to this relative risk was 0.51 to 1.16, indicating a lack of statistical significance.

Still, this 23% reduction from SADHART was suggestive—certainly enough to interest the cardiologists associated with the study. Together with the ENRICHD trial findings and results from case-control studies indicating that SSRI therapy reduces the risk of incident MI,36,37 the SADHART findings have encouraged other investigators to suggest additional studies of the effects of antidepressant therapy on CAD outcomes.38,39

Notably, in both the ENRICHD trial40 and SADHART (unpublished data, manuscript in preparation), patients who recovered from depression (regardless of treatment assignment) had better long­term survival, and this was also true in a long-term longitudinal study of patients following coronary artery bypass graft (CABG) surgery.12 This suggests that interventions to promote recovery from depression should be useful in improving cardiac prognosis, but it does not prove it. It may be that patients whose depression improves are in some way healthier, regardless of their depression intervention.

As noted above, data from observational case-control studies of patients admitted to coronary care units suggest that SSRI therapy reduces incident MI.36,37 On the other hand, a study of mortality among patients undergoing CABG surgery revealed worse outcomes in those taking SSRIs than in those who were not.41 Because this study was observational and not randomized, its findings must be interpreted with caution. The effect observed could be due to an adverse effect of SSRI treatment, an adverse effect of depression, or some other mechanism.

DOES DEPRESSION THERAPY HAVE A BENEFICIAL EFFECT ON INTERMEDIARY MECHANISMS LINKING DEPRESSION TO CORONARY EVENTS?

The answer to this question depends on the specific mechanism being considered.

Platelet activation. In the case of platelet activation, the answer may be yes. In a randomized study of depressed patients with ischemic heart disease, paroxetine but not nortriptyline reduced elevated biomarkers of platelet activation.42 In a substudy of SADHART, blood levels of sertraline and desmethylsertraline were inversely correlated with platelelet activation.43 Moreover, serotonin reuptake inhibitors appear to reduce platelet activation in proportion to their affinity for the serotonin transporter.37,44

Heart rate variability. There is little evidence that depression therapy influences heart rate variability. In SADHART, for instance, sertraline and placebo did not differ in their effects on heart rate variability.31

Nonadherence to CAD therapy. It is clear that nonadherence to therapy is more common in depressed patients with cardiac disease than in their nondepressed counterparts45,46 and that poor adherence is associated with worse cardiac outcomes.47 But no study in depressed patients has yet demonstrated that depression treatment per se results in improved adherence. One study has demonstrated, however, that adherence tends to “travel with” depression over the course of treatment: as symptoms of depression declined, adherence improved.48

FUTURE DIRECTIONS

In the future, a more efficient way to improve cardiac outcomes associated with depression may be to target interventions directly at intermediary mechanisms rather than at depression itself. For example, if depression is robustly associated with a deleterious effect on platelet function that heightens the risk of thrombus formation, it might be helpful to optimize antiplatelet therapy in patients with depression, independent of the depression treatment. Similarly, anti-inflammatory treatments might have added benefit in those cardiac patients who are depressed, because these patients tend to have abnormally elevated inflammatory activity, which is associated with worse outcomes. These hypotheses would need to be specifically tested in randomized controlled trials, of course.

Because depression is associated with smoking, a recent study of a 3-month smoking cessation intervention in patients admitted to a coronary care unit provides an instructive example.49 At 2-year follow-up, significantly more patients had continuously abstained from smoking in the intervention group than in a usual-care control group (33% vs 9%, respectively), and significantly fewer patients had died in the intervention group compared with the control group (2.8% vs 12%, respectively).

Another desirable objective is the development of treatments that are more robust in their effects on depression for patients with CAD than the interventions tested so far. Higher rates of response and remission of depression would be highly desirable in their own right. Moreover, only with more potent interventions, whose effects separate more robustly from those seen with placebo or usual care, is it likely that depression treatments themselves could affect cardiac outcomes.

References
  1. Review Panel on Coronary-Prone Behavior and Coronary Heart Disease. Coronary-prone behavior and coronary heart disease: a critical review. Circulation 1981; 63:1199–1215.
  2. Friedman M, Thoresen CE, Gill JJ, et al. Alteration of type A behavior and its effect on cardiac recurrences in post myocardial infarction patients: summary results of the recurrent coronary prevention project. Am Heart J 1986; 112:653–665.
  3. Booth-Kewley S, Friedman HS. Psychological predictors of heart disease: a quantitative review. Psychol Bull 1987; 101:343–362.
  4. Glassman AH, Shapiro PA. Depression and the course of coronary artery disease. Am J Psychiatry 1998; 155:4–11.
  5. Ariyo AA, Haan M, Tangen CM, et al. Depressive symptoms and risks of coronary heart disease and mortality in elderly Americans. Circulation 2000; 102:1773–1779.
  6. Penninx BWJH, Beekman ATF, Honig A, et al. Depression and cardiac mortality. Results from a community-based longitudinal study. Arch Gen Psychiatry 2001; 58:221–227.
  7. Penninx BWJH, Geerlings SW, Deeg dJH, van Eijk JTM, van Tilburg W, Beekman ATF. Minor and major depression and the risk of death in older persons. Arch Gen Psychiatry 1999; 56:889–895.
  8. Rosengren A, Hawken S, Ôunpuu S, et al. Association of psychosocial risk factors with risk of acute myocardial infarction in 11 119 cases and 13 648 controls from 52 countries (the INTERHEART study): case-control study. Lancet 2004; 364:953–962.
  9. Frasure-Smith N, Lesperance F, Talajic M. Depression following myocardial infarction: impact on 6-month survival. JAMA 1993; 270:1819–1825.
  10. Frasure-Smith N, Lesperance F, Talajic M. Depression and 18­month prognosis following myocardial infarction. Circulation 1995; 91:999–1005.
  11. Connerney I, Shapiro PA, McLaughlin JS, Bagiella E, Sloan RP. Relation between depression after coronary artery bypass surgery and 12-month outcome: a prospective study. Lancet 2001; 358:1766–1771.
  12. Blumenthal JA, Lett HS, Babyak MA, et al. Depression as a risk factor for mortality after coronary artery bypass surgery. Lancet 2003; 362:604–609.
  13. Lesperance F, Frasure-Smith N, Talajic M, Bourassa MG. Five-year risk of cardiac mortality in relation to initial severity and one-year changes in depression symptoms after myocardial infarction. Circulation 2002; 105:1049–1053.
  14. Musselman DL, Evans DL, Nemeroff CB. The relationship of depression to cardiovascular disease. Arch Gen Psychiatry 1998; 55:580–592.
  15. Schleifer SJ, Macari-Hinson MM, Coyle DA, et al. The nature and course of depression following myocardial infarction. Arch Intern Med 1989; 149:1785–1789.
  16. Hance M, Carney RM, Freedland KE, Skala J. Depression in patients with coronary heart disease. Gen Hosp Psychiatry 1996; 18:61–65.
  17. Ruo B, Rumsfeld JS, Hlatky MA, Liu H, Browner WS, Whooley MA. Depressive symptoms and health-related quality of life: the Heart and Soul Study. JAMA 2003; 290:215–221.
  18. Giardina EG, Barnard T, Johnson L, Saroff AL, Bigger JT Jr, Louie M. The antiarrhythmic effect of nortriptyline in cardiac patients with premature ventricular depolarizations. J Am Coll Cardiol 1986; 7:1363–1369.
  19. Giardina EGV, Cooper TB, Suckow R, et al. Cardiovascular effects of doxepin in cardiac patients with ventricular arrhythmias. Clin Pharmacol Ther 1987; 42:20–27.
  20. Glassman AH, Rodriguez AI, Shapiro PA. The use of antidepressant drugs in patients with heart disease. J Clin Psychiatry 1998; 59(Suppl 10):16–21.
  21. Glassman AH, Roose SP, Bigger JT Jr. The safety of tricyclic antidepressants in cardiac patients. Risk-benefit reconsidered. JAMA 1993; 269:2673–2675.
  22. Roose SP, Glassman AH, Dalack GW. Depression, heart disease, and tricyclic antidepressants. J Clin Psychiatry 1989; 50(Suppl):12–16.
  23. Roose SP, Glassman AH, Giardina EGV, et al. Nortriptyline in depressed patients with left ventricular impairment. JAMA 1986; 256:3253–3257.
  24. Roose SP, Glassman AH, Giardina EGV, Walsh BT, Woodring S, Bigger JT. Tricyclic antidepressants in depressed patients with cardiac conduction disease. Arch Gen Psychiatry 1987; 44:273–275.
  25. Shapiro PA. Psychiatric aspects of cardiovascular disease. Psychiatr Clin North Am 1996; 19:613–629.
  26. Roose SP, Dalack GW, Glassman AH, Woodring S, Walsh BT, Giardina EGV. Cardiovascular effects of bupropion in depressed patients with heart disease. Am J Psychiatry 1991; 148:512–516.
  27. Roose SP, Glassman AH, Attia E, Woodring S. Comparative efficacy of selective serotonin reuptake inhibitors and tricyclics in the treatment of melancholia. Am J Psychiatry 1994; 151:1735–1739.
  28. Roose SP, Glassman AH, Attia E, Woodring S, Giardina EGV, Bigger JT. Cardiovascular effects of fluoxetine in depressed patients with heart disease. Am J Psychiatry 1998; 155:660–665.
  29. Roose SP, Laghrissi-Thode F, Kennedy JS, et al. Comparison of paroxetine and nortriptyline in depressed patients with ischemic heart disease. JAMA 1998; 279:287–291.
  30. Strik JJMH, Honig A, Lousberg R, et al. Efficacy and safety of fluoxetine in the treatment of patients with major depression after first myocardial infarction: findings from a double-blind, placebo-controlled trial. Psychosom Med 2000; 62:783–789.
  31. 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.
  32. Glassman AH, Bigger JT Jr, Gaffney M, Shapiro PA, Swenson JR. Onset of major depression associated with acute coronary syndromes. Relationship of onset, major depressive disorder history, and episode severity to sertraline benefit. Arch Gen Psychiatry 2006; 63:283–288.
  33. Writing Committee for the ENRICHD Investigators. 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.
  34. 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.
  35. Taylor CB, Youngblood ME, Catellier D, et al. Effects of antidepressant medication on morbidity and mortality in depressed patients after myocardial infarction. Arch Gen Psychiatry 2005; 62:792–798.
  36. Sauer WH, Berlin JA, Kimmel SE. Selective serotonin reuptake inhibitors and myocardial infarction. Circulation 2001; 104:1894–1898.
  37. Sauer WH, Berlin JA, Kimmel SE. Effect of antidepressants and their relative affinity for the serotonin transporter on the risk of myocardial infarction. Circulation 2003; 108:32–36.
  38. Glassman AH. Does treating post-myocardial infarction depression reduce medical mortality? Arch Gen Psychiatry 2005; 62:711–712.
  39. Davidson KW, Kupfer DJ, Bigger JT, et al. Assessment and treatment of depression in patients with cardiovascular disease: National Heart, Lung, and Blood Institute Working Group Report. Psychosom Med 2006; 68:645–650.
  40. Carney RM, Blumenthal JA, Freedland KE, et al. Depression and late mortality after myocardial infarction in the Enhancing Recovery in Coronary Heart Disease (ENRICHD) study. Psychosom Med 2004; 66:466–474.
  41. Xiong GL, Jiang W, Clare R, et al. Prognosis of patients taking selective serotonin reuptake inhibitors before coronary artery bypass grafting. Am J Cardiol 2006; 98:42–47.
  42. Pollock BG, Laghrissi-Thode F, Wagner WR. Evaluation of platelet activation in depressed patients with ischemic heart disease after paroxetine or nortriptyline treatment. J Clin Psychopharmacol 2000; 20:137–140.
  43. Serebruany VL, Glassman AH, Malinin AI, et al. Platelet/endothelial biomarkers in depressed patients treated with the selective serotonin reuptake inhibitor sertraline after acute coronary events: the Sertraline AntiDepressant Heart Attack Randomized Trial (SADHART) Platelet Substudy. Circulation 2003; 108:939–944.
  44. Shimbo D, Child J, Davidson K, et al. Exaggerated serotonin-mediated platelet reactivity as a possible link in depression and acute coronary syndromes. Am J Cardiol 2002; 89:331–333.
  45. Kronish IM, Rieckmann N, Halm EA, et al. Persistent depression affects adherence to secondary prevention behaviors after acute coronary syndromes. J Gen Intern Med 2006; 21:1178–1183.
  46. Ziegelstein RC, Fauerbach JA, Stevens SS, Romanelli J, Richter DP, Bush DE. Patients with depression are less likely to follow recommendations to reduce cardiac risk during recovery from a myocardial infarction. Arch Intern Med 2000; 160:1818–1823.
  47. Rasmussen JN, Chong A, Alter DA. Relationship between adherence to evidence-based pharmacotherapy and long-term mortality after acute myocardial infarction. JAMA 2007; 297:177–186.
  48. Rieckmann N, Gerin W, Kronish IM, et al. Course of depressive symptoms and medication adherence after acute coronary syndromes: an electronic medication monitoring study. J Am Coll Cardiol 2006; 48:2218–2222.
  49. Mohiuddin SM, Mooss AN, Hunter CB, Grollmes TL, Cloutier DA, Hilleman DE. Intensive smoking cessation intervention reduces mortality in high-risk smokers with cardiovascular disease. Chest 2007; 131:446–452.
References
  1. Review Panel on Coronary-Prone Behavior and Coronary Heart Disease. Coronary-prone behavior and coronary heart disease: a critical review. Circulation 1981; 63:1199–1215.
  2. Friedman M, Thoresen CE, Gill JJ, et al. Alteration of type A behavior and its effect on cardiac recurrences in post myocardial infarction patients: summary results of the recurrent coronary prevention project. Am Heart J 1986; 112:653–665.
  3. Booth-Kewley S, Friedman HS. Psychological predictors of heart disease: a quantitative review. Psychol Bull 1987; 101:343–362.
  4. Glassman AH, Shapiro PA. Depression and the course of coronary artery disease. Am J Psychiatry 1998; 155:4–11.
  5. Ariyo AA, Haan M, Tangen CM, et al. Depressive symptoms and risks of coronary heart disease and mortality in elderly Americans. Circulation 2000; 102:1773–1779.
  6. Penninx BWJH, Beekman ATF, Honig A, et al. Depression and cardiac mortality. Results from a community-based longitudinal study. Arch Gen Psychiatry 2001; 58:221–227.
  7. Penninx BWJH, Geerlings SW, Deeg dJH, van Eijk JTM, van Tilburg W, Beekman ATF. Minor and major depression and the risk of death in older persons. Arch Gen Psychiatry 1999; 56:889–895.
  8. Rosengren A, Hawken S, Ôunpuu S, et al. Association of psychosocial risk factors with risk of acute myocardial infarction in 11 119 cases and 13 648 controls from 52 countries (the INTERHEART study): case-control study. Lancet 2004; 364:953–962.
  9. Frasure-Smith N, Lesperance F, Talajic M. Depression following myocardial infarction: impact on 6-month survival. JAMA 1993; 270:1819–1825.
  10. Frasure-Smith N, Lesperance F, Talajic M. Depression and 18­month prognosis following myocardial infarction. Circulation 1995; 91:999–1005.
  11. Connerney I, Shapiro PA, McLaughlin JS, Bagiella E, Sloan RP. Relation between depression after coronary artery bypass surgery and 12-month outcome: a prospective study. Lancet 2001; 358:1766–1771.
  12. Blumenthal JA, Lett HS, Babyak MA, et al. Depression as a risk factor for mortality after coronary artery bypass surgery. Lancet 2003; 362:604–609.
  13. Lesperance F, Frasure-Smith N, Talajic M, Bourassa MG. Five-year risk of cardiac mortality in relation to initial severity and one-year changes in depression symptoms after myocardial infarction. Circulation 2002; 105:1049–1053.
  14. Musselman DL, Evans DL, Nemeroff CB. The relationship of depression to cardiovascular disease. Arch Gen Psychiatry 1998; 55:580–592.
  15. Schleifer SJ, Macari-Hinson MM, Coyle DA, et al. The nature and course of depression following myocardial infarction. Arch Intern Med 1989; 149:1785–1789.
  16. Hance M, Carney RM, Freedland KE, Skala J. Depression in patients with coronary heart disease. Gen Hosp Psychiatry 1996; 18:61–65.
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Depression in coronary artery disease: Does treatment help?
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Depression in coronary artery disease: Does treatment help?
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Cleveland Clinic Journal of Medicine 2008 March;75(suppl 2):S5-S9
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