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  • Published:

Depression and coronary heart disease

Key Points

  • Depression is prevalent in the general population, and even more common among patients with coronary heart disease (CHD)

  • Depression is a risk factor for incident CHD, and for cardiovascular morbidity and mortality in patients with established CHD

  • Potential biological and behavioural mechanisms for this risk have been identified, but no single factor has been shown to account for more than a fraction of the total risk

  • Very few clinical trials have been conducted to determine whether treating depression decreases the risk of cardiac events in patients with established CHD

  • Each of the trials has substantial shortcomings, and more trials are needed

  • Effective treatments for depression, identification of 'high-risk' depression subtypes, and an improved understanding of the biobehavioural pathways linking depression to cardiac morbidity and mortality are needed

Abstract

Depression is a highly prevalent risk factor for incident coronary heart disease (CHD) and for cardiovascular morbidity and mortality in patients with established CHD. Several biological and behavioural mechanisms have been hypothesized to underlie the relationship between depression and CHD, but none has been shown to account for more than a small proportion of the risk. Only a few clinical trials have examined whether treating depression decreases the risk of cardiac events in patients with established CHD. None of these trials has shown that treatment results in improved cardiac outcomes, but the differences in depression outcomes between the intervention and control groups have been small and not clinically significant. Nevertheless, secondary analyses of these trials suggest that prognosis improves when depression improves. Concerted efforts to develop more potent interventions for depression, identification of high-risk subtypes of depression, and further research on the biobehavioural mechanisms linking depression to CHD are needed to pave the way for definitive clinical trials.

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Figure 1: Potential mechanisms linking depression and coronary heart disease.

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References

  1. Willis, R. The Works of William Harvey (Univ. of Pennsylvania Press, 1989).

    Google Scholar 

  2. Fuller, R. G. What happens to mental patients after discharge from the hospital? Psychiatr. Quart. 9, 95–104 (1935).

    Article  Google Scholar 

  3. Malzberg, B. Mortality among patients with involution melancholia. Am. J. Psychiatry 93, 1231–1238 (1937).

    Article  Google Scholar 

  4. Carney, R. M. et al. Major depressive disorder predicts cardiac events in patients with coronary artery disease. Psychosom. Med. 50, 627–633 (1988).

    Article  CAS  PubMed  Google Scholar 

  5. Frasure-Smith, N., Lesperance, F. & Talajic, M. Depression following myocardial infarction: impact on 6-month survival. JAMA 270, 1819–1825 (1993).

    Article  CAS  PubMed  Google Scholar 

  6. Ladwig, K. H., Kieser, M., Konig, J., Breithardt, G. & Borggrefe, M. Affective disorders and survival after acute myocardial infarction. Results from the post-infarction late potential study. Eur. Heart J. 12, 959–964 (1991).

    CAS  PubMed  Google Scholar 

  7. Silverstone, P. H. Depression and outcome in acute myocardial infarction. Br. Med. J. (Clin. Res. Ed.) 294, 219–220 (1987).

    Article  CAS  Google Scholar 

  8. Bruce, M. L., Leaf, P. J., Rozal, G. P., Florio, L. & Hoff, R. A. Psychiatric status and 9-year mortality data in the New Haven Epidemiologic Catchment Area Study. Am. J. Psychiatry 151, 716–721 (1994).

    Article  CAS  PubMed  Google Scholar 

  9. Murphy, J. M., Monson, R. R., Olivier, D. C., Sobol, A. M. & Leighton, A. H. Affective disorders and mortality: a general population study. Arch. Gen. Psychiatry 44, 473–480 (1987).

    Article  CAS  PubMed  Google Scholar 

  10. Gale, C. R., Batty, G. D., Osborn, D. P., Tynelius, P. & Rasmussen, F. Mental disorders across the adult life course and future coronary heart disease: evidence for general susceptibility. Circulation 129, 186–193 (2014).

    Article  PubMed  Google Scholar 

  11. Roest, A. M., Martens, E. J., de Jonge, P. & Denollet, J. Anxiety and risk of incident coronary heart disease: a meta-analysis. J. Am. Coll. Cardiol. 56, 38–46 (2010).

    Article  PubMed  Google Scholar 

  12. Sowden, G. L. & Huffman, J. C. The impact of mental illness on cardiac outcomes: a review for the cardiologist. Int. J. Cardiol. 132, 30–37 (2009).

    Article  PubMed  Google Scholar 

  13. Vaccarino, V. et al. Post-traumatic stress disorder and incidence of coronary heart disease: a twin study. J. Am. Coll. Cardiol. 62, 970–978 (2013).

    Article  PubMed  Google Scholar 

  14. Bilello, J. A. et al. MDDScore: confirmation of a blood test to aid in the diagnosis of major depressive disorder. J. Clin. Psychiatry 76, e199–e206 (2015).

    Article  PubMed  Google Scholar 

  15. Davidson, K. W. et al. Assessment and treatment of depression in patients with cardiovascular disease: National Heart, Lung, and Blood Institute Working Group Report. Psychosom. Med. 68, 645–650 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-5) 5th edn (American Psychiatric Association, 2013).

  17. Bush, D. E. et al. Even minimal symptoms of depression increase mortality risk after acute myocardial infarction. Am. J. Cardiol. 88, 337–341 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Lesperance, F., Frasure-Smith, N., Talajic, M. & Bourassa, M. G. Five-year risk of cardiac mortality in relation to initial severity and one-year changes in depression symptoms after myocardial infarction. Circulation 105, 1049–1053 (2002).

    Article  PubMed  Google Scholar 

  19. Kroenke, K., Spitzer, R. L. & Williams, J. B. The PHQ-9: validity of a brief depression severity measure. J. Gen. Intern. Med. 16, 606–613 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kroenke, K., Spitzer, R. L. & Williams, J. B. The Patient Health Questionnaire-2: validity of a two-item depression screener. Med. Care 41, 1284–1292 (2003).

    Article  PubMed  Google Scholar 

  21. Thombs, B. D., Ziegelstein, R. C. & Whooley, M. A. Optimizing detection of major depression among patients with coronary artery disease using the patient health questionnaire: data from the Heart and Soul Study. J. Gen. Intern. Med. 23, 2014–2017 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  22. O'Brien, E. C. et al. Depressive symptoms and risk of cardiovascular events in blacks: findings from the Jackson Heart Study. Circ. Cardiovasc. Qual. Outcomes 8, 552–559 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  23. O'Neil, A. et al. Depression is a risk factor for incident coronary heart disease in women: an 18-year longitudinal study. J. Affect. Disord. 196, 117–124 (2016).

    Article  PubMed  Google Scholar 

  24. Penninx, B. W. et al. Cardiovascular events and mortality in newly and chronically depressed persons >70 years of age. Am. J. Cardiol. 81, 988–994 (1998).

    Article  CAS  PubMed  Google Scholar 

  25. Pequignot, R. et al. High level of depressive symptoms at repeated study visits and risk of coronary heart disease and stroke over 10 years in older adults: the Three-City Study. J. Am. Geriatr. Soc. 64, 118–125 (2016).

    Article  PubMed  Google Scholar 

  26. Schulz, R. et al. Association between depression and mortality in older adults: the Cardiovascular Health Study. Arch. Intern. Med. 160, 1761–1768 (2000).

    Article  CAS  PubMed  Google Scholar 

  27. Wassertheil-Smoller, S. et al. Depression and cardiovascular sequelae in postmenopausal women: the Women's Health Initiative (WHI). Arch. Intern. Med. 164, 289–298 (2004).

    Article  PubMed  Google Scholar 

  28. Carney, R. M. & Freedland, K. E. Depression in patients with coronary heart disease. Am. J. Med. 121, S20–S27 (2008).

    Article  Google Scholar 

  29. Cuijpers, P. & Smit, F. Excess mortality in depression: a meta-analysis of community studies. J. Affect. Disord. 72, 227–236 (2002).

    Article  PubMed  Google Scholar 

  30. Nicholson, A., Kuper, H. & Hemingway, H. Depression as an aetiologic and prognostic factor in coronary heart disease: a meta-analysis of 6,362 events among 146,538 participants in 54 observational studies. Eur. Heart J. 27, 2763–2774 (2006).

    Article  PubMed  Google Scholar 

  31. Rugulies, R. Depression as a predictor for coronary heart disease. a review and meta-analysis. Am. J. Prev. Med. 23, 51–61 (2002).

    Article  PubMed  Google Scholar 

  32. Van der Kooy, K. et al. Depression and the risk for cardiovascular diseases: systematic review and meta analysis. Int. J. Geriatr. Psychiatry 22, 613–626 (2007).

    Article  PubMed  Google Scholar 

  33. Wulsin, L. R. & Singal, B. M. Do depressive symptoms increase the risk for the onset of coronary disease? A systematic quantitative review. Psychosom. Med. 65, 201–210 (2003).

    Article  PubMed  Google Scholar 

  34. Gan, Y. et al. Depression and the risk of coronary heart disease: a meta-analysis of prospective cohort studies. BMC Psychiatry 14, 371 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Surtees, P. G. et al. Depression and ischemic heart disease mortality: evidence from the EPIC-Norfolk United Kingdom prospective cohort study. Am. J. Psychiatry 165, 515–523 (2008).

    Article  PubMed  Google Scholar 

  36. Goldstein, B. I. et al. Major depressive disorder and bipolar disorder predispose youth to accelerated atherosclerosis and early cardiovascular disease: a scientific statement from the American Heart Association. Circulation 132, 965–986 (2015).

    Article  PubMed  Google Scholar 

  37. Thombs, B. D. et al. Prevalence of depression in survivors of acute myocardial infarction. J. Gen. Intern. Med. 21, 30–38 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Blazer, D. G., Kessler, R. C., McGonagle, K. A. & Swartz, M. S. The prevalence and distribution of major depression in a national community sample: the National Comorbidity Survey. Am. J. Psychiatry 151, 979–986 (1994).

    Article  CAS  PubMed  Google Scholar 

  39. Meijer, A. et al. Adjusted prognostic association of depression following myocardial infarction with mortality and cardiovascular events: individual patient data meta-analysis. Br. J. Psychiatry 203, 90–102 (2013).

    Article  CAS  PubMed  Google Scholar 

  40. Meijer, A. et al. Prognostic association of depression following myocardial infarction with mortality and cardiovascular events: a meta-analysis of 25 years of research. Gen. Hosp. Psychiatry 33, 203–216 (2011).

    Article  PubMed  Google Scholar 

  41. van Melle, J. P. et al. Prognostic association of depression following myocardial infarction with mortality and cardiovascular events: a meta-analysis. Psychosom. Med. 66, 814–822 (2004).

    Article  PubMed  Google Scholar 

  42. Barth, J., Schumacher, M. & Herrmann-Lingen, C. Depression as a risk factor for mortality in patients with coronary heart disease: a meta-analysis. Psychosom. Med. 66, 802–813 (2004).

    Article  PubMed  Google Scholar 

  43. Carney, R. M. et al. Depression as a risk factor for mortality after acute myocardial infarction. Am. J. Cardiol. 92, 1277–1281 (2003).

    Article  PubMed  Google Scholar 

  44. de Jonge, P. & Roest, A. M. Depression and cardiovascular disease: the end of simple models. Br. J. Psychiatry 201, 337–338 (2012).

    Article  PubMed  Google Scholar 

  45. Babyak, M. A. What you see may not be what you get: a brief, nontechnical introduction to overfitting in regression-type models. Psychosom. Med. 66, 411–421 (2004).

    PubMed  Google Scholar 

  46. Kronish, I. M., Rieckmann, N., Schwartz, J. E., Schwartz, D. R. & Davidson, K. W. Is depression after an acute coronary syndrome simply a marker of known prognostic factors for mortality? Psychosom. Med. 71, 697–703 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Meurs, M., Zuidersma, M., Dickens, C. & de Jonge, P. Examining the relation between post myocardial infarction depression and cardiovascular prognosis using a validated prediction model for post myocardial mortality. Int. J. Cardiol. 167, 2533–2538 (2013).

    Article  PubMed  Google Scholar 

  48. Eagle, K. A. et al. A validated prediction model for all forms of acute coronary syndrome: estimating the risk of 6-month postdischarge death in an international registry. JAMA 291, 2727–2733 (2004).

    Article  CAS  PubMed  Google Scholar 

  49. Fox, K. A. et al. The Global Registry of Acute Coronary Events, 1999 to 2009—GRACE. Heart 96, 1095–1101 (2010).

    Article  CAS  PubMed  Google Scholar 

  50. Lichtman, J. H. et al. Depression as a risk factor for poor prognosis among patients with acute coronary syndrome: systematic review and recommendations: a scientific statement from the American Heart Association. Circulation 129, 1350–1369 (2014).

    Article  PubMed  Google Scholar 

  51. Carney, R. M., Freedland, K. E., Miller, G. E. & Jaffe, A. S. Depression as a risk factor for cardiac mortality and morbidity: a review of potential mechanisms. J. Psychosom. Res. 53, 897–902 (2002).

    Article  PubMed  Google Scholar 

  52. Carney, R. M., Freedland, K. E., Rich, M. W. & Jaffe, A. S. Depression as a risk factor for cardiac events in established coronary heart disease: a review of possible mechanisms. Ann. Behav. Med. 17, 142–149 (1995).

    Article  CAS  PubMed  Google Scholar 

  53. Lett, H. S. et al. Depression as a risk factor for coronary artery disease: evidence, mechanisms, and treatment. Psychosom. Med. 66, 305–315 (2004).

    PubMed  Google Scholar 

  54. Skala, J. A., Freedland, K. E. & Carney, R. M. Coronary heart disease and depression: a review of recent mechanistic research. Can. J. Psychiatry 51, 738–745 (2006).

    Article  PubMed  Google Scholar 

  55. Nemeroff, C. B. & Goldschmidt-Clermont, P. J. Heartache and heartbreak — the link between depression and cardiovascular disease. Nat. Rev. Cardiol. 9, 526–539 (2012).

    Article  CAS  PubMed  Google Scholar 

  56. Esler, M. et al. The peripheral kinetics of norepinephrine in depressive illness. Arch. Gen. Psychiatry 39, 295–300 (1982).

    Article  CAS  PubMed  Google Scholar 

  57. Lake, C. R. et al. High plasma norepinephrine levels in patients with major affective disorder. Am. J. Psychiatry 139, 1315–1318 (1982).

    Article  CAS  PubMed  Google Scholar 

  58. Roy, A., Pickar, D., De Jong, J., Karoum, F. & Linnoila, M. Norepinephrine and its metabolites in cerebrospinal fluid, plasma, and urine: relationship to hypothalamic–pituitary–adrenal axis function in depression. Arch. Gen. Psychiatry 45, 849–857 (1988).

    Article  CAS  PubMed  Google Scholar 

  59. Siever, L. J. & Davis, K. L. Overview: toward a dysregulation hypothesis of depression. Am. J. Psychiatry 142, 1017–1031 (1985).

    Article  CAS  PubMed  Google Scholar 

  60. Veith, R. C. et al. Sympathetic nervous system activity in major depression: basal and desipramine-induced alterations in plasma norepinephrine kinetics. Arch. Gen. Psychiatry 51, 411–422 (1994).

    Article  CAS  PubMed  Google Scholar 

  61. Charlton, B. G., Leake, A., Wright, C., Griffiths, H. W. & Ferrier, I. N. A combined study of cortisol, ACTH and dexamethasone concentrations in major depression. Multiple time-point sampling. Br. J. Psychiatry 150, 791–796 (1987).

    Article  CAS  PubMed  Google Scholar 

  62. Ribeiro, S. C., Tandon, R., Grunhaus, L. & Greden, J. F. The DST as a predictor of outcome in depression: a meta-analysis. Am. J. Psychiatry 150, 1618–1629 (1993).

    Article  CAS  PubMed  Google Scholar 

  63. Carney, R. M. et al. Change in heart rate and heart rate variability during treatment for depression in patients with coronary heart disease. Psychosom. Med. 62, 639–647 (2000).

    Article  CAS  PubMed  Google Scholar 

  64. Carney, R. M. et al. The relationship between heart rate, heart rate variability and depression in patients with coronary artery disease. J. Psychosom. Res. 32, 159–164 (1988).

    Article  CAS  PubMed  Google Scholar 

  65. Stein, P. K. et al. Severe depression is associated with markedly reduced heart rate variability in patients with stable coronary heart disease. J. Psychosom. Res. 48, 493–500 (2000).

    Article  CAS  PubMed  Google Scholar 

  66. Carney, R. M. et al. Major depression, heart rate, and plasma norepinephrine in patients with coronary heart disease. Biol. Psychiatry 45, 458–463 (1999).

    Article  CAS  PubMed  Google Scholar 

  67. Carney, R. M. et al. Depression, heart rate variability, and acute myocardial infarction. Circulation 104, 2024–2028 (2001).

    Article  CAS  PubMed  Google Scholar 

  68. Pitzalis, M. V. et al. Depression but not anxiety influences the autonomic control of heart rate after myocardial infarction. Am. Heart J. 141, 765–771 (2001).

    Article  CAS  PubMed  Google Scholar 

  69. Watkins, L. L. & Grossman, P. Association of depressive symptoms with reduced baroreflex cardiac control in coronary artery disease. Am. Heart J. 137, 453–457 (1999).

    Article  CAS  PubMed  Google Scholar 

  70. Carney, R. M. et al. Effects of depression on QT interval variability after myocardial infarction. Psychosom. Med. 65, 177–180 (2003).

    Article  PubMed  Google Scholar 

  71. Carney, R. M. et al. Heart rate turbulence, depression, and survival after acute myocardial infarction. Psychosom. Med. 69, 4–9 (2007).

    Article  PubMed  Google Scholar 

  72. Carney, R. M., Freedland, K. E. & Veith, R. C. Depression, the autonomic nervous system, and coronary heart disease. Psychosom. Med. 67 (Suppl. 1), S29–S33 (2005).

    Article  PubMed  Google Scholar 

  73. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability: standards of measurement, physiological interpretation and clinical use. Circulation 93, 1043–1065 (1996).

  74. Bigger, J. T. Jr, Fleiss, J. L., Rolnitzky, L. M. & Steinman, R. C. Frequency domain measures of heart period variability to assess risk late after myocardial infarction. J. Am. Coll. Cardiol. 21, 729–736 (1993).

    Article  PubMed  Google Scholar 

  75. Bigger, J. T. Jr et al. Frequency domain measures of heart period variability and mortality after myocardial infarction. Circulation 85, 164–171 (1992).

    Article  PubMed  Google Scholar 

  76. Kleiger, R. E., Miller, J. P., Bigger, J. T. Jr & Moss, A. J. Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. Am. J. Cardiol. 59, 256–262 (1987).

    Article  CAS  PubMed  Google Scholar 

  77. Vaishnav, S. et al. Relation between heart rate variability early after acute myocardial infarction and long-term mortality. Am. J. Cardiol. 73, 653–657 (1994).

    Article  CAS  PubMed  Google Scholar 

  78. Rich, M. W. et al. Correlation of heart rate variability with clinical and angiographic variables and late mortality after coronary angiography. Am. J. Cardiol. 62, 714–717 (1988).

    Article  CAS  PubMed  Google Scholar 

  79. Kang, H. J. et al. Predictors of depressive disorder following acute coronary syndrome: results from K-DEPACS and EsDEPACS. J. Affect. Disord. 181, 1–8 (2015).

    Article  PubMed  Google Scholar 

  80. Krittayaphong, R. et al. Heart rate variability in patients with coronary artery disease: differences in patients with higher and lower depression scores. Psychosom. Med. 59, 231–235 (1997).

    Article  CAS  PubMed  Google Scholar 

  81. Gehi, A., Mangano, D., Pipkin, S., Browner, W. S. & Whooley, M. A. Depression and heart rate variability in patients with stable coronary heart disease: findings from the Heart and Soul Study. Arch. Gen. Psychiatry 62, 661–666 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  82. de Jonge, P., Mangano, D. & Whooley, M. A. Differential association of cognitive and somatic depressive symptoms with heart rate variability in patients with stable coronary heart disease: findings from the Heart and Soul Study. Psychosom. Med. 69, 735–739 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Berkman, L. F. 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 289, 3106–3116 (2003).

    Article  PubMed  Google Scholar 

  84. Carney, R. M. et al. Low heart rate variability and the effect of depression on post-myocardial infarction mortality. Arch. Intern. Med. 165, 1486–1491 (2005).

    Article  PubMed  Google Scholar 

  85. Taylor, J. A., Carr, D. L., Myers, C. W. & Eckberg, D. L. Mechanisms underlying very-low-frequency RR-interval oscillations in humans. Circulation 98, 547–555 (1998).

    Article  CAS  PubMed  Google Scholar 

  86. Whooley, M. A. et al. Depressive symptoms, health behaviors, and risk of cardiovascular events in patients with coronary heart disease. JAMA 300, 2379–2388 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Miller, A. H., Maletic, V. & Raison, C. L. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol. Psychiatry 65, 732–741 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Howren, M. B., Lamkin, D. M. & Suls, J. Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom. Med. 71, 171–186 (2009).

    Article  CAS  PubMed  Google Scholar 

  89. Miller, G. E., Freedland, K. E., Carney, R. M., Stetler, C. A. & Banks, W. A. Cynical hostility, depressive symptoms, and the expression of inflammatory risk markers for coronary heart disease. J. Behav. Med. 26, 501–515 (2003).

    Article  PubMed  Google Scholar 

  90. Miller, G. E., Freedland, K. E., Duntley, S. & Carney, R. M. Relation of depressive symptoms to C-reactive protein and pathogen burden (cytomegalovirus, herpes simplex virus, Epstein-Barr virus) in patients with earlier acute coronary syndromes. Am. J. Cardiol. 95, 317–321 (2005).

    Article  CAS  PubMed  Google Scholar 

  91. Dowlati, Y. et al. A meta-analysis of cytokines in major depression. Biol. Psychiatry 67, 446–457 (2010).

    Article  CAS  PubMed  Google Scholar 

  92. Danesh, J., Collins, R., Appleby, P. & Peto, R. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies. JAMA 279, 1477–1482 (1998).

    Article  CAS  PubMed  Google Scholar 

  93. Ridker, P. M., Glynn, R. J. & Hennekens, C. H. C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction. Circulation 97, 2007–2011 (1998).

    Article  CAS  PubMed  Google Scholar 

  94. Ridker, P. M., Hennekens, C. H., Buring, J. E. & Rifai, N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N. Engl. J. Med. 342, 836–843 (2000).

    Article  CAS  PubMed  Google Scholar 

  95. Ridker, P. M. et al. Elevation of tumor necrosis factor-α and increased risk of recurrent coronary events after myocardial infarction. Circulation 101, 2149–2153 (2000).

    Article  CAS  PubMed  Google Scholar 

  96. Ridker, P. M., Rifai, N., Stampfer, M. J. & Hennekens, C. H. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 101, 1767–1772 (2000).

    Article  CAS  PubMed  Google Scholar 

  97. Gimeno, D. et al. Associations of C-reactive protein and interleukin-6 with cognitive symptoms of depression: 12-year follow-up of the Whitehall II study. Psychol. Med. 39, 413–423 (2009).

    Article  CAS  PubMed  Google Scholar 

  98. Stewart, J. C. One effect size does not fit all — is the depression-inflammation link missing in racial/ethnic minority individuals? JAMA Psychiatry 73, 301–302 (2016).

    Article  PubMed  Google Scholar 

  99. Davidson, K. W. et al. Relation of inflammation to depression and incident coronary heart disease (from the Canadian Nova Scotia Health Survey [NSHS95] Prospective Population Study). Am. J. Cardiol. 103, 755–761 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Empana, J. P. et al. Contributions of depressive mood and circulating inflammatory markers to coronary heart disease in healthy European men: the Prospective Epidemiological Study of Myocardial Infarction (PRIME). Circulation 111, 2299–2305 (2005).

    Article  CAS  PubMed  Google Scholar 

  101. Hiles, S. A. et al. The role of inflammatory markers in explaining the association between depression and cardiovascular hospitalisations. J. Behav. Med. 38, 609–619 (2015).

    Article  PubMed  Google Scholar 

  102. Kop, W. J. et al. Autonomic nervous system dysfunction and inflammation contribute to the increased cardiovascular mortality risk associated with depression. Psychosom. Med. 72, 626–635 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Vaccarino, V. et al. Depression, inflammation, and incident cardiovascular disease in women with suspected coronary ischemia: the National Heart, Lung, and Blood Institute-sponsored WISE study. J. Am. Coll. Cardiol. 50, 2044–2050 (2007).

    Article  PubMed  Google Scholar 

  104. Surtees, P. G. et al. Major depression, C-reactive protein, and incident ischemic heart disease in healthy men and women. Psychosom. Med. 70, 850–855 (2008).

    Article  CAS  PubMed  Google Scholar 

  105. Schins, A. et al. Inflammatory markers in depressed post-myocardial infarction patients. J. Psychiatr. Res. 39, 137–144 (2005).

    Article  PubMed  Google Scholar 

  106. Smolderen, K. G. et al. Association of somatic and cognitive depressive symptoms and biomarkers in acute myocardial infarction: insights from the translational research investigating underlying disparities in acute myocardial infarction patients' health status registry. Biol. Psychiatry 71, 22–29 (2012).

    Article  CAS  PubMed  Google Scholar 

  107. Glassman, A. H. & Miller, G. E. Where there is depression, there is inflammation... sometimes! Biol. Psychiatry 62, 280–281 (2007).

    Article  PubMed  Google Scholar 

  108. Shimbo, D., Rieckmann, N., Paulino, R. & Davidson, K. W. Relation between C reactive protein and depression remission status in patients presenting with acute coronary syndrome. Heart 92, 1316–1318 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Shimokawa, H. Primary endothelial dysfunction: atherosclerosis. J. Mol. Cell. Cardiol. 31, 23–37 (1999).

    Article  CAS  PubMed  Google Scholar 

  110. Broadley, A. J., Korszun, A., Jones, C. J. & Frenneaux, M. P. Arterial endothelial function is impaired in treated depression. Heart 88, 521–523 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Cooper, D. C. et al. Depressed mood and flow-mediated dilation: a systematic review and meta-analysis. Psychosom. Med. 73, 360–369 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Rajagopalan, S. et al. Abnormal brachial artery flow-mediated vasodilation in young adults with major depression. Am. J. Cardiol. 88, 196–198 (2001).

    Article  CAS  PubMed  Google Scholar 

  113. Rybakowski, J. K., Wykretowicz, A., Heymann-Szlachcinska, A. & Wysocki, H. Impairment of endothelial function in unipolar and bipolar depression. Biol. Psychiatry 60, 889–891 (2006).

    Article  CAS  PubMed  Google Scholar 

  114. Sherwood, A., Hinderliter, A. L., Watkins, L. L., Waugh, R. A. & Blumenthal, J. A. Impaired endothelial function in coronary heart disease patients with depressive symptomatology. J. Am. Coll. Cardiol. 46, 656–659 (2005).

    Article  PubMed  Google Scholar 

  115. Corretti, M. C. et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J. Am. Coll. Cardiol. 39, 257–265 (2002).

    Article  PubMed  Google Scholar 

  116. Kuijpers, P. M., Hamulyak, K., Strik, J. J., Wellens, H. J. & Honig, A. Beta-thromboglobulin and platelet factor 4 levels in post-myocardial infarction patients with major depression. Psychiatry Res. 109, 207–210 (2002).

    Article  CAS  PubMed  Google Scholar 

  117. Serebruany, V. L. et al. Enhanced platelet/endothelial activation in depressed patients with acute coronary syndromes: evidence from recent clinical trials. Blood Coagul. Fibrinolysis 14, 563–567 (2003).

    Article  PubMed  Google Scholar 

  118. Shimbo, D. et al. Exaggerated serotonin-mediated platelet reactivity as a possible link in depression and acute coronary syndromes. Am. J. Cardiol. 89, 331–333 (2002).

    Article  CAS  PubMed  Google Scholar 

  119. von Kanel, R. Platelet hyperactivity in clinical depression and the beneficial effect of antidepressant drug treatment: how strong is the evidence? Acta Psychiatr. Scand. 110, 163–177 (2004).

    Article  CAS  PubMed  Google Scholar 

  120. Gurbel, P. A., Becker, R. C., Mann, K. G., Steinhubl, S. R. & Michelson, A. D. Platelet function monitoring in patients with coronary artery disease. J. Am. Coll. Cardiol. 50, 1822–1834 (2007).

    Article  CAS  PubMed  Google Scholar 

  121. DiMatteo, M. R., Lepper, H. S. & Croghan, T. W. Depression is a risk factor for noncompliance with medical treatment: meta-analysis of the effects of anxiety and depression on patient adherence. Arch. Intern. Med. 160, 2101–2107 (2000).

    Article  CAS  PubMed  Google Scholar 

  122. Carney, R. M., Freedland, K. E., Eisen, S. A., Rich, M. W. & Jaffe, A. S. Major depression and medication adherence in elderly patients with coronary artery disease. Health Psychol. 14, 88–90 (1995).

    Article  PubMed  Google Scholar 

  123. Gehi, A., Haas, D., Pipkin, S. & Whooley, M. A. Depression and medication adherence in outpatients with coronary heart disease: findings from the Heart and Soul Study. Arch. Intern. Med. 165, 2508–2513 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  124. Rieckmann, N. et al. Course of depressive symptoms and medication adherence after acute coronary syndromes: an electronic medication monitoring study. J. Am. Coll. Cardiol. 48, 2218–2222 (2006).

    Article  PubMed  Google Scholar 

  125. Ziegelstein, R. C. et al. Patients with depression are less likely to follow recommendations to reduce cardiac risk during recovery from a myocardial infarction. Arch. Intern. Med. 160, 1818–1823 (2000).

    Article  CAS  PubMed  Google Scholar 

  126. Kumbhani, D. J. et al. Adherence to secondary prevention medications and four-year outcomes in outpatients with atherosclerosis. Am. J. Med. 126, 693–700. e1 (2013).

    Article  PubMed  Google Scholar 

  127. Boschloo, L., Reeuwijk, K. G., Schoevers, R. A. & Penninx, B. W. J. H. The impact of lifestyle factors on the 2-year course of depressive and/or anxiety disorders. J. Affect. Disord. 159, 73–79 (2014).

    Article  PubMed  Google Scholar 

  128. Roshanaei-Moghaddam, B., Katon, W. J. & Russo, J. The longitudinal effects of depression on physical activity. Gen. Hosp. Psychiatry 31, 306–315 (2009).

    Article  PubMed  Google Scholar 

  129. Brummett, B. H. et al. Effect of smoking and sedentary behavior on the association between depressive symptoms and mortality from coronary heart disease. Am. J. Cardiol. 92, 529–532 (2003).

    Article  PubMed  Google Scholar 

  130. Kurdyak, P. A., Chong, A., Gnam, W. H., Goering, P. & Alter, D. A. Depression and self-reported functional status: impact on mortality following acute myocardial infarction. J. Eval. Clin. Pract. 17, 444–451 (2011).

    Article  PubMed  Google Scholar 

  131. Win, S. et al. Depressive symptoms, physical inactivity and risk of cardiovascular mortality in older adults: the Cardiovascular Health Study. Heart 97, 500–505 (2011).

    Article  PubMed  Google Scholar 

  132. Larsen, K. K., Christensen, B., Sondergaard, J. & Vestergaard, M. Depressive symptoms and risk of new cardiovascular events or death in patients with myocardial infarction: a population-based longitudinal study examining health behaviors and health care interventions. PLoS ONE 8, e74393 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Kamphuis, M. H. et al. Physical inactivity, depression, and risk of cardiovascular mortality. Med. Sci. Sports Exerc. 39, 1693–1699 (2007).

    Article  PubMed  Google Scholar 

  134. Burg, M. M. et al. The 'perfect storm' and acute coronary syndrome onset: do psychosocial factors play a role? Prog. Cardiovasc. Dis. 55, 601–610 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Freedland, K. E. et al. Treatment of depression after coronary artery bypass surgery. Arch. Gen. Psychiatry 66, 387–396 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  136. Glassman, A. H. et al. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA 288, 701–709 (2002).

    Article  CAS  PubMed  Google Scholar 

  137. Honig, A. et al. Treatment of post-myocardial infarction depressive disorder: a randomized, placebo-controlled trial with mirtazapine. Psychosom. Med. 69, 606–613 (2007).

    Article  CAS  PubMed  Google Scholar 

  138. Lesperance, F. 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 297, 367–379 (2007).

    Article  CAS  PubMed  Google Scholar 

  139. Strik, J. J. 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. 62, 783–789 (2000).

    Article  CAS  PubMed  Google Scholar 

  140. van Melle, J. P. et al. Effects of antidepressant treatment following myocardial infarction. Br. J. Psychiatry 190, 460–466 (2007).

    Article  PubMed  Google Scholar 

  141. Davidson, K. W. et al. Centralized, stepped, patient preference-based treatment for patients with post-acute coronary syndrome depression: CODIACS vanguard randomized controlled trial. JAMA Intern. Med. 173, 997–1004 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Herrmann-Lingen, C. et al. A stepwise psychotherapy intervention for reducing risk in coronary artery disease (SPIRR-CAD): results of an observer-blinded, multicenter, randomized trial in depressed patients with coronary artery disease. Psychosom. Med. 78, 704–715 (2016).

    Article  PubMed  Google Scholar 

  143. Thombs, B. D. et al. Depression screening and patient outcomes in cardiovascular care. JAMA 300, 2161–2171 (2008).

    Article  CAS  PubMed  Google Scholar 

  144. Khan, A., Leventhal, R. M., Khan, S. R. & Brown, W. A. Severity of depression and response to antidepressants and placebo: an analysis of the Food and Drug Administration database. J. Clin. Psychopharmacol. 22, 40–45 (2002).

    Article  PubMed  Google Scholar 

  145. Kirsch, I. et al. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med. 5, e45 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  146. Davidson, K. W. et al. Enhanced depression care for patients with acute coronary syndrome and persistent depressive symptoms: coronary psychosocial evaluation studies randomized controlled trial. Arch. Intern. Med. 170, 600–608 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Ye, S. et al. Long-term outcomes of enhanced depression treatment in patients with acute coronary syndromes. Am. J. Med. 127, 1012–1016 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  148. Pizzi, C. et al. Meta-analysis of selective serotonin reuptake inhibitors in patients with depression and coronary heart disease. Am. J. Cardiol. 107, 972–979 (2011).

    Article  CAS  PubMed  Google Scholar 

  149. Carney, R. M. et al. Depression and late mortality after myocardial infarction in the Enhancing Recovery in Coronary Heart Disease (ENRICHD). Psychosom. Med. 66, 466–474 (2004).

    Article  PubMed  Google Scholar 

  150. Glassman, A. H., Bigger, J. T. Jr & Gaffney, M. Psychiatric characteristics associated with long-term mortality among 361 patients having an acute coronary syndrome and major depression. Arch. Gen. Psychiatry 66, 1022–1029 (2009).

    Article  PubMed  Google Scholar 

  151. de Jonge, P. et al. Nonresponse to treatment for depression following myocardial infarction: association with subsequent cardiac events. Am. J. Psychiatry 164, 1371–1378 (2007).

    Article  PubMed  Google Scholar 

  152. Milani, R. V. & Lavie, C. J. Impact of cardiac rehabilitation on depression and its associated mortality. Am. J. Med. 120, 799–806 (2007).

    Article  PubMed  Google Scholar 

  153. Chung, M. L., Dekker, R. L., Lennie, T. A. & Moser, D. K. Antidepressants do not improve event-free survival in patients with heart failure when depressive symptoms remain. Heart Lung 42, 85–91 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  154. Jiang, W. et al. Characteristics of depression remission and its relation with cardiovascular outcome among patients with chronic heart failure. Am. J. Cardiol. 107, 545–551 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  155. Rafanelli, C., Sirri, L., Grandi, S. & Fava, G. A. Is depression the wrong treatment target for improving outcome in coronary artery disease? Psychother. Psychosom. 82, 285–291 (2013).

    Article  PubMed  Google Scholar 

  156. Hartley, A. et al. Trends in mortality from ischemic heart disease and cerebrovascular disease in Europe: 1980 to 2009. Circulation 133, 1916–1926 (2016).

    Article  PubMed  Google Scholar 

  157. Rodriguez, T. et al. Trends in mortality from coronary heart and cerebrovascular diseases in the Americas: 1970–2000. Heart 92, 453–460 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Duivis, H. E. et al. Depressive symptoms, health behaviors, and subsequent inflammation in patients with coronary heart disease: prospective findings from the Heart and Soul Study. Am. J. Psychiatry 168, 913–920 (2011).

    Article  PubMed  Google Scholar 

  159. Morris, A. A. et al. Association between depression and inflammation — differences by race and sex: the META-Health study. Psychosom. Med. 73, 462–468 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Whooley, M. A. et al. Depression and inflammation in patients with coronary heart disease: findings from the Heart and Soul Study. Biol. Psychiatry 62, 314–320 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Carney, R. M. & Freedland, K. E. Is there a high-risk subtype of depression in patients with coronary heart disease? Curr. Psychiatry Rep. 14, 1–7 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  162. Carney, R. M. & Freedland, K. E. Are somatic symptoms of depression better predictors of cardiac events than cognitive symptoms in coronary heart disease? Psychosom. Med. 74, 33–38 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  163. de Miranda Azevedo, R., Roest, A. M., Hoen, P. W. & de Jonge, P. Cognitive/affective and somatic/affective symptoms of depression in patients with heart disease and their association with cardiovascular prognosis: a meta-analysis. Psychol. Med. 44, 2689–2703 (2014).

    Article  CAS  PubMed  Google Scholar 

  164. Fava, M. et al. A cross-sectional study of the prevalence of cognitive and physical symptoms during long-term antidepressant treatment. J. Clin. Psychiatry 67, 1754–1759 (2006).

    Article  PubMed  Google Scholar 

  165. McClintock, S. M. et al. Residual symptoms in depressed outpatients who respond by 50% but do not remit to antidepressant medication. J. Clin. Psychopharmacol. 31, 180–186 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  166. Nierenberg, A. A. et al. Residual symptoms in depressed patients who respond acutely to fluoxetine. J. Clin. Psychiatry 60, 221–225 (1999).

    Article  CAS  PubMed  Google Scholar 

  167. Zajecka, J. M. Residual symptoms and relapse: mood, cognitive symptoms, and sleep disturbances. J. Clin. Psychiatry 74 (Suppl. 2), 9–13 (2013).

    Article  PubMed  Google Scholar 

  168. Conradi, H. J., Ormel, J. & de Jonge, P. Presence of individual (residual) symptoms during depressive episodes and periods of remission: a 3-year prospective study. Psychol. Med. 41, 1165–1174 (2011).

    Article  CAS  PubMed  Google Scholar 

  169. Carney, C. E., Segal, Z. V., Edinger, J. D. & Krystal, A. D. A comparison of rates of residual insomnia symptoms following pharmacotherapy or cognitive-behavioral therapy for major depressive disorder. J. Clin. Psychiatry 68, 254–260 (2007).

    Article  CAS  PubMed  Google Scholar 

  170. Kang, E. H. et al. Mirtazapine versus venlafaxine for the treatment of somatic symptoms associated with major depressive disorder: a randomized, open-labeled trial. Psychiatry Res. 169, 118–123 (2009).

    Article  CAS  PubMed  Google Scholar 

  171. Nelson, J. C., Portera, L. & Leon, A. C. Are there differences in the symptoms that respond to a selective serotonin or norepinephrine reuptake inhibitor? Biol. Psychiatry 57, 1535–1542 (2005).

    Article  CAS  PubMed  Google Scholar 

  172. Stewart, J. G. & Harkness, K. L. Symptom specificity in the acute treatment of major depressive disorder: a re-analysis of the treatment of depression collaborative research program. J. Affect. Disord. 137, 87–97 (2012).

    Article  PubMed  Google Scholar 

  173. Blumenthal, J. A. et al. Exercise, depression, and mortality after myocardial infarction in the ENRICHD trial. Med. Sci. Sports Exerc. 36, 746–755 (2004).

    Article  PubMed  Google Scholar 

  174. Daley, A. Exercise and depression: a review of reviews. J. Clin. Psychol. Med. Settings 15, 140–147 (2008).

    Article  PubMed  Google Scholar 

  175. Mead, G. E. et al. Exercise for depression. Cochrane Database of Systematic Reviews, Issue 3. Art. No.: CD004366. http://dx.doi.org/10.1002/14651858.CD004366.pub4 (2009).

    Google Scholar 

  176. Rethorst, C. D., Wipfli, B. M. & Landers, D. M. The antidepressive effects of exercise: a meta-analysis of randomized trials. Sports Med. 39, 491–511 (2009).

    Article  PubMed  Google Scholar 

  177. Poirier, P. Exercise, heart rate variability, and longevity: the cocoon mystery? Circulation 129, 2085–2087 (2014).

    Article  PubMed  Google Scholar 

  178. Rutledge, T., Redwine, L. S., Linke, S. E. & Mills, P. J. A meta-analysis of mental health treatments and cardiac rehabilitation for improving clinical outcomes and depression among patients with coronary heart disease. Psychosom. Med. 75, 335–349 (2013).

    Article  PubMed  Google Scholar 

  179. Sandercock, G. R., Bromley, P. D. & Brodie, D. A. Effects of exercise on heart rate variability: inferences from meta-analysis. Med. Sci. Sports Exerc. 37, 433–439 (2005).

    Article  PubMed  Google Scholar 

  180. Beavers, K. M., Brinkley, T. E. & Nicklas, B. J. Effect of exercise training on chronic inflammation. Clin. Chim. Acta 411, 785–793 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Pedersen, B. K. & Fischer, C. P. Physiological roles of muscle-derived interleukin-6 in response to exercise. Curr. Opin. Clin. Nutr. Metab. Care 10, 265–271 (2007).

    Article  CAS  PubMed  Google Scholar 

  182. Pedersen, M. et al. Circulating levels of TNF-α and IL-6-relation to truncal fat mass and muscle mass in healthy elderly individuals and in patients with type-2 diabetes. Mech. Ageing Dev. 124, 495–502 (2003).

    Article  CAS  PubMed  Google Scholar 

  183. Ploeger, H. E., Takken, T., de Greef, M. H. & Timmons, B. W. The effects of acute and chronic exercise on inflammatory markers in children and adults with a chronic inflammatory disease: a systematic review. Exerc. Immunol. Rev. 15, 6–41 (2009).

    PubMed  Google Scholar 

  184. Edinger, J. D., Wohlgemuth, W. K., Radtke, R. A., Marsh, G. R. & Quillian, R. E. Cognitive behavioral therapy for treatment of chronic primary insomnia: a randomized controlled trial. JAMA 285, 1856–1864 (2001).

    Article  CAS  PubMed  Google Scholar 

  185. Morin, C. M. et al. Cognitive behavioral therapy, singly and combined with medication, for persistent insomnia: a randomized controlled trial. JAMA 301, 2005–2015 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Sivertsen, B. et al. Cognitive behavioral therapy versus zopiclone for treatment of chronic primary insomnia in older adults: a randomized controlled trial. JAMA 295, 2851–2858 (2006).

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors are supported by grant number R01HL089336 from the National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, Maryland, USA.

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R.M.C. or a member of his family owns stock in Pfizer. K.E.F. declares no competing interests.

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Carney, R., Freedland, K. Depression and coronary heart disease. Nat Rev Cardiol 14, 145–155 (2017). https://doi.org/10.1038/nrcardio.2016.181

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