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Antidepressant Use, Depression, and Poor Cardiovascular Outcomes: The Chicken or the Egg?: Comment on “Antidepressant Use and Risk of Incident Cardiovascular Morbidity and Mortality Among Postmenopausal Women in the Women's Health Initiative Study”

Antidepressant Use, Depression, and Poor Cardiovascular Outcomes: The Chicken or the Egg?:... Depression is a common comorbidity in patients with chronic heart failure, with reported incidence as high as approximately 48% in this patient population.1-4 Studies have shown that depression in patients with heart failure is strongly associated with worse outcomes and is an independent predictor of increased mortality and hospitalization.5-9 As a result, the use of antidepressants in this population has become more prevalent. Some studies have shown improvements in cardiovascular outcomes and functional status with the use of selective serotonin reuptake inhibitors (SSRIs) with no adverse safety signals observed.6,10,11 However, other studies of tricyclic antidepressants (TCAs) and SSRIs have raised questions regarding the safety of these antidepressants for use in patients with cardiac disease because treatment with these agents was associated with increased risk of myocardial infarction or cardiovascular death.12,13 Most notably, in the Cardiac Arrhythmia Suppression Trial,14 TCAs were found to be associated with an increase in mortality. This long-standing controversy has been fueled by studies with insufficient power to properly address the question. The study by Smoller et al is an important addition to the literature. It prospectively examines the relationship between antidepressant use and cardiovascular morbidity and mortality in a large cohort of postmenopausal women in the Women's Health Initiative (WHI) study.15-20 The findings, in the largest cohort of women yet studied, provide additional warning that antidepressant therapy may in fact be detrimental with respect to stroke and total mortality in this demographic population. In this study of 136 293 community-dwelling postmenopausal women enrolled in the WHI from 1993 to 1998, the authors found that antidepressant use was not associated with incident coronary heart disease. However, SSRI use was associated with an increased risk of stroke and all-cause mortality, and TCA use was associated with an increased risk of all-cause mortality. There were no significant differences between SSRI and TCA use in risk of any of the outcomes. In secondary analyses by stroke type, SSRI use was associated with incident hemorrhagic stroke. This is an interesting finding because SSRIs have been shown to inhibit platelet function, although the clinical relevance of this property has not been established.21 The authors address the limitations and potential confounding aspects of the use of antidepressants by using a propensity score from a logistic regression model to predict incident antidepressant use. Perhaps the most difficult aspect of these trials is that, as others have shown, the patients who are likely to be treated with antidepressants have additional risk factors for mortality and cardiovascular risks that are difficult to control for. The modest C statistic of 0.69 by logistic regression suggests that the ability to discriminate incident use was not strong. Also, the study cannot fully address cases in which antidepressant therapy fails (ie, patients who begin treatment with antidepressants but experience no remission of their depression symptoms); these patients may represent the highest-risk mortality group. While questions remain on the safety and efficacy of antidepressant use in patients with both depression and heart failure, Smoller et al add important information to the body of literature on this topic. As the authors have concluded, their findings should be considered by physicians to help determine the potential benefit in quality of life and the potential mitigation of morbidity and mortality risk associated with untreated depression in patients with cardiovascular disease. Depression remains an important and underrecognized risk factor for cardiovascular morbidity and mortality in men and women with existing heart disease and/or cardiovascular risk factors. Depression is known to be associated with lower quality of life, unhealthy lifestyle choices, poor adherence to medication regimens, and poor outcomes. Unfortunately, therapies used to alleviate depressive symptoms and depression have not been associated with clear-cut cardiovascular benefits. Cognitive behavioral therapy has been shown to not improve cardiovascular outcomes; in fact it potentially worsens outcomes in women.22 Although smaller studies of SSRIs in patients with cardiovascular disease have suggested that SSRIs are safe, these studies have been significantly underpowered and could not be used to evaluate cardiovascular outcomes. Therefore, an important step in this field would be to embark on a national effort to endorse a large-scale simple trial of antidepressant therapy in patients with cardiovascular disease and to evaluate the influence of this therapy on cardiovascular outcomes such as cardiovascular quality of life, nonfatal cardiovascular events, and mortality. Until then, we are left with the chicken or the egg dilemma. Correspondence: Dr O’Connor, Duke University Medical Center, Division of Cardiology and Clinical Pharmacology, PO Box 3356, Durham, NC 27710 (oconn002@mc.duke.edu). Financial Disclosure: None reported. References 1. Havranek EPWare MGLowes BD Prevalence of depression in congestive heart failure. Am J Cardiol 1999;84 (3) 348- 350, A9PubMedGoogle ScholarCrossref 2. Friedmann EThomas SALiu FMorton PGChapa DGottlieb SSSudden Cardiac Death in Heart Failure Trial Investigators, Relationship of depression, anxiety, and social isolation to chronic heart failure outpatient mortality. Am Heart J 2006;152 (5) 940- e1-e8PubMedGoogle ScholarCrossref 3. MacMahon KMLip GY Psychological factors in heart failure: a review of the literature. Arch Intern Med 2002;162 (5) 509- 516PubMedGoogle ScholarCrossref 4. Gottlieb SSKhatta MFriedmann E et al. The influence of age, gender, and race on the prevalence of depression in heart failure patients. J Am Coll Cardiol 2004;43 (9) 1542- 1549PubMedGoogle ScholarCrossref 5. Sherwood ABlumenthal JATrivedi R et al. Relationship of depression to death or hospitalization in patients with heart failure. Arch Intern Med 2007;167 (4) 367- 373PubMedGoogle ScholarCrossref 6. O'Connor CMJiang WKuchibhatla M et al. Antidepressant use, depression, and survival in patients with heart failure. Arch Intern Med 2008;168 (20) 2232- 2237PubMedGoogle ScholarCrossref 7. Joynt KEWhellan DJO'Connor CM Why is depression bad for the failing heart? a review of the mechanistic relationship between depression and heart failure. J Card Fail 2004;10 (3) 258- 271PubMedGoogle ScholarCrossref 8. Jiang WKuchibhatla MClary GL et al. Relationship between depressive symptoms and long-term mortality in patients with heart failure. Am Heart J 2007;154 (1) 102- 108PubMedGoogle ScholarCrossref 9. Pelle AJGidron YYSzabo BMDenollet J Psychological predictors of prognosis in chronic heart failure. J Card Fail 2008;14 (4) 341- 350PubMedGoogle ScholarCrossref 10. Glassman AHO'Connor CMCaliff RM et al. Sertraline Antidepressant Heart Attack Randomized Trial (SADHEART) Group, Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA 2002;288 (6) 701- 709PubMedGoogle ScholarCrossref 11. Gottlieb SSKop WJThomas SA et al. A double-blind placebo-controlled pilot study of controlled-release paroxetine on depression and quality of life in chronic heart failure. Am Heart J 2007;153 (5) 868- 873PubMedGoogle ScholarCrossref 12. Tata LJWest JSmith C et al. General population based study of the impact of tricyclic and selective serotonin reuptake inhibitor antidepressants on the risk of acute myocardial infarction. Heart 2005;91 (4) 465- 471PubMedGoogle ScholarCrossref 13. Xiong GLJiang WClare R et al. Prognosis of patients taking selective serotonin reuptake inhibitors before coronary artery bypass grafting. Am J Cardiol 2006;98 (1) 42- 47PubMedGoogle ScholarCrossref 14. The Cardiac Arrhythmia Suppression Trial (CAST) Investigators, Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med 1989;321 (6) 406- 412PubMedGoogle ScholarCrossref 15. The Women's Health Initiative Study Group, Design of the Women's Health Initiative clinical trial and observational study. Control Clin Trials 1998;19 (1) 61- 109PubMedGoogle ScholarCrossref 16. Curb JDMcTiernan AHeckbert SR et al. WHI Morbidity and Mortality Committee, Outcomes ascertainment and adjudication methods in the Women's Health Initiative. Ann Epidemiol 2003;13 (9) ((suppl)) S122- S128PubMedGoogle ScholarCrossref 17. Jackson RDLaCroix AZCauley JAMcGowan J The Women's Health Initiative calcium-vitamin D trial: overview and baseline characteristics of participants. Ann Epidemiol 2003;13 (9) ((suppl)) S98- S106PubMedGoogle ScholarCrossref 18. Langer RDWhite ELewis CEKotchen JMHendrix SLTrevisan M The Women's Health Initiative Observational Study: baseline characteristics of participants and reliability of baseline measures. Ann Epidemiol 2003;13 (9) ((suppl)) S107- S121PubMedGoogle ScholarCrossref 19. Ritenbaugh CPatterson REChlebowski RT et al. The Women's Health Initiative Dietary Modification trial: overview and baseline characteristics of participants. Ann Epidemiol 2003;13 (9) ((suppl)) S87- S97PubMedGoogle ScholarCrossref 20. Stefanick MLCochrane BBHsia JBarad DHLiu JHJohnson SR The Women's Health Initiative postmenopausal hormone trials: overview and baseline characteristics of participants. Ann Epidemiol 2003;13 (9) ((suppl)) S78- S86PubMedGoogle ScholarCrossref 21. Nair GVGurbel PAO'Connor CMGattis WAMurugesan SRSerebruany VL Depression, coronary events, platelet inhibition, and serotonin reuptake inhibitors. Am J Cardiol 1999;84 (3) 321- 323, A8PubMedGoogle ScholarCrossref 22. Berkman LFBlumenthal JBurg M et al. Enhancing Recovery in Coronary Heart Disease Patients Investigators (ENRICHD), 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 (23) 3106- 3116PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Internal Medicine American Medical Association

Antidepressant Use, Depression, and Poor Cardiovascular Outcomes: The Chicken or the Egg?: Comment on “Antidepressant Use and Risk of Incident Cardiovascular Morbidity and Mortality Among Postmenopausal Women in the Women's Health Initiative Study”

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Publisher
American Medical Association
Copyright
Copyright © 2009 American Medical Association. All Rights Reserved.
ISSN
0003-9926
eISSN
1538-3679
DOI
10.1001/archinternmed.2009.437
Publisher site
See Article on Publisher Site

Abstract

Depression is a common comorbidity in patients with chronic heart failure, with reported incidence as high as approximately 48% in this patient population.1-4 Studies have shown that depression in patients with heart failure is strongly associated with worse outcomes and is an independent predictor of increased mortality and hospitalization.5-9 As a result, the use of antidepressants in this population has become more prevalent. Some studies have shown improvements in cardiovascular outcomes and functional status with the use of selective serotonin reuptake inhibitors (SSRIs) with no adverse safety signals observed.6,10,11 However, other studies of tricyclic antidepressants (TCAs) and SSRIs have raised questions regarding the safety of these antidepressants for use in patients with cardiac disease because treatment with these agents was associated with increased risk of myocardial infarction or cardiovascular death.12,13 Most notably, in the Cardiac Arrhythmia Suppression Trial,14 TCAs were found to be associated with an increase in mortality. This long-standing controversy has been fueled by studies with insufficient power to properly address the question. The study by Smoller et al is an important addition to the literature. It prospectively examines the relationship between antidepressant use and cardiovascular morbidity and mortality in a large cohort of postmenopausal women in the Women's Health Initiative (WHI) study.15-20 The findings, in the largest cohort of women yet studied, provide additional warning that antidepressant therapy may in fact be detrimental with respect to stroke and total mortality in this demographic population. In this study of 136 293 community-dwelling postmenopausal women enrolled in the WHI from 1993 to 1998, the authors found that antidepressant use was not associated with incident coronary heart disease. However, SSRI use was associated with an increased risk of stroke and all-cause mortality, and TCA use was associated with an increased risk of all-cause mortality. There were no significant differences between SSRI and TCA use in risk of any of the outcomes. In secondary analyses by stroke type, SSRI use was associated with incident hemorrhagic stroke. This is an interesting finding because SSRIs have been shown to inhibit platelet function, although the clinical relevance of this property has not been established.21 The authors address the limitations and potential confounding aspects of the use of antidepressants by using a propensity score from a logistic regression model to predict incident antidepressant use. Perhaps the most difficult aspect of these trials is that, as others have shown, the patients who are likely to be treated with antidepressants have additional risk factors for mortality and cardiovascular risks that are difficult to control for. The modest C statistic of 0.69 by logistic regression suggests that the ability to discriminate incident use was not strong. Also, the study cannot fully address cases in which antidepressant therapy fails (ie, patients who begin treatment with antidepressants but experience no remission of their depression symptoms); these patients may represent the highest-risk mortality group. While questions remain on the safety and efficacy of antidepressant use in patients with both depression and heart failure, Smoller et al add important information to the body of literature on this topic. As the authors have concluded, their findings should be considered by physicians to help determine the potential benefit in quality of life and the potential mitigation of morbidity and mortality risk associated with untreated depression in patients with cardiovascular disease. Depression remains an important and underrecognized risk factor for cardiovascular morbidity and mortality in men and women with existing heart disease and/or cardiovascular risk factors. Depression is known to be associated with lower quality of life, unhealthy lifestyle choices, poor adherence to medication regimens, and poor outcomes. Unfortunately, therapies used to alleviate depressive symptoms and depression have not been associated with clear-cut cardiovascular benefits. Cognitive behavioral therapy has been shown to not improve cardiovascular outcomes; in fact it potentially worsens outcomes in women.22 Although smaller studies of SSRIs in patients with cardiovascular disease have suggested that SSRIs are safe, these studies have been significantly underpowered and could not be used to evaluate cardiovascular outcomes. Therefore, an important step in this field would be to embark on a national effort to endorse a large-scale simple trial of antidepressant therapy in patients with cardiovascular disease and to evaluate the influence of this therapy on cardiovascular outcomes such as cardiovascular quality of life, nonfatal cardiovascular events, and mortality. Until then, we are left with the chicken or the egg dilemma. Correspondence: Dr O’Connor, Duke University Medical Center, Division of Cardiology and Clinical Pharmacology, PO Box 3356, Durham, NC 27710 (oconn002@mc.duke.edu). Financial Disclosure: None reported. References 1. Havranek EPWare MGLowes BD Prevalence of depression in congestive heart failure. Am J Cardiol 1999;84 (3) 348- 350, A9PubMedGoogle ScholarCrossref 2. Friedmann EThomas SALiu FMorton PGChapa DGottlieb SSSudden Cardiac Death in Heart Failure Trial Investigators, Relationship of depression, anxiety, and social isolation to chronic heart failure outpatient mortality. Am Heart J 2006;152 (5) 940- e1-e8PubMedGoogle ScholarCrossref 3. MacMahon KMLip GY Psychological factors in heart failure: a review of the literature. Arch Intern Med 2002;162 (5) 509- 516PubMedGoogle ScholarCrossref 4. Gottlieb SSKhatta MFriedmann E et al. The influence of age, gender, and race on the prevalence of depression in heart failure patients. J Am Coll Cardiol 2004;43 (9) 1542- 1549PubMedGoogle ScholarCrossref 5. Sherwood ABlumenthal JATrivedi R et al. Relationship of depression to death or hospitalization in patients with heart failure. Arch Intern Med 2007;167 (4) 367- 373PubMedGoogle ScholarCrossref 6. O'Connor CMJiang WKuchibhatla M et al. Antidepressant use, depression, and survival in patients with heart failure. Arch Intern Med 2008;168 (20) 2232- 2237PubMedGoogle ScholarCrossref 7. Joynt KEWhellan DJO'Connor CM Why is depression bad for the failing heart? a review of the mechanistic relationship between depression and heart failure. J Card Fail 2004;10 (3) 258- 271PubMedGoogle ScholarCrossref 8. Jiang WKuchibhatla MClary GL et al. Relationship between depressive symptoms and long-term mortality in patients with heart failure. Am Heart J 2007;154 (1) 102- 108PubMedGoogle ScholarCrossref 9. Pelle AJGidron YYSzabo BMDenollet J Psychological predictors of prognosis in chronic heart failure. J Card Fail 2008;14 (4) 341- 350PubMedGoogle ScholarCrossref 10. Glassman AHO'Connor CMCaliff RM et al. Sertraline Antidepressant Heart Attack Randomized Trial (SADHEART) Group, Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA 2002;288 (6) 701- 709PubMedGoogle ScholarCrossref 11. Gottlieb SSKop WJThomas SA et al. A double-blind placebo-controlled pilot study of controlled-release paroxetine on depression and quality of life in chronic heart failure. Am Heart J 2007;153 (5) 868- 873PubMedGoogle ScholarCrossref 12. Tata LJWest JSmith C et al. General population based study of the impact of tricyclic and selective serotonin reuptake inhibitor antidepressants on the risk of acute myocardial infarction. Heart 2005;91 (4) 465- 471PubMedGoogle ScholarCrossref 13. Xiong GLJiang WClare R et al. Prognosis of patients taking selective serotonin reuptake inhibitors before coronary artery bypass grafting. Am J Cardiol 2006;98 (1) 42- 47PubMedGoogle ScholarCrossref 14. The Cardiac Arrhythmia Suppression Trial (CAST) Investigators, Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med 1989;321 (6) 406- 412PubMedGoogle ScholarCrossref 15. The Women's Health Initiative Study Group, Design of the Women's Health Initiative clinical trial and observational study. Control Clin Trials 1998;19 (1) 61- 109PubMedGoogle ScholarCrossref 16. Curb JDMcTiernan AHeckbert SR et al. WHI Morbidity and Mortality Committee, Outcomes ascertainment and adjudication methods in the Women's Health Initiative. Ann Epidemiol 2003;13 (9) ((suppl)) S122- S128PubMedGoogle ScholarCrossref 17. Jackson RDLaCroix AZCauley JAMcGowan J The Women's Health Initiative calcium-vitamin D trial: overview and baseline characteristics of participants. Ann Epidemiol 2003;13 (9) ((suppl)) S98- S106PubMedGoogle ScholarCrossref 18. Langer RDWhite ELewis CEKotchen JMHendrix SLTrevisan M The Women's Health Initiative Observational Study: baseline characteristics of participants and reliability of baseline measures. Ann Epidemiol 2003;13 (9) ((suppl)) S107- S121PubMedGoogle ScholarCrossref 19. Ritenbaugh CPatterson REChlebowski RT et al. The Women's Health Initiative Dietary Modification trial: overview and baseline characteristics of participants. Ann Epidemiol 2003;13 (9) ((suppl)) S87- S97PubMedGoogle ScholarCrossref 20. Stefanick MLCochrane BBHsia JBarad DHLiu JHJohnson SR The Women's Health Initiative postmenopausal hormone trials: overview and baseline characteristics of participants. Ann Epidemiol 2003;13 (9) ((suppl)) S78- S86PubMedGoogle ScholarCrossref 21. Nair GVGurbel PAO'Connor CMGattis WAMurugesan SRSerebruany VL Depression, coronary events, platelet inhibition, and serotonin reuptake inhibitors. Am J Cardiol 1999;84 (3) 321- 323, A8PubMedGoogle ScholarCrossref 22. Berkman LFBlumenthal JBurg M et al. Enhancing Recovery in Coronary Heart Disease Patients Investigators (ENRICHD), 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 (23) 3106- 3116PubMedGoogle ScholarCrossref

Journal

Archives of Internal MedicineAmerican Medical Association

Published: Dec 14, 2009

Keywords: antidepressive agents,cardiovascular system,chickens,depressive disorders,postmenopause,morbidity,women's health initiative

References