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Depression and Coronary Artery Disease: Is There a Platelet Link?

2007; Elsevier BV; Volume: 82; Issue: 11 Linguagem: Inglês

10.4065/82.11.1366

1942-5546

Roy C. Ziegelstein, Kapil Parakh, Ankit Sakhuja, Utsav Bhat,

Takotsubo Cardiomyopathy and Associated Phenomena

The potential cardioprotective effects of antidepressants have received substantial attention from the lay press. On March 17, 1999, a reporter for USA Today, summarizing the findings of a presentation that would soon after be given by Jerome Markovitz of the University of Alabama at the American Psychosomatic Society, wrote that "Zoloft, a commonly used antidepressant, also may help prevent heart attacks by thinning the blood."1Elias M Antidepressant may block heart attacks: Zoloft alleviates sticky situation in blood.USA Today. March 17, 1999; : D1Google Scholar Another report in the lay press from the British Broadcasting Company (BBC) News highlighted the work of Stephen Kimmel of the University of Pennsylvania and suggested that antidepressants like Prozac "may protect the heart in the same way that aspirin does—by reducing the risk of blood clots" and "help to reduce the risk of heart attacks."2Prozac 'may cut heart risk'. BBC News Web site. October 15, 2001.Available at: http://news.bbc.co.uk/2/hi/health/1600126.stmGoogle Scholar It is understandable that media attention would be drawn to the possibility that antidepressants might reduce the risk of heart attack. The public is focused on heart disease because it is the leading killer of Americans, and the common occurrence of depression in patients with coronary artery disease has received widespread attention. In 1993, Frasure-Smith and colleagues3Frasure-Smith N Lespérance F Talajic M Depression following myocardial infarction: impact on 6-month survival.JAMA. 1993; 270: 1819-1825Crossref PubMed Scopus (1864) Google Scholar reported that depression is associated with increased mortality in patients recovering from a myocardial infarction, an observation that has since been confirmed many times. Approximately 20% to 30% of patients who sustain a myocardial infarction have depression,4Thombs BD Bass EB Ford DE et al.Prevalence of depression in survivors of acute myocardial infarction: review of the evidence.J Gen Intern Med. 2006; 21: 30-38Crossref PubMed Scopus (629) Google Scholar and comorbid depression is associated with a 2-fold to 3-fold increase in mortality risk in patients who have experienced a myocardial infarction.5Nicholson A Kuper H Hemingway H Depression as an aetiologic and prognostic factor in coronary heart disease: a meta-analysis of 6362 events among 146 538 participants in 54 observational studies.Eur Heart J. 2006 Dec; 27 (Epub 2006 Nov 2.): 2763-2774Crossref PubMed Scopus (1015) Google Scholar Researchers have suggested a number of pathways whereby depression might adversely affect outcomes in patients with coronary artery disease: dysregulation of the hypothalamic-pituitary-adrenal axis, autonomic dysfunction resulting in an increased susceptibility to ventricular arrhythmias, poor adherence to cardiovascular treatment regimens among depressed patients, and increased platelet activation and aggregation. Increased platelet activation and aggregation seemed a plausible explanation because they would result in an increased risk of subsequent cardiovascular events. After all, serotonin (5-hydroxytryptamine, or 5-HT) plays a key role in depression, and more than 99% of the body's serotonin is stored in platelets.6Skop BP Brown TM Potential vascular and bleeding complications of treatment with selective serotonin reuptake inhibitors.Psychosomatics. 1996; 37: 12-16Abstract Full Text PDF PubMed Scopus (173) Google Scholar The central role of abnormal serotonergic neurotransmission in depression has led to the development of selective serotonin reuptake inhibitors (SSRIs), which are now the class of antidepressants most widely used to treat this condition. Platelets share biochemical similarity with central serotonergic neurons in the uptake, storage, and metabolism of serotonin and have been used as a model to study central nervous system serotonin uptake and release.7Da Prada M Cesura AM Launay JM Richards JG Platelets as a model for neurones?.Experientia. 1988; 44: 115-126Crossref PubMed Scopus (231) Google Scholar Although a relatively weak platelet agonist, serotonin potentiates platelet aggregation in the presence of even low concentrations of other platelet agonists.6Skop BP Brown TM Potential vascular and bleeding complications of treatment with selective serotonin reuptake inhibitors.Psychosomatics. 1996; 37: 12-16Abstract Full Text PDF PubMed Scopus (173) Google Scholar Thus, abnormalities of serotonin metabolism could conceivably lead not only to mood disturbance in patients with depression but also to abnormal platelet activity that predisposes these patients to cardiac events. It was this hypothesis that stimulated the research of Markovitz featured by USA Today1Elias M Antidepressant may block heart attacks: Zoloft alleviates sticky situation in blood.USA Today. March 17, 1999; : D1Google Scholar and that of Kimmel and colleagues8Sauer WH Berlin JA Kimmel SE Selective serotonin reuptake inhibitors and myocardial infarction.Circulation. 2001; 104: 1894-1898Crossref PubMed Scopus (293) Google Scholar featured by BBC News.2Prozac 'may cut heart risk'. BBC News Web site. October 15, 2001.Available at: http://news.bbc.co.uk/2/hi/health/1600126.stmGoogle Scholar In the published paper that developed out of the conference presentation, Markovitz and colleagues9Markovitz JH Shuster JL Chitwood WS May RS Tolbert LC Platelet activation in depression and effects of sertraline treatment: an open-label study.Am J Psychiatry. 2000; 157: 1006-1008Crossref PubMed Scopus (126) Google Scholar reported their observations of platelet activation in 21 patients with untreated major depression and 21 age- and sex-matched controls. They found that platelet secretion in response to collagen was higher in depressed controls at baseline and then decreased toward normal after 6 weeks of treatment with sertraline. Although these findings were provocative, the authors studied only a small number of controls, and several of their findings potentially contradicted the hypothesis that depression is associated with increased platelet activation. For example, the density of platelet serotonin receptors, which mediate serotonin-induced platelet aggregation, was actually higher in patients without than with depression, leading one to expect increased platelet aggregation in patients without depression. In addition, whereas sertraline treatment decreased collagen-induced platelet secretion, most other platelet activation measures resulted in minimal change.9Markovitz JH Shuster JL Chitwood WS May RS Tolbert LC Platelet activation in depression and effects of sertraline treatment: an open-label study.Am J Psychiatry. 2000; 157: 1006-1008Crossref PubMed Scopus (126) Google Scholar Kimmel and colleagues8Sauer WH Berlin JA Kimmel SE Selective serotonin reuptake inhibitors and myocardial infarction.Circulation. 2001; 104: 1894-1898Crossref PubMed Scopus (293) Google Scholar found that the use of SSRIs was associated with a significantly lower risk of myocardial infarction. In their case-control study, 653 patients with myocardial infarction were compared with 2990 control patients randomly selected from the same geographic area; the odds ratio for myocardial infarction among patients currently taking SSRIs vs those not receiving such therapy was 0.35 (95% confidence interval, 0.18-0.68). It was hypothesized that this finding might relate to the inhibitory effect of SSRIs on serotonin-mediated platelet activation. These findings, like those of Markovitz and colleagues,9Markovitz JH Shuster JL Chitwood WS May RS Tolbert LC Platelet activation in depression and effects of sertraline treatment: an open-label study.Am J Psychiatry. 2000; 157: 1006-1008Crossref PubMed Scopus (126) Google Scholar are provocative; however, questions remain whether these observational findings in smokers who experienced a first myocardial infarction between the ages of 30 and 65 years will be reproducible in randomized controlled trials and generalizable to other patient groups. Further, it is important to note that those who did not use SSRI antidepressants also exhibited a (nonsignificant) reduction in myocardial infarction with an adjusted odds ratio of 0.48 (95% confidence interval, 0.17-1.32) because of the small number of exposed patients.8Sauer WH Berlin JA Kimmel SE Selective serotonin reuptake inhibitors and myocardial infarction.Circulation. 2001; 104: 1894-1898Crossref PubMed Scopus (293) Google Scholar Thus, the findings reported by Markovitz and colleagues and Kimmel and colleagues are certainly useful for generating hypotheses; however, larger well-controlled studies are needed before the kind of conclusions reported by the lay press1Elias M Antidepressant may block heart attacks: Zoloft alleviates sticky situation in blood.USA Today. March 17, 1999; : D1Google Scholar, 2Prozac 'may cut heart risk'. BBC News Web site. October 15, 2001.Available at: http://news.bbc.co.uk/2/hi/health/1600126.stmGoogle Scholar can be reached by the scientific community. Because of their effects on platelet activation, SSRIs have been suggested to provide potential cardiovascular benefits. Several scientific articles have reported that platelets are activated in patients with depression10Schins A Honig A Crijns H Baur L Hamulyak K Increased coronary events in depressed cardiovascular patients: 5-HT2A receptor as missing link?.Psychosom Med. 2003; 65: 729-737Crossref PubMed Scopus (80) Google Scholar, 11Serebruany VL Glassman AH Malinin AI et al.Enhanced platelet/endothelial activation in depressed patients with acute coronary syndromes: evidence from recent clinical trials.Blood Coagul Fibrinolysis. 2003; 14: 563-567Crossref PubMed Scopus (84) Google Scholar, 12Bruce EC Musselman DL Depression, alterations in platelet function, and ischemic heart disease.Psychosom Med. 2005; 67: S34-S36Crossref PubMed Scopus (97) Google Scholar and that SSRIs inhibit this effect12Bruce EC Musselman DL Depression, alterations in platelet function, and ischemic heart disease.Psychosom Med. 2005; 67: S34-S36Crossref PubMed Scopus (97) Google Scholar, 13Serebruany VL Glassman AH Malinin AI et al.Sertraline AntiDepressant Heart Attack Randomized Trial Study Group. 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 [published correction appears in Circulation. 2003;108(25):3165].Circulation. 2003 Aug 26; 108 (Epub 2003 Aug 11.): 939-944Crossref PubMed Scopus (308) Google Scholar and may even be associated with an increased risk of bleeding.14Serebruany VL Selective serotonin reuptake inhibitors and increased bleeding risk: are we missing something?.Am J Med. 2006; 119: 113-116Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar A substudy of the Sertraline Antidepressant Heart Attack Randomized Trial (SADHART) showed that patients with major depression who were hospitalized for an acute myocardial infarction or unstable angina pectoris exhibited fewer platelet activation markers when treated with sertraline vs placebo.11Serebruany VL Glassman AH Malinin AI et al.Enhanced platelet/endothelial activation in depressed patients with acute coronary syndromes: evidence from recent clinical trials.Blood Coagul Fibrinolysis. 2003; 14: 563-567Crossref PubMed Scopus (84) Google Scholar In a secondary analysis of 1834 patients with depression in the Enhancing Recovery in Coronary Heart Disease (ENRICHD) trial,15Taylor CB Youngblood ME Catellier D ENRICHD Investigators et al.Effects of antidepressant medication on morbidity and mortality in depressed patients after myocardial infarction.Arch Gen Psychiatry. 2005; 62: 792-798Crossref PubMed Scopus (444) Google Scholar patients taking SSRIs had a significantly lower risk of death or recurrent myocardial infarction than those who did not use SSRIs (adjusted hazard ratio, 0.57; 95% confidence interval, 0.38-0.84). Coupled with the known antiplatelet effects of SSRIs,11Serebruany VL Glassman AH Malinin AI et al.Enhanced platelet/endothelial activation in depressed patients with acute coronary syndromes: evidence from recent clinical trials.Blood Coagul Fibrinolysis. 2003; 14: 563-567Crossref PubMed Scopus (84) Google Scholar, 13Serebruany VL Glassman AH Malinin AI et al.Sertraline AntiDepressant Heart Attack Randomized Trial Study Group. 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 [published correction appears in Circulation. 2003;108(25):3165].Circulation. 2003 Aug 26; 108 (Epub 2003 Aug 11.): 939-944Crossref PubMed Scopus (308) Google Scholar these conclusions are compelling and may lead some to question the need to study the effect of SSRIs on end points that involve platelet activation such as stroke and heart attack in patients with cardiovascular disease. However, conclusive evidence, preferably from randomized controlled trials, is still needed. Sometimes concepts seem so plausible, even so obvious, that further study is deemed unnecessary or even unwise. Many cardiologists can remember reviewing 24-hour ambulatory electrocardiograms of patients soon after myocardial infarction and noting the greater risk of death among those with the most frequent ventricular ectopy. Because many of those deaths were sudden and because it was clear from the Cardiac Arrhythmia Pilot Study that certain antiarrhythmic agents (ie, encainide, flecainide, and moricizine) were well tolerated and dramatically reduced the frequency of ventricular ectopy,16Cardiac Arrhythmia Pilot Study (CAPS) Investigators Effects of encainide, flecainide, imipramine and moricizine on ventricular arrhythmias during the year after acute myocardial infarction: the CAPS.Am J Cardiol. 1988; 61: 501-509Abstract Full Text PDF PubMed Scopus (213) Google Scholar it seemed all too obvious that these drugs would reduce mortality after myocardial infarction in at-risk patients. Not only were these drugs commonly prescribed for patients with frequent ventricular ectopy after myocardial infarction, but the validity of doing so was not thought to require confirmation by randomized controlled trial; indeed, some thought proceeding to such trials would be unethical.17Moore TJ Deadly Medicine: Why Tens of Thousands of Heart Patients Died in America's Worst Drug Disaster. Simon & Schuster, New York, NY1995Google Scholar However, once performed, randomized controlled trials in patients who experienced myocardial infarction and who had ventricular ectopy (ie, the First and Second Cardiac Arrhythmia Suppression Trials) told a different story: mortality was higher in those who received these antiarrhythmic agents than in those who did not.18Echt DS Liebson PR Mitchell LB CAST Investigators et al.Mortality and morbidity in patients receiving encainide, flecainide, or placebo: The Cardiac Arrhythmia Suppression Trial.N Engl J Med. 1991; 324: 781-788Crossref PubMed Scopus (2669) Google Scholar Critical examination of the literature shows that the association between depression and platelet activity is not very clear. In part, this lack of clarity may be due to inconsistencies in research methodology. Platelet activity in patients with depression has been assessed using a variety of approaches, including measuring platelet serotonin levels, measuring platelet serotonin receptor density and affinity, assessing the aggregation of platelets to known agonists (particularly serotonin itself), and investigating various platelet-signaling pathways in patients with and without major depression. However, the findings are often inconsistent even when similar methods are used to assess platelet activity. For example, it has been reported that serotonin levels are lower in platelets from patients with depression19Muck-Seler D Pivac N Mustapic M Crncevic Z Jakovljevic M Sagud M Platelet serotonin and plasma prolactin and cortisol in healthy, depressed and schizophrenic women.Psychiatry Res. 2004; 127: 217-226Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar and that no such difference in platelet serotonin levels between patients with and without depression exists.20Franke L Schewe HJ Muller B et al.Serotonergic platelet variables in unmedicated patients suffering from major depression and healthy subjects: relationship between 5HT content and 5HT uptake.Life Sci. 2000; 67: 301-305Crossref PubMed Scopus (56) Google Scholar Some have found that the density of platelet 5-HT2 receptors is higher in patients with depression,21Hrdina PD Bakish D Chudzik J Ravindran A Lapierre YD Serotonergic markers in platelets of patients with major depression: upregulation of 5-HT2 receptors.J Psychiatry Neurosci. 1995; 20: 11-19PubMed Google Scholar whereas other researchers found no differences between those with and without depression.22Neuger J El Khoury A Kjellman BF Wahlund B Aberg-Wistedt A Stain-Malmgren R Platelet serotonin functions in untreated major depression.Psychiatry Res. 1999; 85: 189-198Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar Similarly, some investigators have shown increased23Shimbo 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: 331-333Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar and others decreased24Wood K Swade C Abou-Saleh M Coppen A Peripheral serotonergic receptor sensitivity in depressive illness.J Affect Disord. 1984; 7: 59-65Abstract Full Text PDF PubMed Scopus (20) Google Scholar, 25Alvarez JC Gluck N Arnulf I et al.Decreased platelet serotonin transporter sites and increased platelet inositol triphosphate levels in patients with unipolar depression: effects of clomipramine and fluoxetine.Clin Pharmacol Ther. 1999; 66: 617-624PubMed Google Scholar platelet aggregation in response to serotonin in patients with depression. Still others have found no differences in platelet function between persons with and without depression.26Gomez-Gil E Gasto C Diaz-Ricart M et al.Platelet 5-HT2A-receptor-mediated induction of aggregation is not altered in major depression.Hum Psychopharmacol. 2002; 17: 419-424Crossref PubMed Scopus (16) Google Scholar In conclusion, the relationship between depression and platelet activity is not straightforward, and it is unknown whether patients with coronary artery disease derive special benefits from the effects of SSRIs on platelets. Although many provocative studies show enhanced platelet activation and aggregation in patients with depression, many others show no effect, and some even show that depression is associated with lower levels of platelet activity. Larger, carefully designed, adequately powered studies are needed to resolve this question before clinicians assume that depression is associated with clinically important effects on platelet activation and aggregation and before SSRIs are prescribed to patients with cardiovascular disease to reduce thrombotic events. Until these studies are performed, and regardless of whether an association between depression and platelet activation is ultimately established, clinicians should continue to diagnose and treat depression because it is a serious illness that adversely affects quality of life both in patients with and without cardiovascular disease.