American Heart Journal
Volume 150, Issue 4 , Pages 617-619, October 2005

Treating depression after myocardial infarction: Can selecting patients on the basis of genetic susceptibility improve psychiatric and medical outcomes?

  • Redford B. Williams, MD

      Affiliations

    • Corresponding Author InformationReprint requests: Redford B. Williams, MD, Duke University Medical Center, Box 3926, Durham, NC 27710.

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

Department of Medicine, Duke University Medical Center, Durham, NC

Behavioral Medicine Research Center, Duke University Medical Center, Durham, NC

Received 11 April 2005; accepted 29 April 2005.

This study was supported by the National Heart, Lung, and Blood Institute grant P01HL36587 (Bethesda, Md), National Institute of Mental Health grant K05MH79482 (Bethesda, Md), Clinical Research Unit grant M01RR30 (Bethesda, Md), and the Duke University Behavioral Medicine Research Center (Durham, NC).

Article Outline

 

Based on a considerable body of epidemiologic evidence showing that patients who are depressed or socially isolated after a myocardial infarction (MI) are at higher risk for mortality and recurrent cardiac events, the ENRICHD trial1 randomized 2481 depressed and/or socially isolated post-MI patients to either a behavioral intervention designed to reduce depression and social isolation or to usual care. Contrary to prediction, the intervention did not increase event-free survival. The intervention did reduce depression and social isolation, but the usual care group showed improvements in these psychosocial risk factors that were nearly as large as those observed in the intervention group. The SADHART trial2 evaluated the impact of treatment with the selective serotonin reuptake inhibitor (SSRI) sertraline on depression in patients with acute MI or unstable angina. As with the ENRICHD patients, those randomized to the sertraline arm showed greater improvement in depression than placebo patients. SADHART was not powered to detect an effect of drug treatment on cardiac end points, but there was a nonsignificant trend to fewer events in the sertraline arm. These results, especially the large-scale ENRICHD trial, leave us with a dilemma: depression adversely affects medical prognosis in acute MI, but, despite 2 randomized clinical trials evaluating known effective treatments for depression, it has not been possible to document a positive benefit of treatment on medical prognosis.

The report by Nakatani et al3 in this month's Journal points to a possible solution to this dilemma. They found in a large Japanese sample that carriers of the short allele of the highly researched promoter polymorphism (5-HTTLPR) of the serotonin transporter gene are more likely than those with the long/long genotype to be depressed and experience recurrent cardiac events over a 2-year period after MI. Moreover, after control for depression, which also predicted increased events, the impact of the short allele on events was no longer statistically significant, suggesting that the impact of the short allele on prognosis was mediated by the increased depression associated with it. These findings are consistent with prior research4 showing that short allele carriers are more likely than persons with the long/long 5-HTTLPR genotype to experience depression as a function of stressful life events.

The finding that the 5-HTTLPR short allele is a genetic marker for susceptibility to depression after MI, as well as susceptibility to recurrent cardiac events, likely mediated by the depression, raises an interesting question: if ENRICHD and SADHART had included only those depressed patients who were carriers of the 5-HTTLPR short allele, would they have enrolled an “enriched” sample of patients whose depression results in increased recurrent events—a sample in which they would have been more likely to document a positive benefit of their interventions?

Another implication relates to the fact that both ENRICHD and SADHART excluded patients who did not meet modified criteria for major depression. It has been shown that a substantial proportion of heart patients who do not meet such criteria while in hospital will become depressed during the 6 to 12 months after discharge.5, 6 This finding combines with the results of Nakatani et al3 to suggest that both ENRICHD and SADHART excluded patients who were carriers of the 5-HTTLPR short allele and thus more likely to go on to experience depression, and the associated increase in recurrent cardiac events, after discharge. A recent study evaluating psychosocial skills training in patients undergoing coronary artery bypass graft found that the group randomized to usual care experienced an increase in depression (Center for Epidemiological Studies–Depression) scores during the 3 months after randomization.7

The foregoing observations suggest that any future clinical trial that includes only patients who meet criteria for major depression will be randomizing some patients to usual care—likely those with the long/long 5-HTTLPR genotype—whose depression is going to get better spontaneously, along with those—short allele carriers—who are more likely to account for the increased risk for recurrent cardiac events. The presence of these lower-risk patients in the usual care arm will reduce the power of the trial to detect a positive treatment benefit. Furthermore, by excluding patients who do not meet depression criteria, the trial will miss the opportunity to show a positive benefit for those patients—short allele carriers—who are more likely to experience depression and the associated increase in recurrent cardiac events during the follow-up period. The findings of Nakatani et al3 suggest that a clinical trial evaluating an intervention—behavioral or pharmacologic—targeting depression will be more likely to succeed if it includes all patients, regardless of current depression status, who are carriers of the 5-HTTLPR short allele. It can even be argued that it would be unethical in future clinical trials evaluating treatments for depression in heart patients to exclude those who are not currently depressed but are likely to develop depression and have both its psychological and medical consequences after discharge.

To summarize my argument thus far, the findings of prior research linking the 5-HTTLPR short allele with increased risk for depression in the setting of increased life stress4 combine with the current findings by Nakatani et al3 to suggest a means of identifying this subset of heart patients who are likely to develop depression and have its adverse medical consequences after discharge: genotyping to select those with the 5-HTTLPR short allele. Therefore, a future clinical trial that includes all patients who are carriers of the short allele, regardless of current depression status, should be more likely than the ENRICHD and SADHART trials to document a positive benefit of an intervention targeting depression.

Before starting to write the proposal to secure funding for such a trial, however, a few caveats are in order. Nakatani et al3 cite 2 prior case-control studies, one in Europe and one in Japan, that found the 5-HTTLPR long allele to be associated with increased risk for MI. A more recent case-control study from Europe and including only whites also found increased MI risk in 5-HTTLPR long allele carriers and concluded that the short/short genotype “would seem to have a protective role against MI.”8 Nakatani et al3 suggest that the variance between these findings linking the long allele with increased MI risk and their finding of an adverse impact of the short allele on post-MI depression and cardiac events could result from the actions of antiplatelet medications in >97% of the patients in their study after discharge to mask any effects of the long allele to increase risk for recurrent cardiac events. They were able to support this interpretation by showing that in their patient sample there was a trend (P = .06) toward increased history of MI in those who were carriers of the long allele and who had not been on antiplatelet therapy. In contrast, among those who had been on antiplatelet therapy, the long allele was not associated (P = .34) with MI risk. In addition to its association with increased platelet activation, another possible mechanism whereby the long allele might contribute to increased risk for cardiac events is via increased cardiovascular reactivity to acute mental stress.9

These prior studies suggesting biologic effects of the long allele that could contribute to the development of “hard” cardiac events suggest the possibility that it may be only via effects on events likely to be influenced by depression's effect to increase patient sensitivity to symptoms, such as interventional procedures and hospital readmission, that the short allele is contributing to increased total cardiac events. Inspection of Table 3 in Nakatani et al3 reveals that it was only when the total of a long list of potential recurrent cardiac events was evaluated that the increase in events in short allele carriers became significant (P = .046). The absence a significant effect of the short allele on any of the individual events likely results from the rarity of the long allele in the Japanese population, with only 103 patients of 2509 in this sample having the long/long genotype, which would reduce the power to detect differences between short allele carriers and patients with the long/long genotype. It will be important, therefore, to evaluate the impact of the short allele on depression and medical prognosis in European and African populations, where the frequency of the long allele is higher—40% to 50% in European and >70% in African populations.10

Despite these caveats, it is likely that the overwhelming majority of post-MI patients will be treated with antiplatelet medications in the future, creating a situation where the effects of the short allele to increase risk for depression and associated cardiac events will still be evident. Even if the impact of the short allele on prognosis is only on “soft” events stemming from increased distress among depressed patients, the costs of such events would still be enormous, and an intervention that reduces the depression could, in addition to improving quality of life in high-risk short allele carriers, greatly reduce medical care costs in this patient population.

What treatments should be evaluated? Although both behavioral and pharmacologic interventions deserve attention, a case can be made that at least 1 clinical trial should evaluate the combination of an SSRI and the β-blocker pindolol. Pindolol is also an antagonist for the inhibitory, presynaptic 5-HT1A autoreceptor. It has been shown11 that depression levels fall more slowly with SSRI treatment in patients with the 5-HTTLPR short/short genotype and that concomitant treatment with pindolol makes their response to SSRI therapy as rapid as that of patients with the long/long genotype—a result explained by the effects of pindolol to block the autoreceptor-mediated inhibitory effects of the higher postsynaptic serotonin concentrations likely to occur with SSRI treatment in patients with fewer transporter sites, which is the case in those with the short/short genotype. The combination of an SSRI with pindolol could be especially effective, therefore, in reducing and/or preventing depression and its effects on cardiac events in post-MI patients who carry the 5-HTTLPR short allele.

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References 

  1. 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
  2. Glassman AH, O'Conner CM, Califf RM, et al. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA. 2002;288:701–709
  3. Nakatani D, Sata H, Sakata Y, et al. Influence of serotonin transporter gene polymorphism on depressive symptoms and new cardiac events after acute myocardial infarction. Am Heart J. 2005;150:652–658
  4. Caspi A, Sugden K, Moffitt TE, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003;301:386–389
  5. Hance M, Carney RM, Freedland KE, et al. Depression in patients with coronary heart disease: a 12-month follow-up. Gen Hosp Psychiatry. 1996;18:61–65
  6. Lesperance F, Frasure-Smith N, Talajic M. Major depression before and after myocardial infarction: its nature and consequences. Psychosom Med. 1996;58:99–110
  7. Bishop GD, Kaur D, Tan VLM. Effects of a psychosocial skills training workshop on psychophysiological and psychosocial risk in patients undergoing coronary artery bypass grafting. Am Heart J. 2005;150:602–609
  8. Coto E, Reguero JR, Alvarez V, et al. 5-Hydroxytryptamine 5-HT2A receptor and 5-hydroxytryptamine transporter polymorphisms in acute myocardial infarction. Clin Sci. 2003;104:241–245
  9. Williams RB, Marchuk DA, Gadde KM, et al. Central nervous system serotonin function and cardiovascular responses to stress. Psychosom Med. 2001;63:300–305
  10. Gelernter J, Cubells JF, Kidd JR, et al. Population studies of polymorphisms of the serotonin transporter gene. Am J Med Genet (Neuropsychiatr Genet). 1999;88:61–66
  11. Smeraldi E, Zanardi R, Fenedetti F, et al. Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine. Mol Psychiatry. 1998;3:508–511

 Redford Williams is a founder and major stockholder of Williams LifeSkills, Inc, a company whose mission is to develop, test, and market behavioral interventions to reduce stress and anger.

PII: S0002-8703(05)00448-5

doi:10.1016/j.ahj.2005.04.028

American Heart Journal
Volume 150, Issue 4 , Pages 617-619, October 2005

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