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TREATMENT |
From the Department of Medicine, Duke University Medical Center, Durham, North Carolina.
Address correspondence and reprint requests to Karen E. Joynt, MD, DUMC Box 31091, Durham, NC 27708. E-mail: joynt001{at}mc.duke.edu
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ABSTRACT |
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Key Words: cardiovascular disease • myocardial infarction • major depressive disorder • antidepressant • research methodology • placebo effect
Abbreviations: BDI = Beck Depression Inventory; CAD = coronary artery disease; CBT = cognitive behavioral therapy; CGI-I = Clinical Global Impression Improvement; CVD = cardiovascular disease; ECG = electrocardiogram; ENRICHD = Enhancing Recovery in Coronary Heart Disease; HAM-D = Hamilton Depression; HR = hazard ratio; HRV = heart rate variability; HRSD = Hamilton Rating Scale for Depression; MI = myocardial infarction; MIND-IT = Myocardial Infarction and Depression Intervention Trial; NHLBI = National Heart Lung and Blood Institute; SADHART = Sertraline Anti-Depressant Heart Attack Randomized Trial; SSRI = selective serotonin reuptake inhibitor.
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INTRODUCTION |
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As the relationship between depression and CVD has become increasingly recognized and accepted in the medical community, a number of trials have begun to examine the impact of pharmacologic and nonpharmacologic interventions on depression in patients with heart disease. In theory, if depression has a damaging influence on the cardiovascular system, then treatment of depression should decrease its negative prognostic impact. However, the trials addressing this theory that have been conducted thus far have shown mixed results (8–10). Consequently, concern has arisen in the behavioral medicine community regarding the effect that these inconsistent findings might have on future clinical trials. A very important aspect of continued therapeutic advances in this field will be the ability to show a convincing connection between the treatment of depression in patients with heart disease and a reduction in morbidity and mortality associated with the co-occurrence of these conditions.
The purpose of this paper is to review some of the most important pharmacologic and nonpharmacologic treatment trials in the field of depression and CVD, and discuss what we can learn from these trials. In addition, we outline methodologic complexities commonly enountered in the study of depression and CVD and suggest ways in which future trials might help shed light on the relationship between depression and cardiovascular morbidity and mortality.
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PHARMACOLOGIC TREATMENT OF DEPRESSION |
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Maes et al. reported that treatment with selective serotonin reuptake inhibitors (SSRIs) had no effect on acute-phase or inflammatory markers (13); however, Mikova et al. (14) and Lanquillon et al. (15) showed that responders to treatment demonstrated decreased inflammation, whereas nonresponders showed no change. Musselman et al. found that platelet activation was reduced to levels comparable to controls after 6 weeks of paroxetine treatment, (16) and Serebruany et al. demonstrated that sertraline decreased platelet activation compared with placebo even with concomitant administration of aspirin and clopidogrel in both groups (17).
Taken together, these trials suggest that pharmacologic treatment of depression in patients with CVD might affect physiologic parameters that are dysregulated in depression. None of them, however, addresses the question of whether pharmacologic treatment of depression in patients with existing heart disease might affect cardiac function, morbidity, or mortality.
SADHART
The first trial to investigate the safety and efficacy of sertraline treatment of major depressive disorder in patients with CVD, a patient population not previously included in trials of pharmacologic treatment for depression, was the Sertraline Anti-Depressant Heart Attack Trial (SADHART). SADHART investigators enrolled 369 patients with major depressive disorder and either acute myocardial infarction or unstable angina in a randomized, double-blind, placebo-controlled trial. After a 2-week single-blind placebo run-in, patients were randomly assigned to receive sertraline in flexible doses of 50 to 200 mg or placebo for 24 weeks (18).
From a safety standpoint, SADHART achieved its objectives; no changes were seen in mean left ventricular ejection fraction, prolonged QTc interval, or other cardiac measures (18). In comparison with tricyclic antidepressants, which are known to have potentially harmful cardiac effects and are generally contraindicated in patients with known cardiac pathology (19), the trial demonstrated that sertraline can safely be used in patients with ischemic heart disease.
From an efficacy standpoint, however, findings were mixed. Unexpectedly, sertraline was not extremely effective for the treatment of depression in this population. Among all patients, sertraline was statistically superior to placebo on the Clinical Global Impression Improvement (CGI-I) scale (measured over 24 weeks, 2.57 versus 2.75, p = .049) but not on Hamilton Depression (HAM-D) change score (measured over 16 weeks, –8.4 versus –7.6, p = .14). However, in predefined subgroup analysis examining patients with recurrent or severe depression, sertraline was shown to be more efficacious than placebo on both CGI-I and HAM-D measurements (18). Sertraline was associated with significantly improved quality of life and functioning in this group as well (20). One possible confounder for the overall sample was the placebo response rate of 53%, considerably higher than the rates of 25% to 35% typically seen in antidepressant trials (21).
Possibly the most provocative finding from the SADHART investigations was that the incidence of severe cardiac events (death, myocardial infarction, congestive heart failure, stroke, and recurrent angina) was numerically lower among patients receiving sertraline than those receiving placebo (14.5% versus 22.4%, RR 0.77, 95% CI 0.51–1.16), although this result did not reach statistical significance (18). In a SADHART substudy, investigators determined that sertraline was associated with decreased platelet and endothelial activation markers, suggesting one mechanism via which sertraline might confer a morbidity and mortality advantage (22). Although small, this substudy is important because it combines psychological, cardiovascular, and pharmacologic data into a single database, allowing researchers better insight into the mechanisms that might mediate the outcomes seen in the larger trial. Because SADHART was not powered to detect a difference in morbidity and mortality in this relatively small sample of patients, the impact of sertraline treatment of major depression on hard outcomes in the patient with ischemic heart disease remains unclear. However, SADHART's major contribution was to prove the safety of such treatment, thus opening the door for future investigations adequately powered to more closely examine morbidity and mortality endpoints. The Myocardial INfarction and Depression-Intervention Trial (MIND-IT), currently underway in the Netherlands, will examine mirtazapine, citalopram, and placebo in depressed post-MI patients, and may contribute to our knowledge in this area (23).
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ENRICHD
A trial specifically focusing on nonpharmacologic treatment of depression in patients with CVD had not been performed until ENRICHD (ENhancing Recovery In Coronary Heart Disease). The first trial in behavioral medicine to be funded by the National Heart, Lung, and Blood Institute (NHLBI), ENRICHD enrolled 2481 patients with myocardial infarction as well as depression and/or low perceived social support (8). The intervention tested was an individually tailored CBT-based intervention, initiated 2 to 3 weeks after myocardial infarction and continued for a median of 11 sessions over 6 months. In addition, patients scoring higher than 24 on the Hamilton Rating Scale for Depression (HRSD) or demonstrating a less than 50% reduction in Beck Depression Inventory (BDI) scores after 5 weeks were eligible to receive an SSRI (8).
Results of the ENRICHD trial were mixed. Psychological outcomes were better at the 6-month evaluation for patients receiving the intervention in comparison with the control group, with a mean BDI score 9.1 in the intervention group versus 12.2 in the control group (p < .001), but these effects did not persist to the 30-month evaluation. There was no difference in event-free survival between the two groups (75.9% versus 75.8%, p = not significant) (8). In a follow-up analysis attempting to clarify these results, investigators showed that depression was in fact an independent risk factor for death after MI (HR 2.4, 95% CI 1.2–4.7) (26), despite the fact that successful treatment of depression was not associated with a decrease in this risk. One possible confounding factor in this trial was the concomitant use of antidepressant medication, which reached a prevalence of 20.6% in the control group and 28% in the intervention group by the end of follow-up; interestingly, antidepressant medication use was associated with a significant decrease in risk of death or nonfatal MI (adjusted HR, 0.57; 95% CI, 0.38–0.85) (8).
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METHODOLOGIC COMPLEXITY OF TRIALS IN DEPRESSION AND CVD |
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First, it should be recognized that depression is a complex variable, the definition and measurement of which are inherently difficult. Many patients with cardiovascular disease will experience mild depression that is not easy to differentiate from a normal grief response to the diagnosis of a significant illness, while many others will experience moderate to severe depression (6). The variability of case-finding instruments for depression complicates its diagnosis; Koenig et al. showed that the prevalence of major depression in a population of 460 medically ill older inpatients varied by a factor of 2, from 10% to 21%, depending on which diagnostic scheme was used (28). This difficulty is compounded when symptoms of medical illness overlap symptoms of depression, as most depression inventories do not take such overlap into account. Trials in behavioral medicine and cardiology should utilize instruments designed for use in patients with medical illness.
Further, the conduct of trials examining treatments for depression is difficult. Because of the large SD in psychosocial assessments, sample sizes for trials in depression must often be prohibitively large to be adequately powered to show a connection between changes in psychosocial parameters and hard outcomes. Ethical issues often arise as well; some challenge the use of a placebo arm in depression trials because of the availability of known efficacious treatments for the condition (29), while others argue that placebo-controlled trials are essential for rigorous scientific methodology, and can be conducted while keeping patient safety paramount (21,30). Crossover represents another significant confounder; patients allocated to the placebo group may initiate antidepressant treatment in consultation with their primary care physician or may request pharmacologic treatment from their study physician. Failing to include this likelihood in pretrial power calculations can lead to significant underestimation of the sample size needed to show a particular correlation. Careful pretrial statistical planning should take these possibilities into account.
Interpreting the results of even the most well-designed trials in the field of depression and cardiovascular disease can also be difficult. Because placebo response rates are quite high in most antidepressant efficacy trials (21), it can be difficult to sort out the precise impact of a particular intervention on depressive symptoms. Quantifying a dose-response relationship is not straightforward in biobehavioral research; in the case of cognitive-behavioral therapy, for example, use of one-on-one therapy versus group therapy must somehow be entered into a calculation with therapy frequency and duration to determine the appropriate "dose" to achieve a particular outcome. The intervention being tested should be kept as consistent as possible across sites in multicenter trials to minimize this dose effect.
Measuring outcomes such as morbidity and mortality further complicates research methodology. Even if symptomatic improvement in depression can be demonstrated, an improvement in morbidity and mortality might not necessarily follow. Because we do not yet fully understand the link between depression and CVD on a pathophysiologic level, it is impossible for us to predict which effective depression treatments might affect hard outcomes, such as morbidity and mortality. Combined with the complex and variable cardiovascular physiology that many patients with CVD possess, it comes as little surprise that correlating changes in depression with changes in cardiovascular outcomes can be extremely difficult. Trials should keep careful measurements of both physiologic parameters known to be dysregulated in depression as well as change in depressive symptoms.
In summary, depression and CVD are associated with an incredible burden of morbidity and mortality in this country. Our understanding of the relationship between these two conditions is rapidly increasing, but the precise mechanisms underlying this relationship remain elusive. Further research needs to incorporate both behavioral and pharmacologic therapy for depression, as well as careful measurement of potential intermediates linking depression to CVD. Ongoing trials such as MIND-IT and SADHART-CHF will continue to advance tomorrow's knowledge in this complex and fascinating field, and future trials examining treatment of depression as secondary prevention in stable outpatients with CVD are essential. Ideally, as more is understood regarding the physiologic link between depression and CVD, pharmacotherapy targeted specifically at the dysregulated physiology could curtail the increased morbidity and mortality seen when these two conditions occur together.
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NOTES |
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In accordance with CME accreditation guidelines, author Christopher M. O'Connor disclosed that he has served as a consultant for Pfizer and GlaxoSmithKline. The other author of this article disclosed no real or potential conflicts of interest.
DOI:10.1097/01.psy.0000163454.25036.fc
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