Data Reveal More About Link of Depression, Heart Disease

Patients with heart disease and depression continue to present a conundrum to cardiologists and psychiatrists.

Depression seems associated with increased risk of poor cardiac outcomes, while a heart attack or heart failure might reasonably induce reactive depression in the patient. About 15 percent to 20 percent of patients hospitalized for heart attacks meet DSM-IV criteria for depression, yet decades of research have revealed an association between the two conditions without proving conclusively which causes which. Both biological (heart rate variability, HPA axis dysfunction, increased inflammatory response) and behavioral (lack of exercise, poor medication adherence) factors have been proposed to link the two.

“Registry data can't define cause and effect, and there are too few animal experiments or large randomized controlled trials in humans to determine causation,” said Karina Davison, Ph.D., in an interview. Davison is director of the cardiovascular behavioral health center and Herbert Irving Associate Professor of Medicine and Psychiatry in the College of Physicians and Surgeons at Columbia University. “That leaves us with only observational data,” she said, although several proposals for such trials are under review at the National Institutes of Health.

Whether treating depression will significantly improve cardiovascular outcomes remains an open question. A cautiously worded science advisory from the American Heart Association in the October 2008 journal Circulation offered this conclusion:

“Depression is commonly present in patients with coronary heart disease (CHD) and is independently associated with increased cardiovascular morbidity and mortality. Screening tests for depressive symptoms should be applied to identify patients who may require further assessment and treatment.”

One study, the Sertraline Antidepressant Heart Attack Randomized Trial (SADHART), recently reported results from nearly seven years of follow-up among 361 of 369 patients hospitalized with acute coronary syndrome (ACS) who also had major depressive disorder (MDD) on screening. Of those, 75 died during the follow-up period.

Severity of depression was “strongly and significantly” associated with mortality during 6.7 years of follow-up, but depression prior to ACS and onset before or after hospitalization were not associated with death.

SADHART didn't clarify if treatment helped reduce mortality rates, but it did find that patients whose depression did not get better had twice the risk of dying as those who did improve, wrote Alexander Glassman, M.D., chief of clinical psychopharmacology at New York State Psychiatric Institute and a professor of psychiatry at the College of Physicians and Surgeons of Columbia University, and colleagues in the September Archives of General Psychiatry.

The SADHART researchers randomized patients to 24 weeks of sertraline treatment or placebo, and found that neither cohort showed any advantage in mortality. However, patients whose mood improved, whether or not they were treated, had a lower chance of dying. Only 15.6 percent of patients with a CGI-I score of 1 or 2 at six months died over the next 6.7 years, compared with 28.4 percent of patients whose depression did not improve.

SADHART's lack of success with conventional treatment may arise because not all patient behavior outside the trial's parameters can be controlled or because not all depression is the same, said Davison.

“A patient who exercised might also take omega-3 capsules, for instance,” she said. “Or a patient's depression might be due to white matter hyperintensities, which would not respond to an SSRI.”

Patients whose depression improved had better adherence to the antidepressant, which may be a marker for adherence to cardiovascular drugs, suggested the authors.

“Adherence to cardiovascular medications after ACS reduces mortality and could mediate the relationship between failure of MDD to improve substantially and long-term mortality,” wrote Glassman and colleagues.“ [D]epression impairs quality of life and needs to be treated. When patients with MDD after ACS do not respond to antidepressant treatment, a special effort should be made to promote lifestyle improvements and cardiovascular medication adherence.”

The effect on medication adherence is not bidirectional, said Davison. Depressed patients who don't take their antidepressants are less likely to take their cardiovascular medications, but adherence to these medications does not influence use of antidepressants.

Failure to nail down a causal connection between the two conditions doesn't mean there hasn't been progress in recent years, said C. Barr Taylor, M.D., a professor of psychiatry and behavioral sciences and director of the Laboratory for the Study of Behavioral Medicine at Stanford University School of Medicine.

“In the last two decades, researchers have demonstrated the importance of depression in cardiovascular disease and the value of antidepressants and lifestyle modifications for reducing risk in some populations, and we now have hypotheses about the mechanisms at work,” said Taylor in an interview.

Other studies highlight progress but also illustrate its inconclusive nature. Writing in the July Circulation, longtime researchers Nancy Frasure-Smith, Ph.D., of McGill University and the Université de Montréal; François Lespérance, M.D., of the Université de Montréal; and colleagues studied depression in 974 patients with atrial fibrillation and congestive heart failure. Antidepressant medication use was not recorded. They reported that “elevated depression scores significantly predicted cardiovascular mortality (primary outcome), arrhythmic death, and all-cause mortality.” Adjusted outcomes were similar whether treatment was focused on control of cardiac rate or control of cardiac rhythm. Marital status was a second independent risk factor in this cohort, “with the greatest risk observed in those who were both depressed and unmarried.”

A second study in the same issue of Circulation by Suzanne Arnold, M.D., M.H.A., of Saint Luke's Heart Institute in Kansas City, Mo., and colleagues, looked at the discrepancy between angina severity and ischemia as measured by single-photon emission computed tomography (SPECT). The 735 patients also underwent extensive psychosocial assessment for anxiety, depression, neuroticism, alexithymia, and somatosensory amplification.

Among the 191 patients with verified ischemia, those with prior coronary revascularization, anxiety, and depressive symptoms experienced more frequent angina than those without those characteristics, despite having the same degree of heart vessel blockage. Thus, wrote Arnold and colleagues, “The present results suggest that psychosocial factors may significantly modulate patients' anginal response to myocardial ischemia.”

Since this was a cross-sectional study, the authors could not infer causality, but they noted the prevalence of psychosocial symptoms among their patients and suggested that treatment plans include provision for their treatment.

Taylor, a coauthor on the AHA science advisory with Frasure-Smith, Lespérance, and others, also recently published the results of a small trial that further illustrates the good news–bad news aspect about the relationship of depression and cardiac disease. He and his colleagues randomized 48 depressed patients to treatment with cognitive-behavioral therapy (CBT) or to a waiting list as controls. To avoid confounding caused by drug side effects, they did not use antidepressant drugs.

An average of 15 CBT sessions resulted in a significant decline in Hamilton Depression Inventory and Beck Depression Inventory scores. About 57 percent (13 of 23) of CBT participants achieved remission, compared with 4 percent (1 of 25) of wait-listed patients. Treated patients showed a decline in triglycerides and heart rate, both signs of improvement.

However, there were no changes in respiratory sinus arrhythmia or cortisol levels during stress testing, the primary cardiovascular outcomes.

“The overall lack of change in the primary biological and physiological variables, and the sustained difference between [wait-listed] and CBT and normal controls at post [intervention] suggests that these variables are quite stable and not amenable to change through psychological intervention or affected by change in mood, at least in the short run,” wrote the authors. The study was published online July 3 in the Journal of Psychiatric Research.

“I was frustrated that intervention had such little impact,” said Taylor.

Despite the inconclusive outcomes of these and other trials, the AHA advisory says that “effective depression treatment may improve health outcomes.”

Both heart disease and depression should be treated according to clinical guidelines, even if the details of how they are connected are not fully known, cardiologists and psychiatrists agree. Treating depression may improve adherence to cardiovascular treatment, while even nonpharmaceutical treatment for heart disease—like diet and exercise—may also lighten the burden of depression.

Eventually, however, after more is known about the interrelation of the two conditions, physicians will be able to tailor treatment for one in the context of the other to improve the chances of successful treatment, said Davison.

“Psychiatrists may not see [heart disease] as in their realm, but I see it as very much what psychiatrists should be doing,” said Taylor.

An abstract of “Psychiatric Characteristics Associated With Long-term Mortality Among 361 Patients Having an Acute Coronary Syndrome and Major Depression” is posted at:<http://archpsyc.ama-assn.org/cgi/content/abstract/66/9/1022>. An excerpt from the editorial “Is It Time to Treat Depression in Patients With Cardiovascular Disease?” is posted at<http://circ.ahajournals.org/cgi/content/extract/120/2/99>. An abstract of “Does Improving Mood in Depressed Patients Alter Factors That May Affect Cardiovascular Disease Risk?” can be accessed at<www.sciencedirect.com> by searching on the title and clicking on “Preview.”▪