While depression is far and away the best-studied form of psychological stress in terms of cardiovascular disease causality, anxiety and hostility figure in the mix, too. In a study of 364 patients with coronary artery disease who underwent cardiac rehab, Dr. Lavie and Dr. Milani found that baseline anxiety and hostility were significantly more prevalent among the younger patients – mean age 48 years – than in those older than age 70. But as with depression, rates of anxiety and hostility dropped sharply following cardiac rehab, in young and older patients alike (Arch. Intern. Med. 2006;166:1878-83).
The mechanisms through which depression and other forms of psychological stress boost the risk of secondary cardiac events are thought to include increased platelet reactivity, systemic inflammation, sympathetic activation of the autonomic nervous system, endothelial dysfunction, and increased circulating catecholamines.
Robert M. Carney, Ph.D., pointed out that depression not only is the No. 2 cause of early death and disability in industrialized nations, but the prevalence of major depression in the months following an acute coronary syndrome has been pegged at 12%-23% in various studies, with another 15%-27% of ACS patients having minor depression.
Dr. Robert M. Carney
Thus, close to half of all ACS patients experience significant depressive symptoms (Am. J. Med. 2008;121[11 Suppl 2]:S20-7), according to Dr. Carney, professor of psychiatry at Washington University in St. Louis.
What’s more, there is persuasive evidence to show that depression in patients who’ve experienced an acute coronary syndrome is associated with increased mortality. Dr. Carney cited a recent meta-analysis covering the last 25 years of research on depression and heart disease that concluded that post-MI depression was independently associated with a 2.7-fold increased likelihood of cardiac mortality and a 1.6-fold increase in cardiac morbidity (Gen. Hosp. Psychiatry 2011;33:203-16).
Dr. James A. Blumenthal, Ph.D., commented that most randomized, controlled trials comparing exercise to pharmacotherapy or no-treatment controls have been conducted in otherwise healthy adults with major depressive disorder; patients with CHD or other comorbidities were systematically excluded.
The first and biggest study to suggest that exercise reduces late morbidity and mortality in depressed post-MI patients was the Enhancing Recovery in Coronary Heart Disease (ENRICHD) study involving nearly 2,500 post-MI patients with major or minor depression and/or low social support. During the first several weeks post MI, the participants were randomized to usual care or up to 6 months of cognitive behavioral therapy augmented by up to a year of sertraline in severely depressed patients or psychotherapy nonresponders. For the primary outcome of reinfarction-free survival at 29 months of follow-up, ENRICHD was a negative trial: there was no difference (JAMA 2003;289:3106-16).
However, in a subsequent secondary analysis, Dr. Blumenthal and coinvestigators found that patients who were self-reported regular exercisers at 6 months of follow-up had significantly lower all-cause mortality and reinfarction rates at 2 years (see accompanying chart). And in a separate secondary analysis, ENRICHD participants with remitted depression as evidenced by a Hamilton Depression Rating Score (HAM-D) of 7 or less had a 7% all-cause mortality rate at 2 years, compared to a 20% rate in unimproved patients with a HAM-D greater than 15.
Dr. James A. Blumenthal
But the ENRICHED exercise analysis was observational. Dr. Blumenthal was also principal investigator in the second Standard Medical Intervention and Long-term Exercise (SMILE II) study, in which 202 sedentary patients with major depressive disorder were randomized to 4 months of supervised exercise, home-based exercise, antidepressant therapy with sertraline, or placebo. After 4 months of treatment, major depression was in remission in 46% of subjects, with similar rates in the sertraline and both exercise arms, according to Dr. Blumenthal, professor of psychiatry and behavioral sciences at Duke University, Durham, N.C.
At 16 months of follow-up, the overall remission rate had climbed to 66%; once again, sertraline and exercise, whether supervised or at home, appeared to be similarly effective. Subjects who reported exercising for 180 min/wk averaged a 3.1-point greater improvement in HAM-D scores than did those with 0 minutes (Psychosom. Med. 2011;73:127-33).
In the just-completed Understanding Prognostic Benefits of Exercise and Antidepressant Treatment (UPBEAT) trial, Dr. Blumenthal and coworkers randomized 200 sedentary depressed patients with CHD to sertraline, exercise training, or placebo. At the end of 16 weeks, the exercise group had the lowest HAM-D scores, followed by the sertraline-treated patients, then the placebo-treated controls. Also, heart rate variability, endothelial function, and baroreflex sensitivity were most improved in the exercise group.
Where’s the Survival Benefit?
But while UPBEAT, SMILE II, and other randomized trials have shown that exercise can reduce depression in CHD patients, there is as yet no randomized trial evidence demonstrating that treating depression actually improves survival in patients with heart disease.