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DURHAM, N.C. -- After demonstrating in earlier studies that exercise can be as effective as medications in reducing depression in older persons with clinical depression, Duke researchers have now devised a new trial to better understand the beneficial effects of exercise and anti-depressants on specific physiological indicators of heart disease.

While previous studies at Duke and elsewhere have shown that depression is a significant risk factor for death in patients with coronary artery disease, the underlying mechanism for this added risk is not well-understood, the researchers said. Moreover, there are virtually no data indicating that treating depression is associated with improved clinical outcomes, they added.

As the links between depression and worse outcomes in heart patients have become increasingly recognized over the past decade, physicians have added anti-depressants to the mix of medications for their heart patients. The most popular anti-depressants prescribed are a class known as selective serotonin reuptake inhibitors (SSRI).

"While some studies have shown that SSRIs can effectively reduce depression in patients with coronary artery disease, there are many such patients for whom these drugs are not effective or have unwanted side effects," said Duke medical psychologist James Blumenthal, Ph.D., principal investigator of the new trial. The five-year study is being supported by a $3.8 million grant from the National Heart, Lung, and Blood Institute.

"For this reason, we need to find alternative treatments for coronary artery disease patients who are depressed," Blumenthal continued. "In the past, we have shown that exercise can be an effective treatment for depression; however, more research is needed to confirm the benefits of exercise in heart patients with symptoms of depression. The purpose of this trial is to compare the effectiveness of SSRIs and exercise in reducing depression and to determine what physiological effects these approaches have on important biomarkers of disease."

The researchers plan to enroll 200 patients with demonstrated coronary artery disease, symptoms of depression, and who are currently sedentary and not currently being treated for depression. The researchers plan to enroll a representative mix of under-represented minorities and women.

Participants will be randomized to one of three arms of the study – SSRI therapy, exercise or placebo. Baseline psychological and physiological measurements will be taken at the trial's outset and then repeated 16 weeks later.

In addition to measuring changes in standard tests of depression, the researchers will document changes in five so-called "biomarkers" that have been implicated in coronary artery disease: platelet aggregation, inflammatory markers, heart rate variability, flow-mediated dilation of blood vessels and a phenomenon known as baroreflex sensitivity.

According to Blumenthal, research has shown that depressed patients often exhibit increased clumping of platelets and increased chronic inflammation in the blood, which could place such patients at an increased risk of sustaining a cardiovascular event such as a heart attack. The team will also measure heart rate variability, or the ability of the heart to regulate its pumping action in response to situations such as stress or anxiety.

Another physiological marker to be studied is the health of the endothelium, which forms the inner lining of the blood vessels and controls how the vessels react to changes in blood flow and pressure.

"We will take ultrasound images of the brachial artery of the arm before and after a tourniquet is applied and released to determine how the vessel responds," according to Andrew Sherwood, Ph.D. the co- principal investigator of the study. "Healthy arteries dilate to accommodate the increased blood flow, while diseased arteries are less responsive. In earlier tests of this flow-mediated dilation, we found that depressed patients had reduced responsiveness. We'd like to see if anti-depressant treatment can improve vascular health."

In past studies, the Duke team has also demonstrated that patients who received exercise training or stress management had improved baroreflex sensitivity, or the heart's ability to buffer surges in blood pressure often associated with stress. Receptors located along the walls of blood vessels are connected to the heart by nerves, which carry the message to pump faster or slower in response to pressure changes.

"Our studies have shown that abnormally low baroreflex sensitivity has been associated with worse outcomes for patients with heart disease," Blumenthal said.

The new trial has been named UPBEAT – "Understanding the Psychological Benefits of Exercise and Anti-Depressant Therapy in persons with cardiac disease."

Other members of the Duke team include Robert Waugh, M.D., Michael Babyak, Ph.D., Murali Doraiswamy, M.D., and Lana Watkins, Ph.D. In addition, exercise facilities at Meadowmont in Chapel Hill, Henderson, and Duke Health Raleigh will be used. Additional co-investigators include Alan Hinderliter, M.D. and Paula Miller, M.D., UNC Hospitals; William Sessions, M.D., Maria Parham Hospital, Henderson; and Larry Liao, M.D., Duke Health Raleigh Hospital.