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There is little doubt that depression is bad for the heart. Much as fatty diets, cigarette smoking, inactivity and obesity are linked with an increased risk of heart disease, recent evidence suggests that mental health has a similarly powerful impact. The question has always been, why?

Now, researchers provide the first data that may explain the association. Published in the Journal of the American Medical Association, the findings suggest that depression contributes to heart disease indirectly — by fostering unhealthy behaviors like smoking — rather than directly. Certain biological factors linked with depression, such as inflammation and the levels of brain chemicals like serotonin, may play some role in heart health, researchers say, but the new study found that the factors that most increased heart disease risk in depressed people were the ones you might expect: lack of exercise and smoking.

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"We looked at all sorts of biological markers that could potentially play a role in linking depression and heart disease," says Dr. Mary Whooley, an internist at the VA Medical Center in San Francisco, and lead author of the new study. "We measured all of those, and found that they did not explain the association. All we needed to do was to ask the patient how much they were exercising to be able to explain the link."

Whooley studied more than 1,000 patients with heart disease at the VA for nearly five years. The patients filled out regular questionnaires to determine their mood state, and were asked yearly to report on any heart-related events. Researchers took blood and urine samples to measure their levels of omega-3 fatty acids, cortisol and the inflammatory marker C-reactive protein, as well as the neurotransmitters serotonin and norepinephrine — all agents that may be involved in both depression and heart disease. In all, about 20% of the participants reported depressive symptoms; over five years, those patients had a 50% higher rate of additional heart problems, compared with their non-depressed peers.

Whooley's team studied the depressed group further. Researchers systematically adjusted for each potential risk factor to figure out whether it was mediating the link between depression and heart disease. Physiological factors, such as serotonin levels or CRP, for example, appeared not to have much impact. But when researchers adjusted for physical activity — that is, when they analyzed the data by assuming identical levels of exercise in both depressed and non-depressed patients — the difference in heart disease risk between the groups disappeared. Indeed, inactivity among the depressed patients gave them a 44% greater risk of having a heart event than people who were not depressed, accounting for nearly all of the depressed patients' 50% higher risk. Picking up the remainder of the increased risk was cigarette smoking.

The findings suggest that the effect of depression on heart health may have less to do with changes in hormones or other biochemical pathways, and more to do with behavior. Compared with other people, notes Whooley, the depressed are less healthy overall — they're less likely to exercise or take their heart medications, and are more likely to smoke. The relationship also feeds back on itself; previous studies show that exercise not only improves cardiovascular health, but also elevates mood and can ease depression.

The study may even help to explain why treating depression alone — rather than addressing patients' mental state and accompanying behavioral changes — has not proven successful in reducing the risk of heart disease. "We have always looked at certain behaviors like physical activity and smoking in isolation with respect to their effect on heart disease," says Dr. Clyde Yancy, president-elect of the American Heart Association and medical director of the heart and vascular institute at Baylor College of Medicine. "But one or both could be manifestations of depression, which in turn leads to heart disease."

And while researchers are intrigued by the question of which comes first — depression or heart disease — the study points out that, in practice, it doesn't really matter. "It's hard to tease out which came first," says Whooley. "But our bottom line is that regardless of which is coming first, this study introduces a new pathway that might get at that risk, by focusing not so much on depression itself, but by getting at the behaviors that go along with depression." It may be easier to take Prozac than to take a jog, but as the study suggests, it may not always be as effective.

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