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At his research clinic in Dallas, psychologist Jasper Smits is working on an unorthodox treatment for anxiety and mood disorders, including depression. It is not yet widely accepted, but his treatment is free and has no side effects. Compare that with antidepressant drugs, which cost Americans $10 billion each year and have many common side effects: sleep disturbances, nausea, tremors, changes in body weight.

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This intriguing new treatment? It's nothing more than exercise.

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That physical activity is crucial to good health — both mental and physical — is nothing new. As early as the 1970s and '80s, observational studies showed that Americans who exercised were not only less likely to be depressed than those who did not, but were also less likely become depressed in the future.

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In 1999, Duke University researchers demonstrated in a randomized controlled trial that depressed adults who participated in an aerobic exercise plan improved as much as those treated with sertraline, the drug that was marketed as Zoloft, and was earning Pfizer more than $3 billion annually before its patent expired in 2006.

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Subsequent trials have repeated these results, showing again and again that patients who undergo aerobic exercise regimens see comparable improvement in their depression as those treated with medication, and that both groups do better than patients given only a placebo. But exercise trials on the whole have been small and most have run only for a few weeks; some are plagued by methodological problems. Still, despite limited data, the trials all seem to point in the same direction: Exercise boosts mood. It not only relieves depressive symptoms, but appears to prevent them from recurring.

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"I was really surprised that more people weren't working in this area when I got into it," says Smits, an associate professor of psychology at Southern Methodist University.

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Molecular biologists and neurologists have also begun to show that exercise may alter brain chemistry in much the same way that antidepressant drugs do — regulating the key neurotransmitters serotonin and norepinephrine. At the University of Georgia, neuroscience professor Philip Holmes and colleagues have shown that over the course of several weeks, exercise can switch on certain genes that increase the brain's level of galanin, a peptide neurotransmitter that appears to tone down the body's stress response by regulating another brain chemical, norepinephrine.

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Researchers also wonder whether this interaction between body and brain may, evolutionarily speaking, be hard-wired. "It occurs to us that exercise is the more normal or natural condition, and that being sedentary is really the abnormal situation," Holmes says.

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Humans (and lab rats) never evolved to be cooped up, still, all day long. Our brains simply may not be built for an environment without physical activity. Research has also suggested that exercise may be an effective treatment not just for depression, but also against related anxiety disorders and even substance dependence.

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