James Russo has wrestled for some 60 years with his "black dog" of depression, since the days back in high school when a B left him feeling like an utter failure. Valium didn't help when he tried it in his late 20s, nor did a tricyclic antidepressant. Prozac made him jittery and nervous. Finally, 15 years ago, Paxil offered relief, but he has had to double the dose since—and recently add another medication to handle post-retirement "doom and gloom." Says Russo, 73, of Bernville, Pa.: "My disease lives in the corner of my mind, sometimes sleepy enough to let me enjoy a little optimism but ever ready to ruin a day or a week or a year."

What has become abundantly clear in the antidepressant age—the drugs are now the most commonly prescribed medications in the country—is that depression is terribly difficult, if not impossible, to cure. Many primary-care doctors, who treat 80 percent of depressed people, labor under the assumption that a prescription is a panacea. But antidepressants completely alleviate symptoms in only about 35 to 40 percent of people compared with 15 to 20 percent of those who take a placebo—a fact not publicized in pharmaceutical ads. And about 70 percent of people who successfully beat one bout can expect to face another. "We just don't have one magical pill that will do the whole trick," says Madhukar Trivedi, a professor of psychiatry at the University of Texas Southwestern Medical Center in Dallas. He recently participated in the government-funded "Star*D" trial of more than 4,000 patients with difficult-to-treat depression, which showed success rates of antidepressants could be increased but that it sometimes took four tries of various drugs plus therapy. Even then, in 30 percent of those who completed the yearlong study, symptoms still lingered.

Lifestyle culprits. Gradually, many mental-health practitioners are coming to believe that adjusting brain chemistry with medication isn't enough—that depression is a complex chronic disease, akin to diabetes, requiring lifestyle changes and ongoing monitoring to address underlying causes. As with diabetes, experts have begun to look for culprits in the 21st-century lifestyle. Might the isolating, sedentary, indoor computer culture explain, for example, why the disorder appears to be surging in young adults? Today's 20-somethings have a 1-in-4 lifetime risk of experiencing depression's hallmark black mood, joylessness, fatigue, and suicidal thoughts compared with the 1-in-10 risk of their grandparents' generation. Americans are 10 times as likely to have depression today as they were 60 years ago, a development that is not merely a result of increased awareness and diagnosis.

There's certainly evidence that vigorous exercise has an effect on mood. Trivedi and others have shown that burning off 350 calories three times a week in sustained, sweat-inducing activity can reduce symptoms of depression about as effectively as antidepressants. Brain-imaging studies indicate that exercise stimulates the growth of neurons in certain brain regions damaged during depression. And animal studies have found that physical exertion increases the production of brain molecules that improve connections between nerve cells and act as a natural antidepressant. Sunlight or light-box exposure often helps people prone to seasonal affective disorder. And there's no doubt that getting a decent night's sleep can lift the spirits. Nutrition may play a role, too: It's fairly well established that those who eat the most fish have the lowest rates of depression.

Realizing that primitive societies like the Kaluli of Papua New Guinea experience virtually no depression, Stephen Ilardi, an associate professor of psychology at the University of Kansas, is now testing a cave-man-esque approach to treatment with promising results. His 14-week Therapeutic Lifestyle Change program entails large doses of simulated hunter-gatherer living in people suffering from prolonged, unremitting depression. Participants sign up for 35 minutes of aerobic exercise (running, walking briskly, biking) three days a week, at least 30 minutes of daily sunlight or exposure from a light box that emits 10,000 lux, eight hours of sleep per night, and a daily fish oil supplement containing 1,000 mg of the fatty acid EPA and 500 mg of the fatty acid DHA.

Brooders. They also get plenty of time surrounded by the "clan," in the form of frequent social gatherings with family members, Starbucks dates with friends, and volunteer work. "Hunter-gatherers almost never had time alone," says Ilardi; even a generation or two ago, people grew up supported by extended family and much more engaged with their community. Too much time in isolation, he says, means "opportunities to ruminate," the modern scourge. Studies indicate that brooders are far more likely than nonbrooders to develop depression. "I feel terrific now, but I'm really well plugged in with my old friends," says Russo, who regularly calls and E-mails former colleagues, occasionally traveling 70 miles to Philadelphia to meet them for lunch.

Obsessive thinkers can learn to redirect themselves. Cognitive behavioral therapy, for example, teaches people to recognize when irrational negative thoughts are triggering a mood plunge and to reframe those thoughts in a rational way. Was that coworker really laughing at my outfit? Or just trying to be witty in front of the boss? A 2006 study published in the American Journal of Psychiatry found that people whose symptoms disappeared after cognitive behavioral therapy showed significant changes on MRI scans in two brain regions associated with depression. What's more, the therapy appears to be as effective as medication when used for resistant depression, according to findings from the Star*D trial.

"Drugs are quicker acting and take less work in the short run, but they only suppress the problem," says Michael Thase, a professor of psychiatry at the University of Pennsylvania School of Medicine who led the comparative study for Star*D. The therapy, he says, allows people to take action when their mood is dipping to prevent a full-blown relapse.

After learning anti-rumination strategies in weekly group therapy sessions, TLC participant Becky Foerschler of Lawrence, Kan., now puts a 15-minute limit on her mental rehashings of tense conversations with friends and family. Foerschler, who first developed depression two years ago at age 47, then uses techniques to distract herself, like calling a friend or getting out of bed to read. She says that she's been symptom free for the past 15 months.

Data on all of Ilardi's 73 graduates haven't yet been published. But he reports that 59 percent achieved complete remission, compared with just 10 percent of a control group that continued on antidepressants or therapy. And most of the patients have stayed depression free after one year of follow-up. Ilardi allows that he made things convenient: He provided free fish oil supplements and light boxes; a local fitness club donated gym memberships; and his graduate students volunteered as informal personal trainers. In the real world, people in the throes of depression often have a hard time just getting out of the house to have a prescription filled. "If I had depression, I would probably undertake many of the elements he's talking about," says psychiatrist John Rush, who led the Star*D study at UT Southwestern, "but whether they're sufficient for those with chronic depression remains to be demonstrated."

Better care. Clearly, what most doctors offer is a far cry from the extent of care Ilardi provides. A September study by the Rand Corp. found that most do a poor job of monitoring medications and addressing alcohol abuse and suicide risk; fully one quarter of patients given prescriptions for antidepressants never completed treatment, and many whose symptoms got worse weren't given a higher dose or a different medication. "Doctors shouldn't just ask, 'How are things?' " says Rush, whose symptom assessment questionnaire, available at ids-qids.org, is used widely by researchers to measure treatment effects. "Symptoms should be assessed before treatment and again after six to eight weeks. If the score on the questionnaire doesn't improve, treatment needs to be altered." The Star*D study suggests that genetic differences could explain why some folks feel completely better on a particular drug, while others get some benefit, and still others get no response or develop suicidal tendencies.