About 15 million Americans each year suffer depression, and it is the leading cause of disability in people ages 15 to 44. It often recurs, and doctors sometimes talk of it as an emotional cancer that, rather than cured, is put 'in remission' with successful treatment.

Up to one-third of those who added or changed medicines recovered. When viewed with earlier results, the new findings mean that roughly half the people who suffer from serious, long-term depression can get over it -- not just improve their symptoms -- with adequate medication.

"The goal here was to find treatments that help people to get well, not just better," said Dr. Thomas Insel, director of the National Institute of Mental Health. "We have safe and effective treatments."

Clear Message: Don't Give Up

His agency paid for the $35 million study, which involved thousands of people across the United States and has been widely praised as a real-world test of popular drugs that have received only limited testing until now.

The study found little difference among the five drugs tested -- Celexa, Zoloft, Wellbutrin, Effexor and Buspar -- and wasn't designed to compare them. All proved similarly effective and relatively safe. The clear message, doctors said, was that antidepressants should be given a six- to 12-week chance to work and that if one doesn't help, another should be tried.

"It's important not to give up if the first treatment doesn't work fully," or causes side effects, said one study leader, Dr. John Rush of the University of Texas Southwestern Medical Center in Dallas. Almost as many people were helped the second time around as the first, he said.

Two reports from the study were published today in the New England Journal of Medicine.

Remission vs. Cure

About 15 million Americans each year suffer depression, and it is the leading cause of disability in people ages 15 to 44. It often recurs, and doctors sometimes talk of it as an emotional cancer that, rather than cured, is put "in remission" with successful treatment.

Nearly two dozen antidepressants are on the market -- 189 million prescriptions were filled last year alone -- but they are controversial. Evidence on their effectiveness is limited, and the government recently ordered stronger warnings that some can worsen suicidal tendencies in teenagers in rare cases. The risk in adults is still being studied.

The big federal study first tested Forest Laboratories' Celexa, a newer type of antidepressant called a selective serotonin reuptake inhibitor, or SSRI, mostly because it's an easy-to-take daily pill.

One-third of the roughly 3,000 taking it recovered, though they generally took higher doses and were monitored more closely than most patients, researchers reported several months ago.

Tough-to-Treat Group

The new research, the second step of the study, was on people who didn't get well the first time around, an especially tough-to-treat group.

They had depression for 16 years on average and two-thirds had other mental or physical problems.

Out of this group, 727 chose to switch from Celexa to a different medication and were randomly assigned to get either Zoloft, another SSRI made by Pfizer Inc.; Wellbutrin, a non-SSRI antidepressant made by GlaxoSmithKline; or Effexor, an antidepressant made by Wyeth that works on another brain chemical in addition to the one targeted by SSRIs.

Roughly one-fourth became symptom-free within 14 weeks. No big differences were seen in safety or side effects among the drugs.

Another 565 patients chose to add a second drug to Celexa and were given either Wellbutrin or Buspar, a Bristol-Myers Squibb anti-anxiety medication that can boost the effectiveness of SSRIs.

Within 14 weeks, about one-third were symptom-free. Those on Wellbutrin had slightly fewer symptoms and side effects than those on Buspar.

Long-Term Depression

One study participant, Kasey Thompson, a 40-year-old medical school administrator from Fort Worth, Texas, had suffered depression for nearly 20 years despite having a good job and lots of family and friends.

"Everything should have been fine, but it wasn't. I was not happy and I could not figure out why. And it wasn't just not being happy, I was down. Deep down," she said.

Celexa helped, but she still had sleep problems and avoided friends until she added Wellbutrin.

"Piggybacking these two drugs together made a huge impact on my depression," Thompson said.

The study will continue to test third and even fourth treatment attempts, and to analyze genes to see if any patterns emerge with particular drugs.

"It's quite possible in the near future we may be able to predict who's going to respond to what," said another study leader, Dr. Madhukar Trivedi of University of Texas Southwestern.

In an offshoot of the same study, researchers reported Tuesday that treating depressed mothers can benefit their children.

In an editorial in the New England journal, Dr. David Rubinow of the University of North Carolina at Chapel Hill wrote that the study is encouraging, because half got well on drugs, but discouraging, because half did not.

Roughly 4 out of 10 people in the study were unemployed and nearly that many had no health insurance.

Without access to treatment and less societal stigma toward depression, millions will continue to suffer, he wrote.