Antidepressants fail to cure the symptoms of major depression in half of all patients with the disease even if they receive the best possible care, according to a definitive government study released yesterday.
Significant numbers of patients continue to experience symptoms such as sadness, low energy and hopelessness after intensive treatment, even as about an equal number report an end to such problems -- a result that quickly lent itself to interpretations that the glass was either half empty or half full.

The $35 million taxpayer-funded study was the largest trial of its kind ever conducted. It provided what industry-sponsored trials have rarely captured: Rather than merely ask whether patients are getting better, the study asked what patients most care about -- whether depression can be made to disappear altogether.

The study has been eagerly awaited by physicians, patients and the pharmaceutical industry. According to government statistics, depression afflicts 15 million Americans a year. About 189 million prescriptions for antidepressants were written last year, and the disease costs the nation $83 billion annually because of treatment costs, lost productivity, absenteeism and suicide.

David Rubinow, a professor and the chairman of the psychiatry department at the University of North Carolina at Chapel Hill, said the results are an "illuminating and disconcerting" window into the affliction that is thought to fuel many of the 30,000 suicides committed each year in the United States.

Although the study showed that patients who do not respond well to one drug could be helped by another, the results are "discouraging for several reasons," Rubinow said in an editorial published in the New England Journal of Medicine, which also published the study.
It is troubling that large numbers of patients continued to have problems, he said. Additionally, he noted that the drugs used in the study -- Celexa, Wellbutrin, Zoloft and Effexor -- work in very different ways yet had roughly equal effectiveness when it came to treating depression. This suggests that the underlying brain mechanisms of depression are far more complicated than simple notions of a single chemical imbalance.

Thomas Insel, director of the National Institute of Mental Health, which funded the study, emphasized that patients should seek -- and stick with -- treatment. "The glass is half full from our perspective," he said. But "the glass is half empty in that we need to come up with better treatments in the future."

The study is immediately relevant to physicians because it tracked a large number of patients with the kind of complications and chronic problems that are usually excluded from pharmaceutical industry trials. About one in three patients had seen their depression symptoms go away after an initial round of treatment, a result known as remission. About half achieved that goal after a new round of treatment involving either a new medication or an additional drug, the research found.
Although patients recruited to pharmaceutical industry trials are usually carefully screened to ensure they do not have other psychiatric or medical conditions, those in the government-funded study often suffered from multiple physical and mental problems -- typical of patients whom doctors routinely see.

At the same time, the researchers acknowledged, the care provided in the study was exceptional. Intensive monitoring and careful evaluation was provided to all patients. Such services are available today in perhaps one in 10 medical practices. If the patients in this study had received the kind of care that patients receive on average, the researchers said, the remission rate probably would have been significantly lower -- perhaps even in the single digits.

"People who entered into this trial received a level of care which is quite different than many patients receive when they see a primary-care doc or even a psychiatrist," Insel said as he described what clinical facilities should aim for in terms of care. "This involved a depression-care specialist who made sure there was very careful monitoring of side effects and a relentless effort to optimize the dose. It is not like writing a prescription for penicillin and coming back in four to six weeks."
The study also employed standardized assessment tests that looked more deeply at patients' conditions than the routine conversations about their health that are generally employed in clinical care. Such attention allowed problems to rise to the surface that may otherwise be missed, and kept patients from becoming discouraged about treatment.
Augustus John Rush, a psychiatrist at the University of Texas Southwestern Medical Center in Dallas, who helped organize the study known as the Sequenced Treatment Alternatives to Relieve Depression, said the results are positive, given the many complications that often accompany depression.

"A 50 percent remission rate is extraordinarily good, given the nature of these disorders," he said. "These individuals have had an average of 16 years of depression. Two-thirds have other concomitant psychiatric conditions and two-thirds have concomitant general medical problems. All of these reduce the chances of remission."

Although the study has continued to offer treatment for even longer periods, those results are not yet available. Rush said that with chronic problems, most of the benefit is usually seen in the first couple of rounds of treatment, since the remaining patients are those with the most intractable problems.

Psychiatric drugs have been at the center of growing controversy for nearly two years -- including concerns that antidepressants may increase the risk of suicidal behavior among some children and worries that drugs used to treat attention deficit hyperactivity disorder are overused. Still, researchers and clinicians say they are far more worried about untreated mental illness than any overuse of medications.