In the long and frustrating battle against depression, persistence does pay.
A major government study reports today that at least a quarter of clinically depressed patients who failed to achieve a complete remission with one antidepressant succeeded by adding a drug or by switching drugs.
Overall, about half of the nearly 1,500 patients achieved remission -- the virtual absence of symptoms -- by completing two treatment steps, and at least a quarter more showed improvement.
The six-year, $35-million study is intended to provide the first scientifically based roadmap for treating depression.
Since the introduction of powerful antidepressants in the late 1980s, most treatment "has been driven by anecdotes -- small series of case reports, 10 patients helped by one combination, 15 by another," said Dr. Andrew Leuchter of UCLA, who helped conduct the study.
"This is the largest study ever to look at what is the best next step if you don't get well in the first step" of treatment, he said.
The study, sponsored by the National Institute of Mental Health, is the first part of a series of studies designed to formalize the procedures for a therapy that until now has largely relied on a doctor's intuition and experience.
"They are trying to find some science for what is now an art," said Dr. Jan A. Fawcett of the University of New Mexico, a spokesman for the mental health advocacy group NARSAD.
The study addressed one of the biggest problems with antidepressants: Many patients give up if they don't respond quickly to the first drug they try or if they suffer unpleasant side effects.
The study showed that results often took six to 12 weeks, much longer than expected.
The message to patients and physicians is "Hang in there," said Dr. A. John Rush of the University of Texas Southwestern Medical Center, who led the trials, which are reported today in the New England Journal of Medicine.
"For the depressed person, it may not matter so much what drug is being prescribed, but that the person moves forward and keeps trying," he said.
Depression affects nearly 15 million Americans each year and is the leading cause of disability between the ages of 15 and 44.
It is "an utter sense of hopelessness," said Dr. Thomas R. Insel, director of the National Institute of Mental Health. "Just getting up out of bed and going to work or to school become insurmountable challenges."
The disorder is responsible annually for 30,000 suicides and $86 billion in lost productivity.
More than 189 million prescriptions for antidepressants are written each year, with total sales of about $12 billion.
Still, half of depressed patients receive no treatment.
The Sequenced Treatment Alternatives to Relieve Depression study, commonly known as STAR*D, was designed to determine the optimum protocol for treating depression.
The study initially enrolled nearly 3,000 patients who had suffered from depression for an average of 16 years.
Two-thirds had other medical problems, and 40% were unemployed because of their condition.
All the patients received the antidepressant citalopram, trade-named Celexa. That drug was chosen because it was relatively new at the time, could be given in various doses easily and seemed to be well-tolerated. Nonetheless, about 20% of patients dropped out because of side effects, including nausea, sleep problems, tremors and sexual dysfunction.
About one in three patients given the drug went into remission. Remission was chosen as an endpoint because of "the growing recognition that improvement in symptoms is not enough," said Fawcett, who was not involved in the study. "Usually, it doesn't last."
The doses used were often higher than those in everyday practice, and patients were followed for as long as 12 weeks -- a crucial change, according to Rush. Often, patients and doctors abandon a drug if they don't see results within four weeks, he said. But about half the patients in the study who improved did not show benefits until eight to 10 weeks into the study.
In the second level of the study, patients who did not go into remission were given the option of having a second drug added to their regimen or of switching drugs.
Of those, 727 chose to switch and were randomly assigned to receive either sertraline (trade-named Zoloft), bupropion (Wellbutrin) or venlafaxine (Effexor). In that group, about 25% achieved remission within 14 weeks.
Somewhat surprisingly, Rush said, the three drugs all produced about the same results even though they work differently.
The 565 patients who chose to add a drug to their citalopram were randomly assigned to receive bupropion or buspirone (BuSpar).
Among those, 30% achieved a remission, with both drugs equally effective, although those receiving bupropion had slightly fewer symptoms and side effects.
Patients who did not achieve remission on either regimen had the option of proceeding to levels 3 and 4 of the trial, which incorporated other drugs and talk therapy into the regimen. Those results are to be reported this fall.
In an accompanying journal editorial, Dr. David R. Rubinow of the University of North Carolina at Chapel Hill said the study was encouraging because more than half of the patients went into remission, but discouraging because nearly half did not.
That indicates a need for new drugs and a better understanding of the basic biology of depression, he said.