March 22, 2006 — Don’t give up hope, a new study suggests to people suffering with depression.

It may take 14 weeks and a change of medication, but people with major depression now have a 50-50 chance of getting better and getting well.

What about the 50% of people who don’t get well? There’s still hope they’ll get well, too.

The findings come from the second phase of the STAR-D trial. It’s an ambitious, ongoing study funded by the National Institute of Mental Health. The goal: to see, in a step-by-step fashion, just what it takes to put major depression into full remission.

Phase I of the trial
Phase I of the trial showed that he antidepressant Celexa helps nearly a third of patients get well. Now phase II of the trial shows that switching drugs or adding a new drug makes a third of the remaining patients well.

That adds up to about half of the patients in the study, says study co-leader A. John Rush, MD, professor and vice chairman for research in psychiatry at the University of Texas Southwestern Medical Center at Dallas.

“The big message is that symptoms can be eliminated in over 50% of people who receive two treatment steps,” Rush said at a news conference. “For patients, it is important not to give up if the first treatment does not work fully, or if it causes side effects. … Most patients should expect at least two treatment attempts to become asymptomatic.”

Results of the $35 million study — funded by the NIMH and not by drug companies — appear in two papers in the March 23 issue of The New England Journal of Medicine.

Depression: An Emotional Cancer

The size of this government effort to find effective depression treatments testifies to the severity of the illness. Depression is often seen “as a weakness, if not a vice,” notes an NEJM editorial by David R. Rubinow, MD, chairman of psychiatry at the University of North Carolina at Chapel Hill.

“The STAR-D trial is attempting to discover the best way of treating a destructive, malignant, and life-threatening illness,” Rubinow tells WebMD. “Anything that can help reduce the astronomical burden of depression is well worth the investment of public resources.”

NIMH director Thomas Insel, MD, notes that depression costs the U.S. economy $83 billion each year. Nearly 7% of U.S. adults — 15 million Americans — suffer depression each year. Suicide will claim 4% of these lives.

“Depression is disease defined by emotional pain. It is a total collapse of vitality, an emotional cancer that takes away any hope of joy or feeling,” Insel said at a news conference. “Depression precludes the very effort needed for recovery. Often with major depressive disorder, just getting out of bed to go to work or school becomes an insurmountable challenge.”

The design of the STAR-D trial is both simple and complex. The basic idea is to do something drug company trials don’t do. Instead of trying to see whether a particular drug has an effect, the STAR-D study is trying to find out how depression treatment can make sick people well.

At the start of the trial, all patients received Celexa. Celexa leaves the body relatively quickly, so researchers are unlikely to confuse its effects with the effects of a second drug.

Doctors of patients who, after trying Celexa, didn’t have full remission — that is, whose depressive symptoms don’t go away — got a choice. They could put their patients in the “switch” group or in the “augmentation” group.

Switch patients stopped taking Celexa and were randomly assigned to take Effexor XR, Wellbutrin SR, or Zoloft. These patients had a 25% chance of getting better.

“No one medication was clearly better than another, even though these treatments differ in how they work,” Rush says. “So which treatment a patient gets is less important than that the medications be used diligently, with appropriate dose and management of side effects.”

Augmentation patients added BuSpar or Wellbutrin SR to their Celexa treatment. These patients had a one-in-three chance of getting better.

“We tested two augmentation drugs, and despite the differences in how they worked, both were about the same in terms of efficacy and tolerability,” Rush says. “Both are good choices for patients who have not gotten well with the first treatment step.”

Although augmentation patients had a better chance of remission, this doesn’t mean that augmentation is necessarily a better strategy for all patients. Doctors tended to choose the switch strategy for patients who had more side effects and a lesser symptom benefit from Celexa. Doctors tended to choose the augmentation strategy for patients who did somewhat better with Celexa and wanted to continue.

“The overall net effect [of second-step treatment] is 30% remission — nearly as good as first step treatment,” Rush says.

The Half-Empty Half of the Glass

The good news is overall, about half of people with depression get better after their first or second treatment regimen. And the trial isn’t over yet. The study will go on to offer patients different drug regimens and/or psychotherapy.

“What we have been talking about with this 50% figure is where we are at in this trial,” Insel says. “We still have people who may improve further in follow-up. I suspect that number will go up.”

Even so, the glass is still half empty. Half of patients don’t get better, even after two tries at treatment.

“The glass-is-half-empty view is that, regrettably, no particular antidepressant seems to be maximally effective if one is going to switch,” Rubinow says. “In effect, [this study] may not lead to a significant change in current practice other than a renewed justification for making certain that someone is on an antidepressant for a long enough time before concluding that the antidepressant is ineffective.”

One benefit of the study is that it gives doctors more confidence, even if it doesn’t immediately change the way they treat patients, says Mark I. Levy, MD, a private practice psychiatrist and assistant clinical professor of psychiatry at the University of California, San Francisco.

“The STAR-D results support what I have done, but until now I have done it like most practitioners, without good studies to back it up,” Levy tells WebMD. “The rule of thumb is that a third of depressed patients respond to the first antidepressant. It may take six, eight, or 12 weeks. And then two-thirds will need some tweaking or switching, or something else.”

There’s likely to be more information on what that “something else” might be when the third-stage results of the STAR-D trial become available this fall.

Insel says the full trial results will make treatment better by helping doctors match treatments to the patients they are most likely to help. But he also notes that current treatments simply aren’t good enough.

“We need to come up with better treatments in the future to increase remission to 100% — and to act much quicker than the 12 weeks reported in these studies,” Insel says.

It’s great that treatment can heal depression. It would be even better if treatment could cure depression. But Rubinow warns that depression tends to be an illness that recurs.

“Nobody has demonstrated, and this is a really critical point, whether remission from depression, with or without antidepressants, means that the illness is gone,” he says. “In fact we know depression is a recurrent illness in the vast majority of cases. … If we say the patient is not symptomatic and is functional, you can meaningfully call it remission. But it does not mean that all potential for relapse is not still there.”