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More so than effects and chemistry, experts say, what
distinguishes Prozac is the methodology of the studies that have
been done to test it. Depression is a subjective experience for
which doctors have no blood test, no hard and fast measure.
Especially in children and teenagers, depression is fleeting.
This is one reason that in antidepressant trials the placebo
effect is so large and unpredictable. In a study lasting six or
eight weeks, many participants get better on their own, drug or no
drug. In childhood depression studies the placebo effect can range
from 30 percent up to 59 percent, which is difficult for any
antidepressant to beat.
"The wonderful thing about the F.D.A. panel's findings is that
it's going to force people to talk about these things and look at
the studies very carefully," said Dr. Jane Garland, chief of the
Mood and Anxiety Clinic at British Columbia Children's Hospital in
Vancouver, who has argued that company-sponsored trials have
presented data to make the drugs look more effective than they are.
For example, some researchers questioned the findings of two
studies reported last year, testing Zoloft for depression in
children and adolescents. The placebo response was very high, 59
percent, and some doctors were not convinced that the drug proved
much better, as the study's authors had concluded. The studies were
large, conducted at multiple sites in five countries, and the
criteria for test subjects was not controlled well enough to give a
clear picture of what the drugs were doing, if anything, some
experts said. Other studies of antidepressants have met similar
The exception is Prozac, for which there have been three rigorous
trials. In 1997 and again in 2002, Dr. Graham J. Emslie of the
University of Texas Southwestern Medical Center at Dallas screened
children and adolescents to make sure they had persistent
depression. He found that those on Prozac reported feeling
significantly better than those taking dummy pills after eight
weeks, and in one of the trials, were more likely to meet one
criterion for recovery.
The first trial was government financed, the second was paid for
by Eli Lilly. Dr. Emslie has consulted widely for antidepressant
makers. "If you tested the other drugs in the same way, tightly
controlled, I believe you would get similar results," he said.
The third trial, led by Dr. March, appeared in the Aug. 18 issue
of The Journal of the American Medical Association. The researchers
made sure to include only teenagers who had persistent depression,
for more then 40 weeks on average, with a diagnosis in the moderate
to serious range. The placebo effect was on the lower end, and after
12 weeks those on Prozac were doing significantly better on ratings
of depression. When combined with a brand of counseling called
cognitive behavior therapy, the drug treatment did even better.
But careful experiments are usually better at picking up risk,
too. Although previous studies had not found noticeable association
between Prozac and increased risk of suicidal or self-harmful
behavior, Dr. March's trial did. Six teenagers taking the drug
attempted suicide during the trial, compared with one who was in
therapy but not on the drug.
Considering all the data on self-harmful behavior, Dr. March
said, Prozac has about the same profile as others in the same family
- it is associated with an increased risk of suicidal behavior in
about 1 in 50 teenagers who take it. "But you have to keep in mind
that you can't distinguish that 1 from the 8 or 9 in 50 depressed
teenagers who also would be at risk for suicide because of the
underlying depression," he said.
Individual responses to antidepressants are hardly uniform. Some
children who react badly to Zoloft thrive on Prozac, or another
antidepressant, and vice versa.
Even doctors who are highly skeptical of drug company claims say
that the drugs do help some children overcome a sometimes deadly
condition. That is why many psychiatrists are relieved that the
F.D.A. panel did not follow British regulators and recommend a ban
on use of all but one of the drugs in young people. Although Prozac
is approved for treatment of childhood depression and is off patent
- meaning it costs a fraction of what the others do - it is good to
have options, they say.
"If the recommendations are too derogatory, the use of drugs that
I believe are saving hundreds of lives a year could be diminished or
withdrawn," said Dr. David Shaffer, a professor of psychiatry and
pediatrics at Columbia University. "Then you've got another kind of
tragedy." Dr. Shaffer said he does not receive any money from drug
Doctors and researchers agree that more work on treatment and
diagnosis will be required to sort out the role of drugs. But given
the publicity about suicide risk, some doubt that it will happen
Dr. Emslie said that when he first proposed studying Prozac in
children in the 1990's, Eli Lilly was not interested. "They wouldn't
even give us the pills," he said. "They said it was all risk, no
benefit. Now, I think it's going to much more difficult to do any of
this kind of research."