Specialists challenge claim that fluoxetine plus talk therapy works best
for depressed adolescents
Jeanne Lenzer
BMJ 2004;329:529 (4 September.


A US study of clinically depressed adolescents, showing that a
combination of fluoxetine (Prozac) and cognitive behaviour therapy (CBT)
works best, has sparked concerns over the interpretation of the data.

The multicentre trial randomised 439 depressed adolescents aged 12-17
years to four arms: fluoxetine alone, CBT alone, CBT plus fluoxetine, or
placebo. The results showed that at 12 weeks, 71% of those treated with
CBT plus fluoxetine had improved, compared with just over 60% of those
taking fluoxetine alone, 43% treated with CBT alone, and 35% taking
placebo alone ( JAMA 2004;292: 807-20[Abstract/Free Full Text]).

Fluoxetine is the only anti-depressant in its class to be approved by
the US Food and Drug Administration for depression in adolescents.

Dr Thomas Insel, director of the National Institute of Mental Health,
which sponsored the $17m (£9.5m; 14m) research, described it as a
"landmark study" because "it's the largest publicly funded study and the
only study this size that doesn't have pharmaceutical funding." But six
of the 11 authors, including the lead author, John March, have received
funding from Eli Lilly, the manufacturer of fluoxetine.

Dr March, from Duke University Medical Center, Durham, North Carolina,
said that between 1 in 20 and 1 in 40 US adolescents developed severe
depression. "In some cases it's fatal. Now that we can identify it and
treat it, it seems common sense that you ought to provide the resources
to [do so]," he said. He stood by the authors' recommendation for
mandatory screening and treatment of depressed adolescents and for
fluoxetine to "be made widely available, not discouraged."

But the study fails to blind two of the four study arms—those which
included CBT alone and CBT plus fluoxetine—which raises questions about
the validity of the research, says Dr Michael Wilkes, director of
adolescent medicine at the University of California at Davis: "Most
methodologists would say combining blinded and unblinded arms is less
than ideal. You can't mix apples and oranges and have confidence in the
results."

Critics say the authors focused on only one of the study's two primary
end point scales—the one with the positive result. The other primary end
point showed that fluoxetine performed no better than placebo.

Harmful behaviour, including suicidal tendencies, was twice as high in
adolescents taking fluoxetine (12%) as it was in those receiving placebo
(5%).

Concerns about the authors' interpretation of the data have prompted
Professor David Antonuccio of the department of psychiatry and
behavioural sciences at the University of Nevada School of Medicine to
request the raw data under the terms of the Freedom of Information Act.

"The authors' value judgment is that the benefit of a few extra improved
patients is worth the cost of a few extra harmed patients," said
Professor Antonuccio. "My own risk-benefit analysis leads me to a
different conclusion." He suggested that CBT alone, or exercise, should
be offered as the first line treatment because of the lower risk of side
effects.


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