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By JOHN CLOUD John Cloud Sun May 10, 2:00 pm ET
In the '90s, Americans grew fond of the idea that you can fix depression simply
by taking a pill - most famously fluoxetine (better known as Prozac), though
fluoxetine is just one of at least seven selective serotonin reuptake
inhibitors (SSRIs) that have been prescribed to treat hundreds of millions of
people around the world.
But in the past few years, researchers have challenged the effectiveness of
Prozac and other SSRIs in several studies. For instance, a review published in
the Journal of Affective Disorders in February attributed 68% of the benefit
from antidepressants to the placebo effect. Likewise, a paper published in PLoS
Medicine a year earlier suggested that widely used SSRIs, including Prozac,
Effexor and Paxil, offer no clinically significant benefit over placebos for
patients with moderate or severe depression. Meanwhile, pharmaceutical
companies maintain that their research shows that SSRIs are powerful weapons
against depression. (Here's a helpful blog post that summarizes the debate.)
Now a major new study suggests that both critics and proponents might be right
about SSRIs: the drugs can work, but they appear to work best for only a subset
of depressed patients - those with a limited range of psychological problems.
People whose depression is compounded with, say, substance abuse or a
personality disorder may not get much help from SSRIs - which is unfortunate
for the 45% to 60% of patients in the U.S. who have been diagnosed with a
common mental disorder like depression and also meet the criteria for at least
one other disorder, like substance abuse. (Multiple diagnoses are known in
medical parlance as comorbidities.)
The new study, published online in April by the American Journal of Psychiatry,
was conducted using data from a large, government-funded trial called Sequenced
Treatment Alternatives to Relieve Depression, which usually goes by the moniker
STAR*D. The STAR*D project, which collected data from 2001 to 2004 at 41 U.S.
psychiatric facilities, was one of the most ambitious efforts ever to
understand how best to treat people with major depression. STAR*D participants
comprise a powerful research sample because they are highly representative of
all depressed Americans. Very few depressed people were excluded from STAR*D;
only women who were pregnant, those with seizure disorders and a few others
with acute conditions were kept out. All other psychiatric and medical
comorbidities were allowed.
The authors of the new paper, a team of 11 researchers led by University of
Pittsburgh professor of epidemiology Stephen Wisniewski, were curious how the
STAR*D group would compare with a typical group of patients selected for a
run-of-the-mill drug-company trial for a new antidepressant - the very trials
on which the Food and Drug Administration bases its decisions regarding new
drug approval. Drawing on their own experiences in helping to conduct such
trials, which have far more stringent inclusion criteria than the STAR*D group,
Wisniewski and his team divided the STAR*D patients into two groups - an
"efficacy" sample of patients who would normally be included in a typical Phase
III clinical trial for a new antidepressant and a "nonefficacy" sample of
patients who would normally be rejected.
Depressed STAR*D patients who were classified for inclusion had no more than
one general medical condition (like, say, heart disease) and no more than one
additional primary psychiatric disorder besides depression. All patients with
multiple comorbidities - along with anyone whose depression had lasted more
than two years - were excluded. Once the authors crunched all the numbers, they
found that only 22% of STAR*D patients met entry criteria for a conventional
antidepressant trial.
All the STAR*D patients were taking citalopram, an SSRI marketed in North
America as Celexa. Not surprisingly, those who met standard inclusion criteria
for a clinical trial had significantly better outcomes on the drug. In the
efficacy group, 52% responded to Celexa vs. 40% of the nonefficacy group.
Patients in the latter group also took longer to respond and had to be
readmitted to psychiatric settings more often. "Thus," the authors conclude,
"current efficacy trials suggest a more optimistic outcome than is likely in
practice, and the duration of adequate treatment suggested by data from
efficacy trials may be too short."
To bolster their findings, the authors cite a smaller 2002 study that arrived
at similar results: in that paper, published in the American Journal of
Psychiatry, Dr. Mark Zimmerman of Brown University and his colleagues found
that of 315 patients with major depressive disorder who sought care, only 29,
or 9.2%, met typical criteria for an efficacy trial. Similarly, psychologist
Ronald Kessler of Harvard co-authored a 2003 paper in the Journal of the
American Medical Association that concluded that most "real world" patients
with major depression would be excluded from clinical trials because of
comorbidities.
Such findings help explain why antidepressants haven't quite lived up to their
promise. But the University of Pittsburgh's Wisniewski, the lead author of the
new study, cautions against interpreting the results as an indictment against
greedy drug companies eager to exclude difficult patients in order to show
better results. "If the population in a [clinical] trial were more
representative, that would come at a cost," he says. Researchers expect a
certain number of bad reactions during clinical trials; some of these reactions
can cause serious medical problems. If patients enter a trial with multiple
complications - if they are, say, not only depressed, but also
cocaine-addicted, hypertensive and diabetic - you dramatically increase the
chances of adverse side effects. "That's why trials to determine efficacy are
done on a relatively homogeneous population," Wisniewski says.
That's understandable, but the new study does shed light on the limitations of
antidepressants. Conducting clinical trials with representative samples would
undoubtedly be more complex - and expensive - since patients with multiple risk
factors would have to be monitored more carefully. But for a future generation
of antidepressants to be truly effective for most patients, more-inclusive
trials may be the best answer.