Psychiatr News April 4, 2008
Volume 43, Number 7, page 42
© 2008 American Psychiatric Association
Experts Dispute Report Critical of Antidepressants
Eve Bender
Conclusions about antidepressant efficacy based on a meta-analysis of
FDA clinical trials raise serious questions.
In late February some headlines heralded bad news for those being treated
for depression: "Prozac does not work," declared one headline from
the UK Guardian, "and nor do similar drugs...."
The news was in reaction to a metaanalysis of trials of selective serotonin
reuptake inhibitors submitted to the U.S. Food and Drug Administration (FDA)
from 1987 to 1999. The report appeared in the February 26 PLOS
Medicine.
"These findings suggest that, compared with placebo, the
new-generation antidepressants do not produce clinically significant
improvements in depression in patients who initially have moderate or even
very severe depression," the authors wrote, "but show significant
effects for only the most depressed patients."
Given their findings, Irving Kirsch, Ph.D., and colleagues concluded that
"there seems to be little evidence to support the prescription of
antidepressant medication to any but the most severely depressed patients,
unless alternative treatments have failed to provide benefit."
In an editorial appearing on the Web site of the British Medical
Journal, Eric Turner, M.D., an assistant professor of psychiatry at
Oregon Health and Science University, and Robert Rosenthal, Ph.D., a
distinguished professor of psychology at the University of California,
Riverside, noted that the data derived from their analysis of 12
antidepressant trials submitted to the FDA was similar to that derived from
Kirsch.
"Although these two sets of results were in excellent agreement, our
interpretations of them were quite different. In contrast to Kirsch and
colleagues' conclusion that antidepressants are ineffective, we concluded that
each drug was superior to placebo," the letter stated.
In the meta-analysis of FDA clinical trials, Kirsch obtained data from 35
randomized clinical trials, including five of fluoxetine, six of venlafaxine,
eight of nefazodone, and 16 of paroxetine in which all patients had been
diagnosed with major depressive disorder. The trials were conducted and
submitted to the FDA in an effort by manufacturers to have their medication
approved.
The researchers analyzed the findings in two ways: they calculated a
standardized mean difference between the drug and placebo and the effect size
of both groups.
The researchers examined all available information on the drugs, including
results from the trials that drug manufacturers did not publish during the
licensing period, which they obtained through a Freedom of Information Act
request. This gave them access to nine trials deemed adequate and well
controlled by the FDA, but that according to the report failed to achieve a
statistically significant benefit for drug over placebo.
The results were then compared with the criterion for clinical significance
as measured by the United Kingdom's National Institute for Clinical Excellence
(NICE). That criterion is a three-point difference between placebo and
treatment groups on the Hamilton Rating Scale of Depression (HRSD) scores or a
standardized mean difference of .50.
The HRSD was used to measure depression levels at baseline and throughout
the duration of the trials.
Kirsch and colleagues found that the weighted mean improvement on the HRSD
in the groups receiving antidepressants was 9.60, and for those receiving
placebo was 7.80, yielding a drug-placebo difference of 1.8 on the HRSD, which
though statistically significant, did not meet NICE's three-point drug-placebo
criterion for clinical significance.
In addition, the standardized mean difference for the drug groups was 1.24
and was .92 for placebo groups, which meant that the difference between
improvement in the drug groups and placebo groups was .32, which fell below
the .50 standardized mean difference criterion suggested by NICE.
In their editorial, Turner and Rosenthal pointed out that the criterion set
by NICE is "problematic, because it transforms effect size, a continuous
measure, into a yes or no measure, thereby suggesting that drug efficacy is
either totally present or absent, even when comparing values as close together
as 0.51 and 0.49."
They also noted that the NICE criterion is not a definitive measure, but a
value that could be problematic as a litmus test for drug efficacy.
In the article, Kirsch and his colleagues noted that drug efficacy did not
change as a function of initial depression severity, whereas placebo efficacy
decreased as initial depression severity increased. "Efficacy reaches
clinical significance only in trials involving the most extremely depressed
patients," the authors wrote, "due to a decrease in the response
to placebo rather than to an increase in the response to
medication."
In an interview with Psychiatric News, one of the authors of the
report, Blair Johnson, Ph.D., noted that the average trial's placebo effect
was closer to 100 percent of the size of the average drug effect at lower
observed rates of depression (that is, a score of about 17 on the HRSD) and
dropped to about 50 percent at the higher observed levels of depression (that
is, a score of about 30 on the HRSD).
Johnson is a professor of psychology at the University of Connecticut.
According to Darrel Regier, M.D., M.P.H., executive director of the
American Psychiatric Institute for Research and Education and director of
APA's Division of Research, there is nothing new in the findings to guide
clinical decision making for those prescribing antidepressants.
"We knew from the National Institute of Mental Health Collaborative
Treatment of Depression study in the 1980s that mild to moderate depression
could be treated as effectively with cognitive-behavioral therapy or
interpersonal therapy as with tricyclic antidepressants, but that those with
more severe depression responded better to the medication."
In addition, Regier pointed out, "the FDA is well aware of the high
placebo effect in depression treatment and requires at least two credible
placebo controls to grant an indication for an antidepressant
medication."
After safety and effectiveness are determined by the FDA, Regier noted,
clinicians need to know how to treat their patients most effectively.
The Sequenced Alternatives to Relieve Depression (STAR*D) study
demonstrated that many patients "don't respond to the first
antidepressant at a rate much higher than is found with placebo," but
that different steps of treatment produced cumulative remission rates of 67
percent.
In their editorial, Turner and Rosenthal wrote that they view the
antidepressant " 'glass' as far from full, but we disagree that it is
completely empty."
They recommended to clinicians that "when considering the potential
benefits of treatment with antidepressants, be circumspect but not
dismissive."
Regier, in his assessment of Kirsch's article, agreed.
Regier noted that for some reason Kirsch and colleagues are continuing a
quest to convince patients and physicians that antidepressants are largely
ineffective. In fact, there were a large number of online responses to the
article, many of which were critical of the study and its conclusions.
Commenters covered topics such as charges of author bias, descriptions of
measurement and methodology shortcomings with the original antidepressant
studies and the meta-analysis, discussions of the complexity of understanding
the placebo effect in clinical trials, and patient perspectives on the
efficacy of antidepressants. The comments and Johnson's response are posted at
<http://medicine.plosjournals.org/perlserv/?request=read-response&doi=10.1371/journal.pmed.0050045#r2188>.
Regier also said, "Fortunately for patients suffering from these very
real and disabling disorders, clinicians who follow a logical sequence of
treatment trials informed by research such as STAR*D are able to
maximize treatment effectiveness with a combination of medications and
psychotherapies."
"Initial Severity and Antidepressant Benefits: A Meta-Analysis
of Data Submitted to the Food and Drug Administration" is posted at
<http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371%2Fjournal.pmed.0050045>.
Turner and Rosenthal's editorial, "Efficacy of Antidepressants,"
is posted at
<www.bmj.com/cgi/content/full/336/7643/516>.
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