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By Dr.
Irving Kirsch
E-mail: irving.kirsch@uconn.edu
Although antidepressant medication
is widely regarded as effective, a recent meta-analysis of published clinical
trials indicates that 75 percent of
the response to antidepressants is duplicated by placebo.
The report analyses the data
submitted to the U.S. Food and Drug Administration (FDA) for approval
of recent antidepressant medications.
We analyzed the efficacy data
submitted to the FDA for the six most widely prescribed antidepressants
approved between 1987 and 1999:
- Prozac
- Paxi
- Zoloft
- Effexor
- Serzone and
- Celexa.
Results are reported from all
well controlled efficacy trials of the use of these medications for the
treatment of depression. FDA medical and statistical reviewers had access
to the raw data and evaluated the trials independently. The findings of
the primary medical and statistical reviewers were verified by at least
one other reviewer, and the analysis was also assessed by an independent
advisory panel.
More
important, the FDA data constitute the basis on which these medications
were approved. Approval of these medications implies that these particular
data are strong enough and reliable enough to warrant approval. To the
extent that these data are flawed, the medications should not have been
approved.
In order to generalize the
findings of the clinical trial to a larger patient population, FDA
reviewers sought a completion rate of 70% or better for these typically
6-week trials. Only 4 of 45 trials, however, reached this objective.
In clinical trials, the effect
of the active drug is assumed to be the difference between the drug response
and the placebo response.
This report showed that the
FDA clinical trials data indicate that 18% of the drug response is due
to the pharmacological effects of the medication. Overall, the drug/placebo
difference was less than 2 points on the HAM-D, a highly reliable physician-rated
scale that has been reported to be more sensitive than patient-rated scales
to drug/placebo differences.
Although mean differences were
small, most of them favored the active drug, and overall, the difference
was statistically significant. There were only 4 trials in which mean
improvement scores in the placebo condition were equal to or higher than
those in the drug condition, and in no case was placebo significantly
more effective than active drug. This may indicate a small but significant
drug effect. However, it is also possible that this difference between
drug and placebo is an enhanced placebo effect due to the breaking of
blind.
These data raise questions
about the criteria used by the FDA in approving antidepressant medications.
The FDA required positive findings from at least two controlled clinical
trials, but the total number of trials can vary. Positive findings consist
of statistically significant drug/placebo differences. The clinical significance
of these differences is not considered.
To summarize, the data submitted
to the FDA reveal a small but significant difference between antidepressant
drug and inert placebo. This difference may be a true pharmacological
effect, or it may be an artifact associated with the breaking of blind
by clinical trial patients and the psychiatrists who are rating the severity
of their conditions.
In any case, the difference
is relatively small (about 2 points on the HAM-D), and its clinical significance
is dubious. Research is therefore needed to assess the additivity of antidepressant
drug and placebo effects. If there is a powerful antidepressant effect,
then it is being masked by a nonadditive placebo effect, in which case
current clinical trial methodology may be inappropriate for evaluating
these medications, and alternate methodology need to be developed.
Conversely, if the drug effect
is as small as it appears when drug/placebo differences are estimated,
then there may be little justification for the clinical use of these medications.
The problem, then, would be
to find an alternative, as the clinical response to both drug and placebo
is substantial. Placebo treatment has the advantage of eliciting fewer
side effects. However, the deception that is inherent in clinical administration
of placebos inhibits their use. Thus, the development of nondeceptive
methods of eliciting the placebo effect would be of great importance.
Prevention
& Treatment, Volume 5, Article 23, July
15, 2002
First
Posted in Red
Flags Weekly July 17, 2002
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