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different studies, and then applied it to studies that were different in their subject selection criteria, treatments employed, and statistical
methods used. They published their study because both they and their peers considered their findings to have considerable merit.
The meta-analysis was conducted on 19 studies which fulfilled the following criteria: patients with a primary diagnosis of depression;
sufficient data were reported/obtainable to calculate within-condition effect sizes; there was a placebo control group; random assignment of participants to the experimental drug; antidepressants were prescribed for the acute phase of treatment; any maintenance treatment studies were excluded.
The medications under review were amitriptyline, amylobarbitone, fluoxetine, imipramine, paroxetine, isocarboxazid, trazodone, lithium, liothyronine, adinazolam, amoxapine, phenelzine, venlafaxine, mapro-tiline, tranylcypromine and bupropion.
Kirsch and Sapirstein’s meta-analysis suggested that 75 per cent of the response to the medications was a placebo response and that
at most 25 per cent might be true drug effect. They clarified that this does not mean that only one in four people will respond to the phar-
macologic proprieties of the drug, but that for a typical patient it means
three-quarters of the benefit obtained from the active drug would also have been obtained from a chemically inactive placebo.
An analysis by type of medication (i.e. tricyclics and tetracyclics;
SSRIs; other antidepressants; and other medications), revealed little variability in drug response and even less variability in the ratio of
placebo response to drug response. The inactive placebo response was between 74 per cent and 76 per cent of the active drug response in each of the four groups.
The recent media frenzy over reports that ‘Prozac is no better than
The authors noted the possibility that the drugs could improve depres-
placebo’ was based on research into the efficacy of antidepressants
sion indirectly, for example by improving sleep or reducing anxiety, but
(SSRIs) which goes back many years.1 The article prompting the furore
they discount this explanation because response to non-antidepressant
was the third published by Kirsch and colleagues which focused on
drugs was at least as great as that to conventional antidepressants.
meta-analyses of antidepressant medication – the first was published
They argued that antidepressants may function as active placebos, in
in 1998 and the second in 2002.2 3 So why did the recent publication in
which the side effects amplify the placebo effect by convincing patients
PLoS create such enormous and worldwide media interest?
that they are receiving a potent drug.
Both of the earlier papers are now difficult to access online, with dead
links through Google Scholar, and are absent from other academic
This paper was published in 2002 in response to criticisms of the
search engines like ‘Web of Knowledge’ or ‘Dialog Datastar’. The refer-
methods used in Kirsch and Sapirstein’s first paper. Here, Kirsch and
ence link from the current PLoS paper to the previous work of 2002
colleagues also expand on an earlier analysis of the US Food and
Drug Administration (FDA) data on seven new antidepressant medica-tions.4 The earlier analysis had concluded that depressed patients in
I finally found the 2002 paper using ‘Ovid’. Both the earlier articles
clinical trials who receive placebo treatment are not at greater risk of
were published in Prevention and Treatment, a journal of the American
suicide or attempted suicide than those given ‘active’ treatment, and
Psychological Association, which ceased publication in 2003. The only
that depressed patients given placebo do gain substantial improve-
way to locate the journal was through the APA website, all other links
being dead. But even having found the journal on the APA website it is impossible to access the full articles unless you are an APA member
This 2002 paper reports on an analysis of data submitted to the FDA
or are willing to pay to view. Prevention and Treatment is not a listed
between 1987-1999 for the approval of the six most widely prescribed
antidepressants, namely fluoxetine, paroxetine, sertraline, venlafaxine, nefazodone and citalopram.3
The latest article is published in a major open access journal – perhaps one reason for the media attention. Of course, the media
Kirsch and colleagues undertook their new meta-analysis using the
always likes a ‘scare story’. Frightening the public will boost circula-
FDA data which was used to gain regulatory approval of these drugs.
tion and ratings, as past coverage of HRT, the contraceptive pill and
They used the Freedom of Information Act to obtain medical and
statistical reviews of every placebo controlled clinical trial for depres-sion reported to the FDA for initial approval of the six most widely used
The three articles that Kirsch has published between 1998 and 2008
antidepressant drugs approved within the study period.
are worth reading, and I have attempted to summarise them here.
They analysed forty-seven randomised, placebo-controlled, short-term
efficacy trials conducted for the six drugs in support of an approved
In their 1998 paper, Kirsch and Sapirstein describe how they used a
indication of treatment for depression; data from relapse prevention
‘controversial’ statistical approach, meta-analysis, to pool data from
“there is little evidence to support prescribing antidepressants to anyone but the most severely depressed patients”
The findings of this meta-analysis identified that 80 per cent of the
because of incomplete data from their clinical trials, both on the phar-
response to the antidepressants was duplicated in the placebo
maceutical web sites and within the published literature. The research-
control groups; only 18 per cent of the drug response was due to
ers report that they consider they had access to complete data sets
the pharmacological effects of the medication. Although a small but
(unpublished and published data) for the other four drugs.
significant difference between antidepressant drug and inert placebo was apparent, Kirsch and colleagues concluded that the pharmaco-
Again, this study concluded that the overall effect of new generation
logical benefits of these antidepressants were questionable and could
antidepressant medications is below recommended criteria for clinical
significance. The authors acknowledge that for the most severely depressed patients there is a clinically important effect, but that this is
The placebo effect shown in this analysis was greater than those shown
due to a decrease in response to placebo rather than an increase in
previously.2 4 Kirsch and col eagues suggested this might be due to
two factors: publication bias and missing data in earlier studies. They acknowledged that their assumption that drug effects and placebo
Their final conclusion is that there is little evidence to support prescrib-
effects are additive may not be correct, and that the true drug effect
ing antidepressants to anyone but the most severely depressed
may be greater than drug/placebo difference, and recommended further
patients, unless alternative treatments have already been tried and
research to assess how the drug and placebo effects combined.
Initial Severity and Antidepressant Benefits
Penny Louch is lead nurse practitioner for a nurse-led medical practice
The current 2008 study by Kirsch and colleagues notes that the
meta-analyses of antidepressant effects published by NICE relied only on published studies (so it left out some of the data held by the FDA).5
It reported benefits which, although statistically significant, were of
1 Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnsson BT.
marginal clinical importance. The purpose of this new study was to test
Initial Sever ity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLoS Medicine 2008;5:260-8.
the hypothesis that antidepressants may still be effective for severely depressed patients, even if not for moderately depressed patients.
2 Kirsch I, Sapirstein G. Listening to Prozac but Hearing Placebo: A Meta-Analysis of
Antidepressant Medication. Prevention and Treatment 1998; 1(Article 0002a).
What is not clear is whether the authors of this paper re-analysed the
3 Kirsch I, Moore T, Scoboria A, Nicholls S. The Emperor’s New Drugs: An
published and unpublished data for the six antidepressants which
Analysis of Antidepressant Medication Data Submitted to the US Food and Drug Administration. Prevention and Treatment 2002; 5:Article 23.
formed the basis of the 2002 paper, or used the same analysis from six years previously.
4 Khan A, Warner HA, Brown WA. Symptom reduction and suicide risk in patients
treated with placebo in antidepressant clinical trials – An analysis of the food and drug administration database. Arch Gen Psychiatry 2000;57:311-7.
The drugs under investigation were fluoxetine, paroxetine, venlafaxine, nefazodone, sertraline and citalopram.
5 NICE, National Collaborating Centre for Mental Health. Depression: Management
of depression in primary and secondary care. National Clinical Practice Guideline Number 23. London: NICE, 2004.
Two drugs were susequently excluded (citalopram and sertraline)
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