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Posted by plosmedicine on 31 Mar 2009 at 00:22 GMT

Author: Emmanuelle Corruble
Position: MD, PhD
Institution: Paris South University
Submitted Date: February 27, 2008
Published Date: February 28, 2008
This comment was originally posted as a “Reader Response” on the publication date indicated above. All Reader Responses are now available as comments.

About “Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration"


Based on a meta-analysis of short term randomized controlled trials (RCT), Kirsch and colleagues (1) recently stated that drug–placebo differences in antidepressant efficacy are relatively small even for severely depressed patients, contradicting classical results (2).

We would like to underline three major limitations of this paper.
First, the authors studied four heterogenous second generation antidepressants (fluoxetine, paroxetine, nefazodone, venlafaxine), not all the FDA database, limiting its conclusions.
Second, another weakness of this meta-analysis is that it did not give sufficient attention to the extent to which the antidepressant dosage can affect efficacy. Even if the majority of studies have flexible-dose designs, differences in efficacy were observable among fixed-dose studies of second-generation antidepressants (2,3,4).
Third, the generalizability of its results should be discussed. Actually, randomized controlled trials (RCT) are necessary. However, their generalizability to clinical practice is a matter of concern because patients included in clinical trials are different from daily practice patients. For example, patients with high suicidal risk are systematically excluded from conventional RCT. And this meta-analysis of RCT considered mainly out-patients, whereas many studies have shown that antidepressant efficacy is more pronounced in those studies which included in-patients with severe depression (2).

Finally, based on these major limitations, we do not agree with the conclusions of this meta-analysis, which are excessively pessimistic. In the interest of providing the best possible treatment for those suffering from major depression, we argue for a better knowledge of antidepressant benefits, based not only on companies sponsored RCT but also on antidepressants pharmacoepidemiological studies sponsored by public health research funds.

Emmanuelle CORRUBLE MD PhD
Paris XI University, INSERM U669, Bicetre Universitary Hospital, Assistance Publique - Hôpitaux de Paris, France.

Conflict of interest: none

1. Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, et al. (2008) Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLoS Med 5(2): e45 doi:10.1371/journal.pmed.0050045
2. Khan A, Kolts RL, Thase ME, Krishnan KRG, Brown WA. Research Design features and patient characteristics associated with the outcome of antidepressant clinical trials. Am J Psychiatry. 2004;161:2045-49.

3. Thase ME, Entsuah AR, Rudolph RL. Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. Br J Psychiatry. 2001;178:234-41.

4. Corruble E et al. Antidepressants and major depression: relationship between efficacy and dosage in the therapeutic range? Acta Psychiatr Scand. 2000;101:343-348.

Corresponding author:
Prof Emmanuelle CORRUBLE
Department of Psychiatry,
Bicêtre Hospital - 78 rue du General Leclerc - 94230 Le Kremlin Bicêtre, France.
Tel: 00 33 1 45 21 25 24
Fax: 00 33 1 45 21 28 64

No competing interests declared.