Advertisement
Research Article

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

  • Irving Kirsch mail,

    To whom correspondence should be addressed. E-mail: i.kirsch@hull.ac.uk

    Affiliation: Department of Psychology, University of Hull, Hull, United Kingdom

    X
  • Brett J Deacon,

    Affiliation: University of Wyoming, Laramie, Wyoming, United States of America

    X
  • Tania B Huedo-Medina,

    Affiliation: Center for Health, Intervention, and Prevention, University of Connecticut, Storrs, Connecticut, United States of America

    X
  • Alan Scoboria,

    Affiliation: Department of Psychology, University of Windsor, Windsor, Ontario, Canada

    X
  • Thomas J Moore,

    Affiliation: Institute for Safe Medication Practices, Huntingdon Valley, Pennsylvania, United States of America

    X
  • Blair T Johnson

    Affiliation: Center for Health, Intervention, and Prevention, University of Connecticut, Storrs, Connecticut, United States of America

    X
  • Published: February 26, 2008
  • DOI: 10.1371/journal.pmed.0050045

Reader Comments (47)

Post a new comment on this article

Misinterpretation in Kirsch et al’s article

Posted by plosmedicine on 31 Mar 2009 at 00:24 GMT

Author: Tamar Wohlfarth
Position: Epidemiologist
Institution: Tamar Wohlfarth is employed by the Medicines Evaluation Board of the Netherlands. However, she is submitting this letter on personal title
E-mail: twohlfarth@gmail.com
Additional Authors: Wim van den Brink (Amsterdam Institute for Addiction Research, Academic Medical Center, University of Amsterdam, Department of Psychiatry, Amsterdam, The Netherlands) , Jitschak Storosum (Academic Medical Center, University of Amsterdam, Department of Psychiatry, Amsterdam, The Netherlands)
Submitted Date: March 25, 2008
Published Date: March 27, 2008
This comment was originally posted as a “Reader Response” on the publication date indicated above. All Reader Responses are now available as comments.

The modest effect size of antidepressants in depression studies is well known for many years now (1, 2), as is the fact that placebo response in these studies tends to be large and highly variable (2). Recently it has been shown that the overall magnitude of the effect is smaller in non-published compared to published studies (3). The recent paper by Kirsch et al about the limited benefits of antidepressants in the treatment of depression (4) contains, therefore, nothing new. However the paper does contain some serious misinterpretations that need correction.

First, the authors suggest that increased benefit in severely depressed patients is only due to the lower placebo response in this population and not to a better response to active medication; a suggestion that is already interpreted in the media as indicating that the effect of treatment in severely depressed patients is just as small as in patients who are mildly depressed (e.g. BBC News (5) ; University of Hull Press release (6)). This suggestion of the authors is erroneous because the effect size in an RCT is defined as the difference between the effect of active compound and placebo. Moreover, because severely depressed patients are less likely to experience spontaneous remission there is a stronger need for (pharmacological) interventions than in less severely depressed patients.

Second, the authors refer to the mean difference in improvement between active and placebo arms as being not ‘clinically relevant’ (4). However, “clinical relevance” is a concept that can only be validly applied to change in an individual patient, not to average change across a group of patients. One method to address the clinical relevance of the effect of antidepressants is through responders or remitters analyses which examine the proportion of individual patients in each treatment group who experience a clinically meaningful improvement. Unfortunately, the authors have not examined the data in this way. This is not to say that such an analysis would necessarily result in a more positive evaluation of the effect of antidepressants, but at least the conclusion would be based on a methodologically sound analysis technique.

Third, the conclusion with regard to the differential effectiveness of antidepressants in patients with a moderate and severe depression is based on just one study in moderately severe patients. Again the conclusion may be correct, but it can not be based in the presented analysis of an inadequate database.

In conclusion, the paper of Kirsch and his colleagues presents nothing that was not previously known, but it does introduce empirically unsupported conclusions and erroneous interpretation that are potentially misleading.

Tamar Wohlfarth, PhD
Wim van den Brink, MD PhD (corresponding author)
Jitschak Storosum, MD PhD

1. 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.

2. Storosum JG, Elferink AJ, van Zwieten BJ, van den Brink W, Gersons BP, van Strik R, Broekmans AW. Short-term efficacy of tricyclic antidepressants revisited: a meta-analytic study. Eur Neuropsychopharmacol. 2001 Apr;11(2):173-80. Erratum in: Eur Neuropsychopharmacol 2001 Aug;11(4):325.

3. Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med. 2008;358(3):252-60.

4. Kirsch I, Deacon BJ, Huedo- Medina TB, Scoboria A, Moore TJ, et al. (2008) Initial severity and antidepressant benefits: A metaanalysis of data submitted to the Food and Drug Administration. PLoS Med 5(2): e45. doi:10.1371/journal. pmed.005004

5. BBC News: Anti-depressants ‘of little use’. http://news.bbc.co.uk/go/...

6. The University of Hull: Antidepressants are ineffective for most patients, study finds. Press Release, Tuesday 26 February 2008.

No competing interests declared.