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Poor response or poor methodology?

Posted by plosmedicine on 31 Mar 2009 at 00:21 GMT

Author: Julian Beezhold
Position: Consultant in Emergency Psychiatry
Institution: Hellesdon Hospital, Norwich, United Kingdom
Submitted Date: February 26, 2008
Published Date: February 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.

Kirsch et al (1) have produced an intriguing meta-analysis of data submitted to the Food and Drug Administration regarding some antidepressants. They conclude that "Given these data, 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" and that "the increased benefit for extremely depressed patients seems attributable to a decrease in responsiveness to placebo, rather than an increase in responsiveness to medication".

The evidence presented does not justify these sweeping conclusions, which appear more consistent with an (undeclared) longstanding scepticism towards antidepressant effectiveness that runs through Kirsch’s previous work. (2)(3)(4)(5).

The first conclusion fails because it ignores relevant data such as the evidence regarding long term use of antidepressants such as Geddes et al. (6) who examined data on 4410 subjects in 31 randomised trials and found "Continuing treatment with antidepressants reduced the odds of relapse by 70% (95% CI62-78, 2p lesser than 0.00001) compared with treatment discontinuation. The average rate of relapse on placebo was 41% compared with 18% on active treatment". This conclusion also fails to address the evidence from studies such as Rihmer (7) demonstrating a reduction in suicides in Hungary during 1984-1998 proportional to a steep increase in SSRI prescribing, in the presence of steep increases in per capita alcohol consumption and unemployment.

Their second conclusion is misleading, given the author’s own admission “the difference between these means (placebo vs. antidepressant) easily attained statistical significance” that antidepressants are more effective than placebo. There appears to be no data in the paper to warrant this statement implying the exact opposite of the more reasonable inference, namely that it is easier to measure the effectiveness of antidepressants in extremely depressed people.

A more accurate conclusion may be that a small but significant superiority in reducing Hamilton Rating Scale Depression scores was demonstrated for antidepressants over placebo, but that the clinical implications of this are unclear. This is especially so given that the longest study duration used was only eight weeks.

Ultimately and unfortunately, the most robust inference that can be drawn may be that the methodological limitations of the primary source data may render the author's conclusions unsafe.

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. Moncrieff, J., & Kirsch, I. (2005). Debating antidepressant efficacy in adults. British Medical Journal,331, 155-157.
3. Kirsch, I., & Antonuccio, D. (2002). Antidepressants versus placebos: Meaningful advantages are lacking. Psychiatric Times, 19, 6-8.
4. Kirsch, I., Moore, T.J., Scoboria, A., & Nicholls, S.S. (2002). The emperor.s new drugs: An analysis of antidepressant medication data submitted to the FDA. Prevention and Treatment. Available on the World Wide Web: http://www.journals.apa.o...
5. Kirsch, I. (2002). Yes, there is a placebo effect, but is there a powerful antidepressant drug effect? Prevention and Treatment. Available on the World Wide Web: http://www.journals.apa.o...
6. Geddes JR, Carney SM, Davies C, Furuwawa TA, Kupfer DJ, et al. (2003) Relapse prevention with antidepressant drug treatment in depressive disorders: A systematic review. Lancet 361:653-661
7. Rihmer Z 92001) Can better recognition and treatment of depression reduce suicide rates? A brief review. Eur Psychiatry 16:406-409

Competing interests declared: The author has accepted honoraria from companies including Lilly, Lundbeck, Janssen-Cilag, Wyeth and AstraZeneca for presentations on a variety of medication and non-medication related topics.

The author has direct personal experience of both depression and suicide.