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Response to acute monotherapy for major depressive disorder in randomized, placebo controlled trials submitted to the US Food and Drug Administration: individual participant data analysis

BMJ 2022; 378 doi: https://doi.org/10.1136/bmj-2021-067606 (Published 02 August 2022) Cite this as: BMJ 2022;378:e067606

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Re: Response to acute monotherapy for major depressive disorder in randomized, placebo controlled trials submitted to the US Food and Drug Administration: individual participant data analysis

Dear Editor,

This useful review of the placebo controlled trials confirms that in a database of over 73,000 patients the confidence interval of the effect of antidepressants on HAMD lies below 2, a less than 4% absolute change in this 50-point scale. This confirms the effect size is at a level that cannot be detected by either the consumer, or the prescriber.[1]

This is a fluctuating condition where trials recruit patients during exacerbations. Repeating the assessment at the end of the trial will give a mean value for HAMD that is lower than the mean baseline value because of regression to the mean. This explains the large "effect" of a mean 8-point fall in HAMD in the control arm data. Delving into the ends of the distribution of the curve of results in a search for responders is a post hoc analysis not justified by any of the trial protocols. It is not possible to claim that a patient with a particularly large fall in HAMD score is a "responder". Given the expected fluctuation in symptoms there is no guarantee that a "responder" will have the same response one day, one month, or one year later. The small additional fall in HAMD with active treatment is consistent with the effect of using an active placebo, where experiencing side effects from active treatment adds to the belief in efficacy. Some patients may be more susceptible to this effect, though we cannot confirm this without repeat challenge data.

It is a major concern that the most frequent duration of the trials was six weeks and we have no data beyond 12 weeks. These drugs are frequently given for years and this is not consistent with international requirements for other areas of long term therapeutics.[2] The lack of proof of long term efficacy is important, the lack of long term safety data even more so.

References
1. Warren J B. The trouble with antidepressants: why the evidence overplays benefits and underplays risks—an essay by John B Warren BMJ 2020; 370 :m3200 doi:10.1136/bmj.m3200
2. ICH E1 Population exposure: the extent of population exposure to assess clinical safety. 1995 CPMP/ICH/375/95. https://www.ema.europa.eu/en/ich-e1-population-exposure-extent-populatio...

Competing interests: No competing interests

17 August 2022
John B Warren
Physician
Retired
Ipswich, Suffolk, UK