Intended for healthcare professionals

Analysis And Comment Drug regulation

Did regulators fail over selective serotonin reuptake inhibitors?

BMJ 2006; 333 doi: (Published 06 July 2006) Cite this as: BMJ 2006;333:92
  1. David Healy, professor of psychiatry (
  1. 1 North Wales Department of Psychological Medicine, Cardiff University, Bangor LL57 2PW

    Controversy over the safety of antidepressants has shaken public confidence. Were mistakes made and could they have been avoided?

    GlaxoSmithKline's recent letter to doctors points to a sixfold increase in risk of suicidal behaviour in adults taking paroxetine.1 This contrasts with the data in the UK Medicines and Healthcare Products Regulatory Authority's expert working group report on suicide and antidepressants published in December 2004.2 Many people expect drug companies to be slow to concede that a drug causes hazards, but we do not expect our regulators to be even slower, so any hint that this might have been the case needs to be examined.

    Regulatory problem

    In February 1990 an article raised concerns that the recently licensed fluoxetine might trigger suicide acts in depressed patients.3 A series of meta-analyses of published and unpublished antidepressant trials subsequently failed to show benefit in terms of suicidal acts with active treatment compared with placebo.49 In fact, each analysis showed a small excess risk with active treatment for all classes of antidepressants, although the increases are compatible with chance and the original authors concluded there were no differences. For much of the 1990s campaigners were saying trials with placebo controls in depression were unethical, and these analyses were attempts to justify placebo controlled trials.

    I recently participated in a cumulative meta-analysis of published trials that found an excess of suicide attempts in patients taking selective serotonin reuptake inhibitors (SSRIs) compared with those taking placebo.10 The numbers in the individual trials are small, so that although from 1988 onwards the point estimate indicates roughly a doubling of the risks of suicidal acts with SSRIs, the effect has only recently been consistently significant. Nevertheless, the trend should have been seen by both companies and regulators as something that required investigation before …

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