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Selective serotonin reuptake inhibitors
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     EDITOR—Geddes and Cipriani fear that regulatory bodies overrate the importance of placebo controlled trials.1 We disagree. The placebo controlled randomised trial is still the best test of efficacy available, although several improvements in conventional methodology are necessary to prevent selection biases.2 However, selection bias owing to a placebo washout period has not yet been tackled.

    Although no doctor uses a placebo washout in real life practice, most antidepressant trials use such a period before randomisation. To demonstrate their effect: say, 200 patients are available, and 20 placebo responders are excluded before randomisation. The remaining 180 patients are then randomised to treatment with antidepressant or placebo. However, as it is not known whether all placebo responders in the antidepressant arm would have recovered if they had been given antidepressants, the direction of this differential selection may favour antidepressants.

    Other necessary methodological improvements are: more use of "active" placebos to allow better blinding as they contain substances that mimic the specific side effects of antidepressants3; better concealment of allocation;4 independent outcome assessment4; independent funding4; inclusion of relevant groups such as general practice patients and elderly people; and the use of the preferred more conservative intention to treat analyses.5

    Most known biases inflate the effects of antidepressants. Intention to treat analyses would, for example, decrease the risk difference between antidepressant drugs and placebo from 28% to 19%.2 A large, independently funded, good quality general practice trial of antidepressants versus placebo is much needed now, without placebo washouts.

    Harm W J van Marwijk, senior researcher, department of general practice

    hwj.vanmarwijk@vumc.nl, Institute for Extramural Medicine, VU University Medical Centre, Van der Boechorststraat 7, 1081 BT Amsterdam, Netherlands

    Herman J Adèr, methodologist, department of clinical epidemiology and biostatistics

    Institute for Extramural Medicine, VU University Medical Centre, Van der Boechorststraat 7, 1081 BT Amsterdam, Netherlands

    Competing interests: None declared.

    References

    Geddes JR, Cipriani A. Selective serotonin re-uptake inhibitors remain useful drugs which need careful monitoring. BMJ 2004;329: 809-10. (9 October.)

    Stolk P, ten Berg MJ, Hemels ME, Einarson TR. Meta-analysis of placebo rates in major depressive disorder trials. Ann Pharmacother 2003;37: 1891-9.

    Moncrieff J, Wessely S, Hardy R. Active placebos versus antidepressants for depression. Cochrane Database Syst Rev 2004; CD003012.

    Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273: 408-12.

    Begg C, Cho M, Eastwood S, Horton R, Moher D, Olkin I, et al. Improving the quality of reporting of randomized controlled trials: the CONSORT statement. JAMA 1996;276: 637-9.