> Kirsch concludes from his research that much of the apparent therapeutic benefit of antidepressants may derive from amplification of placebo responding by convincing patients that they are receiving a potent drug. Placebos are found to be approximately 75% as effective as antidepressant medications across all outcome studies in which it is possible to measure pre-post effect sizes. Analysis of the New Drug Application (NDA) data sets sent to the FDA by the manufacturers of the six most widely prescribed antidepressants has shown that although the response to antidepressants was substantial, the response to inert placebo was almost as great. More than half of the clinical trials sponsored by the pharmaceutical companies failed to find significant drug/placebo difference, and there were no advantages for higher doses of antidepressants. These data reinforce the argument that the small size of the average drug/placebo difference is an artifact associated with the breaking of the blind in clinical trials and of questionable clinical significance. The small magnitude of the so-called antidepressant effect in clinical trials should be more widely known. Kirsch proposes the development of nondeceptive methods of eliciting the placebo effect in treatment of depression. Psychotherapies may accomplish their effects by changing expectations, but unlike placebos, they do so without deception.14 The point is that the effectiveness of antidepressants has not been demonstrated empirically.
> The motion is seconded by Joanna Moncrieff, Senior Lecturer in Social and Community Psychiatry at University College London... She discusses "The Antidepressant Debate" in an editorial in the British Journal of Psychiatry. In particular, she highlights the methodological problems of antidepressant trials, including the evidence for the amplification of the placebo effect from studies comparing antidepressants with active placebos. The antidepressant effect does not seem to be specific to identified antidepressants as other drugs not classed as antidepressants have been shown to have positive effects in depression in controlled clinical trials. Moncrieff suggests that the interests of the pharmaceutical industry and the psychiatric profession have helped to establish the notion of the efficacy and specificity of antidepressant drugs.
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What I'm trying to do here is to go some way towards undermining the necessity of medication for recovery.
> (1) Bias in clinical trials
> Randomised controlled trials have replaced uncontrolled studies and become accepted as the scientific "gold-standard". However, randomised controlled trials are too often assumed to produce unbiased evidence (Chalmers, 1998). The most methodically rigorous trials are associated with less treatment benefit than poor quality trials (Moher, et al, 1998). Even the best quality trials may still not completely eliminate bias because of difficulties is sustaining the two key elements of the method: that the trial is conducted "double-blind", which means that neither subjects nor experimenters are aware of their group allocation so that their expectancies do not bias outcome; and that any inherent differences between groups are equalised by randomisation. Randomisation can be confounded because of drop-outs from the trial, leading to bias because of exclusions after randomisation.
> One history of medicine is of doctors prescribing medication which is subsequently regarded as useless and often dangerous (Shapiro and Shapiro, 1997). The question is how much this situation continues into the present. Two examples will be considered (i) the efficacy of antidepressants, including the problem of antidepressant discontinuation and (ii) the efficacy of lithium
> (i) The efficacy of antidepressants
> Reviewing the research on antidepressant trials is a massive task. The first attempts to systematise the data such as Morris and Beck (1974) looked at those trials published between 1958 and 1972 and found that tricyclic antidepressants were significantly more effective than placebo in 61 out of 93 group comparisons. Rogers and Clay (1975) concluded that the evidence for imipramine, the original antidepressant, was so strong that further trials of this drug were not justified in endogenous depression in non-institutionalised patients. Since these two reviews, many new antidepressants have been introduced, particularly the class of SSRIs (serotonin specific reuptake inhibitors).
> However, New Scientist could still report in 1998 that the benefits of antidepressant medication could be "mostly in the mind" (Day, 1998). At least one third of the published clinical trials of approved antidepressants are negative for efficacy (Thase, 1999). The US Agency for Health Care Policy and Research (1999) produced a conservative lower limit to treatment efficacy for newer antidepressants using an intention to treat analysis of response rates of 50% for antidepressants and 32% for placebo in major depression. Antidepressants are not always effective and there is a considerable placebo response.
> The double-blind methodology is inadequate in many antidepressant trials (Even, et al, 2000). Patients and doctors may be cued in to whether patients are taking active or placebo medication by a variety of means. In fact if treatment is clearly superior to placebo, this should be obvious to raters in the trial making it not technically blind. Patients in clinical trials are naturally curious to ascertain whether they are in the active or placebo group, and may for example notice that placebo tablets they have been taking taste differently from medication to which they have previously become accustomed. Active medication may produce side effects which distinguishes it from inert medication. The difference between drug and placebo effect may be a true pharmacological effect, but the possibility that it is an enhanced placebo effect cannot be excluded (Kirsch and Sapirstein, 1998).
> Using active drugs without apparent specific treatment effects as controls generally reduces the effect size of antidepressant treatment, maybe because bias is less likely to be introduced because of the detection of active effects in the control drug (Thomson, 1982). However, the adequacy of these active placebo trials can be questioned (Quitkin, et al, 2000).
> The importance of the placebo response is relevant to problems in discontinuing medication. People may form attachments to their medications more because of what they mean to them than what they do. Psychiatric patients often stay on medications, maybe several at once, even though their actual benefit is questionable. Any change threatens an equilibrium related to a complex set of meanings that their medications have acquired. These issues of dependence should not be minimised, yet commonly treatment is reinforced by emphasising that antidepressants are not addictive. For example, the Defeat Depression Campaign of the Royal College of Psychiatrists criticised the general public for generally taking this view (Priest, et al, 1996). The general public might reasonably expect psychiatrists specialising in disorders of the mind to recognise psychological dependence, base their advice on clinical experience, and use their common sense (Double, 1997).
> A sceptical view about the value of antidepressant medication is commonly rejected because it is regarded as undermining people's faith in their treatment. The issue is really about the scientific validity of claims for the efficacy of antidepressants. There is more uncertainty about this issue that many seem prepared to accept.
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