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2.8 Blindness and placebo response in antidepressant drug trials

One other problem has complicated the scientific evaluation of antidepressant efficacy and has proved hard to avoid. Fundamental to reliable evaluation is the requirement of blindness, and normally the double-blind procedure when neither investigators nor patients know whether they are administering/taking either the test drug or placebo. The FDA requires claims of efficacy to be based on properly blinded studies, the aim being to limit the influence of wishful thinking and bias.

The problem is that some side effects of antidepressants - particularly the older ones - are marked, distinctive and well known, often a give-away to patients and investigators alike. Moreover, "many of the side effects of antidepressants mimic depressive symptoms and it is often difficult to distinguish what is a treatment-emergent effect from the pre-existing depressive symptomatology". (Montgomery & Lambert, 1989) The problem of spontaneous unblinding has been recognised for as long as antidepressant drugs have been around, and has led some to suggest that the only reliable way of testing might be to compare them with a non-inert placebo (eg atropine), or perhaps with an established antidepressant at a sub-therapeutic dose.

"Most antidepressant drugs cause side effects which are recognisable by experienced investigators in a significant proportion of patients. Patients who come into the consulting room for assessment, perhaps for the sixth time and rather bored with the whole thing, but with their mouths so dry that one can hear their tongues scraping and clicking about in their mouths, are likely to be taking, say, amitryptyline, rather than the placebo." (Leyburn, 1967).

"The side effects of imipramine ensure that no trial can be conducted under completely ‘blind’ circumstances. In this study, 15 patients complained of typical side effects and it was suspected they were taking imipramine; the supposition was correct in 13 patients, who represented half of all those on the drug." (Porter, 1970)

There are two ways of looking at placebos. Typically, they are regarded as dummy drugs: they are pharmacologically inert but may trick patient and doctor into thinking they are the real thing. Traditionally, placebos get a bad press: they are generally identified as non-treatments, inferior to active drugs; their use may involve ethical problems; they raise question marks about the accuracy of diagnoses and the authenticity of illness; and no-one likes to feel fooled. As if by definition, placebos are regarded as less desirable things.

An alternative view would be that placebos often do work as effectively as anything else, and sometimes very powerfully, as one might expect with any powerful form of suggestion. Even after pre-screening, about a third of all patients with "major depression" consistently respond as well on placebo as on active drug. This not only seems remarkable, in theory it also makes the placebo much the superior treatment for those patients on grounds of both safety and cost.

Which view one holds about placebo effects would be much influenced by one’s understanding of the nature and origins of depression. Staunch advocates of a biochemical basis of depression might be inclined to argue that it can’t have been a Major Depression if a sugar pill made the condition disappear. Others might conclude that the pill served essentially as a token or symbol and that simple interventions were sometimes enough to make depression go away. Beyond this lie realms of magic and the unknown, and they are not necessarily incompatible with good scientific sense. As Lewis Thomas used to say: "the only solid piece of scientific truth about which I feel totally confident is that we are profoundly ignorant about nature". Science was full of surprises for him and they delighted him:

"I was once told by a distinguished old professor of medicine, one of Sir William Osler’s bright young men, that it was his practice to pain gentian violet over a wart and then assure the patient firmly that it would be gone in a week, and he never saw it fail. There have been several meticulous studies by good clinical investigators, with proper controls. In one of these, fourteen patients with seemingly intractable generalised warts on both sides of the body were hypnotised, and the suggestion was made that all the warts on one side of the body would begin to go away. Within several weeks, the results were indisputably positive; in nine patients all or nearly all the warts on the suggested side had vanished, while the control side had just as many as ever." (Thomas, 1979)

The strength of the placebo effect, and the sometimes dramatic responses that are obtained, might partly explain why GPs usually prescribe tricyclic antidepressants at doses experts say are ineffective - ie no more effective than placebo. The fact that they do makes it seem all the more remarkable that SSRIs apparently have no greater effect on depression than the traditional drugs they have begun to overtake.


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