that the placebos were playing an active role in assisting recovery. Furthermore, the improvement was not just subjective. All the studies examined by Moerman checked whether the ulcers had really healed by using an endoscope to peer inside the patients’ stomachs.
PLACEBOS AND MENTAL DISORDER
What about mental disorders? Can placebos cure diseases of the mind as well as diseases of the body? Unfortunately, the available evidence is once again quite weak. Despite the oft-repeated claims in the medical literature about ‘well-documented’ placebo effects in anxiety and depression, there are no properly controlled studies showing that people with these conditions do better when given a placebo than when deprived of one. In the absence of such studies, we can still look for relevant evidence by sifting through other data and comparing one set of trials with another, but we should bear in mind that the conclusions we draw on this basis must always be treated with a degree of caution. Until someone comes along and does a proper study involving a no-treatment group, it would be wrong to say that the placebo response has been clearly demonstrated for anxiety and depression.
Although there are a few controlled trials comparing placebos to no treatment with patients suffering from various anxiety disorders, these suffer from methodological flaws and do not provide very strong evidence. There are other kinds of evidence, however, which – while by no means conclusive – do provide some basis for suspecting that placebos can reduce anxiety. One study, for example, looked at the effect of tablet colour in the treatment of anxiety states.16 In 1970, a group of researchers based at the University of Newcastle upon Tyne signed up forty-eight patients who had been diagnosed as suffering from anxiety states, and divided them into three groups. All of the patients received a course of oxazepam, which is a cousin of diazepam (Valium), but the pills given to each group were dyed with a different colour – red, yellow and green. The colours were switched around after a week, and then switched once more for the third week, so that each group tried each colour. Anxiety levels were monitored both subjectively (by self-assessment forms) and objectively (by the doctors – who were unaware of which colour pill the patient was taking at any particular time).
When the results came in, some interesting trends were apparent in the data. The colour of the tablets seemed to have a subtle influence on the effect of the medication. In particular, green tablets tended to be most effective in reducing anxiety, and yellow the least effective. Anxiety manifests itself in a number of ways, from psychological symptoms such as worry and irritability to bodily signs such as palpitations, and for all of these phenomena green tablets were superior to the red or yellow ones. The differences were small, though, and did not reach statistical significance, except in one case – phobic symptoms. Phobia is one of the most common manifestations of anxiety, and green tablets were twice as effective as red or yellow ones in reducing phobic symptoms – even though the tablets contained exactly the same drug.
When the effect of a drug varies systematically according to colour of the tablet in which it is administered, it is a fair bet that the condition being treated is placebo-responsive. The only way that something as insubstantial as colour can affect a medical condition is by way of the patient’s mind. The 1970 study on tablet colour does therefore suggest that some anxiety disorders at least may be placebo-responsive. Interestingly, the same study also pointed to a possible placebo effect in depression. This is not particularly surprising in itself, since anxiety and depressive symptoms often occur together, but the curious thing was that the best colour for treating each type of symptom was different. While anxiety levels were reduced most by green tablets, depressive symptoms responded best to yellow tablets. Next best was green, while red was worst for both anxiety and depression. The researchers who conducted the study were at a loss to explain this result. Was it due to chance? Or did it point to certain differences in the patients’ beliefs about the effects of tablet colour? Intrigued, they called for further research on the topic. None came.
WHAT ABOUT DEPRESSION?
Although the 1970 study on tablet colour suggested that depression, too, was placebo-responsive, hard data is thin on the ground. Hundreds of clinical trials have compared the effects of antidepressant medication with those of placebos, but hardly any have included a no-placebo group. In the absence of such studies, we cannot be sure whether or not depression is placebo-responsive. In 1998, however, two American psychologists, Irving Kirsch and Guy Sapirstein, came up with an ingenious way round this problem. None of the drug trials they looked at included a no-treatment control group, but a whole batch of studies of psychotherapeutic treatments did. Many of these studies, for example, compared the recovery rates of depressed patients receiving psychotherapy with the recovery rates of other depressed patients who remained on waiting lists. Kirsch and Sapirstein used the waiting-list recovery rate as a rough measure of the spontaneous remission rate, and compared it with the recovery rate shown by those taking placebos in the drug trials. In this way, they were able to estimate the relative effects of placebos and antidepressant drugs. Their conclusions were startling. Those taking drugs showed, on average, about 33 per cent more improvement than those treated with a placebo. But those taking a placebo showed around 200 per cent more improvement than those who received no treatment at all. If we assume that the placebo component of the real drug is the same as that of the pure placebo, then we must conclude that around 25 per cent of the improvement shown by those taking antidepressants is due to spontaneous remission, 50 per cent to the placebo effect, and only a measly 25 per cent to the antidepressant medication itself.17
Donald Klein, a psychiatrist at Columbia University in New York, has cast doubt on this dramatic conclusion.18 Klein argues that many of the studies on which Kirsch and Sapirstein based their claims were flawed for various reasons. More importantly, Klein also raises questions about the scales used to measure recovery. A typical five-point scale might go something like this:
1 = normal functioning
2 = mild functional impairment
3 = definitely impaired
4 = cannot work
5 = impaired self-care
Now, suppose that all the patients in a trial start out at a mean of 4.5 on this scale – they cannot work, and some of them cannot even take care of themselves properly. If the average patient on medication improves by three points, and the average patient on placebo improves by 2.25 points, Kirsch and Sapirstein would argue that for the typical patient, 75 per cent of the drug effect is attributable to the placebo effect, which makes the superiority of the drug seem relatively trivial. If, however, we look at where the patients end up on the scale, the superiority of the drug begins to look more important, for the average patient on medication is now between normal functioning and mild impairment, while the average patient on placebo is now between mild and definite impairment. This difference is clinically important, and yet it is hidden by the way that Kirsch and Sapirstein report the data.
On the other hand, it may be that the placebo effect in depression is even greater than Kirsch and Sapirstein claim. As they themselves point out, the placebo component of a real drug may be higher than the placebo effect of a pure placebo. Placebo effects depend in large part on the belief that you are being given an effective treatment, and there is evidence that many participants in clinical trials guess correctly whether they are receiving the real drug or the placebo. The real drug tends to have noticeable side-effects that the placebo lacks. In one study comparing two antidepressants (imipramine and phenelzine) with a placebo, 78 per cent of patients and 87 per cent of psychiatrists correctly guessed who was receiving an active drug and who was receiving the placebo.19 In fact, in twenty-three out of twenty-six studies where researchers bothered to check, both patients
