chance at guessing who was receiving the placebo and who was not.20
If patients guess they are taking a placebo, this may reduce the power of the placebo to unleash their internal healing resources. On the other hand, if they guess they are taking the experimental drug, this might enhance the placebo effect. Arguing along these lines, Kirsch and Sapirstein suggested that some of the apparent difference between real drugs and pure placebos may be due to an ‘enhanced placebo effect’. If this is true, the ratio of the specific effect of the real drug to its placebo component becomes even smaller still.
To disentangle the true specific effect of a treatment not only from spontaneous remission and the effect of a pure placebo such as a sugar pill, but also from the enhanced placebo effect of the real drug, Kirsch and Sapirstein suggest that clinical trials should involve not two arms, as most do at present, nor even three, but four. In addition to the experimental group, the no-treatment group and the pure placebo group, a fourth arm would treat patients with a so-called ‘active placebo’. This is a placebo that lacks the key ingredient of the experimental treatment but contains some other active substance designed to produce similar side-effects. Some trials of antidepressants, for example, have used atropine as an active placebo because it produces one of the most noticeable side-effects that many antidepressants do – a dry mouth – but does not have any specific activity against depression itself. Needless to say, such four-arm trials are even less common than three-arm trials. In fact, they are virtually non-existent at present. They would, however, be invaluable in advancing our understanding of the placebo phenomenon.
A few clinical trials of antidepressant drugs have used active placebos instead of pure placebos. That is, they have compared two groups of patients – one that receives the experimental drug, and one that is given an active placebo such as atropine. These trials reduce the chances that the double-blind will be broken – in other words, they make it harder for patients or their doctors to guess who is receiving the experimental drug and who is receiving the placebo. Interestingly, these trials tend to show much lower drug effects than those in which antidepressants are compared to pure placebos.21 This, in itself, provides some evidence for a placebo effect in depression. The argument is a subtle one, but worth exploring.
If depression was not placebo-responsive, then the whole effect of antidepressant drugs would be due to the pharmacological properties of the drugs themselves. It would make no difference whether you believed you were taking the drug or not. The difference in recovery rates between patients taking the drug and patients taking placebos would therefore be the same whether or not patients were able to guess correctly which group they were in. This is not, however, what we find. When patients are able to guess which group they are in, the difference between the experimental group and the placebo group increases. This suggests that belief is indeed playing some role in the efficacy of antidepressant medication. The placebo effect, in other words, does seem to work for depression.
PLACEBOS AND SCHIZOPHRENIA
If placebos worked for every kind of mental disorder, their power would not be limited to anxiety and depression, but would extend even to the most severe psychoses, including schizophrenia. Is there any evidence that placebos can affect such extreme mental conditions?
In the 1950s, many psychiatrists were unwilling to accept the idea that placebos could alleviate depression, let alone schizophrenia. One German psychiatrist, however, decided to test the idea. Heinz Lehmann picked three of the most mute and deteriorated schizophrenics on one of the back wards at Verdun hospital. He told the patients and their nurses that they were going to try out a new experimental hormone, which was, in fact, just a placebo. The injection site was painted with a disinfectant that left a prominent red stain, and the patients were injected twice a week for two weeks. By the third week, two of the three had broken their silence, and were talking quite sensibly.22
This study is, as far as I can tell, the only evidence that schizophrenia might be placebo-responsive, and it is not particularly strong evidence at that. For a start, there was no control group, the sample size was tiny – only three patients – and we do not know how long the improvement lasted. We cannot even be sure that the three patients were all really suffering from schizophrenia. Back in the 1950s, diagnostic standards were extremely variable, and the diagnosis of schizophrenia in particular was often used as a catch-all category to deal with any kind of patient whose prognosis was not good. Many people with learning disabilities, personality disorders or even simply unconventional behaviour were tagged as schizophrenics and confined to locked wards throughout Europe and America, where they eventually became so institutionalised that their behaviour mimicked the very diagnosis they had been given. They became mute and withdrawn, just as those suffering from the catatonic form of schizophrenia were supposed to. A vicious circle would establish itself, in which the condition of the patients and the pessimistic views of the nursing staff regarding their recovery became mutually reinforcing. It is not hard to see how, given a change in the views of the nursing staff, this circle could be broken. Perhaps this is what occurred with Lehmann’s patients. If so, it is not really a case of placebos curing schizophrenia.
In the absence of more conclusive evidence, then, it would be premature to pronounce any verdict on whether or not placebos can affect severe psychotic illnesses such as schizophrenia. For the time being, all we can say is that less serious mental conditions such as anxiety disorders and most types of depression do appear to be placebo-responsive. When it comes to schizophrenia, the jury is still out.
THE LIMITS OF THE PLACEBO RESPONSE
Tracing the limits of the placebo response is not easy. So far, we have seen that there is good evidence that it works for pain and some of the minor signs of injury, such as inflammation and trismus. There is also some evidence that placebos can alleviate depression and anxiety and cure ulcers. On the other hand, there is no real evidence that the placebo response can do anything to reverse cancer or cure schizophrenia. It would be interesting to know if there is any underlying logic to this. What is it that determines whether or not a medical condition responds to a placebo?
To answer this question, we must delve deeper into the underlying mechanisms of the placebo response. The placebo response is simply a rapid readjustment of the body’s own natural healing mechanisms to a surge of hope, and there are limits to what these mechanisms can do, even if fuelled with industrial-strength optimism. The placebo response is not magic; it works by natural mechanisms, and all such mechanisms have their limits. These mechanisms are the subject of the following chapter.
Chapter 3 THE ACUTE PHASE RESPONSE
It is all very well to know which conditions placebos can affect and which they can’t, but a good scientific theory requires more than just a list. Chemistry, for example, only became a true science when the great Russian chemist Dmitri Mendeleyev took the list of known elements and perceived a hidden pattern in the data. The periodic table, which Mendeleyev first formulated in 1869, made this pattern visible to all, and allowed scientists to uncover the fundamental order that underlay the mass of empirical results that they had accumulated in the previous centuries. To put the placebo response on an equally scientific footing, we must look beneath the signs and symptoms described in the previous chapter and ask whether there is some mechanism, or set of mechanisms, which explains why placebos can do the things they can, and why they can’t do the things they can’t.
At first sight, the list of conditions that placebos can alleviate may appear an odd bunch, lacking any common thread, as random as the elements must have appeared to those
