The placebo effect

An interesting phenomenon in pharmacotherapy is called the placebo effect. The dictionary currently sitting in our office (The American Heritage College Dictionary, 3rd edn) provides several definitions of the word placebo, including  

A substance containing no medication and given to reinforce a patient s expectation to get well 

An inactive substance used as a control in an experiment to determine the effectiveness of a medicinal dmg 

Both of these definitions are helpful in the present context. The first is a more general one, and relates to the observation that, if a person is given a substance containing no medication, but that person believes that the substance will have a beneficial therapeutic effect, it is not unusual that improvement may be seen in the person s condition. The second definition is a particularly relevant definition in the context of this book, and the term placebo will be used extensively in later chapters. 

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The neural mechanisms underlying the placebo effect are only partially understood and most of our knowledge comes from pain, although recently Parkinson s disease, immune and endocrine responses, and depression have emerged as interesting models (Fig. 1). In each of these... 

Benedetti F, Mayberg HS, Wager TD et al (2005) Neurobiological mechanisms of the placebo effect. J Neurosci 25 10390-10402... 

Clinical trials should be designed so as to mirtimise potential sources of bias. It is known that patients can demonstrate a positive response to treatments that they believe will benefit them, even if no pharmaceutical agent has been admrrtistered (the placebo effect ). Similarly, investigators may be biased in their observations by an expectation of particular results. To avoid such bias, blinded trial designs are used. 

Swartzman, L. C. 8c Burkell, J. (1998). Expectations and the placebo effect in clinical drug trials why we should not turn a blind eye to unblinding, and other cautionary notes. Clin. Pharmacol. Ther., 64, 1-7. 

It was with that in mind that one of my postgraduate students, Guy Sapirstein, and I set out to investigate the placebo effect in depression - an investigation that I describe in the first chapter of this book, and that produced the first of a series of surprises that transformed my views about antidepressants and their role in the treatment of depression.4 In this book I invite you to share this journey in which I moved from acceptance to dissent, and finally to a thorough rejection of the conventional view of antidepressants. 

The chemical effect of antidepressant drugs may be small or even non-existent, but these medications do produce a powerful placebo effect. In Chapters 5 and 6 1 examine the placebo effect itself. 1 look at the myriad of effects that placebos have been shown to have and explore the theories of how these effects are produced. 1 explain how placebos are able to produce substantial relief from depression, almost as much as that produced by medication, and the implications that this has for the treatment of depression. 

In 1995 Guy Sapirstein and I set out to assess the placebo effect in the treatment of depression. Instead of doing a brand-new study, we decided to pool the results of previous studies in which placebos had been used to treat depression and analyse them together. What we did is called a meta-analysis, and it is a common technique for making sense of the data when a large number of studies have been done to answer a particular question. It was once considered somewhat controversial, but meta-analyses are now common features in all of the leading medical journals. Indeed, it is hard to see how one could interpret the results of large numbers of studies without the aid of a meta-analysis. 

But people recover from colds even if you give them nothing at all. So when the patients in our imaginary study took a dummy pill and their colds got better, the improvement may have had nothing to do with the placebo effect. It might simply have been due to the passage of time and the fact that colds are short-lasting illnesses. 

It is rare for a study to focus on the placebo effect - or on the effect of the simple passage of time, for that matter. So where were we to find our placebo data and no-treatment data We found our placebo data in clinical studies of antidepressants, and... 

For the purpose of our research, Sapirstein and I were not particularly interested in the effects of the antidepressants or psychotherapy. What we were interested in was the placebo effect. But since we had the treatment data to hand, we looked at them as well. And, as it turned out, it was the comparison of drug and placebo that proved to be the most interesting part of our study. 

Because of the power of the placebo effect, almost anything that is believed in seems to work for some types of medical problems. That is why the late Arthur K. Shapiro described the history of medicine as largely the history of the placebo effect.4 It is also why clinical experience alone cannot tell us whether a particular physical substance is an effective treatment. Placebo-controlled trials are required to demonstrate drug efficacy before drugs are approved for marketing. 

There is yet another possibility. The general assumption is that the effect of a drug adds to the placebo effect, so that the total improvement that patients experience is the drug effect in addition to the placebo effect. This assumption is implicit in the design of placebo-controlled clinical trials, in which the drug effect is assessed as the difference between the response to the drug and the response to the placebo. Anne Harrington, an historian of science at Harvard University and the London School of Economics, calls it the oil-and-water hypothesis. 

Despite the weakness of the data, the idea that iproniazid and imipramine were effective antidepressants came to be widely accepted. This is not really surprising, in the context of the times. In the 1950s and 1960s, the power of the placebo effect was just beginning to be recognized, and placebo-controlled clinical trials were rare. New treatments were often accepted on the basis of clinical experience and the testimony of experts in the field. 

When Schildkraut introduced the monoamine theory of depression, he admitted that there was little direct evidence for it. Instead, it was based on the supposed effectiveness of antidepressant medication and the mistaken belief that reserpine makes people depressed. Schildkraut acknowledged that Most of this evidence is indirect, deriving from pharmacological studies with drugs such as reserpine, amphetamine and the monoamine oxidase inhibitor antidepressants which produce affective changes. 21 A half-century has passed since his chemical-imbalance theory of depression was introduced, and the presumed effectiveness of antidepressants remains the primary evidence in its support. But as we have seen, the therapeutic effects of antidepressants are largely due to the placebo effect, and this pretty much knocks the legs out from under the biochemical theory. 

Although the tailoring hypothesis does not fit the data, there is another hypothesis that works just fine. It is the idea that antidepressants are active placebos. That is, they are active drugs, complete with chemically induced side effects, but their therapeutic effects are based on the placebo effect rather than their chemical composition. Their small advantage in clinical trials derives from the production of side effects, which leads patients to realize that they have been given the active drug, thereby increasing their expectancy for improvement. 

I suppose that some ingenious minds will be able to find a way of accommodating the chemical-balance hypothesis to these data, but I suspect that the accommodation will require convoluted circumventions, like those used by the Flat Earth Society in their efforts to maintain their defunct theory in the face of photographic evidence from space. If depression can be equally affected by drugs that increase serotonin, drugs that decrease it and drugs that do not affect it at all, then the benefits of these drugs cannot be due to their specific chemical activity. And if the therapeutic benefits of antidepressants are not due to their chemical composition, then the widely proffered chemical-imbalance theory of depression is without foundation. It is an accident of history produced serendipitously by the placebo effect. 

If the chemical-imbalance theory is wrong, and if depression is not a brain disease, how is it produced and how can it be prevented and treated One way to look for clues is to examine the process by which we were misled into the realm of chemistry. There is a culprit hiding in the history of the chemical-imbalance theory - a culprit that is guilty of leading doctors and patients astray over and over again in the history of medicine. The culprit is the placebo effect, and its darker twin, the nocebo effect. Depressed people got better when given MAO and reuptake inhibitors as antidepressants, and this led researchers to conclude that depression must be caused by a chemical deficiency. But much (if not all) of that improvement turns out to be a placebo effect. So to understand depression and how it might be treated effectively, we need to examine the placebo effect more carefully. That is the topic of the next two chapters. 

How can this be How is it possible that a dummy pill with no active ingredients can produce substantial improvement in a condition as serious as clinical depression As it turns out, placebos can be surprisingly effective, not only in the treatment of depression, but also for various other conditions. As we shall see in this chapter, placebos can reverse the effects of powerful medications. They can affect the body as well as the mind. They produce side effects as well as beneficial effects. They can make people feel sick, and they can make them feel better. Placebo effects are part of a broader phenomenon - the power of suggestion to change how people feel, how they behave, and even their physiology. If placebos can produce such powerful effects, it is important to understand them. Only by unlocking the secrets of the placebo effect can we hope to harness its power so that it can be used in clinical practice. In this chapter we look at the power of the placebo its ability to produce therapeutic change and to cause harm. 

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