Pharmageddon. David Healy

or miss out on a treatment that really would have helped, the consequences may be more serious.

      In these more ambiguous cases—of which there are many in medicine—how do you know whether or not a treatment is likely to have any benefits and what hazards it may entail? For several centuries at least some physicians appreciated that before a proposed new remedy could be accepted, its effects would need to be observed under controlled conditions. There would need to be some way to demonstrate that any improvement in patients was due to the remedy, and not to some other factor, or even to chance. Some group of patients living under similar conditions that could be divided into comparable groups, only some of which were given the remedy, would be needed. But short of imprisonment or quarantine, this is not easily done.

      In 1747, James Lind, the Scottish physician who served as ship's doctor on the South Seas-bound Salisbury, was given the perfect opportunity. Some of the sailors developed scurvy, a fearsome disease that caused tissue breakdown—wounds failed to heal, teeth fell out, and victims began to bleed into their skin or from their bowels. In some long-distance sea voyages up to half a ship's crew might die from it. Faced with twelve sailors whose “cases were as similar as I could have them” and who were all on the same diet, Lind was able to give two of the men cider, two vitriol, two vinegar, two sea-water, two oranges and lemons, and two a mix of nutmeg, garlic, mustard seed, and balsam of Peru. Those given the oranges and lemons improved rapidly, the others languished.⁴ Even though there was limited scope for any other explanation of these recoveries, many attributed the improvement to ventilation (although that was the same for all twelve patients), while even Lind himself was slow to credit the citrus fruits for the favorable response. It took the British navy another fifty years to include lime juice in the provisions for a voyage, after which British sailors were widely termed limeys. In this case, when faced with a choice between their expectations and the evidence, observers at first clung to their expectations—a pattern we shall see again and again.

      On a much grander scale, but in a less controlled fashion, in 1802 in the midst of the revolutionary ferment in France, Philippe Pinel, the general physician now commonly seen as the father of modern psychiatry, working at the Salpêtrière asylum, became the first to commit medicine to an evidence-based approach. At the time typical treatments for mental illness included bloodletting, brutality, forced immersion in cold baths, being hosed down with water jets or subjected to a variety of purgatives, emetics, diuretics, and other drugs. Although there were elegant rationales for some of these treatments, and in some cases the treatments stemmed back to antiquity and had been advocated by history's most distinguished medical names, Pinel was skeptical. Patients often seemed to get better when the doctor waited to intervene, he had observed. Learning the typical course of a disorder, he reasoned, would make it possible to predict when patients might turn a corner for the better on their own. This appreciation underpinned his dictum that the greater art in medicine lay in knowing when to refrain from treatment.⁵

      Between April 1802 and December 1805, 1,002 patients were admitted to the Salpêtrière, and Pinel was able to follow these individuals during their stay to see who recovered and who didn't, whether patients in particular diagnostic groups fared better than others—and hence whether diagnoses in use at the time were worthwhile or not. This was a first example of what later came to be called a statistical approach to illness. Why do it? Pinel laid out his reasons.

      In medicine it is difficult to come to any agreement if a precise meaning is not given to the word experiment, since everyone vaunts their own results, and only more or less cites the facts in favor of their point of view. However, to be genuine and conclusive, and serve as a solid basis for any method of treatment, an experiment must be carried out on a large number of patients following the same rules and a set order. It must also be based on a consistent series of observations recorded very carefully and repeated over a certain number of years in a regular manner. Finally it must equally report both events, which are favorable and those which are not, quoting their respective numbers, and it must attach as much importance to one set of data as to the other. In a nutshell it must be based on the theory of probabilities, which is already so effectively applied to several questions in civil life and on which from now on methods of treating illnesses must also rely if one wishes to establish these on sound grounds. This was the goal I set myself in 1802 in relation to mental alienation when the treatment of deranged patients was entrusted to my care and transferred to the Salpêtrière.⁶

      There had never been anything like this in medicine before. Overall, 47 percent of the patients recovered, Pinel found, but of those who had been admitted for the first time, who had never been treated elsewhere, who had a disorder of acute onset, and who were treated only using Pinel's methods, up to 85 percent responded. When left to recover naturally, many more of the first-timers did so than did those among the patients who had been treated previously by other methods. Not only that, within a short time of admission Pinel could tell who was likely to recover and who was not based on their clinical features. In other words there seemed to be different disorders, and people suffering from some types would recover if left alone while inmates with some other types would not regardless of what treatments they were given. Finally, following the patients after discharge brought a whole new group of periodic disorders into view for the first time, laying the basis for the later discovery of manic-depressive illness and other recurrent mental disorders.

      Aware of the pioneering nature of his research, Pinel presented his data, on February 9, 1807, to the mathematical and physical sciences faculty at the National Institute of France rather than to the country's Academy of Medicine. This was hard science and the first time in medicine that results were presented as ratios across a number of patients studied, rather than as accounts of individual cases.

      In reporting these findings, Pinel showed that he was well aware that his personal bias could have colored the results. But, as he noted, while an individual patient in London could not properly be compared to one in Paris or Munich, the results of complete groups of patients could be, and the registers of Salpêtrière patients were publicly available. So he confidently challenged others to contest his findings based on their outcomes.

      The scientists were impressed. The physicians weren't. It took thirty years before another French physician picked up the baton and further unsettled the medical establishment with numbers. In 1836, Pierre Louis outlined a new numerical method that controlled for variations by using large numbers of patients: “in any epidemic, let us suppose five hundred of the sick, taken indiscriminately, to be subjected to one kind of treatment, and five hundred others, taken in the same manner, to be treated in a different mode; if the mortality is greater among the first than among the second, must we not conclude that the treatment was less appropriate, or less efficacious in the first class than in the second?”⁷

      The treatment Louis assessed was bleeding—which in fact works well in disorders such as heart failure. But when he compared bleeding to doing nothing in a sufficiently large number of patients during the course of an epidemic, he sparked a crisis in therapeutics. Doctors expected bleeding to work better than doing nothing, but “the results of my experiments on the effects of bleeding in inflammatory conditions are so little in accord with common opinion [those who were bled were more likely to die, he found] that it is only with hesitation that I have decided to publish them. The first time I analyzed the relevant facts, I believed I was mistaken, and I repeated my work but the result of this new analysis remains the same.”⁸

      These results led to howls of outrage from physicians who claimed that it was not possible to practice medicine by numbers, that the duty of physicians was always to the patient in front of them rather than to the population at large, and that every doctor had to be guided by what he found at the bedside.

      Ironically, it was Louis and Pinel who were calling on physicians to be guided by what was actually happening to their patients, not by what the medical authorities traditionally had to say. As the marketers from GlaxoSmithKline and other companies might have told Louis and Pinel, though, for many physicians to be convinced there has to be a theory, a concept about the illness and its treatment, to guide the doctor. “The practice of medicine according to this [Louis's] view,” went one dismissal, “is entirely empirical, it is shorn of all rational induction, and takes a position among the lower grades of experimental observations