Readers without a background in medicine or pharmacology may assume that the development of new drugs usually follows from advances in our understanding of the biological bases of disease. For example, it might be expected that some breakthrough in understanding the biochemistry of the brain would lead to the identification of abnormalities in the brains of schizophrenia patients, and from there to the design of novel drugs. In fact, progress in psychopharmacology has nearly always been in the opposite direction – the accidental discovery of an apparently effective drug has led to speculation about its mode of action, and from there to research on the biological origins of mental illness.
In the fifty years before the discovery of chlorpromazine, described by historian of psychiatry Edward Shorter as ‘the first drug that worked’,52 there had been few or no genuine advances in the drug treatment of mental illness. Writing in 1899, Kraepelin had listed the drugs available to him as narcotics (for example, opium and morphine), soporifics (for example, chloral hydrate), chloroform, ether, ethyl bromide, bromides, amyl nitrate and digitalis.53 Many of these compounds were still in use at the outbreak of the Second World War.
The effects of chlorpromazine (later known by the trade name Largactil) were first observed by a French naval surgeon named Henri Laborit, who was something of an eccentric. According to the obituary published in the Guardian newspaper when Laborit died in 1995, ‘The world has just lost the chance of awarding an Oscar, a Pulitzer and a Nobel Prize to the same person.’54 Many years after achieving fame for his pharmacological discovery, he appeared in Alain Renais’ film Mon Oncle d’Amerique, which won the Palme d’Or at the Cannes film festival. He also won several literary awards for his best-selling books on popular science, and campaigned for the abolition of the Paris – Dakar rally because, ‘In our world, competition is disgusting, a most stupid triviality.’
As a consequence of his war experience, Laborit developed an interest in physical shock, a condition that had many manifestations (low temperature, faint pulse and low blood pressure, accompanied by apathy and anxiety), and that affected his patients’ ability to recover from surgery. Believing that this condition resulted from an excessively strong biological emergency reaction involving the chemicals adrenaline, acetylcholine and histamine, Laborit began experimenting with various compounds that were known to have inhibitory effects on these substances. As luck would have it, at this time the Rhône-Poulenc pharmaceutical company was synthesizing novel anti-histamine compounds, some of which were made available to Laborit.
In 1951, aged 37, Laborit was transferred from a marine hospital in Tunisia to the Val-de-Grâce military hospital in Paris, where he continued his experiments. One of the compounds sent to him by Rhône-Poulenc was labelled 4560 RP, and had already been identified as having useful sedative effects. Finding that the drug lessened the anxiety felt by his patients prior to surgery but left them with a curious disinterest in their surroundings, Laborit wondered about its potential value in psychiatry. Perhaps disturbed psychiatric patients would benefit from this kind of psychic indifference. After disastrously testing its tolerability on a volunteer psychiatrist at a nearby hospital (immediately after receiving an intravenous injection of 4560 RP she stood up to go to the toilet and fainted) he finally managed to persuade three colleagues at Val-de-Grâce to try the drug on a manic patient. The results were impressive. Within a few weeks the patient was much calmer and able to lead a relatively normal life.
In 1952, Laborit’s experiments came to the attention of Jean Delay, who worked at the Ste-Anne mental hospital in Paris, and who was one of the best-known French psychiatrists of the day. Delay asked for samples of 4560 RP from Rhône-Poulenc and, together with his colleague Pierre Deniker, conducted the first clinical trial of the new medicine with psychotic patients. Delay and Deniker were able to report the positive results of their experiment just three months later at a meeting of the Société Médico-Psychologique. Their subsequent publications prompted further successful trials elsewhere. By the mid-1950s, the new drug – by now known as chlorpromazine – had become the treatment of choice for schizophrenia, and was in use throughout the developed world. Other similar compounds were rapidly tested, mainly because other pharmaceutical companies wanted to profit from this therapeutic breakthrough, so that by the early 1960s a range of anti-psychotic drugs was available to practising psychiatrists.
Curiously, the mood-stabilizing effects of lithium carbonate, the most widely used drug in the long-term treatment of mania, were also discovered accidentally by a relative outsider, and at almost exactly the same time that Laborit began his experiments with synthetic anti-histamines. John Cade, the medical superintendent of the Repatriation Mental Hospital in Bundoora, Australia, wanted to test his theory that mania was caused by an endogenous toxin, and began injecting guinea pigs with urine from his manic patients. Although these ill-thought-out experiments inevitably ended in the death of the guinea pigs, Cade proceeded to devise a series of studies to investigate the effects of the various chemical constituents of urine. He first used lithium as a solvent for uric acid and then, on impulse, tried injecting lithium alone. Observing that the guinea pigs became lethargic and resistant to startle, Cade injected himself with lithium compounds to discover his ability to tolerate them, and rapidly progressed to a small-scale trial in which the drug was administered to patients diagnosed as suffering from schizophrenia, mania and depression. His results, which showed that lithium calmed schizophrenia patients but had even more dramatic therapeutic effects on those suffering from mania, were published in the Medical Journal of Australia in 1949, where they lay almost unnoticed for years. Despite the success of a more carefully conducted study undertaken by Mogens Schou in Denmark, published in 1952, the first trials of lithium carbonate in North America were not conducted until the 1960s, and the drug was only licensed for use in the USA in 1970. Although a licence was granted earlier in Great Britain, the drug’s impact was similarly negligible at first. Edward Shorter has suggested that these delays partly reflected a lack of enthusiasm by drug companies, who were reluctant to support a compound that was abundant in nature, and therefore difficult to turn into profit.
In the half century since the discovery of the therapeutic effects of chlorpromazine and lithium, the idea that these drugs are diagnostically specific has driven a prodigious volume of biochemical research. This has been especially true for the neuroleptics; analysis of their biological effects led rapidly to the hypothesis that schizophrenia was caused by a disorder of those parts of the brain that contain the neurotransmitter substance dopamine. At one time, this hypothesis was so widely held that it almost acquired the status of an established truth, which only a raving heretic would question. (When I gave a talk about the concept of schizophrenia at Sheffield University only a few years ago, a neurobiologist in the audience angrily challenged me to draw a circuit diagram of the pathways in the brain that utilized dopamine.) I will discuss this theory in more detail in a later chapter; for the moment I am only concerned with one of the principal assumptions behind this kind of research – that the therapeutic effects of neuroleptics and lithium are specific to the two groups of patients who normally receive them. Clearly, evidence of treatment specificity would be strong evidence that schizophrenia and bipolar disorder are separate and distinct conditions.
Of course, the only way of adequately testing the specificity of psychiatric drugs is by randomly assigning them to patients regardless of diagnosis. To my knowledge, only one adequate experiment of this sort has ever been conducted. It was carried out by Eve Johnstone, Tim Crow and their colleagues at the Northwick Park Hospital in Middlesex, England, and their findings were reported in the medical journal the Lancet in 1988.55
One hundred and twenty psychotic patients were carefully assessed for delusions, hallucinations and abnormal mood before being randomly assigned to different drug treatments. Some received pimozide (a neuroleptic) alone, some received lithium carbonate alone, and others received
either both drugs in combination or neither. The study was a double-bind trial, which is to say that neither the patients nor the assessing psychiatrists were aware which treatments the patients were assigned. This was achieved by giving all patients two drugs, one or both of which were sometimes placebos (inert substances). At the end of three weeks, it was found that pimozide had an effect on hallucinations and delusions, regardless of the patients’ DSM-III diagnoses. Lithium carbonate similarly had a specific effect on elevated mood; although its non-specificity for diagnosis was less clear-cut than was the case for pimozide, this was because nearly all the patients who exhibited elevated mood were diagnosed as manic. Drug response, it seemed, was specific to particular symptoms, but not to particular diagnoses.
Biological psychiatrists who were aware of the history of their calling should not have been astonished by these findings. Evidence that the effects of neuroleptic drugs were diagnostically non-specific was available from the very beginning of modern psychopharmacology. Although most clinical trials of neuroleptics have been carried out with schizophrenia patients, the first successful trial – that carried out by Delay and Deniker in 1952 – was conducted on patients suffering from mania.
Categories or Dimensions?
In this chapter I have drawn on a wide range of research. None of the findings we have considered supports Kraepelin’s diagnostic system. Studies of patients’ symptoms, of the role of genes, of the course and outcome of illnesses over time, and of the response of symptoms to treatment, all point to similarities between schizophrenia and bipolar patients, rather than to differences.
Clearly people who suffer from psychiatric problems vary in their experiences. The taxonomists have attempted to accommodate this fact by dividing the geography of psychological distress into separate territories, but their efforts have been neither successful nor consistent. In the face of these difficulties, psychiatrists and psychologists have occasionally suggested alternatives to Kraepelin’s system. Some, like Adolf Meyer, have argued that we should give up the idea of classifying people like plants. Others have argued that there is but one type of psychosis, or einheitspsychose, an idea that was championed by Kraepelin’s rival Hoche.56 This approach is currently favoured by Tim Crow,57 among others.
Still others, mostly psychologists, have advocated the development of dimensional systems of classification, in which an individual is regarded as suffering more or less from different kinds of disorder.58 (This suggestion is given some credence by the editors of DSM-IV. However, as they note, the present lack of consensus about the best way of constructing a dimensional classification means that a workable system may be a long way off.)59 A recent study by Jim van Os and his colleagues provides some empirical support for this approach. Using his sample of over 700 psychotic patients, van Os assessed the power of categories (DSM-III-R diagnoses) and symptom dimensions to predict illness course, employment history, suicidal behaviour, the patients’ perceived quality of life, and a number of other variables. For nearly all of these, the dimensions were more powerful predictors than the categories.60
None of these strategies has received support from the majority of clinicians, perhaps because they have found it difficult to see how these alternatives would work in practice.
5
The Boundaries of Madness
Madness need not be regarded as an illness. Why shouldn’t it be seen as a sudden – more or less sudden – change of character?
Ludwig Wittgenstein1
In 1799 a German bookseller named Nicola read a paper to the Royal Society of Berlin, in which he described a series of hallucinations that he had experienced some nine years earlier.2 They had been provoked by a period of stress, and he first became aware of them when he saw the figure of someone he knew to be dead. The figure, which was unobservable to his wife, disappeared after a few minutes but reappeared later in the day. Over the following months other hallucinatory figures came and went and sometimes spoke to Nicola, who became proficient at differentiating them from living people. Anticipating modern debates about the nature of psychosis, he claimed that his story demonstrated that hallucinations could be experienced by the sane.
Kraepelin’s paradigm, articulated almost 100 years after Nicola’s paper, assumed a non-arbitrary division between sanity and madness, an assumption that was explicitly embraced by the designers of DSM-III (see proposition 4 of Gerald Klerman’s neoKraepelinian manifesto, given in Table 3.3, p. 59). According to Kraepelin, people either suffer from mental illness or they do not, and we are not free to choose whether to regard some kind of unusual behaviour as evidence of madness or mere eccentricity. This attitude was also evident in the theories of most of the other giants of psychiatry whose work we have considered. For Karl Jaspers, the psychiatrist’s inability to form an empathetic appreciation of a patient’s experiences was a sure sign of the patient’s madness. For Kurt Schneider, the observation of certain behaviours and experiences (the first-rank symptoms) carried a similar implication. Only Eugen Bleuler was more flexible, conceiving of a continuum that ran from normality to the extreme experiences of people suffering from psychosis.
In the last chapter I examined Kraepelin’s division of the psychoses into various types. In this chapter and the next, I will focus on this more fundamental division between madness and sanity. In particular, I will address the suggestion (succinctly expressed in the above quotation from the philosopher Ludwig Wittgenstein) that psychosis should be seen as just part and parcel of human variation, rather than as an illness. This claim, in its strongest form, suggests that the attribution of mental illness, either to individuals or to particular types of behaviour, is arbitrary rather than scientific, and that psychotic people are eccentrics who are misunderstood and victimized by society.
How Common are Psychotic Experiences?
Let us begin by considering whether Nicola’s experiences were extraordinary or whether, on the contrary, ordinary people experience psychotic symptoms more commonly than is usually supposed. According to the Kraepelinian model, symptoms should be confined to those who are severely ill. Of course, we can accept that mentally ill people sometimes fail to receive appropriate treatment and consequently are left undetected in the community. However, this should happen only rarely. Evidence that large numbers of otherwise well-adjusted people report psychotic experiences on questioning would therefore further undermine the Kraepelinian paradigm.
Hallucinations
The first systematic study of hallucinations in ordinary people was conducted in Britain at the end of the nineteenth century by the Society for Psychical Research.3 The Society assumed that their findings would have implications for the understanding of apparently supernatural phenomena. A large team of interviewers questioned over 14,000 men and women. Although no attempt was made to obtain a truly random sample, anyone suffering from obvious signs of mental or physical illness was excluded. Of those questioned, nearly 8 per cent of men and 12 per cent of women reported at least one vivid hallucinatory experience, the most common being a vision of a living person who was not present at the time. Hallucinations with a religious or supernatural content were also reported, and auditory hallucinations were recorded less often than visual hallucinations. Fifty years later, the Society attempted to check these findings by conducting a much less extensive survey, obtaining very similar results.4
Modern surveys have continued to provide evidence that hallucinations are experienced by people who appear to be otherwise normal, who do not regard themselves as mentally ill, and who have not felt the need to seek psychiatric treatment. For example, in the United States, psychologists Thomas Posey and Mary Losch5 questioned 375 college students and found that 39 per cent had heard a voice speaking their thoughts aloud – a first-rank symptom of schizophrenia according to Kurt Schneider. Perhaps even more surprisingly, 5 per cent reported holding conversations with their hallucinations. Subsequent surveys of students in Britain (carried out by myself and others)6 and in the United States
(carried out by Tim Barrett and his colleagues)7 have obtained comparable results.
Of course, college students are hardly representative of the population as a whole, so it may be wrong to generalize from student samples. However, this limitation does not apply to the most comprehensive survey of hallucinations in the general population so far conducted, which was reported in 1991 by American psychiatrist Allen Tien.8 Tien’s data were collected as part of the Epidemiological Catchment Area (ECA) Study, the large US population survey of psychiatric symptoms described in the previous chapter. Although the definition of hallucinations used by Tien was taken from DSM-III-R, his findings were remarkably similar to those obtained almost a century earlier by the Society for Psychical Research. He estimated that the proportion of the 18,000 ECA participants who had experienced hallucinations at some time in their lives was between 11 and 13 per cent.* Hallucinations were reported approximately twice as often by women as by men. Tien noted only two differences between his findings and the much earlier findings from Britain. First, the Society for Psychical Research reported that people between 20 and 29 years of age were most likely to experience hallucinations, whereas the ECA data suggested that hallucinations occur across the age spectrum but most often in the elderly. Second, visual hallucinations were recorded less often in the ECA survey in comparison with the Society’s data.*
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