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Medical Milestones

Chlorpromazine: unlocking psychosis

BMJ 2007; 334 doi: http://dx.doi.org/10.1136/bmj.39034.609074.94 (Published 04 January 2007) Cite this as: BMJ 2007;334:s7
  1. Trevor Turner, consultant psychiatrist trevor.turner@elcmht.nhs.uk
  1. 1Homerton Hospital, London E9 6SR

    The discovery of chlorpromazine ushered in a radically changed biological and psychosocial psychiatry that saw an end to the neglect and desperate remedies of the asylums

    The sights, sounds, and smells of untreated psychosis linger down the ages, from Shakespeare's Mad Tom in King Lear to the screaming inmates of the forbidding New York mental hospital in Anatole Litvak's The Snake Pit, 1948's most shocking cinema event (children under 16 not admitted). In his Experiences of an Asylum Doctor of 1921, the retired general practitioner Montague Lomax described the “lunatics in the refractory ward of our public asylums. Bestialised, apathetic, mutinous, greedy, malevolent … their habits quarrelsome and filthy, their persons dirty and malodorous.” The carefully controlled therapeutic aridity of the ever enlarging lunatic asylum system was the institutional response: museums of madness with their collections of certified inmates.

    Yet by the 1940s university research departments and entrepreneurial drug companies were busily synthesising new compounds. By 1926 acetylcholine was known to be a neurotransmitter; in 1937 the antihistamines were discovered and in 1943 LSD. Psychiatry and its patients—stigmatised, dangerous, some psychoanalysed, but mostly hopeless—were receiving new physical treatments, such as insulin coma therapy, electroconvulsive therapy (ECT), and leucotomy. Sedatives such as bromides, barbiturates, and paraldehyde were available, the last overused for “the noisy and troublesome patient.” From the phenothiazine group of the antihistamines, the drug 4560 RP, later called chlorpromazine, was synthesised in 1950 by Paul Charpentier, a chemist with Laboratoires Rhône-Poulenc.

    The rise of psychopharmacology

    A French surgeon, Henri Laborit, had begun experimenting with antihistamines in 1949, to aid anaesthesia when operating on soldiers in shock, and he noted how some patients became obviously calmer. On moving to Paris he asked for the new 4560 RP, hoping it would enhance autonomic blockade. Developing a “lytic cocktail” of pethidine, promethazine, and chlorpromazine, which seemed to provoke a state of “indifference,” he theorised that this could be useful in psychiatry. He persuaded several apparently sceptical psychiatric colleagues to try it out, and on 19 January 1952 a 24 year old man who had mania was injected with chlorpromazine. Their report to a meeting of the Paris Medico-Psychological Society described how he lay calm for several hours with his eyes shut (although his facial expression still looked rather maniacal).1 Within three weeks he had largely settled and was even able to play bridge. But he had also been given ECT, an analgesic, and a barbiturate, so was this a specific effect of chlorpromazine?

    Several trials began, but it was Pierre Deniker and his assistant Jean Delay, at St Anne Hospital in Paris, who won the publication race. They treated 38 psychotic patients with injections of between 75 mg and 150 mg a day of chlorpromazine, reporting their findings to the Paris Medico-Psychological Society in May and June 1952 and publishing them in the Annales Médico-Psychologiques that year. Describing the events in 1970, Deniker commented on the limited information about the drug that was available at the time of the trials (some effects were seen in humans before experiments in animals were reported) and the “sudden, great interest of the nursing personnel,” who were usually “reserved about innovation.” The wards were transformed, “aggressiveness and delusive conditions of schizophrenia improved,” and contact with the patients could be re-established. Deniker, who insisted on continuous, prolonged treatment, noted improvements in behaviour and symptoms but also the side effects of “psychiatric indifference” and unusual dyskinesias.

    By 1954 chlorpromazine had been actively used and researched in double blind trials in Canada, the United Kingdom, and the United States, although diehard US psychoanalysts continued to consider it no substitute for “analytically orientated psychotherapy.” Because of the drug's combination of effects (and side effects), by 1955 its French researchers decided to call it a neuroleptic (“taking hold of the neuron”). From 1956 the numbers of inmates in UK asylums began to fall dramatically, and over the next few years antidepressants and antipsychotics arrived en masse. A new world of a truly biological as well as psychosocial psychiatry had begun.

    Without the discovery of drugs such as chlorpromazine we might still have the miserable confinements witnessed by Montague Lomax—a world of desperate remedies. Then the attendant's role was akin to a zookeeper's: feeding, scrubbing, and forcibly treating hundreds of “demented” patients. The psychiatric workforce was largely cut off from surgical and physician colleagues, was of poor quality, and was readily mocked. Ernest Jones, Freud's biographer, remembered jokes about psychiatrists discussing “varieties of Chubb lock” at their meetings. Our modern, multiskilled mental health workforce, including nurses, occupational therapists, psychologists, and social workers, might never have emerged from the demeaning nature of the tasks required. The modern emphasis on users and their carers would have been impossible, given the inarticulacy of the patients, locked in their mutism and word salads, and the revulsion and despair of the carers.

    A psychic penicillin

    The lifetime prevalence of psychoses (the schizophrenias and severe bipolar disorders) is about 2% to 3% worldwide. Their effects are prolonged, incapacitating (in terms of self neglect and social unacceptability), and sometimes even fatal, with 10% or more of patients committing suicide. It is hard not to see chlorpromazine as a kind of psychic penicillin, enabling patient and carer to communicate and transforming our understanding of human function—neuropsychologically, interpersonally, and in evolutionary terms (as the gene mutation for big forebrains probably carries the risk of psychosis). Most importantly, modern psychopharmacology dynamically reflects brain function, enabling a non-moralistic assessment of emotions and judgments, as well as insights into the history of ideas and the nature of that elusive beast “personality.”

    Every clinician longs for more effective, ever safer treatment, whether it be antipsychotic, antidepressant, anxiolytic, or antibiotic. But the holy grail of psychiatric research probably remains the definitive test or scan that will crack the diagnosis and link psychiatry to scientific medicine. However, genetic markers such as those postulated for schizophrenia tend to attract life insurance salesmen and notions of eugenics; patients prefer being talked to rather than scanned; and clinical skills can become lost in technology. Yet if the progress initiated by the discovery of chlorpromazine means that we can replace baggy words like depression with psychobiological descriptions like monoamine deficiency syndrome, or paranoid schizophrenia with temporal lobe hyperdopaminergia, we may yet eradicate the monsters of stigma and neglect that still beset mentally ill people.

    Footnotes

    • Publication of this online supplement is made possible by an educational grant from AstraZeneca

    • Competing interests: None declared.

    References