Chlorpromazine’s Legacy: Side Effects, Later Research and Laborit’s Later Drugs

When the French naval surgeon Henri Laborit described a “new vegetative stabilizer” in February 1952, he was writing about a drug for the operating theatre. Within a few years that drug, chlorpromazine, was in use in psychiatric hospitals across Europe and North America, and the historian Thomas Ban later wrote that its effectiveness was reflected in “the transformation of disturbed wards” and that it was instrumental in founding the science of neuropsychopharmacology. The story of how the molecule was found is told on the companion page about the discovery of chlorpromazine. This page is about what came after.

That after-story has several strands. One is the drug’s spread and the long argument among historians over whether it really caused a “psychopharmacological revolution”. Another is the record of its side effects, which began with Laborit’s own cautions in 1954 and grew through the 1950s into a catalogue of movement disorders, liver and blood reactions, and later the conditions now called tardive dyskinesia and neuroleptic malignant syndrome. A third is the evidence from modern clinical trials and reviews. The last is Laborit himself, who kept working for four more decades on new molecules — among them gamma-hydroxybutyrate and minaprine — and on a theory of stress he called the “inhibition of action”. All of it is reported here as history and as findings from the published literature.

Table of Contents

  1. 1. From Paris to the World’s Hospitals
  2. 2. A Revolution? What Historians Say
  3. 3. From Asylum to Community
  4. 4. Early Warnings: Laborit’s Own Precautions
  5. 5. Movement Disorders: From Parkinsonism to Tardive Dyskinesia
  6. 6. Jaundice, Blood Disorders and Neuroleptic Malignant Syndrome
  7. 7. Successor Drugs and the ‘Atypicals’
  8. 8. What Fifty Years of Trials Found
  9. 9. Laborit’s Later Drugs: Gamma-OH and Minaprine
  10. 10. The Inhibition of Action
  11. Key Research Papers
  12. Connections

1. From Paris to the World’s Hospitals

Chlorpromazine moved from the laboratory bench to general use in under two years. The chemist Paul Charpentier made the compound, then known only by its laboratory number RP 4560, in December 1950. Laborit and the anaesthetist Pierre Huguenard used it in surgery in 1951, and in early 1952 psychiatrists first at the Val-de-Grâce military hospital and then, under Jean Delay and Pierre Deniker, at the Sainte-Anne hospital in Paris reported its calming effect in mania and psychosis. According to Ban, the drug was available on prescription in France from November 1952, sold under a name, Largactil, meant to suggest its “large action” on many body systems.

The historians Francisco López-Muñoz and colleagues, in their 2005 review of the drug’s introduction, trace a rapid spread through European psychiatry and then into North America in 1954. The decisive English-language paper there came from Montreal: Heinz Lehmann and Gorman Hanrahan at the Verdun Protestant Hospital described chlorpromazine in February 1954 as a “new inhibiting agent for psychomotor excitement and manic states”. Ban writes that it had a major impact on the introduction of chlorpromazine in North America.

The United States came to the drug more slowly than France or Canada. López-Muñoz and colleagues attribute this partly to the strength of the psychoanalytic tradition in American psychiatry at the time, which looked for the causes of mental illness in early experience rather than in brain chemistry. By 1955, the same review concludes, neuroleptic therapy had been consolidated as a treatment. That was also the year Delay and Deniker gave the new class a name: in papers on the “neuroleptic effects of chlorpromazine”, they coined neuroleptic, from Greek roots meaning roughly “that which takes hold of the nerves”.

Recognition followed quickly. The 1957 Albert Lasker Clinical Medical Research Award went to Laborit, Deniker and Lehmann for chlorpromazine, and to Nathan Kline and the American psychiatrist Robert H. Noce for reserpine, a drug from the Rauwolfia plant that had entered psychiatry at almost the same moment. The Lasker Foundation’s citation for the chlorpromazine award reads: “For the development of chlorpromazine as a therapeutic agent in schizophrenia.” Jean Delay was not among the 1957 laureates. Ban also notes a commercial side of the story: the drug’s success encouraged the pharmaceutical industry to look for other drugs that acted on the mind.

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2. A Revolution? What Historians Say

For decades the standard account called chlorpromazine the beginning of a “psychopharmacological revolution”. López-Muñoz and colleagues use that phrase, describing the drug’s introduction as one of the great advances of twentieth-century medicine and the birth of modern psychopharmacology. In popular versions of this story, a single molecule emptied the back wards of locked asylums, replaced older physical treatments and turned psychiatry into a branch of medicine with drugs of its own.

Later historians have examined that story more closely. Sandra Caponi, writing in 2021 in the Brazilian history-of-medicine journal História, Ciências, Saúde – Manguinhos, questions the “so-called psychopharmacological revolution” directly. As the subtitle of her paper — “the discovery of chlorpromazine and the management of madness” — indicates, she reads the drug’s early history as closely tied to the management of agitated patients in psychiatric institutions, and she challenges the idea that its arrival amounted to a clean break with what came before.

Toine Pieters and Benoît Majerus, in a 2011 study of how chlorpromazine entered psychiatry in Belgium and the Netherlands between 1951 and 1968, describe a “tango between old and new treatment features”. In their account the new drug did not replace the older methods overnight. For years it was used as an addition to the existing therapies of the period rather than as a substitute for them. Pieters and Majerus nonetheless still speak of a therapeutic revolution — but one that unfolded slowly and unevenly, inside existing hospital routines.

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3. From Asylum to Community

The largest social change linked with chlorpromazine was the move away from long-stay mental hospitals. Kenneth Kirkby, writing in 2005 on the social context and health consequences of the antipsychotics’ introduction, describes how the emphasis in psychiatric care shifted from the asylum towards the community during the 1960s. Drugs that could quieten severe agitation made it possible to discharge many patients who would previously have stayed in hospital for years, and to treat others as outpatients.

Kirkby also records the costs that came with the change. As the drugs became routine, the burden of their side effects on large numbers of people grew more visible, and the range of conditions for which antipsychotics were prescribed widened well beyond the acute psychoses for which chlorpromazine had first been tested. A 2019 review of chlorpromazine in the series “Classics in Chemical Neuroscience”, by Debra Boyd-Kimball and colleagues, likewise describes the drug as having facilitated the deinstitutionalisation of psychiatric patients in the 1960s and 1970s, and sets this alongside an account of its adverse effects.

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4. Early Warnings: Laborit’s Own Precautions

Laborit was among the first to write about the hazards of the drug he had introduced. As an anaesthetist’s collaborator, he had watched chlorpromazine’s effects on the body in surgical patients from the beginning, including the fall in body temperature that made it useful for “artificial hibernation”. In 1954 he published a paper in the French journal Thérapie titled, in PubMed’s English translation, “Some precautions in neuroplegic therapy with chlorpromazine (R.P. 4560 or largactil)”. The same year he described the drug’s use as a ganglion-blocking agent in surgery for German-speaking readers.

By the mid-1950s psychiatrists were giving chlorpromazine to patients for months and years, not hours, and in larger amounts than surgeons used. The side effects that then emerged in the literature were different in kind from the ones seen in the operating theatre, and the next two sections follow them in the order they were reported.

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5. Movement Disorders: From Parkinsonism to Tardive Dyskinesia

The best-known side effects of chlorpromazine and the drugs that followed it involve movement. In 1954 the Swiss psychiatrist Hans Steck described an “extrapyramidal and diencephalic syndrome” in patients receiving chlorpromazine and reserpine. “Extrapyramidal” refers to the brain circuits, centred on the basal ganglia, that smooth and regulate movement — the same circuits damaged in Parkinson’s disease. Steck’s patients showed stiffness, slowed movement and tremor resembling parkinsonism. That two chemically unrelated drugs, one synthetic and one from a plant, produced the same picture was an early clue that they shared a mechanism.

The explanation came later. In 1963 the Swedish pharmacologist Arvid Carlsson and Margit Lindqvist reported that chlorpromazine and haloperidol changed the turnover of brain catecholamines in a way they interpreted as receptor blockade, and binding studies in the mid-1970s showed that the potency of antipsychotic drugs tracks their ability to block dopamine receptors. Since Parkinson’s disease is caused by loss of dopamine in the basal ganglia, a drug that blocks dopamine there can imitate it. The chemistry is covered on the companion page about phenothiazines.

Other movement effects were described in the same period. In 1957 the German physician M. Schönecker reported a “paroxysmal dyskinesia” — sudden involuntary movements — with chlorpromazine, which was sold in Germany under another name.

Tardive dyskinesia

The most troubling finding was a late one. Tardive means “late”: tardive dyskinesia is a disorder of repetitive, involuntary movements, typically of the mouth, lips and tongue and sometimes of the limbs and trunk, that appears after months or years of treatment and can persist after the drug is stopped. Daniel Tarsy’s 1983 review of the history and definition of tardive dyskinesia traces how these late movements were noticed, debated and finally defined as a distinct syndrome in the decades after chlorpromazine’s introduction.

Pierre Deniker, one of the psychiatrists who had brought chlorpromazine into psychiatry, wrote his own short history of the neuroleptics in 1989 under the title “From chlorpromazine to tardive dyskinesia”. The title itself records how the story of the drug class came to be framed by one of its pioneers: from the first calming effects to the late harm that followed long use.

How common the condition is has been measured many times. A 2017 meta-analysis by Maren Carbon, John Kane, Christoph Correll and colleagues pooled 41 studies with 11,493 participants and found an overall tardive dyskinesia prevalence of 25.3% among people taking antipsychotics. The figure was 30.0% among those currently taking first-generation drugs such as chlorpromazine and 20.7% among those taking second-generation drugs. The authors noted that the severity of the movements was not adequately reported in many of the studies.

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6. Jaundice, Blood Disorders and Neuroleptic Malignant Syndrome

Jaundice

In 1955 the New England Journal of Medicine published a report by R. M. Sussman and P. Sumner titled “Jaundice following the administration of 50 mg. of chlorpromazine”. As the title records, the liver reaction in that report followed a dose of 50 mg. Jaundice — yellowing of the skin and eyes caused by a build-up of bilirubin — became one of the recognised reactions to chlorpromazine in the 1950s; it is usually described as cholestatic, meaning that the flow of bile is impaired.

Agranulocytosis

A rarer but more dangerous reaction affected the blood. Agranulocytosis is a severe fall in the white blood cells called granulocytes, which leaves the body exposed to infection. In 1956 G. Schick and J. Virks reported a case associated with chlorpromazine therapy in the New England Journal of Medicine, together with a review of the cases reported up to then. The reaction was uncommon, but because it could be fatal it became one of the standard warnings attached to the drug.

Neuroleptic malignant syndrome

The most serious acute reaction to antipsychotic drugs was recognised later still. Neuroleptic malignant syndrome is a rare condition in which a person taking a dopamine-blocking drug develops high fever, severe muscle rigidity, changes in consciousness and unstable blood pressure and heart rate; it is a medical emergency. The neurologist Eelco Wijdicks, in a history of the syndrome titled “Turned to Stone” (published online in 2022), traces how the syndrome came to be recognised in the decades after the first neuroleptics. His title refers to the extreme rigidity that is its most striking sign.

Other effects

The 2005 Cochrane review described in section 8 found that, compared with placebo, people given chlorpromazine in trials experienced more sedation, more acute movement disorders and parkinsonism, more low blood pressure with dizziness, and more dry mouth. Boyd-Kimball and colleagues’ 2019 review places these effects in the context of the drug’s wide receptor profile: chlorpromazine blocks not only dopamine receptors but also histamine, acetylcholine and adrenaline-type receptors, and each blockade has its own consequences.

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7. Successor Drugs and the ‘Atypicals’

Chlorpromazine was the first of a long line. The psychiatrist Winston Shen, in a 1999 history of antipsychotic drug development, counts roughly 15 antipsychotic drugs introduced in the United States and about 40 worldwide between 1954 and 1975. Many were close chemical relatives — other phenothiazines with altered side chains — while others, such as the butyrophenone haloperidol, came from different chemical families but shared the same basic action of blocking dopamine receptors. These drugs are now grouped together as the “first-generation” or “typical” antipsychotics.

Shen’s history describes a turning point in 1990, when clozapine was introduced in the United States. Clozapine produced far fewer movement disorders than the older drugs, and it became the model for a group called the “atypical” or “second-generation” antipsychotics. The hope behind the atypicals was to keep the calming and antipsychotic effect that began with chlorpromazine while losing the parkinsonism and tardive dyskinesia that had come with it.

Later research complicated the neat division into two generations. As section 8 describes, a large 2013 analysis found the drugs differed from one another in many individual ways that did not line up with the old “typical” and “atypical” labels, and the second-generation drugs brought side effects of their own, notably weight gain and metabolic changes.

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8. What Fifty Years of Trials Found

Chlorpromazine entered medicine before the modern randomised controlled trial became the standard test of a new drug. Its evidence base was built up afterwards, and in 2005 a Cochrane team led by Clive Adams published a systematic review of fifty years of randomised trials comparing it with placebo in people with schizophrenia.

The 2005 Cochrane review

The review included 50 trials conducted between 1955 and 2000, with 5,276 participants. People given chlorpromazine were less likely to show no global improvement than those given placebo (relative risk 0.76), which the authors expressed as a number needed to treat of 7: on average, seven people had to be treated for one extra person to improve. They also recorded a considerable response to placebo in the trials. On the harm side, sedation was more than twice as common with chlorpromazine (relative risk 2.3, number needed to harm 6), and the drug caused more acute movement disorders, parkinsonism, low blood pressure with dizziness, and dry mouth. The authors concluded that, it was understandable why the World Health Organization had endorsed chlorpromazine; it remains on the WHO’s Model List of Essential Medicines, the list of medicines the organisation considers the minimum needs of a basic health system.

Leucht 2013: fifteen drugs compared

In 2013 Stefan Leucht and an international group published in the Lancet a network meta-analysis of 212 randomised trials with 43,049 participants, comparing 15 antipsychotic drugs with placebo and with each other. All 15 were more effective than placebo. Chlorpromazine’s effect size against placebo was a standardised mean difference of 0.38 (95% confidence interval 0.23–0.54), in the middle-to-lower part of the range. The drugs differed substantially in their side effects — sedation, weight gain, movement disorders and others — and the authors argued that these differences were too varied to be captured by the simple division into first- and second-generation drugs.

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9. Laborit’s Later Drugs: Gamma-OH and Minaprine

Chlorpromazine was only the beginning of Laborit’s work as a pharmacologist. In 1958 he founded his own research laboratory at the Hôpital Boucicaut in Paris, which he ran until his death in 1995. The psychiatrist Edward Kunz, in a 2014 portrait of Laborit, notes that Laborit financed it largely through patents on new molecules, working mostly outside the university system, and credits him with discovering or taking part in the development of several more drugs.

Gamma-hydroxybutyrate (“gamma-OH”)

Around 1960 Laborit began studying sodium 4-hydroxybutyrate — the sodium salt of gamma-hydroxybutyric acid, known in France as “gamma-OH” and now usually abbreviated GHB. The compound itself had been made by chemists in the nineteenth century; Laborit’s contribution was its pharmacology. His interest grew from the brain’s own chemistry: GHB is chemically close to GABA (gamma-aminobutyric acid), the brain’s main calming messenger, and later research found that GHB also occurs naturally in small amounts in the brain. In 1964 he published a long review of the substance in the International Journal of Neuropharmacology, describing its sedative and sleep-inducing actions.

In France gamma-OH was used in anaesthesia, and in 1962 Laborit and the psychiatrists H. Danon-Boileau and colleagues reported on its use in psychiatry in the Presse Médicale. Its later history moved far from Laborit’s laboratory. GHB became a drug of abuse and is now a controlled substance in many countries; a pharmaceutical form of its sodium salt is licensed in some countries for the sleep disorder narcolepsy.

Minaprine

Minaprine was an antidepressant that Laborit helped bring to medicine. In 1981 he wrote a short account of its origins in his own journal, Agressologie, under a title translated in PubMed as “The childhood of minaprine”. It was marketed in France, and Kunz writes that it remained on the market until 1990.

Clomethiazole

Kunz also names clomethiazole, a sedative and anticonvulsant, among the drugs Laborit discovered or helped develop. Chemically, clomethiazole is related to the thiazole part of the vitamin B1 (thiamine) molecule.

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10. The Inhibition of Action

In his later decades Laborit became as well known in France for his ideas about behaviour and stress as for his drugs. The thread linking the two was the same one that had led him to chlorpromazine: an interest in how the body’s own reactions to threat can turn harmful. In surgical shock he had seen the defensive reaction to injury damage the patient it was meant to protect. In his laboratory he extended the idea from the body to behaviour.

The result was his theory of the “inhibition of action”, set out in his 1979 book L’Inhibition de l’action and in a 1988 paper in the Annales Médico-Psychologiques. As Kunz summarises it, an animal — or a person — faced with a threat has two active responses available: to fight or to flee. When neither is possible, the result is behavioural inhibition, a state of enforced waiting and helplessness. Laborit argued that this inhibited state, rather than the threat itself, is what drives many of the physical and mental diseases of stress, through lasting activation of the body’s stress hormones and nervous system.

He took the theory to a wide public. His 1976 book Éloge de la fuite (“In Praise of Flight”) became a popular introduction to neuroscience in France, and in 1980 he appeared as himself in Alain Resnais’s film Mon oncle d’Amérique, explaining animal experiments on stress and inhibition between scenes of the fictional characters’ lives. His wider life and writing are covered on the page about Laborit’s life and career.

His ideas were more influential in French-speaking culture than in English-language science, where, according to Kunz, almost all of Laborit’s 624 Medline-listed papers are in French and only two of his more than fifteen books were translated into English. It brings the story full circle: the surgeon who went looking for a drug to damp the body’s harmful defensive reactions ended his career with a theory about the same reactions in everyday life.

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Key Research Papers

  1. Laborit H. Some precautions in neuroplegic therapy with chlorpromazine (R.P. 4560 or largactil). Therapie. 1954;9(3):302-11. PubMed PMID: 13205514
  2. Laborit H. Ganglion blocking agents in surgery; R. P. 4560. Anaesthesist. 1954;3(1):20-5. PubMed PMID: 13148585
  3. Lehmann HE, Hanrahan GE. Chlorpromazine; new inhibiting agent for psychomotor excitement and manic states. AMA Arch Neurol Psychiatry. 1954;71(2):227-37. PubMed PMID: 13123588
  4. Delay J, Deniker P. Neuroleptic effects of chlorpromazine in therapeutics of neuropsychiatry. J Clin Exp Psychopathol. 1955;16(2):104-12. PubMed PMID: 14392209
  5. López-Muñoz F, Alamo C, Cuenca E, Shen WW, Clervoy P, Rubio G. History of the discovery and clinical introduction of chlorpromazine. Ann Clin Psychiatry. 2005;17(3):113-35. PubMed PMID: 16433053
  6. Ban TA. Fifty years chlorpromazine: a historical perspective. Neuropsychiatr Dis Treat. 2007;3(4):495-500. PubMed PMID: 19300578
  7. Caponi S. On the so-called psychopharmacological revolution: the discovery of chlorpromazine and the management of madness. Hist Cienc Saude Manguinhos. 2021;28(3):661-683. PubMed PMID: 34495111
  8. Pieters T, Majerus B. The introduction of chlorpromazine in Belgium and the Netherlands (1951-1968); tango between old and new treatment features. Stud Hist Philos Biol Biomed Sci. 2011;42(4):443-52. PubMed PMID: 22035718
  9. Kirkby KC. Social context and health consequences of the antipsychotics introduction. Ann Clin Psychiatry. 2005;17(3):141-6. PubMed PMID: 16433055
  10. Boyd-Kimball D, Gonczy K, Lewis B, Mason T, Siliko N, Wolfe J. Classics in Chemical Neuroscience: Chlorpromazine. ACS Chem Neurosci. 2019;10(1):79-88. PubMed PMID: 29929365
  11. Steck H. Extrapyramidal and diencephalic syndrome in the course of largactil and serpasil treatments. Ann Med Psychol (Paris). 1954;112(2:5):737-44. PubMed PMID: 14362101
  12. Schonecker M. Paroxysmal dyskinesia as the effect of megaphen. Nervenarzt. 1957;28(12):550-3. PubMed PMID: 13517450
  13. Tarsy D. History and definition of tardive dyskinesia. Clin Neuropharmacol. 1983;6(2):91-9. PubMed PMID: 6133621
  14. Deniker P. From chlorpromazine to tardive dyskinesia (brief history of the neuroleptics). Psychiatr J Univ Ott. 1989;14(1):253-9. PubMed PMID: 2566183
  15. Sussman RM, Sumner P. Jaundice following the administration of 50 mg. of chlorpromazine. N Engl J Med. 1955;253(12):499-502. PubMed PMID: 13253865
  16. Schick G, Virks J. Agranulocytosis associated with chlorpromazine therapy; report of a case and review of the literature. N Engl J Med. 1956;255(17):798-802. PubMed PMID: 13369718
  17. Wijdicks EFM. Turned to Stone: A History of the Neuroleptic Malignant Syndrome. Neurocrit Care. 2025;43(3):1093-1096. PubMed PMID: 36289157
  18. Shen WW. A history of antipsychotic drug development. Compr Psychiatry. 1999;40(6):407-14. PubMed PMID: 10579370
  19. Carlsson A, Lindqvist M. Effect of chlorpromazine or haloperidol on formation of 3methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol (Copenh). 1963;20:140-4. PubMed PMID: 14060771
  20. Adams CE, Rathbone J, Thornley B, Clarke M, Borrill J, Wahlbeck K, Awad AG. Chlorpromazine for schizophrenia: a Cochrane systematic review of 50 years of randomised controlled trials. BMC Med. 2005;3:15. PubMed PMID: 16229742
  21. Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, Samara M, Barbui C, Engel RR, Geddes JR, Kissling W, Stapf MP, Lässig B, Salanti G, Davis JM. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013;382(9896):951-62. PubMed PMID: 23810019
  22. Carbon M, Hsieh CH, Kane JM, Correll CU. Tardive Dyskinesia Prevalence in the Period of Second-Generation Antipsychotic Use: A Meta-Analysis. J Clin Psychiatry. 2017;78(3):e264-e278. PubMed PMID: 28146614
  23. Kunz E. Henri Laborit and the inhibition of action. Dialogues Clin Neurosci. 2014;16(1):113-7. PubMed PMID: 24733976
  24. Laborit H. Sodium 4-hydroxybutyrate. Int J Neuropharmacol. 1964;3:433-51. PubMed PMID: 14334876
  25. Danon-Boileau H, Lavitry S, Lab P, Levy E, Ruffiot S, Laborit H. Utilization in psychiatry of gamma-OH. Presse Med. 1962;70:2205-7. PubMed PMID: 14025030
  26. Laborit H. The childhood of minaprine. Agressologie. 1981;22(2):43-4. PubMed PMID: 7270793
  27. Laborit H. The inhibition of action. Interdisciplinary approach of its mechanisms and physiopathology. Ann Med Psychol (Paris). 1988;146(6):503-22. PubMed PMID: 2904238

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Further Reading

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Connections