Who Pioneered the Use of Antipsychotics in North America?

Abstract

Objective:

Neuroleptics were introduced into North America 60 years ago. The credit for this advance is generally accorded to Heinz Lehmann. I sought to explore whether Lehmann really was the first North American psychiatrist to study the effects of chlorpromazine (CPZ) and to provide a more balanced view of its application in a clinical context.

Method:

I searched for historical documents and published articles in several libraries and interviewed psychiatrists active from 1952–1970.

Results:

The first article in English was published in the July volume of the Archives of Neurology and Psychiatry in 1954 (n = 71). Another article, written in French by Roland Saucier and published in a journal called Le Saguenay Médical, also described the effects of CPZ on a Canadian psychiatric population in August 1954 (n > 200). However, the first prescription for CPZ was written by Roland Saucier, who brought the product back from Paris after a fellowship there. Ruth Kajander, in Ontario, was also one of the first prescribers of this drug, following her study of its use in anesthesia and a publication in the proceedings of a symposium.

Conclusion:

The contents of the 2 naturalistic studies were compared. Lehmann’s study started 1 month before that of Saucier. Lehmann was the first North American psychiatrist to publish an article on CPZ, but Roland Saucier nevertheless made an important contribution, being the first to prescribe this drug in North America and reporting results for a study with a sample size 3 times that of Lehmann’s study.

Neuroleptics were introduced into North America 60 years ago. The credit for this introduction is generally accorded to Heinz Lehmann, a psychiatrist at the Verdun Hospital, which later became the Douglas Mental Health University Institute, affiliated to McGill University. The first neuroleptic prescribed was CPZ, which Jean Delay and Pierre Deniker had already been using for 2 years in France. In a previous article,¹ published for the 50th anniversary of neuroleptics, I described the history of this AP and its introduction in Europe by Delay and Deniker. I suggest here that it might be erroneous to consider Lehmann as the pioneer of CPZ in North America. This article focuses not only on the first use of CPZ in North America but also provides a more rounded version of CPZ use in the clinical context. I also explore other instances of CPZ use at the time of Lehmann’s work and publications.

Lehmann published his first article on this topic, in English, in 1954. This article, published in the Archives of Neurology and Psychiatry,² is considered to report the first use of APs to treat a North American population. However, I have discovered another article, written in French and published in Le Saguenay Médical,³ that also describes the effects of CPZ (Largactil) on a Canadian psychiatric population.

My examination of these 2 articles suggested that it was highly possible that the first North American study of an AP might actually have been carried out by Roland Saucier, a psychiatrist practicing in the Saguenay Lac-Saint-Jean region of Quebec. Therefore, I decided to compare these 2 articles.

Saucier was born in Chicoutimi, in the Saguenay–Lac-Saint-Jean region, in 1906. He completed his classical studies at the Chicoutimi seminary, where he obtained his baccalaureate in rhetoric in 1919 and his Bachelor of Arts degree in 1926. Despite poor health, and with much effort, he earned a Doctor of Medicine degree in 1948, after which, he specialized in psychiatry. He interned at the Roy-Rousseau Clinic and the Enfant-Jésus Hospital in Quebec City. He continued his studies in France, taking courses in pathological psychology at the Sorbonne and Sainte-Anne Hospital in Paris. He received psychiatric training at the Mental and Brain Illness Clinic of the University of Paris, Faculty of Medicine, and trained in neurology at the Salpêtrière and Paul-Brousse hospitals, and was awarded a Foreign Assistant diploma by the University of Paris, Faculty of Medicine. In September 1950, Saucier returned to Chicoutimi, joining the medical staff of Hôtel-Dieu Saint-Vallier Hospital. In January 1952, Hôtel-Dieu Saint-Vallier opened a neuropsychiatry clinic and Saucier, a pioneer of psychiatry in the region, was appointed its director. He founded the hospital’s psychiatry department, which he directed until August 1971. In 1969, under his direction, the department became affiliated with the department of psychiatry at Laval University. At the time, its staff was composed of 5 psychiatrists, 2 social workers, 1 psychologist, 1 occupational therapist, and several specialist nurses. One of these psychiatrists, Camille Plourde, was able to supply us with detailed information. Under Saucier’s leadership, Hôtel-Dieu Saint-Vallier opened a child psychiatry section, carrying out only outpatient treatment. At his retirement, Saucier left behind a first-rate department, with a team well equipped to continue his work. In 1973, the Quebec government honoured him by creating an institute bearing his name.

Clinical Implications

• There were diverse indications for neuroleptics when these drugs were first introduced into North America.

• Observational studies were useful when APs were first introduced.

• The criteria for drug approval has changed considerably during the last 60 years.

Limitations

• I was unable to meet Lehmann and Saucier. I was able to speak only with Dr Kajander for the writing of this article.

• The historical method of data collection does not lend itself readily to objective and statistical validation.

• There is some confusion about the article by Lehmann, which was published in volume 71 of the American Medical Association’s Archives of Neurology and Psychiatry, but indexed in volume 72, published in July 1954.

Heinz Edgar Lehmann was born in Berlin, Germany, in July 1917. He was educated at the universities of Freiburg, Marburg, Vienna, and Berlin. He emigrated to Canada in 1937. In 1947, he was appointed Clinical Director of Montreal’s Douglas Hospital (Verdun Protestant Hospital). From 1971 to 1975, he was Chair of the McGill University Department of Psychiatry. He published over 300 articles, mostly on psychopharmacology. As suggested by Joel Paris⁴ and many others, Lehmann must therefore be seen as a pioneer in psychiatry. In the spring of 1953, Lehmann was seeking a new treatment for his more severely disturbed patients. A Rhône-Poulenc representative gave him a copy of Delay and Deniker’s article.⁵ Encouraged by the results, he and a resident, Gorman Hanrahan, used CPZ on a series of patients, obtaining encouraging results, as described below. They presented their findings at a psychiatry meeting organized by Ewen Cameron, Head of Psychiatry at McGill, at the Allen Memorial Institute of Montreal in March 1954.

Clinical Description of the Effect of Chlorpromazine

I describe and summarize the results of the 2 articles^2,3 in tables 1 to 4.

Table 1.

The publications of Lehmann and Saucier

Characteristics of the study	Lehmann2	Saucier3
Medication	Chlorpromazine, Largactil, 4560 RP, Compound 2601-A	Chlorpromazine, Largactil, 4560 RP, Compound 2601-A
Indication	Psychiatric disorders	Psychiatric disorders
		Preparation for anesthesia
		Potentialized anesthesia
		Artificial hibernation
		Controlled hypotension
		First aid for major burns
		Anti-emetic for morning sickness
Sample size, n	71	>200
Characteristics of the population	Psychiatric patients, aged 18 to 82 years, recruited at Verdun Protestant Hospital	Patients with neurosis, psychosis, or hysteriform symptoms: 17 hypochondriacs, 46 hysterics.
		See Table 3 for the various disorders treated.
Duration of study	4 months	1 year
Duration of treatment	A few weeks; at least 2 to 3 weeks to avoid relapses	See Table 3
Pharmacodynamics	Mode of action unknown	Acts on autonomic nervous system: parasympathicolytic and sympathicolytic effects
		Acts on central nervous system: sedative effect
		Antispasmodic effect and effect on nerve endings

Table 4.

Summary of psychological and (or) psychiatric effects documented in the 2 studies²,³

Lehmann

An intramuscular dose of 50 to 100 mg generally controls most states of agitation.

Administration of chlorpromazine for 3 to 4 days during prodromal symptoms seems to prevent psychosis.

Emotional tension well controlled with small doses (50 to 200 mg/day).

Controlled agitated delirium in a patient whose condition was refractory to any other treatment.

No effect on hallucinations and delusions.

Marked effect on manic-depressives patients in a chronic manic state for at least 1 year who did not respond to other treatments.

Triggered depression in 4 manic-depressives patients over the age of 45 years in a manic state.

If no normal physiological response after treatment = less likely to respond to medication (except elderly people).

No emotional disinhibition.

If daily doses of 100 to 200 mg given orally do not produce satisfactory results, larger doses will not help.

Lethargy, quiescence.

Patients have a lack of spontaneous interest in the environment, are lucid, and answer questions slowly and monotonously.

Silent and immobile if left alone.

Often aware of their improvement, not euphoric.

Fatigue and weakness in some patients.

Higher psychic functions preserved: attention, reflection, and concentration.

Best results in manic-depressives patients in manic and hypomanic states: ↓ psychomotor agitation in the 24 hours following treatment, patient cooperation.

Saucier

No effect on people with hypochondria.

In hysteria, only temporary cessation, transient sedation.

Series of clinical cases:

Elimination of delirium and hallucinations in 2 days, 37 days, and 3 weeks (3 clinical cases).

Persecution delusions vanished after 2 weeks (1 case).

Relief of headaches (patient’s complaint) in 9 days (1 case).

Eliminated the feeling of chronic sadness, resolved sleep, and appetite problems in 14 days (2 cases) and 19 days (1 case) (3 cases in all).

Disappearance of neurotic symptoms in 14 days, 19 days, and 3 weeks (3 cases).

Gradual elimination of suicidal ideations and of sadness and self-accusation (the patients left after 13 or 17 days, despite the physician’s recommendations) (2 cases).

Elimination of obsessive ideas in 28 days in a patient with an intellectual disability.

Did not enhance intellectual capacities, even after 28 days of treatment.

Both papers^2,3 documented a beneficial effect of the medication. Lehmann’s study population consisted mostly of patients with schizophrenia and mania. Four subjects had undergone a lobotomy, which was a common treatment at the time.^6–9 Saucier included subjects with a broader range of conditions in his study: paranoid psychosis, depressive state, anxiety neurosis, and mystic delusional disorder. Similar dose ranges were used in the 2 studies. No response to treatment was reported for 8% of the patients studied by Saucier and for 15% of those studied by Lehmann.

Chronology

In 1954, Lehmann published an article in Archives of Neurology and Psychiatry, a monthly journal produced by the American Medical Association. The editor was T J Putnam, with Wilder Penfield of Montreal acting as a kind of associate editor. In the bound volume, the article appears on page 227 of the July 1954 (volume 72, number 1) issue. This volume covers the communication period from January to June 1954. Therefore, it is extremely difficult to determine the exact date of publication. On page 135 of the same volume, there is an article entitled “Cortical Ablation in Dogs,” which was published in February 1954 (volume 71, number 2) and Lehmann’s article is followed, on page 271, by an article entitled “Spinal Cord Compression Studies,” published in March 1954 (volume 71, number 3). Therefore, it appears highly plausible that the article was actually published before March 1954. The sample size for Lehmann’s first article² was only 71 subjects; in his second article, which appeared in the Canadian Medical Association Journal in 1955,¹⁰ the authors described the completed study with 289 patients. The study appears to have begun in 1953: “We started using chlorpromazine at the Verdun Protestant Hospital in May 1953.”¹⁰, ^{p 91} The medication was provided by Rhône-Poulenc: “we are indebted to Poulenc Limited for providing us with supplies to carry out our initial investigations.”¹⁰, ^{p 91} Based on this information, I believe that the study began in May 1953 and was published no later than July 1954.

Saucier’s article was published, in French, in the Saguenay Médical August 1954 volume.³ This medical journal was published quarterly by the Hôtel-Dieu Saint-Vallier hospital, in Chicoutimi, Quebec. The editors were Wilfred Lachance and Edmond Potvin. Saucier described the study as commencing in June 1953 and continuing until 1954: “Depuis le 1er juin 1953 jusqu’au 30 juin 1954 nous avons administré le largactil à plus de 200 malades”^{3p 54} [“From June 1, 1953, to June 30, 1954, we administered Largactil to more than 200 patients”]. Therefore, the results were published after the completion of the study, which included at least 200 patients. If this journal had been published monthly, would the results have appeared before July 1954?

The 2 protagonists were probably unaware, at the time, of their race to publish first. Lehmann’s study seems to have started 1 month before that of Saucier, and his article was published in English 1 month before the article in French. However, Saucier’s study included a sample 3 times the size of that studied by Lehmann.

This examination of these 2 seminal articles suggests that it is not incorrect to consider Lehmann to be the first North American psychiatrist to publish an article on CPZ. However, in recognizing this fact, psychiatrists should not forget the contribution of another team—a small French-speaking team, working in a dynamic environment far from the big city, which generated and published interesting and naturalistic results at about the same time.

I was able to question key players and to obtain valuable information about when 4560 RP, as the drug was then known, was first prescribed in Quebec. I interviewed Anne-Marie Bouchard and Chantale Bouchard, psychiatrists and daughters of Grégoire Bouchard, a psychiatrist working with Roland Saucier on his return from France with CPZ in his suitcase, who died in 2011. I was also able to interview Camille Plourde, a retired psychiatrist who worked with Saucier at Hôtel-Dieu Saint-Vallier in 1952–1953 and who remembers the first prescription being issued in late 1952 or early 1953. I was also able to interview Pierre Vincent, a psychiatrist who won the Heinz Lehmann award from the Association des médecins psychiatres du Québec in 2013. He confirmed that Roland Saucier passed this drug on to Maurice Coulombe, a psychiatrist at the Roy-Rousseau Clinic in Quebec City. Coulombe then administered the drug to a patient at Roy-Rousseau Clinic, a few days after Saucier.

This historical account of the introduction of CPZ would not be complete without mention of Ruth Kajander’s early research on CPZ, which she reported to a professional psychiatry forum on November 27, 1953, several months before the publication of the work of Lehmann and Saucier.^11–14 Kajander (née Koeppe) was also originally from Germany, and she moved to Ontario in 1952, after training at the University of Gottingen, Berlin, and in Helsinki. In 1953, she worked with Elizabeth Martin, an anesthetist, during a rotating internship at the Oshawa General Hospital, and she used 4560 RP, obtained from Rhône-Poulenc. Kajander was interested in the calming effect of the drug, without total sedation, during anesthesia. In the fall of 1953, she took up a position as resident in psychiatry at Ontario Hospital, London. She convinced the Medical Director, Douglas Wickware, to let her use CPZ on a small number of patients in November 1953. She described her findings to a meeting of the Ontario Neuropsychiatric Association in Whitby in February 1954. Kajander acted entirely on her own initiative. She knew from the Rhône-Poulenc representative that Lehmann had also used the drug successfully, but her first contact with him was as a discussant for his article at the March meeting in Montreal. The archives of the Canadian Psychiatric Association hold a copy of her paper, but Kajander’s findings were never published in a scientific journal, appearing instead only in the proceedings of the meeting in Ontario. This deprived her of the credit she deserved until the publication of an interview with her carried out by Sam Sussman.¹⁵ She reported 3 cases. The first 2 cases involved women suffering from agitated depression and the third involved an immigrant woman who became psychotic shortly after giving birth to an illegitimate child. She had delusions of having given birth to a dog. She was diagnosed with paranoid schizophrenia, and the clinical effects of the drug were remarkable.

The Nature of Scientific Articles

The clinical research protocols for assessing drug efficacy in 1954 were clearly very different from those prevailing in 2015. The requirements and criteria have evolved, and it is now necessary to demonstrate the superiority of the test molecule to a placebo or a widely used treatment. Adherence to the following conditions is strictly required: statement of hypotheses (and null hypothesis) to be tested, control of the conditions through inclusion and exclusion criteria, double-blind or single-blind design, duration, randomization, statement of statistical power, and required sample size. Four phases of clinical trials are required (phases 1, 2, 3, and 4), and clinical data and results must be presented to regulatory agencies, such as the US Food and Drug Administration, the Institut national d’excellence en santé et en services sociaux in Quebec, and the Therapeutic Products Directorate in Canada, for agency audits and clinical trial registries. Publication criteria include peer review and the use of evidence-based medicine. Further, ethics committees must approve trials and conflicts of interest must be declared. Government agencies may reject drugs owing to a lack of convincing evidence of their efficacy, safety, and economic impact. Moreover, studies of the biological effects of CPZ have generated almost 20 000 published studies listed by PubMed, second only to Aspirin (over 50 000), largely owing to its abundant side effects.

Neither of the studies considered here had an experimental design based on the rejection of a null hypothesis. Nevertheless, observational or naturalistic studies with APs are not uncommon. However, such studies generally follow controlled studies and are conducted after approval of the drug for clinical use. Current guidelines and treatment algorithms for schizophrenia are based on outcome data from randomized controlled trials on selected patients with limited follow-up. Most of these trials have small sample sizes, and most patients displaying physical illness; poor compliance; or suicidal, substance abuse, or antisocial behaviour are excluded. Therefore, it is difficult to generalize data from such trials to broader community settings. Larger-scale observational studies could provide insight into these important aspects. In addition, AP discontinuation rates are a powerful indicator of a drug’s effectiveness in schizophrenia. These aspects have been highlighted by a series of studies, including the Schizophrenia Outpatient Health Outcomes study, a 3-year prospective, observational study in outpatients, which investigated the discontinuation of AP treatment.¹⁶

Moreover, there was no psychopharmacological model in 1954, when neuroleptics were first used. There was only one model, for methylene blue, as an oxidative agent.^17–19 In fact, the phenothiazines are a family of heterocyclic compounds, the structure of which is best exemplified by methylene blue.²⁰ The only justification for their use was Henri Laborit’s clinical impressions during his work with antihistamines and his empirical observation of useful sedation in some subjects, not recruited as psychotic patients per se.²¹ The first DA hypothesis of schizophrenia, according to which hyperactive DA transmission was responsible for the disorder, did not emerge until 10 years after the first publication on Largactil. This hypothesis was based on early observations that DA receptors are activated by psychostimulants, that nonreserpine neuroleptics are DA antagonists, and that DA plays a clear role in the extrapyramidal system. The classical DA hypothesis received further support from the correlation between clinical doses of APs and their potency to block DA D₂ receptors,²² and the psychosis-inducing effects of DA-enhancing drugs. Much of the evidence underlying these concepts came from the seminal work of Arvid Carlsson, who characterized DA in the brain and the effects of neuroleptics on monoaminergic indices, less than 10 years after the first publication on Largactil (see Carlsson and Lindqvist²³ and Carlsson^24,25).

Pharmacological interventions to treat psychosis have generally focused on the modification of dysfunctional neurotransmitter systems (for example, DA) to improve symptoms. Interestingly, Jean Delay’s book, Méthodes biologiques en clinique psychiatrie,²⁶, ^{p 375–382} published in 1950, 2 years before the articles on 4560 RP, indicates that antibiotics, such as penicillin, were among the recommended treatments for psychosis. There is now a growing body of evidence to suggest that inflammation, infection, oxidative stress, changes in the glutamatergic system, and neurotrophins are involved in schizophrenia. These new insights into pathophysiology are leading to the exploration of new treatment strategies. For instance, minocycline, an antibiotic used to treat infections, can modulate glutamate-induced excitotoxicity, with anti-inflammatory, antioxidant, and neuroprotective effects. Clinical trials have indicated that minocycline may be useful for treating schizophrenia. CPZ has antimicrobial activity against Staphylococcus aureus in vitro, at concentrations greatly exceeding those achieved clinically.²⁷ The activity of CPZ against various microorganisms, including intracellular pathogens (Leishmania, trypanosomes, amoebae),^28,29 has been studied in vitro and in vivo.

However, these activities of CPZ reside in the side chains of the molecule and have led to the development of this phenothiazine as an anti-malarial agent.^20,28–30 This creates a kind of loop, bringing us back to the malaria parasite, which was used to treat mental illness from the early 1920s to the late 1950s.^31–33

The first North American prescribers of 4560 RP were probably aware of the limitations of antibiotics in psychiatry and happy to administer the first neuroleptic to help their patients, who, as the articles show, presented a broad range of diagnoses. This was probably the first seroquelization initiative in psychiatry.^34,35

Antecedents to Chlorpromazine Use in North America

The history of medicine is littered with examples of how problematic it can be determining who was first in medical research. Before its arrival in Canada, there had already been debates about who was first to use 4560 RP in France. Largactil, the first neuroleptic, was the product of research into antihistamines, which were discovered in 1937 by the Swiss-born Italian pharmacologist Daniel Bovet, who won the Nobel Prize for Medicine in 1957.^36–38 In 1944, he isolated phenothiazine and diethazine (Diparcol), which Jean Sigwald used to treat Parkinson disease (1946).³⁹ Bernard Halpern introduced the use of antihistamine phenothiazines, such as promethazine (Phenergan), into medicine. French psychiatrists were the first to carry out clinical trials of antihistamines for psychiatric indications. Georges Daumezon used a derivative of benzylaniline to treat manic depressive attacks (1943), whereas Paul Guiraud proposed the use of promethazine to treat agitated states (1950). In the United States, OR Bryant also tested antihistamines for use in manic states (1950).^40–44

CPZ was synthesized in 1950, by Paul Charpentier at the Rhône-Poulenc laboratories.^43,45 Roland Saucier was in Paris, on a fellowship, at the time. In 1952, Henri Laborit, Pierre Huguenard, and Raymond Alluaume published the first clinical study of a new autonomic stabilizer: 4560 RP.²¹ In his work on potentialized anesthesia and artificial hibernation, Laborit reported that some somnolence was observed with 50 to 100 mg of intravenous CPZ, together with, above all, a “lack of interest by the patient in his surroundings.”^{21p 207} He predicted the extension of the use of this drug to obstetric analgesia and psychiatry. In December 1951, a clinical trial of 4560 RP was conducted by 2 psychiatrists, Jean Sigwald (born in 1903, medical degree awarded in 1932) and Daniel Bouttier (qualified in 1948) at the Paul Brousse Psychiatric Hospital. Their article, published in 1953, in Annales de médecine,³⁹ reported CPZ to be effective in a case series of patients showing some change in the mechanism of auditory hallucinations and their interpretation, and as an antidepressant.

Léon Chertok, one of the most remarkable characters in the history of psychiatry and hypnosis, carried out what was probably the first clinical experiment in a psychiatric setting with 4560 RP alone. After interning in psychiatry at Mount Sinai Hospital in New York and undergoing analysis with Jacques Lacan, Chertok served as assistant to the psychiatrist Marcel Montassut at the Villejuif Psychiatric Hospital. In 1950, he and Victor Gachkel founded the Center for Psychosomatic Medicine there. At the time, he was working mainly with anesthetists and urological surgeons. In 1951, the anesthetist Jean Lassner told him about Laborit and his mysterious molecule. In fact, the molecule in question, 4560 RP, was not at all mysterious, as its anti-allergenic properties were already well known, but Laborit had noticed, essentially by chance, that it seemed to have a euphoric effect on patients and he wanted to experiment with it in psychiatry. Chertok was enthusiastic and he convinced his superior, Marcel Montassut. This led to an experiment being carried out in Villejuif on a fellow psychiatrist, Cornelia Quarti, whose comments during the experience were recorded. At the time, Laborit’s molecule was not yet available in tablet form. Therefore, it had to be administered intravenously to Quarti, but Chertok had no idea what dose to use. At the end of the injection, Quarti lost consciousness. However, a quarter of an hour later, she felt optimistic, relaxed, and full of affection for everyone. Chertok was then ready to continue and to begin experimenting on patients, but Montassut was unwilling to do so.

In March 1952, 3 psychiatrists at Val-de-Grâce Hospital in Paris, Hamon, Paraire, and Velluz, published a case study of a patient with manic attacks treated with CPZ, in association with either pentobarbital or pethidine: temporary sedation of the agitation was obtained but the effect was insufficiently strong, and electroconvulsive therapy was eventually required.⁴⁶

The first publication on the continuous, long-term treatment of psychiatric disorders with CPZ, by Delay, Deniker, and Harl, appeared on May 26, 1952, on the occasion of the centenary of the Société medico-psychologique.⁴⁷ Five other publications followed, covering about 40 diseases and describing the properties of CPZ (delay, without prior assumptions concerning the possible therapeutic spectrum of this drug).^5,48–51 The first trials of CPZ took place under constant supervision by physicians and nurses; psychological changes were monitored and vital signs were tested several times daily.^43,52 In France, CPZ was available under the proprietary name Largactil, for large action.^32,40 Advertisements from the period boasted of the 4 areas of use for the drug: surgery, for preparation for anesthesia, and the prevention and treatment of traumatic postoperative shock; obstetrics, for obstetric analgesia, eclampsia, and vomiting during pregnancy; internal medicine, for neurotoxicosis, dermatosis, and vomiting; and psychiatry, for manic excitement, psychosis, and psychomotor agitation. The dose for adults was 75 to 150 mg per day.

Following the first publication on May 26, 1952, at the centennial meeting of the Société médico-psychologique,⁴⁷ the St Anne team published 6 articles during a 6-month period,^5,47–51 paving the way for the introduction of CPZ in psychiatry.^52,53 Other publications in 1952 included a report by Follin,⁵⁴ on the successful treatment of an aggressive paranoid patient at Montauban mental hospital in France,⁴² and an article by Rigotti,⁵⁵ on 20 psychiatric patients in Padua, Italy. The first tests outside France, such as those of Arnold in Vienna and Labhardt in Basel, Switzerland, generated similar results.^{17,45,56–58} Doses were then increased to 150 to 300 mg intramuscularly and 300 to 500 mg by mouth, sometimes more.⁴⁰ The first British report, from Anton-Stephens,⁵⁹ identified indifference as the greatest effect on patients, this response being considered similar to that for psychosurgery, a frontal lobe syndrome.⁴⁰ The term chemical lobotomy was used by some early authors, including Lehmann.¹⁰ By the end of 1955, there were also reports on the effects of CPZ on psychiatric patients from Switzerland,^60,61 Germany,⁶² Hungary,⁶³ Latin America,⁶⁴ Australia,⁶⁵ the Union of Soviet Socialist Republics,⁶⁶ and the United States.⁶⁷ CPZ was marketed in the United States as Thorazine by SmithKline and French, and in England as Largactil by May and Baker.^45,68,69

Conclusion

The problem of the greater visibility of high-impact journals, such as the Archives of Neurology and Psychiatry, than of the lower impact local journals, particularly those publishing in other languages, such as the French-language journal in which Saucier’s article appeared, is not specific to psychiatry. The history of the name change of Les annales de l’Institut Pasteur and the disappearance of the Union medicale du Canada highlight the difficult sociological question of the value of language choice in a scientific domain.⁷⁰ It is no great surprise that the North American psychiatric community first looked (as it still does) at the higher-impact journals and received its information from there. The current status of French-language journals in the world of psychiatry and the rate of publications on CPZ at the time in the European French-language journals highlight the importance of this contextual question. For example, The Canadian Journal of Psychiatry accepts papers for publication in French, but the number of articles published in French decreases the impact factor of the journal, which is also called Revue canadienne de psychiatrie. In conclusion, the introduction of APs (neuroleptics) in North America was a turning point in psychiatry.^{17,68,71–73} I recognize that this “article is neither a comprehensive history of comparative treatment effect size nor a history of mentalities, but falls somewhere in between the two.”¹⁷, ^{p. 394} The first 2 articles^2,3 published on the subject both appeared in 1954 and were both by Canadians based in Quebec. Heinz Lehmann, Roland Saucier, and Ruth Kajander obtained CPZ from Rhône-Poulenc, which had developed this drug and tested it with clinical researchers and psychiatrists in France during the preceding 2 years. Closer inspection shows that Lehmann published at least a month before Saucier, that Saucier’s study included 3 times more patients than that by Lehmann, that both studies were naturalistic, and that patients with a very wide range of diagnoses were included, not just those with schizophrenia-type psychoses. These 2 articles provide information about this period in the history of psychiatry and the first use of chemical treatments for mental illnesses. They also highlight how far physicians have come since those days, in terms of rigour, epistemology, and the drug approval process. The beneficial effect of CPZ was instrumental in the reintegration of psychiatry with other medical disciplines⁷⁴ and in the development of neuropsychopharmacology. These 2 or 3 studies describe the introduction of neuroleptics into North America, during a period that led to a decrease in the number of beds in psychiatric hospitals and the first steps toward deinstitutionalization.³² Sixty years ago, CPZ researchers and prescribers “were not doing science in accordance with conventional theories of how science is suppose to operate.”¹⁷, ^{p 402} In 2014, neuroleptics still work, but psychiatrists now need to find alternatives, with or without a model.

Table 2.

Therapeutic results with chlorpromazine (Lehmann²)

Disorder	n	Clinical outcome
		Preventiona	Recoveryb	Great improvementc	Improvementd	Unchanged	Still being treated
Schizophrenia	22	2	0	3	9	7	1
Schizoaffective disorder	3	0	0	1	2	0	0
Mania, acute	22	2	8	2	7	0	3
Mania, chronic	12	0	4	1	3	1	3
Psychoneurosis	4	0	1	0	1	2	0
Post-lobotomy	4	0	0	0	2	1	1
Mental deficiency	1	0	0	0	0	1	0
Senile psychosis	3	0	0	0	3	0	0

^aPrevention was an aversion of imminent psychotic attacks during the prodromal period.

^bRecovery was a sustained cessation of symptoms within 40 days.

^cGreat improvement was a reduction of symptoms to the point that the patient can leave the hospital within 40 days.

^dImprovement was a constant decrease in symptoms over 40 days, but the patient still unable to leave the hospital.

Table 3.

Therapeutic results with chlorpromazine (Saucier³)

Condition	n	Treatment duration	Progression of condition
			Good	Improved	Not improved
Mania	2	8 to 10 weeks	2	0	0
Paranoid psychosis	10	4 weeks	5	2	3
Schizophrenia	4	0	0	3	1a
Anorexia nervosa	1	154 days	0	1	0
Mystic delusions	7	3 to 8 weeks	4	1	2
Postpartum psychosis	3	3 to 7 weeks	3	0	0
Depressive states	63	2 to 3 weeks	48	6	9
Severe depressive states	4	0	1	3	0
Anxiety neurosis	14	3 to 7 weeks	11	1	2
Obsessions	4	4 weeks	1	3	0
Insomnia	4	3 weeks	4	0	0
Psychogenic headaches	4	1 to 2 weeks	4	0	0

^aComplete relapse 2 or 3 weeks later.

Abbreviations

AP

antipsychotic

CPZ

chlorpromazine

DA

dopamine

RP

Rhône-Poulenc