History of neuroscience
The consolidation of neuroleptic therapy: Janssen, the discovery of haloperidol and its introduction into clinical practice
Introduction
The so-called “psychopharmacological revolution”, within the context of treating schizophrenic patients, was supported by two fundamental developments [7], [9], [40], [64], [68]: the synthesis of chlorpromazine (RP-4560) by Paul Charpentier and Simone Courvoisier, researchers at the Spécia Laboratories (Rhône-Poulenc Pharmaceutical Group, Vitry-sur-Seine, France), in December 1950 [70], [72], and in 1953, the commercial introduction to psychiatric practice, in 1953, of reserpine, a natural substance obtained from the roots of Rauwolfia serpentina, a plant native to Central Asia [3], [73]. The commercialisation a few years later, towards the end of the 1950s, of haloperidol marked a new historical landmark, providing the third cornerstone on which this first stage of antipsychotic pharmacology was based. These drugs brought a new ray of hope to the treatment of psychosis, offering a selective and effective treatment for schizophrenic patients [67]. Following their introduction, the so-called biological therapies, highly aggressive therapeutic procedures and of doubtful efficacy, fell into disuse [74].
This paper describes the research process which, although initially carried out within the framework of research into analgesic agents analogous to methadone conducted in the post-war years by the Belgian Janssen Pharmaceutical company, led exactly 50 years ago to the synthesis of haloperidol. The somewhat chance circumstances which resulted in its incorporation into the field of psychiatry, thanks in part to the perspicacity of Paul A. Janssen, will also be considered. In addition, the authors will analyse the initial difficulty encountered in introducing this drug into therapeutic psychiatric practice both in Europe, where research by a group of psychiatrists at the University of Liège made a major contribution, and in the United States of America, where the psychoanalytical tradition has strong roots.
The incorporation of haloperidol into the therapeutic arsenal of psychotic disorders has had manifold immediate and long-term effects on different areas in the health and social fields. Evidently, haloperidol contributed to the continuing spread of the phenomenon known as “deinstitutionalisation” of psychiatry, which had been initiated by the introduction of chlorpromazine, and to the implication of Primary Care in mental health care. Both events have mitigated somewhat the stigma which accompanied the psychiatric care. Other consequences of this “psychiatric revolution”, consolidated by the discovery of haloperidol, were of a more purely scientific nature, such as the formulation of the first biological hypotheses concerning the etiopathology of schizophrenia, for example. In nosology, the introduction of haloperidol contributed to some extent to the recovery of certain forgotten neuropsychiatric disorders and to the design of new diagnostic criteria, an example being the case of Tourette's syndrome. Finally, basic research methodology (new experimental models for predicting the effects of antipsychotics) and clinical (methodology of clinical trials) also benefitted from the arrival of haloperidol, which precipitated the synthesis of many new drugs aimed at treating mental disorder. These initially came from the same family, the butyrophenones, but later included the atypical antipsychotics.
Section snippets
The scientific bases of the discovery of haloperidol: Janssen Pharmaceutica and Paul A. Janssen
The origins of Janssen Pharmaceutica, an eminently domestic family business, are to be found in the Belgian town of Turnhout, where Jan Constant Janssen, a doctor from the town, created the NV Produkten Richter company on the 23rd October 1934. Having established contact some years before in Vienna with the son of Gedeon Richter, owner of a chemicals and pharmaceuticals company based in Budapest, Janssen initially concentrated on importing their medicines from Hungary. The products of Richter's
The discovery of haloperidol: from opioid analgesics to neuroleptic drugs
Haloperidol constitutes the standard compound for butyrophenones, one of the most important classes of psychotropic drugs within the classic neuroleptics. These antipsychotic drugs have their origins in the research and development of central analgesic molecules derived from pethidine (meperidine) and methadone [44], [45], [76], carried out by the Belgian company Janssen Phamaceutica.
The search for new analgesics with properties similar to methadone was very much in vogue in the 1940s, and also
Clinical research with haloperidol: a contribution of Belgian psychiatry to advances in psychopharmacology
The first clinical trials with haloperidol were conducted by C. Bloch, a psychiatrist from Brussels who was commissioned to investigate the clinical effects of the R-1625 compound five weeks after its synthesis. Bloch administered 2 mg i.v. of haloperidol to a reduced sample of patients presenting delirium tremens, but the results were unsatisfactory and as a result, were never published. However, in a letter contained in the company archives dated 4th April 1958, the head of clinical trials at
The clinical introduction of haloperidol: from European success to American disappointment
Under the brand name Haldol®, haloperidol was licensed and marketed in Belgium in October 1959, a month after initial communications of the Bobon and Divry research team had been confirmed and expanded on at the I International Symposium on Haloperidol, organised by Janssen and held in Beerse on the 15th September 1959. All the prestigious specialists from 11 different countries who had participated in trials over the previous year attended the symposium, including, for example, Jean Delay
The butyrophenone saga
The definitive scientific consolidation of neuroleptic therapy using butyrophenones would come, as Janssen remarked, at the III Congress of the Collegium Internationale Neuro-Psychopharmacologicum, held in Munich in 1962 [46]. Paul Janssen himself was invited to present a paper at the conference, which he later published in 1964, entitled Recent advances in the butyrophenone series, outlining pharmacological data for the 12 compounds in this series, including haloperidol, compared with 5
On the terminology and classifications of antipsychotic drugs: the role of haloperidol
As related by Ginestet, in January 1955 Jean Delay proposed to the Academie Nationale de Médicine in France that the word “neuroleptic” (from the Greek, “that take the nerve”) be used as a generic term for chlorpromazine and other drugs exhibiting a similar effect, such as reserpine [34]. The term refers to the action of these drugs, which diminish neurological activity, producing a reduction in agitation (neurolepsy) and slower motor response. Thus, the first generic term for one of the three
The contributions of haloperidol to the history of biological psychiatry
The significant contributions haloperidol has made to the development of biological psychiatry and currently neuroscience can be divided into two main areas. On the one hand, the new experimental models for predicting antipsychotic effects designed by the Janssen research team whilst developing haloperidol constituted a considerable advance in basic research into psychoactive drugs. On the other hand, haloperidol, together with chlorpromazine and reserpine, played a key role in the formulation
Conclusions
On what is the fiftieth anniversary of the introduction of haloperidol into clinical practice, it is fitting to render a deserved tribute to this antipsychotic agent which contributed to a revolution in psychiatric care and is still employed with success in clinical practice. The discovery of the neuroleptic properties of haloperidol at the end of the 1950s represented a turning point for psychiatric practice, with haloperidol rapidly becoming the progenitor of an entire family of neuroleptic
Conflict of interest
The authors have no financial relationships to disclose, nor conflicts of interest.
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2017, Biochemical PharmacologyCitation Excerpt :However, shortly after their introduction it became evident that their use could cause acute extrapyramidal symptoms (EPS) such as akathisia, Parkinsonism and dyskinesia, and in a dose-related manner, tardive dyskinesia [7]. The development of haloperidol with its significant increase in potency and a reduction in cardiovascular side effects like orthostatic hypotension made the drug the standard of care for the treatment of psychosis for many years [8]. The clinical success of antipsychotics prompted further research into their mechanism of action with an assumption that such findings would also shed light into the biology and pathophysiology of schizophrenia.