History of the discovery of the antipsychotic dopamine D2 receptor: a basis for the dopamine hypothesis of schizophrenia.

The 1975 publication of Seeman et al. (Proc Nat Acad Sci, USA), reporting the discovery of the antipsychotic receptor in the brain, is a classic example of translational medicine research. In searching for a pathophysiological mechanism of psychosis, the team sought to identify sites that bound the antipsychotic drug haloperidol. Their criterion was that haloperidol bound to the site at one to two nanomoles per liter, corresponding to haloperidol concentrations found in spinal fluid or plasma water in treated patients. They requested de novo synthesis of tritiated haloperidol, and it readily detected specific haloperidol binding sites in brain striatum. With dopamine binding the haloperidol-labeled sites with higher potency than other neurotransmitters, the sites were named antipsychotic/dopamine receptors (now designated dopamine D2 receptors). Most significantly, they found that all antipsychotics bound these sites at concentrations and with a rank order of potencies that were directly related to the mean daily antipsychotic dose taken by patients with schizophrenia. Their findings enabled screening for new antipsychotics, initiated D2 receptor measurements in brain of living patients, and determination of minimum occupancy (65%) of D2 receptors for antipsychotic benefit. The collective work is generally viewed as providing a fundamental basis for the dopamine hypothesis of schizophrenia.

CNS drug development. Part I: The early period of CNS drugs.

This column begins a new series on central nervous system (CNS) drug development. This series will review developments up to the present day and end with a forward-looking perspective on what to expect over the next 10-20 years. The goal of this series is to explain to practicing clinicians how drugs are developed and why CNS drug development is at an important juncture involving both significant challenges and opportunities. This column (Part 1) reviews the history of CNS drug development from the period before written history through the golden era (i.e., late 1940s-early 1960s) in which the first modern medications for anxiety, bipolar, depressive, and psychotic disorders were discovered by chance. It also describes the early era of rational drug development in which other agents (e.g., thioridazine, fluphenazine, haloperidol, imipramine) were developed based on those first agents. The blueprint laid down for development of antibiotics is reviewed in relation to its impact on CNS drug development. The impact of the blockbuster business model and modern marketing/sales approaches on CNS drug development is also discussed.

The consolidation of neuroleptic therapy: Janssen, the discovery of haloperidol and its introduction into clinical practice.

The discovery of haloperidol at the end of the 1950s constitutes one of the greatest advances of 20th century psychiatry. This antipsychotic drug has their origin in the research process of central analgesic molecules derived from pethidine and methadone, carried out by the Belgian company Janssen Phamaceutica. After the synthesis of phenoperidine, numerous analogues of this compound were studied, and chemists at Janssen took the decision to substitute the propiophenone group for a butyrophenone group. One of these compounds went the R-1625, a stronger agent with specifically neuroleptic properties but lacking morphine-like activity. This substance was synthesized on the 11th February 1958 and received the generic name of haloperidol because of the two halogenated substitutes incorporated into the molecule. Clinical development of haloperidol was conducted, primarily, by psychiatric research team at the University of Liège that confirmed its efficacy in the treatment of various psychiatric disorders such as acute and chronic paranoid psychosis, mania, or chronic treatment-resistant schizophrenia. Under the brand name Haldol((R)), haloperidol was licensed and marketed in Belgium in October 1959. The direct and differed consequences of its introduction into the psychiatric practice have been multiple, involving different areas of socio-sanitary reality. Moreover, haloperidol has contributed substantially to the development of biological psychiatry and currently neuroscience, because it made possible the development of new experimental models for predicting the effects of antipsychotics, and allowed the postulate of the firsts biological hypotheses about the schizophrenia etiology. Haloperidol has been included in the World Health Organisation's list of essential medicines.

Forty years of antipsychotic Drug research--from haloperidol to paliperidone--with Dr. Paul Janssen.

The authors describe 40 years of antipsychotic drug research with Dr. Paul Janssen, which they have witnessed for a large part from first hand experience. The article describes the start of the Janssen Research and its early successes with antispasmodics and analgesics. The discovery of haloperidol followed from a serendipitous transition from analgesics to antipsychotics and culminated with the historical International Symposium on Haloperidol that was held in Beerse (Belgium) in 1959. The concept of the central role of dopamine receptor binding in schizophrenia has played a decisive part in focusing the Janssen Research on antipsychotics. Paul Janssen did not rest with haloperidol (CAS 52-68-8), but expanded it into the family of butyrophenone antipsychotics, using Haase's handwriting test to clinically characterize the analogues. The emerging significance of serotonin antagonism in schizophrenia is discussed in the light of the discovery of pipamperone (CAS 1893-33-0), a forerunner of the modern so-called atypical neuroleptics. Continued research produced a novel chemical family of neuroleptics, exemplified by pimozide (CAS 2062-78-4) and fluspirilene (CAS 1841-19-6), and yielded selective serotonin 5HT2-antagonists. This research ultimately led to the discovery of risperidone (CAS 106266-06-2) and paliperidone (CAS 144598-75-4), compounds with inbuilt dopamine and serotonin antagonism. The authors discuss the lack of inhibition as a common trait of stereotyped behaviour in schizophrenia and the means of determining it by means of a computerized version of Bente's button press test. Finally the appropriate use of antipsychotics for optimal therapeutic result with minimal side effects is advocated.

Psicofarmacología: una aproximación histórica / Psychopharmacology: a historical approach

La psicofarmacología puede definirse como una disciplina cien-tífica centrada en el estudio de los fármacos que modifican el comportamiento y la función mental a través de su acción sobre el sistema neuroendocrino. Se trata de un campo del saber que tiene un marcado carácter multidisciplinario, al agrupar el interés que comparten farmacólogos, bioquímicos, psiquiatras y psicólogos por el análisis de las sustancias que actúan modificando las funciones del sistema nervioso que se manifiestan en la conducta de los individuos. A lo largo de esta revisión teórica se realiza un análisis conceptual de la psicofarmacología y se revisan los principales acontecimientos históricos que han marcado el curso de la disciplina, destacando los descubrimientos más relevantes que se han sucedido en ámbitos como la práctica clínica psiquiátrica, la investigación farmacológica de laboratorio, y los estudios conductuales realizados con animales y seres humanos

Psychopharmacology can be defined as a scientific discipline that studies drugs able to modify the behaviour and the mental function through its action on the neuroendocrine system. Pharmacology, biochemistry, psychiatry and psychology share their interest for this multidisciplinary field of knowledge, devoted to the analysis of the substances that alter those functions of the nervous system that are shown on the organism’s behaviour. This paper reviews the theoretical concept of psychopharmacology, and the main historical events that occurred in clinical psychiatry, laboratory pharmacological research, and behavioural studies conducted in both animals and human beings

The haloperidol story.

Haloperidol was synthesized on the 11th of February 1958 at the Janssen Laboratories, in Belgium. Soon after its synthesis and animal studies, which suggested to Paul Janssen and his colleagues that this butyrophenone drug would be of great interest as its action was similar but much more powerful than that of chlorpromazine, haloperidol was administered to humans at the Liege hospital. The subsequent clinical studies confirmed that this new drug was particularly active against delusions and hallucinations. The introduction of haloperidol in the United States of America was difficult for clinical and legal reasons. For many years, haloperidol had been widely used in western countries, until the introduction of "new antipsychotics."

[The discovery of haloperidol]. / La découverte de l'halopéridol.

Haloperidol was synthesized on the 11th of February 1958 by Bert Hermans at the Janssen Laboratories, Beerse, Belgium. Simple but ingenuous methods of animal pharmacology suggested to Paul Janssen and his collegues that this butyrophenone derivative, called R1625, then halop-peridol, would be of great interest: qualitatively, the pharmacological action of R1625 was similar to chlorpromazine, but R1625 was very more powerful since it produced effects with much smaller doses than chlorpromazine. Soon after the synthesis and animal studies, haloperidol was administered in humans by Divry, Bobon et Collard, psychiatrists at the Liege Hospital. The first clinical publication, on the 28th of October, 1958, described the effects of haloperidol in agitation states. The subsequent clinical studies, including those of the prestigious French school of Sainte-Anne hospital, confirmed that haloperidol belongs to the pharmacological family of neuroleptics, as it was defined by J. Delay and P. Deniker in 1955. These clinical studies demonstrated also that haloperidol was particularly active against delusions and hallucinations. Numbers of chronically inpatients were able to leave hospital and to live home thanks to this new drug, which remains one of the more prescribed neuroleptics 40 years after its discovery.

Seignot's paper on the treatment of Tourette's syndrome with haloperidol. Classic Text No. 31

The paper of Seignot in 1961 is the first clinical description of the use of haloperidol to treat the symptoms of Gilles de la Tourette syndrome (GTS). It is widely quoted in literature about GTS. However, it is not widely known that the single case involved had been subject to a frontal lobectomy prior to treatment with haloperidol. We present a translation of that paper and a discussion of its significance.

Historias de las butirofenonas / History of butyrophenones

Se relata cómo ocurrió el hallazgo de la fórmula de las butirofenonas y la síntesis de la droga "R-1625"' que se denominó después haloperidol. Se hace una breve descripción de su difusión en Europa y las dificultades que surgieron cuando se usó por primera vez en Norteamérica. Se describen sus principales propiedades y efectos secundarios y se trata, además, de dos derivados difenilpiperidínicos: el fluspirileno y la pimocida

Historias de las butirofenonas / History of butyrophenones

Se relata cómo ocurrió el hallazgo de la fórmula de las butirofenonas y la síntesis de la droga "R-1625"' que se denominó después haloperidol. Se hace una breve descripción de su difusión en Europa y las dificultades que surgieron cuando se usó por primera vez en Norteamérica. Se describen sus principales propiedades y efectos secundarios y se trata, además, de dos derivados difenilpiperidínicos: el fluspirileno y la pimocida

[Tics: from Itard to the neuroleptics]. / La maladie des tics: d'Itard aux neuroleptiques.

When the six DSM-III (1980) diagnostic criteria are applied to the nine cases reported by Gilles de la Tourette in 1885, six of them are found to be in accordance with the diagnosis of Gilles de la Tourette's syndrome (cases nos 4, 5 and 7 do not involve vocal tics). Gilles de la Tourette deserves credit, not only for having regrouped fragmented observations into one remarkably well described clinical entity which held over time (such as Itard's observations nos 9 and 10 in 1825; the latter is the famous Marquise of D ... seen several times by Charcot and the only one which, along with no 1, appears in Gilles de la Tourette's paper), but also for having described the course of this chronic and fluctuating disease. Why Gilles de la Tourette did not use the term "tic", a term which had been in use for a long time in both veterinary and human medicine, to describe "the motor incoordination" of these patients? Did Charcot take some distance from his student's paper as early as 1885? He viewed tics as the basis of "the disease described by Gilles de la Tourette". In addition to coprolalia and echolalia, he alsa reported the existence of "mental tics". How have French neurologists and psychiatrists been able to perpetuate Brissaud's error who, contrary to Gilles de la Tourette, mentioned that the illness "can be associated with severe mental disorders which often lead to dementia"?(ABSTRACT TRUNCATED AT 250 WORDS)

Haloperidol: a quarter century of experience.

Research on haloperidol's pharmacokinetics, side effects, indications, and efficacy is reviewed. Issues related to high-dose therapy, rapid neuroleptization, intravenous administration, use in geriatric patients, and coadministration with lithium in mania are discussed. Overall, 25 years of experience have indicated that haloperidol can be used safely and effectively to manage a variety of psychiatric illnesses, so long as dosage and method of administration are adjusted to individual patients' needs. Research continues on the use of this drug, not only in psychiatry but in several other areas of medical practice.