Neuropsychopharmacology and the Forgotten Language of Psychiatry Madness: From Psychiatry to Neuronology via Neuropsychopharmacology.

This is an outline of a period in the history of "madness." It begins in the mid-19th century with the separation of the diagnostic concept of "psychosis" from the all-embracing diagnostic concept of "neurosis", and the discovery of "psychic refl ex" that was to become known as "conditional reflex." It continues with the development of the language of psychiatry, in "psychopathology" and "psychiatricnosology:" during the late-19th and early 20th century; the forgetting of the "language' by the late 1980s, and the revival of the language in the introduction of "structural psychopathology" and assessment instruments as the Diagnostic Criteria of Research (DCR) and Composite Diagnostic Evaluations (CODE), subsequently. The need for "nosological homotyping" is considered for the generation of pharmacologically homogenous psychiatric populations for neuropsychopharmacological research and the possibility of using "structural psychopathology" for linking mental pathology with conditional refl ex variables is raised. The outline concludes with the assertion that in the light of developments, time has come to replace the term "psychiatry" with the term "neuronology." (Neuropsychopharmacol Hung 2021; 23(2): 249-265).

A clinimetric analysis of a BPRS-6 scale for schizophrenia severity.

OBJECTIVE: A restricted Brief Psychiatric Rating Scale (BPRS-6) with the six schizophrenia specific items from the Positive and Negative Syndrome Scale (PANSS) has been investigated. These six items from the PANSS have recently been found to have both clinical validity and 'unidimensionality' in measuring the severity of schizophrenic states. The primary objective of this study was to evaluate the clinical validity of the BPRS-6. The secondary objective was to evaluate the 'unidimensionality' of the BPRS-6 by an 'item response theory' model. METHODS: The BPRS-6 was scored independently by two psychiatrists and two psychologists while viewing six open-ended videotaped interviews in patients with a DSM-III diagnosis of schizophrenia. The interviews were conducted by Heinz E. Lehmann, an experienced psychiatrist. They were focused on the psychopathology that contributed most to the 'severity' of the patient's clinical state. RESULTS: The BPRS-6 with three positive symptoms (delusions, conceptual disorganisation, hallucinations) and three negative symptoms (blunted affect, emotional withdrawal, poverty of speech) was found to be clinically valid and captured the variables that contribute most to the severity of schizophrenia. The BPRS-6 was also found to have acceptable 'unidimensionality' (coefficient of homogeneity 0.45) and inter-rater reliability (inter-class-coefficient 0.81). CONCLUSION: The BPRS-6 was found to capture the information that translates into the severity of schizophrenia. It has also acceptable psychometric validity.

A short historical review of SCNP with special reference to the UKU.

OBJECTIVE: To give a review of the history of SCNP since the first meeting in 1960 with specific focus on UKU. METHODS: Consulting the appropriate minutes from the meetings. RESULTS: One of the major goals of the SCNP was the standardization of clinical trials with psychotropic drugs. In 1969, the SCNP established a Committee for Clinical Investigations (UKU) with the representation of clinical investigators and the drug industry; moreover, during the 1970s and '80s, the UKU initiated clinical trials and contributed to the methodology of clinical investigations with psychotropic drugs. With the decrease in governmental funding and increasing influence of the US Food and Drug Administration on the methodology of clinical investigations around the world in the 1990s, the UKU was dissolved. The changes had a detrimental effect on the developments on the methodology of clinical investigations, and the lack of clinical feedback led to an impasse in psychotropic drug development with some pharmaceutical companies abandoning research in the central nervous system area. CONCLUSION: It is suggested that a revival of UKU to provide a platform for dialogue among government, industry, and academia could help break the impasse.

Wernicke-Kleist-Leonhard phenotypes of endogenous psychoses: a review of their validity
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While the ICD-DSM paradigm has been a major advance in clinical psychiatry, its usefulness for biological psychiatry is debated. By defining consensus-based disorders rather than empirically driven phenotypes, consensus classifications were not an implementation of the biomedical paradigm. In the field of endogenous psychoses, the Wernicke-Kleist-Leonhard (WKL) pathway has optimized the descriptions of 35 major phenotypes using common medical heuristics on lifelong diachronic observations. Regarding their construct validity, WKL phenotypes have good reliability and predictive and face validity. WKL phenotypes come with remarkable evidence for differential validity on age of onset, familiality, pregnancy complications, precipitating factors, and treatment response. Most impressive is the replicated separation of high- and low-familiality phenotypes. Created in the purest tradition of the biomedical paradigm, the WKL phenotypes deserve to be contrasted as credible alternatives with other approaches currently under discussion.
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Towards a clinical methodology for neuropsychopharmacological research.

Neuropsychopharmacology is dedicated to the study of the pathophysiology and treatment of mental pathology with the employment of centrally acting drugs. In neuropsychopharmacological research the clinical effects of a psychotropic drug are linked to the effects of the substance on brain structures involved in its mode of action. It is assumed, that knowledge about the mode of action of a selectively effective psychotropic drug will provide clues about the pathophysiology of the illness, and conversely, that knowledge about the pathophysiology of an illness, will provide clues for developing clinically more effective psychotropic drugs. Since the currently employed clinical methodology for the demonstration of therapeutic efficacy links the mode of action of psychotropic drugs to pharmacologically heterogeneous populations, neuropsychopharmacological research does not provide the necessary feedback for developing more effective drugs. To resolve the pharmacological heterogeneity within currently used diagnoses, attempts were made to split syndrome-based psychiatric diagnoses into discrete neurobiological deficits, and to replace traditional psychiatric nosology by a genetic psychiatric nosology. Yet, to date, there is no alternative methodology to psychopathology-based psychiatric nosology for classifying mental pathology in a clinically relevant manner. As we are moving from the "neurotransmitter era" to a "genetic era" in neuropsychopharmacology, the need for identifying pharmacologically homogenous populations is becoming imminent. All primary targets of psychotropic drugs in the brain are encoded by genes which are identified, and any nosologic entity or psychiatric syndrome that corresponds with a treatment responsive population is a candidate for the generation of genetic hypotheses relevant to mental illness. Recognition that progress in neuropsychopharmacology, and molecular genetic research, depends on the speed clinical research can resolve the pharmacological heterogeneity within currently used diagnoses, led to the development of methodologies for the identification of treatment responsive form(s) of illness, such as the Composite Diagnostic Evaluation (CODE) System, and nosologic homotyping. The CODE System is a methodology for the identification of treatment responsive forms of illness if covered up by consensus-based diagnoses; it consists of a set of diagnostic algorithms that can assign simultaneously a diagnosis from several classifications to a patient. Nosologic homotypes are identical in elementary units of mental illness and are assigned the same position in the nosologic matrix, based on three "nosologic organizing principles. The empirically derived diagnostic categories are suitable for testing hypotheses relevant to the relationship between the "processing of mental events" and "signal transduction" in the central nervous system.

Academic psychiatry and the pharmaceutical industry.

In the second half of the 19th century new drugs introduced by the pharmaceutical industry helped lead to the establishment of academic departments in psychiatry. Causal treatment of cerebral pellagra by nicotinic acid and cerebral syphilis by penicillin in the first half of the 20th century led to major changes in the diagnostic distribution of psychiatric patients. In the second half of the 20th century with the introduction of a rapidly growing number of psychotropic drugs, pharmacotherapy became the primary form of treatment in mental illness. Psychiatrists today perceive neuropharmacology as one of the basic sciences of psychiatry and psychopharmacology as the bridge between the mode of action and the clinical indications of psychotropic drugs. Pharmacotherapy with psychotropic drugs focused attention on the differential responsiveness to the same drug within the same diagnostic category. Yet, instead of re-evaluating psychiatric nosology and conducting research in psychopathology, a statistical methodology was adopted for the demonstration of therapeutic effectiveness in pharmacologically heterogeneous populations. Employment of consensus-based classifications and psychiatric rating scales in the clinical development of psychotropic drugs led to semi-finished products, which are prescribed indiscriminately. Replacement of single-center clinical trials by multi-center centrally coordinated clinical investigations led to the control of education in pharmacotherapy by the pharmaceutical industry. To separate education from marketing, the identification of the treatment-responsive forms of illness and the delineation of the therapeutic profile of psychotropic drugs are proposed with the employment of a new methodology, the "Composite Diagnostic Evaluation System." It is postulated that development of a pharmacologically valid psychiatric nosology with the employment of a "nosologic matrix" would provide the pharmaceutical industry with the necessary feedback to develop clinically selective drugs in mental illness and to break the impasse of progress in "translational research" in psychiatry.

A history of the Collegium Internationale Neuro-Psychopharmacologicum (1957-2004).

Recognition that one of the essential prerequisites of successful neuro-psychopharmacological research is a continuous dialogue between clinicians and basic scientists led to the founding of the Collegium Internationale Neuro-Psychopharmacologicum (CINP) in Zurich on September 2, 1957. At the time, CINP was the only association in neuro-psychopharmacology. It was hoped that by organizing biennial congresses, it would facilitate the interaction among the many disciplines involved in the new field. It was also envisaged that discussion of findings in translational research would provide guidance for developing more selective and thereby more effective psychotropic drugs. These expectations were not fulfilled. In the years that followed, major developments in neuropharmacology without parallel development in the methodology of clinical investigations, created a widening gap between neuro- and psychopharmacology. Clinical interpretations of neuropharmacological findings filled in the missing information from translational research. In the 1980s, to facilitate the dissemination of these interpretations, CINP established Travel Awards for Young Investigators to assist them in attending the biennial meetings. In the 1990s, the college extended its activities by organizing other meetings, including president's workshops, regional meetings, educational seminars and other programs. By the end of the 20th century CINP was a legal entity that was registered in Switzerland with domicile in Zurich. It had also become a financially secure organization with sufficient funds to support administration and coordination. In the early years of the 21st century CINP established a central office and a congress-organizing group. To meet the needs of its steadily growing membership from Asia, Australia and the Latin Americas, CINP has been regionalized. In order to regain its relevance to all its members it is hoped that CINP will return to its roots.

The role of serendipity in drug discovery.

Serendipity is one of the many factors that may contribute to drug discovery. It has played a role in the discovery of prototype psychotropic drugs that led to modern pharmacological treatment in psychiatry. It has also played a role in the discovery of several drugs that have had an impact on the development of psychiatry. "Serendipity" in drug discovery implies the finding of one thing while looking for something else. This was the case in six of the twelve serendipitous discoveries reviewed in this paper, i.e., aniline purple, penicillin, lysergic acid diethylamide, meprobamate, chlorpromazine, and imipramine. In the case of three drugs, i.e., potassium bromide, chloral hydrate, and lithium, the discovery was serendipitous because an utterly false rationale led to correct empirical results; and in case of two others, i.e., iproniazid and sildenafil, because valuable indications were found for these drugs which were not initially those sought The discovery of one of the twelve drugs, chlordiazepoxide, was sheer luck.

Neuropsychopharmacology and the genetics of schizophrenia: a history of the diagnosis of schizophrenia.

Development of the diagnostic concept of schizophrenia (dementia praecox) is traced from the fourth edition of [Kraepelin, E., 1893. Ein Kurzes Lehrbuch der Psychiatrie. 4 Aufl. Barth, Lepzig] textbook to the DSM-IV [American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders. Fourth ed. American Psychiatric Association, Washington, 273-316]. The differences between the criteria used by Bleuler [Bleuler, E., 1911. Dementia Praecox oder Gruppe der Schizophrenien. Deuticke, Leipzig] and Schneider [Fortschr. Neurol. Psychiatr. 25 (1957) 487] in the diagnosis of schizophrenia are discussed. The nosologic contributions of Kleist [Klin. Wochenschr. 2 (1923) 962] and Leonhard [Leonhard, K., 1957. Aufteilung der endogenen Psychosen. Akademie, Berlin]--which split schizophrenia into two major classes of disease with several forms and subforms--are outlined. Epidemiological findings--which show wide variations in the prevalence of schizophrenia in the general population and in the admission rate of schizophrenics to psychiatric clinics--are presented. Findings in genetic studies are reviewed with special reference to family, twin, and adoption studies which have raised the possibility that heredity plays an important role in the etiology of schizophrenia; mathematical analyses are examined which have ruled out monogenic transmission, as well as molecular genetic investigations indicating that the schizophrenic population is genetically heterogeneous. The relevance of findings with endophenotypes to the genetics of schizophrenia is questioned. The history of pharmacotherapy, neuropharmacology, and psychopharmacology of schizophrenia is outlined. Attention is focused on findings which indicate that the schizophrenic population is pharmacologically heterogenous. It is emphasized that neuropsychopharmacology, through its unique capability of linking the effects of psychotropic drugs to brain structures--encoded by genes which have been identified--offers a pioneering methodology for bridging the gap between the genes and psychiatric nosology. It is pointed out that for the detection of subpopulations within schizophrenia, clinical investigations with antipsychotic drugs have to proceed beyond the demonstration of therapeutic efficacy to the identification of treatment-responsive form(s) of illness. Early findings by Fish [L'Encephale 53 (1964) 245] are presented which indicate that affect-laden paraphrenia, one of the three forms of unsystematic schizophrenia in Leonhard [Leonhard, K., 1957. Aufteilung der endogenen Psychosen. Akademie, Berlin] classification, is the treatment-responsive subpopulation within schizophrenia for typical antipsychotic drugs. It is suggested that if the findings of Fish [L'Encephale 53 (1964) 245] could be verified, affect-laden paraphrenia would qualify for molecular genetic research. Another possible subpopulation that might qualify for genetic research is systematic hebephrenia, one of the three forms of systematic hebephrenia. The paper concludes that resolving the heterogeneity of the schizophrenic population would open up a new perspective for genetic research and for the pharmacotherapy of the different illnesses covered up for a century by the diagnostic label of schizophrenia.

Fifty years chlorpromazine: a historical perspective.

Chlorpromazine was synthesized in December 1951 in the laboratories of Rhône-Poiulenc, and became available on prescription in France in November 1952. Its effectiveness was reflected in the transformation of disturbed wards; its commercial success stimulated the development of other psychotropic drugs. Recognition of chemical mediation at the site of the synapse, followed by the introduction of the spectrophotofluorimeter first, and receptor assays subsequently, led to the demonstration that chlorpromazine blocks dopamine receptors. Treatment with chlorpromazine focused attention on the heterogeneity of schizophrenia in terms of responsiveness to treatment. By the mid-1980s there was sufficient evidence to believe that resolving this heterogeneity is a prerequisite for developing more effective treatments. Chlorpromazine was instrumental in the development of neuropsychopharmacology, a new discipline dedicated to the study of mental pathology with the employment of centrally acting drugs.

In memory of three pioneers.

During the past 6 months three major figures in the history of psychopharmacology passed away: Leo Sternbach, Mogens Schou and Roland Kuhn. The historical contributions of these pioneers opened the path for the development that has led to the current state of the art in pharmacological treatment in psychiatry.

Aspectos nosológicos, genéticos, neurobiológicos y psicofarmacológicos de la esquizofrenia / Nosology, genetics, neurobiology and psychopharmacology of schizophrenia

Se delinea el desarrollo de la nosologia psiquiátrica y se proponen cinco principios para organizar los síntomas psicopatológicos en trastornos psiquiátricos. Centro del marco de referencia de los principios organizativos de la nosología, se pasa revista a la evolución y disolución del concepto unitario de esquizofrenia para discutir, luego, ciertos hallazgos ocurridos en estudios de validación, tanto neurobiológica como genética y psicofarmacológica. Se hace hincapié en que determinados hallazgos (comprobados en estudioso de genética familiar e investigaciones de psicofarmacología clínica) respaldan la opinión de Leonhard (1957) que postulaba que la esquizofrenia sistemática y la no sistemática constituyen dos poblaciones distintas

Nosology in the teaching of psychiatry

Nosologia é a disciplina científica que lida com o estudo dos princípios organizadores empregados na classificaçäo de doenças. Neste artigo os três princípios organizadores primários das doenças mentais (curso e evoluçäo; desenvolvimento vs. processo; polaridade) e os dois secundários (organizaçäo espacial; totalidade) säo apresentados e revistos. A introduçäo de medicamentos com eficácia terapêutica resultou na substituiçäo do modelo psicopatógico da doença mental pelo biológico. Dentro do novo esquema de referência biológico as entidades nosológicas säo vistas como estruturas distintas determinadas pelos estágios de desenvolvimento de diferentes doenças psiquiátricas. De modo diferente da abordagem analítica psicioatológicos e suas apresentaçöes, o modelo nosológico é holístico e baseado na identificaçäo de princípios de organizaçäo da doença mental, primários e secundários. As categorias de doenças identificadas pelo emprego dos princípios de organizaçäo primária e secundária correspondem as entidades de doenças identificadas pela abordagem psicopatlógica tradicional; enquanto que os marcos fornecidos para os estudos dos mecanismos subjacentes às diferentes condiçöes diferem

Aspectos nosológicos, genéticos, neurobiológicos y psicofarmacológicos de la esquizofrenia / Nosology, genetics, neurobiology and psychopharmacology of schizophrenia

Se delinea el desarrollo de la nosologia psiquiátrica y se proponen cinco principios para organizar los síntomas psicopatológicos en trastornos psiquiátricos. Centro del marco de referencia de los principios organizativos de la nosología, se pasa revista a la evolución y disolución del concepto unitario de esquizofrenia para discutir, luego, ciertos hallazgos ocurridos en estudios de validación, tanto neurobiológica como genética y psicofarmacológica. Se hace hincapié en que determinados hallazgos (comprobados en estudioso de genética familiar e investigaciones de psicofarmacología clínica) respaldan la opinión de Leonhard (1957) que postulaba que la esquizofrenia sistemática y la no sistemática constituyen dos poblaciones distintas (AU)

Nosologia no ensino da psiquiatria

Nosologia e a sisciplina cientifica que lida com o estudo dos principios organizadores empregados na classificacao de doencas. Neste artigo os tres principios organizadores primarios das doencas mentais (curso e evolucao;desenvolvimento vs. processo; polaridade) e os dois secundarios(organizacao espacial; totalidade) sao apresentados e revistos. A introducao de medicamentos com eficacia terapeutica resultou na substituicao do modelo psicopatologico da doenca mental pelo biologico. Dentro do novo esquema de referencia biologico as entidades nosologicas sao vistas como estruturas distintas determinadas pelos estagios de desenvolvimento de diferentes doencas psiquiatricas. De modo diferente da abordagem analitica psicopatologica que e baseada na deteccao de sintomas patologicos e suas apresentacoes, o modelo nosologico e holistico e baseado na identificacao de principios de organizacao da doenca mental, primarios e secundarios. As categorias de doencas identificadas pelo emprego dos principais principios de organizacao primaria e secundaria correspondem as entidades doencas identificadas pela abordagem psicopatologica tradicional; enquanto que os marcos fornecidos para os estudos dos mecanismos subjacentes as diferentes condicoes diferem.