Thomas A. Ban
Neuropsychopharmacology in Historical Perspective
Education in the Field in the Post-Neuropsychopharmacology Era
Background to An Oral History of the First Fifty Years

An Overview of Developments in Psychopharmacology and Neuropsychopharmacology*

(Bulletin 74)

       Psychopharmacology is the scientific discipline that is dedicated to the detection of psychopathologic symptoms and syndromes, and the identification of nosologic entities affected by psychotropic drugs (Ban 1996). The term was coined in 1920 by David Macht, an American pharmacologist, to describe the effects of drugs on psychometric performance tests (Macht 1920).

       The roots of the discipline were in the discovery of Moreau de Tours, a French psychiatrist, in 1845, that the effects of dawamsec, an electuary of hashish, were different in the depressed (melancholic) than in the regressed (aliéné stupide) and in the demented (Morea de Tours 1845). In the 1940s, with the availability of lysergic acid diethylamide, research in psychopharmacology was extended to include the “model psychoses,” with the hope that they would provide the key for the understanding of naturally occurring psychoses and in the 1950s, with the rapidly growing number of psychotropic drugs in the pipelines of the pharmaceutical industry, research in psychopharmacology was further extended to efficacy studies with the new compounds (Ban 2004, 2006).

       Introduction of psychotropic drugs in the 1950s focused attention on the differential responsiveness to the same drug within the same diagnostic category and the pharmacological heterogeneity within the diagnoses created difficulties in demonstrating the therapeutic effectiveness of drugs and prescribing the new drugs in a predictable manner (Ban 1969, 1987). Academic psychiatry was confronted with the need to resolve the heterogeneity within the diagnostic categories by developing a pharmacologically relevant classification of mental illness. But this did not happen. Instead, the randomized clinical trial was adopted for the demonstration of therapeutic efficacy in pharmacologically heterogeneous diagnostic populations (Ban 1986, 2006).

       There are two essential prerequisites for the adoption of a statistical methodology for the demonstration of therapeutic efficacy: rating scales, which can detect and document changes, and diagnostic end-points, which can be reliably identified. It was in response to the need of documenting changes that a German-speaking academic group developed a Manual for the Assessment and Documentation of Psychopathology and William Guy, in the United States, assembled rating scales for the assessment of change and published them in the Early Clinical Drug Evaluation Units Manual (Angst, Battegay, Bente et al. 1969; Guy 1976; Guy and Ban1982).

        The need for diagnostic end points that can reliably be identified was met by the Third Edition of the Diagnostic and Statistical Manual (DSM-III) of the American Psychiatric Association, published in 1980. DSM-III, the first consensus-based classification of mental illness with operationalized diagnostic criteria (American Psychiatric Association 1980).

        The adoption of a statistical methodology in psychiatry for the study of therapeutic efficacy of psychotropic drugs had a major impact on academic psychiatry by providing a means to evaluate   the effectiveness of various treatment modalities. It was on the basis of findings in these evaluations that pharmacotherapy has become the primary form of treatment in schizophrenia and mania in the 1960s; in depression and bipolar disorder in the 1970s; in the anxiety disorders in the 1980s; and in Alzheimer’s type of dementia in the 1990s. As decisions regarding the choice of treatment were to become based increasingly on findings in the clinical development of psychotropic drugs, psychiatric nosology was   replaced by consensus-based classifications and psychopathology by rating scale variables used in the clinical studies conducted for the demonstration of the therapeutic efficacy of a rapidly growing number of new psychotropic drugs. (Ban 2006).

       Introduction of consensus–based classifications, based primarily on Kraepelin’s (1896, 1899) nosology, has created an impasse in resolving the heterogeneity within the diagnostic groups. Since these classifications were developed to reconcile widely different diagnostic formulations with the use of broad diagnostic categories, they covered up component diagnoses. One such component diagnosis is “vital depression” – a form of depression in Kurt Schneider’s  clinical psychopathology that is characterized by “corporization,”  “disturbance of vital balance” and the “feeling of loss of vitality” –  which allowed Roland Kuhn to discover imipramine’s antidepressant effect (Kuhn 1957; Schneider 1920, 1950). This diagnosis is covered up to the extent that even in a severely ill patient who displays all the possible symptoms and signs considered for the DSM-IV-TM  diagnosis of “major depression,” one still would not know whether the patient qualifies for “vital depression” (American Psychiatric Association 1994). Another covered up diagnosis is “affect-laden paraphrenia” – a form of “unsystematic schizophrenia” in Karl Leonhard’s  classification of endogenous psychoses that is   characterized by “paranoid delusions with affective loading and mood swings – in which Frank Fish found that more than 4 in 5 patients responded favorably to antipsychotic phenothiazines (Fish 1964; Leonhard 1957).    

        The sensitized scales introduced for the demonstration of therapeutic efficacy compounded the problems created by consensus-based classifications. Rating scales can be sensitized by the omission of psychopathological symptoms, relevant to psychiatric nosology, which are not influenced by treatment, or by retaining only those items (variables) of a scale, which show the largest changes. While the use of sensitized scales helps to demonstrate therapeutic efficacy  in the shortest possible time in the smallest number of patients, the omission of relevant psychopathological symptoms to psychiatric nosology precludes the possibility of finding by regression analyses any relevant information for the identification of treatment- responsive forms of illness in the data collected in efficacy studies with psychotropic drugs. Since one of the essential prerequisites for the development of neuropsychopharmacology is the identification of a treatment responsive form of illness, consensus-based classifications and sensitized rating scales blocked the development of the combined discipline. By interfering with the development of neuropsychopharmacology, they also precluded the possibility of using psychotropic drugs meaningfully in biological research in psychiatry.

          In neuropsychopharmacology the effect of a psychotropic drug on mental illness is linked with the effect of the substance on brain structures involved in its mode of action. Hence, the detection of the mode of action of a psychotropic drug provides clues about the pathophysiology of the mental syndrome affected by the drug; and the identification of a treatment responsive form of illness to a psychotropic drug with a well-defined mode of action provides clues for the development of a pharmacologically based classification of mental illness. Since the primary targets of psychotropic drugs in the brain, e.g., G-protein coupled receptors, nuclear hormonal receptors, ion channels, enzymes, etc., are all encoded by genes which have been identified, neuropsychopharmacology can provide important leads for the generation of hypotheses relevant to the genetics of mental illness (Ban 2002). Furthermore, since neuropsychopharmacology links the mode of action of a drug with a distinct mental syndrome, neuropsychopharmacological research can provide important orientation points  for the rational development of clinically more selective and thereby more effective psychotropic drugs.

        Until the mode of action of psychotropic drugs is linked to pharmacologically heterogeneous populations, the feedback from psychopharmacological to neuropsychopharmacological research will remain relevant only to adverse effects. Without the necessary clinical orientation points, drugs to be developed for psychiatric indications will be selected on pharmacological screens by showing similar pharmacodynamics properties to already available antipsychotic, antidepressant, anxiolytic, etc., drug  (Healy1997, 2002).

References:

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders Fourth Edition DSM-III. Washington: American Psychiatric Association; 1980.

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders Fourth Edition DSM-IV^TM. Washington: American Psychiatric Association; 1994.

Angst J, Battegay R, Bente D, Berner P, Broerer W, Cornu F et al. The Documentation system of the Association for Methodology and Documentation in Psychiatry (AMP). Arzneim Forsch 1969; 19: 399 – 405.

Ban TA. Psychopharmacology. Baltimore: Williams & Wilkins; 1969.

Ban TA. Prolegomenon to the clinical prerequisite; psychopharmacology and the classification of mental disorders. Progress in Neuro-Psychopharmacology and Biological Psychiatry 1987; 11: 527-80.

Ban TA. They used to call it psychiatry. In Healy D, editor. The Psychopharmacologists. London: Chapman and Hill; 1996, 587 – 620.

Ban TA. Neuropsychopharmacology: the interface between genetics and psychiatric nosology. In Lerer B, editor. Pharmacogenetics of Psychotropic Drugs. Cambridge: Cambridge University Press; 2002, pp. 36 – 56. 

Ban TA. Neuropsychopharmacology and the history of pharmacotherapy in psychiatry. A  review of developments in the 20h century. In Ban TA, Healy D, Shorter E, editors. A Review of Developments in the 20^th Century. Budapest: Animula; 2004, pp. 697 – 720.

Ban TA. Academic psychiatry and the pharmaceutical industry. Progress in Biological Psychiatry and Neuro – Psychopharmacology and Biological Psychiatry 2006; 30: 429 -43.

Fish F. The influence of the tranquilizer on the Leonhard schizophrenic syndromes. Ecephale1964; 53: 245: 245-9.

Guy W. ECDEU Assessment Manual for Psychopharmacology. Rockville: National Institute of Mental Health Government Printing Office; 1976.  

Guy W, Ban TA., editors and translators. The AMDP System Manual for the Assessment and Documentation of Psychopathology. Berlin: Springer; 1982.

Healy D. The Antidepressant Era. Cambridge: Harvard University Press; 1997.

Healy D. The Creation of Psychopharmacology. Cambridge: Harvard University Press; 2002.

Kraepelin E.  Ein Lehrbuch fuer Studierende und Aerzte. 5 Auflage. Leipzig: Barth; 1896.

Kraepelin E.  Ein Lehrbuch fuer Studierende und Aerzte. 6 Auflage. Leipzig: Barth; 1899.

Kuhn R. Ueber die Behandlung depressives Zustaende mit einem aminodibenzyl-derivat (G22355). Schweiz Med Wochenschrift 1957; 87: 1135-40.  

Leonhard K. Die Aufteilung der endogenen  Psychosen. Berlin: AkademieVerlag; 1957.   

Macht DL. Contributions to psychopharmacology. Bull Johns Hopkins Hosp 1920; 31: 167–73.

Schneider K. Die Schichtung des emotionalen  Lebens und der Aufbau deer Depressionszustaende. Z Ges Neurol Psychiatr 1920; 59; 281-5.

Schneider K. Klinische Psychopathologie. 3 Auflage. Stuttgar: Thme; 1950.

*Based on Thomas A. Ban’s Academic Psychiatry and the Pharmaceutical Industry, published in Progress in Neuro-Psychopharmacology and  Biological Psychiatry (2006; 30: 429-43).

June 27, 2019