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
The confounding of education with marketing*
(Bulletin 75)
By the dawn of the 21st century there were more than 60 drugs which complied with regulatory requirements of safety and efficacy available in Canada. These included 28 antipsychotic drugs (schizophrenia), 19 antidepressants (depression), nine anxiolytic sedatives (anxiety disorders), three mood stabilizers (bipolar disease), three cognitive enhancers (Alzheimer’s disease) and two central nervous stimulants (attention deficit hyperactivity disorder) (CPS 2004). All of these drugs have proven efficacy by the demonstration of a statistically significant difference (superiority) to an inactive placebo, with a 0.05 or greater level of probability in two randomized clinical trials; known differences between drugs were restricted to side effects.
Generally, it has remained unknown whether any of the drugs in the same pharmacological class would have therapeutic effects different from the others. The observation that responsiveness to a second antidepressant in patients who did not respond to the first medication seemed to be encountered more frequently than what one would have thought could be accounted for by chance was the only indication that the therapeutic profile of at least some of the drugs within the same pharmacological class differed (Ban 2004).
During the 50 years since the first set of psychotropic drugs were introduced there have been major changes in psychiatry: the site of psychiatric practice shifted from psychiatric hospitals to the community; the scope of psychiatry was extended from the psychoses and some neuroses to dimensional anomalies (confounding psychopathology with abnormal psychology); and pharmacotherapy became the primary form of treatment in most psychiatric disorders. By supplying drugs with demonstrated therapeutic efficacy, together with information on their pharmacological profile, the pharmaceutical industry has been a major force in the reintegration of psychiatry with the other medical disciplines. Furthermore, by providing support for research, from genetics through neuropharmacology to brain imaging, the drug industry has been instrumental in establishing psychopharmacology as the dominant paradigm in psychiatry around the world (Ban 2004). Nevertheless, while demonstrating efficacy in consensus-based diagnoses with the employment of behavioral rating scales by the end of the 20th century psychopathology and psychiatric nosology, the two disciplines which seemed to provide a foundation for psychiatry had become “forgotten languages” in psychiatry (Ban 2013). Hence, at the dawn of the 21st century psychiatry lacked the necessary methodology to translate the findings of sophisticated biological measures into clinical effects (Ban 2006).
There were also major changes in the methodology of clinical research in the development of psychotropic drugs during those first 50 years. Single-center isolated clinical studies were, by the end of the 20th century, replaced with multi-center centrally coordinated clinical investigations in which individual contributions became restricted to a small and insignificant proportion of the total sample of collected data. Since findings in these studies provided the evidence base for both the regulatory approval of a drug for clinical use (i.e., distributing – marketing by a drug company) and teaching, at the dawn of the 21st century education in the pharmacotherapy of mental illness had become confounded with the marketing of psychotropic drugs (Ban 2006).
By the time of the introduction of the first set of psychotropic drugs was completed, in the late 1950s, post-Kraepelinian psychiatric research split both diagnosis in Kraepelin’s dichotomy of “endogenous psychoses” into several forms and sub-forms of disease (Kraepelin 1899; Kuhn 1957; Leonhard 1957). The differential responsiveness to the same pharmacological treatment in different patients diagnosed with schizophrenia and in different patients diagnosed with manic-depressive psychosis was in keeping with this development (Astrup 1959).
Despite findings which indicated that some of the forms and sub-forms of disease under the umbrella diagnoses of schizophrenia and manic-depressive psychosis might offer suitable end-points for neuropsychopharmacological research by identifying pharmacologically homogeneous treatment responsive populations, none of these diagnoses were adopted and incorporated either in the Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association, used in North America, or in the International Classification of Mental Disorders of the World Health Organization, used in the rest of the world. This is best illustrated by the dismissal of the diagnosis of “affect-laden paraphrenia,” one of the three forms of “unsystematic schizophrenia” in Karl Leonhard’s classification (Leonhard 1957). In Frank Fish’s study, reported in the mid-1960s, more than four in five patients were found to respond markedly, or at least moderately, to treatment with antipsychotic phenothiazine drugs (Fish 1964). To date, “affect-laden paraphrenia” has remained an idiosyncratic, unvalidated diagnosis.
Instead of pursuing research in psychopathology and psychiatric nosology in the hope that it would resolve the pharmacological heterogeneity within psychiatric diagnoses by identifying pharmacologically homogenous psychiatric populations, a statistical methodology was adopted in the late 1950s that could demonstrate therapeutic efficacy in pharmacologically heterogeneous populations (Ban 1969).
By the mid-1980s there was substantial evidence to believe that adoption of the “methodology” created a deadlock for progress in neuropsychopharmacological research dependent on pharmacologically homogeneous populations. It also blocked progress in the pharmacotherapy of mental illness with psychotropic drugs (Ban 1987).
Whether the development of empirically-derived diagnoses with the employment of psychopathology and psychiatric nosology would have led to the detection of pharmacologically more homogeneous psychiatric populations has remained an open question. Yet, a continuous pharmacological re-evaluation of psychiatric diagnoses, as suggested by Fritz Freyhan in the late 1950s, might have openedthe path for a mutually rewarding interaction between education, with the objective of using psychotropic drugs more discriminately, and marketing, with the objective of prescribing each drug to the widest possible population (Freyhan 1959).
References:
Astrup C. The effects of ataraxic drugs on schizophrenic subgroups related to experimental findings. Acta Psychiatr Scand 1959; 34 (Suppl 136):S388-S93.
Ban TA. Psychopharmacology. Baltimore: Williams and 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 Neuropsychopharmacology and the history of pharmacotherapy in psychiatry. A review of developments in the 20th century. In: Ban TA, Healy D, Shorter E, editors. Reflections on Twentieth-Century Psychopharmacology. 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.
Ban TA. Neuropsychopharmacology and the Forgotten Language of Psychiatry. Madness: From Psychiatry to Neuronology. inhn.org.ebooks. November 14, 2013.
CPS 2004. Compendium of Pharmaceuticals and Specialties. The Canadian Drug Reference for Health Professionals. Ottawa: Canadian Pharmacists Association; 2004.
Freyhan F. Selection of patients from the clinical point of view. In: Cole JO, Gerard RW, editors. Psychopharmacology Problems in Evaluation. Washington: National Academy of Sciences – National Research Council 1959, pp. 372-89.
Kraepelin E. Psychiatrie. Ein Lehrbuch für Studierende und Ärzte. 6 Auflage, Leipzig: Barth; 1899.
Kuhn R. 1957. Über die Behandlung depressives Zustande mit einem iminodibenzyl-derivat (G22355). Schweiz Med Wochenschr 1957; 87: 1135-40.
Leonhard, K. Aufteilung der endogenen Psychosen. Berlin: Akademie Verlag; 1957.
*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).
July 4, 2019