Thomas A. Ban: In historical perspective: Peralta, Cuesta and their associates’ findings on the highest familiality of Leonhard’s classification in polynosologic study  

The first reports on effective drugs for the treatment of “endogenous psychoses” were published in the mid-20th century: lithium, in 1949 by John Cade, for mania; chlorpromazine, in 1952 by Jean Delay and Pierre Deniker, for schizophrenia; and imipramine, in 1957 by Roland Kuhn, for endogenous depression. Treatment with these drugs focused attention on the pharmacological heterogeneity within the diagnoses derived by Kraepelin’s (1909-15) nosology. The heterogeneity in pharmacological response within Kraepelinian diagnoses was to the extent that it compromised the discriminate use of these drugs.

In 1957, the same year Kuhn discovered the therapeutic effect of imipramine in patients with endogenous depression, Karl Leonhard (1957) published his Classification of Endogenous Psychoses. In Leonhard’s classification, Kraepelin’s dichotomy of endogenous psychoses into dementia praecox and manic depressive psychosis, was broken into four classes of disease displayed (manifested) in 35 forms and sub-forms. The signal difference between Kraepelin’s nosology and Leonhard’s was that in Kraepelin’s, diagnoses were derived by course and outcome of clinical manifestations (psyhopathology) exclusively, whereas in Leonhard’s, other factors, such as holistic features (simple or multiform), polarity (unipolar or bipolar) and elementary (dominant) symptoms, were also taken into consideration.

In 1959, two years after Leonhard’s nosology was introduced, Christian Astrup observed that by splitting Kraepelin’s dementia preacox (schizophrenia) into two classes of disease, unsystematic schizophrenia and systematic schizophrenia, Leonhard provided in unsystematic schizophrenia, a pharmacologically more homogeneous population, as measured by favorable response to treatment with chlorpromazine-type of drugs, than the population of Kraepelin’s dementia praecox.

Astrup’s (1959) observations were further substantiated by Frank Fish (1964). In a study with 474 chronic schizophrenic patients, Fish (1964) found that unsystematic schizophrenia provided a pharmacologically more homogeneous population with a 95% overall response rate in 123 patients than systematic schizophrenia (79% overall response rate in 351 patients). By counting those within the treatment responsive populations with a marked to moderate response, the difference in pharmacological homogeneity between the two populations became more pronounced: 95% in the 123 treatment responsive patients with unsystematic schizophrenia and 23% response in the 351 patients with systematic schizophrenia. Fish’s findings, published in 1964, had shown that employment of Leonhard’s diagnoses provided a pharmacologically more homogeneous population in unsystematic schizophrenia than Kraepelin’s dementia praecox. Yet, Leonhard’s classification remained outside the mainstream of psychiatry and diagnoses continued to be based on Kraepelin’s nosology, until they were replaced by consensus-based diagnoses, in the 1980’s (American Psychiatric Association 1980).

In 1957, also in the same year that Kuhn discovered imipramine’s therapeutic effect in endogenous depression and Leonhard introduced his classification, Abraham Wikler published his text on The Relation of Psychiatry to Pharmacology. In his monograph, Wikler raised the possibility that from studying the mode of action of psychotropic drugs with known clinical effects, one might be able to deduce information relevant to the biochemical underpinning of mental disorders. By generating such information, it was envisaged that research in the biology of psychiatric illness will become a driving force for rational drug development (Ban 2011).

Since the introduction of the first set of therapeutically effective psychotropic drugs, half a century passed. During these years, there have been rapid advances in neuropharmacological research, moving from the study of pre-synaptic events in the 1960’s, to the study of membrane receptors in the 1970’s, second messenger-mediated activation of protein kinases in the 1980’s, and early gene expressions in the 1990’s. Yet, in spite of all progress resulting from technological advances, findings in the biology of mental illness remained inconsistent and none of the newer drugs were shown to be more effective or selective than the prototypes introduced in the 1950’s (Ban 2011; Sulser 2011). Although opinions regarding the culprit for the impasse differ, arguably, the inconsistent findings in biological research in psychiatry, and the lack of progress in the pharmacotherapy of mental illness can be explained by the pharmacological heterogeneity of diagnostic end-points used in clinical research (Ban 1969, 1987, 2011).

By the end of the 20th century, it was recognized that the primary targets of psychotropic drugs in the brain are all encoded by genes that have been identified and by the early years of the 21st century, sequencing of the human genome was completed (Ban 2002; Lerer 2002).  With these developments, research in the genetics of mental illness was intensified. But, as time passed, it was recognized that similar to findings in biological research in mental illness during the second half of the 20th century, findings in genetic research in mental illness were inconsistent. 

This was the state of affairs when a Spanish team of investigators led by Victor Peralta and Manuel Cuesta compared the familial aggregation of mental illness in four nosologic systems in order to detect phenotypes that could maximize phenotype-genotype correlation. Their study included 441 families with a total of 2703 individuals, of whom 1094 were affected and 709 were unaffected, by a psychotic disorder; and the four “nosologic systems” included in the comparison were the DSM-IV of the American Psychiatric Association (1994), the ICD-10 of the World Health Organization (1990), a “data-driven approach” and Karl Leonhard’s classification.

Findings of this first ‘polynosologic’ study in genetic research showed that the highest familiality estimate was obtained by using Leonhard’s classification, followed by the empirical classification, the DSM-IV and the ICD-10, in this order. In fact, Leonhard’s classification showed significantly more familaility than the DSM-IV and ICD-10, and the “empirical classification” significantly more familiality than the ICD-10. Based on these findings, authors suggest that Leonhard’s classification may be better suited for molecular genetic research than the official diagnostic systems.

 Similar to Frank Fish’s demonstration in the mid-1960’s that the way psychotic disorders are classified has a strong impact on responsiveness to treatment with psychotropic drugs, Peralta, Cuesta and their associates demonstrate that how psychotic disorders are classified has a strong impact on familiality. The findings in both of these studies, conducted half a century apart, focus attention on the possibility that classifying patients on the basis of Leonhard’s nosology provides more homogeneous and thereby more suitable populations for biological and genetic research in mental illness than any of the other classifications.

Leonhard’s classification was the last classification of mental illness that was based exclusively on psychopathology and derived by traditional organizing principles of psychiatric nosology (Ban 2000). 

Peralta and his associates’ findings were published on December 26, 2015, in the Schizophrenia Bulletin Advance Access.



American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Third Edition. Washington: American Psychiatric Association; 1980.

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fourth Edition. Washington: American Psychiatric Association; 1994.

 Astrup C. The effects of ataraxic drugs on schizophrenic subgroups. Related to experimental findings. Acta Psychiatr Scand 1959; 34 (supplement 136): 388-93.

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

Ban TA. Prolegomenon to the clinical prerequisite. Psychoharmacology and the classification of mental disorders. Prog Neuropsychopharmacol 1987; 11:527-80.

Ban TA. Nosology in the teaching of psychiatry. J bras Psiqiatr 2000; 49: 39-49.

Ban TA. Neuropsychopharmacology: The interface beween genes and psychiatric nosology. In Lerer B, editor. Pharmacogenetics of Psychotropic Drugs. Cambridge: Cambridge University Press; 2001, pp. 36-56.

Ban TA. Postscript to the series. In Ban TA, editor. An Oral Historyof Neuropsychopharmacology. Volume 10 (Katz MM, editor. History of the ACNP). Brentwood: American College of Neuropsychopharmacology; 2011, pp. 229-37.

Cade JF. Lithium salts in the treatment of psychotic excitement. Med J Aust 1949; 2: 349-52.

 Fish F. The influence of the tranquilizers on the Leonhard schizophrenic syndromes. Encephale 1964; 53: 245-9.

Delay J, Deniker P. 38 cas de psychoses traitèes par la cure prolongèe et continuè de 4560 RP. CR Congr Méd Alién Neurol (France), 1952; 50: 503-13.

Kraepelin E. Psychiatrie. Ein Lehrbuch fur Studierende und Arzte. 8. Aufl. .Leipzig: Barth: 1909-15.

Kuhn R. Über die Behandlung depressives Zustände mit einem iminodibenzyl-derivat G22355. Schweiz Med Wochenschrift 1957; 87: 1135-40.

Leonhard K. Aufteilung der endogenen Psychosen. Berlin: Akademie Verlag; 1957.

Lerer B. Genes and psychopharmacology: exploring the interface. In Lerer B, editor. Pharmacogenetics of Psychotropic Drugs. Cambridge: Cambridge University Press; 2001, pp. 3-17

Peralta V, Goldberg X, Ribeiro M, Sanches-Torres AM, Fananas L, Cuesta MJ. Familiality of psychotic disorders: A polynosologic study in multiple families. Schizophrenia Bulletin Advance Access, December 26, 2015.

Sulser F. Introduction and dramatis personae. In Ban TA, editor. An Oral History of Neuropsychopharmacology. Volume 3 (Sulser F, editor. Neuropharmacology). Brentwood: American College of Neuropsychopharmacology; 2011, pp. XXXIX-LX.

Wikler A.The Relation of Psychiatry to Pharmacology. Baltimore: Williams & Wilkins;1957

World Health Organisation. The ICD-10 Classification of Mental and Behavioural Disorders. Geneva: World Health Organization; 1992.


Thomas A. Ban.
March 31, 2016