Thomas A. Ban
Neuropsychopharmacology in Historical Perspective
Education in the Field in the Post-Neuropsychopharmacology Era.

In Historical Perspective: Peralta, Cuesta and their associate’s findings on the highest familiality of Leonhard’s Classification in Polynosologic Study

Collated

Thomas Ban                   March 31, 2016                 essay

Marcelo Cetkovich         April 28, 2016                   comment

Thomas Ban                   May 12, 2016                    reply to Marcelo Cetkovich

Ernst Franzek                June 23, 2016                    comment

Thomas  Ban                  June 30, 2016                    reply to Ernst Franzek

Ernst Franzek                 September 8, 2016            response to Ban´s reply

Thomas Ban                   September 15, 2016           response to Ernst Franzek’s response

Carlos Morra                   April 7, 2016                     comment

Thomas Ban                    April 28, 2016                   reply to Carlos Morra

Larry Stein                      April 14, 2016                   comment

Thomas Ban                    May 5, 2016                       reply to Larry Stein

Ernst Franzek                  August 25, 2016                 comment on Larry Stein´s comment

Victor Peralta                  November 17, 2016           reply to Marcelo Cetkovich, Ernst Franzek, Carlos Morra and Larry Stein’s comments

Ernst Franzek                   December 8, 2016            reply to Peralta’s comments

Victor Peralta                   February 23, 2017            response to Ernst Franzek’ reply

Larry Stein                        December 29, 2016          reply to Peralta´s comments

Victor Peralta                   March 30, 2017                 response to Larry Stein’s reply

Thomas A. Ban                  September 1, 2016           question to Victor Peralta

Victor Peralta                    April 27, 2017                  answer to Thomas Ban’s question

Thomas A. Ban                   November 23, 2017          response to Victor Peralta’s answer

In Historical Perspective: Peralta, Cuesta  and Their Associate’s  Findings  on 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-20^th 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 (psychopathology) 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 1980s (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 1960s, to the study of membrane receptors in the 1970s, second messenger-mediated activation of protein kinases in the 1980s and early gene expressions in the 1990s. 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 1950s (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 20^th 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 21^st 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 20^th 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 familiality 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-1960s 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). 

References:

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. Psychopharmacology 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 between 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 History of 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. Schizophr Bull. 2016 Jul;42(4):975-83.

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

March 31, 2016 

Marcelo Cetkovich’s comment

         Once again, Professor Tom Ban gives us a masterly lecture about the history of psychopharmacology. He succeeds in reviving early findings which gave empirical support for Leonhard’s Classification of Endogenous Psychoses.  Ban revives early findings by Astrup, which showed that by splitting schizophrenia into two main families of disease, unsystematic and systematic schizophrenia, Leonhard provided a more homogenous sample for studying antipsychotic effects. In Astrup’s experience, non-systematic schizophrenics displayed a better response to chlorpromazine than systematic schizophrenics. Fish confirmed Astrup’s findings later on. 

         This helps us to understand Leonhard’s work. After many years of observing clinical traits, family loading, outcome and prognosis, Leonhard came to the conclusion that whenever a clinical construct displays consistent differences in these characteristics, one has the right to assume that they are different disease entities.  There is no better way to study the complex biological underpinnings of schizophrenia, than keeping different disease entities within schizophrenia apart (Leonhard 1999).  Without separating them one kills them. This is what is happening in genetic research in schizophrenia today, where huge studies fail to find a locus clearly associated with the disease (Owen, Craddock, Jablensky 2007), or even falling in the trap of mixing schizophrenia with bipolar disorder, because genetic markers point to that direction (Craddock, O’Donovan and Owen 2007). We reviewed this subject recently (Bakmas 2015) and found only one study that was an exception. It was a reanalysis of the GWAS study of schizophrenia, in which a strong association between schizophrenia and genetic anomalies in inflammatory pathways was found (Ripke, Neale, Corvin et al. 2014). Further analysis revealed an association with a locus related with a variation of the factor (gene 4) that regulates complement. This factor controls synaptic pruning and apoptosis. The findings of this study have opened the path to better understand neuropathological findings in schizophrenia (Sekar, Bialas, de Rivea et al. 2016).

         Peralta, Goldberg, Ribeiro et al. (2016) address the finding of Leonhard and his school in their study that family genetic loading is differentially distributed in different groups of patients with the diagnosis of schizophrenia. Leonhard found that the group of patients with unsystematic schizophrenias have a higher family-genetic load. Several studies are supportive of this finding, albeit with arguable statistical power (Franzek and Beckmann 1998; Beckmann and Franzek 2000). The findings of Peralta, Goldberg, Ribeiro et al. are based on a large sample of clinically well-profiled patients. Yet some of their findings are the opposite to Leonhard’s and of researchers of his school. In Peralta’s findings, the group of patients with systematic schizophrenia show higher family loading than the group of patients with unsystematic schizophrenia, whereas Leonhard and researchers from his school found that the group of patients with systematic schizophrenia have higher family loading. Periodic catatonia, a form of unsystematic schizophrenias, seems to be single clinical form of schizophrenia that was found to have the highest family loading by Stöber, although his findings have still not been confirmed by others. Moreover, Peralta, Goldberg, Ribeiro et al. found that cycloid psychosis has a higher family loading than systematic schizophrenia  (Stöber, Franzek, Lesch and Beckmann 1995), whereas  Leonhard himself and Bruno Pfuhlmann found  that cycloid psychosis have a low genetic loading (Leonhard quoted by Pfuhlmann, Jabs, Althaus et al. 2004).  We are aware how carefully Peralta and Cuesta performed their clinical assessments, but the fact that their findings are the opposite of those of Leonhard and of some of the researchers of his school merits discussion and, perhaps, a reanalysis of their findings taking into account some traits that it seems they did not evaluate, e.g., insidious or abrupt onset, which according to Leonhard best differentiates between the unsystematic and the systematic schizophrenias. Evolution of the disease is another.   Unsystematic schizophrenias tend to show a good prognosis, but with the recurrence of episodes, general deterioration appears.  On the other hand, systematic schizophrenias show marked deterioration, after years of evolution that may not be seen at the beginning. One might investigate the roots of this discrepancy in findings in the future.

         I agree with Peralta et al that examining “domains of psychopathology” could be a good alternative for avoiding the complexities of a pure nosographic approach. Any effort to clarify what is covered under the umbrella of schizophrenia is welcome.

         Recently, a rather sophisticated mathematical analysis confirmed that schizophrenia has a complex genetic and phenotypic “architecture.” Arnedo, Javier, Svrakic et al. (2015) suggest that prior to using complex biological probes to study the neural basis of psychosis, a careful definition of phenotypes is required. 

References:

Arnedo J, Javier A, Svrakic DM, del Val C, Romero-Zaliz R, Hernández-Cuervo H; Molecular Genetics of Schizophrenia Consortium, Fanous AH, Pato MT, Pato CN, de Erausquin GA, Cloninger CR, Zwir I. Uncovering the hidden risk architecture of the schizophrenias: confirmation in three independent genome-wide association studies. Am J Psychiatry. 2015 Feb 1;172(2):139-53.

Bakmas MC. Differentiated Psychopathology and Molecular Genetics of Endogenous Psychosis: Much More than a Misunderstanding. Acta Psychopathol. 2015.

Beckmann H, Franzek E. The genetic heterogeneity of “schizophrenia.” The World Journal of Biological Psychiatry: The Official Journal of the World Federation of Societies of Biological Psychiatry 2000; 1: 35-41.

Craddock N, O'Donovan MC, Owen MJ. Psychosis genetics: modeling the relationship between schizophrenia, bipolar disorder, and mixed (or “schizoaffective”) psychoses. Schizophrenia bulletin, 2009. 35 (3):482-90

Franzek E, Beckmann H. Different genetic background of schizophrenia spectrum psychoses: a twin study. The American Journal of Psychiatry 1998; 155: 76-83.

Leonhard K. Classification of Endogenous Psychoses and their Differentiated Etiology. Revised and enlarged edition. Vienna/New York: Springer; 1999.

Owen MJ, Craddock N, Jablensky A. The genetic deconstruction of psychosis. Schizophrenia Bulletin 2007; 33: 905-911.

Peralta V, Goldberg X, Ribeiro M, Sanches-Torres AM, Fananas L, Cuesta MJ. Familiarity of psychotic disorders: A polynosologic study in multiple families. Schizophr Bull. 2016 Jul;42(4):975-83.

Pfuhlmann B, Jabs B, Althaus G, Schmidtke A, Bartsch A, et al.  Cycloid psychoses are not part of a bipolar affective spectrum: results of a controlled family study. Journal of Affective Disorders 2004; 83: 11-19.

Ripke S, Neale BM, Corvin A, Walters JT, Farh KH, Holmans PA, Pers TH. Biological insights from 108 schizophrenia-associated genetic loci. Nature 2014; 511 (7510), 421-7.

Stöber G, Franzek E, Lesch KP, Beckmann H. Periodic catatonia: a schizophrenic subtype with major gene effect and anticipation. European archives of psychiatry and clinical neuroscience 1995; 245(3): 135-41.

April 28, 2016

Thomas A. Ban’s reply to Marcelo Cetkovich’s comment

         Thank you for your comments. I was glad to see your appreciation of Christian Astrup’s (1959) contributions as it was Astrup first who discovered that by dividing schizophrenia on the basis of Karl Leonhard’s (1957) classification into “unsystematic schizophrenia” and “systematic schizophrenia,” the population with the diagnosis of “unsystematic schizophrenia” was pharmacologically more homogeneous in terms of responsiveness to neuroleptics than the population with the diagnosis of “systematic schizophrenia.” Astrup’s (1959) findings were further elaborated by Frank Fish (1964), who identified “affect-laden paraphrenia”, one of the three subpopulations of “unsystematic schizophrenia,” as the pharmacologically most homogeneous subpopulation of schizophrenia with an 84.4 % marked to moderate response rate to neuroleptics. As pharmacologically homogenous populations are a prerequisite for interpretable findings in neuropsychopharmacological research, “affect-laden paraphrenia” is a suitable subpopulation of schizophrenia for neuropsychopharmacological research. It is also a suitable population for molecular genetic research with the employment of the ”candidate gene” approach. If attention would have been played to Fish’s (1964) findings which were published in 1964, we probably had no dopamine hypothesis of schizophrenia, but a dopamine hypothesis of “affect-laden paraphrenia.”

         You are correct, Peralta and his associates (2016)  finding of higher “familiality” in the “systematic schizophrenias” than in the “unsystematic schizophrenias” is in the opposite direction to the finding of Leonhard (1999) and some other investigators who published on higher “familiality” in “unsystematic schizophrenia” than in “systematic schizophrenias” . The finding of high “familiality” in ”cycloid psychosis” by Peralta and his associates (2016)  is also in  variance with the finding of Leonhard (1999) and some others. It would be important to find out where the discrepancy comes from. Regardless of the discrepancy, the fact remains that in their   “polynosologic” study in psychotic disorders Peralta and associates found the  highest “familiality” with   diagnoses derived by Leonhard’s (1957) nosology, followed by empirically derived diagnoses, DSM-IV diagnoses and ICD-10 diagnoses in this order.

References:

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

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

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

Leonhard K. Classification of Endogenous Psychoses and their Differentiated Etiology. Revised and enlarged edition. Vienna/New York: Springer; 1999.

Peralta V, Goldberg X, Ribeiro M, Sanches-Torres AM, Fananas L, Cuesta MJ. Familiality of psychotic disorders: A polynosologic study in multiple families. Schizophr Bull. 2016 Jul;42(4):975-83.

May 12, 2016

Ernst Franzek’s comment

         It is a pleasure and honour to receive your invitation to give a comment on “In Historical Perspective: Peralta, Cuesta and their associates’ findings on the highest familiality of Leonhard´s classification in polynosologic study.”

         In 1992, Beckmann, Fritze and Franzek published a paper in Pharmacopsychiatry on the influence of neuroleptic medication on specific syndromes and symptoms in schizophrenic patients with unfavourable long-term course who were diagnosed with Leonhard´s (1957) classification. They found   that syndromes were almost unchanged with respect to the preneuroleptic era and concluded that in schizophrenia which leads to severe residual psychopathology, Leonhard´s classification is superior to the DSM classification.

         Let us shortly summarize the findings;

         All eight patients with periodic catatonia, a group with high familial loading, showed a chronic remittent course. Subsequent to good or even full remissions in the early years of the illness, new exacerbations ensued despite continuous treatment with neuroleptic medication. There were remissions of acute episodes with electroconvulsive therapy, insulin coma treatment and with high doses of neuroleptics.  After the introduction of neuroleptic medication, the often dangerously aggressive hyperkinetic psychomotor states, described in the pre-neuroleptic era, became less severe. In the period between acute outbursts of the illness, numbness and lack of motivation with psychomotor stiffness in subtle modulatory behaviour persisted despite continuous treatment with neuroleptic medication. 

         There were 13 patients with affect-laden paraphrenia, a schizophrenic subgroup with high familial loading.  All patients in this subgroup fulfilled DSM-criteria of paranoid type of schizophrenia. The common symptom of these patients was marked delusion of self-reference. Acute illness was characterized by paranoid hallucinatory syndromes with prominent affective features. After treatment with neuroleptic medication, hallucinations became less frequent. However, chronic delusions of self-reference persisted. It appeared to be the decisive defective symptom of patients with affect-laden paraphrenia. Patients with affect-laden paraphrenia had the most benefit of treatment with neuroleptic medication within the group of chronic schizophrenic patients.

         There were three patients with cataphasia, another schizophrenic subgroup with high familial loading.  In every case, the illness brought about a dissolution of thought and speech. The marked disturbance of speech and thought persisted throughout the illness despite continuous treatment with neuroleptic medication.

         The following patient groups belong to sporadic, non-familial forms of systematic schizophrenia.

         There were five patients with systematic paraphrenia. They showed paranoid, bizarre, hallucinatory symptoms and severe disturbance of thinking. There was no free interval without psychotic features during the course of the illness. Despite continuous treatment with high doses of neuroleptic medication, the chronic paranoid-hallucinatory syndromes persisted.

         Ten patients were diagnosed with systematic catatonia. In recent classifications most of these patients were diagnosed as autistic spectrum disorder. The following symptoms were found to be resistant to treatment with neuroleptic medication: autism, ambivalence, ambitendency, negativism, proskinesis, speech sluggishness, speech promptness, parakinetic movements and disturbances of thought.

         Nine patients were diagnosed with hebephrenic schizophrenia. In these patients dysphoric, depressive and occasional euphoric episodes with delusions, hallucinations and ideas of reference often required hospitalization. During treatment with neuroleptic medication the positive symptoms rapidly disappeared in every case, but chronic affective flattening persisted. In some of the cases, the flattening of affect has been already obvious long before first hospitalisation. Dysphoric episodes were characteristic during the entire course of the illness. The following symptoms were resistant to treatment with neuroleptic medication: flatness of affect, querulous behaviour, and stereotype questioning and answering. Dysphoric mood swings appeared to be milder in patients on neuroleptic medication.

         The effect of continuous treatment with neuroleptic medication with respect to the pre-neuroleptic era was a marked reduction of psychomotor excitement whereas the syndromes were more or less unchanged.

         The overall conclusion of the authors was that Leonhard´s classification of schizophrenia provides more suitable populations for future research than some other classifications.

         Based on their findings in other studies authors raised the question that “schizophrenia” is “not a disease entity” (Franzek and Beckmann 1992, 1998)?  To date no response was received to this question.

References:

Beckman H, Fritze J, Franzek E. The influence of neuroleptics on specific syndromes and symptoms in schizophrenics with unfavourable long-term course. Pharmacopsychiatry  1992; 26:50-58.

Franzek E, Beckmann H. Schizophrenia: Not a disease entity? A study of 57 long-term hospitalized chronic schizophrenics. European Journal of Psychiatry 1992; 6:97-108.

Franzek E, Beckmann H. Different genetic background of schizophrenic spectrum psychoses: A twin study. American Journal of Psychiatry 1998; 155: 76 - 83.

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

June 23, 2016

Thomas A. Ban’s reply to Ernst Franzek’s comment

         Thank you for providing details on responsiveness to neuroleptics in the different forms and sub-forms of schizophrenia in Leonhard’s (1957) classification. I was glad to see that your findings with  Beckmann and Fritze were  in keeping with Frank Fish’s (1964) who found that patients with “unsystematic schizophrenia” respond more favourably to neuroleptics than patients with “systematic schizophrenia” and within the “unsystematic schizophrenias” patients with “affect-laden paraphrenia” respond the most favourably (Beckmann, Fritze and Franzek). Your findings with Beckmann (Franzek and Beckmann 1992, 1998) were in keeping also with Peralta and his associates (2016) findings that patients with a diagnosis of schizophrenia represent a genetically heterogenous population. Yet, Peralta and associates findings of higher genetic loading in the “systematic schizophrenia” than in the “non-systematic schizophrenia” are in the opposite direction to Leonhard’s (1957) findings. 

References:

Beckman H, Fritze J, Franzek E. The influence of neuroleptics on specific syndromes and symptoms in schizophrenics with unfavourable long-term course. Pharmacopsychiatry  1992; 26:50-58.

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

Franzek E, Beckmann H. Schizophrenia: Not a disease entity? A study of 57 long-term hospitalized chronic schizophrenics. European Journal of Psychiatry 1992; 6:97-108.

Franzek E, Beckmann H. Different genetic background of schizophrenic spectrum psychoses:

A twin study. American Journal of Psychiatry 1998; 155: 76 - 83.

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

Peralta V, Goldberg X, Ribeiro M, Sanches-Torres AM, Fananas L, Cuesta MJ. Familiality of psychotic disorders: A polynosologic study in multiple families. Schizophr Bull. 2016 Jul;42(4):975-83.

June 30, 2016

Ernst Franzek’s response to Thomas A. Ban’s reply

         It is right that our study on the effect of neuroleptics confirm Fish´s earlier findings. We even could state that in one subtype of the unsystematic schizophrenias, affect-laden paraphrenia, the improvement of the psychopathology was striking and highly significant.

         Peralta´s finding of high familiality in the systematic forms of schizophrenia according to Leonhard´s classification, however, remains a mystery. All other modern studies on familial loading based on Leonhard´s classification showed a very high familial loading in the unsystematic schizophrenias and a very low familial loading in the systematic schizophrenic types (Beckmann and Franzek 1992, 1996; Franzek and Beckmann 1992a,1992b, 1998; Stöber, Beckmann, Franzek and Schmidtke 1992; Stöber, Saar, Ruschendorf et al. 2000). Maybe there is a misunderstanding in the diagnostic procedure?

References:

Beckmann H, Franzek E. Deficit of birth rates in winter and spring months in distinct subgroups of mainly genetically determined schizophrenia. Psychopathology 1992; 25:57-64.

Beckmann H, Franzek E, Stöber G. Genetic heterogeneity in catatonic schizophrenia. A family study. American Journal of Medical Genetics 1996; 67: 289-300.

Franzek E, Beckmann H. Schizophrenia not a disease entity? A study of 57 long-term hospitalized chronic schizophrenic patients. The European Journal of Psychiatry 1992a; 6:97-108.

Franzek E, Beckmann H  Season-of-birth effect reveals the existence of etiologically different subgroups of schizophrenia. Biological Psychiatry1992b;  32:375-378.

Franzek E, Beckmann H. Different genetic background of schizophrenic spectrum psychoses. A twin study. American Journal of Psychiatry 1998; 155:76-83.

Stöber G, Franzek E, Beckmann H, Schmidtke A. Exposure to prenatal infections, genetics and the risk of systematic and periodic catatonia. Journal of Neural transmission 2002;  109:921-929.

Stöber G, Saar K, Rüschendorf F, Meyer J, Nürnber G, Jatzke S, Franzek E, Reis A, Lesch KP, Wienker TF, Beckmann H (2000) Splitting schizophrenia: periodic catatonia – susceptibility locus on chromosome 15q15. American Journal of Human Genetics 2000; 67:1201/1207.

September 8, 2016

Thomas A. Ban’s response to Ernst Franzek’s response to Ban’s reply

         Marcelo Cetkovich in his comment noted the same as you did that in terms of familiality Peralta and his associates’ findings in the “systematic schizophrenias,” “unsystematic schizophrenias” and in “cycloid psychoses” are in variance with the findings of Leonhard himself and of some others.

         We already asked Peralta whether he has any idea where the discrepancy comes from and we should be receiving an answer from him soon. We will also be able to determine whether he used the conventional criteria for diagnosing within Leonhard’s classification. Yet, regardless, the fact remains that by assigning patients to sub-populations on the basis of the criteria he used, he found more familiality in the population than by diagnosing patients on the basis of the DSM-IV or ICD-10 criteria.

September 15, 2016

Carlos Morra’s comment

         I would like to congratulate Peralta, Cuesta and their associates for their report. I agree with Tom Ban concerning the importance of demonstrating that Karl Leonhard’s classification provides more homogenous populations, not only in terms of pharmacological responsiveness, as had been shown by Frank Fish several decades ago, but also, in terms of “familiality.” I do hope their findings that using Leonhard’s classification provided a genetically more homogenous population than current consensus-based classifications and even an empirical classification, will have an impact on molecular genetic research in schizophrenia.

         I think Peralta Cuesta and their associates’ findings provide a strong argument in favor of the contention that “how psychotic disorders are classified have a strong impact on “familiality.” If this is the case, what holds us back in identifying the most homogenous populations in terms of “familiality” instead of embarking blindly on molecular genetic research in mental disorders? In Leonhard’s classification of schizophrenia, both unsystematic schizophrenia and systematic schizophrenia are still widely heterogeneous populations, at least in pharmacological responsiveness. Would it not be desirable to link highly sophisticated molecular genetic research with commensurate research in psychopathology and psychiatric nosology?

         I noted that the Peralta and Cuesta’s team used Leonhard’s symptom-catalogue, published in 1990, for classifying patients. I was not familiar with Leonhard’s paper from 1990; however, if a diagnostic instrument based on that paper for assigning Leonhardian diagnoses was devised, it would be very useful if it could be rendered accessible. 

April 7, 2016

Thomas A. Ban’s reply to Carlos Morra’s comment

         I certainly agree with you. It would be desirable to link highly sophisticated molecular genetic research with commensurate highly sophisticated psychiatric research in differentiated psychopathology and psychiatric nosology. I am wondering why this was not done and how could molecular genetic research in mental illness justify the current fishing expeditions. I hope Peralta, Cuesta and his associates’ findings will call for a re-evaluation of the current situation.

April 28, 2016

Larry Stein’s comment

         Is schizophrenia the price that Homo sapiens pays for abstract problem-solving?     Are the negative/deficit symptoms, in particular, under strong genetic regulation—and are they caused largely by excessive synaptic pruning in adolescence?

         I read your fine Perspective on the psychiatric classification/biological research issue as well as the valuable Peralta, Goldberg, Ribeiro et al. 2016 reference with great interest.   As you have long argued, better psychiatric classification will be necessary both for the development of improved drugs and for biological understanding.  You nicely demonstrate that Leonhard's classification has advantages over other diagnostic systems for neurobiological and genetic research.

         In the reports which you summarize, however, I was surprised to note an apparent discrepancy between the pharmacological and genetic findings in schizophrenia.  The disparity is most salient when Leonhard's classification is employed.  Specifically, I refer here to Leonhard's delineations of unsystematic schizophrenia and systematic schizophrenia.  According to the pharmacological studies of Astrup (1959) and Fish (1964) cited in your review, individuals in Leonhard's unsystematic schizophrenia category respond more reliably to chlorpromazine-like drugs than do those in the systematic schizophrenia category.  On the other hand, Peralta, Goldberg, Ribeiro et al. (2016) show convincingly that unsystematic schizophrenia exhibits a smaller familiality estimate (h2 = 0.39) than systematic schizophrenia (h2 = 0.78).  Thus, contrary to expectation, the pharmacology and genetics go in opposite directions in Leonhard's scheme—i.e., the “less-familial” unsystematic schizophrenia diagnosis is more responsive to drugs than is the “more-familial” diagnosis of systematic schizophrenia.

         If you agree that this observation seems paradoxical, an explanation may be sought in a parallel distinction, which contrasts the “positive” and “negative” symptoms of schizophrenia.  Following Crow (1980), it is recognized that dopamine-blocking antischizophrenic drugs are effective primarily against schizophrenia's “positive/psychotic” symptoms and are relatively ineffective against the “negative/deficit” symptoms.   (Accordingly, only the drug-sensitive positive symptoms are thought to be associated with brain dopamine hyperactivity).  The negative symptoms are largely irreversible as well as drug-resistant.  If these irreversible negative symptoms are featured in Leonhard's definition of systematic schizophrenia (as I presume them to be), then it follows that the genetically-important category of systematic schizophrenia in fact will be relatively resistant to the dopamine-blocking drugs.

         If correct, this argument indicates that the most important genetic factors underpinning schizophrenia are not directly associated with a disordered brain dopamine substrate (although some dopamine involvement is likely to be contributory).  Rather, the critical genetic risk factors for schizophrenia more probably involve some other, but currently obscure, substrate—i.e., the unknown brain circuitries whose dysfunction underlies the negative/deficit symptoms.  Understanding the disordered brain physiology in schizophrenia, it was hoped, might best be approached by turning the problem around and first deciphering the genetics.  This hope has long been frustrated, but now a paper online in Nature may have given the genetic risk factors for schizophrenia their first substantial exposure (Sekar, Bialas, de Rivea et al. 2016).   According to the accompanying News & Views commentary of Dhindsa and Goldstein (2016), “Sekar et al. present a remarkable genomic and neurobiological study that...finally gives us the first real inroad into the molecular aetiology of schizophrenia."

         A huge (>60,000 cases) genome-wide association study reported in Nature two years ago provided the starting point (Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014).  Of 108 schizophrenia risk loci carefully identified, by far the strongest was the major histocompatibility complex (MHC), a region on chromosome 6 related to immunity. Within the MHC locus, the peak was near a pair of genes (C4A and C4B) which code for complement component 4.  This C4 protein is a critical component of the immune system pathway for the recognition of pathogens and cellular debris — but which (if any) of the hundreds of genes in the notoriously challenging MHC region might actually be relevant to schizophrenia was unknown.  Sekar, Bialas, de Rivea et al. make ingenious use of RNA expression data and other evidence to establish the potential relevance of C4, despite the enormous molecular complexity of its many diverse alleles.  Remarkably, they are able to show that the various alleles of the C4 genes associate with schizophrenia in proportion to their ability to generate C4A expression.  In other words, the problematic structural heterogeneity of the many C4 variants is nicely reconciled by their convergence at a common, functionally homogeneous, output—C4A expression—to predictably increase the risk of schizophrenia. 

         Significantly, in the brain, the complement cascade has been implicated in synaptic elimination and remodeling. Sekar, Bialas, de Rivea et al. confirm in a mouse model that C4 expression, in fact, is upregulated during periods of synaptic pruning, and they further hypothesize that a similar elevation of C4A expression in schizophrenia results in excessive synaptic pruning.  Sekar, Bialas, de Rivea et al. thus provide detailed genetic support for Feinberg's (1982/83) prescient and closely-related neurodevelopmental model of schizophrenia.  According to Feinberg, a profound reorganization of human brain function takes place in adolescence, when adult problem-solving “power” begins to appear.  Because a reduction in cortical synaptic density occurs at the same time (Huttenlocher 1979), the cognitive and behavioral changes are explicitly attributed by Feinberg to an increase in synaptic pruning.  Why are fewer synapses better than many?   Feinberg explains that too many competing neural connections in the brains of children may impede information processing, and that the selective pruning of erroneous and irrelevant synapses gradually shapes the adult capacity to solve highly abstract and. complex problems.  But, according to Feinberg, these advantages of pruning can be taken too far.  Genetic variants or mutations that cause excessive synaptic pruning at a critical neurodevelopmental stage may explain the typical manifestation of schizophrenia in late adolescence and early adulthood.

References:

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

Crow TJ.  Positive and negative schizophrenic symptoms and the role of dopamine.The British Journal of Psychiatry 1980; 137 (4) 383-6.

Dhindsa RS, Goldbstein DB. From genetics to physiology last. 2016. Dol: 10.1038/nature16874.

Feinberg I. Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence? J Psychiatr Res 1982/1983; 17: 319–34.

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

Huttenlocher PR Synaptic density in human frontal cortex—developmental changes and effects of aging. Brain Res 1979; 163: 195-205.

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

Peralta V, Goldberg X, Ribeiro M, Sanches-Torres AM, Fananas L, Cuesta MJ. Familiality of psychotic disorders: A polynosologic study in multiple families. Schizophr Bull. 2016 Jul;42(4):975-83.

Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 2014; 511, 421-7.

Sekar A, Bialas AR, de Rivea H, Davis A, Hammond TR, Kamitaki N, Tooley K, Presumey J, Baum M, Van Doren V, Genovese G, Rose S, Handsaker RE; Schizophrenia Working Group of the Psychiatric Genomics Consortium, Daly MJ2, Carroll MC, Stevens B, McCarroll SA. Schizophrenia risk from complex variation of complement component 4.  Nature. 2016 Feb 11;530(7589):177-83.

April 14, 2016

Thomas A. Ban’s reply to Larry Stein’s comment

         Thank you for your comment. I wonder why you find it “paradoxical” that a different sub-population of schizophrenia shows high “familiality” than high response rate to neuroleptics? For me, the findings of Frank Fish (1964) and Peralta and his associates (2016) indicate that the patient population identified by the diagnostic concept of schizophrenia is heterogeneous pharmacologically and genetically. Probably, what even more important is that the findings from these two studies also indicate that by diagnosing patients on the basis of Leonhard’s (1957) classification, one can identify pharmacologically and genetically more homogenous subpopulations of schizophrenia than by diagnosing patients on the basis of some other classifications.

         As genetically homogenous populations are a prerequisite for successful molecular genetic research (association studies-linkage analysis) and pharmacologically homogenous populations for successful neuropsychopharmacological research, findings in these studies imply that patient populations identified on the basis of diagnoses derived by Leonhard’s (1957) nosology would provide more suitable populations for genetic and neuropsychopharmacological research, in general, and in schizophrenia, in particular, than patient populations identified by diagnoses in  some other classifications.

         If patients diagnosed with schizophrenia were diagnosed on the basis of Leonhard’s nosology, it would have become evident that “positive symptoms” and “negative symptoms” do not provide a natural divide in the population (Crow 1980), as in some of the16 forms and sub-forms of schizophrenia “positive symptoms” and “negative symptoms” are present simultaneously all the time and in some other forms, some of the time. It would have also focus attention on the fallacy of the commonly held view that “positive symptom” in schizophrenia as a rule, are responsive, to treatment with neuroleptic drugs whereas negative symptoms are less so. In the “paraphrenias”, one of the three forms of “systematic schizophrenia”, the clinical picture is dominated by “delusions”, a “positive symptom”, yet in Fish’s (1964) study, only 40.3% (58) of 144 patients diagnosed with “paraphrenia” showed a marked to moderate therapeutic response to neuroleptics. Furthermore, if diagnoses based on Leonhard’s (1964) nosology were adopted at the time they were introduced, in the late 1950s, we probably would never had a “dopamine hypothesis schizophrenia”, but a “dopamine hypothesis of affect-laden paraphrenia”, as in Fish’s (1964) study, 84.4% (43) of 51 patients with “affect-laden paraphrenia” showed a marked to moderate therapeutic response to neuroleptics.

         In so far as Sekar, Bialas, de Rivea et al.’s (2016) re-analysis of the data from a study is concerned, it would have been be carried out with consideration that patients with the diagnosis of schizophrenia, represent a genetically heterogeneous population.

References:

Crow TJ.  Positive and negative schizophrenic symptoms and the role of dopamine.The British Journal of Psychiatry 1980; 137 (4) 383-6.

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

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

Peralta V, Goldberg X, Ribeiro M, Sanches-Torres AM, Fananas L, Cuesta MJ. Familiality of psychotic disorders: A polynosologic study in multiple families. Schizophr Bull. 2016 Jul;42(4):975-83.

Sekar A, Bialas AR, de Rivea H, Davis A, Hammond TR, Kamitaki N, Tooley K, Presumey J, Baum M, Van Doren V, Genovese G, Rose S, Handsaker RE; Schizophrenia Working Group of the Psychiatric Genomics Consortium, Daly MJ2, Carroll MC, Stevens B, McCarroll SA. Schizophrenia risk from complex variation of complement component 4.  Nature. 2016 Feb 11;530(7589):177-83.

May 5, 2016

Ernst Franzek’s comment on Larry Stein’s comment

         The comment of Larry Stein is possibly based on a misunderstanding. Every publication on Leonhard’s group of schizophrenias state that the unsystematic forms have a very high familial loading in contrast to the systematic forms which are mostly sporadic. This is very important because it is postulated that systematic schizophrenias are possibly degenerative illnesses of the highest psychological brain functions which override the basic (lower) neurological psychomotor functions (Franzek and Beckmann 1999; Kleist 1953; Teichmann 1990).

References:

Franzek E, Beckmann H. Psychoses of the schizophrenic spectrum in twins. A discussion of the nature-nurture debate in the etiology of “endogenous psychoses”. Vienna: New York: Springer; 1999,

Kleist K.  Die Gliederung der neuropsychischen Erkrankungen. Monatschrift Psychiatrie Neurologie  1953; 125: 526-54.

Teichmann G. The influence of Karl Kleist on the nosology of Karl Leonhard. Psychopathology 1990; 23:267-76.

August 25, 2016

Victor  Peralta’s reply to Marcelo Cetkovich, Ernst Franzek, Carlos Morra and Larry Stein’s comments

         I congratulate Thomas A. Ban and all the commentators of our paper for their fine and insightful comments about the role of Leonhard’s classification in research in genetics and psychopharmacology. I think that the historical perspective presented by Thomas A. Ban provides a rare and precious opportunity for revisiting Leonhard’s classification and its far-reaching implications for research in endogenous psychosis.   

         I am very grateful to all commentators for their comments about our manuscript. In my response, I will focus first on the difference between our findings and those of Leonhard and his followers regarding the familial load of systematic and unsystematic schizophrenias. Second, I’ll present new (unpublished) data from our study on the differential response to antipsychotic treatment in the systematic and unsystematic schizophrenias.   

         Our findings that systematic schizophrenias have more familial aggregation than unsystematic schizophrenias are at odds with the findings of Leonhard and his followers. Although there are numerous factors that could explain the disagreement, I will discuss only four.

1. Family methodology

         Ours was a study with multiple affected families and such a study is different from the common family and twin studies. Therefore, it is not known to what extent our findings are comparable to the common studies of familial aggregation.  High density family studies are more powerful means than common family studies, but less powerful than twin studies, for detecting familial/genetic underpinnings. Another advantage of examining multiplex families is the higher statistical power they have for detecting meaningful effects than common family and twin studies. Considering the high number of multiplex families in our study, it might be stated that our study had more statistical power than the studies of Leonhard and his followers.

2. Sample representativeness

         Leonhard’s twin registry included heterogeneous populations (as acknowledged by Franzek and Beckmann 1988) and consequently, the reported morbidity risks for systematic schizophrenias were very different in different samples (as acknowledged by Ungvári 1985). Furthermore, the twin study by Franzek and Beckmann (1988), although much more rigorous than the one by Leonhard, might have been somewhat biased because it was based on hospital registers. I believe that the higher familial aggregation of unsystematic schizophrenias than systematic schizophrenias has been consistently demonstrated only for the rare condition of periodic catatonia. 

         It might be also important that the samples of Leonhard and Franzek & Beckmann were hospital-based while our sample was mental health service-based. Therefore our results are more representative of the population of psychotic disorders in the general population. In fact, in our sample, of the 1094 affected subjects, 216 (19.7%) had never been hospitalized and 65 (6%) had never been under psychiatric care. We had a couple of families in which most of the affected members with systematic schizophrenia had never been admitted to psychiatric facilities.

3. Blindness to proband diagnosis

         While Leonhard and his followers did not diagnose blindly, in our study, the diagnoses were blindly performed regarding subject identity and group status of both probands and relatives in 75% of the pedigrees.

4. Diagnostic procedure

         Ernst Franzek and Marcelo Cetkovich raised some doubts about our diagnostic procedure related to Leonhard’s system. In this respect it should be clearly understood that in our study all subjects were personally interviewed by trained clinicians and, as stated in our paper, Leonhard’s check-list was supplemented by other clinical information provided by the CASH in order to achieve a diagnosis based on Leonhard’s classification. Course of the disorder was a central criterion for diagnosing all types of psychoses and, for diagnosing systematic schizophrenia, particular attention was paid to mode of onset, continuous course and presence of enduring symptoms. Furthermore, all available information was reviewed by Dr. Cuesta and me to diagnose patients according to the specifications of the different diagnostic systems. Considering the mean time of illness duration in our sample (16.5 years), it is rather unlikely that course of the disorders had not been adequately considered. Indeed, the course pattern of (a) symptoms, (b) syndromes, (c) disorders and (d) other illness-related features was carefully assessed over the illness duration.     

         Additional support for our adequate diagnostic procedure for Leonhard’s system is provided by the following:

1)      The close correspondence between our comparative prevalence rates of systematic schizophrenia, unsystematic schizophrenia and cycloid psychosis and those reported by Leonhard and others (affective psychoses do not apply because we only included psychotic forms). 

2)      The good fit between the associated clinical characteristics of Leonhard’s classes of psychotic disorders and those reported by Leonhard and others. 

3)      The similarity between our empirically derived “core schizophrenia” class and Leonhard’s systematic schizophrenia in terms of external validators, such as familiality estimates, clinical characteristics and diagnostic concordance. The same also applies to the diagnosis of deficit schizophrenia, a diagnosis that fits well within Leonhard’s systematic schizophrenias.  

4)      The similarity of our data to those of Franzek & Beckmann (1998) regarding the correspondence between Leonhard’s and DSM diagnoses.

         In view of these considerations, I firmly believe that our diagnostic procedure was in line with that of Leonhard’s. I must acknowledge, however, that in about 10% of the subjects there were some doubts about their allocation within the Leonhard system, and given that Leonhard’s classification does not provide a residual category of “unspecified psychosis,” they were allocated by consensus to  the “best fitting diagnostic class” in the system. It should be noted that even higher rates of doubtful diagnoses (15%) were encountered in the DSM and ICD classifications. In summary, I believe that the difference between our findings and the findings of Leonhard and his followers is more related to sample representativeness and family study methodology than to diagnosing. Regardless, our findings will need to be corroborated by other investigators using representative samples of psychotic disorders in the general population. 

         A further and strictly personal caveat concerns as to the nature of Leonhard’s systematic catatonias. Reading Leonhard’s description of his patients, one wonders whether some of his patients with these diagnoses had a “functional” psychotic disorder at all or suffered  from an unknown or non-demonstrable brain disorder (for example: encephalitis, brain anoxia during gestation, etc.). But this is an issue that could be the subject matter of another exchange.               

         To examine the differential antipsychotic treatment response in the systematic and unsystematic schizophrenias, we analyzed the data of patients with systematic (n=242) and unsystematic schizophrenia (n=210) from their last admission, using the CGI efficacy index. The level of treatment response is shown below in the Table:

         This Table shows that about two thirds of systematic schizophrenias are unresponsive to antipsychotic medication and that the reverse is the case for unsystematic schizophrenias, i.e., two thirds of unsystematic schizophrenias are responsive to antipsychotic drugs.

         When we examined the efficacy index dimensionally in the two populations we found that the mean scores in systematic and unsystematic schizophrenias were 2.98 (SD=0.80) and 2.07 (SD=0.74), respectively (t=12.448, df=450, p<0.0001).  

         These findings fully corroborate those of Fish and Astrup as reviewed by Thomas Ban. Furthermore they demonstrate that Leonhard’s systematic and unsystematic schizophrenias are different homogeneous classes of disorders in terms of familial-genetic factors and response to antipsychotic drugs.  

References:

Franzek E, Beckmann H. Different genetic background of schizophrenia spectrum psychoses: a twin study. Am J Psychiatry. 1998;155:76-83.

Jablensky A. Classification of nonschizophrenic psychotic disorders: A historical perspective. Curr Psychiat Rep. 2001;3(4):326-331.

Leonhard K. The Classification of Endogenous Psychoses. 5^th ed. Ed E. Robins. New York: Irvington Publishers; 1979.

Leonhard K. Differentierte Diagnostik der Endogenen Psychosen unter Anlehnung an einem Symptommenkatalog. Psychiat Neurol Med Psychol 1990;42(3):136-145.

Ungvári G. A contribution to the validity of Leonhard's contribution of endogenous psychoses. Acta Psychiatr Scand. 1985;72(2):144-149.

November 17, 2016

Ernst Franzek´s response to Victor Peralta´s reply

         I agree with Victor Peralta that the historical perspective presented by Thomas A. Ban provides a rare and precious opportunity for revisiting Leonhard’s classification and its far-reaching implications for research in endogenous psychosis.   

         Peralta´s findings that systematic schizophrenias have more familial aggregation than unsystematic schizophrenias are at odds with the findings of Leonhard and some of his followers. One reason that could explain this disagreement is that Peralta conducted a study with multiple affected families. His argument that high density family studies are more powerful means than common family studies for detecting familial/genetic underpinnings is right. These studies provide much higher statistical power.

         The twin study by Franzek and Beckmann (1998) is based on hospital registers, this is also right. However, it has to be mentioned that the aim of this twin study was to differentiate genetic loading between cycloid psychosis and the schizophrenic group as a whole. The twin study does not provide any data that could distinguish unsystematic and systematic schizophrenia. There were no monozygotic twins suffering from systematic schizophrenia found in the whole twin sample. The main object of this twin study, therefore, is on the genetic distinction of cycloid psychoses and unsystematic schizophrenia: low genetic loading in cycloid psychoses and high genetic loading in unsystematic schizophrenia. The lack of monozygotic twins with systematic schizophrenia in the study sample has been discussed in detail elsewhere (Franzek and Beckmann 1999).

         I agree with Peralta that the higher familial aggregation of unsystematic schizophrenias than systematic schizophrenias has been consistently demonstrated only for the unsystematic subtype of periodic catatonia. 

         The diagnostic procedures in the study of Peralta et al, compared to the twin study of Franzek and Beckmann, did not differ. In both groups the diagnoses were blindly performed regarding subject identity. Peralta described, therefore, an adequate diagnostic procedure for Leonhard´s system.

         Very interesting are Peralta´s findings that out of his 1,094 affected subjects almost 20% had never been hospitalized and even 6 % had never been under psychiatric care. This is in line with the statement that systematic schizophrenic disorders are brain diseases affecting functional brain systems with different heaviness (Franzek and Musalek 2011).

         I fully agree with Peralta´s findings on antipsychotic treatment response. Unsystematic schizophrenic patients, in particular affect laden paraphrenia, show a significantly better response to antipsychotic treatment compared to the systematic schizophrenic group.

         Additionally, I would like to state at this point that my clinical experience during the last 15 years is that many systematic schizophrenic patients (according to Leonhard´s system) are allocated to the autistic spectrum according to the DSM.  

         Finally, I would like to congratulate Peralta for his excellent paper and it would be great to do some investigations on the complexity of brain systems together based on a differentiated psychopathology.             

References:

Franzek E, Beckmann H. Different genetic background of schizophrenia spectrum psychoses: a twin study. Am J Psychiatry. 1998, 155:76-83.

Franzek E, Beckmann H. Psychoses of the Schizophrenic Spectrum in Twins. A discussion on the nature – nurture debate in the etiology of  “endogenous” psychoses. Springer, Wien New York, 1999.

Franzek E, Musalek M. Advances in psychopathology, classification and diagnosis of psychosis and its clinical implications. Minerva Psichiatrica 2011, 52: 171-185.

December 8, 2016

Victor Peralta’s response to Ernst Franzek’ response

         I fully agree with the observation of Dr. Franzek that many of the Leonhard’s systematic schizophrenias belong to the autistic spectrum disorders. Unfortunately, we can’t test this interesting hypothesis in our database because autism spectrum disorders were excluded from the inclusion criteria.

February 23, 2017

Larry Stein’s response to Victor Peralta’s reply

         The second part of Victor Peralta’s carefully-considered response strongly confirms within his own data set a curious observation.  This finding had originally provided the unanticipated and “presumably paradoxical” basis for my own Comment.  Reported here—now on one and the same large population of affected subjects—are Peralta’s measurements both of familial load and responsivity to antipsychotic drugs for Leonhard’s systematic and unsystematic schizophrenias.  Contrary to the expectation of positive correlation, Peralta finds again that the genetics and pharmacology go in opposite directions in Leonhard’s classification, i.e., the less-familial unsystematic schizophrenia diagnosis is substantially more responsive to antipsychotic drugs than is the more-familial diagnosis of systematic schizophrenia. This unexpected observation, if correct, may have some interesting implications for the biology and genetics of schizophrenia, as I had previously noted in my Comment.

         But complicating the arguments above is an unsettling prior issue --raised by various commentators as a simple matter of fact-- in regard to the actual familial load of systematic and unsystematic schizophrenias. Others, including Leonhard himself, are at odds with Peralta and report contrariwise that, in fact, unsystematic schizophrenias exhibit more familial aggregation than systematic schizophrenias. Several factors that might explain this disagreement with Leonhard and his followers are thoughtfully reviewed in the first part of Peralta’s response.  The opposed findings, Peralta concludes, may be due more “to sample representativeness and family study methodology than to diagnosing. Regardless, our findings will need to be corroborated by other investigators using representative samples of psychotic disorders in the general population.”  These considerations bear on suggestions (Peralta, Goldberg, Ribeiro et al. 2016; Ban 2015) that Leonhard’s classification of psychotic disorders may be better suited for molecular genetic studies than other diagnostic systems. Perhaps the disagreements on basic issues of fact within Leonhard’s classification, as noted above, might first be resolved.

References:

Ban TA. In historical perspective. Peralta, Cuesta and their associates’ findings of the highest familiality of Leonhard’s classification in polynosologic study. inhn.org.perspective. March 31, 2016.

Peralta V, Goldberg X, Ribeiro M, Sanches-Torres AM, Fananas L, Cuesta MJ. Familiality of psychotic disorders: A polynosologic study in multiple families. Schizophr Bull. 2016 Jul;42(4):975-83.  

December 29, 2016 

Victor Peralta's response to Larry Stein’s response

         Thank you for your response to my reply to your comment. I was surprised to see your observation of our “presumably paradoxical” finding of a dissociation between treatment response and familial-genetic loading in Leonhard’s concepts of schizophrenia. In line with Thomas Ban's comment (Ban 2016), I also wonder why you find it “paradoxical” that a different sub-population of schizophrenia shows high familiality and low response rate to antipsychotic medication. Our findings only indicate that the patient population identified by the diagnostic concept of schizophrenia is heterogeneous pharmacologically and genetically, and that by diagnosing patients on the basis of Leonhard’s (1957) classification, one can identify pharmacologically and genetically more homogenous subpopulations of schizophrenia than by diagnosing patients on the basis of some other classifications. Obviously, pharmacological and genetic factors do not necessarily converge in schizophrenia as showed by ours (Peralta, Goldberg, Ribeiro et al. 2016) and other studies (Frank, Lang, Witt et al. 2015).

         Leonhard, and afterwards other authors, proposed than schizophrenia is a heterogeneous condition in terms of symptom pattern, response to treatment, course, outcome and other illness-related features, such as age at illness onset. Several subdivisions of schizophrenia have been proposed to capture this heterogeneity and the hypothesized differential pathophysiology. Examples of these classifications are the neurodevelomental/non-neurodevelopmental forms (Reveley, Lewis and Murray 1985), the positive/negative dichotomy (Crow 1980), the good-poor outcome distinctions and the concept of treatment resistant schizophrenia. What these classifications have in common with Leonhard’s systematic schizophrenia is that they define a subgroup of schizophrenia characterized by early onset, enduring symptoms, poor outcome and poor response to treatment. Now, there is a bulk of data supporting different pathological mechanisms for these subgroups, namely more and more severe brain structural abnormalities of neurodevelopmental origin in the poor outcome forms and more involvement of dopamine dysfunction in the good outcome, drug-responsive, forms.

         From a genetic perspective, genetic-molecular studies using polygenic scores indicate the higher genetic validity of narrow schizophrenia definitions (Bigdeli, Javali, Hoebert et al. 2014) or treatment-resistant patients (Frank, Lang, Witt et al. 2015). Furthermore, recent findings indicate that the synaptic pruning, a mechanism that purportedly underlies the most severe schizophrenia forms, and that it is responsive for the reduced number of synapses in the brains of these patients, is under strong genetic control (Sekar, Bialas, de Rivea et al. 2015). The reduced number of synapses due to pruning in these patients would explain both the higher structural brain abnormalities and the poor responsiveness to dopamine blocking drugs. I think that this study is a nice demonstration about the dissociation between drug responsiveness and familial-genetic factors in schizophrenia.                    

         As pointed out by Ban (2016), the key question is to define genetically homogenous populations as a prerequisite for successful molecular genetic research and pharmacologically homogenous populations for successful neuropsychopharmacological research. I believe that our study represents a little advance in this direction by providing evidence that diagnoses derived by Leonhard’s nosology afford more suitable populations for genetic and neuropsychopharmacological research in schizophrenia than patient populations identified by DSM or ICD consensus classifications.

References:

Ban TA. Thomas A. Ban reply to Larry Stein’s comment. inhn.org.perspective. May 5, 2016.

Bigdeli M, Javadi D, Hoebert J, Laing R, Ranson K; Alliance for Health Policy and Systems Research Network of Researchers on Access to Medicines. Health policy and systems research in access to medicines: a prioritized agenda for low- and middle-income countries. Health Res Policy Syst. 2013;11:37.

Crow TJ.  Positive and negative schizophrenic symptoms and the role of dopamine.The British Journal of Psychiatry 1980; 137 (4) 383-6.

Frank J, Lang M, Witt SH, Strohmaier J, Rujescu D, Cichon S, Degenhardt F, Nöthen MM, Collier DA, Ripke S, Naber D, Rietschel M. Identification of increased genetic risk scores for schizophrenia in treatment resistant patients. Mol Psychiatry. 2015 Jul;20(7):913.

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

Peralta V, Goldberg X, Ribeiro M, Sanches-Torres AM, Fananas L, Cuesta MJ. Familiality of psychotic disorders: A polynosologic study in multiple families. Schizophr Bull. 2016 Jul;42(4):975-83.

Reveley AM, Lewis SW, Murray RM. Subgroups in schizophrenia. Lancet 1985; 27;2(8448):216-7.

Sekar A, Bialas AR, de Rivea H, Davis A, Hammond TR, Kamitaki N, Tooley K, Presumey J, Baum M, Van Doren V, Genovese G, Rose S, Handsaker RE Schizophrenia Working Group of the Psychiatric Genomics Consortium, Daly MJ, Carroll MC, Stevens B2, McCarroll SA. Schizophrenia risk from complex variation of complement component 4.  Nature. 2016 Feb 11;530(7589):177-83.

March 30, 2017

Thomas A. Ban’s question to Victor Peralta

         In your polynosologic study in patents with psychotic disorders you found the highest “familiality” estimates obtained by using Leonhard’s classification, followed by an empirical classification, the DSM-IV of the American Psychiatric Association (1994) and the ICD-10 of the World Health Organization  (1994), in this order. In fact, by classifying patients on the basis of Leonhard’s (1999) criteria significantly more “familiality” was obtained than by classifying patients on the basis of DSM-IV and ICD-10 criteria. Based on these findings, you suggested that using Leonhard’s classification may be better suited for molecular genetic research than the official diagnostic systems. Undoubtedly this was the case in the study on which your report was based. Yet, when looking at some of the details of your analyses (Cetkovich 2016; Franzek 2016), as for example the higher “familiality” in the “systematic schizophrenias” than in the “unsystematic schizophrenias” your findings are in the opposite direction to the finding of Leonhard (1999) and some other investigators who published on higher “familiality” in the “unsystematic schizophrenias” than in “systematic schizophrenias” (Beckmann and Franzek 2000; Franzek and Beckmann 1998). Your finding of high “familiality” in ”cycloid psychosis”  is also in  variance with the finding of Leonhard (1999) and some others (Pfuhlman, Jabs, Althaus et al. 2004) It would be important to know where these discrepancies come from? Do you have any idea?

References:

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

Beckmann H, Franzek E. The genetic heterogeneity of “schizophrenia.” The World Journal of Biological Psychiatry: The Official Journal of the World Federation of Societies of Biological Psychiatry2000; 1: 35-41.

Cetkovich M. Comment on Thomas A. Ban: In Historical Perspective: Peralta, Cuesta and their associates findings on the highest familiality of Leonhard’s classification in polynosologic study. inhn.org.perspective. April 28, 2016.

Franzek E. Comment on Larry Stein’s comment on Thomas A. Ban: In Historical Perspective: Peralta, Cuesta and their associates findings on the highest familiality of Leonhard’s classification in polynosologic study. inhn.org.perspective. August 25, 2016.

Franzek E, Beckmann H. Different genetic background of schizophrenia spectrum psychoses: a twin study. The American Journal of Psychiatry 1998; 155: 76-83.

Leonhard K. Classification of Endogenous Psychoses and their Differentiated Etiology. Revised and enlarged edition. Vienna/New York: Springer; 1999.

Peralta V, Goldberg X, Ribeiro M, Sanches-Torres AM, Fananas L, Cuesta MJ. Familiality of psychotic disorders: A polynosologic study in multiple families. Schizophr Bull. 2016 Jul;42(4):975-83.

Pfuhlmann B, Jabs B, Althaus G, Schmidtke A, Bartsch A, Stöber G, Beckmann H, Franzek E. Cycloid psychoses are not part of a bipolar affective spectrum: results of a controlled family study. J Affect Disord. 2004 Nov 15;83(1):11-9.

World Health Organization. International Classification of Diseases 10^th edition. Geneva: World Health Organization; 1994.

September 1, 2016

Victor Peralta’s answer to Thomas A. Ban’s question

         In view of the higher validity of Leonhard’s system in defining more homogeneous groups of schizophrenia in terms of familial aggregation and response to treatment, Thomas Ban poses the appropriate question about if the time has come to implement Leonhard’s nosology in the current classification systems.  My own view about this question is rather pessimistic and there are several reasons for it, although I’ll discuss two, namely some limitations of Leonhard’s nosological system and the influence of the DSM classification.

         Despite the undeniable psychopathological, clinical and research value of Leonhard’s nosology, it is not without some problems. This classification is very complex, lacks operational definitions for types of disorders and it is old fashioned in several ways. For example, several symptom denominations, particularly the motor and behavioral ones, are somewhat idiosyncratic and need reformulation into more modern and recognizable terms. In this regard, the educational program of the INHN headed by Carlos Morra and Ernst Franzek is a good example of this endeavour. The classification of psychosis subtypes is rather rigid, particularly for the lower-order ones, thus leaving no room for the relatively frequent mixed or unspecified forms. Leonhard’s statement that type and subtype diagnoses can be made on the basis of the cross-sectional phenomenology (this despite he considered the course of the disorder a cornerstone in classification) is no longer tenable. For instance, it has been shown that a substantial minority of cases of cycloid psychoses, despite presenting with the typical cycloid symptoms, gradually develop residual symptomatology of several degrees (Peralta and Cuesta 2005). Therefore, the question arises as to whether these patients should be classified as cycloid psychoses (on the basis of their typical symptoms) or unsystematic schizophrenias (on the basis of their residual states).

         A perfect fit between typical or prototypical symptoms/syndromes and specific outcomes does not exist in psychotic disorders nor in other psychiatric disorders. Together with the cross-sectional assessment of psychopathology, for an accurate diagnosis it is absolutely necessary to take into account the course of the disorder. Then the question arises about the illness duration necessary to make the diagnosis. Is it the DSM six-month criterion, the one-year criterion for defining enduring symptoms, or the informal two-year criterion for defining chronicity? Follow-up studies of first-episode samples converge to indicate an overall fair diagnostic stability of psychotic disorders during the first years of the evolution of the psychotic illness (Hesling 2015), and considering the relatively high number of non-schizophrenia cases moving to a diagnosis of schizophrenia over the years, a cautionary note on the diagnosis of psychoses subtypes should be taken into account during the first years of the illness. As a personal opinion, an illness duration of at least five years is the minimum necessary to achieve an accurate diagnosis (i.e., 90% of sensitivity and specificity) of psychotic disorder subtype, this irrespective of the classification system considered. To the best of my knowledge, Leonhard never specified the follow-up time necessary for making reliable or stable diagnoses of psychotic disorders.   

         The complexity of Leonhard’s nosology together with the lack of a clear leadership of this school of thought after Helmut Beckman (Leonhard and Beckmann 1999), among other factors, probably underlies its limited international success in terms of diffusion and validation studies. In this sense, it is frustrating to see, for example, how a recent study on the historical roots of the concept of schizophrenia (Kendler 2016) ignores the contribution of the Wernicke-Kleist-Leonhard school.

         Regarding the DSM, its enormous impact in America and over the world has had a disastrous influence in how phenomenology and classification of psychotic disorders are viewed by mental health academicians, practising psychiatrists and researchers. This has lead Nancy Andreasen (2007) to announce the death of phenomenology in America and, I would add, over the world. She proposed “to make a serious investment in training a new generation of real experts in the science and art of psychopathology” (something with which I fully agree) and stated that “Europeans still have a proud tradition of clinical research and descriptive psychopathology” so that they “can save American science by helping us to figure out who really has schizophrenia or what schizophrenia is.” I disagree with that expectation since European psychiatry, with a few exceptions, has been corrupted by the DSM approach to psychopathology similar to levels in America. It is disappointment to see so many studies conducted over the world (and in Europe) where the clinical assessment of psychotic disorders are conducted by “trained raters” without true clinical expertise who apply structured interviews biased to rate predominantly psychotic experiences, and where sometimes the interviews are conducted telephonically!  As mentioned by Andreasen, too much investment in modern technologies (i.e., neuroimaging, genetics), when accompanied by poor phenomenological and nosological accuracy, inevitably lead to the fruitless enterprise of disentangling the etiopathology of psychotic disorders.  

         Some attempts have been made to (make) render the use of Leonhard’s classification simpler by developing diagnostic decision trees with operationalized diagnostic criteria (simply and/or operational) (Guy 1979; Pethö and Ban 1988; Fritze and Lanzik 1990) (all of them) with limited success in terms of further use (or) WITHOUT validation studies. A broad implementation of Leonhard’s nosology represents an enormous venture requiring three successive steps: 1) a truly international involvement of clinicians with expertise on Leonhard’s psychopathology and nosology; 2) a modernization of this nosology in terms of simplification of the diagnostic scheme and operationalization of symptoms, other diagnostic features and diagnostic rules; and c) research strategies aimed at validating this nosology. Unfortunately, these are issues that I do not actually envision.      

References:

Andreasen NC. DSM and the death of phenomenology in America: an example of unintended consequences. Schizophr Bull 2007;33:108-112. 

Fritze J, Lanzik M. Schedule for operationalized diagnosis according to the Leonhard classification of endogenous psychoses. Psychopathology, 1990;23:303-315.

Guy W. Manual for the classification of endogenous psychoses. 1979. International Network for the History of Neuropsychopharmacology, 2014.

Hesling M. Diagnostic change 10 years after a first episode of psychosis. Psychol Med 2015;45:2257-2769.

Kendler KS. Phenomenology of Schizophrenia and the Representativeness of Modern Diagnostic Criteria. JAMA Psychiatry. 2016;73(10):1082-1092.

Leonhard K, Beckmann H. The classification of endogenous psychoses and their differential etiology. Second, revised and enlarged edition, Springer; 1999.

Pethö B, Ban TA. DCR Budapest-Nashville in the diagnosis and classification of functional psychoses. Psychopathology. 1988;21(4-5):149-240.

Peralta V, Cuesta MJ. Cycloid Psychosis. International Review of Psychiatry, 2005; 17:53–62.

April 27, 2017

Thomas A. Ban’s response  to Victor Peralta’s answer

         Thank you for answering my question whether time has come to implement Leonhard’s diagnostic system in psychiatric research. I understand your pessimistic appraisal of the situation and agree with you about the problems with Leonhard’s classification, even if I would not attribute its lack of success to those problems, but to other factors and especially to the format in which Leonhard presented his classification in his text (Leonhard 1957).

         We certainly agree also about the powerful influence that DSM-III and its successors has had on psychiatric practice, education and research. Yet, by the end of the 20^th century it was evident for all those actively involved that consensus-based diagnoses were inadequate for biological and molecular genetic research. Further, in the new millennium DSM-5 has become vulnerable to the extent that Thomas Insel, as Director of the US National Institute of Mental Health, made it a prerequisite to use the Research Domain Criteria (RDoC) he developed with Bruce Cuthbert in studies supported by the Institute. In the RDoC, DSM diagnoses are replaced by five “domains” of “neurobiological circuits” with the idea that identification of the “sites (domains) of dysregulation” will provide information on the structural underpinning of psychoses (Insel and Cuthbert 2009; Insel, Cuthbert, Garvey, et al. 2010).

         RDoC was discussed on INHN’s website and to open the exchange Samuel Gershon (2015) pointed out that “NIMH ‘jettisoned’ a long tradition of diagnosis-driven research and mandated that all research must begin from a matrix of neuro-scientific structures, such as genes, cells, circuits that cut across behavioral, etc., domains.” He also raised the questions, “How can one do this? What are the benchmarks?”  as “the diagnostic system is in fact very defective, and the data in the genetic realm are undefined?” In his reply to Gershon’s questions, Bernard Carroll (2015) argued that RDoC is “a contrived matrix of metaphysical constructs” and its authors “don’t seem to understand the need to advance nosology by incorporating biomarkers along with clinical symptoms in diagnostic definitions, as happened in general medicine.” In support of his argument, Carroll pointed out how meaningless it would be to “lump together Cushing disease with juvenile onset diabetes mellitus, Type II diabetes mellitus, severe psychological or physiological stress, metabolic syndrome, anorexia nervosa, and pregnancy on the basis of an abnormal glucose tolerance test, which these all can display.”

         Gershon’s questions and Carroll’s reply are in line with the recognition that “In a historical perspective, the RDoC is a tabula rasa, in which 200 years of development in psychiatry is dismissed” (Ban 2015). As presented, it is floating in the air, without any clinical anchors. Nevertheless,  if the population of “circuit-based units”   would be defined  in terms of “nosological homotypes,” by using a matrix in which the rows consist of psychopathological symptoms and the columns, nosological organizing principles (such as form of onset, course, polarity and outcome), the RDoC  could  provide a bridge between psychiatry in the mid-20^th century, based on psychopathology and psychiatric nosology, and a psychiatry in development in the 21^st century with the capability to integrate into its body of knowledge findings generated by rapid advances in the neurosciences (Ban 2002). Considering that Karl Leonhard’s classification of “endogenous psychoses” is the one, among all the different classifications, that would provide diagnoses closest to the diagnoses that nosological homotyping could offer, one would have expected that introduction of the RDoC would generate interest in using Leonhard’s classification in psychiatric research in the “endogenous psychoses.” 

         This was not to be the case as Leonhard’s classification was considered to be complex and difficult to use.

         It is a common contention that Leonhard’s classification is complex and difficult to use. Yes, it is for those without an education in psychopathology and psychiatric nosology, but not for those with a background in these disciplines.  In fact, for those educated in psychopathology and psychiatric nosology, the disciplines which provided a foundation for modern psychiatry by the mid-20^th century, the use of Leonhard’s classification is rather simple. It also spares its users from the burden of having to memorize again and again with every new edition, the artificially derived criteria of consensus-based classifications in which form and content of psychopathology is mixed with behavioral deviations and impairment of social adaptation.

            Leonhard’s classification with its forms and subforms of disease is the culmination of the Wernicke-Kleist-Leonhard (WKL) tradition in psychiatry. It has its roots in: (1) Carl Wernicke’s (1881) adoption of Wilhelm Griesingers’ (1843) notion that mental activity is “reflex” activity; (2) Wernicke’s (1899) classification of psychoses as “hypo (deficit)-functioning,” “hyper (excess)-functioning,” or “para (distorted)-functioning” of one or another component (paths, phases) of the “psychic reflex”; and Wernicke’s identification of subpopulations within the different psychoses with the employment of his “elementary symptoms” approach. An “elementary symptom” within Wernicke’s (1990) frame of reference is a symptom from which, assumedly, all other symptoms of a disease are derived.

         Kraepelin’s (1899) division (“dichotomy”) of the “endogenous psychoses towards the end of the 19^th century, in the 6^th edition of his textbook,” on the basis of “temporal characteristics,” i.e., “course” and “outcome, into “manic depressive insanity,” a disease that follows an episodic course with full remission between episodes, and “dementia praecox,” a disease that follows a continuous deteriorating course, distracted attention from Wernicke’s contributions. Nevertheless, in the 1920s, and ‘30s Kraepelin’s dichotomy of “endogenous psychoses” was re-evaluated by Karl Kleist, a disciple of Wernicke and subsequently, in the 1940s and ‘50s, by Karl Leonhard, a disciple of Kleist. 

         In his re-evaluation, Leonhard employed Edna Neele’s (1948) concept of “polarity” and Wernicke’s concepts of “mental structure” and “elementary symptoms” in classifying patients. With the employment of “polarity,” he divided the population already separated by Kraepelin on the basis of “course” and “outcome,” into “bipolar” and “unipolar diseases,” and separated within both subpopulations (forms) on the basis of the site of the dominant psychopathology, i.e., in the afferent-cognitive (“psychosensory”), central-affective (“intrapsychic”), or efferent-motor (“psychomotor”) component of Wernicke’s “mental structure.” Furthermore, with the employment of Wernicke’s “elementary symptom” approach, he detected within each subpopulation several distinct psychopathology–based subforms.

         In Leonhard’s classification, “bipolar diseases” are characterized by a continuously changing, “polymorph” (multiform), disease picture with a potential to display both extremes in mood, thinking, emotions and/or motility, whereas “unipolar (monopolar) diseases” are characterized by a consistent, unchanging, “monomorph” (simple, also referred to as pure) disease picture with no variation of mood, thinking, emotions and/or motility.

         On the basis of “polarity,” Leonhard splits Kraepelin’s “dementia praecox” into two classes of disease: “(bipolar) unsystematic (non-systematic)  schizophrenias” and “(unipolar) systematic schizophrenias”; and on the basis of Wernicke’s “mental structure,” he divides the  “unsystematic schizophrenias” into three forms of disease, i.e., “cataphasia,” “affect-laden paraphrenia” and “periodic catatonia,” and the “systematic schizophrenias” into paraphrenias (with six elementary symptom-based sub-forms: hypochondriacal, phonemic, incoherent, fantastic, confabulatory and expansive), “hebephrenias” (with four elementary symptom-based sub-forms: silly, eccentric, insipid or shallow and autistic) and “catatonias” (with six sub-forms: parakinetic, affected or manneristic, proskinetic, negativistic, voluble or speech prompt, and sluggish or speech inactive).

         Similarly, on the basis of “polarity,” Leonhard also splits Kraepelin’s “manic depressive insanity” into “(bipolar) manic depressive disease” and “(unipolar) phasic psychoses” and, with consideration of Wernicke’s “mental structure,” he separates from “manic depressive disease” the “cycloid psychoses” and divides the “cycloid psychoses” into “excited-inhibited confusion psychosis,” “anxiety-happiness psychosis” and “hyperkinetic-akinetic motility psychosis.” Furthermore, on the basis of “totality,” the nosological organizing principle introduced by William Cullen (1769, 1776), he separates “pure mania” and “pure melancholia,” “universal” diseases, from the “pure euphorias” (unproductive, hypochondriacal, enthusiastic, confabulatory and non-participatory) and “pure depressions” (harried, hypochondriacal, self-torturing, suspicious and non-participatory), “partial” diseases, each displayed in five distinct elementary symptom-based subforms.

         Within the “bipolar-polymorph” diseases, the signal difference between “manic depressive disease” and the “cycloid psychoses” is that in “manic depressive disease” the “polarity” primarily is in mood, whereas in the “cycloid psychoses” the “polarity” primarily is in thinking (“excited-inhibited confusion psychosis”), emotions (“anxiety-happiness psychosis”) or  psychomotility (“hyperkinetic-akinetic motility psychosis”); and within the “unipolar-monomorph” diseases, the signal difference between “pure mania/melancholia” and the “pure euphorias/depressions” is that in “pure mania” and in “pure melancholia” the entire “mental structure” is affected, whereas in the “pure euphorias” and “pure depressions” only parts of the mental structure is involved. Leonhard’s classification of “endogenous psychoses” was first published in 1957, just about the time when neuropsychopharmacology was born. Yet, in spite of early findings which indicated that therapeutic responsiveness to the same psychotropic drug widely differs in the different subpopulations in Leonhard’s classification, Leonhard’s nosology has remained isolated from the main stream of neuropsychopharmacological and molecular genetic research (Astrup 1959; Fish 1964). In fact, in so far as I know, it was your study, the first and probably still the only one, in which Leonhard’s classification of endogenous psychoses was employed in molecular genetic research (Peralta, Goldberg, Ribeiro et al 2016).

References:

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. Neuropsychopharmacology: The interface between genes and psychiatric nosology. In Lerer B, editor. Pharmacogenetics of Psychotropic Drugs. Cambridge: Cambridge University Press; 2002, pp. 36-56.

Ban TA. The RDoC in historical perspective. Redefining mental illness by Tanya M. Luhrmann. Samuel Gershon’s question. inhn.org.perspective. February 19, 2015.

Carroll B. Bernard Carroll’s reply to Samuel Gershon’s question. in Thomas A. Ban’s

The RDoC in historical perspective. Redefining mental illness by Tanya M. Luhrmann. Samuel Gershon’s question. inhn.org.perspective. March5, 2015.

Cullen W. Synopsis Nosologiae Methodicae. Edinburgh: Kincaid & Creech; 1769.

Cullen W. First Lines of the Practice of Physics. Edinburgh: Kincaid & Creech; 1777.

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

Gershon S. In: Ban TA. The RDoC in historical perspective. Redefining mental illness by Tanya M. Luhrmann. Samuel Gershon’s question. inhn.org.perspective. February 19, 2015.

Griesinger W. Über psychische Reflexactionen. Archiv für Physiologische Heilkunde 1843; 2: 76-112.

Insel T, Cuthbert BN. Endophenotypes: Bridging genomic complexity and disorder heterogeneity 2009; 66: 988-9.

Insel T, Cuthbert B, Garvey M, Heinssen R, Pine DS, Qunn K, Sanislow C, Wang P. Research domain criteria (RDoC): Toward anew classification framework for research on mental disorders. Am J Psychiatry 2010; 167: 748-51

Kraepelin E. Psychiatrie. Ein Lehrbuch für Studierende und Ärzte, 7 Auflage. Leipzig; Barth; 1899.

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

Neele E. Die Phasischen Psychosen. Leipzig: Barth;1949.

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 2016; 42: 975-83.

Wernicke C. Lehrbuch der Gehirnkrankheiten. Breslau; Schlettersche Buchhandlung; 1881.

Wernicke C. Über die Klassifikation der Psychosen. Breslau: Schlettersche Buchhandlung; 1899.

Wernicke C. Grundrisse der Psychiatrie.  Leipzig: Thieme; 2000.

November 23, 2017

August 15, 2019