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

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 (Cetkovich 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 eta 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 et al 2016).

            Peralta et al (2015) 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 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 et al found that cycloid psychosis has a higher family loading than systematic schizophrenia  (Stober et al 1995), whereas  Leonhard himself and Bruno Pfuhlmann found  that cycloid psychosis have a low genetic loading (Leonhard quoted by Pfuhlmann 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 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, Rocío RZ, et al. Molecular Gene tics of Schizophrenia Consortium. Uncovering the Hidden Risk Architecture of the Schizophrenias: Confirmation in Three Independent Genome-Wide Association Studies. The American Journal of Psychiatry 2015; 172: 139-153.

 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 Bakmas M Differentiated psychopathology and molecular genetics of endogenous psychosis: Much more than a misunderstanding. (2015) Acta Psychopathologica 2015; 1 (3): 26.

 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.

OwenMJ,CraddockN,JablenskyA. The genetic deconstruction of psychosis. Schizophrenia Bulletin 2007; 33: 905-911.

Peralta V, Goldberg X, Ribeiro M, Sanches-Torres AM, Fananas L, Cuesta MJ. Familiality of psychotic disorders: A polynosologic study in multiple families. Schizophrenia Bulletin Advance Access 2015 doi: 101093/schbul/sbv192.

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. (2014). 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.

Marcelo Cetkovich

April 28, 2016