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

Victor Peralta's response to Larry Stein’s comment


Thank you for 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 et al., 2015) and other studies (Frank 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 et al., 1985), the positive/negative dichotomy (Crow, 1980), the good-poor outcome dystinctions 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 (Bigdely et al., 2014) or treatment-resistant patients (Frank 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 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.



Ban TA. Thomas A. Ban reply to Larry Stein’s comment. Historical Perspective, May 5, 2016.

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, et al. Identification of increased genetic risk scores for schizophrenia in treatment resistant patients. Mol Psychiatry 2015;20:150-151.

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. Schizophrenia Bulletin Advance Access 2015 doi: 101093/schbul/sbv.

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

Sekar A, Bialas AR, de Rivea H, et al. Schizophrenia risk from complex variation of complement component 4.  Nature 2016


March 30, 2017