Differentiated Psychopathology and Molecular Genetics of Endogenous Psychosis: Much More than a Misunderstanding

Marcelo Cetkovich Bakmas123*

1Department of Psychiatry, Institute of Cognitive Neurology (INECO), Pacheco de Melo 1854 (1126) Buenos Aires, Argentina

2Department of Psychiatry, Institute of Neurosciences, Favaloro Foundation Univeristy Hospital, Argentina

3Department of Mental Health and Psychiatry, School of Medicine, Favaloro Foundation University, Argentina

*Corresponding Author:
Marcelo Cetkovich Bakmas
Director, Department of Psychiatry, Institute of Cognitive Neurology (INECO), Pacheco de Melo 1854 (1126) Buenos Aires, Argentina
(54-1-1) 4781-7684
[email protected], [email protected]@rediffmail.com

Received: November 26, 2015; Accepted: November 27, 2015, Published: December 10, 2015

Citation: Bakmas MC. Differentiated Psychopathology and Molecular Genetics of Endogenous Psychosis: Much More than a Misunderstanding. Acta Psychopathol. 2015, 1:26.doi: 10.4172/2469-6676.100026

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Kenneth Kendler is one of the more lucid researchers in the field of genetic of schizophrenia. In a recent a thoughtful comprehensive paper he grouped predictive variables in psychiatric research in three groups: psychological (that includes symptoms), biological (including genetic, molecular and structural) and environmental (including individual, familial and social) (Kenneth S Kendler, 2014) [16]. Kendler please that researchers must bear in mind this schemata, in order to ascribe their data to one of this levels of research, for the seek of order. Being a supporter of a dimensional approach he has also carried out studies with data showing that psychosis involves several phenotypes, and not only two diseases, like in the Roscommon study (KS Kendler et al., 1998; KS Kendler et al., 1995) [17, 18]. In a recent comprehensive review Kendler highlights the difficulties of genetic research in psychiatry that clearly explain methodological differences between dimensional and categorical approaches, and explain how they are rooted in two different genetic research traditions, “biometricians” and “Mendelians” (KS Kendler, 2014) [19]. In this paper Kendler concludes that “the historical effort to ground the categorical nature of schizophrenia has failed”. This assumption is based mostly in Genome Wide Scan Studies (GWAS), where imprecise clinical profiling of phenotypes under study is almost the rule. Most of this studies struggle to find genetic markers of schizophrenia as an absent-present phenomena, bypassing most subtle clinical traits. Some researchers based on this results argue that, even splitting schizophrenia from bipolar disorders could be an artifact and that boundaries are not clear (Owen et al., 2007) (Craddock et al., 2009) [20, 21]. Our point of view is that these looks like a “post hoc propter hoc” interpretation of results.

A recent and highly debated paper published by Arnedo et al shows strong evidence that such an affirmation could be wrong (Arnedo et al., 2015) [22]. Through a complex statistical analysis of data from three different GWAS studies they show a complex molecular and clinical architecture combination demonstrating the categorical clinical heterogeneity of schizophrenia. They started pointing those complex diseases like schizophrenia could be affected by hundred thousands of genetic variables interacting between them showing a complex genetic architecture. Multiple and different paths of interaction leads to multiple aspects of the disease. The idea of “one gene one disease” must be abandoned. Second, they refer that the architecture of genetic of heritable diseases refers to the number, frequency and size of the effect of genetic risk alleles and the way they are organized in genotypic networks. In complex disorders, same genotypic networks could lead to different clinical outcome (multifinality or genetic pleiotropy) and different genetic networks could lead to the same clinical outcome (equifinality or heterogeneity). Geneticist must expect that several genes affecting each trait and each gene affecting several traits. For Arnedo et al this simple genetic research rules, make understandable that heritable disorder’s research have the chance to lead to weak and inconsistent results, unless their complex genetic and phenotypic complexity is taken in account. This is the key aspect of their research, the very sophisticated combination of two complexities. They lost the assumption of schizophrenia being a single variable: absent or present, and deal with the idea of a complex phenotypic architecture and went for it. They took clinical data from three different GWAS studies and selected 93 clinical traits from the “Diagnostic Interview for Clinical Studies”. They used a generalized factorization method combined with non-negative matrix factorization, in order to identify candidates for functional clusters. In this way they were able to identify 343 different phenotypic groups with chance of overlap, with different clinical characteristics grouped in particular cases of schizophrenia. Moreover: phenotypic groups of clinical syndromes, in an independent way of their genetic base. They also used the same method to find several interacting sets of single nucleotide polymorphisms that clustered in certain individuals, regardless their clinical status. Then, they tested whether SNPs sets were associated with distinct phenotypic sets, and they allow the researchers to find “eight classes of schizophrenias” according a particular combination of clinical profile and SNPs sets. Arnedo et al conclude that their findings indicate that schizophrenia comprise several different clinical syndromes associated with several genotypic networks disassembled. Then, most of heritability of schizophrenia has been not detected when the paradigm present-absent is used. Their purely data driven analysis shows that elusive heritability of schizophrenia is not lost, but encrypted within a complex distribution of relationships between genotypes and phenotypes. They admit that their evidence indicating that schizophrenia is a heterogeneous group of diseases suggest that reduction of clinical information about schizophrenia to a single categorical diagnosis as inadequate.

Shortly after this paper, another one very similar demonstrated a complex phenotype-genotype interaction in the field of Affective disorders (Xu et al., 2015) [23]. Using clinical data from the General Health Questionnaire (GHQ) which have four dimensions, Xu et al were able to find a stronger association sub phenotypes with SNPs with a high size effect. We find in this paper another example of how a better definition of clinical phenotypes, this time extracted from a short questionnaire, clinical-genetic correlation could be improved.

In conclusion: modern mathematical approach to the highly complex issue of the “architecture” of mental disorders ethology, particularly genetics, shows that phenotypes are far more complex than mostly assumed by current diagnostic manuals. For this, a psychopathological dimensional approach has been proposed as an alternative. On the other hand, reviewed studies like Arnedo´s revisit the classic categorical approach in psychiatry: that mental disorders can be subdivided, according clinical traits, in several sub forms like, for example, the Wernicke Kleist Leonhard School of Psychiatry proposed decades ago.

During the last meeting of the International Society of Bipolar Disorder in Toronto Heinz Grunze gave a lecture with the suggestive title of “Apples and Peas are similar but not the same”. After reviewing all clinical differences demonstrating why schizophrenia and bipolar disorder are different conditions he concluded: “The less scientific argument but the more relevant from a clinical point of view: an experimented clinician can say immediately who is who”. And he sums up the problem saying that “finally, all brain diseases meet in some point of continuity of affectation of the same organ, having the same neurotoxic paths, their phenotypes could overlap in a significative way”. We propose that the same principles could be applied to clinical sub forms of schizophrenia.

Following times in Neuroscience research of schizophrenia and other conditions like bipolar disorder, will witness renewal of interest in psychopathology. Explanation and understanding, as proposed by Karl Jaspers one hundred year ago (Stanghellini & Fuchs, 2013) [24], are the two main tools of descriptive psychopathology, the cognitive system that allow us to get access to our patients suffering and complains (Berrios, 1996) [25]. Empathy, core feature of psychopathology, became focus of complex neurobiological research, also (Melloni et al., 2014) [26].

This framework push us to remember the old paragraph: “Looking for news? read the classics”.


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