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Genetic Markers of Treatment-Resistant Schizophrenia

M.V. Ivanov, D.N. Sosin, M.V. Shamanina, M.G. Yanushko
Federal state budgetary institution V. M. Bekhterev national research medical center for psychiatry and neurology of the Russian Federation Ministry of health

ABSTRACT
Approximately one third of patients, suffering from schizophrenia have symptoms of therapeutical resistance. Alongside the difficulties of therapy of such conditions there are also some diagnostic difficulties because nowadays exist many the criteria of determination of treatment resistance. Treatment resistance can be based on different factors, from which genetic predisposition can certainly be emphasized. Many researchers agree that ТR course of schizophrenic spectrum disorders is a separate subgroup and also perhaps it is more genetically determined variant of the of mental disorders course. Researches aimed at the search of the genetic predictors of the therapeutical resistance have been conducted for many years. Risk factors for development TRS are polymorphic variants of genes connected with the exchange of monoamines (serotonin, dopamine, noradrenaline) into central nervous system: receptors of mediators (5-HTR2A, DRD2, DRD3, DRD4), protein-transmitters (SERT), factors of metabolism (TPH1, COMT). The most significant predictors of development TRS are polymorphisms Т102С, -1438-G and Tyr452 of gene 5-HTR2A, SERT-in2 and SERT-PR of gene SERT, A779C of gene TPH1 presence of haplotype rs6280 rs1486012 rs7631540 of gene DRD3, presence of haplotype TaqI A и -141CIns/Del of gene DRD2. Research showed the influence of immune system genes on formation of TRS, more precisely: allelic variant HLA-A1 of gene of main histocompatibility complex of, polymorphic variant rs7085850, haplotypes rs1926203 rs7088326 and rs1926189 rs210543 of gene FAS, polymorphic variants rs11030104, rs10501087, rs6265 of gene BDNF, rs3738401 (Q264R) of gene DISC1 and genes GSTM, GSTT1, RELN. The results of such researches are very contradictory, besides researches showing the connection with TR there are also researches which show opposite results. The results of researches that are using method of full genome sequencing are also contradictory. Two large researches (the first included 384 gene-candidate, the second included 1 178 234 single nucleotide polymorphic variants) did not show any connection with TR, the third research (selection of 174 patients, 79 of which met the criteria of treatment resistance) on the contrary showed the connection of polymorphic variant rs2237457 of gene GRB10.

In general nowadays there are quite a few researches , comparing patients with TR course of schizophrenic spectrum disorders and patients with good respond to antipsychotic therapy, and also comparatively small amount of replicated works. Determination of biomarkers of TR course of schizophrenia can clear the problem of etiology and pathogenesis of disorders in this spectrum. Early detection of such patients will allow to adhere more strictly to the algorithm of the therapy, as well as to introduce anti-resistant methods at an earlier stage, thereby reducing the risk of disadaptation and, accordingly, disability of such patients.

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