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      Clinical and Genetic Factors Associated with Resistance to Treatment in Patients with Schizophrenia: A Case-Control Study

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          Abstract

          Objectives: To assess clinical and genetic factors affecting response to treatment in a sample of patients with schizophrenia (treatment-resistant patients versus treatment responders). We also aimed at examining if these factors are different when we consider two different resistance classifications (the positive and negative syndrome scale, PANSS and the brief psychiatric rating scale, BPRS). Material and Methods: A case-control study included treatment-resistant patients and good responders. Patients were stratified in two groups based on the established criteria for treatment-resistant schizophrenia using BPRS and PANSS. The study was approved by the ethical committees (references: CEHDF1017; HPC-017-2017) and all patients/legal representatives gave their written consent. Clinical factors were assessed. DNA was obtained using a buccal swab and genotyping for OPRM1, COMT, DRD2 et MTHFR genes using the Lightcycler ® (Roche). Results: Some discrepancies between the BPRS and PANSS definitions were noted in our study when assessing the patients’ psychopathological symptoms and response to treatment. The multivariable analysis, taking the presence versus absence of treatment resistance as the dependent variable, showed that that family history of schizophrenia, university studies, time since the beginning of treatment and chlorpromazine equivalent dose as well as the COMT gene are associated with resistance to treatment. In addition, a gender-related difference was noted for COMT SNP; men with at least one Met allele were more prone to be resistant to treatment than Val/Val patients. Conclusion: Uncovering the clinical and genetic factors associated with resistance to treatment could help us better treat our schizophrenic patients in a concept of personalized medicine.

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          Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain.

          Catechol-O-methyltransferase (COMT) is a key enzyme in the elimination of dopamine in the prefrontal cortex of the human brain. Genetic variation in the COMT gene (MIM 116790) has been associated with altered prefrontal cortex function and higher risk for schizophrenia, but the specific alleles and their functional implications have been controversial. We analyzed the effects of several single-nucleotide polymorphisms (SNPs) within COMT on mRNA expression levels (using reverse-transcriptase polymerase chain reaction analysis), protein levels (using Western blot analysis), and enzyme activity (using catechol methylation) in a large sample (n = 108) of postmortem human prefrontal cortex tissue, which predominantly expresses the -membrane-bound isoform. A common coding SNP, Val158Met (rs4680), significantly affected protein abundance and enzyme activity but not mRNA expression levels, suggesting that differences in protein integrity account for the difference in enzyme activity between alleles. A SNP in intron 1 (rs737865) and a SNP in the 3' flanking region (rs165599)--both of which have been reported to contribute to allelic expression differences and to be associated with schizophrenia as part of a haplotype with Val--had no effect on mRNA expression levels, protein immunoreactivity, or enzyme activity. In lymphocytes from 47 subjects, we confirmed a similar effect on enzyme activity in samples with the Val/Met genotype but no effect in samples with the intron 1 or 3' SNPs. Separate analyses revealed that the subject's sex, as well as the presence of a SNP in the P2 promoter region (rs2097603), had small effects on COMT enzyme activity. Using site-directed mutagenesis of mouse COMT cDNA, followed by in vitro translation, we found that the conversion of Leu at the homologous position into Met or Val progressively and significantly diminished enzyme activity. Thus, although we cannot exclude a more complex genetic basis for functional effects of COMT, Val is a predominant factor that determines higher COMT activity in the prefrontal cortex, which presumably leads to lower synaptic dopamine levels and relatively deleterious prefrontal function.
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            Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology.

            Research and clinical translation in schizophrenia is limited by inconsistent definitions of treatment resistance and response. To address this issue, the authors evaluated current approaches and then developed consensus criteria and guidelines.
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              Inflammation in Schizophrenia: Pathogenetic Aspects and Therapeutic Considerations

              This paper discusses the current evidence from animal and human studies for a central role of inflammation in schizophrenia. In animal models, pre- or perinatal elicitation of the immune response may increase immune reactivity throughout life, and similar findings have been described in humans. Levels of pro-inflammatory markers, such as cytokines, have been found to be increased in the blood and cerebrospinal fluid of patients with schizophrenia. Numerous epidemiological and clinical studies have provided evidence that various infectious agents are risk factors for schizophrenia and other psychoses. For example, a large-scale epidemiological study performed in Denmark clearly showed that severe infections and autoimmune disorders are such risk factors. The vulnerability-stress-inflammation model may help to explain the role of inflammation in schizophrenia because stress can increase pro-inflammatory cytokines and may even contribute to a chronic pro-inflammatory state. Schizophrenia is characterized by risk genes that promote inflammation and by environmental stress factors and alterations of the immune system. Typical alterations of dopaminergic, serotonergic, noradrenergic, and glutamatergic neurotransmission described in schizophrenia have also been found in low-level neuroinflammation and consequently may be key factors in the generation of schizophrenia symptoms. Further support for the relevance of a low-level neuroinflammatory process in schizophrenia is provided by the loss of central nervous system volume and microglial activation demonstrated in neuroimaging studies. Last but not least, the benefit of anti-inflammatory medications found in some studies and the intrinsic anti-inflammatory and immunomodulatory effects of antipsychotics provide further support for the role of inflammation in this debilitating disease.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                25 September 2019
                October 2019
                : 20
                : 19
                : 4753
                Affiliations
                [1 ]Laboratory of Pharmacology, Clinical Pharmacy and Drug Quality Control, Faculty of Pharmacy, Pôle Technologie-Santé (PTS), Faculty of Pharmacy, Saint-Joseph University, Beirut 1107 2180, Lebanon; lydia.khabbaz@ 123456usj.edu.lb
                [2 ]Faculty of Pharmacy, Saint-Joseph University, Beirut 1107 2180, Lebanon; saria.sahyoun@ 123456gmail.com
                [3 ]Faculty of Philosophy and Human Sciences, Holy Spirit University (USEK), Jounieh, Lebanon; Saharobeid23@ 123456hotmail.com
                [4 ]Faculty of Pedagogy, Lebanese University, Beirut 14/6573, Lebanon
                [5 ]Psychiatric Hospital of the Cross, Jal Eddib 6096, Lebanon; Chadia_9@ 123456hotmail.com (C.H.); Jossiek@ 123456hotmail.com (J.A.)
                [6 ]INSPECT-LB: Institut National de Sante Publique, Epidemiologie Clinique et Toxicologie, Beirut 1107 2180, Lebanon; souheilhallit@ 123456hotmail.com
                [7 ]Faculty of Medicine, Lebanese American University, Byblos 13-5053, Lebanon
                [8 ]Faculty of Medicine and Medical Sciences, Holy Spirit University of Kaslik (USEK), Jounieh, Lebanon
                Author notes
                [* ]Correspondence: aline.hajj@ 123456usj.edu.lb ; Tel.: +961-1-421-000 (ext. 6826); Fax: +961-1-421-022
                [†]

                Last co-authors.

                Author information
                https://orcid.org/0000-0003-2413-2684
                https://orcid.org/0000-0001-6918-5689
                Article
                ijms-20-04753
                10.3390/ijms20194753
                6801865
                31557839
                c7c13812-59bc-4afc-acb8-ce92a988b6a4
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 10 July 2019
                : 31 July 2019
                Categories
                Article

                Molecular biology
                bprs,comt,drd2,mthfr,oprm1,panss,resistance,response to treatment,schizophrenia
                Molecular biology
                bprs, comt, drd2, mthfr, oprm1, panss, resistance, response to treatment, schizophrenia

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