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Communication Dans Un Congrès Année : 2017

RNA signature and prediction to treatment response in first episode schizophrenia

Résumé

Background: Despite nearly fifty years of pharmacological research, the treatment of schizophrenia remains a challenge and clinical outcomes are still far from optimal. One of the major shortcomings in the current treatment of schizophrenia is that we have no valid criteria in clinical practice to predict who will respond to antipsychotic treatment and how long the treatment should be maintained before changing therapeutic strategy. The identification of blood-based biological markers of drug response with a good sensitivity and specificity would enable physicians to use these tests prior to choosing the antipsychotic treatment and therefore help the practitioner in his daily clinical practice. Methods: Through a European consortium on Optimization of Treatment and Management of Schizophrenia in Europe (OPTiMiSE) [1], we ran analyses on 214 subjects with first episode schizophrenia, schizophreniform or schizoaffective disorder who were included in a clinical trial. Patients had minimal to no exposure to antipsychotics at inclusion and were all treated for four weeks with amisulpride. Blood samples were collected at inclusion and after treatment. DNA and RNA were extracted. Using RNA-Seq, we analysed transcriptome for each patient before and after treatment as well as according to treatment outcome defined as remitter versus non-remitter following remission criteria of Andreasen [2]. The detection of differentially expressed genes and pathways have been achieved using the combination of the DESeq2 package [3] and the Panther’s ontology-based pathway database [4], with the aim of predicting remission before treatment. Genotypic data have been generated for each subject using DNA array containing more than 900,000 probes, and genotypes have been used to detect single nucleotide polymorphisms (SNPs) that have an effect on gene expression (eQTL, expression quantitative trait loci). Results: From almost 11,000 genes expressed in peripheral blood mononuclear cells, we detected significantly more differentially expressed genes in remitted patients than in non-remitted subjects after 4-week treatment with amisulpride ( p = 0.01). A subgroup of these genes was already differentially expressed before treatment between remitted and non-remitted patients and may help predicting treatment response. Among differentially expressed genes after amisulpride treatment, we identified genes for which expression was correlated with clinical symptom improvement. Pathway analyses revealed enrichment of the GABA-B receptor II signalling pathway, including genes that have already been associated with psychiatric disorders in previous studies. In addition, association studies using cis eQTL identified genetic variations, which were both associated with gene expression and treatment response, suggesting they may be used to predict remission before treatment. Conclusion: We demonstrated here that amisulpride affects gene expression in peripheral blood mononuclear cells, mainly in patients who are in remission after four weeks of treatment. Genes and pathway analyses identified molecular mechanisms that were associated with symptom improvement and should help both in the identification of biological signatures of treatment response as well as in the development of new therapeutic strategies
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Dates et versions

cea-04516224 , version 1 (22-03-2024)

Identifiants

  • HAL Id : cea-04516224 , version 1

Citer

Réjane Troudet, W. Bel Haj Ali, C. Barau, Anne Boland-Auge, Jean-François Deleuze, et al.. RNA signature and prediction to treatment response in first episode schizophrenia. 30th ECNP Congress, Sep 2017, Paris, France. pp.S597. ⟨cea-04516224⟩
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