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Etude des facteurs cliniques et pharmacogénétiques prédictifs de la réponse (efficacité) aux traitements neuroleptiques atypiques dans la schizophrénie

Abstract : Schizophrenia is a frequent and serious disease occurring in approximately 1% of the population that usually begins between the ages of 15 and 25 years and constituting a major public health problem. Its evolution is marked by chronicity and high frequency of relapses. Since the early 1950s and the discovery of neuroleptics, and later the apparition of second generation of antipsychotic, the management of schizophrenia has been considerably modified. However, adverse side effects and non response or resistance constitute the main limits of these treatments. Percentage of non response during acute phases remains high, with no possible prediction of non response risk as a function of the selected treatment. Today, the prescription of these drugs follows a try/fail rule and there are no validated criteria to choose between the different treatments. A major progression in clinical research in schizophrenia, particularly for the apprehension of factors associated with prognosis, was obtained by using harmonized diagnosis criteria with good reliability (DSMIV) and by assessing response with dimensional tools (PANSS, BPRS, CGI). There have been descriptions of predictive factors of poor response to antipsychotic treatment mainly with first generation: age of onset of schizophrenia, duration of untreated psychosis and severity of symptomatology for clinical predictors. Pharmacogenetic study genetics mechanisms implicated in treatment response and allow underscoring predictive factors of treatment efficacy. By a literature review we aimed to summarize recent finding into pharmacodynamic approach of pharmacogenetics of antipsychotics and particularly second generation. Published studies in the field have mainly focused on pharmacodynamic hypotheses and genes implicated in monoamine's receptors synthesis. The methodological limits of the first published studies, in particular the lack of ethnic homogeneity of the studied populations and the weak definition of the phenotype, probably explain the lack of replication of such studies. In a prospective study of a sample of Caucasian schizophrenic patients treated with olanzapine or risperidone, clinical and socio-demographical criteria were assessed as factors that may predict drug response. Early onset and duration of the disease, individually predicted an unfavourable drug response. We also studied genetic variants of the norepinephrine transporter (which is inhibited by olanzapine and risperidone) to see how they may affect antipsychotic drug efficacy. Two polymorphisms were associated with a reduction in positive symptoms in treated schizophrenic patients. These results confirm the difficulty in predicting drug response in schizophrenia without developing strong biological markers. For the future the aim of pharmacogenetic research is to help practitioners to choose treatments in a more rational way.
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Submitted on : Wednesday, August 29, 2012 - 2:04:06 PM
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Georges Brousse. Etude des facteurs cliniques et pharmacogénétiques prédictifs de la réponse (efficacité) aux traitements neuroleptiques atypiques dans la schizophrénie. Psychiatrie et santé mentale. Université d'Auvergne - Clermont-Ferrand I; Université Blaise Pascal - Clermont-Ferrand II, 2009. Français. ⟨NNT : 2009CLF1MM11⟩. ⟨tel-00726226⟩



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