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Theses

PHARMACOGENETIQUE DE LA SCHIZOPHRENIE

Abstract : Since the serendipitous discovery of typical antipsychotics in the treatment of schizophrenia, several molecules have been developed for their tolerance and a specific action. However, before any prescription of these molecules, in the spirit of the disorder, the concept of resistance to the treatment was evoked. Indeed, there is an inter-individual variation of response to antipsychotics in schizophrenic subjects that was described by specific scales of evaluation. It appears that clinical factors seem to contribute to the non response of treatment and they are not appreciated so well. Psychotics follow specific pathways and it is know that physiological and biochemical effects depend on factors. Thus, smoking habits, alcohol and diet have been described as factors influencing variability in drug response. While age, gender and genetic factors seem to contribute to the quality of therapeutic response. Evidence from family, twin and adoption studies clearly demonstrate the involvement of genetic factors in schizophrenia. Both linkage and association studies support this hypothesis. Although the results of such studies remain inconsistent regarding the heterogeneity of the disease. Refinement of the phenotype using the pharmacogenetic approach could thus be useful in the genetic studies of schizophrenia. Pharmacogenetic research claim to assess a possible interaction between the therapeutic targets of antispychotics and their specific mutations in candidate genes. High affinity of atypical antipsychotics for 5-HT2A receptors may explain their specific efficacy/tolerability profile compared to conventional antipsychotics. A number of reports have associated a silent 5-HT2A polymorphism (T102) with response to clozapine or risperidone. This polymorphism is in complete linkage disequilibrium with a -1438A/G polymorphism, located within the promoter region of the gene, with conflicting results. Phenotypical heterogeneity of schizophrenia might explain such discrepancies. For example, negative symptoms are known to reflect severity of illness and to restrain therapeutic response. On this basis, we re-assessed the possible influence of the −1438A/G polymorphism of the 5-HT2A receptor gene on the clinical efficacy of atypical antipsychotics with focus on several relevant dimensions. The A allele and the AA genotype of the −1438A/G polymorphism of the gene coding for the 5-HT2A receptor were not associated with therapeutic response to atypical antipsychotics in our sample. Furthermore, the AA genotype appeared to be associated with the SANS score, raising the possibility that negative symptoms in schizophrenia constitute a confounding factor between the 5-HT2A gene and atypical antipsychotic response. Traditionally, dopaminergic and serotoninergic sytems have been used as targets for antipsychotic therapy. Although, most available antipsychotics have a multitarget profile without any clear mechanism of action. Recently, atypical antispychotics have been found to display a wide range of affinities for several neurotransmitters. Neurobiological research suggest a significant role of the endocannabinoid system in schizophrenia vulnerability and also in the quality of response to antipsychotics. Epidemiology studies show that patients consume twice more of cannabis than the general population. An increase of the density of receptors is observed in the dorsolateral prefrontal cortex of schizophrenic post mortem samples. The CNR1 gene, that encodes the CB1 receptor, is located on chromosome 6q14-15, which has been considered as a susceptibility locus for schizophrenia. Recent progress in pharmacogenetics, evaluating the individual risk for antipsychotic refractoriness, has focused notably on the dopaminergic and serotoninergic systems. However, so far, these studies led to discrepant data. This led us to assess the possible influence of the 1359G/A polymorphism as a haplotype tagging SNP of the CNR1 gene, in comparison with three other SNPs covering 14kb across this gene, on the risk of schizophrenia and/or therapeutic response to atypical antipsychotics. We found no difference in 1359G/A polymorphism between patients and control subjects, and no relationships were noted between this polymorphism and any clinical parameter considered as potential intermediate factor. However, the G allele frequency was significantly higher among non-responsive vs responsive patients, with a dose effect of the G allele. In contrast, no association was found for three other genetic polymorphisms of the CNR1 gene. Pharmacogenetics may in future lead to individualized pharmacotherapy based on the specific genetic, environmental and demographic characteristics of each patient. Pharmacogenetics could thus increase the patient comfort in terms of both higher initial response rates and reduced propensity to developing debilitating side-effects.
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Submitted on : Monday, April 8, 2013 - 12:50:38 PM
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  • HAL Id : tel-00808991, version 1

Citation

Nora Hamdani. PHARMACOGENETIQUE DE LA SCHIZOPHRENIE. Sciences cognitives. Université Pierre et Marie Curie - Paris VI, 2007. Français. ⟨NNT : 2007PA066219⟩. ⟨tel-00808991⟩

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