[Pharmacogenetics and treatment response in schizophrenia].
The pharmacogenetic strategy uses the genetic association approach with the aim of identifying genes that influence clinical response to drug treatment. Association studies have focused mainly on neuroleptics (in particular clozapine) and variants in candidate genes of dopamine and serotonin systems in schizophrenic patients. Concerning the serotonin 5-HT(2A) receptor gene, the frequency of allele tyrosine (versus histidine) at 452 was greater among nonresponders, and homozygosity for the cytosine allele at 102 was more frequent among nonresponders. In the serotonin 5-HT(2C) receptor gene, a cysteine to serine substitution at 23 was considered as a predictor of good response to clozapine. Concerning the dopamine D2 receptor gene, the patients with one or two A1 alleles showed greater improvement than those with no A1 allele (Taq1A genotype). In addition, compared with patients who exhibited a Del allele at 141, patients with no Del allele showed better clinical response. Regarding the dopamine D3 receptor gene, the homozygous genotype serine/serine at 9 was found to be more frequent among the nonresponders. Finally, there was a possible relationship between the 48 bp variant number tandem repeat polymorphism in dopamine D4 receptor gene and response to neuroleptics.


CONCLUSIONS
However, some results conflict with other data in the literature. The frequent difficulties in replication of pharmacogenetic findings can be explained by, among others: (i) the lack of a consistent definition of drug response; (ii) the use of different scales to evaluate response to treatment and the use of several cut-offs for the same scale; (iii) the sample heterogeneity and the small sample size; and (iv) the multigenic interactions. In order for research to progress, methodological consistency must be achieved, not only to form the basis of comparison among studies and to confirm or invalidate previous results, but also to allow for meta-analysis between the various studies. Nevertheless Kane et al. [Arch Gen Psychiatry 45 (1988) 789-796] have defined precise criteria of clinical response, but they are restrictive and quite difficult to set up in practice. Pharmacogenetic research has the following advantages: (i) it is based on the individual patient's genotype, invariable data in normal conditions, and can therefore be measured at any time during treatment; (ii) it uses reliable molecular biological techniques; and (iii) it is in constant progress because of the increasing amount of genomic information available.


CONCLUSIONS
In future, a combination of several polymorphisms showing a strong association with a specific neuroleptic response could constitute a clinical test to predict the individual response to such treatment, and therefore participate in the prescription process. A research team has already proposed a combination of six polymorphisms implicating 5-HT(2A) receptor, 5-HT(2C) receptor, 5-HTTLPR, and H2 receptor genes [Lancet 355 (2000) 1615-1616], but this result has to be replicated. Until now, pharmacogenetics has focused on the global clinical response, but in the years to come, it could focus on the genes implied in the effects of treatments on specific symptoms and on physiological mechanisms that would explain how gene polymorphism can influence therapeutic response. This review aims to summarise recent advances and to present future clinical applications for pharmacogenetics.
Moulier
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Unité de recherche clinique, établissement public de santé de Ville-Evrard, 5, rue du Docteur-Delafontaine, 93200 Saint-Denis, France. urcve@freesurf.fr
Januel
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D000483:Alleles; D006801:Humans; D011110:Polymorphism, Genetic / Q000235:genetics; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics*; D050637:Receptors, Dopamine D3 / Q000235:genetics; D050638:Receptors, Dopamine D4 / Q000235:genetics; D012559:Schizophrenia / Q000188:drug therapy* / Q000235:genetics*
C493593:DRD3 protein, human; C493599:DRD4 protein, human; D044402:Receptor, Serotonin, 5-HT2A; D050637:Receptors, Dopamine D3; D050638:Receptors, Dopamine D4