La pharmacogénétique des antipsychotiques : considérations générales et implications cliniques

Abstract

In psychiatry, the first uses of antipsychotics revolutionized the care of patients. Yet, seventy years later, their prescription is still empirical. Furthermore, we still ignore a lot, as much on the mecanisms of action as on the variability of the responses observed. Too often, the occurrence of side effects and/or the absence of a therapeutical response are the rule instead of being the exception. The factors of these failures are multiple and among them, genetics is central. Pharmacogenetics is the science which researches and studies the genetic factors responsible for the response to medication. It focuses as much on pharmacokinetics as on pharmacodynamics: the objective being to abandon the current paradigm which seeks a « fit for all » medication to tend toward « the right drug for the right patient at the right time ». Since the laws of Mendel on heredity, the knowledge regarding DNA and more widely the genome have not stopped evolving and continue to expand considerably every day thanks to the new techniques of analysis and the always bigger collection and processing of huge data. Such improvement has allowed to go from the study of the great laws of heredity to that of more complex genetic factors happening on a molecular level with sometimes an infinitesimal probability of occurrence. They have also allowed to shine a light on the importance of non coding regions and on the impact of the environment on gene expression. These complex hereditary factors account for the tendency for some people to present distinctive pathologies and for the individual variability of the response to neuroleptics. Among them, genetic polymorphisms are studied with a particular focus as they play a central part in the interindividual differences. The case of P450 cytochrome is an illustration of the impact of genetics on the metabolism of antipsychotics and of its consequences on the produced effects. It is also an exemple of the first clinical applications of pharmacogenetics to antipsychotics. Today the genotyping of CYP2D6 cytochrome is indicated before the prescription of aripiprazole and risperidone. Indeed, the prescribed doses have to be adapted in accordance with the patient's phenotype so as to optimize the treatment and to prevent the occurrence of side effects or the absence of a therapeutical response. It represents a first step towards individualized medicine. Currently, several international consortiums are studying these questions, which represent a high promise of progress. However, the guidelines arising from their research show that their work is insufficiently standardized and coordinated: the signs of a science in full growth but still very young. Improvement and discoveries in the domain are making lightning progress and it is sure that in the future pharmacogenetics will be a standard tool in the daily practise of psychiatrists.