Pharmacorésistance aux psychotropes et anomalies pharmacogénétiques du cytochrome P450 2D6 : vers une médecine personnalisée en pédopsychiatrie, présentation d’un protocole de recherche

Abstract

BackgroundPsychotropic drugs such as antipsychotics (AP) and antidepressant (AD) are frequently used in children and adolescents for the treatment of psychiatric diseases, with a constantly increasing prescription rate for atypical AP. Nevertheless, in France, only two atypical AP have marketing authorization in children, and 5 in adolescents. Consequently, a significant part of AP prescriptions in the pediatric population is off-label and depends on the experience of each clinician. In addition, some patients are pharmaco-resistant inducing exposure to several psychotropic molecules, long and/or repeated hospitalizations, relapses, and sometimes interruption of care pathways. Many psychotropic treatments are metabolized at the hepatic level by cytochrome P450 and in particular its subunit CYP2D6. In child psychiatry, most commonly prescribed AP and AD drugs are metabolized by CYP2D6, e.g., risperidone, aripiprazole and fluoxetine. Duplication of the CYP2D6 gene is linked to very rapid metabolizer phenotype and thus typically to clinical inefficiency of treatment. The frequency of this pharmacogenetic anomaly is up to 10 % in the general population in Southern Europe. MethodsWe describe the implementation of a biomedical study, whose main objective is to describe the prevalence of duplication or polymorphisms of CYP2D6 gene associated with very rapid metabolizer phenotype, in the pediatric population pharmaco-resistant to CYP2D6-mebtalized psychotropic drugs (AP or AD). Secondary objectives are to study the associations between the presence of functional anomalies of CYP2D6 gene and the characteristics related to patient and mental health disease. This study will include 22 children or adolescents patients from 4 child and adolescent psychiatry (CAP) departments. CYP2D6 genotyping will be realized from salivary sampling. FindingsThe expected results on the main judgment criterion might highlight a link between pharmacoresistance and duplication of CYP2D6 in our patient population. The results on secondary endpoints should help to better characterize the population of drug-resistant patients and mental health diseases in CAP. PerspectivesThe demonstration of a link between drug resistance and duplication of the CYP2D6 gene should help to develop treatment strategies using molecules not metabolized by CYP2D6 and/or having a very restrictive marketing authorization earlier in the evolution of psychiatric illness, as well as the intensification of non-pharmacological treatment strategies in such patients. Overall, many links between CYP2D6 and psychiatry remain to be studied, and highlighting functional genetic anomalies of CYP2D6 in psychotropic drug-resistant children and adolescents should participate to the development of personalized medicine in CAP, and thus improve the quality of life and the prognosis of our patients.