CYP2D6 and HTR2C polymorphisms in psychiatric pharmacotherapy

Abstract

Antipsychotic and antidepressant drugs are used by the majority of psychiatric patients. The response to these drugs is variable: approximately 20-40% of the psychiatric patients do not respond satisfactorily to pharmacotherapy. In psychiatric pharmacotherapy there usually is a lag time of several weeks before the balance between the therapeutic response and the prevalence of adverse events can be evaluated. This lag time together with the high prevalence of clinically relevant adverse events put psychiatric patients at risk of discontinuing pharmacotherapy. These complications make pharmacogenetics a potentially promising tool in individualising psychiatric pharmacotherapy. Pharmacogenetics has been defined as the research area investigating whether and to what extent genetic variation can explain and predict the response to drugs of individual patients. Determining a patient’s genotype before initiating pharmacotherapy may prevent unsatisfactory response because an individualised advice for the choice of drug and dosage is possible. In this thesis two polymorphisms (CYP2D6 and HTR2C) that might be useful from this perspective in the future will be described. The main objective of this thesis is to elucidate whether polymorphisms in the gene coding for cytochrome P450 2D6 (CYP2D6) and the serotonin 2C (HTR2C) receptor are associated with unsatisfactory response of pharmacotherapy in daily psychiatric practice. Unsatisfactory response encompasses both failure of treatment success and unacceptable adverse events. The first part of this thesis describes the association between CYP2D6 genotype (genetic variation in pharmacokinetics) and global clinical response of both antidepressant and antipsychotic drugs in daily psychiatric practice. The results show that Poor Metabolisers (PM) for CYP2D6 have an increased risk for serum concentrations of antipsychotic and antidepressant drugs outside the presumed therapeutic window compared to Extensive Metabolisers (EM) for CYP2D6. Furthermore, we found that for antidepressant drugs CYP2D6 genotype PM was associated with more frequent switching and with more dosage regimen changes compared to CYP2D6 genotype EM. For antipsychotic drugs an increased risk of changes in dosage regimen and an increased frequency of prescription of antiparkinsonian drugs for treatment of extrapyramidal syndromes (EPS) was found for CYP2D6 genotype PM compared to CYP2D6 genotype EM. The second part of this thesis describes the association between HTR2C genotypes (genetic variation in pharmacodynamics) and metabolic abnormalities in patients using antipsychotic drugs. The results show that HTR2C polymorphisms are associated with an increased risk of the occurrence of obesity and the metabolic syndrome in patients using antipsychotics. The association with the metabolic syndrome is particularly strong in carriers of the HTR2C rs1414334 C allele using clozapine or risperidone. The association between CYP2D6 and HTR2C polymorphisms and unsatisfactory response to psychiatric pharmacotherapy show promising results. There are many challenges in genetic pharmacoepidemiology, genotype translation and application in daily clinical practice that has to be overcome before pharmacogenetic testing (among others CYP2D6 and HTR2C genotypes) will enter daily clinical practice. However, potential solutions are evolving rapidly and hopefully these obstacles will be overcome and pharmacogenetics will enter and improve the treatment of individual patients in the near future.