Experience with CYP2D6 Genotyping in Psychiatry

Background: Inter-individual differences in metabolism of psychotropic drugs have a major impact on clinical outcome. Important discoveries about polymorphic cytochrome P450 enzymes (CYP) raise expectations that pharmacogenetic testing might become a routine tool to identify patients at risk of adverse drug reactions (ADR) or therapeutic failures.

Clinical Genotyping: We receive annually around 100 clinical requests for CYP genotyping. The vast majority (>95%) of samples originate from psychiatry and mainly involves genotyping of CYP2D6, but to a minor extent also of CYP2C19 and CYP2C9. Between Jan 1997 and May 2004, 842 individual cases were analysed. During this period, the main indication for genotyping shifted from being ADR-related in suspected ‘poor metabolisers’ (PM) to include more cases of therapeutic failures and possible ‘ultra-rapid metabolisers’ (UM). In total, 829 samples were genotyped for CYP2D6*3 and *4, leading to the identification of 60 PM (7,2%). Allele frequencies of CYP2D6*3 and *4 were 2,9% and 17,9%, respectively. This is similar to the normal distribution in Caucasian populations, indicating low sensitivity for CYP2D6-PM related problems. In 55% of identified PM, genotype was consistent with clinical details provided in the request; but in 37% relevant information was lacking and in 8% the individual genotype and clinical problem were inconsistent. Interestingly, results from UM typing were more conclusive. In 329 cases, 19 UM were identified (5,8%), which is higher than the frequency in healthy Swedes (~1%). In as much as 89–95% of UM cases, clinical data were consistent with ultra-rapid drug metabolism, suggesting a high predictive power of UM genotyping.

Conclusion: Identification of PM and especially UM by genotyping provides important information that retrospectively helps to explain drug therapy-related problems in individual psychiatric cases. However, strict clinical guidelines for genotyping are required; e.g. that drug plasma levels have been analysed prior to genotyping and that only drugs metabolised by polymorphic enzymes are considered. Prospective studies are needed to understand whether genotyping at the start of drug therapy is cost-effective.