The DRD2/ANKK1 Taq1A polymorphism in CYP2D6 extensive metabolizers is associated with the severity of extrapyramidal side effects of haloperidol treatment in schizophrenia spectrum disorders patients

INTRODUCTION: Schizophrenia is one of the most severe mental disorders. Haloperidol and other first-generation antipsychotics are widely used for schizophrenia treatment, but have prominent side effects, primarily extrapyramidal symptoms (EPS). The EPS severity is highly variable and may be underlied by genetic factors. OBJECTIVES: We performed a prospective study to test the association of DRD2/ANKK1 Taq1A polymorphism (rs18000497) and CYP2D6 phenotype, predicted from genotypes using 8 CYP2D6 alleles (*3, *4, *5, *6,*9, *10,*41, xN) with EPS severity during haloperidol treatment in schizophrenia spectrum disorders patients. METHODS: 57 inpatients with schizophrenia spectrum disorders (42,1% females; mean age - 46,7±11,8 y.o (M±SD) of European ancestry were enrolled in the study. Abnormal Involuntary Movement Scale (AIMS), Barnes Akathisia Rating Scale (BARS), Simpson-Angus Scale (SAS) were used to assess EPS on two timepoints: day 1 and day 21 of haloperidol treatment. RESULTS: TaqIA T-allele carriers in contrast to wild-type allele homozygous patients had higher scores of BARS (p=0.029) and SAS (p=0.024) on day 21. After stratification by CYP2D6 phenotype, these differences were observed only in extensive metabolizers (p=0.006 and p=0.001 respectively), although the CYP2D6 phenotype itself was not associated with EPS severity. The combined effect of TaqIA T allele with CYP2D6 extensive phenotype on BARS score on day 21 was confirmed by General Linear Model (p=0.013). CONCLUSIONS: Our results show that minor TaqIA T-allele is associated with the severity of EPS after 3 weeks of haloperidol treatment only in CYP2D6 extensive metabolizers. That highlights the importance of using both pharmacokinetic and pharmacodynamic genetic markers in pharmacogenetic EPS risk assessment. DISCLOSURE: No significant relationships.