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

E Zmeyeva,A Shmukler,E Kiryanova,A Kibitov,L Salnikova

doi:10.1192/j.eurpsy.2021.346

Abstract

IntroductionSchizophrenia 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.ObjectivesWe 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.Methods57 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.ResultsTaqIA 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).ConclusionsOur 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.DisclosureNo significant relationships.

Highlights

The criminality associated with psychiatric disorders has been extensively studied with some studies showing a greater risk of violence in these patients
A retrospective study was designed, including patients admitted in the Forensic ward of Coimbra Hospital and University Center between 2018 and 2020
We performed a prospective study to test the association of DRD2/ANKK1 Taq1A polymorphism 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

Summary

Methods

We analyzed a national hospitalization database that contained all hospitalization episodes registered in Portuguese public hospitals from 2008 to 2015. All episodes with a primary diagnosis of mental disorder defined as ICD-9-CM codes 290.x319.x were included. Prolonged hospitalizations were defined as having a LoS ≥ P97.5; LOS ≥180 days or LOS ≥1 year. Sex, lengh of stay, in-hospital mortality were analysed. Results: The LoS ≥ P97.5(≥62 days) group comprised 3911 hospitalizations (2.3% of all psychiatric hospitalizations) and 1755 patients. The median LOS was 81 days and the mean age was 51 years. Though a higher frequency of male patients was found on the ≥180 days (n=364) and ≥ 1 year (n=121) groups. In-hospital mortality increased in the higher LoS groups (1.1%; 4.4%; 9.1%, respectively). Conclusions: Overall, middle aged patients with psychotic disorders represent most of the prolonged hospitalizations occurring in acute psychiatric wards.

Introduction

Findings