Abstract
Objectives
Extrapyramidal symptoms (EPS) are one of the most prominent side effects of haloperidol. Variability of EPS severity may be associated with the genetic factors, affecting both haloperidol pharmacokinetics (e.g., CYP2D6) and pharmacodynamics (e.g., DRD2, ANKK1). We conducted a 3-week prospective study to investigate the associations of ANKK1/DRD2 TaqIA (rs1800497), DRD2 −141C Ins/Del (rs1799732) polymorphisms and CYP2D6 metabolic phenotype on the efficacy of haloperidol treatment and severity of EPS in patients with schizophrenia spectrum disorders.
Methods
In total, 57 inpatients with schizophrenia spectrum disorders (24 (42.1%)) females; age −46.7 (11.8) years (M(SD)) of European ancestry were enrolled. BARS and SAS scales were used to assess EPS. PANSS and CGI scales – to assess the efficacy of haloperidol treatment. Genotyping was performed by real-time PCR. CYP2D6 metabolic phenotype was predicted by the CYP2D6 *3, *4, *5, *6, *9, *10, *41 and xN genotypes.
Results
Minor C allele of TaqIA was associated with higher scores of BARS (p=0.029) and SAS (p=0.024) on day 21 and minor Del allele of −141C Ins/Del – with more prominent clinical improvement by CGI scale (p=0.007) but not by PANSS. These differences were observed only in extensive CYP2D6 metabolizers, although no associations with the metabolic type itself were found. General linear model showed that the combination of TaqIA genotype and metabolic type was significantly associated with BARS score on day 21 (p=0.013).
Conclusions
Our results highlight the importance of using both pharmacokinetic and pharmacodynamic genetic markers for predicting haloperidol treatment response to personalize schizophrenia spectrum disorders treatment.
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Research funding: None declared.
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Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
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Competing interests: Authors state no conflict of interest.
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Informed consent: Informed consent was obtained from all individuals included in this study.
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Ethical approval: The research related to human use has been complied with all the relevant national regulations, institutional policies and in accordance the tenets of the Helsinki Declaration and has been approved by the local Ethical Committee of the Serbsky National Medical Research Center on Psychiatry and Addictions (№29/1 02.03.2020).
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