The Relationships between amitriptyline adverse reactions and genetic polymorphism of CYP2D6 in Thai psychiatric patients at Siriraj Hospital

Abstract

Cytochrome P450 2D6 is a major drug-metabolizing enzyme involved with antipsychotic and antidepressant drug metabolism. Amitriptyline, tricyclic antidepressant, was commonly reported with adverse drug reactions (ADRs) because of its non-selective action and other factors. CYP2D6 genotyping was shown to be useful in phenotype prediction. The objective of this study was to find the relationship between amitriptyline ADRs and genetic polymorphism of CYP2D6. The study was designed as matched case-control recruited subjects by Naranjo’s algorithm screening to obtain 75 subjects in each group. Visual analog scales of amitriptyline ADRs in questionnaires were used to identify type of ADRs and scores in both groups. CYP2D6 genotype were detected by multiplex long polymerase chain reaction (PCR) to obtain whole gene and/or gene deletion (CYP2D6*5). Single base extension (SBE) was subsequently performed, coupled with denaturing high-performance liquid chromatography (DHPLC) analysis in order to detect SNPs therein. Gene arrangement was determined in 5-plex PCR analyzed with semi-quantitative DHPLC. Ten SNPs were included in tested panel; three SNPs were not found in recruited subjects and seven SNPs were observed. The most common genotype found in this study are CYP2D6*36-*10B in tandem-associated genotype (25.33%), CYP2D6*10A or *10B-associated genotype (23.33%), and *1/*1 (13.33%), respectively. Some haplotypes are significantly different in two groups. However, the interaction between genotype and ADR scores is insignificantly associated. Hence, there are no association between CYP2D6 genotype and amitriptyline ADRs at Odd ratio 2.5 in recruited subjects. Nevertheless, the most commonly found genotype, CYP2D6*36-*10B and *36-associated alleles including in tandem duplication, is significant higher in control group when compared with CYP2D6*2/*10B of both groups. The association could be found if sample size is greater together with higher challenged dose of amitriptyline. This is the first study providing CYP2D6 genotype in depressive patients in Thai.