The role of CYP2D6 and ABCB1 pharmacogenetics in drug-naïve patients with first-episode schizophrenia treated with risperidone

Abstract

2 AbstractPurpose: To evaluate the role of cytochrome 450 2D6 (CYP2D6) and ABCB1 variants on plasma risperidone concentrations and treatment response in 83 drug naive patients with first episode of psychosis.Methods: All patients were treated with risperidone for 8 weeks. The CYP2D6 genotyping was performed by allele-specific PCR-RFLP (for *3,*4,*6) and long PCR (for duplications and *5), while real-time PCR method was used for ABCB1 G2677T/A and C3435T. Plasma concentrations of risperidone and 9-OH risperidone were measured by high-preformance liquid chromatography.Results: The number of patients with the CYP2D6 wild type (wt/wt), wt/mutation (mut) and mut/mut genotype was 43, 32 and 8, respectively. The number of patients with the ABCB1 2677G/G , G/T, T/T variants was 29, 42 and 12, respectively; those with the 3435C/C, C/T and T/T was 25, 37 and 21, respectively. The CYP2D6 genotype has strong effect on steady-state dose-corrected plasma levels of risperidone, its 9-OH metabolite and active moiety, while ABCB1 2677T/T and 3435T/T genotypes hold similarly strong effects on active moiety C/D. The CYP2D6 poor metabolizers had significantly higher levels of risperidone C/D and active moiety C/D, and lower levels of 9-OH risperidone C/D. The ABCB1 3435T allele and the ABCB1 2667T-3435T haplotype carriers were more frequent among subjects without extrapyramidal syndrome. Patients showed significant improvements in positive and general symptoms, but not in negative symptoms. These changes were not related to variations in genetic and drug concentration data.Conclusion: Our findings suggest that CYP2D6 and ABCB1 G2677T and C3435T might be useful determinants of risperidone plasma concentrations, but the clinical implications of these associations in relation to treatment response and side-effects remains unclear.

Pharmacogenetics of Antipsychotics

“…For CYP1A2, the *1F polymorphism has been associated with poorer treatment response to clozapine and olanzapine. [24][25][26] One other study 27 [29][30][31][32] There are more data available indicating an impact of CYP polymorphisms on side effects: CYP2D6*3, CYP2D6*4, and CYP2D6*10, but not CYP1A2*1F, have been associated with increased AIWG. 24,33,34 Today, most evidence exists for an influence of CYP polymorphisms on motor adverse effects of APs, such as TD.…”

Pharmacogenetic-based risk assessment of antipsychotic-induced extrapyramidal symptoms

“…Некоторые авторы [56] не нашли ассоциации между полиморфизмом С3435Т MDR1 и развитием позд-ней дискинезии, другие исследователи [58] продемон-стрировали положительные результаты. Проводились также исследования относительно риска развития острых экстрапирамидных расстройств: в одних работах [59] была ЖУРНАЛ НЕВРОЛОГИИ И ПСИХИАТРИИ, 4,2015 ОБЗОРЫ установлена связь полиморфизмов MDR1 и экстрапира-мидных нарушений, в других [60] -был получен отрица-тельный результат. В целом необходимы дальнейшие ис-следования, чтобы оценить роль полиморфизмов MDR1 в возникновении побочных эффектов.…”

Genetics of Common Antipsychotic-Induced Adverse Effects

“…Three other studies involving healthy volunteers reported an indirect association between the PM or IM CYP2D6 phenotypes and a greater risk of developing EPS [126,127,128]. Finally, 2 studies involving risperidone-treated samples found no association between CYP2D6 metabolizer status and EPS [130,131]. …”

“…Numerous studies published prior to 2010 have examined the relationship between CYP2D6 and EPS/TD, with the majority having supported a significant association between CYP2D6 metabolizer status and susceptibility to EPS/TD [121,122,123]. Eight studies published since 2010 have been reviewed here [124,125,126,127,128,129,130,131]. …”