Online first
Original article
Published online: 2025-03-12
Potential association of CYPs, COMT, DRD2, 5HTR2A polymorphisms with susceptibility to the adverse effect of aripiprazole: preliminary observations
1
, 1, 1, 1, 1
, 1, 1, 1, 1
Abstract
Introduction: Aripiprazole is a third-generation antipsychotic drug generally well tolerated, but some patients experience adverse effects. Variability in a patient’s response to aripiprazole can be associated with genetic variants in genes involved in drug pharmacokinetics and pharmacodynamics. The purpose of this study was to perform genetic profiling on patients with schizophrenia, bipolar disorder, and personality disorder to find an association between SNPs and adverse events.
Materials and methods: The gDNA of 74 patients was used to assess 71 polymorphisms in 21 genes by mass spectrometric analysis and PCR-RFLP method.
Results: Patients were divided into well- and badly-reacting groups. The CYP2D6 UM/NM phenotypes and the combined homozygous genotype CYP1A2*1F/CYP2B6*1 were observed more frequently in the badly-reacting group. Moreover, the frequency of the combined homozygous status of 5HTR2A (AA/TT rs6311/rs6313) differed significantly between groups. For the polymorphism of the COMT rs4680 variant, the frequency of the A allele was significantly higher in the well-reacting group.
Conclusions: The present preliminary findings showed that polymorphisms of the DRD2 and 5HTR2A genes may be related to adverse drug effects. Alleles determining the higher density of receptors were observed more frequently in the badly reacting group. Moreover, the G allele of COMT was observed significantly more frequently in patients who experienced adverse effects. Surprisingly, it was noticed that patients in the badly reacting group most often had the CYP2D6 UM/NM phenotype, which does not require standard dose adjustments.
Keywords: aripiprazolegenetic polymorphismneurotransmitter receptorspharmacogeneticsschizophrenia
References
- Vardanyan, R. and V. Hruby, Antipsychotics. 2016. https://sci-hub.se/10.1016/B978-0-12-411492-0.00006-7.
- Gattu N, Saadabadi A. Aripiprazole. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing, 2023 .
- Shukla AK, Mehani R, Sadasivam B. Abilify MyCite (Aripiprazole): A Critical Evaluation of the Novel Dosage Form. J Clin Psychopharmacol. 2021; 41(1): 93–94.
- Fleischhacker WW. Aripiprazole. Expert Opin Pharmacother. 2005; 6(12): 2091–2101.
- Shapiro DA, Renock S, Arrington E, et al. Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology. Neuropsychopharmacology. 2003; 28(8): 1400–1411.
- Aitken RJ, Smith TB, Jobling MS, et al. Oxidative stress and male reproductive health. Asian J Androl. 2014; 16(1): 31–38.
- Gaedigk A, Simon SD, Pearce RE, et al. The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. Clin Pharmacol Ther. 2008; 83(2): 234–242.
- Belmonte C, Ochoa D, Román M, et al. Influence of CYP2D6, CYP3A4, CYP3A5 and ABCB1 polymorphisms on pharmacokinetics and safety of aripiprazole in healthy volunteers. Basic Clin Pharmacol Toxicol. 2018; 122(6): 596–605.
- Subuh Surja AA, Reynolds KK, Linder MW, et al. Pharmacogenetic testing of CYP2D6 in patients with aripiprazole-related extrapyramidal symptoms: a case-control study. Per Med. 2008; 5(4): 361–365.
- Koller D, Saiz-Rodríguez M, Zubiaur P, et al. The effects of aripiprazole and olanzapine on pupillary light reflex and its relationship with pharmacogenetics in a randomized multiple-dose trial. Br J Clin Pharmacol. 2020; 86(10): 2051–2062.
- Cendrós M, Arranz M, Torra M, et al. The influence of CYP enzymes and ABCB1 on treatment outcomes in schizophrenia: association of CYP1A2 activity with adverse effects. J Transl Genet Genom. 2020; 4: 210–220.
- Kwon JS, Kim E, Kang DH, et al. APLUS study group. Taq1A polymorphism in the dopamine D2 receptor gene as a predictor of clinical response to aripiprazole. Eur Neuropsychopharmacol. 2008; 18(12): 897–907.
- Chen SF, Shen YC, Chen CH. HTR2A A-1438G/T102C polymorphisms predict negative symptoms performance upon aripiprazole treatment in schizophrenic patients. Psychopharmacology (Berl). 2009; 205(2): 285–292.
- Kaneko H, Miura I, Kanno-Nozaki K, et al. Val 108/158 Met polymorphism and treatment response to aripiprazole in patients with acute schizophrenia. Neuropsychiatr Dis Treat. 2018; 14: 1657–1663.
- Hendset M, Hermann M, Lunde H, et al. Impact of the CYP2D6 genotype on steady-state serum concentrations of aripiprazole and dehydroaripiprazole. Eur J Clin Pharmacol. 2007; 63(12): 1147–1151.
- Suzuki T, Mihara K, Nakamura A, et al. Effects of genetic polymorphisms of CYP2D6, CYP3A5, and ABCB1 on the steady-state plasma concentrations of aripiprazole and its active metabolite, dehydroaripiprazole, in Japanese patients with schizophrenia. Ther Drug Monit. 2014; 36(5): 651–655.
- Jeon JY, Chae SW, Kim MG. Population pharmacokinetics of aripiprazole in healthy Korean subjects. Int J Clin Pharmacol Ther. 2016; 54(4): 293–304.
- Haduch A, Daniel WA. The engagement of brain cytochrome P450 in the metabolism of endogenous neuroactive substrates: a possible role in mental disorders. Drug Metab Rev. 2018; 50(4): 415–429.
- Stingl JC, Brockmöller J, Viviani R. Genetic variability of drug-metabolizing enzymes: the dual impact on psychiatric therapy and regulation of brain function. Mol Psychiatry. 2013; 18(3): 273–287.
- Kirchheiner J, Henckel HB, Franke L, et al. Impact of the CYP2D6 ultra-rapid metabolizer genotype on doxepin pharmacokinetics and serotonin in platelets. Pharmacogenet Genomics. 2005; 15(8): 579–587.
- Just KS, Dormann H, Freitag M, et al. CYP2D6 in the brain: potential impact on adverse drug reactions in the central nervous system-results from the ADRED study. Front Pharmacol. 2021; 12.
- Aklillu E, Kalow W, Endrenyi L, et al. CYP2D6 and DRD2 genes differentially impact pharmacodynamic sensitivity and time course of prolactin response to perphenazine. Pharmacogenet Genomics. 2007; 17(11): 989–993.
- Peñas‐LLedó E, LLerena A.
CYP2D6 variation, behaviour and psychopathology: implications for pharmacogenomics‐guided clinical trials. British Journal of Clinical Pharmacology. 2014; 77(4): 673–683. - Zanger UM, Klein K. Pharmacogenetics of cytochrome P450 2B6 (CYP2B6): advances on polymorphisms, mechanisms, and clinical relevance. Front Genet. 2013; 4: 24.
- Hedrich WD, Hassan HE, Wang H. Insights into CYP2B6-mediated drug-drug interactions. Acta Pharm Sin B. 2016; 6(5): 413–425.
- Hachem A, Godwin J, Ruas M, et al. PLCζ is the physiological trigger of the Ca²⁺ oscillations that induce embryogenesis in mammals but conception can occur in its absence. 2017; 144(16): 2914–2924.
- Ghotbi R, Christensen M, Roh HK, et al. Comparisons of CYP1A2 genetic polymorphisms, enzyme activity and the genotype-phenotype relationship in Swedes and Koreans. Eur J Clin Pharmacol. 2007; 63(6): 537–546.
- Djordjevic N, Ghotbi R, Jankovic S, et al. Induction of CYP1A2 by heavy coffee consumption is associated with the CYP1A2 -163C>A polymorphism. Eur J Clin Pharmacol. 2010; 66(7): 697–703.
- Bondolfi G, Morel F, Crettol S, et al. Increased clozapine plasma concentrations and side effects induced by smoking cessation in 2 CYP1A2 genotyped patients. Ther Drug Monit. 2005; 27(4): 539–543.
- Ferguson CS, Tyndale RF. Cytochrome P450 enzymes in the brain: emerging evidence of biological significance. Trends Pharmacol Sci. 2011; 32(12): 708–714.
- Borgkvist A, Malmlöf T, Feltmann K, et al. Dopamine in the hippocampus is cleared by the norepinephrine transporter. Int J Neuropsychopharmacol. 2012; 15(4): 531–540.
- Sagud M, Tudor M, Uzun S, et al. Haplotypic and Genotypic Association of Catechol-O-Methyltransferase rs4680 and rs4818 Polymorphisms and Treatment Resistance in Schizophrenia. Front Pharmacol. 2018; 9: 705.
- Lotta T, Vidgren J, Tilgmann C, et al. Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. Biochemistry. 1995; 34(13): 4202–4210.
- Chen J, Lipska BK, Halim N, et al. Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am J Hum Genet. 2004; 75(5): 807–821.
- Neville MJ, Johnstone EC, Walton RT. Identification and characterization of ANKK1: a novel kinase gene closely linked to DRD2 on chromosome band 11q23.1. Hum Mutat. 2004; 23(6): 540–545.
- Artigas F. Serotonin receptors involved in antidepressant effects. Pharmacol Ther. 2013; 137(1): 119–131.
- Lin JY, Jiang MY, Kan ZM, et al. Influence of 5-HTR2A genetic polymorphisms on the efficacy of antidepressants in the treatment of major depressive disorder: a meta-analysis. J Affect Disord. 2014; 168: 430–438.
- Polesskaya OO, Sokolov BP. Differential expression of the "C" and "T" alleles of the 5-HT2A receptor gene in the temporal cortex of normal individuals and schizophrenics. J Neurosci Res. 2002; 67(6): 812–822.
- Khait VD, Huang Yy, Zalsman G, et al. Association of serotonin 5-HT2A receptor binding and the T102C polymorphism in depressed and healthy Caucasian subjects. Neuropsychopharmacology. 2005; 30(1): 166–172.
- Lingaiah K, Ramachandra NB. An insight into the understanding of 5-HTR2A variants leading to schizophrenia. Indian J Med Res. 2014; 140(6): 713–715.