Abstract
Background:
Сytochrome P450 CYP2D6 activity affects antipsychotic therapy safety. 1846G>A (CYP2D6*4) polymorphism frequency varies among different ethnic groups.
Methods:
We studied 1846G>A polymorphism in Tatar and Russian schizophrenic patients taking different antipsychotics and association of 1846G>A polymorphism and extrapyramidal disorders (EPD) frequency in schizophrenic patients on haloperidol monotherapy in daily doses up to 20 mg.
Results:
Heterozygous 1846GA genotype frequency among Tatars was lower (23.8% vs. 32.4% in Russians), but the differences did not reach statistical significance. The 1846A allele frequency among Tatars was also lower (11.9% vs. 24.3% in Russians), but the difference was not quite significant (p=0.0592). Average daily haloperidol dose in the group without EPD was significantly higher than in the group with EPD (11.35±4.6 vs. 13.87±3.3 mg, p=0.0252), but average daily haloperidol dose/weight ratios in the compared groups had no significant differences. A statistically significant association between EPD development and heterozygous 1846GA genotype and 1846A allele carrier frequency was revealed among all schizophrenic patients and among those of Tatars.
Conclusions:
Further well-designed pharmacogenetic studies in different Russian regions are needed to improve psychotropic therapy safety and to establish evidence-based indications for pharmacogenetic testing in clinical practice.
Acknowledgments
This project forms part of the PhD thesis in Clinical Pharmacology at Kazan State Medical Academy, of I.S.B. The authors would like to thank the following: The Republican Clinical Psychiatric Hospital administration for their local support and the staff of the Republican Clinical Psychiatric Hospital who volunteered to take the blood samples.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission. I.S.B. conceived the idea of this study, participated in its design, collected the data, performed the analysis and wrote the initial draft of the manuscript. D.A.S. participated in the conception and design of the study, contributed to the analysis and helped to prepare the draft manuscript. R.E.K. participated in the conception and design of the study, performed genotyping and helped to prepare the draft manuscript.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. Haddad PM, Brain C, Scott J. Nonadherence with antipsychotic medication in schizophrenia: challenges and management strategies. Patient Relat Outcome Meas 2014;5:43–62.10.2147/PROM.S42735Search in Google Scholar PubMed PubMed Central
2. Burashnikova IS, Minnekeeva KA, Semenikhin DG. Evaluating the results of use of atypical antipsychotics in psychiatric hospital in the Republic of Tatarstan in 2008–2012: safety and budget burden [in Russian]. Vestnik Roszdravnadzora 2015;1:61–5.Search in Google Scholar
3. Nasyrova RF, Ivanov MV, Neznanov NG, editors. Introduction to psychopharmacogenetics [in Russian]. Saint Petersburg: Saint Petersburg Publishing Centre of St. Petersburg V.M. Bekhterev Psychoneurological Research Institute, 2015:272.Search in Google Scholar
4. The Human Cytochrome P450 (CYP) Allele Nomenclature Database. Available at: http://www.cypalleles.ki.se/cyp2d6.htm. Accessed: 6 June 2016.Search in Google Scholar
5. Sistonen J, Sajantila A, Lao O, Corander J, Barbujani G, Fuselli S. CYP2D6 worldwide genetic variation shows high frequency of altered activity variants and no continental structure. Pharmacogenet Genomics 2007;17:93–101.10.1097/01.fpc.0000239974.69464.f2Search in Google Scholar PubMed
6. Zanger UM, Raimundo S, Eichelbaum M. Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry. Naunyn Schmiedebergs Arch Pharmacol 2004;369:23–37.10.1007/s00210-003-0832-2Search in Google Scholar PubMed
7. Gaedigk A, Sangkuhl K, Whirl-Carrillo M, Klein T, Leeder JS. Prediction of CYP2D6 phenotype from genotype across world populations. Genet Med 2016. Available at https://www.ncbi.nlm.nih.gov/pubmed/27388693 Accessed: 25 September 2016.10.1038/gim.2016.80Search in Google Scholar PubMed PubMed Central
8. LLerena A, Naranjo ME, Rodrigues-Soares F, Penas-LLedó EM, Fariñas H, Tarazona-Santos E. Interethnic variability of CYP2D6 alleles and of predicted and measured metabolic phenotypes across world populations. Expert Opin Drug Metab Toxicol 2014;10:1569–83.10.1517/17425255.2014.964204Search in Google Scholar PubMed
9. Shah RR, Gaedigk A, LLerena A, Eichelbaum M, Stingl J, Smith RL. CYP450 genotype and pharmacogenetic association studies: a critical appraisal. Pharmacogenomics 2016;17: 259–75.10.2217/pgs.15.172Search in Google Scholar PubMed
10. Griese EU, Zanger UM, Brudermanns U, Gaedigk A, Mikus G, Mörike K, et al. Assessment of the predictive power of genotypes for the in-vivo catalytic function of CYP2D6 in a German population. Pharmacogenetics 1998;8:15–26.10.1097/00008571-199802000-00003Search in Google Scholar PubMed
11. Sachse C, Brockmöller J, Bauer S, Roots I. Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences. Am J Hum Genet 1997;60:284–95.Search in Google Scholar
12. Lou YC, Ying L, Bertilsson L, Sjöqvist F. Low frequency of slow debrisoquine hydroxylation in a native Chinese population. Lancet 1987;2:852–3.10.1016/S0140-6736(87)91034-8Search in Google Scholar
13. Ryu SW, Kim YJ, Kim E. Mutation analysis of CYP2D6 locus in the Korean population: identification of rare poor metabolizer alleles at the nucleotide level. Mol Cells 1998;8:758–63.Search in Google Scholar
14. Tiwari AK, Deshpande SN, Lerer B, Nimgaonkar VL, Thelma BK. Genetic susceptibility to tardive dyskinesia in chronic schizophrenia subjects: III. Lack of association of CYP3A4 and CYP2D6 gene polymorphisms. Schizophr Res 2005;75:21–6.10.1016/j.schres.2004.12.011Search in Google Scholar PubMed
15. Plesnicar BK, Zalar B, Breskvar K, Dolzan V. The influence of the CYP2D6 polymorphism on psychopathological and extrapyramidal symptoms in the patients on long-term antipsychotic treatment. Psychopharmacol 2006;20:829–33.10.1177/0269881106062894Search in Google Scholar PubMed
16. Crescenti A, Mas S, Gassó P, Parellada E, Bernardo M, Lafuente A. Cyp2d6*3, *4, *5 and *6 polymorphisms and antipsychotic-induced extrapyramidal side-effects in patients receiving antipsychotic therapy. Clin Exp Pharmacol Physiol 2008;35:807–11.10.1111/j.1440-1681.2008.04918.xSearch in Google Scholar PubMed
17. Kobylecki CJ, Jakobsen KD, Hansen T, Jakobsen IV, Rasmussen HB, Werge T. CYP2D6 genotype predicts antipsychotic side effects in schizophrenia inpatients: a retrospective matched case-control study. Neuropsychobiology 2009;59:222–6.10.1159/000223734Search in Google Scholar PubMed
18. Vyalova NM, Ivanov MV, Ivanova SA, Boiko AS, Bokhan NA, Chomsky AN, et al. The associations between CYP2D6 and HTR2C polymorphisms and development of hyperprolactinaemia in patients with schizophrenia against the background of antipsychotic therapy [in Russian]. V.M. Bekhterev Rev Psychiatr Med Psychol 2014;3:8–13.Search in Google Scholar
19. Wikipedia. Available at: https://ru.wikipedia.org/wiki/%D0%A2%D0%B0%D1%82%D0%B0%D1%80%D1%81%D1%82%D0%B0%D0%BD. Accessed: 10 July 2016.Search in Google Scholar
20. ICD-10 Version: 2010. Available at: http://apps.who.int/classifications/icd10/browse/2010/en. Accessed: 16 July 2016.Search in Google Scholar
21. Chouinard GT, Margolese HC. Manual for the Extrapyramidal Symptom Rating Scale (ESRS). Schizophr Res 2005;76:247–65.10.1016/j.schres.2005.02.013Search in Google Scholar PubMed
22. Roh H-K, Chung J-Y, Oh DY, Park CS, Svensson J-O, Dahl M-L, et al. Plasma concentrations of haloperidol are related to the CYP2D6 genotype at low, but not high doses of haloperidol in Korean schizophrenic patients. Br J Clin Pharmacol 2001;52:265–71.10.1046/j.0306-5251.2001.01437.xSearch in Google Scholar PubMed PubMed Central
23. Website: OEGE - Online Encyclopedia for Genetic Epidemiology studies. Available at: http://www.oege.org/software/hwe-mr-calc.shtml. Accessed: 16 June 2016.Search in Google Scholar
24. Berecz R, Dorado P, De La Rubia A, Cáceres MC, Degrell I, LLerena A. The role of cytochrome P450 enzymes in the metabolism of risperidone and its clinical relevance for drug interactions. Curr Drug Targets 2004;5:573–9.10.2174/1389450043345263Search in Google Scholar PubMed
25. Fang J, Bourin M, Baker GB. Metabolism of risperidone to 9-hydroxyrisperidone by human cytochromes P450 2D6 and 3A4. Naunyn Schmiedebergs Arch Pharmacol 1999;359:147–51.10.1007/PL00005334Search in Google Scholar
26. Mihara K, Kondo T, Suzuki A, Yasui-Furukori N, Ono S, Sano A, et al. Relationship between functional dopamine D2 and D3 receptors gene polymorphisms and neuroleptic malignant syndrome. Am J Med Genet B Neuropsychiatr Genet 2003;117B:57–60.10.1002/ajmg.b.10025Search in Google Scholar PubMed
27. Novalbos J, López-Rodríguez R, Román M, Gallego-Sandín S, Ochoa D, Abad-Santos F. Effects of CYP2D6 genotype on the pharmacokinetics, pharmacodynamics, and safety of risperidone in healthy volunteers. J Clin Psychopharmacol 2010;30:504–11.10.1097/JCP.0b013e3181ee84c7Search in Google Scholar PubMed
28. Fang J, Baker GB, Silverstone PH, Coutts RT. Involvement of CYP3A4 and CYP2D6 in the metabolism of haloperidol. Cell Mol Neurobiol 1997;17:227–33.10.1023/A:1026317929335Search in Google Scholar
29. Kantemirova BI, Griganov VI. Ethnic polymorphism of P-450 citochromium isoenzymes in children residing in Astrakhan region [in Russian]. Theor Experimental Med 2013;1:11–9.Search in Google Scholar
30. Mustafina OE, Tuktarova IA, Karimov DD, Somova RS, Nasibullin TR. CYP2D6, CYP3A5, and CYP3A4 gene polymorphisms in Russian, Tatar, and Bashkir populations [in Russian]. Russ J Genet 2015;51:98–107.10.1134/S1022795415010081Search in Google Scholar
31. Broly F, Gaedigk A, Heim M, Eichelbaum M, Morike K, Meyer UA. Debrisoquine/sparteine hydroxylation genotype and phenotype: analysis of common mutations and alleles of CYP2D6 in a European population. DNA Cell Biol 1991;10:545–58.10.1089/dna.1991.10.545Search in Google Scholar PubMed
32. Saxena R, Shaw GL, Relling MV, Frame JN, Moir DT, Evans WE, et al. Identification of a new variant CYP2D6 allele with a single base deletion in exon 3 and its association with the poor metabolizer phenotype. Hum Mol Genet 1994;3:923–6.10.1093/hmg/3.6.923Search in Google Scholar
33. Tefre T, Daly AK, Armstrong M, Leathart JB, Idle JR, Brøgger A, et al. Genotyping of the CYP2D6 gene in Norwegian lung cancer patients and controls. Pharmacogenetics 1994;4:47–57.10.1097/00008571-199404000-00001Search in Google Scholar
34. Marez D, Legrand M, Sabbagh N, Guidice JM, Spire C, Lafitte JJ, et al. Polymorphism of the cytochrome P450 CYP2D6 gene in a European population: characterization of 48 mutations and 53 alleles, their frequencies and evolution. Pharmacogenetics 1997;7:193–202.10.1097/00008571-199706000-00004Search in Google Scholar
35. Alimova YB, Zhelenina LA, Galustyan AN, Sardaryan IS, Ivaschenko TE. Innovation approach to diagnosing bronchial asthma in children based on research in gene polymorphism of xenobiotics detoxification system. InVestRegion 2012;2:87–93 [in Russian].Search in Google Scholar
36. Alimova YB, Galustyan AN, Zhelenina LA, Glotov AS. Genotypic bases for phenotypic differences in children with bronchial asthma. X International Congress On Pediatric Pulmonology, France-Versailles, 2011;61–2.10.1016/S1526-0542(11)70049-5Search in Google Scholar
37. Gaikovitch EA, Cascorbi I, Mrozikiewicz PM, Brockmöller J, Frotschl R, Köpke K, et al. Polymorphisms of drug-metabolizing enzymes CYP2C9, CYP2C19, CYP2D6, CYP1A1, NAT2 and of P-glycoprotein in a Russian population. Eur J Clin Pharmacol 2003;59:303–12.10.1007/s00228-003-0606-2Search in Google Scholar PubMed
38. Kukes VG, Ramenskaya GV, Kuchumov RS. The value of polymorphic “slow” cytochrome P-450 2D6 alleles genotyping for an individualized assessment of amitriptyline pharmacokinetics in Moscow population. Clinical Studies Drugs Russia 2002; 3–4:40–6 [in Russian].Search in Google Scholar
39. Korchagina RP, Osipova LP, Vavilova NA, Ermolenko NA, Voronina EN, Filipenko ML. Polymorphism of genes for xenobiotics biotransformation, GSTM1, GSTT1, CYP2D6, candidate markers of cancer risk, in indigenous peoples and Russians in Nothern Siberia. Vavilov J Genetics Breeding 2011;15;448–61 [in Russian].10.1134/S2079059712010091Search in Google Scholar
40. Baturin VA, Tzarukyan AA. Genetic polymorphism of cytochrome Р-450 isoenzyme CYP2D6 in population of Stavropol region. Med News North Caucasus 2013;8:86–7 [in Russian].Search in Google Scholar
©2016 Walter de Gruyter GmbH, Berlin/Boston
