Frequencies of Genetic Polymorphisms of Clinically Relevant Gene-Drug Pairs in a German Psychiatric Inpatient Population

Abstract

Introduction Genetic variation is known to affect enzymatic activities allowing differentiating various metabolizer types (e. g., slow or rapid metabolizers), in particular CYP2C19 and CYP2D6.

Methods PGx-testing was conducted in adult major depressive disorder inpatients admitted to the Vitos Klinik Eichberg between 11/2016 and 7/2017 (n=108, 57% female). We conducted a two-sided Z-Test (p=0.05) to analyze and compare frequencies of CYP2D6, CYP2C19, CYP3A4, CYP3A5 and CYP2C9 metabolizer groups with other European and psychiatric inpatient cohorts. The HLA-A and –B genes were also analyzed.

Results Non-normal metabolizer status of CYP2D6 were present in 47%. More specifically, 35 % were intermediate, 7% poor and 4% ultra-rapid metabolizers. 68% were CYP2C19 non-normal metabolizers. 8% were ultra-rapid and 31% rapid metabolizers. Notably, only 13% were NM for CYP2C19 and NM for CYP2D6 (activity score of 1 or more). For CYP2C9 we found 16% to be intermediate metabolizers, 1.0% poor metabolizer. CYP3A4 and CYP3A5 genetic polymorphisms were present in 25% and 19% respectively. HLA-B TAG- SNPs for *15:01 was positive in 25 patients, showing the need for different Tag-SNPs in Caucasians. HLA-B *57:01 TAG-SNP was positive in 8% of the patients, HLA-A TAG-SNP for *31:01 in Caucasians was positive in 9%. Z-Test showed statistical significance for our results.

Discussion Our results suggest that our psychiatric inpatients were enriched with genotypes consistent with non-normal drug metabolism compared to reference populations. We therefore conclude that pharmacogenetic testing should be implemented in clinical practice to guide drug therapy.

Key words

Cytochrome P450 (CYP) enzymes - Pharmacogenetics - psychiatry - Antidepressants - personalized medicine

Publication History

Received: 20 May 2020
Received: 26 October 2020

Accepted: 11 November 2020

Article published online:
16 December 2020

• References

• 1 Müller DJ, Rizhanovsky Z. From the origins of pharmacogenetics to first applications in psychiatry. Pharmacopsychiatry 2019; 52: 1-7
• 2 Bousman CA, Al Maruf A, Mueller DJ. et al. Towards integration of pharmakogenetics in psychiatry: A minimum, evidence-based genetic testing panel. Curr Opin Psychiatry 2019; 32: 7-15
• 3 Menke A, Weber H, Deckert J. Roadmap for routine pharmacogenetic testing in a psychiatric university hospital. Pharmacopsychiatry 2019; 52: 1-55
• 4 Brown L, Eum S, Haga SB. et al. Clinical utilization of pharmacogenetics in psychiatry—perspectives of pharmacists, genetic counselors, implementation science, clinicians, and industry. Pharmacopsychiatry 2019; 52: 1-12
• 5 Hicks JK, Bishop JR, Sangkuhl K. et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 genotypes and dosing of selective serotonine reuptake inhibitors. Clin Pharmacol Ther 2015; 98: 127-134
• 6 Kicks JK, Sangkuhl K, Swen JJ. et al. Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update. Clin Pharmacol Ther 2017; 102: 37-44
• 7 Stingl J, 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: 273-287
• 8 Byeon JY, Kim YH, Lee CM. et al. CYP2D6 allele frequencies in Korean population, comparison with East Asian, Caucasian and African populations, and the comparison of metabolic activity of CYP2D6 genotypes. Arch Pharm Res 2018; 41: 921-930
• 9 LLerena A, Naranjo ME, Rodrigues-Soares F. et al. Interethnic variability of CYP2D6 allels and of predicted measured metabolic phenotypes across world populations. Expert opin Drug Metab Toxicol 2014; 110: 1569-1583
• 10 Cespedes Garrro C, Fricke-Galindo I, Naranjo ME. et al. Worldwide interethnic variability and geographical distribution of CYP2C9 genotypes and phenotypes. Expert Opin Drug Metab Toxicol 2015; 11: 1893-1905
• 11 Kirchheiner J, Brosen K, Dahl ML. et al. CYP2D6 and CYP2C19 genotype-based dose recommendations for antidepressants: A first step towards subpopulation-specific dosages. Acta Psychiatr Scand 2001; 104: 173-192
• 12 Schatzberg AF, De Battista C, Lazzeroni L. et al. ABCB1 genetic effects on antidepressant outcomes: A report from the iSPOT-D trial. Am J Psychiatry 2015; 1172: 751-759
• 13 Swen JJ, Nijenhuis M, De Boer A. et al. Pharmacogenetics: from bench to byte an update of guidelines. Clin Pharmacol Ther 2011; 89: 662-673
• 14 Relling MV, Klein TE. CPIC: Clinical Pharmacogenetics Implementation Consortium of the Pharmacogenomics Research Network. Clin Pharmacol Ther 2011; 89: 464-467
• 15 Tansey KE, Guipponi M, Hu X. et al. Contribution of common genetic variants to antidepressant response. Biol Psychiatry 2013; 73: 679-682
• 16 Rosenblat JD, Lee Y, McIntyre RS. The effect of pharmacogenomic testing on response and remission rates in the acute treatment of major depressive disorder: a meta-analysis. J Affect Disord 2018; 241: 484-491
• 17 Hall-Flavin DK, Winner JG, Allen JD. et al. Utility of integrated pharmacogenomic testing to support the treatment of major depressive disorder in a psychiatric outpatient setting. Pharmacogenet Genomics 2013; 23: 535-548
• 18 Pérez V, Salavert A, Espadaler J. et al. Efficacy of prospective pharmacogenetic testing in the treatment of major depressive disorder: results of a randomized, double-blind clinical trial. BMC Psychiatry 2017; 17: 250
• 19 Bradley P, Shiekh M, Mehra V. et al. Improved efficacy with targeted pharmacogenetic-guided treatment of patients with depression and anxiety: A randomized clinical trial demonstrating clinical utility. J Psychiatr Res 2018; 96: 100-107
• 20 Bättig VAD, Roll SC, Hahn M. Pharmacogenetic testing in depressed patients and interdisciplinary exchange between a pharmacist and psychiatrists results in reduced hospitalization times. Pharmacopsychiatry 2020; 53: 185-192
• 21 Caudle K, Dunnenberger H, Freimuth R. et al. Standardizing terms for clinical pharmacogenetic test results: consensus terms from the Clinical Pharmacogenetics Implementation Consortium (CPIC). Genet Med 2017; 19: 215-223
• 22 Caudle KE, Sangkuhl K, Whirl-Carrillo M. et al. Standardizing CYP 2D6 genotype to phenotype translation: consensus recommendations from the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group. Clin Transl Sci 2020; 13: 116-124
• 23 Phillips EJ, Sukasem C, Whirl-Carillo M. et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for HLA genotype and use of carbamazepine and oxcarbamazepine: 2017 update. Clin Pharmacol Ther 2018; 103: 573-581
• 24 Bradford LD. CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics 2002; 3: 229-243
• 25 Scordo MG, Caputi AP, Árrigo C. et al. Allele and genotype frequencies of CYP2C9, CYP2C19 and CYP2D6 in an Italian population. Pharmacol Res 2004; 50: 195-200
• 26 Herbert D, Neves-Pereira M, Baidya R. et al. Genetic testing are a supporting tool in prescribing psychiatric medication: design and protocol of the IMPACT study. J Psychiatr Res 2018; 96: 265-272
• 27 Ganoci L, Bozina T, Mirosevic Skcvre N. et al. Genetic polymorphisms of cytochrome P450 enzymes: CYP2C9, CYp2C19, CYP2D6, CYP3A4 and CYP3A5 in the Croatian population. Drug Meab Pers Ther 2017; 32: 11-21
• 28 Byeon JY, Kim YH, Lee CM. et al. CYP2D6 allele frequencies in Korean population, comparison with East Asian, Caucasian and African populations, and the comparison of metabolic activity of CYP2D6 genotypes. Arch Pharm Res 2018; 41: 921-930
• 29 Arvanitidis K, Ragia G, Iordaniou M. et al. Genetic polymorphisms of drug-metabolizing enzymes CYP2D6, CYP2C9, CYP2C19 and CYP3A5 in the Greek population. Funam Clin Pharmacol 2007; 21: 419-426
• 30 Hiemke C, Bergemann N, Clement HW. et al. Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: update 2017. Pharmacopsychiatry 2018; 51: 9-62
• 31 Hahn M, Roll SC. Dosing recommendations of aripiprazole depot with strong cytochrome P450 3A4 inhibitors: a relapse risk. Drug Safety Case Rep 2016; 3: 5
• 32 Kim KA, Joo HJ, Lee HM. et al. Influence of ABCB1 and CYP3A5 genetic polymorphisms on the pharmacokinetics of quetiapine in healthy volunteers. Pharmacogenet Genomics 2014; 24: 35-42
• 33 Phillips EJ, Sukasem C, Whirl-Carillo M. et al. Clinical Pharmacogenetics Implementation Consortium Guideline for HLA genotype and use of carbamazepine and oxcarbazepine: 2017 update. Clin Pharmacol Ther 2018; 103: 574-581
• 34 Amstutz U, Shear NH, Rieder MJ. et al. Recommendations for HLA-B*15:02 and HLA-A*31:01 genetic testing to reduce the risk of carbamazepine-induced hypersensitivity reactions. Epilepsia 2014; 55: 496-506
• 35 Leckband SG, Kelsoe JR, Dunnenberger HM. et al. Clinical pharmacogenetics Implementation Cosortium Guideline for HLA-B genotype and carbamazepine dosing. Clin Pharmacol Ther 2013; 94: 324-328
• 36 Zeng T, Long YS, Min FL. et al. Association of HLA-B*1502 allele with lamotrigine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Han Chinese subjects: a meta-analysis. Int J Dermatol 2015; 54: 488-493
• 37 Bloch KM, Sillls GJ, Pirmohamed M. et al. Pharmacogenetics of antiepileptic drug-induced hypersensitivity. Pharmacogenomics 2014; 15: 857-868
• 38 Cheung YK, Cheng SH, Chan EJM. et al. HLA-B alleles associated with severe cutaneous reactions to antiepileptic drugs in Han Chinese. Epilepsia 2013; 54: 1307-1314
• 39 Stingl JC, Vivianie R. The effect of CYP2D6 genetic polymorphism on baseline brain perfusion. Mol Psychiatry 2011; 16: 237
• 40 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: 273-287
• 41 Bozina N, Granić P, Lalić Z. et al. Genetic polymorphisms of cytochromes P450: CYP2C9, CYP2C19, and CYP2D6 in Croatian population. Croat Med J 2003; 44: 425-428
• 42 Sistonen J, Sajantila A, Lao O. et al. CYP2D6 worldwide genetic variation shows high frequency of altered activity variants and no continental structure. Pharmacogenet Genomics 2007; 17: 93-101
• 43 Sistonen J, Fuselli S, Palo JU. et al. Pharmacogenetic variation at CYP2C9, CYP2C19, and CYP2D6 at global and microgeographic scales. Pharmacogenet Genomics 2009; 19: 170-179
• 44 Scott SA, Sangkuhl K, Gardner EE. et al. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy. Clin Pharmacol Ther 2011; 90: 328-332
• 45 Strom C, Goos D, Crossley B. et al. Testing for variants in CYP2C19: population frequencies and testing experience in a clinical laboratory. Genet Med 2012; 14: 95-100
• 46 Gaedigk A. Complexities of CYP2D6 gene analysis and interpretation. Int Rev Psychiatry 2013; 25: 534-553
• 47 Saeed LH, Mayet AY. Genotype-phenotype analysis of CYP2C19 in healthy Saudi individuals and its potential clinical implication in drug therapy. Int J Med Sci 2013; 10: 1497-1502
• 48 Alfirevic A, Jorgensen AL, Williamson PR. et al. HLA-B locus in Caucasian patients with carbamazepine hypersensitivity. Pharmacogenomics 2006; 7: 813-818