Effects of Pharmacokinetic Gene Variation on Therapeutic Drug Levels and Antidepressant Treatment Response

Abstract

Introduction Pharmacogenetic testing is proposed to minimize adverse effects when considered in combination with pharmacological knowledge of the drug. As yet, limited studies in clinical settings have investigated the predictive value of pharmacokinetic (pk) gene variation on therapeutic drug levels as a probable mechanism of adverse effects, nor considered the combined effect of pk gene variation and drug level on antidepressant treatment response.

Methods Two depression cohorts were investigated for the relationship between pk gene variation and antidepressant serum concentrations of amitriptyline, venlafaxine, mirtazapine and quetiapine, as well as treatment response. For the analysis, 519 patients (49% females; 46.6±14.1 years) were included.

Results Serum concentration of amitriptyline was associated with CYP2D6 (higher concentrations in poor metabolizers compared to normal metabolizers), of venlafaxine with CYP2C19 (higher concentrations in intermediate metabolizers compared to rapid/ultrarapid metabolizers) and CYP2D6 (lower metabolite-to-parent ratio in poor compared to intermediate and normal metabolizers, and intermediate compared to normal and ultrarapid metabolizers). Pk gene variation did not affect treatment response.

Discussion The present data support previous recommendations to reduce starting doses of amitriptyline and to guide dose-adjustments via therapeutic drug monitoring in CYP2D6 poor metabolizers. In addition, we propose including CYP2C19 in routine testing in venlafaxine-treated patients to improve therapy by raising awareness of the risk of low serum concentrations in CYP2C19 rapid/ultrarapid metabolizers. In summary, pk gene variation can predict serum concentrations, and thus the combination of pharmacogenetic testing and therapeutic drug monitoring is a useful tool in a personalized therapy approach for depression.

Key words

pharmacogenetics - depressive disorder - serum concentrations - pharmacokinetics

^* shared first authorship

^† shared last authorship

Publication History

Received: 02 December 2021
Received: 27 May 2022

Accepted: 01 June 2022

Article published online:
15 July 2022

• References

• 1 Malsagova KA, Butkova TV, Kopylov AT. et al. Pharmacogenetic testing: A tool for personalized drug therapy optimization. Pharmaceutics 2020; 12: 1240
• 2 Menke A. Precision pharmacotherapy: Psychiatry’s future direction in preventing, diagnosing, and treating mental disorders. Pharmgenomics Pers Med 2018; 11: 211-222
• 3 Vest BM, Wray LO, Brady LA. et al. Primary care and mental health providers’ perceptions of implementation of pharmacogenetics testing for depression prescribing. BMC Psychiatry 2020; 20: 518
• 4 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
• 5 Bousman CA, Arandjelovic K, Mancuso SG. et al. Pharmacogenetic tests and depressive symptom remission: A meta-analysis of randomized controlled trials. Pharmacogenomics 2019; 20: 37-47
• 6 Drozda K, Müller DJ, Bishop JR. Pharmacogenomic testing for neuropsychiatric drugs: Current status of drug labeling, guidelines for using genetic information, and test options. Pharmacotherapy 2014; 34: 166-184
• 7 Bousman CA, Menke A, Müller DJ. Towards pharmacogenetic-based treatment in psychiatry. J Neural Transm (Vienna) 2019; 126: 1-3
• 8 International Society for Psychiatric Genetics (ISPG). Genetic testing statement: A statement from the international society of psychiatric genetics. 2019 https://ispg.net/genetic-testing-statement/ cited: 22 December, 2020
• 9 Liko I, Lai E, Griffin RJ. et al. Patients’ perspectives on psychiatric pharmacogenetic testing. Pharmacopsychiatry 2020; 53: 256-261
• 10 Gartlehner G, Hansen RA, Morgan LC. et al. Comparative benefits and harms of second-generation antidepressants for treating major depressive disorder: An updated meta-analysis. Ann Intern Med 2011; 155: 772-785
• 11 Chen P. Optimized Treatment Strategy for Depressive Disorder. In: Fang Y ed, Depressive Disorders: Mechanisms, Measurement and Management. Singapore: Springer Singapore; 2019: 201-217
• 12 Gaynes BN, Rush AJ, Trivedi MH. et al. The STAR*D study: Treating depression in the real world. Cleve Clin J Med 2008; 75: 57-66
• 13 Wisniewski SR, Rush AJ, Nierenberg AA. et al. Can phase III trial results of antidepressant medications be generalized to clinical practice? A STAR*D report. Am J Psychiatry 2009; 166: 599-607
• 14 Eap CB. Personalized prescribing: A new medical model for clinical implementation of psychotropic drugs. Dialogues Clin Neurosci 2016; 18: 313-322
• 15 Bousman CA, Bengesser SA, Aitchison KJ. et al. Review and consensus on pharmacogenomic testing in psychiatry. Pharmacopsychiatry 2021; 54: 5-17
• 16 Hicks JK, Bishop JR, Sangkuhl K. et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and dosing of selective serotonin reuptake inhibitors. Clin Pharmacol Ther 2015; 98: 127-134
• 17 Hicks 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
• 18 Relling MV, Klein TE. CPIC: Clinical Pharmacogenetics Implementation Consortium of the Pharmacogenomics Research Network. Clin Pharmacol Ther 2011; 89: 464-467
• 19 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
• 20 Hennings JM, Owashi T, Binder EB. et al. Clinical characteristics and treatment outcome in a representative sample of depressed inpatients - findings from the Munich Antidepressant Response Signature (MARS) project. J Psychiatr Res 2009; 43: 215-229
• 21 Rush AJ, Kraemer HC, Sackeim HA. et al. Report by the ACNP Task Force on response and remission in major depressive disorder. Neuropsychopharmacology 2006; 31: 1841-1853
• 22 Zimmerman M, Chelminski I, Posternak M. A review of studies of the Hamilton depression rating scale in healthy controls: Implications for the definition of remission in treatment studies of depression. J Nerv Ment Dis 2004; 192: 595-601
• 23 CPIC - Clinical Pharmacogenetics Implementation Consortium. 2021. Cited: 15 March, 2022
• 24 Hiemke C, Bergemann N, Clement HW. et al. Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: Update 2017. Pharmacopsychiatry 2018; 51: 9-62
• 25 INSTAND Gesellschaft zur Förderung der Qualitätssicherung in medizinischen Laboratorien e. V. 2020 https://www.instand-ev.de/ueber-instand-ev/instand-ev.htmlcited: February 10, 2020
• 26 Purcell S, Neale B, Todd-Brown K. et al. PLINK: A tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559-575
• 27 RCoreTeam. R: A language and environment for statistical computing., R Core Team https://www.R-project.org/ R Foundation for Statistical Computing, Vienna, Austria 2014
• 28 Barrett JC, Fry B, Maller J. et al. Haploview: Analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263-265
• 29 Broad Institute of MIT and Harvard. Haploview. 2006 https://www.broadinstitute.org/haploview/haploview cited: 10 January, 2020
• 30 Pratt VM, Cavallari LH, Del Tredici AL. et al. Recommendations for clinical CYP2D6 genotyping allele selection: A joint consensus recommendation of the Association for Molecular Pathology, College of American Pathologists, Dutch Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association, and the European Society for Pharmacogenomics and Personalized Therapy. J Mol Diagn 2021; 23: 1047-1064
• 31 Pratt VM, Del Tredici AL, Hachad H. et al. Recommendations for clinical CYP2C19 genotyping allele selection: A report of the Association for Molecular Pathology. J Mol Diagn 2018; 20: 269-276
• 32 Xin J, Yuan M, Peng Y. et al. Analysis of the deleterious single-nucleotide polymorphisms associated with antidepressant efficacy in major depressive disorder. Front Psychiatry 2020; 11: 151
• 33 Ji Y, Schaid DJ, Desta Z. et al. Citalopram and escitalopram plasma drug and metabolite concentrations: genome-wide associations. Br J Clin Pharmacol 2014; 78: 373-383
• 34 Owen RP, Sangkuhl K, Klein TE. et al. Cytochrome P450 2D6. Pharmacogenet Genomics 2009; 19: 559-562
• 35 Gaedigk A, Ingelman-Sundberg M, Miller NA. et al. The Pharmacogene Variation (PharmVar) Consortium: Incorporation of the Human Cytochrome P450 (CYP) Allele Nomenclature Database. Clin Pharmacol Ther 2018; 103: 399-401
• 36 Gaedigk A, Sangkuhl K, Whirl-Carrillo M. et al. The Evolution of PharmVar. Clin Pharmacol Ther 2019; 105: 29-32
• 37 Clinical Pharmacogenetics Implementation Consortium. CPIC® Guideline for Tricyclic Antidepressants and CYP2D6 and CYP2C19. 2020 https://cpicpgx.org/guidelines/guideline-for-tricyclic-antidepressants-and-cyp2d6-and-cyp2c19/ cited: 05 January, 2020
• 38 Jiang ZP, Shu Y, Chen XP. et al. The role of CYP2C19 in amitriptyline N-demethylation in Chinese subjects. Eur J Clin Pharmacol 2002; 58: 109-113
• 39 Sangkuhl K, Stingl JC, Turpeinen M. et al. PharmGKB summary: Venlafaxine pathway. Pharmacogenet Genomics 2014; 24: 62-72
• 40 Whirl-Carrillo M, McDonagh EM, Hebert JM. et al. Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther 2012; 92: 414-417
• 41 Sim SC, Risinger C, Dahl ML. et al. A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clin Pharmacol Ther 2006; 79: 103-113
• 42 Rudberg I, Mohebi B, Hermann M. et al. Impact of the ultrarapid CYP2C19*17 allele on serum concentration of escitalopram in psychiatric patients. Clin Pharmacol Ther 2008; 83: 322-327
• 43 Huezo-Diaz P, Perroud N, Spencer EP. et al. CYP2C19 genotype predicts steady state escitalopram concentration in GENDEP. J Psychopharmacol 2012; 26: 398-407
• 44 Kringen MK, Bråten LS, Haslemo T. et al. The influence of combined CYP2D6 and CYP2C19 genotypes on venlafaxine and O-desmethylvenlafaxine concentrations in a large patient cohort. J Clin Psychopharmacol 2020; 40: 137-144
• 45 Veefkind AH, Haffmans PM, Hoencamp E. Venlafaxine serum levels and CYP2D6 genotype. Ther Drug Monit 2000; 22: 202-208
• 46 Hermann M, Hendset M, Fosaas K. et al. Serum concentrations of venlafaxine and its metabolites O-desmethylvenlafaxine and N-desmethylvenlafaxine in heterozygous carriers of the CYP2D6*3, *4 or *5 allele. Eur J Clin Pharmacol 2008; 64: 483-487
• 47 Ng C, Sarris J, Singh A. et al. Pharmacogenetic polymorphisms and response to escitalopram and venlafaxine over 8 weeks in major depression. Hum Psychopharmacol 2013; 28: 516-522
• 48 Shams ME, Arneth B, Hiemke C. et al. CYP2D6 polymorphism and clinical effect of the antidepressant venlafaxine. J Clin Pharm Ther 2006; 31: 493-502
• 49 Springer-Verlag GmbH, Heidelberg. PSIAC. https://www.psiac.de/; cited: 18 March, 2019
• 50 Kroon LA. Drug interactions with smoking. Am J Health Syst Pharm 2007; 64: 1917-1921
• 51 Scherf-Clavel M, Samanski L, Hommers LG. et al. Analysis of smoking behavior on the pharmacokinetics of antidepressants and antipsychotics: Evidence for the role of alternative pathways apart from CYP1A2. Int Clin Psychopharmacol 2019; 34: 93-100
• 52 Fabbri C, Serretti A. Genetics of treatment outcomes in major depressive disorder: Present and future. Clin Psychopharmacol Neurosci 2020; 18: 1-9