CYP2D6 Genotyping and Inhibition as Predictors of Adverse Drug Reactions in Depressive Disorders

Amanda Holck, MD; Marie Asp, MD, PhD; Henrik Green, PhD; Åsa Westrin, MD, PhD; Margareta Reis, PhD

J Clin Psychiatry 2024;85(1):23m14937

ABSTRACT

Objective: The primary aim of this study was to examine the association between the different predicted phenotypes of the polymorphic CYP2D6 gene and the prevalence of adverse drug reactions in patients suffering from depressive disorders. The secondary aim was to investigate if comedication with CYP2D6 inhibitors resulted in more adverse drug reactions due to phenoconversion.

Methods: Between January 2012 and December 2021, 415 patients with a depressive disorder and insufficient treatment response in secondary psychiatric care were included in the naturalistic observational study Genes, Depression, and Suicidality (GEN-DS). The patients were subjected to a semistructured interview and diagnosed according to DSM-IV. Patients were also required to complete the self-rating version of the UKU Side Effect Rating Scale. All patients were genotyped for CYP2D6 and assigned a corresponding predicted CYP2D6 phenotype.

Results: Out of the 415 patients, 147 patients with available genotyping and UKU scale results were also prescribed 1 or more drugs metabolized by CYP2D6. We did not find any evidence of an effect of the predicted CYP2D6 phenotype on the total burden of adverse drug reactions or in any of the specific symptom domains as measured with the UKU scale among these patients. We also investigated if comedication with 1 or more substances that inhibited the effect of the CYP2D6 enzyme resulted in more reported adverse drug reactions due to phenoconversion. Even though the rate of phenotypic PMs increased from 13 to 38 patients, we did not find any support for increased adverse drug reactions in this group.

Conclusions: We did not find that CYP2D6 phenotype could predict the occurrence of adverse drug reactions in patients with depressive disorders in this naturalistic setting. However, information about CYP2D6 genotype may still be important in antidepressant treatment for the selection of appropriate drugs, for dosing recommendations of certain medications, or when the patient is suffering from severe adverse reactions.

J Clin Psychiatry 2024;85(1):23m14937

Author affiliations are listed at the end of this article.

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References (43)

Depression and Other Common Mental Disorders: Global Health Estimates. World Health Organization. Licence: CC BY-NC-SA 3.0 IGO; 2017. https://www.who.int/publications/i/item/depression-global-health-estimates/
Brody DJ, Gu Q. Antidepressant use among adults: United States, 2015-2018. NCHS Data Brief. 2020;(377):1–8. PubMed
Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905–1917. PubMed CrossRef
Gyllensten H, Rehnberg C, Jönsson AK, et al. Cost of illness of patient-reported adverse drug events: a population-based cross-sectional survey. BMJ Open. 2013;3(6):e002574. PubMed CrossRef
Solomon HV, Cates KW, Li KJ. Does obtaining CYP2D6 and CYP2C19 pharmacogenetic testing predict antidepressant response or adverse drug reactions? Psychiatry Res. 2019;271:604–613. PubMed CrossRef
Hiemke C, Bergemann N, Clement HW, et al. Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: update 2017. Pharmacopsychiatry. 2018;51(1-02):e1. PubMed CrossRef
Ingelman-Sundberg M, Sim SC, Gomez A, et al. Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther. 2007;116(3):496–526. PubMed CrossRef
Pharmacogene Variation Consortium (PharmVar). Updated December 20, 2022. Accessed Jan 20, 2023. www.PharmVar.org/genes
Gaedigk A, Casey ST, Whirl-Carrillo M, et al; Pharmacogene Variation Consortium. Pharmacogene Variation Consortium: a global resource and repository for pharmacogene variation. Clin Pharmacol Ther. 2021;110(3):542–545. PubMed CrossRef
Gaedigk A, Ingelman-Sundberg M, Miller NA, et al; PharmVar Steering Committee. The Pharmacogene Variation (PharmVar) consortium: incorporation of the human cytochrome P450 (CYP) allele nomenclature database. Clin Pharmacol Ther. 2018;103(3):399–401. PubMed CrossRef
Gaedigk A, Whirl-Carrillo M, Pratt VM, et al. PharmVar and the landscape of pharmacogenetic resources. Clin Pharmacol Ther. 2020;107(1):43–46. PubMed CrossRef
Altar CA, Hornberger J, Shewade A, et al. Clinical validity of cytochrome P450 metabolism and serotonin gene variants in psychiatric pharmacotherapy. Int Rev Psychiatry. 2013;25(5):509–533. PubMed CrossRef
Shah RR, Smith RL. Addressing phenoconversion: the Achilles’ heel of personalized medicine. Br J Clin Pharmacol. 2015;79(2):222–240. PubMed CrossRef
Asp M, Lindqvist D, Fernström J, et al. Recognition of personality disorder and anxiety disorder comorbidity in patients treated for depression in secondary psychiatric care. PLoS One. 2020;15(1):e0227364. PubMed CrossRef
Sheehan DV, Lecrubier Y, Sheehan KH, et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59(suppl 20):22–33, quiz 34–57. PubMed
First M, Gibbon M, Spitzer RL, et al. Structured Clinical Interview for DSM-IV Axis II Personality Disorders (SCID-II). American Psychiatric Press, Inc; 1997.
Åsberg M, Montgomery SA, Perris C, et al. A comprehensive psychopathological rating scale. Acta Psychiatr Scand suppl. 1978;57(S271):5–27. PubMed CrossRef
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fourth Edition. American Psychiatric Association; 2000.
Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134(4):382–389. PubMed CrossRef
Lingjaerde O, Ahlfors UG, Bech P, et al. The UKU Side Effect Rating Scale: new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients. Acta Psychiatr Scand suppl. 1987;76(s334):1–100. PubMed CrossRef
Lindström E, Lewander T, Malm U, et al. Patient-rated versus clinician-rated side effects of drug treatment in schizophrenia: clinical validation of a self-rating version of the UKU Side Effect Rating Scale (UKU-SERS-Pat). Nord J Psychiatry. 2001;55(suppl 44):5–69. PubMed CrossRef
Söderbäck E, Zackrisson AL, Lindblom B, et al. Determination of CYP2D6 gene copy number by pyrosequencing. Clin Chem. 2005;51(3):522–531. PubMed CrossRef
Zackrisson AL, Lindblom B. Identification of CYP2D6 alleles by single nucleotide polymorphism analysis using pyrosequencing. Eur J Clin Pharmacol. 2003;59(7):521–526. PubMed CrossRef
Caudle KE, Sangkuhl K, Whirl-Carrillo M, et al. Standardizing CYP2D6 genotype to phenotype translation: consensus recommendations from the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group. Clin Transl Sci. 2020;13(1):116–124. PubMed CrossRef
Pharm GKB. Accessed Nov 1, 2022. https://www.PharmGKB.org/
Whirl-Carrillo M, Huddart R, Gong L, et al. An evidence-based framework for evaluating pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther. 2021;110(3):563–572. PubMed CrossRef
Whirl-Carrillo M, McDonagh EM, Hebert JM, et al. Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther. 2012;92(4):414–417. PubMed CrossRef
Flockhart DA, McDonald C, Desta Z. The Flockhart Cytochrome P450 Drug-Drug Interaction Table. Division of Clinical Pharmacology, Indiana University School of Medicine. Updated 2021. Accessed Aug 27, 2023. https://drug-interactions.medicine.iu.edu
Borges S, Desta Z, Jin Y, et al. Composite functional genetic and comedication CYP2D6 activity score in predicting tamoxifen drug exposure among breast cancer patients. J Clin Pharmacol. 2010;50(4):450–458. PubMed CrossRef
Walden LM, Brandl EJ, Tiwari AK, et al. Genetic testing for CYP2D6 and CYP2C19 suggests improved outcome for antidepressant and antipsychotic medication. Psychiatry Res. 2019;279:111–115. PubMed CrossRef
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(5):516–522. PubMed CrossRef
Roberts RL, Mulder RT, Joyce PR, et al. No evidence of increased adverse drug reactions in cytochrome P450 CYP2D6 poor metabolizers treated with fluoxetine or nortriptyline. Hum Psychopharmacol. 2004;19(1):17–23. PubMed CrossRef
Hodgson K, Tansey KE, Uher R, et al. Exploring the role of drug-metabolising enzymes in antidepressant side effects. Psychopharmacology (Berl). 2015;232(14):2609–2617. PubMed CrossRef
Steimer W, Zöpf K, von Amelunxen S, et al. Amitriptyline or not, that is the question: pharmacogenetic testing of CYP2D6 and CYP2C19 identifies patients with low or high risk for side effects in amitriptyline therapy. Clin Chem. 2005;51(2):376–385. PubMed CrossRef
Rau T, Wohlleben G, Wuttke H, et al. CYP2D6 genotype: impact on adverse effects and nonresponse during treatment with antidepressants-a pilot study. Clin Pharmacol Ther. 2004;75(5):386–393. PubMed CrossRef
Sánchez-Iglesias S, García-Solaesa V, García-Berrocal B, et al. Role of pharmacogenetics in improving the safety of psychiatric care by predicting the potential risks of mania in CYP2D6 poor metabolizers diagnosed with bipolar disorder. Medicine (Baltimore). 2016;95(6):e2473. PubMed CrossRef
Preskorn SH, Kane CP, Lobello K, et al. Cytochrome P450 2D6 phenoconversion is common in patients being treated for depression: implications for personalized medicine. J Clin Psychiatry. 2013;74(6):614–621. PubMed CrossRef
Storelli F, Matthey A, Lenglet S, et al. Impact of CYP2D6 functional allelic variations on phenoconversion and drug-drug interactions. Clin Pharmacol Ther. 2018;104(1):148–157. PubMed CrossRef
Funk CSM, Hart XM, Gründer G, et al. Is therapeutic drug monitoring relevant for antidepressant drug therapy? implications from a systematic review and meta-analysis with focus on moderating factors. Front Psychiatry. 2022;13:826138. PubMed CrossRef
Uher R, Farmer A, Henigsberg N, et al. Adverse reactions to antidepressants. Br J Psychiatry. 2009;195(3):202–210. PubMed CrossRef
Zucker I, Prendergast BJ. Sex differences in pharmacokinetics predict adverse drug reactions in women. Biol Sex Differ. 2020;11(1):32. PubMed CrossRef
Gaedigk A, Sangkuhl K, Whirl-Carrillo M, et al. Prediction of CYP2D6 phenotype from genotype across world populations. Genet Med. 2017;19(1):69–76. PubMed CrossRef
Zhou Y, Ingelman-Sundberg M, Lauschke VM. Worldwide distribution of cytochrome P450 alleles: a meta-analysis of population-scale sequencing projects. Clin Pharmacol Ther. 2017;102(4):688–700. PubMed CrossRef