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[Preprint]. 2023 Dec 11:2023.06.26.23291890.

doi: 10.1101/2023.06.26.23291890.

Meta-analysis of CYP2C19 and CYP2D6 metabolic activity on antidepressant response from 13 clinical studies using genotype imputation

Danyang Li¹, Oliver Pain², Chiara Fabbri^{1

3}, Win Lee Edwin Wong^{1

4}, Chris Wai Hang Lo¹, Stephan Ripke^{5

6}, Annamaria Cattaneo^{7

8}, Daniel Souery⁹, Mojca Z Dernovsek¹⁰, Neven Henigsberg¹¹, Joanna Hauser¹², Glyn Lewis¹³, Ole Mors¹⁴, Nader Perroud¹⁵, Marcella Rietschel¹⁶, Rudolf Uher¹⁷, Wolfgang Maier¹⁸, Bernhard T Baune^{19

20

21}, Joanna M Biernacka^{22

23}, Guido Bondolfi¹⁵, Katharina Domschke²⁴, Masaki Kato²⁵, Yu-Li Liu²⁶, Alessandro Serretti³, Shih-Jen Tsai^{27

28}, Richard Weinshilboum²⁹; GSRD Consortium; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; Andrew M McIntosh³⁰, Cathryn M Lewis^{1

31}

Affiliations

¹ Social, Genetic and Developmental Psychiatry Centre, King's College London, London, GB.
² Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, GB.
³ Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, IT.
⁴ Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, SG.
⁵ Department of Psychiatry and Psychotherapy, Universitätsmedizin Berlin Campus Charité Mitte, Berlin, DE.
⁶ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, US.
⁷ Biological Psychiatry Laboratory, IRCCS Fatebenefratelli, Brescia, IT.
⁸ Department of Pharmacological and Biomedical Sciences, University of Milan, Milan, IT.
⁹ Laboratoire de Psychologie Medicale, Universitè Libre de Bruxelles and Psy Pluriel, Centre Européen de Psychologie Medicale, Brussels, BE.
¹⁰ University Psychiatric Clinic, University of Ljubliana, Ljubljana, SI.
¹¹ Department of Psychiatry, Croatian Institute for Brain Research, University of Zagreb Medical School, Zagreb, HR.
¹² Psychiatric Genetic Unit,, Poznan University of Medical Sciences, Poznan, PL.
¹³ Division of Psychiatry, University College London, London, GB.
¹⁴ Psychosis Research Unit, Aarhus University Hospital - Psychiatry, Aarhus, DK.
¹⁵ Department of Psychiatry, Geneva University Hospitals, Geneva, CH.
¹⁶ Department of Genetic Epidemiology in Psychiatry, Medical Faculty Mannheim, University of Heidelberg, Central Institute of Mental Health, Mannheim, DE.
¹⁷ Department of Psychiatry, Dalhousie University, Halifax, NS, CA.
¹⁸ Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, DE.
¹⁹ Department of Psychiatry, University of Münster, Münster, DE.
²⁰ Florey Institute for Neuroscience and Mental Health, University of Melbourne, Melbourne, AU.
²¹ Department of Psychiatry, Melbourne Medical School, University of Melbourne, Melbourne, AU.
²² Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
²³ Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
²⁴ Department of Psychiatry and Psychotherapy, Medical Center, University of Freiburg, Freiburg, DE.
²⁵ Department of Neuropsychiatry, Kansai Medical University, Osaka, JP.
²⁶ Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli, TW.
²⁷ Department of Psychiatry, Taipei Veterans General Hospital, Taipei, TW.
²⁸ Division of Psychiatry, School of Medicine, National Yang-Ming University, Taipei, TW.
²⁹ Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
³⁰ Division of Psychiatry, University of Edinburgh, Edinburgh, GB.
³¹ Department of Medical & Molecular Genetics, King's College London, London, GB.

PMID: 37425775
PMCID: PMC10327261
DOI: 10.1101/2023.06.26.23291890

Meta-analysis of CYP2C19 and CYP2D6 metabolic activity on antidepressant response from 13 clinical studies using genotype imputation

Danyang Li et al. medRxiv. 2023.

[Preprint]. 2023 Dec 11:2023.06.26.23291890.

doi: 10.1101/2023.06.26.23291890.

Authors

Affiliations

¹ Social, Genetic and Developmental Psychiatry Centre, King's College London, London, GB.
² Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, GB.
³ Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, IT.
⁴ Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, SG.
⁵ Department of Psychiatry and Psychotherapy, Universitätsmedizin Berlin Campus Charité Mitte, Berlin, DE.
⁶ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, US.
⁷ Biological Psychiatry Laboratory, IRCCS Fatebenefratelli, Brescia, IT.
⁸ Department of Pharmacological and Biomedical Sciences, University of Milan, Milan, IT.
⁹ Laboratoire de Psychologie Medicale, Universitè Libre de Bruxelles and Psy Pluriel, Centre Européen de Psychologie Medicale, Brussels, BE.
¹⁰ University Psychiatric Clinic, University of Ljubliana, Ljubljana, SI.
¹¹ Department of Psychiatry, Croatian Institute for Brain Research, University of Zagreb Medical School, Zagreb, HR.
¹² Psychiatric Genetic Unit,, Poznan University of Medical Sciences, Poznan, PL.
¹³ Division of Psychiatry, University College London, London, GB.
¹⁴ Psychosis Research Unit, Aarhus University Hospital - Psychiatry, Aarhus, DK.
¹⁵ Department of Psychiatry, Geneva University Hospitals, Geneva, CH.
¹⁶ Department of Genetic Epidemiology in Psychiatry, Medical Faculty Mannheim, University of Heidelberg, Central Institute of Mental Health, Mannheim, DE.
¹⁷ Department of Psychiatry, Dalhousie University, Halifax, NS, CA.
¹⁸ Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, DE.
¹⁹ Department of Psychiatry, University of Münster, Münster, DE.
²⁰ Florey Institute for Neuroscience and Mental Health, University of Melbourne, Melbourne, AU.
²¹ Department of Psychiatry, Melbourne Medical School, University of Melbourne, Melbourne, AU.
²² Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
²³ Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
²⁴ Department of Psychiatry and Psychotherapy, Medical Center, University of Freiburg, Freiburg, DE.
²⁵ Department of Neuropsychiatry, Kansai Medical University, Osaka, JP.
²⁶ Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli, TW.
²⁷ Department of Psychiatry, Taipei Veterans General Hospital, Taipei, TW.
²⁸ Division of Psychiatry, School of Medicine, National Yang-Ming University, Taipei, TW.
²⁹ Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
³⁰ Division of Psychiatry, University of Edinburgh, Edinburgh, GB.
³¹ Department of Medical & Molecular Genetics, King's College London, London, GB.

PMID: 37425775
PMCID: PMC10327261
DOI: 10.1101/2023.06.26.23291890

Update in

Metabolic activity of CYP2C19 and CYP2D6 on antidepressant response from 13 clinical studies using genotype imputation: a meta-analysis.
Li D, Pain O, Fabbri C, Wong WLE, Lo CWH, Ripke S, Cattaneo A, Souery D, Dernovsek MZ, Henigsberg N, Hauser J, Lewis G, Mors O, Perroud N, Rietschel M, Uher R, Maier W, Baune BT, Biernacka JM, Bondolfi G, Domschke K, Kato M, Liu YL, Serretti A, Tsai SJ, Weinshilboum R; GSRD Consortium, the Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; McIntosh AM, Lewis CM. Li D, et al. Transl Psychiatry. 2024 Jul 19;14(1):296. doi: 10.1038/s41398-024-02981-1. Transl Psychiatry. 2024. PMID: 39025838 Free PMC article.

Abstract

Cytochrome P450 enzymes including CYP2C19 and CYP2D6 are important for antidepressant metabolism and polymorphisms of these genes have been determined to predict metabolite levels. Nonetheless, more evidence is needed to understand the impact of genetic variations on antidepressant response. In this study, individual clinical and genetic data from 13 studies of European and East Asian ancestry populations were collected. The antidepressant response was clinically assessed as remission and percentage improvement. Imputed genotype was used to translate genetic polymorphisms to metabolic phenotypes (poor, intermediate, normal, and rapid+ultrarapid) of CYP2C19 and CYP2D6. The association of CYP2C19 and CYP2D6 metabolic phenotypes with treatment response was examined using normal metabolizers as the reference. Among 5843 depression patients, a higher remission rate was found in CYP2C19 poor metabolizers compared to normal metabolizers at nominal significance but did not survive after multiple testing correction (OR=1.46, 95% CI [1.03, 2.06], p=0.033, heterogeneity I²=0%, subgroup difference p=0.72). No metabolic phenotype was associated with percentage improvement from baseline. After stratifying by antidepressants primarily metabolized by CYP2C19 and CYP2D6, no association was found between metabolic phenotypes and antidepressant response. Metabolic phenotypes showed differences in frequency, but not effect, between European- and East Asian-ancestry studies. In conclusion, metabolic phenotypes imputed from genetic variants using genotype were not associated with antidepressant response. CYP2C19 poor metabolizers could potentially contribute to antidepressant efficacy with more evidence needed. CYP2D6 structural variants cannot be imputed from genotype data, limiting inference of pharmacogenetic effects. Sequencing and targeted pharmacogenetic testing, alongside information on side effects, antidepressant dosage, depression measures, and diverse ancestry studies, would more fully capture the influence of metabolic phenotypes.

Keywords: CYP2C19; CYP2D6; antidepressants; pharmacogenetics.

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Conflict of interest statement

Conflict of Interest CML has served on the scientific advisory board for Myriad Neuroscience, and is a consultant for UCB. AS is or has been consultant/speaker for: Abbott, AbbVie, Angelini, AstraZeneca, Clinical Data, Boehringer, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, InnovaPharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi, and Servier. AMM has received research support from the Sackler Trust and speakers fees from Janssen and Illumina. MK has received grant funding from the Japanese Ministry of Health, Labor and Welfare, the Japan Society for the Promotion of Science, SENSHIN Medical Research Foundation, the Japan Research Foundation for Clinical Pharmacology and the Japanese Society of Clinical Neuropsychopharmacology and speaker’s honoraria from Sumitomo Pharma, Otsuka, Meiji-Seika Pharma, Eli Lilly, MSD K.K., Pfizer, Janssen Pharmaceutical, Shionogi, Mitsubishi Tanabe Pharma, Takeda Pharmaceutical, Lundbeck Viatris Inc, Eisai Co., Ltd. and Ono Pharmaceutical and participated in an advisory/review board for Otsuka, Sumitomo Pharma, Shionogi and Boehringer Ingelheim. DS has received grant/research support from GlaxoSmithKline and Lundbeck; and served as a consultant or on advisory boards for AstraZeneca, Bristol Myers Squibb, Eli Lilly, Janssen, and Lundbeck. CF was a speaker for Janssen. NP is or has been consultant/speaker for: Takeda, Janssen and Lundbeck All other authors report no biomedical financial interests or potential conflicts of interest.

Figures

**Figure 1.. Proportion of metabolic phenotypes in each cohort**
DAST: Depression and Sequence of Treatment, GENDEP: Genome Based Therapeutic Drugs for Depression, GENPOD: GENetic and clinical Predictors Of treatment response in Depression, GODS: Geneva Outpatient Depression Study, GSK: Glaxo Smith Kline, GSRD: Group for the Study of Resistant Depression, PFZ: Pfizer, PGRN: Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study, STARD, Sequenced Treatment Alternatives to Relieve Depression. PM: poor metabolizer, IM: intermediate metabolizer, NM: normal metabolizer, RM+UM: rapid+ultrarapid metabolizer

**Figure 2.. Association of CYP2C19 and CYP2D6 metabolizer status with antidepressant outcomes**
PM: poor metabolizer, IM: intermediate metabolizer, RM+UM: rapid+ultrarapid metabolizer, OR: odd ratio, SMD: standard mean difference, CI: confidence interval

See this image and copyright information in PMC

References

1. National Institute for Health and Care Excellence. Depression in adults: treatment and management. NICE guideline NG; 222. (2022). - PubMed
1. Fabbri C. et al. Genetic and clinical characteristics of treatment-resistant depression using primary care records in two UK cohorts. Mol. Psychiatry 26, 3363–3373 (2021). - PMC - PubMed
1. Pain O. et al. Identifying the Common Genetic Basis of Antidepressant Response. Biol. Psychiatry Glob. Open Sci. 2, 115–126 (2022). - PMC - PubMed
1. Trivedi M. H. et al. Evaluation of Outcomes With Citalopram for Depression Using Measurement-Based Care in STAR*D: Implications for Clinical Practice. Am. J. Psychiatry 163, 28–40 (2006). - PubMed
1. Sforzini L. et al. A Delphi-method-based consensus guideline for definition of treatment-resistant depression for clinical trials. Mol. Psychiatry 27, 1286–1299 (2022). - PMC - PubMed

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This is a preprint.

Meta-analysis of CYP2C19 and CYP2D6 metabolic activity on antidepressant response from 13 clinical studies using genotype imputation

Affiliations

Meta-analysis of CYP2C19 and CYP2D6 metabolic activity on antidepressant response from 13 clinical studies using genotype imputation

Authors

Affiliations

Update in

Abstract

Conflict of interest statement

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Update in

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