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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.\n                    <jats:italic>CYP2D6<\/jats:italic>\n                    structural variants cannot be imputed from genotype data, limiting the determination of metabolic phenotypes, and precluding testing for association with response. The association of CYP2C19 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\u2009=\u20091.46, 95% CI [1.03, 2.06],\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.033, heterogeneity I\n                    <jats:sup>2<\/jats:sup>\n                    \u2009=\u20090%, subgroup difference\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.72). No metabolic phenotype was associated with percentage improvement from baseline. After stratifying by antidepressants primarily metabolized by CYP2C19, 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. 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.\n                  <\/jats:p>","DOI":"10.1038\/s41398-024-02981-1","type":"journal-article","created":{"date-parts":[[2024,7,18]],"date-time":"2024-07-18T21:01:37Z","timestamp":1721336497000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Metabolic activity of CYP2C19 and CYP2D6 on antidepressant response from 13 clinical studies using genotype imputation: a 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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 speaker 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\u2019s 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.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"This was a secondary analysis of studies shared by investigators with the Psychiatric Genomics Consortium. Each original study had received ethics approval.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}],"article-number":"296"}}