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Here, we observed dual roles for TSPYLs in mediating serotonin transport and the metabolism of selective serotonin reuptake inhibitors (SSRIs) in patients with major depressive disorder (MDD). The widely prescribed SSRIs, citalopram, and escitalopram are metabolized mainly by CYP2C19. The <jats:italic>TSPYL1<\/jats:italic> rs3828743 single nucleotide polymorphism (SNP), which decreases its suppression of CYP2C19 expression, was associated with rapid escitalopram metabolism and worse treatment response in the Mayo PGRN\u2010AMPS clinical trial. We also found that TSPYLs can regulate expression of the serotonin transporter protein, SLC6A4, and, in turn, serotonin transport into cells. The SNPs in tight linkage disequilibrium with the <jats:italic>TSPYL1<\/jats:italic> rs10223646 SNP were significantly correlated with baseline severity of depression in patients with MDD in the Sequenced Treatment Alternatives to Relieve Depression and International SSRI Pharmacogenomics Consortium clinical trials. Our findings suggest that genetic variation in <jats:italic>TSPYL<\/jats:italic> genes may be novel indicators for baseline severity of depression and SSRI poor response.<\/jats:p>","DOI":"10.1002\/cpt.1692","type":"journal-article","created":{"date-parts":[[2019,10,19]],"date-time":"2019-10-19T19:35:31Z","timestamp":1571513731000},"page":"662-670","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Dual Roles for the TSPYL Family in Mediating Serotonin Transport and the Metabolism of Selective Serotonin Reuptake Inhibitors in Patients with Major Depressive Disorder"],"prefix":"10.1111","volume":"107","author":[{"given":"Sisi","family":"Qin","sequence":"first","affiliation":[{"name":"Department of Molecular Pharmacology and Experimental Therapeutics Mayo Clinic Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andy R.","family":"Eugene","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Experimental Therapeutics Mayo Clinic Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Experimental Therapeutics Mayo Clinic Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingxin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Experimental Therapeutics Mayo Clinic Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Drew","family":"Neavin","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Experimental Therapeutics Mayo Clinic Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna M.","family":"Biernacka","sequence":"additional","affiliation":[{"name":"Department of Health Sciences Mayo Clinic Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Experimental Therapeutics Mayo Clinic Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard M.","family":"Weinshilboum","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Experimental Therapeutics Mayo Clinic Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liewei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Experimental Therapeutics Mayo Clinic Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,11,30]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1002\/wps.20229"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1017\/S1092852914000613"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01244820"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/00008571-199702000-00001"},{"key":"e_1_2_9_5_1","first-page":"927","article-title":"Identification of cytochrome p450 isoforms involved in citalopram N\u2010demethylation by human liver microsomes","volume":"280","author":"Kobayashi K.","year":"1997","journal-title":"J. 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