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Here, effects of different drugs with antidepressant properties (vortioxetine, fluoxetine, and ketamine) on various tryptophan metabolites in different brain regions and plasma were examined using tandem mass spectrometry (<jats:styled-content style=\"fixed-case\">LC<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">MS<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">MS<\/jats:styled-content>), in Flinders Sensitive Line rats, a genetic rat model of depression, and its controls: Flinders Sensitive Line and Sprague\u2013Dawley rats. Protein levels of kynurenine pathway enzymes were measured in the brains and livers of these rat strains. Furthermore, effects of vortioxetine on tryptophan metabolites were assessed in the cortical regions of lupus mice (<jats:styled-content style=\"fixed-case\">MRL<\/jats:styled-content>\/MpJ\u2010Fas<jats:sup>Ipr<\/jats:sup>), a murine model of increased depression\u2010like behavior associated with inflammation. Sustained vortioxetine or fluoxetine (at doses aimed to fully occupy serotonin transporter via food or drinking water for at least 14\u00a0days) reduced levels of the excitotoxin quinolinic acid (<jats:styled-content style=\"fixed-case\">QUIN<\/jats:styled-content>) in various brain regions in all rats. Furthermore, chronic vortioxetine reduced levels of<jats:styled-content style=\"fixed-case\">QUIN<\/jats:styled-content>in<jats:styled-content style=\"fixed-case\">MRL<\/jats:styled-content>\/MpJ\u2010Fas<jats:sup>Ipr<\/jats:sup>mice. Acute i.p. administration of fluoxetine (10\u00a0mg\/kg) or vortioxetine (10\u00a0mg\/kg) led to reduced brain 5\u2010hydroxyindoleacetic acid in Sprague\u2013Dawley rats (2, 4, 6, and 8\u00a0h) and a similar trend was evident in Flinders Sensitive Line and Flinders Sensitive Line rats after 4\u00a0h. In contrast, single or repeated administration of ketamine (15\u00a0mg\/kg i.p.) did not induce significant changes in metabolite levels. In conclusion, sustained vortioxetine and fluoxetine administration decreased<jats:styled-content style=\"fixed-case\">QUIN<\/jats:styled-content>independent of species, while ketamine was ineffective. These results support the hypothesis that modulating tryptophan metabolism may be part of the mechanism of action for some antidepressants.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p><jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc14043-fig-0004-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.14043","type":"journal-article","created":{"date-parts":[[2017,4,13]],"date-time":"2017-04-13T18:33:11Z","timestamp":1492108391000},"page":"118-131","source":"Crossref","is-referenced-by-count":47,"title":["Drugs with antidepressant properties affect tryptophan metabolites differently in rodent models with depression\u2010like behavior"],"prefix":"10.1111","volume":"142","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5754-6651","authenticated-orcid":false,"given":"Amanda","family":"Eskelund","sequence":"first","affiliation":[{"name":"Translational Neuropsychiatry Unit Risskov Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Li","sequence":"additional","affiliation":[{"name":"Lundbeck Research US Paramus New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David P.","family":"Budac","sequence":"additional","affiliation":[{"name":"Lundbeck Research US Paramus New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heidi K.","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Translational Neuropsychiatry Unit Risskov Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Gulinello","sequence":"additional","affiliation":[{"name":"Behavioral Core Facility Department of Neuroscience Albert Einstein College of Medicine Bronx New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Connie","family":"Sanchez","sequence":"additional","affiliation":[{"name":"Translational Neuropsychiatry Unit Risskov Denmark"},{"name":"Lundbeck Research US Paramus New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregers","family":"Wegener","sequence":"additional","affiliation":[{"name":"Translational Neuropsychiatry Unit Risskov Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,5,16]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s002130050924"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1017\/S1461145705005900"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1734-1140(12)70851-4"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/hipo.22617"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/1476-9255-8-25"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(81)90299-9"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1982.tb09269.x"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00485"},{"key":"e_1_2_8_10_1","first-page":"5","article-title":"Inhibition of tryptophan \u2010 pyrrolase activity and elevation of brain tryptophan concentration by fluoxetine in rats","volume":"13","author":"Bano S.","year":"2003","journal-title":"J. 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