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In this study we used electrochemistry-based targeted metabolomics to gain insights into the mechanisms of action of escitalopram\/citalopram focusing on a set of 31 metabolites from neurotransmitter-related pathways. Overall, 290 unipolar patients with major depressive disorder were profiled at baseline, after 4 and 8 weeks of drug treatment. The 17-item Hamilton Depression Rating Scale (HRSD<jats:sub>17<\/jats:sub>) scores gauged depressive symptom severity. More significant metabolic changes were found after 8 weeks than 4 weeks post baseline.<jats:italic>Within the tryptophan pathway<\/jats:italic>, we noted significant reductions in serotonin (5HT) and increases in indoles that are known to be influenced by human gut microbial cometabolism. 5HT, 5-hydroxyindoleacetate (5HIAA), and the ratio of 5HIAA\/5HT showed significant correlations to temporal changes in HRSD<jats:sub>17<\/jats:sub>scores.<jats:italic>In the tyrosine pathway<\/jats:italic>, changes were observed in the end products of the catecholamines, 3-methoxy-4-hydroxyphenylethyleneglycol and vinylmandelic acid. Furthermore, two phenolic acids, 4-hydroxyphenylacetic acid and 4-hydroxybenzoic acid, produced through noncanconical pathways, were increased with drug exposure.<jats:italic>In the purine pathway<\/jats:italic>, significant reductions in hypoxanthine and xanthine levels were observed. Examination of metabolite interactions through differential partial correlation networks revealed changes in guanosine\u2013homogentisic acid and methionine\u2013tyrosine interactions associated with HRSD<jats:sub>17<\/jats:sub>. Genetic association studies using the ratios of these interacting pairs of metabolites highlighted two genetic loci harboring genes previously linked to depression, neurotransmission, or neurodegeneration. Overall, exposure to escitalopram\/citalopram results in shifts in metabolism through noncanonical pathways, which suggest possible roles for the gut microbiome, oxidative stress, and inflammation-related mechanisms.<\/jats:p>","DOI":"10.1038\/s41398-019-0507-5","type":"journal-article","created":{"date-parts":[[2019,7,4]],"date-time":"2019-07-04T14:31:36Z","timestamp":1562250696000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":80,"title":["Metabolomic signature of exposure and response to citalopram\/escitalopram in depressed outpatients"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3493-6029","authenticated-orcid":false,"given":"Sudeepa","family":"Bhattacharyya","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed T.","family":"Ahmed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4666-0923","authenticated-orcid":false,"given":"Matthias","family":"Arnold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1065-246X","authenticated-orcid":false,"given":"Duan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunqiao","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongjie","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siamak","family":"Mahmoudiandehkordi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Drew","family":"Neavin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3267-7070","authenticated-orcid":false,"given":"Gregory","family":"Louie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boadie W.","family":"Dunlop","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark A.","family":"Frye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liewei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard M.","family":"Weinshilboum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ranga R.","family":"Krishnan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. 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A.J.R. has received consulting fees from Akili, Brain Resource Inc., Compass Inc., Curbstone Consultant LLC., Emmes Corp., Johnson and Johnson (Janssen), Liva-Nova, Mind Linc, Sunovion, and Taj Medical; speaking fees from Liva-Nova; and royalties from Guilford Press and the University of Texas Southwestern Medical Center, Dallas, TX (for the Inventory of Depressive Symptoms and its derivatives). He is also named the coinventor on two patents: US Patent No. 7,795,033: Methods to Predict the Outcome of Treatment with Antidepressant Medication and US Patent No. 7,906,283: Methods to Identify Patients at Risk of Developing Adverse Events during Treatment with Antidepressant Medication. M.A.F. has received grant support from AssureRx Health Inc, Myriad, Pfizer Inc, NIMH (R01 MH079261), the National Institute on Alcohol Abuse and Alcoholism (P20AA017830) in the National Institutes of Health at the US Department of Health and Human Services, and the Mayo Foundation. He has been a consultant (for Mayo) to Janssen Global Services, LLC; Mitsubishi Tanabe Pharma Corp; Myriad Genetics, Inc; Sunovion Pharmaceuticals, Inc; and Teva Pharmaceutical Industries Ltd. He has received continuing medical education, travel, and presentation support from the American Physician Institute and CME Outfitters. L.W. was supported by NIH grants U19 GM61388, U54 GM114838, and NSF164615. She is a cofounder and stockholder in OneOme. R.K.-D. is an inventor on key patents in the field of metabolomics. D.N.\u2019s stipend has been supported in part by NIH T32 GM072474 and the Mayo Graduate School. A.T.A.\u2019s research was supported by National Institute of General Medical Sciences of the National Institutes of Health under award number T32 GM008685. M.A. was supported by the National Institute on Aging [R01AG057452, RF1AG051550, and R01AG046171], National Institute of Mental Health [R01MH108348], and Qatar National Research Fund [NPRP8-061-3-011]. 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