Metabolomic signature of exposure and response to citalopram/escitalopram in depressed outpatients

• Type of Material: Article
• Authors: Sudeepa Bhattacharyya, University of Arkansas; Ahmed T. Ahmed, Mayo Clinic; Matthias Arnold, Duke University; Duan Liu, Mayo Clinic; Chunqiao Luo, University of Arkansas; Hongjie Zhu, Sanofi; Siamak Mahmoudiandehkordi, Duke University; Drew Neavin, Mayo Clinic; Gregory Louie, Duke University; Boadie Dunlop, Emory University; Mark A. Frye, Mayo Clinic; Liewei Wang, Mayo Clinic; Richard M. Weinshilboum, Mayo Clinic; Ranga R. Krishnan, Rush University; A. John Rush, Duke University; Rima Kaddurah-Daouk, Duke University
• Language: English
• Date: 2019-07-04
• Publisher: Springer Nature [academic journals on nature.com]: Fully open access journals
• Publication Version: Final Published Version
• Copyright Statement: © 2019, The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41398-019-0507-5
• Title of Journal or Parent Work: Translational Psychiatry
• ISSN: 2158-3188
• Volume: 9
• Issue: 1
• Start Page: 173
• End Page: 173
• Grant/Funding Information: This work was funded by grant support to Rima Kaddurah-Daouk through NIH grants R01MH108348, R01AG046171 & U01AG061359, RF1AG051550.; The research and the authors are supported by funding from the NIH.; Sudeepa Bhattacharyya was supported by 5R01MH108348, 5R01AG046171-03S1.; R.M.W. was supported by NIH grants RO1 GM28157, U19 GM61388, U54 GM114838, and NSF1624615.; A.T.A.’s research was supported by National Institute of General Medical Sciences of the National Institutes of Health under award number T32 GM008685.; The authors are grateful for the support of NIH, to Lisa Howerton for her administrative support, and to the study participants and their families of the Mayo Pharmacogenomics Research Network-Antidepressant Pharmacogenomics Medication Study (PGRN-AMPS).; 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].; 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.; D.N.’s stipend has been supported in part by NIH T32 GM072474 and the Mayo Graduate School.; L.W. was supported by NIH grants U19 GM61388, U54 GM114838, and NSF164615
• Keywords: PURINE; GLOBAL BIOCHEMICAL APPROACH; URIC-ACID LEVELS; DRUG RESPONSE; Science & Technology; TRYPTOPHAN-METABOLISM; CATECHOL-O-METHYLTRANSFERASE; Psychiatry; KYNURENINE PATHWAY; UREMIC TOXINS; Life Sciences & Biomedicine; METHYLATION; DISORDER
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Pharmacology; Psychology, Behavioral

Abstract

Metabolomics provides valuable tools for the study of drug effects, unraveling the mechanism of action and variation in response due to treatment. 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 (HRSD17) scores gauged depressive symptom severity. More significant metabolic changes were found after 8 weeks than 4 weeks post baseline. Within the tryptophan pathway, 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 HRSD17 scores. In the tyrosine pathway, 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. In the purine pathway, significant reductions in hypoxanthine and xanthine levels were observed. Examination of metabolite interactions through differential partial correlation networks revealed changes in guanosine–homogentisic acid and methionine–tyrosine interactions associated with HRSD17. 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.