Metabolomic signature of exposure and response to citalopram/escitalopram in depressed outpatients.
Sudeepa Bhattacharyya,Ahmed T. Ahmed,Matthias Arnold,Duan Liu,Chunqiao Luo,Hongjie Zhu,Siamak MahmoudianDehkordi,Drew Neavin,Gregory Louie,Boadie W. Dunlop,Mark A. Frye,Liewei Wang,Richard M. Weinshilboum,Ranga R. Krishnan,A. John Rush,A. John Rush,A. John Rush,Rima Kaddurah-Daouk +17 more
TLDR
Electrochemistry-based targeted metabolomics revealed changes in guanosine–homogentisic acid and methionine–tyrosine interactions associated with HRSD17, which suggest possible roles for the gut microbiome, oxidative stress, and inflammation-related mechanisms.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.read more
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Book ChapterDOI
Proof of Concept
TL;DR: The GI/BSI/DFKI Protection Profile constitutes after the implementation of the identified improvements as the proposed evaluation methodology for remote electronic voting systems and can now be applied to available systems.
Journal ArticleDOI
Involvement of the microbiota-gut-brain axis in chronic restraint stress: disturbances of the kynurenine metabolic pathway in both the gut and brain.
Yuanyuan Deng,Yuanyuan Deng,Man-Fei Zhou,Junfeng Wang,Jiaxi Yao,Jing Yu,Wenwei Liu,Linlin Wu,Jun Wang,Rong Gao +9 more
TL;DR: In this paper, a murine model of chronic restraint stress (CRS) was established to investigate the metabolic signaling of tryptophan (Trp) neurotransmission at the intestinal and central levels in depression.
Journal ArticleDOI
Current Concepts in Pharmacometabolomics, Biomarker Discovery, and Precision Medicine.
TL;DR: The PMx efforts could simultaneously provide information related to an individual’s pharmacokinetic response during clinical trials and be used to predict patient response to drugs making pharmacometabolomic clinical research valuable for precision medicine.
Journal ArticleDOI
Kynurenic acid is a potential overlapped biomarker between diagnosis and treatment response for depression from metabolome analysis
Hisayuki Erabi,Go Okada,Chiyo Shibasaki,Daiki Setoyama,Dongchon Kang,Masahiro Takamura,Atsuo Yoshino,Manabu Fuchikami,Akiko Kurata,Takahiro A. Kato,Shigeto Yamawaki,Yasumasa Okamoto +11 more
TL;DR: The Hamilton Rating Scale for Depression (HRSD) was measured on 62 patients who completed approximately six-week treatment with escitalopram before and after treatment and found that kynurenic acid and kynurenine were significantly and negatively associated with HRSD reduction.
Journal ArticleDOI
Alterations in acylcarnitines, amines, and lipids inform about the mechanism of action of citalopram/escitalopram in major depression.
Siamak MahmoudianDehkordi,Ahmed T. Ahmed,Sudeepa Bhattacharyya,Xianlin Han,Rebecca Baillie,Matthias Arnold,Michelle K. Skime,Lisa St. John-Williams,M. Arthur Moseley,J. Will Thompson,Gregory Louie,Patricio Riva-Posse,W. Edward Craighead,William M. McDonald,Ranga R. Krishnan,A. John Rush,A. John Rush,Mark A. Frye,Boadie W. Dunlop,Richard M. Weinshilboum,Rima Kaddurah-Daouk +20 more
TL;DR: In this article, a targeted metabolomics approach utilizing a panel of 180 metabolites was used to gain insights into mechanisms of action and response to citalopram and ESCOPRA this article.
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The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: Guidelines for Reporting Observational Studies
E von Elm,Douglas G. Altman,Matthias Egger,Matthias Egger,Stuart J. Pocock,Peter C Gøtzsche,Jan P. Vandenbroucke +6 more
TL;DR: The STROBE Statement is a checklist of items that should be addressed in articles reporting on the 3 main study designs of analytical epidemiology: cohort, casecontrol, and cross-sectional studies; these recommendations are not prescriptions for designing or conducting studies.
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TL;DR: The second-generation versions of PLINK will offer dramatic improvements in performance and compatibility, and for the first time, users without access to high-end computing resources can perform several essential analyses of the feature-rich and very large genetic datasets coming into use.