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Metabolomic signature of exposure and response to citalopram/escitalopram in depressed outpatients.
Transl. Psychiatry 9:173 (2019)
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.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Catechol-o-methyltransferase; Global Biochemical Approach; Uric-acid Levels; Kynurenine Pathway; Tryptophan-metabolism; Uremic Toxins; Drug Response; Disorder; Methylation; Purine
ISSN (print) / ISBN
2158-3188
e-ISSN
2158-3188
Journal
Translational Psychiatry
Quellenangaben
Volume: 9,
Issue: 1,
Article Number: 173
Publisher
Nature Publishing Group
Publishing Place
Macmillan Building, 4 Crinan St, London N1 9xw, England
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Reviewing status
Peer reviewed