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

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...

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Vydáno v:Translational psychiatry Ročník 9; číslo 1; s. 173 - 14
Hlavní autoři: Bhattacharyya, Sudeepa, Ahmed, Ahmed T., Arnold, Matthias, Liu, Duan, Luo, Chunqiao, Zhu, Hongjie, Mahmoudiandehkordi, Siamak, Neavin, Drew, Louie, Gregory, Dunlop, Boadie W., Frye, Mark A., Wang, Liewei, Weinshilboum, Richard M., Krishnan, Ranga R., Rush, A. John, Kaddurah-Daouk, Rima
Médium: Journal Article
Jazyk:angličtina
Vydáno: London Nature Publishing Group UK 04.07.2019
Nature Publishing Group
Témata:
692/699/476/1414
706/648
Acids
Adult
Behavioral Sciences
Biological Psychology
Citalopram - pharmacology
Depressive Disorder, Major - drug therapy
Depressive Disorder, Major - metabolism
Depressive Disorder, Major - physiopathology
Female
Follow-Up Studies
Gastrointestinal Microbiome - drug effects
Humans
Male
Medicine
Medicine & Public Health
Metabolites
Metabolome - drug effects
Metabolomics
Middle Aged
Neurosciences
Pharmacotherapy
Psychiatry
Serotonin Uptake Inhibitors - pharmacology
Severity of Illness Index
Signal Transduction - drug effects
ISSN:2158-3188, 2158-3188
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Shrnutí: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 (HRSD 17 ) 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 HRSD 17 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 HRSD 17 . 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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ISSN:2158-3188
2158-3188
DOI:10.1038/s41398-019-0507-5