Metabolomic signature of exposure and response to citalopram/escitalopram in depressed outpatients
Metabolomic signature of exposure and response to citalopram/escitalopram in depressed outpatients
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DOI：
10.1038/s41398-019-0507-5
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发表时间：
2019-07-04
影响因子：
6.8
通讯作者：
Kaddurah-Daouk, Rima
中科院分区：
文献类型：
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作者：
Bhattacharyya, Sudeepa;Ahmed, Ahmed T.;Kaddurah-Daouk, Rima
代谢组学为研究药物效应提供了有价值的工具，揭示了药物的作用机制和治疗反应的变化。在这项研究中，我们使用基于电化学的靶向代谢组学来深入了解艾司西酞普兰/西酞普兰的作用机制，重点关注来自神经递质相关通路的一组31种代谢物。总体而言，290名患有重度抑郁症的单相患者在基线时，经过4周和8周的药物治疗后进行了分析。采用17项汉密尔顿抑郁评定量表（HRSD 17）评定抑郁症状的严重程度。8周后发现比基线后4周更显著的代谢变化。在色氨酸途径中，我们注意到5-羟色胺（5-HT）的显著减少和吲哚的增加，这是已知的人肠道微生物彗星的影响。5-HT、5-羟吲哚乙酸（5-HIAA）及5-HIAA/5-HT比值与HRSD 17评分的时间变化呈显著相关。在酪氨酸途径中，观察到的变化，在终产物的儿茶酚胺，3-甲氧基-4-羟基苯基乙二醇和乙烯基扁桃酸。此外，两种酚酸，4-羟基苯乙酸和4-羟基苯甲酸，通过noncanconical途径产生的，与药物暴露增加。在嘌呤途径中，观察到次黄嘌呤和黄嘌呤水平显著降低。通过微分偏相关网络检查代谢物相互作用，发现与HRSD 17相关的鸟苷-尿黑酸和甲硫氨酸-酪氨酸相互作用的变化。使用这些相互作用的代谢物对的比例进行的遗传关联研究突出了两个遗传位点，这些基因先前与抑郁症，神经传递或神经变性有关。总体而言，暴露于艾司西酞普兰/西酞普兰导致代谢通过非经典途径发生变化，这表明肠道微生物组、氧化应激和炎症相关机制可能发挥作用。
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.