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.
Highlights
Major depressive disorder (MDD) is a common, often disabling condition affecting over 300 million individuals worldwide[1]
Females comprised of 66% of the study cohort, while males were at 34%
We have applied a “targeted” electrochemistry-based metabolomics platform to quantitate the metabolomic profiles in MDD patients before and after Selective serotonin reuptake inhibitors (SSRIs) treatment
Summary
Major depressive disorder (MDD) is a common, often disabling condition affecting over 300 million individuals worldwide[1]. Selective serotonin reuptake inhibitors (SSRIs) are common first-line treatments for MDD2,3. They are believed to increase the extracellular availability of the neurotransmitter serotonin by limiting its reabsorption into the presynaptic cell, so that serotonin levels are increased in the synaptic cleft and available for binding to postsynaptic receptors. About half the patients respond to the first medication; only one in three. Bhattacharyya et al Translational Psychiatry (2019)9:173 achieves symptom remission, which is the virtual absence of symptoms and the aim of treatment[4]. Some patients do well on a single medication, while others require medication combinations or alternative interventions. Clinical symptoms are insufficient to guide appropriate treatment selection[5] and, presently, treatments are selected empirically relying on a “trial and error” approach[6,7]
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