Browsing by Author "Bhattacharyya, Sudeepa"
Now showing 1 - 4 of 4
Results Per Page
Sort Options
Item Open Access Alterations in acylcarnitines, amines, and lipids inform about the mechanism of action of citalopram/escitalopram in major depression.(Translational psychiatry, 2021-03-02) MahmoudianDehkordi, Siamak; Ahmed, Ahmed T; Bhattacharyya, Sudeepa; Han, Xianlin; Baillie, Rebecca A; Arnold, Matthias; Skime, Michelle K; John-Williams, Lisa St; Moseley, M Arthur; Thompson, J Will; Louie, Gregory; Riva-Posse, Patricio; Craighead, W Edward; McDonald, William; Krishnan, Ranga; Rush, A John; Frye, Mark A; Dunlop, Boadie W; Weinshilboum, Richard M; Kaddurah-Daouk, Rima; Mood Disorders Precision Medicine Consortium (MDPMC)Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for major depressive disorder (MDD), yet their mechanisms of action are not fully understood and their therapeutic benefit varies among individuals. We used a targeted metabolomics approach utilizing a panel of 180 metabolites to gain insights into mechanisms of action and response to citalopram/escitalopram. Plasma samples from 136 participants with MDD enrolled into the Mayo Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) were profiled at baseline and after 8 weeks of treatment. After treatment, we saw increased levels of short-chain acylcarnitines and decreased levels of medium-chain and long-chain acylcarnitines, suggesting an SSRI effect on β-oxidation and mitochondrial function. Amines-including arginine, proline, and methionine sulfoxide-were upregulated while serotonin and sarcosine were downregulated, suggesting an SSRI effect on urea cycle, one-carbon metabolism, and serotonin uptake. Eighteen lipids within the phosphatidylcholine (PC aa and ae) classes were upregulated. Changes in several lipid and amine levels correlated with changes in 17-item Hamilton Rating Scale for Depression scores (HRSD17). Differences in metabolic profiles at baseline and post-treatment were noted between participants who remitted (HRSD17 ≤ 7) and those who gained no meaningful benefits (<30% reduction in HRSD17). Remitters exhibited (a) higher baseline levels of C3, C5, alpha-aminoadipic acid, sarcosine, and serotonin; and (b) higher week-8 levels of PC aa C34:1, PC aa C34:2, PC aa C36:2, and PC aa C36:4. These findings suggest that mitochondrial energetics-including acylcarnitine metabolism, transport, and its link to β-oxidation-and lipid membrane remodeling may play roles in SSRI treatment response.Item Open Access Altered bile acid profile associates with cognitive impairment in Alzheimer's disease-An emerging role for gut microbiome.(Alzheimer's & dementia : the journal of the Alzheimer's Association, 2018-10-08) MahmoudianDehkordi, Siamak; Arnold, Matthias; Nho, Kwangsik; Ahmad, Shahzad; Jia, Wei; Xie, Guoxiang; Louie, Gregory; Kueider-Paisley, Alexandra; Moseley, M Arthur; Thompson, J Will; St John Williams, Lisa; Tenenbaum, Jessica D; Blach, Colette; Baillie, Rebecca; Han, Xianlin; Bhattacharyya, Sudeepa; Toledo, Jon B; Schafferer, Simon; Klein, Sebastian; Koal, Therese; Risacher, Shannon L; Kling, Mitchel Allan; Motsinger-Reif, Alison; Rotroff, Daniel M; Jack, John; Hankemeier, Thomas; Bennett, David A; De Jager, Philip L; Trojanowski, John Q; Shaw, Leslie M; Weiner, Michael W; Doraiswamy, P Murali; van Duijn, Cornelia M; Saykin, Andrew J; Kastenmüller, Gabi; Kaddurah-Daouk, Rima; Alzheimer's Disease Neuroimaging Initiative and the Alzheimer Disease Metabolomics ConsortiumINTRODUCTION:Increasing evidence suggests a role for the gut microbiome in central nervous system disorders and a specific role for the gut-brain axis in neurodegeneration. Bile acids (BAs), products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria. They have major regulatory and signaling functions and seem dysregulated in Alzheimer's disease (AD). METHODS:Serum levels of 15 primary and secondary BAs and their conjugated forms were measured in 1464 subjects including 370 cognitively normal older adults, 284 with early mild cognitive impairment, 505 with late mild cognitive impairment, and 305 AD cases enrolled in the AD Neuroimaging Initiative. We assessed associations of BA profiles including selected ratios with diagnosis, cognition, and AD-related genetic variants, adjusting for confounders and multiple testing. RESULTS:In AD compared to cognitively normal older adults, we observed significantly lower serum concentrations of a primary BA (cholic acid [CA]) and increased levels of the bacterially produced, secondary BA, deoxycholic acid, and its glycine and taurine conjugated forms. An increased ratio of deoxycholic acid:CA, which reflects 7α-dehydroxylation of CA by gut bacteria, strongly associated with cognitive decline, a finding replicated in serum and brain samples in the Rush Religious Orders and Memory and Aging Project. Several genetic variants in immune response-related genes implicated in AD showed associations with BA profiles. DISCUSSION:We report for the first time an association between altered BA profile, genetic variants implicated in AD, and cognitive changes in disease using a large multicenter study. These findings warrant further investigation of gut dysbiosis and possible role of gut-liver-brain axis in the pathogenesis of AD.Item Open Access Metabolomic signature of exposure and response to citalopram/escitalopram in depressed outpatients.(Translational psychiatry, 2019-07-04) 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, RimaMetabolomics 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.Item Open Access Pilot Study of Metabolomic Clusters as State Markers of Major Depression and Outcomes to CBT Treatment.(Frontiers in neuroscience, 2019-01) Bhattacharyya, Sudeepa; Dunlop, Boadie W; Mahmoudiandehkordi, Siamak; Ahmed, Ahmed T; Louie, Gregory; Frye, Mark A; Weinshilboum, Richard M; Krishnan, Ranga R; Rush, A John; Mayberg, Helen S; Craighead, W Edward; Kaddurah-Daouk, RimaMajor depressive disorder (MDD) is a common and disabling syndrome with multiple etiologies that is defined by clinically elicited signs and symptoms. In hopes of developing a list of candidate biological measures that reflect and relate closely to the severity of depressive symptoms, so-called "state-dependent" biomarkers of depression, this pilot study explored the biochemical underpinnings of treatment response to cognitive behavior therapy (CBT) in medication-free MDD outpatients. Plasma samples were collected at baseline and week 12 from a subset of MDD patients (N = 26) who completed a course of CBT treatment as part of the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) study. Targeted metabolomic profiling using the AbsoluteIDQ® p180 Kit and LC-MS identified eight "co-expressed" metabolomic modules. Of these eight, three were significantly associated with change in depressive symptoms over the course of the 12-weeks. Metabolites found to be most strongly correlated with change in depressive symptoms were branched chain amino acids, acylcarnitines, methionine sulfoxide, and α-aminoadipic acid (negative correlations with symptom change) as well as several lipids, particularly the phosphatidlylcholines (positive correlation). These results implicate disturbed bioenergetics as an important state marker in the pathobiology of MDD. Exploratory analyses contrasting remitters to CBT versus those who failed the treatment further suggest these metabolites may serve as mediators of recovery during CBT treatment. Larger studies examining metabolomic change patterns in patients treated with pharmacotherapy or psychotherapy will be necessary to elucidate the biological underpinnings of MDD and the -specific biologies of treatment response.