Abstract
Major depression disorder (MDD) is a mental condition that significantly threatens both physical and psychological health. This study aimed to discern variances in plasma metabolic profiles between MDD sufferers and healthy counterparts. Additionally, we tracked the hospitalization journey of MDD patients to investigate the normalization of metabolic irregularities through conventional treatment in the form of self-control. Ultra-Performance Liquid Chromatography - Mass Spectrometry was employed to analyze the metabolic profiles of 47 plasma samples, including 12 controls and 12 MDD patients at three distinct clinical stages (untreated baseline, 1-month post-treatment, and 2-month post-treatment). Multivariate statistical analysis and K-means clustering were executed to pinpoint significantly different metabolites between the groups and specific metabolites showing an ideal trend of variation. Subsequently, these metabolites were mapped onto Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways to preliminarily explore the potential mechanism of metabolic shifts in MDD. We identified 14 significantly different metabolites between MDD patients and controls. Among these, the relative levels of 9-hydroperoxy octadecadienoic acid, imidazoleacetic acid, thromboxane B2, and arachidonic acid displayed a regular trend of variation post-treatment. Further integration analysis yielded a novel metabolite-pathway network comprising these 4 specific metabolites and 8 pathways. These findings suggest that transitions in metabolic pathways during the onset and treatment of MDD are primarily governed by lipid metabolism and its associated signaling pathway system, with the involvement of histidine metabolism. The identified metabolites hold promise for diagnosing and evaluating the therapeutic efficacy of MDD, and provide a foundation for future research into the potential mechanisms underlying MDD.
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The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.
References
Araque A, Castillo PE, Manzoni OJ, Tonini R (2017) Synaptic functions of endocannabinoid signaling in health and disease. Neuropharmacology 124:13–24. https://doi.org/10.1016/j.neuropharm.2017.06.017
Augustin SM, Lovinger DM (2018) Functional relevance of endocannabinoid-dependent synaptic plasticity in the central nervous system. ACS Chem Neurosci 9:2146–2161. https://doi.org/10.1021/acschemneuro.7b00508
Bao H, Li H, Jia Y et al (2021) Ganoderic acid A exerted antidepressant-like action through FXR modulated NLRP3 inflammasome and synaptic activity. Biochem Pharmacol 188:114561. https://doi.org/10.1016/j.bcp.2021.114561
Basselin M, Ramadan E, Rapoport SI (2012) Imaging brain signal transduction and metabolism via arachidonic and docosahexaenoic acid in animals and humans. Brain Res Bull 87:154–171. https://doi.org/10.1016/j.brainresbull.2011.12.001
Bot M, Milaneschi Y, Al-Shehri T et al (2020) Metabolomics profile in depression: a pooled analysis of 230 metabolic markers in 5283 cases with depression and 10,145 controls. Biol Psychiatry 87:409–418. https://doi.org/10.1016/j.biopsych.2019.08.016
Brunt TM, Bossong MG (2022) The neuropharmacology of cannabinoid receptor ligands in central signaling pathways. Eur J Neurosci 55:909–921. https://doi.org/10.1111/ejn.14982
Calder PC (2017) Omega-3 fatty acids and inflammatory processes: from molecules to man. Biochem Soc Trans 45:1105–1115. https://doi.org/10.1042/BST20160474
Cao S, Anishkin A, Zinkevich NS et al (2018) Transient receptor potential vanilloid 4 (TRPV4) activation by arachidonic acid requires protein kinase A-mediated phosphorylation. J Biol Chem 293:5307–5322. https://doi.org/10.1074/jbc.M117.811075
Caspani G, Kennedy S, Foster JA, Swann J (2019) Gut microbial metabolites in depression: understanding the biochemical mechanisms. Microb Cell 6:454–481. https://doi.org/10.15698/mic2019.10.693
Chahl LA (2011) TRP channels and psychiatric disorders. In: Islam MS (ed) Transient receptor potential channels. Springer Netherlands, Dordrecht, pp 987–1009
Freitas HR, Isaac AR, Malcher-Lopes R et al (2018) Polyunsaturated fatty acids and endocannabinoids in health and disease. Nutr Neurosci 21:695–714. https://doi.org/10.1080/1028415X.2017.1347373
Gai Z, Visentin M, Gui T et al (2018) Effects of farnesoid X receptor activation on arachidonic acid metabolism, NF-kB signaling, and hepatic inflammation. Mol Pharmacol 94:802–811. https://doi.org/10.1124/mol.117.111047
GBD 2015 Disease and Injury Incidence and Prevalence Collaborators (2016) Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the global burden of disease study 2015. Lancet 388:1545–1602. https://doi.org/10.1016/S0140-6736(16)31678-6
Gopaldas M, Zanderigo F, Zhan S et al (2019) Brain serotonin transporter binding, plasma arachidonic acid and depression severity: a positron emission tomography study of major depression. J Affect Disord 257:495–503. https://doi.org/10.1016/j.jad.2019.07.035
Gui S, Liu Y, Zhong X et al (2018) Plasma disturbance of phospholipid metabolism in major depressive disorder by integration of proteomics and metabolomics. Neuropsychiatr Dis Treat 14:1451–1461. https://doi.org/10.2147/NDT.S164134
Hanna VS, Hafez EAA (2018) Synopsis of arachidonic acid metabolism: a review. J Adv Res 11:23–32. https://doi.org/10.1016/j.jare.2018.03.005
Hussain G, Anwar H, Rasul A et al (2020) Lipids as biomarkers of brain disorders. Crit Rev Food Sci Nutr 60:351–374. https://doi.org/10.1080/10408398.2018.1529653
Layé S, Nadjar A, Joffre C, Bazinet RP (2018) Anti-inflammatory effects of Omega-3 fatty acids in the brain: physiological mechanisms and relevance to pharmacology. Pharmacol Rev 70:12–38. https://doi.org/10.1124/pr.117.014092
Liu X, Liu C, Tian J et al (2020) Plasma metabolomics of depressed patients and treatment with Xiaoyaosan based on mass spectrometry technique. J Ethnopharmacol 246:112219. https://doi.org/10.1016/j.jep.2019.112219
Lu S, Han Y, Chu H et al (2017) Characterizing serum metabolic alterations of Alzheimer’s disease and intervention of Shengmai-San by ultra-performance liquid chromatography/electrospray ionization quadruple time-of-flight mass spectrometry. Food Funct 8:1660–1671. https://doi.org/10.1039/c7fo00154a
Malhi GS, Mann JJ (2018) Depression. Lancet 392:2299–2312. https://doi.org/10.1016/S0140-6736(18)31948-2
Mocking RJT, Naviaux JC, Li K et al (2021) Metabolic features of recurrent major depressive disorder in remission, and the risk of future recurrence. Transl Psychiatry 11:37. https://doi.org/10.1038/s41398-020-01182-w
Muller C, Morales P, Reggio PH (2018) Cannabinoid ligands targeting TRP channels. Front Mol Neurosci 11:487. https://doi.org/10.3389/fnmol.2018.00487
Murrough JW, Abdallah CG, Mathew SJ (2017) Targeting glutamate signalling in depression: progress and prospects. Nat Rev Drug Discov 16:472–486. https://doi.org/10.1038/nrd.2017.16
Nedic Erjavec G, Sagud M, Nikolac Perkovic M et al (2021) Depression: biological markers and treatment. Prog Neuropsychopharmacol Biol Psychiatry 105:110139. https://doi.org/10.1016/j.pnpbp.2020.110139
Pan J, Xia J, Deng F et al (2018) Diagnosis of major depressive disorder based on changes in multiple plasma neurotransmitters: a targeted metabolomics study. Transl Psychiatry 8:130. https://doi.org/10.1038/s41398-018-0183-x
Poleszak E, Wośko S, Sławińska K et al (2018) Cannabinoids in depressive disorders. Life Sci 213:18–24. https://doi.org/10.1016/j.lfs.2018.09.058
Pu J, Liu Y, Zhang H et al (2021) An integrated meta-analysis of peripheral blood metabolites and biological functions in major depressive disorder. Mol Psychiatry 26:4265–4276. https://doi.org/10.1038/s41380-020-0645-4
Regulska M, Szuster-Głuszczak M, Trojan E et al (2021) The emerging role of the Double-Edged impact of arachidonic Acid- derived eicosanoids in the neuroinflammatory background of depression. Curr Neuropharmacol 19:278–293. https://doi.org/10.2174/1570159X18666200807144530
Saini RK, Keum Y-S (2018) Omega-3 and omega-6 polyunsaturated fatty acids: dietary sources, metabolism, and significance - a review. Life Sci 203:255–267. https://doi.org/10.1016/j.lfs.2018.04.049
Storozhuk MV, Zholos AV (2018) TRP channels as novel targets for endogenous ligands: focus on endocannabinoids and nociceptive signalling. Curr Neuropharmacol 16:137–150. https://doi.org/10.2174/1570159X15666170424120802
Traina G, Cocchi M (2020) Mast cells, astrocytes, arachidonic acid: do they play a role in depression? Appl Sci 10:3455. https://doi.org/10.3390/app10103455
van Velzen LS, Wijdeveld M, Black CN et al (2017) Oxidative stress and brain morphology in individuals with depression, anxiety and healthy controls. Prog Neuropsychopharmacol Biol Psychiatry 76:140–144. https://doi.org/10.1016/j.pnpbp.2017.02.017
Zou S, Kumar U (2018) Cannabinoid receptors and the endocannabinoid system: signaling and function in the central nervous system. Int J Mol Sci 19:833. https://doi.org/10.3390/ijms19030833
Funding
This work was supported by the Key Research and Development Plan of Hubei Province, China (2023BCB030), Natural Science Foundation of Hubei Province, China (2024AFB645, 2023AFB800) and Project of Administration of Traditional Chinese Medicine of Hubei Province of China (ZY2025Q025).
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Study conception and design: Y.D., X.L., S.Z., J.T., Y.Z., X.Z. and Y.L.; Formal analysis: X.L. and Y.D.; Investigation: Y.D., X.L., S.Z., X.Z. and Y.L.; Resources: S.Z. and Y.L.; Data curation: X.L.; Writing—original draft preparation: X.L.; Writing—review and editing: Y.D. and Y.L.; Project administration: Y.L. and X.Z.; Funding acquisition: Y.L. All authors have read and agreed to the published version of the manuscript.
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The study was carried out in accordance with the principles of the Helsinki Declaration as revised 1989. This study was approved by the Ethics Committee of Huazhong University of Science and Technology ([2013] IEC(S007)).
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Du, Y., Li, X., Zhang, S. et al. Transformations in plasma metabolic profiles of patients with major depression disorder during treatment. Metab Brain Dis 40, 265 (2025). https://doi.org/10.1007/s11011-025-01682-y
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DOI: https://doi.org/10.1007/s11011-025-01682-y