{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T22:55:11Z","timestamp":1793055311481,"version":"4.5.0"},"reference-count":50,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2023,10,19]],"date-time":"2023-10-19T00:00:00Z","timestamp":1697673600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Bern"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Major depressive disorder (MDD) is one of the most common neuropsychiatric disorders, with symptoms including persistent sadness and loss of interest. MDD is associated with neurochemical alterations in GABA, glutamate, and glutamine levels but, to date, few studies have examined changes in glutathione (GSH) in MDD. This study investigated changes in GSH in an unmedicated group of young adults, including 46 participants with current (n = 12) or past MDD (n = 34) and 20 healthy controls. Glutathione levels were assessed from GSH-edited magnetic resonance (MR) spectra, acquired from a voxel in the left prefrontal cortex, and depressive symptoms were evaluated with validated questionnaires and clinical assessments. Cortisol levels were also assessed as a marker for acute stress. Participants with current MDD demonstrated elevated GSH in comparison to participants with past MDD and controls, although the results could be influenced by differences in tissue composition within the MRS voxel. In addition, participants with both current and past MDD showed elevated cortisol levels in comparison to controls. No significant association was observed between GSH and cortisol levels, but elevated GSH levels were associated with a decrease in positive affect. These results demonstrate for the first time that elevated GSH in current but not past depression may reflect a state rather than a trait neurobiological change, related to a loss of positive affect.<\/jats:p>","DOI":"10.3390\/brainsci13101475","type":"journal-article","created":{"date-parts":[[2023,10,19]],"date-time":"2023-10-19T02:54:43Z","timestamp":1697684083000},"page":"1475","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Prefrontal Glutathione Levels in Major Depressive Disorder Are Linked to a Lack of Positive Affect"],"prefix":"10.3390","volume":"13","author":[{"given":"Ruth O\u2019Gorman","family":"Tuura","sequence":"first","affiliation":[{"name":"Center for MR Research, University Children\u2019s Hospital, 8032 Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Buchmann","sequence":"additional","affiliation":[{"name":"Center for MR Research, University Children\u2019s Hospital, 8032 Z\u00fcrich, Switzerland"},{"name":"Psychiatry Research Unit, University of Fribourg, 1752 Villars-sur-Gl\u00e2ne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8768-5652","authenticated-orcid":false,"given":"Christopher","family":"Ritter","sequence":"additional","affiliation":[{"name":"Center for MR Research, University Children\u2019s Hospital, 8032 Z\u00fcrich, Switzerland"},{"name":"Psychiatry Research Unit, University of Fribourg, 1752 Villars-sur-Gl\u00e2ne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian","family":"Hase","sequence":"additional","affiliation":[{"name":"Center for MR Research, University Children\u2019s Hospital, 8032 Z\u00fcrich, Switzerland"},{"name":"Psychiatry Research Unit, University of Fribourg, 1752 Villars-sur-Gl\u00e2ne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Haynes","sequence":"additional","affiliation":[{"name":"Translational Research Center, University Hospital of Psychiatry and Psychotherapy Bern, 3012 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph","family":"Noeske","sequence":"additional","affiliation":[{"name":"GE HealthCare, 80807 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8311-0138","authenticated-orcid":false,"given":"Gregor","family":"Hasler","sequence":"additional","affiliation":[{"name":"Psychiatry Research Unit, University of Fribourg, 1752 Villars-sur-Gl\u00e2ne, Switzerland"},{"name":"Translational Research Center, University Hospital of Psychiatry and Psychotherapy Bern, 3012 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2861","DOI":"10.1038\/s41598-018-21243-x","article-title":"Prevalence of Depression in the Community from 30 Countries between 1994 and 2014","volume":"8","author":"Lim","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1111\/bjc.12333","article-title":"Global prevalence of depression and elevated depressive symptoms among adolescents: A systematic review and meta-analysis","volume":"61","author":"Shorey","year":"2022","journal-title":"Br. J. Clin. Psychol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"271","DOI":"10.31887\/DCNS.2008.10.3\/shkennedy","article-title":"Core symptoms of major depressive disorder: Relevance to diagnosis and treatment","volume":"10","author":"Kennedy","year":"2008","journal-title":"Dialogues Clin. Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1016\/j.psyneuen.2012.03.009","article-title":"A review of Atypical depression in relation to the course of depression and changes in HPA axis organization","volume":"37","author":"Frodl","year":"2012","journal-title":"Psychoneuroendocrinology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1111\/acps.12698","article-title":"Peripheral cytokine and chemokine alterations in depression: A meta-analysis of 82 studies","volume":"135","author":"Freitas","year":"2017","journal-title":"Acta Psychiatr. Scand."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.neubiorev.2011.05.014","article-title":"Region and state specific glutamate downregulation in major depressive disorder: A meta-analysis of (1)H-MRS findings","volume":"36","author":"Luykx","year":"2012","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1001\/jamapsychiatry.2022.3384","article-title":"Evaluation of Prefrontal gamma-Aminobutyric Acid and Glutamate Levels in Individuals With Major Depressive Disorder Using Proton Magnetic Resonance Spectroscopy","volume":"79","author":"Ritter","year":"2022","journal-title":"JAMA Psychiatry"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.ab.2016.12.022","article-title":"Glutathione in the human brain: Review of its roles and measurement by magnetic resonance spectroscopy","volume":"529","author":"Rae","year":"2017","journal-title":"Anal. Biochem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1016\/j.drudis.2020.05.001","article-title":"Role of oxidative stress in depression","volume":"25","author":"Bhatt","year":"2020","journal-title":"Drug Discov. Today"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1002\/mrm.10499","article-title":"Measurement of reduced glutathione (GSH) in human brain using LCModel analysis of difference-edited spectra","volume":"50","author":"Terpstra","year":"2003","journal-title":"Magn. Reson. Med."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Berk, M., Williams, L.J., Jacka, F.N., O\u2019Neil, A., Pasco, J.A., Moylan, S., Allen, N.B., Stuart, A.L., Hayley, A.C., and Byrne, M.L. (2013). So depression is an inflammatory disease, but where does the inflammation come from?. BMC Med., 11.","DOI":"10.1186\/1741-7015-11-200"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"389","DOI":"10.3389\/fphar.2016.00389","article-title":"Fluoxetine Prevents Abeta(1-42)-Induced Toxicity via a Paracrine Signaling Mediated by Transforming-Growth-Factor-beta1","volume":"7","author":"Caraci","year":"2016","journal-title":"Front. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2452","DOI":"10.1038\/npp.2011.132","article-title":"The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: A meta-analysis","volume":"36","author":"Hannestad","year":"2011","journal-title":"Neuropsychopharmacology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1186\/s12974-019-1475-7","article-title":"Role of inflammation in depression relapse","volume":"16","author":"Liu","year":"2019","journal-title":"J. Neuroinflamm."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1007\/s10787-011-0111-7","article-title":"New drug targets in depression: Inflammatory, cell-mediated immune, oxidative and nitrosative stress, mitochondrial, antioxidant, and neuroprogressive pathways. And new drug candidates--Nrf2 activators and GSK-3 inhibitors","volume":"20","author":"Maes","year":"2012","journal-title":"Inflammopharmacology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3143","DOI":"10.1016\/j.bbagen.2012.09.008","article-title":"Glutathione synthesis","volume":"1830","author":"Lu","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1016\/j.phrs.2018.02.007","article-title":"Neurobiological links between depression and AD: The role of TGF-beta1 signaling as a new pharmacological target","volume":"130","author":"Caraci","year":"2018","journal-title":"Pharmacol. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1007\/s11357-012-9402-1","article-title":"The interactions of oxidative stress and inflammation with vascular dysfunction in ageing: The vascular health triad","volume":"35","author":"Wadley","year":"2013","journal-title":"Age"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1111\/imm.12443","article-title":"Immune mechanisms linked to depression via oxidative stress and neuroprogression","volume":"144","author":"Bakunina","year":"2015","journal-title":"Immunology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.neures.2006.01.002","article-title":"Contribution of reduced and oxidized glutathione to signals detected by magnetic resonance spectroscopy as indicators of local brain redox state","volume":"55","author":"Satoh","year":"2006","journal-title":"Neurosci. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.mri.2009.06.008","article-title":"MR spectroscopic imaging of glutathione in the white and gray matter at 7 T with an application to multiple sclerosis","volume":"28","author":"Srinivasan","year":"2010","journal-title":"Magn. Reson. Imaging"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.pscychresns.2017.10.001","article-title":"A pilot study of cortical glutathione in youth with depression","volume":"270","author":"Freed","year":"2017","journal-title":"Psychiatry Res. Neuroimaging"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1002\/nbm.2772","article-title":"Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology","volume":"25","author":"Shungu","year":"2012","journal-title":"NMR Biomed."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.neulet.2014.03.056","article-title":"In vivo H-1 MRS study of potential associations between glutathione, oxidative stress and anhedonia in major depressive disorder","volume":"569","author":"Lapidus","year":"2014","journal-title":"Neurosci. Lett."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1017\/S1461145710000805","article-title":"Decreased levels of glutathione, the major brain antioxidant, in post-mortem prefrontal cortex from patients with psychiatric disorders","volume":"14","author":"Gawryluk","year":"2011","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"745","DOI":"10.30773\/pi.2019.07.17.3","article-title":"Evaluation of Transcranial Magnetic Stimulation Efficiency in Major Depressive Disorder Patients: A Magnetic Resonance Spectroscopy Study","volume":"16","author":"Erbay","year":"2019","journal-title":"Psychiatry Investig."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.jad.2015.03.007","article-title":"Oxidative stress and depressive symptoms in older adults: A magnetic resonance spectroscopy study","volume":"180","author":"Duffy","year":"2015","journal-title":"J. Affect. Disord."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.pnpbp.2018.08.006","article-title":"Antioxidant defense in schizophrenia and bipolar disorder: A meta-analysis of MRS studies of anterior cingulate glutathione","volume":"91","author":"Das","year":"2019","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.pscychresns.2014.09.007","article-title":"Prefrontal GABA and glutathione imbalance in posttraumatic stress disorder: Preliminary findings","volume":"224","author":"Michels","year":"2014","journal-title":"Psychiatry Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1097\/HTR.0000000000000616","article-title":"Associations Between Neurochemistry and Gait Performance Following Concussion in Collegiate Athletes","volume":"35","author":"Charney","year":"2020","journal-title":"J. Head Trauma Rehabil."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"103152","DOI":"10.1016\/j.nicl.2022.103152","article-title":"Glutamate, GABA and glutathione in adults with persistent post-concussive symptoms","volume":"36","author":"Joyce","year":"2022","journal-title":"Neuroimage Clin."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.bbr.2009.03.004","article-title":"The functional neuroanatomy of depression: Distinct roles for ventromedial and dorsolateral prefrontal cortex","volume":"201","author":"Koenigs","year":"2009","journal-title":"Behav. Brain Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1002\/jmri.24611","article-title":"Investigation of glutamine and GABA levels in patients with idiopathic generalized epilepsy using MEGAPRESS","volume":"41","author":"Chowdhury","year":"2015","journal-title":"J. Magn. Reson. Imaging"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Michels, L., Martin, E., Klaver, P., Edden, R., Zelaya, F., Lythgoe, D.J., Luchinger, R., Brandeis, D., and O\u2019Gorman, R.L. (2012). Frontal GABA levels change during working memory. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0031933"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1002\/jmri.24478","article-title":"Gannet: A batch-processing tool for the quantitative analysis of gamma-aminobutyric acid-edited MR spectroscopy spectra","volume":"40","author":"Edden","year":"2014","journal-title":"J. Magn. Reson. Imaging"},{"key":"ref_36","unstructured":"First, M.B., and Gibbon, M. (2004). Comprehensive Handbook of Psychological Assessment, Vol. 2: Personality Assessment, John Wiley & Sons."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1136\/jnnp.23.1.56","article-title":"A rating scale for depression","volume":"23","author":"Hamilton","year":"1960","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1192\/bjp.134.4.382","article-title":"A new depression scale designed to be sensitive to change","volume":"134","author":"Montgomery","year":"1979","journal-title":"Br. J. Psychiatry"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1001\/archpsyc.1961.01710120031004","article-title":"An inventory for measuring depression","volume":"4","author":"Beck","year":"1961","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_40","unstructured":"Hautzinger, M., Bailer, M., Worall, H., and Keller, F. (1994). Beck- Depressions-Inventar (BDI): Bearbeitung der Deutschen Ausgabe, Hans Huber."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1037\/0022-3514.54.6.1063","article-title":"Development and validation of brief measures of positive and negative affect: The PANAS scales","volume":"54","author":"Watson","year":"1988","journal-title":"J. Pers. Soc. Psychol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"385","DOI":"10.2307\/2136404","article-title":"A global measure of perceived stress","volume":"24","author":"Cohen","year":"1983","journal-title":"J. Health Soc. Behav."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3167","DOI":"10.21105\/joss.03167","article-title":"Visualizations with statistical details: The \u2018ggstatsplot\u2019 approach","volume":"6","author":"Patil","year":"2021","journal-title":"J. Open Source Softw."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1111\/j.1600-0404.1995.tb07018.x","article-title":"Multiple-Choice Vocabulary-Test Mwt as a Valid and Short Test to Estimate Premorbid Intelligence","volume":"91","author":"Lehrl","year":"1995","journal-title":"Acta Neurol. Scand."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.arr.2005.02.005","article-title":"The effects of stress and aging on glutathione metabolism","volume":"4","author":"Maher","year":"2005","journal-title":"Ageing Res. Rev."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1016\/j.neuroscience.2006.11.010","article-title":"Role of glutathione in neuroprotective effects of mood stabilizing drugs lithium and valproate","volume":"144","author":"Cui","year":"2007","journal-title":"Neuroscience"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Cortez, I., Brocardo, P.S., and Leasure, J.L. (2021). Changes in Affective Behavior and Oxidative Stress after Binge Alcohol in Male and Female Rats. Brain Sci., 11.","DOI":"10.3390\/brainsci11091250"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.brainres.2006.03.063","article-title":"Age-related changes in glutathione and glutathione-related enzymes in rat brain","volume":"1090","author":"Zhu","year":"2006","journal-title":"Brain Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1002\/nbm.1646","article-title":"Noninvasive quantification of ascorbate and glutathione concentration in the elderly human brain","volume":"24","author":"Emir","year":"2011","journal-title":"NMR Biomed."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.neubiorev.2020.03.015","article-title":"Therapeutic potential of glutathione-enhancers in stress-related psychopathologies","volume":"114","author":"Zalachoras","year":"2020","journal-title":"Neurosci. Biobehav. Rev."}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/13\/10\/1475\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:09:25Z","timestamp":1760130565000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/13\/10\/1475"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,19]]},"references-count":50,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["brainsci13101475"],"URL":"https:\/\/doi.org\/10.3390\/brainsci13101475","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,19]]}}}