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Glutathione-Related Metabolite Levels and Enzyme Activities in Depression: A Systematic Review and Meta-Analysis.

Overview

Authors: Takahide Etani1,2,3, Nobuaki Hondo4, Sho Moriguchi4,5, Kazunari Yoshida4, Sotaro Moriyama4, Koki Takahashi4, Tahichi Moritake4, Yumina Nakamura4, Ryoma Kani6, Shiori Honda4,7, Masataka Wada4,8, Sakiko Tsugawa4,9, Yukino Mori10, Hikari Segawa11, Tony Kaku4, Hiroyuki Uchida4, Shinichiro Nakajima4,12
ORCID iDs: Takahide Etani, Nobuaki Hondo, Sho Moriguchi, Kazunari Yoshida, Sotaro Moriyama, Koki Takahashi, Ryoma Kani, Masataka Wada, Sakiko Tsugawa, Tony Kaku, Hiroyuki Uchida, Shinichiro Nakajima
  1. Keio University Hospital, Shinjuku‐ku, Tokyo, Japan
  2. Japanese Red Cross Ashikaga Hospital, Ashikaga‐shi, Tochigi, Japan
  3. Graduate School of Media and Governance, Keio University, Fujisawa‐shi, Kanagawa, Japan
  4. Department of Neuropsychiatry, Keio University School of Medicine, Shinjuku‐ku, Tokyo, Japan
  5. National Institutes for Quantum Science and Technology, Chiba‐shi, Chiba, Japan
  6. Postgraduate Education Center Kameda Medical Center, Kamogawa‐shi, Chiba, Japan
  7. Department of Psychiatry and Behavioral Health, Renaissance School of Medicine, Stony Brook University, Stony Brook, New York, USA
  8. Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California, USA
  9. Department of Physiology, Graduate School of Medicine, Yokohama City University, Yokohama‐shi, Yokohama, Japan
  10. National Kohnodai Hospital Medical Center, Ichikawa‐shi, Chiba, Japan
  11. National Hospital Organizations Saitama Hospital, Wako‐shi, Saitama, Japan
  12. Multimodal Imaging Group, Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
Institutions: Keio University (Japan); Ashikaga Red Cross Hospital (Japan); Keio University Hospital (Japan); National Institutes for Quantum Science and Technology (Japan); Kameda Medical Center (Japan); Stony Brook University (United States); Stanford University (United States); Yokohama City University (Japan); Kohnodai Hospital, National Center for Global Health and Medicine (Japan); National Hospital Organization Saitama Hospital; Centre for Addiction and Mental Health (Canada)
Journal: Neuropsychopharmacology reports, volume 46, issue 2, article e70125
Dates: received 11 December 2025; accepted 14 April 2026; published online 30 April 2026; in print June 2026
Type: Review · Language: English
License: CC BY
Identifiers: DOI 10.1002/npr2.70125 · PMID 42057765 · PMCID PMC13129703 · OpenAlex W7159109255
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: human (organism), depression (population)
Methods: Statistics
Keywords: depression, glutathione, oxidative stress, systematic review and meta‐analysis
MeSH: Depression*, Glutathione*, Glutamate-Cysteine Ligase, Glutathione Peroxidase, Glutathione Reductase, Glutathione Synthase, Glutathione Transferase, Humans (* major topic)
Topic: Tryptophan and brain disorders (Biological Psychiatry, Neuroscience), according to OpenAlex
Funding: Japan Society for the Promotion of Science (22H03002, 18H02755); Takeda Science Foundation; Naito Foundation; Japan Agency for Medical Research and Development (JP24wm0625302); Japan Research Foundation for Clinical Pharmacology; Watanabe Foundation
Citations: not cited yet (Europe PMC); 70 references in the paper

Abstract

Recently, an increasing number of studies have reported abnormal levels of glutathione (GSH)‐related metabolites and enzyme activities in neuroimaging and peripheral samples in patients with depression, indicating abnormalities in the GSH cycle in patients with depression. However, the abnormalities in the GSH cycle have not been comprehensively investigated. Here, we conducted a systematic review and meta‐analysis to compare the levels of GSH‐related metabolites (GSH and GSH disulfide [GSSG]) and the activities of GSH‐related enzymes (Glutathione‐peroxidase [GPx], GSH reductase [GR], glutamate‐cysteine ligase [GCL], GSH synthetase [GS], and GSH S‐transferase [GST]) between patients with depression and healthy controls (HC). The search was performed with MEDLINE, Embase, and PsychINFO. The inclusion criteria were studies comparing levels of GSH‐related metabolites and enzyme activities between patients with depression and HC. Standardized mean differences were calculated to assess group differences. Thirty studies met the eligibility criteria, which included 1019 patients and 947 HC. Our meta‐analysis indicated significantly decreased activity of GPx in patients with depression compared with HC, while the levels of GSH and GR were not significantly different between the groups. Because no studies, or an insufficient number of studies, have been conducted on GSSG, GST, GCL, and GS, meta‐analyses were not performed for these metabolites and enzyme activities. Our findings suggest that abnormal cycling of the GSH system, particularly decreased GPx activity, is involved in the pathophysiology of depression and may serve as a potential biomarker for this illness. Furthermore, given that no or insufficient studies have been conducted on GSSG, GST, GCL, and GS, this study highlights the need for further research to fully elucidate the GSH cycle in patients with depression.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

Tracing map

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Data

Datasets cited

Data Availability Statement

The data that support the findings of this study are openly available in the Open Science Framework (OSF) at https://osf.io/6f3kz/overview?view_only=690eb99ccd0e464ca9115e9e8e45d302.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 17 authors, 4 keywords, 8 MeSH terms, 6 funders, 62 references.

Cite

This paper

Etani, T., Hondo, N., Moriguchi, S., Yoshida, K., Moriyama, S., Takahashi, K., Moritake, T., Nakamura, Y., Kani, R., Honda, S., Wada, M., Tsugawa, S., Mori, Y., Segawa, H., Kaku, T., Uchida, H., & Nakajima, S. (2026). Glutathione-Related Metabolite Levels and Enzyme Activities in Depression: A Systematic Review and Meta-Analysis. Neuropsychopharmacology reports, 46(2), e70125. https://doi.org/10.1002/npr2.70125

BibTeX

@article{etani2026glutathione,
author = {Etani, Takahide and Hondo, Nobuaki and Moriguchi, Sho and Yoshida, Kazunari and Moriyama, Sotaro and Takahashi, Koki and Moritake, Tahichi and Nakamura, Yumina and Kani, Ryoma and Honda, Shiori and Wada, Masataka and Tsugawa, Sakiko and Mori, Yukino and Segawa, Hikari and Kaku, Tony and Uchida, Hiroyuki and Nakajima, Shinichiro},
title = {{Glutathione-Related Metabolite Levels and Enzyme Activities in Depression: A Systematic Review and Meta-Analysis}},
journal = {Neuropsychopharmacology reports},
year = {2026},
month = jun,
volume = {46},
number = {2},
pages = {e70125},
publisher = {Wiley},
issn = {2574-173X},
doi = {10.1002/npr2.70125},
url = {https://doi.org/10.1002/npr2.70125},
pmid = {42057765},
pmcid = {PMC13129703}
}

RIS

TY - JOUR
AU - Etani, Takahide
AU - Hondo, Nobuaki
AU - Moriguchi, Sho
AU - Yoshida, Kazunari
AU - Moriyama, Sotaro
AU - Takahashi, Koki
AU - Moritake, Tahichi
AU - Nakamura, Yumina
AU - Kani, Ryoma
AU - Honda, Shiori
AU - Wada, Masataka
AU - Tsugawa, Sakiko
AU - Mori, Yukino
AU - Segawa, Hikari
AU - Kaku, Tony
AU - Uchida, Hiroyuki
AU - Nakajima, Shinichiro
TI - Glutathione-Related Metabolite Levels and Enzyme Activities in Depression: A Systematic Review and Meta-Analysis
T2 - Neuropsychopharmacology reports
J2 - Neuropsychopharmacol Rep
PY - 2026
DA - 2026/06/01
VL - 46
IS - 2
SP - e70125
SN - 2574-173X
PB - Wiley
DO - 10.1002/npr2.70125
UR - https://doi.org/10.1002/npr2.70125
LA - en
ER -

CSL-JSON

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