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

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.