Roles of Folate-Dependent Epigenetic Modifications in Major Depressive Disorder

Major depressive disorder (MDD) is a complex psychiatric condition that affects over 280 million individuals globally. MDD etiology remains undefined; however, recent research demonstrates a significant link between epigenetics and its underlying molecular mechanisms. Epigenetic modifications such as DNA and histone methylation require methyl groups, with S-adenosylmethionine (SAM) serving as the methyl-group donor generated through one-carbon metabolism. Folate plays a crucial role in regulating one-carbon metabolism, facilitating the conversion of methionine to SAM. MDD is increasingly associated with altered folate status, one-carbon metabolism, and epigenetic regulation in depression, although the extent to which these mechanisms contribute to MDD remains incompletely understood. This review consolidates evidence linking folate biology to epigenetic mechanisms in MDD, integrating findings from human observational and clinical studies with evidence from cellular and animal models. Overall, current evidence supports a biologically plausible connection between folate-dependent one-carbon metabolism and epigenetic regulation in MDD, while highlighting the need for further mechanistic and clinical studies to clarify these relationships and determine their potential therapeutic relevance.