DNA methylation in bipolar disorder: mechanistic insights and translational challenges.

Bipolar disorder (BD) is a severe and recurrent psychiatric disorder characterized by alternating manic, hypomanic, and depressive episodes, frequent comorbidity, high relapse rates, and an increased risk of suicide. Although the pathophysiology of BD remains incompletely understood, increasing evidence suggests that DNA methylation may represent an important epigenetic regulatory layer involved in BD-related biological heterogeneity. DNA methylation alterations have been reported in genes related to dopamine, serotonin, glutamate, and gamma-aminobutyric acid (GABA) systems, suggesting a potential role in neurotransmitter dysregulation. In addition, methylation changes in genes involved in neurotrophic signaling and ion-channel function may contribute to altered neuroplasticity and neuronal excitability. Clinically, candidate methylation signatures, including brain-derived neurotrophic factor (BDNF)-related methylation changes, specific GRIN2B CpG sites, and epigenetic age acceleration (EAA), have attracted attention for their potential relevance to diagnostic differentiation, disease progression, and treatment-response research. However, these signatures have not been clinically validated, and their reproducibility, tissue specificity, and longitudinal stability remain uncertain. Mood stabilizers, including lithium, valproate, and atypical antipsychotics, may partly influence methylation-related pathways, although their epigenetic effects and clinical significance remain incompletely defined. DNA methylation-targeted interventions remain experimental and require further validation regarding specificity, safety, blood-brain barrier delivery, and clinical applicability. This review summarizes current evidence on DNA methylation abnormalities in BD, focusing on neurotransmitter systems, neuroplasticity, ion-channel excitability, circadian rhythm, immune-inflammatory regulation, candidate methylation signatures and translational challenges. We emphasize that most available findings remain associative rather than causal, and future longitudinal, brain-region-specific, cell-type-resolved, and multi-omics studies are needed to clarify the mechanistic and translational relevance of DNA methylation in BD.