The etiology of bipolar disorder (BD) is still poorly understood, involving genetic and epigenetic mechanisms as well as environmental contributions. This study aimed to investigate the degree of DNA methylation at the promoter region of the brain-derived neurotrophic factor (BDNF) gene, as one of the candidate genes associated with major psychoses, in peripheral blood mononuclear cells isolated from 94 patients with BD (BD I ¼ 49, BD II ¼ 45) and 52 healthy controls. A significant BDNF gene expression downregulation was observed in BD II 0.53±0.11%; Po0.05), but not in BD I (1.13±0.19%) patients compared with controls (CONT: 1±0.2%). Consistently, an hypermethylation of the BDNF promoter region was specifically found in BD II patients (CONT: 24.0±2.1%; BDI: 20.4±1.7%; BDII: 33.3 ± 3.5%, Po0.05). Of note, higher levels of DNA methylation were observed in BD subjects on pharmacological treatment with mood stabilizers plus antidepressants (34.6 ± 4.2%, predominantly BD II) compared with those exclusively on mood-stabilizing agents (21.7 ± 1.8%; Po0.01, predominantly BD I). Moreover, among the different pharmacological therapies, lithium (20.1 ± 3.8%, Po0.05) and valproate (23.6 ± 2.9%, Po0.05) were associated with a significant reduction of DNA methylation compared with other drugs (35.6 ± 4.6%). Present findings suggest selective changes in DNA methylation of BDNF promoter in subjects with BD type II and highlight the importance of epigenetic factors in mediating the onset and/or susceptibility to BD, providing new insight into the mechanisms of gene expression. Moreover, they shed light on possible mechanisms of action of mood-stabilizing compounds vs antidepressants in the treatment of BD, pointing out that BDNF regulation might be a key target for their effects.

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