Estrogen metabolites and hydrogen peroxide - Missing elements in the pathophysiology and possible treatment of treatment-resistant depression?

The pathogenesis of depression is complex and heterogeneous, and the management of this disease remains unsatisfactory, so mechanisms and therapeutic strategies are constantly being sought. This study aimed to determine the potential role of estrogen metabolites in the pathogenesis of treatment-resistant depression (TRD) based on the determination of concentrations of estrogens and their metabolites and hydrogen peroxide (H₂0₂) in the biological material of patients with TRD. In this study, we observed for the first time an association between unbalanced estrogen metabolism and elevated H₂0₂ levels in TRD patients. Reduced concentrations of 2-methoxyestradiol (2-ME2), 17α-estradiol (α-E2) and 17β-estradiol (β-E2) may be due to abnormal estrogen metabolism toward neurotoxic semiquinones and quinones which are a potential as yet undescribed mechanism responsible for generating oxidative stress (OS) in TRD.