A Naturalistic Prospective Study of the Prognostic Impact of EPHX2 in Major Depressive Disorder: Impulsivity may be an Important Factor

<b>Background:</b> Major depressive disorder (MDD) is a leading cause of disability worldwide. The pathophysiology of MDD remains unclear, which limits the development of treatments for MDD. Recently, epoxide hydrolase 2 (EPHX2) has been found to be associated with MDD. Our previous study revealed an association between EPHX2 expression and suicide. However, the effect of EPHX2 on the prognosis of MDD and suicide remains unclear. Previous studies have found that impulsivity at baseline can be a significant predictor of clinical improvement in patients with MDD. Therefore, we inferred that EPHX2 could be associated with the treatment effect of MDD, and impulsivity could mediate the effect of EPHX2 on the treatment effect of MDD. <b>Methods:</b> This naturalistic prospective study included 117 participants with MDD, who were assessed, using clinical questionnaires, cognitive function, and treatment information, at baseline, 2 weeks, and 1, 2, and 3 months. A linear mixed-effects model was used to investigate longitudinal changes in the severity of symptoms, risk of suicide, and cognitive function. <b>Results:</b> The interactive effects of impulsivity and EPHX2 polymorphisms on the risk of suicide (measured by the Columbia-Suicide Severity Rating Scale) were significantly different for rs11288636, rs68012435, and rs11288636. The interactive effects between polymorphisms and time on depression severity (measured by the Hamilton Depression Scale-24) were significantly different and including after adjustment for the total impulsivity score. <b>Conclusions:</b> This study suggests that EPHX2 polymorphisms are associated with the prognosis of MDD, and impulsivity could be a critical factor for the change in suicide risk among different EPHX2 genotypes. <b>Trial Registration:</b> ClinicalTrials.gov identifier: NCT05575713.