Elevated cortisol/DHEA ratio mediates the association between symptom severity and working memory impairment in drug-naive, first-episode OCD.

OBJECTIVE: Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the pathophysiology of obsessive-compulsive disorder (OCD) and its associated cognitive deficits. However, the role of the cortisol/dehydroepiandrosterone (DHEA) ratio, a functional index of the catabolic/anabolic balance, remains poorly characterized in the early stages of the illness. This study aimed to investigate the association between this neuroendocrine marker and executive function in a rigorously defined cohort of drug-naive, first-episode OCD patients.

METHODS: Seventy-five drug-naive, first-episode patients with OCD and 50 age- and sex-matched healthy controls (HCs) were recruited. Plasma concentrations of cortisol and DHEA were quantified by ELISA. Executive functions were assessed using a comprehensive battery, including response inhibition (Stop-Signal Task, SST), working memory (2-back task), and cognitive flexibility (Wisconsin Card Sorting Test, WCST). Data were analyzed using group comparisons, partial correlations, and stepwise multiple regression with Benjamini-Hochberg False Discovery Rate (FDR) correction. Mediation modeling was employed to explore mechanistic pathways.

RESULTS: Compared to HCs, the OCD group exhibited significant deficits in response inhibition and working memory, accompanied by elevated cortisol (P = 0.006), reduced DHEA (P < 0.001), and a markedly higher cortisol/DHEA ratio (P < 0.001). The elevated ratio was robustly correlated with greater symptom severity (Y-BOCS) and poorer inhibitory control (longer SSRT) after FDR correction (Padj < 0.05). Multiple regression analysis identified the cortisol/DHEA ratio as a significant independent predictor of response inhibition deficits (Padj = 0.002), whereas DHEA levels specifically predicted psychomotor slowing in working memory (Padj < 0.001). Critically, mediation analysis revealed that the cortisol/DHEA ratio showed a significant indirect effect on the relationship between symptom severity and working memory accuracy (95% CI: -0.0692 to -0.0096), suggesting a "suppression" effect where neuroendocrine dysregulation serves as a distinct biological pathway for cognitive impairment. No significant hormonal associations were observed for cognitive flexibility (P > 0.05).

CONCLUSION: This study provides novel evidence that an elevated cortisol/DHEA ratio is not only a hallmark of drug-naive OCD but also independently predicts inhibitory dysfunction. Furthermore, this ratio appears to mediate the impact of clinical symptomatology on working memory capacity. These findings highlight the potential utility of the cortisol/DHEA ratio as a state-dependent biomarker and suggest that restoring the neuroendocrine balance could offer a therapeutic avenue for ameliorating cognitive deficits in OCD.