Obsessive-compulsive disorder (OCD) is a debilitating psychiatric condition characterized by recurrent intrusive thoughts (obsessions) and repetitive ritualistic behaviors (compulsions) (1). Despite the established efficacy of first-line interventions, including selective serotonin reuptake inhibitors (SSRIs) and cognitive-behavioral therapy (CBT), a substantial proportion of patients exhibit partial or inadequate response, resulting in persistent functional impairment and a markedly diminished quality of life (2, 3). This therapeutic gap underscores the urgency of elucidating the neurobiological underpinnings of OCD to identify novel therapeutic targets (4, 5).

The pathophysiology of OCD is closely linked to dysregulation of the cortico-striatal-thalamic-cortical (CSTC) circuits, which are significantly modulated by the hypothalamic-pituitary-adrenal (HPA) axis (6). Although cortisol, the primary effector of the HPA axis, has been extensively studied (7–9), the contribution of other adrenal steroids remains largely underappreciated. Of particular interest is dehydroepiandrosterone (DHEA), a pivotal neurosteroid with well-documented mood-regulating properties (10, 11). While clinical studies of DHEA have primarily focused on other psychiatric conditions (12–14), preclinical evidence indicates that it enhances serotonergic neurotransmission in the striatum and amygdala—key structures within the dysregulated CSTC circuitry in OCD (15, 16).

Physiologically, cortisol and DHEA often exert functionally antagonistic effects (17). Therefore, their ratio may provide a more sensitive index of net glucocorticoid activity and HPA axis dysfunction than absolute levels of either hormone alone (18, 19). Notably, an altered cortisol/DHEA ratio has demonstrated superior discriminatory power in distinguishing individuals with depression from healthy controls, surpassing the diagnostic utility of absolute hormone levels (20, 21). Furthermore, clinical improvements have been correlated with a favorable shift in this ratio, independent of changes in cortisol alone (22). These findings suggest that the dynamic interplay between these hormones reflects unique biological information relevant to psychopathology.

In light of this, the present study investigates the association between the cortisol/DHEA ratio and both clinical symptomatology and key domains of executive function in a well-defined cohort of drug-naive patients with OCD. By eliminating the confounding effects of psychotropic medication, this study aims to: (1) evaluate the cortisol/DHEA ratio as a potential peripheral biomarker associated with cognitive deficits in OCD; (2) deepen the understanding of the neuroendocrine mechanisms underlying its pathophysiology; (3) provide a biological rationale for developing novel therapeutic strategies.

All statistical analyses were performed using SPSS version 27.0. Descriptive statistics, including means (M) and standard deviations (SD) for continuous variables and frequencies (n) and percentages (%) for categorical variables, were used to summarize the clinical and demographic characteristics of the participants. Group comparisons on demographic and clinical variables were performed using independent samples t-tests for continuous data and chi-square (χ²) tests for categorical data. To identify independent predictors of executive function performance, multiple linear regression analyses were conducted. Given the exploratory nature of the study, a stepwise selection procedure was primarily employed to maximize model parsimony and manage potential multicollinearity among clinical covariates (e.g., HAMA and HAMD). To ensure the robustness of these findings, key associations were further verified using a hierarchical regression approach. All models included hormonal markers as primary predictors, adjusting for potential confounders including sex, age, education level, and clinical scores. To control for the increased risk of Type I error due to multiple testing, P-values for correlation and regression analyses were adjusted using the Benjamini-Hochberg False Discovery Rate (FDR) procedure. Statistical significance was defined as an FDR-adjusted P-value < 0.05. Mediation analyses were performed using Model 4 of the PROCESS macro for SPSS (version 27.0) with 5000 bootstrap samples; a mediation effect was considered statistically significant if the bias-corrected 95% CI did not include zero.

To the best of our knowledge, this is the first study to comprehensively evaluate DHEA levels, the dynamics of the peripheral cortisol/DHEA ratio, and their collective association with specific domains of executive function in a well-defined cohort of drug-naive, first-episode OCD patients. This research provides a preliminary empirical framework for elucidating the neuroendocrine underpinnings of OCD, utilizing peripheral biomarkers to probe central pathophysiology.

Our primary findings corroborate dysregulated cortisol levels in OCD patients (8, 9), and their normalization often correlates with successful therapeutic outcomes (23). Consistent with this, we observed significantly lower DHEA levels in our cohort of first-episode, drug-naive patients. A central thesis of this study is that the cortisol/DHEA ratio may offer a more functionally relevant index of HPA axis activity than either hormone in isolation. This ratio is conceptualized as an indicator of the “anabolic/catabolic balance,” reflecting the net antagonism between the neuroprotective properties of DHEA and the neurotoxic actions of cortisol (24, 25). Supporting this thesis, our analysis revealed a significant positive correlation between the cortisol/DHEA ratio and OCD symptom severity. This aligns with existing evidence linking an elevated ratio to an increased risk for stress-related psychopathologies (26, 27).

Regarding the association with cognition, the robust correlation observed between inhibitory control deficits (SSRT) and symptom severity (r = 0.778) appears to be specific to the OCD cohort. In our analysis, the healthy control group showed no significant association between these measures. This dissociation suggests that the strong coupling between cognitive slowing and symptom burden is a pathological feature of the disorder’s acute, unmedicated state (‘generalized inhibitory collapse’), rather than a generalized physiological trait inherent to the cognitive task itself. Notably, the cortisol/DHEA ratio emerged as a significant independent predictor of response inhibition deficits in our multiple regression model. This finding provides novel clinical evidence from an OCD cohort that reinforces established neurobiological models of stress-induced prefrontal cortex dysfunction (28, 29).

Furthermore, our mediation analysis revealed a significant indirect effect, indicating that the cortisol/DHEA ratio mediates the relationship between OCD symptom severity and working memory performance. Interestingly, while the total effect of symptom severity on working memory was not statistically significant, the indirect effect via the cortisol/DHEA ratio was robust and negative. This pattern, statistically referred to as “inconsistent mediation” (30), suggests that the cognitive impact of OCD is nuanced. Specifically, this finding implies that OCD symptoms per se (e.g., behavioral rituals) may not linearly predict working memory deficits in surface-level analyses, possibly due to compensatory cognitive control or the increased mental effort often exerted by high-functioning patients to maintain performance (31). However, the physiological cost associated with this chronic distress—manifesting as HPA axis dysregulation (elevated cortisol/DHEA ratio)—exerts a specific and significant deleterious effect on working memory capacity. Thus, the HPA axis imbalance acts as a distinct “biological brake” on cognition. We also rigorously assessed the potential confounding influence of speed-accuracy trade-offs (SAT). Our data argue against a hypothesis of strategic slowing; instead, the OCD group exhibited a ‘double deficit’ profile, characterized by both significantly prolonged reaction times and reduced accuracy compared to healthy controls (Table 1). Furthermore, the absence of a significant correlation between reaction time and accuracy within the OCD cohort following FDR correction (P_adj > 0.05) suggests that psychomotor slowing and executive capacity limitations represent distinct, parallel impairments rather than a compensatory functional trade-off.

These results align with and extend previous research linking neuroactive steroid ratios to cognitive function in other psychiatric disorders. For instance, Silver et al. (32) demonstrated that DHEA levels correlate with cognitive performance in chronic schizophrenia, while Jin et al. (33) linked elevated cortisol/DHEA ratios to reduced hippocampal volume in major depression.

A key finding that warrants specific contextualization is the reduced DHEA level in our cohort. Approximately 80% of circulating DHEA is of adrenal origin, with the remainder synthesized in the gonads and brain (34). Unlike cortisol, DHEA exhibits markedly attenuated diurnal rhythmicity and lacks a significant cortisol awakening response (35), properties that may confer greater stability for biomarker assessment. We specifically chose to measure plasma DHEA rather than its sulfated form (DHEA-S), despite the latter’s higher stability. This decision was based on the lipophilic nature of DHEA, which allows it to readily cross the blood-brain barrier and exert direct neuroactive effects, making it a more immediate proxy for central activity during cognitive tasks compared to the hydrophilic DHEA-S.

Notably, our finding of reduced DHEA contrasts with reports from Erbay et al. describing elevated DHEA in OCD (36, 37). In this model, the cyclical nature of obsessions and compulsions perpetuates a state of persistent distress and low-grade HPA axis activation. The observed elevation in the cortisol/DHEA ratio may reflect a hypothesized functional shift in adrenal steroidogenesis. Under chronic stress, it has been postulated that precursor resources are preferentially diverted towards cortisol synthesis at the expense of DHEA, a phenomenon potentially involving alterations in CYP17A1 enzymatic activity (38). This would mechanistically account for the concurrent findings of elevated cortisol and reduced DHEA in our patient cohort.

While our cross-sectional design necessitates caution, these empirical associations align with established neurobiological models. The established neuroanatomical abnormalities in OCD, notably within the cortico-striatal-thalamic-cortical (CSTC) circuit, hippocampus, and amygdala (39), involve regions known to be particularly sensitive to hypercortisolemia. Anatomically, the prefrontal cortex and hippocampus possess a high density of glucocorticoid receptors (40–42), and cortisol readily crosses the blood-brain barrier (43) to mediate structural alterations (44).

We speculate that an elevated Ratio—reflecting net glucocorticoid activity—may conduce to a state of “neurotoxicity”. Previous preclinical literature indicates that at a cellular level, chronically elevated glucocorticoids can exert neurotoxic effects, such as reducing glial cell proliferation (45) and impairing dendritic morphology (46–48). Conversely, DHEA is known to be neurotrophic and neuroprotective, promoting neurogenesis and neurite outgrowth, while also exerting antioxidant effects (6, 49–53). Given DHEA’s established anti-glucocorticoid properties (54), a deficit in DHEA may conduce to a state of diminished neuroprotection and dysregulated neurotransmission (involving cholinergic, dopaminergic, and glutamatergic systems (55)).

Based on these findings, we postulate that similar sustained neuroendocrine imbalances in OCD may impair the functional integrity of frontostriatal circuits, thereby mediating the observed deficits in response inhibition and working memory, consistent with prior findings in related disorders. While prior studies in healthy individuals and patients with schizophrenia have linked DHEA to improved cognitive functions like working memory and attention (12, 56, 57), our findings provide the first clinical evidence in an OCD cohort to support this model. Additionally, preclinical evidence indicates that DHEA modulates central neurotransmitter systems, increasing serotonin turnover (15) and upregulating 5-HT2A receptor expression (16). Importantly, the anatomical alignment between DHEA-modulated regions and core nodes of the CSTC circuit provides a compelling neurobiological rationale for investigating DHEA’s role in OCD (Figure 3).

Finally, regarding the null findings for cognitive flexibility, while the lack of significant correlations between hormonal ratios and WCST performance might imply a domain-specific vulnerability of inhibitory and working memory circuits, methodological nuances warrant consideration. Crucially, the executive profile of our first-episode, drug-naive cohort appears distinct from chronic OCD populations. The non-significant group difference in perseverative errors suggests that set-shifting deficits may be subtler or preserved in the early stages of the illness relative to the robust impairments observed in inhibition and working memory. Consequently, the absence of hormonal correlations with WCST performance could reflect limited psychometric sensitivity to these mild deficits or range restriction in error rates among high-functioning patients, rather than a definitive absence of biological association.

Several limitations of the present study warrant careful consideration when interpreting the results. First, the study’s cross-sectional design precludes any definitive causal inferences. While our mediation analysis provides statistical support for the involvement of the cortisol/DHEA ratio in working memory deficits, we cannot rule out the possibility of reverse causality, where cognitive deficits induce stress and hormonal dysregulation, or bidirectional relationships. Longitudinal designs are essential to clarify the temporal sequence of these associations. Second, although our sample size was sufficient for the main analyses, it was relatively modest. Third, we measured peripheral hormone levels in plasma, which may not fully capture central neurosteroid activity. Furthermore, while we standardized sampling to a narrow morning window (08:00 - 09:00 AM) to control for clock time, we did not account for the time elapsed since awakening (CAR). Moreover, elevated cortisol lacks specificity for OCD, as it has also been documented in other major psychiatric disorders. Fourth, potential confounders like BMI, objective sleep quality, physical activity levels, and a history of early life stress were not assessed. Fifth, subthreshold affective symptoms may still contribute to HPA variance. Additionally, while stepwise regression was used for model parsimony, we acknowledge its potential for overfitting and Type I error inflation, although our key findings were robust to hierarchical validation.

Finally, to ensure internal validity, we applied stringent exclusion criteria. Future longitudinal studies should examine the dynamic trajectory of the cortisol/DHEA ratio following first-line interventions (e.g., SSRIs or CBT). Determining whether ratio normalization tracks with symptom remission, or if baseline deviations predict treatment resistance, would validate its potential as a state-dependent biomarker and facilitate neuroendocrine-guided precision medicine in OCD.