2026 ECNP Congress

PS02-2091

Estradiol-immune interaction in male depression

Giulia Lombardo — C.M. Pariante, E.J. Giltay, B.W.J.H. Penninx, Y. Milaneschi*, V. Mondelli* · Institute of Psychiatry- Psychology & Neuroscience- King's College London, Department of Psychological Medicine, London, United Kingdom

2026 ECNP Congress

Background

Compelling evidence implicates immune dysregulation in the pathophysiology of depression, with around one-third of patients exhibiting an inflammatory subtype and important sex differences in immunological profiles. Estrogens might exert neuroprotective and immunomodulatory properties and underpin biological sex differences in depression, in both females and males. Notably, research on estrogen-immune interactions in depression, in particular in the male population, remains largely unexplored.

Aims

In this study, we aimed to address this gap by analysing 17β-estradiol (E2), the most potent estrogen, and its interplay with peripheral inflammation in participants from the Netherlands Study of Depression and Anxiety (NESDA), which is a longitudinal, multi-site, naturalistic, case-control cohort study among participants aged 18 through 65 years.

Methods

We included 860 male participants, with 388 with current depressive disorders (major depressive disorder and/or dysthymia in the past 6 months) (mean ± SD age 43.4 ± 11.43), 234 with a history of depressive disorders (remitted, 45.2 ± 11.9), and 238 controls (41.8 ± 15.2). We included 1120 female participants, with 510 with current depressive disorders (42.6 ± 11.7), 374 remitted (45.4 ± 11.6), and 236 controls (45.1 ± 13.2). Circulating C-reactive protein (CRP) and E2 levels were measured. We performed cross-sectional multinomial logistic regression analyses to first estimate the association between CRP and depressive disorders. If significant, we further estimated the main effect of E2 and tested whether it moderated the association between CRP and depressive disorders. All analyses were adjusted for age, years of education, alcohol abuse/dependence, smoking status, anti-inflammatory use, number of chronic diseases under treatment, BMI, and menopausal status (for females only).

Results

In females, we did not detect significant associations between CRP and depressive disorders (current, OR= 1.050, 95% CI [0.897-1.230], p= 0.542; remitted, OR= 1.057, 95% CI [0.897-1.244], p= 0.509). However, in males, higher CRP was significantly associated with the presence of depressive disorders (OR= 1.230, 95% CI [1.039-1.457], p= 0.016), while association with remitted disorders was not significant (OR= 0.974, 95% CI [0.806-1.178], p= 0.786). Higher levels of E2 were associated with a lower likelihood of current depressive disorder, although statistically not significant (current OR= 0.672, 95% CI [0.431-1.050], p= 0.081; remitted, OR= 0.721, 95% CI [0.445-1.169], p= 0.185). Additionally, a significant CRP×E2 interaction was detected (p= 0.015) for current depressive disorders. Stratified analyses illustrating the interaction revealed that with increasing CRP, the odds of current disorders were higher (76.6%) in the lower E2 tertile and progressively declined in the medium (17.5%) and the higher (11.2%) tertiles.

Conclusions

These findings highlight the need for sex-specific investigations in immunopsychiatry of depression and for further research on the role of estrogens in the association between inflammation and depression in males. Higher E2 may attenuate the depressogenic effects of inflammation in males, highlighting its therapeutic potential in the inflammatory subtype of MDD.

References

No references