2026 ECNP Congress

PS04-4109

Sex-specific associations between HSV-1/2 exposure, white matter microstructure, and depressive symptoms in mood disorders

Giulia Semeraro — M. Palladini, F. Colombo, B. Bravi, E. Venturelli, S. Spadini, C. Lorenzi, C. Colombo, R. Zanardi, F. Benedetti, S. Poletti · IRCCS San Raffaele Hospital, Division of Neuroscience - Psychiatry and Clinical Psychobiology Unit, Milan, Italy

2026 ECNP Congress

Introduction

Mood disorders have been increasingly associated with neurotropic viral infections. Among these, human herpesviruses, particularly herpes simplex virus type 1 and 2 (HSV-1, HSV-2), are of considerable interest due to their high global prevalence and their ability to establish lifelong latency in the central nervous system, with periodic reactivation [1]. A growing body of evidence suggests a bidirectional association between HSV infection and depression, potentially mediated by inflammatory processes and immune dysregulation [2]. In this context, biological sex is known to affect immune responses to several viral infections, influencing both susceptibility and disease severity [3]. HSV exposure has also been linked to structural brain abnormalities in psychiatric populations [4]; however, its impact on white matter (WM) microstructure, particularly in relation to sex differences, remains poorly understood.

Aims

In the present study we aimed to investigate sex-specific associations between HSV serostatus and WM microstructure, and to examine the relationship between viral exposure and depressive symptom severity in patients with mood disorders.

Methods

128 hospitalized patients with a diagnosis of major depressive disorder (MDD) or bipolar disorder (BD) underwent 3T MRI acquisition. Diffusion tensor imaging (DTI) data were pre-processed using FSL and analysed with tract-based spatial statistics (TBSS) to assess WM microstructure. Blood samples were collected on the day of MRI acquisition to determine HSV-1/2 IgG antibody titers, which were used to establish lifetime exposure to the virus. Clinical symptom severity was assessed with the Hamilton Depression Rating Scale (HAM-D), and scores were dichotomized based on the sample median. Two-sample t-tests were performed to evaluate the effects of HSV exposure on DTI-derived WM measures within sex groups, controlling for age and diagnosis. Additionally, chi-square analyses were conducted to examine differences in symptom severity between seropositive and seronegative groups.

Results

In the male subgroup, DTI analyses revealed that HSV exposure was associated with widespread reductions in fractional anisotropy (FA), alongside widespread increases in radial diffusivity (RD), involving commissural, projection, and association fibers. Increases in mean diffusivity (MD) were more localized, mainly affecting right hemisphere WM tracts. In contrast, no effects were observed in the female subgroup. Consistently, HSV seropositivity in males was associated with greater depressive symptom severity (χ² = 5.20, p = 0.023), showing a higher proportion of patients above the median HAM-D score compared to seronegative patients (72.7% vs 30%). In females, only a trend toward an association was observed (χ² = 3.79, p = 0.052), with a different distribution of proportions (38.6% vs 69.2%).

Conclusions

These findings suggest that HSV exposure is associated with sex-specific alterations in WM microstructure, with only males showing widespread microstructural abnormalities. In males, viral exposure was also associated with greater depressive symptom severity, whereas females showed an opposite trend in symptom distribution. Overall, these results point to sex-dependent differences in both neurobiological and clinical responses, highlighting their importance in studies investigating the role of infection and immune processes in mood disorders.

References

  1. Andreou, D., Steen, N. E., Jørgensen, K. N., Ueland, T., Wortinger, L. A., Mørch-Johnsen, L., Drabløs, I., Calkova, T., Yolken, R. H., Andreassen, O. A., & Agartz, I. (2024). Increased Herpes simplex virus 1, Toxoplasma gondii and Cytomegalovirus antibody concentrations in severe mental illness. Translational Psychiatry, 14(1), 498.
  2. Jacobsen, H., & Klein, S. L. (2021). Sex Differences in Immunity to Viral Infections. Frontiers in Immunology, 12, 720952.
  3. Shafiee, A., Nakhaee, Z., Amini, M. J., Abianeh, F. E., Goodarzi, M., Omran, S. P., Hajishah, H., Sadeghi, D., Nejad, A. R., & Bakhtiyari, M. (2025). Bidirectional relationship between human herpes virus reactivation and depression: A systematic review and meta-analysis. Journal of NeuroVirology, 31(2), 145–153.
  4. Andreou, D., Jørgensen, K. N., Nerland, S., Ueland, T., Vaskinn, A., Haukvik, U. K., Yolken, R. H., Andreassen, O. A., & Agartz, I. (2022). Herpes simplex virus 1 infection on grey matter and general intelligence in severe mental illness. Translational Psychiatry, 12(1), 276.