2026 ECNP Congress

PS04-4111

Sex-specific metabolic signatures and brain structural integrity in bipolar disorder: potential roles for leptin and ghrelin

Ha Kyung Shin — L. Raffaelli, E.B. Mazza, B. Bravi, M.C. Lorenzi, R. Zanardi, C. Colombo, S. Poletti, F. Benedetti · IRCCS San Raffaele Hospital, Division of Neuroscience- Psychiatry and Clinical Psychobiology Unit, Milan, Italy

2026 ECNP Congress

Background

Bipolar disorder (BD) is characterized by pronounced metabolic dysregulation, including elevated rates of insulin resistance, obesity, and altered levels of appetite-regulating hormones such as leptin and ghrelin [1][2]. Emerging evidence indicates that these metabolic abnormalities may have direct structural correlates in the brain, particularly in white matter (WM) integrity and in choroid plexus (ChP) morphology, a structure critically involved in the transport of peripheral metabolic signals across the blood–cerebrospinal fluid barrier [1][3]. Although human metabolic regulation is sexually dimorphous [4], sex-specific associations between peripheral metabolic biomarkers, WM microstructure, ChP structure, and clinical outcomes in BD are unexplored. The present study aimed to address this gap by examining whether biological sex moderates the relationships between leptin, ghrelin, brain structure, and clinical outcomes in BD patients during a major depressive episode.

Methods

90 inpatients with BD (56 females, 34 males) admitted for a major depressive episode underwent comprehensive clinical assessment including the Hamilton Depression Rating Scale (HDRS) and the Beck Scale for Suicide Ideation (BSI), venous blood sampling for serum leptin, ghrelin, insulin and glucose determination. All participants underwent 3.0 Tesla brain magnetic resonance imaging: diffusion tensor imaging data were analyzed using tract-based spatial statistics to derive voxelwise measures of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). ChP volumes were extracted using FreeSurfer v7.2. Sex-moderated associations and mediation analyses between metabolic hormones, neuroimaging measures, and clinical variables were performed using the PROCESS macro for IBM SPSS.

Results

Female patients exhibited significantly higher circulating leptin and ghrelin levels, whereas males showed larger ChP volumes and greater cardiovascular risk. Sex significantly moderated the association between leptin and left ChP volume, with a positive association exclusively in males. Similarly, leptin and left ChP volume were both positively associated with suicidal ideation in males only, and left ChP significantly mediated the leptin–suicidality link in this group. Regarding WM microstructure no significant differences were found between sexes, however ghrelin showed significant sex-dependent effects on FA, MD, and RD across limbic, frontal, and parietal tracts, with associations confined to males. Leptin was also positively associated with an adverse metabolic profile in both sexes, but markedly stronger in males.

Conclusions

Despite higher levels in females, leptin demonstrated stronger associations with ChP enlargement, WM microstructural alterations, and suicidal ideation in male BD patients, suggesting a sex-specific pathway linking peripheral metabolic dysregulation to neuroinflammatory and structural brain changes through the ChP interface. Lower ghrelin levels in males, combined with their exclusive association with reduced WM integrity, may indicate leptin–ghrelin dysregulation as a potential contributor to neural vulnerability. These findings highlight the necessity of incorporating biological sex as a key variable in metabolic neuropsychiatry research and suggest that sex-stratified approaches may be essential for understanding the neurobiological underpinnings and clinical risk in BD.

References

  1. Mazza, E., Poletti, S., Bollettini, I., Locatelli, C., Falini, A., Colombo, C., & Benedetti, F. (2017). Body mass index associates with white matter microstructure in bipolar depression. Bipolar disorders, 19(2), 116–127. https://doi.org/10.1111/bdi.12484
  2. Misiak, B., Kowalski, K., Stańczykiewicz, B., Bartoli, F., Carrà, G., Samochowiec, J., Samochowiec, A., & Frydecka, D. (2022). Appetite-regulating hormones in bipolar disorder: A systematic review and meta-analysis. Frontiers in neuroendocrinology, 67, 101013. https://doi.org/10.1016/j.yfrne.2022.101013
  3. Gong, W., Wang, Y., Zou, H., Huang, Y., Shen, A., Zhai, Q., Shi, K., Yan, R., Song, M., Yao, Z., & Lu, Q. (2025). Choroid plexus enlargement correlates with cognitive impairment and brain atrophy in patients with mood disorders. Journal of affective disorders, 379, 370–378. https://doi.org/10.1016/j.jad.2025.03.047
  4. McClements, L., Kautzky-Willer, A., Kararigas, G., Ahmed, S. B., & Stallone, J. N. (2025). The role of sex differences in cardiovascular, metabolic, and immune functions in health and disease: a review for “Sex Differences in Health Awareness Day”. Biology of sex differences, 16(1), 33. https://doi.org/10.1186/s13293-025-00714-7