Abstract
Major depressive disorder (MDD) exhibits notable sex differences in prevalence and clinical and neurobiological manifestations. Though the relationship between peripheral inflammation and MDD-related brain changes is well studied, the role of sex as a modifying factor is underexplored. This study aims to assess how sex influences brain and inflammatory markers in MDD. We utilized voxel-based and surface-based morphometry to analyze gray matter (GM) structure, along with GM-based spatial statistics (GBSS) to examine GM microstructure among treatment-naive patients with depression (n = 174) and age-matched healthy controls (n = 133). We uncovered sex-by-diagnosis interactions in several limbic system structures, the frontoparietal operculum and temporal regions. Post hoc analyses revealed that male patients exhibit pronounced brain abnormalities, while no significant differences were noted in females despite their higher depressive scores. Additionally, heightened inflammation levels in MDD were observed in both sexes, with sex-specific effects on sex-specific brain phenotypes, particularly including a general negative correlation in males. Intriguingly, mediation analyses highlight the specific role of the parahippocampal gyrus (PHG) in mediating interleukin (IL)-8 and depression in men. The findings suggest that in clinical practice, it would be beneficial to prioritize sex-specific assessments and interventions for MDD. This includes recognizing the possibility that male patients may experience significant brain alterations, especially when identifying male patients who may underreport symptoms. Possible limitations encompass a small sample size and the cross-sectional design. In future research, the incorporation of longitudinal studies or diverse populations, while considering illness duration, will enhance our understanding of how inflammation interacts with brain changes in depression.