Right Superior Orbitofrontal Gray Matter Volume Reduction Mediates Executive Dysfunction in Schizophrenia Patients With Comorbid Metabolic Syndrome

Background: Patients with schizophrenia (SCZ) are at a markedly increased risk of developing metabolic syndrome (MetS), which substantially reduces life expectancy and adversely affects treatment adherence. Although cognitive impairment is a core feature of SCZ, the neurobiological mechanisms linking comorbid MetS to cognitive dysfunction remain complex and incompletely understood. Previous studies have primarily focused on the effects of abnormal brain function and white matter abnormalities on cognition, whereas the contribution of gray matter volume (GMV) alterations in the context of comorbid MetS has received comparatively less attention. Accordingly, this study examined GMV alterations in patients with SCZ and comorbid MetS and evaluated whether these alterations mediate the association between MetS and cognitive impairment. Methods: Sixty clinically stable patients with SCZ receiving risperidone or clozapine were recruited, including 28 meeting the diagnostic criteria for MetS (SCZ-MetS) and 32 without MetS (SCZ-nMetS), together with 31 demographically matched healthy controls (HCs). High-resolution structural magnetic resonance imaging (MRI) scans were analyzed using voxel-based morphometry (VBM) to quantify GMV. Mediation analyses were performed to determine whether GMV alterations mediated the association between MetS and cognitive function. Results: Compared with the HC group, both the SCZ-nMetS and SCZ-MetS groups exhibited widespread GMV reductions involving the cingulate cortex, left temporal lobe, frontal regions, and insula. Compared with the SCZ-nMetS group, the SCZ-MetS group showed significantly reduced GMV in the right superior orbitofrontal gyrus, as well as in the left amygdala, left insula, and temporal lobe (p < 0.05). Mediation analysis indicated that reduced GMV in the right superior orbitofrontal gyrus significantly mediated the association between MetS and deficits in executive function (p < 0.05). Conclusions: MetS-related executive dysfunction may be partly associated with reduced GMV in the right superior orbitofrontal gyrus, suggesting a potential mediating role of this brain region.