Abstract
Bipolar disorder (BP) and schizophrenia (SZ) share overlapping yet distinct structural brain alterations. Clarifying these differences is essential for improving diagnosis and prognosis. We hypothesized that cortical and subcortical alterations would differ between BP and SZ across illness stages and that these changes would relate to clinical severity. We examined cortical thickness and subcortical volumes using T1-weighted MRI in 438 participants recruited at McLean Hospital: 122 BP, 155 SZ, and 155 healthy controls (HC). Patient groups included both first-episode (FE-BP, FE-SZ) and chronic (CH-BP, CH-SZ) stages. BP patients demonstrated widespread cortical thinning, particularly in frontal, parietal, and temporal regions, with greater reductions in CH-BP. In CH-SZ, thinning was more circumscribed, affecting the precentral, superior frontal, and inferior parietal cortices. Subcortically, FE-BP showed corpus callosum (CC) volume loss, with further reductions in CH-BP, while CH-SZ exhibited central CC thinning. Ventricular enlargement was observed in CH-BP, FE-SZ, and CH-SZ, with marked left lateral ventricle expansion in CH-BP and CH-SZ. FE-BP also showed reduced caudate and amygdala volumes, with similar trends in chronic stages. Clinically, PANSS negative scores were consistently higher in SZ than BP, whereas positive symptoms did not differ. Cortical and subcortical alterations correlated with disease duration and PANSS scores, linking brain changes to symptom burden. BP exhibited larger morphometric effect sizes than SZ, despite greater negative symptom severity in SZ. This dissociation suggests that structural alterations do not necessarily parallel clinical severity, underscoring the importance of integrating neuroimaging and clinical measures to refine disease trajectories and diagnostic boundaries.