Individual-level brain phenotypes in first-episode mania: normative modelling of brain morphometry and brainAGE

Abstract

Background Brain morphological alterations in bipolar disorder are well documented, particularly in chronic cases. This study focuses on first-episode mania (FEM) to quantify neuroanatomical changes at early stages of the disorder. Aims To assess deviations from normative brain morphometry and age-related brain changes in patients with FEM. Method Pretrained models, based on large, independent healthy samples, were applied to structural brain images from FEM patients (n = 83) and healthy individuals (n = 61). Normative deviation z-scores were computed for regional brain morphometry, along with global and voxel-level brain-age-gap estimates (G-brainAGE and L-brainAGE, respectively). The proportions of infranormal (z < -1.96) and supranormal (z > 1.96) deviations were measured for both groups. Ridge regression and support vector machine models were used to evaluate whether z-scores predicted symptom severity, IQ or diagnosis. Case-control differences in L-brainAGE and correlations between G-brainAGE and clinical features were analysed. Results Both FEM and healthy individuals showed similar proportions of infra- and supranormal deviations in regional measures. Morphometric data, whether observed or normative, did not significantly predict clinical outcomes or diagnosis. Mean G-brainAGE in FEM was -1.04 (s.d. 3.26) years and negatively correlated with age of onset, while L-brainAGE did not differ significantly between groups. Conclusions Regional morphometry and local brain-ageing metrics in FEM patients aligned with normative ranges, suggesting minimal abnormalities in early bipolar disorder. However, subtle delays in global brain ageing may reflect variation based on the age of onset, highlighting a potential area for further exploration. © 2025 Elsevier B.V., All rights reserved.