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. 2025 May 9;11(3):e95.
doi: 10.1192/bjo.2025.28.

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

Kevin Yu  1 , Ruiyang Ge  1 , Yuetong Yu  1 , Shalaila Haas  2 , Nicole Sanford  1 , Lakshmi N Yatham  1 , Sophia Frangou  1   2 , Trisha Chakrabarty  1
Affiliations

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

Kevin Yu et al. BJPsych Open. .

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.

Keywords: Bipolar disorder; brainAGE; first-episode mania; structural MRI.

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Conflict of interest statement

L.N.Y. reports consultant/speaker fees from Alkermes, Allergan (currently Abbvie), Sumitomo Pharma, Intracellular Therapies, LivaNova, Merck, Sanofi and Sunovion, and grants from Allergan (now AbbVie), CIHR and Sumitomo, outside the submitted work, over the last 3 years. All other authors report no conflicts of interest.

Figures

Fig. 1
Fig. 1
Distributions of observed regional morphometric measures in patients with first-episode mania (FEM) and healthy individuals.
Fig. 2
Fig. 2
Distributions of regional z-scores in patients with first-episode mania (FEM) and healthy individuals.
Fig. 3
Fig. 3
Distribution of the total number of regions with infra- or supranormal regional normative z-scores in patients with first-episode mania (FEM) and healthy individuals. Bar plots show the distribution of the total number of regions per individual, with infranormal (top) and supranormal (bottom) z-score in patients with FEM and in healthy individuals.
Fig. 4
Fig. 4
Predictive performance of regional z-scores and observed regional brain morphometric measures for psychopathology and general cognition in patients with first-episode mania. Separate ridge regression analyses were conducted for each outcome measure. Lower MAE and RMSE values (top) and higher correlation values (bottom) indicate better performance. MADRS, Montgomery–Åsberg Depression Rating Scale; MAE, mean absolute error; NAART, North American Adult Reading Test; RMSE, root mean square error; YMRS, Young Mania Rating Scale.
Fig. 5
Fig. 5
Receiver operator curves of models using either regional z-scores or observed regional brain morphometric measures for diagnostic classification. A linear support vector machine was applied to distinguish between patients and healthy individuals using either regional brain z-scores (indicated by the blue line, with area under the curve, AUC, 0.51) or observed morphometric measures (red line, with AUC 0.47).
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