2026 ECNP Congress

PS04-4241

Brain age in antipsychotic-naive first episode of psychosis, a longitudinal study

Alejandro Roig-Herrero — S. Francey, B. O'Donoghue, B. Nelson, L.K.M. Han, H.P. Yuen, A. Thompson, K. Allott, M. Álvarez-Jimenez, S. Harringan, C. Pantelis, S.J. Wood, V. Cropley, P. McGorry, A. Fornito, V. Molina, R. De Luis García, S. Chopra · University of Valladolid, Department of psychiatry, Valladolid, Spain

2026 ECNP Congress

Background: Psychotic disorders such as schizophrenia have been associated with older-appearing brain structure, commonly quantified using the brain-age paradigm. Brain-age is typically estimated using a machine learning model trained to predict chronological age from neuroimaging data in healthy individuals. The difference between an individual’s actual age and the predicted age, commonly termed ‘brain-predicted age difference’ (brain-PAD), serves as an indicator of structural brain health. However, it remains unclear whether these alterations are present at illness onset and whether antipsychotic treatment modifies their trajectory ​[1]​.

Aim: The aim of the present study is to disentangle the effects of medication and disease in the aging brain of young people with first-episode of psychosis.

Methods: In this study, 62 antipsychotic-naïve people with first-episode psychosis were randomized to receive either a second-generation antipsychotic (risperidone or paliperidone) or placebo over a 6 month treatment period, alongside intensive psychosocial therapy. A healthy control group (n = 27) was also recruited. Structural MRI scans were collected at baseline, 3 months, and 12 months. Brain age was estimated using two pretrained, validated models (Pyment and CentileBrain). We used analysis of covariance (ANCOVA) to examine differences in baseline brain-PAD between people with FEP and controls, including age, sex, and a scan quality metric as covariates. To examine differences in longitudinal brain-PAD changes between the three groups (placebo, antipsychotic and healthy controls), we computed a linear mixed-effects model with brain-PAD as outcome and group (healthy control, placebo, antipsychotic), time (in days), age, sex and scan quality measure as fixed effects and subjects as random effects. Our contrast of interest was a group-by-time interaction.

Results: Brain-predicted age difference (brain-PAD) did not differ between patients and healthy controls at baseline (p = 0.26). There was no statistically significant main effect of time (F(1,99.13) = 0.38, p = 0.54, group (F(2, 60.54) = 0.61, p = 0.55) or interaction between group and time (F(2, 55.15) = 1.38, p = 0.26). Taken together, brain-PAD did not show evidence of change over time, nor any evidence for being impacted by medication exposure or lack thereof.

Conclusion: These findings suggest that altered structural brain ageing is not evident during the earliest stages of psychosis and is not modified by early antipsychotic exposure over the first year of illness. These findings are consistent with multiple other studies showing a lack of brain age progression in the early stages of psychosis ​(3–5)​. Although our findings may appear to diverge from those of Schnack and colleagues ​(18),​ who reported progressive brain-PAD accumulation peaking within the first two years of illness, their sample comprised people with schizophrenia on typical antipsychotics, and changes accumulating beyond a one-year window would not be detectable in our study. Taken together, this would suggest that exposure, or lack thereof, to antipsychotics does not alter the stable brain age trajectory in the first year of treatment engagement. Longer follow-up and approaches that account for illness heterogeneity may be needed to clarify when brain-age alterations emerge in psychotic disorders.

References

  1. Blake, K.V., Ntwatwa, Z., Kaufmann, T., Stein, D.J., Ipser, J.C., Groenewold, N.A., 2023. Advanced brain ageing in adult psychopathology: A systematic review and meta-analysis of structural MRI studies. J. Psychiatr. Res. 157, 180–191.
  2. Mcwhinney, S. et al., 2021. Obesity as a risk factor for accelerated brain ageing in first-episode psychosis: A longitudinal study. Schizophr. Bull. 47 (6), 1772–1781.
  3. Fan, L. et al., 2025. Brain age gap as a predictor of early treatment response and functional outcomes in first-episode schizophrenia: A longitudinal study. Can. J. Psychiatry 70 (3), 240–250.
  4. Yi-Bin, X. et al., 2022. Neuroimaging-based brain-age prediction of first-episode schizophrenia and the alteration of brain age after early medication. Br. J. Psychiatry 220 (6), 339–346.
  5. Schnack, H.G., Van Haren, N.E.M., Nieuwenhuis, M., Pol, H.E.H., Cahn, W., Kahn, R.S., 2016. Accelerated brain aging in schizophrenia: A longitudinal pattern recognition study. Am. J. Psychiatry 173 (6), 607–616.