Disease Duration, Antipsychotic Use, and Brain Aging in Schizophrenia

• Patients with schizophrenia showed a significantly higher brain age gap than healthy controls, with mean differences of approximately 5–6 years using 2 independent machine-learning (ML) models.
• First-episode psychosis was also associated with an increased Brain Age Gap compared with controls, though effect sizes were smaller than in chronic schizophrenia.
• Antipsychotic medication exposure was not significantly associated with brain age gap in schizophrenia or bipolar disorder cohorts. 

Accelerated brain aging has been consistently reported in schizophrenia, but its progression and relationship to antipsychotic treatment remain unclear. In a study published in Schizophrenia Research, investigators examined whether disease duration or antipsychotic exposure explains increases in brain age among patients with schizophrenia using MRI-based machine-learning models. The study found that accelerated brain aging occurs early in the disease course and is independent of illness duration or antipsychotic medication exposure.

The cross-sectional study included 87 patients with schizophrenia, 80 healthy controls, and 39 patients with bipolar disorder, all of whom underwent high-resolution T1-weighted MRI. Researchers estimated “brain age” using 2 independent machine learning approaches: a transformer-based model trained on volumetric MRI features from more than 4,000 healthy individuals, and the previously validated Pyment deep learning model. 

In comparisons with healthy controls, schizophrenia patients showed a significantly higher brain age gap, defined as the discrepancy between estimated brain age and the individual’s chronological age. Using the transformer model, the mean difference was 5.8 years (p=0.000004), while the Pyment model estimated a difference of 5.9 years (p=0.00001). First-episode psychosis patients also demonstrated an elevated brain age gap, ranging from 4.3 years to nearly 10 years depending on the model, indicating that accelerated brain aging is present early in the disease course. 

To assess medication effects, investigators examined chronic schizophrenia patients using regression models that included illness duration, chlorpromazine-equivalent dose, body mass index, and interaction terms. None of these medication-related variables significantly predicted brain age gap. As a further test, bipolar patients receiving antipsychotics were compared with those not receiving them; no significant differences in brain age gap were observed in either model.

These findings suggest that accelerated brain aging in schizophrenia is present early in the illness and persists across disease stages. Importantly, the absence of a significant association between antipsychotic exposure and brain age gap challenges the assumption that medication alone drives observed brain aging effects.

For clinicians, the results support the interpretation of brain aging markers as reflecting illness-related neurobiological processes rather than cumulative pharmacologic burden. The authors note that disease duration did not predict brain age gap in chronic schizophrenia, which may indicate a nonlinear trajectory with early acceleration and later stabilization. The findings highlight the importance of longitudinal designs to clarify temporal dynamics.

“Both models converge on the conclusion that accelerated brain aging is unlikely to be explained by antipsychotic medication alone,” writes Alejandro Roig-Herrero, PhD, Psychiatry Department, School of Medicine, University of Valladolid, Valladolid, Spain, and coauthors.

The results reinforce accelerated brain aging as a core feature of the disorder and underscore the need for longitudinal studies to better understand its clinical and biological implications.

Reference:

Roig-Herrero A, San-José-Revuelta LM, Navarro-González R, de Luis-García R, Molina V. Effects of disease duration and antipsychotics on brain age in schizophrenia. Schizophr Res. 2026;287:82-90. doi:10.1016/j.schres.2025.11.008