Structural Brain Age Trajectories in Antipsychotic-naive First Episode Psychosis

Background: Psychotic disorders such as schizophrenia have been associated with older-appearing brain structure, commonly quantified using the brain-age paradigm. However, it remains unclear whether these alterations are present at illness onset and whether antipsychotic treatment modifies their trajectory. Methods: In this study, 61 (28 females and 33 males) antipsychotic-naive people with first-episode psychosis were randomised 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, 17 females, 10 males) was also recruited. Structural MRI scans were collected at baseline, 3 months, and 12 months. Brain age was estimated using two pretrained and validated models (Pyment and CentileBrain). Results: Brain-predicted age difference (brain-PAD) did not differ between patients and healthy controls at baseline (F(1,80) = 1.30; p = 0.26). There were also no significant effects of time, treatment group (antipsychotic, placebo, healthy control), or their interaction on brain-PAD across the first year (all p > 0.26). Findings were consistent across both brain-age models, and brain-PAD was not associated with clinical and lifestyle measures. 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. Longer follow-up and approaches that account for illness heterogeneity may be needed to clarify when brain-age alterations emerge in psychotic disorders.