Distinct brain volume abnormalities in clinical high-risk individuals: pre- and post-antipsychotic treatment

Individuals at clinical high risk (CHR) for psychosis exhibit both baseline and progressive brain structural abnormalities. However, the extent to which these changes reflect neurobiological trajectories of illness progression versus iatrogenic effects of antipsychotic (AP) treatment remains unresolved. A total of 148 AP-naïve CHRs and 65 healthy controls (HCs) underwent baseline structural magnetic resonance imaging (MRI) scans. One hundred thirty CHRs received second-generation AP treatment and completed 2-month follow-up scans. HCs also completed the follow-up scans. We compared baseline and longitudinal brain volume changes between CHRs and HCs and explored the relationship between AP treatment and brain structural changes in CHR. At baseline, CHRs showed enlarged third and inferior lateral ventricles compared to HCs. Within CHRs, larger ventricular, as well as smaller hippocampus and amygdala volumes, were associated with more severe symptoms and poorer functioning. No cortical volume differences were observed between groups at baseline, nor were cortical volumes related to clinical symptoms. After 2-month AP treatment, CHRs exhibited continued ventricular enlargement, reduced accumbens volume, and widespread cortical volume loss relative to HCs. Notably, cortical volume reductions were dose-dependent, with higher AP dose correlating with more pronounced cortical reductions. Additionally, cortical volume changes were linked to treatment response, with high-dose responders showing more significant HC-referenced changes compared to high-dose non-responders, low-dose responders, and low-dose non-responders. Our findings underscore the complex, region-specific, and clinically relevant neuroanatomical changes in CHR individuals, emphasizing the critical need to account for AP exposure in CHR neuroimaging studies.