Antipsychotic-related brain changes in first-episode psychosis: a systematic review

Antipsychotics (APs) induce functional, anatomical, and metabolic brain changes in schizophrenia, but the nature and clinical significance of these effects remain debated. Focusing on first-episode psychosis (FEP) allows distinction between medication-induced and illness-related brain changes and facilitates identification of early predictors of treatment response.

Following PRISMA guidelines (PROSPERO: CRD42021240369), we systematically reviewed longitudinal neuroimaging studies in FEP with the objective of 1) identifying APs-induced brain changes, 2) identifying brain changes associated with clinical improvement, and 3) exploring the potential of neuroimaging biomarkers to predict treatment response.

Eighty-six studies were included: 26 structural, 27 functional, and 16 metabolic, including 33 studies specifically addressing predictive biomarkers of treatment response. Across modalities, APs induced measurable brain changes within days to weeks of treatment Ainitiation, particularly in the striatum, thalamus, and prefrontal cortex (PFC), key regions of the striato-thalamo-cortical network. Increased basal ganglia gray matter volume was the most consistent anatomical finding; cortical findings, particularly in the PFC, were more heterogeneous, with both increases and decreases in thickness reported across studies. Functionally, APs normalized abnormal striatal activity and connectivity, correlating with improvement in positive symptoms. In contrast, no reliable imaging correlate has been identified for changes in negative or cognitive symptoms. Metabolic studies showed increased N-acetylaspartate in the thalamus and PFC and normalization of glutamate levels in associative and limbic regions. Baseline brain characteristics, particularly less severe structural or functional abnormalities in the striatum and anterior cingulate cortex, predicted better outcomes.

Together, these findings suggest that APs primarily act through modulation and normalization of striato-cortical circuits, with preserved neuroplasticity favoring recovery. Integrating multimodal neuroimaging and computational approaches may advance biomarker-based, individualized treatment strategies in early psychosis.