Differential effects of illness and antipsychotics on cortical thinning in first episode psychosis

Introduction: Cortical grey matter loss is a common finding in Magnetic Resonance Imaging (MRI) studies of people with psychosis and has been shown to progress with ongoing illness. A major unresolved question concerns whether these changes are driven by the illness itself or represent iatrogenic effects of antipsychotic medication. Methods: We report findings from a triple-blind randomised placebo-controlled MRI study where 62 antipsychotic-naive people with first episode psychosis (FEP) received either an atypical antipsychotic or a placebo pill over a treatment period of 6 months. A healthy control group (n=27) was also recruited. Anatomical T1-weighed scans were collected at baseline, 3-months, and 12-months. Linear mixed effects models were fitted to >160,000 cortical surface loci to examine illness- and antipsychotic-related changes in cortical thickness. We also examined whether cortical changes were enriched within canonical functional networks or cytoarchitectonic types of laminar differentiation, and whether these changes spatially correlated with normative in vivo receptor/transporter densities via PET imaging and ex vivo transcriptomically-imputed cell densities. Results: We found widespread cortical thinning over 12 months (p<.05FDR) in people with FEP who received placebo compared to healthy controls, with the largest effects occurring in frontal, cingulate, and occipital areas. No significant difference was detected in antipsychotic-treated people with FEP compared to healthy controls. Thickness differences in placebo group were not preferentially concentrated within any specific functional networks, although highly differentiated koniocortical areas were relatively protected from cortical thinning (pspin<.05FDR). Thinning in the placebo group spatially aligned with normative distributions of GABAA/BZ, 5HT1B, 5HT2A, and H3 receptors (.17 < r < .28; pspin<.05FDR). No significant associations between cortical thinning and symptom changes were identified. Conclusions: Widespread thinning of cortical grey matter occurs over the first year of FEP in people who do not receive antipsychotic treatment. No such thinning is evident in patients receiving antipsychotics during the study intervention phase. These findings suggest that cortical thinning in the early stages of psychosis is an illness-related phenomenon that may be mitigated by early antipsychotic exposure.