Differential Effects of Illness and Antipsychotics on Cortical Thinning in First-Episode Psychosis: A Randomized, Placebo-Controlled Magnetic Resonance Imaging Study.

BACKGROUND

Cortical gray matter loss is a common finding in magnetic resonance imaging (MRI) studies of psychosis and can progress with ongoing illness. A major unresolved question concerns whether these changes are driven by the illness or represent iatrogenic effects of antipsychotics.

METHODS

In a triple-blind, randomized, placebo-controlled MRI study, 62 antipsychotic-naïve people with first-episode psychosis (FEP) received a second-generation antipsychotic or placebo over 6 months (n = 35 at 12 months) alongside a healthy control group (n = 27 at baseline, n = 21 at 12 months). T1-weighted scans were collected at baseline, 3 months, and 12 months. Linear mixed-effects models fitted to >160,000 cortical loci examined illness- and antipsychotic-related thickness changes. We also examined whether cortical changes were enriched within functional networks or cytoarchitectonic classes and whether they spatially correlated with normative positron emission tomography receptor/transporter densities and transcriptomically imputed cell densities.

RESULTS

Over 12 months, the placebo group showed widespread cortical thinning compared with the control group (false discovery rate [FDR]-corrected p < .05), with the largest effects in frontal, cingulate, and occipital areas. No significant difference was detected between patients treated with antipsychotics and control participants. Thinning was not concentrated within specific functional networks, but highly differentiated koniocortical areas were relatively protected (pspin < .05 FDR-corrected). Thinning spatially aligned with normative distributions of GABAA/BZ, 5-HT1B, 5-HT2A, and H3 receptors (0.17 <r < 0.28; pspin < .05 FDR-corrected). No associations between thinning and symptom change were identified.

CONCLUSIONS

Widespread cortical thinning occurs over the first year of FEP in people not receiving antipsychotics. No such thinning is evident in patients receiving antipsychotics. These findings suggest that cortical thinning in early psychosis is an illness-related phenomenon.