Short Summary/Abstract:

Background: Grey matter abnormalities are a well-established feature of psychotic disorders such as schizophrenia and first-episode psychosis (FEP). However, a significant proportion of individuals with psychosis also use substances including cannabis, alcohol, and tobacco, each of which can independently impact brain structure. Distinguishing the neuroanatomical effects of psychosis from those of substance use remains a major challenge for psychiatric neuroscience.
Objective: This study will investigate whether substance use contributes to, mediates, or moderates grey matter volume (GMV) differences between individuals with psychosis and healthy controls. Leveraging high-quality structural MRI and harmonised clinical data from the PsyShareD consortium, we aim to examine associations between substance use and GMV across multiple brain regions.
Methods: A cross-sectional analysis will be conducted using data from PsyShareD cohorts that include participants with schizophrenia, FEP, or clinical high risk (CHR) and healthy controls. Participants must have T1-weighted MRI data and documented substance use information. Grey matter volumes will be derived using standardised neuroimaging pipelines and harmonised across sites. General linear models will be used to compare GMV between groups, with substance use included as a covariate, moderator, and predictor. Mediation and dose–response analyses will explore the influence of specific substances within the psychosis group.