Neuroimaging biomarkers define neurophysiological subtypes with distinct trajectories in schizophrenia

Technical developments and improved access to neuroimaging techniques have brought us closer to understanding the neuropathological origins of schizophrenia. Using data-driven disease-progression modelling on cross-sectional magnetic resonance imaging (MRI) from 1,124 patients with schizophrenia, we characterize two distinct but stable ‘trajectories’ of brain atrophy, separately beginning in the Broca’s area (subtype1) and the hippocampus (subtype2). The two trajectories are replicated in cross-validation samples. Individuals within each subtype are further classified into two stages (‘pre-atrophy’ and ‘post-atrophy’). These subtypes show different atrophy patterns and symptom profiles. Longitudinal data from 523 patients with schizophrenia treated by antipsychotics only or adjunct transcranial magnetic stimulation (TMS) reveal that antipsychotics-only effects relate to phenotypic subtype (more effective in the subtype1) while adjunct transcranial-magnetic-stimulation effects relate to the stage (superior outcomes in the pre-atrophy stage). These findings suggest distinct pathophysiological processes underlying schizophrenia that potentially yield to stratification and prognostication—a key requirement for personalizing treatments in enduring illnesses.