Neuroanatomical Subtypes of Schizophrenia Reveal Divergent Atrophy Trajectories and Distinct Associations with Long-Term Clozapine Use
Year: 2026
Type: article
Abstract: BACKGROUND AND HYPOTHESIS: Schizophrenia is a heterogeneous disorder, and biology-informed stratification may provide insights into individual differences in disease course and treatment response. We hypothesized that neuroimaging-based subtyping could reveal biologically distinct subgroups characterized by divergent brain atrophy trajectories and unique clinical profiles. STUDY DESIGN: We applied the Subtype and Stage Inference framework to baseline structural MRI data from the 6-year longitudinal Genetic Risk and Outcome of Psychosis cohort (n = 467), including patients, unaffected siblings and healthy controls. We characterized subtype-specific longitudinal brain atrophy and medication profiles. Subtype-specific atrophy patterns were correlated with external molecular maps of neurotransmitter density and schizophrenia-related gene expression. STUDY RESULTS: Two distinct neuroanatomical subtypes were identified: subtype 1 (65.5%), characterized by widespread cortical volume loss at baseline, and stable volume decrease over 6-year follow-up. Conversely, subtype 2 (34.5%) showed baseline volume decrease confined in the hippocampus and amygdala, but accelerated volume loss over follow-up. Clinically, subtype 1 patients had a significantly higher prevalence of clozapine use than subtype 2 (36% vs. 17%; chi2 = 5.62, P = 0.02), and brain atrophy of subtype 1 mirrored patterns observed in clozapine users. The two subtypes showed divergent spatial associations with neurotransmitter systems and risk-gene expression profiles. CONCLUSIONS: We identified two neuroanatomical subtypes of schizophrenia showing divergent brain atrophy over 6-years. The subtypes may represent biologically distinct forms of schizophrenia, as they show different medication profiles and associations with molecular signatures. Our results provide a candidate framework for parsing disease heterogeneity and may offer insights for future stratified treatment strategies.
Source: Schizophrenia Bulletin
Institutions: Fudan University, Frontiers Center for Brain Science of the Ministry of Education, Shenzhen University, Maastricht University Medical Centre, Maastricht University, Radboud University Nijmegen, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Charité – Universitätsmedizin Berlin, Tongji University, Huashan Hospital, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Air Force Medical University, Shanghai Jiao Tong University, Shanghai Mental Health Center, Shanghai Key Laboratory of Psychotic Disorders, Peking University, Technische Universität Dresden, University of Tübingen, Amsterdam Public Health, GGZ inGeest, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam UMC Location Vrije Universiteit Amsterdam, University of Warwick
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7224856561