Psychotic disorders, such as schizophrenia and bipolar disorder with psychotic features, present complex challenges in mental health care, characterized by symptoms like hallucinations, delusions, and disorganized thinking. The origins of psychosis are diverse, stemming from genetic, environmental, and psychological influences. This multifactorial etiology contributes to the significant heterogeneity observed among individuals with psychotic disorders, complicating the development of effective treatment strategies. Traditional diagnostic and treatment approaches often fail to capture the intricate variations among patients, highlighting the need for more nuanced understanding and methodologies. In our recent study, we explored the heterogeneity of brain structural anomalies in schizophrenia by focusing on individual variations in cortical thickness. Utilizing normative models based on data from a vast cohort of healthy individuals, we were able to estimate deviations in cortical thickness among patients with schizophrenia. These deviations were then linked to neurotransmitter systems through the analysis of publicly available molecular imaging data. Employing consensus clustering techniques on the relationship between cortical thickness deviations and neurotransmitter systems, we identified three distinct schizophrenia subtypes. Each subtype exhibits unique patterns of cortical thickness deviations and their associations with specific neurotransmitter systems. This classification was further validated in two independent cohorts of first-episode, treatment-naïve schizophrenia patients, demonstrating the reproducibility and relevance of these subtypes. Interestingly, we found that the burden of clinical symptoms correlates with the profile of cortical thickness deviations across all identified subtypes. This suggests a direct link between the structural brain anomalies observed in schizophrenia and the clinical manifestations of the disorder. Further analysis of human brain gene expression data revealed that these three schizophrenia subtypes are associated with different cell types and stages of neurodevelopment. This insight provides a deeper understanding of the biological underpinnings of schizophrenia subtypes and offers a novel perspective on the disorder's heterogeneity.
