AbstractBackground and HypothesisTwo machine learning derived neuroanatomical signatures were recently described. Signature 1 is associated with widespread grey matter volume reductions and signature 2 with larger basal ganglia and internal capsule volumes. We hypothesized that they represent the neurodevelopmental and treatment-responsive components of schizophrenia respectively.Study DesignWe assessed the expression strength trajectories of these signatures and evaluated their relationships with indicators of neurodevelopmental compromise and with antipsychotic treatment effects in 83 previously minimally treated individuals with a first episode of a schizophrenia spectrum disorder who received standardized treatment and underwent comprehensive clinical, cognitive and neuroimaging assessments over 24 months. Ninety-six matched healthy case–controls were included.Study ResultsLinear mixed effect repeated measures models indicated that the patients had stronger expression of signature 1 than controls that remained stable over time and was not related to treatment. Stronger signature 1 expression showed trend associations with lower educational attainment, poorer sensory integration, and worse cognitive performance for working memory, verbal learning and reasoning and problem solving. The most striking finding was that signature 2 expression was similar for patients and controls at baseline but increased significantly with treatment in the patients. Greater increase in signature 2 expression was associated with larger reductions in PANSS total score and increases in BMI and not associated with neurodevelopmental indices.ConclusionsThese findings provide supporting evidence for two distinct neuroanatomical signatures representing the neurodevelopmental and treatment-responsive components of schizophrenia.