Inflammatory Subtypes in Antipsychotic-Naive First-Episode Schizophrenia are Associated with Altered Brain Morphology and Topological Organization

Background: Peripheral inflammation is implicated in schizophrenia, however, not all individuals demonstrate inflammatory alterations. Recent studies identified inflammatory subtypes in chronic psychosis with high inflammation having worse cognitive performance and displaying neuroanatomical enlargement compared to low inflammation subtypes. It is unclear if inflammatory subtypes exist earlier in the disease course, thus, we aim to identify inflammatory subtypes in antipsychotic naive First-Episode Schizophrenia (FES). Methods: 12 peripheral inflammatory markers, clinical, cognitive, and neuroanatomical measures were collected from a naturalistic study of antipsychotic-naive FES patients. A combination of unsupervised principal component analysis and hierarchical clustering was used to categorize inflammatory subtypes from their cytokine data (17 FES High, 30 FES Low, and 33 healthy controls (HCs)). Linear regression analysis was used to assess subtype differences. Neuroanatomical correlations with clinical and cognitive measures were performed using partial Spearman correlations. Graph theoretical analyses were performed to assess global and local network properties across inflammatory subtypes. Results: The FES High group made up 36% of the FES group and demonstrated significantly greater levels of IL1 beta, IL6, IL8, and TNF alpha compared to FES Low, and higher levels of IL1 beta and IL8 compared to HCs. FES High had greater right parahippocampal, caudal anterior cingulate, and bank superior sulcus thicknesses compared to FES Low. Compared to HCs, FES Low showed smaller bilateral amygdala volumes and widespread cortical thickness. FES High and FES Low groups demonstrated less efficient topological organization compared to HCs. Individual cytokines and/or inflammatory signatures were positively associated with cognition and symptom measures. Conclusions: Inflammatory subtypes are present in antipsychotic-naive FES and are associated with inflammationmediated cortical expansion. These findings support our previous findings in chronic psychosis and point towards a connection between inflammation and blood-brain barrier disruption. Thus, identifying inflammatory subtypes may provide a novel therapeutic avenue for biomarker-guided treatment involving anti-inflammatory medications.

Automated summary

Inflammation plays a role in schizophrenia, and different inflammatory subtypes exist in antipsychotic-naive First-Episode Schizophrenia (FES) patients, with implications for cortical expansion. Identifying these inflammatory subtypes may offer a new direction for inflammation-related treatment in FES patients.