Polyunsaturated fatty acids (PUFA) Bimodality Unmasks xCT-Deficient Schizophrenia: Evidence of Two Distinct Biotypes

Background and Hypothesis: Schizophrenia's heterogeneity hampers research, prevention, and treatment. We previously identified a bimodal distribution of red blood cell polyunsaturated fatty acids (PUFA) during acute schizophrenia, defining Low PUFA (LP) and High PUFA (HP) groups. We hypothesized that LP patients exhibit glutathione system dysfunction representing a distinct biotype characterized by redox dysregulation.Study Design: In this cross-sectional follow-up study, we examined 55 schizophrenia spectrum patients five years after an acute episode alongside 51 healthy controls. We measured amino acids, glutathione and related enzymes, and mRNA expression of glutathione-related proteins. Regularized regression analysis identified key biochemical predictors of group (LP=0 or HP=1) and symptom severity.Study Results: The strongest biochemical predictor of the LP subgroup was elevated plasma 2-aminobutyrate (OR=0.0013). LP patients showed robustly lower gene expression of the cystine/glutamate antiporter (xCT) (OR=10.0), more homogeneous xCT distribution, moderately lower blood glutathione, and elevated plasma valine compared to HP patients. HP patients exhibited significantly lower plasma cystine compared to controls. PUFA group robustly modified the relationship between gene expression of glutathione-related proteins and PANSS symptom scores, with different correlation patterns observed between subgroups.Conclusions: Our findings suggest that schizophrenia comprises two biologically distinct subtypes: a Low PUFA biotype characterized by xCT-deficit and altered 2-aminobutyrate metabolism, and a High PUFA biotype with different glutathione regulatory mechanisms. The Low PUFA/xCT-deficit biotype represents a potential disease entity with distinct pathophysiology and prevention and treatment implications. Genotyping of xCT and glutathione-related enzymes in future studies may further validate these biotypes and guide personalized interventions.