Astrocytic activity in treatment-resistant and ultra-treatment-resistant schizophrenia

Astrocytic dysfunction has been implicated in schizophrenia, but biomarkers of astrocytic activity have shown inconsistent patterns. Studies on disease heterogeneity, specifically treatment-resistant schizophrenia (TRS) and ultra-treatment-resistant schizophrenia (UTRS) are lacking. In this study, plasma glial fibrillary acidic protein (GFAP) was measured using an ultrasensitive Simoa assay in 174 participants (58 controls, 35 first-degree relatives, and 81 patients with TRS, according to Treatment Response and Resistance in Psychosis (TRRIP) criteria. A further n = 35 fulfilled TRRIP criteria for UTRS. Data included symptom severity, cognition, and functioning assessments. Cortical thickness was measured with magnetic resonance imaging (MRI). Associations between GFAP and demographic, clinical, cognitive, and imaging variables were examined using regression models adjusted for age, sex, and BMI. Plasma GFAP concentrations did not differ between controls and TRS or UTRS participants. GFAP showed no associations with symptom severity, cognition, functioning, or cortical thickness. Duration of illness showed a significant interaction with UTRS diagnosis associated to higher GFAP levels (b = 3.67, 95% CI 1.62-5.72, p < 0.001), while individuals with TRS showed the opposite pattern. The axonal marker neurofilament light chain (NfL), showed a positive relationship with disease duration in both disease categories. The results suggest that plasma GFAP does not act as diagnostic or severity marker in schizophrenia, but can highlight astroglial-related processes where UTRS and TRS show different trajectories.