Disrupted white matter integrity in treatment-resistant schizophrenia

Treatment response in schizophrenia is heterogeneous and has been posited to divide into three distinct subcategories: treatment-responsive (first-line responders; FLR), treatment-resistant (TRS, responding to clozapine), and ultra-treatment-resistant schizophrenia (UTRS, requiring augmented antipsychotic therapy). Previous work suggests that white matter abnormalities drive antipsychotic resistance but little work has been carried out to identify differences between those with TRS and those with UTRS. The current study aimed to establish whether differences in white matter structure are present across both treatment-resistant subtypes of schizophrenia or if UTRS is distinct from TRS. Diffusion-weighted images were acquired for 18 individuals with TRS, 14 with UTRS, 18 FLR and 20 healthy controls. Measures of fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and parallel diffusivity (PD) were obtained using tract-based spatial statistics. Analysis of variance (ANOVA) and post-hoc between-groups t-tests interrogating differences were conducted for each white matter measure. Those with TRS had lower FA than healthy controls across widespread regions of the brain, including the superior longitudinal fasciculus, corpus callosum, thalamic radiation, corticospinal tract, internal capsule, corona radiata and fronto-occipital fasciculus (p<.05 FWE-corrected). Lower FA was also observed in those with TRS compared with UTRS in the superior longitudinal fasciculus (p<.05 FWE-corrected). However, post-hoc tests failed to survive corrections for multiple comparisons across the 12 post-hoc contrasts. No differences in MD, PD or RD were observed between groups. These data suggest that TRS is distinct from UTRS and that lower FA could act as a biomarker of treatment resistance in people with schizophrenia.