Microstructural and diffusion tensor imaging of clozapine for treatment-resistant schizophrenia

BACKGROUND: Clozapine (CLZ) demonstrates superior efficacy for treatment-resistant schizophrenia (TRS), but mechanisms underlying its effects remain unknown. Pathophysiologic links between cortical regions and the basal ganglia (BG) characterize schizophrenia and are implicated in the mechanism of CLZ's action. Here, we examined CLZ's efficacy with diffusion weighted imaging (DWI) to examine microstructural and white matter-related measures within and between cortical and BG regions. METHODS: Twenty-six participants with TRS and moderate-to-severe psychosis underwent DWI scanning while starting CLZ, and nineteen were re-scanned after twelve weeks of treatment. Symptoms across treatment were measured via the Brief Psychiatric Rating Scale. DWI scans were processed to derive an array of microstructural measures in frontal and BG gray matter parcels and white matter-related measures in corticostriatal tracts. Exploratory analyses linked results with published functional connectivity findings. RESULTS: We found significant links between CLZ response and increased mean kurtosis (MK) in the left dorsolateral putamen, left ventral caudate, and left globus pallidus. Additionally, significant relationships between striatal segments of corticostriatal white matter tracts and CLZ response were observed, including increased MK, decreased axial diffusivity, and decreased fractional anisotropy. Exploratory findings linked changes in BG microstructure with published corticostriatal connectivity findings. CONCLUSION: Our results implicate microstructural changes within gray matter regions of BG and white matter changes within the striatum as mechanisms underlying CLZ treatment. These findings further elucidate CLZ's mechanism of action and warrant further analyses that explore pharmacologic effects at the microstructural level.