Response to Clozapine in Treatment Resistant Schizophrenia is Related to Alterations in Regional Cerebral Blood Flow

PET and SPECT studies in treatment-resistant schizophrenia (TRS) have revealed significant alterations in regional cerebral blood flow (CBF) during clozapine treatment, which may vary according to the clinical response. Here, we used the more recent MRI approach of arterial spin labelling (ASL) to evaluate regional CBF in participants with TRS (N = 36) before starting treatment with clozapine compared to in healthy volunteers (N = 16). We then compared CBF in the TRS group, before and after 12 weeks of treatment with clozapine (N = 24); and examined the relationship of those differences against changes in Positive and Negative Syndrome Scale for Schizophrenia (PANSS) scores over the treatment period. We observed widespread reductions in CBF in TRS compared to in healthy volunteers (p < 0.05). After covarying for global CBF and age, lower CBF in frontal and parietal regions was still evident (p < 0.05, FWE corrected). Clozapine treatment was associated with longitudinal decreases in CBF in the anterior cingulate cortex (ACC) (p < 0.05). Higher striatal CBF at baseline was associated with greater improvement in total and general symptoms following clozapine, and higher hippocampal CBF was associated with greater improvement in total and positive symptoms. Longitudinal reductions in CBF in the ACC and thalamus were associated with less improvement in negative (ACC), positive (thalamus), and total (thalamus) symptoms. These findings suggest that changes in CBF on clozapine administration in TRS may accompany symptomatic improvement, and that CBF prior to clozapine initiation may determine the degree of clinical response.