The effect of clozapine on regional cerebral blood flow and brain metabolite ratios in schizophrenia: Relationship with treatment response

Abstract 

The purpose of this study was to investigate the effect of clozapine on regional cerebral blood flow (rCBF) and its relationship with response to treatment. In addition, we aimed to study the influence of clozapine on proton magnetic resonance spectroscopy (¹H-MRS) findings in the dorsolateral prefrontal cortex (DLPFC) in a subgroup of patients. Psychopathology, neurocognitive functioning, and SPECT imaging of 22 patients were assessed at the baseline and 8 weeks after the initiation of clozapine treatment. In 10 of these patients intermediate-echo (TE: 135 ms) single-voxel ¹H-MRS was also performed at the baseline and after 8 weeks. Clozapine treatment increased the right frontal (superior and medial)/caudate perfusion ratio in the whole group, while it increased bilateral frontal (superior and medial)/caudate perfusion ratios in treatment responders. In addition, percentage changes in left and right frontal (superior and medial)/caudate perfusion ratios compared to the baseline were higher in treatment responders than in non-responders. The improvement in attention was related to the increase in percentage change in the right frontal (superior and medial)/caudate perfusion ratio, while the improvement in verbal fluency was related to the increase in percentage changes in both right and left frontal (superior and medial)/caudate perfusion ratios and to right frontal (superior and medial)/thalamus perfusion. Baseline frontal (superior and medial)/thalamus perfusion could explain 32% of the variability of percentage improvements in psychopathology. ¹H-MRS showed that the baseline PANSS general psychopathology score was inversely correlated with the baseline NAA/Cre ratio. An increased NAA/Cre ratio in DLPFC after 8 weeks of clozapine treatment was also revealed by ¹H-MRS. Our SPECT imaging results suggest the presence of an imbalance in fronto-striato-thalamic circuitry that changes with clozapine, especially in the responders, while ¹H-MRS results indicate a supportive effect of clozapine on neuronal integrity.

Keywords: Clozapine, Schizophrenia, Regional cerebral blood flow (rCBF), SPECT, N-acetyl aspartate (NAA), Proton magnetic resonance spectroscopy (H-MRS)