Associations between glutamate and cerebral blood flow in treatment-resistant schizophrenia during clozapine treatment

Background: Treatment-resistant schizophrenia (TRS) is associated with alterations in glutamate levels and cerebral blood flow (CBF), and treatment with clozapine appears to have an impact on each of these measures. Here, we examined whether changes in CBF and glutamate levels following clozapine treatment are related. Methods: Glutamate concentrations in the anterior cingulate cortex (ACC), and striatum (measured using proton magnetic resonance spectroscopy, 1 H-MRS); and whole brain regional CBF maps (measured using pseudo-continuous arterial spin labelling (pCASL)), were examined in a cohort of TRS subjects before and after 12 weeks of treatment with clozapine (baseline: N = 30; week 12: N = 20). Results: The longitudinal change in striatal glutamate during treatment was positively associated with the longitudinal change in striatal CBF ( p < 0.05). In the ACC, higher Glx (glutamate + glutamine) and CBF prior to treatment were associated with greater subsequent improvement in total symptom severity. Conclusions: These results indicate that there is a direct relationship between changes in glutamate activity and CBF in the striatum following clozapine treatment. Future research could investigate whether glutamate-CBF relationships exist in other stages of psychosis or schizophrenia and during treatment with other antipsychotic medications. Associations with clinical outcomes could be explored in larger samples.