Changes in Brain Glutamate on Switching to Clozapine in Treatment-Resistant Schizophrenia.

Grant Mcqueen,James M Stone,Alice Egerton,Nynn Chang,Kyra-Verena Sendt,John Lally,Faith Borgan,Philip Mcguire,James H Maccabe,David J Lythgoe,Gareth J Barker,Amy Gillespie,Alessia Avila,Oliver D Howes,Kalliopi Vallianatou,Diogo Ferreira

doi:10.1093/schbul/sbaa156

Abstract

It has been suggested that the antipsychotic clozapine may modulate brain glutamate, and that this effect could contribute to its efficacy in treatment-resistant schizophrenia (TRS). The aim of this study was to examine the effects of clozapine on brain glutamate in TRS longitudinally. This study examined individuals with TRS before and 12 weeks after switching from a non-clozapine antipsychotic to treatment with clozapine as part of their normal clinical care. Proton magnetic resonance spectroscopy (1H-MRS) measured concentrations, corrected for voxel tissue content, of glutamate (Glucorr), and glutamate plus glutamine (Glxcorr) in the anterior cingulate cortex (ACC) and right caudate nucleus. Symptoms were monitored using the Positive and Negative Syndrome Scale (PANSS). Of 37 recruited patients (27 men, 39.30 years old, 84% clozapine naïve), 25 completed 1H-MRS at both timepoints. 12 weeks of clozapine was associated with a longitudinal reduction in Glucorr in the caudate (n = 23, F = 7.61 P = .01) but not in the ACC (n = 24, F = 0.02, P = .59). Percentage reduction in caudate Glucorr was positively correlated with percentage improvement in symptoms (total PANSS score, n = 23, r = .42, P = .04). These findings indicate that reductions in glutamate in the caudate nucleus may contribute to symptomatic improvement during the first months of clozapine treatment.

Highlights

Clozapine is the only antipsychotic recommended for patients with treatment-resistant schizophrenia (TRS).[1]
Cross-sectional proton magnetic resonance spectroscopy (1H-MRS) studies indicate that patients with TRS taking non-clozapine antipsychotics have higher levels of glutamate in the anterior cingulate cortex (ACC) than patients with schizophrenia who have shown a good antipsychotic response[4] and healthy volunteers.[5,6]
Binding to the NMDA receptor intrachannel PCP/ MK-801 site is reduced across the brain in clozapinetreated, but not typical-antipsychotic-treated patients with schizophrenia relative to healthy volunteers, which may indicate that clozapine modulates glutamatergic systems.[11]

Summary

Introduction

Clozapine is the only antipsychotic recommended for patients with treatment-resistant schizophrenia (TRS).[1]. Cross-sectional proton magnetic resonance spectroscopy (1H-MRS) studies indicate that patients with TRS taking non-clozapine antipsychotics have higher levels of glutamate in the anterior cingulate cortex (ACC) than patients with schizophrenia who have shown a good antipsychotic response[4] and healthy volunteers.[5,6] elevated ACC glutamate levels have been linked to a poor response to conventional antipsychotic treatment early in illness.[7,8] In contrast, studies examining participants with TRS taking clozapine at the time of scanning have reported no difference in ACC glutamate or Glx (the combined signal from glutamate and glutamine) in comparison to an antipsychotic-responsive group.[9,10] One explanation for this difference could be that clozapine treatment reduces ACC glutamate levels. In comparison to healthy volunteers, ACC Glx levels were elevated in clozapine-nonresponsive TRS (termed ultra-resistant schizophrenia, URS), but not in patients with TRS who had responded to clozapine.[10]

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Results

Conclusion