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

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.

Subcortical volume reduction and cortical thinning 3 months after switching to clozapine in treatment resistant schizophrenia

“…In line with our previous report in the same cohort 69 , SPC of caudate Glu corr and NAA corr significantly differed from zero, with lower levels after 12 weeks of clozapine treatment (Glu corr : T 20 = 3.04; P = 0.006; NAA corr : T 20 = 2.43; P = 0.03; Table 1 ). There was no significant change in ACC SPC in Glu corr and NAA corr ( P > 0.05, Table 1 ).…”

“…While we detected reductions in caudate, but not ACC, glutamate during clozapine treatment in the same patient cohort 69 , in the current study we found no evidence to implicate changes in glutamate levels with cortical thinning or caudate volume reduction. Instead, reductions in caudate volume during clozapine treatment were associated with local reductions in NAA, which may indicate decreases in the integrity of neurons or oxidative metabolism in mitochondria 76 – 79 .…”

“…After QC, structural data for analyses were available in 24 patients at both baseline and after 12 weeks of clozapine treatment (Table 1 ). The demographic and clinical characteristics of the patient sample are provided in further detail in our previous publication 69 . Co-medication included antidepressant medication in 7 patients (including citalopram, sertraline, venlafaxine, escitalopram, and fluoxetine) and GABAergic medication in 9 patients (including clonazepam lorazepam, chlordiazepoxide, valproate, lithium, and zopiclone).…”

Decreased Brain pH and Pathophysiology in Schizophrenia

“…Increased synaptic glutamate levels due to decreased GLAST membrane expression in NHE9 mutations is consistent with increased synaptic glutamate levels [73][74][75][76][77][78][79][80]. Antipsychotic drugs reduce the increased synaptic levels of glutamate [74,146].…”

A systematic review of TMS and neurophysiological biometrics in patients with schizophrenia

“…121 Further, olanzapine, risperidone and other antipsychotics appear to have different effects on biobehavioural changes induced by phencyclidine, suggesting that these medications may exert a different action on NMDA receptors. 122,123 Finally, clozapine, which has been shown to be the only effective antipsychotic for treatment-resistant patients, modu lates glutamatergic activity that has been correlated with the degree of symptomatic change, 124 further supporting the idea of other mechanisms underlying its therapeutic effects. 119,[125][126][127] It is possible that a more general systems-level explanation may lie in the possibility that antipsychotic medication exerts its effect by altering the cortical E/I balance in patients with schizophrenia.…”