Altered glutamate level and its association with working memory among patients with treatment-resistant schizophrenia (TRS): a proton magnetic resonance spectroscopy study

Abstract

Background Treatment-resistant schizophrenia (TRS) and non-TRS may be associated with different dopaminergic and glutamatergic regulations. The concept of dysregulated glutamatergic concentrations in specific brain regions remains controversial. Herein, we aimed to assess (i) the distribution of the glutamatergic concentration in the brain, (ii) the association between working memory (WM) differences in TRS and non-TRS patients, and (iii) whether an alteration in the glutamate (Glu) level is associated with WM. Methods The participants included 38 TRS patients, 35 non-TRS patients, and 19 healthy controls (HCs), all of whom underwent 1.5-Tesla proton magnetic resonance spectroscopy of anterior cingulate cortex (ACC) and medial prefrontal cortex (MPFC). The ratios of glutamatergic neurometabolites to N-acetylaspartate + N-acetyl aspartylglutamate (NAAx) were calculated. Cognitive function was assessed using the Wechsler Adult Intelligence Scales, 4th Edition, which included the working memory index (WMI). Result The TRS patients had a higher glutamate + glutamine (Glx)/NAAx ratio compared to the non-TRS patients and HCs in the ACC, but this was not significantly different in the MPFC. WM was negatively correlated with Glx/NAAx in the ACC among the non-TRS patients, but not in the TRS patients or HCs. Conclusions Our findings were consistent with most studies indicating that the glutamatergic concentration in the ACC plays important roles in the classification of TRS and cognition. Our results may provide potential evidence for predictors and treatment response biomarkers in TRS patients. Further research is needed to probe the value using the relationship between Glu and WM as a potential prognostic predictor of schizophrenia.

Antipsychotics-Induced Changes in Synaptic Architecture and Functional Connectivity: Translational Implications for Treatment Response and Resistance

“…However, antipsychotics’ effects on functional connectivity have been assessed also after amphetamine administrations as well as in animals that did not model psychotic disorders, as presented in Table 2 . Although the specific drug used to mirror psychosis in the preclinical setting may affect the variability of the results, it should be remembered that patients with schizophrenia also showed alterations in different brain pathways, as highlighted by PET studies [ 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 ]. Thus, the application of drugs capable to reproduce changes in different neurotransmitter systems, including the dopaminergic and glutamatergic ones, is relevant in terms of translatability and clinical implication, through the opportunity to explore the effects of antipsychotics on different backgrounds and by providing the basis for tailoring the therapeutic choice according to the patient-specific characteristics.…”

Rational and Translational Implications of D-Amino Acids for Treatment-Resistant Schizophrenia: From Neurobiology to the Clinics

“…Among other neurotransmitter systems involved in TRS pathophysiology, the glutamatergic pathway has been the strongest related to disease neurobiology. Glutamate levels have been reported significantly different in multiple brain regions of TRS patients compared to responders and healthy controls, as measured by 1 H-magnetic resonance spectroscopy (MRS) [44][45][46][47]. In this regard, the anterior cingulate cortex (ACC) has strongly been implicated in TRS pathophysiology, showing an increase in glutamate concentrations not detectable in antipsychotics responder patients [44][45][46][47].…”

“…Glutamate levels have been reported significantly different in multiple brain regions of TRS patients compared to responders and healthy controls, as measured by 1 H-magnetic resonance spectroscopy (MRS) [44][45][46][47]. In this regard, the anterior cingulate cortex (ACC) has strongly been implicated in TRS pathophysiology, showing an increase in glutamate concentrations not detectable in antipsychotics responder patients [44][45][46][47]. In a multicenter study including 48 responder and 44 non-responder schizophrenia patients, beyond the significant increase in ACC glutamate levels exhibited by the TRS group, the authors measured 18 F-DOPA striatal uptake and no differences were detected between the two groups [44], supporting the glutamatergic and not dopaminergic involvement in TRS pathophysiology.…”

“…In a multicenter study including 48 responder and 44 non-responder schizophrenia patients, beyond the significant increase in ACC glutamate levels exhibited by the TRS group, the authors measured 18 F-DOPA striatal uptake and no differences were detected between the two groups [44], supporting the glutamatergic and not dopaminergic involvement in TRS pathophysiology. Moreover, the ACC (glutamate + glutamine)/N-acetyl aspartate (NAA) ratio not only has been found higher in TRS patients in comparison with schizophrenia responsive and healthy control groups but has also been negatively associated with working memory scores measured by the working memory index (WMI) of the Wechsler Adult Intelligence Scales-Fourth Edition (WAIS-IV) [47]. In line with this trend, a decrease in ACC cortical thickness has been related to an increase in ACC glutamate + glutamine levels within TRS and clozapine-resistant patients [48], suggesting that a possible correlation between central glutamate variations and changes in brain structures might provide a fertile background for antipsychotics unresponsiveness.…”