Reduced Frontal Glutamate + Glutamine and N-Acetylaspartate Levels in Patients With Chronic Schizophrenia but not in Those at Clinical High Risk for Psychosis or With First-Episode Schizophrenia

Abstract

Changes in brain pathology as schizophrenia progresses have been repeatedly suggested by previous studies. Meta-analyses of previous proton magnetic resonance spectroscopy ((1)H MRS) studies at each clinical stage of schizophrenia indicate that the abnormalities of N-acetylaspartate (NAA) and glutamatergic metabolites change progressively. However, to our knowledge, no single study has addressed the possible differences in (1)H MRS abnormalities in subjects at 3 different stages of disease, including those at ultrahigh risk for psychosis (UHR), with first-episode schizophrenia (FES), and with chronic schizophrenia (ChSz). In the current study, 24 patients with UHR, 19 FES, 25 ChSz, and their demographically matched 3 independent control groups (n = 26/19/28 for the UHR, FES, and ChSz control groups, respectively) underwent (1)H MRS in a 3-Tesla scanner to examine metabolites in medial prefrontal cortex. The analysis revealed significant decreases in the medial prefrontal NAA and glutamate + glutamine (Glx) levels, specifically in the ChSz group as indexed by a significant interaction between stage (UHR/FES/ChSz) and clinical status (patients/controls) (P = .008). Furthermore, the specificity of NAA and Glx reductions compared with the other metabolites in the patients with ChSz was also supported by a significant interaction between the clinical status and types of metabolites that only occurred at the ChSz stage (P = .001 for NAA, P = .004 for Glx). The present study demonstrates significant differences in (1)H MRS abnormalities at different stages of schizophrenia, which potentially correspond to changes in glutamatergic neurotransmission, plasticity, and/or excitotoxicity and regional neuronal integrity with relevance for the progression of schizophrenia.

Cannabis use in early psychosis is associated with reduced glutamate levels in the prefrontal cortex

“…Purdon et al (2008) finding the absence of differences in Glu metabolites levels between HR and HC in the same brain region, as was for Yoo et al (2009). Concordantly, analyzing the medial-PFC in HR subjects, EP and schizophrenia patients, Natsubori et al (2014) revealed significant decrease in Glu metabolites only in the schizophrenia group.…”

“…Furthermore, recent studies have shown decreased Glu levels in schizophrenia patients when compared to healthy individuals, particularly in medial frontal region (Marsman et al 2013). Moreover, chronicity in schizophrenia was found to be related to decreased prefrontal Glu (Natsubori et al 2014), Glx (Glu + Gln) and NAA levels (Liemburg et al 2016); with evidence for a time-depending role for Glu (Merritt et al 2016), whereas findings in early psychosis (EP) are still controversial (for a review see Treen et al 2016). While the studies presented above provide evidence that THC leads to glutamatergic dysfunction, they do not unequivocally identify the specific brain circuits or regions involved.…”

Glutamatergic and Neuronal Dysfunction in Gray and White Matter: A Spectroscopic Imaging Study in a Large Schizophrenia Sample

“…[26][27][28][29][30] However, the quality of the spectral fits is not always clear in these reports (except for [27][28][29] ) and the samples were small (9 to 30 for the schizophrenia groups 6 ). More recent studies reported increases, [31][32][33][34][35] reductions 25,[36][37][38] and no differences 39 in Glx or glutamate. Two 33,34 of the 5 recent studies documenting elevations involved more ventral regions.…”

Subanesthetic Ketamine Treatment Promotes Abnormal Interactions between Neural Subsystems and Alters the Properties of Functional Brain Networks

“…For example, recent in vivo 1 H magnetic resonance spectroscopy ( 1 H-MRS) data support altered glutamate and glutamine levels in the brains of schizophrenia patients (De la Fuente-Sandoval et al, 2011;Marsman et al, 2013;Natsubori et al, 2013). Furthermore, both acute and repeated exposure to NMDA receptor antagonists can induce schizophrenia-like symptoms in humans (Cosgrove and Newell, 1991;Krystal et al, 1994) and acute treatment with the NMDA receptor antagonist ketamine exacerbates the symptoms of schizophrenia patients (Lahti et al, 2001;Malhotra et al, 1997).…”