Increased Glutamine in Patients Undergoing Long-term Treatment for Schizophrenia

Abstract

IMPORTANCE The N-methyl-D-aspartic acid receptor hypofunction model of schizophrenia predicts a paradoxical increase in synaptic glutamate release. In vivo measurement of glutamatergic neurotransmission in humans is challenging, but glutamine, the principal metabolite of synaptic glutamate, can be quantified with proton magnetic resonance spectroscopy (1 H-MRS). Although a few studies have measured glutamate, glutamine, and glutamine to glutamate ratio, it is not clear which of these 1 H-MRS indices of glutamatergic neurotransmission is altered in schizophrenia. OBJECTIVE To examine glutamine, glutamate, and glutamine to glutamate ratio in the dorsal anterior cingulate, as well as their relationships with symptoms and cognition in schizophrenia. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional design using 3-T 1 H-MRS in participants recruited from university-based psychiatric outpatient clinics who underwent neuroimaging at an affiliated research facility. Participants were 84 patients with a DSM-IV-TR diagnosis of schizophrenia and 81 psychiatrically healthy volunteers, matched in age, sex, ethnicity, and occupational level to the head of household of family of origin. MAIN OUTCOMES AND MEASURES Glutamine, glutamate, and glutamine to glutamate ratio. Also symptoms and cognition. RESULTS Glutamine was increased in the schizophrenia group (P = .01) as well as the glutamine to glutamate ratio (P = .007) but not glutamate (P = .89). Glutamine levels were positively correlated with severity of psychotic symptoms (P = .02). Choline was also increased in schizophrenia (P = .002). CONCLUSIONS AND RELEVANCE Elevated glutamine, which was directly related to psychotic symptoms, is consistent with increased glutamatergic synaptic release in schizophrenia, as predicted by the N-methyl-D-aspartic acid receptor hypofunction model. Further understanding the underlying mechanism of glutamatergic dysfunction in schizophrenia may lead to new pharmacological strategies to treat psychosis.

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

“…4 In our study of the dorsal anterior cingulate, we did find higher totalcholine in SP but no differences in total-creatine. 40 Again, the current study is by far the largest to examine these 2 neurometabolites in schizophrenia.…”

“…We previously reported increased glutamine but normal glutamate in the dorsal anterior cingulate. 40 We included 72 medicated SP and 76 HC whom also participated in the present study. Since glutamine involves about one-third to one-fifth of the Glx signal 41 we speculate that our current results of increased Glx may represent primarily elevations in glutamine.…”

“…The relationships with psychosis are not consistent with our previous report of a direct correlation between dorsal cingulate glutamine and positive symptoms. 40 Hence findings with respect to correlations of neurometabolites with positive symptoms need replication.…”

Glutathione and glutamate in schizophrenia: a 7T MRS study

“…These studies provide some evidence of elevated glutamine levels in ACC/mPFC, especially in the early phase of illness. Overall, these studies indicate that glutamate may be unchanged or reduced, especially in more chronic cases, depending on the persistence of symptoms or other factors associated with long-term illness [29][30][31][32][33][34][35][36][37].…”

“…However, glutamate and glutamine each participate in several other distinct cell processes and hence may not be closely coupled [28]. MRS studies of glutamate and glutamine concentrations in schizophrenia have been inconsistent, with some studies reporting an increase, others reporting a decrease or no abnormality ( [29][30][31][32][33][34][35], for reviews see [36,37]). One metaanalysis found that glutamate is reduced and glutamine is increased in the ACC in patients with schizophrenia, and both decrease more markedly with age in patients [38].…”