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Original Investigation |

Increased Glutamine in Patients Undergoing Long-term Treatment for Schizophrenia :  A Proton Magnetic Resonance Spectroscopy Study at 3 T

Juan R. Bustillo, MD1,2; Hongji Chen, MS1; Thomas Jones, MS1; Nicholas Lemke, MS1; Christopher Abbott, MD1; Clifford Qualls, PhD3; Jose Canive, MD1,2,4; Charles Gasparovic, PhD5
[+] Author Affiliations
1Department of Psychiatry, University of New Mexico, Albuquerque
2Department of Neurosciences, University of New Mexico, Albuquerque
3Department of Mathematics and Statistics, University of New Mexico, Albuquerque
4Veterans Administration Health Care System, Albuquerque, New Mexico
5Mind Research Network, Albuquerque, New Mexico
JAMA Psychiatry. 2014;71(3):265-272. doi:10.1001/jamapsychiatry.2013.3939.
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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 (1H-MRS). Although a few studies have measured glutamate, glutamine, and glutamine to glutamate ratio, it is not clear which of these 1H-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 1H-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.

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Figure 1.
Representative Voxel Placement and Fitted Spectra

A, Voxel location in the anterior dorsal cingulate cortex. B, Example of 1 fitted spectra (red line). Peak areas for glutamine (Gln), glutamate (Glu), N-acetylaspartate compounds (NAAc), total creatine (Cre), myo-inositol (Ins), and choline (Cho) are labeled. Top irregular line represents the residual signal after fitting. Lower continuous line represents the baseline used for fitting with LCModel.

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Figure 2.
Group Differences in Neurometabolites

Glutamine (Gln), glutamate (Glu), and glutamine to glutamate ratio differences between patients with schizophrenia and healthy controls in the anterior dorsal cingulate: F1,145 = 6.14, P = .01; F1,162 = 0.02, P = .99; and F1,145 = 7.61, P = .007, respectively. (Removal of the most extreme values for glutamine [>9] does not significantly change the results [P = .02]).

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Figure 3.
Relationship Between Anterior Dorsal Cingulate Glutamine and Positive Symptoms in the Schizophrenia Group (F1,61 = 6.07; P = .02) in Multiple Regression Accounting for Negative Symptoms and Antipsychotic Dose
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Figure 4.
Relationship Between Anterior Dorsal Cingulate Glutamate and Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Overall Total Score for Patients With Schizophrenia and Healthy Controls (F1,155 = 4.31; P = .04)
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