Glutamate in schizophrenia: a focused review and meta-analysis of ¹H-MRS studies

Abstract

Schizophrenia is a severe chronic psychiatric illness, characterized by hallucinations and delusions. Decreased brain volumes have been observed in the disease, although the origin of these changes is unknown. Changes in the n-methyl-d-aspartate (NMDA)-receptor mediated glutamatergic neurotransmission are implicated, since it is hypothesized that NMDA-receptor dysfunction in schizophrenia leads to increased glutamate release, which can have excitotoxic effects. However, the magnitude and extent of changes in glutamatergic metabolites in schizophrenia are not clear. With (1)H magnetic resonance spectroscopy ((1)H-MRS), in vivo information about glutamate and glutamine concentrations can be obtained in the brain. A systematic search through the MEDLINE database was conducted to identify relevant (1)H-MRS studies that examined differences in glutamate and glutamine concentrations between patients with schizophrenia and healthy control subjects. Twenty-eight studies were identified and included a total of 647 patients with schizophrenia and 608 healthy-control subjects. For each study, Cohen's d was calculated and main effects for group analyses were performed using the random-effects model. Medial frontal region glutamate was decreased and glutamine was increased in patients with schizophrenia as compared with healthy individuals. Group-by-age associations revealed that in patients with schizophrenia, glutamate and glutamine concentrations decreased at a faster rate with age as compared with healthy controls. This could reflect aberrant processes in schizophrenia, such as altered synaptic activity, changed glutamate receptor functioning, abnormal glutamine-glutamate cycling, or dysfunctional glutamate transport.

Fig. 1.

The glutamatergic synapse. Glutamate is an amino acid, a building block for proteins, therefore, it is abundant in all cells of the body. It is also the most important excitatory neurotransmitter in the central nervous system. Glutamate is synthesized in axon terminals of glutamatergic neurons. It can be produced from α-ketoglutarate -a tricarboxylic acid (TCA)-cycle intermediate- or from glutamine. For glutamate synthesis from glutamine, the enzyme glutamine synthase is transported to the axon terminal. In the cytosol, it converts glutamine into glutamate. Transporters then concentrate glutamate in vesicles. Release of glutamate is triggered by influx of calcium (Ca²⁺) into the presynaptic neuron. The synaptic vesicles fuse with the cell membrane and release glutamate into the synaptic cleft. Glutamate is taken up by the postsynaptic neuron, by glia, or it is recycled in the presynaptic neuron.

Fig. 2.

(A). Meta-analysis on frontal region glutamate. Displayed are the Cohen's d and 95% CI per study. The size of the circles is proportional to the study’s weight in the meta-analysis. Studies are ordered according to mean age of the patient group, from young to old. Data were recorded from the following anatomical regions: anterior cingulate cortex (Stone et al, Théberge et al, Bustillo et al, Öngür et al41), medial prefrontal cortex (Bartha et al, Lutkenhoff et al, Shirayama et al46). The combined Cohen's d is −0.391 (P = .006). (B). Meta-regression of age of patients on effect size in frontal region glutamate. Each circle represents one study; the size of the circles is proportional to the study’s weight in the meta-regression. (Slope, −0.04; SE of the slope, 0.015; P = .008).

Fig. 3.

(A) Meta-analysis of frontal region glutamine. Displayed are the Cohen's d and 95% CI per study. The size of the circles is proportional to the study’s weight in the meta-analysis. Studies are ordered according to mean age of the patient group, from young to old. Data were recorded from the following anatomical regions: anterior cingulate cortex (Stone et al; Théberge et al; Bustillo et al; Öngür et al41), medial prefrontal cortex (Bartha et al; Shirayama et al46). The combined Cohen’s d is 0.403 (P = .045). B. Meta-regression of age of patients on effect size in frontal region glutamine. Each circle represents one study; the size of the circles is proportional to the study’s weight in the meta-regression. (Slope, –0.1; SE of the slope, 0.02; P = .0005).