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

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 ¹H magnetic resonance spectroscopy (¹H-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 ¹H-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.