Abstract
The glutamate hypothesis of schizophrenia, proposed over two decades ago, originated following the observation that administration of drugs that block NMDA glutamate receptors, such as ketamine, could induce schizophrenia-like symptoms. Since then, this hypothesis has been extended to describe how glutamate abnormalities may disturb brain function and underpin psychotic symptoms and cognitive impairments. The glutamatergic system is now a major focus for the development of new compounds in schizophrenia. Relationships between regional brain glutamate function and symptom severity can be investigated using proton magnetic resonance spectroscopy (1H-MRS) to estimate levels of glutamatergic metabolites in vivo. Here we briefly review the 1H-MRS studies that have explored relationships between glutamatergic metabolites, symptoms, and cognitive function in clinical samples. While some of these studies suggest that more severe symptoms may be associated with elevated glutamatergic function in the anterior cingulate, studies in larger patient samples selected on the basis of symptom severity are required.
Highlights
Accumulating evidence suggests that glutamatergic dysfunction may contribute to the pathogenesis of schizophrenia, and the symptoms and cognitive deficits associated with the disorder (1)
Relationships between glutamate levels and symptom severity may be indirect; for example Stone et al showed that hippocampal glutamate may interact with striatal dopamine to determine risk of psychosis (61), and a path analysis has suggested that negative symptoms may be secondary to poor cognition associated with low brain Glx (43)
A recent study showed that elevated frontal Glx at baseline was associated with poor response after 4 weeks of antipsychotic treatment (62)
Summary
Accumulating evidence suggests that glutamatergic dysfunction may contribute to the pathogenesis of schizophrenia, and the symptoms and cognitive deficits associated with the disorder (1). In order to better understand the possible relationships between 1H-MRS glutamate, glutamine, and Glx levels and symptom severity, we identified publications that have reported associations with severity along symptom domains These included studies in individuals at risk of psychosis, and patients with first-episode psychosis or established schizophrenia (Table 1). In brain regions other than the ACC many studies have failed to detect significant relationships between negative symptoms and regional glutamate, glutamine, or Glx levels in high genetic or clinical risk groups (36, 37), first-episode psychosis (18, 37, 39, 40), or chronic schizophrenia (27, 30, 31, 41, 44, 45, 48). Yoo et al (36) de la Fuente-Sandoval et al (37) de la Fuente-Sandoval et al (47) Egerton et al (38)
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