The Bossong et al study titled “Association of Hippocampal Glutamate Levels With Adverse Outcomes in Individuals at Clinical High Risk for Psychosis”1 represents an important step forward in the study of glutamatergic abnormalities in the pathophysiology of psychotic disorders. To our knowledge, this is the largest study of individuals at clinical high risk to date to use proton magnetic resonance spectroscopy (1H-MRS) and document that those with higher hippocampal glutamate are more likely to transition to psychosis. The hippocampus was selected as the region of interest because hippocampal abnormalities prior to the onset of psychosis have been shown in previous studies that used a variety of measures (ie, hypermetabolism, increased perfusion, reduced gray matter, and altered activation).1 Increased glutamate, as suggested by the N-methyl-d-aspartate hypofunction model of psychosis,2 has been proposed as a plausible common mechanism underlying these other abnormalities because of the tight coupling between neuronal activation, metabolism, blood flood, and structural plasticity. Although a relatively large body of literature has documented increases in glutamate concentrations in schizophrenia3 (as has a more limited body of literature on glutamate concentrations in bipolar disorder4), the specificity to psychotic illness and the association with common confounds (such as long-term disease course and medication effects) have not been completely elucidated. The fact that at-risk participants who subsequently developed psychosis had higher glutamate in the study by Bossong et al1 mitigates the possibility that hippocampal glutamate increments are consequences of psychosis or confounds from antipsychotic exposure. The observation that myo-inositol and creatine were also elevated in the participants in clinical high-risk states who transitioned to psychosis is also intriguing.
Bustillo JR, Gaudiot CE, Lenroot RK. The Meaning of Glutamate and the Quest for Biomarkers in the Transition to Psychosis. JAMA Psychiatry. 2019;76(2):115–116. doi:10.1001/jamapsychiatry.2018.3251
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