A meta-analysis of ultra-high field glutamate, glutamine, GABA and glutathione 1HMRS in psychosis: Implications for studies of psychosis risk.

Ultra-high field proton magnetic resonance spectroscopy (HMRS) offers a unique opportunity to measure the concentration of neurometabolites implicated in psychosis (PSY). The extant 7 T HMRS literature measuring glutamate-associated neurometabolites in the brain in PSY in vivo is small, but a comprehensive, quantitative summary of these data can offer insight and guidance to this emerging field. This meta-analysis examines proton spectroscopy (HMRS) measures of glutamate (Glu), glutamine (Gln), glutamate+glutamine (Glx), gamma aminobutyric acid (GABA), and glutathione (GSH) across 255 individuals with PSY (121 first episode) and 293 healthy comparison participants (HC). While all five neurometabolites were lower in PSY as compared to HC, only Glu (Cohen's d = -0.18) and GSH (Cohen's d = -0.21) concentrations were significantly lower in PSY, whereas concentrations of Gln, Glx, and GABA did not significantly differ between groups. Notably, HMRS methodological choices and sample demographic characteristics did not impact study-specific effect sizes for PSY-related Glu or GSH differences. This review thus provides further evidence of neurometabolite dysfunction in first episode and chronic PSY, and thereby suggests that Glu and GSH abnormalities may additionally play a role in more incipient stages of the disorder: in clinical high risk stages. Additional 7 T neurochemical imaging studies in larger, longitudinal, and unmedicated samples and in youth at risk for developing psychosis are needed. Such studies will be critical for elucidating the neurodevelopmental and clinical time course of PSY-related neurometabolite alterations, and for assessing the potential for implicated metabolites to serve as druggable targets for decreasing PSY risk.