Accumulating evidence implicates that individuals at high-risk of psychosis have already exhibited pathophysiological changes in brain metabolites including glutamate, gamma-Aminobutyric Acid (GABA), N-Acetylaspartate (NAA), creatine (Cr), myo-inositol (MI) and choline (Cho). These changes may contribute to the development of schizophrenia and associate with psychotic genes. However, specific metabolic changes of brain sub-regions in individuals at risk have still been controversial. Thus, the current study aimed to investigate the brain metabolic changes including glutamate, Glx, GABA, GABA/Glx, NAA, Cr, MI and Cho levels in individuals at risk by conducting a case-control meta-analysis and meta-regression of proton magnetic resonance spectroscopy studies. Primary outcomes revealed that individuals at risk exhibited increased Cr levels at the rostral medial prefrontal cortex (rmPFC), decreased NAA and Cr levels at the thalamus, and increased MI levels at the dorsolateral prefrontal cortex. Sub-group analyses further indicated that individuals with clinical high-risk (CHR) exhibited increased Cr levels at the medial prefrontal cortex (mPFC) and decreased Glx levels at the thalamus, while individuals with genetic risk (siblings of psychiatric patients) exhibited significant increased Glx and MI levels at the mPFC. However, GABA, GABA/Glx and Cho levels showed no significant result. These findings suggest that the dysfunctional metabolites at the mPFC and the thalamus may be an essential neurobiological basis at the early stage of psychosis.
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