Glutamate, NAA and Energy Metabolism in Clinical High Risk and First Episode Psychosis

Abstract Regulation of brain glutamate is closely related to brain energy metabolism. Changes in both central glutamatergic function and peripheral energy metabolism have been implicated in psychosis risk, onset and long-term illness, but there is a lack of empirical evidence to link these processes. We investigated the relationships between glutamate and N-acetyl-aspartate (NAA, a potential marker of neuronal metabolic integrity) in the anterior cingulate cortex (ACC), measured using proton magnetic resonance spectroscopy (¹H-MRS), and peripheral markers of energy metabolism (mitochondrial I-V activity, pyruvate and lactate) in individuals either at clinical high risk for psychosis or in the first episode of psychosis (N = 36) and healthy controls (N = 20). ACC Glx (glutamate + glutamine) levels were positively related with principal components relating to mitochondrial complex activity, and this relationship did not differ between groups. These findings are consistent with the importance of mitochondrial ATP generation in regulating glutamatergic neurotransmission. While we did not find evidence that this relationship is disrupted in clinical high risk or first episode psychosis, further work is required to understand the mechanisms linking glutamate and energy metabolism in psychosis, including studies in larger cohorts, later stages of illness or in individuals with greater illness burden.