Variations of blood D-serine and D-aspartate homeostasis track psychosis stages

Schizophrenia (SCZ) is a severe psychotic disorder characterized by a disruption in glutamatergic NMDA receptor (NMDAR)-mediated neurotransmission. Compelling evidence has revealed that NMDAR activation is not limited to L-glutamate, L-aspartate, and glycine since other free amino acids (AAs) in the atypical D-configuration, such as D-aspartate and D-serine, also modulate this class of glutamatergic receptors. Although dysregulation of AAs modulating NMDARs has been previously reported in SCZ, it remains unclear whether distinct variations of these biomolecules occur during illness progression from at-risk premorbid to clinically manifest stage. To probe this issue, we used High-Performance Liquid Chromatography (HPLC) to measure serum levels of D- and L-AAs that stimulate NMDARs across four groups of individuals diagnosed with (a) At-Risk Mental State (ARMS) for psychosis, (b) First Episode of Psychosis (FEP), (c) full-blown SCZ and (d) Healthy Donors (HD). We examined how diagnosis, demographic features, and antipsychotic treatment influence the variation of AA levels throughout psychosis progression. Finally, we explored the potential association between AA blood concentrations and clinical and cognitive measures related to psychosis. Our findings identified inter-group differences in serum AA composition, highlighting that the upregulation of D-serine/total serine and D-aspartate/total aspartate ratios represent a peculiar blood biochemical signature of early stages of psychosis progression, while increased L-glutamate, L-aspartate and glycine associate with chronic SCZ diagnosis. The present findings provide direct evidence for early dysregulation of D-AA metabolism and have potential implications for the identification of biomarkers for the early detection and staging of psychosis.