Impact of D-Amino Acids in Schizophrenia

Most amino acids contain a chiral center and thus, can exist as L- and D-isomers. For many years, it was thought that only the L-isomers were present in mammals. However, in recent decades it has been demonstrated that D-isomers are also present. Three of these amino acids, namely D-serine, D-aspartate, and D-alanine, have been proposed to play a role in the etiology of schizophrenia via interactions with glutamate receptors. D-Serine and D-alanine act at the glycine modulatory site on the NMDA receptor, while D-aspartate acts at the glutamate site on the same receptor. D-aspartate also acts on the mGlu5 receptor and can stimulate glutamate release presynaptically. Preclinical studies have reported that manipulations to reduce brain levels of D-serine, D-aspartate, or D-alanine lead to schizophrenia-relevant behaviors, and clinical studies have reported reduced levels of these D-amino acids in the brain tissue (postmortem) and/or body fluids from schizophrenia patients compared to those noted in controls, although there are some contradictory findings. The possible use of these amino acids and/or the manipulation of their relevant enzymes in the treatment of schizophrenia are described. D-Cysteine has been identified recently in human brain tissue, with the highest values in white matter; demonstration of its involvement in brain development has led to speculation that it could be involved in the etiology of schizophrenia, identifying it as a potential therapy in combination with antipsychotics. Future directions and potential problems that should be considered in studies on D-amino acids and their relevant enzymes in schizophrenia are discussed.