Targeting d-Amino Acid Oxidase (DAAO) for the Treatment of Schizophrenia: Rationale and Current Status of Research

In the brain, d-amino acid oxidase (DAAO) is a peroxisomal flavoenzyme. Through oxidative deamination by DAAO, d-serine, the main coagonist of synaptic N-methyl-d-aspartate receptors (NMDARs), is degraded into alpha-keto acids and ammonia; flavin adenine dinucleotide (FAD) is simultaneously reduced to dihydroflavine-adenine dinucleotide (FADH2), which is subsequently reoxidized to FAD, with hydrogen peroxide produced as a byproduct. NMDAR hypofunction is implicated in the pathogenesis of schizophrenia. In previous studies, compared with control subjects, patients with schizophrenia had lower d-serine levels in peripheral blood and cerebrospinal fluid but higher DAAO expression and activity in the brain. Inhibiting DAAO activity and slowing d-serine degradation by using DAAO inhibitors to enhance NMDAR function may be a new strategy for use in the treatment of schizophrenia. The aim of this leading article is to review the current research in DAAO inhibitors.