The enzymes involved in its formation and catabolism are serine racemase (SR) and D-amino acid oxidase (DAAO), respectively, and manipulations of the activity of those enzymes have been useful in developing animal models of schizophrenia and in providing clues to the development of potential new antipsychotic strategies.
A recent randomized, double-blind, placebo-controlled clinical trial found that add-on sodium benzoate, a DAAO inhibitor, improved the clinical symptoms in patients with clozapine-resistant schizophrenia, possibly through DAAO inhibition (and thereby NMDAR activation) and antioxidation as well; additionally, sodium benzoate showed no obvious side effects, indicating the treatment is safe at the doses up to 2 g per day for 6 weeks.
In addition, the validation of DAAO inhibition therapy in alleviating the symptoms of schizophrenia requires further studies on the efficacy of DAAO inhibitors in behavioral assays of animals and on the species differences in D-serine metabolism.
d-Amino acid oxidase (DAAO) is a potential target in the treatment of schizophrenia as its inhibition increases brain d-serine level and thus contributes to NMDA receptor activation.
Therefore, we aimed to evaluate whether glutamatergic variants such as d-amino acid oxidase (<i>DAO</i>), DAO activator (<i>DAOA</i>)/<i>G72</i>, and neuregulin 1 (<i>NRG1</i>) single-nucleotide polymorphisms (SNPs) and their mRNA levels predicted (i) transition to schizophrenia spectrum disorders and (ii) research domain criteria (RDoC) domains, mainly negative valence and cognitive systems.
Dysregulation of D-serine metabolism due to an altered DAAO functionality is related to pathological NMDARs dysfunctions such as in amyotrophic lateral sclerosis and schizophrenia.
There were significantly lower mean serum levels of d-Ser and SR and significantly higher mean serum levels of DAAO (<i>P</i>-value <0.01 for each) among schizophrenia patients when compared with the control group.
These results provide additional evidence and indicate that the DAOA gene and DAOA-DAO gene-gene interactions might play a role for schizophrenia in a Taiwanese sample.
The glutamate hypothesis of schizophrenia has proposed that increased DAO activity leads to decreased D-serine, which subsequently may lead to N-methyl-D-aspartate (NMDA) receptor hypofunction.
Our data and methods may be useful in understanding the effects of sodium benzoate that have been seen in clinical trials of schizophrenia and Alzheimer's disease and to support the potential clinical assessment of other DAO inhibitors, such as PGM030756, which demonstrate good enzyme occupancy and D-serine increases following administration of low oral doses.
This region has been of significant interest to psychiatric genetics as it contains the Darier's disease locus and other proposed susceptibility genes (e.g., DAO, NOS1), and it has been linked to affective disorders and schizophrenia in multiple populations.
Between-gene interactions including DAO*DISC1 , DAO*NRG1 and DAO*RASD2 and a within-gene interaction for CACNG2 were found among schizophrenia subjects with severe sustained attention deficits, suggesting a modifying effect of impaired neuropsychological functioning.
The aim of this study was therefore to examine the impact of G72 rs746187 and DAAOrs2111902 genotypes on brain function in schizophrenia, bipolar disorder and healthy volunteers.
Our findings suggest an influence of the gene in the neural substrate mediating sensorimotor gating and working memory, especially when combined with high anxiety and further validate DAO as a candidate gene for schizophrenia and spectrum disorders.
We tested the hypothesis that a variation in DAAO genotype would be associated with altered prefrontal function and altered functional connectivity in schizophrenia and bipolar disorder.
These results raise doubt on the use of the rat as a model system for testing new drugs against schizophrenia and indicate a different physiological function of DAAO in rodents and humans.
One such susceptibility gene encoding D-amino acid oxidase (DAO), an enzyme that metabolizes the NMDA receptor (NMDAR) co-agonist D-serine, has the potential to modulate NMDAR function in the context of schizophrenia.
This review also highlights issues that have a broader relevance beyond DAO itself: how should we weigh up convergent and cumulatively impressive, but individually inconclusive, pieces of evidence regarding the role that a given gene may have in the aetiology, pathophysiology and pharmacotherapy of schizophrenia?