Symptomatic and cognitive effects of D-amino acid oxidase inhibitors in patients with schizophrenia: a meta-analysis of double-blind randomized controlled trials

D-amino acid oxidase inhibitors (DAOI) have demonstrated potential therapeutic benefits for schizophrenia and cognitive impairment; however, existing studies present conflicting results. This meta-analysis aimed to assess the symptomatic and cognitive effects of DAOI on the treatment of schizophrenia. An electronic search was conducted using PubMed, Cochrane Systematic Reviews, and the Cochrane Central Register of Controlled Clinical Trials for double-blinded, randomized controlled trials evaluating DAOI for the treatment of schizophrenia. Published trials up to November 2024 were included in the analysis. A random-effects model was employed to pool data for comparing the treatment effects of DAOI. Participants diagnosed with schizophrenia were recruited. Clinical and cognitive improvements were compared between baseline and post-DAOI treatment using standardized mean differences (SMDs) with 95% confidence intervals (CIs). Heterogeneity across the trials was assessed through funnel plots and the I² statistic. A total of five trials with 530 participants met the inclusion criteria. Four trials utilized sodium benzoate, while one trial employed luvadaxistat. The Positive and Negative Syndrome Scale (PANSS) was used in all studies to evaluate clinical symptoms, with four studies also assessed cognitive function. This analysis highlighted that DAOI surpassed the comparator in reducing the scores of PANSS total (SMD = -0.270, P = 0.035), PANSS positive (SMD = -0.399, P = 0.022), PANSS negative (SMD = -0.171, P = 0.026), and PANSS general psychopathology (SMD = -0.180, P = 0.019). Subgroup analyses identified significant effects in trials using sodium benzoate (SMD = 0.368, P = 0.021). Moreover, DAOI showed greater improvements in cognitive functions (SMD = 0.359, P = 0.017), with a better effect correlated with more female participants. The findings of this meta-analysis suggest that DAOI may be effective in improving clinical symptoms and cognitive function in patients with schizophrenia. Further studies with larger sample sizes are needed to confirm these results.