In recent years, the pursuit of novel treatments for schizophrenia has increasingly focused on targeting the glutamatergic system, particularly the function of N-methyl-D-aspartate (NMDA) receptors. A groundbreaking meta-analysis published in Schizophrenia journal offers compelling evidence that inhibitors of D-amino acid oxidase (DAOI) may represent a promising modality not only for alleviating the clinical symptoms of schizophrenia but also for enhancing cognitive function—a critical domain often resistant to conventional antipsychotic medications.
This comprehensive meta-analysis synthesized data from five double-blind randomized controlled trials, encompassing a total of 530 participants diagnosed with schizophrenia. Two classes of DAO inhibitors were evaluated: sodium benzoate, a compound historically recognized for its enzymatic inhibitory properties, and luvadaxistat, a newer, highly selective DAAO inhibitor. The analysis underscores significant improvements across multiple symptom domains, including positive symptoms, negative symptoms, general psychopathology, and cognitive deficits, particularly in trials involving sodium benzoate.
The earlier landscape, marked by more limited investigations predominantly involving sodium benzoate, suggested some efficacy confined mainly to positive symptoms without consistent cognitive benefits. However, the expanded scope of this meta-analysis reveals that incorporating data from the newer trials, including those examining luvadaxistat, broadens the apparent therapeutic profile of DAO inhibition. Notably, sodium benzoate consistently demonstrated superior effects relative to placebo in improving overall clinical symptomatology and cognition, whereas luvadaxistat’s results were less pronounced and lacked statistical significance, although promising trends were observed.
One of the principal challenges identified within the meta-analysis stems from the heterogeneity among included studies in terms of medication type, participant demographics such as age, baseline illness severity, and treatment durations ranging from six to twelve weeks. Such variability undoubtedly complicates the consolidation of findings and underscores the critical need for further subgroup analyses and meta-regression approaches. Indeed, subgroup analysis indicated that sodium benzoate’s benefits were more robust than those seen with luvadaxistat, potentially due to differing mechanistic pathways beyond simple DAAO inhibition, including modulation of immune responses and oxidative stress pathways.
The mechanistic underpinnings of sodium benzoate’s clinical effect merit particular attention. Its role as a DAAO inhibitor leads to an increase in endogenous D-amino acids like D-serine, key co-agonists at the NMDA receptor, thus potentially reversing NMDA receptor hypofunction—a well-established pathophysiological theory in schizophrenia. Moreover, sodium benzoate appears to exert immunoregulatory effects, influencing inflammatory cascades that have been increasingly implicated in the neurobiology of schizophrenia. Its antioxidant capacity, manifested by modulation of enzymes like catalase, suggests further neuroprotective potential through mitigation of oxidative stress, a known contributor to neuroinflammation and neuronal dysfunction in schizophrenia.
Conversely, luvadaxistat, despite greater enzymatic selectivity, has yet to demonstrate consistent benefits across symptom domains. The reasons for this disparity remain unclear but may relate to its limited influence on immune or oxidative pathways, or possibly differences in pharmacodynamics and pharmacokinetics. This raises intriguing questions about whether the clinical efficacy of DAOIs depends on a multifaceted mode of action beyond DAAO inhibition alone—a hypothesis that warrants rigorous exploration in future clinical and preclinical studies.
Age also emerged as a variable of interest, with subgroup analyses suggesting that patients aged between 40 and 49 experienced more pronounced clinical improvement with DAOI treatment, compared to younger cohorts where benefits were less evident. However, this observation was not corroborated by meta-regression analyses, indicating the current evidence base is insufficiently powered to draw definitive conclusions. Similarly, baseline disease severity and treatment duration exhibited inconsistent associations with therapeutic response, though shorter six-week treatment periods appeared more favorable in some analyses.
From a cognitive perspective, the results are particularly noteworthy. Sodium benzoate demonstrated superiority over placebo in enhancing cognitive functioning across multiple trials, while luvadaxistat showed only nonsignificant trends. These findings are compelling against the backdrop of previous meta-analyses that largely failed to demonstrate cognitive benefits from various NMDA receptor–targeting agents, positioning DAO inhibition as a potentially viable avenue for addressing one of schizophrenia’s most intractable challenges—cognitive impairment.
Gender differences represent another intriguing dimension revealed by this study. A higher proportion of female patients correlated with greater cognitive improvement following DAOI treatment. This aligns with prior research suggesting that women with schizophrenia may exhibit more favorable cognitive outcomes during the illness course and may respond better to NMDA receptor–modulating agents. Biological or hormonal factors likely underpin these effects, prompting calls for gender-stratified investigations to elucidate mechanisms and optimize personalized treatment approaches.
Despite these encouraging signals, the meta-analysis authors appropriately caution that many results derive from a limited number of studies and relatively small sample sizes, which constrain interpretability and generalization. The diversity in trial designs, concomitant medications, and short durations further underscore the need for large-scale, well-powered clinical trials with longer follow-up to assess sustained clinical and cognitive outcomes and to understand safety profiles, especially given the adjunctive nature of the interventions evaluated to date.
The biological rationale for targeting DAO in schizophrenia treatment is firmly grounded in the well-documented NMDA receptor hypofunction hypothesis. Reduced levels of endogenous NMDA co-agonists such as D-serine have been consistently reported in schizophrenia, implicating dysregulated amino acid metabolism as a critical pathological mechanism. Intriguingly, DAO enzyme expression is regionally variable in the brain, with lower levels in forebrain regions implicated in schizophrenia symptomatology compared to the cerebellum. This spatial distribution may influence therapeutic response and informs strategies for drug targeting.
Emerging preclinical studies advocate for combination therapies that pair DAO inhibition with D-serine supplementation, hypothesizing synergistic effects given that DAO degrades D-serine. Such combinations could theoretically amplify NMDA receptor activation more effectively than single agents alone. Clinical trials leveraging this paradigm may open new frontiers in schizophrenia therapeutics, as clinicians increasingly seek to move beyond dopaminergic antagonism towards more nuanced modulation of glutamatergic neurotransmission and neuroinflammation.
The current meta-analysis also highlights important limitations inherent in DAOI research. Chief among these is the short duration of most clinical trials, typically not exceeding 12 weeks, leaving the long-term cognitive and symptomatic effects unclear. Moreover, all studies to date have examined DAOIs as adjuncts to existing antipsychotic regimens, thereby introducing confounding medication effects and leaving the efficacy of DAOIs as monotherapy unexplored. Addressing these gaps will require methodologically rigorous trials with diverse study designs, extended follow-up, and holistic assessments including adverse event monitoring.
Taken as a whole, the mounting evidence positions DAO inhibition as a compelling therapeutic target in schizophrenia, with a capacity to improve both the cardinal clinical symptoms and the persistent cognitive dysfunction that undermines patients’ quality of life. Sodium benzoate, with its multifactorial mechanistic profile, currently stands as the most promising candidate, while luvadaxistat’s therapeutic potential remains to be fully determined. The nuanced interplay of biological, demographic, and treatment-related variables demands a precision medicine approach, integrating neurobiological insights with clinical trials designed to unravel the complex pathophysiology at the heart of schizophrenia.
In the broader context of psychiatric pharmacotherapy, these findings reinforce the importance of re-examining legacy compounds like sodium benzoate within a modern neuroscientific framework, as well as the need for innovative drug discovery targeting previously overlooked enzymatic pathways. Furthermore, the observed gender differences and age-related variations call for tailored interventions and highlight the crucial role of personalized medicine in future psychiatric care.
As the field progresses, it is imperative to expand the evidence base through larger, longer-term, and more diverse studies that can confirm and extend these findings. Only through such concerted efforts can DAO inhibition be validated as a novel and effective approach for treating both symptomatology and cognitive deficits in schizophrenia, ultimately transforming the therapeutic landscape and improving outcomes for millions worldwide afflicted by this debilitating disorder.
Subject of Research: Therapeutic effects of D-amino acid oxidase inhibitors (DAOIs) on clinical symptoms and cognitive function in patients with schizophrenia.
Article Title: Symptomatic and cognitive effects of D-amino acid oxidase inhibitors in patients with schizophrenia: a meta-analysis of double-blind randomized controlled trials.
Article References:
Chang, CH., Hsia, YD., Liu, WC. et al. Symptomatic and cognitive effects of D-amino acid oxidase inhibitors in patients with schizophrenia: a meta-analysis of double-blind randomized controlled trials. Schizophr 11, 73 (2025). https://doi.org/10.1038/s41537-025-00604-2
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