Summary: A randomized, double-blind, placebo-controlled trial found that sodium benzoate, a common food preservative and D-amino acid oxidase inhibitor, improved negative symptoms and overall outcomes for people with schizophrenia who remained symptomatic despite treatment with clozapine.
Source: Elsevier
The common preservative sodium benzoate improves symptoms in clozapine-resistant schizophrenia patients, according to a new clinical trial published in Biological Psychiatry.
This randomized, double-blind, placebo-controlled study, led by Hsien-Yuan Lane, M.D., Ph.D., at China Medical University, Taiwan, examined whether adding sodium benzoate to ongoing clozapine therapy could benefit patients whose symptoms did not respond to clozapine alone. Clozapine is widely regarded as the last-line antipsychotic for treatment-resistant schizophrenia, but 40–70% of patients who are categorized as refractory still fail to improve on clozapine. The trial is the first to demonstrate clinically meaningful benefit of sodium benzoate in patients with clozapine-resistant illness.
Sixty patients with schizophrenia who were stabilized on clozapine were randomized to receive six weeks of add-on treatment with either placebo, 1 gram per day of sodium benzoate, or 2 grams per day of sodium benzoate. The research team, including first author Chieh-Hsin Lin, M.D., Ph.D., evaluated symptoms using standard rating scales, measured quality of life and global functioning, tracked cognitive performance, and monitored side effects.
Compared with placebo, both sodium benzoate doses produced greater improvement in negative symptoms, such as reduced emotional expression and low motivation—symptoms that strongly influence long-term functioning. The 2 g/day dose also produced additional gains in overall symptom severity and quality of life ratings. Cognitive performance did not improve over the six-week period in this trial, although the authors suggest that higher doses or a longer treatment duration might be needed to detect cognitive benefits that have appeared in other studies combining sodium benzoate with different antipsychotics. Importantly, sodium benzoate was well tolerated at the tested doses, with no significant adverse effects reported in the study population.
Mechanistically, sodium benzoate inhibits D-amino acid oxidase, an enzyme that breaks down D-serine. D-serine is a co-agonist at N-methyl-D-aspartate (NMDA) receptors, and NMDA receptor signaling is implicated in the pathophysiology of schizophrenia. By preventing D-serine breakdown, sodium benzoate may enhance NMDA receptor function and thereby help normalize disrupted brain circuits. John Krystal, M.D., Editor of Biological Psychiatry, noted that sodium benzoate offers a tangible way to influence a long-studied molecular target in schizophrenia treatment.
The authors emphasize that while the trial provides encouraging evidence for sodium benzoate as an adjuvant to clozapine, additional research is needed to determine optimal dosing, treatment duration, and the precise biological mechanisms underlying the clinical effects. Larger and longer trials will help define whether benefits extend to cognitive outcomes and whether specific patient subgroups derive the greatest advantage.
Source: Rhiannon Bugno, Elsevier
Publisher note: Organized by NeuroscienceNews.com (original press release summary)
Image source: Public domain
Original research: Abstract published in Biological Psychiatry (2018). DOI: 10.1016/j.biopsych.2017.12.006
Abstract
Sodium Benzoate, a D-Amino Acid Oxidase Inhibitor, Added to Clozapine for the Treatment of Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled Trial
Background
Clozapine is the last-line antipsychotic for refractory schizophrenia, yet many patients remain symptomatic despite clozapine. Activation of NMDA receptors and inhibition of D-amino acid oxidase, which metabolizes D-amino acids such as D-serine, have shown benefit in schizophrenia when combined with antipsychotics other than clozapine. This trial evaluated the efficacy and safety of sodium benzoate, a D-amino acid oxidase inhibitor, as add-on therapy for patients with poor response to clozapine.
Methods
A randomized, double-blind, placebo-controlled design enrolled 60 inpatients with schizophrenia stabilized on clozapine. Participants received 6 weeks of add-on treatment with either 1 g/day sodium benzoate, 2 g/day sodium benzoate, or placebo. Primary outcomes included the Positive and Negative Syndrome Scale (PANSS) total score, the Scale for the Assessment of Negative Symptoms, the Quality of Life Scale, and Global Assessment of Functioning. Side effects and cognitive function were also assessed.
Results
Both sodium benzoate doses showed greater improvement than placebo on the Scale for the Assessment of Negative Symptoms. The 2 g/day dose also improved PANSS total score, PANSS positive symptom score, and Quality of Life Scale ratings compared with placebo. Sodium benzoate was well tolerated with no obvious side effects. Changes in catalase activity, an antioxidant marker, differed across groups and correlated with clinical improvement in the sodium benzoate-treated patients.
Conclusions
Add-on sodium benzoate improved symptoms in patients with clozapine-resistant schizophrenia. Further studies should determine the optimal dose and treatment duration and clarify the mechanisms by which sodium benzoate augments clozapine therapy.