The common food preservative sodium benzoate improves symptoms in clozapine-resistant schizophrenia patients, according to a Taiwanese study. The randomised, double-blind, placebo-controlled trial led by Dr Hsien-Yuan Lane, of China Medical University, Taiwan, showed that adding on sodium benzoate to the anti-psychotic clozapine improved symptoms in patients who did not see results with any other medications, providing a new option for the hardest-to-treat patients.
“Clozapine is considered the last-line anti-psychotic agent for patients with refractory schizophrenia,” said Lane, referring to patients whose symptoms do not respond to available anti-psychotics. But an estimated 40%-70% of patients with refractory schizophrenia fail to improve even with clozapine, referred to as “clozapine-resistant,” exhausting all potential options for treatment. The new study is the first to demonstrate that sodium benzoate-which has been shown to enhance other anti-psychotic drugs-works in clozapine-resistant patients.
“If the finding can be confirmed, this approach may bring hope for treating patients with the most refractory schizophrenia,” said Lane.
The 60 patients with schizophrenia included in the study were all taking clozapine, and received a placebo or sodium benzoate as an add-on treatment for six weeks. First author Dr Chieh-Hsin Lin, of Chang Gung University College of Medicine, Taiwan, and colleagues tested two different doses of sodium benzoate (1g or 2g per day) to find which offered the biggest impact on symptoms with minimal side effects.
Compared with the placebo, sodium benzoate improved negative symptoms, such as lack of emotion and motivation, which have a greater influence on a patient’s functional outcome than the more prominent psychotic symptoms. The higher dose of sodium benzoate also improved ratings of overall symptoms and quality of life.
Although sodium benzoate has improved cognitive function when combined with other antipsychotics in previous studies, the add-on treatment had no influence on cognitive function in this study-in the paper, Lin and colleagues suggest that a higher dose or longer duration of treatment may be needed for these effects. Importantly, the patients taking sodium benzoate had no side effects, confirming the treatment is safe to use at the doses tested.
Sodium benzoate works by preventing the breakdown of D-serine, a brain chemical that plays an important role in signalling that is disrupted in the brains of people with schizophrenia. “Receptors for D-serine are long-standing targets for medication development in schizophrenia and sodium benzoate is probably the first meaningful tool that we have had to influence this target,” said Dr John Krystal. Although more studies are needed to learn how sodium benzoate enhances clozapine treatment in these patients, Krystal says that “this study highlights the importance for schizophrenia treatment of understanding the molecular switches that can be thrown to normalise brain circuit function.”
Background: Clozapine is the last-line antipsychotic agent for refractory schizophrenia. To date, there is no convincing evidence for augmentation on clozapine. Activation of N-methyl-D-aspartate receptors, including inhibition of D-amino acid oxidase that may metabolize D-amino acids, has been reported to be beneficial for patients receiving antipsychotics other than clozapine. This study aimed to examine the efficacy and safety of a D-amino acid oxidase inhibitor, sodium benzoate, for schizophrenia patients who had poor response to clozapine.
Methods: We conducted a randomized, double-blind, placebo-controlled trial. Sixty schizophrenia inpatients that had been stabilized with clozapine were allocated into three groups for 6 weeks’ add-on treatment of 1 g/day sodium benzoate, 2 g/day sodium benzoate, or placebo. The primary outcome measures were Positive and Negative Syndrome Scale (PANSS) total score, Scale for the Assessment of Negative Symptoms, Quality of Life Scale, and Global Assessment of Functioning. Side effects and cognitive functions were also measured.
Results: Both doses of sodium benzoate produced better improvement than placebo in the Scale for the Assessment of Negative Symptoms. The 2 g/day sodium benzoate also produced better improvement than placebo in PANSS-total score, PANSS-positive score, and Quality of Life Scale. Sodium benzoate was well tolerated without evident side effects. The changes of catalase, an antioxidant, were different among the three groups and correlated with the improvement of PANSS-total score and PANSS-positive score in the sodium benzoate group.
Conclusions: Sodium benzoate adjuvant therapy improved symptomatology of patients with clozapine-resistant schizophrenia. Further studies are warranted to elucidate the optimal dose and treatment duration as well as the mechanisms of sodium benzoate for clozapine-resistant schizophrenia.
Chieh-Hsin Lin, Ching-Hua Lin, Yue-Cune Chang, Yu-Jhen Huang, Po-Wei Chen, Hui-Ting Yang, Hsien-Yuan Lane