Food Preservative for Early Psychosis:
Final Word?

Batya Swift Yasgur, MA, LSW

November 18, 2020

Adjunctive use of sodium benzoate (BZ), a common food preservative that has previously shown promise in the treatment of chronic refractory psychosis, appears to be ineffective in the early stages of the disorder, new research suggests.

Results of a randomized control trial show the agent was no more effective than placebo in reducing early psychosis symptoms, although it was safe and well tolerated.

"Both groups of patients improved over the 12 weeks of the study, [suggesting] that most people with early psychosis will get well with antipsychotic medication and psychosocial interventions and adding sodium benzoate to their treatment does not add any additional benefits," the study's lead author, James Scott, MBBS, PhD, head of mental health research, QIMR Berghofer Medical Research Institute, Herston, Australia, told Medscape Medical News.

The paper was published online November 10 in JAMA Network Open.

Positive Outcomes in Chronic Disease

Despite treatment with antipsychotics, many patients with psychosis experience persistent impairment, the investigators note.

Most antipsychotics are dopaminergic in action, but it is now recognized that the pathophysiology underlying psychosis extends beyond dopaminergic dysregulation with hypofunction of the N-methyl-D-aspartate (NMDA) receptors also implicated but not addressed by standard antipsychotics, they add.

NMDA receptors consist of two main subunits – the glutamate and glycine-binding sites. D-amino acids (DAAs) are agonists of the glycine subunit and have shown promise as adjunctive therapies for the treatment of schizophrenia, the investigators note.  

DAAs are subject to oxidation by the flavoenzyme D-amino acid oxidase (DAAO). The oxidation limits their bioavailability and can cause nephrotoxic side effects. The food preservative BZ, which is not related to the benzodiazepine class of medications, inhibits DAAO and therefore may make DAAs safer and more effective.

Scott noted that two previous trials of BZ — a 2013 study and a 2017 investigation — in chronic, treatment-refractory schizophrenia have "reported excellent outcomes with significant improvement in clinical symptoms."

"We saw that sodium benzoate was a safe and well-tolerated agent and we thought it was important to conduct a trial of this medication in people in the early stages of psychotic illness," he said.

To investigate, the researchers randomly assigned 100 individuals who were experiencing early psychosis, which was defined as illness onset within the last 2 years, to receive either 500 mg of BZ twice daily or placebo for 12 weeks.

Participants (mean [SD] age 21.4 [4.1] years, 73% male) were required to be taking antipsychotic medications for at least 1 continuous month during the previous 2 years and to be free of comorbid physical illnesses requiring additional treatment or hospitalization.

Most participants (84%) had schizophrenia and the remainder had affective psychoses. Most participants (88%) lived independently.

The BZ and the placebo groups were similar with respect to baseline characteristics, except that the mean waist circumference was higher in the placebo group than in the BZ group.

The majority of patients were being treated with antipsychotics alone (83%), followed by antipsychotics in combination with mood stabilizers (13%) and a small number were taking mood stabilizers alone (4%). The most commonly used antipsychotics were olanzapine and aripiprazole.

Not Recommended

Psychosis was confirmed using the Positive and Negative Syndrome Scale (PANSS) and the inclusion criteria was a baseline score of ≥ 55. Secondary outcomes were scores on the Hamilton Depression Rating Scale, the clinician-rated Global Assessment of Function, and the Assessment of Quality of Life Scale.

The researchers also measured concentrations of the amino acids oxidized by DAAO (D-alanine and L-alanine, D-serine and L-serine).

Although both groups experienced a reduction in total PANSS scores during the study, there were no significant differences in PANSS total score between the BZ and the placebo groups at 12 weeks (endpoint least-square mean difference [SE] −1.2 [2.4] t = −0.49, P = .63).

There were also no significant differences between the groups on all PANSS subscales as well as any of the secondary clinical measures (P < .007).

A total of 122 adverse events (AEs) overall were reported by 66 participants, but rates of AEs were comparable between the BZ and placebo groups at 55% vs 46% respectively. There were 11 serious AEs reported by 10 participants. Only one of these was related to the study drug.

There were no statistically significant changes in amino acid concentrations between the two groups.

The authors note several limitations of the study, including the possibility that protective agents may need longer times than 12 weeks — possibly as long as 6 to 12 months — to show efficacy. Moreover, the dose of BZ needed to produce a response remains "uncertain."

"Future clinical trials should restrict participants to those who are treatment refractory and should further investigate whether benzoate acts by altering amino acid levels or by reducing oxidative stress in people with schizophrenia," the authors suggest.

Scott added that further research in patients with treatment-refractory schizophrenia is needed to determine whether BZ "has a role in this patient population."

The authors conclude that at present, "the routine use of this agent as an adjunctive treatment for early psychosis is not recommended."

No Surprise?

Commenting on the study for Medscape Medical News, Kenji Hashimoto, PhD, Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan, said that although previous studies of BZ showed benefit in stable patients with chronic schizophrenia, "it is unlikely that [sodium] benzoate may have beneficial effects in the acute phase of psychosis.

Hashimoto, who was not involved with the study, noted that BZ is a "weak DAAO inhibitor and that DAAO expression in the frontal cortex of human beings is very low."

This project was supported by a John Cade Fellowship from the NHMRC and support from the Queensland Centre for Mental Health Research, which receives funding from the Queensland Health Department. Scott is supported by an NHMRC Practitioner Fellowship. The other authors' disclosures are listed on the original article. Hashimoto has disclosed no relevant financial relationships.

JAMA Netw Open. Published online November 10, 2020. Full text

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