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Lane HY, Lin CH, Green MF, Hellemann G, Huang CC, Chen PW, Tun R, Chang YC, Tsai GE. Add-on Treatment of Benzoate for Schizophrenia: A Randomized, Double-blind, Placebo-Controlled Trial of d-Amino Acid Oxidase Inhibitor. JAMA Psychiatry. 2013 Dec 1 ; 70(12):1267-75. Pubmed Abstract

Comments on News and Primary Papers
Comment by:  Hugo Geerts
Submitted 20 October 2013
Posted 20 October 2013
  I recommend the Primary Papers

The group around Dr. Hsien-Yuan Lane has published a number of papers on clinical trials in schizophrenia patients with agents that act on co-agonist sites of the NMDA-receptor. This time they report on the beneficial effects of augmentation therapy with high-dose benzoate, a D-amino acid oxidase inhibitor, on a number of clinical scales (about 25 subjects/treatment arm). The effect is substantial (effect sizes between 1.16 on the PANSS negative and 1.69 on the PANSS positive subscale). For instance, this effect size is about twice the value seen in clinical trials with bitopertin, a glycine transporter-1 inhibitor in a larger Phase II study (Umbricht et al., 2010). Only one dose of benzoate has been tested, so the issue of a possible inverse U-shape response that has been observed earlier for a similar target and supported by theoretical-mechanistic insights has not been addressed in this study. They took great care in balancing the treatment arms with regard to the type of basal antipsychotic medication and found that haldol and risperidone were particularly receptive for benzoate augmentation therapy.

Of interest is the observation that benzoate is a food additive (E210-E213) with an impressive record of safety, opening up the possibility of an easier treatment approach of lower levels of the drug be achieved using food strategies. It might therefore be of interest to test lower levels of benzoate as well.

Antipsychotics are often considered deleterious or neutral at best for cognitive improvement, so this augmentation study suggests that benzoate is able to reverse this trend of worsening. In addition, there were no correlations between changes in PANSS positive or EPS changes and changes in both PANSS negative or cognitive outcome. This suggests that the observed effect of the compound is unlikely to be indirectly due to an improvement in PANSS positive symptoms or motor side effects, suggesting a genuine impact on the negative or cognitive subscales.

With regard to cognition, from the MATRICS subscale, the authors only found speed of processing and visual learning and memory to be significantly improved with the active treatment. However, this is one of the few trials in which the global composite score increased more with treatment than the placebo, despite the possible practice effect. Nevertheless, it underscores the difficulty of improving all seven domains of the cognitive MATRICS scale.

With the caveat of low numbers in the treatment arm, this study has to be recommended because it once again suggests a path forward for glutamatergic strategies. The glutamatergic system is currently the focus of much research in psychiatric indications (such as ketamine in depression). However the major problem, unlike older dopaminergic and neuromodulatory strategies, is finding a balance between excitation and inhibition in the human brain, and the feedback mechanism that operates, that makes it sometimes difficult to find the best dose-range for any treatment paradigm. The authors of this paper, however, show that this is possible.


Umbricht D, Yoo K, Youssef E, Dorflinger E, Martin-Facklam M, Bausch A, Arrowsmith R, Alberati D, Marder S, Santarelli L. Glycine Transporter Type 1 (GLYT1) Inhibitor RG1678: Positive Results of the Proof-of-Concept Study for the Treatment of Negative Symptoms in Schizophrenia. Neuropsychopharmacology. 2010; 35:S320-321.

View all comments by Hugo GeertsComment by:  Michael McFarland
Submitted 5 November 2013
Posted 11 November 2013

Sodium benzoate combined with ascorbic acid produces benzene, a known carcinogen. I hope that another D-amino acid oxidase inhibitor can be found easily.

View all comments by Michael McFarland