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Boosting NMDA Receptors Improves Symptoms, Cognition in Schizophrenia

October 4, 2013. Adding an NMDA receptor-enhancing drug to existing antipsychotic drug treatment improves a variety of symptoms of schizophrenia, according to a preliminary trial published online October 2, 2013, in JAMA Psychiatry. Guochuan Tsai of the Harbor-UCLA Medical Center in Torrance, California, and colleagues report that six weeks of treatment with the D-amino acid oxidase inhibitor sodium benzoate improved scores on the Positive and Negative Syndrome Scale (PANSS) by an average of 21 percent, and also boosts performance in several cognitive domains, providing promising evidence for this class of drugs as a novel treatment for schizophrenia.

A large body of basic and clinical evidence points to a disturbance in glutamate signaling through NMDA receptors as a potential pathogenic mechanism in schizophrenia, including the observation that antagonists of this receptor can induce both positive and negative symptoms, as well as cognitive deficits, that mimic the illness (see SRF Current Hypotheses by Bita Moghaddam and Daniel Javitt, and SRF related news story).

This NMDA hypofunction hypothesis has prompted several pharmacological attempts to enhance NMDA receptor function in schizophrenia, with mixed results (see SRF related news story and SRF conference story). Glutamate can only drive activity at NMDA receptors when they are co-activated by D-serine or glycine, and several trials targeting co-agonists have reported promising but limited efficacy on clinical symptoms (Tsai and Lin, 2010). A newer approach to boosting NMDA signaling is to block D-amino acid oxidase (DAAO), the enzyme that degrades NMDA co-agonists D-serine and D-alanine (Smith et al., 2010). Although this enzyme is elevated in schizophrenia, and a knockout mouse lacking the enzyme enhances NMDA receptor function, a DAAO inhibitor had yet to be tried in schizophrenia patients.

First author Hsien-Yuan Lane, of China Medical University Hospital in Taichung, Taiwan, examined the effect of DAAO inhibitor (and widely used food preservative) sodium benzoate on schizophrenia subjects receiving a stable dose of antipsychotics for at least three months. Patients from two medical centers in Taiwan were randomized to receive sodium benzoate (n = 25) or placebo (n = 27) in a double-blinded fashion in addition to their established antipsychotic regimen. Clinical efficacy and side effects were monitored biweekly, while cognition was assessed at the onset and conclusion of the trial.

There were no differences in PANSS scores between the two groups at baseline, but those who received six weeks of add-on benzoate had significantly better PANSS total scores (effect size 1.53) than those in the placebo group, with an average decrease of 21 percent. Scores on the positive, negative, and general psychopathology subscales of the PANSS also improved with the drug.

Although the benzoate group’s composite global cognition score (an aggregate of seven domains recommended by the MATRICS initiative) was not significantly better than placebo, significant improvement was found when social cognition was excluded from the composite score (effect size 0.67). This improvement was specific to two neurocognitive domains: speed of processing (effect size 0.65) and visual learning and memory (0.70). Although the effect sizes are relatively modest, this report is the first double-blind study of an NMDA-enhancing agent to find improvement in a MATRICS-like cognitive battery, noted the authors.

The improvement in symptoms and cognition with the benzoate add-on appeared to be clinically meaningful, as the drug significantly improved scores on the Global Assessment of Function (GAF), Quality of Life Scale (QOLS), Hamilton Depression Rating Scale (HDRS), and Clinical Global Impression (CGI) (effect sizes ranged from 0.74 to 1.56).

Benzoate also seemed to be well tolerated. There were no significant differences between groups in levels of extrapyramidal symptoms, dyskinesia (lack of movement), or akathisia (motor restlessness) at the trial endpoint. Other adverse effects reported were mild and present in a minority of patients, and no participants dropped out of the study due to side effects.

The finding that short-term sodium benzoate add-on therapy improved multiple features of schizophrenia, including cognition, is certainly promising. “Inhibition of DAAO … represents a novel therapeutic target for the development of new pharmacotherapy for the clinical efficacy and improvement of life functioning in patients with schizophrenia…,” conclude the authors, while also emphasizing that larger, long-term studies are needed to validate their findings.—Allison A. Curley.

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 Oct 2. 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

Comments on Related News

Related News: New Antipsychotic Drug? Bypassing the NMDA Receptor With mGluR5

Comment by:  Foster Olive
Submitted 5 June 2015
Posted 7 June 2015

These exciting findings represent a paradigm shift in current theories and drug development efforts for neuropsychiatric disorders. The ability of this novel mGluR5 PAM to produce behavioral effects independent of secondary NMDA receptor activation has implications that extend into numerous areas of neuroscience. Recent work by our laboratory and others indicates that mGluR5 PAMs facilitate the extinction of drug-seeking behavior in rodent models of addiction and reverse cognitive deficits associated with high levels of methamphetamine intake. The work by Conn and colleagues opens the door to exciting new directions for future research and drug development efforts in neuroscience and neuropsychiatry.


Gass JT, Olive MF. Positive allosteric modulation of mGluR5 receptors facilitates extinction of a cocaine contextual memory. Biol Psychiatry. 2009 Apr 15; 65(8):717-20. Abstract

Reichel CM, Schwendt M, McGinty JF, Olive MF, See RE. Loss of object recognition memory produced by extended access to methamphetamine self-administration is reversed by positive allosteric modulation of metabotropic glutamate receptor 5. Neuropsychopharmacology. 2011 Mar; 36(4):782-92. Abstract

Gass JT, Trantham-Davidson H, Kassab AS, Glen WB, Olive MF, Chandler LJ. Enhancement of extinction learning attenuates ethanol-seeking behavior and alters plasticity in the prefrontal cortex. J Neurosci. 2014 May 28; 34(22):7562-74. Abstract

View all comments by Foster Olive