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