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 mGluR5Comment 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
Related News: New Compounds May Help Probe the Glutamate Hypothesis of Schizophrenia
Comment by: John Krystal, SRF Advisor
Submitted 23 February 2016
Posted 23 February 2016
Positive allosteric modulators of NR2A-containing NMDA receptors (NMDARs) represents an important new pharmacologic advance for probing the role of NMDARs in cognition and behavior and the pathophysiology and treatment of psychiatric disorders. There is a long-standing interest in finding ways to enhance NMDAR function using allosteric modulators of NMDARs that might avoid the potential of direct agonists to cause neurotoxicity. There are a number of psychiatric disorders and addictions where deficits in NMDAR function are implicated in disturbances in network function or plasticity that compromise recovery. This has been a particular focus in the area of schizophrenia research, where compromised glutamate synaptic signaling has been mimicked by the administration of NMDA glutamate receptor antagonists. Since at least the late 1980s, investigators have been interested in the possibility that drugs that enhance NMDAR function might have value in the treatment of symptoms and functional impairment associated with schizophrenia.
The first area of focus was amino acids that enhanced NMDAR function by stimulating the glycine/D-serine co-agonist site of the NMDAR. The initial approach was to orally administer naturally occurring glycine or D-amino acids, D-serine, or D-alanine. Studies with these agents produced small and somewhat inconsistent benefits across studies, raising concerns that this approach could not be successful. However, these amino acids were not really developed as drugs. The optimal dose level and pattern of administration was never established with these agents. From this perspective, any positive data provided tantalizing support for the hypothesis even though there were ongoing efforts to find alternatives with superior pharmacologic properties to enhance NMDAR function.
The first of these alternative agents was D-cycloserine, a partial agonist of the glycine site with a complex pharmacology. D-cycloserine has 30 to 50 percent of the activity of glycine at NR2A- and NR2B-containing NMDARs, meaning that in many behavioral assays, high-dose D-cycloserine produces effects (weak sedation, weak euphoria, memory impairment, etc.) that resemble low doses of NMDAR antagonists. Importantly, at high doses, D-cycloserine seemed to worsen symptoms in some patients diagnosed with schizophrenia. However, D-cycloserine is a nearly full or even super (greater activity than glycine) agonist at NR2C- and NR2D-containing NMDARs, and it is able to stimulate NR3-containing NMDARs that are not directly stimulated by glutamate. It is likely that by stimulating NR2C-, NR2D-, or NR3-containing receptors, beneficial NMDAR agonist-like effects attributed to D-cycloserine emerge. But the complex pharmacology of D-cycloserine limits its therapeutic potential.
The next class of drugs developed was glycine transporter-1 antagonists (GlyT1 inhibitors). These drugs are based on the premise that GlyT1 is a high-activity transporter that controls synaptic glycine levels below the saturation level, allowing receptors to be stimulated by exogenous glycine or GlyT1 inhibition. Some early agents had limited pharmacologic development but showed promising clinical results. Later agents received systematic study, and Roche initially developed exciting initial data, but positive results could not be replicated. Many questions remain, including the following:
1. Is glycine the right amino acid to target relative to D-serine? D-serine appears to have greater synaptic function relative to glycine, which may be more important for extrasynaptic signaling.
2. Is tonic inhibition of GlyT1 detrimental due to its potential to stimulate downregulation of NMDAR function? Instead, should these agents be administered intermittently to enhance network function and plasticity? (
3. Do GlyT1 inhibitors have an inverted U dose response to avoid stimulating NMDAR downregulation and to optimally modulate network functions?
There are a number of reasons that NR2A-containing NMDARs are an interesting target. NR2A-containing NMDARs are predominately synaptic receptors, while NR2B-containing NMDARs are widely distributed in synaptic and extrasynaptic spaces. When "overstimulated," extrasynaptic NR2B-containing NMDARs suppress BDNF levels and cause the pruning of dendritic spines and even dendrites themselves. They also have the potential to produce even more severe forms of toxicity. NR2A-containing NMDARs also emerge early in life and gradually displace NR2B-containing receptors during childhood and adolescence in many circuit elements. Since the risk for many psychiatric disorders also emerges during this period, the NR2A subunit is an intriguing target. In addition, while overstimulation of NR2B-containing receptors has negative effects on synaptic connectivity, NR2A-containing NMDARs are implicated in some neurotrophic processes. Further, there is interest in drugs that facilitate NR2A-mediated signaling (positive allosteric modulation) rather than stimulating NMDARs in order to avoid neurotoxicity that might be associated with directly stimulating these receptors. In this way, one might think of NR2A-positive allosteric modulators (PAMs) as analogous to the way that benzodiazepines enhance the activation of GABAA receptors.
The exciting paper by Hackos et al. in Neuron represents an important advance in the effort to develop NR2A PAMs. The researchers present an elegant story about the identification and validation of these drugs. Schizophrenia is an obvious disorder where these medications might play a role. But there are many other conditions where modulating NMDAR function via NR2A could be predicted to produce benefits. I think that this paper will stimulate interest and discussion in the field.
View all comments by John Krystal