Efficacy of N-methyl-D-aspartate receptor modulator augmentation in schizophrenia: A meta-analysis of randomised, placebo-controlled trials

Abstract

Background: Dysfunction of the N-methyl- D-aspartate glutamate receptor is involved in the putative pathology of schizophrenia. There is growing interest in the potential of N-methyl- D-aspartate receptor modulators to improve the symptoms of schizophrenia, but the evidence for the use of glutamatergic agents for augmenting schizophrenia remains inconclusive. Aims: We conducted a meta-analysis to test the efficacy and safety of N-methyl- D-aspartate receptor modulator supplements in patients with schizophrenia. Methods: Following a systemic search in MEDLINE, Embase, Cochrane and Scopus, 40 double-blinded, randomised, placebo-controlled trials involving 4937 patients with schizophrenia were included in this meta-analysis. The change in the severity of symptoms among patients with schizophrenia was defined as the primary outcome, whereas the safety profiles of the intervention, including the discontinuation rate and adverse events, were defined as secondary outcomes. Results: When added to antipsychotic treatments, N-methyl- D-aspartate receptor modulators improved multiple schizophrenia symptoms, particularly negative symptoms, and had satisfactory side effects and safety profile. Among the seven glutamatergic agents analysed, glycine, D-serine and sarcosine had better treatment profiles than other agents, and NMDA receptor co-agonists, as a group, provided a reduction in schizophrenia symptoms compared to antipsychotic treatments without supplementation. Augmentation with N-methyl- D-aspartate receptor modulators was only effective among patients treated with antipsychotics other than clozapine. Conclusions: The results indicate that N-methyl- D-aspartate receptor modulators, particularly with glycine, D-serine and sarcosine, are more beneficial than the placebo in treating schizophrenia, and the effects extended to both positive and negative symptoms, when augmented with antipsychotics other than clozapine.

How do we address treating the negative symptoms of schizophrenia pharmacologically?

“…Overall, recent meta-analyses [11] support significant, moderate to large effect size improvements in negative symptoms compared to placebo for pooled NMDA receptor modulators adjunctive to antipsychotics group (SMD = −0.43). Individual compounds with efficacy include glycine (SMD = −0.4), D-serine (SMD = −0.56), and sarcosine (SMD = −0.74).…”

D-Serine: A Cross Species Review of Safety

“…A high dose study in a clinically high risk (CHR) for schizophrenia group (47) also showed significant improvement in prodromal negative symptoms (d = 0.68). Meta-analysis including high dose studies demonstrate moderate to large effect sizes for negative symptoms (3,48), improving on meta-analysis that only include low dose studies (46). D-serine as an adjunct to cognitive remediation has been also been proposed (39,76,77).…”

“…D- Serine was originally reported to be beneficial in schizophrenia based upon studies conducted in Taiwan ( 52 ) and Israel ( 54 ). A recent meta-analysis of NMDAR modulators in schizophrenia ( 3 ) has found specific improvement for D -serine adjunctive to antipsychotics for negative symptoms measured by both the Scale for the Assessment of Negative Symptoms (SANS) ( 68 ), with a standardized mean difference (SMD) = −0.56 and the Positive and Negative Symptom Scale (PANSS) negative symptom subscale ( 69 ), with a SMD of −0.49. The meta-analysis for D -serine for total PANSS symptoms was not significant (SMD = −0.3).…”

“…Glutamate-targeted drugs remain a high priority for the treatment of schizophrenia ( 1 , 2 ). While no compounds have successfully navigated the difficult process from Phase I to regulatory approval, recent meta-analyses support significant, moderate to large effect size improvements for both schizophrenia symptoms in general, along with specific improvements in negative symptoms, for pooled N-methyl-D-aspartate-type glutamate receptors (NMDAR) modulators adjunctive to antipsychotics compared to placebo ( 3 ). In addition to overall improvements in residual psychotic and negative symptoms, glutamatergic based medications have also targeted cognitive deficits ( 4 , 5 ).…”

“…The present report focuses on the safety of D- serine, one of the more thoroughly studied NMDAR modulators ( 3 ), with a specific focus on potential nephrotoxicity. A review of D- serine's safety is timely and pertinent, as D- serine remains under active study, both directly ( 10 ), and indirectly through D- amino acid oxidase ( D AAO) inhibitors such as Luvadaxistat (NBI-1065844/TAK-831) and NaBen (sodium benzoate).…”