Meta-analysis of the efficacy of adjunctive NMDA receptor modulators in chronic schizophrenia

Abstract

Background: Based on the glutamatergic NMDA receptor hypofunction theory of schizophrenia, NMDA receptor modulators (NMDARMs) may have therapeutic potential in the treatment of schizophrenia. Objective: This meta-analysis aimed to evaluate the potential of modulators of the NMDA receptor as adjunctive therapy for schizophrenia, using the results from published trials. Data Sources: A primary electronic search for controlled clinical trials using NMDARMs in schizophrenia was conducted on the PubMed, Cochrane Library, EMBASE, CINAHL® and PsycINFO databases. A secondary manual search of references from primary publications was also performed. Study Selection: Inclusion criteria were the application of an established method of diagnosis, randomized case assignment, comparison of NMDARM add-on therapy with placebo, and double-blind assessment of symptoms in chronic schizophrenia using standardized rating scales. Results were based on a total sample size of 1253 cases from 29 trials that fulfilled the specified criteria. Data Extraction: Scores on rating scales or on their relevant subscales were obtained for all selected studies from published results for the minimum dataset to compute the difference between post-and pre-trial scores and their pooled standard deviation for NMDARM add-on therapy and placebo groups for negative, positive and total symptoms. Results: A negative standardized mean difference (SMD) indicates therapeutic benefit in favour of NMDARM add-on therapy and all SMDresults mentioned here are statistically significant. The overall effect size for NMDARMs as a group was small for negative (SMD-0.27) and medium for total (SMD-0.40) symptoms of chronic schizophrenia. Subgroup analysis revealed medium effect sizes for D-serine and N-acetyl-cysteine (NAC) for negative (SMD-0.53 and-0.45, respectively) and total (SMD-0.40 and-0.64, respectively) symptoms, and for glycine (SMD-0.66) and sarcosine (SMD-0.41) for total symptoms. As adjuvants to non-clozapine antipsychotics, additional therapeutic benefits were observed for NMDARM as a group (SMD-0.14) and glycine (SMD-0.54) for positive symptoms; D-serine (SMD-0.54), NAC (SMD-0.45) and sarcosine (SMD-0.39) for negative symptoms; and NMDARM as a group (SMD-0.38), D-serine (SMD-0.40), glycine (SMD-1.12), NAC (SMD-0.64) and sarcosine (SMD-0.53) for total symptoms. When added to clozapine, none of the drugs demonstrated therapeutic potential, while addition of glycine (SMD +0.56) worsened positive symptoms. Conclusions: Taking into consideration the number of trials and sample size in subgroup analyses,D-serine,NAC and sarcosine as adjuncts to non-clozapine antipsychotics have therapeutic benefit in the treatment of negative and total symptoms of chronic schizophrenia. While glycine improves positive and total symptoms as an adjuvant to non-clozapine antipsychotics, it worsens them when added to clozapine. © 2011 Adis Data Information BV. All rights reserved.