CNS Drugs

, Volume 25, Issue 10, pp 859–885 | Cite as

Meta-Analysis of the Efficacy of Adjunctive NMDA Receptor Modulators in Chronic Schizophrenia

  • Surendra P. Singh
  • Vidhi Singh
Original Research Article

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 SMD results 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.

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Copyright information

© Adis Data Information BV 2011

Authors and Affiliations

  • Surendra P. Singh
    • 1
    • 2
  • Vidhi Singh
    • 3
  1. 1.General Adult Psychiatry, Mental Health DirectorateWolverhampton City Primary Care TrustWolverhamptonUK
  2. 2.Centre for Health and Social Care ImprovementUniversity of WolverhamptonWolverhamptonUK
  3. 3.MediWare Computer Software EngineeringWolverhamptonUK

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