title: NMDA receptor antagonists interventions in schizophrenia: Meta-analysis of randomized, placebo-controlled trials.
abstract: BACKGROUND
  We examined whether N-methyl d-aspartate (NMDA) receptor antagonists as adjunctive therapy have therapeutic potential for schizophrenia treatment.
  
  
  METHODS
  Systematic review of PubMed, Cochrane Library, PsycINFO and Google Scholar up until October 2012 and meta-analysis of randomized placebo-controlled trials were performed. Risk ratio (RR), 95% confidence intervals (CI), numbers-needed-to-harm (NNH), and standardized mean difference (SMD) were calculated.
  
  
  RESULTS
  Results were across 8 studies and 406 patients (85.5% schizophrenia related disorder and 14.5% bipolar disorder) were included (amantadine: 5 trials and 220 patients, memantine: 3 trials and 186 patients). NMDA receptor antagonists (NMDAR-ANTs) as adjunctive therapy were not superior to placebo in overall (SMD = -0.25, CI = -0.72, 0.23, p = 0.31, N = 6, n = 347), positive symptoms (SMD = -0.20, CI = -0.70, 0.31, p = 0.44, N = 4, n = 205), and negative symptoms (SMD = -0.69, CI = -1.65, 0.27, p = 0.16, N = 4, n = 205), and Clinical Global Impression Severity scale (SMD = -0.27, CI = -1.20, 0.65, p = 0.56, N = 3, n = 177). There was also no significant difference in discontinuation rate between NMDAR-ANTs and placebo treatments (all cause: RR = 1.23, CI = 0.89-1.70, p = 0.20, N = 8, n = 396, side effects: RR = 1.86, CI = 0.84-4.13, p = 0.13, N = 6, n = 359, inefficacy/worsening psychosis: RR = 0.70, CI = 0.20-2.38, p = 0.56, N = 7, n = 380). However, memantine was favorable compared with placebo in Mini-Mental State Examination in schizophrenia (SMD = -0.77, CI = -1.27, -0.28, p = 0.002, N = 3, n = 71). While NMDAR-ANTs caused weight loss compared with placebo (SMD = -0.42, CI = -0.73, -0.11, p = 0.008, N = 3, n = 165), amantadine caused more frequent insomnia than placebo (RR = 3.83, CI = 1.41-10.38, p = 0.008, NNH = 9, p = 0.002, N = 2, n = 147).
  
  
  CONCLUSIONS
  Our results indicate that NMDAR-ANTs as adjunctive therapy may improve cognitive function in patients with schizophrenia. Because the included studies were small, a replication study using larger samples is needed.
authors.affiliation: Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan. tarok@fujita-hu.ac.jp
authors.forename: Taro
authors.initials: T
authors.lastname: Kishi
authors.forename: Nakao
authors.initials: N
authors.lastname: Iwata
mesh_terms: D016208:Databases, Factual / Q000706:statistics & numerical data; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D012307:Risk Factors; D012559:Schizophrenia / Q000188:drug therapy*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate
keywords: Amantadine; Efficacy; Memantine; Meta-analysis; NMDA receptor antagonists; Systematic review; Tolerability