Background: We examined whether N-methyl d-aspartate (NMDA) receptor antagonists as adjunctive therapy have therapeutic potential for schizophrenia treatment. Method: 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). Conclusion: 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.
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