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.
