The review by Singh and Singh [24▪▪] is the largest published to date, and is notable for being authored by an independent team with no previous involvement with NMDA theory. It includes 1253 cases from 29 trials, and differs from earlier meta-analysis by the decision to use a broader definition of NMDA-based treatments. This decision appears to have reduced the overall effect size, as this review included CX516, an AMPA receptor modulator, and memantine, a weak nonselective NMDA receptor antagonist, which were largely ineffective as adjuncts to nonclozapine antipsychotics. Unlike traditional NMDA-based treatments, however, subgroup analysis for CX516 and memantine suggests efficacy when adjunctive to clozapine in treatment-resistant schizophrenia. Neither meta-analysis included metabotropic glutamate receptor (mGlu2/3 agonist) treatments.
