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Memantine and ketamine block open NMDAR channels via apparently similar mechanisms.Memantine is a very well-tolerated drug approved for treatment of Alzheimer's disease.Ketamine has rapid antidepressant effects, but replicates symptoms of schizophrenia.The drugs’ differential effects may require inhibition of distinct NMDAR populations.The clinical benefits of the glutamate receptor antagonists memantine and ketamine have helped sustain optimism that glutamate receptors represent viable targets for development of therapeutic drugs. Both memantine and ketamine antagonize N-methyl-d-aspartate receptors (NMDARs), a glutamate receptor subfamily, by blocking the receptor-associated ion channel. Although many of the basic characteristics of NMDAR inhibition by memantine and ketamine appear similar, their effects on humans and to a lesser extent on rodents are strongly divergent. Some recent research suggests that preferential inhibition by memantine and ketamine of distinct NMDAR subpopulations may contribute to the drugs’ differential clinical effects. Here we review studies that shed light on possible explanations for differences between the effects of memantine and ketamine.