The role of NMDA-receptor type glutamatergic antagonists dextromethorphan or ketamine in the treatment of nonketotic hyperglycinemia: A critical reassessment

The recognition of glycine as an endogenous ligand at the allosteric activation site of the NMDA-type glutamatergic receptor led to the assumption that the excess glycine in nonketotic hyperglycinemia would result in overactivation of these receptors, and of the proposed use of inhibitors such as dextromethorphan or ketamine as a therapeutic agent. Years later it was recognized that these same receptors have an alternative endogenous activator d-serine, which is markedly decreased in nonketotic hyperglycinemia. This may result in underactivation of these NMDA-type glutamatergic receptors, challenging the earlier hypothesis. Clear clinical evidence of an added therapeutic benefit beyond the use of glycine reduction strategies from use of either dextromethorphan or ketamine in nonketotic hyperglycinemia has not been documented. The systematic use of these NMDA-type receptor antagonists in nonketotic hyperglycinemia should be reevaluated, particularly in light of emerging potential adverse effects.