Safety and effectiveness of NMDA receptor antagonists for depression: A multidisciplinary review

Ketamine, an anesthetic available since 1970, and esketamine, its newer S‐enantiomer, provide a novel approach for the treatment of depression and other psychiatric disorders. At subanesthetic doses, the two drugs, along with their older congener, phencyclidine (PCP), induce a transient, altered mental state by blocking the N‐methyl‐D‐aspartate (NMDA) receptor for glutamate, the primary excitatory neurotransmitter in the mammalian central nervous system. This multidisciplinary review examines the pharmacology/direct effects on consciousness, effectiveness in depression and acute suicidality, and safety of these fast‐acting NMDA antagonists. To capture the essence of 60 years of peer‐reviewed literature, we used a semi‐structured approach to the subtopics, each of which required a different search strategy. We review the evidence for the three primary reported benefits of the two clinical drugs when used for depression: success in difficult‐to‐treat patients, rapid onset of action within a day, and immediate effects on suicidality. Key safety issues include the evidence—and lack thereof—for the effects of repeatedly inducing this altered mental state, and whether an adequate safety margin exists to rule out the neurotoxic effects seen in animal studies. This review includes evidence from multiple sources that raise substantial questions about both safety and effectiveness of ketamine and esketamine for psychiatric disorders.