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Ketamine and nitrous oxide: The evolution of NMDA receptor antagonists as antidepressant agents

2020; Elsevier BV; Volume: 412; Linguagem: Inglês

10.1016/j.jns.2020.116778

1878-5883

Molly C. Kalmoe, Alvin M. Janski, Charles F. Zorumski, Peter Nägele, Ben Julian A. Palanca, Charles R. Conway,

Anesthesia and Sedative Agents

Highlights•Ketamine and nitrous oxide show promise as rapid acting antidepressants.•Esketamine has FDA approval for TRD, requiring special regulation and monitoring.•Both ketamine and nitrous oxide have potential for misuse and abuse.•Nitrous oxide is unscheduled, possibly with lower addictive potential than ketamine.•Mechanisms of action are complex and under continued intense investigation.AbstractN-methyl-d-aspartate receptor (NMDAR) antagonists, including ketamine and nitrous oxide, are currently intensely studied as rapid-acting antidepressant agents. Interestingly, both of these compounds are also drugs of abuse.Intravenous ketamine, a dissociative anesthetic that induces complex downstream effects via NMDARs, rapidly reduces depressive and suicidal symptoms in treatment-resistant depression (TRD), as demonstrated by several trials. Recently, the United States Food and Drug Administration (FDA) approved an intranasal version of ketamine (esketamine) for TRD. The United States Drug Enforcement Agency (DEA) lists ketamine as a Class III scheduled drug (moderate-low potential for physical and psychological abuse). The FDA has established a Risk Evaluation and Management Strategy (REMS) program to ensure proper drug storage, handling, dispensing, and monitoring intranasal esketamine to minimize misuse/abuse opportunities.Nitrous Oxide is a colorless, odorless, gas that has been in medical use for over 150 years. The mechanisms of action of nitrous oxide are not fully understood; however, it is known to act as a non-competitive inhibitor of NMDA-type glutamate receptors. Currently, nitrous oxide is used for inhalational general anesthesia and analgesia for short procedures. Inhaled nitrous oxide is also used recreationally, primarily by teens and young adults, but is not believed to have strong addiction potential. In contrast to ketamine, nitrous oxide is not a controlled substance and can be legally purchased without a prescription. A recent double-blind, prospective, cross-over study demonstrated that nitrous oxide reduced depressive symptoms in a group of severely ill TRD patients. Though this is a promising initial study, further investigation is needed.