NMDA antagonists, particularly ketamine, show promise for the 15-30% of patients with major depressive disorder who do not respond to monoaminergic antidepressants. A brief low-dose infusion of ketamine rapidly improves depressive symptoms for several days, though it produces psychotomimetic and cognitive side effects. Multiple infusions (e.g., 2-3 times per week for several weeks) provide relief, but symptoms return when treatment stops. A 96-hour higher-dose infusion with add-on clonidine mitigated side effects and resulted in about 40% of subjects still having a good response 8 weeks later, though this was a pilot study requiring confirmation. Nitrous oxide also showed positive results.
NMDA glutamate receptor antagonists like PCP, ketamine, and CGS-19755 cause cognitive and behavioral changes in humans and histopathological and neurochemical changes in rodents. These effects appear to be dose-dependent manifestations of a disinhibition process where NMDA antagonists reduce GABAergic inhibition, leading to excessive release of acetylcholine and glutamate. Low doses can produce memory dysfunction without psychosis, while more severe NMDA receptor hypofunction (NRHypo) can mimic psychotic schizophrenic exacerbation. Sustained severe NRHypo in adult brains is associated with neurotoxicity. This paper reviews these effects, their likely mechanism, and the possible role of NRHypo in idiopathic psychotic disorders.