Ketamine: Leading us into the future for development of antidepressants

Abstract Numerous randomized double-blind clinical trials have consistently shown that that a single intravenous administration of a subanesthetic dose of ketamine to treatment-resistant depressed patients significantly improved depressive symptomatology rapidly, within two hours, with the effect lasting up to seven days. Despite its very promising effects, ketamine has long been associated with potential for abuse as it can cause psychotropic side effects, such as hallucinations, false beliefs, and severe impairments in judgment and other cognitive processes. Consequently, within the last two decades preclinical research has been carried out aimed at understanding its mechanisms of action and the brain circuits involved in ketamine’s antidepressant effects, both of which are discussed in this review. Furthermore, with the hippocampus being a key target for ketamine’s beneficial antidepressant effects, we and others have begun to examine behavioral and neurochemical effects of drugs that act selectively on the hippocampus due to the preferential location of their receptor targets. Such drugs are negative allosteric modulators (NAMs) and positive allosteric modulator (PAM) of the α5-GABAA receptor. Such compounds are discussed within the framework of how lessons learned with ketamine point to novel classes of drugs, targeting the GABAergic system, that can recapitulate the antidepressant effects of ketamine without its adverse effects.