Molecular Pharmacology and Neurobiology of Rapid-Acting Antidepressants

For decades, symptoms of depression have been treated primarily with medications that directly target the monoaminergic brain systems, which typically take weeks to exert measurable effects and months to exert remission of symptoms. Low, subanesthetic doses of ( R,S)-ketamine (ketamine) result in the rapid improvement of core depressive symptoms, including mood, anhedonia, and suicidal ideation, occurring within hours following a single administration, with relief from symptoms typically lasting up to a week. The discovery of these actions of ketamine has resulted in a reconceptualization of how depression could be more effectively treated in the future. In this review, we discuss clinical data pertaining to ketamine and other rapid-acting antidepressant drugs, as well as the current state of pharmacological knowledge regarding their mechanism of action. Additionally, we discuss the neurobiological circuits that are engaged by this drug class and that may be targeted by a future generation of medications, for example, hydroxynorketamine; metabotropic glutamate receptor 2/3 antagonists; and N-methyl-d-aspartate, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and γ-aminobutyric acid receptor modulators.