From Ketamine to Drugs Targeting Subtype-Selective Benzodiazepine Site-Containing Gamma-Aminobutyric Acid A Receptors as Novel Rapid-Acting Antidepressants

Abstract

Ketamine is a rapidly acting antidepressant and has shown consistent clinical benefits for about 20 years. In 2019, the U.S. Food and Drug Administration approved its (S)-isomer, (S)-ketamine (intranasal Spravato), for use in patients with treatment-refractory depression. In addition, the fact that ketamine is mechanistically distinct from conventional monoamine-based antidepressants has stimulated research for drugs that would reproduce its rapid therapeutic effects associated with improvement of depressive symptomatology, without the confounds of its psychotomimetic and abuse-related properties.