Novel mechanisms underlying rapid-acting antidepressants: ketamine-like compounds, neurosteroid GABAkines, and psychedelics

• Novel mechanisms of action have been identified for rapid-acting antidepressant drugs (RAADs) and are new therapeutic targets for the treatment of depression. • The three major categories of RAADs are: rapid-acting glutamatergic, GABAergic, and serotoninergic antidepressants. • The activation of Akt and/or ERK allows mTOR activation and, consequently, protein synaptic synthesis that improves neuroplasticity in depression patients. • BDNF and GABA A receptors are key mediators in overcoming the limitations of conventional antidepressants. • These findings have significant implications for the development of next-generation antidepressants that offer faster relief and greater efficacy to a broader patient population. The discovery of the rapid antidepressant action of ketamine accelerated the identification of new molecules that are associated with fast and prolonged relief of depressive symptoms. As a result, a new group of antidepressants have emerged, some of them already approved for clinical use, classified as rapid-acting antidepressant drugs (RAADs). Potentiation of brain-derived neurotrophic factor (BDNF) or activation of the GABA A receptors are the main mechanisms behind the notable properties of RAADs, a mainstream topic in the field of pharmacology and drug discovery that deserves an updated review.