Molecular mechanisms of rapid-acting antidepressants: New perspectives for developing antidepressants

Major depressive disorder is a chronic relapsing condition. Conventional antidepressants take weeks to work and are ineffective for many patients. The NMDA receptor antagonist ketamine produces rapid antidepressant effects, not only by blocking postsynaptic NMDA receptors or GABA interneurons but also by affecting AMPA receptors, adenosine A1 receptors, and L-type calcium channels. The 5-HT2A receptor agonist psilocybin has also shown potential for rapid antidepressant effects in mouse models and clinical studies. This review examines new pharmacological targets of emerging rapid-acting antidepressants like ketamine and hallucinogens (e.g., psilocybin) and discusses possible strategies for future antidepressant research.

Study at a glance

Abstract

Major depressive disorder (MDD) is a chronic relapsing psychiatric disorder. Conventional antidepressants usually require several weeks of continuous administration to exert clinically significant therapeutic effects, while about two-thirds of the patients are prone to relapse of symptoms or are completely ineffective in antidepressant treatment. The recent success of the N-methyl-D-aspartic acid (NMDA) receptor antagonist ketamine as a rapid-acting antidepressant has propelled extensive research on the action mechanism of antidepressants, especially in relation to its role in synaptic targets. Studies have revealed that the mechanism of antidepressant action of ketamine is not limited to antagonism of postsynaptic NMDA receptors or GABA interneurons. Ketamine produces powerful and rapid antidepressant effects by affecting α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors, adenosine A1 receptors, and the L-type calcium channels, among others in the synapse. More interestingly, the 5-HT2A receptor agonist psilocybin has demonstrated potential for rapid antidepressant effects in depressed mouse models and clinical studies. This article focuses on a review of new pharmacological target studies of emerging rapid-acting antidepressant drugs such as ketamine and hallucinogens (e.g., psilocybin) and briefly discusses the possible strategies for new targets of antidepressants, with a view to shed light on the direction of future antidepressant research.