Rapastinel, a novel glutamatergic agent with ketamine-like antidepressant actions: Convergent mechanisms.

Ketamine produces rapid (within hours) and long-lasting (7 to 10 days) antidepressant effects by blocking NMDA receptor channels. Rapastinel, a novel glutamatergic compound that acts as an NMDAR partial agonist, also produces rapid antidepressant actions in depressed patients and preclinical rodent models without ketamine-like side effects such as cognitive impairment and psychotomimetic symptoms. Despite recent negative clinical trials, rapastinel may still prove effective as an alternative rapid-acting antidepressant with reduced side effects. This review discusses rapastinel's pharmacological profile and the molecular and cellular mechanisms underlying its rapid and sustained antidepressant actions.

Study at a glance

Abstract

Conventional antidepressant medications, which act on monoaminergic systems, have significant limitations, including a time lag of weeks to months and low rates of therapeutic efficacy. Recently, clinical findings demonstrate that ketamine, a dissociative anesthetic that blocks N-methyl-d-aspartate (NMDA) receptor channel activity, causes rapid (within hours) and long-lasting (7 to 10 days) antidepressant effects. Rapastinel is a novel glutamatergic compound that acts as an NMDAR partial agonist properties, and produces rapid antidepressant actions in depressed patients and in preclinical rodent models. In addition, rapastinel has no ketamine-like side effect such as cognitive impairment and psychotomimetic symptoms. Despite recent negative clinical trials, it remains possible that rapastinel could prove effective as an alternative rapid agent with reduced side effects. In this review, we discuss the pharmacological profile of rapastinel and the molecular and cellular mechanisms underlying the rapid and sustained antidepressant actions of this novel agent.