Rapid-acting antidepressants: mechanistic insights and future directions

Abstract

Ketamine produces rapid (within hours) antidepressant actions, even in patients considered treatment resistant, and even shows promise for suicidal ideation. Here, we review current research on the molecular and cellular mechanisms of ketamine and other novel rapid-acting antidepressants, and briefly explore gender differences in the pathophysiology and treatment of MDD. Ketamine, an NMDA receptor antagonist, increases BDNF release and synaptic connectivity, opposing the deficits caused by chronic stress and depression. Efforts are focused on the development of novel rapid agents that produce similar synaptic and rapid antidepressant actions, but without the side effects of ketamine. The impact of gender on the response to ketamine and other rapid-acting antidepressants is in early stages of investigation.The discovery that ketamine produces rapid therapeutic actions for depression and suicidal ideation represents a major breakthrough and much needed alternative to currently available medications. However, novel fast acting agents with fewer side effects are needed, as well as elucidation of the efficacy of these rapid-acting antidepressants for depression in women.