Rapid-Acting Antidepressants: Mechanistic Insights and Future Directions

Abstract

Purpose of Review 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. Recent Findings 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. Summary 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.

GABA interneurons are the cellular trigger for ketamine’s rapid antidepressant actions

“…Postmortem studies have reported that female depressed subjects had increased expression of several glutamate receptor subtypes in the dorsolateral PFC, and that female depressed suicide subjects had significantly increased expression of Grin2b (37). Only one study to date has analyzed sex differences in ketamine response and found no differences in efficacy or tolerability (38,39). These studies highlight the need for further studies of sex differences in the behavioral, neural, molecular, and genetic phenotypes of major depressive disorder to inform the development of more effective treatment options (40).…”

Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective

“…The molecular and cellular mechanisms underlying ketamine’s antidepressant effects have been proposed in several preclinical studies …”

The Effect of Propofol on a Forced Swim Test in Mice at 24 Hours

“…10 , 37 However, the behavioral, cognitive, neurophysiological and synaptic plasticity effects of propofol, ketamine, and brexanolone and other anesthetic agents have been reported to persist in rodents and humans substantially longer than would be anticipated by their pharmacokinetic and pharmacodynamic profiles alone. 2 , 4 , 11 , 17 , 26 , 27 , 33 , 34 , 38 , 39 , 40 , 41 For example, in their review, Browne and Lucki 41 observed that “the majority of studies indicate that the FST remains sensitive to the protracted effects of ketamine up to 1 week after a single injection.” Thus, the rapid clearance of propofol is unlikely to explain the lack of influence on an FST at 24 hours.…”

“… 1 Ketamine, esketamine, rapastinel, and other investigational agents with varying properties of NMDA receptor activity have produced rapid-onset antidepressant-like effects in rodent models of depression and in human patients with depressive illness. 2 , 3 , 4 , 5 , 6 , 7 A nasally inhaled version of ketamine, esketamine (Spravato; Janssen Pharmaceuticals, Inc, Titusville, New Jersey), was recently approved by the Food and Drug Administration in combination with an orally administered antidepressant for treatment-resistant depression. Intravenously administered brexanolone, which modulates GABA type A (GABA-A) and has a rapid onset of action, was recently approved by the Food and Drug Administration for treatment of postpartum depression.…”