Rapid-acting antidepressants.

A new class of antidepressants, emerging since 2006, offers rapid onset, large effect size, and efficacy after single or few doses, even in treatment-refractory patients and against symptoms like anhedonia. Controlled clinical studies have demonstrated rapid-acting effects for ketamine, other NMDA receptor antagonists, and scopolamine, with less clinical data for psychedelic drugs such as psilocybin, LSD, and ayahuasca. The mechanisms are not fully understood, but potentiation of AMPA receptor function appears to be a general trigger. Durability is limited for ketamine and scopolamine, while psychedelics may produce effects lasting months. Side effects and lack of enduring effects are primary impediments. Esketamine is FDA-approved; compounds in clinical development include (R)-ketamine, Rapastinel, and TAK-653. Preclinical evidence suggests potential for mGlu2/3 receptor antagonists, AMPA receptor potentiators, and GABAA(α5) negative allosteric modulators.

Study at a glance

Abstract

Conventional antidepressants (biogenic amine mechanisms) are not fully efficacious (e.g., symptoms remain after treatment, not all patients respond), produce effects only after weeks of daily dosing, and do not impact all disease symptoms. In contrast, a new class of antidepressants has been emerging since 2006 that has demonstrated rapid onset, large effect size, activity after only a single or few dose applications, and positive impact in treatment refractory patients and against some treatment-resistant symptoms (e.g., anhedonia). Rapid-acting antidepressant drug action has been demonstrated in controlled clinical studies for ketamine, a few other NMDA receptor antagonists, and scopolamine. Less clinical data are currently available for psychedelic drugs such as psilocybin, lysergic acid diethylamide, and ayahuasca. The mechanisms of action of rapid-acting antidepressants are not fully understood. However, a general triggering mechanism appears to involve the potentiation of AMPA receptor function. Although the durability of antidepressant effects of ketamine and scopolamine is limited, psychedelic drugs have been reported to produce effects for many months. The primary impediment to generating a medicine of this type for depressed patients is side effects and the lack of methods to ensure enduring antidepressant effects. Thus, further exploration of drug possibilities continues. Esketamine ((S)-ketamine) was recently FDA approved. Compounds currently in clinical development include the NMDA receptor antagonist (R)-ketamine, the NMDA receptor modulator, GLYX-13 (Rapastinel), and the AMPA receptor potentiator TAK-653. Additional pharmacological classes have produced effects in the preclinical laboratory to suggest their potential as rapid-acting agents. These include mGlu2/3 receptor antagonists, AMPA receptor potentiators, and negative allosteric modulators of GABAA(α5) receptors. In all cases, molecules exist that could be used to provide clinical proof of concept testing.