Arketamine, a new rapid-acting antidepressant: A historical review and future directions

The NMDAR antagonist (R,S)-ketamine produces rapid and sustained antidepressant effects in treatment-resistant major depressive disorder and other psychiatric conditions. (R,S)-ketamine is a racemic mixture of (R)-ketamine (arketamine) and (S)-ketamine (esketamine), with esketamine having greater NMDAR affinity. An esketamine nasal spray was approved in 2019 for treatment-resistant depression. Preclinical studies indicate arketamine has greater potency and longer-lasting antidepressant-like effects than esketamine in rodents, despite lower NMDAR binding affinity, and causes fewer side effects such as psychotomimetic and dissociative effects and abuse liability. An open-label study showed rapid and sustained antidepressant effects of arketamine in treatment-resistant MDD patients, and a phase 2 trial is underway. This review covers the history, molecular mechanisms, and future directions of arketamine.

Study at a glance

Abstract

The N-methyl-d-aspartate receptor (NMDAR) antagonist (R,S)-ketamine causes rapid onset and sustained antidepressant actions in treatment-resistant patients with major depressive disorder (MDD) and other psychiatric disorders, such as bipolar disorder and post-traumatic stress disorder. (R,S)-ketamine is a racemic mixture consisting of (R)-ketamine (or arketamine) and (S)-ketamine (or esketamine), with (S)-enantiomer having greater affinity for the NMDAR. In 2019, an esketamine nasal spray by Johnson & Johnson was approved in the USA and Europe for treatment-resistant depression. In contrast, an increasing number of preclinical studies show that arketamine has greater potency and longer-lasting antidepressant-like effects than esketamine in rodents, despite the lower binding affinity of arketamine for the NMDAR. Importantly, the side effects, i.e., psychotomimetic and dissociative effects and abuse liability, of arketamine are less than those of (R,S)-ketamine and esketamine in animals and humans. An open-label study demonstrated the rapid and sustained antidepressant effects of arketamine in treatment-resistant patients with MDD. A phase 2 clinical trial of arketamine in treatment-resistant patients with MDD is underway. This study was designed to review the brief history of the novel antidepressant arketamine, the molecular mechanisms underlying its antidepressant actions, and future directions.