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

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. This article is part of the Special Issue on ‘Ketamine and its Metabolites’.