Antidepressants in the post-ketamine Era: Pharmacological approaches targeting the glutamatergic system

The efficacy of currently available medications for depression is unsatisfactory, and that has spurred the development of novel antidepressants based on a hypothesis other than the monoamine hypothesis. Recent studies have revealed the importance of the glutamatergic system as a drug target for depression, and the validity of this hypothesis has been underpinned by the discovery of the antidepressant effects of ketamine, leading to the market launch of Spravato® nasal spray which delivers (S)-ketamine (esketamine). However, both ketamine and esketamine have unwanted adverse effects that hinder their routine use in daily practice. Extensive studies have elucidated the mechanisms underlying the antidepressant effects of ketamine, and that has encouraged numerous drug discovery activities to search for agents that retain a ketamine-like antidepressant profile but with lesser adverse effect liabilities. The discovery activities have included attempts to identify 1) the active substance(s) in the circulation after ketamine administration and 2) agents that act on the proposed mechanisms of action of ketamine. Clinical trials of agents discovered in the course of these activities are underway, and in 2022, AUVELITY™ (AXS-05; dextromethorphan with bupropion) was approved by the United States Food and Drug Administration. Drug development of post-ketamine agents should provide novel antidepressants that are safer, but as potent and rapidly acting as ketamine.