A new age of antidepressants arose in 2006 with the publication of data describing the rapid-acting antidepressant effects of ketamine and scopolamine. These clinical findings led to the approval of (S)-ketamine for treatment-resistant depression in 2019 and a dextromethorphan/bupropion combination in 2022. The 2006 report of spirituality-evoking effects of psilocybin led to subsequent striking observations of rapid and enduring antidepressant effects of psyilocybin and other psychedelic drugs and the launch of numerous biotech companies. Clinical trial listings for ongoing studies with numerous other potential rapid-acting medicines (e.g., (R)-ketamine, esmethadone, zuranolone, psychedelics, mGlu2/3 receptor antagonists and NMDA receptor modulators) are prevalent [1].

AMPA receptors (AMPARs) are pivotal to the transduction of the antidepressant effects of conventional and rapid-acting antidepressants but have yet to be successfully utilized to generate a rapid-acting medication [2]. Potentiation of AMPARs by small molecules (AMPAkines) has raised neurotoxicity concerns, tolerability issues, and difficulties in identifying a potentiator with the optimal ability to energize (but not over-energize) excitatory neurotransmission. Although a Phase 1b study showed both mood and executive function improvements with the AMPAkine Org 26576, the development of this compound did not proceed. Clinical investigation of the AMPAkine TAK-653 in depressed patients is currently undergoing patient enrollment. TAK-653 has been studied in healthy volunteers where it demonstrated good tolerability and biological and antidepressant-associated biological activation [3]. There are also two Phase 2-ready AMPAkines under clinical development for sleep apnea, opioid-induced respiratory depression, and spinal cord injury (http://respirerx.com/product-pipeline/).

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