Ketamine and serotonergic psychedelics An update on the mechanisms and biosignatures underlying rapid-acting antidepressant treatment.
The discovery of ketamine as a rapid-acting antidepressant spurred significant research to understand its underlying mechanisms of action and to identify other novel compounds that may act similarly. Serotonergic psychedelics (SPs) have shown initial promise in treating depression, though the challenge of conducting randomized controlled trials with SPs and the necessity of long-term clinical observation are important limitations. This review summarizes the similarities and differences between the psychoactive effects associated with both ketamine and SPs and the mechanisms of action of these compounds, with a focus on the monoaminergic, glutamatergic, gamma-aminobutyric acid (GABA)-ergic, opioid, and inflammatory systems. Both molecular and neuroimaging aspects are considered. While their main mechanisms of action differ-SPs increase serotonergic signaling while ketamine is a glutamatergic modulator-evidence suggests that the downstream mechanisms of action of both ketamine and SPs include mechanistic target of rapamycin complex 1 (mTORC1) signaling and downstream GABA