Ketamine and serotonergic psychedelics: An update on the mechanisms and biosignatures underlying rapid-acting antidepressant treatment

Abstract

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_A receptor activity. The similarities in downstream mechanisms may explain why ketamine, and potentially SPs, exert rapid-acting antidepressant effects. However, research on SPs is still in its infancy compared to the ongoing research that has been conducted with ketamine. For both therapeutics, issues with regulation and proper controls should be addressed before more widespread implementation. This article is part of the Special Issue on "Ketamine and its Metabolites".

Keywords: Biosignatures; Depression; Ketamine; Rapid-acting therapeutics; Serotonergic psychedelics.

Figure 1.. Hypothesized convergent and divergent mechanisms of ketamine and serotonergic psychedelics (SPs).

Ketamine increases glutamate release into the synapse through preferential blockade of NMDARs on GABAergic interneurons (disinhibition hypothesis) or other methods. This glutamate “surge” leads to downstream signaling that transiently activates mTORC1, increasing synaptic protein translation of PSD-95, AMPARs, and others. SPs trigger this glutamate surge through downstream GPCR pathways after 5-HT receptor activation, which leads to parallel mTORC1 activation and subsequent increases in synaptic protein translation. Other proposed mechanisms of antidepressant effects include binding to mu-opioid receptors and normalizing GABAergic activity through either mGluR2/3 (ketamine/(2R,6R)-HNK) or post-synaptic 5-HT2A receptors (SPs). Figure is approximate for illustrative purposes. Abbreviations: 5-HT: 5-hydroxytryptamine; AMPAR: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; GPCR: G protein-coupled receptors; HNK: hydroxynorketamine; mGluR: metabotropic glutamate receptor; mTORC1: mechanistic target of rapamycin complex 1; PSD-95: postsynaptic density protein 95.