Ketamine for Depression: Advances in Clinical Treatment, Rapid Antidepressant Mechanisms of Action, and a Contrast with Serotonergic Psychedelics
Marina Kojić, Johan Saelens, Bashkim Kadriu, Carlos A. Zarate, Christoph Kraus
Current Topics in Behavioral Neurosciences March 22, 2022 DOI: 10.1007/7854_2022_313 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Depression Esketamine Ketamine Serotonin |
| Citations | 11 |
| Key findings | Ketamine and serotonergic psychedelics, despite distinct primary targets, may both produce rapid antidepressant effects through a glutamate surge that activates AMPA receptor throughput and increases BDNF levels. |
Abstract
The approval of ketamine for treatment-resistant depression has created a model for a novel class of rapid-acting glutamatergic antidepressants. Recent research into other novel rapid-acting antidepressants – most notably serotonergic psychedelics (SPs) – has also proven promising. Presently, the mechanisms of action of these substances are under investigation to improve these novel treatments, which also exhibit considerable side effects such as dissociation. This chapter lays out the historical development of ketamine as an antidepressant, outlines its efficacy and safety profile, reviews the evidence for ketamine’s molecular mechanism of action, and compares it to the proposed mechanism of SPs. The evidence suggests that although ketamine and SPs act on distinct primary targets, both may lead to rapid restoration of synaptic deficits and downstream network reconfiguration. In both classes of drugs, a glutamate surge activates α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) throughput and increases in brain-derived neurotrophic factor (BDNF) levels. Taken together, these novel antidepressant mechanisms may serve as a framework to explain the rapid and sustained antidepressant effects of ketamine and may be crucial for developing new rapid-acting antidepressants with an improved side effect profile.
Comparable studies
Other narrative reviews on ketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation Adults with treatment-resistant depression | 2021 | Review | |
| Ketamine: a paradigm shift for depression research and treatment | 2019 | Review | |
| Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective | 2019 | Review | |
| Ketamine: A tale of two enantiomers | 2020 | Review | |
| Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor | 2021 | Review |