Mechanisms of Ketamine and its Metabolites as Antidepressants
E. Hess, L. Riggs, Michael Michaelides, T. Gould
Biochemical Pharmacology December 1, 2021 DOI: 10.1016/j.bcp.2021.114892 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Esketamine Ketamine |
| Citations | 167 |
| Key findings | Ketamine's metabolites, particularly (2R,6R)-hydroxynorketamine, may contribute to its rapid antidepressant effects while avoiding adverse effects like dissociation and abuse potential. |
Abstract
Treating major depression is a medical need that remains unmet by monoaminergic therapeutic strategies that commonly fail to achieve symptom remission. A breakthrough in the treatment of depression was the discovery that the anesthetic (R,S)-ketamine (ketamine), when administered at sub-anesthetic doses, elicits rapid (sometimes within hours) antidepressant effects in humans that are otherwise resistant to monoaminergic-acting therapies. While this finding was revolutionary and led to the FDA approval of (S)-ketamine (esketamine) for use in adults with treatment-resistant depression and suicidal ideation, the mechanisms underlying how ketamine or esketamine elicit their effects are still under active investigation. An emerging view is that metabolism of ketamine may be a crucial step in its mechanism of action, as several metabolites of ketamine have neuroactive effects of their own and may be leveraged as therapeutics. For example, (2R,6R)-hydroxynorketamine (HNK), is readily observed in humans following ketamine treatment and has shown therapeutic potential in preclinical tests of antidepressant efficacy and synaptic potentiation while being devoid of the negative adverse effects of ketamine, including its dissociative properties and abuse potential. We discuss preclinical and clinical studies pertaining to how ketamine and its metabolites produce antidepressant effects. Specifically, we explore effects on glutamate neurotransmission through N-methyl D-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), synaptic structural changes via brain derived neurotrophic factor (BDNF) signaling, interactions with opioid receptors, and the enhancement of serotonin, norepinephrine, and dopamine signaling. Strategic targeting of these mechanisms may result in novel rapid-acting antidepressants with fewer undesirable side effects compared to ketamine.
Comparable studies
Other narrative reviews on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms | 2018 | Review | |
| Mechanisms of Ketamine Action as an Antidepressant | 2018 | Review | |
| 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 Pharmacology: An Update (Pharmacodynamics and Molecular Aspects, Recent Findings) | 2013 | Review | |
| A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders | 2017 | Review and consensus statement |
Citations in the library
Cited by 92
- NMDA Receptor Activation-Dependent Antidepressant-Relevant Behavioral and Synaptic Actions of Ketamine Journal of Neuroscience January 3, 2023
- Randomized trial of ketamine masked by surgical anesthesia in patients with depression Nature Mental Health October 19, 2023
- Arketamine, a new rapid-acting antidepressant: A historical review and future directions Neuropharmacology August 14, 2022
- The Psychedelic Future of Post-Traumatic Stress Disorder Treatment Current Neuropharmacology January 5, 2024
- Ketamine and serotonergic psychedelics: An update on the mechanisms and biosignatures underlying rapid-acting antidepressant treatment Neuropharmacology January 13, 2023
and 87 more in the library
Cites 53
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate British Journal of Pharmacology June 1, 1983
and 48 more in the library