The Ketamine Antidepressant Story: New Insights
Tahani K. Alshammari
Molecules December 7, 2020 DOI: 10.3390/molecules25235777 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Intervention | Ketamine |
| Dose | single subanesthetic dose |
| Topics | Esketamine Ketamine |
| Key findings | Argues that ketamine's rapid and sustained antidepressant effects, achieved with a single subanesthetic dose, challenge the monoamine theory of depression and point to new molecular pathways. The authors propose that hydroxynorketamine metabolites and other dose-dependent mechanisms warrant further study to inform development of novel antidepressants for treatment-resistant depression. |
Abstract
Ketamine is a versatile agent primarily utilized as a dissociative anesthetic, which acts by blocking the excitatory receptor N-methyl-d-aspartate receptor (NMDA). It functions to inhibit the current of both Na+ and K+ voltage-gated channels, thus preventing serotonin and dopamine reuptake. Studies have indicated that administering a single subanesthetic dose of ketamine relieves depression rapidly and that the effect is sustained. For decades antidepressant agents were based on the monoamine theory. Although ketamine may not be the golden antidepressant, it has opened new avenues toward mechanisms involved in the pathology of treatment-resistant depression and achieving rapid antidepressant effects. Thus, preclinical studies focusing on deciphering the molecular mechanisms involved in the antidepressant action of ketamine will assist in the development of a new antidepressant. This review was conducted to elucidate the emerging pathways that can explain the complex dose-dependent mechanisms achieved by administering ketamine to treat major depressive disorders. Special attention was paid to reviewing the literature on hydroxynorketamines, which are ketamine metabolites that have recently attracted attention in the context of depression.
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 9
- Ketamine as a therapeutic agent in major depressive disorder and posttraumatic stress disorder: Potential medicinal and deleterious effects. Ibrain 2023
- Efficacy and safety of ketamine and esketamine in reducing the incidence of postpartum depression: an updated systematic review and meta-analysis. BMC Pregnancy and Childbirth February 6, 2025
- Is ketamine safe for individuals in higher level of care treatment for eating disorders? Analysis of safety of subanesthetic ketamine in 104 patients. Journal of Psychiatric Research August 1, 2025
- Ketamine retards recovery from reward downshift and supports conditioned taste aversion. Pharmacology, Biochemistry, and Behavior October 28, 2023
- Neurobiological Mechanisms of Ketamine Use, its Addiction, and Withdrawal: A Mini Review. Current reviews in clinical and experimental pharmacology March 3, 2025
and 4 more in the library
Cites 23
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Translational Psychiatry September 1, 2015
- Ketamine for chronic pain: risks and benefits British Journal of Clinical Pharmacology February 21, 2013
- GABA interneurons are the cellular trigger for ketamine's rapid antidepressant actions. Journal of Clinical Investigation November 19, 2019
- Mechanistic Target of Rapamycin-Independent Antidepressant Effects of (R)-Ketamine in a Social Defeat Stress Model. Biological Psychiatry 2018
and 18 more in the library