Antidepressant Efficacy and Tolerability of Ketamine and Esketamine: A Critical Review.
Patricio Molero, J A Ramos-Quiroga, Rocío Martín‐Santos, E Calvo-Sánchez, Luis Gutiérrez-Rojas, J J Meana
CNS Drugs May 2018 DOI: 10.1007/s40263-018-0519-3 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Interventions | Ketamine Esketamine |
| Topics | Esketamine Ketamine |
| Key findings | The authors report that single and repeated doses of intravenous ketamine produce rapid antidepressant and probably antisuicidal effects in treatment-resistant depression, with response rates over 60% at 4.5 hours and over 40% at 7 days, and that intranasal esketamine shows comparable effects. They argue that long-term safety concerns, including neurocognitive and urologic toxicity and substance use disorder risk, remain unresolved. |
Abstract
Ketamine and its enantiomer S-ketamine (esketamine) are promising candidates to produce a rapid-onset antidepressant effect in treatment-resistant depression. Ketamine causes continued blockade of the glutamate N-methyl-D-aspartate (NMDA) receptor, though this might not primarily mediate the antidepressant effect. Alternative hypotheses include selectivity for the NMDA receptor subtype containing the NMDA receptor subunit 2B (NR2B), inhibition of the phosphorylation of the eukaryotic elongation factor 2 (eEF2) kinase, increased expression of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrKB), and activation of the mammalian target of rapamycin (mTOR) signaling pathway, alongside other independent actions attributed to the ketamine metabolism to R-hydroxynorketamine (R-HNK). The enantiomer S-ketamine (esketamine) displays approximately fourfold greater affinity for the glutamate NMDA receptor in vitro than R-ketamine. Proof-of-concept single-dose and repeat-dose studies with intravenous ketamine show a significant antidepressant and probably antisuicidal effect in the short term, with response rates over 60% as early as 4.5 h after a single dose, with a sustained effect after 24 h, and over 40% after 7 days. This response can be further sustained over several weeks with repeated doses (two to three doses per week). Tolerability seems acceptable in the short term, with transient elevation of blood pressure and mild and transient dissociative and psychotomimetic effects. Intranasal esketamine has shown a comparable antidepressant effect, which has resulted in the US FDA granting the drug a "breakthrough therapy" designation, and theoretically it may offer an improved tolerability profile. However, major concerns remain regarding an effective protocol to maintain the clinical antidepressant effect of ketamine seen with acute administration and the safety of ketamine and esketamine in the long term, specifically related to potential neurocognitive and urologic toxicity, together with the potential induction of substance use disorders. Ketamine and esketamine are not currently approved treatments for depression, but the clinical use of ketamine is increasing in a variety of practice settings internationally.
Comparable studies
Other narrative reviews on esketamine, 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 | |
| Long-term safety of ketamine and esketamine in treatment of depression | 2022 | Review | |
| Ketamine, Esketamine, and Arketamine: Their Mechanisms of Action and Applications in the Treatment of Depression and Alleviation of Depressive Symptoms. | 2024 | Review | |
| The potential of ketamine for posttraumatic stress disorder: a review of clinical evidence. | 2023 | Review | |
| Variations in BDNF and Their Role in the Neurotrophic Antidepressant Mechanisms of Ketamine and Esketamine: A Review. Patients with depression | 2024 | Narrative review |
Citations in the library
Cited by 95
- Ketamine as an antidepressant: overview of its mechanisms of action and potential predictive biomarkers Therapeutic Advances in Psychopharmacology 2020
- Glutamatergic Neurotransmission: Pathway to Developing Novel Rapid-Acting Antidepressant Treatments The International Journal of Neuropsychopharmacology November 14, 2018
- Substance-Induced Psychoses: An Updated Literature Review Frontiers in Psychiatry December 23, 2021
- Rapid-acting antidepressants. Advances in pharmacology (San Diego, Calif.) 2019
- Efficacy of a single low dose of esketamine after childbirth for mothers with symptoms of prenatal depression: randomised clinical trial. BMJ April 10, 2024
and 90 more in the library
Cites 28
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial American Journal of Psychiatry August 28, 2013
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
- Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression JAMA Psychiatry December 27, 2017
and 23 more in the library