Safety and effectiveness of NMDA receptor antagonists for depression: A multidisciplinary review.
Thomas J Moore, Abdallah Alami, G Caleb Alexander, Donald R Mattison
Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy July 2022 DOI: 10.1002/phar.2707 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Interventions | Ketamine Esketamine |
| Dose | subanesthetic doses |
| Topics | Esketamine Depression |
| Keywords | Drug approval Evidence-based toxicology Ketamine hydrochloride Phencyclidine-related disorders |
| Key findings | The authors argue that evidence from multiple sources raises substantial questions about both the safety and effectiveness of ketamine and esketamine for psychiatric disorders. They review reported benefits in difficult-to-treat depression, rapid onset within a day, and immediate effects on suicidality, while highlighting unresolved safety concerns about repeatedly inducing an altered mental state and about whether an adequate safety margin exists to rule out neurotoxic effects seen in animal studies. |
Abstract
Ketamine, an anesthetic available since 1970, and esketamine, its newer S-enantiomer, provide a novel approach for the treatment of depression and other psychiatric disorders. At subanesthetic doses, the two drugs, along with their older congener, phencyclidine (PCP), induce a transient, altered mental state by blocking the N-methyl-D-aspartate (NMDA) receptor for glutamate, the primary excitatory neurotransmitter in the mammalian central nervous system. This multidisciplinary review examines the pharmacology/direct effects on consciousness, effectiveness in depression and acute suicidality, and safety of these fast-acting NMDA antagonists. To capture the essence of 60 years of peer-reviewed literature, we used a semi-structured approach to the subtopics, each of which required a different search strategy. We review the evidence for the three primary reported benefits of the two clinical drugs when used for depression: success in difficult-to-treat patients, rapid onset of action within a day, and immediate effects on suicidality. Key safety issues include the evidence-and lack thereof-for the effects of repeatedly inducing this altered mental state, and whether an adequate safety margin exists to rule out the neurotoxic effects seen in animal studies. This review includes evidence from multiple sources that raise substantial questions about both safety and effectiveness of ketamine and esketamine for psychiatric disorders.
Comparable studies
Other narrative reviews on esketamine 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 | |
| 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 | |
| Variations in BDNF and Their Role in the Neurotrophic Antidepressant Mechanisms of Ketamine and Esketamine: A Review. Patients with depression | 2024 | Narrative review | |
| The Possible Application of Ketamine in the Treatment of Depression in Alzheimer’s Disease | 2022 | Review |
Citations in the library
Cited by 10
- Long-Term Safety and Maintenance of Response With Esketamine Nasal Spray in Participants With Treatment-Resistant Depression: Interim Results of the SUSTAIN-3 Study Neuropsychopharmacology May 12, 2023
- Demystifying the Antidepressant Mechanism of Action of Stinels, a Novel Class of Neuroplastogens: Positive Allosteric Modulators of the NMDA Receptor. Pharmaceuticals January 24, 2025
- Towards an expanded neurocognitive account of ketamine's rapid antidepressant effects. The International Journal of Neuropsychopharmacology February 4, 2025
- Substance Abuse and Cognitive Decline: The Critical Role of Tau Protein as a Potential Biomarker International Journal of Molecular Sciences August 7, 2025
- Intranasal esketamine significantly alleviates depression severity and suicidal ideations in electroconvulsive therapy (ECT) non-responders. European Archives of Psychiatry and Clinical Neuroscience July 1, 2025
and 5 more in the library
Cites 22
- Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study American Journal of Psychiatry May 21, 2019
- Measurement of dissociative states with the Clinician‐Administered Dissociative States Scale (CADSS) Journal of Traumatic Stress 1998
- Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study American Journal of Psychiatry April 16, 2018
- Ketamine use: a review Addiction July 21, 2011
- Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1) The International Journal of Neuropsychopharmacology July 9, 2019
and 17 more in the library