What clinicians need to know about intranasal esketamine for treatment-resistant depression?
Judith D. Hope, David L Copolov, John Tiller, M. Galbally, Malcolm Hopwood, Richard Newton, Nick Keks
Australasian Psychiatry November 14, 2023 DOI: 10.1177/10398562231211171 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Narrative review Peer reviewed |
|---|---|
| Population | Adults with treatment-resistant depression in pivotal esketamine trials |
| Interventions | Esketamine oral antidepressant |
| Duration | 4-week treatment phase; 6-month follow-up after withdrawal in stable remitters |
| Topics | Depression Esketamine Ketamine |
| Key findings | Intranasal esketamine plus an oral antidepressant produced 37% higher remission at four weeks than placebo plus antidepressant, with comparable improvement in suicidality. Relapse occurred in 45% of stable remitters after esketamine withdrawal over six months versus 25% who continued it. The authors conclude esketamine is moderately effective and acceptably tolerable, but note cost and the need for long-term use and abuse vigilance. |
Abstract
Objective: To review the usefulness of esketamine for treatment-resistant depression.
Method: Pivotal trials of intranasal esketamine in treatment-resistant depression were synthesized as a narrative review.
Results: Esketamine is postulated to act through antagonism of N-methyl-D-aspartate (NMDA) glutamate receptors, but opioidergic effects may also be involved. Unlike intravenous ketamine, esketamine is given intranasally (under clinical observation), usually in addition to an oral antidepressant. Trials compared esketamine plus antidepressant versus placebo plus antidepressant. At 4 weeks, remission was 37% higher with esketamine/antidepressant than placebo/antidepressant. Speed of response and improvement in suicidality were comparable. In stable remitters on esketamine/antidepressant, 45% relapsed when esketamine was withdrawn over the following 6 months (whereas 25% relapsed on esketamine/antidepressant). Response appears less likely in patients with multiple antidepressant failures. Adverse effects include dissociation, dizziness, nausea, sedation, and headache but no psychosis. Hypertension affected 13%, especially older patients. Dose frequency is twice-weekly for 4 weeks, then weekly/fortnightly thereafter. No abuse has been reported. Unsubsidised cost may be beyond the reach of many Australians.
Conclusion: Intranasal esketamine plus antidepressant has been approved by regulators as moderately effective and acceptably tolerable for treatment-resistant depression. Cost is a drawback. Use often needs to be long-term and vigilance for abuse is essential.
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 5
- Novel rapid treatment options for adolescent depression. Pharmacological Research March 1, 2024
- Major challenges in youth psychopathology: treatment-resistant depression. A narrative review. Frontiers in Psychiatry 2024
- Efficacy and safety of esketamine for pediatric gastrointestinal endoscopy: a meta-analysis and trial sequential analysis. Frontiers in Pharmacology 2024
- 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
- Dose-dependent adverse events of esketamine in treatment-resistant depression: a systematic review and meta-analysis of randomized controlled trials. Frontiers in Pharmacology 2026
Cites 14
- 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
- Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression JAMA Psychiatry June 5, 2019
- Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation American Journal of Psychiatry March 17, 2021
- 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
- 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 9 more in the library