Esketamine Nasal Spray: Mechanism of Action, Clinical, and Translational Science.
Matthijs W Van Hoogdalem, Dong-Jing Fu, Wayne C. Drevets, Peter Zannikos
Clinical and Translational Science April 1, 2026 DOI: 10.1111/cts.70527 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Intervention | Esketamine nasal spray |
| Dose | 56 mg or 84 mg |
| Topics | Esketamine |
| Keywords | Treatment‐resistant depression |
| Key findings | Esketamine nasal spray provides rapid antidepressant effects through NMDA receptor antagonism and is approved as monotherapy for treatment-resistant depression. |
Abstract
Major depressive disorder (MDD) imposes a substantial burden worldwide, with treatment-resistant depression (TRD) and major depressive disorder with acute suicidal ideation or behavior (MDSI) representing two of the most severe clinical challenges. Conventional antidepressants often require several weeks to exert benefit, leaving patients symptomatic and at risk during this delay. Esketamine nasal spray was the first glutamate-modulating antidepressant to enter clinical practice and was recently approved as the first and only monotherapy for adults with TRD. Administered at 56 mg or 84 mg, esketamine offers a rapid onset of action. Intranasal delivery yields approximately 50% bioavailability and peak concentrations within 20-40 min, correlating with early clinical effects. N-methyl-D-aspartate (NMDA) receptor antagonism on inhibitory interneurons disinhibits glutamate release and modulates downstream synaptic plasticity pathways, providing a mechanistic basis for the rapid antidepressant effects of esketamine. This review summarizes the regulatory approval, mechanism of action, and pharmacokinetic/pharmacodynamic characteristics, together with key clinical trial efficacy and safety data for esketamine nasal spray in TRD and MDSI.
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
Cites 24
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Journal of Neuroscience April 15, 1997
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- 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
and 19 more in the library