Is the antidepressant efficacy of ketamine and esketamine mediated via opioid mechanisms?
Andy Lu, Heidi Xu, Gia Han Le, Christine E. Dri, Sabrina Wong, Roger Ho, Bing Cao, Heidi Ka Ying Lo, Taeho Greg Rhee, Liyang Yin, Hernán F Guillen-Burgos, Roger S McIntyre
European Psychiatry 2026 DOI: 10.1192/j.eurpsy.2026.10157 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Esketamine Ketamine |
| Citations | 4 |
| Key findings | The opioid system likely functions as a context-dependent modulator of ketamine's antidepressant effects rather than a primary mediator. |
Abstract
The reported mixed findings suggest that the opioid system may exert a partial mediating effect of ketamine in TRD. However, given the inconsistent attenuation of ketamine's antidepressant effects by opioid receptor antagonists, the opioid system likely functions as a context-dependent modulator rather than a primary mediator, particularly at standard antidepressant doses.
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 4
- Integrating multi-receptor and neuron–glia mechanisms of ketamine's antidepressant action: a convergence framework for understanding efficacy Frontiers in Molecular Neuroscience October 21, 2026
- A conceptual framework based on current and emerging treatments for treatment-resistant depression: mechanistic evolution, clinical evidence, and future directions. Expert Review of Neurotherapeutics July 1, 2026
- Ketamine and Evolving Neuroplasticity. Clinical drug investigation June 13, 2026
- The Montreal model of ketamine-therapy for alcohol use disorder and comorbid treatment-resistant depression: protocol for a feasibility trial BMJ Open March 1, 2026