Innovative Approaches to Depression Therapy: The Antidepressant Efficacy and Mechanisms of General Anesthetics.
Xiangying Wei, Shan Xu, Zhaoqiong Zhu
Current Neuropharmacology April 16, 2026 DOI: 10.2174/011570159x458197260226055817 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Population | Depression |
| Topics | Depression |
| Keywords | Anesthetic therapeutics. General anesthetics |
| Key findings | Several general anesthetics, including ketamine, propofol, isoflurane, and specific opioids, exhibit rapid and sustained antidepressant effects, with mechanisms involving modulation of glutamate and GABA signals and restoration of synaptic plasticity. |
Abstract
Depression represents a critical global health burden, ranking as the second leading cause of disability worldwide. Although drug therapies remain an important cornerstone in treating depression, we must acknowledge their significant shortcomings: they often take too long to work, cause difficult side effects, and fail to prevent relapse. Critically, while current drugs target specific symptoms, the disorder itself stems from a far more complex interplay of genetic, environmental, and biological factors. Notably, emerging evidence indicates that several general anesthetics exhibit both rapid and sustained antidepressant effects. Ketamine, through blocking N-methyl-D-aspartate (NMDA) receptors, has established a new paradigm for rapid-acting antidepressant intervention. Building on this breakthrough, researchers are now finding that other agents, including propofol, isoflurane, and specific opioids, show promising results across preclinical and clinical settings. This expanding evidence base significantly advances the therapeutic scope of anesthesiology while addressing treatment-resistant depression(TRD) affecting approximately one-third of patients. This review examines intravenous/inhalational anesthetics and opioid analgesics for depression manage-ment, synthesizing contemporary preclinical and clinical evidence with particular focus on random-ized controlled trials and mechanistic studies. Our review highlights the specific biological changes that drive these effects. Beyond monoamine regulation, key factors include modulation of glutamate and GABA signals, which contribute to the restoration of synaptic plasticity in damaged brain circuits. Through combining what is known with what remains unclear, specifically focusing on dosing and long-term outcomes. We argue that targeting these mechanisms is key to creating new rapid antidepressants for patients who do not respond to standard care. Yet, success depends on balancing benefits against risks and establishing consistent treatment rules.
Comparable studies
Other narrative reviews on depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Synaptic Dysfunction in Depression: Potential Therapeutic Targets | 2012 | Review | |
| Mindfulness-Based Cognitive Therapy for Depression: A New Approach to Preventing Relapse | 2003 | Review | |
| 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 | |
| Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function. General population | 2019 | Integrative review | |
| Sudarshan Kriya Yogic Breathing in the Treatment of Stress, Anxiety, and Depression: Part II—Clinical Applications and Guidelines | 2005 | Review |
Citations in the library
Cites 30
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- Sustained antidepressant effect of ketamine through NMDAR trapping in the LHb Nature October 18, 2023
- Modulation of the antidepressant effects of ketamine by the mTORC1 inhibitor rapamycin Neuropsychopharmacology February 24, 2020
- Eradicating Suicide at Its Roots: Preclinical Bases and Clinical Evidence of the Efficacy of Ketamine in the Treatment of Suicidal Behaviors International Journal of Molecular Sciences September 23, 2018
- NMDA Receptor Activation-Dependent Antidepressant-Relevant Behavioral and Synaptic Actions of Ketamine Journal of Neuroscience January 3, 2023
and 25 more in the library