A review of potential neuropathological changes associated with ketamine
Danica Nogo, Hana Nazal, Yuetong Song, Kayla M Teopiz, Roger Ho, Roger S McIntyre, Leanna M.W. Lui, Joshua D. Rosenblat
Expert Opinion on Drug Safety May 3, 2022 DOI: 10.1080/14740338.2022.2071867 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Depression Ketamine Esketamine |
| Keywords | Neuropathology Anesthetic Adverse effect Antidepressant Dosing Nmda receptor Pharmacology Anesthesia Disease Hippocampus |
| Citations | 17 |
| Key findings | Chronic high-dose ketamine exposure in substance use disorder populations is associated with neurotoxic effects, but it is unknown whether repeated sub-anesthetic doses used for treatment-resistant depression cause similar neuropathology. |
Abstract
INTRODUCTION: Ketamine is an established intervention for treatment-resistant depression (TRD). However, long-term adverse effects with repeated doses remain insufficiently characterized. Although several animal models have shown N-methyl-D-aspartate glutamate receptor antagonists to produce various neuropathological reactions, attention surrounding the risk of brain lesions has been minimal. AREAS COVERED: The current review focuses on potential neuropathological changes associated with ketamine. Search terms included variations of ketamine, Olney lesions, tau hyperphosphorylation, and parvalbumin interneurons. EXPERT OPINION: Daily high-dose ketamine use in substance use disorder (SUD) populations was associated with clear neurotoxic effects, while no studies specifically evaluated effects of ketamine protocols used for TRD. It is difficult to discern effects directly attributable to ketamine due to methodological factors, such as comorbidities and dramatic differences in dose in SUD populations versus infrequent sub-anesthetic doses typically prescribed for TRD. Taken together, animal models and human ketamine SUD populations suggest potential neuropathology with chronic high-dose ketamine exposure exceeding those recommended for adults with TRD. It is unknown whether repeat sub-anesthetic dosing of ketamine in adults with TRD is associated with Olney lesions or other neuropathologies. In the interim, practitioners should be vigilant for this possibility recognizing that the condition itself is associated with neurodegenerative processes.
Comparable studies
Other narrative reviews on ketamine 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 | |
| Ketamine: a paradigm shift for depression research and treatment | 2019 | Review | |
| Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective | 2019 | Review | |
| Ketamine: A tale of two enantiomers | 2020 | Review | |
| Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor | 2021 | Review |
Citations in the library
Cited by 6
- Ketamine for Depression, but at What Cost? A Review of Ketamine’s Neurotoxic Effects From Preclinical and Human Studies American Journal of Psychiatry September 10, 2025
- Structural Neurotoxic and Neuroprotective Effects of Ketamine and Esketamine in Preclinical and Human Studies: A Systematic Review Research Square May 27, 2026
- Esketamine in Geriatric Depression and Pseudodementia: A Case Study Clinical Neuropsychopharmacology and Addiction April 2, 2025
- The potential therapeutic effect of donepezil on a ketamine rat model of psychosis Journal of advanced pharmacy education and research 2025
- Oral ketamine may offer a solution to the ketamine conundrum Psychopharmacology December 1, 2023
and 1 more in the library
Cites 18
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- NMDA Antagonist Neurotoxicity: Mechanism and Prevention Science December 6, 1991
- R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Translational Psychiatry September 1, 2015
- Ketamine-Induced Loss of Phenotype of Fast-Spiking Interneurons Is Mediated by NADPH-Oxidase Science December 6, 2007
- GABA interneurons are the cellular trigger for ketamine's rapid antidepressant actions. Journal of Clinical Investigation November 19, 2019
and 13 more in the library