The cognitive neuroscience of ketamine in major depression.
Sara Costi, Chloe Wigg, Erdem Pulcu, Susannah E Murphy, Catherine J Harmer
Brain June 30, 2025 DOI: 10.1093/brain/awaf242 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Intervention | Ketamine |
| Topics | Depression Ketamine Esketamine |
| Keywords | Fast-acting antidepressant Ketamine treatment Ketamine therapy Ketamine medication Ketamine drug Ketamine antidepressant Depression therapy Depression treatment Depression medication Mental health treatment Antidepressant therapy Neurocognitive impact Neurocognitive effects Brain effects Cognitive changes Neurological impact Rapid antidepressant Quick antidepressant Fast-acting medication |
| Citations | 3 |
| Key findings | Ketamine rapidly alleviates depressive symptoms including anhedonia within hours, with effects lasting days, and preclinical evidence suggests it influences punishment- and reward-related brain systems and reverses negative affective biases. |
Abstract
Ketamine's potential as a rapid-acting antidepressant was first identified in 2000, despite its long-standing use as an anesthetic agent. Clinically, ketamine alleviates depressive symptoms, including the difficult to treat symptom of anhedonia, within hours, with the effects of a single dose lasting for days. Since then, research has focused on uncovering the mechanisms underlying its rapid antidepressant effects in both humans and animal models. While its molecular and cellular effects have been extensively characterized, its impact on cognitive and neuropsychological mechanisms - potential mediators of its clinical efficacy - remains an area of ongoing investigation. Preclinical studies suggest that ketamine rapidly influences the lateral habenula (involved in punishment processing) and fronto-striatal (reward) systems, reverses negative affective biases in established memories, and promotes long-term stress resilience. Translating these findings to human models is crucial, and emerging evidence suggests that ketamine engages similar mechanisms in healthy volunteer and patient groups. However, its clinical application is constrained by acute side effects and an unknown long-term safety profile. Further research into ketamine's mechanisms of action will be essential to inform the development of novel, safer, and more accessible rapid-acting antidepressants.
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 4
- KET-MCI: A Pilot Safety and Tolerability Study of Single Infusion Intravenous Ketamine for Older Adults with Depression and Mild Cognitive Impairment American Journal of Geriatric Psychiatry February 24, 2026
- Ketamine attenuates habenula activity in response to aversive outcomes during Pavlovian learning bioRxiv (Cold Spring Harbor Laboratory) February 10, 2026
- Psilocybin rapidly, but not immediately, reverses reward learning deficits in a durable manner in an inflammatory rat model of depressive symptoms bioRxiv (Cold Spring Harbor Laboratory) January 15, 2026
- Depression: Ketamine quiets an unruly habenula. Current Biology October 19, 2026
Cites 43
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- 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
- Synaptic Dysfunction in Depression: Potential Therapeutic Targets Science October 4, 2012
- Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial American Journal of Psychiatry August 28, 2013
and 38 more in the library