How ketamine works: An actionable hypothesis.
Roberto Malinow
Proceedings of the National Academy of Sciences May 5, 2026 DOI: 10.1073/pnas.2533728123 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Theoretical or philosophical paper Peer reviewed |
|---|---|
| Topics | Depression Ketamine Esketamine |
| Keywords | Nmda |
| Key points | Proposes that ketamine's antidepressant effects arise from synaptic and circuit plasticity. |
Abstract
Ketamine has been shown to reduce depression and suicidality in individuals resistant to treatment by other drugs. Exactly how ketamine works is not known. Here, I propose a new hypothesis that involves synaptic and circuit plasticity and may lead to enhanced efficacy in treating depression as well as other conditions.
Comparable studies
Other theoretical and historical papers on ketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| An Integrative Approach to Ketamine Therapy May Enhance Multiple Dimensions of Efficacy: Improving Therapeutic Outcomes With Treatment Resistant Depression. | 2021 | Theoretical or philosophical paper | |
| Arketamine for cognitive impairment in psychiatric disorders | 2023 | Theoretical or philosophical paper | |
| The Montreal model: an integrative biomedical-psychedelic approach to ketamine for severe treatment-resistant depression | 2023 | Theoretical or philosophical paper | |
| Ketamine in Bipolar Disorder: A Review | 2020 | Theoretical or philosophical paper | |
| Rethinking the role of TRKB in the action of antidepressants and psychedelics. | 2024 | Theoretical or philosophical paper |
Citations in the library
Cites 11
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate British Journal of Pharmacology June 1, 1983
- Ketamine and rapid antidepressant action: new treatments and novel synaptic signaling mechanisms Neuropsychopharmacology July 24, 2023
- Sustained antidepressant effect of ketamine through NMDAR trapping in the LHb Nature October 18, 2023
and 6 more in the library