How ketamine works: An actionable hypothesis.
Roberto Malinow
Proceedings of the National Academy of Sciences of the United States of America 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 |