From psychache to neuroplasticity: A unified rescue-repair model of Ketamine's anti-suicidal action.
Yoav Domany, Aviv Solomon-Shashua
Neuroscience & Biobehavioral Reviews June 7, 2026 DOI: 10.1016/j.neubiorev.2026.106804 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Theoretical or philosophical paper Peer reviewed |
|---|---|
| Intervention | Ketamine |
| Topics | Esketamine Ketamine Neuroplasticity |
| Key points | Proposes a Unified Rescue-Repair Model of Ketamine's Anti-Suicidal Action, describing a two-phase mechanism: acute glutamatergic rescue and delayed structural repair. |
Abstract
Suicide, the individual desire to take one's own life, at whose core lies the unbearable psychological pain Shneidman called psychache, is a uniquely human experience. Unlike depression, suicidality has no preclinical analog. Suicidality and chronic depression, long treated as a single clinical entity, are increasingly recognized as partly separable in neurobiology and treatment response. Suicidality therefore cannot be captured in any single voice; grasping it requires an integrative reading across phenomenology, clinical presentation, and neurobiology spanning receptors, cells, circuits, and networks. Ketamine offers such a view, producing rapid reductions in suicidal ideation that precede, and appear partly separable from, its antidepressant action. Its mechanism, from glutamatergic surge to synaptogenesis, is partly characterized at every level, yet cannot be explained from any one of them alone. We propose the Unified Rescue-Repair Model of Ketamine's Anti-Suicidal Action: a two-phase integrative reading. The first phase, an acute rescue, opens within minutes: a glutamatergic surge silences the lateral habenula, transiently disrupts default-mode and salience network connectivity, and modulates mu-opioid signaling in social pain circuitry, with acute alterations in subjective experience. The second phase, a structural repair, opens simultaneously but unfolds over hours to days: an adenosine surge restores neuronal bioenergetics, resolves neuroinflammation, and drives the formation of new synapses. Within this architecture the model identifies two candidate phenotypes and proposes three empirically tractable predictions for validation. Ketamine's singular therapeutic effect affords a glance into the complex neuroscience underlying suicidality. The integrative reading we develop sheds light on the devastating human experience of suicidality itself.
Comparable studies
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| Study | Year | Design | Participants |
|---|---|---|---|
| A Dendrite-Focused Framework for Understanding the Actions of Ketamine and Psychedelics | 2020 | Theoretical or philosophical paper | |
| Does Psychedelic Therapy Have a Transdiagnostic Action and Prophylactic Potential? | 2021 | Theoretical or philosophical paper | |
| A complex systems perspective on psychedelic brain action. | 2023 | Theoretical or philosophical paper | |
| Critical Period Plasticity as a Framework for Psychedelic-Assisted Psychotherapy | 2021 | Theoretical or philosophical paper | |
| Therapeutic mechanisms of psychedelics and entactogens. | 2023 | Theoretical or philosophical paper |
Citations in the library
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- Synaptic Dysfunction in Depression: Potential Therapeutic Targets Science October 4, 2012
- Trial of Psilocybin versus Escitalopram for Depression New England Journal of Medicine April 14, 2021
and 53 more in the library