From Psychache to Neuroplasticity: A Unified Rescue-Repair Model of Ketamine’s Anti-Suicidal Action

AI Summary

Unified Rescue-Repair Model posits two phases: rapid rescue within minutes and concurrent structural repair unfolding over hours to days.
Acute rescue involves a glutamatergic surge, lateral habenula silencing, disrupted default mode and salience networks, and mu opioid modulation reducing suicidal ideation.
Structural repair features an adenosine surge restoring bioenergetics, resolving neuroinflammation, and driving synaptogenesis, yielding testable phenotypes and predictions.

Neurosci Biobehav Rev. 2026 Jun 7:106804. doi: 10.1016/j.neubiorev.2026.106804. Online ahead of print.

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.

PMID:42259434 | DOI:10.1016/j.neubiorev.2026.106804

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