From psychache to neuroplasticity: A unified rescue-repair model of Ketamine's anti-suicidal action.
Neurosci Biobehav Rev June 7, 2026 Yoav Domany, Aviv Solomon-Shashua
Suicidality, driven by unbearable psychological pain, is a uniquely human experience increasingly recognized as partly separable from depression in neurobiology and treatment response. Ketamine produces rapid reductions in suicidal ideation that precede and are partly separable from its antidepressant effects. The proposed Unified Rescue-Repair Model describes a two-phase mechanism: an acute rescue phase within minutes involving glutamatergic surge silencing the lateral habenula and disrupting network connectivity, and a structural repair phase unfolding over hours to days involving adenosine surge restoring neuronal bioenergetics and driving synaptogenesis. The model identifies two candidate phenotypes and proposes three predictions for validation.