From model psychosis to rapid antidepressant: a historical and conceptual review of ketamine's psychiatric history.
Ther Adv Psychopharmacol December 11, 2025 Casimiro Cabrera Abreu, Aleksandar Biorac, Ross J. Baldessarini et al.
Ketamine, originally developed as a dissociative anesthetic and a tool for modeling psychosis, has been repositioned as a rapidly acting antidepressant for treatment-resistant depression. This narrative review traces its trajectory over six decades, drawing on historical sources, clinical trials, and regulatory documents. By the early 2000s, trials showed rapid and robust antidepressant effects, challenging older monoamine-based theories and spurring new models involving glutamate and neuroplasticity. Its dissociative effects, once seen as drawbacks, are now debated but evidence suggests they are not necessary for efficacy.