From model psychosis to rapid antidepressant: a historical and conceptual review of ketamine's psychiatric history.

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.

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Abstract

Ketamine’s development in psychiatry exemplifies the evolution of psychopharmacology over six decades. Originally introduced as a dissociative anesthetic and psychotomimetic probe, ketamine has been repositioned as a rapidly acting antidepressant, particularly for treatment-resistant depression (TRD). This narrative review draws on historical sources, clinical trials, regulatory documents, and conceptual analyses to examine ketamine’s psychiatric trajectory, integrating historiographical and clinical perspectives to contextualize its shifting roles. Ketamine was initially valued in experimental psychopathology for modeling psychosis via N -methyl-D-aspartate receptor antagonism. By the early 2000s, clinical trials demonstrated rapid and robust antidepressant effects, challenging monoaminergic paradigms and stimulating new glutamatergic and neuroplasticity-based models of depression. Its dissociative effects, once interpreted as liabilities, became focal points of debate, though evidence suggests they are not essential for antidepressant efficacy. Intranasal esketamine received U.S. Food and Drug Administration approval in 2019 for TRD, while off-label intravenous racemic ketamine is widely used in practice. Ongoing challenges include safety, equity of access, regulatory oversight, and commercialization pressures. Ketamine’s psychiatric history illustrates the fluidity of therapeutic meaning and the interplay of pharmacology, diagnosis, and culture. Its repositioning highlights new opportunities for rapid-acting treatments while underscoring the ethical and clinical responsibilities of integrating innovative agents into psychiatric care.