From model psychosis to rapid antidepressant: a historical and conceptual review of ketamine’s psychiatric history
Bibliographic record
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.004 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.004 | 0.003 |
| Science and technology studies | 0.001 | 0.005 |
| Scholarly communication | 0.003 | 0.005 |
| Open science | 0.001 | 0.002 |
| Research integrity | 0.002 | 0.004 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".