ArticleNature2016
NMDAR inhibition-independent antidepressant actions of ketamine metabolites.
Article in Nature, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to 2 registered trials, which are not on this map. Cited by 842 papers, 4 of them syntheses that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
The Prevention of Post Operative Cognitive Dysfunction by Ketamine: a Prospective Multicenter Randomized Blinded Placebo-controlled Trial in Elderly Patients Undergoing Elective Orthopaedic Surgery
(2R,6R)-Hydroxynorketamine a Novel Therapeutic Analgesic for the Treatment of Neuropathic Pain: A Randomized Double Blind Cross-Over Trial.
Who cites it
842 citing papers in PubMed, 4 syntheses or guidelines pooled it, 1,565 citations in OpenAlex.
- Efficacy of racemic ketamine or esketamine monotherapy for reducing suicidal ideation in uni- or bipolar depression: a systematic review and meta-analysis.European archives of psychiatry and clinical neuroscience · 2025Pooled it
- Clinical trials since 2020 of rapid anti-suicidal ideation effects of ketamine and its enantiomers: a systematic review.Translational psychiatry · 2025Pooled it
- Effect and safety of perioperative ketamine/esketamine administration on postoperative pain and depression after breast cancer surgery: a systematic review and meta-analysis.Frontiers in pharmacology · 2025Pooled it
- Effects of psychedelics on neurogenesis and broader neuroplasticity: a systematic review.Molecular medicine (Cambridge, Mass.) · 2024Pooled it
- Modulation of early non-rapid eye movement slow wave activity by ketamine in treatment-resistant depression.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2026Trial
- Subacute effects of ketamine on neural correlates of reward processing.Translational psychiatry · 2026Trial
- The role of cytochrome P450 polymorphisms in the pharmacokinetics of oral esketamine.The pharmacogenomics journal · 2026Trial
- Esketamine hydrochloride in the management of moderate-to-severe depressive symptoms in patients undergoing multiple wound repair surgeries: A multi-centre randomized, double-blind, placebo-controlled trial.Clinical and translational medicine · 2026Trial
- Esketamine combined with hydromorphone versus hydromorphone for post-operative patient-controlled intravenous analgesia in children: a randomized controlled trial.European journal of medical research · 2026Trial
- Effect of Intraoperative Intravenous Infusion of Esketamine Combined with Dexmedetomidine on Postoperative Sleep Disturbance in Patients Undergoing Radical Mastectomy.Drug design, development and therapy · 2025Trial
- A Phase 1 Assessment of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of (2R,6R)-Hydroxynorketamine in Healthy Volunteers.Clinical pharmacology and therapeutics · 2024Trial
- Entactogen Effects of Ketamine: A Reverse-Translational Study.The American journal of psychiatry · 2024Trial
- Subanesthetic Ketamine Suppresses Locus Coeruleus-Mediated Alertness Effects: A 7T fMRI Study.The international journal of neuropsychopharmacology · 2024Trial
- Trial
- Acute Dissociation and Ketamine's Antidepressant and Anti-Suicidal Ideation Effects in a Midazolam-Controlled Trial.The international journal of neuropsychopharmacology · 2024Trial
- Ketamine Beyond Anaesthesia: Analgesic, Psychiatric, Antitumour, and Immunomodulatory Actions and Their Signalling Mechanisms.Current oncology reports · 2026Review
- Is (S)-norketamine an active mediator of esketamine's antidepressant effects?Molecular psychiatry · 2026Article
- From depression to bone health: examining the skeletal effects of classical and rapid-acting antidepressants.The international journal of neuropsychopharmacology · 2026Review
- Impaired contingency judgement in mice under ketamine: an implication for an altered sense of agency in schizophrenia.Psychopharmacology · 2026Article
- Determination of Enantiomers of Deschloroketamine and Its Metabolites in Wistar Rat Brains.Journal of separation science · 2026Article
782 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
20 authors at 7 institutions in 1 country.
Funding
Abstract
Major depressive disorder affects around 16 per cent of the world population at some point in their lives. Despite the availability of numerous monoaminergic-based antidepressants, most patients require several weeks, if not months, to respond to these treatments, and many patients never attain sustained remission of their symptoms. The non-competitive, glutamatergic NMDAR (N-methyl-d-aspartate receptor) antagonist (R,S)-ketamine exerts rapid and sustained antidepressant effects after a single dose in patients with depression, but its use is associated with undesirable side effects. Here we show that the metabolism of (R,S)-ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and that the (2R,6R)-HNK enantiomer exerts behavioural, electroencephalographic, electrophysiological and cellular antidepressant-related actions in mice. These antidepressant actions are independent of NMDAR inhibition but involve early and sustained activation of AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors). We also establish that (2R,6R)-HNK lacks ketamine-related side effects. Our data implicate a novel mechanism underlying the antidepressant properties of (R,S)-ketamine and have relevance for the development of next-generation, rapid-acting antidepressants.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.