{"doi":"10.17615/wfvq-kk18","title":"NMDAR inhibition-independent antidepressant actions of ketamine metabolites","abstract":"Major depressive disorder afflicts ~16 percent of the world population at some point in their lives. Despite a number of available monoaminergic-based antidepressants, most patients require many weeks, if not months, to respond to these treatments, and many patients never attain sustained remission of their symptoms. The non-competitive glutamatergic N-methyl-D-aspartate receptor (NMDAR) antagonist, (R,S)-ketamine (ketamine), exerts rapid and sustained antidepressant effects following a single dose in depressed patients. Here we show that the metabolism of 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 actions in vivo. Notably, we demonstrate that these antidepressant actions are NMDAR inhibition-independent but they involve early and sustained α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor activation. We also establish that (2R,6R)-HNK lacks ketamine-related side-effects. Our results indicate a novel mechanism underlying ketamine’s unique antidepressant properties, which involves the required activity of a distinct metabolite and is independent of NMDAR inhibition. These findings have relevance for the development of next generation, rapid-acting antidepressants.","journal":"Carolina Digital Repository (University of North Carolina at Chapel Hill)","year":2020,"id":139606,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9519,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":276754,"name":"Peixiong Yuan","orcid":null,"position":1,"is_corresponding":false},{"id":317767,"name":"Yuhong Fang","orcid":"0000-0001-6742-5677","position":2,"is_corresponding":false},{"id":414733,"name":"Cheryl L. Mayo","orcid":null,"position":3,"is_corresponding":false},{"id":103670,"name":"Xi‐Ping Huang","orcid":"0000-0002-2585-653X","position":4,"is_corresponding":false},{"id":294820,"name":"Todd D. Gould","orcid":"0000-0003-1511-7183","position":5,"is_corresponding":false},{"id":603164,"name":"Katina S. S. Dossou","orcid":null,"position":6,"is_corresponding":false},{"id":291303,"name":"Ruin Moaddel","orcid":"0000-0002-6812-0127","position":7,"is_corresponding":false},{"id":471033,"name":"Irving W. Wainer","orcid":"0000-0003-1643-5845","position":8,"is_corresponding":false},{"id":258191,"name":"Craig J. Thomas","orcid":"0000-0001-9386-9001","position":9,"is_corresponding":false},{"id":602367,"name":"Scott M. Thompson","orcid":"0000-0001-7853-3278","position":10,"is_corresponding":false},{"id":603165,"name":"Jonathan Fischell","orcid":null,"position":11,"is_corresponding":false},{"id":384567,"name":"Edson X. Albuquerque","orcid":null,"position":12,"is_corresponding":false},{"id":603166,"name":"Manickavasagom Alkondon","orcid":null,"position":13,"is_corresponding":false},{"id":602368,"name":"Heather J. Pribut","orcid":"0000-0002-3166-6409","position":14,"is_corresponding":false},{"id":602369,"name":"N. Singh","orcid":"0000-0003-0419-0684","position":15,"is_corresponding":false},{"id":344498,"name":"Panos Zanos","orcid":"0000-0002-1968-8648","position":16,"is_corresponding":false},{"id":413308,"name":"Gregory I. Elmer","orcid":"0000-0002-1483-3690","position":17,"is_corresponding":false},{"id":230008,"name":"Carlos A. Zarate","orcid":"0000-0003-4442-7412","position":18,"is_corresponding":false},{"id":602370,"name":"Polymnia Georgiou","orcid":"0000-0003-3171-9993","position":19,"is_corresponding":false},{"id":449146,"name":"Patrick J. Morris","orcid":"0000-0003-2380-4178","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:17:10.185988Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}