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Ketamine, a rapid-acting antidepressant, increases SWA during the first period of non-rapid eye movement (NREM1) sleep. However, research into how ketamine affects sleep and its connection to treatment outcomes in TRD has been limited by small sample sizes and a lack of comparison with healthy volunteers (HVs). This placebo-controlled study compared the effects of ketamine on NREM1 SWA in a large sample of unmedicated TRD patients (n\u2009=\u200991; 51\u2009F\/40\u2009M) and HVs (n\u2009=\u200942; 23\u2009F\/19\u2009M). Linear mixed-effects models and regression analyses, with post-hoc testing (paired\n                    <jats:italic>t<\/jats:italic>\n                    tests and Wilcoxon matched-pairs signed rank tests), were used to assess condition-related effects across baseline, ketamine, and placebo in TRD and HV participants. Age-related moderation of ketamine-associated NREM1 SWA changes and condition-related changes in sleep variables were also examined. At baseline, TRD patients had lower NREM1 SWA than HVs. Ketamine, but not placebo, increased NREM1 SWA in TRD patients, particularly in responders. In contrast, ketamine had no effect on NREM1 SWA in HVs. Following ketamine, TRD patients also showed significant increases in total sleep time and sleep efficiency and a reduction in sleep latency. In TRD patients, the ketamine-related increase in NREM1 SWA diminished with increasing age. Together, the results indicate that ketamine\u2019s antidepressant effects appear closely associated with its ability to modulate early SWA. These effects may also be linked to ketamine\u2019s ability to improve sleep architecture in TRD. Clinical Trials Identifier:\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.clinicaltrials.gov\" ext-link-type=\"uri\">www.clinicaltrials.gov<\/jats:ext-link>\n                    , NCT00088699, NCT01204918.\n                  <\/jats:p>","DOI":"10.1038\/s41386-026-02465-4","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T16:09:53Z","timestamp":1781626193000},"page":"2008-2015","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Modulation of early non-rapid eye movement slow wave activity by ketamine in treatment-resistant depression"],"prefix":"10.1038","volume":"51","author":[{"given":"Nadia","family":"Hejazi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mina","family":"Kheirkhah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brady","family":"Riedner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiaoping","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6437-7750","authenticated-orcid":false,"given":"Robin","family":"Chholak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7624-9676","authenticated-orcid":false,"given":"Reza","family":"Momenan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory","family":"Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Goldman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"Carlos A.","family":"Zarate","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,16]]},"reference":[{"key":"2465_CR1","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/0361-9230(93)90016-5","volume":"31","author":"P Achermann","year":"1993","unstructured":"Achermann P, Dijk DJ, Brunner DP, Borbely AA. 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Psychiatry Res. 1989;30:165\u201380.","journal-title":"Psychiatry Res"}],"container-title":["Neuropsychopharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41386-026-02465-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41386-026-02465-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41386-026-02465-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T14:23:31Z","timestamp":1790087011000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41386-026-02465-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,16]]},"references-count":43,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["2465"],"URL":"https:\/\/doi.org\/10.1038\/s41386-026-02465-4","relation":{},"ISSN":["0893-133X","1740-634X"],"issn-type":[{"value":"0893-133X","type":"print"},{"value":"1740-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,16]]},"assertion":[{"value":"13 March 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 May 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 May 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 June 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"CAZ is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation; as a co-inventor on a patent for the use of (2\u2009\n                      R\n                      ,6\u2009\n                      R\n                      )-hydroxynorketamine, (\n                      S\n                      )-dehydronorketamine, and other stereoisomeric dehydroxylated and hydroxylated metabolites of (\n                      R,S\n                      )-ketamine in the treatment of depression and neuropathic pain; and as a co-inventor on a patent application for the use of (2\u2009\n                      R\n                      ,6\u2009\n                      R\n                      )-hydroxynorketamine and (2\n                      S\n                      ,6\n                      S\n                      )-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorder. He has assigned his patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. BR is co-inventor on several joint patents between the Wisconsin Alumni Research Foundation and Koninklijke Philips NV related to sleep monitoring and sleep enhancement technology. He previously received royalty payments managed by the Wisconsin Alumni Research Foundation. All other authors have no conflict of interest to disclose, financial or otherwise.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}