{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T01:30:08Z","timestamp":1788485408882,"version":"build-2803163510"},"reference-count":33,"publisher":"American Medical Association (AMA)","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"\n Importance<\/jats:title>\n Ketamine exerts rapid antidepressant effects. However, currently available ketamine-based treatments are associated with dissociative and cardiovascular adverse effects.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To evaluate the antidepressant efficacy and tolerability of KET01, a novel, oral, prolonged-release racemic ketamine tablet formulation.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n KET01-03 was an active-comparator, double-blind, double-dummy, crossover phase 1 randomized clinical trial (RCT) conducted among healthy adult male volunteers (aged \u226518 years) between July and August 2023 at a single trial site in Germany. KET01-02 was a placebo-controlled, double-blind phase 2 RCT conducted between May 2022 and May 2023 among adult outpatients (aged \u226518 years) with treatment-resistant depression across 29 trial sites in the Czech Republic, Germany, and Poland. KET01-02 data were analyzed from May to October 2023 and KET01-03 data from August to October 2024.<\/jats:p>\n <\/jats:sec>\n \n Interventions<\/jats:title>\n KET01-03 investigated a single dose of KET01 (240 mg) vs intranasal esketamine (84 mg), and KET01-02 evaluated KET01 dosages of 120 or 240 mg\/d (adjunctive to ongoing standard therapy) against placebo for 3 weeks.<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n The primary end points were the difference in mean maximum change in Clinician-Administered Dissociative States Scale (CADSS) score between KET01 and intranasal esketamine within the first 24 hours in KET01-03 and the least squares (LS) mean change in Montgomery-\u00c5sberg Depression Rating Scale (MADRS) score from baseline to day 21 for 240 mg\/d of KET01 vs placebo in KET01-02.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n KET01-03 randomized 26 males (median age, 32 years [range, 21-45 years]), and KET01-02 randomized 122 outpatients with treatment-resistant depression (72 [59.0%] female; median age, 41 years [range, 19-65 years]). In KET01-03, intranasal esketamine but not KET01 induced significant dissociation within 24 hours after dosing (mean [SD] maximum change in CADSS score, 29.6 [12.5] points vs 0.7 [1.7] points;\n P<\/jats:italic>\n \u2009&amp;lt;\u2009.001). The maximum plasma concentration was lower for KET01 (39.1 ng\/mL) than esketamine (104.1 ng\/mL); conversely, exposure to metabolites was higher for KET01 (eg, area under the curve [AUC] from baseline to last measurement for norketamine was 3.5 \u00b5g\u2009\u00d7\u2009h\/mL) than esketamine (AUC for [S]-norketamine, 1.4 \u00b5g\u2009\u00d7\u2009h\/mL). Pulse and blood pressure did not change markedly in the KET01 group in both trials, in contrast to rapid increases after intranasal esketamine in KET01-03. In KET01-02, the primary efficacy end point at day 21 was not met: LS mean MADRS score difference for 240 mg\/d of KET01 vs placebo was \u22121.82 points (95% CI, \u22126.21 to 2.57 points;\n P<\/jats:italic>\n \u2009=\u2009.41). However, a reduction in MADRS scores was observed 7 hours after administering the first 240 mg dose of KET01, with an LS mean difference vs placebo at day 4 (\u22123.66 [95% CI, \u22126.74 to \u22120.59] points; nominal\n P<\/jats:italic>\n \u2009=\u2009.02) and day 7 (\u22123.95 [95% CI, \u22127.75 to \u22120.15] points; nominal\n P<\/jats:italic>\n \u2009=\u2009.04). During follow-up, the LS mean MADRS point difference vs placebo at 4 weeks was \u22123.35 (95% CI, \u22127.62 to 0.93; nominal\n P<\/jats:italic>\n \u2009=\u2009.13).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n The antidepressant properties and tolerability profile of KET01 in these RCTs, including minimal dissociation and cardiovascular effects, support further development of oral KET01 formulation for at-home administration.<\/jats:p>\n <\/jats:sec>\n \n Trial Registration<\/jats:title>\n \n EU Clinical Trials Register Identifiers:\n 2023-503971-45-00<\/jats:ext-link>\n and\n 2021-004927-34<\/jats:ext-link>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2026.19121","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T15:32:00Z","timestamp":1782315120000},"page":"e2619121","source":"Crossref","is-referenced-by-count":2,"title":["Oral Prolonged-Release Ketamine for Treatment-Resistant Depression"],"prefix":"10.1001","volume":"9","author":[{"given":"Martin","family":"Walter","sequence":"first","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, University Hospital Jena, Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"zu Eulenburg","sequence":"additional","affiliation":[{"name":"HMNC Brain Health, Munich, Germany"},{"name":"University Medical Center Hamburg-Eppendorf, Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ani","family":"Damyanova","sequence":"additional","affiliation":[{"name":"HMNC Brain Health, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Schmid","sequence":"additional","affiliation":[{"name":"Develco Pharma Schweiz AG, Pratteln, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Schwienbacher","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim, Ingelheim am Rhein, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evangelos","family":"Papanastasiou","sequence":"additional","affiliation":[{"name":"HMNC Brain Health, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarina","family":"Maiboe","sequence":"additional","affiliation":[{"name":"HMNC Brain Health, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Arvastson","sequence":"additional","affiliation":[{"name":"HMNC Brain Health, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caren","family":"Strote","sequence":"additional","affiliation":[{"name":"HMNC Brain Health, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Gehrlach","sequence":"additional","affiliation":[{"name":"HMNC Brain Health, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans","family":"Eriksson","sequence":"additional","affiliation":[{"name":"HMNC Brain Health, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","published-online":{"date-parts":[[2026,6,24]]},"reference":[{"issue":"5","key":"zoi260531r1","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1176\/appi.ajp.2020.20081251","article-title":"Synthesizing the evidence for ketamine and esketamine in treatment-resistant depression: an international expert opinion on the available evidence and implementation.","volume":"178","author":"McIntyre","year":"2021","journal-title":"Am J Psychiatry"},{"issue":"4","key":"zoi260531r2","doi-asserted-by":"publisher","DOI":"10.1093\/ijnp\/pyv124","article-title":"Effects of low-dose and very low-dose ketamine among patients with major depression: a systematic review and meta-analysis.","volume":"19","author":"Xu","year":"2016","journal-title":"Int J Neuropsychopharmacol"},{"key":"zoi260531r3","doi-asserted-by":"publisher","first-page":"831","DOI":"10.1016\/j.jad.2020.09.007","article-title":"A systematic review and meta-analysis of the efficacy of intravenous ketamine infusion for treatment resistant depression: January 2009 - 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