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The safety and tolerability of racemic ketamine may be improved if given orally, as an extended-release tablet (R-107), compared with other routes of administration. In this phase 2 multicenter clinical trial, male and female adult patients with TRD and Montgomery\u2013Asberg Depression Rating Scale (MADRS) scores \u226520 received open-label R-107 tablets 120\u2009mg per day for 5\u2009days and were assessed on day 8 (enrichment phase). On day 8, responders (MADRS scores \u226412 and reduction \u226550%) were randomized on a 1:1:1:1:1 basis to receive double-blind R-107 doses of 30, 60, 120 or 180\u2009mg, or placebo, twice weekly for a further 12\u2009weeks. Nonresponders on day 8 exited the study. The primary endpoint was least square mean change in MADRS for each active treatment compared with placebo at 13\u2009weeks, starting with the 180\u2009mg dose, using a fixed sequence step-down closed test procedure. Between May 2019 and August 2021, 329 individuals were screened for eligibility, 231 entered the open-label enrichment phase (days 1\u20138) and 168 responders were randomized to double-blind treatment. The primary objective was met; the least square mean difference of MADRS score for the 180\u2009mg tablet group and placebo was \u22126.1 (95% confidence interval 1.0 to 11.16,\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.019) at 13\u2009weeks. Relapse rates during double-blind treatment showed a dose response from 70.6% for placebo to 42.9% for 180\u2009mg. Tolerability was excellent, with no changes in blood pressure, minimal reports of sedation and minimal dissociation. The most common adverse events were headache, dizziness and anxiety. During the randomized phase of the study, most patient dosing occurred at home. R-107 tablets were effective, safe and well tolerated in a patient population with TRD, enriched for initial response to R-107 tablets. ClinicalTrials.gov registration:\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.anzctr.org.au\/Trial\/Registration\/TrialReview.aspx?id=375359&amp;isReview=true\">ACTRN12618001042235<\/jats:ext-link>\n                    .\n                  <\/jats:p>","DOI":"10.1038\/s41591-024-03063-x","type":"journal-article","created":{"date-parts":[[2024,6,24]],"date-time":"2024-06-24T12:05:43Z","timestamp":1719230743000},"page":"2004-2009","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":62,"title":["Extended-release ketamine tablets for treatment-resistant depression: a randomized placebo-controlled phase 2 trial"],"prefix":"10.1038","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7305-2800","authenticated-orcid":false,"given":"Paul","family":"Glue","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colleen","family":"Loo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johnson","family":"Fam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2162-8174","authenticated-orcid":false,"given":"Hsien-Yuan","family":"Lane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allan H.","family":"Young","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Surman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"BEDROC study investigators","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nick","family":"Glozier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Fitzgerald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanthi","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Grunfeld","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Barton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malcolm","family":"Hopwood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wayne","family":"Miles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mike","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Carson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johnson","family":"Fam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phern-Chern","family":"Tor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsien-Yuan","family":"Lane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Hsin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Jui","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,24]]},"reference":[{"key":"3063_CR1","doi-asserted-by":"publisher","first-page":"102127","DOI":"10.1016\/j.eclinm.2023.102127","volume":"62","author":"S Nikolin","year":"2023","unstructured":"Nikolin, S. et al. 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C.L. is on the Clinical Advisory Board for Douglas Pharmaceuticals and has received fees for attending Janssen Cilag advisory board meetings. J.F. and H.-Y.L. have no disclosures. A.H.Y. receives payment for lectures from AstraZeneca, Eli Lilly, Lundbeck, Sunovion, Servier, Janssen, Allegan, Bionomics, Sumitomo Dainippon Pharma, COMPASS, Sage and Novartis. He receives payment for being on advisory boards from Livanova, Janssen, COMPASS, Novartis and Neurocentrx. He is a consultant for Johnson & Johnson. He is a consultant to Livanova. He has received honoraria for attending advisory boards and presenting talks at meetings organized by LivaNova. He is the principal investigator in the Restore-Life VNS Global Prospective, Multi-center, Observational Post-market Study to Assess Short-, Mid- and Long-term Effectiveness and Efficiency of Vagus Nerve Stimulation Therapy (VNS Therapy) as Adjunctive Therapy in Real-world Patients with Difficult to Treat Depression (RESTORE-LIFE) registry study funded by Livanova, ESKETINTRD3004, and several psilocybin studies in participants with TRD. He is the UK Chief Investigator for Novartis Major Depressive Disorder MIJ821A12201. He receives grant funding from the National Institute of Mental Health (United States), the Canadian Institutes of Health Research, the National Association for Research on Schizophrenia And Depression (United States), the Stanley Medical Research Institute (United States), the Medical Research Council (United Kingdom), the Wellcome Trust (United Kingdom), the Royal College of Physicians, the British Medical Association (United Kingdom), the UBC-VGH Foundation (Canada), the WEDC (Canada), the CCS Depression Research Fund (Canada), Michael Smith Health Research BC (Canada), the National Institute for Health and Care Research (United Kingdom) and Janssen (United Kingdom). P.S. is an employee of Douglas Pharmaceuticals.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}