Oral esketamine in patients with treatment-resistant depression: a double-blind, randomized, placebo-controlled trial with open-label extension

Oral esketamine in patients with treatment-resistant depression: a double-blind, randomized, placebo-controlled trial with open-label extension | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Oral esketamine in patients with treatment-resistant depression: a double-blind, randomized, placebo-controlled trial with open-label extension Sanne Smith-Apeldoorn, JKE Veraart, Jeanine Kamphuis, Jan Spijker, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3373293/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract About one-third of patients with depression do not achieve adequate response to current treatment options. Although intravenous and intranasal administrations of (es)ketamine have shown antidepressant properties, their accessibility and scalability are limited. We investigated the efficacy, safety, and tolerability of generic oral esketamine in patients with treatment-resistant depression (TRD) in a randomized placebo-controlled trial with open-label extension. This study consisted of 1) a six-week fixed low-dose treatment phase during which 111 participants received oral esketamine 30 mg or placebo three times a day; 2) a four-week wash-out phase; and 3) an optional six-week open-label individually titrated treatment phase during which participants received 0.5 to 3.0 mg/kg oral esketamine two times a week. The primary outcome measure was change in depressive symptom severity, assessed with the Hamilton Depression Rating Scale (HDRS17), from baseline to 6 weeks. Fixed low-dose oral esketamine when compared to placebo had no benefit on the HDRS17 total score (p=0.626). Except for dizziness and sleep hallucinations scores, which were higher in the esketamine arm, we found no significant difference in safety and tolerability aspects. During the open-label individually titrated treatment phase, the mean HDRS17 score decreased from 21.0 (SD 5.09) to 15.1 (SD 7.27) (mean difference -6.0, 95% CI -7.71 to -4.29, p<0.001). Our results suggest that fixed low-dose esketamine is not effective in TRD. In contrast, individually titrated higher doses of oral esketamine might have antidepressant properties. Health sciences/Diseases/Psychiatric disorders/Depression Biological sciences/Drug discovery Full Text Additional Declarations JV has received a speakers fee from Janssen Pharmaceuticals, outside the submitted work. RS has received research funding for two randomized clinical trials with generic oral esketamine from the Netherlands Organisation for Health Research & Development and the National Health Care Institute, a speakers fee and an investigator initiated research grant from Janssen Pharmaceuticals, and consultancy fees from Clexio biosciences, GH Research, Beckley PsyTech, and QPS. All other authors declare no competing interests. Supplementary Files SupplementaryInformation.pdf Supplementary Information Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: revise 20 Oct, 2023 Review # 2 received at journal 16 Oct, 2023 Review # 1 received at journal 10 Oct, 2023 Reviewer # 2 agreed at journal 29 Sep, 2023 Reviewer # 1 agreed at journal 25 Sep, 2023 Reviewers invited by journal 22 Sep, 2023 Submission checks completed at journal 21 Sep, 2023 Editor assigned by journal 20 Sep, 2023 First submitted to journal 20 Sep, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3373293","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":235303533,"identity":"13726249-dd98-4871-a2cb-ffcb21283e55","order_by":0,"name":"Sanne Smith-Apeldoorn","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA30lEQVRIiWNgGAWjYBADGYYDIKoCyn1AhBYeiJYzUG4C0VoY24jQIt/AY8Dwc4cND9/x5mOfC+cdjubvX8D2AJ8WgwM8Boy9Z9J4JM8cS549c9vh3Bk3HrAb4NXCALSFt+0wj8GNHGNmXqCWDRIH2CQIOYzxb9t/qJY5RGhhADqMmbftAFRLA1ALfwN+LQaH2QoOy55JBvuFmedYOtAvjG34HdbevPHh2x12csAQO8zMU2Od299/+JjEB3wOY+YwOMDYgCwikdiAXSkcsD9gQNXCf4CAjlEwCkbBKBhpAAC9Ek1ygnfxRAAAAABJRU5ErkJggg==","orcid":"","institution":"University of Groningen, University Medical Center Groningen","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Sanne","middleName":"","lastName":"Smith-Apeldoorn","suffix":""},{"id":235303534,"identity":"9a374991-64f1-4a30-afa4-9f2a03500d0a","order_by":1,"name":"JKE Veraart","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"JKE","middleName":"","lastName":"Veraart","suffix":""},{"id":235303535,"identity":"e0eef0cd-ea7f-4d5f-980c-4a203b388f7f","order_by":2,"name":"Jeanine Kamphuis","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jeanine","middleName":"","lastName":"Kamphuis","suffix":""},{"id":235303536,"identity":"6a13a22b-fd78-4c0b-b70e-cd9ffdb49887","order_by":3,"name":"Jan Spijker","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jan","middleName":"","lastName":"Spijker","suffix":""},{"id":235303537,"identity":"643857af-85dd-405c-82f4-ea5608f462b7","order_by":4,"name":"Annemarie van der Meij","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Annemarie","middleName":"van der","lastName":"Meij","suffix":""},{"id":235303538,"identity":"2383e43a-0a3d-4ef1-9f08-7d05d7555be6","order_by":5,"name":"Antoinette van Asselt","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Antoinette","middleName":"van","lastName":"Asselt","suffix":""},{"id":235303539,"identity":"b2f1ba85-ce71-494c-bb07-c2ffcc5f3860","order_by":6,"name":"Marije aan het Rot","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Marije","middleName":"aan het","lastName":"Rot","suffix":""},{"id":235303540,"identity":"5fd4348d-f46c-448e-be9b-cdf507dba3fd","order_by":7,"name":"Robert Schoevers","email":"","orcid":"https://orcid.org/0000-0003-0760-9866","institution":"University of Groningen","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Robert","middleName":"","lastName":"Schoevers","suffix":""}],"badges":[],"createdAt":"2023-09-20 15:02:38","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3373293/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3373293/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":43848513,"identity":"5db7f85e-31e0-4854-94f0-c02fb5d18cd6","added_by":"auto","created_at":"2023-09-28 18:18:50","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":308987,"visible":true,"origin":"","legend":"","description":"","filename":"Manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3373293/v1_covered_057e9e96-8d37-49a7-b46f-eec1a4d4543d.pdf"},{"id":43848365,"identity":"8f91a9f0-5218-4e6b-9502-88a34fc627a0","added_by":"auto","created_at":"2023-09-28 18:10:45","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":268298,"visible":true,"origin":"","legend":"Supplementary Information","description":"","filename":"SupplementaryInformation.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3373293/v1/4847585cd2ae1365796fcf51.pdf"}],"financialInterests":"\nJV has received a speakers fee from Janssen Pharmaceuticals, outside the submitted work. RS has received research funding for two randomized clinical trials with generic oral esketamine from the Netherlands Organisation for Health Research \u0026 Development and the National Health Care Institute, a speakers fee and an investigator initiated research grant from Janssen Pharmaceuticals, and consultancy fees from Clexio biosciences, GH Research, Beckley PsyTech, and QPS. All other authors declare no competing interests.","formattedTitle":"Oral esketamine in patients with treatment-resistant depression: a double-blind, randomized, placebo-controlled trial with open-label extension","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"molecular-psychiatry","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"mp","sideBox":"Learn more about [Molecular Psychiatry](http://www.nature.com/mp/)","snPcode":"41380","submissionUrl":"https://mts-mp.nature.com/cgi-bin/main.plex","title":"Molecular Psychiatry","twitterHandle":"@molpsychiatry","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-3373293/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3373293/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"About one-third of patients with depression do not achieve adequate response to current treatment options. Although intravenous and intranasal administrations of (es)ketamine have shown antidepressant properties, their accessibility and scalability are limited. We investigated the efficacy, safety, and tolerability of generic oral esketamine in patients with treatment-resistant depression (TRD) in a randomized placebo-controlled trial with open-label extension. This study consisted of 1) a six-week fixed low-dose treatment phase during which 111 participants received oral esketamine 30 mg or placebo three times a day; 2) a four-week wash-out phase; and 3) an optional six-week open-label individually titrated treatment phase during which participants received 0.5 to 3.0 mg/kg oral esketamine two times a week. The primary outcome measure was change in depressive symptom severity, assessed with the Hamilton Depression Rating Scale (HDRS17), from baseline to 6 weeks. Fixed low-dose oral esketamine when compared to placebo had no benefit on the HDRS17 total score (p=0.626). Except for dizziness and sleep hallucinations scores, which were higher in the esketamine arm, we found no significant difference in safety and tolerability aspects. During the open-label individually titrated treatment phase, the mean HDRS17 score decreased from 21.0 (SD 5.09) to 15.1 (SD 7.27) (mean difference -6.0, 95% CI -7.71 to -4.29, p\u003c0.001). Our results suggest that fixed low-dose esketamine is not effective in TRD. In contrast, individually titrated higher doses of oral esketamine might have antidepressant properties.","manuscriptTitle":"Oral esketamine in patients with treatment-resistant depression: a double-blind, randomized, placebo-controlled trial with open-label extension","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-09-28 18:10:40","doi":"10.21203/rs.3.rs-3373293/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2023-10-20T13:27:22+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2023-10-16T16:22:38+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2023-10-10T23:30:29+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2023-09-29T08:40:46+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2023-09-25T11:23:16+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2023-09-22T04:00:10+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-09-21T09:58:16+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-09-20T14:58:55+00:00","index":"","fulltext":""},{"type":"submitted","content":"Molecular Psychiatry","date":"2023-09-20T14:58:54+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"molecular-psychiatry","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"mp","sideBox":"Learn more about [Molecular Psychiatry](http://www.nature.com/mp/)","snPcode":"41380","submissionUrl":"https://mts-mp.nature.com/cgi-bin/main.plex","title":"Molecular Psychiatry","twitterHandle":"@molpsychiatry","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"06f412f5-7a2f-4892-a17d-d4688e0b5e40","owner":[],"postedDate":"September 28th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":24924181,"name":"Health sciences/Diseases/Psychiatric disorders/Depression"},{"id":24924182,"name":"Biological sciences/Drug discovery"}],"tags":[],"updatedAt":"2024-02-05T14:25:20+00:00","versionOfRecord":[],"versionCreatedAt":"2023-09-28 18:10:40","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3373293","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3373293","identity":"rs-3373293","version":["v1"]},"buildId":"FbvkV6FR0MCFSLy54lSbu","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}