Suicide-related events and the new generation of antidepressants: a comprehensive review

Suicide-related events and the new generation of antidepressants: a comprehensive review | 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 Research Article Suicide-related events and the new generation of antidepressants: a comprehensive review Yoshinari Oka, Tatsuya Takagi This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8537181/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 8 You are reading this latest preprint version Abstract Antidepressants are widely used worldwide for the treatment of depression. The risk of suicide-related events during antidepressant use has been reported, leading to warnings in product labeling. However, this association has not been conclusively established, and meta-analyses to date have yielded inconsistent results. Therefore, an umbrella review and reanalysis were conducted to address this inconsistency. We performed a systematic search of meta-analyses and systematic reviews in PubMed and the Cochrane Library regarding the associations between new-generation antidepressants and suicide-related events. A comprehensive review and reanalysis of the data from the 25 ultimately selected studies were conducted to estimate the pooled odds ratio (OR) of suicide-related events between antidepressants and placebo. Additional analyses were also performed for different antidepressant categories and patient age subgroups. The pooled OR for suicide-related events associated with new-generation antidepressants, adjusted for publication bias via the trim-and-fill method, was 1.00 [0.90–1.12]. In the SSRI group, SNRI group, and non-SSRI/SNRI group, the adjusted ORs were 1.04 [0.91–1.19], 0.89 [0.71–1.12], and 0.98 [0.67–1.42], respectively, none of which were statistically significant. Similar nonsignificant results were observed in the pediatric and adolescent groups (1.11 [0.93–1.34]). Furthermore, the adjusted ORs for the SSRI and SNRI groups in children and adolescents were 1.06 [0.88–1.28] and 0.91 [0.39–2.15], respectively, which was not statistically significant. However, among the individual medications in these groups, venlafaxine alone had a high and statistically significant OR of 5.77 [2.18–15.31]. This study has several limitations, including the ambiguity of the definition of suicidal tendencies, inconsistencies in the definition and classification of depression, and the possibility of publication bias; thus, further research is needed to validate these findings. Nevertheless, this study highlights the warning that venlafaxine, a new-generation antidepressant, may increase the risk of suicide-related events in children and adolescents. Physicians and pharmacists should exercise caution when prescribing venlafaxine and be fully aware of the potential for suicide-related events associated with this new-generation antidepressant. (Grant: None. (Registration: None)). antidepressants suicide umbrella review SNRIs SSRIs Full Text Additional Declarations No competing interests reported. Supplementary Files SupplementaryMaterialTTfinal.docx Appendix.docx Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Revision requested 04 Apr, 2026 Reviews received at journal 26 Mar, 2026 Reviewers agreed at journal 26 Mar, 2026 Reviewers agreed at journal 23 Feb, 2026 Reviewers invited by journal 18 Feb, 2026 Editor assigned by journal 13 Jan, 2026 Submission checks completed at journal 13 Jan, 2026 First submitted to journal 07 Jan, 2026 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-8537181","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":570578119,"identity":"9f34e3ec-55aa-4f8a-b856-35538bd1bc4c","order_by":0,"name":"Yoshinari Oka","email":"","orcid":"","institution":"Tanaka Hospital, Akemikai Medical Corporation","correspondingAuthor":false,"prefix":"","firstName":"Yoshinari","middleName":"","lastName":"Oka","suffix":""},{"id":570578120,"identity":"2985c88c-b978-4560-b1e3-b6f5fe842c78","order_by":1,"name":"Tatsuya Takagi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABDklEQVRIiWNgGAWjYHACZiCWkGOQgPAMkIWxAh42iBZjkrUwJDaga8EJ7OWbHxv8+GWRvl26/QHDhz92xvwNPAYMP2oY2M1x2sJmnNjbJ5G7c84ZA8aZbclmEgd4DBh7jjEwWzbgdJjxAd4eidwNN3IYmHkbmG0Y7r8xYOBtYGA2OIBLC/vng397JNINbqQ/YOb5U28jD7LlL14tPMbJPD8kEgxuJBgw87AdNjMAamHGa8uxnGJj2QYJw50zcgwOzmw7bmx4gK3gsMwxCZx+YW8+vlnyzZ86eXOJ9IcPPvypNpx3gHnjwzc1Nsm4QgwMGNsg8QF3CZAhkYw/hv5giUI7wpE6CkbBKBgFIwQAAFGyUapGok3hAAAAAElFTkSuQmCC","orcid":"","institution":"The University of Osaka","correspondingAuthor":true,"prefix":"","firstName":"Tatsuya","middleName":"","lastName":"Takagi","suffix":""}],"badges":[],"createdAt":"2026-01-07 05:53:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8537181/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8537181/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":99797064,"identity":"16310732-aac1-4b39-b721-dfd878be17d1","added_by":"auto","created_at":"2026-01-08 13:44:32","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":3773697,"visible":true,"origin":"","legend":"","description":"","filename":"reviewedManuscriptTTfinal.docx","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/571e0788d19d8067cf79e785.docx"},{"id":99687116,"identity":"0410fbc1-45fc-4dd0-ad81-de4de11b102c","added_by":"auto","created_at":"2026-01-07 09:43:31","extension":"json","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":3957,"visible":true,"origin":"","legend":"","description":"","filename":"599a47b98f4b4a62a10e4b2d9532c068.json","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/e7ab702614505e25abfdf908.json"},{"id":99795986,"identity":"91b84e78-ccfd-4709-94f8-22c918b455a7","added_by":"auto","created_at":"2026-01-08 13:40:11","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":190256,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterialTTfinal.docx","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/8e11553df66cd878e10bf934.docx"},{"id":99795844,"identity":"b2c8af44-686f-495a-8425-df16d0f8dbcd","added_by":"auto","created_at":"2026-01-08 13:39:49","extension":"xml","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":455013,"visible":true,"origin":"","legend":"","description":"","filename":"599a47b98f4b4a62a10e4b2d9532c0681enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/50528edd7a5871943aaf6f0c.xml"},{"id":99795944,"identity":"34bee31c-6816-4e18-9e83-99b63eacf9f8","added_by":"auto","created_at":"2026-01-08 13:40:06","extension":"jpeg","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":668834,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/b4561dfdb6f7a95aafc316f9.jpeg"},{"id":99687118,"identity":"d5c88784-48ec-4a1f-b6ed-64c8c2220e39","added_by":"auto","created_at":"2026-01-07 09:43:31","extension":"png","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":10809,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage10.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/5d885182e962dde1c7ffa6b1.png"},{"id":99687119,"identity":"60189cf6-da7b-4562-97c6-4bb830d351f9","added_by":"auto","created_at":"2026-01-07 09:43:32","extension":"png","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":10663,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage11.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/d87eebb7e084c22cf7c0667e.png"},{"id":99687141,"identity":"5b49e67c-5b41-47bd-bb4a-545ba5c3c20d","added_by":"auto","created_at":"2026-01-07 09:43:32","extension":"png","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":557412,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage12.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/40a56f21f12cd233c7fd1c37.png"},{"id":99795073,"identity":"b5c7a42f-58de-4b4b-a962-c2a66e473e7b","added_by":"auto","created_at":"2026-01-08 13:36:55","extension":"png","order_by":15,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":74416,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage13.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/3ba4727e04d58cd39b7d8c6f.png"},{"id":99687122,"identity":"240c8de9-0825-4d06-895f-30c1020f9fad","added_by":"auto","created_at":"2026-01-07 09:43:32","extension":"png","order_by":16,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":12367,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage14.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/0af3bd06906a25e5ff5e9542.png"},{"id":99687125,"identity":"a7feb0c2-d2b3-4d01-b550-cb51c1cf7664","added_by":"auto","created_at":"2026-01-07 09:43:32","extension":"png","order_by":17,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":10504,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage15.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/49c02ba056c7ef85161554d9.png"},{"id":99795899,"identity":"570cd428-abb5-48be-ae45-b07291ba8669","added_by":"auto","created_at":"2026-01-08 13:40:01","extension":"png","order_by":18,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":202475,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage16.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/e9fc8307a22c5c812dc6cfac.png"},{"id":99796436,"identity":"94766695-6211-44ab-a775-f0252b75e880","added_by":"auto","created_at":"2026-01-08 13:41:46","extension":"png","order_by":19,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":429844,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage17.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/7f1f4a2015e5434940d39149.png"},{"id":99687127,"identity":"792a2399-ea67-4f1b-b2ca-2ff768debcb1","added_by":"auto","created_at":"2026-01-07 09:43:32","extension":"png","order_by":20,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":29483,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage18.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/3dc49a0a1cb1479d1de1c2eb.png"},{"id":99797160,"identity":"9c266ead-a141-425a-b7c8-e095f89846a8","added_by":"auto","created_at":"2026-01-08 13:45:20","extension":"png","order_by":21,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":11056,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage19.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/bba7f04ace0a5e308570edc8.png"},{"id":99795791,"identity":"8f2a4e97-4dac-4c24-98f0-f8b2c7515f70","added_by":"auto","created_at":"2026-01-08 13:39:42","extension":"jpeg","order_by":22,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":99358,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/b794b64872912266cc27923d.jpeg"},{"id":99796167,"identity":"3c8ac0d7-ca2f-4535-af64-f13387c73b23","added_by":"auto","created_at":"2026-01-08 13:40:34","extension":"png","order_by":23,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":11838,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage20.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/b6441a4b3b0076baefa5d2b3.png"},{"id":99796647,"identity":"a13d5629-737a-43f6-9528-b4695d174e8d","added_by":"auto","created_at":"2026-01-08 13:43:03","extension":"png","order_by":24,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":10160,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage21.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/6e2c93032720f010ea7f7e41.png"},{"id":99795926,"identity":"ed44e972-df07-4eb1-bfad-6da1668f841c","added_by":"auto","created_at":"2026-01-08 13:40:02","extension":"png","order_by":25,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":165150,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage22.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/74d38e8549372c77b99f4eba.png"},{"id":99687123,"identity":"37764c84-17b9-4ffc-8500-e06089aebeee","added_by":"auto","created_at":"2026-01-07 09:43:32","extension":"png","order_by":26,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":48250,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage23.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/dd6a14646dccde8daf899566.png"},{"id":99687144,"identity":"a46d16ef-5914-4646-81a8-b9908dd68473","added_by":"auto","created_at":"2026-01-07 09:43:32","extension":"png","order_by":27,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":10874,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage24.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/e232047610e4b5a855765a8f.png"},{"id":99796619,"identity":"a44c0a4a-66cf-49a1-9520-48da146ec87a","added_by":"auto","created_at":"2026-01-08 13:42:59","extension":"png","order_by":28,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":10348,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage25.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/4649f876f623c75d5be01ca5.png"},{"id":99796573,"identity":"44b60893-40a4-4824-b60b-2a67a7958b16","added_by":"auto","created_at":"2026-01-08 13:42:46","extension":"png","order_by":29,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":26767,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage26.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/befe49754dd49e0bd6a00362.png"},{"id":99796090,"identity":"31fe8649-afe1-4a33-99af-6d4b185b58f1","added_by":"auto","created_at":"2026-01-08 13:40:26","extension":"png","order_by":30,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":51909,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage27.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/d27c4eb2d6ea43307dbc5fa2.png"},{"id":99795066,"identity":"dd77177a-9552-45e8-8e1f-e8307d53e533","added_by":"auto","created_at":"2026-01-08 13:36:54","extension":"png","order_by":31,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":37999,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage28.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/9c3d7ba411925fcd02d53829.png"},{"id":99796588,"identity":"3ef7a440-b046-44a5-8d6f-a80881ee557f","added_by":"auto","created_at":"2026-01-08 13:42:49","extension":"png","order_by":32,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":9839,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage29.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/2d94595c063915e066c04e92.png"},{"id":99796496,"identity":"307ff05f-042c-480b-92d2-444ede5c0427","added_by":"auto","created_at":"2026-01-08 13:42:29","extension":"jpeg","order_by":33,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":152831,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/08ed0ab684715c4bcdb139c7.jpeg"},{"id":99796234,"identity":"3e162eec-c5a6-4949-b22a-9557ce090952","added_by":"auto","created_at":"2026-01-08 13:40:46","extension":"png","order_by":34,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":10401,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage30.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/956943b66d99c6171a41e239.png"},{"id":99687135,"identity":"ac42938b-5b70-442e-b967-46ead4cf694d","added_by":"auto","created_at":"2026-01-07 09:43:32","extension":"png","order_by":35,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":9953,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage31.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/31bd63ec46e65514126143a9.png"},{"id":99687149,"identity":"26b6adb0-8b95-4f9c-8389-256dc9b1a09b","added_by":"auto","created_at":"2026-01-07 09:43:32","extension":"png","order_by":36,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":718369,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/0fedced401efeb3ca43bd78a.png"},{"id":99797131,"identity":"5f7434e6-ce25-48d5-be3f-dacd451676d0","added_by":"auto","created_at":"2026-01-08 13:45:16","extension":"png","order_by":37,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":12594,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/0e3b7db051f5c6ed9b092b09.png"},{"id":99796177,"identity":"2fb3e49f-7da8-4b73-a5bd-fc4a884c3e25","added_by":"auto","created_at":"2026-01-08 13:40:35","extension":"png","order_by":38,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":417300,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/3c76fd989fceb85beb5b539e.png"},{"id":99687150,"identity":"64ca00c2-5ea3-4ffc-9aab-4fc150ebbff5","added_by":"auto","created_at":"2026-01-07 09:43:32","extension":"png","order_by":39,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":506763,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage7.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/4326ac413213b119503f1238.png"},{"id":99687155,"identity":"d885739f-c620-44c1-aed9-09258b1140c6","added_by":"auto","created_at":"2026-01-07 09:43:32","extension":"png","order_by":40,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":544647,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage8.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/a32561357a23fccdfe095ce5.png"},{"id":99687147,"identity":"2690d146-6147-4a13-ae04-d45f578f9b40","added_by":"auto","created_at":"2026-01-07 09:43:32","extension":"png","order_by":41,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":11720,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage9.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/0c78a5117cd824123869cf4d.png"},{"id":99687153,"identity":"f99e0cb5-57bf-4517-8e5e-c8a329fe7408","added_by":"auto","created_at":"2026-01-07 09:43:32","extension":"png","order_by":42,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":140840,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/bb27a796ee2d484a34d22c67.png"},{"id":99687160,"identity":"dc050bf2-b2d0-4870-883a-78d319857976","added_by":"auto","created_at":"2026-01-07 09:43:32","extension":"png","order_by":43,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":5946,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage10.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/105b81d5e2e4a2e151069579.png"},{"id":99687154,"identity":"ff24ccd0-5aeb-4c22-abef-ae4e106acf81","added_by":"auto","created_at":"2026-01-07 09:43:32","extension":"png","order_by":44,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":5776,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage11.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/203e63e168ceee19c97f904d.png"},{"id":99794816,"identity":"a90e0ac0-9993-406e-aff1-4a96bdcc2154","added_by":"auto","created_at":"2026-01-08 13:36:22","extension":"png","order_by":45,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":218673,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage12.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/9da968431e521f381df2dfc7.png"},{"id":99796514,"identity":"15b9571c-d6d9-4755-b62a-44b18c4bc28d","added_by":"auto","created_at":"2026-01-08 13:42:37","extension":"png","order_by":46,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":29738,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage13.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/b0d4c0e9bb128657be329ffe.png"},{"id":99795064,"identity":"7453b10e-0872-409d-8161-75470b5da9bd","added_by":"auto","created_at":"2026-01-08 13:36:54","extension":"png","order_by":47,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":6882,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage14.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/da276a5d53094fe84a2aa3cc.png"},{"id":99687151,"identity":"affd7f50-9e39-44fe-b289-6f3453c83061","added_by":"auto","created_at":"2026-01-07 09:43:32","extension":"png","order_by":48,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":5712,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage15.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/e51bcc1218c37b3cce66ab10.png"},{"id":99687171,"identity":"a405eb56-3827-452d-a782-dc3c6ca2e999","added_by":"auto","created_at":"2026-01-07 09:43:33","extension":"png","order_by":49,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":79848,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage16.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/52792c357130ba6139fc0025.png"},{"id":99795661,"identity":"45506999-330f-4c87-bb66-c372b70987d3","added_by":"auto","created_at":"2026-01-08 13:39:10","extension":"png","order_by":50,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":168422,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage17.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/31964ca105e41e99f47da067.png"},{"id":99794851,"identity":"473c333f-7c45-43fc-91c2-95889a3d2bec","added_by":"auto","created_at":"2026-01-08 13:36:28","extension":"png","order_by":51,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":11726,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage18.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/ab8a9c8e8cbf33702b7253b0.png"},{"id":99687161,"identity":"1fd6c437-0f44-4ccf-a628-f221223be71b","added_by":"auto","created_at":"2026-01-07 09:43:32","extension":"png","order_by":52,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":6062,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage19.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/e2209e2f7bd43c002b49d4b5.png"},{"id":99687166,"identity":"6e10853e-2412-467d-a189-03e485cce5da","added_by":"auto","created_at":"2026-01-07 09:43:32","extension":"png","order_by":53,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":21279,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/b8569660e8903b288a223393.png"},{"id":99795338,"identity":"2d3898f7-e6ae-463b-b061-c7e318b93016","added_by":"auto","created_at":"2026-01-08 13:37:47","extension":"png","order_by":54,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":6574,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage20.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/3cf6451ef4474764db1a239b.png"},{"id":99796370,"identity":"0e245878-5d7f-4448-8720-5659df671f6f","added_by":"auto","created_at":"2026-01-08 13:41:21","extension":"png","order_by":55,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":5574,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage21.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/de10bfb761d45e3993e686c5.png"},{"id":99687169,"identity":"58c45d13-c727-4023-9aab-0897d15c4396","added_by":"auto","created_at":"2026-01-07 09:43:33","extension":"png","order_by":56,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":64651,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage22.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/c443c8f9b48d00e292381ff8.png"},{"id":99796198,"identity":"771580af-7325-45d5-95a6-b9ba5ace692b","added_by":"auto","created_at":"2026-01-08 13:40:42","extension":"png","order_by":57,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":19313,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage23.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/e116b69682161f24adedff5e.png"},{"id":99687176,"identity":"a2beff2f-7d2e-40d4-b2b2-fa7f8637817a","added_by":"auto","created_at":"2026-01-07 09:43:33","extension":"png","order_by":58,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":5981,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage24.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/e92e10a9e2dfc39101c231d3.png"},{"id":99687156,"identity":"509b4fd5-40fd-4728-8991-f060388c297b","added_by":"auto","created_at":"2026-01-07 09:43:32","extension":"png","order_by":59,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":5628,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage25.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/f72afb5be1604619e22e64a9.png"},{"id":99687175,"identity":"e5d5d326-f67f-4fe8-911e-5ce4a67edcdb","added_by":"auto","created_at":"2026-01-07 09:43:33","extension":"png","order_by":60,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":10595,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage26.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/badaf16d779b04dc84b0f02e.png"},{"id":99687179,"identity":"7073c9ca-56a9-47d7-89c5-3e1d57000023","added_by":"auto","created_at":"2026-01-07 09:43:33","extension":"png","order_by":61,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":20768,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage27.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/f8698b354d46c071f8de468f.png"},{"id":99687165,"identity":"a67b7613-7703-4933-80e6-b68f66e78a61","added_by":"auto","created_at":"2026-01-07 09:43:32","extension":"png","order_by":62,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":15198,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage28.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/1a62c18fdfc3f686679d208b.png"},{"id":99796362,"identity":"686508ba-a627-4a6b-95fd-d56bf9f2e09e","added_by":"auto","created_at":"2026-01-08 13:41:18","extension":"png","order_by":63,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":5388,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage29.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/cb2f2f6d2c9a3d9012ea6ff6.png"},{"id":99687173,"identity":"d1cc952b-2971-4d11-a3a2-d98721046bcc","added_by":"auto","created_at":"2026-01-07 09:43:33","extension":"png","order_by":64,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":47713,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/8e855fc935cda87160ae28be.png"},{"id":99795306,"identity":"6b7d8ba7-9586-4508-8785-5cf77f505670","added_by":"auto","created_at":"2026-01-08 13:37:41","extension":"png","order_by":65,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":5669,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage30.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/9869c4ac4ef7e1541221e140.png"},{"id":99797231,"identity":"8c53b011-f123-4047-a67a-9fa5f4e98629","added_by":"auto","created_at":"2026-01-08 13:45:28","extension":"png","order_by":66,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":5492,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage31.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/e4370f95e868515e421ad8fa.png"},{"id":99796203,"identity":"7154ca61-c0b7-4e0c-9b49-b898e386461b","added_by":"auto","created_at":"2026-01-08 13:40:43","extension":"png","order_by":67,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":70600,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/c2eb94b071fee08f3844b64c.png"},{"id":99687183,"identity":"6eecbd49-626e-45a8-9f79-fd24fece185b","added_by":"auto","created_at":"2026-01-07 09:43:33","extension":"png","order_by":68,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":6958,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/5d88fdc3e53793a00b9dd98b.png"},{"id":99797098,"identity":"041ac258-1928-4e12-8982-bdbbdc38fe19","added_by":"auto","created_at":"2026-01-08 13:44:34","extension":"png","order_by":69,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":162130,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/13fa46a1fe296c3342292c5a.png"},{"id":99796169,"identity":"82e6569f-7706-4e31-a2f5-1318eb8f31da","added_by":"auto","created_at":"2026-01-08 13:40:34","extension":"png","order_by":70,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":43082,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage7.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/f4983e3b7feeb675936d30f6.png"},{"id":99796355,"identity":"4bd67540-8c61-405f-8140-3c85e5e46fdb","added_by":"auto","created_at":"2026-01-08 13:41:18","extension":"png","order_by":71,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":54022,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage8.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/7e478f6ed9e025fa131b1db7.png"},{"id":99795092,"identity":"6cc65f35-1600-44f6-8734-bcb06ec521ec","added_by":"auto","created_at":"2026-01-08 13:36:58","extension":"png","order_by":72,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":6484,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage9.png","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/208809cbb69ad5ee33383474.png"},{"id":99687180,"identity":"1aaf7d05-134d-4b0e-ba28-b53da746abad","added_by":"auto","created_at":"2026-01-07 09:43:33","extension":"xml","order_by":73,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":450016,"visible":true,"origin":"","legend":"","description":"","filename":"599a47b98f4b4a62a10e4b2d9532c0681structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/54e94ee4ada1dce07778b45d.xml"},{"id":99687181,"identity":"6283c5cb-2953-4988-b797-c0fa155dc937","added_by":"auto","created_at":"2026-01-07 09:43:33","extension":"html","order_by":74,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":469663,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/29b85be461d942113b73c122.html"},{"id":99805024,"identity":"43b6ee36-1edc-496b-9591-a1ceba8b60f0","added_by":"auto","created_at":"2026-01-08 14:15:27","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2286722,"visible":true,"origin":"","legend":"","description":"","filename":"reviewedManuscriptTTfinal.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1_covered_0df748ec-942b-4492-b42c-c6124963edb9.pdf"},{"id":99797185,"identity":"3faa59e6-8767-465a-943a-4e92b2d8f4cd","added_by":"auto","created_at":"2026-01-08 13:45:23","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":190256,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterialTTfinal.docx","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/a324eb271713e89fcdf12fc5.docx"},{"id":99796038,"identity":"de561b21-be17-417f-905b-3c9e063ec546","added_by":"auto","created_at":"2026-01-08 13:40:16","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":24198,"visible":true,"origin":"","legend":"","description":"","filename":"Appendix.docx","url":"https://assets-eu.researchsquare.com/files/rs-8537181/v1/7de33cdfcf73ceacf7608f2b.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Suicide-related events and the new generation of antidepressants: a comprehensive review","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"therapeutic-innovation-and-regulatory-science","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"tirs","sideBox":"Learn more about [Therapeutic Innovation \u0026 Regulatory Science](https://link.springer.com/journal/43441)","snPcode":"43441","submissionUrl":"https://www.editorialmanager.com/tirs/default.aspx","title":"Therapeutic Innovation \u0026 Regulatory Science","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"antidepressants, suicide, umbrella review, SNRIs, SSRIs","lastPublishedDoi":"10.21203/rs.3.rs-8537181/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8537181/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eAntidepressants are widely used worldwide for the treatment of depression. The risk of suicide-related events during antidepressant use has been reported, leading to warnings in product labeling. However, this association has not been conclusively established, and meta-analyses to date have yielded inconsistent results. Therefore, an umbrella review and reanalysis were conducted to address this inconsistency.\u003c/p\u003e \u003cp\u003eWe performed a systematic search of meta-analyses and systematic reviews in PubMed and the Cochrane Library regarding the associations between new-generation antidepressants and suicide-related events. A comprehensive review and reanalysis of the data from the 25 ultimately selected studies were conducted to estimate the pooled odds ratio (OR) of suicide-related events between antidepressants and placebo. Additional analyses were also performed for different antidepressant categories and patient age subgroups.\u003c/p\u003e \u003cp\u003eThe pooled OR for suicide-related events associated with new-generation antidepressants, adjusted for publication bias via the trim-and-fill method, was 1.00 [0.90\u0026ndash;1.12]. In the SSRI group, SNRI group, and non-SSRI/SNRI group, the adjusted ORs were 1.04 [0.91\u0026ndash;1.19], 0.89 [0.71\u0026ndash;1.12], and 0.98 [0.67\u0026ndash;1.42], respectively, none of which were statistically significant. Similar nonsignificant results were observed in the pediatric and adolescent groups (1.11 [0.93\u0026ndash;1.34]). Furthermore, the adjusted ORs for the SSRI and SNRI groups in children and adolescents were 1.06 [0.88\u0026ndash;1.28] and 0.91 [0.39\u0026ndash;2.15], respectively, which was not statistically significant. However, among the individual medications in these groups, venlafaxine alone had a high and statistically significant OR of 5.77 [2.18\u0026ndash;15.31].\u003c/p\u003e \u003cp\u003eThis study has several limitations, including the ambiguity of the definition of suicidal tendencies, inconsistencies in the definition and classification of depression, and the possibility of publication bias; thus, further research is needed to validate these findings. Nevertheless, this study highlights the warning that venlafaxine, a new-generation antidepressant, may increase the risk of suicide-related events in children and adolescents. Physicians and pharmacists should exercise caution when prescribing venlafaxine and be fully aware of the potential for suicide-related events associated with this new-generation antidepressant. (Grant: None. (Registration: None)).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e","manuscriptTitle":"Suicide-related events and the new generation of antidepressants: a comprehensive review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-07 09:43:24","doi":"10.21203/rs.3.rs-8537181/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-04T23:23:36+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-27T02:01:03+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"56021449774839914766393033633053862854","date":"2026-03-27T01:34:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"79113101838150595811307544332987182972","date":"2026-02-23T23:22:43+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-18T22:08:22+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-13T14:37:06+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-13T12:36:24+00:00","index":"","fulltext":""},{"type":"submitted","content":"Therapeutic Innovation \u0026 Regulatory Science","date":"2026-01-07T05:34:27+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"therapeutic-innovation-and-regulatory-science","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"tirs","sideBox":"Learn more about [Therapeutic Innovation \u0026 Regulatory Science](https://link.springer.com/journal/43441)","snPcode":"43441","submissionUrl":"https://www.editorialmanager.com/tirs/default.aspx","title":"Therapeutic Innovation \u0026 Regulatory Science","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"a6582e04-e62f-4d30-9e6a-8af96f6804de","owner":[],"postedDate":"January 7th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-04-04T23:38:11+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-07 09:43:24","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8537181","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8537181","identity":"rs-8537181","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}