{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T04:03:57Z","timestamp":1784174637428,"version":"3.55.0"},"reference-count":37,"publisher":"BMJ","issue":"7","license":[{"start":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:00:00Z","timestamp":1784073600000},"content-version":"unspecified","delay-in-days":14,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100021856","name":"Ministero dell\u2019Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["1409 del 14-09-2022"],"award-info":[{"award-number":["1409 del 14-09-2022"]}],"id":[{"id":"10.13039\/501100021856","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021856","name":"Ministero dell\u2019Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["P2022LY3RF"],"award-info":[{"award-number":["P2022LY3RF"]}],"id":[{"id":"10.13039\/501100021856","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2026,6,22]]},"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Antidepressant overprescribing and unnecessary long-term use are common and can increase the risk of adverse effects and withdrawal symptoms on discontinuation. Although gradual tapering strategies have been proposed, empirical evidence from randomised trials is lacking. This study will compare the efficacy of two antidepressant discontinuation strategies\u2014linear and hyperbolic tapering\u2014in adults with remitted depressive disorders.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>This pragmatic, multicentre, open-label, parallel-group superiority randomised controlled trial will recruit adults (\u226518 years) with remitted depressive disorders who have been taking an antidepressant for at least 6 months. During an 8-month recruitment period, participants in outpatient psychiatric and primary care settings will be randomised (1:1) to (a) linear tapering (dose reduced by 50% of the minimum effective dose every 2 weeks until cessation) or (b) hyperbolic tapering (dose reduced by 20\u201325%\u2009every 2 weeks until cessation). The primary outcome is the proportion of participants who fail to discontinue the antidepressant by the end of the predefined tapering schedule or who re-initiate antidepressant therapy within 16 weeks of discontinuation. Secondary outcomes include safety, tolerability (including withdrawal symptoms), acceptability, clinical effectiveness, social functioning, quality of life and cost-effectiveness. Recruiters and participants will be aware of their treatment allocation; however, outcome assessors and the biostatistician will remain blinded throughout follow-up. Validated rating scales measuring depression, anxiety, withdrawal symptoms and social functioning will be administered at baseline and at scheduled follow-up visits up to 36 weeks. Based on observational data, we aim to recruit 150 participants (75 per arm).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>The study was approved by institutional Ethics Committees and regulatory authorities. Written informed consent will be obtained from all participants and data processed in accordance with General Data Protection Regulation. Study insurance and pharmacovigilance procedures are in place. Findings will be published in open-access journals, presented at scientific meetings and communicated to policy and regulatory stakeholders.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT07393919\">NCT07393919<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2026-119492","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T03:20:57Z","timestamp":1784172057000},"page":"e119492","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Safe discontinuation of antidepressants in individuals with clinically remitted depressive disorders: study protocol for a randomised controlled trial"],"prefix":"10.1136","volume":"16","clinical-trial-number":[{"clinical-trial-number":"nct07393919","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2248-9524","authenticated-orcid":false,"given":"Giovanni","family":"Ostuzzi","sequence":"first","affiliation":[{"name":"WHO Collaborating Centre for Research and Training in Mental Health and Service Evaluation, Department of Neurosciences, Biomedicine and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Gastaldon","sequence":"additional","affiliation":[{"name":"WHO Collaborating Centre for Research and Training in Mental Health and Service Evaluation, Department of Neurosciences, Biomedicine and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debora","family":"Zaccoletti","sequence":"additional","affiliation":[{"name":"WHO Collaborating Centre for Research and Training in Mental Health and Service Evaluation, Department of Neurosciences, Biomedicine and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Bartoli","sequence":"additional","affiliation":[{"name":"School of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy"},{"name":"Department of Mental Health, IRCCS San Gerardo dei Tintori Foundation Hospital, Monza, Lombardy, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Belnome","sequence":"additional","affiliation":[{"name":"WHO Collaborating Centre for Research and Training in Mental Health and Service Evaluation, Department of Neurosciences, Biomedicine and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Carr\u00e0","sequence":"additional","affiliation":[{"name":"School of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy"},{"name":"Department of Mental Health, IRCCS San Gerardo dei Tintori Foundation Hospital, Monza, Lombardy, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Cavallotti","sequence":"additional","affiliation":[{"name":"Department of Mental Health and Addiction, ASST Santi Paolo e Carlo, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioana","family":"Cristea","sequence":"additional","affiliation":[{"name":"Department of General Psychology, University of Padua, Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2126-799X","authenticated-orcid":false,"given":"Armando","family":"D\u2019Agostino","sequence":"additional","affiliation":[{"name":"Department of Mental Health and Addiction, ASST Santi Paolo e Carlo, Milan, Italy"},{"name":"Department of Health Sciences, University of Milan, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pasquale","family":"De Fazio","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Magna Graecia University of Catanzaro, Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renato","family":"de Filippis","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Magna Graecia University of Catanzaro, Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Gottardi","sequence":"additional","affiliation":[{"name":"WHO Collaborating Centre for Research and Training in Mental Health and Service Evaluation, Department of Neurosciences, Biomedicine and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caterina","family":"Novara","sequence":"additional","affiliation":[{"name":"Department of General Psychology, University of Padua, Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Papola","sequence":"additional","affiliation":[{"name":"WHO Collaborating Centre for Research and Training in Mental Health and Service Evaluation, Department of Neurosciences, Biomedicine and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Riboldi","sequence":"additional","affiliation":[{"name":"School of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy"},{"name":"Department of Mental Health, IRCCS San Gerardo dei Tintori Foundation Hospital, Monza, Lombardy, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Tedeschi","sequence":"additional","affiliation":[{"name":"WHO Collaborating Centre for Research and Training in Mental Health and Service Evaluation, Department of Neurosciences, Biomedicine and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Amaddeo","sequence":"additional","affiliation":[{"name":"WHO Collaborating Centre for Research and Training in Mental Health and Service Evaluation, Department of Neurosciences, Biomedicine and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corrado","family":"Barbui","sequence":"additional","affiliation":[{"name":"WHO Collaborating Centre for Research and Training in Mental Health and Service Evaluation, Department of Neurosciences, Biomedicine and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2026,7,15]]},"reference":[{"key":"2026071520201700000_16.7.e119492.1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(17)32802-7"},{"key":"2026071520201700000_16.7.e119492.2","unstructured":"NICE guideline [NG222]:National Institute for Health and Care Excellence . Depression in adults: treatment and management. NICE; 2022. Available: https:\/\/www.nice.org.uk\/guidance\/ng222 [Accessed 1 Jun 2026]."},{"key":"2026071520201700000_16.7.e119492.3","doi-asserted-by":"crossref","DOI":"10.1136\/ebmh.13.2.61","article-title":"Increase in proportion of patients on long-term medication accounts for increase in antidepressant prescribing in UK","volume":"13","author":"Morrison","year":"2010","journal-title":"Evid Based Ment Health"},{"key":"2026071520201700000_16.7.e119492.4","doi-asserted-by":"crossref","first-page":"2730","DOI":"10.1136\/bmj.p2730","article-title":"Politicians, experts, and patient representatives call for the UK government to reverse the rate of antidepressant prescribing","volume":"383","author":"Davies","year":"2023","journal-title":"BMJ"},{"key":"2026071520201700000_16.7.e119492.5","unstructured":"National report on medicines use in Italy - year 2020. Agenzia Italiana Del Farmaco; 2022. Available: https:\/\/www.aifa.gov.it\/en\/-\/rapporto-nazionale-osmed-2020-sull-uso-dei-farmaci-in-italia [accessed 1 Jun 2026]"},{"key":"2026071520201700000_16.7.e119492.6","doi-asserted-by":"crossref","unstructured":"Taylor DMB , Thomas RE , Young AH . Prescribing Guidelines in Psychiatry. 14th edn. Wiley Blackwell, 2021.","DOI":"10.1002\/9781119870203"},{"key":"2026071520201700000_16.7.e119492.7","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1038\/s41380-020-0843-0","article-title":"Discontinuation of antidepressants after remission with antidepressant medication in major depressive disorder: a systematic review and meta-analysis","volume":"26","author":"Kato","year":"2021","journal-title":"Mol Psychiatry"},{"key":"2026071520201700000_16.7.e119492.8","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1016\/j.amjmed.2025.04.037","article-title":"Antidepressant Trial Duration Versus Duration of Real-World Use: A Systematic Analysis","volume":"138","author":"Ward","year":"2025","journal-title":"Am J Med"},{"key":"2026071520201700000_16.7.e119492.9","doi-asserted-by":"crossref","DOI":"10.1192\/bjo.2022.563","article-title":"Antidepressant use and risk of adverse outcomes: population-based cohort study","volume":"8","author":"Bansal","year":"2022","journal-title":"BJPsych Open"},{"key":"2026071520201700000_16.7.e119492.10","doi-asserted-by":"publisher","DOI":"10.2147\/PPA.S110632"},{"key":"2026071520201700000_16.7.e119492.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.addbeh.2018.08.027"},{"key":"2026071520201700000_16.7.e119492.12","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1016\/S2215-0366(24)00133-0","article-title":"Incidence of antidepressant discontinuation symptoms: a systematic review and meta-analysis","volume":"11","author":"Henssler","year":"2024","journal-title":"Lancet Psychiatry"},{"key":"2026071520201700000_16.7.e119492.13","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1001\/jamapsychiatry.2025.1362","article-title":"Incidence and Nature of Antidepressant Discontinuation Symptoms: A Systematic Review and Meta-Analysis","volume":"82","author":"Kalfas","year":"2025","journal-title":"JAMA Psychiatry"},{"key":"2026071520201700000_16.7.e119492.14","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1007\/s40264-022-01246-4","article-title":"Withdrawal Syndrome Following Discontinuation of 28 Antidepressants: Pharmacovigilance Analysis of 31,688 Reports from the WHO Spontaneous Reporting Database","volume":"45","author":"Gastaldon","year":"2022","journal-title":"Drug Saf"},{"key":"2026071520201700000_16.7.e119492.15","doi-asserted-by":"crossref","DOI":"10.1177\/20451253211067656","article-title":"Clinical practice guideline recommendations on tapering and discontinuing antidepressants for depression: a systematic review","volume":"12","author":"S\u00f8rensen","year":"2022","journal-title":"Ther Adv Psychopharmacol"},{"key":"2026071520201700000_16.7.e119492.16","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1016\/S2215-0366(19)30032-X","article-title":"Tapering of SSRI treatment to mitigate withdrawal symptoms","volume":"6","author":"Horowitz","year":"2019","journal-title":"The Lancet Psychiatry"},{"key":"2026071520201700000_16.7.e119492.17","article-title":"Approaches for discontinuation versus continuation of long-term antidepressant use for depressive and anxiety disorders in adults","volume":"4","author":"Van Leeuwen","year":"2021","journal-title":"Cochrane Database Syst Rev"},{"key":"2026071520201700000_16.7.e119492.18","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/S2215-0366(25)00330-X","article-title":"Comparison of antidepressant deprescribing strategies in individuals with clinically remitted depression: a systematic review and network meta-analysis","volume":"13","author":"Zaccoletti","year":"2026","journal-title":"The Lancet Psychiatry"},{"key":"2026071520201700000_16.7.e119492.19","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2025.4486"},{"key":"2026071520201700000_16.7.e119492.20","doi-asserted-by":"crossref","first-page":"1998","DOI":"10.1001\/jama.2025.4347","article-title":"CONSORT 2025 Statement: Updated Guideline for Reporting Randomized Trials","volume":"333","author":"Hopewell","year":"2025","journal-title":"JAMA"},{"key":"2026071520201700000_16.7.e119492.21","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1007\/s00103-022-03625-9","article-title":"The new approval procedure for clinical trials of medicinal products in the European Union-challenges for the pharmaceutical industry in Germany","volume":"66","author":"Henn","year":"2023","journal-title":"Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz"},{"key":"2026071520201700000_16.7.e119492.22","doi-asserted-by":"publisher","DOI":"10.1007\/s11948-000-0025-z"},{"key":"2026071520201700000_16.7.e119492.23","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2013.281053"},{"key":"2026071520201700000_16.7.e119492.24","doi-asserted-by":"publisher","DOI":"10.1159\/000069736"},{"key":"2026071520201700000_16.7.e119492.25","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2106356"},{"key":"2026071520201700000_16.7.e119492.26","doi-asserted-by":"publisher","DOI":"10.1097\/00005650-199603000-00003"},{"key":"2026071520201700000_16.7.e119492.27","doi-asserted-by":"crossref","first-page":"S57","DOI":"10.1016\/S0924-977X(97)00420-3","article-title":"Development and validation of a social functioning scale, the Social Adaptation Self-evaluation Scale","volume":"7 Suppl 1","author":"Bosc","year":"1997","journal-title":"Eur Neuropsychopharmacol"},{"key":"2026071520201700000_16.7.e119492.28","doi-asserted-by":"publisher","DOI":"10.1192\/bjp.177.39.s28"},{"key":"2026071520201700000_16.7.e119492.29","doi-asserted-by":"publisher","DOI":"10.1016\/0165-1781(92)90005-N"},{"key":"2026071520201700000_16.7.e119492.30","doi-asserted-by":"publisher","DOI":"10.1016\/j.jrp.2006.02.001"},{"key":"2026071520201700000_16.7.e119492.31","unstructured":"Official Journal of the European Union, talian Medicines Agency. EU pharmacovigilance legislation: Italian Medicines Agency (AIFA) . Regulation (EU) no 536\/2014 on clinical trials on medicinal products for human use. European Parliament and the Council of the European Union; 2012. Available: https:\/\/eur-lex.europa.eu\/eli\/reg\/2014\/536\/oj\/eng [Accessed 1 Jun 2026]."},{"key":"2026071520201700000_16.7.e119492.32","unstructured":"Italian Medicines Agency . EU pharmacovigilance legislation: Italian Medicines Agency (AIFA). 2012. Available: https:\/\/www.aifa.gov.it\/en\/normativa-di-riferimento-farmacovigilanza [Accessed 1 Jun 2026]."},{"key":"2026071520201700000_16.7.e119492.33","doi-asserted-by":"publisher","DOI":"10.1080\/17522439.2018.1469163"},{"key":"2026071520201700000_16.7.e119492.34","unstructured":"PASS N . Power analysis and sample size software. Kaysville, Utah, USA: NCSS, Available: https:\/\/www.ncss.com\/software\/pass\/"},{"key":"2026071520201700000_16.7.e119492.35","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwh090"},{"key":"2026071520201700000_16.7.e119492.36","unstructured":"Stata statistical software. College Station, TX StataCorp LLC; 2021."},{"key":"2026071520201700000_16.7.e119492.37","doi-asserted-by":"crossref","DOI":"10.1136\/bmj.l2238","article-title":"Clinical guidelines on antidepressant withdrawal urgently need updating","volume":"365","author":"Davies","year":"2019","journal-title":"BMJ"}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2026-119492","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T03:21:03Z","timestamp":1784172063000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2026-119492"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7]]},"references-count":37,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7,15]]},"published-print":{"date-parts":[[2026,7]]}},"alternative-id":["10.1136\/bmjopen-2026-119492"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2026-119492","relation":{},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"value":"2044-6055","type":"print"},{"value":"2044-6055","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7]]}}}