{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T07:02:44Z","timestamp":1791442964795,"version":"4.3.3"},"reference-count":51,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2023,10,5]],"date-time":"2023-10-05T00:00:00Z","timestamp":1696464000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Wellcome Trust Clinical Research Career Development","award":["224625\/Z\/21\/Z"],"award-info":[{"award-number":["224625\/Z\/21\/Z"]}]},{"DOI":"10.13039\/501100000272","name":"National Institute for Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012176","name":"Maudsley Charity","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012176","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Wellcome Trust Clinical Research Career Development","award":["224625\/Z\/21\/Z"],"award-info":[{"award-number":["224625\/Z\/21\/Z"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,4,30]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Antipsychotics are recommended for prevention of relapse in schizophrenia. It is unclear whether increased risk of relapse following antipsychotic discontinuation is predominantly associated with an absolute magnitude of dose reduction or rate of antipsychotic reduction. Establishing the responsible mechanism is important because prolonged withdrawal schedules have been suggested to reduce risk of relapse.<\/jats:p><\/jats:sec><jats:sec><jats:title>Study Design<\/jats:title><jats:p>Individual patient data from antipsychotic discontinuation studies were obtained. We estimated the occupancy of receptors over time using half-lives and median effective dose ED50 values obtained from pharmacokinetic and receptor occupancy studies. Hazard ratios for relapse events were calculated using Cox proportional hazards models to assess the influence of formulation (oral, 1-monthly, and 3-monthly injections). The change in hazard ratio over time was estimated, and the effect of time-varying covariates was calculated, including rate of occupancy reduction and absolute receptor occupancy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Study Results<\/jats:title><jats:p>Five studies including 1388 participants with schizophrenia were identified (k\u2005=\u20052: oral, k\u2005=\u20052: 1-monthly injection, k\u2005=\u20051: 3-monthly injection). Withdrawal of long-acting injectable medication did not lead to a lower hazard ratio compared with withdrawal of oral medication, and this included the period immediately following randomization. Hazard ratios were not associated with the rate of decline of receptor occupancy; however, they were associated with reduced absolute occupancy in trials of long-acting injections (P\u2005=\u2005.038).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Antipsychotic discontinuation is associated with an increased risk of psychotic relapse, related to receptor occupancy. Although relapse does not appear to be related to the rate of discontinuation, gradual discontinuation strategies may allow for easier antipsychotic reinstatement in case of symptomatic worsening.<\/jats:p><\/jats:sec>","DOI":"10.1093\/schbul\/sbad139","type":"journal-article","created":{"date-parts":[[2023,10,5]],"date-time":"2023-10-05T20:22:07Z","timestamp":1696537327000},"page":"513-520","source":"Crossref","is-referenced-by-count":26,"title":["Does Slow and Steady Win the Race? Rates of Antipsychotic Discontinuation, Antipsychotic Dose, and Risk of Psychotic Relapse"],"prefix":"10.1093","volume":"50","author":[{"given":"Robert A","family":"McCutcheon","sequence":"first","affiliation":[{"name":"Department of Psychiatry, University of Oxford , Oxford , UK"},{"name":"Oxford Health NHS Foundation Trust , Oxford , UK"},{"name":"Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience , London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Taylor","sequence":"additional","affiliation":[{"name":"South London and Maudsley NHS Foundation Trust , London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose","family":"Rubio","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Northwell Health, The Zucker Hillside Hospital , Glen Oaks, NY , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Nour","sequence":"additional","affiliation":[{"name":"East London NHS Foundation Trust , London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6074-2626","authenticated-orcid":false,"given":"Toby","family":"Pillinger","sequence":"additional","affiliation":[{"name":"Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience , London , UK"},{"name":"South London and Maudsley NHS Foundation Trust , London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin M","family":"Murray","sequence":"additional","affiliation":[{"name":"Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience , London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sameer","family":"Jauhar","sequence":"additional","affiliation":[{"name":"South London and Maudsley NHS Foundation Trust , London , UK"},{"name":"Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience , London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,10,5]]},"reference":[{"key":"2024043011194489100_CIT0001","doi-asserted-by":"crossref","first-page":"204512531987003","DOI":"10.1177\/2045125319870033","article-title":"Are we getting any better at staying better? The long view on relapse and recovery in first episode non-affective psychosis and schizophrenia","volume":"9","author":"Taylor","year":"2019","journal-title":"Ther Adv Psychopharmacol."},{"key":"2024043011194489100_CIT0002","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/0920-9964(91)90178-T","article-title":"The effect of early neuroleptic intervention on the course of schizophrenia","volume":"4","author":"Wyatt","year":"1991","journal-title":"Schizophr Res."},{"key":"2024043011194489100_CIT0003","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.schres.2010.11.021","article-title":"Early risk factors for suicide in an epidemiological first episode psychosis cohort","volume":"126","author":"Dutta","year":"2011","journal-title":"Schizophr Res."},{"key":"2024043011194489100_CIT0004","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1007\/s40273-017-0515-3","article-title":"The cost of relapse in schizophrenia","volume":"35","author":"Pennington","year":"2017","journal-title":"PharmacoEcon."},{"key":"2024043011194489100_CIT0005","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1093\/schbul\/sbx180","article-title":"Defining the locus of dopaminergic dysfunction in schizophrenia: a meta-analysis and test of the mesolimbic hypothesis","volume":"44","author":"McCutcheon","year":"2018","journal-title":"Schizophr Bull."},{"key":"2024043011194489100_CIT0006","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1177\/0269881119889296","article-title":"Evidence-based guidelines for the pharmacological treatment of schizophrenia: updated recommendations from the British Association for Psychopharmacology","volume":"34","author":"Barnes","year":"2020","journal-title":"J Psychopharmacol."},{"key":"2024043011194489100_CIT0007","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1192\/bjp.bp.111.096594","article-title":"Putting the efficacy of psychiatric and general medicine medication into perspective: review of meta-analyses","volume":"200","author":"Leucht","year":"2012","journal-title":"Br J Psychiatry."},{"key":"2024043011194489100_CIT0008","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1002\/wps.20972","article-title":"Oral and long-acting antipsychotics for relapse prevention in schizophrenia-spectrum disorders: a network meta-analysis of 92 randomized trials including 22,645 participants","volume":"21","author":"Ostuzzi","year":"2022","journal-title":"World Psychiatry."},{"key":"2024043011194489100_CIT0009","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/S0140-6736(21)01730-X","article-title":"Schizophrenia","volume":"399","author":"Jauhar","year":"2022","journal-title":"Lancet."},{"key":"2024043011194489100_CIT0010","first-page":"64","article-title":"Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with \u2026","volume-title":"Lancet.","author":"Pillinger","year":"2020"},{"key":"2024043011194489100_CIT0011","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1002\/wps.20579","article-title":"Tardive dyskinesia risk with first- and second-generation antipsychotics in comparative randomized controlled trials: a meta-analysis","volume":"17","author":"Carbon","year":"2018","journal-title":"World Psychiatry."},{"key":"2024043011194489100_CIT0012","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1093\/schbul\/sbab017","article-title":"A method for tapering antipsychotic treatment that may minimize the risk of relapse","volume":"47","author":"Horowitz","year":"2021","journal-title":"Schizophr Bull."},{"key":"2024043011194489100_CIT0013","doi-asserted-by":"crossref","first-page":"2063","DOI":"10.1016\/S0140-6736(12)60239-6","article-title":"Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis","volume":"379","author":"Leucht","year":"2012","journal-title":"Lancet."},{"key":"2024043011194489100_CIT0014","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.schres.2012.05.007","article-title":"Risk factors for relapse following treatment for first episode psychosis: a systematic review and meta-analysis of longitudinal studies","volume":"139","author":"Alvarez-Jimenez","year":"2012","journal-title":"Schizophr Res."},{"key":"2024043011194489100_CIT0015","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/S2215-0366(22)00015-3","article-title":"Real-world effectiveness of antipsychotic doses for relapse prevention in patients with first-episode schizophrenia in Finland: a nationwide, register-based cohort study","volume":"9","author":"Taipale","year":"2022","journal-title":"Lancet Psychiatry."},{"key":"2024043011194489100_CIT0016","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/S2215-0366(21)00078-X","article-title":"Standard versus reduced dose of antipsychotics for relapse prevention in multi-episode schizophrenia: a systematic review and meta-analysis of randomised controlled trials","volume":"8","author":"H\u00f8jlund","year":"2021","journal-title":"Lancet Psychiatry."},{"key":"2024043011194489100_CIT0017","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1001\/jamapsychiatry.2021.2130","article-title":"Examination of dosing of antipsychotic drugs for relapse prevention in patients with stable schizophrenia: a meta-analysis","volume":"78","author":"Leucht","year":"2021","journal-title":"JAMA Psychiatry."},{"key":"2024043011194489100_CIT0018","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1001\/archpsyc.1997.01830130055011","article-title":"Clinical risk following abrupt and gradual withdrawal of maintenance neuroleptic treatment","volume":"54","author":"Viguera","year":"1997","journal-title":"Arch Gen Psychiatry."},{"key":"2024043011194489100_CIT0019","first-page":"862","article-title":"Immediate vs gradual discontinuation in antipsychotic switching: a systematic review and meta-analysis","volume":"43","author":"Takeuchi","year":"2017","journal-title":"Schizophr Bull."},{"key":"2024043011194489100_CIT0020","author":"Yale University Open Data Access (YODA) clinical trials database"},{"key":"2024043011194489100_CIT0021","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/0006-3223(93)90288-O","article-title":"Central D2-dopamine receptor occupancy in relation to antipsychotic drug effects: a double-blind PET study of schizophrenic patients","volume":"33","author":"Nordstr\u00f6m","year":"1993","journal-title":"Biol Psychiatry."},{"key":"2024043011194489100_CIT0022","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1176\/ajp.153.7.948","article-title":"High levels of dopamine D2 receptor occupancy with low-dose haloperidol treatment: a PET study","volume":"153","author":"Kapur","year":"1996","journal-title":"Am J Psychiatry."},{"key":"2024043011194489100_CIT0023","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.eurpsy.2007.02.005","article-title":"Antipsychotic efficacy: relationship to optimal D2-receptor occupancy","volume":"22","author":"Pani","year":"2007","journal-title":"Eur Psychiatry."},{"key":"2024043011194489100_CIT0024","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/s00213-007-1029-z","article-title":"Dose-finding study of paliperidone ER based on striatal and extrastriatal dopamine D2 receptor occupancy in patients with schizophrenia","volume":"197","author":"Arakawa","year":"2008","journal-title":"Psychopharmacology (Berl)."},{"key":"2024043011194489100_CIT0025","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1002\/cpdd.144","article-title":"Pharmacokinetic profile after multiple deltoid or gluteal intramuscular injections of paliperidone palmitate in patients with schizophrenia","volume":"4","author":"Rossenu","year":"2015","journal-title":"Clin Pharmacol Drug Dev."},{"key":"2024043011194489100_CIT0026","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1093\/ijnp\/pyab071","article-title":"A randomized, double-blind, multicenter, noninferiority study comparing paliperidone palmitate 6-month versus the 3-month long-acting injectable in patients with schizophrenia","volume":"25","author":"Najarian","year":"2022","journal-title":"Int J Neuropsychopharmacol."},{"key":"2024043011194489100_CIT0027","volume-title":"Invega (Paliperidone) Extended-Release Tablets [Package Insert]","author":"Janssen Pharmaceuticals","year":"2017"},{"key":"2024043011194489100_CIT0028","volume-title":"Invega Sustenna (Paliperidone Palmitate) Extended-Release Injectable Suspension, for Intramuscular Use [Package Insert]","author":"Janssen Pharmaceuticals","year":"2017"},{"key":"2024043011194489100_CIT0029","volume-title":"Invega Trinza (Paliperidone Palmitate) Extended-Release Injectable Suspension, for Intramuscular Use [Package Insert]","author":"Janssen Pharmaceuticals"},{"key":"2024043011194489100_CIT0030","volume-title":"Survival Analysis [R package survival version 3.5-0]","author":"Therneau","year":"2023"},{"key":"2024043011194489100_CIT0031","doi-asserted-by":"crossref","DOI":"10.32614\/CRAN.package.casebase","article-title":"Fitting Flexible Smooth-in-Time Hazards and Risk Functions via Logistic and Multinomial Regression","volume-title":"R package version 0.9.0","author":"Bhatnagar"},{"key":"2024043011194489100_CIT0032","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.2202\/1557-4679.1125","article-title":"Fitting smooth-in-time prognostic risk functions via logistic regression","volume":"5","author":"Hanley","year":"2009","journal-title":"Int J Biostat."},{"key":"2024043011194489100_CIT0033","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v036.i03","article-title":"Conducting meta-analyses in R with the metafor","volume":"36","author":"Viechtbauer","year":"2010","journal-title":"J Stat Softw."},{"key":"2024043011194489100_CIT0034","doi-asserted-by":"crossref","first-page":"121","DOI":"10.21037\/atm.2018.02.12","article-title":"Time-varying covariates and coefficients in Cox regression models","volume":"6","author":"Zhang","year":"2018","journal-title":"Ann Transl Med."},{"key":"2024043011194489100_CIT0035","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1001\/jamapsychiatry.2015.0241","article-title":"Efficacy and safety of the 3-month formulation of paliperidone palmitate vs placebo for relapse prevention of schizophrenia: a randomized clinical trial","volume":"72","author":"Berwaerts","year":"2015","journal-title":"JAMA Psychiatry."},{"key":"2024043011194489100_CIT0036","doi-asserted-by":"crossref","first-page":"253","DOI":"10.4088\/JCP.14m09416","article-title":"Paliperidone palmitate once-monthly reduces risk of relapse of psychotic, depressive, and manic symptoms and maintains functioning in a double-blind, randomized study of schizoaffective disorder","volume":"76","author":"Fu","year":"2015","journal-title":"J Clin Psychiatry."},{"key":"2024043011194489100_CIT0037","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.schres.2009.10.026","article-title":"Paliperidone palmitate maintenance treatment in delaying the time-to-relapse in patients with schizophrenia: a randomized, double-blind, placebo-controlled study","volume":"116","author":"Hough","year":"2010","journal-title":"Schizophr Res."},{"key":"2024043011194489100_CIT0038","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1097\/JCP.0b013e31802dda4a","article-title":"Paliperidone extended-release tablets for prevention of symptom recurrence in patients with schizophrenia: a randomized, double-blind, placebo-controlled study","volume":"27","author":"Kramer","year":"2007","journal-title":"J Clin Psychopharmacol."},{"key":"2024043011194489100_CIT0039","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.pnpbp.2014.02.007","article-title":"Relapse prevention study of paliperidone extended-release tablets in Chinese patients with schizophrenia","volume":"53","author":"Rui","year":"2014","journal-title":"Prog Neuropsychopharmacol Biol Psychiatry."},{"key":"2024043011194489100_CIT0040","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1093\/schbul\/sbac138","article-title":"Risk factors for psychotic relapse after dose reduction or discontinuation of antipsychotics in patients with chronic schizophrenia. A meta-analysis of randomized controlled trials","volume":"49","author":"Bogers","year":"2023","journal-title":"Schizophr Bull."},{"key":"2024043011194489100_CIT0041","doi-asserted-by":"crossref","first-page":"e813","DOI":"10.4088\/JCP.16m11308","article-title":"Does half-life matter after antipsychotic discontinuation","volume":"78","author":"Weiden","year":"2017","journal-title":"J Clin Psychiatry."},{"key":"2024043011194489100_CIT0042","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1093\/schbul\/sbab091","article-title":"Predictors of lack of relapse after random discontinuation of oral and long-acting injectable antipsychotics in clinically stabilized patients with schizophrenia: a re-analysis of individual participant data","volume":"48","author":"Schoretsanitis","year":"2022","journal-title":"Schizophr Bull."},{"key":"2024043011194489100_CIT0043","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/S2215-0366(23)00008-1","article-title":"Predicting psychotic relapse following randomised discontinuation of paliperidone in individuals with schizophrenia or schizoaffective disorder: an individual participant data analysis","volume":"10","author":"Brandt","year":"2023","journal-title":"Lancet Psychiatry."},{"key":"2024043011194489100_CIT0044","volume-title":"Statistical Issues in Drug Development","author":"Senn","year":"2008","edition":"2"},{"key":"2024043011194489100_CIT0045","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1093\/schbul\/sbs150","article-title":"Long-acting injectable vs oral antipsychotics for relapse prevention in schizophrenia: a meta-analysis of randomized trials","volume":"40","author":"Kishimoto","year":"2014","journal-title":"Schizophr Bull."},{"key":"2024043011194489100_CIT0046","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/S2215-0366(21)00039-0","article-title":"Long-acting injectable versus oral antipsychotics for the maintenance treatment of schizophrenia: a systematic review and comparative meta-analysis of randomised, cohort, and pre-post studies","volume":"8","author":"Kishimoto","year":"2021","journal-title":"Lancet Psychiatry."},{"key":"2024043011194489100_CIT0047","doi-asserted-by":"crossref","first-page":"1955","DOI":"10.1038\/s41386-019-0440-6","article-title":"Disconnection of drug-response and placebo-response in acute-phase antipsychotic drug trials on schizophrenia? Meta-regression analysis","volume":"44","author":"Leucht","year":"2019","journal-title":"Neuropsychopharmacology."},{"key":"2024043011194489100_CIT0048","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1176\/ajp.152.2.173","article-title":"D2 dopamine receptor occupancy during low-dose treatment with haloperidol decanoate","volume":"152","author":"Nyberg","year":"1995","journal-title":"Am J Psychiatry."},{"key":"2024043011194489100_CIT0049","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.4088\/JCP.v69n0811","article-title":"Monthly administration of long-acting injectable risperidone and striatal dopamine D2 receptor occupancy for the management of schizophrenia","volume":"69","author":"Uchida","year":"2008","journal-title":"J Clin Psychiatry."},{"key":"2024043011194489100_CIT0050","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.2147\/NDT.S210340","article-title":"Relationship between the timing of relapse and plasma drug levels following discontinuation of cariprazine treatment in patients with schizophrenia: indirect comparison with other second-generation antipsychotics after treatment discontinuation","volume":"15","author":"Correll","year":"2019","journal-title":"Neuropsychiatr Dis Treat."},{"key":"2024043011194489100_CIT0051","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1002\/wps.20977","article-title":"Reappraising the variability of effects of antipsychotic medication in schizophrenia: a meta-analysis","volume":"21","author":"McCutcheon","year":"2022","journal-title":"World Psychiatry."}],"container-title":["Schizophrenia Bulletin"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/schizophreniabulletin\/article-pdf\/50\/3\/513\/57360415\/sbad139.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/schizophreniabulletin\/article-pdf\/50\/3\/513\/57360415\/sbad139.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,28]],"date-time":"2024-10-28T08:19:45Z","timestamp":1730103585000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/schizophreniabulletin\/article\/50\/3\/513\/7292877"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,5]]},"references-count":51,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,10,5]]},"published-print":{"date-parts":[[2024,4,30]]}},"URL":"https:\/\/doi.org\/10.1093\/schbul\/sbad139","relation":{},"ISSN":["0586-7614","1745-1701"],"issn-type":[{"value":"0586-7614","type":"print"},{"value":"1745-1701","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,5,1]]},"published":{"date-parts":[[2023,10,5]]}}}