{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T11:07:22Z","timestamp":1791544042291,"version":"4.3.4"},"reference-count":45,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2020,11,26]],"date-time":"2020-11-26T00:00:00Z","timestamp":1606348800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,11,26]],"date-time":"2020-11-26T00:00:00Z","timestamp":1606348800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Neuropsychopharmacol."],"published-print":{"date-parts":[[2021,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The remarkably high and growing placebo response rates in clinical trials for CNS indications, such as depression and schizophrenia, constitute a major challenge for the drug development enterprise. Despite extensive literature on participant expectancies and other potent psychosocial factors that perpetuate placebo response, no empirically validated participant-focused strategies to mitigate this phenomenon have been available. This study evaluated the efficacy of the Placebo-Control Reminder Script (PCRS), a brief interactive procedure that educates participants about factors known to cause placebo response, which\u00a0was administered prior to the primary outcome assessments to subjects with major depressive or psychotic disorders who had at least moderate depression. Participants were informed they would participate in a 2-week randomized clinical trial with a 50% chance of receiving either an experimental antidepressant medication or placebo. In actuality, all participants received placebo. Participants randomly assigned to receive the PCRS (<jats:italic>n<\/jats:italic>\u2009=\u200970) reported significantly smaller reductions (i.e., less placebo response) in depression than those who did not receive the PCRS (<jats:italic>n<\/jats:italic>\u2009=\u200967). The magnitude of this effect was medium (Cohen\u2019s d\u2009=\u20090.40) and was not significantly impacted by diagnostic status. The number of adverse events (i.e., nocebo effect) was also lower in the PCRS group, particularly in the first week of the study. These findings suggest that briefly educating participants about placebo response factors can help mitigate the large placebo response rates that are increasingly seen in failed CNS drug development programs.<\/jats:p>","DOI":"10.1038\/s41386-020-00911-5","type":"journal-article","created":{"date-parts":[[2020,11,26]],"date-time":"2020-11-26T15:02:43Z","timestamp":1606402963000},"page":"844-850","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Placebo response mitigation with a participant-focused psychoeducational procedure: a randomized, single-blind, all placebo study in major depressive and psychotic disorders"],"prefix":"10.1038","volume":"46","author":[{"given":"Elan A.","family":"Cohen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Howard H.","family":"Hassman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larry","family":"Ereshefsky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David P.","family":"Walling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vera M.","family":"Grindell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0173-8897","authenticated-orcid":false,"given":"Richard S. E.","family":"Keefe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarzyna","family":"Wyka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William P.","family":"Horan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,11,26]]},"reference":[{"key":"911_CR1","unstructured":"Thomas DW, Burns J, Audette J, Carroll A, Dow-Hygelund C, Hay M. Clinical Development Success Rates 2006\u20132015. Washington, DC: Biotechnology Industry Organization; 2016."},{"key":"911_CR2","first-page":"12","volume":"16","author":"HJ Riordan","year":"2016","unstructured":"Riordan HJ, Cutler NR. The Dearth of CNS Drug Development: Overstatment or Omen? J Clin Stud. 2016;16:12\u201315.","journal-title":"J Clin Stud"},{"key":"911_CR3","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.1176\/appi.ajp.2013.13081129","volume":"170","author":"S Leucht","year":"2013","unstructured":"Leucht S, Heres S, Davis JM. Increasing placebo response in antipsychotic drug trials: let\u2019s stop the vicious circle. Am J Psychiatry. 2013;170:1232\u20134.","journal-title":"Am J Psychiatry"},{"key":"911_CR4","doi-asserted-by":"crossref","first-page":"1967","DOI":"10.1038\/s41380-020-0646-3","volume":"25","author":"NC Salloum","year":"2020","unstructured":"Salloum NC, et al. Success and efficiency of phase 2\/3 adjunctive trials for MDD funded by industry: a systematic review. Mol Psychiatry. 2020;25:1967\u201374.","journal-title":"Mol Psychiatry"},{"key":"911_CR5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1365-2125.2011.04021.x","volume":"72","author":"J van Gerven","year":"2011","unstructured":"van Gerven J, Cohen A. Vanishing clinical psychopharmacology. Br J Clin Pharmacol. 2011;72:1\u20135.","journal-title":"Br J Clin Pharmacol"},{"key":"911_CR6","first-page":"107","volume":"24","author":"BJ Kinon","year":"2011","unstructured":"Kinon BJ, Potts AJ, Watson SB. Placebo response in clinical trials with schizophrenia patients. Curr Opin Psychiatry. 2011;24:107\u201313.","journal-title":"Curr Opin Psychiatry"},{"key":"911_CR7","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1001\/jamapsychiatry.2014.1319","volume":"71","author":"BR Rutherford","year":"2014","unstructured":"Rutherford BR, et al. Placebo response in antipsychotic clinical trials: a meta-analysis. JAMA Psychiatry. 2014;71:1409\u201321.","journal-title":"JAMA Psychiatry"},{"key":"911_CR8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jad.2009.01.029","volume":"118","author":"W Rief","year":"2009","unstructured":"Rief W, et al. Meta-analysis of the placebo response in antidepressant trials. J Affect Disord. 2009;118:1\u20138.","journal-title":"J Affect Disord"},{"key":"911_CR9","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1002\/wps.20241","volume":"14","author":"A Khan","year":"2015","unstructured":"Khan A, Brown WA. Antidepressants versus placebo in major depression: an overview. World Psychiatry. 2015;14:294\u2013300.","journal-title":"World Psychiatry"},{"key":"911_CR10","doi-asserted-by":"crossref","first-page":"19r12960","DOI":"10.4088\/JCP.19r12960","volume":"81","author":"M Gopalakrishnan","year":"2020","unstructured":"Gopalakrishnan, M, et al. The Trend of Increasing Placebo Response and Decreasing Treatment Effect in Schizophrenia Trials Continues: an Update From the US Food and Drug Administration. J Clin Psychiatry. 2020;81:19r12960.","journal-title":"J Clin Psychiatry"},{"key":"911_CR11","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1002\/wps.20421","volume":"16","author":"A Khan","year":"2017","unstructured":"Khan A, et al. Has the rising placebo response impacted antidepressant clinical trial outcome? Data from the US Food and Drug Administration 1987\u20132013. World Psychiatry. 2017;16:181\u201392.","journal-title":"World Psychiatry"},{"key":"911_CR12","first-page":"53","volume":"43","author":"CH Mallinckrodt","year":"2010","unstructured":"Mallinckrodt CH, et al. Signal detection and placebo response in schizophrenia: parallels with depression. Psychopharmacol Bull. 2010;43:53\u201372.","journal-title":"Psychopharmacol Bull"},{"key":"911_CR13","doi-asserted-by":"crossref","first-page":"19com13110","DOI":"10.4088\/JCP.19com13110","volume":"81","author":"TP Laughren","year":"2020","unstructured":"Laughren TP. A Growing Crisis in Schizophrenia Drug Development: failing Signal Detection at North American and Other Clinical Trial Sites. J Clin Psychiatry. 2020;81:19com13110.","journal-title":"J Clin Psychiatry"},{"key":"911_CR14","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/bs.irn.2018.07.025","volume":"139","author":"P Zis","year":"2018","unstructured":"Zis P, Mitsikostas DD. Nocebo Responses in Brain Diseases: a Systematic Review of the Current Literature. Int Rev Neurobiol. 2018;139:443\u201362.","journal-title":"Int Rev Neurobiol"},{"key":"911_CR15","doi-asserted-by":"crossref","first-page":"502","DOI":"10.3389\/fphar.2019.00502","volume":"10","author":"S Palermo","year":"2019","unstructured":"Palermo S, et al. Are Patients With Schizophrenia Spectrum Disorders More Prone to Manifest Nocebo-Like-Effects? A Meta-Analysis of Adverse Events in Placebo Groups of Double-Blind Antipsychotic Trials. Front Pharm. 2019;10:502.","journal-title":"Front Pharm"},{"key":"911_CR16","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.jad.2017.03.024","volume":"215","author":"R Meister","year":"2017","unstructured":"Meister R, et al. Placebo and nocebo reactions in randomized trials of pharmacological treatments for persistent depressive disorder. A meta-regression analysis. J Affect Disord. 2017;215:288\u201398.","journal-title":"J Affect Disord"},{"key":"911_CR17","first-page":"5","volume":"8","author":"K Wartolowska","year":"2019","unstructured":"Wartolowska K. The nocebo effect as a source of bias in the assessment of treatment effects. F1000Res. 2019;8:5.","journal-title":"F1000Res"},{"key":"911_CR18","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1038\/nrn3976","volume":"16","author":"TD Wager","year":"2015","unstructured":"Wager TD, Atlas LY. The neuroscience of placebo effects: connecting context, learning and health. Nat Rev Neurosci. 2015;16:403\u201318.","journal-title":"Nat Rev Neurosci"},{"key":"911_CR19","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1007\/164_2019_269","volume":"260","author":"P Enck","year":"2019","unstructured":"Enck P, Klosterhalfen S. Placebos and the Placebo Effect in Drug Trials. Handb Exp Pharm. 2019;260:399\u2013431.","journal-title":"Handb Exp Pharm"},{"key":"911_CR20","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1016\/S1474-4422(16)00066-1","volume":"15","author":"F Benedetti","year":"2016","unstructured":"Benedetti F, Carlino E, Piedimonte A. Increasing uncertainty in CNS clinical trials: the role of placebo, nocebo, and Hawthorne effects. Lancet Neurol. 2016;15:736\u201347.","journal-title":"Lancet Neurol"},{"key":"911_CR21","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/bs.irn.2018.01.003","volume":"138","author":"I Kirsch","year":"2018","unstructured":"Kirsch I. Response Expectancy and the Placebo Effect. Int Rev Neurobiol. 2018;138:81\u201393.","journal-title":"Int Rev Neurobiol"},{"key":"911_CR22","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1017\/S1461145711001738","volume":"15","author":"L Alphs","year":"2012","unstructured":"Alphs L, et al. Placebo-related effects in clinical trials in schizophrenia: what is driving this phenomenon and what can be done to minimize it? Int J Neuropsychopharmacol. 2012;15:1003\u201314.","journal-title":"Int J Neuropsychopharmacol"},{"key":"911_CR23","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1176\/appi.ajp.2016.16020225","volume":"174","author":"BR Rutherford","year":"2017","unstructured":"Rutherford BR, et al. Patient Expectancy as a Mediator of Placebo Effects in Antidepressant Clinical Trials. Am J Psychiatry. 2017;174:135\u201342.","journal-title":"Am J Psychiatry"},{"key":"911_CR24","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1002\/wps.20242","volume":"14","author":"I Kirsch","year":"2015","unstructured":"Kirsch I. Clinical trial methodology and drug-placebo differences. World Psychiatry. 2015;14:301\u20132.","journal-title":"World Psychiatry"},{"key":"911_CR25","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1016\/j.neuron.2014.10.023","volume":"84","author":"F Benedetti","year":"2014","unstructured":"Benedetti F. Placebo effects: from the neurobiological paradigm to translational implications. Neuron. 2014;84:623\u201337.","journal-title":"Neuron"},{"key":"911_CR26","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1002\/wps.20247","volume":"14","author":"M Fava","year":"2015","unstructured":"Fava M. The role of regulators, investigators, and patient participants in the rise of the placebo response in major depressive disorder. World Psychiatry. 2015;14:307\u20138.","journal-title":"World Psychiatry"},{"key":"911_CR27","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.2165\/00023210-200317150-00005","volume":"17","author":"GA Fava","year":"2003","unstructured":"Fava GA, Ruini C, Sonino N. Treatment of recurrent depression: a sequential psychotherapeutic and psychopharmacological approach. CNS Drugs. 2003;17:1109\u201317.","journal-title":"CNS Drugs"},{"key":"911_CR28","doi-asserted-by":"crossref","first-page":"456","DOI":"10.4088\/JCP.14r09297","volume":"76","author":"GI Papakostas","year":"2015","unstructured":"Papakostas GI, Ostergaard SD, Iovieno N. The nature of placebo response in clinical studies of major depressive disorder. J Clin Psychiatry. 2015;76:456\u201366.","journal-title":"J Clin Psychiatry"},{"key":"911_CR29","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1207\/s15327752jpa6703_13","volume":"67","author":"AT Beck","year":"1996","unstructured":"Beck AT, et al. Comparison of Beck Depression Inventories -IA and -II in psychiatric outpatients. J Pers Assess. 1996;67:588\u201397.","journal-title":"J Pers Assess"},{"key":"911_CR30","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1002\/jcph.689","volume":"56","author":"TM Shiovitz","year":"2016","unstructured":"Shiovitz TM, et al. Mitigating the Effects of Nonadherence in Clinical Trials. J Clin Pharm. 2016;56:1151\u201364.","journal-title":"J Clin Pharm"},{"key":"911_CR31","first-page":"240","volume":"43","author":"R Upthegrove","year":"2017","unstructured":"Upthegrove R, Marwaha S, Birchwood M. Depression and Schizophrenia: cause, Consequence, or Trans-diagnostic Issue? Schizophr Bull. 2017;43:240\u20134.","journal-title":"Schizophr Bull"},{"key":"911_CR32","doi-asserted-by":"crossref","first-page":"2463","DOI":"10.1017\/S0033291719002344","volume":"49","author":"SE Herniman","year":"2019","unstructured":"Herniman SE, et al. Depressive psychopathology in first-episode schizophrenia spectrum disorders: a systematic review, meta-analysis and meta-regression. Psychol Med. 2019;49:2463\u201374.","journal-title":"Psychol Med"},{"key":"911_CR33","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.jad.2011.10.014","volume":"140","author":"IM Lako","year":"2012","unstructured":"Lako IM, et al. A systematic review of instruments to measure depressive symptoms in patients with schizophrenia. J Affect Disord. 2012;140:38\u201347.","journal-title":"J Affect Disord"},{"key":"911_CR34","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1590\/1516-4446-2012-1048","volume":"35","author":"YP Wang","year":"2013","unstructured":"Wang YP, Gorenstein C. Psychometric properties of the Beck Depression Inventory-II: a comprehensive review. Braz J Psychiatry. 2013;35:416\u201331.","journal-title":"Braz J Psychiatry"},{"key":"911_CR35","doi-asserted-by":"crossref","first-page":"42","DOI":"10.3109\/10601331003777444","volume":"27","author":"H Bang","year":"2010","unstructured":"Bang H, et al. Blinding assessment in clincal trials: a review of statistical methods and a proposal of blinding assessment protocol. Clincial Res Regulatory Aff. 2010;27:42\u201351.","journal-title":"Clincial Res Regulatory Aff"},{"key":"911_CR36","doi-asserted-by":"crossref","first-page":"3269","DOI":"10.1017\/S0033291715001270","volume":"45","author":"KS Button","year":"2015","unstructured":"Button KS, et al. Minimal clinically important difference on the Beck Depression Inventory\u2013II according to the patient\u2019s perspective. Psychol Med. 2015;45:3269\u201379.","journal-title":"Psychol Med"},{"key":"911_CR37","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.jpsychires.2014.01.001","volume":"51","author":"M Mancini","year":"2014","unstructured":"Mancini M, et al. Impact of patient selection and study characteristics on signal detection in placebo-controlled trials with antidepressants. J Psychiatr Res. 2014;51:21\u20139.","journal-title":"J Psychiatr Res"},{"key":"911_CR38","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1016\/j.jpsychires.2013.02.016","volume":"47","author":"SD Targum","year":"2013","unstructured":"Targum SD, et al. A comparative analysis between site-based and centralized ratings and patient self-ratings in a clinical trial of Major Depressive Disorder. J Psychiatr Res. 2013;47:944\u201354.","journal-title":"J Psychiatr Res"},{"key":"911_CR39","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1002\/j.2051-5545.2011.tb00061.x","volume":"10","author":"D Goldberg","year":"2011","unstructured":"Goldberg D. The heterogeneity of \u201cmajor depression\u201d. World Psychiatry. 2011;10:226\u20138.","journal-title":"World Psychiatry"},{"key":"911_CR40","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1097\/YIC.0000000000000229","volume":"33","author":"A Khan","year":"2018","unstructured":"Khan A, Mar KF, Brown WA. The conundrum of depression clinical trials: one size does not fit all. Int Clin Psychopharmacol. 2018;33:239\u201348.","journal-title":"Int Clin Psychopharmacol"},{"key":"911_CR41","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1016\/j.drudis.2016.11.022","volume":"22","author":"T Kube","year":"2017","unstructured":"Kube T, Rief W. Are placebo and drug-specific effects additive? Questioning basic assumptions of double-blinded randomized clinical trials and presenting novel study designs. Drug Disco Today. 2017;22:729\u201335.","journal-title":"Drug Disco Today"},{"key":"911_CR42","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1007\/s11013-011-9242-y","volume":"36","author":"KM Ninnemann","year":"2012","unstructured":"Ninnemann KM. Variability in the efficacy of psychopharmaceuticals: contributions from pharmacogenomics, ethnopsychopharmacology, and psychological and psychiatric anthropologies. Cult Med Psychiatry. 2012;36:10\u201325.","journal-title":"Cult Med Psychiatry"},{"key":"911_CR43","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1111\/acps.12422","volume":"132","author":"D Bhugra","year":"2015","unstructured":"Bhugra D, Ventriglio A. Do cultures influence placebo response? Acta Psychiatr Scand. 2015;132:227\u201330.","journal-title":"Acta Psychiatr Scand"},{"key":"911_CR44","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.schres.2018.05.009","volume":"201","author":"S Leucht","year":"2018","unstructured":"Leucht S, et al. 60years of placebo-controlled antipsychotic drug trials in acute schizophrenia: meta-regression of predictors of placebo response. Schizophr Res. 2018;201:315\u201323.","journal-title":"Schizophr Res"},{"key":"911_CR45","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1016\/j.jpsychires.2011.03.001","volume":"45","author":"CH Mallinckrodt","year":"2011","unstructured":"Mallinckrodt CH, Tamura RN, Tanaka Y. Recent developments in improving signal detection and reducing placebo response in psychiatric clinical trials. J Psychiatr Res. 2011;45:1202\u20137.","journal-title":"J Psychiatr Res"}],"container-title":["Neuropsychopharmacology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.nature.com\/articles\/s41386-020-00911-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/s41386-020-00911-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/s41386-020-00911-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,20]],"date-time":"2023-05-20T21:07:59Z","timestamp":1684616879000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41386-020-00911-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,26]]},"references-count":45,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2021,3]]}},"alternative-id":["911"],"URL":"https:\/\/doi.org\/10.1038\/s41386-020-00911-5","relation":{},"ISSN":["0893-133X","1740-634X"],"issn-type":[{"value":"0893-133X","type":"print"},{"value":"1740-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,26]]},"assertion":[{"value":"24 July 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 October 2020","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 November 2020","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 November 2020","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}]}}