{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T17:12:03Z","timestamp":1771607523291,"version":"3.50.1"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,10,31]],"date-time":"2023-10-31T00:00:00Z","timestamp":1698710400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Psychiatry"],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Treatment resistant depression (TRD) affects 10\u201330% of patients with major depressive disorder. In 4-week trials, esketamine nasal spray (NS) was efficacious vs. placebo when both were initiated in addition to a new selective serotonin or serotonin norepinephrine reuptake inhibitor. However, comparison with an extended range of real-world treatments (RWT) is lacking.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>ICEBERG was an adjusted indirect treatment comparison using propensity score-based inverse probability weighting, performed on 6-month response and remission data from patients receiving esketamine NS plus oral antidepressant from the SUSTAIN-2 (NCT02497287; clinicaltrials.gov) study, compared with patients receiving other RWT from the European Observational TRD Cohort (EOTC; NCT03373253; clinicaltrials.gov) study. SUSTAIN-2 was a long-term open-label study of esketamine NS, while the EOTC was conducted at a time when esketamine NS was not available as RWT. Threshold and sensitivity analyses were conducted to assess how robust the primary analyses were.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Patients receiving esketamine NS had a higher probability of 6-month response (49.7% [95% confidence interval (CI) 45.6\u201353.9]) and remission (33.6% [95% CI 29.7\u201337.6]) vs. patients receiving RWT (26.4% [95% CI 21.5\u201331.4] and 18.2% [95% CI 13.9\u201322.5], respectively), according to rescaled average treatment effect among treated estimates. Resulting adjusted odds ratios (OR) and relative risk (RR) favoured esketamine NS over RWT for 6-month response (OR 2.756 [95% CI 2.034\u20133.733], <jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.0001; RR 1.882 [95% CI 1.534\u20132.310], <jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.0001) and remission (OR 2.276 [95% CI 1.621\u20133.196], <jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.0001; RR 1.847 [95% CI 1.418\u20132.406], <jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.0001). Threshold analyses suggested that differences between the two studies were robust, and results were consistent across extensive sensitivity analyses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>ICEBERG supports that, at 6\u2009months, esketamine NS has a substantial and significant benefit over RWT for patients with TRD. While results may be affected by unobserved confounding factors, threshold analyses suggested these were unlikely to impact the study conclusions.<\/jats:p><jats:p>To view an animated summary of this publication, please click on the <jats:xref>Supplementary video<\/jats:xref>.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fpsyt.2023.1250980","type":"journal-article","created":{"date-parts":[[2023,10,31]],"date-time":"2023-10-31T12:38:57Z","timestamp":1698755937000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["ICEBERG study: an indirect adjusted comparison estimating the long-term benefit of esketamine nasal spray when compared with routine treatment of treatment resistant depression in general psychiatry"],"prefix":"10.3389","volume":"14","author":[{"given":"Albino J.","family":"Oliveira-Maia","sequence":"first","affiliation":[]},{"given":"Joachim","family":"Morrens","sequence":"additional","affiliation":[]},{"given":"Benoit","family":"Rive","sequence":"additional","affiliation":[]},{"given":"Yordan","family":"Godinov","sequence":"additional","affiliation":[]},{"given":"Jedelyn","family":"Cabrieto","sequence":"additional","affiliation":[]},{"given":"Nolen","family":"Perualila","sequence":"additional","affiliation":[]},{"given":"Sebastien","family":"Barbreau","sequence":"additional","affiliation":[]},{"given":"Siobh\u00e1n","family":"Mulhern-Haughey","sequence":"additional","affiliation":[]}],"member":"1965","published-online":{"date-parts":[[2023,10,31]]},"reference":[{"key":"ref1","year":"2013"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1905","DOI":"10.1176\/ajp.2006.163.11.1905","article-title":"Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report","volume":"163","author":"Rush","year":"2006","journal-title":"Am J Psychiatry"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1186\/s12888-019-2222-4","article-title":"The humanistic and economic burden of treatment-resistant depression in Europe: a cross-sectional study","volume":"19","author":"Jaffe","year":"2019","journal-title":"BMC Psychiatry"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"369","DOI":"10.2147\/PPA.S29716","article-title":"Treatment-resistant depression: therapeutic trends, challenges, and future directions","volume":"6","author":"Al-Harbi","year":"2012","journal-title":"Patient Prefer Adherence"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"221","DOI":"10.2147\/NDT.S198774","article-title":"Management of Treatment-Resistant Depression: challenges and strategies","volume":"16","author":"Voineskos","year":"2020","journal-title":"Neuropsychiatr Dis Treat"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1080\/15622975.2019.1635270","article-title":"Results of the European Group for the Study of resistant depression (GSRD) \u2014 basis for further research and clinical practice","volume":"20","author":"Bartova","year":"2019","journal-title":"World J Biol Psychiatry"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1016\/j.jad.2021.12.134","article-title":"Augmentation strategies for treatment resistant major depression: a systematic review and network meta-analysis","volume":"302","author":"Nu\u00f1ez","year":"2022","journal-title":"J Affect Disord"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1016\/j.jad.2021.03.073","article-title":"Real-world evidence from a European cohort study of patients with treatment resistant depression: treatment patterns and clinical outcomes","volume":"290","author":"Heerlein","year":"2021","journal-title":"J Affect Disord"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1439","DOI":"10.1176\/ps.2009.60.11.1439","article-title":"What did STAR*D teach us? Results from a large-scale, practical, clinical trial for patients with depression","volume":"60","author":"Gaynes","year":"2009","journal-title":"Psychiatr Serv"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/j.jad.2020.11.124","article-title":"Real-world evidence from a European cohort study of patients with treatment resistant depression: baseline patient characteristics","volume":"283","author":"Heerlein","year":"2021","journal-title":"J Affect Disord"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/j.jad.2018.06.045","article-title":"The burden of treatment-resistant depression: a systematic review of the economic and quality of life literature","volume":"242","author":"Johnston","year":"2019","journal-title":"J Affect Disord"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"442","DOI":"10.1016\/j.jad.2021.11.004","article-title":"Real-world evidence from a European cohort study of patients with treatment resistant depression: healthcare resource utilization","volume":"298","author":"Heerlein","year":"2021","journal-title":"J Affect Disord"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"111","DOI":"10.31887\/DCNS.2015.17.2\/dionescu","article-title":"Pharmacological approaches to the challenge of treatment-resistant depression","volume":"17","author":"Ionescu","year":"2015","journal-title":"Dialogues Clin Neurosci"},{"key":"ref14","year":"2019"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"2042098620937899","DOI":"10.1177\/2042098620937899","article-title":"Esketamine: new hope for the treatment of treatment-resistant depression? A narrative review","volume":"11","author":"Salahudeen","year":"2020","journal-title":"Ther Adv Drug Saf"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1016\/S2215-0366(19)30533-4","article-title":"Approval of esketamine for treatment-resistant depression","volume":"7","author":"Singh","year":"2020","journal-title":"Lancet Psychiatry"},{"key":"ref17","year":"2019"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1001\/jamapsychiatry.2019.1189","article-title":"Efficacy of Esketamine nasal spray plus Oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial","volume":"76","author":"Daly","year":"2019","journal-title":"JAMA Psychiatry"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1093\/ijnp\/pyz039","article-title":"Efficacy and safety of fixed-dose Esketamine nasal spray combined with a new Oral antidepressant in treatment-resistant depression: results of a randomized, double-blind, active-controlled study (TRANSFORM-1)","volume":"22","author":"Fedgchin","year":"2019","journal-title":"Int J Neuropsychopharmacol"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/j.jagp.2019.10.008","article-title":"Efficacy and safety of Esketamine nasal spray plus an Oral antidepressant in elderly patients with treatment-resistant depression-TRANSFORM-3","volume":"28","author":"Ochs-Ross","year":"2020","journal-title":"Am J Geriatr Psychiatry"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1176\/appi.ajp.2019.19020172","article-title":"Efficacy and safety of flexibly dosed Esketamine nasal spray combined with a newly initiated Oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study","volume":"176","author":"Popova","year":"2019","journal-title":"Am J Psychiatry"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1001\/jamapsychiatry.2017.3739","article-title":"Efficacy and safety of intranasal Esketamine adjunctive to Oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial","volume":"75","author":"Daly","year":"2018","journal-title":"JAMA Psychiatry"},{"key":"ref23","year":"2015"},{"key":"ref24","year":"2018"},{"key":"ref25","first-page":"1250987","article-title":"Indirect adjusted comparison of 6-month clinical outcomes between esketamine nasal spray and other real-world polypharmacy treatment strategies for treatment resistant depression: results from the ICEBERG study","volume-title":"Front. Psychiatry","author":"Oliveira-Maia","year":"2023"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"19m12891","DOI":"10.4088\/JCP.19m12891","article-title":"Esketamine nasal spray plus Oral antidepressant in patients with treatment-resistant depression: assessment of long-term safety in a phase 3, open-label study (SUSTAIN-2)","volume":"81","author":"Wajs","year":"2020","journal-title":"J Clin Psychiatry"},{"key":"ref27","volume-title":"Diagnostic and statistical manual of mental disorders","year":"2013"},{"key":"ref28","volume-title":"ICD-10: International statistical classification of diseases and related health problems: 10th revision","year":"2004"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1159\/000054761","article-title":"Assessing the clinical importance of statistically significant improvement in anti-dementia drug trials","volume":"20","author":"Rockwood","year":"2001","journal-title":"Neuroepidemiology"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"919","DOI":"10.1002\/gps.1166","article-title":"The place of memantine in the treatment of Alzheimer's disease: a number needed to treat analysis","volume":"19","author":"Livingston","year":"2004","journal-title":"Int J Geriatr Psychiatry"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1016\/j.psychres.2016.04.034","article-title":"Socio-demographic and clinical predictors of non-response\/non-remission in treatment resistant depressed patients: a systematic review","volume":"240","author":"De Carlo","year":"2016","journal-title":"Psychiatry Res"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1016\/j.jad.2018.09.067","article-title":"A systematic meta-review of predictors of antidepressant treatment outcome in major depressive disorder","volume":"243","author":"Perlman","year":"2019","journal-title":"J Affect Disord"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1016\/j.jval.2011.01.011","article-title":"Conducting indirect-treatment-comparison and network-meta-analysis studies: report of the ISPOR task force on indirect treatment comparisons good research practices: part 2","volume":"14","author":"Hoaglin","year":"2011","journal-title":"Value Health"},{"key":"ref34","volume-title":"NICE DSU technical support document 17: The use of observational data to inform estimates of treatment effectiveness for technology appraisal: Methods for comparative individual patient data","author":"Faria","year":"2015"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"716","DOI":"10.1055\/a-1237-4011","article-title":"Manual for methods and use of routine practice data for knowledge generation","volume":"82","author":"Klinkhammer-Schalke","year":"2020","journal-title":"Gesundheitswesen"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1177\/0272989X12472398","article-title":"Survival analysis for economic evaluations alongside clinical trials--extrapolation with patient-level data: inconsistencies, limitations, and a practical guide","volume":"33","author":"Latimer","year":"2013","journal-title":"Med Decis Making"},{"key":"ref37","year":"2020"},{"key":"ref38","author":"Developing NICE guidelines","year":"2023"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"4546","DOI":"10.1002\/sim.7021","article-title":"Too many covariates and too few cases? - a comparative study","volume":"35","author":"Chen","year":"2016","journal-title":"Stat Med"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1161\/HYPERTENSIONAHA.111.171074","article-title":"Participation in a clinical trial enhances adherence and persistence to treatment: a retrospective cohort study","volume":"58","author":"van Onzenoort","year":"2011","journal-title":"Hypertension"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1093\/ijnp\/pyaa034","article-title":"Treatment response of add-on Esketamine nasal spray in resistant major depression in relation to add-on second-generation antipsychotic treatment","volume":"23","author":"Dold","year":"2020","journal-title":"Int J Neuropsychopharmacol"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"1841","DOI":"10.1038\/sj.npp.1301131","article-title":"Report by the ACNP task force on response and remission in major depressive disorder","volume":"31","author":"Rush","year":"2006","journal-title":"Neuropsychopharmacology"},{"key":"ref43","year":"2020"}],"container-title":["Frontiers in Psychiatry"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpsyt.2023.1250980\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,13]],"date-time":"2023-11-13T12:39:37Z","timestamp":1699879177000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpsyt.2023.1250980\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,31]]},"references-count":43,"alternative-id":["10.3389\/fpsyt.2023.1250980"],"URL":"https:\/\/doi.org\/10.3389\/fpsyt.2023.1250980","relation":{},"ISSN":["1664-0640"],"issn-type":[{"value":"1664-0640","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,31]]},"article-number":"1250980"}}