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Intranasal esketamine in treatment-resistant depression: long-term dosing patterns and clinical outcomes in a 5-year observational study.

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Title: Intranasal esketamine in treatment-resistant depression: long-term dosing patterns and clinical outcomes in a 5-year observational study.
Authors: Cuomo A; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.; Brain and Cognition Discovery Foundation, Toronto, ON, Canada.; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada., McIntyre R; Division of Psychiatry, Department of Molecular Medicine, University of Siena, Siena, Italy., Koukouna D; Division of Psychiatry, Department of Molecular Medicine, University of Siena, Siena, Italy., Pinzi M; Division of Psychiatry, Department of Molecular Medicine, University of Siena, Siena, Italy., Pardossi S; Division of Psychiatry, Department of Molecular Medicine, University of Siena, Siena, Italy., Firenzuoli B; Division of Psychiatry, Department of Molecular Medicine, University of Siena, Siena, Italy., Barillà G; Division of Psychiatry, Department of Molecular Medicine, University of Siena, Siena, Italy., Carmellini P; Division of Psychiatry, Department of Molecular Medicine, University of Siena, Siena, Italy., Alamia A; Division of Psychiatry, Department of Molecular Medicine, University of Siena, Siena, Italy., Fagiolini A; Division of Psychiatry, Department of Molecular Medicine, University of Siena, Siena, Italy.
Source: Therapeutic advances in psychopharmacology [Ther Adv Psychopharmacol] 2026 Apr 20; Vol. 16, pp. 20451253261437597. Date of Electronic Publication: 2026 Apr 20 (Print Publication: 2026).
Publication Type: Journal Article
Language: English
Journal Info: Publisher: Sage Country of Publication: England NLM ID: 101555693 Publication Model: eCollection Cited Medium: Print ISSN: 2045-1253 (Print) Linking ISSN: 20451253 NLM ISO Abbreviation: Ther Adv Psychopharmacol Subsets: PubMed not MEDLINE
Imprint Name(s): Original Publication: London : Sage
Abstract: Background: Treatment-resistant depression (TRD) remains a major clinical challenge, and long-term real-world data on intranasal esketamine are limited.
Objectives: To describe long-term dosing patterns and clinical outcomes associated with intranasal esketamine in routine clinical practice.
Design: Single-center observational cohort study with descriptive analyses.
Methods: We analyzed 45 patients with TRD treated with intranasal esketamine in a naturalistic setting, with follow-up extending up to 260 weeks. Esketamine was used adjunctively with ongoing oral antidepressants. Outcomes included the Montgomery-Åsberg Depression Rating Scale (MADRS), the Young Mania Rating Scale (YMRS), and the Glasgow Antipsychotic Side-effect Scale (GASS). Treatment patterns were summarized using person-time (person-weeks).
Results: Baseline MADRS was 40.0 (SD 4.63). Mean MADRS decreased to 22.9 (SD 7.99) at week 4 and to 9.70 (SD 5.35) at week 52, with mean scores remaining around 9-10 at later time points among patients with available follow-up. Eight patients (17.8%) discontinued treatment (lack of efficacy n = 4; intolerable adverse effects n = 3; lost to follow-up n = 1). No treatment-emergent hypomania or manic symptoms were observed; YMRS scores decreased over time. GASS scores were low overall, with median values of 0 from week 13 onwards.
Conclusion: In a real-world TRD cohort with complex comorbidities, intranasal esketamine used adjunctively was associated with sustained symptom improvement and a favorable long-term safety profile among patients who continued treatment, with dosing evolving from induction to individualized maintenance schedules. Findings are limited by the observational design, concomitant treatments, and survivor bias.
Trial Registration: Not applicable.
(© The Author(s), 2026.)
Competing Interests: Alessandro Cuomo, Andrea Fagiolini, and Roger McIntyre declare the following potential conflicts of interest in relation to the research, authorship, and/or publication of this article: Advisory board or similar committee: Angelini, Apsen, GlaxoSmithKline, Merck, Recordati, Pfizer, Sanofi-Aventis. Clinical trials or studies: Angelini; Boehringer Ingelheim; GlaxoSmithKline; Janssen; Lundbeck; Viatris; Otsuka. Honoraria or other fees: Angelini; Janssen; Lundbeck; Otsuka; Recordati; Sanofi-Aventis; Viatris; Vifor. Research grants: Angelini; Boehringer Ingelheim; Janssen; Lundbeck; Recordati; Viatris; Otsuka. All other authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Note: None of the companies listed above was involved in the design, conduct, analysis, or reporting of this study. The research was conducted independently, and the findings and conclusions presented are those of the authors alone.
Comments: Erratum in: Ther Adv Psychopharmacol. 2026 May 19;16:20451253261452482. doi: 10.1177/20451253261452482.. (PMID: 42179909)
References: Front Psychiatry. 2021 Nov 05;12:769693. (PMID: 34803777)
Mol Psychiatry. 2023 Aug;28(8):3243-3256. (PMID: 35854107)
JAMA Psychiatry. 2019 Sep 1;76(9):893-903. (PMID: 31166571)
Int J Neuropsychopharmacol. 2019 Oct 1;22(10):616-630. (PMID: 31290965)
Psychiatry Res. 2022 Oct;316:114749. (PMID: 35940087)
World Psychiatry. 2023 Oct;22(3):394-412. (PMID: 37713549)
J Affect Disord. 2017 Jan 15;208:191-197. (PMID: 27792962)
Lancet Psychiatry. 2019 Dec;6(12):977-979. (PMID: 31680014)
Psychiatr Serv. 2014 Aug 1;65(8):977-87. (PMID: 24789696)
J Clin Psychiatry. 2002 Nov;63(11):963-71. (PMID: 12444808)
Arch Gen Psychiatry. 2004 Mar;61(3):310-7. (PMID: 14993119)
Biol Psychiatry. 2003 Apr 15;53(8):640-8. (PMID: 12706950)
PLoS Med. 2007 Oct 16;4(10):e296. (PMID: 17941714)
Psychol Methods. 2011 Dec;16(4):373-90. (PMID: 22040372)
Adv Pharmacol. 2019;86:47-96. (PMID: 31378256)
J Affect Disord. 2022 Dec 15;319:646-654. (PMID: 36167246)
J Pers Assess. 2005 Jun;84(3):228-38. (PMID: 15907159)
JAMA Psychiatry. 2022 Dec 1;79(12):1162-1172. (PMID: 36260324)
J Pers Disord. 2013 Oct;27(5):554-79. (PMID: 24044659)
J Affect Disord. 2021 Mar 15;283:115-122. (PMID: 33545659)
BMC Psychiatry. 2019 Aug 7;19(1):247. (PMID: 31391065)
Am J Geriatr Psychiatry. 2020 Feb;28(2):121-141. (PMID: 31734084)
Neuropsychopharmacology. 2023 Jul;48(8):1225-1233. (PMID: 37173512)
Stat Med. 2009 Nov 30;28(27):3363-85. (PMID: 19731223)
Eur Neuropsychopharmacol. 2025 Apr;93:29-39. (PMID: 39923271)
Am J Psychiatry. 2006 Nov;163(11):1905-17. (PMID: 17074942)
J Mem Lang. 2008 Nov;59(4):434-446. (PMID: 19884961)
J Affect Disord. 2020 Apr 15;267:264-282. (PMID: 32217227)
Int J Mol Sci. 2024 Jun 20;25(12):. (PMID: 38928508)
Br J Psychiatry. 2025 Feb;226(2):72-78. (PMID: 39618237)
Exp Clin Psychopharmacol. 2023 Dec;31(6):1092-1101. (PMID: 37126036)
Am J Psychiatry. 2019 Jun 1;176(6):428-438. (PMID: 31109201)
Am J Geriatr Psychiatry. 2022 May;30(5):541-556. (PMID: 34750057)
N Engl J Med. 2023 Oct 5;389(14):1298-1309. (PMID: 37792613)
Contributed Indexing: Keywords: MADRS; dosing patterns; esketamine; intranasal; long-term outcomes; observational study; person-time analysis; real-world evidence; treatment tolerability; treatment-resistant depression
Entry Date(s): Date Created: 20260429 Date Completed: 20260429 Latest Revision: 20260813
Update Code: 20261011
PubMed Central ID: PMC13111888
DOI: 10.1177/20451253261437597
PMID: 42052285
Database: MEDLINE
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  Data: Intranasal esketamine in treatment-resistant depression: long-term dosing patterns and clinical outcomes in a 5-year observational study.
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  Data: <searchLink fieldCode="AU" term="%22Cuomo+A%22">Cuomo A</searchLink>; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.; Brain and Cognition Discovery Foundation, Toronto, ON, Canada.; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.<br /><searchLink fieldCode="AU" term="%22McIntyre+R%22">McIntyre R</searchLink>; Division of Psychiatry, Department of Molecular Medicine, University of Siena, Siena, Italy.<br /><searchLink fieldCode="AU" term="%22Koukouna+D%22">Koukouna D</searchLink>; Division of Psychiatry, Department of Molecular Medicine, University of Siena, Siena, Italy.<br /><searchLink fieldCode="AU" term="%22Pinzi+M%22">Pinzi M</searchLink>; Division of Psychiatry, Department of Molecular Medicine, University of Siena, Siena, Italy.<br /><searchLink fieldCode="AU" term="%22Pardossi+S%22">Pardossi S</searchLink>; Division of Psychiatry, Department of Molecular Medicine, University of Siena, Siena, Italy.<br /><searchLink fieldCode="AU" term="%22Firenzuoli+B%22">Firenzuoli B</searchLink>; Division of Psychiatry, Department of Molecular Medicine, University of Siena, Siena, Italy.<br /><searchLink fieldCode="AU" term="%22Barillà+G%22">Barillà G</searchLink>; Division of Psychiatry, Department of Molecular Medicine, University of Siena, Siena, Italy.<br /><searchLink fieldCode="AU" term="%22Carmellini+P%22">Carmellini P</searchLink>; Division of Psychiatry, Department of Molecular Medicine, University of Siena, Siena, Italy.<br /><searchLink fieldCode="AU" term="%22Alamia+A%22">Alamia A</searchLink>; Division of Psychiatry, Department of Molecular Medicine, University of Siena, Siena, Italy.<br /><searchLink fieldCode="AU" term="%22Fagiolini+A%22">Fagiolini A</searchLink>; Division of Psychiatry, Department of Molecular Medicine, University of Siena, Siena, Italy.
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  Data: <searchLink fieldCode="JN" term="%22101555693%22">Therapeutic advances in psychopharmacology</searchLink> [Ther Adv Psychopharmacol] 2026 Apr 20; Vol. 16, pp. 20451253261437597. <i>Date of Electronic Publication: </i>2026 Apr 20 (<i>Print Publication: </i>2026).
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  Data: Background: Treatment-resistant depression (TRD) remains a major clinical challenge, and long-term real-world data on intranasal esketamine are limited.<br />Objectives: To describe long-term dosing patterns and clinical outcomes associated with intranasal esketamine in routine clinical practice.<br />Design: Single-center observational cohort study with descriptive analyses.<br />Methods: We analyzed 45 patients with TRD treated with intranasal esketamine in a naturalistic setting, with follow-up extending up to 260 weeks. Esketamine was used adjunctively with ongoing oral antidepressants. Outcomes included the Montgomery-Åsberg Depression Rating Scale (MADRS), the Young Mania Rating Scale (YMRS), and the Glasgow Antipsychotic Side-effect Scale (GASS). Treatment patterns were summarized using person-time (person-weeks).<br />Results: Baseline MADRS was 40.0 (SD 4.63). Mean MADRS decreased to 22.9 (SD 7.99) at week 4 and to 9.70 (SD 5.35) at week 52, with mean scores remaining around 9-10 at later time points among patients with available follow-up. Eight patients (17.8%) discontinued treatment (lack of efficacy n = 4; intolerable adverse effects n = 3; lost to follow-up n = 1). No treatment-emergent hypomania or manic symptoms were observed; YMRS scores decreased over time. GASS scores were low overall, with median values of 0 from week 13 onwards.<br />Conclusion: In a real-world TRD cohort with complex comorbidities, intranasal esketamine used adjunctively was associated with sustained symptom improvement and a favorable long-term safety profile among patients who continued treatment, with dosing evolving from induction to individualized maintenance schedules. Findings are limited by the observational design, concomitant treatments, and survivor bias.<br />Trial Registration: Not applicable.<br /> (© The Author(s), 2026.)
– Name: Abstract
  Label: Competing Interests
  Group: Ab
  Data: Alessandro Cuomo, Andrea Fagiolini, and Roger McIntyre declare the following potential conflicts of interest in relation to the research, authorship, and/or publication of this article: Advisory board or similar committee: Angelini, Apsen, GlaxoSmithKline, Merck, Recordati, Pfizer, Sanofi-Aventis. Clinical trials or studies: Angelini; Boehringer Ingelheim; GlaxoSmithKline; Janssen; Lundbeck; Viatris; Otsuka. Honoraria or other fees: Angelini; Janssen; Lundbeck; Otsuka; Recordati; Sanofi-Aventis; Viatris; Vifor. Research grants: Angelini; Boehringer Ingelheim; Janssen; Lundbeck; Recordati; Viatris; Otsuka. All other authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Note: None of the companies listed above was involved in the design, conduct, analysis, or reporting of this study. The research was conducted independently, and the findings and conclusions presented are those of the authors alone.
– Name: Comment
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  Data: Erratum in: Ther Adv Psychopharmacol. 2026 May 19;16:20451253261452482. doi: 10.1177/20451253261452482.. (PMID: <searchLink fieldCode="PM" term="%2242179909%22">42179909)</searchLink>
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  Data: Front Psychiatry. 2021 Nov 05;12:769693. (PMID: <searchLink fieldCode="PM" term="%2234803777%22">34803777)</searchLink><br />Mol Psychiatry. 2023 Aug;28(8):3243-3256. (PMID: <searchLink fieldCode="PM" term="%2235854107%22">35854107)</searchLink><br />JAMA Psychiatry. 2019 Sep 1;76(9):893-903. (PMID: <searchLink fieldCode="PM" term="%2231166571%22">31166571)</searchLink><br />Int J Neuropsychopharmacol. 2019 Oct 1;22(10):616-630. (PMID: <searchLink fieldCode="PM" term="%2231290965%22">31290965)</searchLink><br />Psychiatry Res. 2022 Oct;316:114749. (PMID: <searchLink fieldCode="PM" term="%2235940087%22">35940087)</searchLink><br />World Psychiatry. 2023 Oct;22(3):394-412. (PMID: <searchLink fieldCode="PM" term="%2237713549%22">37713549)</searchLink><br />J Affect Disord. 2017 Jan 15;208:191-197. (PMID: <searchLink fieldCode="PM" term="%2227792962%22">27792962)</searchLink><br />Lancet Psychiatry. 2019 Dec;6(12):977-979. (PMID: <searchLink fieldCode="PM" term="%2231680014%22">31680014)</searchLink><br />Psychiatr Serv. 2014 Aug 1;65(8):977-87. (PMID: <searchLink fieldCode="PM" term="%2224789696%22">24789696)</searchLink><br />J Clin Psychiatry. 2002 Nov;63(11):963-71. (PMID: <searchLink fieldCode="PM" term="%2212444808%22">12444808)</searchLink><br />Arch Gen Psychiatry. 2004 Mar;61(3):310-7. (PMID: <searchLink fieldCode="PM" term="%2214993119%22">14993119)</searchLink><br />Biol Psychiatry. 2003 Apr 15;53(8):640-8. (PMID: <searchLink fieldCode="PM" term="%2212706950%22">12706950)</searchLink><br />PLoS Med. 2007 Oct 16;4(10):e296. (PMID: <searchLink fieldCode="PM" term="%2217941714%22">17941714)</searchLink><br />Psychol Methods. 2011 Dec;16(4):373-90. (PMID: <searchLink fieldCode="PM" term="%2222040372%22">22040372)</searchLink><br />Adv Pharmacol. 2019;86:47-96. (PMID: <searchLink fieldCode="PM" term="%2231378256%22">31378256)</searchLink><br />J Affect Disord. 2022 Dec 15;319:646-654. (PMID: <searchLink fieldCode="PM" term="%2236167246%22">36167246)</searchLink><br />J Pers Assess. 2005 Jun;84(3):228-38. (PMID: <searchLink fieldCode="PM" term="%2215907159%22">15907159)</searchLink><br />JAMA Psychiatry. 2022 Dec 1;79(12):1162-1172. (PMID: <searchLink fieldCode="PM" term="%2236260324%22">36260324)</searchLink><br />J Pers Disord. 2013 Oct;27(5):554-79. (PMID: <searchLink fieldCode="PM" term="%2224044659%22">24044659)</searchLink><br />J Affect Disord. 2021 Mar 15;283:115-122. (PMID: <searchLink fieldCode="PM" term="%2233545659%22">33545659)</searchLink><br />BMC Psychiatry. 2019 Aug 7;19(1):247. (PMID: <searchLink fieldCode="PM" term="%2231391065%22">31391065)</searchLink><br />Am J Geriatr Psychiatry. 2020 Feb;28(2):121-141. (PMID: <searchLink fieldCode="PM" term="%2231734084%22">31734084)</searchLink><br />Neuropsychopharmacology. 2023 Jul;48(8):1225-1233. (PMID: <searchLink fieldCode="PM" term="%2237173512%22">37173512)</searchLink><br />Stat Med. 2009 Nov 30;28(27):3363-85. (PMID: <searchLink fieldCode="PM" term="%2219731223%22">19731223)</searchLink><br />Eur Neuropsychopharmacol. 2025 Apr;93:29-39. (PMID: <searchLink fieldCode="PM" term="%2239923271%22">39923271)</searchLink><br />Am J Psychiatry. 2006 Nov;163(11):1905-17. (PMID: <searchLink fieldCode="PM" term="%2217074942%22">17074942)</searchLink><br />J Mem Lang. 2008 Nov;59(4):434-446. (PMID: <searchLink fieldCode="PM" term="%2219884961%22">19884961)</searchLink><br />J Affect Disord. 2020 Apr 15;267:264-282. (PMID: <searchLink fieldCode="PM" term="%2232217227%22">32217227)</searchLink><br />Int J Mol Sci. 2024 Jun 20;25(12):. (PMID: <searchLink fieldCode="PM" term="%2238928508%22">38928508)</searchLink><br />Br J Psychiatry. 2025 Feb;226(2):72-78. (PMID: <searchLink fieldCode="PM" term="%2239618237%22">39618237)</searchLink><br />Exp Clin Psychopharmacol. 2023 Dec;31(6):1092-1101. (PMID: <searchLink fieldCode="PM" term="%2237126036%22">37126036)</searchLink><br />Am J Psychiatry. 2019 Jun 1;176(6):428-438. (PMID: <searchLink fieldCode="PM" term="%2231109201%22">31109201)</searchLink><br />Am J Geriatr Psychiatry. 2022 May;30(5):541-556. (PMID: <searchLink fieldCode="PM" term="%2234750057%22">34750057)</searchLink><br />N Engl J Med. 2023 Oct 5;389(14):1298-1309. (PMID: <searchLink fieldCode="PM" term="%2237792613%22">37792613)</searchLink>
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