{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T23:09:06Z","timestamp":1787612946984,"version":"build-2736575974"},"reference-count":78,"publisher":"National Institute for Health and Care Research","license":[{"start":{"date-parts":[[2023,10,1]],"date-time":"2023-10-01T00:00:00Z","timestamp":1696118400000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000664","name":"Health Technology Assessment programme","doi-asserted-by":"publisher","award":["13\/115\/76"],"award-info":[{"award-number":["13\/115\/76"]}],"id":[{"id":"10.13039\/501100000664","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journalslibrary.nihr.ac.uk"],"crossmark-restriction":false},"short-container-title":["Health Technol Assess"],"abstract":"<jats:sec id=\"abs1-1\"><jats:title>Background<\/jats:title>\n<jats:p>Agitation is common and impacts negatively on people with dementia and carers. Non-drug patient-centred care is first-line treatment, but we need other treatment when this fails. Current evidence is sparse on safer and effective alternatives to antipsychotics.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"abs1-2\"><jats:title>Objectives<\/jats:title>\n<jats:p>To assess clinical and cost-effectiveness and safety of mirtazapine and carbamazepine in treating agitation in dementia.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"abs1-3\"><jats:title>Design<\/jats:title>\n<jats:p>Pragmatic, phase III, multicentre, double-blind, superiority, randomised, placebo-controlled trial of the clinical effectiveness of mirtazapine over 12 weeks (carbamazepine arm discontinued).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"abs1-4\"><jats:title>Setting<\/jats:title>\n<jats:p>Twenty-six UK secondary care centres.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"abs1-5\"><jats:title>Participants<\/jats:title>\n<jats:p><jats:italic>Eligibility:<\/jats:italic> probable or possible Alzheimer\u2019s disease, agitation unresponsive to non-drug treatment, Cohen-Mansfield Agitation Inventory score\u2005\u2265\u200545.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"abs1-6\"><jats:title>Interventions<\/jats:title>\n<jats:p>Mirtazapine (target 45\u2009mg), carbamazepine (target 300\u2009mg) and placebo.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"abs1-7\"><jats:title>Outcome measures<\/jats:title>\n<jats:p><jats:italic>Primary:<\/jats:italic> Cohen-Mansfield Agitation Inventory score 12 weeks post randomisation. <jats:italic>Main economic outcome evaluation:<\/jats:italic> incremental cost per six-point difference in Cohen-Mansfield Agitation Inventory score at 12 weeks, from health and social care system perspective. Data from participants and informants at baseline, 6 and 12 weeks. Long-term follow-up Cohen-Mansfield Agitation Inventory data collected by telephone from informants at 6 and 12 months.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"abs1-8\"><jats:title>Randomisation and blinding<\/jats:title>\n<jats:p>Participants allocated 1 : 1 : 1 ratio (to discontinuation of the carbamazepine arm, 1 : 1 thereafter) to receive placebo or carbamazepine or mirtazapine, with treatment as usual. Random allocation was block stratified by centre and residence type with random block lengths of three or six (after discontinuation of carbamazepine, two or four). Double-blind, with drug and placebo identically encapsulated. Referring clinicians, participants, trial management team and research workers who did assessments were masked to group allocation.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"abs1-9\"><jats:title>Results<\/jats:title>\n<jats:p>Two hundred and forty-four participants recruited and randomised (102 mirtazapine, 102 placebo, 40 carbamazepine). The carbamazepine arm was discontinued due to slow overall recruitment; carbamazepine\/placebo analyses are therefore statistically underpowered and not detailed in the abstract. <jats:italic>Mean difference<\/jats:italic> placebo-mirtazapine (\u22121.74, 95% confidence interval \u22127.17 to 3.69; <jats:italic>p<\/jats:italic>\u2005=\u20050.53). <jats:italic>Harms:<\/jats:italic> The number of controls with adverse events (65\/102, 64%) was similar to the mirtazapine group (67\/102, 66%). However, there were more deaths in the mirtazapine group (<jats:italic>n<\/jats:italic>\u2005=\u20057) by week 16 than in the control group (<jats:italic>n<\/jats:italic>\u2005=\u20051). Post hoc analysis suggests this was of marginal statistical significance (<jats:italic>p<\/jats:italic>\u2005=\u20050.065); this difference did not persist at 6- and 12-month assessments. At 12 weeks, the costs of unpaid care by the dyadic carer were significantly higher in the mirtazapine than placebo group [difference: \u00a31120 (95% confidence interval \u00a356 to \u00a32184)]. In the cost-effectiveness analyses, mean raw and adjusted outcome scores and costs of the complete cases samples showed no differences between groups.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"abs1-10\"><jats:title>Limitations<\/jats:title>\n<jats:p>Our study has four important potential limitations: (1) we dropped the proposed carbamazepine group; (2) the trial was not powered to investigate a mortality difference between the groups; (3) recruitment beyond February 2020, was constrained by the COVID-19 pandemic; and (4) generalisability is limited by recruitment of participants from old-age psychiatry services and care homes.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"abs1-11\"><jats:title>Conclusions<\/jats:title>\n<jats:p>The data suggest mirtazapine is not clinically or cost-effective (compared to placebo) for agitation in dementia. There is little reason to recommend mirtazapine for people with dementia with agitation.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"abs1-12\"><jats:title>Future work<\/jats:title>\n<jats:p>Effective and cost-effective management strategies for agitation in dementia are needed where non-pharmacological approaches are unsuccessful.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"abs1-13\"><jats:title>Study registration<\/jats:title>\n<jats:p>This trial is registered as ISRCTN17411897\/NCT03031184.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"abs1-14\"><jats:title>Funding<\/jats:title>\n<jats:p>This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in <jats:italic>Health Technology Assessment<\/jats:italic>; Vol. 27, No. 23. See the NIHR Journals Library website for further project information.<\/jats:p>\n<\/jats:sec>","DOI":"10.3310\/vpdt7105","type":"journal-article","created":{"date-parts":[[2023,11,6]],"date-time":"2023-11-06T10:27:05Z","timestamp":1699266425000},"page":"1-108","update-policy":"https:\/\/doi.org\/10.3310\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":9,"title":["A pragmatic, multicentre, double-blind, placebo-controlled randomised trial to assess the safety, clinical and cost-effectiveness of mirtazapine and carbamazepine in people with Alzheimer\u2019s disease and agitated behaviours: the HTA-SYMBAD trial"],"prefix":"10.3310","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8083-7649","authenticated-orcid":true,"given":"Sube","family":"Banerjee","sequence":"first","affiliation":[{"name":"Faculty of Health, University of Plymouth, Plymouth, 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World Alzheimer Report 2015: The Global Impact of Dementia. Alzheimer\u2019s Disease International; 2015. URL: www.alz.co.uk\/research\/world-report-2015 (accessed 10 January 2017)."},{"key":"key2023110615555600_ref3-bib3","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1192\/bjp.bp.108.049619","article-title":"Prevalence, correlates and course of behavioural and psychological symptoms of dementia in the population","volume":"194","author":"Savva","year":"2009","journal-title":"Br J Psychiatry J Ment Sci"},{"key":"key2023110615555600_ref4-bib4","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1192\/bjp.bp.114.148403","article-title":"Longitudinal course of behavioural and psychological symptoms of dementia: systematic review","volume":"209","author":"van der Linde","year":"2016","journal-title":"Br J Psychiatry J Ment Sci"},{"key":"key2023110615555600_ref5-bib5","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1111\/j.1532-5415.1986.tb04302.x","article-title":"Agitated behaviors in the elderly. I. A conceptual review","volume":"34","author":"Cohen-Mansfield","year":"1986","journal-title":"J Am Geriatr Soc"},{"key":"key2023110615555600_ref6-bib6","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1111\/j.1532-5415.2009.02680.x","article-title":"Prevalence of neuropsychiatric symptoms and their association with functional limitations in older adults in the United States: the aging, demographics, and memory study","volume":"58","author":"Okura","year":"2010","journal-title":"J Am Geriatr Soc"},{"key":"key2023110615555600_ref7-bib7","first-page":"976","article-title":"Persistence of and changes in neuropsychiatric symptoms in Alzheimer disease over 6 months: the LASER-AD study","volume":"13","author":"Ryu","year":"2005","journal-title":"Am J Geriatr Psychiatry"},{"key":"key2023110615555600_ref8-bib8","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1097\/JGP.0b013e3181f60fa1","article-title":"Course of neuropsychiatric symptoms in residents with dementia in nursing homes over 2-year period","volume":"18","author":"Wetzels","year":"2010","journal-title":"Am J Geriatr Psychiatry"},{"key":"key2023110615555600_ref9-bib9","doi-asserted-by":"crossref","first-page":"e007382","DOI":"10.1136\/bmjopen-2014-007382","article-title":"Monetary costs of agitation in older adults with Alzheimer\u2019s disease in the UK: prospective cohort study","volume":"5","author":"Morris","year":"2015","journal-title":"BMJ Open"},{"key":"key2023110615555600_ref10-bib10","doi-asserted-by":"crossref","first-page":"e0211953","DOI":"10.1371\/journal.pone.0211953","article-title":"Healthcare resource utilisation and costs of agitation in people with dementia living in care homes in England \u2013 the Managing Agitation and Raising QUality of LifE in Dementia (MARQUE) study","volume":"14","author":"Panca","year":"2019","journal-title":"PLOS ONE"},{"key":"key2023110615555600_ref11-bib11","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1017\/S1041610219002059","article-title":"Healthcare utilization and monetary costs associated with agitation in UK care home residents with advanced dementia: a prospective cohort study","volume":"32","author":"Buylova Gola","year":"2020","journal-title":"Int Psychogeriatr"},{"key":"key2023110615555600_ref12-bib12","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1017\/S104161022000037X","article-title":"Time to invest in prevention and better care of behaviors and psychological symptoms associated with dementia","volume":"32","author":"Burley","year":"2020","journal-title":"Int Psychogeriatr"},{"key":"key2023110615555600_ref13-bib13","doi-asserted-by":"crossref","first-page":"h369","DOI":"10.1136\/bmj.h369","article-title":"Assessment and management of behavioral and psychological symptoms of dementia","volume":"350","author":"Kales","year":"2015","journal-title":"BMJ"},{"key":"key2023110615555600_ref14-bib14","first-page":"110","article-title":"Guideline Watch (October 2014): Practice Guideline for the Treatment of Patients With Alzheimer\u2019s Disease and Other Dementias","volume":"15","author":"Rabins","year":"2017","journal-title":"Focus Am Psychiatr Publ"},{"key":"key2023110615555600_ref15-bib15","unstructured":"Banerjee S. The Use of Antipsychotic Medication for People with Dementia: Time for Action. A Report for the Minister of State for Care Services. London: Department of Health; 2009."},{"key":"key2023110615555600_ref16-bib16","doi-asserted-by":"crossref","first-page":"e149","DOI":"10.1016\/S2468-2667(17)30031-2","article-title":"Trends in diagnosis and treatment for people with dementia in the UK from 2005 to 2015: a longitudinal retrospective cohort study","volume":"2","author":"Donegan","year":"2017","journal-title":"Lancet Public Health"},{"key":"key2023110615555600_ref17-bib17","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1056\/NEJMoa066583","article-title":"Donepezil for the treatment of agitation in Alzheimer\u2019s disease","volume":"357","author":"Howard","year":"2007","journal-title":"N Engl J Med"},{"key":"key2023110615555600_ref18-bib18","doi-asserted-by":"crossref","first-page":"e35185","DOI":"10.1371\/journal.pone.0035185","article-title":"Efficacy of Memantine for agitation in Alzheimer\u2019s dementia: a randomised double-blind placebo controlled 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