Study of mirtazapine for agitated behaviours in dementia (SYMBAD): a randomised, double-blind, placebo-controlled trial

Sube Banerjee; Juliet High; Susan Stirling; Lee Shepstone; Ann Marie Swart; Tanya Telling; Catherine Henderson; Clive Ballard; Peter Bentham; Alistair Burns; Nicolas Farina; Chris Fox; Paul Francis; Robert Howard; Martin Knapp; Iracema Leroi; Gill Livingston; Ramin Nilforooshan; Shirley Nurock; John O'Brien; Annabel Price; Alan J. Thomas; Naji Tabet

doi:10.1016/s0140-6736(21)01210-1

Study of mirtazapine for agitated behaviours in dementia (SYMBAD): a randomised, double-blind, placebo-controlled trial

Sube Banerjee^*
, Juliet High
, Susan Stirling
, Lee Shepstone
, Ann Marie Swart
, Tanya Telling
, Catherine Henderson
, Clive Ballard
, Peter Bentham
, Alistair Burns
, Nicolas Farina
, Chris Fox
, Paul Francis
, Robert Howard
, Martin Knapp
, Iracema Leroi
, Gill Livingston
, Ramin Nilforooshan
, Shirley Nurock
, John O'Brien

Annabel Price, Alan J. Thomas, Naji Tabet

^*Corresponding author for this work

Faculty of Health

University of East Anglia
University of Sussex
The London School of Economics and Political Science
University of Exeter
Birmingham and Solihull Mental Health NHS Foundation Trust
University of Manchester
University College London
Trinity College Dublin
Surrey and Borders Partnership NHS Foundation Trust
University of Cambridge
Cambridgeshire and Peterborough NHS Foundation Trust
Newcastle University

Research output: Contribution to journal › Article › peer-review

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Abstract

Background
Agitation is common in people with dementia and negatively affects the quality of life of both people with dementia and carers. Non-drug patient-centred care is the first-line treatment, but there is a need for other treatment when this care is not effective. Current evidence is sparse on safer and effective alternatives to antipsychotics. We assessed the efficacy and safety of mirtazapine, an antidepressant prescribed for agitation in dementia.
Methods
This parallel-group, double-blind, placebo-controlled trial—the Study of Mirtazapine for Agitated Behaviours in Dementia trial (SYMBAD)—was done in 26 UK centres. Participants had probable or possible Alzheimer's disease, agitation unresponsive to non-drug treatment, and a Cohen-Mansfield Agitation Inventory (CMAI) score of 45 or more. They were randomly assigned (1:1) to receive either mirtazapine (titrated to 45 mg) or placebo. The primary outcome was reduction in CMAI score at 12 weeks. This trial is registered with ClinicalTrials.gov, NCT03031184, and ISRCTN17411897.
Findings
Between Jan 26, 2017, and March 6, 2020, 204 participants were recruited and randomised. Mean CMAI scores at 12 weeks were not significantly different between participants receiving mirtazapine and participants receiving placebo (adjusted mean difference –1·74, 95% CI –7·17 to 3·69; p=0·53). The number of controls with adverse events (65 [64%] of 102 controls) was similar to that in the mirtazapine group (67 [66%] of 102 participants receiving mirtazapine). However, there were more deaths in the mirtazapine group (n=7) by week 16 than in the control group (n=1), with post-hoc analysis suggesting this difference was of marginal statistical significance (p=0·065).
Interpretation
This trial found no benefit of mirtazapine compared with placebo, and we observed a potentially higher mortality with use of mirtazapine. The data from this study do not support using mirtazapine as a treatment for agitation in dementia.

Original language	English
Pages (from-to)	1487-1497
Number of pages	0
Journal	The Lancet
Volume	398
Issue number	10310
Early online date	21 Oct 2021
DOIs	https://doi.org/10.1016/s0140-6736(21)01210-1
Publication status	Published - 23 Oct 2021

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Banerjee, S., High, J., Stirling, S., Shepstone, L., Swart, A. M., Telling, T., Henderson, C., Ballard, C., Bentham, P., Burns, A., Farina, N., Fox, C., Francis, P., Howard, R., Knapp, M., Leroi, I., Livingston, G., Nilforooshan, R., Nurock, S., ... Tabet, N. (2021). Study of mirtazapine for agitated behaviours in dementia (SYMBAD): a randomised, double-blind, placebo-controlled trial. The Lancet, 398(10310), 1487-1497. https://doi.org/10.1016/s0140-6736(21)01210-1

@article{bb597b4c37d945a89e06feab570f35ab,

title = "Study of mirtazapine for agitated behaviours in dementia (SYMBAD): a randomised, double-blind, placebo-controlled trial",

abstract = "Background Agitation is common in people with dementia and negatively affects the quality of life of both people with dementia and carers. Non-drug patient-centred care is the first-line treatment, but there is a need for other treatment when this care is not effective. Current evidence is sparse on safer and effective alternatives to antipsychotics. We assessed the efficacy and safety of mirtazapine, an antidepressant prescribed for agitation in dementia. Methods This parallel-group, double-blind, placebo-controlled trial—the Study of Mirtazapine for Agitated Behaviours in Dementia trial (SYMBAD)—was done in 26 UK centres. Participants had probable or possible Alzheimer's disease, agitation unresponsive to non-drug treatment, and a Cohen-Mansfield Agitation Inventory (CMAI) score of 45 or more. They were randomly assigned (1:1) to receive either mirtazapine (titrated to 45 mg) or placebo. The primary outcome was reduction in CMAI score at 12 weeks. This trial is registered with ClinicalTrials.gov, NCT03031184, and ISRCTN17411897. Findings Between Jan 26, 2017, and March 6, 2020, 204 participants were recruited and randomised. Mean CMAI scores at 12 weeks were not significantly different between participants receiving mirtazapine and participants receiving placebo (adjusted mean difference –1·74, 95\% CI –7·17 to 3·69; p=0·53). The number of controls with adverse events (65 [64\%] of 102 controls) was similar to that in the mirtazapine group (67 [66\%] of 102 participants receiving mirtazapine). However, there were more deaths in the mirtazapine group (n=7) by week 16 than in the control group (n=1), with post-hoc analysis suggesting this difference was of marginal statistical significance (p=0·065). Interpretation This trial found no benefit of mirtazapine compared with placebo, and we observed a potentially higher mortality with use of mirtazapine. The data from this study do not support using mirtazapine as a treatment for agitation in dementia.",

author = "Sube Banerjee and Juliet High and Susan Stirling and Lee Shepstone and Swart, \{Ann Marie\} and Tanya Telling and Catherine Henderson and Clive Ballard and Peter Bentham and Alistair Burns and Nicolas Farina and Chris Fox and Paul Francis and Robert Howard and Martin Knapp and Iracema Leroi and Gill Livingston and Ramin Nilforooshan and Shirley Nurock and John O'Brien and Annabel Price and Thomas, \{Alan J.\} and Naji Tabet",

year = "2021",

month = oct,

day = "23",

doi = "10.1016/s0140-6736(21)01210-1",

language = "English",

volume = "398",

pages = "1487--1497",

journal = "The Lancet",

issn = "0140-6736",

publisher = "Elsevier B.V.",

number = "10310",

}

Banerjee, S, High, J, Stirling, S, Shepstone, L, Swart, AM, Telling, T, Henderson, C, Ballard, C, Bentham, P, Burns, A, Farina, N, Fox, C, Francis, P, Howard, R, Knapp, M, Leroi, I, Livingston, G, Nilforooshan, R, Nurock, S, O'Brien, J, Price, A, Thomas, AJ & Tabet, N 2021, 'Study of mirtazapine for agitated behaviours in dementia (SYMBAD): a randomised, double-blind, placebo-controlled trial', The Lancet, vol. 398, no. 10310, pp. 1487-1497. https://doi.org/10.1016/s0140-6736(21)01210-1

TY - JOUR

T1 - Study of mirtazapine for agitated behaviours in dementia (SYMBAD): a randomised, double-blind, placebo-controlled trial

AU - Banerjee, Sube

AU - High, Juliet

AU - Stirling, Susan

AU - Shepstone, Lee

AU - Swart, Ann Marie

AU - Telling, Tanya

AU - Henderson, Catherine

AU - Ballard, Clive

AU - Bentham, Peter

AU - Burns, Alistair

AU - Farina, Nicolas

AU - Fox, Chris

AU - Francis, Paul

AU - Howard, Robert

AU - Knapp, Martin

AU - Leroi, Iracema

AU - Livingston, Gill

AU - Nilforooshan, Ramin

AU - Nurock, Shirley

AU - O'Brien, John

AU - Price, Annabel

AU - Thomas, Alan J.

AU - Tabet, Naji

PY - 2021/10/23

Y1 - 2021/10/23

N2 - Background Agitation is common in people with dementia and negatively affects the quality of life of both people with dementia and carers. Non-drug patient-centred care is the first-line treatment, but there is a need for other treatment when this care is not effective. Current evidence is sparse on safer and effective alternatives to antipsychotics. We assessed the efficacy and safety of mirtazapine, an antidepressant prescribed for agitation in dementia. Methods This parallel-group, double-blind, placebo-controlled trial—the Study of Mirtazapine for Agitated Behaviours in Dementia trial (SYMBAD)—was done in 26 UK centres. Participants had probable or possible Alzheimer's disease, agitation unresponsive to non-drug treatment, and a Cohen-Mansfield Agitation Inventory (CMAI) score of 45 or more. They were randomly assigned (1:1) to receive either mirtazapine (titrated to 45 mg) or placebo. The primary outcome was reduction in CMAI score at 12 weeks. This trial is registered with ClinicalTrials.gov, NCT03031184, and ISRCTN17411897. Findings Between Jan 26, 2017, and March 6, 2020, 204 participants were recruited and randomised. Mean CMAI scores at 12 weeks were not significantly different between participants receiving mirtazapine and participants receiving placebo (adjusted mean difference –1·74, 95% CI –7·17 to 3·69; p=0·53). The number of controls with adverse events (65 [64%] of 102 controls) was similar to that in the mirtazapine group (67 [66%] of 102 participants receiving mirtazapine). However, there were more deaths in the mirtazapine group (n=7) by week 16 than in the control group (n=1), with post-hoc analysis suggesting this difference was of marginal statistical significance (p=0·065). Interpretation This trial found no benefit of mirtazapine compared with placebo, and we observed a potentially higher mortality with use of mirtazapine. The data from this study do not support using mirtazapine as a treatment for agitation in dementia.

AB - Background Agitation is common in people with dementia and negatively affects the quality of life of both people with dementia and carers. Non-drug patient-centred care is the first-line treatment, but there is a need for other treatment when this care is not effective. Current evidence is sparse on safer and effective alternatives to antipsychotics. We assessed the efficacy and safety of mirtazapine, an antidepressant prescribed for agitation in dementia. Methods This parallel-group, double-blind, placebo-controlled trial—the Study of Mirtazapine for Agitated Behaviours in Dementia trial (SYMBAD)—was done in 26 UK centres. Participants had probable or possible Alzheimer's disease, agitation unresponsive to non-drug treatment, and a Cohen-Mansfield Agitation Inventory (CMAI) score of 45 or more. They were randomly assigned (1:1) to receive either mirtazapine (titrated to 45 mg) or placebo. The primary outcome was reduction in CMAI score at 12 weeks. This trial is registered with ClinicalTrials.gov, NCT03031184, and ISRCTN17411897. Findings Between Jan 26, 2017, and March 6, 2020, 204 participants were recruited and randomised. Mean CMAI scores at 12 weeks were not significantly different between participants receiving mirtazapine and participants receiving placebo (adjusted mean difference –1·74, 95% CI –7·17 to 3·69; p=0·53). The number of controls with adverse events (65 [64%] of 102 controls) was similar to that in the mirtazapine group (67 [66%] of 102 participants receiving mirtazapine). However, there were more deaths in the mirtazapine group (n=7) by week 16 than in the control group (n=1), with post-hoc analysis suggesting this difference was of marginal statistical significance (p=0·065). Interpretation This trial found no benefit of mirtazapine compared with placebo, and we observed a potentially higher mortality with use of mirtazapine. The data from this study do not support using mirtazapine as a treatment for agitation in dementia.

UR - https://pearl.plymouth.ac.uk/pms-research/765/

U2 - 10.1016/s0140-6736(21)01210-1

DO - 10.1016/s0140-6736(21)01210-1

M3 - Article

SN - 0140-6736

VL - 398

SP - 1487

EP - 1497

JO - The Lancet

JF - The Lancet

IS - 10310

ER -

Study of mirtazapine for agitated behaviours in dementia (SYMBAD): a randomised, double-blind, placebo-controlled trial

Abstract

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