Banerjee S, High J, Stirling S, et al. Study of mirtazapine for agitated behaviours in dementia (SYMBAD): a randomised, double-blind, placebo-controlled trial. Lancet. 2021 Oct 23;398(10310):1487-1497. doi: 10.1016/S0140-6736(21)01210-1. (Original study)

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.

FUNDING: UK National Institute for Health Research Health Technology Assessment Programme.

Discipline Area Score
Geriatrics 7 / 7
Psychiatry 7 / 7
FM/GP/Mental Health 6 / 7
General Internal Medicine-Primary Care(US) 6 / 7
Family Medicine (FM)/General Practice (GP) 6 / 7
Neurology 4 / 7
Comments from MORE raters

Family Medicine (FM)/General Practice (GP) rater

What's important to know is that not only was mirtazapine not beneficial but there were more deaths in the mirtazapine group.

Geriatrics rater

Relatively small (N = 204) randomized trial that had protocol changes made (initial plan for a third arm involving carbamazepine was dropped due to low recruitment). The trial suggests mirtazapine is not effective as compared to placebo for managing agitation in persons with dementia. It would have been valuable to have an arm with an atypical antipsychotic as these drugs are still widely used in clinical practice even with concerns about their safety. This trial was likely published in the Lancet rather than a specialty journal because of the small (and not statistically significant) excess of deaths in the mirtazapine arm vs. the control arm. As the authors themselves highlight, this imbalance in deaths is likely a chance finding but it does warrant follow up. There will likely be another 10 papers about this potential risk in the next year. In the meantime, we are still left with few effective options to manage agitation in persons with dementia.

Neurology rater

For agitated dementia patients, we only explain to those who care for the patients about the nature and extent of the problems since there is no effective therapy.

Psychiatry rater

This study provides information that has relevance for psychiatrist’s clinical practice.
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