Study of mirtazapine for agitated behaviours in dementia (SYMBAD): a randomised, 1 double-blind, placebo-controlled trial

Background: Agitation is common in people with dementia and impacts negatively on 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 fails. Current evidence is sparse on safer and effective alternatives to antipsychotics. We assessed efficacy and safety of mirtazapine, an antidepressant prescribed for agitation in dementia. Methods: Parallel-group, double-blind, placebo-controlled trial, the Study of Mirtazapine for Agitated Behaviours in Dementia trial (SYMBAD) 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 ≥ 45. They were randomly allocated 1:1 to mirtazapine titrated to 45 mg or placebo. The primary outcome was reduction in CMAI score at 12 weeks. ISRCTN17411897, ClinicalTrials.gov NCT03031184. Findings: Between January 2017 and February 2020, 204 participants were recruited and randomised. Mean CMAI scores at 12 weeks were not significantly different between participants allocated to receive mirtazapine and placebo (adjusted mean difference -1.74, 60 95% CI -7.17 to 3.69, p=0.53). The number of controls with adverse events (65/102 [64%]) 61 was similar to that in the mirtazapine group (67/102, 66%). 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 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 of Health Research Health Technology Assessment 70 Programme.