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. MethodsThis 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.

No benefit from mirtazapine for treating agitation in dementia

“…The severity of agitation decreased in both groups at 6 weeks (by about 10 CMAI points) and remained lower than the baseline scores at 12 weeks, but the difference between the groups (estimated adjusted mean difference: −1.74, 95% CI −7.17 to 3.69) was not statistically significant 1. At 12 weeks the mean CMAI score was 61.4 for mirtazapine and 60.8 for placebo.…”

“…However, antipsychotics cause harms and increased mortality in people with dementia and in 2012, following safety concerns, the Medicines and Healthcare products Regulatory Agency published advice on reducing use of antipsychotics to treat behavioural and psychological symptoms of dementia 5. As a result there has been interest in the use of other pharmacological interventions, including antidepressants, in the management of agitation associated with dementia 1. In a clinical study of people with probable or possible dementia, mirtazapine, which is only licensed for treatment of major depression, was noted to have a possible positive effect on neuropsychiatric symptoms, which led to the current study 1.…”

“…This multicentre, parallel-group, double-blind, placebo-controlled randomised trial evaluated mirtazapine against placebo in addition to standard care for agitation 1. Participants with possible or probable Alzheimer’s disease and agitation that had not responded to non-pharmacological management were recruited from 26 NHS clinical centres.…”

“…A total of 204 patients (mean age 82 years; 66% female) were randomised equally to the two treatment arms, with 79 patients in the mirtazapine group and 87 in the placebo group assessed at the 12-week follow-up. The primary outcome was clinical effectiveness of mirtazapine in terms of reduction of agitation, measured using the Cohen Mansfield Agitation Inventory (CMAI) score (range: 29–203) at 12 weeks (minimum important difference=7 points) 1 2…”

“…A large UK trial found no benefit for mirtazapine compared with placebo for treating agitation in people with probable or possible dementia but identified a possible increase in mortality associated with mirtazapine 1…”