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.

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

Figure 1

Trial profile CMAI=Cohen Mansfield Agitation Inventory. *Reasons for ineligibility: one no diagnosis of probable or possible Alzheimer's disease; one no diagnosis of coexisting agitated behaviour; one no evidence that behaviour does not respond to management according to Alzheimer's Society and Department of Health algorithm; 15 no assessment of CMAI score of 45 or greater; one no written informed consent to enter and be randomised into the trial; one current treatment with antidepressant (including monoamine oxidase inhibitors), anticonvulsants, or antipsychotics; two case too critical for randomisation; 12 other or unknown reasons (following text taken from text entries: one psychiatrist decided to proceed with an alternative medication; one patient admitted to hospital and no longer appropriate; one patient not eligible: completed no further assessments after CMAI; six patients ineligible; one patient scored less than 45 on CMAI; one started memantine which reduced agitation; one not randomised as behaviour settled and did not require medication). †One abnormal blood results, one patient, carer, or legal representative withdrew consent. ‡One non-compliance and general practitioner prescription of mirtazapine, one too agitated to continue, one transient ischaemic attack. §One deteriorating health and readmission to hospital. ¶One local Principal Investigator determined that it was no longer in patient's best interests, one compliance problems due to participant and carer capability and ill health.

Figure 2

Unadjusted mean CMAI scores (95% CI) by treatment group Please note that the y-axis does not start at 0 in this figure. CMAI=Cohen Mansfield Agitation Inventory.