Use of Mirtazapine for Reducing Agitation in Dementia

April 2022

Agitation, which the study investigators describe as “inappropriate verbal, vocal, or motor activity,” is common in people with dementia and burdensome for caregivers and patients. When the initiating cause cannot be identified, nonpharmacologic interventions are the first-line treatment, but these are sometimes unsuccessful. When nonpharmacologic approaches fail, they are increasingly replaced with antidepressants to avoid the use of antipsychotics or anticholinergics; however, evidence for the efficacy of antidepressants in treating agitation in patients with dementia is lacking.

In a previous study by the same group testing mirtazapine for depression in patients with dementia, secondary analyses indicated a reduction in neuropsychiatric symptoms, although mirtazapine was ineffective for depression. Based on these secondary analyses, the SYMBAD trial was initiated to test whether mirtazapine could improve agitation in patients with Alzheimer disease.

SYMBAD was a double-blind, randomized trial with 204 participants recruited from 26 UK National Health Service clinical centers. Each participant had a diagnosis of possible or probable Alzheimer disease and agitation that had not responded to nonpharmacologic treatment. Agitation was measured by the Cohen-Mansfield Agitation Inventory (CMAI). The primary outcome was a reduction in CMAI score at 12 weeks.

CMAI scores for agitation decreased approximately 10 points in both the mirtazapine and placebo groups by week 6 compared with baseline but were not significantly different between groups at any time point. The decline in CMAI scores was maintained through week 12 in both groups.

At a 16-week safety assessment, 7 deaths were noted in the mirtazapine group compared with 1 death in the placebo group with no evident pattern in causes of death. By post-hoc analyses, the difference in mortality between groups was borderline significant (P = .065). The investigators noted no difference in mortality between the mirtazapine and placebo groups in their previous study and are unsure whether the result in this study was by chance. A limitation of this study is that it was not powered to detect differences in mortality.

The investigators noted several implications of this study. The antidepressant mirtazapine is commonly prescribed for older patients, including those with dementia. As the investigators stated, their result “implies a need to change the present practice of prescription of mirtazapine, and possibly other sedative antidepressants, for agitation in dementia.” Another implication of the study comes from the observation that agitation was reduced by 6 weeks in both the treatment and placebo groups. The investigators suggested that if nonpharmacologic treatments fail to reduce agitation in patients with dementia, 6 weeks of watchful waiting is a reasonable course of action before considering other treatment options.

Source

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;398:1487-1497.

Related Items

Subscribe to Value-Based Care in Neurology

Stay up to date with personalized medicine by subscribing to receive the free VBCN e‑Newsletter.