Mirtazapine of no benefit for agitated behaviours in dementia

Results of a randomized, double-blind, placebo-controlled trial show no benefit with mirtazapine, given with normal clinical care, for treatment of clinically significant agitation in patients with dementia compared with placebo, with a potentially higher mortality observed with the use of mirtazapine.

“The negative findings [with mirtazapine for treatment of agitation in dementia] shown in our study imply a need to change the present practice of prescription of mirtazapine, and possibly other sedative antidepressants, for agitation in dementia, and add to the evidence base demonstrating the limited effectiveness and the risk of harm of pharmacological intervention for treatment of agitation in dementia,” the researchers commented. [Lancet 2021;398:1487-1497]

In the current SYMBAD study (Study of Mirtazapine for Agitated Behaviours in Dementia), 204 patients with probable or possible Alzheimer’s Disease (AD), agitation unresponsive to non-drug treatment, and a Cohen-Mansfield Agitation Inventory (CMAI) score of ≥45 were recruited from 26 UK National Health Service clinical centres between 26 January 2017 and 6 March 2020. Recruited patients were randomized (1:1) to receive either mirtazapine (titrated to 45 mg) or placebo.

No significant improvement in the primary outcome (ie, reduction of agitation, as measured by mean CMAI score at 12-week follow-up) was found in the mirtazapine group vs the placebo group (adjusted mean difference, -1.74; 95 percent confidence interval [Cl], -7.17 to 3.69; p=0.530).

No evidence of differences in secondary outcomes was found between the mirtazapine group and the placebo group either, apart from a single significant difference in the Zarit Carer Burden Inventory at 12 weeks in the mirtazapine group (adjusted difference, 5.01 points; 95 percent CI, 0.80 to 9.23; p=0.020), and a weak association with higher proxy-rated EQ-5D quality of life in the placebo group at 6 weeks (-0.07; 95 percent CI, -0.13 to 0.00; p=0.061) that was not maintained at 12 weeks (-0.01; -0.08 to 0.07; p=0.822).

Although the rate of adverse events was similar between the mirtazapine group (66 percent) and the placebo group (64 percent), more deaths were reported in the mirtazapine vs placebo group by week 16.