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Psychiatry Research Review

Sanjay Gupta, MD
Released: December 22, 2021
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Mirtazapine for Agitation in Dementia: Results of the Double-Blind, Placebo-Controlled SYMBAD Trial

Banerjee S, et al. Lancet. 2021;398:1487-1497.

People with dementia often have agitation, which negatively affects the quality of life of both patients and caregivers. The first-line treatment for agitation is nonpharmacologic intervention. Antipsychotics are the most common second-line therapies despite their adverse event (AE) profiles and low efficacy. There is little information on the safety and efficacy of antipsychotic alternatives. This study evaluated the safety and efficacy of mirtazapine, an antidepressant widely prescribed for patients with dementia-associated agitation.

The SYMBAD study was a parallel-group, double-blind, placebo-controlled phase III trial. Enrolled patients were from 26 centers in the United Kingdom and had a clinical diagnosis of probable or possible Alzheimer disease based on the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association criteria. All patients had coexisting agitation unresponsive to nonpharmacological intervention and a Cohen-Mansfield Agitation Inventory (CMAI) score ≥45. Of the 737 patients assessed for eligibility, 204 were recruited and randomized 1:1 to receive mirtazapine (target dose 45 mg) or placebo. The primary outcome of SYMBAD was clinical efficacy as measured by a reduction in CMAI score at 12 weeks.

At 12 weeks, there was not a significant difference in mean CMAI scores in patients receiving mirtazapine (61.4) vs placebo (60.8; P = .530). The frequency of AEs was similar between the arms (64% and 66%), although 7 deaths occurred in the mirtazapine arm by Week 16 compared with only 1 death in the placebo arm (P = .065).

This trial found that mirtazapine is no better than placebo in the treatment of dementia-related agitation.

Clinical Commentary
SYMBAD was a randomized, double-blind, placebo-controlled trial comparing mirtazapine with placebo for the treatment of dementia-related agitation. Patients had probable Alzheimer disease or mixed dementia, so these results may not apply to vascular, Lewy body, or frontotemporal dementia. The 45-mg target dose of mirtazapine was sufficient to observe an effect, as the maximum dose used in most clinical settings is 15-30 mg. Agitation levels were measured using CMAI, which was an excellent choice for this purpose. Because this was a negative study, I would like to thank the journal for publishing it, as negative studies play a vital role in our overall assessment of medication trials.

The strengths of this study were its design, which was randomized and placebo-controlled; the number of patients in each arm; and the high rates of retention and completion. The CMAI is an excellent and appropriate outcome measure for this study. In addition, >50% of patients reached the target dose of 45 mg of mirtazapine, which is a sufficient dose for this study; most clinical settings use does of 15-30 mg at bedtime. The limitations of this study include a major protocol adjustment to drop an arm evaluating carbamazepine due to slow recruitment. Carbamazepine has prior efficacy data but unwanted effects, including autoinduction. The results observed in this trial with mirtazapine cannot be generalized to other antidepressants, although citalopram has been shown to have modest efficacy in dementia-associated agitation. The study was not powered to assess mortality, so no conclusions can be drawn about the nonsignificant difference seen there.

Clinical Insights

  • Mirtazapine (target dose 45 mg) was not efficacious in treating dementia-related agitation in this trial.
  • The enrolled patients were from the United Kingdom, and most were recruited from the practices of geriatric psychiatrists and care homes. It is unclear if the findings from this trial apply to community-dwelling adults treated by primary care providers alone.
  • The increased mortality observed with mirtazapine was not statistically significant. A previous study evaluating mirtazapine in older patients with depression had not found increased mortality with mirtazapine.

Currently, there are no FDA-approved medications for dementia-related agitation. This is the first study providing efficacy data for mirtazapine. Although this was a negative trial, it does not preclude the use of mirtazapine. In my opinion, mirtazapine has a role in anxiety, sleep, and appetite issues in older patients. For dementia-associated agitation, my clinical experience is that antipsychotics work the best, but there are FDA warnings for increased mortality, and gradual dose reductions are required. Below is my clinical strategy for treating dementia-related agitation.

  • Agitation with psychosis (paranoia): I use risperidone, as it is the most studied drug for this purpose.
  • Agitation with depressive type symptoms: antidepressants (sertraline, citalopram, mirtazapine).
  • Agitation with aggression and sexual issues: valproic acid. One could use an antipsychotic in the short term while titrating valproic acid.
  • For more immediate needs, I use lorazepam (oral or IM), but only for the short term.
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