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Many of us get questions from our primary care colleagues for which we try to provide some answers. Here’s a common one. In a patient with dementia, how should I manage agitation? Of course, after an appropriate diagnostic assessment looking for things like pain, dehydration, and fever, the first-line options are environmental, regular physical activity, familiar music, and combined stimuli, such as small tasks, reading, and live social interaction.
Beyond those, what are the options? The National Institute for Health and Care Excellence (NICE) guidelines associated with the UK’s National Health Service specifically recommend against the use of antipsychotics except when there is a risk of harm to self or others or severe distress. Perhaps as an alternative you’ve suggested mirtazapine for nighttime sedation. Many of our colleagues have. It accounted for over one-third of all new prescriptions for patients with dementia in a recent study.
Hi! Jim Phelps here for the Psychopharmacology Institute. Let’s look at a randomized trial of mirtazapine for agitation in dementia. It’s great to have data on such a commonly used generic medication such as mirtazapine, especially since this was not a little pilot study. It had 200 participants across the UK. In their introduction, the authors note that in a given month, agitation is experienced by nearly half of all patients with Alzheimer’s, and 80% of those cases continue to experience agitation 6 months later. Their study was prompted in part by increasing recognition of the need for an alternative to antipsychotics which, according to the American Psychiatric Association guidelines, have “little or no efficacy” and pose significant risks. For example, in the UK, antipsychotic use among people with dementia was associated with 1800 deaths and 1500 cerebrovascular adverse events in 2009.
How about mirtazapine? The study was designed just as we’d wish—with very few exclusion criteria so as to maximize generalizability. The primary outcome measure was a standard agitation inventory. The authors required evidence that the etiology of agitated behavior had been investigated and that it had not responded to nonpharmacologic management. How did mirtazapine do relative to placebo?
At 6 and 12 weeks after study inception, mirtazapine was no better than the placebo, so this is a negative study. What doses were they using? Everyone started at 15 mg and then increased every 2 weeks by 15 mg to a target of 45 mg nightly if tolerated. At the end of the study, the average dose was 30 mg. So, they pushed it pretty hard and still it did not work better than placebo. Moreover, although the total number of adverse events did not differ between mirtazapine and placebo, 7 patients in the mirtazapine group vs 1 in the placebo group died. The cause of those deaths displayed no particular pattern, and the difference between groups was only marginally statistically significant at 0.065.
A similarly large study found citalopram to be significantly better than placebo for agitation in Alzheimer’s dementia, but among 95 patients on citalopram, 3 had QT prolongation. That was with a dose that began at 10 mg but targeted 30 mg daily, with 80% of the patients in the study achieving 30 mg. The authors of that study concluded that despite the improvements noted, “citalopram showed mild cognitive and concerning cardiac adverse events and cannot be generally recommended as an alternative treatment at that dose.” Only 15% of their patients were taking 20 mg and that was in a random group, so efficacy at that lower dose could not be assessed.
So these studies only tell you what not to give—that is, neither mirtazapine nor higher-dose citalopram. They don’t tell you what works. Nevertheless, there are 4 clear conclusions. The first 3 come from this new study and the last from the citalopram study. First, the first line of management for agitation in dementia is a full assessment to identify any potentially modifiable causes for the behavior, such as infection, pain, and hypoxia. Second, in all but the most urgent of situations, the next step is nonpharmacologic treatment because such approaches have been shown to be at least as effective as drug treatment. Third, this study found that benefits of mirtazapine treatment were not greater than placebo, and the 7 deaths from the mirtazapine group vs 1 from the placebo group, though not statistically very significant, raise concerns about safety. Finally, citalopram 30 mg per day was significantly more effective than placebo but was associated with QT prolongation in 3% of patients, and there is no clear data on the 20 mg dose.
So, these are the responses with which you could answer your primary care colleague when they call looking for guidance for a patient with agitated dementia. Be gracious. Begin by noting that they very likely know the general principles just discussed, and then regret that the latest data don’t lead to great new options.
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.
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Reference
Banerjee, S., High, J., Stirling, S., Shepstone, L., Swart, A. M., Telling, T., … & Tabet, N. (2021). Study of mirtazapine for agitated behaviours in dementia (SYMBAD): a randomised, double-blind, placebo-controlled trial. The Lancet, 398(10310), 1487-1497
