Mirtazapine and Carbamazepine Fail to Demonstrate Clinical and Cost Effectiveness as Alzheimer Agitation Treatments


Over a 12-week treatment period, investigators found no significant differences in mean Cohen Mansfield Agitation Inventory scores between mirtazapine and placebo, with similar rates in adverse events.

Sube Banerjee, MD, MSc, MBA, FRCPsych, professor of dementia and executive dean of the Faculty of Health at the University of Plymouth

Sube Banerjee, MD, MSc, MBA, FRCPsych

Findings from the SYMBAD trial (NCT03031184) suggested that mirtazapine, an antidepressant commonly prescribed for Alzheimer disease (AD) agitation, is not clinically effective or cost-effective for this condition. Additionally, the trial also provided no evidence of potential benefit for carbamazepine, an anticonvulsant, as a treatment option for AD agitation.

Led by Sube Banerjee, MD, MSc, MBA, FRCPsych, professor of dementia and executive dean of the Faculty of Health at the University of Plymouth, mean CMAI scores after 12 weeks of treatment were not significantly different between mirtazapine-treated patients and placebo (adjusted mean difference, ­–1.74; 95%, –7.17 to 3.69; P = .53). Presented at the 2022 Clinical Trials on Alzheimer Disease (CTAD) conference, November 29 to December 2, in San Francisco, California, the data bring into the question the use of antidepressants for agitation in dementia.

"Agitation is a really important issue for people with dementia and for the carers of people with dementia. It’s what drives poor quality of life," Banerjee told NeurologyLive®. "The take-home message from [this trial] is that these drugs that are commonly used to treat agitation in dementia simply don’t work. They’re associated with harms, but not associated with benefits."

A total of 244 patients were randomly assigned mirtazapine (n = 102) at a target dose of 45 mg, carbamezapine (n = 40) at a target dose of 300 mg, or placebo (n = 102), for 12 weeks, with long-term follow-up at 6 and 12 months. Due to slower than expected recruitment, the carbamezapine arm was discontinued in August 2018 with 1:1 randomization to mirtazapine or placebo thereafter. Patients had baseline CMAI scores of at least 45, had co-existing agitated behaviors, and were not on antidepressants, anticonvulsants, or antipsychotics coming in the study. The primary outcome was CMAI scores at 12 weeks, analyzed using a linear regression model.

At 12 weeks, there was a similar, but slightly higher rate of adverse events in the mirtazapine group (66%) than those on placebo (64%). Additionally, there were more deaths in the mirtazapine group (n = 7) by week 16 than the control group (n = 1), with post-hoc analysis suggesting this was of marginal statistical significance (P = .065), but this difference did not persist at 6- and 12-month follow-up.

"Since it’s [mirtazapine] been shown to not work for depression, it’s being used for agitation in dementia. It’s time to take a step back with respect to agitation and dementia," Banerjee said. "If you think about the things that cause agitation, it’s a very broad and complex group of things that are about social adaption, the reactions of people to the memory problems they have, and the reaction of others to people with dementia. Very little of that is likely to be treatable with medication."

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Additional findings at 12 weeks indicated that the costs of unpaid care by the dyadic caretaker over the prior 6 weeks were significantly higher in the mirtazapine group than those on placebo (difference, £1,120; 95% CI £56-£2,184). Between the 2 groups, there were no difference in in mean raw and adjusted outcome scores and costs of the complete case samples, suggesting no cost-effectiveness benefit to mirtazapine.

Due to the lower number of participants on carbamazepine, statistical analyses couldn’t have been powered; however, in exploratory analyses using the same model for mirtazapine vs placebo, there was no evidence of any benefits over placebo after 12 weeks (adjusted mean difference, 2.46; 95% CI, ­–5.01 to 9.93; P = .52) or at long-term follow-up, with similar levels of adverse events reported.

"We need to take a step back and ensure there are non-drug treatments. These are about good, quality, multidisciplinary assessments. These are about working out the problems people are having and coming up with imaginative solutions," Banerjee added. "If we provide people with psychosocial care and support, which is what they actually need, in addition to the drugs for their Alzheimer disease, that’s the way forward. Looking for a single, magic drug that will get rid of this complex problem is a failure to our patients."

Click here for more coverage of CTAD 2022.

1. Banerjee S, Symbad group. Long-term and economic outcomes for mirtazapine and carbamazepine vs placebo: new data from the SYMBAD RCT. Presented at: 2022 CTAD Conference; November 29-December 2; San Francisco, CA. OC05.
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