Negative trial raises broader questions

Dementia patients who had clinically significant agitation improved over 12 weeks whether they were treated with the antidepressant mirtazapine or placebo, the randomized double-blind SYMBAD trial found.

Mean scores on the Cohen-Mansfield Agitation Inventory (CMAI) at 12 weeks were 61.4 in the mirtazapine group and 60.8 for placebo (adjusted mean difference –1.74, 95% CI –7.17 to 3.69, P=0.53), reported Sube Banerjee, MD, of the University of Plymouth, England, and co-authors, in The Lancet.

There were seven deaths in the mirtazapine group and one death in the placebo group at 16 weeks. Post-hoc statistical analyses suggested weak evidence of a mortality difference between groups.

“This study adds to the evidence base that shows pharmacological interventions for agitation in dementia are limited in their effectiveness and associated with risk of harm,” Banerjee and colleagues wrote.

“Our results indicate that mirtazapine, given with normal clinical care, is not clinically effective compared with placebo for the treatment of clinically significant agitation in people with dementia,” they continued. “This finding implies a need to change the present practice of prescription of mirtazapine, and possibly other sedative antidepressants, for agitation in dementia.”

“There are also reasons to be positive that treatment-as-usual by current primary and secondary health-care services could well enable people with agitation and dementia to recover from that agitation without the use of medication and its potential harms,” Banerjee and co-authors added. “Data from this study support the active monitoring of agitation in dementia without the prescription of medication.”

The researchers recruited 204 participants with probable or possible Alzheimer’s disease and co-existing agitation that was unresponsive to non-pharmacologic treatment between January 2017 and March 2020. The cohort had a mean age of 82.5; women made up 75% of the mirtazapine group and 58% of the placebo group.

Participants were randomized to placebo (n=102) or mirtazapine (n=102) titrated to a target of 45 mg daily, though doses were clinician-adjustable and the mean dose was 30.5 mg. Both groups received treatment as usual in addition to the study intervention. The use of permitted rescue medication (lorazepam 0.5 mg or risperidone 0.5 to 1 mg) was similar in both groups.

Agitation was assessed with the CMAI, a measure of agitation with possible scores ranging from 29 to 203, with higher scores indicating more severe agitation. The baseline CMAI score was around 70 to 71.

The primary outcome analysis included 81 participants in the mirtazapine group and 90 in the placebo group. Decreased severity of agitation by about 10 CMAI points was evident in both groups at 6 weeks. At no point was the unadjusted or adjusted CMAI between-group difference statistically significant. Including sex in the model did not substantially alter results.

“Our study provides strong evidence that the overall improvement seen over the 12 weeks of the study is not attributable to mirtazapine,” Banerjee and colleagues wrote.

The improvement seen in both groups “might be a function of the potential therapeutic value of the non-drug treatment-as-usual provided by old-age psychiatric and primary care services, or it could be part of the natural course of agitation in dementia where symptoms can come and go,” among other possible causes, they added.

“Decreases in agitation in a placebo group can reflect non-specific effects of trial participation and regression to the mean,” observed Krista Lanctôt, PhD, of University of Toronto, Canada, and Nathan Herrmann, MD, of Merchavim Medical Center in Be’er Yaacov, Israel, in an accompanying editorial.

“Other agitation trials have noted a range of placebo responses with designs intended to minimize the effect of placebo response including sequential parallel comparisons, placebo run in, and manualized psychosocial interventions,” they noted.

“Moving forward, a greater understanding of the neurobiology of neuropsychiatric symptoms, and consistent use of diagnostic criteria for neuropsychiatric symptoms, combined with biomarkers that are mechanistically relevant to the underlying disease, medication, or neuropsychiatric symptom, will help to identify which patients and which behaviors are most likely to respond to a pharmacological approach when non-pharmacological approaches do not suffice,” Lanctôt and Hermann added.

Agitation—inappropriate behavior or activity, including physical and verbal aggression, not thought to be caused by an unmet need—affected 76% of those with Alzheimer’s disease in a 2019 study. Multifactorial and often combined causes for agitation include medical comorbidities, polypharmacy, and environmental factors, in addition to features of dementia itself.

“The first line of management for agitation in dementia is a full assessment to identify if there is a modifiable cause for the behavior,” the authors noted. “In all but the most urgent of situations, the next line is non-pharmacological treatment because such approaches have been shown to be at least as effective as drug treatment.”

Pharmacologic treatments used for agitation include antipsychotics, which carry a FDA black box warning for increased mortality in dementia patients that may have shifted prescribing patterns among benzodiazepines, mood stabilizing anticonvulsants, the dementia medications donepezil and memantine, and antidepressants.

“Antidepressants are not mentioned as a potential treatment for agitation in the English National Institute for Health and Care Excellence guideline on dementia assessment and management, but they are increasingly used to treat agitation in dementia,” Banerjee and colleagues noted. “This substitution strategy to avoid antipsychotic prescription was reported in a large U.S. nursing homes study, which showed that mood stabilizers such as sodium valproate, carbamazepine, and particularly gabapentin prescription rates increased as antipsychotics decreased.”

The authors previously studied mirtazapine, a presynaptic α2-antagonist noradrenergic/serotonergic antidepressant, as a treatment for depression in dementia in a multicenter study. They found no benefit versus placebo, but secondary analysis suggested a possible benefit on neuropsychiatric symptoms, leading to the present study.

In the SYMBAD trial, 12-week results showed no differences in measures of cognition, quality of patient and caregiver life, or general and specific neuropsychiatric symptoms, except for one measure that showed higher caregiver burden in the mirtazapine group at 12 weeks.

At 16 weeks (or 4 weeks after the last dose), safety data showed 192 and 225 events overall for the mirtazapine group and placebo groups, respectively. Causes of death showed no consistent pattern. The study was not powered to investigate a mortality difference between groups and post-hoc analysis suggested the difference in deaths was of marginal statistical significance (Fisher’s exact test P=0.065).

“Although we do not know whether the deaths were related to mirtazapine, in the absence of clinical benefit attributable to mirtazapine, these potential harms mean that mirtazapine cannot be recommended for the treatment of agitation in dementia,” Banerjee and co-authors wrote.

The study had several limitations, including the possibility that the mortality difference was due to chance. In addition, the original study protocol was changed; the trial did not also test the clinical effectiveness of carbamazepine as planned.

  1. Dementia patients who had clinically significant agitation improved over 12 weeks whether they were treated with the antidepressant mirtazapine or placebo, the randomized double-blind SYMBAD trial found.

  2. There were seven deaths in the mirtazapine group and one death in the placebo group at 16 weeks. Post-hoc statistical analyses suggested weak evidence of a mortality difference between groups.

Paul Smyth, MD, Contributing Writer, BreakingMED™

This study was funded by the UK National Institute for Health Research Health Technology Assessment Program.

Banerjee reported personal fees and non-financial support from Lilly; personal fees from Boehringer-Ingelheim, Axovant, Lundbeck, and Nutricia; and honoraria from the Hamad Medical Service for lectures and talks. He is a Trustee of the Alzheimer’s Society and has research grants from U.K. National Institute for Health Research, Economic and Social Research Council, and Engineering and Physical Sciences Research Council.

Lanctot reported consulting fees from BioXcel Therapeutics, Cerevel Therapeutics, Eisai Company, ICG Pharma, Kondor Pharma, and Praxis Precision Medicines, and has stock options in Highmark Interactive. Herrmann declared no competing interests.

Cat ID: 130

Topic ID: 82,130,282,404,730,130,33,361,192,146,362,925