Dementia is a progressive condition that involves declining cognitive and behavioral symptoms including memory loss, problems with reasoning and communication, personality changes and a decreased ability to perform activities of daily living (such as body washing, dressing, cooking and shopping). Alzheimer’s disease is the most common cause of dementia in the elderly. Other causes include vascular dementia (caused by strokes) and Lewy body dementia (which is associated with abnormal...
Dementia is a progressive condition that involves declining cognitive and behavioral symptoms including memory loss, problems with reasoning and communication, personality changes and a decreased ability to perform activities of daily living (such as body washing, dressing, cooking and shopping). Alzheimer’s disease is the most common cause of dementia in the elderly. Other causes include vascular dementia (caused by strokes) and Lewy body dementia (which is associated with abnormal protein deposits in the brain).
People with dementia often develop agitation — defined as inappropriate verbal, vocal or physical activity that is not thought to be caused by an unmet need — resulting in decreased quality of life, institutionalization and increased burden on caregivers.
Atypical antipsychotics — such as aripiprazole (ABILIFY), olanzapine (ZYPREXA, ZYPREXA ZYDIS) and risperidone (RISPERDAL) — often are prescribed for the treatment of agitation in patients with dementia. However, such use is considered off-label because the Food and Drug Administration (FDA) has never approved the use of these medications for dementia.
Furthermore, federal guidelines issued in 2013 discourage the use of antipsychotics in dementia patients without an adequate rationale or to solely limit or control behavior of an unidentified cause in these patients. This is because such use is associated with treatment failure; increased risk of death; and multiple adverse effects, mainly abnormal body movements (including akathisia and tardive dyskinesia), falls and fractures as well as impaired blood-sugar and blood-pressure control.
In recent years, off-label use of sedating antidepressants, including mirtazapine (REMERON, REMERON SOLTAB), which is commonly prescribed in the elderly, has increased as a controversial alternative to antipsychotics for treating agitated behaviors in people with dementia.
A new well-designed study conducted by U.K. researchers found that mirtazapine is not beneficial for treating agitated behaviors in dementia patients and is potentially linked to an increased risk of death. This study adds to prior evidence showing that drug therapy for agitation in dementia is likely limited in its effectiveness and is associated with significant harm. The study was conducted with funding from the U.K. government and was published in the Oct. 23, 2021, issue of The Lancet.
The mirtazapine study
The new study was a randomized, double-blinded, placebo-controlled trial that recruited subjects receiving psychiatric services either in their own households or in care-home facilities who had probable or possible Alzheimer’s disease (as ascertained by referring psychiatrists) from 26 clinical centers in the U.K. The subjects had agitation behaviors that had not responded to nondrug treatment at the time of their enrollment. The trial excluded agitated subjects who were deemed critically unwell (such as those at risk of suicide) and those who were already taking antidepressants or antipsychotics.
Overall, 204 subjects (mean age was approximately 83 years) enrolled in the trial. Half of those were randomly assigned to receive mirtazapine and the other half were randomly assigned to receive a placebo. Subjects in both groups also received usual clinical care.
The severity of agitation behaviors, as measured by a standardized assessment tool called the Cohen-Mansfield Agitation Inventory (CMAI), served as the primary endpoint of the trial. Higher CMAI scores reflect more severe levels of agitation. Study researchers calculated the CMAI score for each subject before randomization and at six and 12 weeks after randomization.
The study researchers found that the average CMAI scores (agitation severity) declined among subjects in both groups after six weeks of follow-up and this favorable decline persisted at 12 weeks of follow-up. There was no evidence that mirtazapine improved CMAI scores more than the placebo at any point during the trial. Any improvement likely could have been due to the usual care (nondrug treatment) received by the subjects in both groups or due to the natural resolution of agitation among dementia patients as symptoms can “come and go,” according to the researchers.
The total number of adverse events was similar among subjects in both groups (66% of subjects in the mirtazapine and 64% of subjects in the placebo group). However, there were seven deaths among subjects in the mirtazapine group, compared with a single death among subjects in the placebo group, a finding that reached marginal statistical significance. The study researchers were not certain that the six additional deaths were due to mirtazapine. Nonetheless, they argued that given the lack of clinical benefit for mirtazapine and its potentially fatal harms, the drug — and possibly other sedating antidepressants — should not be used to treat agitation in dementia patients.
Surprisingly, additional analyses also showed a higher burden among caregivers of subjects in the mirtazapine group than among caregivers of subjects in the placebo group.
In conclusion, the study researchers recommended against using mirtazapine for agitation in dementia patients. They also cautioned that antipsychotics appear to achieve their effects in agitated dementia patients through their sedative adverse effects, resulting in other harms in these frail patients.
Finally, the researchers pointed out that a better approach for managing agitated behaviors in patients with dementia is an individualized assessment to identify and alleviate any underlying cause for such behaviors.
What You Can Do
If you have a loved one with dementia who is exhibiting agitation, discuss this article with their health care professionals and ask them not to give them mirtazapine or other sedating antidepressants. If your loved one is already taking mirtazapine, ask the prescribing health care professional to reduce the dosage slowly and discontinue the drug. Do not stop mirtazapine suddenly because doing so can cause serious adverse effects, including anxiety, confusion, dizziness, headache, increased agitation, irritability, mood changes, low body temperature, nausea and vomiting, and seizures.
Instead of drug therapy, talk with your loved one’s health care professionals about identifying and mitigating any possible underlying causes of the agitated behaviors (such as physical or psychological distress or pain) as well as trying nondrug therapy. You also should consider other options, such as increased skilled nursing care.
As a general rule, if any elderly person on any psychoactive medication — sleeping pills, antianxiety tranquilizers, antidepressants or antipsychotic drugs — appears to be doing poorly, think about reducing the dosage or stopping the drug rather than adding another drug.
Report all serious adverse events related to mirtazapine or other medications to the FDA’s MedWatch adverse event reporting program by visiting http://www.fda.gov/MedWatch or by calling 800-FDA-1088.
 National Institute for Health and Care Excellence (NICE). Dementia: assessment, management and support for people living with dementia and their carers. NICE guideline. June 20, 2018. https://www.nice.org.uk/guidance/ng97. Accessed February 2, 2022.
 Moore TJ, Furberg CD. The harms of antipsychotic drugs: Evidence from key studies. Drug Saf. 2017;40(1):3-14.
 Centers for Medicare & Medicaid Services, Center for Clinical Standards and Quality/Survey and Certification Group. Advanced copy: Dementia care in nursing homes: Clarification to Appendix P, State Operations Manual (SOM) and Appendix PP in the SOM for F309 – Quality of Care and F329 – Unnecessary Drugs. May 24, 2013. http://www.cms.gov/Medicare/Provider-Enrollment-and-Certification/SurveyCertificationGenInfo/Downloads/Survey-and-Cert-Letter-13-35.pdf. Accessed February 4, 2022.
 Maust DT, Kim HM, Seyfried LS, et al. Antipsychotics, other psychotropics, and the risk of death in patients with dementia: Number needed to harm. JAMA Psychiatry. 2015;72(5):438-445.
 Merck Sharp & Dohme Corporation. Label: mirtazapine (REMERON). November 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/020415s038,021208s028lbl.pdf. February 2, 2022.
 Banerjee S, High J, Stirling S, et al. Study of mirtazapine for agitated behaviours in dementia (SYMBAD): a randomised, double-blind, placebo-controlled trial. Lancet. 2021;398(10310):1487-1497.
 Cohen-Mansfield J, Marx MS, Rosenthal AS. A description of agitation in a nursing home. J Gerontol. 1989;44(3):M77-M84.
 Merck Sharp & Dohme Corporation. Label: mirtazapine (REMERON). November 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/020415s038,021208s028lbl.pdf. Accessed February 2, 2022.