Brexpiprazole: Do Not Use for Agitation Due to Alzheimer’s Dementia

Brexpiprazole (REXULTI) is an atypical antipsychotic that was initially approved by the Food and Drug Administration (FDA) in 2015 as an adjunctive treatment to antidepressants for major depressive disorder.[1] Brexpiprazole also is approved for treatment of schizophrenia in adults and pediatric patients aged 13 years and older. Like other drugs in its class, brexpiprazole is associated with serious safety concerns, including an increased risk of death among elderly patients with dementia-related psychosis. Therefore, the prescribing information for brexpiprazole includes a boxed warning (the most prominent warning the FDA can require). Public Citizen’s Health Research Group has previously designated brexpiprazole as a Limited Use drug.

In May 2023, the FDA extended the indications for brexpiprazole to include the treatment of agitation associated with dementia due to Alzheimer’s disease. Brexpiprazole is the first drug approved by the agency for this condition.[2] Public Citizen’s Health Research Group strongly urged the FDA not to approve brexpiprazole for this new indication.[3] Accordingly, Public Citizen’s Health Research Group has designated brexpiprazole as a Do Not Use drug for the treatment of Alzheimer’s disease-associated dementia. It is important to add that the FDA did not approve brexpiprazole as an “as needed” (often referred to as “prn”) treatment for agitation associated with dementia due to Alzheimer’s disease.

Use of antipsychotics for agitation associated with dementia due to Alzheimer’s disease

In addition to the continuous decline in thinking, memory and the ability to perform daily activities associated with Alzheimer’s disease, more than 90% of patients also develop one or several behavioral and psychological symptoms, such as irritability, sleep disturbances, hallucinations, depression, apathy and agitation.[4],[5]

Symptoms of agitation such as hitting, pacing, complaining, being verbally aggressive or restlessness can be very distressing for patients and their caregivers.[6] They affect about 40% of Alzheimer’s disease patients and become more prevalent in the later stages of the disease.

Even prior to the approval of brexpiprazole as a treatment for agitation associated with dementia due to Alzheimer’s disease, antipsychotics often were prescribed off-label (for an indication not approved by the FDA) for this condition. For example, at least 21% of nursing-home residents were prescribed these drugs to control behavioral problems, according to a 2021 New York Times investigation.[7]

Several studies, however, have raised concerns that the limited benefits of this class of drugs, including brexpiprazole, do not outweigh the serious risks for patients with dementia.[8] For example, for older patients with dementia, antipsychotics were associated with higher rates of cerebrovascular events (such as stroke), sedation and increased risk of death. Moreover, in such patients, use of antipsychotics may lead to a faster cognitive decline and higher rates of hospitalization.[9] Also of concern is that, for some patients with dementia, behavioral symptoms worsen when they stop taking these medications.[10]

Furthermore, the Centers for Medicare & Medicaid Services (CMS) has stated that antipsychotic medications are dangerous, particularly for nursing-home residents, and as a CMS spokesperson recently told the medical journal The BMJ, “[w]e cannot speak to the hypothetical future use of brexpiprazole; however, CMS will continue its efforts to reduce the prescribing of unnecessary antipsychotics in nursing homes.”[11]

For this reason, nonpharmacological approaches (such as exercise or music therapy) are recommended as initial treatments for patients with dementia due to Alzheimer’s disease.[12]

Evidence regarding the safety and efficacy of brexpiprazole

To assess the safety of brexpiprazole for the treatment of agitation associated with dementia due to Alzheimer’s disease, the FDA considered five small, short-term studies. These studies showed that brexpiprazole, like all antipsychotics, increased the risk of death.[13] Subjects in the brexpiprazole groups also experienced more adverse events than patients in the placebo groups, including nasopharyngitis (common cold), urinary tract infections, somnolence and insomnia.

The data regarding efficacy was based on three of these studies.[14] Only two of these trials showed that treatment with brexpiprazole led to “statistically significant” improvements compared with placebo, and only for some subjects taking the medication. The improvements, however, were so small that they may not be clinically meaningful for patients or their caregivers.

In one of the two favorable studies, 433 adults were randomized to take a daily fixed dose of 1 or 2 milligrams (mg) of brexpiprazole or a placebo. Subjects taking the drug showed some improvement on only one of several measurement tools used by the researchers. This tool, called the Cohen Mansfield Agitation Inventory, measures how frequently patients show agitated behavior on a scale that ranges from 29 to 203 points. After 12 weeks of follow-up, subjects receiving 2 mg of the drug, but not those who received the 1-mg dose, showed an improvement on this scale. The difference, however, was only 4 points more than the improvement for patients in the placebo group. The FDA did not consider this finding “statistically persuasive.”[15]

In the other study, 345 adults were randomized to a fixed dose of 2 or 3 mg of brexpiprazole or a placebo.[16] All patients treated with the drug had a significant improvement on the Cohen Mansfield Agitation Inventory compared with those receiving the placebo, but again the difference between groups of 5 points may not be clinically meaningful. In this study, subjects in the brexpiprazole group also had slightly better results than those in the placebo group when they were assessed using a secondary measurement tool (called the Clinical Global Impression of Severity). The improvement, however, was again small and only “significant” for patients taking 3 mg of brexpiprazole.[17]

The results of these studies also may not be generalizable, because the subjects were relatively young (on average 74 years of age), predominantly White and several patient groups (such as those with a history of stroke or probable vascular or mixed dementia or a history of delirium) were excluded.[18],[19]

What You Can Do

Agitation symptoms associated with dementia due to Alzheimer’s disease are a frequent and challenging clinical problem. Better treatments are needed. Brexpiprazole is not the answer, however. The reasons include the limited benefit of the drug and the increased risk of death in elderly patients with dementia-related psychosis treated with antipsychotic drugs.

The best approach to the agitation symptoms can be discussed with the patient’s clinician. It is important to make sure that all other possible causes for agitation (including use of some prescription drugs or other medical conditions) are ruled out first.[20] Non-pharmacological approaches can be tried. For patients who are already taking brexpiprazole or another antipsychotic, the drug should not be discontinued without speaking to the patient’s clinician first.
 

References

[1] Otsuka America Pharmaceutical, Inc. Label: brexpiprazole (REXULTI). May 2023. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=2d301358-6291-4ec1-bd87-37b4ad9bd850&type=display. Accessed August 7, 2023.

[2] Food and Drug Administration. FDA news release. FDA approves first drug to treat agitation symptoms associated with dementia due to Alzheimer’s disease. May 11, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-treat-agitation-symptoms-associated-dementia-due-alzheimers-disease. Accessed August 7, 2023.

[3] Public Citizen. Letter to the FDA opposing approval of brexpiprazole for the treatment of agitation associated with Alzheimer’s dementia. May 3, 2023. https://www.citizen.org/article/letter-to-the-fda-opposing-approval-of-brexpiprazole-for-the-treatment-of-agitation-associated-with-alzheimers-dementia/. Accessed August 7, 2023.

[4] Herrmann N, Wang HJ, Song BX, et al. Risks and benefits of current and novel drugs to treat agitation in Alzheimer’s disease. Expert Opin Drug Saf. 2022;21(10):1289-1301.

[5] Rogowska M, Thornton M, Creese B, et al. Implications of adverse outcomes associated with antipsychotics in older patients with dementia: A 2011–2022 Update. Drugs Aging. 2023;40(1):21-32.

[6] Food and Drug Administration. FDA briefing document, NDA 205422/S-009, drug name: brexpiprazole; joint meeting of the Psychopharmacologic Drugs Advisory Committee and the Peripheral and Central Nervous System. April 14, 2023. https://www.fda.gov/media/167066/download. Accessed August 7, 2023.

[7] Thomas K, Gebeloff R, Silver-Greenberg J. Phony diagnoses hide high rates of drugging at nursing homes. The New York Times. Updated October 15, 2021. https://www.nytimes.com/2021/09/11/health/nursing-homes-schizophrenia-antipsychotics.html. Accessed August 7, 2023.

[8] Herrmann N, Wang HJ, Song BX, et al. Risks and benefits of current and novel drugs to treat agitation in Alzheimer’s disease. Expert Opin Drug Saf. 2022;21(10):1289-1301.

[9] Rogowska M, Thornton M, Creese B, et al. Implications of adverse outcomes associated with antipsychotics in older patients with dementia: A 2011–2022 Update. Drugs Aging. 2023;40(1):21-32.

[10] Tampi RR, Tampi DJ, Balachandran S, et al. Antipsychotic use in dementia: a systematic review of benefits and risks from meta-analyses. Ther Adv Chronic Dis. 2016;7(5):229-245.

[11] Whitaker R. How the FDA approved an antipsychotic that failed to show a meaningful benefit but raised the risk of death. BMJ. 2023.382:p1801.

[12] Herrmann N, Wang HJ, Song BX, et al. Risks and benefits of current and novel drugs to treat agitation in Alzheimer’s disease. Expert Opin Drug Saf. 2022;21(10):1289-1301.

[13] Food and Drug Administration. FDA briefing document, NDA 205422/S-009, drug name: brexpiprazole; joint meeting of the Psychopharmacologic Drugs Advisory Committee and the Peripheral and Central Nervous System. April 14, 2023. https://www.fda.gov/media/167066/download. Accessed August 7, 2023.

[14] Ibid.

[15] Ibid.

[16] Ibid.

[17] Ibid.

[18] Otsuka America Pharmaceutical, Inc. Label: brexpiprazole (REXULTI). May 2023. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=2d301358-6291-4ec1-bd87-37b4ad9bd850&type=display. Accessed August 7, 2023.

[19] Grossberg GT, Kohegyi E, Mergel V, et al. Efficacy and safety of brexpiprazole for the treatment of agitation in Alzheimer's dementia: Two 12-week, randomized, double-blind, placebo-controlled trials. Am J Geriatr Psychiatry. 2020;28(4):383-400.

[20] Herrmann N, Wang HJ, Song BX, et al. Risks and benefits of current and novel drugs to treat agitation in Alzheimer’s disease. Expert Opin Drug Saf. 2022;21(10):1289-1301.