Evaluating Brexpiprazole for the Management of Behavioral and Psychological Symptoms of Dementia

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Premiere Date: October 20, 2024

Expiration Date: April 20, 2026

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ACTIVITY GOAL

To inform readers of the efficacy and tolerability of brexpiprazole in treating agitation in individuals with Alzheimer disease dementia.

LEARNING OBJECTIVES

Discuss the efficacy of brexpiprazole for the treatment of agitation among individuals with Alzheimer disease dementia

Describe the tolerability of brexpiprazole when used to treat agitation among individuals with Alzheimer disease dementia

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This accredited continuing education (CE) activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

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The term behavioral and psychological symptoms of dementia (BPSD) describes a constellation of symptoms and behaviors that occur in more than 90% of individuals with dementia.¹ BPSD is associated with a faster decline in cognition and function among individuals with dementia and contributes significantly to the greater rates of morbidity and mortality among those with dementia.

Brexpiprazole is an atypical antipsychotic that is approved by the US Food and Drug Administration (FDA) as monotherapy treatment for schizophrenia and as an adjunctive treatment to antidepressants for major depressive disorder.² Brexpiprazole is a partial agonist at the serotonin 5-hydroxytryptamine_1A and dopamine D₂ receptors and an antagonist at serotonin 5-hydroxytryptamine_2A; noradrenergic α_1B, and noradrenergic α_2C receptors.³ In May 2023, the FDA provided supplemental approval for brexpiprazole oral tablets for the treatment of agitation associated with dementia due to Alzheimer disease (AD), making it the first FDA-approved treatment option for this indication.⁴ The FDA, however, retained the boxed warning for brexpiprazole that is included for medications in this class indicating that older adults with dementia-related psychosis are at an increased risk of death when treated with antipsychotic medications, with the rewording in the Boxed Warning that it did not apply if the primary diagnosis was agitation associated with dementia due to AD, even if psychosis was present. Significantly, brexpiprazole is not FDA-approved as an as-needed medication.

Table 1. Study Characteristics

Three 12-week randomized controlled trials (RCTs) that evaluated the efficacy, safety, and tolerability of brexpiprazole among individuals with BPSD and AD were reviewed. One article by Grossberg et al included data from 2 RCTs.⁵ We also used data from the recently published version of the third study.⁶ The trials were of good quality and were rated as a 5/5 on the Jadad scale.⁷ Table 1 discusses the characteristics of the included studies, Table 2 describes study results, and Table 3 reviews the quality of included studies.⁷

Exploring Efficacy

Table 2. Study Results

Study 1

In this multicenter, randomized, double-blind, placebo-controlled, parallel-arm study, 433 participants were randomized to receive brexpiprazole 2 mg/day (n = 140), brexpiprazole 1 mg/day (n = 137), brexpiprazole 0.5 mg/day (n = 20), or placebo (n = 136) for 12 weeks.5 The 0.5-mg/day brexpiprazole arm was removed early in the study when information from other ongoing and completed studies demonstrated that 0.5 mg was a nonefficacious dose. Although these patients were not included in the efficacy analyses because there were not many of them, these individuals were pooled with the 1 mg/day arm in the safety analyses (ie, the Sheehan Suicidality Tracking Scale, Mini Mental State Examination [MMSE], and extrapyramidal symptoms scales [EPS; the Simpson-Angus Scale, the Abnormal Involuntary Movement Scale, and Barnes Akathisia Rating Scale]).

Participants were randomized to receive brexpiprazole doses or placebo in a 1:1:1 fashion. The medication was titrated over a period of 2 to 4 weeks (days 1-3, 0.25 mg/day; days 4-14, 0.5 mg/day; days 15-28, 1 mg/day; day 29 onward, assigned dose). Participants who were not able to tolerate their assigned dose of drug (or matching placebo) had to discontinue the trial. Baseline characteristics were similar across the brexpiprazole 2-mg/day and 1-mg/day and placebo groups.

A majority (79.6%) of the participants had received treatment for agitation in AD (AAD) and psychosis prior to the study, with the most common medications being risperidone (17.4%), quetiapine (15.5%), lorazepam (14.1%), and haloperidol (11.1%). During the study period, 74.8% of participants used 1 or more medications for AD including memantine (45.1%), donepezil (27.8%), and rivastigmine (11.8%). The study was completed by 122 patients (87.1%) in the brexpiprazole 2-mg/day group, 121 (88.3%) in the brexpiprazole 1-mg/day group, 13 (65.0%) in the brexpiprazole 0.5-mg/day group, and 121 (89.0%) in the placebo group.

Table 3. Quality of Included Studies

The brexpiprazole 2-mg/day group showed statistically significant improvements on the primary efficacy end point (Cohen-Mansfield Agitation Inventory [CMAI] Total score), when compared with placebo (Cohen d effect size = -0.25, P = .040). Brexpiprazole 2 mg/day also demonstrated improvements, although not statistically significant results on the key secondary efficacy end point (Clinical Global Impressions-Severity of illness [CGI-S]) as related to agitation (Cohen d effect size = -0.17, P = .16), as well as on the Neuropsychiatric Inventory-Nursing Home Version (NPI-NH) Agitation/Aggression domain (Cohen d effect size = -0.19, P = .12). No benefits were noted for the brexpiprazole 1 mg/day dosing when compared with placebo on either the primary efficacy end point (CMAI Total score; Cohen d effect size = 0.02, P = .90), or key secondary end points (CGI-S as related to agitation; Cohen d effect size = 0.09, P = .44); (NPI-NH Agitation/Aggression domain; Cohen d effect size = -0.03, P = .78).

Study 2

In this study, which was not used by the FDA for analysis for approval, participants (n = 270) were randomized to receive brexpiprazole 0.5-2 mg/day (n = 133) or placebo (n = 137).⁵ Eligible participants were randomly assigned in a 1:1 proportion to receive either flexible doses of brexpiprazole 0.5-2 mg/day or placebo for 12 weeks. Brexpiprazole treatment commenced at 0.25 mg/day (days 1-3), was raised to 0.5 mg/day (days 4-14), and subsequently escalated to a targeted dose of 1 mg/day (days 15-28, with the option to revert to 0.5 mg/day). Starting from day 29 (week 4 visit), an additional escalation to 2 mg/day was possible. Beyond week 4, dose adjustments (increases or decreases) could occur at any point during scheduled or unscheduled visits, guided by the investigator’s assessment of the participant’s response and tolerability. Participants who were unable to tolerate brexpiprazole 0.5 mg/day or corresponding placebo were discontinued from the trial. Patients (n = 270) were randomized to receive brexpiprazole 0.5-2 mg/day (n = 133) or placebo (n = 137) for 12 weeks.¹

Baseline characteristics were similar between the brexpiprazole and the placebo groups. About half (66.5%) of participants had received treatment for AAD and psychosis, with common prior medications being risperidone (14.5%), chlorprothixene (14.1%), haloperidol (11.5%), and quetiapine (10%). During the study, 83.3% of participants used 1 or more medications for AD, with memantine (51.7%) and donepezil (31.2%) being common.

The study was completed by 117 participants (88.0%) in the brexpiprazole group and 121 (88.3%) in the placebo group. The brexpiprazole 0.5-2 mg/day group did not achieve statistical superiority on the primary efficacy end point (CMAI Total score) when compared with placebo (Cohen d effect size = -0.18, P = .15). However, benefit was noted for brexpiprazole 0.5-2 mg/day on the key secondary end points of CGI-S as related to agitation (Cohen d effect size = -0.30, P = .016) and the NPI-NH Agitation/Aggression domain (Cohen d effect size = -0.34, P = .0068). The post hoc analyses showed that the subgroup of individuals who were titrated to the maximum dose of brexpiprazole at 2 mg/day at week 4 demonstrated improvements on the CMAI Total score when compared with individuals who were titrated similarly on placebo (Cohen d effect size = -0.41, P = .012). These individuals also demonstrated improvements on CGI-S as related to agitation (Cohen d effect size = −0.59, P <.001).

Study 3

Lee et al conducted a multicenter, randomized, double-blind, placebo-controlled, parallel-arm trial of brexpiprazole among 345 individuals with AAD who were randomized to receive either brexpiprazole (n = 228) or placebo (n = 117) for 12-weeks.⁶ Participants in the brexpiprazole group were further randomized 1:2 to receive brexpiprazole fixed doses of 2 or 3 mg/day. The dose titration for brexpiprazole was as follows; first week, 0.5 mg/day; second week, 1 mg/day; third and fourth weeks, 2 mg/day; beyond fourth week, 2 or 3 mg/day (fixed doses). The primary efficacy end point was a change from baseline to week 12 on the CMAI Total score. Secondary efficacy measures were the CGI-S and the Clinical Global Impressions-Improvement (CGI-I) scales, specifically applied to agitation, and the NPI-NH Agitation/Aggression domain. In contrast to the other 2 trials, the participants in this trial needed to meet the International Psychogeriatric Association definition of agitation to be eligible for participation in the study.

The baseline demographic and clinical characteristics between the 2 groups were generally similar. A total of 184 (81.4%) individuals in the brexpiprazole group and 95 (81.9%) individuals in the placebo received standard medications for AD, mainly memantine or donepezil.

The study was completed by 198 (86.8%) individuals in the brexpiprazole groups and 104 (88.9%) individuals in the placebo group. On the CMAI Total score, individuals receiving brexpiprazole 2 or 3 mg/day showed statistically significant improvements when compared with placebo (Cohen d effect size = 0.35, P = .003). Additionally, benefits were noted for the brexpiprazole 2 or 3 mg/day group on the CGI-S score as related to agitation (Cohen d effect size = 0.31, P = .008). Furthermore, benefits were also noted for the brexpiprazole 2 or 3 mg/day group on the following exploratory end points: CMAI factor 1: aggressive behavior score (Cohen d effect size = 0.33, P = .004); CMAI factor 2: physically nonaggressive behavior score (Cohen d effect size = 0.25, P = .03) and the CMAI factor 3: verbally agitated behavior score (Cohen d effect size = 0.29, P = .01) and the CGI-I score (P = .007). Additionally, on the NPI-NH Total score, the brexpiprazole 2 or 3 mg/day group did better than placebo (Cohen d effect size = 0.39, P = .001).

Safety and Tolerability

Study 1

The incidence rates of treatment-emergent adverse events (TEAEs) were 65.0% for brexpiprazole 2 mg/day, 49.0% for 0.5-1 mg/day, and 45.9% for placebo.⁵ Most of the TEAEs were rated as being mild or moderate. Serious TEAEs were seen in about 10% of the brexpiprazole groups and about 5% of the placebo group. Agitation in a participant on brexpiprazole 0.5 mg/day was the only TEAE that was considered related to the study drug.

Discontinuation rates due to TEAEs were 4.3% for brexpiprazole 2 mg/day, 8.9% for brexpiprazole 0.5-1 mg/day, and 5.2% for placebo. Agitation (4 vs 1) and QTc interval prolongation (2 vs 0) led to discontinuation from the study in the brexpiprazole vs placebo groups. The investigators did not find any significant differences between the groups on suicidality, EPS, QTc interval, body weight, metabolic parameters, and cognitive dysfunction. Although 5 participants in the brexpiprazole groups died during the study, none of the deaths were attributable to the medication. There were no reported deaths in the placebo group.

Study 2

TEAE incidence was similar between brexpiprazole 0.5-2-mg/day (56.8%) and placebo (58.4%) groups,6 and most were rated as being mild to moderate.⁵ Serious TEAEs were similar for both groups (occurring in 5.3% of the brexpiprazole 0.5-2 mg/day group and 4.4% of the placebo group, respectively). A total of 6.8% of the individuals in the brexpiprazole group discontinued the study due to TEAEs compared with 0.7% of the individuals in the placebo group. Post hoc analysis showed no TEAE differences for participants titrated to 2 mg/day brexpiprazole at week 4 vs placebo. No clinically meaningful between-group differences were observed in other safety assessments, including suicidality, EPS, QTc interval, body weight, metabolic parameters, and cognitive dysfunction. Two patients died during the study and the deaths were considered unrelated to the study drug.

Study 3

Approximately 40.7% of the individuals in the brexpiprazole groups reported TEAEs, compared with 31.0% in the placebo group.⁶ Other TEAEs (brexpiprazole vs placebo groups) were headache, 6.6% vs 6.9%; cardiovascular events, 0.9% vs 0.9%; any EPS, 3.5% vs 0%; somnolence/sedation, 4.0% vs 0.9%; accident or injury TEAE, including fall, 2.2% vs 3.4%; and metabolism and nutrition disorder, 1.3% vs 1.7%. The investigators rated the majority of TEAEs as being of mild or moderate severity; 5.3% and 4.3% of brexpiprazole and placebo groups, respectively, discontinued the study due to AEs. There was 1 death in the brexpiprazole group, but it was thought to be unrelated to the drug.

The mean standard deviation increase in body weight from baseline to week 12 was 0.3 kg in the brexpiprazole group. Weight gain of 7% or more from baseline to week 12 was experienced by 1.5% of individuals in the brexpiprazole group, and 0% of the individuals in the placebo group. From baseline to week 12, weight loss of 7% or more was noted in 1.0% of participants in both groups. None of the participants in either group reported suicidal ideation or behavior as a TEAE. On the MMSE score, the mean change from baseline to week 12 was 0.7 for the brexpiprazole group and 0.4 in the placebo group. The investigators reported that there were no clinically meaningful differences noted on the laboratory test results, vital signs, or electrocardiograms between the brexpiprazole and placebo groups. In addition, the EPS rating scale score changes were also rated as being minimal.

(It is important to note that the primary outcome of the aforementioned 3 brexpiprazole studies was limited to agitation [as assessed by the Cohen-Mansfield Agitation Inventory], which is just one of the many symptoms that are included in the list of BPSD. Additionally, the studies did not require the presence of psychosis, nor did they evaluate any symptoms of psychosis. Because there is a paucity of published literature looking only at improvement in agitation in dementia, it limits direct comparisons with other studies. Meanwhile, the following 2 meta-analyses by Yunusa et al^7,8 allow for some degree of comparison with brexpiprazole, albeit in a very general manner.—Ed)

Making Sense of the Data

Brexpiprazole titrated to 2 or 3 mg/day over 2 to 4 weeks provides statistically significant, although modest benefits among individuals with AD who present with agitation. Additionally, brexpiprazole appears to be well tolerated compared with placebo. No significant differences were noted between brexpiprazole and placebo on rates of suicidality, EPS, QTc interval, body weight, metabolic parameters, and cognitive dysfunction. There were no cerebrovascular events (CVAEs) noted in the studies, and the deaths in the study population were deemed as not being attributable to brexpiprazole.

A previous meta-analysis looked at the use of other atypical antipsychotic medications among individuals with BPSD; interestingly, the data for brexpiprazole appear similar (standardized mean difference [SMD] = effect size). The meta-analysis from Yunusa et al found benefits for aripiprazole among individuals with BPSD when compared with placebo on the NPI (SMD = −0.17), the Brief Psychiatric Rating Scale (BPRS, SMD = −0.20), and on the CMAI (SMD = −0.30).⁸ Benefits were noted for quetiapine on the BPRS (SMD = −0.24), and risperidone on the CMAI (SMD = −0.26) when compared with placebo. In another meta-analysis, Yunusa et al found that aripiprazole (SMD = −0.12) and olanzapine (SMD = −0.17) demonstrated small although nonsignificant numerical improvements in NPI-NH psychosis scores, compared with placebo.9 However, quetiapine (SMD = 0.04) did not show any benefits among individuals with dementia-related psychosis.

The tolerability of brexpiprazole in individuals with BPSD appears to be favorable when compared with other atypical antipsychotics.^5,6 There were no CVAEs noted and none of the deaths were attributable to brexpiprazole. Additionally, there was no cognitive decline noted with the use of brexpiprazole. Sedation may be an adverse effect to watch for when using brexpiprazole among individuals with BPSD.

When looking at other antipsychotics, Yunusa et al noted that the risk for CVAEs was greater with olanzapine (OR = 4.28) and risperidone (OR = 3.85) when compared with placebo.⁸ Additionally, the investigators noted that risperidone (OR = 2.23) produced greater risk of EPS. Furthermore, somnolence was greater with aripiprazole (OR = 3.14), olanzapine (OR = 4.08), quetiapine (OR = 4.47), and risperidone (OR = 2.57). When compared with placebo, quetiapine (OR = 2.11) was associated with increased urinary incontinence or urinary tract infections. In their second meta-analysis, Yunusa et al found that mortality was noted to be higher for aripiprazole (OR = 1.58), olanzapine (OR = 2.21), quetiapine (OR = 1.68), and risperidone (OR = 1.63).⁹ Additionally, risperidone (OR = 3.68) and olanzapine (OR = 4.47) appeared to increase the risk of CVAEs.

The investigators noted that the odds of mortality were numerically higher in the brexpiprazole group when compared with the placebo group (OR = 2.22, 95% CI, 0.3-16.56).⁸ These data differ from the data that we obtained from the 3 brexpiprazole studies that are reviewed in this article. There were no brexpiprazole-related deaths identified in these studies. This difference in data is probably due to pooling of data from the 2 individual studies for the meta-analysis by Yunusa et al.⁸

Strengths and Limitations

There are several strengths of the 3 included studies: They were well conducted, multicenter RCTs (Jadad 5/5) that included 1000 or more participants with AAD; also, they used varying doses of brexpiprazole (0.5-3 mg/day). However, there are limitations: mostly Caucasian participants, limited to 12 weeks in duration, concomitant therapies were restricted, and functioning was not assessed. Moreover, they included more participants from care facilities and those participants who had comorbidities. Additionally, these trials were designed primarily to study the efficacy, safety, and tolerability of brexpiprazole for the management of AAD. Together, these issues limit its generalizability, including the use of brexpiprazole among other BPSD symptoms (ie, apathy, anxiety, psychosis, etc), and among individuals with dementia due to other etiologies (eg, vascular disease, frontotemporal dementia, dementia with Lewy bodies, and Parkinson disease dementia). Brexpiprazole is also not indicated for as-needed dosing for treating agitation among individuals with AD dementia. Brexpiprazole is only available in an oral formulation, so it cannot be used in situations where intramuscular (IM) or intravenous dosing is required to manage emergent agitation among individuals with dementia.

Treatment algorithms provide additional insights. A Canadian algorithm recommends sequential trials of risperidone, aripiprazole, quetiapine, carbamazepine, citalopram, gabapentin, and prazosin after completion of a baseline assessment and discontinuation of medications that potentially exacerbate BPSD.¹⁰ A Harvard South Shore program proposes 3 separate algorithms in emergent, urgent, and nonurgent settings.¹¹ IM olanzapine is recommended as first-line treatment for emergent BPSD. Haloperidol injection is the recommended second choice, followed by a possible consideration for IM benzodiazepine. Oral second-generation antipsychotics (SGAs) aripiprazole and risperidone are recommended as first-line treatment in an urgent setting. Prazosin is recommended as a possible next option, and electroconvulsive therapy could be a final treatment option. The authors recommend the following order of medications: trazodone, donepezil and memantine, antidepressants such as escitalopram and sertraline, SGAs, prazosin, and finally carbamazepine for nonemergent agitation.

Based on available evidence, brexpiprazole can possibly be placed along with aripiprazole and risperidone in the Canadian algorithm for sequential medication trials. In the Harvard South Shore algorithm, it can possibly be a first-line treatment option in the urgent setting along with aripiprazole and risperidone.

We recommend using nonpharmacological management strategies as first-line treatment. Given the consistent lack of efficacy of brexpiprazole doses at 1 mg and below in the clinical trials, additional studies and time will be needed to determine if lower doses can be effective in a subset of agitated patients with dementia due to AD. We are only beginning to learn about brexpiprazole; current data supports its use in minimizing future episodes of agitation in patients with AD whose agitation symptoms have become dangerous or damaging despite the use of nonpharmacological treatments. Thus, we recommend pharmacological management strategies including brexpiprazole at the lowest effective doses and for the shortest time. Medications should only be trialed for partially responsive or refractory symptoms of BPSD, and should be done in conjunction with nonpharmacological treatments to optimize outcomes.

Concluding Thoughts

Available evidence from 3 high-quality RCTs indicated that brexpiprazole at 2-3 mg/day is more efficacious than placebo at reducing agitation among individuals with AD dementia. Brexpiprazole at these doses is well tolerated among individuals with AD, with no evidence for CVAEs or deaths attributed to the drug.

Robust data from multiple additional high-quality trials of longer duration using brexpiprazole among individuals with different etiologies for dementia and targeting different BPSD symptoms are needed to cement its place as definitive first-line treatment for the management of BPSD. Otherwise, the use of brexpiprazole will be limited to just the management of agitation among individuals with AD dementia.

Dr Bachu is a psychiatrist at Baptist Health Behavioral Health Clinic in North Little Rock, AR. Dr Subhedar is a clinical extern at Saint Elizabeths Hospital in Washington, DC. Dr Ansari is a psychiatrist at Pramukhswami Medical College in Anand, Gujarat, India. Dr Manoharan is a psychiatrist at Creighton University School of Medicine in Omaha, NE. Dr Tampi is professor and chairman of the Department of Psychiatry at Creighton University School of Medicine and Catholic Health Initiatives (CHI) Health Behavioral Health Services. He is also an adjunct professor of psychiatry at Yale School of Medicine in New Haven, CT, and a member of the Psychiatric Times editorial board.

References

1. Tampi RR, Jeste DV. Dementia is more than memory loss: neuropsychiatric symptoms of dementia and their nonpharmacological and pharmacological management. Am J Psychiatry. 2022;179(8):528-543.

2. Diefenderfer LA, Iuppa C. Brexpiprazole: a review of a new treatment option for schizophrenia and major depressive disorder. Ment Health Clin. 2018;7(5):207-212.

3. Edinoff AN, Wu NW, Maxey BS, et al. Brexpiprazole for the treatment of schizophrenia and major depressive disorder: a comprehensive review of pharmacological considerations in clinical practice. Psychopharmacol Bull. 2021;51(2):69-95.

4. FDA approves first drug to treat agitation symptoms associated with dementia due to Alzheimer’s disease. US Food & Drug Administration. Press release. May 11, 2023. Accessed April 3, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-treat-agitation-symptoms-associated-dementia-due-alzheimers-disease

5. 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.

6. Lee D, Slomkowski M, Hefting N, et al. Brexpiprazole for the treatment of agitation in Alzheimer dementia: a randomized clinical trial. JAMA Neurol. 2023;80(12):1307-1316.

7. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17(1):1-12.

8. Yunusa I, Alsumali A, Garba AE, et al. Assessment of reported comparative effectiveness and safety of atypical antipsychotics in the treatment of behavioral and psychological symptoms of dementia: a network meta-analysis. JAMA Netw Open. 2019;2(3):e190828.

9. Yunusa I, Rashid N, Demos GN, et al. Comparative outcomes of commonly used off-label atypical antipsychotics in the treatment of dementia-related psychosis: a network meta-analysis. Adv Ther. 2022;39(5):1993-2008.

10. Davies SJ, Burhan AM, Kim D, et al. Sequential drug treatment algorithm for agitation and aggression in Alzheimer’s and mixed dementia. J Psychopharmacol. 2018;32(5):509-523.

11. Chen A, Copeli F, Metzger E, et al. The Psychopharmacology Algorithm Project at the Harvard South Shore Program: an update on management of behavioral and psychological symptoms in dementia. Psychiatry Res. 2021;295:113641.