Brexpiprazole is an atypical antipsychotic that is approved by the FDA as monotherapy treatment for schizophrenia and as an adjunctive treatment to antidepressants for major depressive disorder (MDD). Brexpiprazole is a partial agonist at the serotonin 5-hydroxytryptamine1A and dopamine D2 receptors and an antagonist at serotonin 5-hydroxytryptamine2A; it is also equally potent at 2 norepinephrine receptors – an antagonist at the noradrenergic α1B and α2C receptors. A meta-analysis of efficacy in schizophrenia by Reyad et al that included data from 14 randomized controlled trials (RCTs) found that on the positive and negative syndrome scale (PANSS) the mean difference (MD) among individuals taking brexpiprazole when compared to placebo was -4.48 points. On the clinical global impressions - severity of illness (CGI-S) scale, the MD between the 2 groups was -0.23. On the personal and social performance scale (PSP), the MD was 3.24. All these results favored brexpiprazole when compared with placebo among individuals with schizophrenia. In MDD, those receiving brexpiprazole did better than those receiving placebo on the Montgomery-Åsberg depression rating scale (MADRS, MD=-1.25), the Sheehan disability scale (SDS, MD=-0.37), and the Hamilton depression rating scale (HDRS17, MD=-1.28). The investigators noted that the use of brexpiprazole was associated with greater risk for akathisia [risk ratio (RR)=1.72], weight gain (RR=2.74), and somnolence (RR=1.87) compared with placebo. They also noted that 2 mg/day dosing of brexpiprazole was associated with less risk of akathisia, when compared with the 3 mg/day dosing (7% at 2 mg, 14% at 3 mg, 2% for placebo).
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. 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 a prn medication.
The goal of this review is to evaluate the data from published randomized controlled trials (RCTs) on the use of brexpiprazole among individuals with behavioral and psychological symptoms of dementia (BPSD) to assist clinicians with making an informed treatment decision.
A total of 3 RCTs that evaluated the efficacy, safety, and tolerability of brexpiprazole among individuals with BPSD were included. One article by Grossberg et al included data from 2 RCTs that evaluated the use of brexpiprazole in the treatment of people with BPSD. We also used data from the recently published version of the third study. The quality of the identified studies was assessed using the Jadad scale. Table 1 discusses the characteristics of the included studies, Table 2 describes study results, and Table 3 reviews the quality of included studies.
One study evaluated 1 mg versus 2 mg versus placebo; 1 study evaluated 2 mg and 3 mg versus placebo (these 2 studies are described in the FDA-approved product insert); and 1 study evaluated the flexible dose of 0.5 – 2 mg versus placebo. The trials were of good quality and were rated as a 5/5 on the Jadad Scale.
Exploring Efficacy
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.4 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 non-efficacious dose. As there were very few patients in the brexpiprazole 0.5 mg/day arm, these patients were not included in the efficacy analyses. Additionally, these individuals were pooled with the 1 mg/day arm in the safety analyses. However, these individuals were included in the analyses of 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 onwards, assigned dose). Participants who were not able to tolerate their assigned dose of the drug or matching placebo had to discontinue the trial. Baseline characteristics were similar across the brexpiprazole 2 mg/day, brexpiprazole 1 mg/day, and placebo groups.
A total of 79.6% of the participants had received treatment for agitation in Alzheimer disease (AAD) and psychosis prior to the study. The most common medications used to treat AAD in this group were risperidone (17.4%), quetiapine (15.5%), lorazepam (14.1%), and haloperidol (11.1%). During the study period, a total of 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 small sample brexpiprazole 0.5 mg/day group, and 121 (89.0%) in the placebo group.
The brexpiprazole 2 mg/day group showed statistically significant improvements on the primary efficacy endpoint (CMAI Total score), when compared with placebo (P=0.040; Cohen’s d effect size= -0.25). Brexpiprazole 2 mg/day also demonstrated numerical improvements, although not statistically significant results on the key secondary efficacy endpoint [Clinical Global Impression – Severity of illness (CGI-S)] as related to agitation (Cohen’s d effect size= -0.17, P=0.16), as well as on the NPI-Nursing Home (NPI-NH) Agitation/Aggression domain (Cohen’s d effect size= -0.19, P=0.12). No benefits were noted for the brexpiprazole 1 mg/day dosing when compared with placebo on either the primary efficacy endpoint (CMAI Total score; Cohen’s d effect size= 0.02, P=0.90), or key secondary end points [(CGI-S as related to agitation; Cohen’s d effect size= 0.09, P=0.44); (NPI-NH Agitation/Aggression domain; Cohen’s d effect size= -0.03, P=0.78].
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). 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. Baseline characteristics were similar between the brexpiprazole and the placebo groups. A total of 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 endpoint (CMAI Total score) when compared with placebo (Cohen’s d effect size= -0.18, P=0.15). However, benefit was noted for brexpiprazole 0.5-2 mg/day on the key secondary endpoints of CGI-S as related to agitation (Cohen’s d effect size= -0.30, P=0.016) and the NPI-NH Agitation/Aggression domain (Cohen’s d effect size= -0.34, P=0.0068). 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’s d effect size= -0.41, P=0.012). These individuals also demonstrated improvements on CGI-S as related to agitation (Cohen’s d effect size= −0.59, P<0.001).
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. 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 Impression 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’s d effect size=0.35, P=0.003). Additionally, benefits were noted for the brexpiprazole 2 or 3 mg/day group on the CGI-S score as related to agitation (Cohen’s d effect size=0.31, P=0.008). Furthermore, benefits were also noted for brexpiprazole 2 or 3 mg/day group on the following exploratory end points: CMAI factor 1: aggressive behavior score (Cohen’s d effect size=0.33, P=0.004); CMAI factor 2: physically nonaggressive behavior score (Cohen’s d effect size=0.25, P=0.03) and the CMAI factor 3: verbally agitated behavior score (Cohen’s d effect size=0.29, P=0.01) and the CGI-I score (P=0.007). Additionally, on the NPI-NH Total score, the brexpiprazole 2 or 3 mg/day group did better than placebo (Cohen’s d effect size=0.39, P=0.001).
Safety and Tolerability
Study 1
Over 12 weeks, treatment emergent adverse events (TEAE) incidence rates were as follows: 65.0% (brexpiprazole 2 mg/day), 49.0% (brexpiprazole 0.5-1 mg/day), and 45.9% (placebo) groups respectively.4 Most of the TEAEs were rated as being mild or moderate. Serious TEAEs were seen in 9.3% (brexpiprazole 2 mg/day), 10.2% (brexpiprazole 0.5-1 mg/day), and 5.2% (placebo) groups respectively. Agitation in 1 participant on brexpiperazole 0.5 mg/day was the only TEAE that was considered related to the study drug. Discontinuation due to TEAEs was as follows: 4.3% (brexpiprazole 2 mg/day), 8.9% (brexpiprazole 0.5-1 mg/day), and 5.2% (placebo) groups respectively. Agitation (4 vs 1) and QTc interval prolongation (2 vs 0) led to the discontinuation from the study in the brexpiprazole vs placebo groups. The investigators did not find any significant differences between the groups on suicidality, extrapyramidal symptoms (EPS), QTc interval, body weight, metabolic parameters, and cognitive dysfunction. A total of 5 participants in the brexpiprazole groups and 0 in the placebo group died during the study. However, it was determined that none of these deaths were attributable to the study medication.
Study 2
TEAE incidence over 12 weeks was similar between brexpiprazole 0.5-2 mg/day (56.8%) and placebo (58.4%) groups.5 Most of the TEAEs were rated as being mild to moderate. Serious TEAEs were as follows: 5.3% for brexpiprazole 0.5-2 mg/day and 4.4% for placebo groups respectively. A total of 6.8% of the individuals in the brexpiprazole group discontinued the study due to TEAEs when 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, with neither of the deaths being considered related to the study drug.
Study 3
Approximately 40.7% of the individuals in the brexpiprazole 2 or 3 mg/day reported TEAEs, when compared with 31.0% in the placebo group.5 Headache was noted in 6.6% of individuals in the brexpiprazole group and in 6.9% of individuals in the placebo group. Other TEAEs seen in the brexpiprazole vs placebo groups were as follows: cardiovascular events, 0.9% vs 0.9%; any cerebrovascular events, 0% vs 0%; any extrapyramidal symptoms, 3.5% vs 0%; somnolence/sedation, 4.0% vs 0.9%; accident or injury TEAE, including falls, 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 the brexpiprazole and placebo groups, respectively, discontinued treatment due to AEs. There was 1 death in the brexpiprazole group, but it was thought to be unrelated to the use of the drug. The mean standard deviation (SD), increase in body weight from baseline to week 12 was 0.3 kg in the brexpiprazole group vs 0.0 kg in the placebo group. Weight gain of ≥7% 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% 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.
Making Sense of the Data
Brexpiprazole titrated to 2 or 3 mg/day over 2 to 4 weeks (3 mg dose only following 28 days of 2 mg) provides statistically significant, although modest benefits among individuals with AD who present with agitation. Additionally, brexpiprazole appears to be well tolerated when 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 dementia-related psychosis; interestingly, the data for brexpiprazole appears similar (SMD=effect size). Yunusa et al in their meta-analysis found benefits for aripiprazole among individuals with BPSD when compared with placebo on the NPI (SMD= −0.17), the BPRS (SMD= −0.20), and on the CMAI (SMD= −0.30).7 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.8 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. There were no CVAEs noted in the studies and none of the deaths were deemed as being attributable to brexpiprazole. Additionally, there was no cognitive decline noted with the use of brexpiprazole. Sedation is the adverse effect to watch for when using brexpiprazole among individuals BPSD.
When looking at other antipsychotics, Yunusa et al noted that the risk for CVAEs were greater with olanzapine (OR=4.28) and risperidone (OR=3.85), when compared with placebo.7 Additionally, the investigators noted that risperidone (OR=2.23) produces 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).8 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). 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.
Strengths and Limitations of the Studies
The strengths of the included studies are that they are all well conducted, multicenter RCTs (Jadad 5/5) that included ≥1000 participants with AAD. Additionally, they used varying doses of brexpiprazole. The limitations of the studies are that they mainly had Caucasian participants, were only 12 weeks in duration, included more participants who were living in care facilities, included participants who had limited comorbidities, there was a restriction in concomitant therapies, and the functioning on these participants were not assessed. Additional limitations were that these trials were designed primarily to study the efficacy, safety, and tolerability of brexpiprazole for the management of AAD. These issues limit the generalizability of the data obtained from these studies including the use of brexpiprazole among other BPSD symptoms namely apathy, anxiety, psychosis, etc, and among individuals with dementia due to other etiologies including 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. As brexpiprazole is only available in an oral formulation, it cannot be used in situations where intramuscular (IM) or intravenous (IV) dosing is required to manage emergent agitation among individuals with dementia; it is not to be used as prn.
In an algorithm from Canada, the authors recommend 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.9 The second algorithm from the Harvard South Shore program proposes 3 separate algorithms in emergent, urgent, and nonurgent settings. 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, where can brexpiprazole be placed in these treatment algorithms for the management of BPSD? 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 among individuals with BPSD. Additionally, we recommend using pharmacological management strategies including brexpiprazole at the lowest effective doses and for the shortest time-period. Given the consistent lack of efficacy of brexpiprazole doses at 1 mg and below in the clinical trials, time will tell if these lower doses can be effective in a subset of agitated patients with dementia due to AD. We are clearly only beginning to learn about brexpiprazole; the data supports its use in minimizing future episodes of agitation in patients with AD when symptoms of agitation are dangerous and damaging despite the use of non-pharmacological treatments. Furthermore, medications should only be trialed for partially responsive or refractory symptoms of BPSD, and that too in conjunction with nonpharmacological treatments to optimize outcomes among these individuals.
Concluding Thoughts
Available evidence from 3 high quality, 12-week RCTs indicate that brexpiprazole at 2-3 mg/day, is more efficacious than placebo at reducing agitation among individuals with AD dementia. Some benefits may also be noted with 0.5-1 mg/day dosing of brexpiprazole among these individuals. Additionally, brexpiprazole at these doses is well tolerated among individuals with AD, with no evidence for CVAEs or deaths being attributed to the drug. However, 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 a 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.
Note: This article originally appeared on Psychiatric Times.
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