糖心vlog

Key Points

Question听 Is brexpiprazole an efficacious, safe, and well-tolerated treatment for agitation in patients with Alzheimer dementia?

Findings听 In this randomized clinical trial with 345 patients, brexpiprazole, 2 mg/d or 3 mg/d, demonstrated a statistically significant reduction in agitation (Cohen-Mansfield Agitation Inventory score) vs placebo over 12 weeks. No treatment-emergent adverse events had an incidence of 5% or greater with brexpiprazole and greater than placebo, and the discontinuation rates due to adverse events were similar across the groups.

Meaning听 Brexpiprazole, 2 or 3 mg, reduced agitation in Alzheimer dementia and was generally well tolerated over 12 weeks.

Importance听 Agitation is a prevalent, distressing, and burdensome manifestation of Alzheimer dementia in need of an efficacious, safe, and well-tolerated treatment.

Objective听 To confirm the efficacy, safety, and tolerability of brexpiprazole in patients with agitation in Alzheimer dementia.

Design, Setting, and Participants听 This randomized clinical trial was a 12-week, double-blind, placebo-controlled, fixed-dose, parallel-arm trial that ran from May 2018 to June 2022 at 123 clinical trial sites in Europe and the United States. Participants included patients with agitation in Alzheimer dementia in a care facility or community-based setting. Stable Alzheimer disease medications were permitted.

Interventions听 In this 2-arm trial, patients were randomized to receive oral brexpiprazole or placebo (2:1 ratio) for 12 weeks. Within the brexpiprazole arm, patients were further randomized to receive fixed doses of 2 mg/d or 3 mg/d in a 1:2 ratio.

Main Outcomes and Measures听 The primary end point was change in Cohen-Mansfield Agitation Inventory total score (which measures the frequency of 29 agitated behaviors) from baseline to week 12 for brexpiprazole, 2 or 3 mg, vs placebo. Safety was assessed by standard measures, including treatment-emergent adverse events.

Results听 A total of 345 patients were randomized to receive brexpiprazole (n鈥�=鈥�228) or placebo (n鈥�=鈥�117); completion rates were 198 (86.8%) for brexpiprazole and 104 (88.9%) for placebo. Mean (SD) age was 74.0 (7.5) years, and 195 of 345 patients were female (56.5%). Patients receiving brexpiprazole, 2 or 3 mg (n鈥�=鈥�225), demonstrated statistically significantly greater improvement than those taking placebo (n鈥�=鈥�116) in Cohen-Mansfield Agitation Inventory total score from baseline to week 12 (brexpiprazole baseline, 80.6, mean change, 鈭�22.6; placebo baseline, 79.2, mean change, 鈭�17.3; least-squares mean difference, 鈭�5.32; 95% CI, 鈭�8.77 to 鈭�1.87; P鈥�=鈥�.003; Cohen d effect size, 0.35). No treatment-emergent adverse events had an incidence of 5% or more with brexpiprazole and greater incidence than placebo. The proportion of patients who discontinued because of adverse events was 12 of 226 (5.3%) for brexpiprazole and 5 of 116 (4.3%) for placebo.

Conclusions and Relevance听 In this study, patients with Alzheimer dementia who took brexpiprazole, 2 or 3 mg, showed a statistically significant improvement vs placebo in agitation over 12 weeks. Brexpiprazole was generally well tolerated over 12 weeks in this vulnerable patient population.

Trial Registration听 ClinicalTrials.gov Identifier:

Agitation associated with dementia is defined as excessive motor activity (eg, pacing, rocking, restlessness), verbal aggression (eg, speaking excessively loudly, screaming), or physical aggression (eg, grabbing, pushing, throwing objects), which causes excess distress or disability and cannot be solely attributed to a suboptimal care environment or another disorder (International Psychogeriatric Association criteria).¹ Agitation in dementia is common^2,3; has a negative effect on patient functioning, health outcomes, and quality of life^3-5; increases caregiver distress and time spent caring^5,6; and may contribute to the patient being institutionalized.⁷ Due to the lack of health-authority鈥揳pproved pharmacological treatment options for agitation in dementia, physicians may prescribe off-label medications,^8,9 despite having insufficient information about dosing, efficacy, and safety. Certain atypical antipsychotics have demonstrated efficacy on agitation in dementia but have an unfavorable benefit/risk profile that must be taken into consideration by patients and prescribing clinicians.^10,11

Brexpiprazole is an atypical antipsychotic that acts on noradrenergic, serotonergic, and dopaminergic neurotransmitter systems,¹² which are implicated in the neurochemistry of agitation in Alzheimer disease.¹³ Two prior randomized clinical trials suggested that brexpiprazole, 2 mg, may be efficacious, safe, and well tolerated in patients with agitation in Alzheimer dementia,¹⁴ indicating its potential as a new treatment for agitation, provided that results could be replicated. The aim of the present clinical trial was to confirm the efficacy, safety, and tolerability of brexpiprazole in patients with agitation in Alzheimer dementia.

This was a phase 3, multicenter, 12-week, randomized, double-blind, placebo-controlled, parallel-arm trial of brexpiprazole in patients with agitation in Alzheimer dementia (ClinicalTrials.gov identifier: ). The trial protocol and statistical analysis plan are available in Supplement 1.

The trial was conducted in accordance with the International Council for Harmonisation Good Clinical Practice guidelines and local regulatory requirements. The study protocol was approved by the governing institutional review board or independent ethics committee for each investigational site or country. All patients and/or their legal representatives provided electronic informed consent prior to the start of the study, after the intervention and possible adverse effects had been fully explained. Patients in the United States and their caregivers received a stipend to cover travel and meal costs.

Patients (a volunteer sample) were enrolled by investigators at 123 Alzheimer disease clinical trial sites in Europe (Bulgaria, Hungary, Serbia, Slovakia, Spain, Ukraine) and the United States. Key inclusion criteria were age 55 to 90 years; diagnosis of probable Alzheimer disease, defined by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer鈥檚 Disease and Related Disorders Association (NINCDS-ADRDA) criteria¹⁵; Mini-Mental State Examination (MMSE)¹⁶ score of 5 to 22 at screening and baseline; previous computed tomography or magnetic resonance imaging scan of the brain with findings consistent with a diagnosis of Alzheimer disease; a diagnosis of agitation that meets the International Psychogeriatric Association definition (which was a provisional definition at the time)¹; onset of agitation at least 2 weeks prior to screening; Neuropsychiatric Inventory (NPI) or NPI鈥揘ursing Home version (NPI-NH) Agitation/Aggression domain score (frequency鈥壝椻�塻everity) of 4 or greater at screening and baseline^17,18; requiring pharmacotherapy for the treatment of agitation in the investigator鈥檚 judgment after an evaluation for reversible factors (eg, pain, infection, polypharmacy) and a trial of nonpharmacological interventions (eg, redirecting behavior, group activities, music therapy); living in a care facility or community-based setting (not living alone); and having an identified caregiver who has sufficient contact to describe the patient鈥檚 symptoms and behavior. An additional required inclusion criterion based on positivity for Cohen-Mansfield Agitation Inventory (CMAI) factor 1 (aggressive behavior [12 items: hitting, kicking, scratching, grabbing, pushing, hurting self or others, throwing things, cursing or verbal aggression, spitting, tearing things or destroying property, screaming, and biting]) was blinded to patients, caregivers, and investigators.^19,20 To meet the CMAI factor 1 positivity criterion, 1 of the following must have been established at screening and baseline: 1 or more aggressive behaviors occurring several times per week, 2 or more aggressive behaviors occurring once or twice per week, or 3 or more aggressive behaviors occurring less than once per week.^19-21 Key exclusion criteria were dementia or memory impairment due to a reason other than Alzheimer disease and any clinically significant neurological, psychiatric (except as specified), or unstable medical condition. Stable diabetes and asymptomatic major depressive disorder were permitted.

After screening, patients entered a 12-week double-blind treatment period in which they were randomized 2:1 to receive oral brexpiprazole or placebo. Although this was a 2-arm trial, patients in the brexpiprazole arm were further randomized 1:2 to receive brexpiprazole fixed doses of 2 mg/d or 3 mg/d. The 3-mg dose was included as recommended by the US Food and Drug Administration to explore the efficacy, safety, and tolerability of a higher dose of brexpiprazole than had previously been studied in Alzheimer disease. The trial design, including titration, is illustrated in eFigure 1 in Supplement 2.

Study drugs were taken orally once daily at the same time each day, preferably in the morning, without regard to meals. Brexpiprazole tablets and matching placebo tablets were provided by the sponsor, packaged in numbered, weekly blister cards. Treatments were assigned to patients using an eSource method via a fixed-block (block size 3) computer-generated randomization code provided by the sponsor and stratified by site. Treatment assignments were blinded to patients, caregivers, investigators, and sponsor personnel, including those involved in data analysis. Visits occurred every 2 weeks. Stable background medications for the treatment of Alzheimer disease were permitted, whereas antipsychotics, mood stabilizers, and anticonvulsants were prohibited. Limited use of benzodiazepines was permitted during the first 4 weeks of the double-blind treatment period and prohibited thereafter.

Demographic information and medical history were recorded at the screening visit. Sex, race, and ethnicity were reported using US Census Bureau classifications; the protocol did not specify a method of collection.

Efficacy was assessed using the CMAI, a validated measure of the frequency of occurrence of 29 agitated behaviors in care facilities and community-based settings.^19,22,23 Each item is scored from 1 (never occurs) to 7 (occurs a few times an hour), giving a total score range from 29 to 203 points.¹⁹ The CMAI was completed at each visit by the clinician based on an interview with the patient鈥檚 caregiver. Efficacy was also assessed using the clinician-rated Clinical Global Impression Severity of illness (CGI-S) and Improvement (CGI-I) scales,²⁴ specifically applied to agitation, and the NPI-NH.¹⁸

Safety was assessed via treatment-emergent adverse events (TEAEs), body weight, laboratory tests, vital signs, electrocardiograms, the Sheehan Suicidality Tracking Scale,²⁵ the MMSE (to assess cognitive dysfunction),¹⁶ and 3 extrapyramidal symptom rating scales: Simpson-Angus Scale,²⁶ Abnormal Involuntary Movement Scale,²⁴ and Barnes Akathisia Rating Scale.²⁷

The primary estimand was defined by the following components:

• Population: patients with agitation in Alzheimer dementia.

• Treatments: brexpiprazole, 2 mg/d or 3 mg/d (a single arm), or placebo.

• Primary end point: change from baseline to week 12 in CMAI total score.

• Measure of intervention effect: mean difference between the brexpiprazole and placebo arms.

• Intercurrent events: premature treatment discontinuation (ie, early dropout) before week 12 attributable to adverse events, lack of efficacy, withdrawal of consent/assent, or any other cause.

Treatment effect was estimated under the hypothetical situation that no patients discontinued early from treatment. However, in clinical trial practice, some patients are likely to discontinue, and a mixed model for repeated measures was used to account for such patients, including all observed data regardless of completion status.

To control for experiment-wise type I error, a testing hierarchy was used in which the key secondary end point (change from baseline to week 12 in CGI-S score) was tested only if the primary end point was significant at the .035 level (2-sided). Other secondary end points (CMAI factor scores, CGI-I score, CMAI/CGI-I response rates) and prespecified exploratory end points (NPI-NH total score, CMAI total score by dose, CGI-S score by dose) were tested at a nominal .05 level (2-sided), with no adjustment for multiplicity.

Subgroup analyses of the primary efficacy end point were performed by region, sex, race, age, dementia severity, and psychosis status. Details of the sample size calculation, interim analysis, and statistical analysis methods are provided in the eMethods in Supplement 2.

The trial was conducted between May 16, 2018, and June 1, 2022. Of 123 included sites (listed in eTable 1 in Supplement 2), 68 sites enrolled patients, of which 16 were classified as small sites. A total of 345 patients were randomized to receive brexpiprazole (n鈥�=鈥�228) or placebo (n鈥�=鈥�117) across the United States (152, 44.1%), Ukraine (107, 31.0%), Bulgaria (37, 10.7%), Serbia (19, 5.5%), Slovakia (13, 3.8%), Spain (11, 3.2%), and Hungary (6, 1.7%). Completion rates were 198 (86.8%) for brexpiprazole and 104 (88.9%) for placebo (Figure 1 and by dose in eFigure 2 in Supplement 2).

Baseline demographic and clinical characteristics were generally similar between treatment groups (Table 1). Mean (SD) age was 74.0 (7.5) years (range, 56-90 years), 195 patients (56.5%) were female, 150 (43.5%) were male, 4 (1.2%) were Asian, 12 (3.5%) were Black, 108 (31.3%) were Hispanic, 329 (95.4%) were White, and 193 (55.9%) had moderate cognitive impairment (MMSE score of 13-18). During the trial, standard medications for Alzheimer disease (mostly memantine or donepezil) were taken by 184 patients (81.4%) receiving brexpiprazole and 95 (81.9%) receiving placebo, and concomitant medications for agitation (mostly lorazepam) were received at least once by 44 patients (19.5%) receiving brexpiprazole and 17 (14.7%) receiving placebo.

Brexpiprazole, 2 or 3 mg, demonstrated statistically significant greater improvement vs placebo on the change in CMAI total score from baseline to week 12, with a Cohen d effect size of 0.35 (Figure 2A, Table 2, absolute scores in eFigure 3A in Supplement 2, changes by subgroup in eFigure 4 in Supplement 2, and missing-not-at-random sensitivity analysis in eTable 2 in Supplement 2).

Brexpiprazole, 2 or 3 mg, demonstrated statistically significant greater improvement vs placebo on the change in CGI-S score as related to agitation from baseline to week 12 (the key secondary end point), with a Cohen d effect size of 0.31 (Figure 2B, Table 2, and absolute scores in eFigure 3B in Supplement 2). Brexpiprazole, 2 or 3 mg, showed nominally significant greater improvement vs placebo on all other secondary end points (CMAI factor scores, CGI-I score, CMAI/CGI-I response rates) at week 12 (Table 2).

Brexpiprazole, 2 or 3 mg, showed nominally significant greater improvement vs placebo on NPI-NH total score at week 12 (Table 2). By dose, both brexpiprazole dose subgroups, 2 and 3 mg, showed similar greater improvement than placebo on CMAI total score at week 12, with nominal significance (eFigure 5A in Supplement 2). On CGI-S score, brexpiprazole, 2 and 3 mg, showed similar improvements at week 12, with nominal significance vs placebo for brexpiprazole, 3 mg (eFigure 5B in Supplement 2).

Ninety-two patients (40.7%) reported TEAEs with brexpiprazole, 2 or 3 mg, and 36 (31.0%) with placebo, with no apparent effect of dose (Table 3). Headache was the only TEAE with an incidence 5% or greater in the brexpiprazole, 2 or 3 mg, group (15 [6.6%] vs 8 [6.9%] with placebo). The incidence of TEAEs in specific categories of interest for brexpiprazole and placebo, respectively, was as follows: any cardiovascular TEAE: 2 (0.9%), 1 (0.9%); any cerebrovascular TEAE: 0, 0; any extrapyramidal symptom鈥搑elated TEAE: 8 (3.5%), 0; any somnolence/sedation TEAE: 9 (4.0%), 1 (0.9%); any accident or injury TEAE, including fall: 5 (2.2%), 4 (3.4%); any metabolism and nutrition disorder TEAE: 3 (1.3%), 2 (1.7%). The majority of TEAEs were mild or moderate in severity.

One patient died during the trial, in the brexpiprazole, 3 mg, subgroup, of cardiac failure (age, 78 years). The patient withdrew from the trial after 28 days because of the adverse event of hallucinations. The patient also had serious adverse events of pneumonia and cachexia. Death occurred 23 days after the last dose of brexpiprazole. An autopsy revealed coronary atherosclerosis, and the death was considered unrelated to brexpiprazole.

Mean (SD) increase in body weight from baseline to week 12 was 0.3 (2.8) kg in the brexpiprazole, 2 or 3 mg, group (n鈥�=鈥�196) and 0.0 (2.0) kg in the placebo group (n鈥�=鈥�104). At week 12, weight gain of 7% or more from baseline was experienced by 3 of 196 patients (1.5%) in the brexpiprazole, 2 or 3 mg, group and 0 of 104 in the placebo group; the corresponding values for weight loss of 7% or more were 2 of 196 (1.0%) and 1 of 104 (1.0%).

No patients reported TEAEs of suicidal ideation or behavior during the trial. Mean (SD) change in MMSE score from baseline to week 12 was 0.7 (2.8) in the brexpiprazole, 2 or 3 mg, group (n鈥�=鈥�192) and 0.4 (2.1) in the placebo group (n鈥�=鈥�103). There were no clinically meaningful between-group mean differences in laboratory test parameters, vital signs, or electrocardiograms, and extrapyramidal symptom rating scale score changes were minimal (eTable 3 in Supplement 2).

In patients with agitation in Alzheimer dementia, treatment with brexpiprazole (fixed doses of 2 or 3 mg) resulted in statistically significant greater improvements vs placebo in CMAI total score (primary end point) and CGI-S score as related to agitation (key secondary end point), supported by all other secondary efficacy end points. CMAI total score changes indicated an overall reduction in the frequency of agitated behaviors, and CMAI factor score changes indicated improvement of 3 distinct types of agitated behavior: aggressive, physically nonaggressive (excessive motor activity), and verbally agitated.^19,20,22,28 At the individual patient level, responder analyses (secondary end points) suggested that brexpiprazole treatment may be clinically meaningful: first, a greater proportion of patients receiving brexpiprazole than placebo achieved a CGI-I score of 1, very much improved, or 2, much improved (52.4% vs 40.5%), which are widely regarded as clinically meaningful outcomes. Second, a greater proportion of patients receiving brexpiprazole than placebo achieved a meaningful within-patient change in CMAI total score of 鈭�20 points (57.2% vs 36.9% in a post hoc analysis); this meaningful within-patient change was determined by anchor- and distribution-based methods and approximately corresponds to a 2-point improvement in CGI-S score and a score of 2 on the CGI-I.²⁹

This study was powered for analyses of the modified intention-to-treat (efficacy) sample and not for analyses of individual brexpiprazole doses or subgroups, the results from which should be interpreted with caution. Exploratory analyses by dose found no clinically relevant differences in efficacy between brexpiprazole, 2 and 3 mg. Results of subgroup analyses were generally consistent with the primary analysis. In the analysis by region, brexpiprazole response was consistent in the United States and Europe; however, there was an unexpectedly high placebo response in the United States with no discernible reason, which was not observed in a previous phase 3 trial of fixed-dose brexpiprazole.^14,30

Two previous randomized phase 3 trials have investigated brexpiprazole for the treatment of agitation in Alzheimer dementia.¹⁴ In a fixed-dose trial, brexpiprazole, 2 mg (but not 1 mg), showed significant improvement vs placebo on CMAI total score (least-squares mean difference [LSMD], 鈭�3.77; P鈥�=鈥�.04; effect size, 0.25). In a flexible-dose trial, brexpiprazole, 0.5 mg to 2 mg, was not significantly different from placebo at week 12 (LSMD, 鈭�2.34; P鈥�=鈥�.15; effect size, 0.18); a post hoc analysis of patients titrated to 2 mg showed nominally significant separation vs placebo (LSMD, 鈭�5.06; P鈥�=鈥�.01; effect size, 0.41),¹⁴ with a comparable drug-placebo difference to the current study (LSMD, 鈭�5.32; P鈥�=鈥�.003; effect size, 0.35). Thus, observations from prior trials suggested that brexpiprazole, 2 mg, was an efficacious dose in patients with agitation in Alzheimer dementia. The current trial provides further evidence for efficacy of the 2-mg dose, as well as support for the 3-mg dose; the trial design does not allow for clinical recommendations on whether patients not responding to 2 mg might respond to 3 mg. An evaluation for reversible factors (such as pain) and a trial of nonpharmacological therapy should be performed before administration of brexpiprazole for agitation.

The trial reported here differed from the previous 2 trials in that it required patients to meet the International Psychogeriatric Association definition of agitation at entry, which was not available at the time of the previous trials.^1,14 Furthermore, a post hoc analysis of the first 2 trials indicated that patients who did not meet the CMAI factor 1 (aggressive behavior) positivity criterion at baseline had insufficient baseline agitation severity to show measurable change over time.³¹ Hence, the present trial recruited an enriched sample who met the CMAI factor 1 positivity criterion at baseline, resulting in higher baseline CMAI total scores (79-81, depending on treatment group) than the previous trials (64-72),¹⁴ and a broad range of agitation symptoms across the CMAI factors. This enrichment may have enhanced signal detection (as shown by a higher LSMD in the current trial) and is likely to reflect the population of patients with Alzheimer dementia who require treatment for agitation in clinical practice.

Based on safety and tolerability data from the first 2 trials, the current trial used a faster titration schedule than the previous trials, reaching the 2-mg dose after 2 weeks as opposed to 4 weeks.¹⁴ Faster titration did not appear to affect the safety or tolerability of brexpiprazole in the current trial (with similar rates of discontinuation due to adverse events between trials) or the time point at which brexpiprazole, 2 mg, first separated from placebo on CMAI total score (week 8 in the present trial compared with week 6 or week 12 in the previous trials).

Brexpiprazole acts as an antagonist at noradrenergic 伪_1B and 伪_2C and serotonergic 5-HT_2A receptors, as well as a partial agonist at 5-HT_1A and dopaminergic D₂ receptors, all with subnanomolar affinity.¹² Thus, brexpiprazole acts on multiple receptors in the brain related to agitation, aggression, impulsiveness, arousal, and psychosis.^13,32-34 Brexpiprazole has a moderate affinity for histamine H₁ receptors, meaning that its effects on agitation are unlikely to be due to sedation.^12,35

Comparing the efficacy of different antipsychotics for the treatment of agitation in Alzheimer dementia is challenging because of differences in trial design (including duration), study population (different settings, forms of dementia, and target symptom: psychosis or agitation), and outcome measure (BEHAVE-AD, NPI, CMAI, etc).³⁶ A Cochrane review of these diverse trials concluded that atypical antipsychotics as a group (including olanzapine, quetiapine, and risperidone) have a small effect on agitation in dementia (standardized mean difference, 鈭�0.21).³⁶

Since 2005, US prescribing information for atypical antipsychotics contains a boxed warning for increased risk of cerebrovascular events and mortality in elderly patients with dementia-related psychosis, supported by meta-analyses of data from randomized placebo-controlled trials.^37-40 There were no cerebrovascular TEAEs in the current trial; however, patients and clinicians should be aware of this possible risk. Seven patients died during the 3 randomized phase 3 trials: 6 (0.9%) in the brexpiprazole groups and 1 (0.3%) in the placebo groups; these deaths were considered unrelated to brexpiprazole treatment by the investigators.³¹ Other warnings in the US prescribing information include neuroleptic malignant syndrome, tardive dyskinesia, orthostatic hypotension, syncope, and seizures (none of which were observed in this trial, although 2.7% of patients receiving brexpiprazole reported dizziness), and falls/fractures⁴⁰ (a general concern with atypical antipsychotics in elderly patients,⁴¹ but which had placebo-level incidence in this trial). Somnolence, sedation, extrapyramidal symptoms, and urinary tract infection, which are associated with atypical antipsychotic treatment in elderly patients with dementia,^10,42 had a low incidence with brexpiprazole (all <5%), albeit higher than placebo. Finally, whereas certain atypical antipsychotics have been associated with an increased risk of cognitive decline,⁴³ mean MMSE score changes on brexpiprazole suggested that there was no worsening of cognition over 12 weeks. Overall, while the total incidence of TEAEs was higher with brexpiprazole than placebo, the rate of discontinuation due to adverse events was low and comparable between groups, and no new safety concerns were raised by observations in this trial.

Standard of care for Alzheimer disease may differ between countries, which is difficult to account for in a multinational trial.⁴⁴ The CMAI is completed based on information from caregivers, who may observe different behaviors according to their level of caregiving experience and the amount of time spent with the patient per day. A larger number of study sites was needed than originally anticipated (some sites did not recruit any patients and other sites were classified as small) due to the difficulty in recruiting patients with agitation in Alzheimer disease and due to the COVID-19 pandemic. The exclusion of patients with certain comorbidities and restrictions on concomitant therapy could limit the generalizability of the findings. The sample was predominantly White, and care should be taken when extrapolating tolerability data to other races. The trial did not include a measure of patient functioning. Finally, this study had limited duration of treatment, and longer-term efficacy and safety data are needed, particularly with regard to cognition and mortality; an extension trial providing data on longer-term brexpiprazole treatment has recently been completed (ClinicalTrials.gov identifier: ).

Treatment of agitation is essential to increase the comfort, quality of life, and safety of patients with Alzheimer dementia; to ease the burden on their caregivers; and to allow patients to live at home longer. In this 12-week clinical trial, brexpiprazole, 2 or 3 mg, showed a statistically significant improvement vs placebo on agitation in patients with Alzheimer dementia. Brexpiprazole was generally well tolerated over 12 weeks in this vulnerable patient population. Overall, brexpiprazole, 2 or 3 mg, appears to have a favorable benefit/risk profile in the treatment of agitation in Alzheimer dementia. Based on the results of this trial, together with a previous trial, brexpiprazole was approved in the United States for the treatment of agitation associated with dementia due to Alzheimer disease.

Accepted for Publication: August 16, 2023.

Published Online: November 6, 2023. doi:10.1001/jamaneurol.2023.3810

Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. 漏 2023 Lee D et al. JAMA Neurology.

Corresponding Author: George T. Grossberg, MD, Department of Psychiatry and Behavioral Neuroscience, St Louis University School of Medicine, 1438 South Grand Blvd, St Louis, MO 63104 (george.grossberg@health.slu.edu).

Author Contributions: Dr Lee had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Lee, Slomkowski, Hefting, Chen, Kohegyi, Hobart, Grossberg.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Lee, Chen, Hobart, Cummings.

Critical review of the manuscript for important intellectual content: Lee, Slomkowski, Hefting, Chen, Larsen, Kohegyi, Cummings, Grossberg.

Statistical analysis: Lee, Chen, Larsen, Kohegyi.

Obtained funding: Lee, Hefting.

Administrative, technical, or material support: Lee, Slomkowski, Hefting, Hobart, Cummings.

Supervision: Lee, Slomkowski, Hefting, Kohegyi, Hobart, Grossberg.

Conflict of Interest Disclosures: Dr Cummings has provided consultation to Acadia, Alkahest, AriBio, Avanir, Axsome, Behren Therapeutics, Biogen, Cassava, Cerecin, Cerevel, Cortexyme, EIP Pharma, Eisai, GemVax, Genentech, Green Valley, Grifols, Janssen, Jazz, Karuna, Lundbeck, Merck, Novo Nordisk, Otsuka, ReMYND, Resverlogix, Roche, Samumed, Samus, Signant Health, Sunovion, Suven, United Neuroscience, and Unlearn AI outside the submitted work and reported owning the copyright of the Neuropsychiatric Inventory with royalties paid. Dr Grossberg has received consulting fees from Acadia, Avanir, Axsome, Biogen, BioXcel, Eisai, Eli Lilly, Genentech, Karuna, Lundbeck, Otsuka, Roche, and Takeda outside the submitted work. No other disclosures were reported.

Funding/Support: This study was supported by Otsuka Pharmaceutical Development & Commercialization and H. Lundbeck.

Role of the Funder/Sponsor: The sponsors were involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 3.

Additional Contributions: We acknowledge the contributions of the late Joan Amatniek, MD, to the study of brexpiprazole in agitation in Alzheimer dementia. Denise Chang, PhD, Otsuka Pharmaceutical Development & Commercialization, conducted the data analysis. Writing support was provided by Chris Watling, PhD, assisted by his colleagues at Cambridge鈥揳 Prime Global agency and funded by Otsuka Pharmaceutical Development & Commercialization and H. Lundbeck.