Brexpiprazole improves agitation in Alzheimer’s dementia

A double-blind, placebo-controlled, randomized clinical trial reports significant improvement in agitation with brexpiprazole vs placebo among patients with Alzheimer’s dementia.

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. [Int Psychogeriatr 2023;doi:10.1017/S1041610222001041] Agitation is common with Alzheimer’s dementia and has a negative effect on patients’ functioning, health outcomes and quality of life. It also increases caregiver stress and time spent caring, and may contribute to patients being institutionalized. [Int J Geriatr Psychiatry 2021;36:1959-1969; Alzheimer Dis Assoc Disord 2011;25:116-121; Alzheimers Dement (N Y) 2019;5:851-861]

“Brexpiprazole is an atypical antipsychotic that acts on noradrenergic, serotonergic and dopaminergic neurotransmitter systems, which are implicated in the neurochemistry of agitation in Alzheimer’s disease,” wrote the researchers. [J Pharmacol Exp Ther 2014;350:589-604; Ageing Res Rev 2018;43:99-107] “The aim of the present clinical trial was to confirm the efficacy, safety and tolerability of brexpiprazole in patients with agitation in Alzheimer’s dementia.”

In the two-arm 12-week trial, 345 patients (mean age, 74.0 years; female, 56.5 percent) with Alzheimer’s dementia–related agitation were randomized to receive brexpiprazole (n=228) or placebo (n=117). Within the brexpiprazole arm, patients were further randomized to receive fixed doses of 2 mg/day or 3 mg/day of brexpiprazole in a 1:2 ratio. Baseline demographic and clinical characteristics were generally similar between treatment groups. Standard medications for Alzheimer’s disease (mostly memantine or donepezil) were taken by 81.4 percent and 81.9 percent of patients receiving brexpiprazole and placebo, respectively. Concomitant medications for agitation (mostly lorazepam) were received at least once by 19.5 percent and 14.7 percent of patients in the brexpiprazole and placebo groups, respectively. [JAMA Neurol 2023;doi:10.1001/jamaneurol.2023.3810]

Brexpiprazole, 2 mg/day or 3 mg/day, was associated with a statistically significantly greater improvement vs placebo in the primary endpoint of Cohen-Mansfield Agitation Inventory (CMAI) total score from baseline at week 12 (mean change, -22.6 vs -17.3; p=0.003). In addition, treatment with brexpiprazole, 2 mg/day or 3 mg/day, resulted in a statistically significantly greater improvement from baseline in the key secondary endpoint of Clinical Global Impression Severity of Illness (CGI-S) score as related to agitation vs placebo (mean change, -1.2 vs -0.9; p=0.008). Nominally greater improvements vs placebo were noted with brexpiprazole 2 mg and 3 mg in all other secondary endpoints (CMAI factor scores, CGI–Improvement [CGI-I] score, CMAI/CGI-I response rates) at week 12.

“CMAI total score changes indicated an overall reduction in the frequency of agitated behaviours, and CMAI factor score changes indicated improvement in three distinct types of agitated behaviour: aggressive, physically nonaggressive [excessive motor activity], and verbally agitated,” elaborated the researchers. “At the individual patient level, responder analyses suggested that brexpiprazole treatment may be clinically meaningful, as a greater proportion of patients on brexpiprazole vs placebo [52.4 percent vs 40.5 percent] achieved a CGI-I score of 1 [very much improved] or 2 [much improved], which are widely regarded as clinically meaningful outcomes. In addition, a greater proportion of patients receiving brexpiprazole vs placebo [57.2 percent vs 36.9 percent in a post hoc analysis] achieved a meaningful within-patient change in CMAI total score of -20 points.”

Treatment-emergent adverse events (TEAEs) were reported in 40.7 percent and 31.0 percent of patients on brexpiprazole and placebo, respectively, with no apparent dose effect. Headache was the only TEAE with an incidence of ≥5 percent in the brexpiprazole group (6.6 percent; placebo, 6.9 percent). The majority of TEAEs were mild or moderate in severity.