Brexpiprazole: A new option in treating agitation in Alzheimer's dementia—Insights from transgenic mouse models

• Published in: Neuropsychopharmacology reports Vol. 44; no. 3; pp. 557 - 568
• Main Authors: Amada, Naoki, Sato, Shinji, Ishikawa, Dai, Nakamura, Mai, Suzuki, Mikio, Futamura, Takashi, Maeda, Kenji
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01-09-2024; John Wiley and Sons Inc; Wiley
• Subjects: aggression; Aggressiveness; agitation; Alzheimer's disease; Behavior; behavioral and psychological symptoms associated with dementia (BPSD); Body temperature; brexpiprazole; Circadian rhythm; Dementia; Dopamine; Mutation; Original; Serotonin; Statistical analysis; Japan; agitation; aggression; brexpiprazole; behavioral and psychological symptoms associated with dementia (BPSD); Alzheimer's disease
• ISSN: 2574-173X; 2574-173X
• DOI: 10.1002/npr2.12461

Aim
Brexpiprazole is the first FDA‐approved treatment for agitation associated with dementia due to Alzheimer's disease. Agitation in Alzheimer's dementia (AAD) occurs in high prevalence and is a great burden for patients and caregivers. Efficacy, safety, and tolerability of brexpiprazole were demonstrated in the AAD clinical trials. To demonstrate the agitation‐ameliorating effect of brexpiprazole in animals, we evaluated brexpiprazole in two AAD mouse models.
Methods
The resident–intruder test was conducted in 5‐ to 6‐month‐old Tg2576 mice, given vehicle or brexpiprazole (0.01 or 0.03 mg/kg) orally 1 h before the test. Locomotor activity was measured in 6‐month‐old APPSL‐Tg mice given vehicle or brexpiprazole (0.01 or 0.03 mg/kg) orally the evening before the start of locomotor measurement for 3 days.
Results
In the resident–intruder test, Tg2576 mice showed significantly higher attack number and shorter latency to first attack compared to non‐Tg mice. In the Tg mice, brexpiprazole treatment (0.03 mg/kg) significantly delayed the latency to first attack and showed a trend toward a decrease in attack number. APPSL‐Tg mice (≧6 months old) showed significantly higher locomotion during dark period Phase II (Zeitgeber time [ZT] 16–20) and Phase III (ZT20‐24) compared to non‐Tg mice, correlating with the clinical observations of late afternoon agitation in Alzheimer's disease. Brexpiprazole treatment (0.01 and 0.03 mg/kg) significantly decreased hyperlocomotion during the Phase III in APPSL‐Tg mice.
Conclusion
The suppression of attack behavior and the reduction of nocturnal hyperlocomotion in these Tg mice may be indicative of the therapeutic effect of brexpiprazole on AAD, as demonstrated in the clinical trials.
Brexpiprazole was evaluated on agitation‐related behaviors in two transgenic mouse models of Alzheimer's dementia. Brexpiprazole suppressed attack behavior and reduced nocturnal hyperlocomotion in these model mice, which may be indicative of the therapeutic effect of brexpiprazole on agitation in Alzheimer's dementia, as demonstrated in the clinical trials.