Differential effects of brexpiprazole on cognitive recovery and cortical volume after experimental traumatic brain injury

Managing agitation after traumatic brain injury (TBI) often involves antipsychotic drugs, despite evidence that dopamine D 2 antagonists can impair recovery. Brexpiprazole, a third-generation APD with partial agonist activity at dopamine D 2 and serotonin 5-HT 1A receptors, may provide a safer alternative. To test the hypothesis that brexpiprazole would not hinder recovery and might improve functional outcomes after TBI, anesthetized adult male rats received a controlled cortical impact or sham injury and were treated with brexpiprazole (0.5, 1, or 2 mg/kg, i.p.) or vehicle beginning 24 h post-injury for 21 days. Motor and cognitive performance were assessed during recovery, and cortical lesion volume was measured on day 21. Sham groups did not differ by treatment and were pooled. Relative to vehicle-treated TBI controls, brexpiprazole did not impair motor recovery at any dose. The 0.5 mg/kg dose improved spatial learning, while the 2 mg/kg dose reduced cortical lesion volume ( p < 0.05). Memory retention in the 0.5 mg/kg group was comparable to sham controls. These findings demonstrate dose-specific behavioral and histological benefits of brexpiprazole following experimental TBI without detectable adverse effects on recovery. Although the mechanisms underlying these effects remain unclear, brexpiprazole warrants further investigation as a treatment option after TBI.