Adjunctive treatment of brexpiprazole with fluoxetine shows a rapid antidepressant effect in social defeat stress model: Role of BDNF-TrkB signaling

Addition of low doses of the atypical antipsychotic drug brexpiprazole with selective serotonin reuptake inhibitors (SSRIs) could promote antidepressant effect in patients with major depressive disorder although the precise mechanisms underlying the action of the combination are unknown. Combination of low dose of brexpiprazole (0.1 mg/kg) and SSRI fluoxetine (10 mg/kg) could promote a rapid antidepressant effect in social defeat stress model although brexpiprazole or fluoxetine alone did not show antidepressant effect. Furthermore, the combination significantly improved alterations in the brain-derived neurotrophic factor (BDNF) - TrkB signaling and dendritic spine density in the prefrontal cortex, hippocampus, and nucleus accumbens in the susceptible mice after social defeat stress. Interestingly, TrkB antagonist ANA-12 significantly blocked beneficial effects of combination of brexpiprazole and fluoxetine on depression-like phenotype. These results suggest that BDNF-TrkB signaling plays a role in the rapid antidepressant action of the combination of brexpiprazole and fluoxetine.