Antidepressant effects of combination of brexpiprazole and fluoxetine on depression-like behavior and dendritic changes in mice after inflammation

Addition of low doses of atypical antipsychotic drugs with selective serotonin reuptake inhibitors (SSRIs) could promote a rapid antidepressant effect in treatment-resistant patients with major depression. Brexpiprazole, a new atypical antipsychotic drug, has been used as adjunctive therapy for the treatment of major depression. The present study was undertaken to examine whether brexpiprazole could augment antidepressant effects of the SSRI fluoxetine in an inflammation model of depression. We examined the effects of fluoxetine (10 mg/kg), brexpiprazole (0.1 mg/kg), or the combination of the two drugs on depression-like behavior, alterations in the brain-derived neurotrophic factor (BDNF) - TrkB signaling, and dendritic spine density in selected brain regions after administration of lipopolysaccharide (LPS) (0.5 mg/kg). Combination of brexpiprazole and fluoxetine promoted a rapid antidepressant effect in inflammation model although brexpipazole or fluoxetine alone did not show antidepressant effect. Furthermore, the combination significantly improved LPS-induced alterations in the BDNF - TrkB signaling and dendritic spine density in the prefrontal cortex, CA3 and dentate gyrus, and nucleus accumbens. These results suggest that add-on of brexpiprazole to fluoxetine can produce a rapid antidepressant effect in the LPS inflammation model of depression, indicating that adjunctive therapy of brexpiprazole to SSRIs could produce a rapid antidepressant effect in depressed patients with inflammation.