Abstract
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.
Highlights
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 the precise mechanisms underlying the action of the combination are unknown
Fluoxetine or brexpiprazole alone did not alter the immobility time for TST and Forced swimming test (FST), and decreased sucrose preference in the susceptible mice (Fig. 1c–e). These findings suggest that adjunctive treatment of brexpiprazole with fluoxetine showed a rapid antidepressant effect in the susceptible mice after repeated social defeat stress
We examined whether combination of brexpiprazole and fluoxetine could cause alterations in the dendritic spines density in the prelimbic (PrL) and infralimbic (IL) regions of medial PFC (mPFC), shell and core of nucleus accumbens (NAc), CA1, CA3 and dentate gyrus (DG) of the hippocampus (Fig. 3a–h)
Summary
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 the precise mechanisms underlying the action of the combination are unknown. 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. The purpose of this study is to examine whether brexpiprazole could demonstrate antidepressant-like effects in combination with sub-threshold dose of the SSRI fluoxetine in depression-like behaviors and alterations in the spine density in stress susceptible mice after repeated social defeat stress. We examined the role of BDNF-TrkB signaling in the mechanisms of a rapid antidepressant action of combination of brexpiprazole and fluoxetine
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