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

• Published in: Scientific reports Vol. 6; no. 1; p. 39209
• Main Authors: Ma, Min, Ren, Qian, Yang, Chun, Zhang, Ji-chun, Yao, Wei, Dong, Chao, Ohgi, Yuta, Futamura, Takashi, Hashimoto, Kenji
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.12.2016; Nature Publishing Group
• Subjects: 631/378/1689/1414; 692/699/476/1414; 82/80; Animals; Antidepressants; Antidepressive Agents - pharmacology; Antidepressive Agents - therapeutic use; Antipsychotics; Azepines - pharmacology; Behavior, Animal - drug effects; Benzamides - pharmacology; Brain-derived neurotrophic factor; Brain-Derived Neurotrophic Factor - metabolism; Dendritic spines; Dendritic Spines - drug effects; Dendritic Spines - physiology; Depressive Disorder, Major - drug therapy; Depressive Disorder, Major - pathology; Disease Models, Animal; Drug Therapy, Combination; Fluoxetine; Fluoxetine - pharmacology; Fluoxetine - therapeutic use; Humanities and Social Sciences; Male; Mental depression; Mice; Mice, Inbred C57BL; multidisciplinary; Nucleus accumbens; Phenotype; Prefrontal cortex; Psychotropic drugs; Quinolones - pharmacology; Quinolones - therapeutic use; Receptor, trkB - antagonists & inhibitors; Receptor, trkB - metabolism; Rodents; Science; Selective Serotonin Reuptake Inhibitors - pharmacology; Selective Serotonin Reuptake Inhibitors - therapeutic use; Serotonin uptake inhibitors; Signal Transduction - drug effects; Social interactions; Thiophenes - pharmacology; Thiophenes - therapeutic use; TrkB receptors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep39209

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.