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

Psychopharmacology (Berl). 2017 Feb;234(4):525-533. doi: 10.1007/s00213-016-4483-7. Epub 2016 Nov 15.


Rationale: 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.

Objectives: The present study was undertaken to examine whether brexpiprazole could augment antidepressant effects of the SSRI fluoxetine in an inflammation model of depression.

Methods: 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).

Results: 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.

Conclusions: 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.

Keywords: Brexpiprazole; Fluoxetine; Inflammation; SSRI; Spine.

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology*
  • Antidepressive Agents / therapeutic use
  • Antipsychotic Agents / pharmacology*
  • Antipsychotic Agents / therapeutic use
  • Behavior, Animal / drug effects*
  • Brain-Derived Neurotrophic Factor / metabolism
  • Dendritic Spines / drug effects*
  • Dendritic Spines / metabolism
  • Depression / drug therapy*
  • Depression / metabolism
  • Fluoxetine / pharmacology*
  • Fluoxetine / therapeutic use
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • Male
  • Mice
  • Neurons / drug effects
  • Neurons / metabolism
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / metabolism
  • Quinolones / pharmacology*
  • Quinolones / therapeutic use
  • Signal Transduction / drug effects
  • Thiophenes / pharmacology*
  • Thiophenes / therapeutic use


  • Antidepressive Agents
  • Antipsychotic Agents
  • Brain-Derived Neurotrophic Factor
  • Quinolones
  • Thiophenes
  • Fluoxetine
  • brexpiprazole