Preclinical Evidence for the Use of Brexpiprazole + Antidepressant Treatment for Major Depressive Disorder and Post-Traumatic Stress Disorder: A Systematic Review.

Purpose: Brexpiprazole, when administered with antidepressant therapy, may provide additional benefits due to complementary actions on noradrenaline (norepinephrine), serotonin, and dopamine neurotransmitter systems. This review addressed the question: what information can preclinical studies provide on the use of brexpiprazole + antidepressant treatment?

Methods: A systematic literature review was conducted to search for preclinical studies of brexpiprazole + antidepressant therapy that included a behavioral test relating to any psychiatric disorder. Ovid MEDLINE, Ovid Embase, and conference abstracts were searched (January 1, 2011-July 5, 2021). The statistically significant (p<0.05) findings for brexpiprazole + antidepressant were extracted.

Results: Of 296 records screened, nine articles were eligible, describing seven unique studies. In rodent models, including three models of depression (unpredictable chronic mild stress, social defeat stress, and lipopolysaccharide-induced depression), brexpiprazole + selective serotonin reuptake inhibitor (SSRI) or serotonin-noradrenaline reuptake inhibitor (SNRI) consistently showed statistically significant benefits over vehicle on depression-like behaviors (forced swim test, tail suspension test, sucrose preference), whereas brexpiprazole and antidepressant monotherapies did not. In the predator scent stress model of post-traumatic stress disorder (PTSD), brexpiprazole + SSRI (escitalopram) showed a significant benefit over vehicle and/or monotherapy on anxiety-like behaviors (elevated plus-maze) and hyperalertness (acoustic startle response), whereas brexpiprazole and escitalopram monotherapies did not significantly differ from vehicle. In the fear conditioning model of PTSD, brexpiprazole showed significant improvements whether administered as monotherapy or in combination with escitalopram.

Conclusion: Based on a small number of studies, the administration of brexpiprazole with an antidepressant appears to have a greater treatment effect than either brexpiprazole or antidepressant monotherapies in preclinical studies of depression- and PTSD-like behaviors. Thus, preclinical studies support evidence from randomized clinical trials for the therapeutic effects of adjunctive brexpiprazole in the treatment of major depressive disorder, and brexpiprazole in combination with sertraline in the treatment of PTSD. Funding: Otsuka/Lundbeck.