Abstract Introduction Major depressive disorder (MDD) is frequently accompanied by residual symptoms such as anxiety and sleep disturbances, even after adequate antidepressant treatment. Brexpiprazole, a serotonin–dopamine activity modulator, has shown efficacy as adjunctive therapy for MDD. However, its mechanistic contribution to anxiety and sleep regulation remains unclear. This study aimed to evaluate the combined effects of brexpiprazole and paroxetine, a selective serotonin reuptake inhibitor (SSRI), on anxiety-like behavior and sleep architecture in mice. Methods We used male Crl:CD1 and C57BL/6J mice. Anxiety-like behavior was assessed using the marble-burying behavior (MBB) test using Crl:CD1 mice. We also evaluated locomotor activity monitored to exclude sedative effects. Sleep architecture was evaluated via cortical electroencephalography and electromyography, quantifying Wake, rapid eye movement (REM) sleep, and non-REM (NREM) sleep stages using C57BL/6J mice. Results In MBB test, paroxetine reduced buried marbles without affecting locomotor activity, whereas brexpiprazole alone was ineffective. The combination of brexpiprazole (0.1 mg/kg) and paroxetine (0.75 mg/kg) significantly decreased buried marbles. Next, to explore the role of α2C adrenoreceptor (AR) antagonism, JP-1302 (a selective α2C AR antagonist) was also tested. Similarly, JP-1302 (30 mg/kg) combined with paroxetine (0.75 mg/kg) decreased buried marbles. In sleep architecture, brexpiprazole dose-dependently decreased Wake and increased NREM sleep, while paroxetine primarily reduced REM sleep. Combined administration decreased Wake and REM sleep and increased NREM sleep. The combination showed effects comparable to each drug administered alone. Conclusions In this study, we demonstrated that the combination of brexpiprazole and paroxetine produced anxiolytic-like effects and altered sleep architecture in mice. Furthermore, the anxiolytic-like effect of the combination suggests that brexpiprazole’s α2C AR antagonistic activity may be one of several plausible contributors. Adjunctive brexpiprazole may influence anxiety and sleep architecture, potentially contributing to the management of residual symptoms in MDD.
Maruoka et al. (Fri,) studied this question.