Brexpiprazole augmentation and mitochondrial gene expression changes in major depressive disorder.

Background: Overall, 20% of patients with major depressive disorder (MDD) are treatment-resistant and do not respond to multiple antidepressant monotherapies. For such patients, augmentation therapy with antipsychotics is one of the therapeutic options. However, the mechanism of augmentation therapy is essentially unknown.

Aim: This study aimed to elucidate the mechanism of brexpiprazole (BREX) augmentation at gene expression levels.

Methods: Vehicle, escitalopram (ES), BREX, and ES + BREX (augmentation therapy) were administered to mouse neuroblastoma (Neuro2a) cells and submitted to RNA-sequencing. Gene expressions were also measured in the whole blood of MDD patients and the frontal cortices and hippocampi of mice after treatment for 20 days.

Results: On RNA-seq and gene ontology analyses, upregulation of mitochondria (MT)-related genes was confirmed by quantitative Polymerase Chain Reaction (PCR). These upregulated genes were successfully validated in both Neuro2a and Caco2 cells. Decreased MT-ATP8 expression was found in the whole blood of MDD patients. Furthermore, changes in MT-mRNA expression were confirmed in the frontal cortices and hippocampi of mice with augmentation therapy.

Conclusions: BREX augmentation modified MT-mRNA expressions in both in vitro and in vivo experiments. This may be a key finding in improving our understanding of MDD pathogenesis and clinical practice.