MicroRNAs 146a/b-5p, 425-3p and 24-3p are markers of antidepressant response and regulate MAPK/Wnt-system genes

Background: Antidepressants (ADs) are the most common treatment for major depressive disorder (MDD). However, only about 30% of patients experience adequate response after a single AD trial, and this variability remains poorly understood. Here, we investigated microRNAs (miRNAs) as biomarkers of AD response using small RNA-sequencing in paired samples from MDD patients enrolled in a large, randomized placebo-controlled trial of duloxetine collected before and eight weeks after treatment. Results: Our results revealed differential expression of miR-146a-5p, miR-146b-5p, miR-425-3p and miR-24-3p according to treatment response. These results were replicated in two independent clinical trials of MDD, a well-characterized animal model of depression, and post-mortem human brains. Furthermore, using a combination of bioinformatics, mRNA studies and functional in vitro experiments, we showed significant dysregulation of genes involved in MAPK/Wnt signaling pathways. Conclusions: Together, our results indicate that these miRNAs are consistent markers of treatment response and regulators of the MAPK/Wnt systems. Overall design: MicroRNAs as biomarkers of antidepressant response