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

• Published in: Nature communications Vol. 8; no. 1; p. 15497
• Main Authors: Lopez, Juan Pablo, Fiori, Laura M., Cruceanu, Cristiana, Lin, Rixing, Labonte, Benoit, Cates, Hannah M., Heller, Elizabeth A., Vialou, Vincent, Ku, Stacy M., Gerald, Christophe, Han, Ming-Hu, Foster, Jane, Frey, Benicio N., Soares, Claudio N., Müller, Daniel J., Farzan, Faranak, Leri, Francesco, MacQueen, Glenda M., Feilotter, Harriet, Tyryshkin, Kathrin, Evans, Kenneth R., Giacobbe, Peter, Blier, Pierre, Lam, Raymond W., Milev, Roumen, Parikh, Sagar V., Rotzinger, Susan, Strother, Steven C., Lewis, Cathryn M., Aitchison, Katherine J., Wittenberg, Gayle M., Mechawar, Naguib, Nestler, Eric J., Uher, Rudolf, Kennedy, Sidney H., Turecki, Gustavo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.05.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 13/100; 38/109; 64/60; 692/308/53/2422; 692/53/2422; Adult; Aged; Animals; Antidepressive Agents - therapeutic use; Biomarkers; Brain - pathology; Brain research; Cognitive science; Computational Biology; Depressive Disorder, Major - drug therapy; Depressive Disorder, Major - genetics; Duloxetine Hydrochloride - therapeutic use; Female; Gene Expression Regulation; Genes; HEK293 Cells; Humanities and Social Sciences; Humans; Kinases; Male; MAP Kinase Signaling System; Mental depression; Mental disorders; Mental health; Mice; Mice, Inbred C57BL; MicroRNAs; MicroRNAs - genetics; Middle Aged; multidisciplinary; Neuroscience; Neurosciences; Psychiatry; R&D; Research & development; Science; Science (multidisciplinary); Wnt Signaling Pathway; Young Adult; Ontario Canada; New York; Canada; Toronto Ontario Canada; United States > US
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms15497

Antidepressants (ADs) are the most common treatment for major depressive disorder (MDD). However, only ∼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 8 weeks after treatment. 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 signalling pathways. Together, our results indicate that these miRNAs are consistent markers of treatment response and regulators of the MAPK/Wnt systems. Antidepressant drugs are the most common treatment for depressive episodes but only a fraction of patients experience adequate response. Here the authors find dysregulation of miRNAs in peripheral blood samples from depressed patients after antidepressant treatment, and show that the miRNAs are regulators of psychiatrically relevant signalling pathways.