MicroRNAs 146a/b-5 and 425-3p and 24-3p are markers of antidepressant response and regulate MAPK/Wnt-system genes
Open accessAbstract
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.
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Duloxetine treatment downregulates miR-3074-5p, miR-146a-5p, miR-24-3p, miR-425-3p, and miR-146b-5p expression in peripheral blood of depression patients.
“Downregulation of miR-3074-5p, miR-146a-5p, miR-24-3p, miR-425-3p, and miR-146b-5p expression in the peripheral blood of depression patients after duloxetine treatment was found.340”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [340]
The Results section (“MicroRNA dysregulation after antidepressant treatment”) reports that all five listed miRNAs were downregulated in blood after treatment. The finding was confined to patients who responded; the paper found no corresponding changes in nonresponders. It also reports the same directional changes among placebo responders, so the sentence overstates the finding as an unqualified effect of duloxetine treatment. (LLM, conf=0.88)
Experimental — accuracy not yet measuredVarious miRNA alterations are present in cerebrospinal fluid, serum, and the ventral prefrontal cortex in patients with major depression disorder.
“various miRNA alterations are present in cerebrospinal fluid, serum, and the ventral prefrontal cortex in patients with major depression disorder (MDD).26”
From Microglia secrete miR-146a-5p-containing exosomes to regulate neurogenesis in depression (2022) · cites this paper as [26]
The identified pathways include TGF-β, glutamatergic synapse, and long-term depression pathways, which are associated with major depressive disorder.
“In silico pathway analysis enabled us to identify 21 pathways associated with the 228 miRNAs and their interacting genes such as TGFBR2, TNF, MAPK, SMAD, including the TGF-β, glutamatergic synapse, and long-term depression pathways, associated with major depressive disorder, as well as the MAPK signaling pathway reported in previous studies [30,59,63,64,65,66,67,68].”
The MAPK signaling pathway has been reported in previous studies.
“In silico pathway analysis enabled us to identify 21 pathways associated with the 228 miRNAs and their interacting genes such as TGFBR2, TNF, MAPK, SMAD, including the TGF-β, glutamatergic synapse, and long-term depression pathways, associated with major depressive disorder, as well as the MAPK signaling pathway reported in previous studies [30,59,63,64,65,66,67,68].”
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- Authors
- Lopez, J. P., Fiori, L. M., Cruceanu, C., Lin, R., Labonte, B., Cates, H. M., Heller, E. A., Vialou, V., Ku, S. M., Gerald, C., Han, M.-H., Foster, J., Frey, B. N., Soares, C. N., Müller, D. J., Farzan, F., Leri, F., MacQueen, G. M., Feilotter, H., Tyryshkin, K., Evans, K. R., Giacobbe, P., Blier, P., Lam, R. W., Milev, R., Parikh, S. V., Rotzinger, S., Strother, S. C., Lewis, C. M., Aitchison, K. J., Wittenberg, G. M., Mechawar, N., Nestler, E. J., Uher, R., Kennedy, S. H., & Turecki, G.
- Affiliations
- Douglas Mental Health University Institute (CA)
- Icahn School of Medicine at Mount Sinai (US)
- University Health Network (CA)
- St. Joseph’s Healthcare Hamilton (CA)
- University of Guelph (CA)
- University of Calgary (CA)
- Queen's University (CA)
- Institute of Mental Health Research (CA)
- Vancouver Coastal Health (CA)
- University of Michigan (US)
- King's College London (GB)
- Dalhousie University (CA)
- Janssen Research & Development (United States) (US)
- Corresponding author
- Turecki, Gustavo
- ORCID
- Fiori, Laura M.
- Cruceanu, Cristiana
- Lin, Rixing
- Cates, Hannah M.
- Heller, Elizabeth A.
- Vialou, Vincent
- Foster, Jane
- Frey, Benicio 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
- Lewis, Cathryn M.
- Aitchison, Katherine J.
- Wittenberg, Gayle M.
- Mechawar, Naguib
- Nestler, Eric J.
- Uher, Rudolf
- Kennedy, Sidney H.
- Turecki, Gustavo
- Venue
- Nature Communications
- Published
- 2017-05-22
- Volume
- 8
- Issue
- 1
- Pages
- 15497-15497
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5477510
- OpenAlex
- W2617341365
- Cited by
- 201
- References
- 51
- Citations by year
- 2026: 9 · 2025: 27 · 2024: 22 · 2023: 19 · 2022: 32 · 2021: 33 · 2020: 21 · 2019: 21 · 2018: 11 · 2017: 6
- FWCI
- 11.27
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Research Portal (King's College London) (submittedVersion, cc-by)
- Funders
- Ontario Brain Institute
- Government of Alberta
- Government of Ontario
- European Commission (LSHB-CT-2003–503428, 503428, LSHB-CT-2003)
- National Institutes of Health
- Canadian Institutes of Health Research (MOP119430, MOP11260, MOP93775, MOP119429, MOP93775, MOP11260, MOP119429, and MOP119430)
- Fonds de Recherche du Québec - Santé
- National Institute of Mental Health (R21MH112081, P50MH096890)
- National Institute on Drug Abuse (R01DA033684)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- microRNA, antidepressant response, major depressive disorder, miR-146a, miR-146b-5p, miR-24-3p, biomarkers, duloxetine, MAPK signaling, Wnt signaling, gene expression regulation, postmortem brain, animal models of depression
- MeSH terms
- Duloxetine Hydrochloride, Adult, Aged, Animals, Antidepressive Agents, Brain, Depressive Disorder, Major, Major Depressive Disorder, Female, Gene Expression Regulation, Humans, Male, Mice, Inbred C57BL, Middle Aged, Biomarkers, Computational Biology, MAP Kinase Signaling System, MicroRNAs, Mice, Young Adult, HEK293 Cells, Wnt Signaling Pathway
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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