1. Please check and comment entries here.
Table of Contents

    Topic review

    MiR in Major Depressive Disorder

    Subjects: Neurosciences
    View times: 8
    Submitted by:

    Definition

    Major depressive disorder (MDD) is a complex neuropsychiatric disorder with an increasing incidence and a 2–20% prevalence in the worldwide general population, being the leading cause of disability around the world. A significant decrease in life quality, functional impairment, and other psychosocial aspects, as well as comorbidities are associated with MDD, among others.

    1. Introduction

    Major depressive disorder (MDD) is a complex neuropsychiatric disorder with an increasing incidence and a 2–20% prevalence in the worldwide general population [1], being the leading cause of disability around the world [2]. A significant decrease in life quality, functional impairment, and other psychosocial aspects, as well as comorbidities are associated with MDD, among others. What is more, a high degree of disability, morbidity, and mortality by suicide (suicidal ideation) causes MDD to be considered a major public health concern in developed countries [3].

    Although tremendous efforts have been made in order to better understand and characterize this debilitating illness, current knowledge regarding MDD pathophysiology and neurobiology have failed to completely elucidate its molecular particularities to a greater extent. As a consequence, about 40% of patients with MDD do not respond to antidepressant treatment (AD) and eventually become treatment-resistant as the disease burden increases [4]. In addition, although being diagnosed at relatively early ages in a somewhat efficient fashion, the lack of uniform and accurate diagnostic tools (biomarkers) may lead to difficulties in assessing the differences between MDD and other etiologically related diseases, such as bipolar disorder (BD) [5]. Performing the Diagnosis and Statistical Manual of Mental Disorders (DSM-5) and the 11th Revision of the International Classification of Diseases (ICD 11) as the gold standard diagnostic criterion applied to patients was shown to induce interviewer bias, especially if performed by only one health specialist, which might lead to misdiagnosis in many cases [6]. Moderate reliability has been attributed to the Structured Clinical Interview for DSM-IV Axis I Disorders as well (SCID-I) [7][8][9].

    To date, it is known that MDD patients suffer multiple alterations in different regions of the brain, compared to healthy subjects. Studies have shown that qualitatively, synaptic circuits and neural, functional, and structural plasticity are steadily impaired, while connectivity between different brain regions is disrupted. The latter affects communication between subcortical areas involved in modulating negative emotions, the frontal lobe with other brain regions, ultimately affecting cognition, memory, and learning [10][11][12]. Evidence reveals that MDD subjects present a smaller hippocampal volume, a modified morphology (number and shape) of dendrites, and the atrophy of neurons [13][14][15][16][17][18].

    2. Research Articles

    All research articles included in this study were retrieved by interrogating the PubMed, Web of Knowledge, and DirectScience databases (up to 20 of March 2021) with the following combination of key words: (“depression” or “depressive disorder”), and (“microRNA” or “miR”), and (“blood compartments”), and (“diagnosis”), and (“treatment” or “antidepressant treatment” or “antidepressant” or “therapy”), and (“biomarker”). The references from the articles of interest were analyzed to identify other relevant reports.

    Research articles’ inclusion criteria were: (1) case-control studies in human subjects on depression assessing miRs’ expression level, with or without AD, (2) studies evaluating the diagnostic potential of different miRs in MDD, (3) MDD diagnosed based on the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I), (4) a control group consisting of healthy subjects, and (5) published in the English language.

    Research articles’ exclusion criteria were: (1) studies not conducted on human subjects, (2) studies assessing miR expression in body fluids other than blood, (3) nonoriginal papers, such as conference abstracts, letters to editors, and reviews, (4) duplicate studies, and (5) papers not written in the English language.

    Researchers further considered for analysis only research articles that presented data related to the screening and validation of miRs in MDD from blood compartments (whole blood, serum, total plasma (TP) , plasma exosomes, exosome-depleted plasma (EDP), and peripheral blood mononuclear cells (PBMCs)). Extracellular vesicle (EV)-entrapped miRs, such as in exosomes, have also been explored as sources of biomarkers for MDD.

    3. Current Studies

    Table 1 presents for each study the sample size (number of cases/controls), the blood compartment used for the analyses (some authors did not specify this), and miR findings and expression (upregulated, downregulated, or unchanged miRs) in depressive patients compared to healthy controls.

    Table 1. miRs’ expression in different blood compartments of patients with MDD compared to healthy controls.
    Study (Year, Reference No) Patients Controls Blood Compartment Upregulated miRs Downregulated miRs Unchanged miRs Total
    Belzeaux et al., 2012 [19] 16 13 PBMCs miR-107
    miR-133a
    miR-148a
    miR-425-3p
    miR-494
    miR-579
    miR-652
    miR-941
    miR-589
    miR-200c
    miR-381
    miR-571
    miR-636
    miR-1243
    - 9 upregulated, 5 downregulated
    Li YJ et al., 2013 [20] 40 40 Serum miR-132
    miR-182
    - - 2 upregulated
    Fan et al., 2014 [21] 81 46 PBMCs miR-26b
    miR-1972
    miR-4485
    miR-4498
    miR-4743
    - - 5 upregulated
    Li J et al., 2015 [22] 18 18 Whole blood miR-644
    miR-450b
    miR-328
    miR-182
    miR-335
    miR-583
    miR-708a
    miR-650
    miR-654a
    miR-541
    miR-663
    miR-578
    4 upregulated, 5 downregulated, 3 unchanged
    Camkurt et al., 2015 [23] 50 41 Plasma miR-451a
    miR-17-5p
    miR-223-3p
    miR-320a miR-25-3p
    miR-126-3p
    miR-16-5p
    miR-93-5p
    3 upregulated, 1 downregulated, 4 unchanged
    Wan et al., 2015 [24] 38 27 Serum let-7d-3p
    miR-34a-5p
    miR-221-3p
    miR-125a-5p
    miR-30a-5p
    miR-29b-3p
    miR-10a-5p
    miR-375
    miR-155–5p
    miR-33a-5p
    miR-139–5p
    miR-451a
    miR-15b-5p
    miR-106-5p
    miR-590-5p
    miR-185-5p
    - 11 upregulated, 5 downregulated
    Wang X et al., 2015 [25] 169 52 Plasma - miR-144-5p - 1 downregulated
    Mafioletti et al., 2016 [26] 20 20 Peripheral venous blood hsa-miR-199a-5p
    hsa-miR-24-3p
    hsa-miR-425-3p
    hsa-miR-29c-5p
    hsa-miR-330-3p
    hsamiR-345-5p
    hsa-let-7a-5p
    hsa-let-7d-5p
    has-let-7f-5p
    has-miR-1915-3p
    hsa-miR-720
    hsa-miR-140-3p
    hsa-miR-1973
    hsa-miR-30d-5p
    hsa-miR-3158-3p
    hsa-miR-330-5p
    hsa-miR-378a-5p
    hsa-miR-1915-5p
    hsa-miR-1972
    hsa-miR-21-3p
    hsa-miR-4521
    hsa-miR-4793-3p
    hsa-miR-4440
    6 upregulated, 4 downregulated, 13 unchanged
    Sun et al., 2016 [27] 32 32 Peripheral blood leukocytes miR-34b-5p
    miR-34c-5p
    - miR-369–3p
    miR-381
    miR-107
    2 upregulated, 3 unchanged
    He et al., 2016 [28] 32 30 PBMCs miR-124 - - 1 upregulated
    Roy et al., 2017 [29] 18 17 Serum miR-124-3p - - 1 upregulated
    Kuang et al., 2018 [30] 84 78 Serum miR-34a-5p
    miR-221-3p
    miR-451a - 2 upregulated, 1 downregulated
    Fang Y et al., 2018 [31] 45 32 Plasma miR-124
    miR-132
    - - 2 upregulated
    Gheysarzadeh et al., 2018 [32] 39 36 Serum - miR-16
    miR-135a
    miR-1202
    - 3 downregulated
    Hung et al., 2019 [33] 84 43 PBMCs miR-21-5p
    miR-145
    miR-223
    miR-146a
    miR-155
    let-7e
    - 3 upregulated, 3 downregulated

    Table 2 shows the sample characteristics for each study investigating miRs before and after AD in MDD patients, the blood compartment used for the analyses, and miR findings and expression level changes in depressive patients, before and after AD.

    Table 2. miR changes in expression levels before and after antidepressant (AD) treatment.
    Study Patients AD Treatment and Duration Blood Compartment Upregulated miRs Downregulated miR Unchanged miRs Total
    Enatescu et al., 2016 [34] 5 Escitalopram 12 weeks Plasma miR-1193
    miR-3173-3p
    miR-3154
    miR-129-5p
    miR-3661
    miR-1287
    miR-532-3p
    miR-2278
    miR-3150a-3p
    miR-3909
    miR-937
    miR-676
    miR-489
    miR-637
    miR-608
    miR-4263
    miR-382
    miR-3691-5p
    miR-375
    miR-433
    miR-1298
    miR-1909
    miR-1471
    miR-99b
    miR-151-5p
    miR-223
    miR-181b
    miR-26a
    miR-744
    miR-301b
    miR-27a
    miR-24
    miR-146a-
    miR-146b-5p
    miR-126
    miR-151-3p
    let-7d
    miR-221
    miR-125a-5p
    miR-652
    - 23 upregulated, 17 downregulated
    Li J et al., 2015 [22] 18 Citalopram, 1 week Whole blood miR-335 - - 1 upregulated
    Wang X et al., 2015 [25] 169 Not mentioned, 8 weeks Plasma miR-144-5p
    miR-30a-5p
    - - 2 upregulated
    He et al., 2016 [28] 32 Venlafaxine (N = 7), paroxetine (N = 7), fluoxetine (N = 3), escitalopram (N = 11), duloxetine (N = 1), sertraline (N = 3), mirtazapine (N = 2) PBMCs - miR-124 - 1 downregulated
    Kuang et al., 2018 [30] 84 Paroxetine 8 weeks Serum miR-34a-5p
    miR-221a-3p
    miR-451a - 2 upregulated, 1 downregulated
    Fang Y et al., 2018 [31] 32 Citalopram 8 weeks Plasma miR-124 miR-132 - 1 upregulated, 1 downregulated
    Hung YY et al., 2019 [33] 84 Not mentioned, 4 weeks PBMCs miR-146a
    miR-155
    let-7e
    - - 3 upregulated
    Bocchio-Chiavetto et al., 2013 [35] 10 Escitalopram 10 weeks Whole blood miR-130b
    miR-505
    miR-29b-2
    miR-26b
    miR-22
    miR-26a
    miR-64
    miR-494
    let-7d
    let-7g
    let-7e
    let-7f
    miR-629
    miR-106b
    miR-103
    miR-191
    miR-128
    miR-502-3p
    miR-374b
    miR-132
    miR-30d
    miR-500
    miR-589
    miR-183
    miR-574-3p
    miR-140-3p
    miR-335
    miR-361-5p
    miR-34c-5p
    miR-770-5p
    - 26 upregulated, 2 downregulated
    Zhang et al., 2014 [36] 20 Venlafaxine, sertraline, mirtazapine 6 weeks PBMCs - miR-1972
    miR-4485
    miR-4498
    miR-4743
    miR-26b 4 upregulated, 1 downregulated
    Lopez et al., 2017 [37] 23 Escitalopram 8 weeks Peripheral blood miR-1202 - - 1 upregulated
    Lin CC et al., 2018 [38] 33 Not mentioned, 4 weeks Whole blood miR-16
    miR-183
    miR-212
    - - 3 upregulated

    Interestingly, the majority of miRs studies changed their expression pattern after AD treatment, but some maintained their expression level. This is the case of miR-494, -589, -26b, -34a-5p, -124, and -132, which remained upregulated even after treatment, while miR-451a remained downregulated after treatment.

    4. Discussion

    Mounting evidence suggests that a tremendous number of miR species possess a dysregulated expression pattern in MDD patients relative to healthy controls. miR-132 was among the top-ranked upregulated miRs within the studies, with evidence demonstrating its direct involvement in the pathophysiology of MDD. Animal studies have shown that the increase in miR-132 expression negatively correlated with brain-derived neurotrophic factor (BDNF) expression and that inhibiting miR-132 leads to an increase in BDNF expression and to the reduction of depression symptoms. Moreover, a high miR-132 expression level leads to short-term memory and learning impairment [20].

    In addition, some miRs kept their expression levels constant even after administration of AD treatment (let-7e, miR-183, and miR-335); however, contradictory studies exist, and their exact role in MDD etiopathogenesis is yet to be understood [39][40].

    This entry is adapted from 10.3390/life11101073

    References

    1. Weissman, M.M.; Bland, R.C.; Canino, G.J.; Faravelli, C.; Greenwald, S.; Hwu, H.G.; Joyce, P.R.; Karam, E.G.; Lee, C.K.; Lellouch, J.; et al. Cross-national epidemiology of major depression and bipolar disorder. JAMA 1996, 276, 293–299.
    2. Friedrich, M.J. Depression Is the Leading Cause of Disability Around the World. JAMA 2017, 317, 1517.
    3. Kessler, R.C.; Berglund, P.; Demler, O.; Jin, R.; Merikangas, K.R. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the national comorbidity survey replication. Arch. Gen. Psychiatry 2005, 62, 593–602.
    4. Fava, M. Definition and epidemiology of treatment-resistant depression. Psychiatr. Clin. N. Am. 1996, 19, 179–200.
    5. Hashimoto, K. Metabolomics of Major Depressive Disorder and Bipolar Disorder: Overview and Future Perspective. Adv. Clin. Chem. 2018, 84, 81–99.
    6. Singh, T. Misdiagnosis of bipolar disorder. Psychiatry (Edgmont) 2006, 3, 57–63.
    7. Zajecka, J.M. Treating depression to remission. J. Clin. Psychiatry 2003, 64, 7–12.
    8. Schmidt, H.D.; Shelton, R.C. Functional biomarkers of depression: Diagnosis, treatment, and pathophysiology. Neuropsychopharmacology 2011, 36, 2375–2394.
    9. Takahashi, S.; Kitamura, T.; Okano, T.; Tomita, T.; Kikuchi, A. Structured Clinical Interview for DSM-IV Axis I Disorders Version 2.0; Nippon Hyouron Sha: Tokyo, Japan, 2003.
    10. Andreasen, N.C. Linking mind and brain in the study of mental illnesses: A project for a scientific psychopathology. Science 1997, 275, 1586–1593.
    11. Honer, W.G. Assessing the machinery of mind: Synapses in neuropsychiatric disorders. J. Psychiatry Neurosci. 1999, 24, 116–121.
    12. Anand, A.; Li, Y.; Wang, Y.; Wu, J.W.; Gao, S.J.; Bukhari, L.; Mathews, V.P.; Kalnin, A.; Lowe, M.J. Activity and connectivity of brain mood regulating circuit in depression: A functional magnetic resonance study. Biol. Psychiatry 2005, 57, 1079–1088.
    13. Toni, N.; Buchs, P.A.; Nikonenko, I.; Bron, C.R.; Muller, D. LTP promotes formation of multiple spine synapses between a single axon terminal and a dendrite. Nature 1999, 402, 421–425.
    14. Hajsza, T.; MacLusky, N.J.; Leranth, C. Short-term treatment with the antidepressant fluoxetine triggers pyramidal dendritic spine synapse formation in rat hippocampus. Eur. J. Neurosci. 2005, 21, 1299–1303.
    15. McEwen, B.S. Effects of adverse experiences for brain structure and function. Biol. Psychiatry 2000, 48, 721–731.
    16. Sheline, Y.I. 3D MRI studies of neuroanatomic changes in unipolar major depression: The role of stress and medical comorbidity. Biol. Psychiatry 2000, 48, 791–800.
    17. Sala, M.; Perez, J.; Soloff, P.; Ucelli di Nemi, S.; Caverzasi, E.; Soaresd, J.C.; Brambillab, P. Stress and hippocampal abnormalities in psychiatric disorders. Eur. Neuropsychopharmacol. 2004, 14, 393–405.
    18. Rajkowska, G.; Miguel-Hidalgo, J.J. Gliogenesis and glial pathology in depression. CNS Neurol. Disord.-Drug Targets 2007, 6, 219–233.
    19. Belzeaux, R.; Bergon, A.; Jeanjean, V.; Loriod, B.; Formisano-Tréziny, C.; Verrier, L.; Loundou, A.; Baumstarck-Barrau, K.; Boyer, L.; Gall, V.; et al. Responder and nonresponder patients exhibit different peripheral transcriptional signatures during major depressive episode. Transl. Psychiatry 2012, 2, e185.
    20. Li, Y.J.; Xu, M.; Gao, Z.H.; Wang, Y.Q.; Yue, Z.; Zhang, Y.X.; Li, X.X.; Zhang, C.; Xie, S.Y.; Wang, P.Y. Alterations of serum levels of BDNF-related miRNAs in patients with depression. PLoS ONE 2013, 8, e63648.
    21. Fan, H.M.; Sun, X.Y.; Guo, W.; Zhong, A.F.; Niu, W.; Zhao, L.; Dai, Y.H.; Guo, Z.M.; Zhang, L.Y.; Lu, J. Differential expression of microRNA in peripheral blood mononuclear cells as specific biomarker for major depressive disorder patients. J. Psychiatr. Res. 2014, 59, 45–52.
    22. Li, J.; Meng, H.; Cao, W.; Qiu, T. MiR-335 is involved in major depression disorder and antidepressant treatment through targeting GRM4. Neurosci. Lett. 2015, 606, 167–172.
    23. Camkurt, M.A.; Acar, S.; Coskun, S.; Güneş, M.; Güneş, S.; Yılmaz, M.F.; Görür, A.; Tamer, L. Comparison of plasma MicroRNA levels in drug naive, first episode depressed patients and healthy controls. J. Psychiatr. Res. 2015, 69, 67–71.
    24. Wan, Y.; Liu, Y.; Wang, X.; Wu, J.L.; Liu, K.Z.; Zhou, J.; Liu, L.; Zhang, C.H. Identification of differential microRNAs in cerebrospinal fluid and serum of patients with major depressive disorder. PLoS ONE 2015, 10, e0121975.
    25. Wang, X.; Sundquist, K.; Hedelius, A.; Palmér, K.; Memon, A.A.; Sundquist, J. Circulating microRNA-144-5p is associated with depressive disorders. Clinical. Epigenet. 2015, 7, 69.
    26. Maffioletti, E.; Cattaneo, A.; Rosso, G.; Maina, G.; Maj, C.; Gennarellia, M.; Tardito, D.; Bocchio-Chiavetto, L. Peripheral whole blood microRNA alterations in major depression and bipolar disorder. J. Affect. Disord. 2016, 200, 250–258.
    27. Sun, N.; Lei, L.; Wang, Y.; Yang, C.X.; Liu, Z.F.; Li, X.R.; Zhang, K. Preliminary comparison of plasma notch-associated microRNA-34b and -34c levels in drug naive, first episode depressed patients and healthy controls. J. Affect. Disord. 2016, 194, 109–114.
    28. He, S.; Liu, X.; Jiang, K.; Peng, D.H.; Hong, W.; Fang, Y.R.; Qian, Y.P.; Yu, S.Y.; Li, H.F. Alterations of microRNA-124 expression in peripheral blood mononuclear cells in pre- and post-treatment patients with major depressive disorder. J. Psychiatr. Res. 2016, 78, 65–71.
    29. Roy, B.; Dunbar, M.; Shelton, R.; Dwivedi, Y. Identification of MicroRNA-124-3p as a Putative Epigenetic Signature of Major Depressive Disorder. Neuropsychopharmacol 2017, 42, 864–875.
    30. Kuang, W.H.; Dong, Z.Q.; Tian, L.T.; Li, J. MicroRNA-451a, microRNA-34a-5p, and microRNA-221-3p as predictors of response to antidepressant treatment. Braz. J. Med. Biol. Res. 2018, 51, e7212.
    31. Fang, Y.; Qiu, Q.; Zhang, S.; Sun, L.; Li, G.J.; Xiao, S.F.; Lia, X. Changes in miRNA-132 and miR-124 levels in non-treated and citalopram-treated patients with depression. J. Affect. Disord. 2018, 227, 745–751.
    32. Gheysarzadeh, A.; Sadeghifard, N.; Afraidooni, L.; Pooyan, F.; Mofid, M.R.; Valadbeigi, H.; Bakhtiari, H.; Keikhavani, S. Serum-based microRNA biomarkers for major depression: MiR-16, miR-135a, and miR-1202. J. Res. Med. Sci. 2018, 23, 69.
    33. Hung, Y.Y.; Wu, M.K.; Tsai, M.C.; Huang, Y.L.; Kang, H.Y. Aberrant Expression of Intracellular let-7e, miR-146a, and miR-155 Correlates with Severity of Depression in Patients with Major Depressive Disorder and Is Ameliorated after Antidepressant Treatment. Cells 2019, 8, 647.
    34. Enatescu, V.R.; Papava, I.; Enatescu, I.; Antonescu, M.; Anghel, A.; Seclaman, E.; Sirbu, I.O.; Marian, C. Circulating Plasma Miro RNAs in Patients with Major Deppresive Disorder Treated with Antidepressants: A Pilot Study. Psychiatry Investig. 2016, 13, 549–557.
    35. Bocchio-Chiavetto, L.; Maffioletti, E.; Bettinsoli, P.; Giovannini, C.; Bignotti, S.; Tardito, D.; Corrada, D.; Milanesi, L.; Gennarellie, M. Blood microRNA changes in depressed patients during antidepressant treatment. Eur. Neuropsychopharmacol. 2013, 23, 602–611.
    36. Zhang, Q.L.; Lu, J.; Sun, X.Y.; Guo, W.; Zhao, L.; Fan, H.M.; Zhong, A.F.; Niu, W.; Dai, Y.H.; Zhang, L.Y.; et al. A preliminary analysis of association between plasma microRNA expression alteration and symptomatology improvement in Major Depressive Disorder (MDD) patients before and after antidepressant treatment. Eur. J. Psychiatry 2014, 28, 252–264.
    37. Lopez, J.P.; Fiori, L.M.; Cruceanu, C.; Lin, R.; Labonte, B.; Cates, H.M.; Heller, A.E.; Vialou, V.; Ku, S.M.; Gerald, C.; et al. MicroRNAs 146a/b-5 and 425-3p and 24-3p are markers of antidepressant response and regulate MAPK/Wnt-system genes. Nat. Commun. 2017, 8, 15497.
    38. Lin, C.C.; Tsai, M.C.; Lee, C.T.; Sun, M.H.; Huang, T.L. Antidepressant treatment increased serum miR-183 and miR-212 levels in patients with major depressive disorder. Psychiatry Res. 2018, 270, 232–237.
    39. Scott, H.L.; Tamagnini, F.; Narduzzo, K.E.; Howarth, J.L.; Lee, Y.B.; Wong, L.F.; Brown, M.W.; Warburton, E.C.; Bashir, Z.I.; Uney, J.B. MicroRNA-132 regulates recognition memory and synaptic plasticity in the perirhinal cortex. Eur. J. Neurosci. 2012, 36, 2941–2948.
    40. Griffiths, S.; Scott, H.; Glover, C.; Bienemann, A.; Ghorbel, M.T.; Uney, J.; Brown, M.W.; Warburton, E.C.; Bashir, Z.I. Expression of long-term depression underlies visual recognition memory. Neuron 2008, 58, 186–194.
    More