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MiR in Major Depressive Disorder
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This entry is adapted from the peer-reviewed paper 10.3390/life11101073

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.

major depressive disorder microRNAs biomarkers antidepressant treatment

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.
Table
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.
Table
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].

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