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 (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. 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 .
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 . 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) . 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 . Moderate reliability has been attributed to the Structured Clinical Interview for DSM-IV Axis I Disorders as well (SCID-I) .
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 . Evidence reveals that MDD subjects present a smaller hippocampal volume, a modified morphology (number and shape) of dendrites, and the atrophy of neurons .
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.
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.
|Study (Year, Reference No)||Patients||Controls||Blood Compartment||Upregulated miRs||Downregulated miRs||Unchanged miRs||Total|
|Belzeaux et al., 2012 ||16||13||PBMCs||miR-107
|-||9 upregulated, 5 downregulated|
|Li YJ et al., 2013 ||40||40||Serum||miR-132
|Fan et al., 2014 ||81||46||PBMCs||miR-26b
|Li J et al., 2015 ||18||18||Whole blood||miR-644
|4 upregulated, 5 downregulated, 3 unchanged|
|Camkurt et al., 2015 ||50||41||Plasma||miR-451a
|3 upregulated, 1 downregulated, 4 unchanged|
|Wan et al., 2015 ||38||27||Serum||let-7d-3p
|-||11 upregulated, 5 downregulated|
|Wang X et al., 2015 ||169||52||Plasma||-||miR-144-5p||-||1 downregulated|
|Mafioletti et al., 2016 ||20||20||Peripheral venous blood||hsa-miR-199a-5p
|6 upregulated, 4 downregulated, 13 unchanged|
|Sun et al., 2016 ||32||32||Peripheral blood leukocytes||miR-34b-5p
|2 upregulated, 3 unchanged|
|He et al., 2016 ||32||30||PBMCs||miR-124||-||-||1 upregulated|
|Roy et al., 2017 ||18||17||Serum||miR-124-3p||-||-||1 upregulated|
|Kuang et al., 2018 ||84||78||Serum||miR-34a-5p
|miR-451a||-||2 upregulated, 1 downregulated|
|Fang Y et al., 2018 ||45||32||Plasma||miR-124
|Gheysarzadeh et al., 2018 ||39||36||Serum||-||miR-16
|Hung et al., 2019 ||84||43||PBMCs||miR-21-5p
|-||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.
|Study||Patients||AD Treatment and Duration||Blood Compartment||Upregulated miRs||Downregulated miR||Unchanged miRs||Total|
|Enatescu et al., 2016 ||5||Escitalopram 12 weeks||Plasma||miR-1193
|-||23 upregulated, 17 downregulated|
|Li J et al., 2015 ||18||Citalopram, 1 week||Whole blood||miR-335||-||-||1 upregulated|
|Wang X et al., 2015 ||169||Not mentioned, 8 weeks||Plasma||miR-144-5p
|He et al., 2016 ||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 ||84||Paroxetine 8 weeks||Serum||miR-34a-5p
|miR-451a||-||2 upregulated, 1 downregulated|
|Fang Y et al., 2018 ||32||Citalopram 8 weeks||Plasma||miR-124||miR-132||-||1 upregulated, 1 downregulated|
|Hung YY et al., 2019 ||84||Not mentioned, 4 weeks||PBMCs||miR-146a
|Bocchio-Chiavetto et al., 2013 ||10||Escitalopram 10 weeks||Whole blood||miR-130b
|-||26 upregulated, 2 downregulated|
|Zhang et al., 2014 ||20||Venlafaxine, sertraline, mirtazapine 6 weeks||PBMCs||-||miR-1972
|miR-26b||4 upregulated, 1 downregulated|
|Lopez et al., 2017 ||23||Escitalopram 8 weeks||Peripheral blood||miR-1202||-||-||1 upregulated|
|Lin CC et al., 2018 ||33||Not mentioned, 4 weeks||Whole blood||miR-16
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.
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 .
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 .