A circulating miRNA profile is associated with response to cognitive remediation in major depressive disorder

A circulating miRNA profile is associated with response to cognitive remediation in major depressive disorder | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article A circulating miRNA profile is associated with response to cognitive remediation in major depressive disorder Analia Bortolozzi, Lluis Miquel-Rio, Muriel Vicent-Gil, Judith Jercicó-Escolar, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8113450/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Cognitive symptoms are a core and debilitating feature of major depressive disorder (MDD), often persisting and poorly addressed by current treatments, underscoring the need for objective biomarkers to guide therapeutic interventions. This study investigated whether circulating microRNAs (miRNAs) are associated with cognitive response to two distinct psychological interventions: integral cognitive remediation (INCREM) and psychoeducation (PSYCHOED). A panel of 38 miRNAs was analyzed in plasma from MDD patients before and after interventions. Our results reveal two distinct, non-overlapping miRNA patterns associated with therapeutic response. Specifically, a seven-miRNA profile ‒let-7b-3p, miR-100-5p, miR-129-5p, miR-135a-5p, miR-151a-5p, miR-4516, and miR-451a‒ was associated with response to INCREM. Bioinformatic analysis of their predicted target genes showed significant enrichment in molecular pathways crucial for neuroplasticity, synaptic function, and cognition, which correlated with objective improvements in cognitive performance. Conversely, a distinct two-miRNA profile involving miR-126-5p and miR-195-5p was associated with response to PSYCHOED. The targets of these miRNAs converge on pathways related to systemic cellular processes such as cell structure and intercellular communication, including Wnt signaling, cellular senescence, and the cell cycle. These findings provide novel mechanistic insights, suggesting that INCREM directly modulates gene networks related to neuroplasticity, whereas PSYCHOED affects more general cellular pathways. These circulating miRNA profiles are promising, minimally invasive biomarkers that could be used to personalize treatment strategies for cognitive dysfunction in MDD. Health sciences/Biomarkers/Predictive markers Health sciences/Diseases/Psychiatric disorders/Depression Major Depressive Disorder Cognitive Dysfunction Cognitive Remediation microRNA Biomarker Neuroplasticity Figures Figure 1 Figure 2 Figure 3 Figure 4 INTRODUCTION Major depressive disorder (MDD) is a prevalent and recurrent mental illness, affecting one in five adults during their lifetime and representing a leading contributor to disability worldwide [ 1 ]. A defining aspect of this disorder involves a wide array of cognitive symptoms, including difficulties in attention, memory, processing speed, and executive function [ 2 – 4 ]. These cognitive deficits are not merely a secondary consequence of the depressive mood, but are a core component of the illness [ 5 ]. Indeed, they play a key role in the psychosocial impairment experienced by people with depression, hindering their performance at work and in education, and disrupting their social interactions [ 3 , 6 ]. Consequently, the cognitive symptoms lead to a lower quality of life and an increased risk of recurrent depressive episodes [ 7 , 8 ]. Although the precise biological origins of MDD remain elusive, the hypothesis of impaired neuroplasticity has emerged as a compelling explanatory framework [ 9 – 12 ]. Neuroplasticity refers to the capacity of neural circuits to reorganize themselves structurally and functionally in response to new stimuli [ 13 ]. The neuroplasticity process involves changes in synaptic strength, such as neurotransmitter release, ion channel density, as well as structural modifications, including the remodeling of axons, dendritic spines, and myelination, among others [ 14 , 15 ]. When this process becomes maladaptive, especially following adverse experiences, it can elevate the risk for developing psychiatric disorders [ 16 ]. Evidence from neuropathological and neuroimaging studies in patients with MDD point to compromised brain plasticity, including reduced synaptogenesis, dendritic atrophy, glial cell dysfunction, deficiencies in neurotrophic factors, as well as dysregulation of functional connectivity [ 10 , 17 – 20 ], which may be a result from altered molecular pathways and underlying gene regulatory networks. Current first-line treatments, both psychotherapy and pharmacotherapy, are believed to work by targeting and reversing neuroplasticity deficits in MDD-vulnerable brain regions to achieve clinical benefits. For instance, antidepressants such as fluoxetine and sertraline (selective serotonin reuptake inhibitors - SSRI) have been shown to increase the volume of dorsolateral prefrontal cortex (dlPFC) in patients with MDD [ 21 , 22 ]. Recent studies have also reported that the normalization of amygdala hyperactivity and the decrease in its functional connectivity with the dlPFC underlie successful response to SSRI and ketamine treatments [ 23 ]. Similarly, cognitive behavioral therapy (CBT) has been shown to induce changes in connectivity between the dlPFC and the anterior cingulate cortex, which correlates with improvements in depressive symptoms [ 24 , 25 ]. Furthermore, therapeutic approaches such as electroconvulsive therapy (ECT) involve neurotrophic processes that normalize brain networks in MDD [ 26 ]. MicroRNAs (miRNAs), which are a type of small non-coding RNAs, have recently received much attention due to their unique ability to control complex gene regulatory networks [ 27 , 28 ]. MiRNAs regulate gene expression by interacting with messenger RNA (mRNA) transcripts, thereby leading to their degradation or the inhibition of their translation. The gene regulatory network involving miRNAs is extensive, as each miRNA can target hundreds of mRNA transcripts, while conversely, multiple miRNAs can converge to regulate a single mRNA transcript [ 29 , 30 ]. This broad regulatory capacity makes them attractive targets for various brain disorders. Indeed, there is compelling evidence linking changes in the regulation of miRNAs and their mRNA targets to the development of MDD and antidepressant efficacy [ 31 – 36 ]. Furthermore, miRNAs possess a remarkable ability to be transported to different subcellular compartments, cross the blood-brain barrier, and contribute to inter-tissue communication [ 37 – 39 ]. This capacity positions circulating miRNAs as valuable biomarkers for brain disorders, as their expression profile in liquid biopsies may mirror changes occurring in the brain. In support of this, increasing evidence shows miRNA dysregulation in both the blood and brain tissue of patients with neuropsychiatric diseases [ 40 – 43 ], including MDD. The treatment of cognitive symptoms in MDD remains a developing area of research. Although pharmacological and non-pharmacological strategies have shown limited success, growing evidence supports the efficacy of functional remediation. Programs such as integral cognitive remediation (INCREM) for depression [ 44 ] have been shown to improve both cognitive functioning and daily performance in affected individuals. However, the molecular mechanisms driving these beneficial effects remain poorly understood. This study aims to investigate whether circulating miRNAs are associated with cognitive responses to INCREM and psychoeducation (PSYCHOED) in patients with MDD. We analyzed a panel of 38 miRNAs, selected based on their prior dysregulation in the dlPFC of patients with MDD [ 45 , 46 ], to test their efficacy as blood-based predictive biomarkers. Our findings provide mechanistic insights by revealing that INCREM and PSYCHOED are associated with distinct molecular pathways. METHODS Participants The Research Ethics Board of the Hospital de la Santa Creu i Sant Pau approved the present study. All participants provided written informed consent after receiving a detailed explanation of the procedures. The research followed the ethical standards outlined in the Declaration of Helsinki and the principles of Good Clinical Practice, in full compliance with current data protection regulations. A comprehensive description of the study protocol was previously published [ 47 ], and the project is registered at ClinicalTrials.gov (NCT07014683). The present analysis is part of a broader project designed to evaluate the functional and cognitive outcomes of the INCREM program. Patients diagnosed with MDD according to DSM-5 criteria were included in the study. Inclusion criteria were: (i) age between 18 and 60 years, (ii) partial response (HDRS-17 ≤ 18) [ 48 , 49 ], (iii) the presence of objective (SCIP ≤ 80) [ 50 ] and/or subjective (PDQ > 20) [ 51 ] cognitive symptoms, and (iv) psychosocial dysfunction (FAST ≥ 12) [ 52 ]. Exclusion criteria have been reported in detail elsewhere [ 47 ]. Treatment The current randomized clinical trial evaluated two intervention conditions: the INCREM program, focused on cognitive remediation, and an active control condition based on psychoeducation (PSYCHOED). Full details of both approaches are described in Vicent-Gil et al., [ 47 ]. At baseline (T 0 ), participants completed an evaluation including sociodemographic and clinical data, neuropsychological testing, a measure of psychosocial functioning, and a blood sample collection. Following this assessment, participants were randomly assigned to one of the treatment arms. Both programs were delivered concurrently through structured online group sessions held weekly for 12 weeks. Immediately post-intervention (T 1 ), outcome measures were administered and a second blood sample was obtained. Participants were reassessed six months later (T 2 ) using the same outcome measures to evaluate the maintenance of treatment effects. Outcome measures Sociodemographic and clinical variables, including age, sex, years of schooling, estimated IQ (Vocabulary subtest of the Wechsler Adult Intelligence Scale version-IV, WAIS-IV [ 53 ], age at illness onset, number of depressive episodes, depressive symptomatology (HDRS-17) [ 48 , 49 ]; months of clinical stability and antidepressant medication trials (Antidepressant Treatment History Form, ATHF) [ 54 ] were obtained through a semi-structured interview. Psychosocial functioning was measured using the Functioning Assessment Short Test (FAST) [ 52 ], which assesses six domains: autonomy, occupational performance, cognitive functioning, interpersonal relationships, financial management, and leisure activities. FAST scores range from 0 to 72, with scores of 12 or higher indicating a moderate level of functional impairment. Objective cognitive performance was assessed using the Screening for Cognitive Impairment in Psychiatry (SCIP), which includes five subtests targeting immediate and verbal learning and memory, working memory, verbal fluency, and processing speed. Scores below 80 are indicative of objective cognitive deficits [ 50 ]. Subjective cognitive functioning was evaluated with the Perceived Deficit Questionnaire (PDQ-20), a 20-item self-report measure examining self-perceived cognitive difficulties in attention and concentration, retrospective and prospective memory, planning and organization, and executive functioning. Items are rated on a 5-point Likert scale (0 = never, 4 = almost always), with higher scores reflecting greater perceived cognitive impairment [ 51 ]. These instruments were applied not only to establish baseline characteristics but also to monitor changes in cognitive and psychosocial functioning over the course of the study. Plasma collection Blood samples were collected by venipuncture into 10 ml K 2 EDTA BD Vacutainer tubes (Becton, Franklin Lakes, NJ). Tubes were stored at room temperature and centrifugation within 1 h of collection. Blood was centrifuged at room temperature (22–25°C) for 10 min at 450×g (Beckman Coulter, Inc., Pasadena, CA). The plasma layer was transferred to a fresh 15 ml Falcon tube. Plasma was centrifuged for 15 min at 2500×g (Eppendorf 5702, Hamburg, Germany) and the supernatant transferred to 1.5 ml Eppendorf tubes in 500 µl aliquots. Aliquots were kept at − 80°C until RNA isolation. RNA isolation, miRNA analysis, and functional pathway analysis based on predictions and gene ontology All experimental procedures and data are included in the Supplementary information ( Suppl. Figure 1A-1C, Suppl. Table 1, and Suppl. Excel File 1 ). Materials and protocols are available upon request from the corresponding author (A.B.). Statistical analyses All values are presented as the mean ± standard error of the mean (SEM), with individual data points shown. Data distribution was assessed for normality using the Shapiro-Wilk test. Outlier values within datasets were identified and excluded using the ROUT test (Q = 1%). Descriptive statistics of sociodemographic and clinical characteristics were calculated for the total sample. Statistical analyses were performed using the Statistical Package for Social Sciences (SPSS, IBM Corp., Chicago, IL, version 30). Between-group comparisons (INCREM vs . PSYCHOED) were conducted using either parametric or non-parametric tests depending on data distribution. Independent samples t-tests were applied for normally distributed variables, and Mann–Whitney U tests were used when the assumption of normality was not met. Given the small sample size, non-parametric tests were used to examine temporal changes within each intervention group. Specifically, the Friedman test was employed to assess changes over time in each outcome variable within both groups. A significance level of p < 0.05 was set for all analyses. MiRNA analyses were performed using GraphPad Prism 10.4.1 software. Comparisons between two groups were conducted using paired or independent Student’s t-tests (or equivalent non-parametric tests). Analyses involving multiple factors, such as pre- and post-treatment comparisons between intervention groups, were conducted using two-way ANOVA with repeated measures, followed by appropriate post-hoc tests for multiple comparisons. All tests were two-tailed, and differences were considered statistically significant if p < 0.05. A detailed summary of all statistical tests, data, and results is provided in the Suppl Excel File 2 . RESULTS Descriptive analysis Table 1 A shows the baseline sociodemographic and clinical characteristics of the whole sample and compares the two psychotherapeutic intervention groups. A total of 22 patients diagnosed with MDD in partial remission participated in the study. Of these, 15 received the INCREM intervention and the remaining participants received PSYCHOED. No statistically significant differences were found between the groups for any of the assessed sociodemographic or clinical variables. Psychological interventions significantly modulate plasma miRNA levels As circulating miRNA levels have been shown to correlate with disease states, the levels of 36 miRNAs were quantified in the plasma of patients with MDD before (pre- treatment) and after (post-treatment) psychological intervention (Fig. 1 A). These miRNAs were chosen based on a previous analysis, in which they were identified as being differentially expressed in post-mortem dlPFC samples from MDD patients (men and women) through miRNA-sequencing and validation by qPCR [ 45 ]. The different miRNAs analyzed are shown in Table 2 and Supplementary Figs. 1 and 2 . Psychological interventions (INCREM and PSYCHOED) significantly increased the levels of miR-126-5p (p < 0.05), miR-129-5p (p < 0.01), miR-1299 (p < 0.05), miR-135a-5p (p < 0.01), miR-151a-5p (p < 0.05), miR-4516 (p < 0.05), and miR-451a (p < 0.001), and decreased the levels of miR-34c-5p (p < 0.05) and miR-625-5p (p < 0.05) when comparing pre-treatment to post-treatment (Fig. 1 B). Table 1 Participant characteristics and functional-cognitive outcomes A. Baseline sociodemographic and clinical characteristics: whole sample and intervention groups WHOLE SAMPLE (n = 22) INCREM (n = 15) PSYCHOED (n = 7) F p-value Age, years 50.36 (± 1.94) 50.8 (± 1.84) 49.43 (± 4.90) 3.4 0.750 Years of schooling, n # 16.14 (± 0.62) 15.87 (± 0.74) 16.71 (± 1.19) 43.0 0.535 Estimated IQ, T-score 61.50 (± 1.84) 63.07 (± 2.15) 58.14 (± 3.38) 0.12 0.221 Age at illness onset, years 34.95 (± 2.75) 35.53 (± 3.53) 33.71 (± 4.50) 0.13 0.766 Depressive episodes, n # 4.91 (± 1.60) 5.40 (± 2.31) 3.86 (± 1.12) 39.5 0.368 Clinical stability, months # 100.64 (± 34.89) 112.33 (± 44.67) 75.57 (± 57.10) 40.0 0.407 ATHF, total score # 2.64 (± 0.21) 2.6 (± 0.3) 2.71 (± 0.19) 50.5 0.891 HDRS-17, total score 11.05 (± 1.09) 10.8 (± 1.31) 11.57 (± 2.10) 0.04 0.750 B. Functional and cognitive outcomes at baseline, post-intervention and at follow-up assessment INCREM Baseline Post Follow F p-value FAST, total score 28.86 (± 2.40) 21.21 (± 2.74) 14.0 (± 3.19) 12.69 0.002** SCIP, total score 73.00 (± 3.44) 82.79 (± 2.41) 82.86 (± 3.20) 13.0 0.002** PDQ, total score 41.93 (± 2.92) 33.93 (± 2.97) 32.43 (± 3.66) 8.71 0.013* PSYCHOED Baseline Post Follow F p-value FAST, total score 33.67 (± 5.70) 26.17 (± 6.62) 17.67 (± 6.21) 10.33 0.006** SCIP, total score 68.33 (± 3.46) 76.83 (± 3.78) 74.83 (± 5.46) 4.26 0.119 PDQ, total score 48.33 (± 3.67) 42.33 (± 5.18) 39.83 (± 7.22) 5.33 0.069 IQ: Intelligence Quotient, ATHF: Antidepressant Treatment History Questionnaire, HDRS-17: 17-item Hamilton Depression Rating Scale, FAST: Functioning Assessment Short Test, SCIP: Screening for Cognitive Impairment in Psychiatry, PDQ: Perceived Deficit Questionnaire. # Comparison by Mann-Whitney U test. Data are presented as mean ± SEM. *p < 0.05, **p < 0.01 for within-group changes over time. Table 2 Panel of analyzed miRNAs used in the study miRNA miRbase (ACC. No) Locus Fold change p-value hsa-let-7b-3p MIMAT0004482 chr22: 46113686–46113768 0.7921 0.0982 hsa-let-7b-5p MIMAT0000063 chr22: 46113686–46113768 1.036 0.7943 hsa-miR-100-5p MIMAT0000098 chr11: 122152229–122152308 0.7886 0.0869 hsa-miR-126-5p MIMAT0000444 chr9: 136670602–136670686 1.453 0.0156* hsa-miR-129-5p MIMAT0000242 chr7: 128207872–128207943 1.571 0.0040** hsa-miR-1299 MIMAT0005887 chr9: 40929010–40929092 1.540 0.0359* hsa-miR-135a-5p MIMAT0000428 chr9: 40929010–40929092 1.701 0.0017** hsa-miR-144-3p MIMAT0000436 chr17: 28861533–28861618 1.064 0.4589 hsa-miR-151a-3p MIMAT0000757 chr8: 140732564–140732653 1.177 0.2581 hsa-miR-151a-5p MIMAT0004697 chr8: 140732564–140732653 1.418 0.0141* hsa-miR-151b MIMAT0010214 chr14: 100109419–100109514 N/A N/A hsa-miR-181a-3p MIMAT0000270 chr1: 198859044–198859153 1.095 0.7593 hsa-miR-187-3p MIMAT0000262 chr18: 35904818–35904926 0.8559 0.2187 hsa-miR-195-5p MIMAT0000461 chr17: 7017615–7017701 1.297 0.0587 hsa-miR-199a-3p MIMAT0000232 chr19: 10817426–10817496 0.8081 0.3169 hsa-miR-199a-5p MIMAT0000231 chr19: 10817426–10817496 1.206 0.1375 hsa-miR-21-5p MIMAT0000076 chr17: 59841266–59841337 0.8537 0.0760 hsa-miR-219a-2-3p MIMAT0004675 chr9: 128392618–128392714 0.9437 0.7404 hsa-miR-219a-5p MIMAT0000276 chr6: 33207835–33207944 0.9307 0.6556 hsa-miR-23b-3p MIMAT0000276 chr9: 95085208–95085304 1.119 0.6327 hsa-miR-27b-3p MIMAT0000419 chr9: 95085445–95085541 1.371 0.0566 hsa-miR-27b-5p MIMAT0004588 chr9: 95085445–95085541 N/A N/A hsa-miR-320c MIMAT0005793 chr18: 21683518–21683589 0.9815 0.1765 hsa-miR-335-5p MIMAT0000765 chr7: 130496111–130496204 1.241 0.2290 hsa-miR-338-5p MIMAT0004701 chr17: 81125883–81125949 0.8831 0.4628 hsa-miR-33a-3p MIMAT0004506 chr22: 41900944–41901012 1.200 0.1375 hsa-miR-34c-5p MIMAT0000686 chr11: 111513439–111513515 0.7313 0.0435* hsa-miR-378a-3p MIMAT0000732 chr5: 149732825–149732890 0.7931 0.1762 hsa-miR-423a-5p MIMAT0004748 chr17: 30117079–30117172 1.186 0.1649 hsa-miR-4516 MIMAT0019053 chr16: 2133119–2133204 1.444 0.0391* hsa-miR-451a MIMAT0001631 chr17: 28861369–28861440 1.420 0.0005*** hsa-miR-483-5p MIMAT0004761 chr11: 2134134–2134209 1.208 0.3369 hsa-miR-499a-5p MIMAT0002870 chr20: 34990376–34990497 0.8296 0.3209 hsa-miR-5584-5p MIMAT0022283 chr1: 44545493–44545552 0.7567 0.2615 hsa-miR-574-5p MIMAT0004795 chr4: 38868032–38868127 0.7863 0.2285 hsa-miR-625-5p MIMAT0003294 chr14: 65471102–65471186 0.7227 0.0187* hsa-miR-642a-5p MIMAT0003312 chr19: 45674928–45675024 1.270 0.1317 hsa-miR-6734-5p MIMAT0027369 chr1: 43364648–43364715 0.9644 0.9493 Significantly changed miRNAs in the plasma of patients with MDD after psychotherapy intervention. For normalization, expression stability of the 38-miRNA panel was assessed using the NormFinder algorithm, which identified hsa-miR-151b and hsa-miR-27b-5p as the most stable reference pair. N/A Not applicable. *p < 0.05, **p < 0.01, ***p < 0.0001 pre-treatment vs. post-treatment. Subsequently, a cluster analysis was performed based on the expression of miRNAs modulated by both psychological interventions, revealing that INCREM treatment clustered together and was distinct from the PSYCHOED treatment (Fig. 1 C). An additional analysis identified a profile of miRNAs in plasma that was differentially expressed between the two psychological interventions. In particular, significant increases were observed in the levels of miR-129-5p (p < 0.05), miR-135a-5p (p < 0.01), miR-151a-5p (p < 0.05), miR-4516 (p < 0.05), and miR-451a (p < 0.001) along with decreases in the levels of let-7b-3p (p < 0.05) and miR-100-5p (p < 0.05) in plasma from patients with MDD when comparing pre-INCREM and post-INCREM treatment ( Supplementary Fig. 3 ). However, plasma levels of miR-126-5p (p < 0.05) and miR-195-5p (p < 0.01) were increased only after PSYCHOED treatment in MDD patients ( Supplementary Fig. 4 ). INCREM and PSYCHOED interventions trigger differences in the miRNA-based functional targetome Next, a two-way ANOVA analysis was performed to confirm the differential effects on plasma miRNA levels of both psychotherapies. Šídák's multiple comparisons test revealed a significant effect of treatment for seven miRNAs: let-7b-3p (p < 0.05), miR-100-5p (p < 0.05), miR-129-5p (p < 0.01), miR-135a-5p (p < 0.01), miR-151a-5p (p < 0.05), miR-4516 (p < 0.05), and miR-451a (p < 0.01), specifically in the INCREM group (Fig. 2 A). Importantly, these miRNAs are not significantly altered by PSYCHOED. To elucidate the biological function of the INCREM-specific miRNA profile, a functional enrichment analysis on its consensus-predicted target genes was performed (Fig. 2 B-D). The KEGG pathway analysis revealed that the target genes were significantly enriched in pathways integral to neuroplasticity, cellular signaling, and nervous system function (Fig. 2 B, 2 D). Among the most significant were pathways related to synaptic function, including neurotrophin signaling (FDR = 1.59x10⁻⁵), axon guidance (FDR = 5.85x10⁻ 4 ), long-term potentiation (FDR = 0.024), and dopaminergic synapse (FDR = 4.40x10 − 3 ). Furthermore, a strong enrichment was observed in critical intracellular signaling cascades that regulate neuronal survival and plasticity, such as TGFβ signaling (FDR = 2.50x10⁻⁷), FoxO signaling (FDR = 1.37x10⁻⁷), PI3K-Akt signaling (FDR = 2.86x10⁻⁴), mTOR signaling (FDR = 5.42x10⁻⁵), MAPK signaling (FDR = 2.29x10⁻⁵), and NFκB signaling (FDR = 4.40x10 − 3 ). Complementing these findings, GO analysis of biological processes confirmed a significant over-representation of terms associated with synaptic function. The most relevant enriched terms included regulation of synapse structure or activity (FDR = 4.88x10⁻ 4 ), neuron projection development (FDR = 8.76x10⁻⁴), and cognition (FDR = 2.59x10⁻⁴). Supporting a direct role in synaptic communication, the analysis revealed a significant enrichment in both excitatory and inhibitory signaling processes. Specifically, GO glutamatergic synaptic transmission pathways (FDR = 0.037) and the KEGG pathway for long-term potentiation (FDR = 0.024), a primary cellular mechanism for learning and memory, were identified. Crucially, this was offset by the enrichment of the GABA signaling pathway (FDR = 0.046), suggesting that the INCREM-modulated miRNAs may contribute to restore the balance between excitation and inhibition. Additionally, processes related to cellular homeostasis and stress response, such as regulation of autophagy (FDR = 5.39x10⁻⁵) and intrinsic apoptotic signaling (FDR = 1.30x10⁻⁶), were also significantly enriched (Fig. 2 C). Collectively, these bioinformatic analyses suggest that INCREM therapy modifies a pattern of circulating miRNAs that converge on gene networks governing cognitive processes, synaptic plasticity, and the homeostatic balance of glutamatergic and GABAergic neurotransmission, providing a powerful molecular basis for its clinical benefits in MDD. By contrast, plasma levels of miR-126-5p and miR-195-5p increased significantly in response to the PSYCHOED intervention, but not the INCREM intervention. A two-way ANOVA followed by Šidák's multiple comparisons test revealed significant treatment effects for miR-126-5p (p < 0.05) and miR-195-5p (p < 0.01) in the PSYCHOED group (Fig. 3 A). The functional implications of the PSYCHOED-specifically modulated miRNAs were further analyzed (Fig. 3 B-D). An ORA analysis revealed a biological profile distinct from that observed for INCREM. Instead of pathways related to synaptic function, the target genes for PSYCHOED-responsive miRNAs converged on general cellular and signaling processes. The KEGG pathway analysis revealed a significant enrichment in pathways integral to fundamental cell-fate decisions and cellular signaling. The most significant pathways included cellular senescence (FDR = 1.26x10 − 4 ), Wnt signaling (FDR = 3.26x10 − 4 ), cell cycle (FDR = 5.83 x10 − 4 ), Hippo signaling (FDR = 1.07x10 − 3 ), and PI3K-Akt signaling (FDR = 1.34 x10 − 3 ) (Fig. 3 B, 3 D). These findings were further supported by GO analysis of biological processes (Fig. 3 C). The most prominent enriched terms were linked to fundamental cellular communication and stress responses, including stress-activated protein kinase signaling (FDR = 1.42x10 − 4 ), cell-cell signaling by Wnt (FDR = 1.42x10 − 4 ), nucleus organization (FDR = 5.71 x10 − 3 ), and the intrinsic apoptotic signaling pathway (FDR = 0.023). Surprisingly, in contrast to the INCREM-modulated miRNAs, the target genes for PSYCHOED-responsive miRNAs did not show significant enrichment in pathways directly related to synaptic plasticity and cognition. This divergence suggests that, whereas INCREM may exert its therapeutic effects by directly modulating gene networks involved in synaptic function, PSYCHOED appears to affect more general, systemic signaling pathways related to cell structure and intercellular communication. These results highlight a fundamental difference in the molecular mechanisms underlying the functional effects of these two types of non-pharmacological interventions. Improvement in functional and cognitive outcomes following the INCREM intervention in patients with MDD Table 1 B summarizes the functional and cognitive outcomes at the different assessment points (T 0 pre-treatment, T 1 post-treatment, and T 2 follow-up). Functional outcomes, as assessed by FAST, improved significantly in both the INCREM and PSYCHOED groups, with a decrease in scores indicating moderate to mild functional impairment (Fig. 4 A). This suggests that both interventions had a positive impact on daily functioning. However, while the INCREM intervention improved functional outcomes at T 1 and T 2 , the PSYCHOED intervention only improved them at T 2 . Two-ANOVA followed by Dunnett’s test revealed significant changes in the time: for INCREM (T 1 , p < 0.05; T 2 , p < 0.0001), for PSYCHOED (T 2 , p < 0.001). Regarding cognitive outcomes, the INCREM group showed significant improvements in objective cognitive performance (SCIP) and perceived cognitive deficits (PDQ), as assessed at T 1 and T 2 (Fig. 4 B and 4 C). Two-ANOVA followed by Dunnett’s test revealed significant changes over time: SCIP (both T 1 and T 2 , p < 0.0001), PDQ (T 1 , p < 0.05; T 2 , p < 0.01). In contrast, the PSYCHOED intervention produced no significant changes in SCIP or PDQ scores (Fig. 4 B and 4 C). These cognitive data align with the bioinformatic findings, suggesting that the INCREM-specific modulation of neuroplasticity and synaptic pathways translates into measurable improvements in higher-order cognitive functions. DISCUSSION The present study provides compelling molecular evidence that the psychological interventions INCREM and PSYCHOED elicit distinct and specific biological responses in patients with MDD. This finding represents a significant conceptual advance, shifting the understanding of psychological interventions from a purely psychological framework to one with a measurable and differential biological basis. Identifying unique circulating miRNA profiles for each intervention not only validates their biological impact and suggests that the content and target of the intervention ‒whether specific cognitive-functional performance or general knowledge about the disorder and relapse prevention‒ determine its molecular footprint. Previous research has shown that psychotherapy, particularly CBT, induced neuroplasticity changes in the brain areas involving modifications in functional connectivity [ 24 , 25 , 55 ]. By directly comparing two active psychological interventions, this study shows that therapeutic effects translate into specific, non-random biological responses. This provides a biological rationale for selecting therapies based on symptom patterns and, ultimately, a patient's molecular profile. The seven-miRNA profile, comprising let-7b-3p, miR-100-5p, miR-129-5p, miR-135a-5p, miR-151a-5p, miR-4516, and miR-451a, associated with the response to INCREM offers profound insight into the molecular mechanisms underlying the improvement in cognitive function in MDD. Analysis of the most prominent miRNAs modulated by INCREM intervention points to pathways previously implicated in MDD pathophysiology and antidepressant response. Notably, the post-INCREM increase in plasma levels of miR-129-5p and miR-135a-5p is particularly insightful. Expression of miR-129-5p is reduced in extracellular vesicles from postmortem brain tissue and in dlPFC samples from patients with MDD [ 45 , 56 ], yet raised in plasma after 12 weeks of SSRI escitalopram treatment [ 57 ]. In mouse models, miR-129-5p downregulation accompanies depressive-like phenotypes, whereas its hippocampal overexpression mitigates such behaviors by reducing microglial activation and NFκB pathway-dependent neuroinflammation [ 58 ]. Likewise, miR-135a is a well-established regulator of stress resilience and antidepressant response, acting on the serotonergic system by targeting the serotonin transporter (SERT) and 5-HT 1A autoreceptor [ 33 , 59 ]. Its levels have been shown to decrease in plasma and postmortem brain samples from MDD patients, as well as in mouse models exhibiting depressive-like behavior [ 33 , 60 , 61 ]. In contrast, antidepressant treatments with duloxetine (8 weeks) or venlafaxine (12 weeks) elevate its plasma levels [ 62 , 63 ]. Beyond its serotonergic role, miR-135a contributes to synaptic plasticity and memory formation. Interestingly, a three-months CBT program ‒where cognitive refers to restructuring maladaptive thoughts, unlike the process-based cognitive remediation used here‒ also increased blood miR-135a levels in MDD [ 33 ]. The parallel rise of miR-129-5p and miR-135a-5p following INCREM suggests activation of molecular pathways linked to antidepressant response (both pharmacological and non-pharmacological), partly mediated by enhanced serotonergic and synaptic plasticity mechanisms. In addition, the significant increase in miR-451a following INCREM suggests a molecular link to key synaptic dysfunction in MDD. This finding aligns with extensive evidence demonstrating that miR-451a levels are decreased in the serum and cerebrospinal fluid (CSF) of patients with MDD, where they negatively correlate with the depressive symptom severity on the 24-item Hamilton Depression Scale [ 64 , 65 ], although this association was not observed in another study [ 66 ]. MiR-451a is a promising therapeutic marker, as its baseline levels predict antidepressant efficacy, and its plasma levels were increased following 8 weeks of paroxetine treatment [ 64 ]. Preclinical studies provide crucial mechanistic support for this association. In mouse models of chronic stress-induced depression, miR-451a is significantly downregulated in both serum and the medial prefrontal cortex (mPFC). Overexpression of miR-451a in the mPFC of these mice reverses dendritic spine loss and improves the depressive-like phenotype by inhibiting corticotrophin-releasing factor receptor 1 expression via targeting transcription factor 2 [ 67 ]. This establishes a mechanistic bridge between the change in a circulating biomarker and the restoration of structural neuroplasticity in the brain, a goal of pro-cognitive treatments. Convergent evidence from other neurological conditions further underscores the importance of miR-451a in the relationship between mood and cognition. In patients with Alzheimer's disease (AD), reduced CSF levels of miR-451a were associated with both lower cognitive scores and higher depression ratings [ 68 ]. The same study found reduced miR-451a levels in neuronal and microglial cultures from AD-like APP/PS1 transgenic mice, while its overexpression in the mPFC improved behavioral and pathological alterations, including long-term memory deficits, depression-like phenotype, and NFκB activation and downstream neuroinflammation [ 68 ]. Overall, these data highlight miR-451a as a key regulator of synaptic integrity and a potential target for therapies addressing both cognitive and depressive symptoms. The upregulation of miR-151a-5p and miR-4516, along with the downregulation of let-7b-3p and miR-100-5p following INCREM treatment points to additional regulatory pathways. Although less studied in MDD, miR-4516 levels are reduced in CSF extracellular vesicles and in dlPFC of individuals with MDD who died by suicide [ 45 , 69 , 70 ]. The link between miR-4516 and suicide is mainly based on its predicted regulation of the SLC6A4 gene (which encodes the SERT protein) and other genes involved in cell adhesion and synaptic signaling (e.g., NR3C1 which encodes the glucocorticoid receptor) [ 69 , 71 ]. Similarly, miR-151a-5p is reduced in circulating extracellular vesicles from adolescents with anxiety disorders [ 72 ], while miR-151-3p (originating from the same precursor gene hsa-mir-151a) is modulated by SSRI paroxetine in human lymphoblastic cell lines derived from healthy adult females [ 73 ]. The let-7 family is involved in neurodegeneration, cell survival and synaptic development [ 74 ]. Recently, we reported that this miRNA family is consistently downregulated by lithium treatment in both responders or non-responders groups of patients with bipolar disorder [ 75 ], and elevated levels have been found in the plasma of patients with substance use disorders, which share overlapping neural circuits with MDD [ 76 , 77 ]. While miR-100-5p is known in terms of its function as a tumor suppressor and its involvement in vital cellular processes through the regulation of targets such as mTOR, FOXO1, AGO2 mRNAs, among others [ 78 , 79 ], its role in MDD remains unclear. Recently, it has been linked to shared gene networks between amyotrophic lateral sclerosis and depression [ 80 ]. Overall, this four-miRNA profile, though requiring validation, suggests that INCREM targets master regulators of MDD-related pathways, including serotonergic plasticity and synaptic function. These mechanisms are supported by the functional enrichment analysis, which revealed that the INCREM-specific miRNAs target a pro-cognitive biological network. The enriched pathways identified, including neurotrophin signaling, axonal guidance, long-term potentiation (LTP), and glutamatergic and GABAergic synaptic transmission, as well as the cognitive pathway itself, are known to contribute to learning and memory [ 81 – 83 ]. Cognitive remediation is, in essence, a form of structured, guided learning that can strengthen specific neural circuits, particularly in prefrontal and parietal networks, through mechanisms of brain plasticity [ 84 – 86 ]. The findings of this study suggest a potential molecular correlate for these processes. INCREM therapy might act as an environmental stimulus with changes in miRNA expression that, in turn, could influence genes involved in synaptic strengthening (LTP), structural remodeling (axon guidance), and rebalancing of excitatory/inhibitory tone. Therefore, it could be hypothesized that this therapy (INCREM) improves cognitive and functional performance in MDD by modulating a specific set of circulating miRNAs that regulate molecular pathways implicated in neuroplasticity and brain function. Unlike the INCREM intervention, the miRNA profile associated with the PSYCHOED response points to fundamentally different mechanisms of action, providing insight into how supportive interventions may exert their therapeutic benefits. The two miRNAs, miR-126-5p and miR-195-5p, significantly increased after the PSYCHOED are involved in key cellular processes rather than in synaptic plasticity per se . A growing body of literature demonstrates that miR-195-5p is a potent negative regulator of the Wnt/β-catenin signaling pathway [ 87 , 88 ]. This pathway is a master regulator of cell fate, including proliferation, differentiation, and apoptosis, and its dysregulation is implicated in numerous diseases with inflammatory components [ 89 , 90 ]. However, there are few studies on the role of miR-195-5p in MDD. Changes in plasma miR-195-5p levels have recently been reported in patients with treatment-resistant depression following ECT, although the effect was not sustained [ 91 ]. A preclinical study reported that, in rats exposed to chronic stress, miR-195-5p expression levels decreased in the mPFC and increased in the ventral tegmental area, with stronger effects in resilient versus anhedonic rats [ 92 ]. The role of miR-126-5p in MDD remains unclear, though recent findings showed altered expression in plasma extracellular vesicles of adolescents with MDD compared to healthy peers [ 93 ]. However, miR-126-5p has been mainly involved in multiple sclerosis with high psychiatric comorbidity, being a key regulator of vascular health and neuroinflammation. Its dysregulation (either too high or too low) appears to be a common mechanism in neurological disorders involving blood-brain barrier dysfunction and oxidative stress [ 94 , 95 ]. The functional analysis of the PSYCHOED targetome did not show clear enrichment of pathways related to neuroplasticity or cognitive processing. Instead, the analysis indicated enrichment in pathways involved in cell fate and intercellular communication, such as cell senescence, Wnt signaling, cell cycle, and Hippo signaling. This distinct profile suggests that PSYCHOED may influence different biological processes to those associated with INCREM, opening up new hypothesis on how supportive therapies exert their effects. MDD is increasingly recognized as a systemic disorder associated with chronic inflammation, oxidative stress, and accelerated biological ageing [ 96 – 98 ]. By providing patients with tools to manage their disease and reduce psychological distress, psychoeducation may act as a buffer against the systemic consequences of chronic stress. It is therefore biologically plausible that the benefits of PSYCHOED do not derive from direct remodeling of synaptic circuits, but rather from improved cellular health and resilience at the systemic level. Modulation of the Wnt pathway, a key regulator of tissue homeostasis, is consistent with this interpretation of a broad, systemic effect on cellular integrity. Thus, “targeted” interventions, such as INCREM, may function by directly modulating cognitive circuits and their plasticity, while “supportive” therapies like PSYCHOED may act through broader effects on systemic resilience to stress. In conclusion, this work provides novel mechanistic insight into how cognitive remediation and psychoeducation exert their therapeutic effects in MDD, demonstrating that these psychological interventions induce distinct and measurable molecular biological responses. The specific circulating miRNA profile identified for INCREM and PSYCHOED represent a significant advance, establishing a solid foundation for the development of clinically actionable biomarkers. This research paves the way for a future of precision psychiatry, in which psychological interventions can be personalized and optimized based on the individual biological profile of patients suffering from cognitive dysfunction in MDD. Strengths, methodological considerations, and future directions The results of this study have direct translational implications, addressing the critical need for biomarkers in psychiatry to overcome the trial-and-error approach to treatment selection [ 99 ]. Circulating miRNAs are ideal candidates, stable in plasma, reflecting pathophysiological processes in the central nervous system (CNS), and accessible through minimally invasive methods. This study has several strengths, including a prospective design with an active comparator, allowing specific molecular changes to be attributed to specific interventions. The selection of miRNAs, based on previous findings in post-mortem brain tissue [ 45 ], enriched the analysis with neurobiological relevant candidates. However, certain limitations must be acknowledged. The sample analyzed in this work corresponds to an exploratory cohort within a larger project, intended to initially characterize the relationship between plasma miRNA levels and response to psychological interventions. Multiple-comparison corrections (Šidák adjustment) were applied to the miRNA analyses, while non-parametric tests were used for cognitive and functioning variables, providing partial support for the robustness of the findings despite the limited sample size. These findings require confirmation in larger, independent cohorts. Moreover, while clinical follow-up data were available, miRNA measurements were limited to pre- and post-intervention time-points, preventing longitudinal molecular analyses. Although plasma miRNAs may reflect CNS processes, their cellular origin is heterogeneous; future studies using neuron-derived extracellular vesicles could provide greater specificity [ 39 , 40 ]. MiRNA signatures showed an association with response, but the correlational nature of the study limits causal interpretations. Due to the small sample size, reliable correlation analyses between changes in miRNA expression and functional and cognitive outcomes could not be performed. Clarifying whether baseline levels of these miRNAs serve as predictors or merely reflect post-response changes, remains essential. Future directions should focus on validating these findings in multicenter and diverse cohorts. Longitudinal studies are needed to track miRNA profiles from baseline, during treatment, and at follow-up to establish their predictive value for both acute response and long-term relapse prevention. Experimental validation of key interactions between miRNAs and their targets in cellular and animal models is essential to confirm functional mechanisms. Finally, integrating miRNA profiling with other modalities, such as functional neuroimaging, will allow changes in circulating biomarkers to be directly linked to the activity and connectivity of the brain circuits involved. Declarations COMPETING INTERESTS The authors declare no competing interests. ETHICS APPROVAL This study was conducted in accordance with the national ethical standards and norms and with the 1964 Helsinki Declaration by its later amendments (version of Fortaleza, 2013). Ethical approval was obtained from the local ethics committee of Hospital de la Santa Creu i Sant Pau (CEIm Sant Pau; ref. 21/119). All participants provided written informed consent prior to their inclusion in the study. FUNDING This work was supported by MCIU/AEI/FEDER, UE grant (PID2022-141700OB-I00, MCIN/AEI/ 10.13039/501100011033 to AB), ISCIII (PI20/00270 to MJP), Fundació La Marató de TV3 and Generalitat de Catalunya (202207-30-32 to AB and JDA, and 202227-30 to MJP), and AGAUR 2021-SGR-01358 to AB and 2021-SGR-00832 to MJP of the Generalitat de Catalunya. We also thank the Spanish Stress Research Network, MCIN/AEI / 10.13039/501100011033 , and CB/07/09/0010 and CB/07/09/0034 Centre for Biomedical Research in Mental Health Network (CIBERSAM). JJE is a recipient of a predoctoral fellowship (2025 FI-AGAUR) from the Catalan Government (AGAUR, Generalitat de Catalunya). AUTHOR CONTRIBUTIONS LMR and JJE contributed to the conceptualization and experimental design of the study, performed miRNA analyses: qPCR, GO, KEGG pathways, and statistical analyses interpreted the results and co-drafted the original version of the manuscript under the supervision of AB and MJP. MVG designed the protocol, conducted the INCREM intervention groups, performed the statistical analysis, interpreted the results, co-drafted the original version of the manuscript under the supervision of AB and MJP. VP and ERB managed the collection of human plasma samples and performed the RNA isolation and first-strand cDNA synthesis experiments. JCH conducted clinical and neuropsychological assessments. MJ did the blood sample collection throughout the study. LG, JV, CMB conducted the PSYCHOED intervention groups. DP, CA, NC, JDA were responsible for patient selection, and reviewed and approved the final version of the manuscript. AB and MJP contributed to the conceptualization and experimental design of the study, contributed to the statistical analyses and interpretation of the findings, co-wrote and edited the manuscript, supervised the entire study and provided the necessary resources. All authors reviewed and approved the final manuscript. ACKNOWLEDGEMENTS Grateful acknowledgment is extended to the patients who participated in this study and to the staff of the Department of Psychiatry at Hospital de la Santa Creu i Sant Pau for their valuable collaboration. References GBD 2019 Mental Disorders Collaborators. Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Psychiatry. 2022;9:137–150. 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Precision Psychiatry: Biomarker-Guided Tailored Therapy for Effective Treatment and Prevention in Major Depression. Adv Exp Med Biol. 2021;1305:535–563. Additional Declarations The authors have declared there is NO conflict of interest to disclose Supplementary Files SupplementalMaterial.pdf Supplemental Information Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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1","display":"","copyAsset":false,"role":"figure","size":380475,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStudy design and identification of plasma miRNAs modulated by psychotherapy in MDD patients.\u003c/strong\u003e \u003cstrong\u003e(A)\u003c/strong\u003eSchematic of the experimental design. A panel of 36 miRNAs, which were previously found to be dysregulated in the post-mortem dorsolateral prefrontal cortex (dlPFC) of MDD patients, was analyzed in plasma samples from a separate cohort of MDD patients before (pre-treatment, T0) and after (post-treatment, T1) intervention with either integral cognitive remediation (INCREM, n = 15) or psychoeducation (PSYCHOED, n = 7). \u003cstrong\u003e(B)\u003c/strong\u003e Bar graphs showing 9 miRNA levels that were significantly modulated by psychotherapy (combined INCREM and PSYCHOED groups) compared to baseline (pre-treatment). \u003cstrong\u003e(C)\u003c/strong\u003e Hierarchical clustering shows the expression of 36 miRNAs among INCREM- and PSYCHOED-treated patients with MDD. The intensity of the color represents the expression status. Red represents higher expression and blue represents reduced expression. Data are presented as mean ± SEM. *p \u0026lt; 0.05, **p \u0026lt; 0.01, ***p \u0026lt; 0.001 when comparing the values before and after intervention (detailed statistical analysis in Supplementary Excel File 2).\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8113450/v1/ceba7a62d5834a0dfcaf3c8e.jpg"},{"id":96053823,"identity":"8124390d-bbc7-4aa2-a291-1a370cc2108f","added_by":"auto","created_at":"2025-11-17 07:09:23","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":387839,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe functional targetome of circulating miRNAs specifically regulated by INCREM. (A) \u003c/strong\u003eRelative plasma levels of the 7 miRNAs significantly modulated by integral cognitive remediation (INCREM, n = 15) intervention. The graphs show the significant changes in let-7b-3p, miR-100-5p, miR-129-5p, miR-135a-5p, miR-151a-5p, miR-4516, and miR-451a comparing pre-INCREM vs. post-INCREM. \u003cstrong\u003e(B) \u003c/strong\u003eKyoto Encyclopedia of Genes and Genomes (KEGG)-based pathway analysis of the predicted target genes of the dysregulated miRNAs. The bar chart shows the enrichment ratio of the most significantly enriched pathways.\u003cstrong\u003e (C)\u003c/strong\u003e Gene Ontology (GO) analysis for the biological process category. The bar chart displays the enrichment ratio of the most significant processes associated with the predicted miRNA target genes.\u003cstrong\u003e D)\u003c/strong\u003e Enrichment network visualizing the relationships among the identified KEGG functional pathways. Each node represents an enriched term, color-coded by functional cluster. The connecting edges indicate the degree of overlap based on shared genes between the terms. Data are presented as mean ± SEM. *p \u0026lt; 0.05, **p \u0026lt; 0.01 when comparing the values before and after intervention (detailed statistical analysis in Supplementary Excel File 2).\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8113450/v1/51931ded1da7c3e57f8bb977.jpg"},{"id":96247236,"identity":"c90d3c8c-5b76-455d-b960-b4fab885370e","added_by":"auto","created_at":"2025-11-19 07:27:16","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":360389,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe functional targetome of circulating miRNAs specifically regulated by PSYCHOED. (A) \u003c/strong\u003eRelative plasma levels of the 2 miRNAs significantly modulated by psychoeducation (PSYCHOED, n = 7) intervention. The graphs show the significant changes in miR-126-5p and miR-195-5p comparing pre-PSYCHOED vs. post-PSYCHOED. \u003cstrong\u003e(B) \u003c/strong\u003eKyoto Encyclopedia of Genes and Genomes (KEGG)-based pathway analysis of the predicted target genes of the dysregulated miRNAs. The bar chart shows the enrichment ratio of the most significantly enriched pathways.\u003cstrong\u003e (C)\u003c/strong\u003e Gene Ontology (GO) analysis for the biological process category. The bar chart displays the enrichment ratio of the most significant processes associated with the predicted miRNA target genes.\u003cstrong\u003e D)\u003c/strong\u003e Enrichment network visualizing the relationships among the identified KEGG functional pathways. Each node represents an enriched term, color-coded by functional cluster. The connecting edges indicate the degree of overlap based on shared genes between the terms. Data are presented as mean ± SEM. *p \u0026lt; 0.05, **p \u0026lt; 0.01 when comparing the values before and after intervention (detailed statistical analysis in Supplementary Excel File 2).\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8113450/v1/2e71bf8c1666751193ddfd97.jpg"},{"id":96053810,"identity":"d3769083-f8b0-4874-822b-bc697eb723f2","added_by":"auto","created_at":"2025-11-17 07:09:19","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":834546,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eINCREM therapy, but not PSYCHOED, improves cognitive function in MDD patients. \u003c/strong\u003eBar graphs showing cognitive performance in MDD patients before (pre-treatment, T\u003csub\u003e0\u003c/sub\u003e), after (post-treatment, T\u003csub\u003e1\u003c/sub\u003e), and follow-up (T\u003csub\u003e2\u003c/sub\u003e) intervention with either integral cognitive remediation (INCREM, n = 15) or psychoeducation (PSYCHOED, n = 7). \u003cstrong\u003e(A) \u003c/strong\u003ePsychosocial dysfunction (FAST) \u003cstrong\u003e(B)\u003c/strong\u003e Objective cognitive performance (SCIP)\u003cstrong\u003e (C) \u003c/strong\u003ePerceived cognitive deficits (PDQ). Data are presented as mean ± SEM. *p \u0026lt; 0.05, **p \u0026lt; 0.01, ***p \u0026lt; 0.001, and ****p \u0026lt; 0.0001 when comparing the values before (T\u003csub\u003e0\u003c/sub\u003e) and after intervention (T\u003csub\u003e1\u003c/sub\u003e and T\u003csub\u003e2\u003c/sub\u003e). Detailed statistical analysis in Supplementary Excel File 2.\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8113450/v1/2c1b78e21bc6e161b9daca01.jpg"},{"id":97251102,"identity":"ea3b9063-44d0-44c6-8df1-f982f5e673cc","added_by":"auto","created_at":"2025-12-02 13:16:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3407539,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8113450/v1/598020b6-51bd-440b-946d-f94b01e94686.pdf"},{"id":96053787,"identity":"f936bc4c-2c6e-4123-b7d7-22ca23ff0fa7","added_by":"auto","created_at":"2025-11-17 07:09:19","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1174425,"visible":true,"origin":"","legend":"Supplemental Information","description":"","filename":"SupplementalMaterial.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8113450/v1/6338911bad04ce2b90c3125b.pdf"}],"financialInterests":"The authors have declared there is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose","formattedTitle":"A circulating miRNA profile is associated with response to cognitive remediation in major depressive disorder","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eMajor depressive disorder (MDD) is a prevalent and recurrent mental illness, affecting one in five adults during their lifetime and representing a leading contributor to disability worldwide [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. A defining aspect of this disorder involves a wide array of cognitive symptoms, including difficulties in attention, memory, processing speed, and executive function [\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. These cognitive deficits are not merely a secondary consequence of the depressive mood, but are a core component of the illness [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Indeed, they play a key role in the psychosocial impairment experienced by people with depression, hindering their performance at work and in education, and disrupting their social interactions [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Consequently, the cognitive symptoms lead to a lower quality of life and an increased risk of recurrent depressive episodes [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAlthough the precise biological origins of MDD remain elusive, the hypothesis of impaired neuroplasticity has emerged as a compelling explanatory framework [\u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Neuroplasticity refers to the capacity of neural circuits to reorganize themselves structurally and functionally in response to new stimuli [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The neuroplasticity process involves changes in synaptic strength, such as neurotransmitter release, ion channel density, as well as structural modifications, including the remodeling of axons, dendritic spines, and myelination, among others [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. When this process becomes maladaptive, especially following adverse experiences, it can elevate the risk for developing psychiatric disorders [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Evidence from neuropathological and neuroimaging studies in patients with MDD point to compromised brain plasticity, including reduced synaptogenesis, dendritic atrophy, glial cell dysfunction, deficiencies in neurotrophic factors, as well as dysregulation of functional connectivity [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan additionalcitationids=\"CR18 CR19\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], which may be a result from altered molecular pathways and underlying gene regulatory networks. Current first-line treatments, both psychotherapy and pharmacotherapy, are believed to work by targeting and reversing neuroplasticity deficits in MDD-vulnerable brain regions to achieve clinical benefits. For instance, antidepressants such as fluoxetine and sertraline (selective serotonin reuptake inhibitors - SSRI) have been shown to increase the volume of dorsolateral prefrontal cortex (dlPFC) in patients with MDD [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Recent studies have also reported that the normalization of amygdala hyperactivity and the decrease in its functional connectivity with the dlPFC underlie successful response to SSRI and ketamine treatments [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Similarly, cognitive behavioral therapy (CBT) has been shown to induce changes in connectivity between the dlPFC and the anterior cingulate cortex, which correlates with improvements in depressive symptoms [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Furthermore, therapeutic approaches such as electroconvulsive therapy (ECT) involve neurotrophic processes that normalize brain networks in MDD [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eMicroRNAs (miRNAs), which are a type of small non-coding RNAs, have recently received much attention due to their unique ability to control complex gene regulatory networks [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. MiRNAs regulate gene expression by interacting with messenger RNA (mRNA) transcripts, thereby leading to their degradation or the inhibition of their translation. The gene regulatory network involving miRNAs is extensive, as each miRNA can target hundreds of mRNA transcripts, while conversely, multiple miRNAs can converge to regulate a single mRNA transcript [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. This broad regulatory capacity makes them attractive targets for various brain disorders. Indeed, there is compelling evidence linking changes in the regulation of miRNAs and their mRNA targets to the development of MDD and antidepressant efficacy [\u003cspan additionalcitationids=\"CR32 CR33 CR34 CR35\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Furthermore, miRNAs possess a remarkable ability to be transported to different subcellular compartments, cross the blood-brain barrier, and contribute to inter-tissue communication [\u003cspan additionalcitationids=\"CR38\" citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. This capacity positions circulating miRNAs as valuable biomarkers for brain disorders, as their expression profile in liquid biopsies may mirror changes occurring in the brain. In support of this, increasing evidence shows miRNA dysregulation in both the blood and brain tissue of patients with neuropsychiatric diseases [\u003cspan additionalcitationids=\"CR41 CR42\" citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e], including MDD.\u003c/p\u003e\u003cp\u003eThe treatment of cognitive symptoms in MDD remains a developing area of research. Although pharmacological and non-pharmacological strategies have shown limited success, growing evidence supports the efficacy of functional remediation. Programs such as integral cognitive remediation (INCREM) for depression [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e] have been shown to improve both cognitive functioning and daily performance in affected individuals. However, the molecular mechanisms driving these beneficial effects remain poorly understood. This study aims to investigate whether circulating miRNAs are associated with cognitive responses to INCREM and psychoeducation (PSYCHOED) in patients with MDD. We analyzed a panel of 38 miRNAs, selected based on their prior dysregulation in the dlPFC of patients with MDD [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e], to test their efficacy as blood-based predictive biomarkers. Our findings provide mechanistic insights by revealing that INCREM and PSYCHOED are associated with distinct molecular pathways.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eParticipants\u003c/h2\u003e\u003cp\u003e The Research Ethics Board of the Hospital de la Santa Creu i Sant Pau approved the present study. All participants provided written informed consent after receiving a detailed explanation of the procedures. The research followed the ethical standards outlined in the Declaration of Helsinki and the principles of Good Clinical Practice, in full compliance with current data protection regulations. A comprehensive description of the study protocol was previously published [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e], and the project is registered at ClinicalTrials.gov (NCT07014683).\u003c/p\u003e\u003cp\u003eThe present analysis is part of a broader project designed to evaluate the functional and cognitive outcomes of the INCREM program. Patients diagnosed with MDD according to DSM-5 criteria were included in the study. Inclusion criteria were: (i) age between 18 and 60 years, (ii) partial response (HDRS-17\u0026thinsp;\u0026le;\u0026thinsp;18) [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e], (iii) the presence of objective (SCIP\u0026thinsp;\u0026le;\u0026thinsp;80) [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e] and/or subjective (PDQ\u0026thinsp;\u0026gt;\u0026thinsp;20) [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e] cognitive symptoms, and (iv) psychosocial dysfunction (FAST\u0026thinsp;\u0026ge;\u0026thinsp;12) [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e]. Exclusion criteria have been reported in detail elsewhere [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eTreatment\u003c/h3\u003e\n\u003cp\u003eThe current randomized clinical trial evaluated two intervention conditions: the INCREM program, focused on cognitive remediation, and an active control condition based on psychoeducation (PSYCHOED). Full details of both approaches are described in Vicent-Gil et al., [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. At baseline (T\u003csub\u003e0\u003c/sub\u003e), participants completed an evaluation including sociodemographic and clinical data, neuropsychological testing, a measure of psychosocial functioning, and a blood sample collection. Following this assessment, participants were randomly assigned to one of the treatment arms. Both programs were delivered concurrently through structured online group sessions held weekly for 12 weeks. Immediately post-intervention (T\u003csub\u003e1\u003c/sub\u003e), outcome measures were administered and a second blood sample was obtained. Participants were reassessed six months later (T\u003csub\u003e2\u003c/sub\u003e) using the same outcome measures to evaluate the maintenance of treatment effects.\u003c/p\u003e\n\u003ch3\u003eOutcome measures\u003c/h3\u003e\n\u003cp\u003eSociodemographic and clinical variables, including age, sex, years of schooling, estimated IQ (Vocabulary subtest of the Wechsler Adult Intelligence Scale version-IV, WAIS-IV [\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e], age at illness onset, number of depressive episodes, depressive symptomatology (HDRS-17) [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]; months of clinical stability and antidepressant medication trials (Antidepressant Treatment History Form, ATHF) [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e] were obtained through a semi-structured interview.\u003c/p\u003e\u003cp\u003ePsychosocial functioning was measured using the Functioning Assessment Short Test (FAST) [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e], which assesses six domains: autonomy, occupational performance, cognitive functioning, interpersonal relationships, financial management, and leisure activities. FAST scores range from 0 to 72, with scores of 12 or higher indicating a moderate level of functional impairment. Objective cognitive performance was assessed using the Screening for Cognitive Impairment in Psychiatry (SCIP), which includes five subtests targeting immediate and verbal learning and memory, working memory, verbal fluency, and processing speed. Scores below 80 are indicative of objective cognitive deficits [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. Subjective cognitive functioning was evaluated with the Perceived Deficit Questionnaire (PDQ-20), a 20-item self-report measure examining self-perceived cognitive difficulties in attention and concentration, retrospective and prospective memory, planning and organization, and executive functioning. Items are rated on a 5-point Likert scale (0\u0026thinsp;=\u0026thinsp;never, 4\u0026thinsp;=\u0026thinsp;almost always), with higher scores reflecting greater perceived cognitive impairment [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]. These instruments were applied not only to establish baseline characteristics but also to monitor changes in cognitive and psychosocial functioning over the course of the study.\u003c/p\u003e\n\u003ch3\u003ePlasma collection\u003c/h3\u003e\n\u003cp\u003eBlood samples were collected by venipuncture into 10 ml K\u003csub\u003e2\u003c/sub\u003eEDTA BD Vacutainer tubes (Becton, Franklin Lakes, NJ). Tubes were stored at room temperature and centrifugation within 1 h of collection. Blood was centrifuged at room temperature (22\u0026ndash;25\u0026deg;C) for 10 min at 450\u0026times;g (Beckman Coulter, Inc., Pasadena, CA). The plasma layer was transferred to a fresh 15 ml Falcon tube. Plasma was centrifuged for 15 min at 2500\u0026times;g (Eppendorf 5702, Hamburg, Germany) and the supernatant transferred to 1.5 ml Eppendorf tubes in 500 \u0026micro;l aliquots. Aliquots were kept at \u0026minus;\u0026thinsp;80\u0026deg;C until RNA isolation.\u003c/p\u003e\n\u003ch3\u003eRNA isolation, miRNA analysis, and functional pathway analysis based on predictions and gene ontology\u003c/h3\u003e\n\u003cp\u003eAll experimental procedures and data are included in the Supplementary information (\u003cb\u003eSuppl. Figure\u0026nbsp;1A-1C, Suppl. Table\u0026nbsp;1, and Suppl. Excel File 1\u003c/b\u003e). Materials and protocols are available upon request from the corresponding author (A.B.).\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analyses\u003c/h2\u003e\u003cp\u003eAll values are presented as the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard error of the mean (SEM), with individual data points shown. Data distribution was assessed for normality using the Shapiro-Wilk test. Outlier values within datasets were identified and excluded using the ROUT test (Q\u0026thinsp;=\u0026thinsp;1%). Descriptive statistics of sociodemographic and clinical characteristics were calculated for the total sample. Statistical analyses were performed using the Statistical Package for Social Sciences (SPSS, IBM Corp., Chicago, IL, version 30). Between-group comparisons (INCREM \u003cem\u003evs\u003c/em\u003e. PSYCHOED) were conducted using either parametric or non-parametric tests depending on data distribution. Independent samples t-tests were applied for normally distributed variables, and Mann\u0026ndash;Whitney U tests were used when the assumption of normality was not met. Given the small sample size, non-parametric tests were used to examine temporal changes within each intervention group. Specifically, the Friedman test was employed to assess changes over time in each outcome variable within both groups. A significance level of p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was set for all analyses.\u003c/p\u003e\u003cp\u003eMiRNA analyses were performed using GraphPad Prism 10.4.1 software. Comparisons between two groups were conducted using paired or independent Student\u0026rsquo;s t-tests (or equivalent non-parametric tests). Analyses involving multiple factors, such as pre- and post-treatment comparisons between intervention groups, were conducted using two-way ANOVA with repeated measures, followed by appropriate post-hoc tests for multiple comparisons. All tests were two-tailed, and differences were considered statistically significant if p\u0026thinsp;\u0026lt;\u0026thinsp;0.05. A detailed summary of all statistical tests, data, and results is provided in the \u003cb\u003eSuppl Excel File 2\u003c/b\u003e.\u003c/p\u003e\u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003eDescriptive analysis\u003c/h2\u003e\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA shows the baseline sociodemographic and clinical characteristics of the whole sample and compares the two psychotherapeutic intervention groups. A total of 22 patients diagnosed with MDD in partial remission participated in the study. Of these, 15 received the INCREM intervention and the remaining participants received PSYCHOED. No statistically significant differences were found between the groups for any of the assessed sociodemographic or clinical variables.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003ePsychological interventions significantly modulate plasma miRNA levels\u003c/h2\u003e\u003cp\u003eAs circulating miRNA levels have been shown to correlate with disease states, the levels of 36 miRNAs were quantified in the plasma of patients with MDD before (pre- treatment) and after (post-treatment) psychological intervention (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). These miRNAs were chosen based on a previous analysis, in which they were identified as being differentially expressed in post-mortem dlPFC samples from MDD patients (men and women) through miRNA-sequencing and validation by qPCR [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. The different miRNAs analyzed are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e \u003cb\u003eand Supplementary Figs.\u0026nbsp;1 and 2\u003c/b\u003e. Psychological interventions (INCREM and PSYCHOED) significantly increased the levels of miR-126-5p (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), miR-129-5p (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), miR-1299 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), miR-135a-5p (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), miR-151a-5p (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), miR-4516 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), and miR-451a (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and decreased the levels of miR-34c-5p (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and miR-625-5p (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) when comparing pre-treatment to post-treatment (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eParticipant characteristics and functional-cognitive outcomes\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e\u003cp\u003eA. Baseline sociodemographic and clinical characteristics: whole sample and intervention groups\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eWHOLE SAMPLE\u003c/b\u003e (n\u0026thinsp;=\u0026thinsp;22)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003eINCREM\u003c/b\u003e\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;15)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003ePSYCHOED\u003c/b\u003e\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003ep-value\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge, \u003cem\u003eyears\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e50.36 (\u0026plusmn;\u0026thinsp;1.94)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e50.8 (\u0026plusmn;\u0026thinsp;1.84)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e49.43 (\u0026plusmn;\u0026thinsp;4.90)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.750\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eYears of schooling, \u003cem\u003en\u003c/em\u003e\u003csup\u003e\u003cem\u003e#\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16.14 (\u0026plusmn;\u0026thinsp;0.62)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15.87 (\u0026plusmn;\u0026thinsp;0.74)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e16.71 (\u0026plusmn;\u0026thinsp;1.19)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e43.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.535\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEstimated IQ, \u003cem\u003eT-score\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e61.50 (\u0026plusmn;\u0026thinsp;1.84)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e63.07 (\u0026plusmn;\u0026thinsp;2.15)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e58.14 (\u0026plusmn;\u0026thinsp;3.38)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.221\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge at illness onset, \u003cem\u003eyears\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e34.95 (\u0026plusmn;\u0026thinsp;2.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e35.53 (\u0026plusmn;\u0026thinsp;3.53)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e33.71 (\u0026plusmn;\u0026thinsp;4.50)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.766\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDepressive episodes, \u003cem\u003en\u003c/em\u003e\u003csup\u003e\u003cem\u003e#\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4.91 (\u0026plusmn;\u0026thinsp;1.60)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.40 (\u0026plusmn;\u0026thinsp;2.31)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3.86 (\u0026plusmn;\u0026thinsp;1.12)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e39.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.368\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eClinical stability, \u003cem\u003emonths\u003c/em\u003e\u003csup\u003e\u003cem\u003e#\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e100.64 (\u0026plusmn;\u0026thinsp;34.89)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e112.33 (\u0026plusmn;\u0026thinsp;44.67)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e75.57 (\u0026plusmn;\u0026thinsp;57.10)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e40.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.407\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eATHF, \u003cem\u003etotal score\u003c/em\u003e\u003csup\u003e\u003cem\u003e#\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.64 (\u0026plusmn;\u0026thinsp;0.21)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.6 (\u0026plusmn;\u0026thinsp;0.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.71 (\u0026plusmn;\u0026thinsp;0.19)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e50.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.891\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHDRS-17, \u003cem\u003etotal score\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11.05 (\u0026plusmn;\u0026thinsp;1.09)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10.8 (\u0026plusmn;\u0026thinsp;1.31)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e11.57 (\u0026plusmn;\u0026thinsp;2.10)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.750\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e\u003cp\u003eB. Functional and cognitive outcomes at baseline, post-intervention and at follow-up assessment\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e\u003cp\u003eINCREM\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eBaseline\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003ePost\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003eFollow\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003ep-value\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFAST, \u003cem\u003etotal score\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e28.86 (\u0026plusmn;\u0026thinsp;2.40)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e21.21 (\u0026plusmn;\u0026thinsp;2.74)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e14.0 (\u0026plusmn;\u0026thinsp;3.19)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e12.69\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.002**\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSCIP, \u003cem\u003etotal score\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e73.00 (\u0026plusmn;\u0026thinsp;3.44)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e82.79 (\u0026plusmn;\u0026thinsp;2.41)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e82.86 (\u0026plusmn;\u0026thinsp;3.20)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e13.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.002**\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePDQ, \u003cem\u003etotal score\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e41.93 (\u0026plusmn;\u0026thinsp;2.92)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e33.93 (\u0026plusmn;\u0026thinsp;2.97)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e32.43 (\u0026plusmn;\u0026thinsp;3.66)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e8.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.013*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e\u003cp\u003ePSYCHOED\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eBaseline\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003ePost\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003eFollow\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003ep-value\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFAST, \u003cem\u003etotal score\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e33.67 (\u0026plusmn;\u0026thinsp;5.70)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e26.17 (\u0026plusmn;\u0026thinsp;6.62)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e17.67 (\u0026plusmn;\u0026thinsp;6.21)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e10.33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.006**\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSCIP, \u003cem\u003etotal score\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e68.33 (\u0026plusmn;\u0026thinsp;3.46)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e76.83 (\u0026plusmn;\u0026thinsp;3.78)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e74.83 (\u0026plusmn;\u0026thinsp;5.46)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4.26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.119\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePDQ, \u003cem\u003etotal score\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e48.33 (\u0026plusmn;\u0026thinsp;3.67)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e42.33 (\u0026plusmn;\u0026thinsp;5.18)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e39.83 (\u0026plusmn;\u0026thinsp;7.22)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e5.33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.069\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003eIQ: Intelligence Quotient, ATHF: Antidepressant Treatment History Questionnaire, HDRS-17: 17-item Hamilton Depression Rating Scale, FAST: Functioning Assessment Short Test, SCIP: Screening for Cognitive Impairment in Psychiatry, PDQ: Perceived Deficit Questionnaire. \u003csup\u003e\u003cem\u003e#\u003c/em\u003e\u003c/sup\u003eComparison by Mann-Whitney U test. Data are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SEM. *p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, **p\u0026thinsp;\u0026lt;\u0026thinsp;0.01 for within-group changes over time.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePanel of analyzed miRNAs used in the study\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003emiRNA\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003emiRbase (ACC. No)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLocus\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eFold change\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ehsa-let-7b-3p\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIMAT0004482\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003echr22: 46113686\u0026ndash;46113768\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.7921\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.0982\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ehsa-let-7b-5p\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIMAT0000063\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003echr22: 46113686\u0026ndash;46113768\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.036\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.7943\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ehsa-miR-100-5p\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIMAT0000098\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003echr11: 122152229\u0026ndash;122152308\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.7886\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.0869\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ehsa-miR-126-5p\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIMAT0000444\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003echr9: 136670602\u0026ndash;136670686\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.453\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.0156*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ehsa-miR-129-5p\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIMAT0000242\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003echr7: 128207872\u0026ndash;128207943\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.571\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.0040**\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ehsa-miR-1299\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIMAT0005887\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003echr9: 40929010\u0026ndash;40929092\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.540\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.0359*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ehsa-miR-135a-5p\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIMAT0000428\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003echr9: 40929010\u0026ndash;40929092\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.701\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.0017**\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ehsa-miR-144-3p\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIMAT0000436\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003echr17: 28861533\u0026ndash;28861618\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.064\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.4589\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ehsa-miR-151a-3p\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIMAT0000757\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003echr8: 140732564\u0026ndash;140732653\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.177\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.2581\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ehsa-miR-151a-5p\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIMAT0004697\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003echr8: 140732564\u0026ndash;140732653\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.418\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.0141*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ehsa-miR-151b\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIMAT0010214\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003echr14: 100109419\u0026ndash;100109514\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN/A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eN/A\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ehsa-miR-181a-3p\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIMAT0000270\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003echr1: 198859044\u0026ndash;198859153\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.095\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.7593\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ehsa-miR-187-3p\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIMAT0000262\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003echr18: 35904818\u0026ndash;35904926\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.8559\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.2187\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ehsa-miR-195-5p\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIMAT0000461\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003echr17: 7017615\u0026ndash;7017701\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.297\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.0587\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ehsa-miR-199a-3p\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIMAT0000232\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003echr19: 10817426\u0026ndash;10817496\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.8081\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.3169\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ehsa-miR-199a-5p\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIMAT0000231\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003echr19: 10817426\u0026ndash;10817496\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.206\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.1375\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ehsa-miR-21-5p\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIMAT0000076\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003echr17: 59841266\u0026ndash;59841337\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.8537\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.0760\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ehsa-miR-219a-2-3p\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIMAT0004675\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003echr9: 128392618\u0026ndash;128392714\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.9437\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.7404\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ehsa-miR-219a-5p\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIMAT0000276\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003echr6: 33207835\u0026ndash;33207944\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.9307\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.6556\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ehsa-miR-23b-3p\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIMAT0000276\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003echr9: 95085208\u0026ndash;95085304\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.119\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.6327\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ehsa-miR-27b-3p\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIMAT0000419\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003echr9: 95085445\u0026ndash;95085541\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.371\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" 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colname=\"c4\"\u003e\u003cp\u003e0.9815\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.1765\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ehsa-miR-335-5p\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIMAT0000765\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003echr7: 130496111\u0026ndash;130496204\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.241\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.2290\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ehsa-miR-338-5p\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIMAT0004701\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003echr17: 81125883\u0026ndash;81125949\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.8831\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.4628\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ehsa-miR-33a-3p\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIMAT0004506\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003echr22: 41900944\u0026ndash;41901012\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.200\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.1375\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ehsa-miR-34c-5p\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIMAT0000686\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003echr11: 111513439\u0026ndash;111513515\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.7313\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.0435*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ehsa-miR-378a-3p\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIMAT0000732\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003echr5: 149732825\u0026ndash;149732890\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.7931\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.1762\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ehsa-miR-423a-5p\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIMAT0004748\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003echr17: 30117079\u0026ndash;30117172\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.186\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.1649\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ehsa-miR-4516\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIMAT0019053\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003echr16: 2133119\u0026ndash;2133204\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.444\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.0391*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ehsa-miR-451a\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIMAT0001631\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003echr17: 28861369\u0026ndash;28861440\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.420\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.0005***\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ehsa-miR-483-5p\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIMAT0004761\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003echr11: 2134134\u0026ndash;2134209\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.208\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.3369\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ehsa-miR-499a-5p\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIMAT0002870\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003echr20: 34990376\u0026ndash;34990497\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.8296\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.3209\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ehsa-miR-5584-5p\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIMAT0022283\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003echr1: 44545493\u0026ndash;44545552\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.7567\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.2615\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ehsa-miR-574-5p\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIMAT0004795\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003echr4: 38868032\u0026ndash;38868127\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.7863\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.2285\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ehsa-miR-625-5p\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIMAT0003294\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003echr14: 65471102\u0026ndash;65471186\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.7227\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.0187*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ehsa-miR-642a-5p\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIMAT0003312\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003echr19: 45674928\u0026ndash;45675024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.270\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.1317\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ehsa-miR-6734-5p\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIMAT0027369\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003echr1: 43364648\u0026ndash;43364715\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.9644\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.9493\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003eSignificantly changed miRNAs in the plasma of patients with MDD after psychotherapy intervention. For normalization, expression stability of the 38-miRNA panel was assessed using the NormFinder algorithm, which identified hsa-miR-151b and hsa-miR-27b-5p as the most stable reference pair. N/A Not applicable. *p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, **p\u0026thinsp;\u0026lt;\u0026thinsp;0.01, ***p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 pre-treatment vs. post-treatment.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eSubsequently, a cluster analysis was performed based on the expression of miRNAs modulated by both psychological interventions, revealing that INCREM treatment clustered together and was distinct from the PSYCHOED treatment (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC). An additional analysis identified a profile of miRNAs in plasma that was differentially expressed between the two psychological interventions. In particular, significant increases were observed in the levels of miR-129-5p (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), miR-135a-5p (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), miR-151a-5p (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), miR-4516 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), and miR-451a (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) along with decreases in the levels of let-7b-3p (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and miR-100-5p (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) in plasma from patients with MDD when comparing pre-INCREM and post-INCREM treatment (\u003cb\u003eSupplementary Fig.\u0026nbsp;3\u003c/b\u003e). However, plasma levels of miR-126-5p (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and miR-195-5p (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) were increased only after PSYCHOED treatment in MDD patients (\u003cb\u003eSupplementary Fig.\u0026nbsp;4\u003c/b\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eINCREM and PSYCHOED interventions trigger differences in the miRNA-based functional targetome\u003c/h2\u003e\u003cp\u003eNext, a two-way ANOVA analysis was performed to confirm the differential effects on plasma miRNA levels of both psychotherapies. Š\u0026iacute;d\u0026aacute;k's multiple comparisons test revealed a significant effect of treatment for seven miRNAs: let-7b-3p (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), miR-100-5p (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), miR-129-5p (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), miR-135a-5p (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), miR-151a-5p (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), miR-4516 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), and miR-451a (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), specifically in the INCREM group (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). Importantly, these miRNAs are not significantly altered by PSYCHOED.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eTo elucidate the biological function of the INCREM-specific miRNA profile, a functional enrichment analysis on its consensus-predicted target genes was performed (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB-D). The KEGG pathway analysis revealed that the target genes were significantly enriched in pathways integral to neuroplasticity, cellular signaling, and nervous system function (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB, \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD). Among the most significant were pathways related to synaptic function, including neurotrophin signaling (FDR\u0026thinsp;=\u0026thinsp;1.59x10⁻⁵), axon guidance (FDR\u0026thinsp;=\u0026thinsp;5.85x10⁻\u003csup\u003e4\u003c/sup\u003e), long-term potentiation (FDR\u0026thinsp;=\u0026thinsp;0.024), and dopaminergic synapse (FDR\u0026thinsp;=\u0026thinsp;4.40x10\u003csup\u003e\u0026minus;\u0026thinsp;3\u003c/sup\u003e). Furthermore, a strong enrichment was observed in critical intracellular signaling cascades that regulate neuronal survival and plasticity, such as TGFβ signaling (FDR\u0026thinsp;=\u0026thinsp;2.50x10⁻⁷), FoxO signaling (FDR\u0026thinsp;=\u0026thinsp;1.37x10⁻⁷), PI3K-Akt signaling (FDR\u0026thinsp;=\u0026thinsp;2.86x10⁻⁴), mTOR signaling (FDR\u0026thinsp;=\u0026thinsp;5.42x10⁻⁵), MAPK signaling (FDR\u0026thinsp;=\u0026thinsp;2.29x10⁻⁵), and NFκB signaling (FDR\u0026thinsp;=\u0026thinsp;4.40x10\u003csup\u003e\u0026minus;\u0026thinsp;3\u003c/sup\u003e).\u003c/p\u003e\u003cp\u003eComplementing these findings, GO analysis of biological processes confirmed a significant over-representation of terms associated with synaptic function. The most relevant enriched terms included regulation of synapse structure or activity (FDR\u0026thinsp;=\u0026thinsp;4.88x10⁻\u003csup\u003e4\u003c/sup\u003e), neuron projection development (FDR\u0026thinsp;=\u0026thinsp;8.76x10⁻⁴), and cognition (FDR\u0026thinsp;=\u0026thinsp;2.59x10⁻⁴). Supporting a direct role in synaptic communication, the analysis revealed a significant enrichment in both excitatory and inhibitory signaling processes. Specifically, GO glutamatergic synaptic transmission pathways (FDR\u0026thinsp;=\u0026thinsp;0.037) and the KEGG pathway for long-term potentiation (FDR\u0026thinsp;=\u0026thinsp;0.024), a primary cellular mechanism for learning and memory, were identified. Crucially, this was offset by the enrichment of the GABA signaling pathway (FDR\u0026thinsp;=\u0026thinsp;0.046), suggesting that the INCREM-modulated miRNAs may contribute to restore the balance between excitation and inhibition. Additionally, processes related to cellular homeostasis and stress response, such as regulation of autophagy (FDR\u0026thinsp;=\u0026thinsp;5.39x10⁻⁵) and intrinsic apoptotic signaling (FDR\u0026thinsp;=\u0026thinsp;1.30x10⁻⁶), were also significantly enriched (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC). Collectively, these bioinformatic analyses suggest that INCREM therapy modifies a pattern of circulating miRNAs that converge on gene networks governing cognitive processes, synaptic plasticity, and the homeostatic balance of glutamatergic and GABAergic neurotransmission, providing a powerful molecular basis for its clinical benefits in MDD.\u003c/p\u003e\u003cp\u003eBy contrast, plasma levels of miR-126-5p and miR-195-5p increased significantly in response to the PSYCHOED intervention, but not the INCREM intervention. A two-way ANOVA followed by Šid\u0026aacute;k's multiple comparisons test revealed significant treatment effects for miR-126-5p (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and miR-195-5p (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) in the PSYCHOED group (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). The functional implications of the PSYCHOED-specifically modulated miRNAs were further analyzed (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB-D). An ORA analysis revealed a biological profile distinct from that observed for INCREM. Instead of pathways related to synaptic function, the target genes for PSYCHOED-responsive miRNAs converged on general cellular and signaling processes. The KEGG pathway analysis revealed a significant enrichment in pathways integral to fundamental cell-fate decisions and cellular signaling. The most significant pathways included cellular senescence (FDR\u0026thinsp;=\u0026thinsp;1.26x10\u003csup\u003e\u0026minus;\u0026thinsp;4\u003c/sup\u003e), Wnt signaling (FDR\u0026thinsp;=\u0026thinsp;3.26x10\u003csup\u003e\u0026minus;\u0026thinsp;4\u003c/sup\u003e), cell cycle (FDR\u0026thinsp;=\u0026thinsp;5.83 x10\u003csup\u003e\u0026minus;\u0026thinsp;4\u003c/sup\u003e), Hippo signaling (FDR\u0026thinsp;=\u0026thinsp;1.07x10\u003csup\u003e\u0026minus;\u0026thinsp;3\u003c/sup\u003e), and PI3K-Akt signaling (FDR\u0026thinsp;=\u0026thinsp;1.34 x10\u003csup\u003e\u0026minus;\u0026thinsp;3\u003c/sup\u003e) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB, \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eD).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThese findings were further supported by GO analysis of biological processes (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC). The most prominent enriched terms were linked to fundamental cellular communication and stress responses, including stress-activated protein kinase signaling (FDR\u0026thinsp;=\u0026thinsp;1.42x10\u003csup\u003e\u0026minus;\u0026thinsp;4\u003c/sup\u003e), cell-cell signaling by Wnt (FDR\u0026thinsp;=\u0026thinsp;1.42x10\u003csup\u003e\u0026minus;\u0026thinsp;4\u003c/sup\u003e), nucleus organization (FDR\u0026thinsp;=\u0026thinsp;5.71 x10\u003csup\u003e\u0026minus;\u0026thinsp;3\u003c/sup\u003e), and the intrinsic apoptotic signaling pathway (FDR\u0026thinsp;=\u0026thinsp;0.023). Surprisingly, in contrast to the INCREM-modulated miRNAs, the target genes for PSYCHOED-responsive miRNAs did not show significant enrichment in pathways directly related to synaptic plasticity and cognition. This divergence suggests that, whereas INCREM may exert its therapeutic effects by directly modulating gene networks involved in synaptic function, PSYCHOED appears to affect more general, systemic signaling pathways related to cell structure and intercellular communication. These results highlight a fundamental difference in the molecular mechanisms underlying the functional effects of these two types of non-pharmacological interventions.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eImprovement in functional and cognitive outcomes following the INCREM intervention in patients with MDD\u003c/h2\u003e\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB summarizes the functional and cognitive outcomes at the different assessment points (T\u003csub\u003e0\u003c/sub\u003e pre-treatment, T\u003csub\u003e1\u003c/sub\u003e post-treatment, and T\u003csub\u003e2\u003c/sub\u003e follow-up). Functional outcomes, as assessed by FAST, improved significantly in both the INCREM and PSYCHOED groups, with a decrease in scores indicating moderate to mild functional impairment (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA). This suggests that both interventions had a positive impact on daily functioning. However, while the INCREM intervention improved functional outcomes at T\u003csub\u003e1\u003c/sub\u003e and T\u003csub\u003e2\u003c/sub\u003e, the PSYCHOED intervention only improved them at T\u003csub\u003e2\u003c/sub\u003e. Two-ANOVA followed by Dunnett\u0026rsquo;s test revealed significant changes in the time: for INCREM (T\u003csub\u003e1\u003c/sub\u003e, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05; T\u003csub\u003e2\u003c/sub\u003e, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), for PSYCHOED (T\u003csub\u003e2\u003c/sub\u003e, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eRegarding cognitive outcomes, the INCREM group showed significant improvements in objective cognitive performance (SCIP) and perceived cognitive deficits (PDQ), as assessed at T\u003csub\u003e1\u003c/sub\u003e and T\u003csub\u003e2\u003c/sub\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eB and \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eC). Two-ANOVA followed by Dunnett\u0026rsquo;s test revealed significant changes over time: SCIP (both T\u003csub\u003e1\u003c/sub\u003e and T\u003csub\u003e2\u003c/sub\u003e, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), PDQ (T\u003csub\u003e1\u003c/sub\u003e, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05; T\u003csub\u003e2\u003c/sub\u003e, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). In contrast, the PSYCHOED intervention produced no significant changes in SCIP or PDQ scores (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eB and \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eC). These cognitive data align with the bioinformatic findings, suggesting that the INCREM-specific modulation of neuroplasticity and synaptic pathways translates into measurable improvements in higher-order cognitive functions.\u003c/p\u003e\u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe present study provides compelling molecular evidence that the psychological interventions INCREM and PSYCHOED elicit distinct and specific biological responses in patients with MDD. This finding represents a significant conceptual advance, shifting the understanding of psychological interventions from a purely psychological framework to one with a measurable and differential biological basis. Identifying unique circulating miRNA profiles for each intervention not only validates their biological impact and suggests that the content and target of the intervention ‒whether specific cognitive-functional performance or general knowledge about the disorder and relapse prevention‒ determine its molecular footprint. Previous research has shown that psychotherapy, particularly CBT, induced neuroplasticity changes in the brain areas involving modifications in functional connectivity [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e]. By directly comparing two active psychological interventions, this study shows that therapeutic effects translate into specific, non-random biological responses. This provides a biological rationale for selecting therapies based on symptom patterns and, ultimately, a patient's molecular profile.\u003c/p\u003e\u003cp\u003eThe seven-miRNA profile, comprising let-7b-3p, miR-100-5p, miR-129-5p, miR-135a-5p, miR-151a-5p, miR-4516, and miR-451a, associated with the response to INCREM offers profound insight into the molecular mechanisms underlying the improvement in cognitive function in MDD. Analysis of the most prominent miRNAs modulated by INCREM intervention points to pathways previously implicated in MDD pathophysiology and antidepressant response. Notably, the post-INCREM increase in plasma levels of miR-129-5p and miR-135a-5p is particularly insightful. Expression of miR-129-5p is reduced in extracellular vesicles from postmortem brain tissue and in dlPFC samples from patients with MDD [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e], yet raised in plasma after 12 weeks of SSRI escitalopram treatment [\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e]. In mouse models, miR-129-5p downregulation accompanies depressive-like phenotypes, whereas its hippocampal overexpression mitigates such behaviors by reducing microglial activation and NFκB pathway-dependent neuroinflammation [\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e]. Likewise, miR-135a is a well-established regulator of stress resilience and antidepressant response, acting on the serotonergic system by targeting the serotonin transporter (SERT) and 5-HT\u003csub\u003e1A\u003c/sub\u003e autoreceptor [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e]. Its levels have been shown to decrease in plasma and postmortem brain samples from MDD patients, as well as in mouse models exhibiting depressive-like behavior [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e, \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e]. In contrast, antidepressant treatments with duloxetine (8 weeks) or venlafaxine (12 weeks) elevate its plasma levels [\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e, \u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e]. Beyond its serotonergic role, miR-135a contributes to synaptic plasticity and memory formation. Interestingly, a three-months CBT program ‒where cognitive refers to restructuring maladaptive thoughts, unlike the process-based cognitive remediation used here‒ also increased blood miR-135a levels in MDD [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. The parallel rise of miR-129-5p and miR-135a-5p following INCREM suggests activation of molecular pathways linked to antidepressant response (both pharmacological and non-pharmacological), partly mediated by enhanced serotonergic and synaptic plasticity mechanisms.\u003c/p\u003e\u003cp\u003eIn addition, the significant increase in miR-451a following INCREM suggests a molecular link to key synaptic dysfunction in MDD. This finding aligns with extensive evidence demonstrating that miR-451a levels are decreased in the serum and cerebrospinal fluid (CSF) of patients with MDD, where they negatively correlate with the depressive symptom severity on the 24-item Hamilton Depression Scale [\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e, \u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e], although this association was not observed in another study [\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e]. MiR-451a is a promising therapeutic marker, as its baseline levels predict antidepressant efficacy, and its plasma levels were increased following 8 weeks of paroxetine treatment [\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e]. Preclinical studies provide crucial mechanistic support for this association. In mouse models of chronic stress-induced depression, miR-451a is significantly downregulated in both serum and the medial prefrontal cortex (mPFC). Overexpression of miR-451a in the mPFC of these mice reverses dendritic spine loss and improves the depressive-like phenotype by inhibiting corticotrophin-releasing factor receptor 1 expression via targeting transcription factor 2 [\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e]. This establishes a mechanistic bridge between the change in a circulating biomarker and the restoration of structural neuroplasticity in the brain, a goal of pro-cognitive treatments. Convergent evidence from other neurological conditions further underscores the importance of miR-451a in the relationship between mood and cognition. In patients with Alzheimer's disease (AD), reduced CSF levels of miR-451a were associated with both lower cognitive scores and higher depression ratings [\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e]. The same study found reduced miR-451a levels in neuronal and microglial cultures from AD-like APP/PS1 transgenic mice, while its overexpression in the mPFC improved behavioral and pathological alterations, including long-term memory deficits, depression-like phenotype, and NFκB activation and downstream neuroinflammation [\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e]. Overall, these data highlight miR-451a as a key regulator of synaptic integrity and a potential target for therapies addressing both cognitive and depressive symptoms.\u003c/p\u003e\u003cp\u003eThe upregulation of miR-151a-5p and miR-4516, along with the downregulation of let-7b-3p and miR-100-5p following INCREM treatment points to additional regulatory pathways. Although less studied in MDD, miR-4516 levels are reduced in CSF extracellular vesicles and in dlPFC of individuals with MDD who died by suicide [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e, \u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e]. The link between miR-4516 and suicide is mainly based on its predicted regulation of the \u003cem\u003eSLC6A4\u003c/em\u003e gene (which encodes the SERT protein) and other genes involved in cell adhesion and synaptic signaling (e.g., \u003cem\u003eNR3C1\u003c/em\u003e which encodes the glucocorticoid receptor) [\u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e, \u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e]. Similarly, miR-151a-5p is reduced in circulating extracellular vesicles from adolescents with anxiety disorders [\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e], while miR-151-3p (originating from the same precursor gene hsa-mir-151a) is modulated by SSRI paroxetine in human lymphoblastic cell lines derived from healthy adult females [\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e]. The let-7 family is involved in neurodegeneration, cell survival and synaptic development [\u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e]. Recently, we reported that this miRNA family is consistently downregulated by lithium treatment in both responders or non-responders groups of patients with bipolar disorder [\u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e], and elevated levels have been found in the plasma of patients with substance use disorders, which share overlapping neural circuits with MDD [\u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e, \u003cspan citationid=\"CR77\" class=\"CitationRef\"\u003e77\u003c/span\u003e]. While miR-100-5p is known in terms of its function as a tumor suppressor and its involvement in vital cellular processes through the regulation of targets such as mTOR, FOXO1, AGO2 mRNAs, among others [\u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e, \u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e], its role in MDD remains unclear. Recently, it has been linked to shared gene networks between amyotrophic lateral sclerosis and depression [\u003cspan citationid=\"CR80\" class=\"CitationRef\"\u003e80\u003c/span\u003e]. Overall, this four-miRNA profile, though requiring validation, suggests that INCREM targets master regulators of MDD-related pathways, including serotonergic plasticity and synaptic function.\u003c/p\u003e\u003cp\u003eThese mechanisms are supported by the functional enrichment analysis, which revealed that the INCREM-specific miRNAs target a pro-cognitive biological network. The enriched pathways identified, including neurotrophin signaling, axonal guidance, long-term potentiation (LTP), and glutamatergic and GABAergic synaptic transmission, as well as the cognitive pathway itself, are known to contribute to learning and memory [\u003cspan additionalcitationids=\"CR82\" citationid=\"CR81\" class=\"CitationRef\"\u003e81\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR83\" class=\"CitationRef\"\u003e83\u003c/span\u003e]. Cognitive remediation is, in essence, a form of structured, guided learning that can strengthen specific neural circuits, particularly in prefrontal and parietal networks, through mechanisms of brain plasticity [\u003cspan additionalcitationids=\"CR85\" citationid=\"CR84\" class=\"CitationRef\"\u003e84\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR86\" class=\"CitationRef\"\u003e86\u003c/span\u003e]. The findings of this study suggest a potential molecular correlate for these processes. INCREM therapy might act as an environmental stimulus with changes in miRNA expression that, in turn, could influence genes involved in synaptic strengthening (LTP), structural remodeling (axon guidance), and rebalancing of excitatory/inhibitory tone. Therefore, it could be hypothesized that this therapy (INCREM) improves cognitive and functional performance in MDD by modulating a specific set of circulating miRNAs that regulate molecular pathways implicated in neuroplasticity and brain function.\u003c/p\u003e\u003cp\u003eUnlike the INCREM intervention, the miRNA profile associated with the PSYCHOED response points to fundamentally different mechanisms of action, providing insight into how supportive interventions may exert their therapeutic benefits. The two miRNAs, miR-126-5p and miR-195-5p, significantly increased after the PSYCHOED are involved in key cellular processes rather than in synaptic plasticity \u003cem\u003eper se\u003c/em\u003e. A growing body of literature demonstrates that miR-195-5p is a potent negative regulator of the Wnt/β-catenin signaling pathway [\u003cspan citationid=\"CR87\" class=\"CitationRef\"\u003e87\u003c/span\u003e, \u003cspan citationid=\"CR88\" class=\"CitationRef\"\u003e88\u003c/span\u003e]. This pathway is a master regulator of cell fate, including proliferation, differentiation, and apoptosis, and its dysregulation is implicated in numerous diseases with inflammatory components [\u003cspan citationid=\"CR89\" class=\"CitationRef\"\u003e89\u003c/span\u003e, \u003cspan citationid=\"CR90\" class=\"CitationRef\"\u003e90\u003c/span\u003e]. However, there are few studies on the role of miR-195-5p in MDD. Changes in plasma miR-195-5p levels have recently been reported in patients with treatment-resistant depression following ECT, although the effect was not sustained [\u003cspan citationid=\"CR91\" class=\"CitationRef\"\u003e91\u003c/span\u003e]. A preclinical study reported that, in rats exposed to chronic stress, miR-195-5p expression levels decreased in the mPFC and increased in the ventral tegmental area, with stronger effects in resilient versus anhedonic rats [\u003cspan citationid=\"CR92\" class=\"CitationRef\"\u003e92\u003c/span\u003e]. The role of miR-126-5p in MDD remains unclear, though recent findings showed altered expression in plasma extracellular vesicles of adolescents with MDD compared to healthy peers [\u003cspan citationid=\"CR93\" class=\"CitationRef\"\u003e93\u003c/span\u003e]. However, miR-126-5p has been mainly involved in multiple sclerosis with high psychiatric comorbidity, being a key regulator of vascular health and neuroinflammation. Its dysregulation (either too high or too low) appears to be a common mechanism in neurological disorders involving blood-brain barrier dysfunction and oxidative stress [\u003cspan citationid=\"CR94\" class=\"CitationRef\"\u003e94\u003c/span\u003e, \u003cspan citationid=\"CR95\" class=\"CitationRef\"\u003e95\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe functional analysis of the PSYCHOED targetome did not show clear enrichment of pathways related to neuroplasticity or cognitive processing. Instead, the analysis indicated enrichment in pathways involved in cell fate and intercellular communication, such as cell senescence, Wnt signaling, cell cycle, and Hippo signaling. This distinct profile suggests that PSYCHOED may influence different biological processes to those associated with INCREM, opening up new hypothesis on how supportive therapies exert their effects. MDD is increasingly recognized as a systemic disorder associated with chronic inflammation, oxidative stress, and accelerated biological ageing [\u003cspan additionalcitationids=\"CR97\" citationid=\"CR96\" class=\"CitationRef\"\u003e96\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR98\" class=\"CitationRef\"\u003e98\u003c/span\u003e]. By providing patients with tools to manage their disease and reduce psychological distress, psychoeducation may act as a buffer against the systemic consequences of chronic stress. It is therefore biologically plausible that the benefits of PSYCHOED do not derive from direct remodeling of synaptic circuits, but rather from improved cellular health and resilience at the systemic level. Modulation of the Wnt pathway, a key regulator of tissue homeostasis, is consistent with this interpretation of a broad, systemic effect on cellular integrity. Thus, \u0026ldquo;targeted\u0026rdquo; interventions, such as INCREM, may function by directly modulating cognitive circuits and their plasticity, while \u0026ldquo;supportive\u0026rdquo; therapies like PSYCHOED may act through broader effects on systemic resilience to stress.\u003c/p\u003e\u003cp\u003eIn conclusion, this work provides novel mechanistic insight into how cognitive remediation and psychoeducation exert their therapeutic effects in MDD, demonstrating that these psychological interventions induce distinct and measurable molecular biological responses. The specific circulating miRNA profile identified for INCREM and PSYCHOED represent a significant advance, establishing a solid foundation for the development of clinically actionable biomarkers. This research paves the way for a future of precision psychiatry, in which psychological interventions can be personalized and optimized based on the individual biological profile of patients suffering from cognitive dysfunction in MDD.\u003c/p\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eStrengths, methodological considerations, and future directions\u003c/h2\u003e\u003cp\u003eThe results of this study have direct translational implications, addressing the critical need for biomarkers in psychiatry to overcome the trial-and-error approach to treatment selection [\u003cspan citationid=\"CR99\" class=\"CitationRef\"\u003e99\u003c/span\u003e]. Circulating miRNAs are ideal candidates, stable in plasma, reflecting pathophysiological processes in the central nervous system (CNS), and accessible through minimally invasive methods. This study has several strengths, including a prospective design with an active comparator, allowing specific molecular changes to be attributed to specific interventions. The selection of miRNAs, based on previous findings in post-mortem brain tissue [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e], enriched the analysis with neurobiological relevant candidates. However, certain limitations must be acknowledged. The sample analyzed in this work corresponds to an exploratory cohort within a larger project, intended to initially characterize the relationship between plasma miRNA levels and response to psychological interventions. Multiple-comparison corrections (Šid\u0026aacute;k adjustment) were applied to the miRNA analyses, while non-parametric tests were used for cognitive and functioning variables, providing partial support for the robustness of the findings despite the limited sample size. These findings require confirmation in larger, independent cohorts. Moreover, while clinical follow-up data were available, miRNA measurements were limited to pre- and post-intervention time-points, preventing longitudinal molecular analyses. Although plasma miRNAs may reflect CNS processes, their cellular origin is heterogeneous; future studies using neuron-derived extracellular vesicles could provide greater specificity [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. MiRNA signatures showed an association with response, but the correlational nature of the study limits causal interpretations. Due to the small sample size, reliable correlation analyses between changes in miRNA expression and functional and cognitive outcomes could not be performed. Clarifying whether baseline levels of these miRNAs serve as predictors or merely reflect post-response changes, remains essential. Future directions should focus on validating these findings in multicenter and diverse cohorts. Longitudinal studies are needed to track miRNA profiles from baseline, during treatment, and at follow-up to establish their predictive value for both acute response and long-term relapse prevention. Experimental validation of key interactions between miRNAs and their targets in cellular and animal models is essential to confirm functional mechanisms. Finally, integrating miRNA profiling with other modalities, such as functional neuroimaging, will allow changes in circulating biomarkers to be directly linked to the activity and connectivity of the brain circuits involved.\u003c/p\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003ch2\u003eCOMPETING INTERESTS\u003c/h2\u003e\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\u003ch2\u003eETHICS APPROVAL\u003c/h2\u003e\u003cp\u003e This study was conducted in accordance with the national ethical standards and norms and with the 1964 Helsinki Declaration by its later amendments (version of Fortaleza, 2013). Ethical approval was obtained from the local ethics committee of Hospital de la Santa Creu i Sant Pau (CEIm Sant Pau; ref. 21/119). All participants provided written informed consent prior to their inclusion in the study.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFUNDING\u003c/h2\u003e\u003cp\u003eThis work was supported by MCIU/AEI/FEDER, UE grant (PID2022-141700OB-I00, MCIN/AEI/\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.13039/501100011033\u003c/span\u003e\u003cspan address=\"10.13039/501100011033\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e to AB), ISCIII (PI20/00270 to MJP), Fundaci\u0026oacute; La Marat\u0026oacute; de TV3 and Generalitat de Catalunya (202207-30-32 to AB and JDA, and 202227-30 to MJP), and AGAUR 2021-SGR-01358 to AB and 2021-SGR-00832 to MJP of the Generalitat de Catalunya. We also thank the Spanish Stress Research Network, MCIN/AEI /\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.13039/501100011033\u003c/span\u003e\u003cspan address=\"10.13039/501100011033\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e, and CB/07/09/0010 and CB/07/09/0034 Centre for Biomedical Research in Mental Health Network (CIBERSAM). JJE is a recipient of a predoctoral fellowship (2025 FI-AGAUR) from the Catalan Government (AGAUR, Generalitat de Catalunya).\u003c/p\u003e\u003ch2\u003eAUTHOR CONTRIBUTIONS\u003c/h2\u003e\u003cp\u003e\u003cb\u003eLMR\u003c/b\u003e and \u003cb\u003eJJE\u003c/b\u003e contributed to the conceptualization and experimental design of the study, performed miRNA analyses: qPCR, GO, KEGG pathways, and statistical analyses interpreted the results and co-drafted the original version of the manuscript under the supervision of AB and MJP. \u003cb\u003eMVG\u003c/b\u003e designed the protocol, conducted the INCREM intervention groups, performed the statistical analysis, interpreted the results, co-drafted the original version of the manuscript under the supervision of AB and MJP. \u003cb\u003eVP and ERB\u003c/b\u003e managed the collection of human plasma samples and performed the RNA isolation and first-strand cDNA synthesis experiments. \u003cb\u003eJCH\u003c/b\u003e conducted clinical and neuropsychological assessments. \u003cb\u003eMJ\u003c/b\u003e did the blood sample collection throughout the study. \u003cb\u003eLG, JV, CMB\u003c/b\u003e conducted the PSYCHOED intervention groups. \u003cb\u003eDP, CA, NC, JDA\u003c/b\u003e were responsible for patient selection, and reviewed and approved the final version of the manuscript. \u003cb\u003eAB\u003c/b\u003e and \u003cb\u003eMJP\u003c/b\u003e contributed to the conceptualization and experimental design of the study, contributed to the statistical analyses and interpretation of the findings, co-wrote and edited the manuscript, supervised the entire study and provided the necessary resources. All authors reviewed and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eACKNOWLEDGEMENTS\u003c/h2\u003e\u003cp\u003e Grateful acknowledgment is extended to the patients who participated in this study and to the staff of the Department of Psychiatry at Hospital de la Santa Creu i Sant Pau for their valuable collaboration.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGBD 2019 Mental Disorders Collaborators. Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990\u0026ndash;2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Psychiatry. 2022;9:137\u0026ndash;150.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVicent-Gil M, Trujols J, Sagu\u0026eacute;s T, Serra-Blasco M, Navarra-Ventura G, Mantellini CL, et al. Insights on the cognitive enhancement effect of desvenlafaxine in major depressive disorder. 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Adv Exp Med Biol. 2021;1305:535\u0026ndash;563.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Major Depressive Disorder, Cognitive Dysfunction, Cognitive Remediation, microRNA, Biomarker, Neuroplasticity","lastPublishedDoi":"10.21203/rs.3.rs-8113450/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8113450/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eCognitive symptoms are a core and debilitating feature of major depressive disorder (MDD), often persisting and poorly addressed by current treatments, underscoring the need for objective biomarkers to guide therapeutic interventions. This study investigated whether circulating microRNAs (miRNAs) are associated with cognitive response to two distinct psychological interventions: integral cognitive remediation (INCREM) and psychoeducation (PSYCHOED). A panel of 38 miRNAs was analyzed in plasma from MDD patients before and after interventions. Our results reveal two distinct, non-overlapping miRNA patterns associated with therapeutic response. Specifically, a seven-miRNA profile ‒let-7b-3p, miR-100-5p, miR-129-5p, miR-135a-5p, miR-151a-5p, miR-4516, and miR-451a‒ was associated with response to INCREM. Bioinformatic analysis of their predicted target genes showed significant enrichment in molecular pathways crucial for neuroplasticity, synaptic function, and cognition, which correlated with objective improvements in cognitive performance. Conversely, a distinct two-miRNA profile involving miR-126-5p and miR-195-5p was associated with response to PSYCHOED. The targets of these miRNAs converge on pathways related to systemic cellular processes such as cell structure and intercellular communication, including Wnt signaling, cellular senescence, and the cell cycle. These findings provide novel mechanistic insights, suggesting that INCREM directly modulates gene networks related to neuroplasticity, whereas PSYCHOED affects more general cellular pathways. These circulating miRNA profiles are promising, minimally invasive biomarkers that could be used to personalize treatment strategies for cognitive dysfunction in MDD.\u003c/p\u003e","manuscriptTitle":"A circulating miRNA profile is associated with response to cognitive remediation in major depressive disorder","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-17 07:08:25","doi":"10.21203/rs.3.rs-8113450/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fff14b85-a8e3-411b-9b7a-0f297b16ab82","owner":[],"postedDate":"November 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":57991716,"name":"Health sciences/Biomarkers/Predictive markers"},{"id":57991717,"name":"Health sciences/Diseases/Psychiatric disorders/Depression"}],"tags":[],"updatedAt":"2025-12-02T10:07:47+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-17 07:08:25","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8113450","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8113450","identity":"rs-8113450","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}