Multiple Pre-Treatment miRNAs Levels in Untreated Major Depressive Disorder Patients Predict Early Response to Antidepressants and Interact with Key Pathways
Open accessAbstract
Major depressive disorder (MDD) is a life-impairing disorder, and early successful treatment is important for a favorable prognosis. However, early response to antidepressants differs widely among individuals, and is difficult to predict pre-treatment. As miRNAs have been reported to play important roles in depression, identification of miRNAs associated with antidepressant treatment responses and their interacting genes and pathways will be beneficial in understanding the predictors and molecular mechanisms of depression treatment. This randomized control trial examined miRNAs correlated with the early therapeutic effect of selective serotonin reuptake inhibitors (SSRIs; paroxetine or sertraline) and mirtazapine monotherapy. Before medication, we comprehensively analyzed the miRNA expression of 92 depressed participants and identified genes and pathways interacting with miRNAs. A total of 228 miRNAs were significantly correlated with depressive symptoms improvements after 2 weeks of SSRIs treatment, with miR-483.5p showing the most robust correlation. These miRNAs are involved in 21 pathways, including TGF-β, glutamatergic synapse, long-term depression, and the mitogen-activated protein kinase (MAPK) signaling pathways. Using these miRNAs enabled us to predict SSRI response at week 2 with a 57% difference. This study shows that pre-treatment levels of miRNAs could be used to predict early responses to antidepressant administration, a knowledge of genes, and an identification of genes and pathways associated with the antidepressant response.
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Written from the paper’s full text.
TL;DR
Pre-treatment plasma miRNA levels in untreated MDD patients were associated with early SSRI response; 228 miRNAs correlated with week-2 HAM-D improvement, with miR-483-5p showing the most robust correlation. A top-10 miRNA set mapped to 21 pathways and separated week-2 SSRI responders from nonresponders by 57%, while no miRNA remained significant for mirtazapine after FDR correction.
Key findings
- In 78 analyzed MDD outpatients (MIR 40/SSRI 38; paroxetine 21/sertraline 17), 228 miRNAs were significantly correlated with week-2 HAM-D score change after FDR correction in SSRI-treated patients, all inversely correlated with improvement. miR-483-5p was most robust (coefficient = 2.50, P = 7.90 × 10−5, F = 8.26, R2 = 0.59), followed by miR-3151-5p (coefficient = 3.51, P = 0.0001, F = 8.95, R2 = 0.61).
- The top 10 SSRI-response miRNAs were associated with 21 pathways, including TGF-β signaling, glutamatergic synapse, long-term depression, and MAPK signaling; TGF-β was identified from two or more databases.
- Heatmap/PCA analysis using 17 miRNAs classified subjects into four clusters; week-2 response percentages were 57.1%, 0.0%, and 22.2% in clusters 1, 2/3, and 4, respectively, compared with an average of 21.1%, described as a 57% difference.
- For mirtazapine, nine miRNAs correlated with week-2 HAM-D change before FDR correction (two inversely, seven positively; miR-483-3p p = 0.031), but none remained significant after FDR correction.
Methods
- GUNDAM Step I: open-label, randomized, flexible-dose 8-week study; Step I lasted 4 weeks. Participants were 20- to 75-year-old Japanese outpatients with DSM-IV MDD and HAM-D17 ≥14, drug-free for ≥14 days, randomized to mirtazapine or SSRI (paroxetine or sertraline); response was ≥50% reduction from baseline HAM-D.
- Pre-treatment plasma miRNA expression was measured with a 3D-Gene Human miRNA Oligo Chip designed to detect 2,555 miRBase release 20 sequences; 684 miRNAs were considered reliable after QC, and 78 of 92 baseline samples were analyzed.
- Multiple regression for continuous outcomes and logistic regression for binary outcomes controlled for age, sex, duration of current depressive episode, and pre-treatment HAM-D; Benjamini–Hochberg FDR correction was used. Top 10 miRNAs underwent in silico target/pathway analysis with DIANA: miRPath v3, and hierarchical clustering/PCA was used for heatmap analysis.
Limitations
- Stated: small cohort size requiring validation in larger MDD cohorts; no placebo or non-treatment groups; primary outcome was week-2 response and secondary outcome week-4 response, so findings cannot predict long-term treatment course.
- Evident from the text: mirtazapine findings did not survive FDR correction; the heatmap cluster analysis is described as exploratory; and target genes/pathways were derived from in silico databases rather than experimentally validated in this study.
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- Findingown data
In patients administered SSRIs, the plasma levels of 228 miRNAs were significantly correlated with changes in HAM-D score at week 2 after FDR correction.
“In patients administered SSRIs, the plasma levels of 228 miRNAs were observed to be significantly correlated with changes in HAM-D score at week 2, after FDR correction for multiple statistical tests”
- Also stated in: § 3. Discussion · boosted
“we identified 228 miRNAs that were strongly correlated with an early response to SSRIs”
Quote in the paperSubstantial claim - Also stated in: § 3. Discussion · boosted
- Findingown data
A network of these five pathways and 95 genes showed a strong interaction with these 10 miRNAs.
“A network of these five pathways and 95 genes that showed a strong interaction with these 10 miRNAs is presented in Figure 2B.”
Quote in the paperSubstantial claim - Findingown data
A further 23 miRNAs showed a significant association with responses at week 2.
“In addition, a further 23 miRNAs showed a significant association with responses at week 2.”
Quote in the paperNot a substantial claim - Findingown data
Apart from the HAM-D score change at week 2, the significance of the association with outcomes disappeared following FDR correction.
“However, apart from the HAM-D score change at week 2, the significance of the association with outcomes disappeared following FDR correction.”
Quote in the paperSubstantial claim - Findingown data
miR-451a was significantly associated with the response at week 2 in MIR patients.
“The miR-451a was also significantly associated with the response at week 2”
Quote in the paperNot a substantial claim
- Findingown data
Among patients receiving MIR, the plasma levels of nine miRNAs were significantly correlated with the change in HAM-D score at week 2.
“Among patients receiving MIR, the plasma levels of nine miRNAs were found to be significantly correlated with the change in HAM-D score at week 2”
Quote in the paperSubstantial claim - Findingown data
miR-483.5p and miR-3151.5p were also significantly associated with HAM-D score changes at week 4.
“and were also significantly associated with HAM-D score changes at week 4.”
Quote in the paperSubstantial claim - Findingown data
miR-483-3p, miR-6893-3p, and miR-4740-3p were significantly associated with the HAM-D score change at week 4 in MIR patients.
“whereas miR-483-3p, miR-6893-3p, and miR-4740-3p were significantly associated with the HAM-D score change at week 4.”
Quote in the paperSubstantial claim - Findingown data
Of the top 10 miRNAs, eight (miR-3151-5p, miR-6807-5p, miR-30c-1-3p, miR-6769a-3p, miR-7111-3p, miR-6796-3p, miR-1249-5p, and miR-4534) were shown to be associated with the TGF-β pathway.
“Of these top 10 miRNAs, eight (miR-3151-5p, miR-6807-5p, miR-30c-1-3p, miR-6769a-3p, miR-7111-3p, miR-6796-3p, miR-1249-5p, and miR-4534) were shown to be associated with this pathway.”
Quote in the paperSubstantial claim - Findingown data
The pathways that interacted robustly (adjusted p < 0.01) with these 10 miRNAs were TGF-β signaling pathway, Proteoglycans in cancer, Long-term depression, Glutamatergic synapse, and Thyroid hormone signaling pathway.
“The pathways that interacted robustly (adjusted p < 0.01) with these 10 miRNAs were as follows: TGF-β signaling pathway, Proteoglycans in cancer, Long-term depression, Glutamatergic synapse, and Thyroid hormone signaling pathway”
Quote in the paperSubstantial claim - Findingown data
Among participants, 19.2% (n = 15; MIR 7/SSRI 8) showed responses 2 weeks after the initiation of treatment.
“Among the participants, 19.2% (n = 15; MIR 7/SSRI 8) showed responses 2 weeks after the initiation of treatment”
Quote in the paperNot a substantial claim - Findingown data
Among the 228 miRNAs, miR-483.5p showed the highest correlation with HAM-D score change at week 2.
“Among these miRNAs, miR-483.5p (coefficient = 2.50, P = 7.90 × 10−5, F = 8.26, R2 = 0.59; Figure 1) and miR-3151.5p (coefficient = 3.51, P = 0.0001, F = 8.95, R2 = 0.61) showed the highest and second-highest correlations, respectively”
Quote in the paperSubstantial claim - Findingown data
None of the assessed miRNAs showed an association with baseline severity as assessed by the HAM-D score.
“None of the assessed miRNAs showed an association with baseline severity, as assessed by the HAM-D score”
Quote in the paperNot a substantial claim - Findingown data
Principal component analysis revealed that subjects could be classified into four clusters.
“principal component analysis (PCA), which revealed that subjects could be classified into four clusters”
Quote in the paperSubstantial claim - Findingown data
The baseline HAM-D score was correlated with the HAM-D score change at weeks 2 and 4.
“the baseline HAM-D score was correlated with the HAM-D score change at weeks 2 and 4.”
Quote in the paperNot a substantial claim - Findingown data
All 228 miRNAs were inversely correlated with an improvement in HAM-D score.
“all of which were inversely correlated with an improvement in HAM-D score.”
- Also stated in: § 3. Discussion · plain
“Prior to treatment, the levels of these miRNAs were inversely correlated with an improvement in depressive symptoms.”
Quote in the paperSubstantial claim - Also stated in: § 3. Discussion · plain
- Findingown data
miR-3151.5p showed the second-highest correlation with HAM-D score change at week 2.
“Among these miRNAs, miR-483.5p (coefficient = 2.50, P = 7.90 × 10−5, F = 8.26, R2 = 0.59; Figure 1) and miR-3151.5p (coefficient = 3.51, P = 0.0001, F = 8.95, R2 = 0.61) showed the highest and second-highest correlations, respectively”
Quote in the paperNot a substantial claim - Findingown data
After conservative analysis based on the probability of a jackknifing test and FDR correction, 21 pathways were significantly associated with these 10 miRNAs.
“After conservative analysis based on the probability of a jackknifing test and FDR correction, we identified 21 pathways (Table 2; micro-T-CDS, 20; Tarbase, 1; TagetScan, 1) that were significantly associated with these 10 miRNAs”
Quote in the paperSubstantial claim - Findingown data
miR-483-3p showed the most robust positive correlation (p = 0.031) among MIR patients.
“The miR-483-3p showed the most robust positive correlation (p = 0.031).”
Quote in the paperNot a substantial claim - Findingown data
The TGF-β signaling pathway was identified from two or more databases.
“Among these, the TGF-β signaling pathway was identified from two or more databases.”
- Also stated in: § 3. Discussion · plain
“the TGF-β signaling pathway was the only one that was identified in more than one database.”
Quote in the paperNot a substantial claim - Also stated in: § 3. Discussion · plain
- Findingown data
After 4 weeks of treatment, 50.0% (n = 39; MIR 17/SSRI 22) of subjects showed responses.
“after 4 weeks of treatment, 50.0% (n = 39; MIR 17/SSRI 22) of the subjects showed responses.”
Quote in the paperNot a substantial claim - Findingown data
The response rate after 2 weeks of SSRI treatment is 21% in the usual treatment.
“That is, the response rate after 2 weeks of SSRI treatment is 21% in the usual treatment, but by evaluating pre-treatment miRNAs, it is possible to divide the group into two groups: one that can expect a 57% response and the other that can expect almost no response (0%).”
Quote in the paperSubstantial claim - Findingown data
Plasma levels of miR483-5p were inversely correlated with early improvements in patients receiving SSRIs.
“We found that the plasma levels of miR483-5p were inversely correlated with early improvements in patients receiving SSRIs”
Quote in the paperSubstantial claim - Findingown data
In silico pathway analysis identified 21 pathways associated with the 228 miRNAs and their interacting genes such as TGFBR2, TNF, MAPK, and SMAD.
“In silico pathway analysis enabled us to identify 21 pathways associated with the 228 miRNAs and their interacting genes such as TGFBR2, TNF, MAPK, SMAD, including the TGF-β, glutamatergic synapse, and long-term depression pathways, associated with major depressive disorder, as well as the MAPK signaling pathway reported in previous studies [30,59,63,64,65,66,67,68].”
Quote in the paperSubstantial claim - Findingown data
No miRNAs were significantly correlated with mirtazapine treatment response after statistical correction.
“In contrast to SSRIs, we detected no miRNAs significantly correlated with a mirtazapine treatment response after statistical correction.”
Quote in the paperSubstantial claim - Findingown data
miR483-5p was the most strongly correlated of the 228 miRNAs associated with early SSRI response.
“The most strongly correlated of these, miR483-5p, has previously been reported to be dysregulated in the postmortem brains of depressed patients and reduced at the synapses therein [43].”
Quote in the paperSubstantial claim - Findingown data
miR-1202 was correlated with treatment response based on our genome-wide approach.
“In addition, we found that miR-1202, which has consistently been reported to be associated with treatment response to antidepressants using the candidate approach [46,50], was also correlated with treatment response based on our genome-wide approach.”
Quote in the paperSubstantial claim - Findingown data
Plasma levels of miR483-3p were positively correlated with early improvement in patients administered MIR.
“whereas the levels of miR483-3p were positively correlated with early improvement in those administered MIR.”
Quote in the paperSubstantial claim - Findingown data
Pre-treatment levels of 228 miRNAs were associated with an early response to selective serotonin reuptake inhibitors.
“We found that the pre-treatment levels of 228 miRNAs were associated with an early response to selective serotonin reuptake inhibitors.”
Quote in the paperSubstantial claim - Findingcitation
The present study also identified the MAPK signaling pathway as associated with antidepressant response.
“Lopez et al. concluded that the pathway associated with an antidepressant response in depressed patients is the MAPK signaling pathway, which we also identified in the present study.”
Quote in the paperSubstantial claim - Findingown data
In the present study, miR-483-5p is associated with the long-term depression pathway along with miR-3151-5p, miR-7109-5p, miR-7111-3p, and miR-1249-5p.
“we demonstrated that miR-483-5p, which is dysregulated in the postmortem brains and reduced in synapses of depressed patients, is associated with a long-term depression pathway (Figure 1), along with miR-3151-5p, miR-7109-5p, miR-7111-3p, and miR-1249-5p.”
Quote in the paperNot a substantial claim - Findingown data
The present study detected significant associations among the top 10 miRNAs and other glutamate-related genes such as GRM5, 7, GIN2B, GRIA3, GNAO1, HOMER1, and the Glutamatergic synapse pathway.
“we did, nevertheless, detect significant associations among the top10 miRNAs and other glutamate-related genes, such as GRM5, 7, GIN2B, GRIA3, GNAO1, HOMER1, and the Glutamatergic synapse pathway.”
Quote in the paperSubstantial claim - Findingown data
In the present study, miR1202 was inversely correlated with 2-week HAM-D score improvement and response at week 2 in patients administered SSRIs.
“we established that miR1202 was inversely correlated with 2-week HAM-D score improvement and response at week 2 in patients administered SSRIs (Supplementary Table S1).”
Quote in the paperSubstantial claim - Interpretationown data
These miRNAs can be used to predict the group with the highest and lowest likelihood of response at 2 weeks with a significant difference of 57%.
“The results indicate that these miRNAs can be used to predict the group with the highest and lowest likelihood of response at 2 weeks with a significant difference of 57%.”
- Also stated in: § 3. Discussion · plain
“we were able to predict the response at week 2 with a 57% difference.”
Quote in the paperSubstantial claim - Also stated in: § 3. Discussion · plain
- Study design and conductown data
With the exception of the duration of the current depressive episode, there were no significant differences among patients assigned to the different therapeutic agent groups.
“With the exception of the duration of the current depressive episode, there were no significant differences among the patients assigned to the different therapeutic agent groups.”
Quote in the paperNot a substantial claim - Premisecitation
miR-1202 has consistently been reported to be associated with treatment response to antidepressants using the candidate approach.
“In addition, we found that miR-1202, which has consistently been reported to be associated with treatment response to antidepressants using the candidate approach [46,50], was also correlated with treatment response based on our genome-wide approach.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [46] Lopez, 2014, miR-1202 is a primate-specific and brain-enriched microRNA involved in major depression and antidepressant treatment, Nat. Med. source
Not checked in the free run.
- cites [50] Fiori, 2017, Investigation of miR-1202, miR-135a, and miR-16 in Major Depressive Disorder and Antidepressant Response, Int. J. Neuropsychopharmacol. source
Not checked in the free run.
- Interpretationreasoning
The findings cannot be used to predict the long-term course of treatment.
“our findings cannot be used to predict the long-term course of treatment, which is important in MDD.”
Quote in the paperSubstantial claim - Study design and conductreasoning
The influence of known patient characteristics and unknown events was minimized.
“We are thus confident that the influence of known patient characteristics and unknown events was minimized.”
Quote in the paperSubstantial claim - Interpretationreasoning
Factors determining whether miR483-3p or 5p functions on the maturation of double-stranded miRNAs may influence the early response to SSRI and MIR treatment.
“These findings may thus indicate that the factors determining whether miR483-3p or 5p functions on the maturation of double-stranded miRNAs may influence the early response to SSRI and MIR treatment.”
Quote in the paperSubstantial claim- Rests on an assumption: miR-483-3p and miR-483-5p are derived from the same double-stranded RNA.
- Interpretationreasoning
miR-1202 and constituents of the interacting pathways are among the key molecules involved in the pathogenesis and treatment of depression.
“these observations would tend to indicate that miR-1202 and constituents of the interacting pathways are among the key molecules involved in the pathogenesis and treatment of depression [53].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [53] Dadkhah, 2017, A genetic variant in miRNA binding site of glutamate receptor 4, metabotropic (GRM4) is associated with increased risk of major depressive disorder, J. Affect. Disord. source
Not checked in the free run.
- Study design and conductreasoning
The randomized controlled trial design had no drug selection bias.
“we used a randomized controlled trial design, and consequently there was no drug selection bias.”
Quote in the paperSubstantial claim - Interpretationown data
By evaluating pre-treatment miRNAs, it is possible to divide SSRI-treated patients into two groups: one that can expect a 57% response and the other that can expect almost no response (0%) at 2 weeks.
“That is, the response rate after 2 weeks of SSRI treatment is 21% in the usual treatment, but by evaluating pre-treatment miRNAs, it is possible to divide the group into two groups: one that can expect a 57% response and the other that can expect almost no response (0%).”
Quote in the paperSubstantial claim - Study design and conductreasoning
The use of a comprehensive genome-wide approach and conservative statistical methods enabled analysis of not only known but also unknown miRNAs.
“the use of a comprehensive genome-wide approach and conservative statistical methods, rather than a hypothesis-based candidate approach for the targeted miRNAs, enabled us to analyze not only known but also unknown miRNAs.”
Quote in the paperSubstantial claim - Premisecitation
Partial responses at 2 weeks have been shown to be strongly correlated with subsequent remission.
“the partial responses at 2 weeks have, nonetheless, been shown to be strongly correlated with subsequent remission [19,51].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [19] Szegedi, 2009, Early improvement in the first 2 weeks as a predictor of treatment outcome in patients with major depressive disorder: A meta-analysis including 6562 patients, J. Clin. Psychiatry source
Not checked in the free run.
- cites [51] Wagner, 2017, Early improvement as a resilience signal predicting later remission to antidepressant treatment in patients with Major Depressive Disorder: Systematic review and meta-analysis, J. Psychiatry Res. source
Not checked in the free run.
- Study design and conductown data
The study did not include placebo and/or non-treatment groups in the analysis.
“we did not include placebo and/or non-treatment groups in the analysis.”
Quote in the paperSubstantial claim - Interpretationown data
The findings indicate that these miRNAs could be used to predict groups with the highest and least likelihood of antidepressant response at 2 weeks.
“Although preliminary, the findings of this study indicate that these miRNAs could be used to predict groups with the highest and least likelihood of antidepressant response at 2 weeks.”
Quote in the paperSubstantial claim
- May combine two claims. 12
- Classified as probably not a substantial claim. 16
May combine two claims.
Findingown dataWeek 2 response percentages were higher in cluster 1 and lower in clusters 2 and 3 compared with the average percentage of 21.1%.
“These were higher in cluster 1 and lower in clusters 2 and 3 compared with the average percentage of 21.1%.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataChanges in HAM-D score from baseline for MIR and SSRIs were −6.8 and −5.3 at week 2, and −9.8 and −9.6 at week 4, respectively.
“the changes in HAM-D score from the study baseline for MIR and SSRIs were −6.8 and −5.3 at week 2, and −9.8 and −9.6 at week 4, respectively.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataOf the nine MIR-associated miRNAs, two were inversely correlated with an improvement in HAM-D score, whereas the remaining seven were positively correlated.
“of which, two were inversely correlated with an improvement in HAM-D score, whereas the remaining seven were positively correlated.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataHeat map analysis using 17 miRNAs showed a statistically significant association with HAM-D score change at week 2 (adjusted p < 0.05) and correlated with the week 2 response with an unadjusted p-value < 0.01.
“we performed heat map analysis using 17 miRNAs that showed a statistically significant association with HAM-D score change at week 2 (adjusted p < 0.05) and were also correlated with the week 2 response with an unadjusted p-value < 0.01”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn MIR patients, the significance of each miRNA association disappeared following FDR correction, and no miRNAs correlated with an early response remained significant after correction.
“In each case, however, the significance of the association disappeared following FDR correction.”
- Also stated in: § 3. Discussion · plain
“Notably, in the case of patients receiving MIR, having performed correction for multiple testing, we were unable to identify any miRNAs correlated with an early response.”
Quote in the paperSubstantial claim- Also stated in: § 3. Discussion · plain
May combine two claims.
Findingnone givenAmong the top hit miRNAs that showed significant pre-correction associations, miRNA levels were not only inversely correlated with the improvement in depressive symptoms but also more often positively correlated.
“Among the top hit miRNAs that showed significant pre-correction associations, miRNA levels were not only inversely correlated with the improvement in depressive symptoms but also were more often positively correlated.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe top 10 miRNAs (miR-483-5p, miR-3151-5p, miR-7109-5p, miR-6807-5p, miR-30c-1-3p, miR-6769a-3p, miR-7111-3p, miR-6796-3p, miR-1249-5p, and miR-4534) were positively intercorrelated and strongly associated with HAM-D score reduction after 2 weeks of SSRI treatment even after FDR correction.
“The top 10 miRNAs (miR-483-5p, miR-3151-5p, miR-7109-5p, miR-6807-5p, miR-30c-1-3p, miR-6769a-3p, miR-7111-3p, miR-6796-3p, miR-1249-5p, and miR-4534), which were positively intercorrelated (Figure 2A) and strongly associated with a HAM-D score reduction after 2 weeks of SSRI treatment, even after FDR correction”
Quote in the paperSubstantial claimMay combine two claims.
FindingcitationIn the present analyses, miR-6511a-3p did not appear to be associated with a treatment response, whereas miR-2110 was highly correlated with an early response with a statistically significant adjusted p-value.
“of which, miR-6511a-3p did not appear to be associated with a treatment response, whereas the second, miR-2110, was observed to be highly correlated with an early response with a statistically significant adjusted p-value.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe long-term depression pathway comprises glutaminergic synapse-related genes, and MAPK3, IGF1, GRIA3, CACNA1, GNA11, GNAO1, PLA2G4E, and PRKCA interact with SSRI early response-related miRNAs.
“This pathway comprises glutaminergic synapse-related genes, and we established that MAPK3, IGF1, GRIA3, CACNA1, GNA11, GNAO1, PLA2G4E, and PRKCA interact with SSRI early response-related miRNAs.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationPrevious studies indicated that blood miR1202 in pre-treatment depressed patients was inversely correlated with the treatment response to antidepressants.
“They have indicated that blood miR1202 in pre-treatment depressed patients was inversely correlated with the treatment response to antidepressants [46,50].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [46] Lopez, 2014, miR-1202 is a primate-specific and brain-enriched microRNA involved in major depression and antidepressant treatment, Nat. Med. source
Not checked in the free run.
- cites [50] Fiori, 2017, Investigation of miR-1202, miR-135a, and miR-16 in Major Depressive Disorder and Antidepressant Response, Int. J. Neuropsychopharmacol. source
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductown dataAfter quality control, 78 participants (MIR 40/SSRI 38; paroxetine 21 or sertraline 17) were included in the subsequent analysis.
“After undertaking quality control, 78 (MIR 40/SSRI 38; paroxetine (PAX) 21 or sertraline (SER) 17) participants were included in the subsequent analysis.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductown dataThe statistical models were controlled for age, sex, duration of current depressive episode, and pre-treatment HAM-D score.
“The models were controlled for age, sex, duration of current depressive episode, and pre-treatment HAN-D score.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationYoshino et al. found that miR-483-5p was significantly more down-regulated in a synaptic fraction from the dorsolateral prefrontal cortex of MDD subjects compared with healthy controls.
“the authors found miR-483-5p found to be significantly more down-regulated in a synaptic fraction from the dorsolateral prefrontal cortex (dlPFC) of MDD subjects compared with healthy controls [43].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [43] Yoshino, 2021, Differential and unique patterns of synaptic miRNA expression in dorsolateral prefrontal cortex of depressed subjects, Neuropsychopharmacology source
Not checked in the free run.
May combine two claims.
Premiseown dataThe identified pathways include TGF-β, glutamatergic synapse, and long-term depression pathways, which are associated with major depressive disorder.
“In silico pathway analysis enabled us to identify 21 pathways associated with the 228 miRNAs and their interacting genes such as TGFBR2, TNF, MAPK, SMAD, including the TGF-β, glutamatergic synapse, and long-term depression pathways, associated with major depressive disorder, as well as the MAPK signaling pathway reported in previous studies [30,59,63,64,65,66,67,68].”
Quote in the paperSubstantial claim0 of 8 sources checked- cites [30] Atake, 2022, Pretreatment plasma cytokine levels as potential predictors of short-term remission of depression, World J. Biol. Psychiatry
Not checked in the free run.
- cites [59] Lopez, 2017, MicroRNAs 146a/b-5 and 425-3p and 24-3p are markers of antidepressant response and regulate MAPK/Wnt-system genes, Nat. Commun. source
Not checked in the free run.
- cites [63] Caraci, 2018, Neurobiological links between depression and AD: The role of TGF-β1 signaling as a new pharmacological target, Pharmacol. Res. source
Not checked in the free run.
- cites [64] Liput, 2022, 2-Arachidonoylglycerol mobilization following brief synaptic stimulation in the dorsal lateral striatum requires glutamatergic and cholinergic neurotransmission, Neuropharmacology source
Not checked in the free run.
- cites [65] Hiew, L.F., Poon, C.H., You, H.Z., and Lim, L.W. (2021). TGF-β/Smad Signalling in Neurogenesis: Implications for Neuropsychiatric Diseases. Cells, 10. source
Not checked in the free run.
- cites [66] Krieglstein, 2011, More than being protective: Functional roles for TGF-β/activin signaling pathways at central synapses, Trends Neurosci. source
Not checked in the free run.
- cites [67] Behl, 2022, Polyphenols inhibiting MAPK signalling pathway mediated oxidative stress and inflammation in depression, Biomed. Pharmacother. source
Not checked in the free run.
- cites [68] Wang, 2020, Regulation of Circadian Genes by the MAPK Pathway: Implications for Rapid Antidepressant Action, Neurosci. Bull. source
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductnone givenThe diagnoses were performed by two independent senior psychiatrists and confirmed by a third.
“The diagnoses were performed by two independent senior psychiatrists and confirmed by a third.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductown dataThe Benjamini-Hochberg false discovery rate correction was used to correct for multiple testing, with an adjusted p-value of 0.05.
“The Benjamini–Hochberg false discovery rate (FDR) correction was used to correct for the proportion of miRNAs likely to be identified as significant by chance by multiple tests (adjusted p-value of 0.05).”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductreasoningOf the 2555 miRNAs assessed, data for 684 were considered sufficiently reliable and used for subsequent statistical analysis after quantile normalization.
“Of the 2555 miRNAs assessed, data obtained for 684 were considered sufficiently reliable and used for subsequent statistical analysis, having initially undergone quantile normalization.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductnone givenParticipants were randomly assigned to an MIR or SSRI (PAX or SER) group.
“Participants were randomly assigned to an MIR or SSRI (PAX or SER) group.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenSignals less than the average background signal value ±2 SD or considered abnormal in scanned images were removed as missing areas.
“Signals that were less than the average background signal value ±2 SD or considered abnormal in the scanned images and thus unsuitable as data were removed as missing areas.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductreasoningThe findings are to a certain extent limited by the small cohort size.
“our findings are to a certain extent limited by the small cohort size”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductnone givenmiRNA assays detected in less than 80% of subjects were regarded as unreliable.
“When an miRNA was detected in only a proportion of the subjects (less than 80%), the assay of the miRNA was regarded as unreliable.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationChanges in miR-1202 levels during antidepressant treatment are correlated with changes in brain activity.
“changes in miR-1202 levels during antidepressant treatment are correlated with changes in brain activity [52]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [52] Lopez, 2017, Co-Variation of Peripheral Levels of miR-1202 and Brain Activity and Connectivity during Antidepressant Treatment, Neuropsychopharmacology source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationmiR483-5p has previously been reported to be dysregulated in the postmortem brains of depressed patients and reduced at the synapses therein.
“The most strongly correlated of these, miR483-5p, has previously been reported to be dysregulated in the postmortem brains of depressed patients and reduced at the synapses therein [43].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [43] Yoshino, 2021, Differential and unique patterns of synaptic miRNA expression in dorsolateral prefrontal cortex of depressed subjects, Neuropsychopharmacology source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe MAPK signaling pathway has been reported in previous studies.
“In silico pathway analysis enabled us to identify 21 pathways associated with the 228 miRNAs and their interacting genes such as TGFBR2, TNF, MAPK, SMAD, including the TGF-β, glutamatergic synapse, and long-term depression pathways, associated with major depressive disorder, as well as the MAPK signaling pathway reported in previous studies [30,59,63,64,65,66,67,68].”
Quote in the paperNot a substantial claim0 of 8 sources checked- cites [30] Atake, 2022, Pretreatment plasma cytokine levels as potential predictors of short-term remission of depression, World J. Biol. Psychiatry
Not checked in the free run.
- cites [59] Lopez, 2017, MicroRNAs 146a/b-5 and 425-3p and 24-3p are markers of antidepressant response and regulate MAPK/Wnt-system genes, Nat. Commun. source
Not checked in the free run.
- cites [63] Caraci, 2018, Neurobiological links between depression and AD: The role of TGF-β1 signaling as a new pharmacological target, Pharmacol. Res. source
Not checked in the free run.
- cites [64] Liput, 2022, 2-Arachidonoylglycerol mobilization following brief synaptic stimulation in the dorsal lateral striatum requires glutamatergic and cholinergic neurotransmission, Neuropharmacology source
Not checked in the free run.
- cites [65] Hiew, L.F., Poon, C.H., You, H.Z., and Lim, L.W. (2021). TGF-β/Smad Signalling in Neurogenesis: Implications for Neuropsychiatric Diseases. Cells, 10. source
Not checked in the free run.
- cites [66] Krieglstein, 2011, More than being protective: Functional roles for TGF-β/activin signaling pathways at central synapses, Trends Neurosci. source
Not checked in the free run.
- cites [67] Behl, 2022, Polyphenols inhibiting MAPK signalling pathway mediated oxidative stress and inflammation in depression, Biomed. Pharmacother. source
Not checked in the free run.
- cites [68] Wang, 2020, Regulation of Circadian Genes by the MAPK Pathway: Implications for Rapid Antidepressant Action, Neurosci. Bull. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe study was registered in the UMIN (University Hospital Medical Information; No. 000006417).
“The study was registered in the UMIN (University Hospital Medical Information; No. 000006417).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPrevious studies showed that miR-1202 is correlated with the expression of the gene encoding metabotropic glutamate receptor-4 (GRM4).
“These previous studies have also shown that miR-1202 is correlated with the expression of the gene encoding metabotropic glutamate receptor-4 (GRM4).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [46] Lopez, 2014, miR-1202 is a primate-specific and brain-enriched microRNA involved in major depression and antidepressant treatment, Nat. Med. source
Not checked in the free run.
- cites [50] Fiori, 2017, Investigation of miR-1202, miR-135a, and miR-16 in Major Depressive Disorder and Antidepressant Response, Int. J. Neuropsychopharmacol. source
Not checked in the free run.
The authors state this as an assumption.
There is a common pathway associated with the treatment response at 2 and 8 weeks.
“Thus, it would be reasonable to assume that there is a common pathway associated with the treatment response at 2 and 8 weeks.”
The paper relies on this without support.
TGF-β, glutamatergic synapse, and long-term depression pathways are associated with MDD.
“including TGF-β, glutamatergic synapse and long-term depression, which are known to be associated with MDD.”
The paper relies on this without support.
miR-483-3p and miR-483-5p are derived from the same double-stranded RNA.
“the top hit miRNA, namely, miR483-3p, derived from the same dsRNA as the SSRI top hit miRNA, miR483-5p.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Some evidence suggests that SSRIs, SNRIs, or ketamine may exert their influence by affecting miRNAs.
“Some evidence suggests that SSRIs, SNRIs, or ketamine may exert their influence by affecting miRNAs.249,325–328”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [249]
The Conclusions (page unavailable) link pre-treatment miRNA levels to early SSRI response, and the Discussion (page unavailable) reports changes in miRNAs following duloxetine treatment, an SNRI. These passages connect miRNAs with antidepressant response, but the study does not show that SSRIs exert their effects by changing miRNAs, and it provides no evidence for that mechanism with ketamine. (LLM, conf=0.83)
Experimental — accuracy not yet measuredThe link between miRNAs and the pathophysiology of depression may be implicated by the fact that miRNAs regulate neuronal regulation, neurotransmitter regulation, and microglia activation.
“The link between miRNAs and the pathophysiology of depression248–252 may be implicated by the fact that miRNAs regulate neuronal regulation, neurotransmitter regulation, and microglia activation.253,254”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [249]
The citation lists haven’t been fetched yet
References 70 · Cited by 23
- Authors
- Kato, M., Ogata, H., Tahara, H., Shimamoto, A., Takekita, Y., Koshikawa, Y., Nishida, K., Nonen, S., Higasa, K., & Kinoshita, T.
- Affiliations
- Kansai Medical University (JP)
- Hiroshima University (JP)
- Sanyo-Onoda City University (JP)
- Hyogo University of Health Sciences (JP)
- Corresponding author
- Kato, Masaki
- ORCID
- Venue
- International Journal of Molecular Sciences
- Publisher
- MDPI AG
- Published
- 2022-03-31
- Volume
- 23
- Issue
- 7
- Pages
- 3873
- ISSN
- 1422-0067 (ISSN-L)
- PMC
- PMC8999364
- OpenAlex
- W4220671154
- Semantic Scholar
- a59fe9c0d9df89b0d7687c2fc914316339563470
- Cited by
- 23
- References
- 70
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 9 · 2023: 6 · 2022: 4
- FWCI
- 3.14
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- International Journal of Molecular Sciences (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Grant-in-Aid for Scientific Research (No. 23591684)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- major depressive disorder, microRNA, antidepressant response prediction, selective serotonin reuptake inhibitors, paroxetine, sertraline, mirtazapine, miR-483-5p, TGF-beta signaling, glutamatergic synapses, long-term depression, MAPK signaling, biomarkers, treatment response
- MeSH terms
- Mirtazapine, Antidepressive Agents, Major Depressive Disorder, Humans, Selective Serotonin Reuptake Inhibitors, MicroRNAs
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