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Cited by 32Electroconvulsive Therapy StudiesEpigenetics and DNA MethylationTreatment of Major Depression

Methylome-wide change associated with response to electroconvulsive therapy in depressed patients

Open access
Sirignano, Lea, Frank, Josef, Kranaster, Laura, Witt, Stephanie H., Streit, Fabian, Zillich, Lea, Sartorius, Alexander, Rietschel, Marcella +1 more·2021·Translational Psychiatry
DOI 10.1038/s41398-021-01474-9PMC PMC8179923
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Abstract

Electroconvulsive therapy (ECT) is a quick-acting and powerful antidepressant treatment considered to be effective in treating severe and pharmacotherapy-resistant forms of depression. Recent studies have suggested that epigenetic mechanisms can mediate treatment response and investigations about the relationship between the effects of ECT and DNA methylation have so far largely taken candidate approaches. In the present study, we examined the effects of ECT on the methylome associated with response in depressed patients ( n = 34), testing for differentially methylated CpG sites before the first and after the last ECT treatment. We identified one differentially methylated CpG site associated with the effect of ECT response (defined as >50% decrease in Hamilton Depression Rating Scale score, HDRS), TNKS ( q < 0.05; p = 7.15 × 10 −8 ). When defining response continuously (ΔHDRS), the top suggestive differentially methylated CpG site was in FKBP5 ( p = 3.94 × 10 −7 ). Regional analyses identified two differentially methylated regions on chromosomes 8 (Šídák’s p = 0.0031) and 20 (Šídák’s p = 4.2 × 10 −5 ) associated with ΔHDRS. Functional pathway analysis did not identify any significant pathways. A confirmatory look at candidates previously proposed to be involved in ECT mechanisms found CpG sites associated with response only at the nominally significant level ( p < 0.05). Despite the limited sample size, the present study was able to identify epigenetic change associated with ECT response suggesting that this approach, especially when involving larger samples, has the potential to inform the study of mechanisms involved in ECT and severe and treatment-resistant depression.

AI snapshot

Written from the paper’s full text.

TL;DR

In 34 depressed patients receiving ECT, methylome-wide testing before and after treatment identified one CpG site significantly associated with binary response in TNKS and suggestive/regional signals including FKBP5 and two differentially methylated regions. No significant functional pathways emerged, and most previously proposed candidate genes showed only nominal associations.

Key findings

  • For binary response (>50% decrease in HDRS; 25 responders, 9 non-responders), one CpG site, cg10005358 in TNKS, was significantly differentially methylated (q < 0.05; p = 7.15 × 10−8); eight additional sites reached a suggestive threshold of p < 1 × 10−5.
  • For continuous response (ΔHDRS), no CpG site reached q < 0.05; the top suggestive site was in FKBP5 (abstract p = 3.94 × 10−7; ΔHDRS model p = 4.46 × 10−7).
  • Two differentially methylated regions were associated with ΔHDRS: chromosome 8 in LRATD2 (FAM84B) (3 probes, Šídák’s p = 0.0031) and chromosome 20 in BLCAP and the NNAT promoter (13 probes, Šídák’s p = 4.2 × 10−5).
  • Pathway analysis found no significant pathways; candidate CpG sites were mostly associated only at nominal p < 0.05, except FKBP5 in the continuous candidate analysis survived secondary correction (q = 0.0004).

Methods

  • Longitudinal epigenome-wide study of 34 patients with a major unipolar depressive episode assigned to ECT at the Central Institute of Mental Health, Mannheim, Germany, between 2014 and 2016; HDRS and blood were collected before the first (T1) and after the last (T2) ECT session (average 10.82 sessions, range 5–25).
  • DNA methylation was measured with the Illumina Infinium Methylation EPIC array (>850,000 CpG sites); analyses used mixed linear models in Limma with participant ID as a blocking factor and covariates including estimated cell fractions, 10 control-probe principal components, age, sex, and smoking status.
  • Response was modeled both as binary (>50% HDRS decrease) and continuous (ΔHDRS); additional analyses examined baseline methylation, differentially methylated regions with comb-p, Gene Ontology enrichment with missMethyl, and targeted candidate CpG sites from prior depression/ECT literature.

Limitations

  • Stated by the authors: the sample size was limited despite being the largest such study to date; whole-blood methylation may not reflect brain effects of ECT; anesthesia and pharmacotherapy are potential confounders, although medication was kept constant during ECT and anesthesia/dosage did not differ between patients; confirmation in larger samples is needed.
  • Evident from the text: no significant pathways were identified, baseline methylation was not significantly associated with response, and most candidate-gene findings were only nominally significant and did not survive secondary FDR correction; the sample was all Caucasian and excluded substance-use disorders other than tobacco/alcohol and lifetime schizophrenia, limiting generalizability.

Model-written summary. Check it against the paper before relying on it.

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Registry

Crossref · 10.1038/s41398-021-01474-9

Cites

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Statistics

Nothing to recompute.

Claims the paper makes

0 of 52 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The chromosome 8 DMR (CHR 8: 127568854-127569023) is located in the LRATD2 (FAM84B) gene.

    “The DMR on chromosome 8 (CHR 8: 127568854-127569023) is located in the LRATD2 (FAM84B) gene”
    Quote in the paperNot a substantial claim
  • Findingnone given

    No significant pathways were observed in any of the models.

    “No significant pathways were observed in any of the models.”
    Quote in the paperNot a substantial claim
  • Findingown data

    The top 3 candidate CpG sites associated with continuous response were FKBP5 (cg01294490, p = 4.46 × 10−7), BDNF (cg15710245, p = 0.0033), and BDNF-AS (cg09878183, p = 0.0034).

    “The top 3 candidate CpG sites associated with continuous response were, FKBP5 (cg01294490, p = 4.46 × 10−7), BDNF (cg15710245, p = 0.0033), and BDNF-AS (cg09878183, p = 0.0034).”
    Quote in the paperSubstantial claim
  • Findingown data

    The site annotated to FKBP5 survived the secondary correction for multiple testing (q = 0.0004).

    “The site annotated to FKBP5 survived the secondary correction for multiple testing (q = 0.0004).”
    Quote in the paperSubstantial claim
  • Findingown data

    In the continuous response model, 42 CpG sites were nominally associated with ΔHDRS × timepoint interaction.

    “In the continuous response model, 41, 43, and 42 CpG sites were nominally associated with ΔHDRS, timepoint and ΔHDRS × timepoint interaction, respectively.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 35
  • Classified as probably not a substantial claim. 42

  • May combine two claims.

    Findingown data

    Regional analysis identified two differentially methylated regions associated with ΔHDRS: one on chromosome 8 (Šídák's p = 0.0031) and one on chromosome 20 (Šídák's p = 4.2 × 10−5).

    “Regional analyses identified two differentially methylated regions on chromosomes 8 (Šídák’s p = 0.0031) and 20 (Šídák’s p = 4.2 × 10−5) associated with ΔHDRS.”
    • Also stated in: § Differentially methylated region analysis · plain
      “Two DMRs were identified as associated with effect of ΔHDRS in the continuous response model. One significant DMR on chromosome 8 was identified (3 probes, Šídák’s corrected p = 0.0031) and another on chromosome 20 (13 probes, Šídák’s corrected p = 4.2 × 10−5).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the binary response model, no significantly differentially methylated CpG sites were observed for the effect of timepoint or for the interaction effect at p < 1 × 10−5.

    “No significantly differentially methylated CpG sites were observed for the effect of timepoint (at p < 1 × 10−5; 22 CpG sites), or interaction effect (at p < 1 × 10−5; 12 CpG sites).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    At a suggestive threshold of p < 1 × 10−5, baseline methylation was associated with binary response at 9 CpG sites and with ΔHDRS at 6 CpG sites.

    “At a suggestive threshold of p < 1 × 10−5 baseline methylation was associated with binary response at 9 CpG sites and with ΔHDRS at 6 CpG sites (see Tables S3.1 and S3.2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the sample analyzed, using binary criteria (defined as decrease of HDRS score of more than 50%), 25 were responders and 9 were non-responders to ECT.

    “In the sample analyzed, using binary criteria, (defined as decrease of HDRS score of more than 50%) 25 were responders and 9 were non-responders to ECT.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Binary response to ECT was positively correlated with sex (being male), while continuous response (ΔHDRS score) was also associated with male sex and positively correlated with increased age.

    “Briefly, as also reported for the total sample in11, binary response to ECT was positively correlated with sex (being male) while continuous response (ΔHDRS score) was also associated with male sex and positively correlated with increased age.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Foo, J. C. et al. Evidence for increased genetic risk load for major depression in patients assigned to electroconvulsive therapy. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 180, 35–45 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    The chromosome 20 DMR (CHR 20: 36148620-36148861) is located in the BLCAP gene and in the promoter region of NNAT (791 base pairs upstream of the transcription start site).

    “the chromosome 20 DMR (CHR 20: 36148620-36148861) is located in the BLCAP gene and in the promoter region of NNAT (791 base pairs upstream of the transcription start site, TSS).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Baseline methylation was not significantly associated with either binary or continuous response.

    “Methylation at baseline was not significantly associated with either binary or continuous response.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the continuous response model (ΔHDRS), the top suggestive differentially methylated CpG site was in FKBP5 (cg01294490), with p = 4.46 × 10−7 for ΔHDRS and p < 3.94 × 10−7 for the ΔHDRS × timepoint interaction.

    “When defining response continuously (ΔHDRS), the top suggestive differentially methylated CpG site was in FKBP5 (p = 3.94 × 10−7).”
    • Also stated in: § Single CpG site analysis · plain
      “FKBP5 (CHR 6: cg01294490) was the top hit for both effect of ΔHDRS (p = 4.46 × 10−7) and effect of interaction of ΔHDRS × timepoint (p < 3.94 × 10−7).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Several candidate genes proposed in the literature were found harboring CpG sites with nominally significant changes between T1 and T2, and T1 methylation values for a number of them were also nominally associated with response (both binary and continuous).

    “Several candidate genes proposed in the literature were found harboring CpG sites with nominally significant changes between T1 and T2, and T1 methylation values for a number of them were also nominally associated with response (both binary and continuous) (see Tables S4.1–S6.2)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The DMR on chromosome 20 is located in BLCAP and in the promoter region of NNAT.

    “The DMR on chromosome 20 is located in BLCAP and in the promoter region of NNAT.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    DNA methylation is thought to be involved in disease pathology through its influence on gene expression and cellular function.

    “DNA methylation is thought to be involved in disease pathology through its influence on gene expression and cellular function5,6.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [5] Jones, P. A. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat. Rev. Genet. 13, 484–492 (2012). source

      Not checked in the free run.

    • cites [6] Meissner, A. et al. Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 454, 766–770 (2008). source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductcitation

    White blood cell fractions were estimated and five of six estimates were included as covariates in downstream analyses to control for influences of cell type distribution on DNA methylation.

    “White blood cell fractions were estimated according to28. Five of the six resulting estimates were subsequently included as covariates in downstream analyses to control for influences of cell type distribution on DNA methylation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Houseman, E. A. et al. DNA methylation arrays as surrogate measures of cell mixture distribution. BMC Bioinformatics 13, 86 (2012). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Levene's test found no significant differences between group variances.

    “Levene’s test found no significant differences between group variances.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Premisereasoning

    Investigating change of methylation levels during treatment may inform the biological processes underlying both depression and antidepressant response.

    “Investigating change of methylation levels during treatment may inform the biological processes underlying both depression and antidepressant response.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Samples with insufficient DNA quality as denoted by a call rate of <95% were excluded.

    “Samples with insufficient DNA quality as denoted by a call rate of <95% were excluded.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Sex was highly correlated with the 5th control probe PC, so this PC was not included in statistical models to avoid collinearity issues.

    “It was observed that sex was highly correlated with the 5th control probe PC, thus this PC was not included in the statistical models to avoid collinearity issues.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    ECT patients tend to show a higher genetic burden for major depression than those with less severe forms, and this subgroup is likely clinically and genetically more homogenous.

    “It is likely that this subgroup is not only clinically but also genetically more homogenous, especially as these patients tend to show a higher genetic burden for major depression than those with less severe forms11.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Foo, J. C. et al. Evidence for increased genetic risk load for major depression in patients assigned to electroconvulsive therapy. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 180, 35–45 (2019). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    BDNF is involved in neuroplastic changes associated with stress and depression.

    “Another candidate gene is brain-derived neurotrophic factor (BDNF) which is involved in neuroplastic changes associated with stress and depression13,14.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [13] Levy, M. et al. Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression. Psychopharmacology 235, 2195–2220 (2018). source

      Not checked in the free run.

    • cites [14] Pittenger, C. & Duman, R. S. Stress, depression, and neuroplasticity: a convergence of mechanisms. Neuropsychopharmacology 33, 88–109 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Despite the limited sample size, the present study was able to identify epigenetic change associated with ECT response, suggesting that this approach, especially when involving larger samples, has the potential to inform the study of mechanisms involved in ECT and severe and treatment-resistant depression.

    “Despite the limited sample size, the present study was able to identify epigenetic change associated with ECT response suggesting that this approach, especially when involving larger samples, has the potential to inform the study of mechanisms involved in ECT and severe and treatment-resistant depression.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Time of blood collection was kept constant between 8:30 and 9:30 a.m. at both timepoints to preclude potential confounding effects from ward routines and circadian fluctuations.

    “Time of collection was kept constant between 8:30 and 9:30 a.m. at both timepoints to keep it close to the clinical interview conducted around the same time, as well as preclude any potential confounding effects arising from ward routines and circadian fluctuations23,24.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [23] Rijo-Ferreira, F. & Takahashi, J. S. Genomics of circadian rhythms in health and disease. Genome Med. 11, 82 (2019). source

      Not checked in the free run.

    • cites [24] Liu, C. & Chung, M. Genetics and epigenetics of circadian rhythms and their potential roles in neuropsychiatric disorders. Neurosci. Bull. 31, 141–159 (2015). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Patients were excluded if they had any substance-use-related disorders (other than tobacco and alcohol use disorders) or a lifetime diagnosis of schizophrenia.

    “Patients were excluded if they had any substance-use-related disorders (other than tobacco and alcohol use disorders) or a lifetime diagnosis of schizophrenia.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    Examining methylation changes in ECT patients offers an optimal research setting because treatment effects are substantial and occur soon after the intervention, and ECT patients represent a subgroup with the most severe form of depression.

    “Examining these changes in ECT patients offers an optimal research setting as: (1) treatment effects are substantial and occur soon after the intervention, and (2) ECT patients represent a subgroup of patients with the most severe form of depression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A translational study observed that response to electroconvulsive stimulation (ECS) in rats was predicted by higher p11 promoter methylation, and this was also found in two human samples (n = 11; n = 65) in response to ECT.

    “A translational study observed that the response to electroconvulsive stimulation (ECS) in rats was predicted by higher p11 promoter methylation and found this also to be the case in two human samples (n = 11; n = 65) in response to ECT12.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] Neyazi, A. et al. P11 promoter methylation predicts the antidepressant effect of electroconvulsive therapy. Transl. Psychiatry 8, 25 (2018). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Associations between pre-treatment BDNF levels and ECT outcome have been described.

    “Furthermore, associations between pre-treatment BDNF levels and ECT outcome have been described, but whether BDNF levels are indicative of response remains to be determined20,21.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [20] Rocha, R. B. et al. Increased BDNF levels after electroconvulsive therapy in patients with major depressive disorder: a meta-analysis study. J. Psychiatr. Res. 83, 47–53 (2016). source

      Not checked in the free run.

    • cites [21] van Zutphen, E. M. et al. Brain-derived neurotrophic factor as a possible predictor of electroconvulsive therapy outcome. Transl. Psychiatry 9, 155 (2019). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Premisereasoning

    As ECT is a non-specific treatment with widespread, yet uncertain effects on biological processes, the selection of predefined candidates relying on prior knowledge may not give the full picture.

    “However, as ECT is a non-specific treatment with widespread, yet uncertain effects on biological processes, the selection of predefined candidates, relying on prior knowledge may not give the full picture.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    CpG sites were filtered by removing cross-hybridizing probes, probes with high missing rate (>0.02), and probes linked to X- and Y-chromosomes.

    “CpG sites were filtered by removing cross-hybridizing probes, probes with high missing rate (>0.02), and probes linked to X- and Y-chromosomes.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    A secondary FDR correction was applied to the list of all candidate CpG sites to control for false positives.

    “A secondary FDR correction was applied to the list of all candidate CpG sites to control for false positives.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    Research on ECT-related changes in methylation levels has largely focused on candidate genes.

    “Research on ECT-related changes in methylation levels has largely focused on candidate genes.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Patients kept the same medication regimens throughout ECT treatment.

    “The patients kept the same medication regimens throughout ECT treatment.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Studies in animals and humans propose an involvement of BDNF in response to ECT: after ECS/ECT, alterations of BDNF levels have been found in rats, and in humans, differences in expression of BDNF have been described.

    “Studies in animals and humans also propose an involvement of BDNF in response to ECT: after ECS/ECT, alterations of BDNF levels have been found in rats17, and in humans, differences in expression of BDNF have been described18,19.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [17] Sartorius, A. et al. Correlations and discrepancies between serum and brain tissue levels of neurotrophins after electroconvulsive treatment in rats. Pharmacopsychiatry 42, 270–276 (2009). source

      Not checked in the free run.

    • cites [18] Kleimann, A. et al. BDNF serum levels and promoter methylation of BDNF exon I, IV and VI in depressed patients receiving electroconvulsive therapy. J. Neural Transm. 122, 925–928 (2014). source

      Not checked in the free run.

    • cites [19] Stelzhammer, V. et al. Electroconvulsive therapy exerts mainly acute molecular changes in serum of major depressive disorder patients. Eur. Neuropsychopharmacol. 23, 1199–1207 (2013). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Association testing of methylation M-values used a mixed linear model with participant ID as a blocking factor and estimated cell fractions, 10 control probe PCs, age, sex, and smoking status as covariates to adjust for confounding factors.

    “Association testing of methylation M-values for each CpG site was done using a mixed linear model approach as implemented in the Limma R package. Participant ID was used as a blocking factor, and estimated cell fractions, 10 control probe PCs, age, sex, and smoking status were included as additional covariates to adjust for confounding factors.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The literature on DNA methylation in depression has pointed to several possible genes of interest (e.g., BDNF, SLC6A4, NR3C1, FKBP5) as being related to antidepressant response.

    “the literature on DNA methylation in depression has pointed to several possible genes of interest (e.g., BDNF, SLC6A4, NR3C1, FKBP5, etc. for reviews, see7–10) as being related to antidepressant response.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [7] Webb, L.M., Phillips, K.E., Ho, M.C., Veldic, M. & Blacker, C.J. The relationship between DNA methylation and antidepressant medications: a systematic review.Int. J. Mol. Sci. 21, 826 (2020). source

      Not checked in the free run.

    • cites [8] Chen, D., Meng, L., Pei, F., Zheng, Y. & Leng, J. A review of DNA methylation in depression. J. Clin. Neurosci. 43, 39–46 (2017). source

      Not checked in the free run.

    • cites [9] Lisoway, A. J., Zai, C. C., Tiwari, A. K. & Kennedy, J. L. DNA methylation and clinical response to antidepressant medication in major depressive disorder: a review and recommendations. Neurosci. Lett. 669, 14–23 (2018). source

      Not checked in the free run.

    • cites [10] Menke, A., Klengel, T. & Binder, E. B. Epigenetics, depression and antidepressant treatment. Curr. Pharm. Des. 18, 5879–5889 (2012). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Premisereasoning

    An approach investigating the whole methylome is expected to yield new and relevant insights.

    “As such, an approach investigating the whole methylome is expected to yield new and relevant insights.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Methylation differences of the promoter region of BDNF have been observed in many psychiatric disorders and after use of antidepressant medication.

    “Methylation differences of the promoter region of BDNF have been observed in many psychiatric disorders15, and also after use of antidepressant medication16.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [15] Zheleznyakova, G. Y., Cao, H. & Schioth, H. B. BDNF DNA methylation changes as a biomarker of psychiatric disorders: literature review and open access database analysis. Behav. Brain Funct. 12, 17 (2016). source

      Not checked in the free run.

    • cites [16] Tadic, A. et al. Methylation of the promoter of brain-derived neurotrophic factor exon IV and antidepressant response in major depression. Mol. Psychiatry 19, 281–283 (2014). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    D2HGDH encodes for the enzyme D-2-hydroxyglutarate dehydrogenase, and is suggested to be downregulated in depressed patients during remission.

    “D2HGDH encodes for the enzyme D-2-hydroxyglutarate dehydrogenase, and is suggested to be downregulated in depressed patients during remission54.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Scifo, E. et al. Sustained molecular pathology across episodes and remission in major depressive disorder. Biol. Psychiatry 83, 81–89 (2018). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    RAPGEF2 is a protein-coding gene suggested to be involved in signal transmission, in BDNF receptor pathway signaling, in schizophrenia, and is found to be a target for regulated miRNAs in MDD.

    “RAPGEF2, a protein-coding gene suggested to be involved in signal transmission, in BDNF receptor pathway signaling45, in schizophrenia46, and is found to be a target for regulated miRNAs in MDD47.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [45] GeneCards. RAPGEF2 Gene-Genecards | RPGF2 Protein | RPGF2 Antibody (accessed 22 January 2021); https://www.genecards.org/cgi-bin/carddisp.pl?gene=RAPGEF2&keywords=RAPGEF2.

      Not checked in the free run.

    • cites [46] Han, J. & Gage, F.H. A role for miR-19 in the migration of adult-born neurons and schizophrenia.Neurogenesis 3, e1251873 (2016). source

      Not checked in the free run.

    • cites [47] Garbett, K. A. et al. Coordinated messenger RNA/microRNA changes in fibroblasts of patients with major depression. Biol. Psychiatry 77, 256–265 (2015). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    RAB21 was previously reported to be associated with remission (p = 0.0103) in a GWAS of selective serotonin reuptake inhibitors in MDD patients.

    “RAB21 was previously reported to be associated with remission (p = 0.0103) in a GWAS of selective serotonin reuptake inhibitors in MDD patients43”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Ji, Y. et al. Pharmacogenomics of selective serotonin reuptake inhibitor treatment for major depressive disorder: genome-wide associations and functional genomics. Pharmacogenomics J. 13, 456–463 (2013). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.

    Interpretationown data

    The present results appear to lend support to previous research which has suggested the importance of these candidates but these results are preliminary and further investigation is warranted.

    “The present results appear to lend support to previous research which has suggested the importance of these candidates but these results are preliminary and further investigation is warranted.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation

    Methylation was assessed in whole blood while ECT is applied to the brain, so care should be taken with interpretation of these findings.

    “While we assessed methylation levels in whole blood, ECT is applied to the brain; both central and peripheral mechanisms may be affected by the global nature of the treatment and care should be taken with the interpretation of these findings65.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] Hannon, E., Lunnon, K., Schalkwyk, L. & Mill, J. Interindividual methylomic variation across blood, cortex, and cerebellum: implications for epigenetic studies of neurological and neuropsychiatric phenotypes. Epigenetics 10, 1024–1032 (2015). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Telomere length is associated with psychiatric disorders including major depressive disorder, as well as depressive symptoms.

    “Telomere length, a marker associated with aging is also known to be associated with psychiatric disorders35 including major depressive disorder36, as well as depressive symptoms37.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [35] Darrow, S. M. et al. The association between psychiatric disorders and telomere length: a meta-analysis involving 14,827 persons. Psychosom. Med. 78, 776–787 (2016). source

      Not checked in the free run.

    • cites [36] Ridout, K. K., Ridout, S. J., Price, L. H., Sen, S. & Tyrka, A. R. Depression and telomere length: a meta-analysis. J. Affect. Disord. 191, 237–247 (2016). source

      Not checked in the free run.

    • cites [37] Humphreys, K. L., Sisk, L. M., Manczak, E. M., Lin, J. & Gotlib, I. H. Depressive symptoms predict change in telomere length and mitochondrial DNA copy number across adolescence. J. Am. Acad. Child Adolesc. Psychiatry 59, 1364–1370 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductnone given

    Medication in each patient was kept constant during the ECT course, and there were no differences between patients regarding anesthesia administration or treatment dosage.

    “medication in each patient was kept constant during the ECT course, and there were no differences between patients regarding anesthesia administration or treatment dosage.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    FKBP5 is known to be an important endogenous regulator of the stress hormone system possibly linked to stress-related psychiatric disorders such as depression.

    “FKBP5, a gene which is known to be an important endogenous regulator of the stress hormone system possibly linked to stress-related psychiatric disorders such as depression50.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] Binder, E. B. The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders. Psychoneuroendocrinology 34, 186–195 (2009). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Depressive phenotypes are shown to be associated with the age-related decrease in FKBP5 methylation.

    “Depressive phenotypes are shown to be associated with the age-related decrease in FKBP5 methylation52.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Zannas, A. S. et al. Epigenetic upregulation of FKBP5 by aging and stress contributes to NF-kappaB-driven inflammation and cardiovascular risk. Proc. Natl Acad. Sci. USA 116, 11370–11379 (2019). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    The genes implicated in our findings have been previously involved in the etiology of depression and treatment response, but confirmation in larger samples is needed.

    “The genes implicated in our findings have been previously involved in the etiology of depression and treatment response, but confirmation in larger samples is needed.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    FKBP5 demethylation resulting from childhood trauma has been linked to long-term stress hormone system deregulation and effects on immune function and brain areas associated with stress regulation.

    “FKBP5 demethylation resulting from childhood trauma has been linked to long-term stress hormone system deregulation and effects on immune function and brain areas associated with stress regulation51.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Klengel, T. et al. Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nat. Neurosci. 16, 33–41 (2013). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In a recent large genome-wide gene-environment analysis, LRATD1 was observed to be associated with unipolar depression and response to trauma exposure.

    “In a recent large genome-wide gene-environment analysis, its paralog, LRATD1, was observed to be associated with unipolar depression and response to trauma exposure58.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] Coleman, J. R. I. et al. Genome-wide gene-environment analyses of major depressive disorder and reported lifetime traumatic experiences in UK Biobank. Mol. Psychiatry 25, 1430–1446 (2020). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    TNKS is a protein-coding gene associated with blood pressure, alcohol consumption, implicated in cancer pathology, and involved in various processes such as the Wnt signaling pathway, telomere length, and vesicle trafficking.

    “TNKS, which is a protein-coding gene associated with blood pressure, alcohol consumption, implicated in cancer pathology, and involved in various processes such as the Wnt signaling pathway, telomere length, and vesicle trafficking34.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] GeneCards. TNKS Gene-GeneCards | TNKS1 Protein | TNKS1 Antibody (accessed 22 January 2021); https://www.genecards.org/cgi-bin/carddisp.pl?gene=TNKS.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Altered epigenetic and genetic FKBP5 regulation may contribute to stress-related disease risk.

    “Altered epigenetic and genetic FKBP5 regulation may contribute to stress-related disease risk.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Zannas, A. S., Wiechmann, T., Gassen, N. C. & Binder, E. B. Gene-stress-epigenetic regulation of FKBP5: clinical and translational implications. Neuropsychopharmacology 41, 261–274 (2016). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    NNAT is involved in brain development and neuronal differentiation.

    “NNAT is involved in brain development and neuronal differentiation60.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] NCBI. NNAT Neuronatin-Gene (accessed 22 Jan 2021); https://www.ncbi.nlm.nih.gov/gene/4826.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    Together with the single site results, these findings are in line with previous works in the field of ECT; alterations in mechanisms such as neurogenesis and neuroinflammatory immune response are proposed to be among the mechanisms of ECT action.

    “Together with the single site results, these findings are in line with previous works in the field of ECT; alterations in mechanisms such as neurogenesis and neuroinflammatory immune response are proposed to be among the mechanisms of ECT action61–63.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [61] Nakamura, K. et al. Effects of single and repeated electroconvulsive stimulation on hippocampal cell proliferation and spontaneous behaviors in the rat. Brain Res. 1491, 88–97 (2013). source

      Not checked in the free run.

    • cites [62] van Buel, E.M. et al. Immune and neurotrophin stimulation by electroconvulsive therapy: is some inflammation needed after all?. Transl. Psychiatry 5, e609 (2015). source

      Not checked in the free run.

    • cites [63] Mindt, S., Neumaier, M., Hoyer, C., Sartorius, A. & Kranaster, L. Cytokine-mediated cellular immune activation in electroconvulsive therapy: a CSF study in patients with treatment-resistant depression. World J. Biol. Psychiatry 21, 139–147 (2019). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationown data

    The findings support FKBP5 as an important gene requiring further investigation in the present context.

    “the findings support FKBP5 as an important gene requiring further investigation in the present context.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    BLCAP encodes a protein that regulates cell proliferation and reduces cell growth by stimulating apoptosis.

    “BLCAP encodes a protein that regulates cell proliferation and reduces cell growth by stimulating apoptosis59”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [59] NCBI. BLCAP BLCAP Apoptosis Inducing Factor – Gene (accessed 22 January 2021); https://www.ncbi.nlm.nih.gov/gene/10904.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Findings related to FKBP5 have pointed to it as important in the interaction with environment in stress-related disorders such as major depression.

    “Findings related to FKBP5 have pointed to it as important in the interaction with environment in stress-related disorders such as major depression53.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Zannas, A. S., Wiechmann, T., Gassen, N. C. & Binder, E. B. Gene-stress-epigenetic regulation of FKBP5: clinical and translational implications. Neuropsychopharmacology 41, 261–274 (2016). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    AQR is related to neuroticism (p = 9.58 × 10−8) and worry (p = 2.06 × 10−6).

    “AQR as related to neuroticism (p = 9.58 × 10−8) and worry (p = 2.06 × 10−6)44”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Nagel, M., Watanabe, K., Stringer, S., Posthuma, D. & van der Sluis, S. Item-level analyses reveal genetic heterogeneity in neuroticism. Nat. Commun. 9, 905 (2018). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Proteins of the FXR family have commonly been reported in autism spectrum disorders, and evidence from GWASs in mood disorders and schizophrenia suggests that Fragile X mental retardation syndrome-related proteins are involved in the development of mental disorders.

    “Proteins of the FXR family have commonly been reported in autism spectrum disorders, and evidence from GWASs in mood disorders and schizophrenia suggests that Fragile X mental retardation syndrome-related proteins are involved in the development of mental disorders55.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Khlghatyan, J. & Beaulieu, J. M. Are FXR family proteins integrators of dopamine signaling and glutamatergic neurotransmission in mental illnesses? Front. Synaptic Neurosci. 10, 22 (2018). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    LRATD2 (FAM84B) is known to be involved in gastric and prostate cancer.

    “which is known to be involved in gastric and prostate cancer56,57.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [56] Zhang, Y. et al. Long non-coding RNA FAM84B-AS promotes resistance of gastric cancer to platinum drugs through inhibition of FAM84B expression. Biochem. Biophys. Res. Commun. 509, 753–762 (2019). source

      Not checked in the free run.

    • cites [57] Wong, N. et al. Upregulation of FAM84B during prostate cancer progression. Oncotarget 8, 19218–19235 (2017). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    PCM1, located in chromosomal region 8p, which has been implicated in various neuropsychiatric disorders including schizophrenia and depression, is a protein-coding gene critical for cell division, and is involved in the proliferation and neurogenesis of neuroprecursors.

    “PCM1, located in a chromosomal region on 8p, which has been implicated in various neuropsychiatric disorders including schizophrenia and depression48, is a protein-coding gene critical for cell division, and is involved in the proliferation and neurogenesis of neuroprecursors49.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [48] Tabares-Seisdedos, R. & Rubenstein, J. L. Chromosome 8p as a potential hub for developmental neuropsychiatric disorders: implications for schizophrenia, autism and cancer. Mol. Psychiatry 14, 563–589 (2009). source

      Not checked in the free run.

    • cites [49] Zhang, W. et al. MiRNA-128 regulates the proliferation and neurogenesis of neural precursors by targeting PCM1 in the developing cortex. eLife 5, e11324 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In several GWASs of depression-related traits, TNKS was found to be associated with depression-related traits (p = 7.68 × 10−10), bipolar disorder (p = 3 × 10−6), and positive affect (p = 0.0003).

    “In several genome-wide association studies (GWASs) of depression-related traits, TNKS was found to be associated with (p = 7.68 × 10−10)38, bipolar disorder (p = 3 × 10−6)39, and positive affect (p = 0.0003)40.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [38] Jones, S. E. et al. Genome-wide association analyses of chronotype in 697,828 individuals provides insights into circadian rhythms. Nat. Commun. 10, 343 (2019). source

      Not checked in the free run.

    • cites [39] Stahl, E. A. et al. Genome-wide association study identifies 30 loci associated with bipolar disorder. Nat. Genet. 51, 793–803 (2019). source

      Not checked in the free run.

    • cites [40] Baselmans, B. M. et al. Multivariate genome-wide analyses of the well-being spectrum. Nat. Genet. 51, 445–451 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The present study identified several potential CpG sites involved in ECT response and outlines potential differences between response groups.

    “By investigating the relationship between response status and change in methylation levels, this study identified several potential CpG sites involved in ECT response and outlines potential differences between response groups.”
    Quote in the paperSubstantial claim
59 of 59

  • The paper relies on this without support.

    The possible effect of anesthesia and pharmacotherapy is a potential confounding factor in methylation studies.

    “The possible effect of anesthesia and pharmacotherapy is a potential confounding factor in methylation studies.”
1 of 1

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Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. NCBI. BLCAP BLCAP Apoptosis Inducing Factor – Gene (accessed 22 January 2021); https://www.ncbi.nlm.nih.gov/gene/10904.
  2. NCBI. NNAT Neuronatin-Gene (accessed 22 Jan 2021); https://www.ncbi.nlm.nih.gov/gene/4826.

Cited by

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Related

Authors
Sirignano, L., Frank, J., Kranaster, L., Witt, S. H., Streit, F., Zillich, L., Sartorius, A., Rietschel, M., & Foo, J. C.
Affiliations
Heidelberg University (DE)
Corresponding author
Foo, Jerome C.
ORCID
Venue
Translational Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2021-06-05
Volume
11
Issue
1
Pages
347-347
ISSN
2158-3188 (ISSN-L)
DOI
10.1038/s41398-021-01474-9
PMC
PMC8179923
OpenAlex
W3170079502
Cited by
32
References
60
Citations by year
2026: 7 · 2025: 7 · 2024: 11 · 2023: 3 · 2022: 4
FWCI
3.23
Type
journal article
Language
en
Open access
Licence
Locations
  • Translational Psychiatry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Informationszentrum Lebenswissenschaften (ZB MED) (submittedVersion)
Funders
  • Deutsche Forschungsgemeinschaft (grant FOR2107, RI908/11–2, WI3429/3-2, FOR 2107)
  • Bundesministerium für Bildung und Forschung (01EE1409C, 01ZX1314G, 01ZX1614G, 01EW1810, 01EW1904, 031L0190A, 01EE1406C)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Keywords
electroconvulsive therapy, treatment response, depression, DNA methylation, epigenetics, differentially methylated CpG sites, tankyrase, FKBP5, treatment-resistant depression, severe depression
MeSH terms
Epigenome, Antidepressive Agents, Electroconvulsive Therapy, Humans, Psychiatric Status Rating Scales, Treatment Outcome

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

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