Epigenetic ECT Study From Germany

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

Sirignano L, Frank J, Kranaster L, Witt SH, Streit F, Zillich L, Sartorius A, Rietschel M, Foo JC.Transl Psychiatry. 2021 Jun 5;11(1):347. doi: 10.1038/s41398-021-01474-9.PMID: 34091594

The abstract is copied below:

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.

The pdf is here.

And from the text:

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

...In the present study, we aimed to identify changes in methylation levels associated with the effects of ECT and to find potential biomarkers for antidepressant response. We obtained and compared epigenome-wide DNA methylation levels of ECT patients (n = 34) before and after ECT. Differentially methylated CpG sites and regions associated with response were examined. Pathway analyses were employed to search for functional pathways affected by ECT. Finally, we took a targeted look at methylation in genes which have been previously implicated in ECT response and depression-related studies.

And from the discussion:

The top CpG site associated with binary response is located in 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 trafficking. Telomere length, a marker associated with aging is also known to be associated with psychiatric disorders35 including major depressive disorder, as well as depressive symptoms. In several genome-wide association studies (GWASs) of depression-related traits, TNKS was found to be associated with (p = 7.68 × 10−10), bipolar disorder (p = 3 × 10−6 ), and positive affect (p = 0.0003)40. Among the top 5 CpG sites suggestively associated with binary response, genes associated with processes such as cell adhesion, cell growth, apoptosis in malignant tumors, protein metabolism (RAB21), and signaling in glucose metabolism (AQR) were found.

...This study had several limitations. Although the largest study to date, the present sample size was limited, and it is expected that future studies using a similar approach in larger samples will be able to further clarify our results. Sample size notwithstanding, we identified a single significantly differentially methylated CpG site, as well as some suggestive ones which need further investigation. 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. The possible effect of anesthesia and pharmacotherapy is a potential confounding factor in methylation studies. However, medication in each patient was kept constant during the ECT course, and there were no differences between patients regarding anesthesia administration or treatment dosage. Therefore, the observed changes are unlikely to have resulted from these medications. 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. Multi-center approaches and collaborative efforts could help in obtaining the sample sizes required to allow a more robust characterization of ECT response and give insights into the biological processes underlying the striking antidepressant effects of ECT.

This is a very interesting preliminary investigation of epigenetic changes associated with ECT response. I particularly like the authors' opening statement (see above, highlighted) about ECT being a good treatment to study because of its rapid, powerful effects and ECT patients being a good population to study because of disease severity and likely greater genetic homogeneity.

These studies have complex methods and a full read will appeal to a subset of ECT professionals with sophisticated genetics backgrounds, ~25 minutes.

We wish these authors, and others, pursuing similar lines of genetic research the best of luck in elucidating the mechanism of action of ECT.