Abstract
BackgroundMajor depressive disorder (MDD) represents a tremendous health threat to the world’s population. Electroconvulsive therapy (ECT) is the most effective treatment option for refractory MDD patients. Ample evidence suggests brain-derived neurotrophic factor (BDNF) to play a crucial role in ECT’s mode of action. Tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) are involved in BDNF production.HypothesisThe DNA methylation of gene regions encoding for t-PA and PAI-1 might be a suitable biomarker for ECT response prediction.MethodsWe withdrew blood from two cohorts of treatment-resistant MDD patients receiving ECT. In the first cohort (n = 59), blood was collected at baseline only. To evaluate DNA methylation changes throughout the treatment course, we acquired a second group (n = 28) and took blood samples at multiple time points. DNA isolated from whole blood and defined immune cell subtypes (B cells, monocytes, natural killer cells, and T cells) served for epigenetic analyses.ResultsMixed linear models (corrected for multiple testing by Sidak’s post-hoc test) revealed (1) no detectable baseline blood DNA methylation differences between ECT remitters (n = 33) and non-remitters (n = 53) in the regions analyzed, but (2) a significant difference in t-PA’s DNA methylation between the investigated immune cell subtypes instead (p < 0.00001). This difference remained stable throughout the treatment course, showed no acute changes after ECT, and was independent of clinical remission.ConclusionDNA methylation of both proteins seems to play a minor role in ECT’s mechanisms. Generally, we recommend using defined immune cell subtypes (instead of whole blood only) for DNA methylation analyses.
Highlights
According to the World Health Organization, major depressive disorder (MDD) can, nowadays, primarily be accounted for approximately 800,000 suicide deaths per year
We further suggest the DNA methylation of these regions to serve as a possible biomarker for Electroconvulsive therapy (ECT) response prediction
Among all study participants (n = 87), 33 individuals remitted upon ECT; 53 responded. 13 patients had minimally elevated levels for leukocytes, but no signs of infection
Summary
According to the World Health Organization, major depressive disorder (MDD) can, nowadays, primarily be accounted for approximately 800,000 suicide deaths per year. Regarding MDD, no robust risk genes have been identified so far [9, 10], but various experiments underline the influence of maternal care on DNA methylation, stress reactivity, and anxiety-related behavior in mice [11] In line with these findings, Fuchikami et al were able to distinguish healthy subjects from depressed patients by DNA methylation analysis of gene regions encoding for BDNF (brain-derived neurotrophic factor) [12]—a protein playing a pivotal role in various neuropsychiatric diseases, including depression [13,14,15]. Hypothesis: The DNA methylation of gene regions encoding for t-PA and PAI-1 might be a suitable biomarker for ECT response prediction
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