Electroconvulsive therapy response prediction: A new role for plasminogen activator inhibitor and tissue-type plasminogen activator?

Introduction:

According to the WHO, Major Depressive Disorder (MDD) is one of the leading contributors to the global burden worldwide. A broad variety of antidepressants are available; nonetheless, 30%-50% of the depressed patients do not respond to common treatment approaches (WHO, 2017). Electroconvulsive therapy (ECT) is one of the most effective options for these patients. Little is known about its mechanism of action, and only a few predictors of response are used in the clinical practice. Several lines of evidence underline BDNFs (brain-derived neurotrophic factor) pivotal role in the therapeutic effect of antidepressants. tPA (tissue-type plasminogen activator) and PAI-1 (plasminogen activator inhibitor 1) are implicated in BDNF production (Jiang et al. 2017).

We aim to find a predictive biomarker for ECT responsiveness. We further hypothesize ECT to influence the number and activity of immune cells, the latter effect being mediated by changing epigenetics and linked to therapeutic effects. To find new treatment options for MDD patients, we, therefore, analyze the impact of ECT on the immune system.

Methods:

For our study, blood was withdrawn from MDD patients undergoing a course of ECT. In our first cohort, blood was taken at baseline only. To replicate our findings, a second cohort is currently collected. In the latter group, blood is taken directly before and 15 minutes after ECT number one, four, the last and two maintenance ECTs. After isolating PBMCs from these samples, we count and sort defined populations of immune cells by using fluorescence-activated cell sorting. DNA isolated from all three sample types (whole blood, PBMCs and sorted immune cell populations) serves for epigenetic analyses. Gene regions encoding for tPA and PAI-1 are some of our main targets, but additional studies will be conducted to identify further target regions.

Results:

(I) Methylation analysis of a multi-hormone responsive enhancer element (-7.1kbp upstream of the tPA gene) revealed significant baseline changes between ECT remitters (n = 21; mean methylation = 47.4%; SE = 0.5%) and non-remitters (n = 40; mean methylation = 51.2%; SE = 0.4%; p < 1e-10). (II) Baseline DNA methylation of a CpG in a regulatory region of PAI-1 predicts ECT responsiveness with an accuracy of 80%.

Conclusion:

Our findings point to a subgroup of MDD patients being sensitive to ECT. Future experiments are needed to assess whether DNA methylation is directly modulated by electroconvulsive stimulation and leads to changes in protein production. Because of the small sample size of our study, the results have to be considered as preliminary and have to be replicated in larger cohorts.