P11 promoter methylation predicts the antidepressant effect of electroconvulsive therapy

Alexandra Neyazi,Wolfgang Löscher,Nobuaki Matsui,Stefan Bleich,Wolfgang Sperling,Mathias Rhein,Johannes Kornhuber,Malek Bajbouj,Claudia Brandt,Wiebke Theilmann,Tomi Rantamäki,Helge Frieling

doi:10.1038/s41398-017-0077-3

Abstract

Although electroconvulsive therapy (ECT) is among the most effective treatment options for pharmacoresistant major depressive disorder (MDD), some patients still remain refractory to standard ECT practise. Thus, there is a need for markers reliably predicting ECT non/response. In our study, we have taken a novel translational approach for discovering potential biomarkers for the prediction of ECT response. Our hypothesis was that the promoter methylation of p11, a multifunctional protein involved in both depressive-like states and antidepressant treatment responses, is differently regulated in ECT responders vs. nonresponders and thus be a putative biomarker of ECT response. The chronic mild stress model of MDD was adapted with the aim to obtain rats that are resistant to conventional antidepressant drugs (citalopram). Subsequently, electroconvulsive stimulation (ECS) was used to select responders and nonresponders, and compare p11 expression and promoter methylation. In the rat experiments we found that the gene promoter methylation and expression of p11 significantly correlate with the antidepressant effect of ECS. Next, we investigated the predictive properties of p11 promoter methylation in two clinical cohorts of patients with pharmacoresistant MDD. In a proof-of-concept clinical trial in 11 patients with refractory MDD, higher p11 promoter methylation was found in responders to ECT. This finding was replicated in an independent sample of 65 patients with pharmacoresistant MDD. This translational study successfully validated the first biomarker reliably predicting the responsiveness to ECT. Prescreening of this biomarker could help to identify patients eligible for first-line ECT treatment and also help to develop novel antidepressant treatment procedures for depressed patients resistant to all currently approved antidepressant treatments.

Highlights

Electroconvulsive therapy (ECT) is among the most effective treatment options for pharmacoresistant major depressive disorder (MDD), some patients still remain refractory to standard electroconvulsive therapy (ECT) practise
In experiment I, chronic mild stress (CMS)-induced anhedonic-like behavior was present in 66.7% (10/15) of the animals, whereas hedonic-like behavior was detected in 13.3% (2/ 15) of the rats (Fig. 2b and Table 1)
POC study in patients with pharmacoresistant MDD Based on the preclinical data, we examined whether patients (N = 11) differing in their response to ECT differ in peripheral p11 promoter methylation

Summary

Introduction

Electroconvulsive therapy (ECT) is among the most effective treatment options for pharmacoresistant major depressive disorder (MDD), some patients still remain refractory to standard ECT practise. Based on a recent study with this animal model of depression[13], showing a rat breeder-dependent effect of CMS on p11 methylation, our hypothesis was that the expression and promoter methylation of p11, a member of the S100 EFhand family[14], might be differently regulated in ECT responders compared with nonresponders and be a putative biomarker of ECT response. This hypothesis is supported by several lines of evidence. We included BDNF promoter methylation measurements in the present animal experiments

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Conclusion