P11 promoter methylation predicts the antidepressant effect of electroconvulsive therapy

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.

Lack of antidepressant effects of burst-suppressing isoflurane anesthesia in adult male Wistar outbred rats subjected to chronic mild stress

“…Rats were exposed to mild stressors at varying time points during light and dark period as described [47,48]. The stressors were delivered daily except when isoflurane/sham treatments were given, and the behavioral performances of the animals were assessed as shown in Fig 1. Stressors included periods of (1) continuous light (24 h/d), (2) food deprivation (24 h), (3) water deprivation (14 h), (5) swim sessions in 40˚C water (10 minutes in a transparent plexiglas cylinder (50 cm deep, 25 cm diameter) containing 20 cm of water), (6) swim sessions in 15˚C water (5 minutes in similar conditions to swim sessions in 40˚C water), (7) wet bedding (16 h, 300 ml of tap water on Altromin soft wood granulate), (8) restraint stress (30 min) and (9) social crowding (four rats in one Makrolon type III cage).…”

“…The strength of this model is that animals respond to chronic, but not acute, administration of antidepressant drugs (and to ECS), as compared to drugs without clinical antidepressant properties that show no effects [56]. We recently employed this model using a stress-sensitive substrain of male outbred Wistar rats (Crl:WI(Han)) [47]. Repeated ECS ameliorated depression-like phenotypes induced by CMS and significantly increased BDNF levels.…”

“…To further test "the cerebral silence hypothesis" of ECT and the antidepressant effects of isoflurane anesthesia in particular, we investigated whether repeated isoflurane exposures increase BDNF protein, while ameliorating depressive-like symptoms in Wistar outbred rats (Crl:WI(Han)) subjected to chronic mild stress (CMS). We have recently shown that the depressive-like phenotype in these rats is restored by repeated ECS treatments, which also readily increases BDNF synthesis, while the selective serotonin reuptake inhibitor (SSRI) citalopram was ineffective [47].…”

TrkB neurotrophin receptor at the core of antidepressant effects, but how?

“…The effects appear faster and are in magnitude greater than those observed after classical antidepressants (Nibuya et al 1995). Indeed, ECS, especially when delivered repeatedly during a course of several days or weeks, increases BDNF protein levels (Altar et al 2003;Hansen et al 2007;Segawa et al 2013;Neyazi et al 2018). To nail down the putative involvement of TrkB signaling, we investigated the effects of ECS on TrkB phosphorylation.…”

Consequences of housing conditions and interindividual diversity in rodent models of acquired epilepsy

“…[12][13][14] Furthermore, male Wistar rats from Charles River exhibited enhanced stress vulnerability in a model of chronic mild stress compared to Wistar rats from other vendors, 15 and this enhanced stress vulnerability was resistant to chronic treatment with antidepressant drugs. 16 On the other hand, SD rats from Janvier, which was the only vendor that used group housing, environmental cage enrichment, and intense socialization to humans, exhibited a low premorbid anxiety level and low stress response but also low response to SE induction. 12,15 These data indicate that handling habituation and environmental enrichment in rats during rearing at the vendor, and possibly genetic and epigenetic factors, may outreach the influence of group housing on models of acquired epilepsy.…”