Study of effect of nimodipine and acetaminophen on postictal symptoms in depressed patients after electroconvulsive therapy (SYNAPSE)

Abstract

Background Postictal phenomena as delirium, headache, nausea, myalgia, and anterograde and retrograde amnesia are common manifestations after seizures induced by electroconvulsive therapy (ECT). Comparable postictal phenomena also contribute to the burden of patients with epilepsy. The pathophysiology of postictal phenomena is poorly understood and effective treatments are not available. Recently, seizure-induced cyclooxygenase (COX)-mediated postictal vasoconstriction, accompanied by cerebral hypoperfusion and hypoxia, has been identified as a candidate mechanism in experimentally induced seizures in rats. Vasodilatory treatment with acetaminophen or calcium antagonists reduced postictal hypoxia and postictal symptoms. The aim of this clinical trial is to study the effects of acetaminophen and nimodipine on postictal phenomena after ECT-induced seizures in patients suffering major depressive disorder. We hypothesize that (1) acetaminophen and nimodipine will reduce postictal electroencephalographic (EEG) phenomena, (2) acetaminophen and nimodipine will reduce magnetic resonance imaging (MRI) measures of postictal cerebral hypoperfusion, (3) acetaminophen and nimodipine will reduce clinical postictal phenomena, and (4) postictal phenomena will correlate with measures of postictal hypoperfusion. Methods We propose a prospective, three-condition cross-over design trial with randomized condition allocation, open-label treatment, and blinded end-point evaluation (PROBE design). Thirty-three patients (age > 17 years) suffering from a depressive episode treated with ECT will be included. Randomly and alternately, single doses of nimodipine (60 mg), acetaminophen (1000 mg), or water will be given two hours prior to each ECT session with a maximum of twelve sessions per patient. The primary outcome measure is ‘postictal EEG recovery time’, expressed and quantified as an adapted version of the temporal brain symmetry index, yielding a time constant for the duration of the postictal state on EEG. Secondary outcome measures include postictal cerebral perfusion, measured by arterial spin labelling MRI, and the postictal clinical ‘time to orientation’. Discussion With this clinical trial, we will systematically study postictal EEG, MRI and clinical phenomena after ECT-induced seizures and will test the effects of vasodilatory treatment intending to reduce postictal symptoms. If an effect is established, this will provide a novel treatment of postictal symptoms in ECT patients. Ultimately, these findings may be generalized to patients with epilepsy. Trial registration Inclusion in SYNAPSE started in December 2019. Prospective trial registration number is NCT04028596 on the international clinical trial register on July 22, 2019.

Medication preventing postictal hypoperfusion and cognitive side-effects in electroconvulsive therapy: A retrospective cohort study

“…ECT-patients with different physical comorbidities, who used acetaminophen, NSAIDs or calcium antagonists for these comorbidities, might have confounded the cognitive outcome. Therefore, our explorative and preliminary findings deserve further prospective, randomized controlled studies, of which one is in progress (NCT04028596) ( 27 ).…”

Changes in postictal cerebral perfusion are related to the duration of electroconvulsive therapy‐induced seizures

“…In the case of severe postictal confusion, midazolam 2–5 mg was provided intravenously 17 . A detailed overview of the study protocol is given elsewhere 20,24 …”

“…This study is a post hoc analysis of ASL-MRI data of patients included in the preregistered prospective SYNAPSE study (NCT04028596), which had a randomized crossover design to test vasodilatory drugs to reduce postictal symptoms. 20 For the current analysis, we used ASL-MRI scans at baseline (<1 week before start of the ECT course) and 1 h after an ECT-induced seizure from each patient, but only in the control ("placebo") condition of SYNAPSE (i.e., a cup of water administered 2 h before ECT). To correct for normal variability over time and test-retest effects of the repeated ASL-MRI measurements, a group of healthy controls was included (ERB study number 2020-BC-12375), who were measured on the same MRI-scanner at two separate time points (i.e., baseline and after 6 weeks).…”

“…This study is a post hoc analysis of ASL‐MRI data of patients included in the preregistered prospective SYNAPSE study (NCT04028596), which had a randomized crossover design to test vasodilatory drugs to reduce postictal symptoms 20 . For the current analysis, we used ASL‐MRI scans at baseline (<1 week before start of the ECT course) and 1 h after an ECT‐induced seizure from each patient, but only in the control ("placebo") condition of SYNAPSE (i.e., a cup of water administered 2 h before ECT).…”

Cortical excitation/inhibition ratios in patients with major depression treated with electroconvulsive therapy: an EEG analysis

“…Patients received nimodipine, acetaminophen, or a placebo (water) in random and counterbalanced order at a maximum of 2 h before each ECT session. The order of the treatment conditions was randomized and differed across patients [ 16 ]. Repeated EEG measures before, during, and until one hour after the ECT sessions were collected.…”