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.

Keywords: Acetaminophen; Arterial spin labelling (or perfusion weighted imaging); Cerebral perfusion; Depression; Electroconvulsive therapy; Electroencephalography; Epilepsy; Nimodipine; PROBE design; Postictal.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1

Induced seizure (upper panel) and immediate postictal state (middle panel) EEG epochs of 10 seconds in an ECT patient. Note the flattening of the EEG immediately after the seizure. EEG activity gradually returns after approximately 15 min (lower panel). This EEG evolution is very similar to post-ictal patterns after spontaneous epileptic seizures. Data from an ECT patient treated in Rijnstate Hospital

Fig. 2

Left: EEG-recovery from global ischaemia in a patient after cardiac arrest (t = 0). The nearly iso-electric EEG (blue dot) evolves to a diffusely slowed pattern (yellow dot) to a normal pattern (green dot). Right: EEG traces in a patient with a generalized seizure (red bar, start around t = 4.5 min). After the seizure, the EEG is nearly iso-electric (blue dot) and evolves to a diffusely slowed pattern (yellow dot) to a normal pattern (green dot). While the time courses are different in these examples (hours versus minutes), EEG patterns are similar. Only channel P4-O2 is plotted. Data from MST hospital

Fig. 3

Schematic representation of an ECT course with the intended interventions (n = 12) and clinical (n = 15), EEG (n = 15), and MRI (n = 6) measurements. Every patient is randomized to four times a sequence of three conditions (A, B, and C) for three consecutive ECT sessions. A scheme consisting of 12 sessions is depicted, which will be the maximum and intended included number of ECT sessions, save early discontinuation of ECT because of clinical reasons. Baseline includes the ECT titration session (t = 0). Blue highlights indicate EEG and clinical measurements, which will be done at baseline, shortly before, during, and after each ECT session, after finishing the total index ECT course, and at 3 months follow-up. Orange highlights indicate MRI measurements (i.e. arterial spin labelling and others), which will be performed at baseline, once in every treatment condition (A, B, and C) directly after the ECT session, after finishing the index ECT course, and at 3 months follow-up

Fig. 4

Schematic depiction of the route of stay of patients on the day of an ECT session. Two hours before ECT, patients receive one of the interventions or control on the psychiatric ward. Next, ECT is performed in the operation room (OR). Afterwards, patients are transferred to the recovery room and adjacently back to the psychiatric ward. This route does not differ from standard treatment. Specifically for SYNAPSE, after 3 of the ECT sessions, patients will be transferred directly to the radiology department for the MRI outcome measures before returning to the psychiatric ward

Fig. 5

Schematic representation of time schedule and applied measures during SYNAPSE. At baseline, the psychometry battery, EEG and MRI measurements are taken. During and after a maximum of 13 ECT sessions (the first session will be without intervention; in the other 12 ECT sessions, the interventions are applied), intermittent ROT (interval: 5 min) and continuous EEG measures are recorded. Within 1 h after 3 ECT sessions, MRI will take place (one for each intervention). The psychometric measures, EEG, and MRI measurements will be repeated at follow-up within 2 weeks after completion of the ECT course and after 3 months. ROT, reorientation time. ASL, arterial spin labelling. PCM, paracetamol (acetaminophen). ND, nimodipine. NI, no intervention. EEG, electroencephalography. ECT, electroconvulsive therapy