Measuring Blood Flow in the Brain After Epileptic Activity (SYNAPSE)

In this clinical trial, postictal phenomena (i.e., headache, delirium) will be investigated after administration of acetaminophen and nimodipine in depressed patients receiving electroconvulsive therapy (ECT). Postictal phenomena are thought to result from decreased cerebral blood flow and decreased oxygen concentration in the brain. It is expected that acetaminophen and nimodipine will reduce these postictal phenomena, compared to no treatment, because they target these mechanisms.

Postictal phenomena, such as sensory, motor or memory deficits, headache, delirium, and psychosis, are common manifestations after electroconvulsive therapy (ECT) induced seizures. Also, postictal phenomena add to the burden of seizures in patients with epilepsy. The pathophysiology of these phenomena is poorly understood and effective treatments are not available (Fisher RS, 2000; Krauss & Theodore, 2010). Recently, seizure-induced postictal vasoconstriction with cerebral hypoperfusion was observed in experimentally induced seizures in rats. Treatment with acetaminophen or calcium antagonists decreased hypoperfusion and postictal phenomena (Farrell, 2016, 2017). The objective of this research is to study the effect of acetaminophen and nimodipine to reduce postictal phenomena after ECT induced seizures. A prospective, three conditions crossover trial will be conducted, with randomized condition allocation, open-label treatment, and blinded end-point evaluation (PROBE design; Hansson, Hedner, & Dahlof, 1992). Thirty-three adult (age >17 years) patients referred to treatment with ECT for a depressive episode will be included to achieve a statistical power of .80. This will be feasible in one year. A single dose of nimodipine (60 mg) or acetaminophen (1000 mg) or no additional treatment will be given prior to a maximum of 12 ECT-sessions per patient. Patients will be randomly assigned to predefined treatment sequences. EEG and MRI measures will serve as main outcome measures, as well as psychometric tests. Data will be stored on two separate hard disks, one including patient sensitive information for identification, the other with anonymized data only (for the sponsor). Patients will be recruited by doctors at Rijnstate Hospital Arnhem. A mixed model with repeated measurements analysis will be conducted for the primary outcome measures.

Epilepsy, Depression, Electroconvulsive Therapy, Postictal, Clinical Trial, Postictal hypoperfusion/hypoxia

This study makes use of a 3 x 3 crossover design, in which patients receive a randomized sequence of interventions in pairs of 3 (acetaminophen, nimodipine, no intervention), with a maximum of 12 interventions/measurements.

The PROBE design will be used in this study, in which the principal investigator will be blinded to the administration of drugs until the end of the study. The other principal investigator will know about administration, but will not be involved in testing patients.

Trade name: Paracetamol Pharmaceutical form: Tablet (oral use) Once 1000 mg 2h before the ECT-session. Total maximum of five times over the course of weeks

Trade name: Nimotop Pharmaceutical form: Film-coated tablet (oral use) Once 60mg 2h before the ECT-session. Total maximum of five times over the course of weeks.

Glass of water (50cc) only. Once 2h before the ECT-session. Total maximum of five times over the course of weeks.

quantitative metric of EEG background evolution over time, in seconds (will be assessed at baseline, during electroconvulsive therapy, and immediately afterwards for approximately 1 hour)

Five questions regarding reorientation will be asked in an interval of 5 minutes after electroconvulsive shock therapy has ended. If the patient can answer 4 out of the 5 questions correctly, this is determined as the final score (in minutes). The scale ranges from 5 to 100 minutes. These scores indicate the time frame a patient needs until he/she is fully conscious and reoriented. Higher values indicate that a patient needs more time to regain reorientation.

Isovoxel T1-weighted data (to make volumetric changes); is part of the MRI sequence (takes in total approximately 25 minutes)

baseline, in the first hour after 3 electroconvulsive therapy sessions, after approx. 3 months, after approx. 6 months, lasts approx. 5 min.

baseline, in the first hour after 3 electroconvulsive therapy sessions, after approx. 3 months, after approx. 6 months, lasts approx. 7 min.

baseline, in the first hour after 3 electroconvulsive therapy sessions, after approx. 3 months, after approx. 6 months, lasts approx. 5 min.

baseline, in the first hour after 3 electroconvulsive therapy sessions, after approx. 3 months, after approx. 6 months, lasts approx. 5 min.

Inclusion Criteria: Adulthood (age > 17 years); Current clinical diagnosis of depressive episode (unipolar, bipolar, schizoaffective); Willingness and ability to give written informed consent and willingness and ability to understand, to participate and to comply with the study requirements. Exclusion Criteria: Known adverse or allergic reactions to acetaminophen or nimodipine; Chronic use of acetaminophen, calcium-antagonists or NSAID's that cannot be interrupted for less than two days before the ECT-session;

The EEG, MRI, and psychometric data will be shared with the University of Twente and the Amsterdam UMC. All patient data will be anonymized so that it cannot be connected to the patients. Demographic data will also be included in these files and anonymized.

Data will be archived for 15 years (according to the standard practice of Rijnstate Hospital). Data will become available as of the last date of testing (approx. December 2020).

Farrell JS, Gaxiola-Valdez I, Wolff MD, David LS, Dika HI, Geeraert BL, Rachel Wang X, Singh S, Spanswick SC, Dunn JF, Antle MC, Federico P, Teskey GC. Postictal behavioural impairments are due to a severe prolonged hypoperfusion/hypoxia event that is COX-2 dependent. Elife. 2016 Nov 22;5:e19352. doi: 10.7554/eLife.19352.

Farrell JS, Colangeli R, Wolff MD, Wall AK, Phillips TJ, George A, Federico P, Teskey GC. Postictal hypoperfusion/hypoxia provides the foundation for a unified theory of seizure-induced brain abnormalities and behavioral dysfunction. Epilepsia. 2017 Sep;58(9):1493-1501. doi: 10.1111/epi.13827. Epub 2017 Jun 20.

Fisher RS, Schachter SC. The postictal state: a neglected entity in the management of epilepsy. Epilepsy Behav. 2000 Feb;1(1):52-9. doi: 10.1006/ebeh.2000.0023.

Hansson L, Hedner T, Dahlof B. Prospective randomized open blinded end-point (PROBE) study. A novel design for intervention trials. Prospective Randomized Open Blinded End-Point. Blood Press. 1992 Aug;1(2):113-9. doi: 10.3109/08037059209077502.

Krauss G, Theodore WH. Treatment strategies in the postictal state. Epilepsy Behav. 2010 Oct;19(2):188-90. doi: 10.1016/j.yebeh.2010.06.030. Epub 2010 Aug 17.

Sobin C, Sackeim HA, Prudic J, Devanand DP, Moody BJ, McElhiney MC. Predictors of retrograde amnesia following ECT. Am J Psychiatry. 1995 Jul;152(7):995-1001. doi: 10.1176/ajp.152.7.995.

Verdijk JPAJ, Pottkamper JCM, Verwijk E, van Wingen GA, van Putten MJAM, Hofmeijer J, van Waarde JA. Study of effect of nimodipine and acetaminophen on postictal symptoms in depressed patients after electroconvulsive therapy (SYNAPSE). Trials. 2022 Apr 18;23(1):324. doi: 10.1186/s13063-022-06206-y.