Measuring Blood Flow in the Brain After Epileptic Activity

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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StudY of Effect of Nimodipine and Acetaminophen on Postictal Symptoms After ECT

Conditions
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Epilepsy, Depression, Postictal Delirium, Electroconvulsive Therapy

Intervention / Treatment
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* Drug: Paracetamol
* Drug: Nimotop


Participation Criteria
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Eligibility Criteria
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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;

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: 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.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Acetaminophen<br>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 | Drug: Paracetamol<br>* once, 1000mg, 2 h before ECT session<br>* Other names: RVG 107336;|
| Active Comparator: Nimodipine<br>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. | Drug: Nimotop<br>* once, 60mg, 2 h before ECT session<br>* Other names: RVG 12060;|
| No Intervention: Control<br>Glass of water (50cc) only. Once 2h before the ECT-session. Total maximum of five times over the course of weeks. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to EEG normalization | 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) | Change from ictal to baseline EEG activity, up to 12 times per patient (across 6 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Postictal reorientation time (by Sobin, 1995) | 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. | immediately after each ECT session, up to 12 times per patient (across 6 weeks) | 
| Structural MRI | 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. | 
| Arterial Spin Labeling MRI | measures cerebral perfusion levels | baseline, in the first hour after 3 electroconvulsive therapy sessions, after approx. 3 months, after approx. 6 months, lasts approx. 7 min. | 
| Resting state functional MRI | used for brain mapping, measures functional organization (and connectivity) of certain brain areas | baseline, in the first hour after 3 electroconvulsive therapy sessions, after approx. 3 months, after approx. 6 months, lasts approx. 5 min. | 
| Diffusion Tensor Imaging | measures diffusion in the brain to estimate the axonal organization of the brain | baseline, in the first hour after 3 electroconvulsive therapy sessions, after approx. 3 months, after approx. 6 months, lasts approx. 5 min. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Epilepsy, Depression, Electroconvulsive Therapy, Postictal, Clinical Trial, Postictal hypoperfusion/hypoxia