• Postictal reorientation time (by Sobin, 1995) [ Time Frame: immediately after each ECT session, up to 12 times per patient (across 6 weeks) ]
  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.
• Structural MRI [ Time Frame: baseline, in the first hour after 3 electroconvulsive therapy sessions, after approx. 3 months, after approx. 6 months, lasts approx. 5 min. ]
  Isovoxel T1-weighted data (to make volumetric changes); is part of the MRI sequence (takes in total approximately 25 minutes)
• Arterial Spin Labeling MRI [ Time Frame: baseline, in the first hour after 3 electroconvulsive therapy sessions, after approx. 3 months, after approx. 6 months, lasts approx. 7 min. ]
  measures cerebral perfusion levels
• Resting state functional MRI [ Time Frame: baseline, in the first hour after 3 electroconvulsive therapy sessions, after approx. 3 months, after approx. 6 months, lasts approx. 5 min. ]
  used for brain mapping, measures functional organization (and connectivity) of certain brain areas
• Diffusion Tensor Imaging [ Time Frame: baseline, in the first hour after 3 electroconvulsive therapy sessions, after approx. 3 months, after approx. 6 months, lasts approx. 5 min. ]
  measures diffusion in the brain to estimate the axonal organization of the brain

• Postictal reorientation time (by Sobin, 1995) [ Time Frame: in the first hour after electroconvulsive therapy (once per intervention), up to 12 times per patient (across 6 weeks) ]
  Five questions regarding reorientation will be asked in an interval of 5 minutes after electronvulsive 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 patients needs more time to regain reorientation.
• Structural MRI [ Time Frame: in the first hour after electroconvulsive therapy (once per intervention, in total 3 times per participant), lasts approx. 5 min. ]
  Isovoxel T1-weighted data (to make volumetric changes); is part of the MRI sequence (takes in total approximately 25 minutes)
• Arterial Spin Labeling MRI [ Time Frame: in the first hour after electroconvulsive therapy (once per intervention, in total 3 times per participant), lasts approx. 7 min. ]
  measures cerebral perfusion levels
• Resting state functional MRI [ Time Frame: in the first hour after electroconvulsive therapy (once per intervention, in total 3 times per participant), lasts approx. 5 min. ]
  used for brain mapping, measures functional organization (and connectivity) of certain brain areas
• Magnetic resonance angiography [ Time Frame: in the first hour after electroconvulsive therapy (once per intervention, in total 3 times per participant), lasts approx. 5 min. ]
  measures the vessel diameter

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
• Postictal Delirium
• Electroconvulsive Therapy

• Drug: Paracetamol
  once, 1000mg, 2 h before ECT session
  Other Name: RVG 107336
• Drug: Nimotop
  once, 60mg, 2 h before ECT session
  Other Name: RVG 12060

• Active Comparator: Acetaminophen
  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
  Intervention: Drug: Paracetamol
• Active Comparator: Nimodipine
  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.
  Intervention: Drug: Nimotop
• No Intervention: Control
  Glass of water (50cc) only. Once 2h before the ECT-session. Total maximum of five times over the course of weeks.

• 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. pii: 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. Review.
• 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, Dahlöf 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.
• 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. Review.
• 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.

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;
• Contraindications for magnetic resonance imaging (e.g. ferromagnetic implants, pacemakers, claustrophobia)

• University of Twente
• Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)