EpilepsyPhase 2SYNAPSENCT04028596
Measuring Blood Flow in the Brain After Epileptic Activity
A Phase 2 study testing Paracetamol and Nimotop in people with Epilepsy and Depression, run by Rijnstate Hospital at 1 site in Netherlands.
Trial summary
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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Epilepsy, Depression, Postictal Delirium
- What is being tested?
- Paracetamol and Nimotop
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 34 participants
- Where
- 1 siteNetherlands
- Study dates
- 5 Dec 2019to 15 Apr 2023
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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;
Trial locations and contacts
1 site in 1 country.
About this study
Official title: StudY of Effect of Nimodipine and Acetaminophen on Postictal Symptoms After ECT
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.
Read the detailed description
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.
- Conditions
- Epilepsy, Depression, Postictal Delirium, Electroconvulsive Therapy
- Being tested
- Paracetamol, Nimotop
- Keywords
- Epilepsy, Depression, Electroconvulsive Therapy, Postictal, Clinical Trial, Postictal hypoperfusion/hypoxia
- Medical subject headings
- Epilepsy, Depression, Hypoxia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ParacetamolDrug
Also called RVG 107336
once, 1000mg, 2 h before ECT session
NimotopDrug
Also called RVG 12060
once, 60mg, 2 h before ECT session
| Study group | Role | What they receive |
|---|---|---|
| Acetaminophen | Active comparator | 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 Receives: Drug: Paracetamol |
| Nimodipine | Active comparator | 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. Receives: Drug: Nimotop |
| Control | No intervention | Glass of water (50cc) only. Once 2h before the ECT-session. Total maximum of five times over the course of weeks. |
What is being measured
The primary outcome is the main question the study is designed to answer.
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)
Measured: Change from ictal to baseline EEG activity, up to 12 times per patient (across 6 weeks)
Secondary outcomes (5)
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.
Measured: 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)
Measured: 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
Measured: 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
Measured: 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
Measured: baseline, in the first hour after 3 electroconvulsive therapy sessions, after approx. 3 months, after approx. 6 months, lasts approx. 5 min.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Jul 2019
- Study start5 Dec 2019
- Primary completion30 Dec 2022
- Study completion15 Apr 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (8)Papers the sponsor has linked to this study.
- Other trials for EpilepsyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- 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 blind
- Who is masked
- Investigator
- Enrolment
- 34 participants (actual)
Sponsor and investigators
- Lead sponsor
- Rijnstate Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- University of Twente, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
- Responsible party
- Sponsor
- Investigators
- Jeroen A van Waarde, MD, Principal investigator, Rijnstate Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04028596
- Sponsor's protocol ID
- NL68690.091.18
- Acronym
- SYNAPSE
- Status last verified
- Nov 2023
- First submitted
- 8 Jul 2019
- Last updated
- 18 Nov 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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.
Publications
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.
PubMed 27874832Farrell 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.
PubMed 28632329Fisher 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.
PubMed 12609127Hansson 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.
PubMed 1366259Krauss 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.
PubMed 20719574Sobin 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.
PubMed 7793470Pottkamper JCM, Verdijk JPAJ, Stuiver S, Doesschate FT, van Putten MJAM, Hofmeijer J, van Waarde JA, van Wingen GA. Postictal resting-state connectivity changes after electroconvulsive therapy-induced seizures. Eur Arch Psychiatry Clin Neurosci. 2026 Mar;276(2):851-862. doi: 10.1007/s00406-025-02043-7. Epub 2025 Jul 14.
PubMed 40659830Verdijk 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.
PubMed 35436940
Study at a glance
From the registry record, last updated by the sponsor on 18 Nov 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- StudY of Effect of Nimodipine and Acetaminophen on Postictal Symptoms After ECT
- ClinicalTrials.gov ID
- NCT04028596
- Acronym / sponsor ID
- SYNAPSE / NL68690.091.18
- Conditions
- Epilepsy, Depression, Postictal Delirium, Electroconvulsive Therapy
- Keywords
- Epilepsy, Depression, Electroconvulsive Therapy, Postictal, Clinical Trial, Postictal hypoperfusion/hypoxia
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 34 participants (actual)
- Lead sponsor
- Rijnstate HospitalUniversity, hospital or other
- Collaborators
- University of Twente, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
- Study start
- 5 Dec 2019 (actual)
- Primary completion
- 30 Dec 2022 (actual)
- Study completion
- 15 Apr 2023 (actual)
- First posted
- 22 Jul 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Single blind (investigator)
- Number of arms
- 3
- 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.
| Arm | Type | Receives |
|---|---|---|
| Acetaminophen | Active comparator | Drug: ParacetamolTrade 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 |
| Nimodipine | Active comparator | Drug: NimotopTrade 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. |
| Control | No intervention | –Glass of water (50cc) only. Once 2h before the ECT-session. Total maximum of five times over the course of weeks. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- 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.
Key exclusion criteria (2 listed)
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ParacetamolAlso: RVG 107336once, 1000mg, 2 h before ECT session | Drug | Acetaminophen |
| NimotopAlso: RVG 12060once, 60mg, 2 h before ECT session | Drug | Nimodipine |
Primary outcome
Time to EEG normalization
Time frame: Change from ictal to baseline EEG activity, up to 12 times per patient (across 6 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)
5 secondary outcomes
Postictal reorientation time (by Sobin, 1995)
Time frame: immediately after each ECT session, up to 12 times per patient (across 6 weeks)
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.
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.
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.
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.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Nov 2023.
- Background: PubMed 27874832Farrell 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.
- Background: PubMed 28632329Farrell 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.
- Background: PubMed 12609127Fisher 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.
- Background: PubMed 1366259Hansson 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.
- Background: PubMed 20719574Krauss 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.
- Background: PubMed 7793470Sobin 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.
- Derived from this study: PubMed 40659830Pottkamper JCM, Verdijk JPAJ, Stuiver S, Doesschate FT, van Putten MJAM, Hofmeijer J, van Waarde JA, van Wingen GA. Postictal resting-state connectivity changes after electroconvulsive therapy-induced seizures. Eur Arch Psychiatry Clin Neurosci. 2026 Mar;276(2):851-862. doi: 10.1007/s00406-025-02043-7. Epub 2025 Jul 14.
- Derived from this study: PubMed 35436940Verdijk 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.
- Individual participant dataSharing planned: Yes. 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jeroen A van Waarde, MD principal investigator
Rijnstate Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Paracetamol and Nimotop in people with Epilepsy and Depression, run by Rijnstate Hospital at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 18 Nov 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Time to EEG normalization (time frame: Change from ictal to baseline EEG activity, up to 12 times per patient (across 6 weeks)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04028596, which also lists 8 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Nov 2023.