Flumazenil for Benzodiazepine Reversal in Electroconvulsive Therapy (FLEET)

May 27, 2026 updated by: Anders Jørgensen

Flumazenil for Benzodiazepine Reversal in Electroconvulsive Therapy (FLEET): A Randomized Controlled Trial

The goal of this study is to investigate whether administering flumazenil to reverse the effects of benzodiazepines and/or zopiclone during electroconvulsive therapy (ECT) can help reduce cognitive side effects without diminishing treatment effectiveness in hospitalized patients with depression.

The investigators hypothesize that blockade of the GABA receptor with flumazenil will reduce cognitive side effects through improved seizures and a reduced need for electrical charge escalation during the ECT series. Cognitive side effects will be measured by the total score on the Screening for Cognitive Impairment in Psychiatry (SCIP) (primary outcome) at follow-up after completion of the ECT series. Furthermore, it is expected that the flumazenil strategy will reduce pre-treatment anxiety and improve patient satisfaction (secondary outcomes). In addition, flumazenil strategy is hypothesized to have beneficial effects on subjective cognitive complaints, autobiographical memory, and executive functioning (secondary outcomes). Finally, the flumazenil strategy is expected to be associated with more favorable structural and functional changes in executive functioning and memory-related brain networks after completion of the ECT series, which may, in turn, be linked to better overall cognition and autobiographical memory (secondary outcome measures). For exploratory purposes, the study will also examine longitudinal changes in depressive symptoms and cognitive outcomes from baseline to follow-up (tertiary outcomes).

Investigators will compare two different pre-ECT benzodiazepine management strategies:

  1. Flumazenil strategy (experimental): continued benzodiazepine and/or zopiclone use up until the time of the ECT session, followed by administration of flumazenil immediately prior to ECT
  2. Benzodiazepine withholding strategy (treatment as usual):

discontinuation of benzodiazepines and/or zopiclone prior to the ECT in accordance with standard clinical practice

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

The study will include adult inpatients (≥18 years of age) diagnosed with a mood disorder (major depressive disorder or bipolar disorder), currently experiencing a depressive episode (ICD-10: F31.3-5, F32 or F33), who are deemed eligible for ECT by a treating psychiatrist who is not affiliated with the study. Based on a power analysis, 132 participants (66 per group) are required to achieve adequate statistical power. To account for an anticipated 10% dropout rate from baseline to follow-up, the investigators will recruit 145 participants. Recruitment will be carried out through psychiatric hospital wards within the Mental Health Services of the Capital Region of Denmark.

Participants will be randomized following an initial screening to confirm eligibility. Randomization will be conducted using the automated randomization module in the Research Electronic Data Capture (REDCap) system, based on a pre-generated randomization list with variable block sizes of two and four. Allocation will be stratified by age (< 60 or ≥ 60 years) and electrode placement (unilateral vs. bilateral). Randomization will occur no later than the day prior to the second ECT session of the treatment series. Primary outcome assessors are blinded to the group allocation.

Baseline assessments will be conducted the day before the first ECT session or, if not otherwise possible, the day before the second ECT session. Participants will complete a brief neuropsychological assessment comprising the Screen for Cognitive Impairment in Psychiatry (SCIP) and additional measures of executive functioning and autobiographical memory. Participants will also complete self-report questionnaires assessing subjective cognitive complaints. Depressive symptom severity will be rated using the Hamilton Depression Rating Scale (HDRS).

During the ECT treatment series, repeated assessments will be conducted for each session. Participants will provide self-reported ratings of pre-treatment anxiety shortly before the session, while clinicians will record measures of seizure architecture, and time to reorientation following the session.

Follow-up assessments will be conducted 3-7 days after completion of the ECT-series, which serves as the primary end point. At follow-up, the brief neuropsychological assessment, self-report questionnaires, and HDRS ratings will be repeated. Participants will also complete a short self-report questionnaire of their treatment satisfaction. Structural and functional magnetic resonance imaging (MRI) is conducted within the 3-7 days after completion of the ECT series, coinciding with the follow-up assessment.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
145

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

  • Denmark
    • Capital Region
      • Frederiksberg, Capital Region, Denmark, 2000
        • Recruiting
        • Mental Health Centre Copenhagen, Bispebjerg and Frederiksberg Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion criteria:

  • Current depressive episode (unipolar or bipolar), corresponding to ICD-10 codes F31.3-5, F32 or F33.
  • Admitted at a study affiliated department in the Mental Health Services of the Capital Region of Denmark
  • Referred to ECT by the regular psychiatrist and has given consent to ECT
  • Currently receiving treatment with a benzodiazepine and/or zopiclone, at a minimum daily dose equivalent to 0.5 mg lorazepam.

Exclusion criteria:

  • Involuntary treatment with ECT
  • Known gross abnormalities in brain structure deemed likely to influence cognitive functioning
  • Pregnancy or breast-feeding
  • Inability to read or understand Danish
  • Acute organic brain disease (e.g., delirium) influencing the ability to give informed consent
  • Any pre-existing condition associated with an increased risk of prolonged or uncontrollable seizures, including but not limited to epilepsy or alcohol- or benzodiazepine withdrawal states
  • Conditions associated with reduced metabolism of flumazenil (e.g., liver failure)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Flumazenil for benzodiazepine reversal
Participants continue benzodiazepine and/or zopiclone treatment up until the ECT session, receiving flumazenil to reverse their effects
Drug: Flumazenil
The intervention involves continuation of benzodiazepine and/or zopiclone treatment up to the time of ECT, followed by administration of flumazenil immediately prior to anesthesia to transiently reverse the effect of benzodiazepines and/or zopiclone. Otherwise, ECT is administered according to standard clinical procedures.
Active Comparator: Treatment as usual (benzodiazepine hold)
Participants discontinue benzodiazepine and/or zopiclone treatment the day prior to the ECT session.
Procedure: Electroconvulsive therapy (ECT)
Standard ECT treatment performed in accordance with clinical practice, with benzodiazepines and/or zopiclone withheld after 5:00 p.m. on the day before each session

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Screen for Cognitive Impairment in Psychiatry (SCIP)
Time Frame: Baseline (the day before the first or second session in the ECT series) and follow-up (3-7 days after completion of the ECT series)
The primary outcome measure is the total score on the SCIP at follow-up (post-ECT). The SCIP is a brief neuropsychological assessment tool designed to detect cognitive deficits in individuals with psychotic and affective disorders. It comprises five subtests assessing key cognitive domains: verbal learning and memory (VLT-I and VLT-D), working memory (WMT), verbal fluency (VFT), and processing speed (PST). The total score provides a broad indicator of overall cognitive functioning. Higher scores mean a better outcome.
Baseline (the day before the first or second session in the ECT series) and follow-up (3-7 days after completion of the ECT series)

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Hamilton Depression Rating Scale (HDRS)
Time Frame: Baseline (the day before the first or second session in the ECT series) and follow-up (3-7 days after completion of the ECT series)
Clinician-administered depression assessment scale of 17 items. Score range: 0-52. Clinical response at follow-up (primary endpoint) is assessed using the HAM-D6 subscale, collectively comprising the core symptoms of depression with score range: 0-22. Higher scores mean a worse outcome.
Baseline (the day before the first or second session in the ECT series) and follow-up (3-7 days after completion of the ECT series)
Cognitive Complaints in Bipolar Disorder Rating Scale (COBRA)
Time Frame: Baseline (the day before the first or second session in the ECT series) and follow-up (3-7 days after completion of the ECT series)
Self-report questionnaire assessing subjective cognitive complaints. Score range: 0-48. Higher scores mean a worse outcome.
Baseline (the day before the first or second session in the ECT series) and follow-up (3-7 days after completion of the ECT series)
Squire Subjective Memory Questionnaire (SSMQ)
Time Frame: Baseline (the day before the first or second session in the ECT series) and follow-up (3-7 days after completion of the ECT series)
Self-report questionnaire assessing subjective memory complaints. Score range: -72 - +72. Higher (more positive) scores mean a better outcome.
Baseline (the day before the first or second session in the ECT series) and follow-up (3-7 days after completion of the ECT series)
Autobiographical Memory Test (AMT)
Time Frame: Baseline (the day before the first or second session in the ECT series) and follow-up (3-7 days after completion of the ECT series)
Neuropsychological instrument used to assess the ability to retrieve autobiographical memories and their specificity. Higher scores mean a better outcome.
Baseline (the day before the first or second session in the ECT series) and follow-up (3-7 days after completion of the ECT series)
Trail Making Test B (TMT-B)
Time Frame: Baseline (the day before the first or second session in the ECT series) and follow-up (3-7 days after completion of the ECT series)
Neuropsychological test assessing executive function. Scored by time to completion. Higher scores mean a worse outcome.
Baseline (the day before the first or second session in the ECT series) and follow-up (3-7 days after completion of the ECT series)
Verbal learning and memory (VLT-I)
Time Frame: Baseline (the day before the first or second session in the ECT series) and follow-up (3-7 days after completion of the ECT series)
SCIP subtest assessing verbal learning and immediate recall. Score range: 0-30. Higher scores mean a better outcome.
Baseline (the day before the first or second session in the ECT series) and follow-up (3-7 days after completion of the ECT series)
Delayed verbal recall (VLT-D)
Time Frame: Baseline (the day before the first or second session in the ECT series) and follow-up (3-7 days after completion of the ECT series)
SCIP subtest assessing delayed verbal recall. Score range: 0-10. Higher scores mean a better outcome.
Baseline (the day before the first or second session in the ECT series) and follow-up (3-7 days after completion of the ECT series)
Working memory test (WMT)
Time Frame: Baseline (the day before the first or second session in the ECT series) and follow-up (3-7 days after completion of the ECT series)
SCIP subtest assessing working memory capacity. Score: 0-24. Higher scores mean a better outcome.
Baseline (the day before the first or second session in the ECT series) and follow-up (3-7 days after completion of the ECT series)
Verbal fluency test (VFT)
Time Frame: Baseline (the day before the first or second session in the ECT series) and follow-up (3-7 days after completion of the ECT series)
SCIP subtest assessing verbal fluency. No score range. Higher scores mean a better outcome.
Baseline (the day before the first or second session in the ECT series) and follow-up (3-7 days after completion of the ECT series)
Processing speed test (PST)
Time Frame: Baseline (the day before the first or second session in the ECT series) and follow-up (3-7 days after completion of the ECT series)
SCIP subtest assessing processing speed. Score range: 0-30. Higher scores mean a better outcome.
Baseline (the day before the first or second session in the ECT series) and follow-up (3-7 days after completion of the ECT series)
Patient Satisfaction Survey (PSS)
Time Frame: Follow-up (3-7 days after completion of the ECT series)
Self-report questionnaire assessing patient satisfaction following ECT treament. A subset of items are used. Higher scores mean a better outcome.
Follow-up (3-7 days after completion of the ECT series)
Visual Analogue Scale for Anxiety (VAS-A)
Time Frame: Per ECT session
Visual analogue self-report scale assessing anxiety severity within the last 24 hours. Score range: 0-100. Higher scores mean a worse outcome.
Per ECT session
Time to reorientation
Time Frame: Per ECT session
Clinician-administered structured interview measuring time to reorientation (in minutes) according to Sobin et al. (1995) and Stuiver et al. (2024). Patients are screened every 5 minutes after EEG-offset for orientation in five domains: name, location, age, date of birth, and day of the week. Reorientation is defined as the time in minutes from EEG-offset until the patient provides at least 4 out of 5 correct answers. If the patient fails to reach reorientation within 60 minutes, a score of 70 minutes is registered. Higher scores indicate a longer recovery period and a worse outcome.
Per ECT session
Seizure quality
Time Frame: Per ECT session
Clinician-rated categorical EEG classification of seizure quality (A, A-T, T, O, S). A-seizures represent the optimal therapeutic pattern.
Per ECT session
Seizure length (EEG)
Time Frame: Per ECT session
EEG seizure duration (seconds) from the end of stimulation to the last unequivocal ictal discharge. Continuous physiological measure.
Per ECT session
Stimulus dose
Time Frame: Per ECT session
Stimulus dose recorded as the percentage of the device's maximum output (%) delivered during each treatment, as displayed on the ECT device readout. Range: 0-200%.
Per ECT session
Prefrontal and medial temporal activation during autobiographical memory retrieval
Time Frame: Follow-up (3-7 days after completion of the ECT series)
Functional magnetic resonance imaging (fMRI) measure of brain activity during an autobiographical memory test
Follow-up (3-7 days after completion of the ECT series)
Prefrontal, parietal and medial temporal activation during memory encoding
Time Frame: Follow-up (3-7 days after completion of the ECT series)
Functional magnetic resonance imaging (fMRI) measure of brain activity during a memory encoding task
Follow-up (3-7 days after completion of the ECT series)
Prefrontal and parietal activation during spatial N-back
Time Frame: Follow-up (3-7 days after completion of the ECT series)
Functional magnetic resonance imaging (fMRI) measure of brain activity during a working memory task
Follow-up (3-7 days after completion of the ECT series)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Anders Jørgensen

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Anders Jørgensen, MD, Ph.D., Mental Health Services of the Capital Region

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
January 15, 2026

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
August 1, 2028

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
August 1, 2028

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
September 24, 2025

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 27, 2026

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
June 1, 2026

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
June 1, 2026

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 27, 2026

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
May 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 2025-522506-20-00

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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