Flumazenil for Benzodiazepine Reversal in Electroconvulsive Therapy

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

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.

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)