Evaluation of Rivastigmine and EEG in Predicting ECT Response and Mitigating Cognitive Side Effects in Patients with Severe Depression

The primary objective of this study is twofold: firstly, to enhance **cognition** following Electroconvulsive Therapy (ECT), thereby improving its acceptability and tolerability, which could lead to increased application. This is clinically relevant as ECT is a treatment option for patients with chronic severe **depression**, and its broader use could significantly reduce the morbidity and mortality associated with this disorder. Secondly, the study aims to develop a prediction method based on clinical and EEG characteristics to accurately forecast which patients will respond to ECT. Accurate prediction of ECT response is crucial to prevent patients with a low likelihood of recovery from undergoing ECT without benefit, thus avoiding unnecessary exposure to associated risks.

Secondary objectives include: - Investigating quality of life measures after the addition of **rivastigmine**. - Assessing whether free speech can predict antidepressant effects. - Evaluating if EEG can predict cognitive impairment. - Analyzing changes in network-related measures during an ECT course. - Examining changes in blood and DNA methylation during ECT. - Developing a comprehensive prediction method based on available parameters. - Investigating subjective measures of response anticipation and side effects.

The clinical trial focuses on individuals diagnosed with **depression**, specifically targeting those with a clinical indication for electroconvulsive therapy (ECT) as determined by a psychiatrist. The study population includes both male and female participants over the age of 18, with no upper age limit specified. Participants are required to have Dutch as their first language. The trial does not specify the total number of participants, as this information was not provided by the sponsor. The selection criteria include individuals with either unipolar or bipolar depression. The trial population is considered vulnerable, indicating that additional ethical considerations are in place to protect the participants. Lifestyle factors such as diet, physical activity, or habits are not detailed in the available data. The study aims to enhance cognition post-ECT, improve its acceptability and tolerability, and develop a prediction method for ECT response based on clinical and EEG characteristics.

The clinical trial is designed to evaluate the efficacy of **rivastigmine** in reducing cognitive side effects associated with electroconvulsive therapy (ECT) in patients with depression. This study employs a **randomized**, **double-blind**, and **controlled** design to ensure the reliability and validity of the results. Participants will be randomly assigned to receive either a transdermal patch containing rivastigmine or a placebo patch. The trial is expected to span approximately four years, with an estimated end date of July 31, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age over 18 years, a clinical indication for ECT, and a diagnosis of uni- or bipolar depression. Following successful screening, participants will be enrolled in the study and attend regular follow-up visits to monitor treatment effects and collect data on cognitive and memory-related measures. The end-of-study visit will conclude the trial, where final assessments will be conducted to evaluate the primary and secondary endpoints.

The expected length of participant involvement is up to three months, depending on the treatment period assigned. Conditions that may lead to early termination from the study include adverse reactions to the treatment, withdrawal of consent, or any significant protocol deviations. The primary endpoints focus on the interaction between placebo and rivastigmine on cognitive measures, while secondary endpoints include quality of life assessments and the development of predictive algorithms for ECT response and side effects. The trial aims to provide insights into the potential benefits of rivastigmine in enhancing the tolerability and effectiveness of ECT in treating depression.

The clinical trial involves the use of **Rivastigmine**, an experimental medication formulated as a transdermal patch. This patch is designed for **transdermal use** and is available in two dosages: 9.5 mg and 4.6 mg. The maximum daily dose for the 9.5 mg patch is 9.5 mg, with a treatment period of up to 1 month. For the 4.6 mg patch, the maximum daily dose is 4.6 mg, with a treatment period of up to 3 months. The active substance, **Rivastigmine**, is of chemical origin and is intended to provide an additional dosing option for patients with moderate to severe dementia. The administration of the patch is monitored to ensure participant compliance with the dosing schedule.

In addition to the experimental medication, the study includes the use of placebo treatments. These are adhesive plasters designed to mimic the appearance and application of the Rivastigmine patches but contain 0 mg of the active substance. The placebo is available in two forms: a 9.5 mg adhesive plaster and a 4.6 mg adhesive plaster, both containing no active **Rivastigmine**. The placebo serves as a comparator treatment to evaluate the efficacy and safety of the experimental medication. The placebo patches are applied in the same manner as the active patches to maintain blinding and ensure the integrity of the study results.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include evaluating the cognitive and memory-related measures in the **rivastigmine** group compared to the placebo group, with a focus on identifying significant interaction terms and non-significant comparisons within the rivastigmine group at a p-value of less than 0.05. Additionally, the development of a classification algorithm for predicting Electroconvulsive Therapy (ECT) response and side effects will be assessed for accuracy and statistical significance at p<0.05.

Secondary endpoints will explore various aspects, such as the impact of rivastigmine on quality of life measures, the predictive value of free speech for antidepressant effects, and the potential of EEG to predict cognitive impairment, all evaluated for statistical significance at p<0.05. Changes in network-related measures during an ECT course, as well as alterations in blood and DNA methylation, will also be investigated for their predictive capabilities, with significant changes between timepoints being a key focus. Furthermore, the trial aims to develop a comprehensive prediction method based on available parameters and to assess subjective measures of response anticipation and side effects, all with statistical significance at p<0.05.