Title: Safety and Feasibility of Individualized Low Amplitude Seizure Therapy (iLAST)

  • STATUS
    Recruiting
  • End date
    Dec 31, 2025
  • participants needed
    20
  • sponsor
    National Institute of Mental Health (NIMH)
Updated on 25 November 2020
Investigator
Zhi-De Deng, Ph.D.
Primary Contact
National Institutes of Health Clinical Center (9.7 mi away) Contact
anesthesia
depression
depressive disorder
depressed mood
severe depression
electroconvulsive therapy

Summary

Background

Electroconvulsive therapy (ECT) is used to treat people with severe depression. During ECT, the brain is given electric pulses that cause a seizure. Although it is effective, it can cause side effects, including memory loss. Researchers want to study a new way to give ECT called iLAST.

Objective

To see if iLAST is safe and feasible in treating depression.

Eligibility

People ages 22 70 years old who have major depressive disorder and are eligible for ECT

Design

Participants will be screened under protocol 01-M-0254. This includes:

Medical and psychiatric history and exam

Blood and urine tests

Participants will be inpatients at the Clinical Center. They study has 3 phases and will last up to 20 weeks.

Phase I will last 1 week. It includes:

MRI: Participants will lie in a scanner that takes pictures of the body

MEG: A cone over the participant s head will record brain activity.

TMS: A wire coil placed on the participant s scalp will produce an electrical current to affect brain activity.

SEP: An electrode on the participant s wrist will give a small electrical shock to test nerve function.

Phase II will last 2 and a half weeks. It includes:

Seven sessions of iLAST under general anesthesia. Participants may also get standard ECT.

EEG: A small electrode placed on the participant s scalp will record brain waves.

Interviews about mood, symptoms, and side effects. Participants facial expressions may be video recorded.

TMS

Phase III will last at least 1 week. It will include:

MRI

EEG

TMS

MEG

Standard ECT if needed. Participants will have sessions every other day, 3 times a week.

Sponsoring Institution: National Institute of Mental Health

...

Description

Despite advances in antidepressant interventions, none has replaced electroconvulsive therapy (ECT) in its acute efficacy and spectrum of action in severely depressed patients, including in psychotic depression, catatonia, and acutely suicidal patients. However, ECT carries a risk of significant adverse effects including cognitive and physiological side effects, some of which can be long term. The side effects are thought to be related to stimulation of brain areas beyond those implicated in depression, so called non-target regions. While these advances have improved the safety and tolerability of seizure therapy, a risk of cognitive side effects remains, and none of the currently used procedures individualize the current amplitude for each patient despite knowledge that anatomical variation significantly impacts the strength of the current delivered to the brain. We propose a first-in-human safety and feasibility study of this approach (termed individualized low amplitude seizure therapy , or iLAST). iLAST introduces three areas of improvement over conventional ECT:

  1. use of a multi-electrode array to selectively target different regions of the brain coupled

with computational electric field modeling on an individual patient basis to examine the

current flow in the brain.

2. an alternative dosing strategy in which the stimulus is titrated in the current amplitude

domain.

3. use of high-density EEG electrodes that are weaved into the multi-stimulation electrode

array so that topographical ictal EEG is recorded. As mandated by the US FDA, a first in human (FIH) study is a type of study in which a device for a specific indication is evaluated for the first time in human subjects. We propose a FIH study of iLAST in 10 subjects. If safety and feasibility of iLAST are supported, this could lead to the development of a practical and safer alternative to ECT that could be rapidly disseminated through modification of ECT devices already cleared by the FDA, lowering regulatory barriers and development cost. If the aims are not supported, this would provide further support that development of the magnetic approach to seizure therapy is warranted.

The primary aim of the current protocol is to evaluate the safety and feasibility of iLAST in 10 adults with major depressive episode (unipolar) eligible for ECT. We hypothesize that iLAST will result in superior neurocognitive outcomes than conventional ECT. In addition, we will evaluate the feasibility of alternative methods to individualize the pulse amplitude. The approach to individualizing pulse amplitude is to apply trains of pulses of increasing amplitude until a seizure is induced. To be practical in the clinical setting, the motor threshold (MT) procedure will be completed rapidly to minimize time under anesthesia. To this end, we will evaluate a rapid- estimation motor thresholding algorithm under anesthesia. This will allow us to determine the relationships among measured amplitude-titrated seizure threshold (STa), measured MT, and simulated MT derived from electric field modeling. Our hypothesis is that both measured and simulated MT are correlated with STa, thus providing a clinically useful predictor of current amplitude necessary to perform seizure therapy under the time-constraints of anesthesia.

Study Population

The study will consist of 10 individuals between 22 and 70 years old, with a major depressive disorder.

Study Design

This is a within-subject safety and feasibility study that comprises three phases. Phase I includes medication taper (as clinically indicated), and baseline assessments.

In Phase II, patients will receive the 7 ultrabrief pulse width (0.3 ms) seizure therapy conditions. As treatments will be delivered on a 3 per week schedule.

On each experimental condition day, patients will undergo a number of procedures to assess clinical status and safety. Post procedure acute battery assessments will include: a) side effect questionnaire, b) neurocognitive battery, and c) neuroplasticity battery.

In Phase III, patients will be offered routine clinical management consisting of a conventional ECT course (typically 6 12 treatments) based on clinical need. Patients will receive pre- and post- course measures including: clinical rating scales, neurocognitive testing, neuroimaging, and a neuroplasticity battery.

Patients will also receive optional TMS EEG and ictal EEG recording at the 2nd, 8th or final treatment.

Outcome Measures

Primary Outcome measures: successful seizure induction as measured by topographical EEG and motor manifestations, vital signs, ECG, subjective side effect scale, and adverse events/significant adverse events.

Secondary Outcome measures: Neurocognitive battery known to be sensitive to the cognitive effects of ECT, with alternative versions to avoid practice effects; and, Amplitude-titrated seizure threshold (STa), measured electrical MT, and simulated MT derived from realistic head modeling.

Details
Treatment MRI, Multichannel Stimulation Interface, MagPro TMS stimulator and coil, MECTA paired with the 4X1 HD-ECT
Clinical Study IdentifierNCT03895658
SponsorNational Institute of Mental Health (NIMH)
Last Modified on25 November 2020

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Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age between 22 yrs and 70 yrs?
Gender: Male or Female
Do you have any of these conditions: Affective Disorders or mood disorder or Endogenous depression or Mood Disorders (Pediatric) or Mood Disorders?
Do you have any of these conditions: Affective Disorders or Endogenous depression or Mood Disorders or major depressive disorder or Mood Disorders (Pediatric) or mood disorder?
Do you have any of these conditions: Affective Disorders or Mood Disorders (Pediatric) or mood disorder or major depressive disorder or Endogenous depression or Mood Disorders?
Do you have any of these conditions: Mood Disorders or Endogenous depression or Affective Disorders or Mood Disorders (Pediatric) or mood disorder or major depressive disorder?
Do you have any of these conditions: Mood Disorders or Endogenous depression or major depressive disorder or Mood Disorders (Pediatric) or mood disorder or Affective Disorders?
Male and female, 22 70 years old
Use of effective method of birth control for women of childbearing capacity. Women who are able to get pregnant must be willing to use at least one form of effective birth control during the entire period of study participation (or until last clinical labs and rating) and have a negative pregnancy test at screening
DSM-5 diagnosis of major depressive disorder, confirmed by the MINI
Eligible for ECT, including patients receiving maintenance ECT
Each subject must have a level of understanding sufficient to agree to all required tests and examinations and sign an informed consent document
Subjects are willing and able to adhere to the intensive treatment schedule and all required study procedures

Exclusion Criteria

Pregnant or nursing women or women who plan to become pregnant
Current or recent (within the past 6 months) substance abuse or dependence (excluding nicotine and caffeine)
Current serious medical illness judged to be clinically significant, such as high blood pressure, diabetes, heart or lung disease
History of seizure except those therapeutically induced by ECT (childhood febrile seizures are acceptable and these subjects may be included in the study), history of epilepsy in self or first degree relatives, stroke, brain surgery, concussion resulted in loss of consciousness or hospitalization, cranial metal implants, known structural brain lesion, devices that may be affected by TMS or MRI (pacemaker, medication pump, cochlear implant, implanted brain stimulator, vagus nerve stimulator)
Diagnosed with the following conditions (current unless otherwise stated)
Any other current primary Axis I mood, anxiety, or psychotic disorder
Depression secondary to a general medical condition, or substance-induced
Psychotic disorder (lifetime), including schizoaffective disorder, or major depression with psychotic features in the current episode
Eating disorder (current or within the past year)
Obsessive compulsive disorder (current or within the past year)
Post-traumatic stress disorder (current or within the past year)
ADHD (currently being treated)
Subjects meeting criteria based upon DSM-5 criteria, which in the judgment of the Investigator, may hinder the subjects in completing the procedures required by the study protocol
Actively suicidal
Increased risk of seizure for any reason, including prior diagnosis of increased intracranial pressure (such as after large infarctions or trauma), or currently taking medication that lowers the seizure threshold
Subjects with a clinically defined neurological disorder including, but not limited
to
Any condition likely to be associated with increased intracranial pressure
Space occupying brain lesion
History of stroke
Transient ischemic attack within two years
Cerebral aneurysm
Dementia
Mini Mental Status Exam (MMSE) score < 24
Parkinson s disease
Huntington s disease
Multiple sclerosis
Subjects with any of the following treatment histories
Failure to respond to TMS or ECT treatment (i.e., consistent with ATHF confidence level 3 or higher) in this or any previous episode
Lifetime history of treatment with Deep Brain Stimulation or Vagus Nerve Stimulation
Use of any investigational drug or device within 4 weeks of the screening
MRI contraindications (any metal in the body, claustrophobia, etc.)
Current visual, auditory, or motor impairment that compromises ability to complete evaluations
Positive HIV test
NIMH employees and staff and their immediate family members will be excluded from the study per NIMH policy
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