Nonconvulsive Electrotherapy: a Proof-of-concept Trial

• Sponsor: University of Maryland (Other)
• Overall Status: Completed
• CT.gov ID: NCT01065597
• Collaborator: Brain & Behavior Research Foundation (Other)
• Enrollment: 13
• Location: 1
• Arm: 1
• Duration (Months): 47
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This study involves pilot testing of a modified version of a proven treatment for mental illness. The treatment, electroconvulsive therapy (ECT) is used to treat more than 100,000 Americans yearly. ECT is the most effective treatment for major depression, a disorder that affects approximately 5 to 8 percent of the adult US population yearly. It is also an effective treatment for mania and mixed mood states associated with bipolar disorder and schizoaffective disorder.

The aim of ECT is to induce a seizure, which is thought to be responsible for both its therapeutic and its adverse cognitive effects. The proposed modification consists of reducing the ECT electrical stimulus dose below the amount necessary to induce seizures so that adverse cognitive effects, such as confusion and memory problems, are minimized.

The investigators intend to determine whether ECT-related cognitive impairment can be reduced without diminishing the therapeutic effect of ECT. In addition to distressing patients, ECT-related cognitive impairment has significant public health consequences. These include increased morbidity and mortality among severely ill individuals who refuse ECT due to concern over its adverse cognitive effects as well as increased falls among the elderly receiving ECT. Elderly patients are far more likely to receive ECT and are also more vulnerable to ECT-related cognitive impairment. They often require hospitalization for ECT and a longer hospital stay with greater spacing of treatments to minimize adverse cognitive effects.

The hypothesis driving this research is that electrical brain stimulation applied in the same manner as standard ECT, but at a lower dose, can have therapeutic effects and fewer adverse cognitive effects without inducing seizures. This hypothesis is based on the following: 1) the investigators clinical experience of patients who have improved with ECT despite having only one or no seizure, 2) animal studies showing that electrical brain stimulation can induce antidepressant like effects in animals without inducing seizures, 3) reports from the 1950s that "subconvulsive" and "nonconvulsive" electrotherapy was effective for some patients, and 4) the recent approval by the US Food and Drug Administration of the use of transcranial magnetic stimulation --a technique that uses a magnet to induce an electrical current in the brain without inducing seizures--for treatment of medication resistant major depression.

The primary aim of the research is to conduct a proof of concept, open trial investigating the therapeutic efficacy and safety of nonconvulsive electrotherapy (NET). The investigators plan to enroll 16 subjects, which is the minimum number of subjects needed to show that the therapeutic effect of NET is better than would be expected of placebo. If the investigators show that the therapeutic effect of NET exceeds that expected of placebo and does not induce significant cognitive impairment, then the investigators will go on to propose a blind, randomized, controlled clinical trial that more definitively tests the investigators' hypothesis. The investigators would use the information gathered from the pilot trial to estimate the number of subjects needed to definitively test the efficacy and safety of NET.

The secondary aim of the study is to find out whether NET affects blood levels of brain-derived neurotrophic factor (BDNF). BDNF is a substance that is important to the nervous system and may be related to how treatments like ECT or possibly NET improve symptoms. The investigators would draw a blood sample before and after NET treatment to assess this.

Condition or Disease	Intervention/Treatment	Phase
Depressive Disorder; Bipolar Disorder; Schizoaffective Disorder	Device: Nonconvulsive electrotherapy	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Nonconvulsive Electrotherapy: a Proof-of-concept Trial
• Study Start Date: May 1, 2010
• Actual Primary Completion Date: Mar 1, 2014
• Actual Study Completion Date: Apr 1, 2014

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Nonconvulsive electrotherapy Open label single arm study of nonconvulsive electrotherapy

Device: Nonconvulsive electrotherapy; An electrical stimulus will be given as in electroconvulsive therapy (ECT)using bifrontal electrode placement and a Thymatron System IV device; however, the device will be set at a lower energy level that is 12.5%(1/8) of the expected energy needed to induce a seizure rather than at an energy level that is at or above the seizure threshold.; Other Names: Thymatron System IV device made by Somatics, LLC.

Outcome Measures

Primary Outcome Measures

1. Change in Score on the 17-item Hamilton Depression Rating Scale [Baseline and at the end of the NET treatment course 2-4 weeks later, depending on the number of NET treatments]

   Score range is 0 to 54 points. The higher the score, the more depressed symptoms.

Secondary Outcome Measures

1. Change in Score on Mini-mental State Exam [Baseline and at the end of the NET treatment course 2-4 weeks later, depending on the number of NET treatments]

   Score range is 0 to 30 points. The higher the score, the better the cognition. So a higher score means less cognitive impairment.

2. Change in Score on the Autobiographical Memory Inventory Short Form (AMI-S) [Baseline and at the end of the NET treatment course 2-4 weeks later, depending on the number of NET treatments]

   The Autobiographical Memory Inventory Short Form (AMI-S ) assesses effects on retrograde memory for autobiographical information including information related to a family member, recent travel, events of last New Year's eve, events of last birthday, employment information, and events of last non-psychiatric illness and its treatment. Subjects responded to specific questions regarding these topics before and after their course of NET treatment. Subjects were scored based on the percent of responses post-NET treatment that correctly matched their responses prior to NET treatment. The score range is 0 to 100%. The higher the percent, the less impaired is the autobiographical memory.

3. Change in Brain-derived Neurotrophic Factor (BDNF) Blood Level [Baseline and at the end of the NET treatment course 2-4 weeks later, depending on the number of NET treatments]

   Change in plasma level of BDNF in pg/ml pre and post NET treatment course.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Men and women, aged 18 years and older meeting structured clinical interview for the DSM IV (SCID) criteria for unipolar major depressive disorder, bipolar disorder, or schizoaffective disorder.

2. Subjects of child-bearing potential must agree to have a pregnancy test prior to enrollment and agree to use a reliable method of birth-control during the study.

3. Willingness and ability to provide informed consent as determined by satisfactorily completing the study-specific Evaluation to Sign Consent Form Test.

4. Baseline score ≥ 16 on the 21-item version of the Hamilton Depression Rating Scale (HAMD-21) for unipolar depression, the Bipolar Depression Rating Scale (BDRS) for bipolar depression, or the Young Mania rating scale (YMRS) for mania.

5. Willingness to allow the Principal Investigator to discuss study participation with treating psychiatrist

6. Taking the same regimen of psychiatric medications with no changes for at least one month prior to NET treatment and willingness to not have any medication changes during NET treatment.

7. Currently an outpatient.

8. History of or currently refusing ECT due to experience of or anticipation of adverse effects.

Exclusion Criteria:

1. Pregnancy.

2. Use of any investigational drugs within 30 days of baseline or at any time during the study.

3. Ongoing substance abuse or dependence.

4. Current suicidal ideas.

5. Presence of any condition that would contraindicate ECT or bifrontal electrode placement.

6. Medical or neurologic condition etiologically related to mood disorder.

7. History of coronary artery disease or cardiac arrhythmia.

8. History of serious, potentially life-threatening reaction to anesthesia.

9. For individuals who need to have brain imaging, presence of metal in the body that would make a head MRI unsafe.

10. For individuals who need to have brain imaging, history of claustrophobia or anxiety associated with previous MRI.

11. Allergy or adverse reaction to methohexital or succinylcholine.

12. Epilepsy or seizure disorder.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Maryland Medical Center	Baltimore	Maryland	United States	21201

Sponsors and Collaborators

• University of Maryland
• Brain & Behavior Research Foundation

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

• BERAN M, PERKINS JC, SCOLLON RW. Psychological studies on patients undergoing nonconvulsive electric-stimulation treatment. Am J Psychiatry. 1952 Nov;109(5):367-74.
• Gersner R, Toth E, Isserles M, Zangen A. Site-specific antidepressant effects of repeated subconvulsive electrical stimulation: potential role of brain-derived neurotrophic factor. Biol Psychiatry. 2010 Jan 15;67(2):125-32. doi: 10.1016/j.biopsych.2009.09.015.

• Responsible Party: William T Regenold, Associate Professor of Psychiatry, University of Maryland
• ClinicalTrials.gov Identifier: NCT01065597
• Other Study ID Numbers: HP-00040324
• First Posted: Feb 9, 2010
• Last Update Posted: Aug 28, 2015
• Last Verified: Aug 1, 2015

• Keywords provided by William T Regenold, Associate Professor of Psychiatry, University of Maryland: electroconvulsive therapy; seizure; nonconvulsive; subconvulsive; major depression; bipolar disorder
• Additional relevant MeSH terms: Disease; Depressive Disorder; Bipolar Disorder; Psychotic Disorders

Study Results

Participant Flow

Arm/Group Title	Nonconvulsive Electrotherapy
Arm/Group Description	Open label single arm study of nonconvulsive electrotherapy Nonconvulsive electrotherapy: An electrical stimulus will be given as in electroconvulsive therapy (ECT)using bifrontal electrode placement and a Thymatron System IV device; however, the device will be set at a lower energy level that is 12.5%(1/8) of the expected energy needed to induce a seizure rather than at an energy level that is at or above the seizure threshold.
Period Title: Overall Study
STARTED	13
COMPLETED	12
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Nonconvulsive Electrotherapy
Arm/Group Description	Open label single arm study of nonconvulsive electrotherapy Nonconvulsive electrotherapy: An electrical stimulus will be given as in electroconvulsive therapy (ECT)using bifrontal electrode placement and a Thymatron System IV device; however, the device will be set at a lower energy level that is 12.5%(1/8) of the expected energy needed to induce a seizure rather than at an energy level that is at or above the seizure threshold.
Overall Participants	13
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	13 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41.3 (13)
Sex: Female, Male (Count of Participants)
Female	7 53.8%
Male	6 46.2%
Region of Enrollment (participants) [Number]
United States	13 100%

Outcome Measures

1. Primary Outcome

Title	Change in Score on the 17-item Hamilton Depression Rating Scale
Description	Score range is 0 to 54 points. The higher the score, the more depressed symptoms.
Time Frame	Baseline and at the end of the NET treatment course 2-4 weeks later, depending on the number of NET treatments

Outcome Measure Data

Analysis Population Description

2 of 13 subjects had seizures during first treatment; therefore, there are no seizure-free data for them that would qualify as nonconvulsive treatment data

Arm/Group Title	Nonconvulsive Electrotherapy
Arm/Group Description	Open label single arm study of nonconvulsive electrotherapy Nonconvulsive electrotherapy: An electrical stimulus will be given as in electroconvulsive therapy (ECT)using bifrontal electrode placement and a Thymatron System IV device; however, the device will be set at a lower energy level that is 12.5%(1/8) of the expected energy needed to induce a seizure rather than at an energy level that is at or above the seizure threshold.
Measure Participants	11
Mean (Standard Deviation) [units on a scale]	-11.6 (8.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nonconvulsive Electrotherapy
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	t-test, 2 sided
	Comments	This was a paired t-test.

2. Secondary Outcome

Title	Change in Score on Mini-mental State Exam
Description	Score range is 0 to 30 points. The higher the score, the better the cognition. So a higher score means less cognitive impairment.
Time Frame	Baseline and at the end of the NET treatment course 2-4 weeks later, depending on the number of NET treatments

Outcome Measure Data

Analysis Population Description

2 of 13 subjects had seizures during first treatment; therefore, there are no seizure-free data for them that would qualify as nonconvulsive treatment data

Arm/Group Title	Nonconvulsive Electrotherapy
Arm/Group Description	Open label single arm study of nonconvulsive electrotherapy Nonconvulsive electrotherapy: An electrical stimulus will be given as in electroconvulsive therapy (ECT)using bifrontal electrode placement and a Thymatron System IV device; however, the device will be set at a lower energy level that is 12.5%(1/8) of the expected energy needed to induce a seizure rather than at an energy level that is at or above the seizure threshold.
Measure Participants	11
Mean (Standard Deviation) [units on a scale]	0.9 (2.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nonconvulsive Electrotherapy
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	t-test, 2 sided
	Comments	This was a paired t-test.

3. Secondary Outcome

Title	Change in Score on the Autobiographical Memory Inventory Short Form (AMI-S)
Description	The Autobiographical Memory Inventory Short Form (AMI-S ) assesses effects on retrograde memory for autobiographical information including information related to a family member, recent travel, events of last New Year's eve, events of last birthday, employment information, and events of last non-psychiatric illness and its treatment. Subjects responded to specific questions regarding these topics before and after their course of NET treatment. Subjects were scored based on the percent of responses post-NET treatment that correctly matched their responses prior to NET treatment. The score range is 0 to 100%. The higher the percent, the less impaired is the autobiographical memory.
Time Frame	Baseline and at the end of the NET treatment course 2-4 weeks later, depending on the number of NET treatments

Outcome Measure Data

Analysis Population Description

2 of 13 subjects had seizures during first treatment; therefore, there are no seizure-free data for them that would qualify as nonconvulsive treatment data

Arm/Group Title	Nonconvulsive Electrotherapy
Arm/Group Description	Open label single arm study of nonconvulsive electrotherapy Nonconvulsive electrotherapy: An electrical stimulus will be given as in electroconvulsive therapy (ECT)using bifrontal electrode placement and a Thymatron System IV device; however, the device will be set at a lower energy level that is 12.5%(1/8) of the expected energy needed to induce a seizure rather than at an energy level that is at or above the seizure threshold.
Measure Participants	11
Mean (Standard Deviation) [% correct responses]	97 (2.2)

4. Secondary Outcome

Title	Change in Brain-derived Neurotrophic Factor (BDNF) Blood Level
Description	Change in plasma level of BDNF in pg/ml pre and post NET treatment course.
Time Frame	Baseline and at the end of the NET treatment course 2-4 weeks later, depending on the number of NET treatments

Outcome Measure Data

Analysis Population Description

2 subjects had a seizure during the first treatment and therefore had no seizure-free (nonconvulsive) data, and 2 subjects declined blood draw

Arm/Group Title	Nonconvulsive Electrotherapy
Arm/Group Description	Open label single arm study of nonconvulsive electrotherapy Nonconvulsive electrotherapy: An electrical stimulus will be given as in electroconvulsive therapy (ECT)using bifrontal electrode placement and a Thymatron System IV device; however, the device will be set at a lower energy level that is 12.5%(1/8) of the expected energy needed to induce a seizure rather than at an energy level that is at or above the seizure threshold.
Measure Participants	9
Median (Full Range) [pg/ml]	22

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nonconvulsive Electrotherapy
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Time Frame	4 years
Adverse Event Reporting Description	Subjects each participated for 2-4 weeks over the 4 year total duration of study. Participants were queried for adverse events, defined as an unwelcome change in physical or mental status that required clinical assessment, prior to and following each treatment.
Arm/Group Title	Nonconvulsive Electrotherapy
Arm/Group Description	Open label single arm study of nonconvulsive electrotherapy Nonconvulsive electrotherapy: An electrical stimulus will be given as in electroconvulsive therapy (ECT)using bifrontal electrode placement and a Thymatron System IV device; however, the device will be set at a lower energy level that is 12.5%(1/8) of the expected energy needed to induce a seizure rather than at an energy level that is at or above the seizure threshold.
All Cause Mortality
	Nonconvulsive Electrotherapy
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Nonconvulsive Electrotherapy
	Affected / at Risk (%)	# Events
Total	0/13 (0%)
Other (Not Including Serious) Adverse Events
	Nonconvulsive Electrotherapy
	Affected / at Risk (%)	# Events
Total	10/13 (76.9%)
Cardiac disorders
Cardiac arrhythmia	1/13 (7.7%)
General disorders
Fatigue	3/13 (23.1%)
Musculoskeletal and connective tissue disorders
Jaw pain	2/13 (15.4%)
Nervous system disorders
Induced seizure	3/13 (23.1%)
Headache	3/13 (23.1%)
Dizziness	1/13 (7.7%)
Psychiatric disorders
Anxiety dream	1/13 (7.7%)
Respiratory, thoracic and mediastinal disorders
Sore throat	1/13 (7.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.