Effect of Bupropion on Seizure Threshold in Depressed Patients

• Sponsor: Duke University (Other)
• Overall Status: Completed
• CT.gov ID: NCT03126682
• Collaborator: (none)
• Enrollment: 10
• Location: 1
• Arms: 2
• Actual Duration (Months): 9.2
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief Summary

The purpose of the study is to examine the effect of bupropion on seizure threshold and duration in depressed patients receiving right unilateral ultra-brief electroconvulsive therapy (ECT). The investigators plan to recruit 10 patients into the study, administer sustained release (SR) bupropion 4 hours prior to receiving ECT. The investigators plan to compare the seizure threshold and seizure durations between ECT sessions with and without bupropion administration. The study's implication is to examine how ECT can be optimized by rational combination with medications that lower seizure threshold.

Condition or Disease	Intervention/Treatment	Phase
MDD	Drug: Wellbutrin SR 300Mg Extended-Release Tablet	Phase 4

Detailed Description

Background and significance Depression is the leading cause of disability in individuals aged 15-44, resulting in 400 million disability days in a year (1). The total economic burden of the disease is estimated to be composed of $26.1 billion in direct medical costs, $5.4 billion in suicide-related mortality costs, and $51.5 billion in indirect workplace cost (1). Electroconvulsive therapy (ECT) is the gold-standard treatment for major depressive disorder (MDD) that is severe (2-5). The standard method of ECT used in the US now is right unilateral ultra-brief study. RUL ECT uses a pulse width of </= 0.3 ms, this optimizes electrical dosing and causes decreased severity of cognitive side effects. With right unilateral ECT it is essential for the stimulus to be above seizure threshold. The stimulus dosing is titrated to establish what seizure threshold is and this is titrated over the course of ECT sessions (6). Because the maximum ECT output is limited by FDA, a frequent problem encountered by ECT clinicians is high seizure threshold which at times cannot be provided by the ECT device and this compromises efficacy (7). Hence it would be useful to develop means to lower seizure threshold.

In addition, some studies show a reduction in efficacy with ultra-brief as compared to brief ECT with the former requiring higher number of ECTs to achieve remission in depression symptoms (8). There represents a need for increasing the efficacy for RUL ultra brief ECT given its favorable cognitive-side effect profile. Combining RUL ultra brief ECT with appropriate psychopharmacological agents to alter seizure profile is a feasible way of optimizing the efficacy.

Design and Procedures The study is designed to evaluate the effect of bupropion on seizure threshold in patients with major depressive disorder (MDD) referred for RUL ultra brief ECT. The study is powered to determine changes in seizure duration and seizure threshold by enrolling 10 subjects. The investigators plan to screen 20 subjects to have 10 participants. Potential participants will be discussed with the ECT team to which the patient would have been referred. Once a potential participant has been identified, a study team person will discuss the study and desire for participation in person with that individual during the ECT consult session which is needed prior to scheduling of the ECT session. If participants are found to be eligible they will be invited to participate in the study and the study will be initiated in conjunction with their first ECT session. Participants will go through the informed consent procedure. After providing informed consent participants will undergo a clinical assessment to confirm the inclusion/exclusion criteria.

Patients will receive ECT treatment as usual, but for this study if they choose to participate they will be randomized to receive bupropion (sustained release preparation 300 mg) (Wellbutrin ®), to be taken by mouth, in the morning (4 hours prior to ECT) on the day of ECT session 1 or session 2. There will be a one-time administration of bupropion at this dose with no discontinuation of medications that patient is already on. There will also be no washout period before bupropion administration or ECT.

The study is powered to determine changes in seizure duration and seizure threshold by enrolling 10 subjects (5 subjects will receive bupropion prior to ECT session 1 and 5 will receive it prior to ECT session 2). Counterbalanced randomization will be used to assign subject drug administration to ECT session 1 or 2 with inter-individual cross-over. The PI (Steven T Szabo Jr MD PhD) and coordinator (Gopalkumar Rakesh) would be blind to randomization details. Computer generated randomization would be done by Richard Weiner MD PhD - the director of the ECT program.

ECT administration The clinical procedure of ultra brief RUL ECT in these subjects will not be deviated from the usual procedure that is described below. ECT treatments will be provided three times a week, with standard right unilateral electrode placement with a MECTA spectrum device (MECTA Corporation, Portland, Ore.) with a pulse width </= 0.3 and a current of 0.8 A. A standard dose titration procedure to determine seizure threshold will be conducted at the first and second treatments, subjects would receive bupropion during one of these sessions. Subsequent treatments would be administered at 5.5 times seizure threshold from the treatment session without bupropion administration.

Clinical assessments The Montgomery-Asberg Depression Rating Scale (MADRS) is an assessment tool for depression symptom severity and will be carried out at baseline at every ECT visit. This is usual practice that the ECT clinician employs prior to the clinical administration of ECT. The investigators will also measure time to orientation recovery post ECT after the first and second ECT treatments.

Blood Collection During ECT sessions 1 and 2, just prior to administration of right unilateral (RUL) ECT, patients will be placed with a venous catheter and the investigators will acquire from consenting study patients a serum sample to be used to ascertain serum bupropion level.

Study Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: 2 Arms of randomization - one wherein patients get Wellbutrin in first ECT and another arm wherein patients get it with second ECT. Counterbalanced randomization2 Arms of randomization - one wherein patients get Wellbutrin in first ECT and another arm wherein patients get it with second ECT. Counterbalanced randomization
• Masking: Double (Care Provider, Outcomes Assessor)
• Masking Description: Blinding to be done - Outcome assessor and care provider will be blinded to randomization arm of subject
• Primary Purpose: Treatment
• Official Title: Effect of Bupropion on Seizure Threshold in Depressed Patients
• Actual Study Start Date: Aug 25, 2017
• Actual Primary Completion Date: May 31, 2018
• Actual Study Completion Date: May 31, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Wellbutrin during ECT 1 Drug - Wellbutrin SR 300Mg Extended-Release Tablet during ECT session 1	Drug: Wellbutrin SR 300Mg Extended-Release Tablet; Wellbutrin SR 300Mg Extended-Release Tablet; Other Names: Bupropion sustained release formulation
Active Comparator: Wellbutrin during ECT 2 Drug - Wellbutrin SR 300Mg Extended-Release Tablet during ECT session 2.	Drug: Wellbutrin SR 300Mg Extended-Release Tablet; Wellbutrin SR 300Mg Extended-Release Tablet; Other Names: Bupropion sustained release formulation

Outcome Measures

Primary Outcome Measures

1. Change in Seizure Threshold [Measured at day 1 and day 2]

   Charge in Millicoulombs at which subject gets a seizure with ECT. First measurement on day 1 of electroconvulsive treatment (ECT) and second measurement on day 2 of electroconvulsive therapy (ECT), separated by 1 day interval. This outcome measure was not measured at baseline.

2. Change in Seizure Duration [Measured at day 1 and day 2]

   Duration of seizures with ECT. First measurement on day 1 of electroconvulsive treatment (ECT) and second measurement on day 2 of electroconvulsive therapy (ECT), separated by 1 day interval. This outcome measure was not measured at baseline.

Secondary Outcome Measures

1. Change in MADRS Score [Scored on day 1 and day 2 after ECT session]

   Scoring of depressive symptoms on the Montgomery Asberg Depression Rating Scale, maximum 60 , minimum 0. Higher scores mean worse outcome. First measurement on day 1 of electroconvulsive treatment (ECT) and second measurement on day 2 of electroconvulsive therapy (ECT), separated by 1 day interval. This outcome measure was not measured at baseline.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Male and female subjects, age >18.

2. Meeting diagnostic criteria for major depressive disorder or bipolar disorder per DSM5.

3. Referred for ultra brief RUL ECT.

4. Right motor dominant.

5. Competent to provide informed consent.

6. Able to read or comprehend English.

7. H/O treatment with bupropion.

8. Concomitant treatment with benzodiazepines, dosing of which has remained stable for a week prior to study ECT session.

Exclusion Criteria:

1. Lifetime history of schizophrenia, schizoaffective disorder, mental retardation, seizure disorder.

2. Current alcohol abuse or dependence within past 6 months.

3. Current substance abuse or dependence within past 6 months.

4. Recently received ECT within preceding 3-6 months.

5. Currently on any formulation of bupropion.

6. Currently on any anticonvulsants or clozapine.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Duke University Medical Center	Durham	North Carolina	United States	27710

Sponsors and Collaborators

• Duke University

Investigators

• Principal Investigator: Steven Szabo, MD PhD, Duke University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 2, 2017

More Information

Publications

• Beckford-Ball J. An overview of the new NICE guidelines on bipolar disorder. Nurs Times. 2006 Aug 22-28;102(34):23-4.
• Fountoulakis KN, Vieta E, Sanchez-Moreno J, Kaprinis SG, Goikolea JM, Kaprinis GS. Treatment guidelines for bipolar disorder: a critical review. J Affect Disord. 2005 May;86(1):1-10. Review.
• Frances AJ, Kahn DA, Carpenter D, Docherty JP, Donovan SL. The Expert Consensus Guidelines for treating depression in bipolar disorder. J Clin Psychiatry. 1998;59 Suppl 4:73-9.
• Greenberg PE, Fournier AA, Sisitsky T, Pike CT, Kessler RC. The economic burden of adults with major depressive disorder in the United States (2005 and 2010). J Clin Psychiatry. 2015 Feb;76(2):155-62. doi: 10.4088/JCP.14m09298.
• Lisanby SH, Devanand DP, Nobler MS, Prudic J, Mullen L, Sackeim HA. Exceptionally high seizure threshold: ECT device limitations. Convuls Ther. 1996 Sep;12(3):156-64.
• Sackeim HA, Devanand DP, Prudic J. Stimulus intensity, seizure threshold, and seizure duration: impact on the efficacy and safety of electroconvulsive therapy. Psychiatr Clin North Am. 1991 Dec;14(4):803-43. Review.
• Tor PC, Bautovich A, Wang MJ, Martin D, Harvey SB, Loo C. A Systematic Review and Meta-Analysis of Brief Versus Ultrabrief Right Unilateral Electroconvulsive Therapy for Depression. J Clin Psychiatry. 2015 Sep;76(9):e1092-8. Review.
• Yatham LN, Kennedy SH, Parikh SV, Schaffer A, Beaulieu S, Alda M, O'Donovan C, Macqueen G, McIntyre RS, Sharma V, Ravindran A, Young LT, Milev R, Bond DJ, Frey BN, Goldstein BI, Lafer B, Birmaher B, Ha K, Nolen WA, Berk M. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2013. Bipolar Disord. 2013 Feb;15(1):1-44. doi: 10.1111/bdi.12025. Epub 2012 Dec 12.

• Responsible Party: Duke University
• ClinicalTrials.gov Identifier: NCT03126682
• Other Study ID Numbers: Pro00078738
• First Posted: Apr 24, 2017
• Last Update Posted: Jul 10, 2019
• Last Verified: Jun 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Keywords provided by Duke University: Wellbutrin; Electroconvulsive therapy; Right Unilateral Ultra Brief
• Additional relevant MeSH terms: Seizures; Bupropion

Study Results

Participant Flow

Arm/Group Title	Wellbutrin During ECT 1	Wellbutrin During ECT 2
Arm/Group Description	Drug - Wellbutrin SR 300Mg Extended-Release Tablet during ECT session 1 Wellbutrin SR 300Mg Extended-Release Tablet: Wellbutrin SR 300Mg Extended-Release Tablet	Drug - Wellbutrin SR 300Mg Extended-Release Tablet during ECT session 2. Wellbutrin SR 300Mg Extended-Release Tablet: Wellbutrin SR 300Mg Extended-Release Tablet
Period Title: Overall Study
STARTED	5	5
COMPLETED	5	5
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Wellbutrin During ECT 1	Wellbutrin During ECT 2	Total
Arm/Group Description	Drug - Wellbutrin SR 300Mg Extended-Release Tablet during ECT session 1 Wellbutrin SR 300Mg Extended-Release Tablet: Wellbutrin SR 300Mg Extended-Release Tablet	Drug - Wellbutrin SR 300Mg Extended-Release Tablet during ECT session 2. Wellbutrin SR 300Mg Extended-Release Tablet: Wellbutrin SR 300Mg Extended-Release Tablet	Total of all reporting groups
Overall Participants	5	5	10
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	4 80%	5 100%	9 90%
>=65 years	1 20%	0 0%	1 10%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50.2 (17.1)	45.2 (6.5)	47.7 (12.5)
Sex: Female, Male (Count of Participants)
Female	1 20%	4 80%	5 50%
Male	4 80%	1 20%	5 50%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	1 20%	1 10%
White	5 100%	4 80%	9 90%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	5 100%	5 100%	10 100%

Outcome Measures

1. Primary Outcome

Title	Change in Seizure Threshold
Description	Charge in Millicoulombs at which subject gets a seizure with ECT. First measurement on day 1 of electroconvulsive treatment (ECT) and second measurement on day 2 of electroconvulsive therapy (ECT), separated by 1 day interval. This outcome measure was not measured at baseline.
Time Frame	Measured at day 1 and day 2

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Wellbutrin During ECT 1	Wellbutrin During ECT 2
Arm/Group Description	Drug - Wellbutrin SR 300Mg Extended-Release Tablet during ECT session 1 Wellbutrin SR 300Mg Extended-Release Tablet: Wellbutrin SR 300Mg Extended-Release Tablet	Drug - Wellbutrin SR 300Mg Extended-Release Tablet during ECT session 2. Wellbutrin SR 300Mg Extended-Release Tablet: Wellbutrin SR 300Mg Extended-Release Tablet
Measure Participants	5	5
Mean (Standard Deviation) [millicoulombs]	23.04 (5.3)	19.68 (6)

2. Primary Outcome

Title	Change in Seizure Duration
Description	Duration of seizures with ECT. First measurement on day 1 of electroconvulsive treatment (ECT) and second measurement on day 2 of electroconvulsive therapy (ECT), separated by 1 day interval. This outcome measure was not measured at baseline.
Time Frame	Measured at day 1 and day 2

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Wellbutrin During ECT 1	Wellbutrin During ECT 2
Arm/Group Description	Drug - Wellbutrin SR 300Mg Extended-Release Tablet during ECT session 1 Wellbutrin SR 300Mg Extended-Release Tablet: Wellbutrin SR 300Mg Extended-Release Tablet	Drug - Wellbutrin SR 300Mg Extended-Release Tablet during ECT session 2. Wellbutrin SR 300Mg Extended-Release Tablet: Wellbutrin SR 300Mg Extended-Release Tablet
Measure Participants	5	5
Mean (Standard Deviation) [seconds]	26.2 (14.1)	29.6 (19.3)

3. Secondary Outcome

Title	Change in MADRS Score
Description	Scoring of depressive symptoms on the Montgomery Asberg Depression Rating Scale, maximum 60 , minimum 0. Higher scores mean worse outcome. First measurement on day 1 of electroconvulsive treatment (ECT) and second measurement on day 2 of electroconvulsive therapy (ECT), separated by 1 day interval. This outcome measure was not measured at baseline.
Time Frame	Scored on day 1 and day 2 after ECT session

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Wellbutrin During ECT 1	Wellbutrin During ECT 2
Arm/Group Description	Drug - Wellbutrin SR 300Mg Extended-Release Tablet during ECT session 1 Wellbutrin SR 300Mg Extended-Release Tablet: Wellbutrin SR 300Mg Extended-Release Tablet	Drug - Wellbutrin SR 300Mg Extended-Release Tablet during ECT session 2. Wellbutrin SR 300Mg Extended-Release Tablet: Wellbutrin SR 300Mg Extended-Release Tablet
Measure Participants	5	5
Mean (Standard Deviation) [Scored on a scale]	2.60 (3.2)	3.60 (3.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Wellbutrin During ECT 1, Wellbutrin During ECT 2
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.212
	Comments	Threshold of <0.05
	Method	t-test, 2 sided
	Comments

Adverse Events

Time Frame	Adverse events were assessed on days 1 and 2 of treatment and for a week after treatment 2.
Arm/Group Title	Wellbutrin During ECT 1		Wellbutrin During ECT 2
Arm/Group Description	Drug - Wellbutrin SR 300Mg Extended-Release Tablet during ECT session 1 Wellbutrin SR 300Mg Extended-Release Tablet: Wellbutrin SR 300Mg Extended-Release Tablet		Drug - Wellbutrin SR 300Mg Extended-Release Tablet during ECT session 2. Wellbutrin SR 300Mg Extended-Release Tablet: Wellbutrin SR 300Mg Extended-Release Tablet
All Cause Mortality
	Wellbutrin During ECT 1		Wellbutrin During ECT 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/5 (0%)
Serious Adverse Events
	Wellbutrin During ECT 1		Wellbutrin During ECT 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/5 (0%)
Other (Not Including Serious) Adverse Events
	Wellbutrin During ECT 1		Wellbutrin During ECT 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/5 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.