Effect of Bupropion on Seizure Threshold in Depressed Patients
Phase: PHASE4
Conditions: MDD
Sponsor: Duke University

 
 
 
Effect of Bupropion on Seizure Threshold in Depressed Patients 
Study Protocol and Statistical Analysis Plan 
 
NCT03126682 
 
Document Date: May 2, 2017 
 
 

 
Effect of Bupropion on Seizure Threshold in Depressed Patients 
 
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1. Protocol Title – Effect of Bupropion on Seizure Threshold in Depressed Patients 
 
2. Purpose of the study 
Aim: Evaluate the effects of bupropion on seizure duration and seizure threshold during ultra brief right 
unilateral (RUL) electroconvulsive therapy (ECT). Hypothesis: Addition of Bupropion will increase seizure 
duration and lower seizure threshold. 
3. 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. 
4. Design and Procedures 
4.1 Study protocol overview 
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.  We plan to screen 20 subjects to have 10 
participants.   
The participant is not responsible for any research-related costs. The participants will be under the purview of 
their physician who is responsible for the participant’s care. The study team will ask for participants’ 
permission to contact ECT team so that information can be provided to the ECT team regarding the 
participant’s enrollment during the study.  
 
 4.2 Screening 
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 

 
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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.  
 
All female subjects in the reproductive age group will be tested for pregnancy using a commercially available 
test kit specified by Department of Obstetrics and Gynecology. The Pregnancy test must be negative to 
continue in the study. If sexually active, subjects must agree to use appropriate contraceptive measures for 
the duration of the study for inclusion. Medically acceptable contraceptives include: (1) surgical sterilization 
(such as a tubal ligation or hysterectomy), (2) approved hormonal contraceptives (such as birth control pills, 
patches, implants or injections), (3) barrier methods (such as a condom or diaphragm) used with a spermicide, 
or (4) an intrauterine device (IUD). Contraceptive measures such as Plan B (TM), sold for emergency use after 
unprotected sex, are not acceptable methods for routine use and will result in exclusion from the study. 
 
4.3 Bupropion administration 
Patients will receive ECT treatment as usual, however, study participants will be randomized to receive a 
single, extended-release bupropion (Wellbutrin® XL) 300 mg tablet to be taken by mouth, in the morning (4 
hours prior to ECT) on the day of ECT session 1 or session 2.  This 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) will be 
blinded to randomization details. Computer generated randomization would be done by Richard Weiner MD 
PhD – the director of the ECT program. The sleep lab clinical care coordinator (Mark Mayo) would be backup 
to generate randomization if Dr Weiner is absent. 
 
The medication would be dispensed from Central Pharmacy in Duke North. It would be stored in the sleep lab 
in the red zone on the fifth floor of Duke South and carried by sleep lab clinical care coordinator (Mark Mayo) 
to the ECT suite for administration to study patients. 
 
4.4 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.  
 
4.5 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.  We will also measure time to orientation recovery post 

 
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ECT after the first and second ECT treatments. 
 
4.6 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 we will acquire a 3 mL blood sample to be used to ascertain serum bupropion 
level. 
 
4.7 Timeline of Assessments 
Assessments 
ECT Session 1 
ECT Session 2 
Screening 
X 
X 
RUL ECT seizure profile 
X 
X 
MADRS Rating Score 
X 
X 
 
5. Subject Selection - Inclusion and exclusion criteria 
Inclusion Criteria 
(1) Male and female subjects, age >25 years. 
(2) Meeting diagnostic criteria for major depressive 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.  Subjects need to be off bupropion for at least a week to be 
included. 
(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, bipolar disorder, 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. 
(7) Pregnancy test positive 
(8) Contraindications to use of bupropion, which include the following: 
 Eating disorder 
 MOAI use in the past 14 days 
 Levodopa or amantadine use 
 Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs 
 Known hypersensitivity to bupropion or other components of study drug 
(9) BUN > 20 mg/dl or serum creatinine >1.5 or AST> 41 U/L or ALT > 63 U/L or total bilirubin >1.5 
mg/dl 
 

 
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6. Subject recruitment and compensation 
We will recruit both inpatients and outpatients referred for ECT. Patients are referred by private physicians 
and by clinical services within Duke University Health Systems and other psychiatric facilities. Inpatients 
admitted on Williams’ Ward in Duke South (4th floor red zone) will be approached for participation after 
discussion with the ECT team they have been referred to. Outpatients will be recruited in the manner as 
described in section 4.2. Selection criteria for subjects has been described in Section 5. Capacity to consent 
will be assessed by a member of the treatment team who is not an investigator on this study (such as the 
inpatient attending psychiatrist or the unit director). Study team members (who are not members of the 
subject's clinical team) will approach potential subjects after the study is introduced to potential subjects 
first by the ECT Team attending. For both inpatients/outpatients referred to ECT recruitment would 
proceed as follows: 1) study team member reviews charts for ECT consult roster to ID potential eligible 
individuals 2) Discuss with ECT team whether someone is appropriate 3) A member of patient's clinical ECT 
team asks patient if they want to hear about study and 4) With patient agreement, study team member 
discusses study with them. Study team member discussing informed consent will fully disclose and explain 
the risks and benefits of the study procedures, and answer the patient’s questions about the study and the 
material presented in the informed consent form. Alternatives to study participation will be discussed, and 
the voluntary nature of participation in the study will be emphasized. This consent discussion will be 
documented in a consent note placed in the patient’s chart. 
 
There would be no compensation for patients in this study. We do not deviate from usual course of 
treatment except for a one-time administration of bupropion which is an antidepressant and an additional 
session of seizure threshold titration. Subjects would receive standard of care and there are no additional 
visits or rating scales applied as part of the study.  
 
7. Consent Process – see Section 14 of the e-IRB submission form 
8. Subject’s Capacity to Give Legally Effective Consent – All patients recruited for this study must have 
capacity to give legally effective consent. 
 
9. Study Interventions – This has been described in detail in section 4.3 
 
10. Risk/benefit assessment 
The potential risks of the study design are problems associated with ECT and administration of 
extended-release bupropion administration and possible suicidal ideation.  Risk and benefits are for 
procedures done specifically for the study.  
10.1 Potential risks 
10.1.1 ECT 
Immediately following ECT, patients are typically disoriented or confused. Following ECT sessions, 
some patients report headache, muscle soreness, or nausea. These side effects usually respond to 
simple treatment.  Serious medical complications are rare. Cardiac complications are more common 
and constitute the leading cause of morbidity and mortality with ECT. The likelihood of these 
complications is reduced by (1) careful medical workup and the use of cardiology consultants in 
patients with significant preexisting cardiac disease; (2) careful monitoring of cardiac status during 
ECT; (3) modification of anesthetic procedures for prophylactic purposes (e.g., use of 
pharmacological agents to block hemodynamic changes). Fatality associated with ECT is estimated 
to occur in 1/10,000 patients, and to our knowledge has never occurred at Duke. 

 
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ECT commonly results in memory deficits. These memory deficits are of two types: anterograde and 
retrograde amnesia. There is little objective evidence that memory impairments persist more than 
four weeks following an ECT course. The effect of ECT on memory is cumulative, depending on 
number of sessions. It is unusual to see these deficits after the first or second treatments. 
 
The magnitude of both memory deficits depends on parameters used in the conduct of ECT.  In 
general, these deficits are more severe with bilateral (BT) versus right unilateral (RUL) electrode 
placement. Spacing of treatments may be increased or the treatment course terminated in the 
context of unacceptable side effects. 
For the study, patients would have seizure threshold estimated during second ECT in addition to 
seizure threshold estimation during the first. This exposes them to debatable cardiovascular risk 
from sub convulsive stimulations (9). Some rare but concerning adverse effects related to supra-
threshold stimulus titration of ECT in elderly patients are post-ECT delirium/confusion and persistent 
memory impairment (6) 
 
10.1.2 Specific risks/side effects of bupropion  
 
Like all antidepressants, bupropion increases the risk of suicidal thoughts and behavior in children, 
adolescents, and young adults in short-term trials. These trials did not show an increase in the risk of 
suicidal thoughts and behavior with antidepressant use in subjects aged 65 and older. Other 
common side effects are tachycardia, insomnia, headache, agitation, dizziness, constipation, weight 
loss and nausea. Patients with a history of a seizure disorder or head trauma with loss of 
consciousness could have a seizure with bupropion. 
 
10.1.3 Risk of spontaneous seizure with simultaneous administration of bupropion and ECT 
Seizure risk is 0.1 % for 450 mg of sustained release Bupropion. This risk is comparable to that of other 
antidepressants (10).  
Regarding safety for combined use of Bupropion and ECT, we found 3 case reports that reported the 
occurrence of seizures when this combination was used together. In 2 case reports there were other 
medications used in addition to bupropion, and one case report had discontinuation of benzodiazepine 
such as clonazepam contributing to seizure occurrence (11-13). In all these patient scenarios, they received 
bilateral (BT) ECT, and the bupropion administered was immediate release (IR) and not sustained release 
(SA). Another set of 3 case reports do talk about the safe administration of the combination of bupropion 
with ECT with no occurrence of spontaneous seizures other than those that occurred as part of ECT(14, 15).  
 
     10.1.4 Risk of spontaneous seizures with ECT 
 
There are case reports and studies that detail the development of spontaneous seizures after a course of 
ECTs or after a few ECTs (16-18). The incidence of the phenomenon is less than 0.1%. We plan to use only 
300 mg sustained release bupropion. The SA preparation offers a steady level of bupropion, thus 
minimizing risk of seizures. 
 

 
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10.1.5 Evaluation procedures 
The medical evaluations present no risks beyond what is expected for routine clinical care of a 
patient undergoing a course of ECT.   
 
 
10.1.6 Risks of blood collection 
As described above, blood collection will occur twice (3 ml each time) through a catheter placed in 
the individual’s arm vein just before they receive ECT. Complications of drawing blood from a 
catheter which is placed in an individual’s arm vein for a brief period occur at approximately 2% of 
the time, and include discomfort at the site of puncture, possible bruising and swelling around the 
puncture site, and rarely infection or faintness from the procedure. 
 
10.2 Methods to minimize risks: - The following are methods to minimize risks associated with this 
study 
 
10.2.1 Screening of participants prior to study enrollment 
As described above, the screening assessment of potential participants will identify and exclude 
from participation individuals with current or past medical conditions that may place them at 
increased risk for adverse effects from ECT.  Screening will include assessment of medical history, 
neurological history (seizure, stroke, and brain lesion), head trauma, pregnancy, and substance 
abuse/dependence. Screening will be performed by physician evaluation, physical examination, and 
blood work.   
 
10.2.2 Supervision of participants during ECT sessions 
ECT sessions will be conducted by the study investigators and physicians.  These personnel will be in 
visual and auditory contact with the patients always.  Health status will be monitored continuously 
as described in the protocol. 
 
10.2.3 ECT device safety features 
The ECT device has internal limits on stimulation parameters.  These limits prevent the device from 
being programmed to deliver pulses that exceed predetermined limits.  The device logs all 
parameter values. 
 
10.2.4 Minimizing risks associated with blood collection 
To minimize the risks of drawing blood from a catheter vein, sterile techniques will be used by 
trained individuals. 
 
10.2.5 Minimizing risk of seizures with bupropion 
We will use the sustained release formulation of bupropion. Review of literature indicates 300 mg of 
sustained release formulation to be a safe dose in patients (10). The sustained release preparation 
reaches peak level more gradually compared to other preparations of bupropion.  
 
10.3 Risk and benefit analysis 
As outlined above, extensive precautions will be taken to ensure of the safety of study participants. 
All patients participating in this study will receive treatment with a full course of electroconvulsive 
therapy as part of their routine clinical care.  The study is proof of concept and would provide data 

 
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to design a larger trial aimed to optimize psychopharmacology in conjunction with RUL ultra brief 
ECT to lower seizure threshold.  
Estimation of seizure thresholds will be done twice in this study, which exposes subjects to debatable 
cardiovascular risk due to sub convulsive stimulations. However, for the study, it is imperative that we 
measure differences in seizure threshold between the first and second ECT sessions to estimate the 
differences in seizure threshold caused by bupropion administration. The study will inform us about the 
effect of bupropion on seizure parameters in patients with major depressive disorder. This would help us 
optimize ECT treatments for patients with depression. 
 
Costs to the Subject – Subjects would not incur any costs because of participation in this research study. 
There would be no compensation for patients in this study. We do not deviate from usual course of 
treatment except for a one-time administration of bupropion which is an antidepressant and an additional 
session of seizure threshold titration. Subjects would receive standard of care and there are no additional 
visits or rating scales applied as part of the study. The study sponsor would pay for the study drug and 
blood draws to obtain bupropion serum levels. 
 
 
11. Data Analysis & Statistical Considerations We will use mixed effects modeling to see if extended-release 
bupropion influences seizure parameters in ECT. The independent grouping variable will be session (ECT 
session 1 vs ECT session 2) with primary outcome variables being seizure duration and seizure threshold.  
There are no previous studies that have looked at effect of bupropion on seizure threshold apart from case 
reports and hence it becomes difficult to calculate an ideal sample size to get good study power. We plan 
to recruit only 10 patients as this would be a pilot study.  
 
12. Data & Safety Monitoring  
 
Data and safety monitoring will follow standard protocol procedures. Any serious adverse event will be 
reported within 24 hours to the Duke IRB. Adverse events will be documented and addressed accordingly. 
The participants will be fully informed of the nature of the study requirements prior to enrollment and 
periodically throughout the study. The participants’ well-being will be continuously monitored by the 
experimenter, and the Principal Investigator will report all serious adverse events in an expedited manner 
to the Duke University Health System (DUHS) Institutional Review Board (IRB) office and all applicable 
regulatory authorities in accordance with the Center’s standard operating procedures. The study monitor 
will be Dr. Steven Szabo. Dr. Szabo will ensure the quality of the study and establish that all study staff are 
complying with the investigational plan and IRB regulations.  Monitoring of this protocol is simplified by 
the fact that this study involves a small number of investigators and a single facility in which the study is 
being conducted. Throughout the investigation, the monitor will ensure that the facilities being used 
continue to be acceptable for the purposes of the study, that the investigational plan is being followed, 
that any changes to the protocol have received IRB approval and have been reported to the sponsor, that 
accurate, complete, and current records are maintained, that accurate, complete, and timely reports are 
made to the IRB.  This will be accomplished through quarterly meetings during which the status of the 
protocol, investigators, and IRB compliance are reviewed.  The monitor will review each research chart for 
completeness and accuracy. He will confirm that inclusion and exclusion criteria have been met for each 
subject enrolled, and compliance with all other aspects of the investigational plan are met. 
 

 
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13. Privacy, Data Storage & Confidentiality – see Section 12 of the e-IRB submission form and complete the 
questions in that section 
 
References 
1. 
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). The Journal of clinical psychiatry. 
2015;76(2):155-62. 
2. 
Beckford-Ball J. An overview of the new NICE guidelines on bipolar disorder. Nursing times. 
2006;102(34):23-4. 
3. 
Fountoulakis KN, Vieta E, Sanchez-Moreno J, Kaprinis SG, Goikolea JM, Kaprinis GS. Treatment 
guidelines for bipolar disorder: a critical review. Journal of affective disorders. 2005;86(1):1-10. 
4. 
Frances AJ, Kahn DA, Carpenter D, Docherty JP, Donovan SL. The Expert Consensus Guidelines for 
treating depression in bipolar disorder. The Journal of clinical psychiatry. 1998;59 Suppl 4:73-9. 
5. 
Yatham LN, Kennedy SH, Parikh SV, Schaffer A, Beaulieu S, Alda M, et al. 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 disorders. 2013;15(1):1-44. 
6. 
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;14(4):803-43. 
7. 
Lisanby SH, Devanand DP, Nobler MS, Prudic J, Mullen L, Sackeim HA. Exceptionally high seizure 
threshold: ECT device limitations. Convuls Ther. 1996;12(3):156-64. 
8. 
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. The Journal of 
clinical psychiatry. 2015;76(9):e1092-8. 
9. 
Mizen L, Morton C, Scott A. The cardiovascular safety of the empirical measurement of the seizure 
threshold in electroconvulsive therapy. BJPsych Bull. 2015;39(1):14-8. 
10. 
Fava M, Rush AJ, Thase ME, Clayton A, Stahl SM, Pradko JF, et al. 15 years of clinical experience with 
bupropion HCl: from bupropion to bupropion SR to bupropion XL. Prim Care Companion J Clin Psychiatry. 
2005;7(3):106-13. 
11. 
Doellinger OV, Ribeiro JP, Ribeiro A, Freitas C, Ribeiro B, Silva JC. Spontaneous seizures after ECT in 
a patient medicated with bupropion, sertraline and risperidone. Trends in psychiatry and psychotherapy. 
2016;0:0. 
12. 
Conway CR, Nelson LA. The combined use of bupropion, lithium, and venlafaxine during ECT: a case 
of prolonged seizure activity. The journal of ECT. 2001;17(3):216-8. 
13. 
Dersch R, Zwernemann S, Voderholzer U. Partial status epilepticus after electroconvulsive therapy and 
medical treatment with bupropion. Pharmacopsychiatry. 2011;44(7):344-6. 
14. 
Kellner CH, Pritchett JT, Jackson CW. Bupropion coadministration with electroconvulsive therapy: two 
case reports. Journal of clinical psychopharmacology. 1994;14(3):215-6. 
15. 
Figiel GS, Jarvis MR. Electroconvulsive therapy in a depressed patient receiving bupropion. Journal of 
clinical psychopharmacology. 1990;10(5):376. 
16. 
Rasmussen KG, Lunde ME. Patients who develop epilepsy during extended treatment with 
electroconvulsive therapy. Seizure. 2007;16(3):266-70. 
17. 
Blackwood DH, Cull RE, Freeman CP, Evans JI, Mawdsley C. A study of the incidence of epilepsy 
following ECT. J Neurol Neurosurg Psychiatry. 1980;43(12):1098-102. 
18. 
Ray AK. Does electroconvulsive therapy cause epilepsy? J ECT. 2013;29(3):201-5.