Effect of Bupropion on Seizure Threshold in Depressed Patients

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 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 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.

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.