Effect of Bupropion on Seizure Threshold in Depressed Patients
Condition: MDD
MeSH terms: Seizures
Study type: Interventional
Phase: Phase 4

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.
    

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.
    

Intervention name(s): Wellbutrin SR 300Mg Extended-Release Tablet
Intervention type(s): Drug
Intervention description(s): Wellbutrin SR 300Mg Extended-Release Tablet
Other intervention name(s): Bupropion sustained release formulation
Intervention MeSH terms: Bupropion
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 randomization
Masking: Double (Care Provider, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Wellbutrin; Electroconvulsive therapy; Right Unilateral Ultra Brief