D-Cycloserine+iTBS PK Study
Condition: Major Depressive Disorder
MeSH terms: Depressive Disorder; Depression; Depressive Disorder, Major
Study type: Interventional
Phase: Phase 1

Summary: 
      Background & Rationale: Major Depressive Disorder (MDD) is a common and debilitating illness
      that that commonly does not respond to conventional treatments. Transcranial magnetic
      stimulation (TMS) and intermittent theta-burst stimulation (iTBS) are non-invasive
      neurostimulation treatments for depression that are Health Canada approved. These work by
      generating magnetic fields outside of the body to change the activity of brain cells to
      change how the brain works. They have a very favorable profile, with many patients
      experiencing improvement with minimal side effects.

      The investigators recently completed a study pairing iTBS with an FDA approved medication
      that was chosen because it might enhance iTBS improvements. This medication is called
      D-cycloserine, an old antibiotic that is rarely used in modern times. Years after it stopped
      being useful as an antibiotic, scientists recognized other properties that the molecule has,
      and it is some of these that make it interesting to pair with iTBS. When the investigators
      did so, they found that compared to iTBS with a placebo, participants who received
      iTBS+D-cycloserine were more likely to benefit from treatment.

      In this original study, all participants received a fixed dose of 100mg daily. This means
      that people of very different sizes could have had different drug levels, and the
      investigators do not know how that impacted outcomes. With this study, there will be no
      placebo condition because the purpose is to understand whether dosing according to weight
      matters.

      Research Question and Objectives: To describe the pharmacokinetic profile of 100mg oral
      D-cycloserine and weight-based oral D-cycloserine dosed 25mg/17.5kg among individuals with
      depression undergoing non-invasive intermittent theta-burst stimulation to the left
      dorsolateral prefrontal cortex (DLPFC) in Major Depressive Disorder.
    

Detailed description: 
      Methods: An open-label study of D-cycloserine (DCS) pharmacokinetics will be performed in
      patients undergoing iTBS to the left DLPFC as a treatment for Major Depressive Disorder.
      Twelve patients (males and females aged 18-65, with a score ≥18 on the Hamilton Rating Scale
      for Depression-17 items, and stable pharmacological and psychological regimens) with an acute
      Major Depressive Episode will be recruited. Bloodwork and an echocardiogram will be obtained
      prior to the initiation of the study, and enrollment in the study will be contingent on
      normal lab results.

      Prior to initiating iTBS treatment, participants will receive one oral dose of 100mg DCS. A
      pharmacokinetic curve will be generated from D-Cycloserine levels obtained at 6 timepoints;
      pre-ingestion, +30 mins, + 60 mins, + 90mins, +120mins and +24 hrs.

      Participants will receive iTBS daily for 4 weeks (20 sessions). All participants will be
      provided with weight-based dosing of DCS to take 120 minutes prior to each iTBS session.
      Serum levels of weight-based DCS dosing will be measured by blood draws at several time
      points throughout iTBS treatment. Specifically, a pharmacokinetic curve will be generated on
      Day 1 of iTBS treatment from D-Cycloserine levels obtained at 6 timepoints; pre-ingestion,
      +30 mins, + 60 mins, + 90mins, +120mins and +24 hrs. Additional time points will be obtained
      prior to and 120 minutes after the fifth dose (Day 5 of TMS) and prior to and 120 minutes
      after the sixth dose (Day 6 of TMS, corresponding to the beginning of the second week of
      TMS).

      Antidepressant effects will be quantified using the Montgomery Asberg Depression Rating
      Scale, a gold standard clinician rated instrument. Participants will complete a short battery
      of cognitive tests at the beginning and end of the study. Blood work and echocardiogram will
      be repeated after 4 weeks to confirm safety of low-dose DCS.

      Participants will return to the lab for a follow-up assessment 4 weeks after they have
      finished the TMS protocol (week 8).
    

Intervention name(s): D-cycloserine; Transcranial Magnetic Stimulator
Intervention type(s): Drug; Device
Intervention description(s): Daily oral D-cycloserine dosed 25mg/17.5kg body weight during TMS treatment days (20 days).; Repetitive Transcranial magnetic stimulation (rTMS) will be delivered using a MagPro X100 device with B70 coil and the intermittent theta burst (iTBS) protocol to the left dorsolateral prefrontal cortex. Participants will receive daily treatments (Monday-Friday) over four weeks.
Other intervention name(s): Seromycin
Intervention MeSH terms: Cycloserine
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment