Cycloserine rTMS Plasticity Augmentation in Depression
Condition: Major Depressive Disorder
MeSH terms: Depressive Disorder; Depression; Depressive Disorder, Major
Study type: Interventional
Phase: Phase 1

Summary: 
      Transcranial magnetic stimulation (rTMS) is an investigational and therapeutic modality that
      impacts the connection strength between neurons by delivering patterned energy. In response
      to this patterned energy neurons fire and adapt by changing their connection strengths. This
      change in connection strengths is believed to be the underlying mechanism whereby this
      intervention has therapeutic benefit for this intervention in conditions such as depression.
      The purpose of this study is to test a means of enhancing the effect of rTMS using a
      medication (cycloserine) that has been shown to augment and stabilize activity dependent
      neuronal changes. The investigators wish to use the motor system, where the associated muscle
      response to brain stimulation can be measured, to probe activity dependent changes in
      connection strength between neurons.
    

Detailed description: 
      This randomized, placebo-controlled, crossover trial will enroll 12 participants with Major
      Depressive Disorder. In one arm of the study, participants will randomly receive either 100mg
      of d-cycloserine (DCS, an antibiotic) or a placebo capsule, and participants will receive the
      other intervention one week later.

        1. We will recruit 12 participants aged 18-60 through community advertisement, carefully
           screened for exclusion factors related to rTMS and DCS.

        2. After screening, participants will come to the lab for a semi-structured interview
           involving the MINI-International Neuropsychiatric Interview for confirmation of the
           diagnosis of depression, and the absence of substance use disorders, absence of
           psychosis, and absence of bipolar disorder. The severity of their depressive symptoms
           will be quantified with the semi-structured clinical instrument Hamilton Depression
           Rating Scale, and participants will be retained in the study if their score is ≥15,
           indicating moderate severity. Finally, the antidepressant treatment history will be
           collected using the Antidepressant Treatment History Form.

        3. Eligible participants will be randomly assigned by random number sequence with
           allocation concealment to one of two first arms of the crossover study: a) placebo-DCS
           100mg and b) DCS 100mg-placebo.

        4. Participants will complete the QIDS-SR (Quick Inventory of Depressive Symptoms-Self
           Report), the MDQ (Mood Disorders Questionnaire), the BAI (Beck Anxiety Inventory), and
           the STAI (State Trait Anxiety Inventory). Participants will report their perception of
           physical symptoms (potential side effects) in the 7 days before participating in the
           study taking the randomized capsule (Toronto Side Effects Scale - 1 Week).

        5. Participants will take their blinded capsule at least 30 minutes prior to TBS (we
           anticipate that it will take approximately 30 minutes to do steps 5-7).

        6. Electromyographic (EMG) electrodes will be positioned over the first dorsal interosseous
           (FDI) bilaterally. These are non-invasive electrodes that use an adhesive to stick to
           the skin.

        7. Using neuronavigation in conjunction with an atlas brain, the M1 hand strip will be
           localized using single pulse TMS (MagPro X100).

        8. Motor evoked potentials are measurements of muscle activation, in this case in response
           to TMS stimulation of the brain. We will use single pulse TMS to record the magnitude of
           responses. As a baseline, we will collect twenty single-pulse (120% resting motor
           threshold (RMT), 0.25Hz) MEPs every 5 minutes for the 15 minutes preceding TBS rTMS.

        9. We will characterize a stimulus response curve by delivering single pulse TMS at
           stimulation intensities ranging from 100-150% of resting motor threshold in random
           order.

       10. TBS rTMS will be applied to the FDI 'hotspot'. TBS consists of 2s trains every 10s.
           Trains are composed of 3 pulses at 50Hz, 200ms intervals, 80% RMT. Total time 190s and
           600 pulses.

       11. After TBS, twenty MEPs will be acquired (single pulse, 120% RMT, 0.25Hz) every 5 minutes
           for the first 30 minutes, at 60 minutes, at 90 minutes, and at 16Hrs (the following
           morning).

       12. At the 90 minute and 16 Hrs timepoints, we will characterize stimulus response curves
           (MEPs at stimulus intensities ranging from 100-150% resting motor threshold presented in
           random order).

       13. Participants will report their perception of side effects since taking the randomized
           capsule (Toronto Side Effects Scale - 1 Day). Participants will be asked if they believe
           they received the study medication or placebo in this first phase of the crossover
           trial.

      This study involves a crossover design, therefore after a minimum of 7 days, participants
      will return to the laboratory to repeat steps 4-13 with the other arm of the trial (i.e.
      participants who initially received the active study medication will instead receive the
      placebo, and the converse).
    

Intervention name(s): Cycloserine; Transcranial Magnetic Stimulation; Placebo Oral Tablet
Intervention type(s): Drug; Device; Drug
Intervention description(s): Cycloserine 100mg; Single-pulse transcranial magnetic stimulation and theta-burst stimulation; Placebo tablet matched to cycloserine tab
Intervention MeSH terms: Cycloserine
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Basic Science