D-Cycloserine+iTBS PK Study

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.

Inclusion Criteria:Males and females aged 18 to 65 yearsare competent to consent to treatmenthave a confirmed diagnosis of DSM-5 criteria Major Depressive Disorder with a current episode of at least moderate severity of depression, single or recurrenthave failed to achieve a clinical response to one adequate trial of antidepressant medication within the current episode, or been unable to tolerate antidepressant medications.have current episode of at least moderate severity of depression, as defined by a score ≥ 18 on the HAMD-17 itemhave had no change in dose, or initiation of any psychotropic medication in the 4 weeks prior to randomizationare able to adhere to the treatment schedulepass the TMS adult safety screening (TASS) questionnairehave had blood work (complete blood count, electrolytes, BUN, creatinine, eGFR, AST, ALT and GGT, and ECG) within the reference range. Female participants must have a negative pregnancy test.Exclusion Criteria:Allergy to cycloserine.have failed adequate trials of ≥4 antidepressant treatments in the current episode.have an alcohol or substance use disorder within the last 3 monthshave suicidal ideation (score of 4 ≥ on item 10 of MADRS)are at a significant risk of harm to themselves or otherscurrent symptoms of psychosishistory of psychosisare currently pregnant, breast feeding or plan to become pregnant over the duration of the studyhave a diagnosis of other primary psychiatric diagnoses as assessed by a study investigator to be primary and causing greater impairment than Major Depressive Disorder.have failed a course of ECT in the current episode. Previous ECT treatment outside of the current episode does not influence inclusion.history of non-response to TMS treatment.have any significant neurological disorder or insult including, but not limited to: any condition likely to be associated with increased intracranial pressure, space occupying brain lesion, any history of epilepsy, cerebral aneurysm, Parkinson's disease, Huntington's chorea, multiple sclerosis, significant head trauma with loss of consciousness for greater than or equal to 5 minuteshave concomitant major unstable medical illness, cardiac pacemaker or implanted medication pumphave an intracranial implant (e.g., aneurysm clips, shunts, stimulators, cochlear implants, or electrodes) or any other metal object within or near the head, excluding the mouth, that cannot be safely removedif participating in psychotherapy, must have been in stable treatment for at least 3 months prior to entry into the study, with no anticipation of change in the frequency of therapeutic sessions, or the therapeutic focus over the duration of the studyare currently (or in the last 4 weeks) taking any benzodiazepine, cyclopyrrolone, gabapentin/pregabalin or anticonvulsant due to the potential to limit TMS efficacyhave an exclusion criteria for MRI: Those with a history of cranial, thoracic or abdominal surgery, with pacemakers, artificial joints or other metallic implants will be excluded from the MRI scan. Subjects that have agreed to participate in the MRI portion of the study will be pre-screened for any potential metal fragments in the body (particularly in the orbits) if they have had any history of doing metal work or have been involved in use/deployment of ammunitions/explosives, welding, piping etc).are being currently treated with ethionamide or isoniazid (contraindicated with D-cycloserine)