D-Cycloserine+iTBS PK Study

NCT ID: NCT05731323

Last Updated: 2023-09-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 12 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-10-12
• Study Completion Date: 2023-06-22

Brief 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).

Conditions

Major Depressive Disorder

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

D-Cycloserine

Prior to initiating TMS therapy, participants will orally ingest a capsule containing 100mg of the antibiotic d-cycloserine.

During TMS therapy, participants will orally ingest a capsule containing a weight-based dose of the antibiotic d-cycloserine (dosed 25mg/17.5kg body weight) daily (Monday-Friday) for 4 weeks of rTMS treatment (20 sessions).

Group Type: EXPERIMENTAL

D-cycloserine

Intervention Type: DRUG

Daily oral D-cycloserine dosed 25mg/17.5kg body weight during TMS treatment days (20 days).

Transcranial Magnetic Stimulator

Intervention Type: DEVICE

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.

Interventions

D-cycloserine

Daily oral D-cycloserine dosed 25mg/17.5kg body weight during TMS treatment days (20 days).

Intervention Type: DRUG

Transcranial Magnetic Stimulator

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.

Intervention Type: DEVICE

Other Intervention Names

Seromycin

Eligibility Criteria

Inclusion Criteria

1. Males and females aged 18 to 65 years

2. are competent to consent to treatment

3. have a confirmed diagnosis of DSM-5 criteria Major Depressive Disorder with a current episode of at least moderate severity of depression, single or recurrent

4. have failed to achieve a clinical response to one adequate trial of antidepressant medication within the current episode, or been unable to tolerate antidepressant medications.

5. have current episode of at least moderate severity of depression, as defined by a score ≥ 18 on the HAMD-17 item

6. have had no change in dose, or initiation of any psychotropic medication in the 4 weeks prior to randomization

7. are able to adhere to the treatment schedule

8. pass the TMS adult safety screening (TASS) questionnaire

9. have 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

1. Allergy to cycloserine.

2. have failed adequate trials of ≥4 antidepressant treatments in the current episode.

3. have an alcohol or substance use disorder within the last 3 months

4. have suicidal ideation (score of 4 ≥ on item 10 of MADRS)

5. are at a significant risk of harm to themselves or others

6. current symptoms of psychosis

7. history of psychosis

8. are currently pregnant, breast feeding or plan to become pregnant over the duration of the study

9. have a diagnosis of other primary psychiatric diagnoses as assessed by a study investigator to be primary and causing greater impairment than Major Depressive Disorder.

10. have failed a course of ECT in the current episode. Previous ECT treatment outside of the current episode does not influence inclusion.

11. history of non-response to TMS treatment.

12. 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 minutes

13. have concomitant major unstable medical illness, cardiac pacemaker or implanted medication pump

14. have 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 removed

15. if 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 study

16. are currently (or in the last 4 weeks) taking any benzodiazepine, cyclopyrrolone, gabapentin/pregabalin or anticonvulsant due to the potential to limit TMS efficacy

18. are being currently treated with ethionamide or isoniazid (contraindicated with D-cycloserine)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Calgary

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Alexander McGirr, MD PhD

Role: PRINCIPAL_INVESTIGATOR

University of Calgary

Locations

University of Calgary

Calgary, Alberta, Canada

Countries

Canada

Other Identifiers

REB22-0547

Identifier Type: -

Identifier Source: org_study_id