iTBS+D-Cycloserine for Youth Suicide

NCT06121284 | Recruiting Phase 2 DMC

• 1 other identifier: REB22-1115
• Study Type: interventional
• Target: 54
• Locations: 1 country
• Sites: 1

Brief Summary

Background and Rationale: Suicide is the second leading cause of death in Canadian Emerging Adults (EAs; 18-24yrs). Current treatments for suicidal thoughts and behaviors are limited and novel treatments are required to save lives. Transcranial Magnetic Stimulation (TMS) is a non-invasive neurostimulation treatment for major depressive disorder, a mental health condition at high risk for suicide. It is well tolerated and effective. However, in the child and youth population, it does not appear to be superior to sham-TMS. Therefore, strategies for enhancing TMS outcomes are required. Over time, TMS can change the function of brain regions important in depression to reduce the symptoms of depression, including suicidal ideation. The investigators believe this occurs through a process called 'synaptic plasticity', or the process by which neurons change their connectivity with other neurons in an activity-dependent manner. Using an adjunct to facilitate these changes in the EA population may improve TMS outcomes, including both implicit and explicit measures of suicide risk. The investigators\' previous data indicates that, in adults, the effects of a TMS protocol called intermittent theta-burst stimulation (iTBS) can be enhanced by pairing stimulation with a medication called D-Cycloserine. This FDA-approved medication leads to enhanced synaptic plasticity with iTBS. In adults, this combination led to greater improvements in depression symptoms and both implicit and explicit suicide risk. Implicit suicide risk is measured with a computerized test, called the death/suicide implicit association test (Death/Suicide IAT), and explicit suicide risk is defined as suicidal thoughts reported by the individual. In the current study, we aim to determine whether the effects of iTBS can be augmented with D-Cycloserine to reduce suicide risk in the EA population. Typical courses of iTBS involve daily treatments over 6 weeks, a timeframe that is not acceptable in individuals experiencing suicidal ideation. For this reason, we will build on data indicating that treatment courses can be condensed by delivering multiple treatments in a single day to accelerate symptomatic improvements. Specifically, our data suggests that (1) 4-weeks of daily iTBS+D-Cycloserine significantly improves implicit and explicit suicide risk and (2) a single-dose of D-Cycloserine paired with two iTBS treatments separated by one hour, enhances the physiological effects of iTBS. As such, in this study, participants will receive two treatments per day, separated by an hour, thereby accelerating a typical 4-week course to 2 weeks. Research Question and Objectives: To conduct a 2-week double-blind placebo-controlled randomized clinical trial where 54 participants will be randomly assigned to one of two groups: 1) accelerated iTBS+D-Cycloserine, and 2) accelerated iTBS+placebo. The primary outcome of the study is performance on the Death/Suicide-IAT, a measure of suicide risk; however, we will also determine whether pairing stimulation with D-Cycloserine enhances the antidepressant effects of iTBS, reduces suicidal ideation in this population, and reduces the likelihood of engaging in suicidal behavior or having suicidal crises over the following six months.

Conditions

Suicidal Ideation; Suicide, Attempted; Depression, Anxiety

Keywords

Transcranial Magnetic Stimulation; Emerging Adults; Youth; Suicidal Ideation; Depression; D-Cycloserine; Cognition

Outcome Measures

Primary Outcomes (1)

• Performance on the Death Implicit Association Test (D-IAT) at treatment end

  The D-IAT measures reaction time in categorizing life and death-related words. Different pairings of target attributes (Life/Death) and attribute dimensions (Me/Not Me) create implicit associations between the self with life and death. The D-IAT score is interpreted as a difference in strength of implicit association of the self with life and death. Scores range from -2 (strong implicit association with life) to +2 (strong implicit association with death).

  Change from baseline to end of treatment (week 2)

Secondary Outcomes (20)

• Performance on the Death Implicit Association Test (D-IAT) at follow up

  Baseline, treatment end (2-weeks), 1-month, 6-months

• Change on the Scale for Suicidal Ideation (SSI) at end of treatment (week 2)

  SSI score from baseline to end of treatment (week 2)

• SSI at 1-month post treatment

  SSI score at 1-month post treatment

• SSI at 6-months post treatment

  Administered at 6-months post treatment

• Change on the Montgomery Asberg Depression Rating Scale (MADRS) post treatment

  MADRS score at week 2 (post treatment)

Other Outcomes (20)

• Incidence of Treatment Emergent Adverse Events

  Daily (monday-friday) throughout 2-weeks of treatment, at 1-month, and 6-months post treatment

• Side Effects

  The TSES will be administered at baseline, end of week 1 (halfway), and end of week 2 (end of treatment)

• Complete Blood Count (CBC): Hemoglobin

  Screening and end of treatment (end of week 2)

Study Arms (2)

D-Cycloserine

EXPERIMENTAL

Participants will orally ingest a standard 100mg dose of D-Cycloserine daily (Monday-Friday) during 2 weeks of accelerated rTMS treatments (20 sessions; 2 sessions/day separated by 1 hour). D-Cycloserine will be ingested 60-120 minutes prior to the first rTMS treatment of the day.

Drug: D-Cycloserine; Device: intermittent Theta-Burst-repetitive Transcranial Magnetic Stimulation

Placebo

PLACEBO COMPARATOR

Participants will orally ingest a standard 100mg dose of a microcrystalline placebo capsule daily (Monday-Friday) during 2 weeks of accelerated rTMS treatments (20 sessions; 2 sessions/day separated by 1 hour). The Placebo will be ingested 60-120 minutes prior to the first rTMS treatment of the day.

Device: intermittent Theta-Burst-repetitive Transcranial Magnetic Stimulation; Drug: Placebo oral tablet

Interventions

D-Cycloserine DRUG

Participants will orally ingest a capsule containing a 100mg dose of the antibiotic d-cycloserine daily (Monday-Friday) during 2 weeks of twice daily rTMS treatment (20 sessions) 60-120 minutes prior to the first rTMS treatment of the day.

D-Cycloserine

intermittent Theta-Burst-repetitive Transcranial Magnetic Stimulation 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 twice daily treatments (Monday-Friday) over two weeks (20-sessions).

D-Cycloserine; Placebo

Placebo oral tablet DRUG

Participants will orally ingest a capsule identical to that containing the study medication, however, this capsule will contain a placebo. They will ingest this capsule daily (Monday-Friday) for 2 weeks of twice-daily rTMS treatment (20 sessions) 60 - 120 minutes prior to the first rTMS treatment of the day.

Placebo

Eligibility Criteria

• Age: 18 Years - 24 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Individuals aged 18 to 24 years
• Any sex or gender
• Are competent to consent to treatment
• Have previously attempted suicide as defined by the Columbia Suicide Severity Rating Scale
• Currently have suicidal ideation as defined by a score ≥4 on item 10 of the MADRS in the past week. Individuals with active suicidal ideation, defined as suicidal ideation with the intention to act on a plan that might result in death, are only eligible if currently hospitalized
• Moderate depression measured on the 17-item Hamilton Rating Scale for Depression (HAMD-17) ≥15
• Are able to adhere to the treatment schedule
• Pass the TMS adult safety screening (TASS) questionnaire
• Have a normal ECG, CBC, electrolytes, BUN, creatinine, eGFR, AST, ALT, and GGT within the last month.

You may not qualify if:

• Allergy to cycloserine or any excipients due to possible anaphylaxis or other reactions.
• Current alcohol or substance misuse.
• Current symptoms or history of psychosis, as this can be aggravated by D-Cycloserine.
• Are currently pregnant, breast feeding or plan to become pregnant during the study, as the effects of D-Cycloserine on the fetus are unknown. Health Canada requires that women of reproductive potential utilize either highly effective birth control or double barrier method of contraception. Abstinence is only acceptable when it is the usual and preferred lifestyle of the participant.
• Have previously failed a course of rTMS treatment
• Have any significant neurological disorder or insult as this increased the risk of adverse events with rTMS 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 15 minutes
• Have concomitant major unstable medical illness, cardiac pacemaker or implanted medication pump
• 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 because these can heat or move due to the rapidly alternating magnetic field generated by rTMS.
• Are currently being treated with GABA agonists such as benzodiazepines, cyclopyrrolones, gabapentin/pregabalin, or anticonvulsant due to the potential to limit TMS efficacy
• Those with a history of intracranial implants or metal, or with any potential metal fragments in the body (particularly in the orbits).

Sponsors & Collaborators

• University of Calgary: lead
• University of Alberta: collaborator

Study Sites (1)

University of Calgary

Calgary, Alberta, T2N 1N4, Canada

RECRUITING

MeSH Terms

Conditions

Suicidal Ideation; Suicide, Attempted; Depression; Anxiety Disorders

Interventions

Cycloserine

Condition Hierarchy (Ancestors)

Suicide; Self-Injurious Behavior; Behavioral Symptoms; Behavior; Mental Disorders

Intervention Hierarchy (Ancestors)

Isoxazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Oxazolidinones; Oxazoles; Serine; Amino Acids, Neutral; Amino Acids; Amino Acids, Peptides, and Proteins

Study Officials

• Alexander McGirr, MD PhD

  University of Calgary

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Alexander McGirr, MD PhD

CONTACT

403 210 6410; alexander.mcgirr@ucalgary.ca

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 25, 2023
• First Posted: November 7, 2023
• Study Start: March 11, 2024
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): September 1, 2026
• Last Updated: November 12, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)