Clinical trial NCT06121284: iTBS+D-Cycloserine for Youth Suicide
Official title: A Randomized Placebo-controlled Trial of Adjunctive D-Cycloserine and Accelerated Intermittent Theta Burst Stimulation for Emerging Adults With Suicidal Ideation
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Suicidal Ideation
Suicide, Attempted
Depression, Anxiety
Keywords: Transcranial Magnetic Stimulation
Emerging Adults
Youth
Suicidal Ideation
Depression
D-Cycloserine
Cognition
Lead sponsor: University of Calgary
Sponsor class: OTHER
Collaborators: name: University of Alberta
First posted: 2023-11-07
Enrollment: 54
Sex: ALL
Minimum age (years): 18
Maximum age (years): 24
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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\&#39; 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.

Detailed description: Methods: 54 participants between 18-24 years old with clinically significant past week suicidal ideation, defined as a score ≥4 on item 10 of the Montgomery Asberg Depression Rating Scale (MADRS), at least moderate depressive symptoms (≥15 Hamilton Depression Rating Scale-17 \[HAMD-17\]), and a history of at least one suicide attempt will be recruited. It is important to note that suicidal ideation occurs on a spectrum and that scores on the MADRS item 10 range from 0-6. A score of 4 = "Probably better off dead. Suicidal thoughts are common, and suicide is considered as a possible solution, but without specific plans or intention." A score of 6 = "Explicit plans for suicide when there is an opportunity. Active preparations for suicide." Within this range, an individual may have active or passive suicidal ideation with or without intent or a plan. Individuals with active suicidal ideation, intent, or plan will be eligible to participate in the study if they are currently admitted as an inpatient.

Participants will complete a screening visit to determine eligibility based on the inclusion/exclusion criteria. If the participants are not eligible, no further study procedures will be conducted. Eligible subjects will be randomized in a 1:1 ratio to receive either accelerated iTBS+placebo or accelerated iTBS+D-Cycloserine. The randomization sequence will be generated with random number generation, a block size of 6, and allocation concealment.

Double-blind assignment and allocation concealment will be maintained by sequential numbering. Patients will be randomly assigned to receive either accelerated iTBS+D-Cycloserine or accelerated iTBS+placebo treatments. Patients without blood work within the past month will have laboratory tests done to rule out hematological, hepatic, and renal disease.

The primary outcome of interest is change in performance on the Death/Suicide-IAT from baseline to treatment end. Performance on this measure and other cognitive tasks will also be assessed at 1-month and 6-month follow-ups.

Clinical outcomes will be quantified using change on the clinician-rated Scale for Suicidal Ideation (SSI) and MADRS and self-reported measures of depression and anxiety. These symptoms will be assessed at baseline, week-1 (halfway), week-2 (end of treatment), one month, and 6-months post-treatment. Change in suicidal behaviors over the 6-months prior and following treatment will also be assessed using the Columbia Suicide Severity Rating Scale (CSSRS) and medical record review.

Eligibility criteria: Inclusion Criteria:

1. Individuals aged 18 to 24 years
2. Any sex or gender
3. Are competent to consent to treatment
4. Have previously attempted suicide as defined by the Columbia Suicide Severity Rating Scale
5. 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
6. Moderate depression measured on the 17-item Hamilton Rating Scale for Depression (HAMD-17) ≥15
7. Are able to adhere to the treatment schedule
8. Pass the TMS adult safety screening (TASS) questionnaire
9. Have a normal ECG, CBC, electrolytes, BUN, creatinine, eGFR, AST, ALT, and GGT within the last month.

Exclusion Criteria:

1. Allergy to cycloserine or any excipients due to possible anaphylaxis or other reactions.
2. Current alcohol or substance misuse.
3. Current symptoms or history of psychosis, as this can be aggravated by D-Cycloserine.
4. 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.
5. Have failed a course of ECT in the current episode. Previous ECT treatment outside of the current episode does not influence inclusion.
6. Have previously failed a course of rTMS treatment
7. 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
8. Have concomitant major unstable medical illness, cardiac pacemaker or implanted medication pump
9. 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.
10. Are currently being treated with GABA agonists such as benzodiazepines, cyclopyrrolones, gabapentin/pregabalin, or anticonvulsant due to the potential to limit TMS efficacy
11. Those with a history of intracranial implants or metal, or with any potential metal fragments in the body (particularly in the orbits).

Primary outcomes:
measure: Performance on the Death Implicit Association Test (D-IAT) at treatment end
timeFrame: Change from baseline to end of treatment (week 2)
Secondary outcomes:
measure: Performance on the Death Implicit Association Test (D-IAT) at follow up
timeFrame: Baseline, treatment end (2-weeks), 1-month, 6-months
measure: Change on the Scale for Suicidal Ideation (SSI) at end of treatment (week 2)
timeFrame: SSI score from baseline to end of treatment (week 2)
measure: SSI at 1-month post treatment
timeFrame: SSI score at 1-month post treatment
measure: SSI at 6-months post treatment
timeFrame: Administered at 6-months post treatment
measure: Change on the Montgomery Asberg Depression Rating Scale (MADRS) post treatment
timeFrame: MADRS score at week 2 (post treatment)
measure: Montgomery Asberg Depression Rating Scale (MADRS) at 1-month
timeFrame: MADRS score at 1-month follow up
measure: Montgomery Asberg Depression Rating Scale (MADRS) at 6-months
timeFrame: MADRS score assessed at 6-month follow up
measure: Clinical Global Impression (CGI) - Severity
timeFrame: The CGI will be administerd at baseline, week 1, week 2 (end of treatment), 1-month follow up (week 6), and 6-month follow up.
measure: Clinical Global Impression (CGI) - Improvement
timeFrame: The CGI will be administerd at baseline, week 1, week 2 (end of treatment), 1-month follow up (week 6), and 6-month follow up.
measure: Change on the Borderline Symptom List-23 (BSL-23)
timeFrame: The BSL-23 will be completed at baseline, week 2 (end of treatment), 1-month, and 6-month follow up visits
measure: Self-Reported Quick Inventory of Depressive Symptoms (QIDS-SR)
timeFrame: The QIDS-SR will be completed at baseline, week 2, 1-month, and 6-month follow up visits.
measure: Generalized Anxiety Disorder-7 item questionnaire (GAD-7)
timeFrame: The GAD-7 will be completed at baseline, week 2, 1-month, and 6-month follow up visits.
measure: Difficulties in Emotional Regulation Scale (DERS)
timeFrame: The DERS will be completed at baseline, week 2, 1-month, and 6-month follow up visits.
measure: WHO Quality of Life Questionnaire (WHOQOL-BREF)
timeFrame: The WHOQOL-BREF will be completed at baseline, week 2, 1-month, and 6-month follow up visits.
measure: Beck Hopelessness Scale (BHS)
timeFrame: The BHS will be completed at baseline, week 2, 1-month, and 6-month follow up visits.
measure: Performance on the Spatial Working Memory Task (SWM; CANTAB)
timeFrame: the SWM task will be completed at baseline, week 2 (end of treatment), 1-month, and 6-month follow up
measure: Performance on the Stroop Word-Colour Task (SWCT)
timeFrame: The SWCT will be completed at baseline, week 2 (end of treatment), 1-month and 6-month follow up
measure: Performance on the Intra-Extra Dimensional Set Shift (IED; CANTAB)
timeFrame: The IED will be completed at baseline, week 2 (end of treatment), 1-month, and 6-month follow up
measure: Suicidal behaviors over 6-months post-treatment
timeFrame: Columbia Suicide Severity Rating Scale and electronic medical record verification assessed 6-months post treatment
measure: Change in psychiatric emergency department visits and hospitalizations over 6 months pre and post-treatment
timeFrame: The medical record will be accessed six months after the completion of treatment.
Other outcomes:
measure: Incidence of Treatment Emergent Adverse Events
timeFrame: Daily (monday-friday) throughout 2-weeks of treatment, at 1-month, and 6-months post treatment
measure: Side Effects
timeFrame: The TSES will be administered at baseline, end of week 1 (halfway), and end of week 2 (end of treatment)
measure: Complete Blood Count (CBC): Hemoglobin
timeFrame: Screening and end of treatment (end of week 2)
measure: Complete Blood Count (CBC): Hematocrit
timeFrame: Screening and end of treatment (end of week 2)
measure: Complete Blood Count (CBC): White Blood Cell Count (WBC)
timeFrame: Screening and end of treatment (end of week 2)
measure: Complete Blood Count (CBC): Red Blood Cell count (RBC)
timeFrame: Screening and end of treatment (end of week 2)
measure: Complete Blood Count (CBC): Platelets
timeFrame: Screening and end of treatment (end of week 2)
measure: Electrolyte Panel: Sodium Level
timeFrame: Screening and end of treatment (end of week 2)
measure: Electrolyte Panel: Potassium Level
timeFrame: Screening and end of treatment (end of week 2)
measure: Electrolyte Panel: Chloride Level
timeFrame: Screening and end of treatment (end of week 2)
measure: Bloodwork: Blood Urea Nitrogen (BUN) Test
timeFrame: Screening and end of treatment (end of week 2)
measure: Bloodwork: Creatinine
timeFrame: Screening and end of treatment (end of week 2)
measure: Bloodwork: estimated Glomerular Filtration Rate (eGFR) Test
timeFrame: Screening and end of treatment (end of week 2)
measure: Bloodwork: Gamma Glutamyl Transferase Test
timeFrame: Screening and end of treatment (end of week 2)
measure: Bloodwork: Alanine Transaminase (ALT)
timeFrame: Screening and end of treatment (end of week 2)
measure: Bloodwork: Aspartate Aminotransferase (AST)
timeFrame: Screening and end of treatment (end of week 2)
measure: Electrocardiogram (ECG): Heart Rate
timeFrame: Screening visit and end of treatment (end of week 2)
measure: Electrocardiogram (ECG): PR Interval
timeFrame: Screening visit and end of treatment (end of week 2)
measure: Electrocardiogram (ECG): QRS Interval
timeFrame: Screening visit and end of treatment (end of week 2)
measure: Electrocardiogram (ECG): QTc Interval
timeFrame: Screening visit and end of treatment (end of week 2)
Locations:
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
Study officials:
affiliation: University of Calgary
name: Alexander McGirr, MD PhD
role: PRINCIPAL_INVESTIGATOR
References: