iTBS+D-Cycloserine for Youth Suicide

Study Overview
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Brief Summary
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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 its effect on suicidal ideation. 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, with a notable rapid resolution of suicidal thoughts as well as improvements on a computerized test that is associated with future suicidal behavior. Research Question and Objectives: To conduct a 2-week double-blind placebo-controlled randomized clinical trial where 60 participants will be randomly assigned to one of two groups: 1) accelerated iTBS+D-Cycloserine, and 2) accelerated iTBS+placebo. Participants will receive a weight-based dose of D-Cycloserine or placebo as an adjunct to iTBS (25mg/17.5kg of body weight).

Detailed Description
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Methods: 60 participants between 18-24 years old with suicidal ideation, defined as a score ≥4 on the Depression Symptom Inventory-Suicidality Subscale (DSI-SS), will be recruited. It is important to note that suicidal ideation occurs on a spectrum and that scores on the DSI-SS range from 0-12. A score of 4 on the DSI-SS is considered high enough to warrant additional screening but does not indicate active suicidal ideation, intent, or plan. However, those 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 10, and allocation concealment, and the investigators will stratify blocks based on whether the participant is a psychiatric inpatient or outpatient. 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. Clinical outcomes will be quantified using change on the Scale for Suicidal Ideation (SSI) and self-reported measures of depression and anxiety. These symptoms will be assessed at baseline, week-1 (halfway), week-2 (end of treatment), and one month. Suicidal behaviors over a 6-month follow-up period will also be assessed using the Columbia Suicide Severity Rating Scale (CSSRS) and medical records. Cognition will be assessed at baseline and end of treatment (week 2).

Official Title
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A Randomized Placebo-controlled Trial of Adjunctive D-Cycloserine and Accelerated Intermittent Theta Burst Stimulation for Emerging Adults With Suicidal Ideation

Conditions
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Suicidal Ideation, Suicide, Attempted, Depression, Anxiety

Intervention / Treatment
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* Drug: D-Cycloserine
* Device: intermittent Theta-Burst-repetitive Transcranial Magnetic Stimulation
* Drug: Placebo oral tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 the DSI-SS. For 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. Exclusion Criteria: 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 failed a course of ECT in the current episode. Previous ECT treatment outside of the current episode does not influence inclusion. 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).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 24 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: D-Cycloserine<br>Participants will orally ingest a weight-based dose of D-Cycloserine (25mg/17.5kg) 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<br>* Participants will orally ingest a capsule containing a weight-based dose (25mg/17.5kg) 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.<br>Device: intermittent Theta-Burst-repetitive Transcranial Magnetic Stimulation<br>* 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).<br>|
| Placebo Comparator: Placebo<br>Participants will orally ingest a weight-based dose of a microcrystalline placebo capsule (25mg/17.5kg) 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<br>* 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).<br>Drug: Placebo oral tablet<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change on the Scale for Suicidal Ideation (SSI) at end of treatment (week 2) | Change in score on the clinician administered SSI. This consists of 19 items rated on a Likert-scale from 0 to 2. Higher scores are indicative of worse suicidal ideation. | SSI score at end of treatment (week 2) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SSI at 1-month post treatment | Score on the clinician-administered SSI. This consists of 19 items rated on a Likert scale from 0 to 2. Higher scores are indicative of worse suicidal ideation. | SSI score at 1-month post treatment | 
| SSI at 6-months post treatment | Score on the clinician administered SSI. This consists of 19 items rated on a Likert-scale from 0 to 2. Higher scores are indicative of worse suicidal ideation. | Administered at 6-months post treatment | 
| Change on the Montgomery Asberg Depression Rating Scale (MADRS) post treatment | Change in severity of depressive symptoms as measured by the MADRS, a clinician-rated instrument. The MADRS is a ten-item diagnostic questionnaire used to measure the severity of depressive episodes. The overall score ranges from 0 - 60. Cutoff points are 0-6 = normal, 7-9 = mild depression, 20-34 = moderate depression, >34 = severe depression. | MADRS score at week 2 (post treatment) | 
| Montgomery Asberg Depression Rating Scale (MADRS) at 1-month | Severity of depressive symptoms as measured by the MADRS, a clinician-rated instrument. The MADRS is a ten-item diagnostic questionnaire used to measure the severity of depressive episodes. The overall score ranges from 0 - 60. Cutoff points are 0-6 = normal, 7-9 = mild depression, 20-34 = moderate depression, >34 = severe depression. | MADRS score at 1-month follow up | 
| Montgomery Asberg Depression Rating Scale (MADRS) at 6-months | Severity of depressive symptoms as measured by the MADRS, a clinician-rated instrument. The MADRS is a ten-item diagnostic questionnaire used to measure the severity of depressive episodes. The overall score ranges from 0 - 60. Cutoff points are 0-6 = normal, 7-9 = mild depression, 20-34 = moderate depression, >34 = severe depression. | MADRS score assessed at 6-month follow up | 
| Clinical Global Impression (CGI) - Severity | The CGI-Severity scale is clinician rated from 1-7 representing 'Not at all ill' to 'Severely ill'. | 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. | 
| Clinical Global Impression (CGI) - Improvement | The CGI-Severity scale is clinician rated from 1-7 representing 'Not at all ill' to 'Severely ill'. | 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. | 
| Change on the Borderline Symptom List-23 (BSL-23) | The BSL is a self-report measure of 23 questions assessing symptoms of borderline personality disorder on a Likert scale from 0-4. | The BSL-23 will be completed at baseline, week 2 (end of treatment), 1-month, and 6-month follow up visits | 
| Self-Reported Quick Inventory of Depressive Symptoms (QIDS-SR) | The Quick Inventory of Depressive Symptomatology (QIDS) rates depression symptoms via self-assessment.Severity of depression can be judged based on the total score. 1-5 = No depression 6-10 = Mild depression 11-15 = Moderate depression 16-20 = Severe depression 21-27 = Very severe depression | The QIDS-SR will be completed at baseline, week 2, 1-month, and 6-month follow up visits. | 
| Generalized Anxiety Disorder-7 item questionnaire (GAD-7) | Anxiety symptoms will be assessed using the 7 item Generalized Anxiety Disorder (GAD-7) questionnaire. The GAD-7 measures self-reported feelings of anxiety within the last 2 weeks. Scores range from 0-21. Scores of 5, 10, and 15 represent cut points for mild, moderate, and severe anxiety, respectively. | The GAD-7 will be completed at baseline, week 2, 1-month, and 6-month follow up visits. | 
| Difficulties in Emotional Regulation Scale (DERS) | The DERS is a 36-item self-reported measure of emotional regulation ability, rated on a Likert-Scale from 0 (almost never) to 5 (almost always). | The DERS will be completed at baseline, week 2, 1-month, and 6-month follow up visits. | 
| WHO Quality of Life Questionnaire (WHOQOL-BREF) | The WHOQOL-BREF is a self-reported questionnaire which assesses individual's perception of their quality of life across 4 domains; physical health, psychological, social relationships and environment. Domains scores are calculated to range from 0-20 and scaled in a positive direction (ie. higher scores denote higher quality of life). | The WHOQOL-BREF will be completed at baseline, week 2, 1-month, and 6-month follow up visits. | 
| Beck Hopelessness Scale (BHS) | The BHS is a self-reported measure of hopelessness that includes 20 true/false questions that assess three different aspects of hopelessness: feelings about the future, loss of motivation, and future expectations. Higher scores reflect higher levels of hopelessness. | The BHS will be completed at baseline, week 2, 1-month, and 6-month follow up visits. | 
| Performance on the Death Implicit Association Test (D-IAT) | 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). | The D-IAT will be completed at baseline, week 2 (end of treatment), and 1-month follow up | 
| Performance on the Stroop Word-Colour Task (SWCT) | The SWCT is a measure of cognitive control which uses reaction times to assess an individual's ability to inhibit a pre-potent response. | The SWCT will be completed at baseline, week 2 (end of treatment) and 1-month follow up | 
| Performance on the Spatial Working Memory Task (SWM; CANTAB) | The SWM task requires the retention and manipulation of visuo-spatial information. It acts as a measure of strategy and errors when using spatial working memory. | the SWM task will be completed at baseline, week 2 (end of treatment), and 1-month follow up | 
| Performance on the Intra-Extra Dimensional Set Shift (IED; CANTAB) | The IED measures an individual's ability to understand and apply the rules of a game as the rules change (acquisition and reversal). | The IED will be completed at baseline, week 2 (end of treatment), and 1-month follow up | 
| Suicidal behaviors over 6-months post-treatment | Suicide attempts, aborted suicide attempts, interrupted suicide attempts, suicidal ideation and non-suicidal self-injury will be measured using the Columbia Suicide Severity Rating Scale (CSSRS). Higher scores on the CSSRS are indicative of more severe suicidal behaviors. | Columbia Suicide Severity Rating Scale and electronic medical record verification assessed 6-months post treatment | 
| Psychiatric emergency department visits and hospitalizations over 6 months post-treatment | Participants' medical record will be reviewed for emergency department presentations for a psychiatric chief complaint and psychiatric hospitalizations in the six months following treatment. | The medical record will be accessed six months after the completion of treatment. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Transcranial Magnetic Stimulation, Emerging Adults, Youth, Suicidal Ideation, Depression, D-Cycloserine, Cognition