iTBS+D-Cycloserine for Youth Suicide

Официальное название

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

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат D-Cycloserine
  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.
• Устройство intermittent Theta-Burst-repetitive Transcranial Magnetic Stimulation
  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).
• Препарат Placebo oral tablet
  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.

Первичные конечные точки

• Performance on the Death Implicit Association Test (D-IAT) at treatment end [Срок оценки: Change from baseline to end of treatment (week 2)]

Вторичные конечные точки (12)

• Performance on the Death Implicit Association Test (D-IAT) at follow up [Срок оценки: Baseline, treatment end (2-weeks), 1-month, 6-months]
• Change on the Scale for Suicidal Ideation (SSI) at end of treatment (week 2) [Срок оценки: SSI score from baseline to end of treatment (week 2)]
• SSI at 1-month post treatment [Срок оценки: SSI score at 1-month post treatment]
• SSI at 6-months post treatment [Срок оценки: Administered at 6-months post treatment]
• Change on the Montgomery Asberg Depression Rating Scale (MADRS) post treatment [Срок оценки: MADRS score at week 2 (post treatment)]
• Montgomery Asberg Depression Rating Scale (MADRS) at 1-month [Срок оценки: MADRS score at 1-month follow up]
• Montgomery Asberg Depression Rating Scale (MADRS) at 6-months [Срок оценки: MADRS score assessed at 6-month follow up]
• Clinical Global Impression (CGI) - Severity [Срок оценки: 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 [Срок оценки: 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) [Срок оценки: 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) [Срок оценки: 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) [Срок оценки: The GAD-7 will be completed at baseline, week 2, 1-month, and 6-month follow up visits.]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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).

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Лечение

Центры проведения

Канада · 1 центр

• University of Calgary — Calgary

Идентификаторы

NCT: NCT06121284 · REB22-1115

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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