Clinical trial NCT06372834: Adjuvant Accelerated piTBS for Reducing Suicidal Ideation in TRD Patients
Official title: Efficacy of Adjuvant Accelerated Prolonged Intermittent Theta Burst Stimulation for Reducing Suicidal Ideation in Therapy-resistant Depressed Patients: A Randomized, Sham-controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Major Depressive Disorder
Treatment-Resistant Depression
Suicide Ideations
Keywords: Major Depressive Disorder
Treatment-Resistant Depression
Dorsolateral prefrontal cortex
rTMS
piTBS
Lead sponsor: Tri-Service General Hospital
Sponsor class: OTHER
First posted: 2024-04-18
Enrollment: 100
Sex: ALL
Minimum age (years): 20
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: In this double-blind, randomized, sham-controlled trial, the investigators aimed to examine the effect of accelerated piTBS on suicide risk in a group of treatment-resistant patients with MDD (i.e., TRD), using an extensive suicide assessment scale the primary outcome. The investigators hypothesized that this intensified treatment protocol would be safe in TRD patients with suicide ideations and would result in significant decreases in suicide risk in the active treatment condition as compared to the sham condition.

Detailed description: Less than half of patients with major depressive disorder (MDD) remit after first-line therapy (i.e., pharmacotherapy and/or psychotherapy). A progressively smaller proportion of patients remit with each subsequent medication trial, and a remission rate of only 10-15% after a fourth antidepressant trial. Patients with MDD are considered to have a treatment-resistant depression (TRD) whey they do not achieve response to first-line antidepressants. Repetitive Transcranial Magnetic Stimulation (rTMS) applied over the DLPFC for modulating brain activity and network connectivity has well-documented positive effects on major depressive disorder (MDD), especially TRD. rTMS research in treating MDD has shown a dose-response relationship and more recently, studies have shown a trend towards administering more stimuli over a shorter period of time and at higher frequencies leading to accelerated protocols. An optimized rTMS parameter called intermittent theta burst stimulation (iTBS) is a novel protocol that consists of intermittently delivering bursts of 3 TMS pulses at high frequency (50 Hz) every 200 ms for 2 s (5Hz) every 10 s (total 600 pulses), allowing for greater long-lasting effects on cortical excitability and a more important number of rTMS pulses to be delivered in a shorter duration than standardized high frequency (HF) rTMS protocols. iTBS induces a long-term potentiation (LTP)-like effect by increasing the postsynaptic concentration of calcium ions and has been applied to treat MDD. iTBS has been proved to be safe and well tolerated and to have antidepressant properties. Prolonged iTBS (piTBS, total 1800 pulses) has been recently applied to treat MDD with favorable antidepressant properties. An accelerated protocol of piTBS has been recently approved to treat medication-refractory MDD by FDA.

MDD is associated with a 2.3 fold increase in prevalence of suicidal ideation as compared to the general population. The lifetime rate of death due to suicide among MDD patients is 15-20%. Research indicates that 30% of TRD patients will attempt suicide during their lifetime, which is a two-to-four times greater proportion than MDD patients who respond to treatment. Research indicates that rTMS improves several preconditions for suicide, including mood, memory, attention, executive functioning. rTMS is thought to have molecular effects similar to those seen with electroconvulsive therapy (ECT), which is effective in treating suicidal patients, such as increased BDNF, increased monoamine turnover and normalization of the hypothalamic-pituitary-adrenal axis. Some research indicates that rTMS may reduce suicidal ideations of patients with MDD. However, powered sham-controlled rTMS clinical trials focusing on the efficacy to improve suicide risks are limited.

The study aims to investigate the efficacy of accelerated piTBS over the left DLPFC as an add-on therapy to improve suicide ideations in TRD patients. Moreover, it provides data on other secondary outcomes and neurophysiological data for this intervention condition.

Eligibility criteria: Inclusion Criteria:

* Subjects aged 20-65 years, met criteria for DSM-V major depressive disorder.
* A depression severity score of 18 or more on the 17-item Hamilton Rating Scale for Depression (HRSD-17) as well as a score of 1 or more on the item of the HDRS-17 (item 3).
* Meeting criteria for TRD defined as no clinical response to at least one adequate trial of one major class of antidepressants.
* Having been receiving stable antidepressant medications regimen for more than 4 weeks before enrollment and having their original medication regimen unchanged throughout the trial.

Exclusion Criteria:

* Having MDD with psychotic features, bipolar disorder, schizophrenia, organic brain syndrome or active substance (except for tobacco and coffeine) use disorder.
* Having previous intracranial surgery and ferromagnetic metallic implants in the head.
* History of brain abnormalities (e.g., brain neoplasms, arteriovenous malformations, meningitis, encephalitis, epilepsy, neurodegenerative disorders).
* Pregnancy at enrollment.
* History of treatment with electroconvulsive therapy (ECT) or no response to rTMS over the left DLPFC.
* Those who had attempted a suicide within six months from the screening date.
* Skin lesions on scalp at the area of coil application.
* In addition to those listed above, those who were deemed unsuitable for participating in this clinical trial by the medical judgment of the investigator due to other reasons (e.g., lack of competence to consent to research or any other contraindications to receiving rTMS).

Primary outcomes:
measure: The change over time in the score of Beck Scale for Suicide Ideation (BSS) (from baseline to the timepoints at 1 week after piTBS, at the end of piTBS, and at 1, 2, and 4 weeks after piTBS).
timeFrame: 6 weeks
Secondary outcomes:
measure: The change over time in the score of Snaith-Hamilton Pleasure Scale (SHAPS) (from baseline to the timepoints at 1 week after piTBS, at the end of piTBS, and at 1, 2, and 4 weeks after piTBS).
timeFrame: 6 weeks
measure: The change over time in the score of Beck Hopelessness Scale (BHS) (from baseline to the timepoints at 1 week after piTBS, at the end of piTBS, and at 1, 2, and 4 weeks after piTBS).
timeFrame: 6 weeks
measure: The change over time in the score of Montgomery-Å sberg Depression Rating Scale (MADRS) (from baseline to the timepoints at 1 week after piTBS, at the end of piTBS, and at 1, 2, and 4 weeks after piTBS).
timeFrame: 6 weeks
measure: The change over time in the score of 17-item Hamilton Depression Rating Scale (HDRS) (from baseline to the timepoints at 1 week after piTBS, at the end of piTBS, and at 1, 2, and 4 weeks after piTBS).
timeFrame: 6 weeks
measure: The change over time in the score of Hamilton Anxiety Rating Scale (HAM-A) (from baseline to the timepoints at 1 week after piTBS, at the end of piTBS, and at 1, 2, and 4 weeks after piTBS).
timeFrame: 6 weeks
measure: The change over time in the score of Young Mania Rating Scale (YMRS) (from baseline to the timepoints at 1 week after piTBS, at the end of piTBS, and at 1, 2, and 4 weeks after piTBS).
timeFrame: 6 weeks
measure: The changes over time in the results of Wisconsin Card Sorting Test (WCST) (from baseline to the timepoint at the end of piTBS).
timeFrame: 2 weeks
measure: The changes over time in the results of Color Trails Test (CTT) (from baseline to the timepoint at the end of piTBS).
timeFrame: 2 weeks
measure: The changes over time in the results of Stroop Color Word Test (SCWT) (from baseline to the timepoint at the end of piTBS).
timeFrame: 2 weeks
measure: The changes over time in the results of indices of heart rate variability (HRV) (from baseline to the timepoint at the end of piTBS) and the HRV indices during each piTBS session.
timeFrame: 2 weeks
measure: The changes over time in EEG absolute power and lag phase synchronization in the frontal electrodes in the delta, theta, alpha, beta and gamma range (from baseline to the end of piTBS).
timeFrame: 2 weeks
measure: The changes over time in high density near infrared spectroscopy (from baseline to the end of piTBS).
timeFrame: 2 weeks
measure: The changes over time in the results of Digit Symbol Substitution Test (DSST) (from baseline to the timepoint at the end of piTBS).
timeFrame: 2 weeks
Other outcomes:
Locations:
city: Taipei
country: Taiwan
facility: Tri-service general hospital
Study officials:
affiliation: Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
name: Hsin-An Chang, MD
role: PRINCIPAL_INVESTIGATOR
References: