Sequential bilateral accelerated theta burst stimulation in adolescents with suicidal ideation associated with major depressive disorder: Protocol for a randomized controlled trial

Abstract

Background: Suicide is a leading cause of death in adolescents worldwide. Previous research findings suggest that suicidal adolescents with depression have pathophysiological dorsolateral prefrontal cortex (DLPFC) deficits in γ-aminobutyric acid neurotransmission. Interventions with transcranial magnetic stimulation (TMS) directly address these underlying pathophysiological deficits in the prefrontal cortex. Theta burst stimulation (TBS) is newer dosing approach for TMS. Accelerated TBS (aTBS) involves administering multiple sessions of TMS daily as this dosing may be more efficient, tolerable, and rapid acting than standard TMS.

Materials and methods: This is a randomized, double-blind, sham-controlled trial of sequential bilateral aTBS in adolescents with major depressive disorder (MDD) and suicidal ideation. Three sessions are administered daily for 10 days. During each session, continuous TBS is administered first to the right DPFC, in which 1,800 pulses are delivered continuously over 120 seconds. Then intermittent TBS is applied to the left DPFC, in which 1,800 pulses are delivered in 2-second bursts and repeated every 10 seconds for 570 seconds. The TBS parameters were adopted from prior research, with 3-pulse, 50-Hz bursts given every 200 ms (at 5 Hz) with an intensity of 80% active motor threshold. The comparison group will receive 3 daily sessions of bilateral sham TBS treatment for 10 days. All participants will receive the standard of care for patients with depression and suicidal ideation including daily psychotherapeutic skill sessions. Long-interval intracortical inhibition (LICI) biomarkers will be measured before and after treatment. Exploratory measures will be collected with TMS and electroencephalography for biomarker development.

Discussion: This is the first known randomized controlled trial to examine the efficacy of sequential bilateral aTBS for treating suicidal ideation in adolescents with MDD. Results from this study will also provide opportunities to further understand the neurophysiological and molecular mechanisms of suicidal ideation in adolescents.

Trial registration: Investigational device exemption (IDE) Number: G200220, ClinicalTrials.gov (ID: NCT04701840). Registered August 6, 2020. https://clinicaltrials.gov/ct2/show/NCT04502758?term=NCT04701840&draw=2&rank=1.

Fig 1. Schedule of enrollment, interventions, and assessments.

Legend. Abbreviations: aTBS, accelerated theta burst stimulation; ATHF, Antidepressant Treatment History Form; NIH, National Institutes of Health; t, timepoint; TASS, Transcranial Magnetic Stimulation Safety Screen; TMS-EEG, transcranial magnetic stimulation and electroencephalography; TMS-EMG, transcranial magnetic stimulation and electromyography; X, occurs at that time. ^a If symptoms of mania occur.

Fig 2. Study schema.

Legend. aTBS, accelerated theta burst stimulation; CDRS-R, Children’s Depression Rating Scale Revised; C-SSRS, Columbia–Suicide Severity Rating Scale; LICI, long-interval intracortical inhibition; MINI, Mini-International Neuropsychiatric Interview; N45, TMS-EEG evoked potential at 45 milliseconds; N100, TMS-EEG evoked potential at 100 milliseconds; TBS, theta burst stimulation; TMS-EEG, transcranial magnetic stimulation and electroencephalography; TMS-EMG, transcranial magnetic stimulation and electromyography. Additional screening assessments (Table 2) include the Transcranial Magnetic Stimulation Safety Screen [69], Antidepressant Treatment History Form [70], Pubertal Development Scale [71], Mini-International Neuropsychiatric Interview for Children and Adolescents (MINI-KID) for participants aged 12 to 17 years [72] or the Mini-International Neuropsychiatric Interview for participants aged 18 years [73], Young Mania Rating Scale [74], Children’s Depression Rating Scale Revised (CDRS-R) [75], C-SSRS [68], Beck Depression Interview-II [76], and Clinical Global Impressions–Severity Scale [77]. Also discussed and noted at the screening visit are concurrent use of medications, adverse events (AEs), serious AEs (SAEs), the case report form (CRF), and concurrent psychotherapy. The screening visit can occur on the same day or across 2 consecutive days depending on participant preference.