Feasibility, Safety, and Preliminary Clinical Efficacy of Magnetic Resonance Imaging-guided Repetitive Transcranial Magnetic Stimulation (rTMS) in Adolescents With Depression: A Randomized, Double-Blind, Controlled Pilot Study

Overview

This study aims to assess the feasibility, safety, acceptability, and preliminary efficacy trends of a Magnetic Resonance Imaging-guided Repetitive Transcranial Magnetic Stimulation (rTMS) intervention for adolescent depression through a pilot clinical trial. The findings will inform the design and optimization of subsequent formal randomized controlled trials, providing essential evidence for their execution.

Detailed description

This study is a randomized, double-blind, controlled pilot trial aimed at evaluating the feasibility, safety, acceptability, and preliminary efficacy trends of Magnetic Resonance Imaging-guided Repetitive Transcranial Magnetic Stimulation (rTMS) for the treatment of adolescent depression.

Adolescents diagnosed with Major Depressive Disorder (MDD) will be randomly assigned in a 1:1:1 ratio to one of three groups: the experimental target rTMS treatment group, the conventional target rTMS treatment group, and the sham stimulation group. All three groups will receive 4 weeks of rTMS stimulation (10 Hz, 120% RMT) or sham stimulation intervention, using the Blackdolphin TMS Robot (SLD-YXRJ) by Xi'an Solide Brain Modulation Ltd. Co., with 20 sessions (administered on weekdays) in total. The intervention frequency and procedure will remain consistent across all groups.

In the experimental target rTMS treatment group, participants will undergo MRI-guided identification of the left dorsolateral prefrontal cortex (DLPFC) region, where the voxel most negatively correlated with the functional connectivity of the subgenual anterior cingulate cortex (sgACC) will serve as the stimulation target. In the conventional target rTMS treatment group, participants will receive MRI-guided stimulation at the left DLPFC location. Participants in the sham stimulation group will receive a placebo treatment, simulating the rTMS procedure without generating an effective magnetic field output.

Primary outcomes include feasibility and acceptability indicators, such as recruitment, retention, adherence, assessment completion, and tolerability, as well as preliminary clinical efficacy. Secondary outcomes include anxiety, suicidal ideation and behaviour, and global clinical improvement. Safety will be monitored throughout.

Interventions

• Device Experimental target rTMS treatment
  Participants will undergo MRI-guided identification of the voxel in the left dorsolateral prefrontal cortex (DLPFC) that is most negatively correlated with the functional connectivity of the subgenual anterior cingulate cortex (sgACC) as the stimulation site.
• Device Conventional target rTMS treatment
  participants will receive MRI-guided stimulation at the left DLPFC location.
• Device Sham stimulation treatment
  Participants will receive a sham stimulation treatment designed to simulate the rTMS procedure without generating an effective magnetic field output.

Primary outcome measures

• Recruitment Feasibility (Number of Participants Enrolled) [Time frame: 2 years]
• Intervention adherence (number of participants who completed the full 20 treatment sessions) [Time frame: Throughout the entire course of treatment (up to 1 month)]
• Retention Rate (Number of Participants Remaining at 6-Month Follow-up) [Time frame: Throughout the entire course of treatment (up to 1 month) and follow-up (up to 6 months)]
• Response rate and remission rate of depressive symptoms [Time frame: Baseline, throughout the entire course of treatment (up to 1 month) and follow-up (up to 6 months)]
• Incidence of Adverse Events and Serious Adverse Events [Time frame: Throughout the entire course of treatment (up to 1 month) and follow-up (up to 6 months)]

Secondary outcome measures (9)

• Change in BDI-II (Beck Depression Inventory-II) scores from baseline [Time frame: Baseline, throughout the entire course of treatment (up to 1 month) and follow-up (up to 6 months)]
• Change in HAMA score from baseline [Time frame: Baseline, throughout the entire course of treatment (up to 1 month) and follow-up (up to 6 months)]
• Change in SCARED (The Screen for Child Anxiety-Related Emotional Disorders) scores from baseline [Time frame: Baseline, throughout the entire course of treatment (up to 1 month) and follow-up (up to 6 months)]
• Change in suicide risk from baseline on the C-SSRS (Columbia Suicide Severity Rating Scale) [Time frame: Baseline, throughout the entire course of treatment (up to 1 month) and follow-up (up to 6 months)]
• Change in PSQI (Pittsburgh Sleep Quality Index) scores from baseline [Time frame: Baseline, throughout the entire course of treatment (up to 1 month) and follow-up (up to 6 months)]
• Change in CGI-S (Clinical Global Impressions-Severity Scales) scores from baseline [Time frame: Baseline, throughout the entire course of treatment (up to 1 month) and follow-up (up to 6 months)]
• Change in CGI-I (Clinical Global Impressions-Improvement Scales) scores from baseline [Time frame: Throughout the entire course of treatment (up to 1 month) and follow-up (up to 6 months)]
• Change in RRS (Ruminative Responses Scale) [Time frame: Baseline, throughout the entire course of treatment (up to 1 month) and follow-up (up to 6 months)]
• Change in PedsQL 4.0 score from baseline [Time frame: Baseline, throughout the entire course of treatment (up to 1 month) and follow-up (up to 6 months)]

Eligibility criteria

Inclusion criteria

• Age 12 - 18
• Diagnosis of major depressive disorder (MDD) according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), confirmed through the Kiddie Schedule for Affective Disorders and Schizophrenia - Present and Lifetime version (K-SADS-PL), currently in a depressive episode
• Score≥40 on the CDRS-R
• Stable pharmacological treatment: At least 4 weeks of stable psychiatric medication use prior to enrollment, with continuation of the same psychiatric medication regimen throughout the study.

Exclusion criteria

• Psychiatric comorbidities other than anxiety disorders
• Depression with psychotic symptoms
• Young Mania Rating Scale (YMRS) score >13
• A history of neurological disorders (e.g., epilepsy, brain injury) or severe somatic diseases (e.g., thyroid disorders, lupus, diabetes, pulmonary, hepatic, or renal impairment, major trauma)
• Patients currently using anticonvulsants or high-dose benzodiazepines
• A history of electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), or other neuromodulation treatments
• A history of alcohol or substance abuse or dependence
• Women who are pregnant or breastfeeding
• Current high suicide risk
• Potential complicating factors related to transcranial magnetic stimulation, such as scalp conditions or perforations that may affect magnetic field delivery
• Contraindications to MRI

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

China · 1 center

• The First Affiliated Hospital of Chongqing Medical University — Chongqing

Publications

• Lefaucheur JP, Aleman A, Baeken C, Benninger DH, Brunelin J, Di Lazzaro V, Filipovic SR, Grefkes C, Hasan A, Hummel FC, Jaaskelainen SK, Langguth B, Leocani L, Londero A, Nardone R, Nguyen JP, Nyffeler T, Oliveira-Maia AJ, Oliviero A, Padberg F, Palm U, Paulus W, Poulet E, Quartarone A, Rachid F, Rektorova I, Rossi S, Sahlsten H, Schecklmann M, Szekely D, Ziemann U. Evidence-based guidelines on th PMID 31901449
• Croarkin PE, Elmaadawi AZ, Aaronson ST, Schrodt GR Jr, Holbert RC, Verdoliva S, Heart KL, Demitrack MA, Strawn JR. Left prefrontal transcranial magnetic stimulation for treatment-resistant depression in adolescents: a double-blind, randomized, sham-controlled trial. Neuropsychopharmacology. 2021 Jan;46(2):462-469. doi: 10.1038/s41386-020-00829-y. Epub 2020 Sep 12. PMID 32919400
• Allen CH, Kluger BM, Buard I. Safety of Transcranial Magnetic Stimulation in Children: A Systematic Review of the Literature. Pediatr Neurol. 2017 Mar;68:3-17. doi: 10.1016/j.pediatrneurol.2016.12.009. Epub 2017 Jan 4. PMID 28216033
• Sigrist C, Vockel J, MacMaster FP, Farzan F, Croarkin PE, Galletly C, Kaess M, Bender S, Koenig J. Transcranial magnetic stimulation in the treatment of adolescent depression: a systematic review and meta-analysis of aggregated and individual-patient data from uncontrolled studies. Eur Child Adolesc Psychiatry. 2022 Oct;31(10):1501-1525. doi: 10.1007/s00787-022-02021-7. Epub 2022 Jun 24. PMID 35751003
• Berlim MT, Van den Eynde F, Daskalakis ZJ. Efficacy and acceptability of high frequency repetitive transcranial magnetic stimulation (rTMS) versus electroconvulsive therapy (ECT) for major depression: a systematic review and meta-analysis of randomized trials. Depress Anxiety. 2013 Jul;30(7):614-23. doi: 10.1002/da.22060. Epub 2013 Jan 24. PMID 23349112
• O'Reardon JP, Solvason HB, Janicak PG, Sampson S, Isenberg KE, Nahas Z, McDonald WM, Avery D, Fitzgerald PB, Loo C, Demitrack MA, George MS, Sackeim HA. Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. Biol Psychiatry. 2007 Dec 1;62(11):1208-16. doi: 10.1016/j.biopsych.2007.01.018. Epub 2007 Jun 14. PMID 17573044
• George MS, Lisanby SH, Avery D, McDonald WM, Durkalski V, Pavlicova M, Anderson B, Nahas Z, Bulow P, Zarkowski P, Holtzheimer PE 3rd, Schwartz T, Sackeim HA. Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: a sham-controlled randomized trial. Arch Gen Psychiatry. 2010 May;67(5):507-16. doi: 10.1001/archgenpsychiatry.2010.46. PMID 20439832
• Hetrick SE, McKenzie JE, Bailey AP, Sharma V, Moller CI, Badcock PB, Cox GR, Merry SN, Meader N. New generation antidepressants for depression in children and adolescents: a network meta-analysis. Cochrane Database Syst Rev. 2021 May 24;5(5):CD013674. doi: 10.1002/14651858.CD013674.pub2. PMID 34029378

Identifiers

NCT: NCT07185438 · 1stChongqingCQMU___ZXY

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗