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Learn more: PMC Disclaimer | PMC Copyright Notice Trials . 2026 Apr 13;27:299. doi: 10.1186/s13063-026-09705-4 Search in PMC Search in PubMed View in NLM Catalog Add to search Clinical efficacy of intermittent theta burst stimulation in the acute phase of adolescent depression: study protocol of a double-blind, randomized controlled trial Qian Ye Qian Ye 1 School of Nursing, Guangdong Pharmaceutical University, No. 283 Jianghai Avenue, Haizhu District, Guangzhou, Guangdong China Find articles by Qian Ye 1, # , Yiling Yang Yiling Yang 1 School of Nursing, Guangdong Pharmaceutical University, No. 283 Jianghai Avenue, Haizhu District, Guangzhou, Guangdong China Find articles by Yiling Yang 1, # , Weiyu Cai Weiyu Cai 2 Department of Child and Adolescent Psychiatry, Third People’s Hospital of Zhongshan City, No. 80 Tianbian Main Street, Zhongshan, Guangdong China Find articles by Weiyu Cai 2 , Jianzhao Wen Jianzhao Wen 2 Department of Child and Adolescent Psychiatry, Third People’s Hospital of Zhongshan City, No. 80 Tianbian Main Street, Zhongshan, Guangdong China Find articles by Jianzhao Wen 2 , Yutao Lan Yutao Lan 1 School of Nursing, Guangdong Pharmaceutical University, No. 283 Jianghai Avenue, Haizhu District, Guangzhou, Guangdong China Find articles by Yutao Lan 1, ✉ Author information Article notes Copyright and License information 1 School of Nursing, Guangdong Pharmaceutical University, No. 283 Jianghai Avenue, Haizhu District, Guangzhou, Guangdong China 2 Department of Child and Adolescent Psychiatry, Third People’s Hospital of Zhongshan City, No. 80 Tianbian Main Street, Zhongshan, Guangdong China ✉ Corresponding author. # Contributed equally. Received 2025 Oct 9; Accepted 2026 Apr 2; Collection date 2026. © The Author(s) 2026 Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/ . PMC Copyright notice PMCID: PMC13077927 PMID: 41975503 Abstract Background Adolescent depression is a significant health problem, and developing safe and rapid treatments for it is crucial. Intermittent theta burst stimulation (iTBS), a novel form of repetitive transcranial magnetic stimulation (rTMS), enhances synaptic transmission and cortical excitability by simulating cortical rhythms and has demonstrated certain therapeutic effects in adults. Adolescents in the acute phase of depression present with more severe symptoms and are pressed for time, so a short, effective modality like iTBS could be particularly advantageous. However, studies on the effects of iTBS during the acute phase of adolescent depression are still fairly limited. Therefore, this study aims to explore the clinical efficacy of iTBS in adolescents with depression during the acute phase through a viable research design. Methods This is a single-center, randomized, double-blind, and sham-stimulation-controlled clinical trial. We plan to recruit approximately 76 adolescent patients with depression aged 14–18 years. Eligible participants will be randomly assigned to the treatment group ( n = 38) or the sham control group ( n = 38). Each participant will receive 10 sessions of iTBS over 10 days, delivered at 80% of the active threshold, with 1,800 pulses per session. The treatment target will be the left dorsolateral prefrontal cortex. Clinical and neurophysiological assessments will be conducted at baseline, at the end of treatment, and during follow-up at weeks 2 and 4 after treatment completion. Safety will be monitored through semi-structured interviews and the reporting of adverse events. Discussion Conventional rTMS treatment faces logistical challenges due to its standard course requiring daily treatment over 4–6 weeks. This study aims to explore a safe and effective iTBS protocol for adolescent patients with depression to complement existing treatments. By evaluating clinical symptoms and the most sensitive neurophysiological features after treatment, we hope to optimize the iTBS protocol. This study aims to reduce the treatment duration, alleviate the economic burden on families and society, and expedite the clinical response for adolescent patients. Trial registration The trial was registered with the Chinese Clinical Trial Registry. Registration number: ChiCTR2500101152. Retrospectively registered on 21 April 2025. Supplementary Information The online version contains supplementary material available at 10.1186/s13063-026-09705-4. Keywords: Adolescence, Depression, Intermittent theta burst stimulation, Repetitive transcranial magnetic stimulation, Randomized controlled trial Introduction Depression is a common mental disorder in adolescents, characterized by low mood, diminished interest, slowed thinking, reduced will, and significantly impaired cognitive function [ 1 ]. In recent years, depression has become one of the most prominent issues in the mental health of adolescents. Data from global surveys show that the prevalence of depression among adolescents is as high as 34% [ 2 ]. The condition not only severely impairs the mental health of adolescents but can also lead to a host of adverse consequences, such as difficulties in interpersonal relationships, declining academic performance, substance abuse, and reduced social adaptation skills [ 3 ]. In more severe cases, it may also induce extreme behaviors, such as violent conflicts, self-harm, and even suicide [ 4 , 5 ]. Currently, the main treatments for adolescent depression include pharmacotherapy, psychotherapy, and physical therapy [ 6 ]. However, antidepressants require long-term use, often with many adverse reactions, such as nausea, drowsiness, weight gain, etc. They may also exacerbate patients’ cognitive deficits, leading to issues such as decreased concentration and slower cognitive processing [ 7 , 8 ]. Psychotherapy, though widely used, usually takes a long time to show effects and often has problems like unclear clinical effects, high time and economic costs. So, there is an urgent clinical need to develop more effective and safer alternative or supplementary treatments. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation modality. It converts electrical and magnetic energy to induce electromagnetic phenomena, promoting neurotransmitter production and neuroplasticity, and exerting antidepressant effects [ 9 ]. In addition to improving depressive symptoms, rTMS has also demonstrated certain efficacy in improving patients’ cognitive function status. Extensive research indicates that rTMS applied to the left dorsolateral prefrontal cortex can lead to improvements in various cognitive domains for patients, including attention, memory, and information processing speed [ 10 , 11 ]. Extensive research confirms rTMS as a front-line treatment for depression, yet the U.S. Food and Drug Administration (FDA)-approved protocol demands 40-min sessions over roughly 6 weeks, incurring high time costs and limiting efficiency [ 12 ]. Moreover, the traditional rTMS repetitive and fixed single-pulse stimulation pattern may lead to the development of tolerance and fatigue in neurons, thereby affecting the improvement of synaptic plasticity in neurons [ 13 ]. Thus, a novel rTMS stimulation mode—theta burst stimulation (TBS)—with advantages like short stimulation duration, long-lasting effects, and closer alignment with neurophysiological states, is gaining increasing attention [ 14 ]. TBS replicates the hippocampus’s signature burst firing, producing a train of theta-timed pulses that elicits responses matching or surpassing those of conventional rTMS [ 15 ]. Thus, TBS has become a highly attractive option for neuromodulation therapy in clinical diseases. TBS has two types: intermittent theta burst stimulation (iTBS) and continuous theta burst stimulation (cTBS) [ 16 ]. iTBS increases cortical excitability. Compared to traditional rTMS, a single iTBS session takes only about 3 min. Cumulative evidence indicates that iTBS matches conventional rTMS in efficacy and tolerability for treating depression in adults and adolescents [ 17 – 20 ]. Compared with traditional rTMS, iTBS not only has a shorter stimulation duration but also has not been reported to cause serious adverse events in adolescents. Such as epileptic seizures or cognitive function deterioration [ 21 ]. Emerging evidence also suggests that, beyond its antidepressant action, iTBS may confer anti-suicidal benefits in adults with depression. A randomized controlled trial indicated that suicidal ideation among adolescents with depression rapidly decreased following a 2-week course of iTBS treatment [ 22 ]. However, the study lacked a longer-term follow-up, assessing only depressive symptoms and suicidality without examining cognitive outcomes. Currently, various clinical tools are available for assessing cognitive function levels. Common ones include the Stroop Word-Color Interference Test (STROOP) [ 23 ], the Wisconsin Card Sorting Test (WCST) [ 24 ], and event-related potentials (ERP) [ 25 ]. ERP can effectively reflect the brain’s electrophysiological changes in response to specific stimuli. It is an objective form of psychobehavioral manifestation. ERP has high temporal resolution, is low-cost, and non-invasive [ 26 ]. Different components, including P1, N1, P2, N2, and P3, are identified based on the direction of waveform deflection and the specific time process of deflection after stimulation. Among them, P3 is the most studied component of ERP. It is a positive wave that appears in the central-parietal region about 300 ms after the stimulus and is related to attention allocation and working memory [ 27 ]. Previous studies have shown that [ 28 , 29 ], compared to the control group, patients with depressive disorders have reduced P3 amplitudes and prolonged latencies in event-related potentials. These findings confirm marked cognitive impairments in attention, working memory, and executive function among these patients. During depressive episodes, P3 typically exhibits a “two-down, one-up” pattern: amplitudes to neutral targets decrease, and latencies lengthen, indicating depleted attention and slowed processing. In contrast, responses to negative stimuli paradoxically increase, reflecting a negative bias. These abnormalities recede as symptoms improve. Accumulating evidence confirms ERP’s utility for diagnosing depression, monitoring its progression, and predicting treatment outcomes, with high sensitivity and specificity for unipolar depression [ 30 ]. Finally, based on the classic iTBS protocol established by Huang et al. [ 31 ], its validation in adolescents by Dhami et al. [ 32 ], and subsequent corroboration from two trials [ 18 , 33 ], this study employs a standardized intervention protocol (F3 localization, 1800 pulses per session, 5 sessions per week for 2 consecutive weeks). Building upon this foundation, it addresses key limitations regarding efficacy persistence and unclear neural mechanisms through three expansions: First, extending the follow-up period by adding 2-week and 4-week post-intervention assessment points to systematically evaluate the maintenance of immediate effects and potential delayed effects, compensating for previous studies’ focus solely on acute-phase endpoints; Second, objective neural biomarkers were introduced by adding the ERP-P300 metric. This explored iTBS’s impact on adolescent cognitive processing functions (attention allocation, working memory) at the neurophysiological level, providing biological evidence independent of subjective reports for efficacy assessment. Third, multidimensional risk monitoring dynamically tracks the evolution of depression, anxiety, self-harm, and suicidal ideation throughout follow-up to identify early relapse signals or symptom fluctuation patterns, enabling timely clinical intervention. This study is designed as a double-blind, randomized, sham-stimulation-controlled trial. Given the high recurrence, high volatility, and high suicide risk associated with adolescent depression, along with the significant heterogeneity in symptom phenotypes and patterns of neurocognitive impairment, this study explores the clinical efficacy of iTBS for acute-phase adolescent depression across multiple dimensions including mood, self-harm, suicide, and cognitive function. The aim is to provide evidence-based support for stratified treatment decisions in future research, such as determining optimal treatment duration and identifying subgroups requiring enhanced intervention. Although this study protocol itself does not involve personalized treatment, its findings may provide important clinical reference for future personalized therapeutic approaches. Objectives The primary objective of this study is to evaluate the efficacy and safety of iTBS in the acute phase of adolescent depression, with a focus on its impact on core symptoms. As a secondary objective, we plan to use neurophysiological techniques after the intervention to assess the neurobiological effects of this protocol on the cerebral cortex of adolescents with depression, providing a basis for optimizing the iTBS protocol and future personalized treatments. Additionally, follow-up assessments at weeks 2 and 4 after the end of treatment will be conducted to evaluate the durability of the treatment effects and the potential need for booster sessions. Methods Study design The study is a randomized, controlled, single-center study. It will recruit 76 patients, all of whom will receive pharmacotherapy and will be randomly assigned (1:1) to the iTBS group or the control group (sham iTBS). The left dorsolateral prefrontal cortex will be selected as the target for stimulation. A series of assessments will be conducted before treatment, at the end of treatment, and at weeks 2 and 4 after the end of treatment. The study protocol follows the SPIRIT recommendations [ 34 ]. Please refer to the additional file for the SPIRIT checklist (see Supplementary File 1). The overall study design is shown in Fig. 1 . Fig. 1. Open in a new tab Study flow diagram. HAMD-24, 24-item Hamilton Depression Rating Scale; HAMA, Hamilton Anxiety Rating Scale; BSI, Beck Scale for Suicide Ideation; OSI, Ottawa Self-Injury Inventory; SCWT, Stroop Word-Color Interference Test; WSCT, Wisconsin card sorting test; ERP-P300, Event-related potentials P300 Ethical issues Eligibility screening for adolescent patients with depression will be conducted in the inpatient department of the Third People’s Hospital of Zhongshan City. After confirming eligibility, researchers will provide participants and their families with a detailed introduction to the trial, including its purpose, procedures, and requirements. All participants and their families will voluntarily participate in the study and sign the informed consent form (see Supplementary File 2). The study protocol has been approved by the Ethics Committee of the Third People’s Hospital of Zhongshan City (ethics approval number: SSYLL-KY-20240903) and registered with the Chinese Clinical Trial Registry (registration number: ChiCTR2500101152). The study will be conducted in accordance with the Declaration of Helsinki, Good Clinical Practice for Drug Clinical Trials, and applicable regulatory requirements. To ensure proper oversight, key researchers will conduct on-site visits monthly to monitor study progress. These visits will include verification of original records, case report forms (CRFs), and other relevant information. These checks aim to ensure that researchers comply with the study protocol, procedures, and regulations, and that the. After the study ends, inspectors will be responsible for verifying and archiving all documents related to the study conducted at the center. Study setting This study will be conducted at the Third People’s Hospital of Zhongshan City. Between September 2024 and March 2026, the research team will screen adolescent patients with depressive disorders aged 14 to 18 in both outpatient and inpatient departments to invite them to participate in this trial. Although children aged 12 to 13 also suffer from depression, their brains are still in rapid development, and the stability and tolerance of their nervous systems are relatively low. As a neurostimulation technique, iTBS has been proven to be safe and effective in adults, but its safety and potential side effects in younger children have not been fully studied. Therefore, to reduce the potential risks associated with immature nervous system development and to ensure the safety of the study, adolescents aged 14 to 18 are chosen as the subjects of this study. A total of 76 patients will be recruited for the intervention. Patients who meet the inclusion criteria will receive the corresponding treatment at the Third People’s Hospital of Zhongshan City. Sample size calculation The sample size calculated by G*Power 3.1 [ 35 ] is required to accurately estimate the total score difference in HAMD-24 between the two groups. The parameters used included an effect size of 0.4, 95% statistical power, a two-sided test at the 5% significance level, an F -test, and a repeated measures ANOVA with a between-factor model. Assuming a correlation coefficient of 0.5 between repeated measurements and considering a dropout rate of 20%, the minimum total sample size required is 76 participants. Inclusion/exclusion criteria Adolescent participants who meet the following criteria will be included in the study: (1) meet the diagnostic criteria for the depressive episode (F32.1, F32.2) in the International Classification of Diseases, 10th Revision (ICD-10); (2) are 14–18 years of age, regardless of gender; (3) the patient is in the acute phase of a depressive episode; (4) with a HAMD-24 score of ≥ 20 points, and a score of > 0 on item 4 or 5 of the Beck Scale for Suicide Ideation (BSI); (5) have at least received primary school education or above; (6) understand the purpose and content of the study and are willing to cooperate to complete it; (7) the patient and their guardian have signed the informed consent form. General exclusion criteria include the following: (1) history of central nervous system disorders or severe physical illnesses (e.g., uncontrolled asthma, type 1 diabetes, congenital heart disease, thyroid dysfunction, and epilepsy); (2) individuals at risk of seizures or with a family history of epilepsy (e.g., abnormal electroencephalogram); (3) history of psychoactive substance abuse or dependence; (4) presence of absolute contraindications for rTMS, namely intracranial metallic implants; (5) receipt of rTMS, electroconvulsive therapy, or other electrical/magnetic stimulation treatments within the past month. Withdrawal criteria: (1) the subject withdraws informed consent; (2) individual participants experience the occurrence of intolerable and/or unexpected undesirable side effects during the therapy with iTBS. Randomization, blinding, and allocation concealment This study will employ block randomization with a block size of 4 to ensure balanced allocation of participants throughout the trial. Randomly generated codes will be sealed in opaque envelopes and stored at the neuromodulation center. A nurse not involved in the study will extract these codes. Eligible participants will be assigned 1:1 to the active iTBS group and the sham stimulation group. The operators and study nurse will be aware of the group assignments, while the patients, clinicians, and assessors will remain blinded to the participants’ group allocations. Serious adverse events will make unblinding permissible. A serious event will also stop the data collection until the reason for the event is clarified. Study process Study intervention description The Mag TD (Yiruide Medical Equipment New Technology Co., Ltd., Wuhan, China) with an active, 70-mm figure-of-eight, air-cooled coil was used to apply the iTBS stimulation. Before joining the experiment, all subjects should undergo a psychiatric diagnosis to ensure their suitability. Furthermore, after enrollment, patients will undergo a series of assessments and motor threshold tests to determine the appropriate stimulation intensity. To ensure standardized implementation of the intervention and participant safety. The intervention site was the Department of Psychiatric Rehabilitation. Interventions were administered by physical therapists with at least 5 years of clinical experience who had completed standardized iTBS training and obtained operational competency certification. And any adverse reactions of the subjects will be recorded. Pre-intervention preparation for iTBS: To prevent serious adverse reactions such as seizures, each subject must undergo a comprehensive electroencephalogram examination prior to iTBS. Only subjects with no significant abnormalities in their electroencephalogram results may proceed with subsequent intervention treatment. Active motor threshold (AMT): First, guide the patient to a slightly relaxed state, position the center of the “figure-eight” coil over the left motor cortex area, and then apply pulse stimulation to elicit a motor response in the right finger. Observe and record the minimum single-pulse stimulation intensity required to induce a motor evoked potential with an amplitude exceeding 200 μV in the right abductor pollicis brevis muscle in at least 5 out of 10 pulse stimulations; this stimulation intensity is the AMT value. Stimulation site: The treatment site over the left DLPFC will be localized using the modified BeamF3 scalp heuristic method [ 36 ]. Active iTBS group The stimulation intensity will be 80% of the AMT, with 2-s bursts and 8-s intervals, totaling 1800 pulses, with a stimulation duration of 10 min per session, once daily, for 5 consecutive days per week over 2 weeks, amounting to 10 sessions in total. Sham stimulation group To ensure the rigor of the double-blind design while addressing the ethical considerations for adolescents with depression—a vulnerable population—(avoiding the unethical nature of a placebo control and the potential confounding of positive controls on the independent effect of iTBS), this study employs a sham-stimulation control. This control effectively mitigates the placebo effect by using sham stimulation that is identical to the real stimulation in appearance, sound, and skin sensation. The procedure will be identical in the sham group, except that the coil will be positioned at a 90° angle to the scalp surface, thereby mimicking the procedure without delivering active stimulation. Strategies to improve intervention adherence During the study period, all participants will receive free assessments, ERP tests, two gifts, and transportation subsidies for post-discharge visits. To reduce dropout rates and accommodate participants’ schedules, reminders will be sent to parents or guardians via phone call or text message 1 day before each intervention. Finally, to ensure all patients receive effective treatment, those who have not met the response criteria (less than 50% improvement in HAMD-24 scores from baseline) by the end of the follow-up will be offered free rTMS treatment, regardless of whether they initially received real or sham stimulation. Medication Additionally, both groups of patients will receive pharmacological treatment. Both groups will be treated with the serotonin reuptake inhibitor sertraline hydrochloride (Pfizer Pharmaceuticals Co., Ltd., Approval Number: National Drug Standard No. H10980141) at an initial dose of 50 mg daily, administered orally after meals. The dose may be adjusted based on the patient’s condition, with a maximum daily dose not exceeding 200 mg. If sleep disturbances occur during treatment, sedative-hypnotic medications (benzodiazepines or non-benzodiazepines, such as alprazolam or lorazepam) may be used. However, such use must be reported to the study physician and documented in the case report form (CRF). Assessments Record patients’ general information and clinical outcome measures will be assessed before and after treatment. A safety evaluation will also be conducted during the treatment period. There is a detailed breakdown of all study assessments and timeframes in Fig. 2 . Fig. 2. Open in a new tab Study schedule. MINI: Mini-International Neuropsychiatric Interview; TASS, Transcranial Magnetic Stimulation Adult Safety Screen; iTBS, intermittent θ burst stimulation; HAMD-24, 24-Hamilton Depression Scale; HAMA, Hamilton Anxiety Rating scale; BSI, Beck Scale for Suicide Ideation; OSI, Ottawa self-injury inventory; SCWT, Stroop Word-Color Interference Test; WCST, Wisconsin Card Sorting Test; ERP-P300, Event-Related Potentials-P300; EEG, electroencephalogram; ATHF, Antidepressant Treatment History Form General information The following variables were collected: age, gender, height, weight, ethnicity, family structure, educational attainment, status as an only child, registered residence location, status as a left-behind child, history of school bullying, age at onset, presence of self-harm or suicidal behavior in the past month, smoking habits, drinking habits, family history of other diseases (excluding epilepsy), patient’s past medical history, and medication history. Outcome measures Primary and secondary outcome measures will be assessed at baseline, at the end of treatment, and at 2 weeks and 4 weeks post-treatment. The primary outcome measure is the change in scores on the HAMD-24 [ 37 ], specifically the difference in scores before and after treatment (at baseline and 10 days post-treatment). Developed by Hamilton in 1960, the HAMD-24 is widely used in clinical practice to assess the severity of depressive symptoms. This trial will utilize the HAMD-24 for evaluation. A higher total score on the scale indicates more severe depressive symptoms, with the following scoring criteria: a total score of less than 7 indicates no depression; 7 to 17 points indicates mild depression; 18 to 24 points indicates moderate depression; and more than 24 points indicates severe depression. A reduction rate of ≥ 75% in the HAMD-24 scores is considered remission, a reduction rate between 50 and 75% is considered significantly effective, a reduction rate between 25 and 50% is considered effective, and a reduction rate of less than 25% is considered ineffective. The reduction rate is calculated as (pre-treatment score − post-treatment score)/pre-treatment score × 100%. Secondary outcome measures include the Hamilton Anxiety Rating Scale (HAMA) [ 38 ], Brief Symptom Inventory (BSI) [ 39 ], Ottawa Self-Injury Inventory (OSI) [ 40 ], SCWT, WCST, and ERP-P300. These will be assessed at corresponding follow-up points. HAMA evaluates anxiety symptoms; BSI measures suicidal ideation intensity and risk level; OSI assesses non-suicidal self-injury frequency in the past month; SCWT, WCST, and ERP-P300 evaluate cognitive function. The ERP-P300 test is performed by certified EEG technicians in the hospital’s electrophysiology laboratory using a Shenzhen Boshi NVX36 event-related potential system. Patients are seated in a quiet, soundproof lab, remaining conscious, focused, emotionally stable, and relaxed. The ERP-P300 test uses the international 10/20 system for electrode placement, with impedance between electrodes and skin < 5 kΩ. Recording electrodes are at Fz and Cz, reference electrodes at A1 and A2, and the ground electrode at E. Patients sit quietly in a soundproof lab, staying alert, focused, emotionally calm, and relaxed. The test uses an oddball auditory stimulation paradigm: 80% are standard stimuli (1000 Hz, 60 dB) and 20% are deviant stimuli (2000 Hz, 80 dB). Patients are instructed to press the marker upon hearing the high-frequency/deviant stimulus. The computer records the EEG signals, which are overlapped 30 times to reduce noise and enhance signal extraction. The test stops automatically after 30 valid overlaps, and the waveform is smoothed, sorted, and marked for P300. ERP-P300 includes P1, N1, P2, N2, and P3. P1, N1, and P2 are exogenous components related to objective stimulus features, whereas N2 and P3 are endogenous components that reflect psychological activities such as attention, discrimination, and working memory. This study uses the amplitude and latency of N2 and P3 to indicate cognitive function. All medical technicians are professionally trained, mastering the test procedure and simulating it in detail to standardize instructions, conditions, and waveform extraction. These instruments possess acceptable reliability and validity. To ensure consistency in data collection, the questionnaire will be administered in Chinese following standardized translation procedures. All questionnaires will be administered face-to-face in an interview format among all participants to ensure data completeness and accuracy. Data collection forms may be obtained by sending a reasonable request via email to the principal investigator. ERP data processing The ERP data processing workflow comprises five steps: (1) preprocessing—apply a low-pass filter (cutoff frequency 30–70 Hz) to remove high-frequency noise and a high-pass filter (cutoff frequency 0.1–0.5 Hz) to eliminate low-frequency drift, thereby enhancing signal quality; (2) artifact removal—employ independent component analysis (ICA) to decompose EEG signals, identifying and eliminating components related to electrooculography (EOG) and electromyography (EMG) to obtain relatively pure signals; (3) baseline correction—correct the entire recording period using the average pre-stimulus baseline EEG signal as the zero reference to eliminate baseline drift; (4) average superposition—superimpose and average EEG signals corresponding to identical stimuli dozens to hundreds of times, canceling out stimulus-independent random brain activity to highlight ERP components; (5) component analysis—within the typical P300 time window (300–600 ms), the baseline-to-peak method measures latency (stimulus onset to peak onset) and amplitude (amplitude difference from baseline to peak). The P300 component is defined as the largest positive peak occurring between 300 and 600 ms after stimulus onset. To ensure measurement consistency, all data were independently analyzed by two trained technicians, and the average values were taken. Safety assessments The potential adverse events of iTBS treatment are assessed using the TMS treatment adverse reactions record form. The most common adverse effect is the transient head or scalp discomfort in and around the treatment site which may affect adjacent areas of the face including the area around the ipsilateral eyes, ears, nose, and chin; muscle twitching in these areas may occur during stimulation; headache is also a common adverse effect but it is usually mild and resolves with an increasing number of treatments. A rare adverse effect is the risk of inducing mania or hypomania; the most severe adverse effect is the induction of seizures, which occurred in less than 0.1% of patients. Before the subjects are formally enrolled in the project, all medical staff will be informed about the clinical manifestations of seizures and related treatment procedures. An emergency seizure rescue team will be established in advance. Adverse events that met the criteria for serious adverse events (SAEs) between the subject’s participation in the study and discharge were reported to the ethics committee as SAEs. Patients who discontinued treatment due to adverse events had their circumstances and data leading to the discontinuation recorded. SAEs in this study referred to any adverse medical events that the researchers believed were causally related. Ancillary and post-trial care This study plan provides an emergency response protocol for patients experiencing serious adverse events. Patients exhibiting adverse reactions will receive routine care as directed by medical professionals. Furthermore, should any related injuries occur during the study period, Zhongshan Third People’s Hospital will provide free treatment to participants and offer compensation in accordance with relevant laws and regulations. Statistical methods All data will be analyzed according to the intention-to-treat principle to preserve the actual status of the intervention as much as possible. Baseline data for each group (demographic information and baseline scale scores) will be tabulated. Quantitative data analysis will employ Student’s t -tests and analysis of variance (ANOVA); qualitative data and ordinal categorical variables will be analyzed using chi-square tests and Fisher’s exact tests. Data collected at different time points will be analyzed using repeated measures covariance analysis for clinical scale scores and behavioral data to investigate interactions between pre- and post-treatment periods and between different treatment protocols. Factors included: multiple measurements as within-subjects factors, real vs. sham stimulation as between-subjects factors, with gender, age, education level, and body mass index (BMI) as covariates. Post hoc analyses will employ paired t -tests. Differences in scale scores and behavioral data before and after treatment between the two treatment groups will be analyzed using two-sample t -tests and chi-square tests, respectively. Response rates and remission rates for both treatment groups will be calculated using chi-square tests. All missing data in this study will be handled using multiple imputation methods [ 41 ]. All tests are two-tailed, with a significance level set at P ≤ 0.05. Survival analysis: The product-moment method was used to evaluate response and remission rates and compare differences between treatment regimens. Interim analyses After careful consideration, this study will not conduct a formal interim analysis due to its short intervention period (10 days) and limited sample size. However, participant safety is ensured through quarterly reviews by the Master’s Committee and a 24-h reporting mechanism for serious adverse events. Should any unexpected safety signals emerge during the study, the intervention will be immediately halted, the emergency protocol activated, and an urgent meeting of the Master’s Committee convened. If necessary, the Ethics Committee will be consulted to review protocol amendments or early termination. All analyses will be conducted after data collection is completed. Data monitoring and quality control Personal and clinical information will be collected directly from participants during in-person assessments. It will be anonymously recorded on case report forms (CRFs) using unique study identification codes instead of personal names. Collected data will be accurately, completely, and promptly entered into Excel spreadsheets. Two researchers will independently enter the data to verify the completeness and accuracy of both paper records and electronic entries. Identifiable information (including consent forms and contact details) will be stored separately from research data in locked cabinets and password-protected electronic devices, accessible only to authorized research team members. The final dataset will be protected and stored in accordance with institutional data management policies. Confidentiality will be maintained throughout the study and beyond, adhering to institutional ethical guidelines. All trial datasets will be continuously shared with the master’s thesis supervisor (corresponding author). Plans to communicate trial results to participants, healthcare professionals, the public, and other relevant groups The findings of this study will be reported through three channels: publication as peer-reviewed articles in domestic and international journals specializing in psychiatry or neuromodulation; updating trial status and summarizing results on the China Clinical Trials Registry Platform and ClinicalTrials.gov; and presenting oral reports at relevant domestic and international academic conferences to share research discoveries with peers. Composition of the coordinating center and trial steering committee This study forms part of the principal investigator’s master’s thesis. The trial oversight was conducted by a four-member master’s committee comprising experts in psychiatry, clinical psychology, neuroimaging, and statistics. This committee was responsible for overseeing the trial’s overall implementation, providing academic, methodological, and operational guidance, and regularly reviewing research progress. All major decisions concerning the trial required unanimous approval from all committee members before implementation. The research protocol was also drafted under the committee’s supervision. Composition of the Data Monitoring Committee, its role and reporting structure This study has not established an independent Data Monitoring Committee. The Master’s Thesis Advisory Committee will assume ongoing oversight responsibilities, conducting regular assessments of trial implementation and subject safety. This committee is responsible for reviewing research progress, discussing issues related to data quality or subject safety, and providing recommendations for improvement to the Principal Investigator. Frequency and plans for auditing trial conduct The Master’s Committee shall convene at least once every 3 months to review trial progress, evaluate protocol implementation, and discuss operational or methodological issues identified during the research process. Any problems identified during the review must be documented in detail and addressed promptly. Plans for communicating important protocol amendments to relevant parties Any major protocol amendments involving research design, inclusion criteria, intervention protocols, outcome measures, or statistical strategies must be submitted to the Institutional Review Board for approval before implementation. Before this, draft amendments will be submitted to the Master Committee meeting for review. Approved amendments will be simultaneously updated on the China Clinical Trial Registry and incorporated into the trial documentation. If amendments involve treatment changes, the investigator must obtain renewed informed consent and notify participants. All protocol deviations must be documented using the deviation report form. Patient public involvement This study did not involve any public or patient involvement in the design of the research protocol. Discussion This study is a double-blind, randomized, sham-stimulation-controlled clinical trial focusing on assessing the therapeutic effect of iTBS on adolescent depression during the acute phase. Given the high incidence and therapeutic complexity of adolescent depression, this research considers iTBS as an optimized neuromodulatory strategy [ 2 ]. iTBS mimics the brain’s endogenous theta rhythms, enhancing cortical excitability in brief treatments lasting only 3 min each, and has demonstrated significant efficacy in treating adult depression [ 15 ]. Therefore, exploring its applicability and safety in developing adolescents is particularly important [ 42 , 43 ]. The DLPFC is a key node in the emotional regulation network, playing a significant role in modulating negative emotions. The imbalance between cortical excitation and inhibition is considered a key mechanism of depression [ 44 , 45 ]. ERP, as an objective tool for assessing neuroplasticity, provides detailed information about the brain’s response to specific stimuli, thus allowing for the objective detection of neural changes induced by iTBS treatment and revealing how iTBS modulates the prefrontal and reward circuits [ 46 ]. Additionally, studies have shown that during late adolescence and early adulthood, the structure and function of the DLPFC undergo age-related functional changes, making this population more adaptable and reorganizable in terms of brain structure and function when undergoing iTBS treatment, potentially leading to superior therapeutic outcomes [ 47 , 48 ]. Therefore, investigating the clinical efficacy of iTBS for adolescent depression is crucial for elucidating the antidepressant mechanisms of iTBS and identifying factors that influence treatment outcomes, offering an innovative therapeutic strategy for adolescents with depression. Moreover, as a non-invasive treatment method, iTBS offers a low-risk therapeutic option for adolescents due to its short treatment duration and minimal side effects [ 22 ]. If our iTBS protocol demonstrates superiority over sham stimulation, it could be rapidly integrated into clinical practice using existing equipment and with minimal modifications to clinic schedules. This could serve as an important foundation, paving the way for subsequent studies with larger sample sizes, more TMS treatment sessions, and potentially different TMS protocols. Trial status This study began recruiting participants in September 2024 and is expected to complete recruitment by March 2026. So far, 45 participants have been recruited and have taken part in the trial. The current version of the protocol is V1.1. Supplementary Information 13063_2026_9705_MOESM1_ESM.docx (35.5KB, docx) Supplementary Material 1: SPIRIT checklist. 13063_2026_9705_MOESM2_ESM.zip (66.7KB, zip) Supplementary Material 2: Informed Consent Form. Acknowledgements We sincerely thank the adolescents who enrolled and their parents for their support and cooperation. We would also like to express our gratitude to the nurses in our clinical wards. Abbreviations iTBS Intermittent theta burst stimulation rTMS Repetitive transcranial magnetic stimulation TBS Theta burst stimulation cTBS Continuous theta burst stimulation SCWT Stroop Word-Color Interference Test WCST Wisconsin Card Sorting Test ERP Event-related potentials HAMD-24 24-Hamilton Depression Scale ICD-10 International Classification of Diseases, 10th Revision CRF Case report form AMT Active motor threshold DLPFC Dorsolateral prefrontal cortex HAMA Hamilton Anxiety Rating scale BSI Beck Scale for Suicide Ideation OSI Ottawa self-injury inventory ATHF Antidepressant Treatment History Form TASS Transcranial Magnetic Stimulation Adult Safety Screen MINI Mini-International Neuropsychiatric Interview MRI Brain magnetic resonance imaging EEG Electroencephalography Authors’ contributions All authors were involved in the study design. The study was conceived and designed by Weiyu Cai and Jianzhao Wen. Qian Ye and Yiling Yang drafted the protocol, while Yutao Lan reviewed and revised the manuscript. All authors read and approved the final manuscript. Funding This study was funded by the Guangdong Provincial Medical Research Fund Project (Grant Number: A2024452). The funder had no role in the data collection, analysis, and interpretation, or in writing the manuscript. Data availability All research data will be stored in the Child and Adolescent Psychology Department of the Third People’s Hospital of Zhongshan City. The final dataset will be made available after publication of the study outcomes and upon reasonable request to the corresponding author/principal investigator. Declarations Ethics approval and consent to participate The Ethics Committee of the Third People’s Hospital of Zhongshan City has approved this study, with the registration number SSYLL-KY-20240903, and it is registered with the Chinese Clinical Trial Registry (ChiCTR2500101152). 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