Abstract
Background
Depression is extremely common among adolescents and can significantly increase the risk of suicide when severe. High-dose intermittent theta burst stimulation (iTBS) is a secure and efficacious physical treatment. However, clinical evidence in adolescents remains limited. This research is designed to assess the therapeutic impacts of high-dose iTBS on depressive symptoms, anxiety symptoms, and suicidal ideation in adolescents suffering from acute depression, along with the factors linked to treatment response.
Methods
A total of 61 patients were randomly assigned to either the high-dose iTBS group or the sham stimulation group. All participants received 10 daily sessions of high dose iTBS stimulation over a two-week period, targeting the left dorsolateral prefrontal cortex (DLPFC). Outcome measures assessed at baseline, post-intervention, and 1-month follow-up included 24-item Hamilton Depression Rating Scale (HAMD-24) scores, Beck Scale for Suicide Ideation - Chinese Version (BSI-CV), and Hamilton Anxiety Rating Scale (HAMA). Clinical factors influencing iTBS efficacy were further analyzed.
Result
At the end of the 10-day intervention, the high-dose iTBS group exhibited significantly lower HAMD-24 (p = 0.008, Cohen`s d = 0.71 [95%CI: 0.188–1.224]) and BSI-CV (p = 0.011, Cohen`s d = 0.67[95%CI: 0.154–1.186]) scores compared with the sham group, and this advantage persisted at the 1-month follow-up (Week 6) (HAMD-24: Cohen`s d = 0.96[ 95%CI: 0.43–1.49]; BSI-CV: Cohen`s d = 0.76[95%CI: 0.24–1.28]). In contrast, between-group differences in HAMA scores were non-significant both post-intervention (Week 2) and at the 1-month follow-up (Week 6) (p > 0.05). Moreover, poorer family functioning within the high-dose iTBS cohort was associated with diminished therapeutic benefit (p < 0.05).
Conclusion
Current research indicates that a 10-day course of high-dose iTBS is effective in alleviating depressive symptoms and suicidal ideation in adolescents with depression, and that the therapeutic effects persist for up to one month after the end of treatment. We also found that high-dose iTBS was less effective in patients with poor baseline family functioning.
Trial registration
Chinese clinical trial Registry (ChiCTR2500101152), trial registration date: April 21, 2025(retrospectively registered).
Keywords: Adolescense, Depression, Intermittent theta burst stimulation (iTBS), Suicidal ideation
Introduction
Major Depressive Disorder (MDD) is a common and severe chronic mental illness among adolescents, with a lifetime prevalence that can reach up to 11% [1]. Patients typically exhibit persistent symptoms, including low mood, cognitive slowing, and reduced motivation, as well as potential somatic manifestations. In severe cases, self-harm and suicidal behaviors may emerge during acute phases, potentially leading to long-term impacts on adolescents’ academic performance, daily living, and social functioning [2, 3]. Current treatments for adolescent depression encompass a range of approaches, with medication and psychotherapy being the most commonly studied and utilized. Pharmacological treatments face issues such as slow onset of action, low response rates, and side effects [4, 5], while psychotherapy is constrained by its lengthy treatment duration and inability to provide rapid symptom relief [6]. Although electroconvulsive therapy (ECT) is considered the most effective treatment for depression, its application is constrained by significant side effects and limitations imposed by geographic and legal factors [7]. Consequently, the search for treatments that are safe, effective, rapidly symptom-relieving, and enhance patient compliance and quality of life has become a critical issue in clinical research.
Transcranial magnetic stimulation (TMS) is a physical therapy technique characterised by its high safety profile, rapid onset of action and minimal side effects [8]. This therapy involves the application of high-intensity, short-duration, focused magnetic pulses to the DLPFC, thereby modulating the depolarisation of neurons in the cortical regions responsible for cognition and emotion. The US Food and Drug Administration (FDA) has recently approved repetitive Transcranial Magnetic Stimulation (rTMS) for the treatment of depression in adolescents [9]. Cao et al. conducted a meta-analysis of 18 studies investigating adolescents; the results showed that, compared with sham stimulation, rTMS combined with antidepressants enhanced the efficacy of the antidepressants, and safety and tolerability were comparable between the two groups [10].
However, some adolescents with depression still show an inadequate response to treatment or discontinue treatment due to its lengthy duration [11]. In view of the limitations of these treatments, an increasing number of studies are focusing on identifying alternative or adjunctive interventions that offer greater efficacy, enhanced safety and improved tolerability. Intermittent theta burst stimulation (iTBS), a novel form of TMS, mimics the brain’s endogenous theta rhythms and can effectively adjust neural activity and affect emotion-related neural circuits within a short period of time [12–14]. The FDA has now approved iTBS for the treatment of treatment-resistant depression in adults; its efficacy is comparable to that of conventional rTMS, whilst the treatment course is shorter [15].
In recent years, iTBS has gradually been applied in the treatment of MDD in adolescents. A study by Qin et al. found that iTBS can effectively alleviate depressive symptoms and non-suicidal self-injury (NSSI) in adolescents with MDD in the acute phase [16]. A study by Zhao et al. also indicated that an iTBS regimen comprising 1,800 pulses per day over a 10-day period significantly reduced suicidal ideation and depressive symptoms in adolescent patients [17]. However, owing to the overall scarcity of high-quality, reproducible data, the efficacy of iTBS in alleviating symptoms of depression and anxiety, suicidal ideation and neurocognitive deficits is not yet sufficient to establish clinical significance, and most studies have not systematically reported adverse events [18]. Furthermore, the findings of existing studies remain inconsistent. A recent randomized controlled trial reporting on the use of neuro-navigation-guided accelerated iTBS (twice daily) to treat MDD in adolescents and young adults (aged 12–25) found no significant difference in antidepressant efficacy between the twice-daily iTBS group, the once-daily iTBS group, and the sham stimulation group [19]. This negative result has raised questions about the optimal approach to using iTBS in adolescents. For example, the 12–25 age range encompasses different stages of neurodevelopment, and responses to neuromodulation may vary; furthermore, heterogeneity in patients’ psychosocial circumstances prior to treatment may also influence clinical responses to iTBS. In this context, the following methodological refinements were incorporated into the design of this study.
The age range will be narrowed (14–18 years) to focus on the more homogeneous adolescent stage, during which the prefrontal cortex is undergoing active remodelling and may exhibit enhanced responsiveness to neuromodulation; Secondly, given that an insufficient stimulus dose may be one of the factors contributing to differences in efficacy, this study adopts the protocol proposed by Zhao et al., namely treatment parameters of 1,800 pulses per session, once daily, for 10 consecutive days; Finally, exploratory analyses will be conducted to examine whether baseline family functioning and life events can predict treatment response, thereby investigating whether the efficacy of iTBS is moderated by psychosocial contextual factors. Adolescents are at a crucial stage of development, and their mental health is closely linked to family dynamics, parenting styles and life events; for many patients, depressive symptoms often stem from family disputes and negative life events [20, 21]. Consequently, this study aims to evaluate the effects of accelerated iTBS on depressive symptoms, anxiety symptoms and suicidal ideation in adolescents with acute depressive disorder, and to explore the predictors associated with its therapeutic efficacy, with a view to providing a solid foundation for future personalised clinical treatment.
Methods
study design
This study enrolled inpatients who visited the Department of Child and Adolescent Psychiatry at Zhongshan Third People’s Hospital between September 2024 and September 2025. The research was approved by the Medical Ethics Committee of the Third People’s Hospital of Zhongshan City (SSYLL-KY-20240903) and strictly adhered to the principles of the Declaration of Helsinki. Every participant along with their family members signed consent forms acknowledging their understanding of the study. Additionally, the trial was registered with the China Clinical Trial Registry (ChiCTR2500101152).
Participants
The patients who were enrolled had to meet the following criteria: (1) meet the diagnostic criteria for the depressive episode (F32.1, F32.2) in the International Classification of Diseases, 10th Revision (ICD-10); (2) aged 14–18 years, 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 BSI-CV; (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.
Patients who meet the following criteria will be excluded: (1) A history of diseases affecting the central nervous system or severe physical illnesses; (2) Previous epilepsy or a familial background of epilepsy; (3) A history of abuse or dependence on psychoactive substances; (4) Absolute contraindications for rTMS, that is, metal implants in the skull; (5) Received rTMS, ECT, or other electrical or magnetic stimulation treatments within the past month.
The withdrawal criteria were as follows: (1) The subject forgoes informed consent; (2) Individual participants experience the occurrence of intolerable and/or unexpected undesirable side effects during the therapy with iTBS.
Randomization and blinding
A nurse who was not involved in the study was responsible for generating the random number table using SPSS 26.0. The generated coded numbers were placed in an opaque box and stored in the physical therapy room. Eligible patients were randomly assigned in a 1:1 ratio to either the high-dose iTBS group or the sham group. Although this study employed a single-blind design, to further minimize the potential impact of subjective bias on the findings, not only were patients unaware of their specific group assignments, but the scale evaluators and data analysts were also completely unaware of the grouping details. However, the researchers (including doctors, nurses, and therapists) were aware of the group assignments.
Basic medical treatment
All enrolled patients received drug treatment; the drug selected was a serotonin reuptake inhibitor (sertraline), manufactured by Pfizer Inc., in 50 mg tablets. The dosage was 25 mg per day for the first 1–3 days, and 50 mg daily from days 4 to 7. Provided there were no adverse reactions, the dose was increased to 100 mg daily from the second week onwards, with the dosage range adjustable between 100 and 150 mg daily. After two weeks, the medication and dosage were maintained as consistently as possible.
Intervention
Mag TD (Wuhan Yirui De Medical Equipment New Technology Co., Ltd., China) was used for performing iTBS stimulation. Before the intervention, all subjects underwent a psychiatric evaluation to ensure their suitability. Additionally, all enrolled patients underwent motor threshold testing prior to treatment to determine the optimal stimulation intensity. Throughout the intervention period, procedures were conducted by qualified therapists, and any adverse reactions experienced by the subjects were documented. ①Active Motor Threshold (AMT): Initially, the patient was guided into a slightly relaxed state. The center of the figure-eight coil was positioned over the left motor cortex area. Then, pulse stimulation was applied to elicit a motor response in the right finger. The least single-pulse stimulation intensity able to evoke motor evoked potentials with an amplitude surpassing 200 µV in the right abductor pollicis brevis muscle during at least 5 out of 10 pulse stimulations was documented. This intensity was designated as the AMT value. ②Stimulation Site: The treatment site over the left DLPFC was localized using the modified Beam F3 scalp heuristic method. The high-dose iTBS group received triplets of 50-Hz bursts repeated at 5 Hz, with a 2-second on and 8-second off pattern. Each high-dose iTBS treatment session was administered at 80% of the AMT intensity, comprising a total of 1,800 pulses. The sham stimulation group followed the internationally accepted sham stimulation protocol, with the coil rotated to a 90° angle perpendicular to the scalp; its appearance, frequency and duration were identical to those of the active stimulation group [22]. As the magnetic field was parallel to the skull, the magnetic flux was unable to penetrate the scalp and induce cortical currents, resulting in ineffective stimulation. Finally, to ensure each patient’s treatment rights and clinical benefits, patients in the control group continued to receive conventional rTMS treatment for no less than two weeks following the conclusion of the study.
Clinical assessments
The primary outcome measure was the HAMD-24 [23]. The secondary indices were also subjected to scale assessment at these temporal junctures, including the BSI-CV scale to evaluate the intensity of suicide risk and the HAMA scale to assess anxiety symptoms [24]. In addition, at the baseline time point, demographic information and several scale were assessed and collected, including the Adolescent Self-Rating Life Events Checklist (ASLEC) to evaluate life events in adolescents and the Family Assessment Device (FAD) to assess family functioning [25].
Safety and adverse events
Adverse reactions occurring during treatment were closely monitored and documented. Common adverse reactions associated with iTBS included headache and dizziness, while other adverse reactions included headache, nausea, and chest tightness. Serious adverse events (SAEs) included seizures [26, 27].
Sample size calculation
G*Power 3.1 was used to estimate the sample size for testing the difference in HAMD-24 total scores between the two groups. An effect size of 0.25, a power of 80%, and a two-tailed α of 0.05 were employed. A repeated-measures ANOVA with an F test (including between-group factors) was selected, and a repeated-measures correlation coefficient of 0.5 was assumed. The results indicated that at least 56 participants needed to be included. Assuming a dropout rate of 10%, the plan was to recruit 62 participants.
Statistical analysis
All data in this article were processed with SPSS 26. Normality was appraised by means of the Shapiro-Wilk test, whereas sphericity and homogeneity of variance were scrutinized by way of Mauchly’s and Levene’s tests, respectively. Normality was assessed using the Shapiro-Wilk test; data were considered normally distributed if P ≥ 0.05 and reported as mean ± standard deviation; data were considered non-normally distributed if P < 0.05 and reported as median (interquartile range) [M (IQR)]. Discrepancies among groups regarding Demographic and clinical factors were scrutinized employing t-tests, nonparametric tests, and chi-square tests. Incomplete data were dealt with by means of the Intention-to-treat approach. For missing data, the Last Observation Carried Forward method will be applied, whereby the last measured value will be carried forward to subsequent missing time points. Repeated-measures variational analysis was utilized to evaluate changes in HAMD-24 and BSI-CV scores across three time points: Baseline (Week 0), Post-treatment (Week 2), and Month 1 follow-up (Week 6), as well as between the two groups. Generalized estimating equations were employed to evaluate changes in HAMA scores across the three time points and between the two groups. The effect size for each factor or interaction was assessed using the partial eta-squared statistic (η²), and a Bonferroni adjustment was utilized to account for multiple testing. Additionally, to assess whether adolescents’ life events and family functioning were associated with the reduction rate of depression scores after a 2-week intervention, researchers analyzed relevant factors using linear regression models, controlling for age, gender, and educational level as covariates. The significance level is defined as 0.05.
Result
Participants
Between September 2024 and September 2025, a total of 105 patients were screened. Of these, 20 patients did not meet the inclusion criteria, 16 patients declined to participate because they had opted for conventional rTMS treatment, and 8 patients were excluded because they had been transferred to other hospitals. Consequently, a total of 61 patients ultimately received treatment in this study. Among them, one 15-year-old female in the high-dose iTBS group (baseline HAMD-24 = 28) had her treatment terminated early due to severe suicidal behaviour during follow-up and was subsequently transferred to a secure ward for standardised treatment; two patients in the sham stimulation group discontinued treatment early: one 16-year-old female (baseline HAMD-24 = 31) was transferred to a secure ward due to severe non-suicidal self-harm behaviour, and another 14-year-old female patient (baseline HAMD-24 = 33) chose to discharge herself voluntarily due to family circumstances. All three patients were assessed at the conclusion of their final treatment session; the HAMD-24 score for the iTBS group had decreased to 25 points, whilst the scores for the two patients in the sham group had decreased to 29 and 28 points respectively (Fig. 1).
Fig. 1.
Consort flow diagram
Baseline demographic and clinical characteristics
No statistically significant differences were observed between the two groups during the baseline period (Table 1).
Table 1.
Comparing baseline data of two patient groups
| Demographic variables | high-dose iTBS group (n = 31) |
Sham group (n = 30) |
t/χ2/Z | P |
|---|---|---|---|---|
| Age(years) | 15.48 ± 1.26 | 15.90 ± 1.30 | -1.271 | 0.209a |
| BMI(kg/m2) | 20.51 ± 3.34 | 19.36 ± 1.50 | 1.750 | 0.087a |
| Gender(N,%) | ||||
| Male | 5(16.1) | 6(20.0) | 0.155 | 0.694b |
| Female | 26(83.9) | 24(80.0) | ||
| Handedness (N,%) | ||||
| Right | 31(100.0) | 30(100.0) | ||
| Left | 0(0.0) | 0(0.0) | ||
| Education(N,%) | ||||
| Primary school | 0(0.0) | 0(0.0) | 0.403 | 0.525b |
| Junior high school | 22(71.0) | 19(63.3) | ||
|
High school or secondary College degree or higher |
9(29.0) | 11(36.7) | ||
| Place of household registration(N,%) | ||||
| countryside | 15(48.4) | 15(50.0) | 0.016 | 0.900b |
| town | 16(51.6) | 15(50.0) | ||
| Family history of mental illness(N,%) | 4(12.9) | 2(6.7) | 0.150 | 0.698b |
| No. of subjects with adverse events(N,%) | 4(12.90) | 4(13.33) | 0.452 | 0.178b |
| ASLEC scale | ||||
| Total Score | 84.10 ± 14.45 | 78.40 ± 12.72 | 1.632 | 0.108a |
| Interpersonal relationship | 19.84 ± 4.28 | 18.60 ± 4.26 | 1.132 | 0.262a |
| Study pressure | 19.19 ± 4.85 | 17.80 ± 3.88 | 1.237 | 0.221a |
| Punishment | 19.23 ± 5.36 | 17.63 ± 5.42 | 1.154 | 0.253a |
| Losing | 6.39 ± 4.19 | 7.00 ± 4.18 | -0.572 | 0.570a |
| Health adaptation | 9.68 ± 4.21 | 8.03 ± 4.12 | 1.541 | 0.129a |
| Others | 9.74 ± 2.71 | 9.93 ± 2.35 | -0.295 | 0.769a |
| FAD scale | ||||
| Problem solving | 2.10 ± 0.63 | 2.26 ± 0.36 | -1.245 | 0.219a |
| Communication | 2.21 ± 0.46 | 2.21 ± 0.56 | -0.006 | 0.995a |
| Role | 2.17 ± 0.42 | 2.36 ± 0.48 | -1.638 | 0.107a |
| Emotional response | 2.31 ± 0.75 | 2.26 ± 0.55 | 0.279 | 0.781a |
| Emotional Involvement | 2.26 ± 0.64 | 2.39 ± 0.44 | -0.909 | 0.367a |
| Behavioral control | 2.20 ± 0.55 | 2.37 ± 0.33 | -1.416 | 0.163a |
| Overall function | 2.30 ± 0.73 | 2.23 ± 0.55 | 0.445 | 0.658a |
a, t value; b, χ2 value; BMI, Body Mass Index; iTBS, intermittent theta burst stimulation; FAD, Family Assessment Device; ASLEC, adolescent self-rating life events checklist
Scale results
Following the treatment, the decrease in HAMD-24 scores was more pronounced in the high-dose iTBS group compared to the sham group (t = 4.07, p = 0.008). The high-dose iTBS treatment had a statistically significant effect on the reduction of HAMD-24 scores (t = 4.475, p < 0.001) and the rate of reduction in HAMD-24 scores (t = 5.303, p < 0.001) between the two groups. There were also significant differences in the response rates between the two groups at the end of the intervention (week 2) (P = 0.022) and four weeks after the end of the intervention (week 6) (P = 0.011). Additionally, it had a significant statistical effect on the decrease of BSI-CV scores (t = 2.666, p = 0.010) between the groups. However, the iTBS treatment did not have a significant effect on the reduction of HAMA scores between the two groups (t = -1.359, p = 0.174) (Table 2) (Table 3).
Table 2.
Compare the point deductions at each time point between the two patient groups
| HAMD-24 reduction | high-dose iTBS group (n = 31) |
Sham group (n = 30) |
t/z | p |
|---|---|---|---|---|
| 13.45 ± 4.00 | 9.47 ± 2.84 | 4.475 | <0.001 | |
| HAMD-24 reduction rates | 31.65 ± 7.61 | 22.30 ± 6.05 | 5.303 | <0.001 |
| BSI-CV reduction | 5.52 ± 1.79 | 4.27 ± 1.87 | 2.666 | 0.010 |
| HAMA reduction | 4.00(2.00, 6.00) | 3.00(2.00, 4.00) | -1.359 | 0.174 |
HAMD-24: 24-item Hamilton Depression Rating Scale; BSI-CV, Beck Scale for Suicide Ideation - Chinese Version; HAMA, Hamilton Anxiety Rating Scale
Table 3.
Comparison of HAMD-24 response rates between the two groups at the end of the intervention (week 2) and four weeks after the intervention (week 6)
| Timeline | Effectiveness of the intervention | high-dose iTBS group (n = 31) |
sham group (n = 30) |
χ2 | P |
|---|---|---|---|---|---|
| Week 2 | Significantly effective | 1(3.2%) | 0(0.0%) | 6.779 | 0.022 |
| Effective | 24(77.4%) | 15(50.0%) | |||
| ineffective | 6(19.4%) | 15(50.0%) | |||
| Week 6 | Significantly effective | 0(0.0%) | 0(0.0%) | 10.356 | 0.011 |
| Effective | 7(22.6%) | 0(0.0%) | |||
| ineffective | 24(77.4%) | 30(100.0%) |
Primary outcome
The results of the repeated measures Analysis of Variance (ANOVA) revealed a significant interaction effect between time (Week 0, Week 2, Week 6) and group (high-dose iTBS group and sham stimulation group) on HAMD-24 scores (F2,118=21.548, p < 0.001, η²=0.268). The main effect of time was significant (F2,118=379.561, p < 0.001, η²=0.865), and the group effect was also significant (F1,59=4.584, p = 0.036, η²=0.072). Prior to intervention, the mean HAMD-24 score was 42.45 in the high-dose iTBS group and 42.53 in the sham group, with a mean difference of 0.08 (Cohen’s d = 0.01 [95% CI: -0.49, 0.51]), which was not statistically significant (p = 0.963). After the intervention (Week 2), the mean HAMD-24 score in the high-dose iTBS group was 29.00, significantly lower than the sham group’s 33.07, with a mean difference of 4.07 (p = 0.008, Cohen’s d = 0.71 [95% CI: 0.19, 1.22]). At the 1-month follow-up (Week 6), the mean HAMD-24 score was 33.55 in the high-dose iTBS group and 38.87 in the sham group, with a mean difference of 5.32 (p < 0.001, Cohen’s d = 0.96 [95% CI: 0.43, 1.49]) (Table 4; Fig. 2A).
Table 4.
A comparative analysis was conducted between the high-dose iTBS group and the sham group for the HAMD-24 and BSI-CV total scores at each time point
| Outcome | high-dose iTBS group (n = 31) |
Sham group (n = 30) |
Mean difference | P | Cohen’s d (95%Cl) |
Group effect, F/η2/P |
Time effect, F/η2/P |
Group ⋅ time effect, F/η2/P |
|---|---|---|---|---|---|---|---|---|
| Primary result of HAMD-24 scores at every time point | ||||||||
| Week 0 | 42.45 ± 7.72 | 42.53 ± 5.74 | 0.08 | 0.963 | 0.01 (-0.49,0.51) | 4.584/0.072/0.036 | 379.561/0.865/<0.001 | 21.548/0.268/<0.001 |
| Week 2 | 29.00 ± 6.15 | 33.07 ± 5.28 | 4.07 | 0.008 | 0.71 (0.19,1.22) | |||
| Week 6 | 33.55 ± 5.67 | 38.87 ± 5.37 | 5.32 | <0.001 | 0.96 (0.43,1.49) | |||
| Secondary result of BSI-CV scores at every time point | ||||||||
| Week 0 | 27.23 ± 5.48 | 28.80 ± 4.45 | 1.57 | 0.224 | 0.32 (-0.19,0.82) | 5.349/0.083/0.024 | 138.328/0.701/<0.001 | 4.274/0.068/0.023 |
| Week 2 | 21.71 ± 4.80 | 24.53 ± 3.46 | 2.82 | 0.011 | 0.67 (0.15,1.19) | |||
| Week 6 | 23.74 ± 3.81 | 26.97 ± 4.62 | 3.23 | 0.004 | 0.76 (0.24,1.28) | |||
HAMD-24: 24-item Hamilton Depression Rating Scale; BSI-CV, Beck Scale for Suicide Ideation - Chinese Version
Fig. 2.
Between-group comparisons of depression, suicidal ideation, and anxiety scores over time in adolescents with depressive disorders. * indicates p < 0.05, ** indicates p < 0.01; ns indicates non-significant
Secondary outcome
For the BSI-CV scores, the group effect (F1,59=5.349, p = 0.024, η²=0.083), the time effect (F2,118=138.328, p = 0.015, η²=0.701), and the interaction effect between group and time (F2,118=4.274, p = 0.023,η²=0.068) were all statistically significant. Prior to intervention, the mean BSI-CV score was 27.23 in the high-dose iTBS group and 28.80 in the sham group, with a mean difference of 1.57 (Cohen’s d = 0.32 [95% CI: -0.19, 0.82]), which was not statistically significant (p = 0.224). After intervention, the mean BSI-CV score in the high-dose iTBS group was 21.71, significantly lower than the sham group’s 24.53, with a mean difference of 2.82 (p = 0.011, Cohen’s d = 0.67 [95% CI: 0.15, 1.19]). At the 1-month follow-up, the mean BSI-CV score was 23.74 in the high-dose iTBS group and 26.97 in the sham group, with a mean difference of 3.23 (p = 0.004, Cohen’s d = 0.76 [95% CI: 0.24, 1.28]) (Table 4; Fig. 2B).
For the secondary outcome measures, generalized estimating equations were applied in this study to analyze the repeated-measures data of the HAMA scale. The results revealed a significant effect of different time points on the HAMA scale (p < 0.001). In contrast, no significant statistical differences were detected in the primary effect of group (p = 0.826) or the interaction effect involving group and time point (p = 0.177). Additionally, the difference in HAMA scores between the two groups at baseline was not significant (p = 0.510). In the two follow-up visits, HAMA scores in both groups showed a trend of first decreasing and then increasing, but no significant between-group differences were observed (p < 0.05). These results indicate that iTBS treatment did not show a significant effect in alleviating patients’ anxiety symptoms. However, the significant time effect indicates that the combined effect of medication and placebo has a certain therapeutic effect in the short term, but the placebo effect does not persist after the treatment ends (Table 5; Fig. 2C).
Table 5.
A comparative analysis of HAMA scores at each time point for the two patient groups was conducted
| Outcome | high-dose iTBS group (n = 31) |
Sham group (n = 30) |
Group Wald χ2 P |
Time Wald χ2 P |
Group ⋅ time Wald χ2 P |
|||
|---|---|---|---|---|---|---|---|---|
| Secondary outcome of HAMA scores at each time point | ||||||||
| Week 0 | 32.00(25.00, 39.00) | 28.50(23.00, 39.00) | 0.048 | 0.826 | 93.081 | <0.001 | 3.468 | 0.177 |
| Week 2 | 26.00(22.00, 34.00) | 24.50(22.00, 35.00) | ||||||
| Week 6 | 25.00(23.00, 35.00) | 28.00(22.75, 38.00) | ||||||
HAMA, Hamilton Anxiety Rating Scal
Safety
During the study, the safety of high-dose iTBS treatment was confirmed, with no serious complications such as epilepsy observed. Nevertheless, some patients reported adverse reactions, the most common of which were dizziness, headache and tinnitus. In the high-dose iTBS group, there were two cases of dizziness and two cases of headache. In the sham stimulation group, two cases of dizziness and two cases of tinnitus were reported. There was no statistically significant difference in the incidence of adverse reactions between the two groups (χ² = 0.452, p = 0.178).
Relationship between clinical data
Table 6 summarises the relationship between changes in depression scores and influencing factors in the high-dose iTBS group. After the completion of treatment, changes in HAMD-24 scores were significantly correlated with family functioning (95%CI: -5.833 to -0.700, p = 0.017). A lack of information and emotional communication within the family (95%CI: -6.122 to -0.345, p = 0.031) and unclear role and responsibility distribution among family members (95%CI: -7.135 to -0.836, p = 0.017) were both significantly associated with smaller reductions in HAMD-24 scores. Furthermore, insufficient participation, interest, and engagement in family activities by family members (95%CI: -5.168 to -0.419, p = 0.025) was also significantly associated with less change in HAMD-24 scores. However, we found no significant association between ASLEC scores and changes in depression scores.
Table 6.
Correlation analysis of the 24-HAMD score reduction in the high-dose iTBS group
| Measures | B | 95% CI | P |
|---|---|---|---|
| ASLEC scale | |||
| ASLEC total scores | 0.657 | (-0.155, 1.469) | 0.104 |
| Interpersonal relationship | 0.154 | (-0.537, 0.845) | 0.637 |
| Study pressure | -1.239 | (-2.605, 0.128) | 0.072 |
| Punishment | -0.328 | (-2.605, 0.128) | 0.252 |
| Losing | -0.333 | (-1.096, 0.429) | 0.362 |
| Health adaptation | -0.518 | (-1.432, 0.396) | 0.242 |
| Others | -0.313 | (-1.392, 0.765) | 0.541 |
| FAD scale | |||
| Problem solving | -0.087 | (-2.352, 2.177) | 0.935 |
| Communication | -3.233 | (-6.122, -0.345) | 0.031 |
| Role | -3.986 | (-7.135, -0.836) | 0.017 |
| Emotional response | -1.201 | (-3.036, 0.634) | 0.181 |
| Emotional Involvement | -2.794 | (-5.168, -0.419) | 0.025 |
| Behavioral control | -1.452 | (-3.494, 0.590) | 0.149 |
| Overall function | -3.267 | (-5.833, -0.700) | 0.017 |
FAD, Family Assessment Device; ASLEC, adolescent self-rating life events checklist; 95%CI: confidence interval of 95%
HAMD-24 score reduction classification: Significantly effective: score reduction of 50%–70%; Effective: score reduction of 25%–50%; Ineffective: score reduction < 25%.
Discussion
This study aims to evaluate the effects of the intervention on depressive symptoms, anxiety symptoms, and suicidal ideation in adolescents with depressive disorders during the acute phase, as well as the factors associated with its therapeutic efficacy. As expected, significant differences emerged in depression symptom and suicidal ideation scores between the two groups at the conclusion of high dose iTBS treatment and at week 4 post-treatment. Contrary to our expectations, no significant between-group differences in HAMA scores were observed at any assessment time point. Furthermore, this study found that family functioning was associated with the degree of improvement in depressive symptoms following high-dose iTBS treatment. Our findings indicate that the high dose iTBS treatment employed in this study is safe and well-tolerated for adolescents with depressive disorders. Although both the high-dose iTBS group and the sham stimulation group experienced common adverse reactions in adolescents with depressive disorders, no serious adverse events occurred in either group during the entire iTBS treatment period.
Our findings indicate that the antidepressant effects of iTBS observed in our study are comparable to those reported in most other studies. Previous systematic reviews and meta-analyses have shown that accelerated rTMS protocols using the iTBS mode demonstrate a higher clinical response rate in the treatment of depressive disorders than standard protocols or sham stimulation [28, 29]. Research by Liu et al., demonstrated that iTBS administered five times daily, with each session delivering 1,800 pulses, significantly alleviated depressive symptoms in patients [30]. Another study involving adolescents with depressive disorders and a history of suicide attempts showed that high-dose iTBS treatment (1,800 magnetic pulses) significantly improved patients depressive symptoms [31]. Nevertheless, Zhang et al., conducted iTBS treatment for 10 days under neuronavigation, with either 2 sessions per day (two 600-pulse sessions) or 1 session per day (one 600-pulse session), or sham stimulation, and found that neither of these treatment groups was superior to the sham stimulation group [19]. The analysis suggests that this might be related to insufficient pulse dosage of iTBS. Research indicates [29] that the higher the total pulse dosage of iTBS (targeting the left DLPFC), the greater the alleviation rate. Additionally, follow-up studies [15] have found that patients with depression treated with Stanford Neuromodulation Therapy exhibit a sustained effect in the short term. A follow-up of patients with depressive disorders four weeks after treatment showed that their depression scale scores remained improved compared to pre-treatment levels. This further illustrates that a treatment session with 1800 pulses can provide benefits to patients and maintain effects in the short term. Nevertheless, it should be noted that during the follow-up period of this study, the HAMD-24 score in the high-dose iTBS group rose from 29.00 at the end of treatment to 33.55. Although this value remained lower than that of the sham group, this upward trend indicates a partial relapse of symptoms, suggesting that the initial treatment effect was not fully maintained over time. Furthermore, data from the three participants who discontinued follow-up prematurely were retained in the final analysis. For their missing final follow-up data, the last-observation-carried-forward method was applied; this approach may overestimate the sustained efficacy of iTBS, thereby exaggerating between-group differences and limiting the robustness and interpretability of the results. Consequently, future studies should increase sample size and extend the follow-up period to more comprehensively assess treatment maintenance dynamics and predictors of relapse. Furthermore, given that iTBS, as a non-invasive brain stimulation technique, demonstrates good safety and tolerability, its potential application in preventing the relapse of depression should be further explored, thereby providing new intervention strategies for the long-term management of depressive disorders in adolescents.
This study utilised the BSI-CV scale to compare changes in suicidal ideation levels between the two groups of participants before and after the intervention. The data revealed that, following the 10-day intervention, post-intervention scores in the high-dose iTBS group had decreased significantly compared to both baseline scores and those of the sham stimulation group. These findings suggest that high-dose iTBS has a positive effect on alleviating suicidal ideation associated with depression in adolescents. However, the evidence base in this field regarding adolescent populations remains relatively limited. A previous randomised controlled trial indicated that an iTBS protocol targeting the left dorsolateral prefrontal cortex daily for two consecutive weeks can safely and effectively reduce suicidal ideation in adolescents with severe depression, with more pronounced clinical benefits observed in those with more severe baseline symptoms [31]. Sohn et al. [32]. further investigated the efficacy of iTBS combined with D-cycloserine in an adult population, finding that this combination was superior to iTBS combined with a placebo in reducing suicide scores and was associated with rapid relief of suicidal ideation; whereas the acute administration of D-cycloserine alone (without iTBS treatment) had no significant effect on latent suicide risk. Other studies have also confirmed that iTBS can effectively reduce the risk of suicidal ideation in adults with depression [33]. From a neurobiological perspective, it is hypothesised that iTBS may exert its beneficial effects on suicidal ideation by modulating abnormal activity in large-scale brain functional networks, such as the default mode network and the central executive network.
However, contrary to the study’s expectations, although the HAMA scores decreased over time compared to pre-treatment levels, there was no significant intergroup difference in HAMA scores between the two patient groups. We hypothesize that this phenomenon may be associated with an imbalance in prefrontal cortex activation in patients with depressive disorders [34, 35]. The DLPFC holds a significant function in emotional management and cognitive governance. The left DLPFC is involved in the processing of positive emotions and the downregulation of emotional responses. The right DLPFC correlates with negative emotions, emotional activation, and stress reactions [35]. iTBS, as a form of high-frequency stimulation, can enhance the excitability of the cortex in the left DLPFC when applied, thereby improving the processing of positive emotions and the ability to downregulate emotional responses [29]. But, this enhancement may not be sufficient to counteract the negative emotions and physiological stress responses associated with anxiety symptoms, especially in cases where anxiety symptoms are more severe. Anxiety symptoms often involve multiple brain regions, including the amygdala and the hypothalamic-pituitary-adrenal (HPA) axis, which play key roles in stress responses and emotional arousal [36, 37]. The connections of the right DLPFC with these areas may be more critical in modulating anxiety symptoms. Concurrently, Research by Diefenbach et al., has shown that low-frequency rTMS applied to the right DLPFC results in higher response and remission rates in the active treatment group compared to the sham treatment group [38]. Additionally, Dilkov and Bystritsky et al., conducted intense or subdued frequency rTMS on the left and right DLPFC, respectively [39, 40]. The findings indicated that intense frequency TMS applied to the right DLPFC showed enhanced clinical effectiveness.
Yet it must be cautiously noted that the above explanation is primarily based on theoretical speculation regarding neural mechanisms. In this study, baseline anxiety scores in both groups were at moderate to high levels; however, in the absence of evidence from randomised controlled trials directly comparing the effects of left- and right-sided DLPFC stimulation, the view that right-sided stimulation is superior remains speculative. Furthermore, there may be other important explanations for the negative results regarding anxiety symptoms: Firstly, the sample size in this study was limited (only 31 participants in the active intervention group), resulting in insufficient statistical power for anxiety outcomes and a risk of “Type II errors” (false negatives), meaning that iTBS may actually be effective for anxiety but the true effect was not detected due to the small sample size; secondly, all patients received concurrent treatment with sertraline, a drug that has a certain efficacy on anxiety symptoms in its own right, thereby masking the additive effect of iTBS. Consequently, future studies should directly compare the effects of left- and right-sided DLPFC targeting in larger samples, whilst fully accounting for statistical power and drug interactions, in order to clarify the true efficacy of iTBS on anxiety symptoms comorbid with adolescent depressive disorders.
In addition, we investigated factors that may influence treatment outcomes. Our study found a significant correlation between reductions in patients’ depression scores and family functioning scores, suggesting that poor family functioning may be associated with the efficacy of high-dose iTBS treatment. The underlying mechanism may be that the DLPFC is a key area influencing individual emotions, with the DLPFC on both sides of the brain involved in the generation and regulation of both positive and negative emotions [41, 42]. Patients with depression often exhibit dysfunction in the DLPFC on both sides. rTMS treatment can help to rebalance this by improving the function of the dorsolateral prefrontal cortex and thereby adjusting the patients’ depressive mood [43]. Adolescents are at a critical stage of cognitive development, and prolonged family dysfunction may affect their brain development and the formation of cognitive and behavioural patterns [43]. Particularly during treatment, persistent family issues [44], such as a lack of emotional support among family members [45, 46] and unclear parental responsibilities and obligations [47], may to varying degrees lead adolescents to develop internalised critical thinking, thereby affecting the effectiveness of treatment.
However, given the limited sample size in the high-dose iTBS group (n = 31) and the fact that family functioning was assessed only at baseline, it is difficult to determine the direction of the association described above; that is, it is impossible to distinguish whether poor family functioning undermined the treatment effect, or whether a poor treatment response led to a deterioration in family interactions over time. Consequently, this finding is exploratory in nature and requires further validation in independent studies with larger samples and longitudinal designs involving repeated assessments.
This study also has the following limitations: firstly, it is a retrospective registry study; secondly, it is a single-centre study with a limited sample size, which restricts the generalisability of the results, leading to insufficient statistical power for subgroup analyses, and no blinding integrity checks were performed for patients or assessors; thirdly, structured neuropsychological testing was not used to assess the potential impact of high-dose iTBS on cognitive function in adolescents, and the evidence regarding safety remains insufficient; Fourthly, some patients discontinued follow-up prematurely due to worsening symptoms, limiting the evaluation of long-term efficacy; fifthly, all patients were concurrently treated with antidepressants during the study, making it difficult to fully distinguish between the effects of iTBS and those of the medication. Therefore, future research should conduct multicentre, large-sample, prospective, double-blind, randomised controlled trials, systematically record medication dosages, and incorporate standardised cognitive outcome measures.
Conclusion
The findings of this study indicate that high-dose iTBS targeting the left DLPFC has a positive therapeutic effect on adolescents with depressive disorders, with particularly significant improvements in depressive symptoms and suicidal ideation; these therapeutic effects may persist for up to one month following the conclusion of treatment. Furthermore, the therapeutic efficacy of iTBS may be associated with family functioning. Consequently, future research should further investigate the factors influencing treatment outcomes to provide guidance for precision medicine in adolescents with depressive disorders; at the same time, given that iTBS, as a non-invasive brain stimulation technique, demonstrates good safety and tolerability, its potential role in preventing the recurrence of depression should also be explored in the future.
Acknowledgements
The author acknowledges support from the following funding agencies: the Guangdong Provincial Medical Science and Technology Research Fund Project, the Guangdong Provincial Department of Education’s Specialized Innovation Project for Regular Higher Education Institutions, and the Guangdong Pharmaceutical University Overseas Distinguished Faculty Program. We would also like to extend our gratitude to Director Lu of the Rehabilitation Department and the corresponding technicians; the nursing staff of the Child and Adolescent Psychiatry Department; and the guardians of the pediatric patients for their support and cooperation in this research.
Abbreviations
- MDD
Major Depressive Disorder
- iTBS
intermittent Theta Burst Stimulation
- HAMD-24
Hamilton Depression Rating Scale – 24 items
- HAMA
Hamilton Anxiety Rating Scale
- BSI-CV
Beck Scale for Suicide Ideation - Chinese Version
- rTMS
repetitive Transcranial Magnetic Stimulation
- DLPFC
Dorsolateral Prefrontal Cortex
- HPA
Hypothalamic–Pituitary–Adrenal
- FAD
Family Assessment Device
- ASLEC
Adolescent Self-Rating Life Events Checklist
- AMT
Active Motor Threshold
- ICD-10
International Classification of Diseases, 10th Revision
- NSSI
Non-Suicidal Self-injury
- ECT
Electroconvulsive Therapy
- SAEs
Serious Adverse Events
Author contributions
YY and QY conceived the study, participated in its conceptualization, methodology, visualization, project administration, and writing – original draft; QY also participated in investigation, data curation, visualization, and writing – original draft. ZP and WC were responsible for data curation and software; JW conducted formal analysis and software implementation; JZ participated in investigation, visualization, and writing – review & editing; YL participated in investigation, visualization, and writing – review & editing. All authors read and approved the final manuscript.
Funding
The financial backing for this study was provided by the Guangdong Provincial Medical Science and Technology Research Fund (No. A2024452、No.A2024629). It was also supported by the Guangdong Provincial Department of Education’s Innovation Project for Regular Higher Education Institutions (No.2023WTSCX0401) and the Guangdong Pharmaceutical University Overseas Distinguished Faculty Program (No. GDPUODS20250141).
Data availability
The datasets generated and/or analyzed during the current study are notpublicly available but are available from the corresponding author on reasonable request.
Declarations
Human ethics and consent to participate
This study was conducted in accordance with ethical principles and guidelines for research involving human subjects. Prior to participating in the study, all participants and their families signed informed consent forms after receiving a comprehensive explanation of the study’s objectives, procedures, potential risks and benefits, and their right to withdraw from the study at any time without penalty. The informed consent process was conducted in a clear and understandable manner, and participants and their families were given the opportunity to ask questions and seek clarification. All data were kept strictly confidential, and participants remained anonymous throughout the study. The study protocol was reviewed and approved by the Medical Ethics Committee of the Third People’s Hospital of Zhongshan City (SSYLL-KY-20240903) to ensure compliance with ethical standards and to safeguard the rights and welfare of the participants.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Yiling Yang and Qian Ye contributed equally to this work and are co-first authors.
Jie Zhang and Yutao Lan contributed equally to this work and are co-corresponding authors.
Contributor Information
Jie Zhang, Email: jiezhang01@cuhk.edu.cn.
Yutao Lan, Email: lanyutao@gdpu.edu.cn.
References
- 1.Thapar A, Collishaw S, Pine DS, Thapar AK. Depression in adolescence. Lancet Lond Engl. 2012;379(9820):1056–67. 10.1016/S0140-6736(11)60871-4. PMID: 22305766. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Benasi G, Fava GA, Guidi J. Prodromal symptoms in depression: a systematic review. Psychother Psychosom. 2021;90(6):365–72. 10.1159/000517953. PMID: 34350890. [DOI] [PubMed]
- 3.Lu W, Muñoz-Laboy M. Screening for depression and suicide risk in children and adolescents. J Pediatr. 2023;261:113320. 10.1016/j.jpeds.2022.12.022. PMID: 37741679. [DOI] [PubMed]
- 4.Glass RM. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: treatment for adolescents with depression study (TADS) randomized controlled trial. J Pediatr. 2005;146(1):145. 10.1016/j.jpeds.2004.10.032. PMID: 15644846. [DOI] [PubMed]
- 5.Bridge JA, Iyengar S, Salary CB, Barbe RP, Birmaher B, Pincus HA, et al. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials. JAMA. 2007;297(15):1683–96. 10.1001/jama.297.15.1683. PMID: 17440145. [DOI] [PubMed]
- 6.Hazell P. Updates in treatment of depression in children and adolescents. Curr Opin Psychiatry. 2021;34(6):593–9. 10.1097/YCO.0000000000000749. PMID: 34456305. [DOI] [PubMed]
- 7.Haq AU, Sitzmann AF, Goldman ML, Maixner DF, Mickey BJ. Response of depression to electroconvulsive therapy: a meta-analysis of clinical predictors. J Clin Psychiatry. 2015;76(10):1374–84. 10.4088/JCP.14r09528. PMID: 26528644. [DOI] [PubMed]
- 8.Rossi S, Hallett M, Rossini PM, Pascual-Leone A. Safety of TMS consensus group. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol Off J Int Fed Clin Neurophysiol. 2009;120(12):2008–39. 10.1016/j.clinph.2009.08.016. PMID: 19833552. [DOI] [PMC free article] [PubMed]
- 9.Srivastava AV, Nemeroff CB, O’Sullivan SJ. TMS in adolescent depression: A milestone FDA clearance. Mol Psychiatry. 2026. 10.1038/s41380-026-03455-0. PMID: 41667837. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Cao P, Li Y, An B, Ye L, Xu Z. Efficacy and safety of repetitive transcranial magnetic stimulation combined with antidepressants in children and adolescents with depression: a systematic review and meta-analysis. J Affect Disord. 2023 Sept 1;336:25–34. 10.1016/j.jad.2023.05.051. PMID: 37211054. [DOI] [PubMed]
- 11.Sigrist C, Vöckel J, MacMaster FP, Farzan F, Croarkin PE, Galletly C, et al. 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;31(10):1501–25. 10.1007/s00787-022-02021-7. PMID: 35751003. [DOI] [PMC free article] [PubMed]
- 12.Huang Y-Z, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC. Theta burst stimulation of the human motor cortex. Neuron. 2005;45(2):201–6. 10.1016/j.neuron.2004.12.033. PMID: 15664172. [DOI] [PubMed]
- 13.Ct L, Mh C, Ch J, Hh H, Lf C, Jc H, et al. Efficacy of prefrontal theta-burst stimulation in refractory depression: a randomized sham-controlled study. Brain J Neurol. 2014 July;137(Pt 7):2088–98. 10.1093/brain/awu109. PMID: 24817188. [DOI] [PubMed]
- 14.Lee C-W, Wu H-F, Chu M-C, Chung Y-J, Mao W-C, Li C-T, et al. Mechanism of intermittent theta-burst stimulation in synaptic pathology in the prefrontal cortex in an antidepressant-resistant depression rat model. Cereb Cortex N Y N 1991. 2021;31(1):575–90. 10.1093/cercor/bhaa244. PMID: 32901273. [DOI] [PubMed]
- 15.Cole EJ, Phillips AL, Bentzley BS, Stimpson KH, Nejad R, Barmak F et al. Stanford Neuromodulation Therapy (SNT): a double-blind randomized controlled trial. Am J Psychiatry. 2022;179(2):132–41. 10.1176/appi.ajp.2021.20101429 PMID: 34711062. [DOI] [PubMed]
- 16.Qin Y, Chen H, Liu F, Zou T, Jin K, Teng Z, et al. Intermittent theta burst stimulation for non-suicidal self-injury in adolescents with major depressive disorder: a randomized, sham-controlled trial. Mol Psychiatry. 2025. 10.1038/s41380-025-03183-x. PMID: 40883451. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Zhao Y, He Z, Luo W, Yu Y, Chen J, Cai X et al. Effect of intermittent theta burst stimulation on suicidal ideation and depressive symptoms in adolescent depression with suicide attempt: a randomized sham-controlled study. J Affect Disord. 2023;325:618–26. 10.1016/j.jad.2023.01.061. PMID: 36682694. [DOI] [PubMed]
- 18.Deng Y-Y, Shi Z-M, Tang Y-Y, Li Z, Cai D-B, Si Z-X et al. Intermittent theta burst stimulation for adolescent patients with major depressive disorder or bipolar depression: a systematic review. J Affect Disord. 2026;394(Pt A):120435. 10.1016/j.jad.2025.120435. PMID: 41101467. [DOI] [PubMed]
- 19.Zhang M, Li W, Ye Y, Hu Z, Zhou Y, Ning Y. Efficacy and safety of intermittent theta burst stimulation on adolescents and young adults with major depressive disorder: a randomized, double blinded, controlled trial. J Affect Disord. 2024;350:214–21. 10.1016/j.jad.2024.01.025 PMID: 38199406. [DOI] [PubMed]
- 20.Schwartz OS, Sheeber LB, Dudgeon P, Allen NB. Emotion socialization within the family environment and adolescent depression. Clin Psychol Rev. 2012;32(6):447–53. 10.1016/j.cpr.2012.05.002. PMID: 22717335. [DOI] [PubMed]
- 21.Stikkelbroek Y, Bodden DHM, Kleinjan M, Reijnders M, van Baar AL. Adolescent depression and negative life events, the mediating role of cognitive emotion regulation. PLOS One. 2016;11(8):e0161062. 10.1371/journal.pone.0161062. PMID: 27571274. [DOI] [PMC free article] [PubMed]
- 22.Pan F, Shen Z, Jiao J, Chen J, Li S, Lu J et al. Neuronavigation-guided rTMS for the treatment of depressive patients with suicidal ideation: a double-blind, randomized, sham-controlled trial. Clin Pharmacol Ther. 2020;108(4):826–32. 10.1002/cpt.1858 PMID: 32319673. [DOI] [PubMed]
- 23.Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol. 1967;6(4):278–96. 10.1111/j.2044-8260.1967.tb00530.x. PMID: 6080235. [DOI] [PubMed]
- 24.H M. The assessment of anxiety states by rating. Br J Med Psychol. 1959;32(1):50–5. 10.1111/j.2044-8341.1959.tb00467.x. PMID: 13638508. [DOI] [PubMed]
- 25.Mansfield AK, Keitner GI, Dealy J. The family assessment device: an update. Fam Process. 2015;54(1):82–93. 10.1111/famp.12080. PMID: 24920469. [DOI] [PubMed]
- 26.Elmaghraby R, Sun Q, Ozger C, Shekunov J, Romanowicz M, Croarkin PE. A systematic review of the safety and tolerability of theta burst stimulation in children and adolescents. Neuromodulation J Int Neuromodulation Soc. 2022 June;25(4):494–503. 10.1111/ner.13455. PMID: 35670061. [DOI] [PMC free article] [PubMed]
- 27.Wang W-L, Wang S-Y, Hung H-Y, Chen M-H, Juan C-H, Li C-T. Safety of transcranial magnetic stimulation in unipolar depression: a systematic review and meta-analysis of randomized-controlled trials. J Affect Disord. 2022;301:400–25. 10.1016/j.jad.2022.01.047. PMID: 35032510. [DOI] [PubMed]
- 28.Lefaucheur J-P, Colzi C, Hollander E, Pampaloni I, Van Ameringen M, Baeken C, et al. Comparison between accelerated and standard or sham rTMS in the treatment of depression: A systematic review. Neurosci Biobehav Rev. 2025 June;173:106140. 10.1016/j.neubiorev.2025.106140. PMID: 40252882. [DOI] [PubMed]
- 29.Kishi T, Ikuta T, Sakuma K, Hatano M, Matsuda Y, Wilkening J, et al. Theta burst stimulation for depression: a systematic review and network and pairwise meta-analysis. Mol Psychiatry. 2024;29(12):3893–9. 10.1038/s41380-024-02630-5. PMID: 38844532. [DOI] [PMC free article] [PubMed]
- 30.Liu X, Peng Z, Cheng F, Li G, Wang B, Hu C, et al. Efficacy and safety of accelerated intermittent theta-burst stimulation for adolescents with major depressive disorder: a randomized, double-blind, sham-controlled study. Biol Psychiatry. 2025 July 28;S0006-3223(25)01356-3. 10.1016/j.biopsych.2025.07.018. PMID: 40738417. [DOI] [PubMed]
- 31.Y Z ZH, Y WL et al. Y, J C, X C,. Effect of intermittent theta burst stimulation on suicidal ideation and depressive symptoms in adolescent depression with suicide attempt: a randomized sham-controlled study. J Affect Disord. 2023;325:618–26. 10.1016/j.jad.2023.01.061. PMID: 36682694. [DOI] [PubMed]
- 32.Sohn MN, Cole J, Bray SL, McGirr A. Intermittent theta-burst stimulation with adjunctive D-cycloserine rapidly resolves suicidal ideation and decreases implicit association with death/suicide. Psychol Med. 2025;55:e13. 10.1017/S0033291724003313. PMID: 39905763. [DOI] [PMC free article] [PubMed]
- 33.Zapf L, Kaster TS, Vila-Rodriguez F, Daskalakis ZJ, Downar J, Blumberger DM. The effect of once-daily vs. twice-daily intermittent theta burst stimulation on suicidal ideation in treatment-resistant depression. Eur Arch Psychiatry Clin Neurosci. 2025 Sept;275(6):1787–98. 10.1007/s00406-024-01929-2. PMID: 39545967. [DOI] [PubMed]
- 34.Fox MD, Liu H, Pascual-Leone A. Identification of reproducible individualized targets for treatment of depression with TMS based on intrinsic connectivity. Neuroimage. 2013;66:151–60. 10.1016/j.neuroimage.2012.10.082. PMID: 23142067. [DOI] [PMC free article] [PubMed]
- 35.Henriques JB, Davidson RJ. Left frontal hypoactivation in depression. J Abnorm Psychol. 1991;100(4):535–45. 10.1037//0021-843x.100.4.535 PMID: 1757667. [DOI] [PubMed]
- 36.Kenwood MM, Kalin NH, Barbas H. The prefrontal cortex, pathological anxiety, and anxiety disorders. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol. 2022;47(1):260–75. 10.1038/s41386-021-01109-z. PMID: 34400783. [DOI] [PMC free article] [PubMed]
- 37.Miller EK, Cohen JD. An integrative theory of prefrontal cortex function. Annu Rev Neurosci. 2001;24:167–202. 10.1146/annurev.neuro.24.1.167. PMID: 11283309. [DOI] [PubMed]
- 38.Diefenbach GJ, Bragdon LB, Zertuche L, Hyatt CJ, Hallion LS, Tolin DF, et al. Repetitive transcranial magnetic stimulation for generalised anxiety disorder: a pilot randomised, double-blind, sham-controlled trial. Br J Psychiatry J Ment Sci. 2016 Sept;209(3):222–8. 10.1192/bjp.bp.115.168203. PMID: 27198484. [DOI] [PubMed]
- 39.Dilkov D, Hawken ER, Kaludiev E, Milev R. Repetitive transcranial magnetic stimulation of the right dorsal lateral prefrontal cortex in the treatment of generalized anxiety disorder: a randomized, double-blind sham controlled clinical trial. Prog Neuropsychopharmacol Biol Psychiatry. 2017;78:61–5. 10.1016/j.pnpbp.2017.05.018. PMID: 28533148. [DOI] [PubMed]
- 40.Bystritsky A, Kerwin LE, Feusner JD. A preliminary study of fMRI-guided rTMS in the treatment of generalized anxiety disorder: 6-month follow-up. J Clin Psychiatry. 2009;70(3):431–2. 10.4088/JCP.08l04641 PMID: 19317960. [DOI] [PubMed]
- 41.Morawetz C, Bode S, Derntl B, Heekeren HR. The effect of strategies, goals and stimulus material on the neural mechanisms of emotion regulation: a meta-analysis of fMRI studies. Neurosci Biobehav Rev. 2017;72:111–28. 10.1016/j.neubiorev.2016.11.014. PMID: 27894828. [DOI] [PubMed]
- 42.Kohn N, Eickhoff SB, Scheller M, Laird AR, Fox PT, Habel U. Neural network of cognitive emotion regulation–an ALE meta-analysis and MACM analysis. Neuroimage. 2014;87:345–55. 10.1016/j.neuroimage.2013.11.001 PMID: 24220041. [DOI] [PMC free article] [PubMed]
- 43.Chen J-J, Zhao L-B, Liu Y-Y, Fan S-H, Xie P. Comparative efficacy and acceptability of electroconvulsive therapy versus repetitive transcranial magnetic stimulation for major depression: a systematic review and multiple-treatments meta-analysis. Behav Brain Res. 2017;320:30–6. 10.1016/j.bbr.2016.11.028. PMID: 27876667. [DOI] [PubMed]
- 44.Yang L, Zhao Q, Liu H, Zhu X, Wang K, Man J. Family functioning mediates the relationship between activities of daily living and poststroke depression. Nurs Res. 2021;70(1):51–7. 10.1097/NNR.0000000000000472. PMID: 32956257. [DOI] [PubMed]
- 45.Benoit A, Lacourse E, Claes M. Pubertal timing and depressive symptoms in late adolescence: the moderating role of individual, peer, and parental factors. Dev Psychopathol. 2013;25(2):455–71. 10.1017/S0954579412001174. PMID: 23627956. [DOI] [PubMed]
- 46.da Silva AHS, de Freitas LA, Shuhama R, Del-Ben CM, Vedana KGG, Martin IDS et al. Family environment and depressive episode are associated with relapse after first-episode psychosis. J Psychiatr Ment Health Nurs. 2021;28(6):1065–78. 10.1111/jpm.12735. PMID: 33544947. [DOI] [PubMed]
- 47.Bickham DS, Hswen Y, Rich M. Media use and depression: exposure, household rules, and symptoms among young adolescents in the USA. Int J Public Health. 2015;60(2):147–55. 10.1007/s00038-014-0647-6. PMID: 25586816. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets generated and/or analyzed during the current study are notpublicly available but are available from the corresponding author on reasonable request.