Zhi Li1†
Zhan-Ming Shi2†
Xin-Hu Yang3,4†
Zhi-Ang Su3,4†Wei Wei1
Zhen-Juan Qin1
Xian-Jun Lan1
Xin Wei1*
Wei Zheng3,4*- 1The Brain Hospital of Guangxi Zhuang Autonomous Region, Liuzhou, China
- 2Chongqing Jiangbei Mental Health Center, Chongqing, China
- 3The Affiliated Brain Hospital, Guangzhou Medical University, Guangzhou, China
- 4Guangzhou Medical University, Guangdong Engineering Technology Research Center for Translational Medicine of Mental Disorders, Guangzhou, China
Background: The therapeutic efficacy and safety profiles of daily or accelerated intermittent theta-burst stimulation (iTBS) in comparison to daily or accelerated continuous theta-burst stimulation (cTBS) for patients with major depressive disorder (MDD) or bipolar depression (BD) remain inadequately explored, respectively. This systematic review evaluates the efficacy, safety, and tolerability of daily or accelerated iTBS compared to daily or accelerated cTBS in patients with MDD or BD.
Methods: A comprehensive search was conducted in both Chinese (WanFang, China National Knowledge Infrastructure) and English (PubMed, EMBASE, PsycINFO, Cochrane Library) databases to identify randomized controlled trials (RCTs) examining the efficacy and safety of daily or accelerated iTBS compared to daily or accelerated cTBS in patients with MDD or BD.
Results: Three studies (n = 87) investigated the efficacy, safety, and tolerability of daily iTBS versus daily cTBS (1 RCT, n = 30) in patients with MDD, and accelerated iTBS versus accelerated cTBS (2 RCTs, n = 57) in patients with MDD or BD. In patients with MDD, daily iTBS outperformed daily cTBS in terms of antidepressant efficacy, with comparable safety and tolerability profiles (1 RCT). Accelerated cTBS demonstrated superior anxiolytic (1 RCT) and anti-suicidal efficacy (1 RCT) compared to accelerated iTBS in MDD, with similar antidepressant efficacy, safety, and tolerability profiles for patients with MDD or BD (2 RCTs).
Conclusion: Among the limited number of available studies, the efficacy and safety of daily or accelerated iTBS compared to daily or accelerated cTBS in patients with MDD or BD were uncertain. Future research with larger sample sizes and standardized assessments is essential to confirm these findings.
1 Introduction
Major depressive disorder (MDD) and bipolar depression (BD) are severe mental health conditions characterized by persistent sadness, anhedonia, and significant impairment in neurocognitive and daily functioning (1, 2). Due to their chronic nature, these disorders impose a substantial burden on patients, caregivers, and society (3, 4). The prolonged course of MDD and BD contributes to a diminished quality of life, an increased risk of comorbidities, and greater economic strain (5, 6). Effective treatment of MDD and BD could enhance interpersonal relationships, reduce relapse risk, and facilitate social functioning (7–10).
Psychopharmacological interventions have been the cornerstone of MDD and BD treatment (11, 12). However, antidepressants exhibit an efficacy rate of only 54% (13), with at least 30% of patients with MDD or BD developing treatment-resistant depression (TRD) (14). Although novel antidepressants, including psilocybin (15) and ketamine (16), have shown potent antidepressant effects, their long-term safety profiles remain uncertain. Given the risks and the urgent need for more effective treatments for MDD and BD, the development of neurostimulation interventions is critical.
Neurostimulation interventions such as repetitive transcranial magnetic stimulation (rTMS) have been investigated as standalone treatments as well as augmentation strategy for MDD and BD in clinical practice (17). However, conventional rTMS requires 37.5 minutes per session and multiple weeks of treatment to achieve a clinical response in these conditions (17). Accelerated TMS, defined as a protocol delivering more than one daily TMS session, is one emerging delivery schedule of TMS aimed to reduce treatment duration and improve response time, with the goal of achieving similar (or superior) levels of efficacy (18). To alleviate the time burden of rTMS, new protocols with higher dosing frequencies and multiple daily sessions, such as theta-burst stimulation (TBS), have been developed (19, 20). TBS involves delivering three magnetic pulses at a 20-ms interval (50 Hz), repeated every 200 ms to align with the 5-Hz theta rhythm, inducing more robust and lasting alterations in cortical excitability (21). Intermittent TBS (iTBS) induces long-term potentiation (LTP)-like effects, whereas continuous TBS (cTBS) results in long-term depression (LTD)-like reductions in cortical excitability (22). Daily or accelerated (≥2 sessions/day) TBS (e.g., iTBS or cTBS) effectively modulates brain activity and influences mood circuits, offering a powerful treatment alternative for patients with MDD or BD (23, 24).
The effectiveness, safety, and tolerability of daily or accelerated iTBS compared to daily or accelerated cTBS for MDD and BD remain uncertain. Several studies comparing these two protocols had yielded mixed findings (25–27). For instance, Li et al. demonstrated that daily iTBS was more effective in alleviating depressive symptoms than daily cTBS in patients with MDD (26), while other studies indicated that the antidepressant effects of accelerated iTBS were comparable to those of accelerated cTBS in patients with MDD or BD (25, 27). Several systematic reviews and meta-analyses (24, 28, 29) have assessed the efficacy, safety, and tolerability of TBS for patients with MDD or BD, concluding that TBS was more effective than standard rTMS (28) and sham stimulation (24, 29). A recent network meta-analysis (24) showed a significant superiority of active over sham iTBS in improving depressive symptoms in depression, while cTBS alone had no therapeutic efficacy in depression. However, this meta-analysis (24) did not include a recent randomized controlled trial (RCT) (27) that directly compared the two protocols in MDD. To fill this gap, a systematic review of head-to-head RCTs examining the efficacy and safety of daily or accelerated iTBS compared to daily or accelerated cTBS for patients with MDD or BD was conducted. This systematic review seeks to offer a more comprehensive assessment of the comparative effectiveness and safety of these two stimulation methods using daily or accelerated protocols, respectively.
2 Material and methods
2.1 Search strategy and selection criteria
Three researchers (ZL, ZMS, and ZAS) independently performed a thorough literature search across four international databases (PubMed, EMBASE, PsycINFO, and Cochrane Library) and two Chinese databases (WanFang database and China National Knowledge Infrastructure), covering their inception to February 16, 2025. For example, the search strategy for PubMed was as follows: (“transcranial magnetic stimulation”[Mesh] OR transcranial magnetic stimulation OR trans-cranial magnetic stimulation OR rTMS OR TMS OR theta-burst stimulation OR theta burst transcranial magnetic stimulation OR transcranial theta burst stimulation OR TBS OR intermittent theta-burst stimulation OR intermittent theta burst stimulation OR (intermittent* AND theta burst stimulation) OR iTBS) OR (continuous theta-burst stimulation OR continuous theta burst stimulation OR (continuous* AND theta burst stimulation) OR cTBS) AND (“depression”[Mesh] OR “depressive disorder”[Mesh] OR depressive disorder* OR depressive neuros* OR endogenous depression* OR unipolar depression* OR depressive syndrome* OR neurotic depression* OR depress* OR dysphor* OR melanchol* OR antidepress*). Additionally, reference lists of eligible studies (25–27) and related systematic reviews or meta-analyses (24, 28–30) were examined for potential inclusion.
In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (31), study inclusion criteria were established based on the PICOS framework. Participants: adult patients diagnosed with MDD or BD, including those with TRD, according to any internationally recognized diagnostic criteria. For example, TRD is defined by failure to respond to at least two prior adequate antidepressant trials (26). Intervention vs. Comparison: 1) daily iTBS plus treatment as usual (TAU) (e.g., stable medication regimens) versus daily cTBS plus TAU; and 2) accelerated iTBS plus TAU versus accelerated cTBS plus TAU. Outcomes: the primary outcome was the change in depressive symptoms, evaluated using standardized depression scales, such as the Hamilton Depression Rating Scale (HAMD) (32). Secondary outcomes included changes in anxiety symptoms, suicidal ideation, neurocognitive function, discontinuation rates, and adverse events (e.g., dizziness and headache). Study design: only published RCTs assessing the efficacy, safety, and tolerability of daily or accelerated iTBS compared to daily or accelerated cTBS in patients with MDD or BD were considered. Studies with randomized within-subjects designs (33, 34), retrospective studies, and case reports/series were excluded. For multiple publications based on the same dataset (26, 35, 36), only the study with the most comprehensive data was included (26).
2.2 Data extraction
Data extraction was independently conducted by the same three researchers (ZL, ZMS, and ZAS) using a standardized form, which captured study authorship, publication year, design, TBS protocol, and both primary and secondary outcomes. When additional information was required, corresponding authors were contacted via email. Disagreements were resolved through consensus among the researchers (ZL, ZMS, and ZAS), with the senior researcher (WZ) consulted when necessary.
2.3 Study quality assessment
The quality of each included RCT was independently evaluated by the same three investigators (ZL, ZMS, and ZAS) using the Jadad scale (37) and the Cochrane Risk of Bias tool (38). Studies scoring ≥3 on the Jadad scale were classified as high-quality (39).
3 Results
3.1 Literature search
As shown in Figure 1, a total of 432 studies were identified. After screening titles, abstracts, and full texts, three RCTs (25–27) met the inclusion criteria. Due to insufficient data, a meta-analysis could not be conducted.
Figure 1. PRISMA flow diagram. PRISMA, Preferred Reporting Items for Systematic reviews and Meta-Analyses.
3.2 Study characteristics
Table 1 summarizes patient characteristics and TBS protocols for each included RCT. These three RCTs, published between 2010 and 2024, involved 87 participants. One RCT (n = 30) compared daily iTBS to daily cTBS in patients with MDD, while two RCTs (n = 57) assessed accelerated iTBS versus accelerated cTBS in patients with MDD or BD. The weighted mean age of participants was 34.1 years, with males representing 28.7% of the sample (range: 15.4%–40.0%). Daily or accelerated iTBS was applied to the left dorsolateral prefrontal cortex (L-DLPFC), and daily or accelerated cTBS was applied to the right DLPFC (R-DLPFC). The intensity for daily iTBS/cTBS was set at 80% motor threshold (MT), delivering 18,000 pulses (26). For accelerated iTBS or cTBS, the stimulation intensity ranged from 90% to 100% MT, with a pulse range of 12,000–90,000 (25, 27). Treatment durations ranged from five days to two weeks (Table 1).
Table 1. Patient characteristics and iTBS or cTBS parameters of each included RCT.
3.3 Quality assessment
Quality assessment using the Cochrane Risk of Bias tool revealed that all RCTs (3/3, 100%) had a low risk of bias for incomplete outcome data and selective reporting. Two studies (2/3, 66.7%) showed a low risk of bias for blinding of outcome assessment, while one RCT (1/3, 33.3%) demonstrated a low risk of bias for random sequence generation, allocation concealment, and blinding of participants and personnel (Figure 2). The weighted mean Jadad score was 3.0 (range: 2–4), with two RCTs (66.7%) classified as high quality (Jadad score ≥3) (Table 1).
Figure 2. Cochrane risk of bias.
3.4 Changes in clinical symptoms
3.4.1 Daily iTBS versus daily cTBS
A single RCT (26) evaluated the antidepressant efficacy of daily iTBS versus daily cTBS in patients with MDD, demonstrating a significant superiority of daily iTBS over cTBS in alleviating depressive symptoms (Table 2).
Table 2. iTBS versus cTBS for patients with MDD or BD: clinical efficacy.
3.4.2 Accelerated iTBS versus accelerated cTBS
Two RCTs (25, 27) (2/2, 100.0%) compared the antidepressant effects of accelerated iTBS and accelerated cTBS in patients with MDD or BD, reporting no significant differences between the groups (Table 2). In addition Zhao et al. (27) assessed the anxiolytic and anti-suicidal effects of accelerated iTBS versus accelerated cTBS in patients with MDD. Specifically, their results showed that accelerated cTBS was superior to accelerated iTBS in reducing both anxiety symptoms and suicidal ideation (Table 2).
3.5 Neurocognitive function
3.5.1 Daily iTBS versus daily cTBS
A single RCT (26) investigated the effects of daily iTBS and daily cTBS on executive function, without direct group comparison (Table 3).
Table 3. iTBS versus cTBS for patients with MDD or BD: neurocognitive function.
3.5.2 Accelerated iTBS versus accelerated cTBS
A single RCT (27) examined neurocognitive function between the two groups and found no significant differences (Table 3).
3.6 Rates of discontinuation and adverse events
3.6.1 Daily iTBS versus daily cTBS
No significant differences in adverse effects (e.g., headache, dizziness, nausea) or discontinuation rates were reported between the groups in Li et al.’s study (all Ps > 0.05) (26) (Supplementary Table 1).
3.6.2 Accelerated iTBS versus accelerated cTBS
No significant differences in adverse effects (e.g., discomfort at treatment site, fatigue, headache, dizziness, nausea) or discontinuation rates were observed between the groups in the two included RCTs (all Ps > 0.05) (25, 27) (Supplementary Table 1).
4 Discussion
This is the first systematic review of three RCTs (25–27) (n = 87) directly comparing the efficacy, acceptability, and safety of daily or accelerated iTBS compared to daily or accelerated cTBS in patients with MDD or BD. The key findings are as follows: 1) insufficient evidence exists to determine the effectiveness of daily iTBS compared to cTBS, as well as accelerated iTBS versus cTBS in alleviating suicidal ideation, anxiety, depressive symptoms, or neurocognitive deficits in patients with MDD or BD; 2) the rates of discontinuation and adverse effects were similar between daily iTBS and daily cTBS (1 RCT); they were also similar between accelerated iTBS and accelerated cTBS (2 RCTs) in patients with MDD or BD.
The efficacy of daily or accelerated iTBS compared to daily or accelerated cTBS for reducing depressive symptoms in patients with MDD or BD was uncertain. Several factors may influence the antidepressant effects of daily or accelerated TBS in patients with MDD or BD. For example, the precision of the stimulation site seems to be a critical consideration (40, 41), and functional targeting might further augment treatment outcomes (27, 41). Generally, iTBS targets the L-DLPFC, which is closely associated with negative emotional judgment, while cTBS targets the R-DLPFC, which is linked to attentional modulation (42). The antidepressant effect of daily iTBS may be attributed to the induction of lasting central effects through the LTP-like effects on neuronal synapses in Li et al.’s study (26). However, under intensive treatment protocols, both modalities may yield comparable outcomes (27). iTBS and cTBS exhibit robust nonlinear plasticity effects (43), and the accelerated protocols may diminish the differential plasticity effects between the two techniques. In Blumberger et al.’s study (44), no significant difference was found between daily iTBS and accelerated iTBS protocols in terms of antidepressant efficacy. Notably, the limited number of RCTs and small sample sizes in this systematic review may partially account for the inconsistent results. Therefore, further well-powered RCTs are necessary to directly compare the efficacy of daily or accelerated iTBS compared to daily or accelerated cTBS in patients with MDD or BD.
In this systematic review, only one RCT assessed the comparative anxiolytic effects of accelerated iTBS versus accelerated cTBS, finding that accelerated cTBS significantly outperformed accelerated iTBS in alleviating anxiety symptoms in patients with MDD (27). Although anxiety and depression are generally considered distinct conditions in diagnostic criteria, anxious depression is a relatively common syndrome (45, 46). However, Zhao et al.’s study did not specifically evaluate the anxiolytic effects of accelerated cTBS over iTBS in patients with anxious depression (27). Anxious depression, compared to non-anxious depression, exhibits distinct neurobiological profiles, including differences in hypothalamic-pituitary-adrenal (HPA) axis function (47), brain structure and function (48, 49), and inflammation markers (50). While anxious depression is associated with poorer treatment outcomes, adjunctive rTMS has shown significant anxiety reduction in such patients while maintaining comparable antidepressant efficacy to non-anxious depression (51). A noninferiority RCT also found comparable anxiolytic effects between iTBS and rTMS (52). Thus, the comparative anxiolytic effects of daily or accelerated iTBS compared to daily or accelerated cTBS in patients with anxious depression warrant further investigation.
Suicide risk is often an exclusion criterion in TBS trials for MDD, leaving suicidal patients with limited treatment options. While accelerated iTBS shows promise in reducing suicidality (53), the evidence base remains inconclusive. In this systematic review, no RCT has assessed the anti-suicidal efficacy of daily iTBS versus daily cTBS, and only one RCT (27) has evaluated the anti-suicidal efficacy of accelerated iTBS versus accelerated cTBS in patients with depression. Consequently, the anti-suicidal effects of both treatment protocols were inadequately established in patients with MDD or BD. Zhao et al.’s study (27) found that accelerated cTBS was significantly more effective than accelerated iTBS in reducing suicidal ideation in MDD patients, as measured by the Beck Scale for Suicidal Ideation. However, scales have limited sensitivity and predictive validity for suicidal behaviors (54, 55), and there is not yet a single instrument considered to be the gold standard for suicide risk assessment (56). When scales such as the Columbia Suicide Severity Rating Scale (57) for suicide risk are used, the results need to be quickly reviewed and followed by a clinical evaluation if the scores suggest a risk (58). The suicide module of the Mini-International Neuropsychiatric Interview was generally agreed upon as a better tool for measuring suicide risk (59, 60). Although accelerated cTBS shows promise in reducing suicidality in patients with MDD (27), further research with larger cohorts and more rigorous methodologies is required to clarify the therapeutic potential of accelerated cTBS in patients with MDD or BD.
Non-invasive brain stimulation (NIBS) techniques may improve certain neurocognitive function in both patients with depression (61, 62) and healthy individuals (63, 64). In this systematic review, two RCTs examined the neurocognitive effects of daily or accelerated iTBS compared to daily or accelerated cTBS in patients with MDD (26, 27). However, the differences in neurocognitive effects of daily or accelerated iTBS compared to daily or accelerated cTBS were uncertain. Li et al. (26) used the Wisconsin Card Sorting Test to compare the neurocognitive effects of daily iTBS and daily cTBS, while Zhao et al. (27) employed the THINC-integrated tool to assess the effects of accelerated iTBS and accelerated cTBS. Notably, Zhao et al.’s study found no significant group differences in neurocognitive function (27). Preliminary evidence suggests that daily iTBS may improve certain neurocognitive functions in patients with MDD (65). A notable increase in left hippocampal grey matter volume in part of the dentate gyrus was observed following accelerated iTBS (66), potentially contributing to enhanced neurocognitive function in patients with MDD. In contrast, cTBS has been shown to impair attention, inhibitory control, planning, and goal-directed behavior, while enhancing decision-making by reducing impulsivity in healthy individuals (67). However, the effects of cTBS on neurocognitive functions in patients with MDD or BD remain uncertain. Although there is currently no gold standard for assessing cognitive impairment in depression (68), neurocognitive assessment tools, such as the MATRICS Consensus Cognitive Battery (69) or the Repeatable Battery for the Assessment of Neuropsychological Status (70), should be employed to evaluate the effects of daily or accelerated iTBS compared to daily or accelerated cTBS on neurocognitive function in patients with MDD or BD.
Both daily and accelerated TBS (i.e., iTBS and cTBS) are considered to be relatively safe as adjunctive therapies for patients with MDD or BD (23, 71) and healthy individuals (72, 73), with no serious adverse events reported. Mild side effects, such as headache, dizziness, nausea, and discomfort, were common. The majority of TBS-related adverse events were mild, affecting 5% of both healthy individuals and clinical patients (74). Given the high-frequency bursts of TBS, there is a potential risk of inducing seizures in patients with MDD or BD. While no seizures were reported in the current systematic review, a case report documented cTBS-induced seizures in a healthy individual (75). Consequently, appropriate preventive measures, including physician supervision and access to emergency medical care, should be in place during daily or accelerated TBS treatments.
Several limitations should be considered when interpreting the findings of this systematic review. First, despite a comprehensive search, only three RCTs with small sample sizes were included. Second, due to significant heterogeneity (such as variations in intervention parameters, patient characteristics (e.g., the use of pharmacologic agents), and treatment duration) among the included studies, a meta-analysis could not be conducted. Therefore, the optimal stimulation protocol of TBS (i.e., iTBS and cTBS) for patients with MDD or BD should be investigated. Third, patients with TRD may respond differently to TBS than patients without TRD, affecting result interpretation. However, only three RCTs were included in this systematic review, making it difficult to compare the efficacy and safety of TBS (e.g., iTBS or cTBS) in patients with TRD versus non-TRD. Fourth, the included RCTs with a varied patient population, such as those with MDD and BD, limited the clarity of these findings. Finally, this systematic review was not registered.
In conclusion, the preliminary evidence available is insufficient to determine the comparative efficacy of daily or accelerated iTBS compared to daily or accelerated cTBS for patients with MDD or BD. Further research with larger sample sizes and standardized protocols is required to validate these findings.
Data availability statement
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding authors.
Author contributions
ZL: Writing – original draft. Z-MS: Writing – original draft. X-HY: Writing – review & editing. Z-AS: Writing – original draft. WW: Writing – original draft, Data curation. Z-JQ: Data curation, Writing – original draft. X-JL: Writing – original draft, Data curation. XW: Writing – review & editing. WZ: Writing – review & editing.
Funding
The author(s) declared that financial support was received for this work and/or its publication. This study was funded by the Science and Technology Program of Guangzhou (2023A03J0839, 2023A03J0436, 20251A011047, 20252A011018, 2025B03J0164, 2025B03J0121), National Clinical Key specialty construction project [(2023) 33], The Natural Science Foundation Program of Guangdong (2023A1515011383, 2024A1515012578), the Science and Technology Program of Guangzhou (202206010077),Guangzhou Science and Technology Plan Project (2023A03J0827), Guangxi Zhuang Autonomous Region Health Commission Self-Funded Research Project (Z20211399, Z-B20240375), the Chongqing Key Public Health Specialty Construction Project (Mental Health), Guangzhou Clinical High-tech, Major and Characteristic Technology Program (2026C-TS040), Youth S&T Talent Support Programme of Guangdong Provincial Association for Science and Technology (GDSTA) (SKXRC2025115), Guangzhou Key Clinical Specialty (Clinical Medical Research Institute), Guangzhou High-level Clinical Key Specialty, Department of Emergency Medicine of National clinical key specialty, Guangzhou Research-oriented Hospital. The founders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The reviewer CL declared a past co-authorship with author WZ to the handling editor.
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Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fpsyt.2026.1656576/full#supplementary-material
Supplementary Table 1 | iTBS versus cTBS for patients with MDD and BD: rates of discontinuation and adverse effects.
References
1. De S, Singh A, and Bhandari AK. A novel vision transformer based multimodal fusion approach for clinical MDD diagnosis using EEG and audio signals. IEEE Trans Comput Biol Bioinform. (2025) 22:3399–409. doi: 10.1109/tcbbio.2025.3626210
2. Grande I, Berk M, Birmaher B, and Vieta E. Bipolar disorder. Lancet. (2016) 387:1561–72. doi: 10.1016/s0140-6736(15)00241-x
3. Zhang M, Wei X, Li SY, Liu QM, Huang X, Huang XB, et al. Sex differences in the antidepressant and neurocognitive effects of nonconvulsive electrotherapy in patients with treatment-refractory depression. Alpha Psychiatry. (2024) 25:68–74. doi: 10.5152/alphapsychiatry.2024.231402
4. Miller S, Dell'Osso B, and Ketter TA. The prevalence and burden of bipolar depression. J Affect Disord. (2014) 169:S3–11. doi: 10.1016/s0165-0327(14)70003-5
5. Culpepper L, Martin A, Nabulsi N, and Parikh M. The humanistic and economic burden associated with major depressive disorder: a retrospective cross-sectional analysis. Adv Ther. (2024) 41:1860–1884. doi: 10.1007/s12325-024-02817-w
6. Teneralli RE, Kern DM, Cepeda MS, Gilbert JP, and Drevets WC. Exploring real-world evidence to uncover unknown drug benefits and support the discovery of new treatment targets for depressive and bipolar disorders. J Affect Disord. (2021) 290:324–333. doi: 10.1016/j.jad.2021.04.096
7. Spence SH, O'Shea G, and Donovan CL. Improvements in interpersonal functioning following interpersonal psychotherapy (IPT) with adolescents and their association with change in depression. Behav Cognit Psychother. (2016) 44:257–72. doi: 10.1017/s1352465815000442
8. Geddes JR, Carney SM, Davies C, Furukawa TA, Kupfer DJ, Frank E, et al. Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review. Lancet. (2003) 361:653–61. doi: 10.1016/s0140-6736(03)12599-8
9. Kremer S, Wiesinger T, Bschor T, and Baethge C. Antidepressants and social functioning in patients with major depressive disorder: systematic review and meta-analysis of double-blind, placebo-controlled RCTs. Psychother Psychosom. (2023) 92:304–14. doi: 10.1159/000533494
10. Elgie R and Morselli PL. Social functioning in bipolar patients: the perception and perspective of patients, relatives and advocacy organizations - a review. Bipolar Disord. (2007) 9:144–57. doi: 10.1111/j.1399-5618.2007.00339.x
11. Abdulhaq B, Sarhan W, Saadeh M, Alkayid S, Libzo DT, Sadaqa M, et al. Knowledge gaps and systemic challenges in antidepressant prescribing: insights from Jordanian psychiatry practice. Healthc (Basel). (2025) 13:2954. doi: 10.3390/healthcare13222954
12. Hussain Z, Iffi II, and Khosa RA. Integrating psychopharmacology and psychotherapy in the treatment of mood disorders: a comparative analysis of combined vs. standalone interventions. IJBR. (2025) 3:260–271. doi: 10.70749/ijbr.v3i2.671
13. Cuijpers P, Stringaris A, and Wolpert M. Treatment outcomes for depression: challenges and opportunities. Lancet Psychiatry. (2020) 7:925–7. doi: 10.1016/s2215-0366(20)30036-5
14. McIntyre RS, Alsuwaidan M, Baune BT, Berk M, Demyttenaere K, Goldberg JF, et al. Treatment-resistant depression: definition, prevalence, detection, management, and investigational interventions. World Psychiatry. (2023) 22:394–412. doi: 10.1002/wps.21120
15. Li LJ, Mo Y, Shi ZM, Huang XB, Ning YP, Wu HW, et al. Psilocybin for major depressive disorder: a systematic review of randomized controlled studies. Front Psychiatry. (2024) 15:1416420. doi: 10.3389/fpsyt.2024.1416420
16. Huang XB and Zheng W. Ketamine and electroconvulsive therapy for treatment-refractory depression. Alpha Psychiatry. (2023) 24:244–6. doi: 10.5152/alphapsychiatry.2023.231358
17. Lan XJ, Yang XH, Qin ZJ, Cai DB, Liu QM, Mai JX, et al. Efficacy and safety of intermittent theta burst stimulation versus high-frequency repetitive transcranial magnetic stimulation for patients with treatment-resistant depression: a systematic review. Front Psychiatry. (2023) 14:1244289. doi: 10.3389/fpsyt.2023.1244289
18. van Rooij SJH, Arulpragasam AR, McDonald WM, and Philip NS. Accelerated TMS - moving quickly into the future of depression treatment. Neuropsychopharmacology. (2024) 49:128–37. doi: 10.1038/s41386-023-01599-z
19. Kishi T, Sakuma K, Matsuda Y, Kito S, and Iwata N. Intermittent theta burst stimulation vs. high-frequency repetitive transcranial magnetic stimulation for major depressive disorder: a systematic review and meta-analysis. Psychiatry Res. (2023) 328:115452. doi: 10.1016/j.psychres.2023.115452
20. Tao X, Jing ZW, Yuan WK, Yun GH, Fang XJ, and Sheng LM. A meta-analysis comparing the effectiveness and safety of repetitive transcranial magnetic stimulation versus theta burst stimulation for treatment-resistant depression. Front Psychiatry. (2024) 15:1504727. doi: 10.3389/fpsyt.2024.1504727
21. Hsu YF, Liao KK, Lee PL, Tsai YA, Yeh CL, Lai KL, et al. Intermittent θ burst stimulation over primary motor cortex enhances movement-related β synchronisation. Clin Neurophysiol. (2011) 122:2260–7. doi: 10.1016/j.clinph.2011.03.027
22. Purushotham A, Goyal N, Sinha VK, Tikka SK, Garg S, and Desarkar P. Motor cortical plasticity in adolescents with early onset schizophrenia: a TMS-EMG study assessing the perturbation effect of intermittent and continuous theta burst stimulation. Int J Dev Neurosci. (2022) 82:576–83. doi: 10.1002/jdn.10210
23. Cai DB, Qin XD, Qin ZJ, Lan XJ, Wang JJ, Ng CH, et al. Adjunctive continuous theta burst stimulation for major depressive disorder or bipolar depression: a meta-analysis of randomized controlled studies. J Affect Disord. (2024) 346:266–72. doi: 10.1016/j.jad.2023.10.161
24. 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) 29:3893–9. doi: 10.1038/s41380-024-02630-5
25. Chistyakov AV, Rubicsek O, Kaplan B, Zaaroor M, and Klein E. Safety, tolerability and preliminary evidence for antidepressant efficacy of theta-burst transcranial magnetic stimulation in patients with major depression. Int J Neuropsychopharmacol. (2010) 13:387–93. doi: 10.1017/s1461145710000027
26. Li CT, Chen MH, Juan CH, Huang HH, Chen LF, Hsieh JC, et al. Efficacy of prefrontal theta-burst stimulation in refractory depression: a randomized sham-controlled study. Brain. (2014) 137:2088–98. doi: 10.1093/brain/awu109
27. Zhao H, Jiang C, Zhao M, Ye Y, Yu L, Li Y, et al. Comparisons of accelerated continuous and intermittent theta burst stimulation for treatment-resistant depression and suicidal ideation. Biol Psychiatry. (2024) 96:26–33. doi: 10.1016/j.biopsych.2023.12.013
28. Chu HT, Cheng CM, Liang CS, Chang WH, Juan CH, Huang YZ, et al. Efficacy and tolerability of theta-burst stimulation for major depression: a systematic review and meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. (2021) 106:110168. doi: 10.1016/j.pnpbp.2020.110168
29. Voigt JD, Leuchter AF, and Carpenter LL. Theta burst stimulation for the acute treatment of major depressive disorder: a systematic review and meta-analysis. Transl Psychiatry. (2021) 11:330. doi: 10.1038/s41398-021-01441-4
30. Mutz J, Edgcumbe DR, Brunoni AR, and Fu CHY. Efficacy and acceptability of non-invasive brain stimulation for the treatment of adult unipolar and bipolar depression: a systematic review and meta-analysis of randomised sham-controlled trials. Neurosci Biobehav Rev. (2018) 92:291–303. doi: 10.1016/j.neubiorev.2018.05.015
31. Moher D, Liberati A, Tetzlaff J, and Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol. (2009) 62:1006–12. doi: 10.1016/j.jclinepi.2009.06.005
32. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. (1960) 23:56–62. doi: 10.1136/jnnp.23.1.56
33. Gupta T, Karim HT, Jones NP, Ferrarelli F, Nance M, Taylor SF, et al. Continuous theta burst stimulation to dorsomedial prefrontal cortex in young adults with depression: changes in resting frontostriatal functional connectivity relevant to positive mood. Behav Res Ther. (2024) 174:104493. doi: 10.1016/j.brat.2024.104493
34. Dhami P, Knyahnytska Y, Atluri S, Lee J, Courtney DB, Croarkin PE, et al. Feasibility and clinical effects of theta burst stimulation in youth with major depressive disorders: an open-label trial. J Affect Disord. (2019) 258:66–73. doi: 10.1016/j.jad.2019.07.084
35. Li CT, Chen MH, Juan CH, Liu RS, Lin WC, Bai YM, et al. Effects of prefrontal theta-burst stimulation on brain function in treatment-resistant depression: a randomized sham-controlled neuroimaging study. Brain Stimul. (2018) 11:1054–62. doi: 10.1016/j.brs.2018.04.014
36. Cheng CM, Juan CH, Chen MH, Chang CF, Lu HJ, Su TP, et al. Different forms of prefrontal theta burst stimulation for executive function of medication-resistant depression: evidence from a randomized sham-controlled study. Prog Neuropsychopharmacol Biol Psychiatry. (2016) 66:35–40. doi: 10.1016/j.pnpbp.2015.11.009
37. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Ctrl Clin Trials. (1996) 17:1–12. doi: 10.1016/0197-2456(95)00134-4
38. Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. Bmj. (2011) 343:d5928. doi: 10.1136/bmj.d5928
39. Linde K, Clausius N, Ramirez G, Melchart D, Eitel F, Hedges LV, et al. Are the clinical effects of homeopathy placebo effects? A Beta-Anal Placebo-Ctrl Trials Lancet. (1997) 350:834–43. doi: 10.1016/s0140-6736(97)02293-9
40. Modak A and Fitzgerald PB. Personalising transcranial magnetic stimulation for depression using neuroimaging: a systematic review. World J Biol Psychiatry. (2021) 22:647–69. doi: 10.1080/15622975.2021.1907710
41. 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) 179:132–41. doi: 10.1176/appi.ajp.2021.20101429
42. Grimm S, Beck J, Schuepbach D, Hell D, Boesiger P, Bermpohl F, et al. Imbalance between left and right dorsolateral prefrontal cortex in major depression is linked to negative emotional judgment: an fMRI study in severe major depressive disorder. Biol Psychiatry. (2008) 63:369–76. doi: 10.1016/j.biopsych.2007.05.033
43. Fung PK and Robinson PA. Neural field theory of synaptic metaplasticity with applications to theta burst stimulation. J Theor Biol. (2014) 340:164–76. doi: 10.1016/j.jtbi.2013.09.021
44. Blumberger DM, Vila-Rodriguez F, Wang W, Knyahnytska Y, Butterfield M, Noda Y, et al. A randomized sham controlled comparison of once vs twice-daily intermittent theta burst stimulation in depression: a Canadian rTMS treatment and biomarker network in depression (CARTBIND) study. Brain Stimul. (2021) 14:1447–55. doi: 10.1016/j.brs.2021.09.003
45. Fava M, Rush AJ, Alpert JE, Carmin CN, Balasubramani GK, Wisniewski SR, et al. What clinical and symptom features and comorbid disorders characterize outpatients with anxious major depressive disorder: a replication and extension. Can J Psychiatry. (2006) 51:823–35. doi: 10.1177/070674370605101304
46. Lin CH, Wang FC, Lin SC, Chen CC, and Huang CJ. A comparison of inpatients with anxious depression to those with nonanxious depression. Psychiatry Res. (2014) 220:855–60. doi: 10.1016/j.psychres.2014.08.048
47. Menke A, Lehrieder D, Fietz J, Leistner C, Wurst C, Stonawski S, et al. Childhood trauma dependent anxious depression sensitizes HPA axis function. Psychoneuroendocrinology. (2018) 98:22–9. doi: 10.1016/j.psyneuen.2018.07.025
48. Peng W, Jia Z, Huang X, Lui S, Kuang W, Sweeney JA, et al. Brain structural abnormalities in emotional regulation and sensory processing regions associated with anxious depression. Prog Neuropsychopharmacol Biol Psychiatry. (2019) 94:109676. doi: 10.1016/j.pnpbp.2019.109676
49. Qiao J, Tao S, Wang X, Shi J, Chen Y, Tian S, et al. Brain functional abnormalities in the amygdala subregions is associated with anxious depression. J Affect Disord. (2020) 276:653–9. doi: 10.1016/j.jad.2020.06.077
50. Baek JH, Kim HJ, Fava M, Mischoulon D, Papakostas GI, Nierenberg A, et al. Reduced venous blood basophil count and anxious depression in patients with major depressive disorder. Psychiatry Investig. (2016) 13:321–6. doi: 10.4306/pi.2016.13.3.321
51. Diefenbach GJ, Bragdon L, and Goethe JW. Treating anxious depression using repetitive transcranial magnetic stimulation. J Affect Disord. (2013) 151:365–8. doi: 10.1016/j.jad.2013.05.094
52. Trevizol AP, Downar J, Vila-Rodriguez F, Konstantinou G, Daskalakis ZJ, and Blumberger DM. Effect of repetitive transcranial magnetic stimulation on anxiety symptoms in patients with major depression: an analysis from the THREE-D trial. Depress Anx. (2021) 38:262–71. doi: 10.1002/da.23125
53. Neuteboom D, Zantvoord JB, Goya-Maldonado R, Wilkening J, Dols A, van Exel E, et al. Accelerated intermittent theta burst stimulation in major depressive disorder: a systematic review. Psychiatry Res. (2023) 327:115429. doi: 10.1016/j.psychres.2023.115429
54. American Psychiatric Association. Practice guideline for the assessment and treatment of patients with suicidal behaviors. Am J Psychiatry. (2003) 160:1–60.
55. Chinese Society of Psychiatry, Depressive Disorder Research Coordination Group. Expert consensus on the clinical management of suicidal behaviors in adults with major depressive disorder (In Chinese). Chin J Psychiatry. (2025) 58:331–46. doi: 10.3760/cma.j.cn113661-20240918-00309
56. Andreotti ET, Ipuchima JR, Cazella SC, Beria P, Bortoncello CF, Silveira RC, et al. Instruments to assess suicide risk: a systematic review. Trends Psychiatry Psychother. (2020) 42:276–81. doi: 10.1590/2237-6089-2019-0092
57. Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. (2011) 168:1266–77. doi: 10.1176/appi.ajp.2011.10111704
58. Lam RW, Kennedy SH, Adams C, Bahji A, Beaulieu S, Bhat V, et al. Canadian network for mood and anxiety treatments (CANMAT) 2023 update on clinical guidelines for management of major depressive disorder in adults. Can J Psychiatry. (2024) 69:641–87. doi: 10.1177/07067437241245384
59. Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. (1998) 59:22–33.
60. Su Y, Ye C, Xin Q, and Si T. Major depressive disorder with suicidal ideation or behavior in Chinese population: a scoping review of current evidence on disease assessment, burden, treatment and risk factors. J Affect Disord. (2023) 340:732–42. doi: 10.1016/j.jad.2023.08.106
61. Begemann MJ, Brand BA, Ćurčić-Blake B, Aleman A, and Sommer IE. Efficacy of non-invasive brain stimulation on cognitive functioning in brain disorders: a meta-analysis. Psychol Med. (2020) 50:2465–86. doi: 10.1017/s0033291720003670
62. Martin DM, McClintock SM, Forster JJ, Lo TY, and Loo CK. Cognitive enhancing effects of rTMS administered to the prefrontal cortex in patients with depression: a systematic review and meta-analysis of individual task effects. Depress Anx. (2017) 34:1029–39. doi: 10.1002/da.22658
63. Pabst A, Proksch S, Médé B, Comstock DC, Ross JM, and Balasubramaniam R. A systematic review and meta-analysis of the efficacy of intermittent theta burst stimulation (iTBS) on cognitive enhancement. Neurosci Biobehav Rev. (2022) 135:104587. doi: 10.1016/j.neubiorev.2022.104587
64. Hoy KE, Bailey N, Michael M, Fitzgibbon B, Rogasch NC, Saeki T, et al. Enhancement of working memory and task-related oscillatory activity following intermittent theta burst stimulation in healthy controls. Cereb Cort. (2016) 26:4563–73. doi: 10.1093/cercor/bhv193
65. Zhao Y. Effects of intermittent theta burst stimulation on suicidal ideation and executive function in adolescent depression with suicide attempt (In Chinese). Univ Electron Sci Technol China. (2022).
66. Baeken C, Wu G, and Sackeim HA. Accelerated iTBS treatment applied to the left DLPFC in depressed patients results in a rapid volume increase in the left hippocampal dentate gyrus, not driven by brain perfusion. Brain Stimul. (2020) 13:1211–7. doi: 10.1016/j.brs.2020.05.015
67. Ngetich R, Zhou J, Zhang J, Jin Z, and Li L. Assessing the effects of continuous theta burst stimulation over the dorsolateral prefrontal cortex on human cognition: a systematic review. Front Integr Neurosci. (2020) 14:35. doi: 10.3389/fnint.2020.00035
68. Naguy A, Moodliar-Rensburg S, and Alamiri B. Cognitive symptoms domain in major depressive disorder-revisited. Asian J Psychiatr. (2020) 53:102216. doi: 10.1016/j.ajp.2020.102216
69. Nuechterlein KH, Barch DM, Gold JM, Goldberg TE, Green MF, and Heaton RK. Identification of separable cognitive factors in schizophrenia. Schizophr Res. (2004) 72:29–39. doi: 10.1016/j.schres.2004.09.007
70. Gold JM, Queern C, Iannone VN, and Buchanan RW. Repeatable battery for the assessment of neuropsychological status as a screening test in schizophrenia I: sensitivity, reliability, and validity. Am J Psychiatry. (1999) 156:1944–50. doi: 10.1176/ajp.156.12.1944
71. Rachid F. Safety and efficacy of theta-burst stimulation in the treatment of psychiatric disorders: a review of the literature. J Nerv Ment Dis. (2017) 205:823–39. doi: 10.1097/nmd.0000000000000742
72. Kruithof ES, Drop EM, Gerits D, Klaus J, and Schutter D. Continuous theta burst stimulation to the medial posterior cerebellum impairs reversal learning in healthy volunteers. Cognit Affect Behav Neurosci. (2025) 25:618–30. doi: 10.3758/s13415-025-01273-5
73. Liu P, Song D, Deng X, Shang Y, Ge Q, Wang Z, et al. The effects of intermittent theta burst stimulation (iTBS) on resting-state brain entropy (BEN). Neurotherapeutics. (2025) 22:e00556. doi: 10.1016/j.neurot.2025.e00556
74. Oberman L, Edwards D, Eldaief M, and Pascual-Leone A. Safety of theta burst transcranial magnetic stimulation: a systematic review of the literature. J Clin Neurophysiol. (2011) 28:67–74. doi: 10.1097/WNP.0b013e318205135f
Keywords: bipolar depression, continuous theta-burst stimulation, intermittent theta-burst stimulation, major depressive disorder, systematic review
Citation: Li Z, Shi Z-M, Yang X-H, Su Z-A, Wei W, Qin Z-J, Lan X-J, Wei X and Zheng W (2026) Efficacy and safety of intermittent theta-burst stimulation versus continuous theta-burst stimulation for major depressive disorder and bipolar depression: a systematic review. Front. Psychiatry 17:1656576. doi: 10.3389/fpsyt.2026.1656576
Received: 30 June 2025; Accepted: 12 January 2026; Revised: 08 January 2026;
Published: 04 February 2026.
Edited by:
Shen Li, Tianjin Medical University, ChinaReviewed by:
Chaomeng Liu, Capital Medical University, ChinaLi Jinbiao, Sun Yat-sen University, China
Copyright © 2026 Li, Shi, Yang, Su, Wei, Qin, Lan, Wei and Zheng. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Wei Zheng, emhlbmd3ZWkwNzAyQDE2My5jb20=; Xin Wei, d2VpeGluQDE2My5jb20=
†These authors have contributed equally to this work