Acute and long-term effects of repetitive transcranial magnetic stimulation in major depressive episodes: a systematic review and dose-response meta-analysis of randomized sham-controlled trials

Acute and long-term effects of repetitive transcranial magnetic stimulation in major depressive episodes: a systematic review and dose-response meta-analysis of randomized sham-controlled trials | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Acute and long-term effects of repetitive transcranial magnetic stimulation in major depressive episodes: a systematic review and dose-response meta-analysis of randomized sham-controlled trials Zuxing Wang, Ruanmei Sheng, Ruifeng Shi, Zhili Zou, Vaughn R. Steele, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8648926/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract Background To characterize the dose-response relationships between key repetitive transcranial magnetic stimulation (rTMS) dosing parameters and clinical outcomes in major depressive episodes (MDE), and to identify optimal dosing ranges. Methods We performed a systematic review and one-stage dose-response meta-analysis of randomized sham-controlled trials investigating rTMS for adults with MDE. Outcomes were symptom severity, response, and remission, assessed acutely and in follow-up (> 7 days). Four key dosing dimensions (total pulses, pulses/session, sessions, duration) were modeled using restricted cubic spline models, and the maximum effective dose (EDmax) within the observed range was derived from the fitted model. Effect sizes were expressed as standardized mean differences and risk ratios with 95% confidence interval. Results Across 108 trials (134 active arms; n = 5,621), total pulses, pulses per session, total sessions and treatment duration showed significant non-linear associations with acute efficacy. Peak efficacy for acute treatment was observed at 30,000–39,000 total pulses, 1,800–2,200 pulses per session, 14–16 sessions, and 2.7–3.1 weeks of treatment, with no additional benefit from higher doses across all parameters. Long-term analyses showed smaller and mostly linear associations: the best outcomes were generally observed at 26,000–33,000 total pulses, 1,300–1,800 pulses per session, 10–14 sessions, and 2.8–3.3 weeks of treatment. Sensitivity analyses confirmed the stability of these estimates, and publication bias was minimal. Conclusions rTMS efficacy in MDE is maximized within a moderate dose range, beyond which additional stimulation yields minimal gain. Thus, sustained remission likely depends on maintenance strategies, not dose escalation. Transcranial magnetic stimulation Major depressive episodes Acute efficacy Follow-up Dose-response relationship Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Major depressive episode (MDE) remains a leading cause of disability worldwide and imposes substantial clinical and economic burden [1]. Transcranial magnetic stimulation (TMS) is an established, guideline-endorsed, noninvasive treatment for depression [2]. However, clinical protocols vary widely in stimulation targets and dosing parameters (total pulses, pulses per session, number of sessions, and overall treatment duration), resulting in considerable heterogeneity in reported efficacy [3-6]. Recent dose-response syntheses point in complementary directions while leaving practical gaps [7-9]. In treatment-resistant depression (TRD), a multivariable meta-analysis reported that intensity, frequency, pulses per session, treatment duration, number of sessions, and total pulses explained meaningful variance [7]. Similarly, in TRD, a total-pulse-based analysis suggested a non-linear relationship peaking near 26,660 pulses, with frequency and age as significant moderators [8]. A trajectory-focused analysis showed a logarithmic improvement pattern with a plateau around weeks 3–4 and larger cumulative benefit at ≥3000 pulses per session and higher total pulses [9]. Additionally, a cross-protocol meta-analysis estimated near-maximal effective doses (ED95) and identified bell-shaped or ascending dose-response curves across paradigms using end-of-treatment assessments, across multiple psychiatric disorders [10]. Despite these advances, decision-relevant evidence remains limited. Previous studies have rarely examined the four dose dimensions together (total pulses, pulses per session, number of sessions, and treatment duration) or quantified their independent contributions while linking dosing to both acute and follow-up outcomes across continuous scores and binary endpoints (response and remission) in MDE. To address these gaps, we conducted a dose-response meta-analysis of major depressive episodes to examine the nonlinear associations of total pulses, pulses per session, number of sessions, and treatment duration with acute and follow-up outcomes, including depressive-symptom severity, treatment response, and remission. Methods This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [ 11 ], and was prospectively registered in PROSPERO (registration number CRD420251051992). Search strategy We systematically searched CENTRAL (Cochrane Central Register of Controlled Trials), Embase, and PubMed from inception to May 1, 2025, for randomized controlled trials (RCTs) of TMS in MDE, restricted to English-language publications. Reference lists of relevant reviews and articles were screened, and corresponding authors were contacted for missing data. Two reviewers independently screened titles, abstracts, and full texts in duplicate, resolving disagreements by discussion or a third reviewer. Complete search strategies are provided in the Supplement. Eligibility criteria Participants (P) . Adults aged 18–65 years with a MDE in MDD or bipolar depression, diagnosed by DSM Diagnostic and Statistical Manual of Mental Disorders (DSM) [ 12 ] or International Classification of Diseases (ICD) [ 13 ]. Exclusion criteria included age 65, secondary mood disorders, severe cognitive impairment, or relapse-prevention/maintenance designs. Interventions (I) . Therapeutic TMS at any cortical site, frequency, or coil type. Eligible modalities included repetitive TMS (high-frequency, low-frequency, bilateral, accelerated), theta-burst stimulation (TBS: intermittent [iTBS] and continuous [cTBS]), and deep TMS. Trials in which TMS was not the primary intervention were excluded. Comparators (C) . Sham TMS using accepted inert methods (e.g., sham coil or angled coil). For cross-over trials, only pre-cross-over data were used. Outcomes (O) . The six prespecified primary outcomes were assessed at two time points: an acute phase (end of treatment or within 7 days) and a follow-up phase (more than 7 days after treatment). Each window included three endpoints: continuous depressive-symptom severity, treatment response, and remission. Symptom severity was preferentially extracted from Hamilton Rating Scale for Depression (HAMD) [ 14 ], Montgomery-Asberg Depression Rating Scale (MADRS) [ 15 ], or Beck Depression Inventory (BDI) [ 16 ]. Symptom severity was extracted according to a prespecified hierarchy: HAMD first, then MADRS, and BDI if neither clinician-rated scale was available. Binary endpoints (response and remission) were extracted as reported in each trial, adhering to the trial’s prespecified definitions and analyses. We did not derive response or remission from continuous data when not reported. Where provided, common criteria included ≥ 50% reduction from baseline for response and instrument-specific remission cut-offs (e.g., HAMD-17 ≤ 7, MADRS ≤ 10). Study design (S) . Peer-reviewed RCTs comparing active versus sham TMS, with extractable data. Data extraction Two reviewers independently extracted trial-level data using a piloted form, with disagreements resolved by a third reviewer. For each study arm, we recorded author, year, and country; intervention details (active TMS parameters and sham control method); diagnosis (major depressive episode in MDD or bipolar depression) and diagnostic criteria (DSM or ICD); treatment-resistance status; sample size (randomized and completed); sex distribution (male/female); age (mean, SD); rating scale used; depression severity (mean, SD) at baseline, post-treatment, and follow-up; concomitant medication status and any washout period; stimulated brain region (no restriction); stimulation frequency (Hz); intensity as % of motor threshold (MT%); pulses per session and number of sessions; total pulses (calculated when not explicitly reported as pulses-per-session × sessions); and treatment duration. Outcomes were extracted at post-treatment and follow-up, prioritizing the 2-week post-treatment timepoint. Endpoints comprised continuous depressive-symptom severity and the binary outcomes of response and remission. Where necessary, missing dispersion metrics (e.g., SD) were derived from SEs, CIs, or p values using standard formulae. For cross-over studies, only pre-cross-over data were extracted; multi-arm trials were extracted by arm. We preferentially used intention-to-treat denominators for response/remission when available; otherwise, available-case data were extracted as reported. Quality assessment Risk of bias was assessed using the Cochrane Risk of Bias tool [ 17 ]. Two reviewers independently rated each domain as low, unclear, or high risk; disagreements were resolved by consensus or third-party adjudication. An overall risk-of-bias judgment was then assigned for each study. Statistical analyses TMS dose was defined a priori across four dimensions: total pulses, pulses per session, number of sessions, and treatment duration in weeks. For the clinical interpretation of dose-response curves, we pre-specified categorical dose levels (low, mid-range, high) for each dimension, based on established therapeutic ranges from previous studies [ 7 , 8 ]. Mid-range dose was defined as follows: 30,000–40,000 total pulses; 1,500–2,000 pulses/session; 10–20 sessions; and 2–3 weeks' duration. Doses below and above these ranges were classified as low and high, respectively. Each dimension was analyzed separately. Treatment effects were summarized as standardized mean differences (SMD) for continuous depressive-symptom scores and log risk ratios (logRR) for binary endpoints (response, remission), with 95% confidence intervals (CIs). For binary data, logRRs and standard errors were computed from 2×2 tables; when any cell count was zero, the Haldane-Anscombe 0.5 continuity correction was applied [ 18 ]. Binary outcomes were modeled on the log-risk-ratio scale and are reported as RRs (by exponentiation) with 95% CIs. Dose-response relations were estimated using a one-stage random-effects model with the between-study variance estimated by restricted maximum likelihood (REML), implemented in dosresmeta [ 19 ]. Non-linearity was accommodated with restricted cubic splines (three knots at the 10th, 50th, and 90th centiles of the observed dose distribution) [ 20 ]. Wald χ² tests evaluated the overall association and departure from linearity. The maximum effective dose (EDmax), defined as the dose associated with the highest predicted benefit within the observed range, was estimated from the fitted spline. Pointwise 95% confidence intervals were obtained using the delta method. We prespecified a tiered approach for sensitivity analysis. When both the overall dose-response and the non-linearity test were significant, we assessed robustness of the EDmax with leave-one-out re-fits of the spline model, recording interior peaks only [ 19 , 21 ]. When the overall association was significant but non-linearity was not, we focused on the linear dose trend: a one-stage random-effects meta-regression [ 22 , 23 ]. We summarized leave-one-out slopes (median, interquartile range, sign reversals, and loss of significance) and compared the linear and spline specifications using the Akaike Information Criterion and a Wald test for non-linearity. Publication bias and small-study effects were examined using contour-enhanced funnel plots and dose-adjusted Egger-type meta-regressions [ 24 ]. Two-sided p < 0.05 was considered statistically significant. Analyses were conducted in R (version 4.4.3). Results Study characteristics We retrieved 6,962 published records in all three literature databases, of which 108 RCTs with sham arms met inclusion criteria, comprising 134 intervention arms (Fig. 1 A) [ 25 – 132 ]. In total, 5,621 participants were enrolled: 3,021 randomized to active rTMS (mean age 43.3 years; 59.2% female) and 2,590 to sham (mean age 42.5 years; 55.8% female). Among the trials, 38 focused on MDD [ 25 , 29 , 41 , 45 , 46 , 49 – 53 , 64 , 67 , 69 , 71 , 77 , 79 , 80 , 82 , 84 , 90 – 92 , 96 , 97 , 101 , 103 , 110 , 111 , 114 , 118 , 119 , 121 – 123 , 125 , 126 , 129 , 130 ], 12 on bipolar disorder (BD) [ 30 , 32 , 37 , 48 , 56 , 68 , 72 , 75 , 85 , 105 , 106 , 117 ], 42 on TRD [ 26 , 28 , 31 , 33 , 35 – 39 , 42 , 44 , 54 , 57 – 63 , 66 , 70 , 73 , 74 , 76 , 78 , 83 , 86 , 87 , 93 , 94 , 98 , 99 , 102 , 104 , 107 – 109 , 112 , 113 , 116 , 128 , 131 , 132 ], and 16 included mixed MDD and BD populations [ 27 , 34 , 40 , 43 , 47 , 55 , 65 , 81 , 88 , 89 , 95 , 100 , 115 , 120 , 124 , 127 ]. Full study characteristics and demographics are presented in Supplementary Table S1 . Across the 134 active arms, 104 used conventional rTMS [ 25 – 36 , 40 – 45 , 47 – 50 , 53 – 55 , 57 – 62 , 64 – 67 , 69 , 71 – 74 , 76 – 81 , 83 – 87 , 89 – 91 , 94 , 96 – 105 , 107 , 108 , 112 – 125 , 128 – 132 ] and 30 applied TBS (iTBS and cTBS) [ 37 – 39 , 45 , 46 , 50 – 52 , 56 , 57 , 63 , 68 , 70 , 75 , 82 , 88 , 90 , 92 , 93 , 95 , 106 , 109 – 111 , 113 , 119 , 126 , 127 ]. Most targeted the left dorsolateral prefrontal cortex (DLPFC; Fig. 1 B, 69 .4%) [ 25 – 28 , 31 – 33 , 36 – 40 , 42 – 45 , 47 , 49 , 53 , 54 , 57 – 59 , 62 , 64 – 74 , 77 – 85 , 89 – 91 , 94 , 96 – 105 , 107 , 109 – 125 , 128 – 130 ]. The most frequent parameters were 110% of resting motor threshold (MT; Fig. 1 C, 29 .1%) [ 26 , 30 , 32 , 35 , 36 , 39 , 41 – 45 , 47 – 50 , 54 – 56 , 73 , 74 , 76 , 78 , 85 – 87 , 107 , 108 , 110 , 111 , 115 – 117 , 122 , 129 – 131 ], 10 Hz frequency (Fig. 1 D, 35.8%) [ 26 , 28 , 32 , 33 , 35 , 42 – 45 , 53 , 54 , 57 , 58 , 62 , 64 , 67 , 69 , 71 – 74 , 77 , 80 , 81 , 84 , 90 , 91 , 96 , 97 , 99 , 101 – 103 , 105 , 107 , 113 – 115 , 117 , 119 , 121 , 122 , 124 , 132 ], 2-week treatment duration (Fig. 1 E, 45.5%) [ 25 , 27 , 31 , 32 , 34 , 35 , 40 , 41 , 44 , 45 , 49 , 51 – 53 , 55 , 57 , 59 , 69 , 70 , 73 , 76 , 81 – 83 , 85 – 87 , 89 , 90 , 94 , 95 , 97 , 99 , 101 , 104 , 107 , 108 , 112 , 113 , 118 , 119 , 122 , 124 , 125 ], 10 total sessions (Fig. 1 F, 38.8%) [ 25 , 27 , 31 , 32 , 40 , 41 , 44 , 45 , 49 , 51 , 53 , 55 , 57 , 59 , 69 , 70 , 76 , 81 , 83 , 85 , 87 , 89 , 94 , 95 , 99 , 101 , 104 , 107 , 108 , 112 – 114 , 118 , 122 , 124 , 125 ], 1,600 pulses per session (Fig. 1 G, 17.6%) [ 26 , 27 , 40 , 44 , 45 , 47 , 53 , 55 , 57 , 81 , 85 , 107 , 114 , 122 , 128 ], and 16,000 total pulses (Fig. 1 H, 13.9%, ranged widely from 1,200 to 160,000 pulses) [ 27 , 40 , 44 , 45 , 53 , 55 , 57 , 81 , 85 , 107 , 114 , 122 ]. Panel A Diagram of the preferred reporting items for systematic review and meta-analysis (PRISMA). B shows the flow of TMS treatment modalities and stimulation sites across different types of depressive episodes. Panels C–F summarize stimulation intensity, frequency, treatment duration, and total number of sessions. Panels G–H display the distributions of pulses per session and total pulses across all included trials. BD, bipolar disorder; MDD, major depressive disorder; TRD, treatment-resistant depression; TBS, theta-burst stimulation; rTMS, repetitive transcranial magnetic stimulation; R.PFC, right prefrontal cortex; L.PFC, left prefrontal cortex; R.DLPFC, right dorsolateral prefrontal cortex; L.DLPFC, left dorsolateral prefrontal cortex; DMPFC, dorsomedial prefrontal cortex. Quality of evidence Risk-of-bias assessments are summarized in Supplementary Table S2 and Figure S1 . Sequence generation was low risk in 65 trials (60.2%) and unclear in 43 (39.8%). Allocation concealment was low in 45 (41.7%), unclear in 60 (55.6%), and high in 3 (2.8%). Blinding of participants and personnel was low in 66 (61.1%) and unclear in 42 (38.9%). Blinding of outcome assessment was low in 103 (95.4%) and unclear in 5 (4.6%). Incomplete outcome data were low in 91 (84.3%), unclear in 11 (10.2%), and high in 6 (5.6%). Selective reporting was low in 104 (96.3%) and unclear in 4 (3.7%). Overall risk of bias was rated low in 54 trials (50.0%), unclear in 45 (41.7%), and high in 9 (8.3%). Dose-response meta-analysis for total pulses The dose-response associations for total pulses are shown in Fig. 2 and Supplementary Table S3 . For depressive symptoms, a significant non-linear pattern emerged. In acute analyses (105 studies, 126 effect sizes), improvement peaked at 30,800 pulses (95% CI 16,100–45,600), with a predicted SMD of 0.73 (95% CI 0.58–0.88), after which the curve plateaued. At follow-up (30 studies; 35 effect sizes), the overall association remained significant but was approximately linear across the observed range, with no evidence of a distinct peak. For treatment response, the acute effect (87 studies, 100 effect sizes) peaked at 37,000 pulses (95% CI 30,700–43,400), with a predicted RR of 2.61 (95% CI 2.18–3.16), and decreased thereafter. At follow-up (14 studies, 16 effect sizes), the optimum was 32,300 pulses (95% CI 25,000–39,700), with a predicted RR of 2.12 (95% CI 1.32–3.35), but effects diminished at higher exposures. For remission, the acute optimum (58 studies, 72 effect sizes) was 39,100 pulses (95% CI 32,000–46,100), with a predicted RR of 2.77 (95% CI 2.10–3.67), followed by gradual decline. At follow-up (11 studies, 11 effect sizes), the curve was flatter, with no clear peak. Dose-response meta-analysis for pulses per session Associations between pulses per session and outcomes are shown in Fig. 3 and Supplementary Table S4 . In acute analyses, depressive symptoms indicated an optimum at 1,800 pulses/session (95% CI 870–2,740), with a predicted SMD of 0.73 (95% CI 0.59–0.87), then gradually declined. At follow-up, the optimum was 1,300 pulses/session (95% CI 870–1,680), with a predicted SMD of 1.23 (95% CI 0.63–1.83), followed by decline. Regarding treatment response, the acute effect peaked at 2,200 pulses/session (95% CI 1,830–2,510), with a predicted RR of 2.56 (95% CI 2.14–3.03), then decreased. At follow-up, the optimum was 1,600 pulses/session (95% CI 1,480–1,760), with a predicted RR of 2.12 (95% CI 1.43–3.16), again followed by decline. Similarly, for remission, the acute peak was 1,800 pulses/session (95% CI 1,610–2,000), with a predicted RR of 2.83 (95% CI 2.27–3.56), after which the effect tapered. At follow-up, the maximum was 1,840 pulses/session (95% CI 1,490–2,190), with a predicted RR of 1.48 (95% CI 1.13–1.92). Dose-response meta-analysis for total sessions The associations for total number of sessions are shown in Fig. 4 and Supplementary Table S5 . In terms of depressive symptoms, acute analyses peaked at 14 sessions (95% CI 11–17), with a predicted SMD of 0.81 (95% CI 0.64–0.98), followed by decline. At follow-up, the association appeared linear across the examined range, with no indication of a distinct peak. For treatment response, the acute optimum was 16 sessions (95% CI 12–19), with a predicted RR of 2.29 (95% CI 1.90–2.77). At follow-up, the dose–response relation remained broadly linear without evidence of a peak or downturn. Regarding remission, acute effects peaked at 23 sessions (95% CI 17–29), with a predicted RR of 2.59 (95% CI 1.99–3.39), followed by gradual decline. At follow-up, no clear maximum was identified; the overall association was not statistically significant (χ²=5.09, df = 2; p = 0.078). Dose-response meta-analysis for treatment duration The associations between treatment duration and outcomes are shown in Fig. 5 and Supplementary Table S6 . Analysis of acute depressive symptoms revealed peak occurred at 2.9 weeks (95% CI 2.4–3.5), with a predicted SMD of 0.84 (95% CI 0.67–1.00). At follow-up, the test for non-linearity was not significant. Acute treatment response rose to a peak at 2.7 weeks (95% CI 2.2–3.2; predicted RR 2.39, 95% CI 1.99–2.89). This outcome at follow-up was maximized at 2.9 weeks (95% CI 2.4–3.5; predicted RR 2.03, 95% CI 1.36–3.00), after which it declined. Finally, the optimum for acute remission was 3.1 weeks (95% CI 2.5–3.7; predicted RR 2.56, 95% CI 2.01–3.32), while the follow-up maximum was 3.3 weeks (95% CI 2.6–4.0; predicted RR 1.36, 95% CI 1.12–1.66), with no further gains beyond this point. Subgroup analysis Eight prespecified subgroup models were examined (rTMS and TBS each assessed for total pulses, pulses per session, total sessions, and treatment duration). For conventional rTMS, acute outcomes consistently demonstrated non-linear associations with mid-range optima: 30,000 to 40,000 total pulses, 1,500 to 2,300 pulses per session, 15 to 17 sessions, and about 3 weeks of treatment. At follow-up, effects were weaker and largely linear; where peaks appeared, they were small and exploratory. For TBS, acute outcomes showed similar patterns but at lower dose levels, with optima around 2,000 pulses per session, 8 to 10 sessions, and 2 to 2.5 weeks of treatment. Total pulse analyses suggested peaks near 40,000 for response, but follow-up evidence was inconsistent, with sparse data (≤ 5 studies in several strata) yielding unstable curves and wide uncertainty. Taken together, the subgroup analyses indicate that moderate dosing regimens, rather than the highest exposures, are associated with the greatest acute benefit for both rTMS and TBS. Follow-up effects were smaller, often linear, and less precisely estimated, especially for TBS. We therefore highlight acute non-linearity and mid-range plateaus as the most reproducible findings, while treating apparent follow-up peaks as hypothesis-generating given limited data. Full subgroup outputs are reported in Supplementary Tables S7 – S14 and Figs. S2 – S9 . Sensitivity analyses and publication bias The robustness of our dose-response findings was supported by leave-one-out sensitivity analyses, which demonstrated stable EDmax estimates and linear slopes without sign reversals. Publication bias, evaluated using Egger’s test, was generally absent. Significant small-study effects were observed only in a few outcomes, particularly those assessing follow-up efficacy. Comprehensive results for these sensitivity and publication bias analyses are presented in the Supplementary material (see the Sensitivity analysis section), including detailed summaries ( Table S15 ) and supporting visualizations (leave-one-out analyses in Figures S10 – S13 ; funnel plots in Figures S14 – S17 ). Discussion In this dose-response meta-analysis of 108 randomized, sham-controlled clinical trials, four rTMS dosing parameters (total pulses, pulses per session, number of sessions, and treatment duration) showed consistent non-linear associations with acute outcomes in MDE [ 7 , 8 , 10 ]. Across continuous and binary endpoints, benefits generally peaked at mid-range exposures and then plateaued or declined, indicating that more stimulation is not invariably better. For conventional rTMS, the dose ranges associated with the highest predicted acute benefit were 30,000–40,000 total pulses, 1,500–2,300 pulses per session, 15–17 sessions, and approximately 3 weeks of treatment. Follow-up effects were smaller, often near-linear, and imprecisely estimated. TBS showed a qualitatively similar pattern, with optima at lower exposures of approximately 2 000 pulses per session, 8–10 sessions, and about 2–2.5 weeks of treatment. However, the evidence base was relatively sparse, particularly for follow-up outcomes. A key observation is that estimated “best” doses differ across depressive-symptom change (continuous), response (≥ 50% reduction), and remission (scale-defined thresholds). This divergence is expected and clinically informative for three reasons. First, the endpoints capture progressively stricter clinical goals: continuous scores detect early, broad improvements; response requires surpassing a relative threshold; remission requires crossing an absolute low-symptom boundary. As targets become more stringent, curves tend to shift rightward or flatten because additional “consolidation” of benefit is needed to convert partial improvement into threshold-crossing events. Second, the endpoints are modeled on different statistical scales with distinct variance structures and inherent saturation: continuous outcomes summarize mean change on an approximately linear scale, whereas response and remission are estimated on the log-risk scale for Bernoulli outcomes with an implicit sigmoidal link. Even when underlying symptom improvement rises smoothly with increasing dose, probability curves derived from binary outcomes tend to flatten and saturate as they approach their 0–1 limits. This produces different apparent slopes and internal peaks compared with standardized mean differences, reflecting differences in modeling scale rather than in subgroup composition. Third, the four dosing parameters correspond to different phases of clinical change. Pulses per session primarily represent within-session induction, whereas the number of sessions and overall duration reflect between-session consolidation. Total pulses combine these components and can be achieved through heterogeneous schedules with distinct neuroplastic and tolerability profiles. As a result, each endpoint-specific EDmax represents a different perspective on the same underlying dose–response curve. Because many confidence intervals overlap, these differences should be viewed as indicative rather than prescriptive. These findings have clear clinical relevance. When the primary goal is to reduce symptoms, treatment regimens set at the moderate dose ranges identified above achieve most of the acute benefit with good efficiency [ 133 , 134 ]. Achieving remission depends more on adequate consolidation through sufficient sessions and treatment duration, but gains diminish at higher exposures. This pattern is consistent with metaplastic counter-regulation [ 135 ] and with practical limits on adherence and tolerability observed in real-world settings [ 136 , 137 ]. The modest and largely linear associations observed at follow-up suggest that sustaining treatment effects may require additional strategies beyond dose escalation. These include continuation or maintenance TMS [ 138 , 139 ], optimization of pharmacotherapy [ 140 ], and psychotherapy [ 141 ] tailored to individual risk profiles and early treatment response. Beyond these clinical implications, our findings build on and help reconcile previous meta-analyses. Earlier studies reported bell-shaped or plateauing dose–response patterns when total pulses were used to quantify exposure, with indications of a clinical plateau around 3–4 weeks and possible moderation by stimulation frequency [ 7 ]. By modelling the four dosing parameters separately and evaluating both acute and follow-up outcomes across continuous and binary measures, our analysis shows that the most consistent pattern is a mid-range plateau during the acute phase. The estimated maxima for total exposure and treatment duration align with findings from total-pulse–based and trajectory analyses [ 7 , 8 ], but also suggest that increasing exposure beyond typical clinical regimens offers little additional benefit and, in some models, even a decline in efficacy. Several mechanisms may underlie these plateaus. rTMS involves neural plasticity mechanisms regulated by homeostatic or metaplastic processes [ 142 ], and excessive or prolonged stimulation can trigger counter-regulatory responses that reduce overall benefit [ 143 ]. Clinically, higher stimulation doses can lead to greater fatigue and scalp discomfort, which may limit tolerability. Higher dropout rates have been reported in TMS programmes and can, in turn, reduce the effective dose delivered and overall adherence [ 144 ]. Greater pulses per session also tend to co-vary with other parameters, such as inter-train interval, frequency, and intensity, which may alter the balance between facilitatory and inhibitory effects [ 145 ]. Although these dose-response analyses cannot fully separate such co-variations, the consistent shape of the curves across endpoints argues against a purely statistical explanation. Several limitations should be acknowledged. Follow-up data, particularly for TBS, were limited, resulting in wide uncertainty at the extremes of the dose distribution. Although one-stage random-effects spline models help reduce ecological bias and capture non-linear trends, each dose parameter was analyzed separately. Residual confounding by unmeasured factors such as stimulation frequency, target site, intensity, coil type, or navigation method therefore remains possible, and total pulses are mathematically dependent on the other components [ 146 ]. Moreover, potential interactions among dose dimensions, including total pulses, pulses per session, number of sessions, and treatment duration, were not directly modeled [ 147 ]. Specific combinations of these parameters may exert synergistic or antagonistic influences on treatment outcomes (e.g., depressive-symptom change, treatment response, or remission) [ 147 ], which should be further explored in future research. In addition, most included trials targeted the left DLPFC using 10 Hz stimulation at about 110% of the motor threshold for 2–3 weeks of treatment. Generalizability to other stimulation targets (e.g., dorsomedial or right prefrontal cortex) remains limited, and target-specific efficacy differences may exist [ 66 ]. Future research could employ network meta-analysis to systematically compare and rank target sites [ 5 ]. Finally, variation in sham procedures, concomitant treatments, definitions of treatment-resistant depression, and rating scales also contributes to heterogeneity across studies [ 148 ]. In summary, rTMS efficacy increases sharply at lower exposures, reaches its greatest effect at moderate doses, and then levels off or declines. The dose–response maxima vary across endpoints, reflecting differences in clinical definition, statistical scale, and the relative roles of induction and consolidation. These findings support a dosing approach focused on well-calibrated, mid-range regimens that are matched to the therapeutic goal, such as symptom improvement, treatment response, or remission, and highlight the importance of maintenance strategies to sustain benefit over time. Declarations Contributors ZXW and RMS contributed equally to this work. XYG and TFY contributed equally to this work and are joint senior authors. ZXW, RMS, XYG and TFY conceived and designed the study. XYG and TFY supervised the study. ZXW, RMS and ZLZ performed the statistical analysis. ZXW, RMS and RFS extracted the data. All authors contributed to the acquisition, analysis, or interpretation of data. ZXW, RMS, VRS, XYG and TFY drafted the manuscript. All authors revised the report and approved the final version before submission. XYG and TFY are the guarantors. Declaration of interests All authors hereby attest that they do not have any conflicts of interest related to this article. Acknowledgements This work was supported by the National Key Research and Development Program of China (2023YFC2506202); Fundamental Research Funds for the Central Universities (project number YG2024ZD25); Zhejiang Key Laboratory of Precision Psychiatry (Grant No. 2025A4); Sichuan Science and Technology Program (2024NSFSC1564); Three-year action plan for Shanghai’s public health system construction (GWVI-2.1.4); National Institute on Mental Health (R01MH132044) and the National Institute on Drug Abuse (R21DA05871). Ethical approval Not required. Data sharing statement The data used in this meta-analysis were extracted from previously published studies cited in the reference list. The data extraction and analytical code are available from the corresponding author upon reasonable request. Declaration of generative AI and AI-assisted technologies in the writing process During the preparation of this work the authors used ChatGPT in order to language polishing. 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The priming effect of repetitive transcranial magnetic stimulation on clinical response to electroconvulsive therapy in treatment-resistant depression: a randomized, double-blind, sham-controlled study. Psychol Med. 2023;53(5):2060–71. Wang X, He K, Chen T, Shi B, Yang J, Geng W, et al. Therapeutic efficacy of connectivity-directed transcranial magnetic stimulation on anticipatory anhedonia. Depress Anxiety. 2021;38(9):972–84. Zhou D, Li X, Wei S, Yu C, Wang D, Li Y, et al. Transcranial Direct Current Stimulation Combined With Repetitive Transcranial Magnetic Stimulation for Depression: A Randomized Clinical Trial. JAMA Netw Open. 2024;7(11):e2444306. Rumi DO, Gattaz WF, Rigonatti SP, Rosa MA, Fregni F, Rosa MO, et al. Transcranial magnetic stimulation accelerates the antidepressant effect of amitriptyline in severe depression: a double-blind placebo-controlled study. Biol Psychiatry. 2005;57(2):162–6. Fitzgerald PB, Brown TL, Marston NA, Daskalakis ZJ, De Castella A, Kulkarni J. 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Efficacy and tolerability of theta-burst stimulation for major depression: A systematic review and meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2021;106:110168. Rachid F, Bertschy G. Safety and efficacy of repetitive transcranial magnetic stimulation in the treatment of depression: a critical appraisal of the last 10 years. Neurophysiol Clin. 2006;36(3):157–83. Senova S, Cotovio G, Pascual-Leone A, Oliveira-Maia AJ. Durability of antidepressant response to repetitive transcranial magnetic stimulation: Systematic review and meta-analysis. Brain Stimul. 2019;12(1):119–28. d'Andrea G, Mancusi G, Santovito MC, Marrangone C, Martino F, Santorelli M, et al. Investigating the Role of Maintenance TMS Protocols for Major Depression: Systematic Review and Future Perspectives for Personalized Interventions. J Pers Med. 2023;13(4):697. Rakesh G, Cordero P, Khanal R, Himelhoch SS, Rush CR. Optimally combining transcranial magnetic stimulation with antidepressants in major depressive disorder: A systematic review and Meta-analysis. J Affect Disord. 2024;358:432–9. Walther S, Maderthaner L, Chapellier V, von Känel S, Müller DR, Bohlhalter S et al. Gesture deficits in psychosis and the combination of group psychotherapy and transcranial magnetic stimulation: A randomized clinical trial. Mol Psychiatry. 2025. Karabanov A, Ziemann U, Hamada M, George MS, Quartarone A, Classen J, et al. Consensus Paper: Probing Homeostatic Plasticity of Human Cortex With Non-invasive Transcranial Brain Stimulation. Brain Stimul. 2015;8(5):993–1006. Anil S, Lu H, Rotter S, Vlachos A. Repetitive transcranial magnetic stimulation (rTMS) triggers dose-dependent homeostatic rewiring in recurrent neuronal networks. PLoS Comput Biol. 2023;19(11):e1011027. Caulfield KA, Fleischmann HH, George MS, McTeague LM. A transdiagnostic review of safety, efficacy, and parameter space in accelerated transcranial magnetic stimulation. J Psychiatr Res. 2022;152:384–96. Gershon AA, Dannon PN, Grunhaus L. Transcranial magnetic stimulation in the treatment of depression. Am J Psychiatry. 2003;160(5):835–45. Discacciati A, Crippa A, Orsini N. Goodness of fit tools for dose-response meta-analysis of binary outcomes. Res Synth Methods. 2017;8(2):149–60. Oostra E, Jazdzyk P, Vis V, Dalhuisen I, Hoogendoorn AW, Planting C, et al. More rTMS pulses or more sessions? The impact on treatment outcome for treatment resistant depression. Acta Psychiatr Scand. 2025;151(4):485–505. Brini S, Brudasca NI, Hodkinson A, Kaluzinska K, Wach A, Storman D, et al. Efficacy and safety of transcranial magnetic stimulation for treating major depressive disorder: An umbrella review and re-analysis of published meta-analyses of randomised controlled trials. Clin Psychol Rev. 2023;100:102236. Additional Declarations No competing interests reported. Supplementary Files Supplementarymaterials.docx PRISMAChecklist.doc Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 20 Mar, 2026 Reviews received at journal 20 Mar, 2026 Reviews received at journal 19 Mar, 2026 Reviews received at journal 08 Mar, 2026 Reviewers agreed at journal 06 Mar, 2026 Reviewers agreed at journal 04 Mar, 2026 Reviewers agreed at journal 04 Mar, 2026 Reviewers invited by journal 29 Jan, 2026 Editor assigned by journal 20 Jan, 2026 Submission checks completed at journal 20 Jan, 2026 First submitted to journal 20 Jan, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8648926","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":582678042,"identity":"b9623bde-ac73-41ee-a968-e796110a81e0","order_by":0,"name":"Zuxing Wang","email":"","orcid":"","institution":"Shanghai Jiao Tong University","correspondingAuthor":false,"prefix":"","firstName":"Zuxing","middleName":"","lastName":"Wang","suffix":""},{"id":582678052,"identity":"11b8bca0-9912-472d-b969-cb27355533e2","order_by":1,"name":"Ruanmei Sheng","email":"","orcid":"","institution":"Shanghai Jiao Tong University","correspondingAuthor":false,"prefix":"","firstName":"Ruanmei","middleName":"","lastName":"Sheng","suffix":""},{"id":582678062,"identity":"5257b8c9-e571-4598-8e68-021d1a5fb244","order_by":2,"name":"Ruifeng Shi","email":"","orcid":"","institution":"University of Electronic Science and Technology of China","correspondingAuthor":false,"prefix":"","firstName":"Ruifeng","middleName":"","lastName":"Shi","suffix":""},{"id":582678065,"identity":"330cf90e-9b68-4ab4-b0e0-e2ba74d74087","order_by":3,"name":"Zhili Zou","email":"","orcid":"","institution":"University of Electronic Science and Technology of China","correspondingAuthor":false,"prefix":"","firstName":"Zhili","middleName":"","lastName":"Zou","suffix":""},{"id":582678072,"identity":"63307610-b480-4a27-8887-4fd0837aec2a","order_by":4,"name":"Vaughn R. Steele","email":"","orcid":"","institution":"Yale University","correspondingAuthor":false,"prefix":"","firstName":"Vaughn","middleName":"R.","lastName":"Steele","suffix":""},{"id":582678073,"identity":"46e464a0-f2f8-4d9c-8d7f-ae59e14ac249","order_by":5,"name":"Xiaoyun Guo","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0klEQVRIiWNgGAWjYDACZgTrwIEPP0jTwpZ4cGYPafbxGB/mYCNCncFx5oePedvu2G043vPhMAMPgzy/2AH8WiSb2YyNedueJW84c3bD4QILBsOZsxPwa+FnZjCT5m07nGxwI3fD4Rk8DAkGtwloYWNm/wbVkvPgMA8bEVr4mXnAttgBtTAQp0WymafYcM65wwmSZ44ZAANZgrBfDM4f3/jgTdlhe77jzY8/fPhhI88vTUALCDDxMDAkNkDYEoSVgwAjMJnYE6d0FIyCUTAKRiQAAKD0Rc7M1WJYAAAAAElFTkSuQmCC","orcid":"","institution":"Shanghai Jiao Tong University","correspondingAuthor":true,"prefix":"","firstName":"Xiaoyun","middleName":"","lastName":"Guo","suffix":""},{"id":582678075,"identity":"89e00319-b9b4-4cef-aa14-5b782860ed2b","order_by":6,"name":"Tifei Yuan","email":"","orcid":"","institution":"Shanghai Jiao Tong University","correspondingAuthor":false,"prefix":"","firstName":"Tifei","middleName":"","lastName":"Yuan","suffix":""}],"badges":[],"createdAt":"2026-01-20 12:06:40","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8648926/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8648926/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":101679861,"identity":"4383ffc9-f987-417c-b896-fe4ea4a3d513","added_by":"auto","created_at":"2026-02-02 14:14:10","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":780701,"visible":true,"origin":"","legend":"\u003cp\u003eOverview of study characteristics and stimulation parameter distributions among 108 included randomized sham-controlled trials.\u003c/p\u003e\n\u003cp\u003ePanel A Diagram of the preferred reporting items for systematic review and meta-analysis (PRISMA). B shows the flow of TMS treatment modalities and stimulation sites across different types of depressive episodes. Panels C–F summarize stimulation intensity, frequency, treatment duration, and total number of sessions. Panels G–H display the distributions of pulses per session and total pulses across all included trials. BD, bipolar disorder; MDD, major depressive disorder; TRD, treatment-resistant depression; TBS, theta-burst stimulation; rTMS, repetitive transcranial magnetic stimulation; R.PFC, right prefrontal cortex; L.PFC, left prefrontal cortex; R.DLPFC, right dorsolateral prefrontal cortex; L.DLPFC, left dorsolateral prefrontal cortex; DMPFC, dorsomedial prefrontal cortex.\u003c/p\u003e","description":"","filename":"Picture1.png","url":"https://assets-eu.researchsquare.com/files/rs-8648926/v1/472fd22a05ffc9d7df432eaa.png"},{"id":101679863,"identity":"864b8612-984d-47b3-a923-c7693489e56e","added_by":"auto","created_at":"2026-02-02 14:14:12","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":342111,"visible":true,"origin":"","legend":"\u003cp\u003eDose-response associations of rTMS with total pulses across depressive-symptom, treatment-response, and remission outcomes.\u003c/p\u003e\n\u003cp\u003ePanels A, D display standardized mean differences (SMDs) for continuous depressive-symptom scores, and Panels B, C, E, F display risk ratios (RR) for binary endpoints (treatment response and remission), during acute and follow-up periods. Curves were fitted using one-stage random-effects restricted cubic spline models with REML estimation. Shaded areas indicate pointwise 95% confidence intervals.\u003c/p\u003e","description":"","filename":"Picture2.png","url":"https://assets-eu.researchsquare.com/files/rs-8648926/v1/64f334980db8d6c83cd70c77.png"},{"id":101679857,"identity":"e245d407-c53d-4145-b54a-23003a877ccb","added_by":"auto","created_at":"2026-02-02 14:14:09","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":345823,"visible":true,"origin":"","legend":"\u003cp\u003eDose-response associations of rTMS with pulses per session across depressive-symptom, treatment-response, and remission outcomes.\u003c/p\u003e\n\u003cp\u003ePanels A, D display standardized mean differences (SMDs) for continuous depressive-symptom scores, and Panels B, C, E, F display risk ratios (RR) for binary endpoints (treatment response and remission), during acute and follow-up periods. Curves were fitted using one-stage random-effects restricted cubic spline models with REML estimation. Shaded areas indicate pointwise 95% confidence intervals.\u003c/p\u003e","description":"","filename":"Picture3.png","url":"https://assets-eu.researchsquare.com/files/rs-8648926/v1/d44848188b65f2f449e7a617.png"},{"id":101679862,"identity":"95a8e05f-9491-4404-b665-8f0313c5c370","added_by":"auto","created_at":"2026-02-02 14:14:10","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":229943,"visible":true,"origin":"","legend":"\u003cp\u003eDose-response associations of rTMS with total sessions across depressive-symptom, treatment-response, and remission outcomes.\u003c/p\u003e\n\u003cp\u003ePanels A, D display standardized mean differences (SMDs) for continuous depressive-symptom scores, and Panels B, C, E, F display risk ratios (RR) for binary endpoints (treatment response and remission), during acute and follow-up periods. Curves were fitted using one-stage random-effects restricted cubic spline models with REML estimation. Shaded areas indicate pointwise 95% confidence intervals.\u003c/p\u003e","description":"","filename":"Picture4.png","url":"https://assets-eu.researchsquare.com/files/rs-8648926/v1/f786afa9ebc230fcb13dbbf7.png"},{"id":101753400,"identity":"c2478dcd-d819-4123-ad4c-9e9cab3f7eae","added_by":"auto","created_at":"2026-02-03 10:39:58","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":336730,"visible":true,"origin":"","legend":"\u003cp\u003eDose-response associations of rTMS withtreatment duration (week) across depressive-symptom, treatment-response, and remission outcomes.\u003c/p\u003e\n\u003cp\u003ePanels A, D display standardized mean differences (SMDs) for continuous depressive-symptom scores, and Panels B, C, E, F display risk ratios (RR) for binary endpoints (treatment response and remission), during acute and follow-up periods. Curves were fitted using one-stage random-effects restricted cubic spline models with REML estimation. Shaded areas indicate pointwise 95% confidence intervals.\u003c/p\u003e","description":"","filename":"Picture5.png","url":"https://assets-eu.researchsquare.com/files/rs-8648926/v1/1e8341814a8043527401b221.png"},{"id":101755702,"identity":"b6e3d61f-2051-4945-b5a9-01eb5d71557d","added_by":"auto","created_at":"2026-02-03 10:53:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3060000,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8648926/v1/0a84bfce-8f57-432d-8128-6dc0d1a1f7e0.pdf"},{"id":101679860,"identity":"b81ccd0e-424d-442b-9908-ad1766ac32e8","added_by":"auto","created_at":"2026-02-02 14:14:10","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":7361253,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterials.docx","url":"https://assets-eu.researchsquare.com/files/rs-8648926/v1/7c6fcff7ca856aa72a9b3209.docx"},{"id":101679856,"identity":"26d8963e-5e7f-466d-8b20-d00829578df3","added_by":"auto","created_at":"2026-02-02 14:14:09","extension":"doc","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":70144,"visible":true,"origin":"","legend":"","description":"","filename":"PRISMAChecklist.doc","url":"https://assets-eu.researchsquare.com/files/rs-8648926/v1/a72c315e5bc5c15c07bfe09d.doc"}],"financialInterests":"No competing interests reported.","formattedTitle":"Acute and long-term effects of repetitive transcranial magnetic stimulation in major depressive episodes: a systematic review and dose-response meta-analysis of randomized sham-controlled trials","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMajor depressive episode (MDE) remains a leading cause of disability worldwide and imposes substantial clinical and economic burden [1]. Transcranial magnetic stimulation (TMS) is an established, guideline-endorsed, noninvasive treatment for depression [2]. However, clinical protocols vary widely in stimulation targets and dosing parameters (total pulses, pulses per session, number of sessions, and overall treatment duration), resulting in considerable heterogeneity in reported efficacy [3-6].\u003c/p\u003e\n\u003cp\u003eRecent dose-response syntheses point in complementary directions while leaving practical gaps [7-9]. In treatment-resistant depression (TRD), a multivariable meta-analysis reported that intensity, frequency, pulses per session, treatment duration, number of sessions, and total pulses explained meaningful variance [7]. Similarly, in TRD, a total-pulse-based analysis suggested a non-linear relationship peaking near 26,660 pulses, with frequency and age as significant moderators [8].\u0026nbsp;A trajectory-focused analysis showed a logarithmic improvement pattern with a plateau around weeks 3\u0026ndash;4 and larger cumulative benefit at \u0026ge;3000 pulses per session and higher total pulses\u0026nbsp;[9]. Additionally, a cross-protocol meta-analysis estimated near-maximal effective doses (ED95) and identified bell-shaped or ascending dose-response curves across paradigms using end-of-treatment assessments, across multiple psychiatric disorders\u0026nbsp;[10].\u003c/p\u003e\n\u003cp\u003eDespite these advances, decision-relevant evidence remains limited. Previous studies have rarely examined the four dose dimensions together (total pulses, pulses per session, number of sessions, and treatment duration) or quantified their independent contributions while linking dosing to both acute and follow-up outcomes across continuous scores and binary endpoints (response and remission) in MDE. To address these gaps, we conducted a dose-response meta-analysis of major depressive episodes to examine the nonlinear associations of total pulses, pulses per session, number of sessions, and treatment duration with acute and follow-up outcomes, including depressive-symptom severity, treatment response, and remission.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], and was prospectively registered in PROSPERO (registration number CRD420251051992).\u003c/p\u003e\n\u003ch3\u003eSearch strategy\u003c/h3\u003e\n\u003cp\u003eWe systematically searched CENTRAL (Cochrane Central Register of Controlled Trials), Embase, and PubMed from inception to May 1, 2025, for randomized controlled trials (RCTs) of TMS in MDE, restricted to English-language publications. Reference lists of relevant reviews and articles were screened, and corresponding authors were contacted for missing data. Two reviewers independently screened titles, abstracts, and full texts in duplicate, resolving disagreements by discussion or a third reviewer. Complete search strategies are provided in the Supplement.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eEligibility criteria\u003c/h2\u003e \u003cp\u003e \u003cb\u003eParticipants (P)\u003c/b\u003e. Adults aged 18\u0026ndash;65 years with a MDE in MDD or bipolar depression, diagnosed by DSM Diagnostic and Statistical Manual of Mental Disorders (DSM) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] or International Classification of Diseases (ICD) [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Exclusion criteria included age\u0026thinsp;\u0026lt;\u0026thinsp;18 or \u0026gt;\u0026thinsp;65, secondary mood disorders, severe cognitive impairment, or relapse-prevention/maintenance designs.\u003c/p\u003e \u003cp\u003e \u003cb\u003eInterventions (I)\u003c/b\u003e. Therapeutic TMS at any cortical site, frequency, or coil type. Eligible modalities included repetitive TMS (high-frequency, low-frequency, bilateral, accelerated), theta-burst stimulation (TBS: intermittent [iTBS] and continuous [cTBS]), and deep TMS. Trials in which TMS was not the primary intervention were excluded.\u003c/p\u003e \u003cp\u003e \u003cb\u003eComparators (C)\u003c/b\u003e. Sham TMS using accepted inert methods (e.g., sham coil or angled coil). For cross-over trials, only pre-cross-over data were used.\u003c/p\u003e \u003cp\u003e \u003cb\u003eOutcomes (O)\u003c/b\u003e. The six prespecified primary outcomes were assessed at two time points: an acute phase (end of treatment or within 7 days) and a follow-up phase (more than 7 days after treatment). Each window included three endpoints: continuous depressive-symptom severity, treatment response, and remission. Symptom severity was preferentially extracted from Hamilton Rating Scale for Depression (HAMD) [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], Montgomery-Asberg Depression Rating Scale (MADRS) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], or Beck Depression Inventory (BDI) [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Symptom severity was extracted according to a prespecified hierarchy: HAMD first, then MADRS, and BDI if neither clinician-rated scale was available. Binary endpoints (response and remission) were extracted as reported in each trial, adhering to the trial\u0026rsquo;s prespecified definitions and analyses. We did not derive response or remission from continuous data when not reported. Where provided, common criteria included\u0026thinsp;\u0026ge;\u0026thinsp;50% reduction from baseline for response and instrument-specific remission cut-offs (e.g., HAMD-17\u0026thinsp;\u0026le;\u0026thinsp;7, MADRS\u0026thinsp;\u0026le;\u0026thinsp;10).\u003c/p\u003e \u003cp\u003e \u003cb\u003eStudy design (S)\u003c/b\u003e. Peer-reviewed RCTs comparing active versus sham TMS, with extractable data.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData extraction\u003c/h3\u003e\n\u003cp\u003eTwo reviewers independently extracted trial-level data using a piloted form, with disagreements resolved by a third reviewer. For each study arm, we recorded author, year, and country; intervention details (active TMS parameters and sham control method); diagnosis (major depressive episode in MDD or bipolar depression) and diagnostic criteria (DSM or ICD); treatment-resistance status; sample size (randomized and completed); sex distribution (male/female); age (mean, SD); rating scale used; depression severity (mean, SD) at baseline, post-treatment, and follow-up; concomitant medication status and any washout period; stimulated brain region (no restriction); stimulation frequency (Hz); intensity as % of motor threshold (MT%); pulses per session and number of sessions; total pulses (calculated when not explicitly reported as pulses-per-session \u0026times; sessions); and treatment duration.\u003c/p\u003e \u003cp\u003eOutcomes were extracted at post-treatment and follow-up, prioritizing the 2-week post-treatment timepoint. Endpoints comprised continuous depressive-symptom severity and the binary outcomes of response and remission. Where necessary, missing dispersion metrics (e.g., SD) were derived from SEs, CIs, or p values using standard formulae. For cross-over studies, only pre-cross-over data were extracted; multi-arm trials were extracted by arm. We preferentially used intention-to-treat denominators for response/remission when available; otherwise, available-case data were extracted as reported.\u003c/p\u003e\n\u003ch3\u003eQuality assessment\u003c/h3\u003e\n\u003cp\u003eRisk of bias was assessed using the Cochrane Risk of Bias tool [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Two reviewers independently rated each domain as low, unclear, or high risk; disagreements were resolved by consensus or third-party adjudication. An overall risk-of-bias judgment was then assigned for each study.\u003c/p\u003e\n\u003ch3\u003eStatistical analyses\u003c/h3\u003e\n\u003cp\u003eTMS dose was defined a priori across four dimensions: total pulses, pulses per session, number of sessions, and treatment duration in weeks. For the clinical interpretation of dose-response curves, we pre-specified categorical dose levels (low, mid-range, high) for each dimension, based on established therapeutic ranges from previous studies [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Mid-range dose was defined as follows: 30,000\u0026ndash;40,000 total pulses; 1,500\u0026ndash;2,000 pulses/session; 10\u0026ndash;20 sessions; and 2\u0026ndash;3 weeks' duration. Doses below and above these ranges were classified as low and high, respectively. Each dimension was analyzed separately. Treatment effects were summarized as standardized mean differences (SMD) for continuous depressive-symptom scores and log risk ratios (logRR) for binary endpoints (response, remission), with 95% confidence intervals (CIs). For binary data, logRRs and standard errors were computed from 2\u0026times;2 tables; when any cell count was zero, the Haldane-Anscombe 0.5 continuity correction was applied [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Binary outcomes were modeled on the log-risk-ratio scale and are reported as RRs (by exponentiation) with 95% CIs.\u003c/p\u003e \u003cp\u003eDose-response relations were estimated using a one-stage random-effects model with the between-study variance estimated by restricted maximum likelihood (REML), implemented in \u003cem\u003edosresmeta\u003c/em\u003e [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Non-linearity was accommodated with restricted cubic splines (three knots at the 10th, 50th, and 90th centiles of the observed dose distribution) [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Wald χ\u0026sup2; tests evaluated the overall association and departure from linearity. The maximum effective dose (EDmax), defined as the dose associated with the highest predicted benefit within the observed range, was estimated from the fitted spline. Pointwise 95% confidence intervals were obtained using the delta method.\u003c/p\u003e \u003cp\u003eWe prespecified a tiered approach for sensitivity analysis. When both the overall dose-response and the non-linearity test were significant, we assessed robustness of the EDmax with leave-one-out re-fits of the spline model, recording interior peaks only [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. When the overall association was significant but non-linearity was not, we focused on the linear dose trend: a one-stage random-effects meta-regression [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. We summarized leave-one-out slopes (median, interquartile range, sign reversals, and loss of significance) and compared the linear and spline specifications using the Akaike Information Criterion and a Wald test for non-linearity. Publication bias and small-study effects were examined using contour-enhanced funnel plots and dose-adjusted Egger-type meta-regressions [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Two-sided p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. Analyses were conducted in R (version 4.4.3).\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStudy characteristics\u003c/h2\u003e \u003cp\u003eWe retrieved 6,962 published records in all three literature databases, of which 108 RCTs with sham arms met inclusion criteria, comprising 134 intervention arms (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA) [\u003cspan additionalcitationids=\"CR26 CR27 CR28 CR29 CR30 CR31 CR32 CR33 CR34 CR35 CR36 CR37 CR38 CR39 CR40 CR41 CR42 CR43 CR44 CR45 CR46 CR47 CR48 CR49 CR50 CR51 CR52 CR53 CR54 CR55 CR56 CR57 CR58 CR59 CR60 CR61 CR62 CR63 CR64 CR65 CR66 CR67 CR68 CR69 CR70 CR71 CR72 CR73 CR74 CR75 CR76 CR77 CR78 CR79 CR80 CR81 CR82 CR83 CR84 CR85 CR86 CR87 CR88 CR89 CR90 CR91 CR92 CR93 CR94 CR95 CR96 CR97 CR98 CR99 CR100 CR101 CR102 CR103 CR104 CR105 CR106 CR107 CR108 CR109 CR110 CR111 CR112 CR113 CR114 CR115 CR116 CR117 CR118 CR119 CR120 CR121 CR122 CR123 CR124 CR125 CR126 CR127 CR128 CR129 CR130 CR131\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR132\" class=\"CitationRef\"\u003e132\u003c/span\u003e]. In total, 5,621 participants were enrolled: 3,021 randomized to active rTMS (mean age 43.3 years; 59.2% female) and 2,590 to sham (mean age 42.5 years; 55.8% female). Among the trials, 38 focused on MDD [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan additionalcitationids=\"CR50 CR51 CR52\" citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e, \u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e, \u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e, \u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e, \u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e, \u003cspan citationid=\"CR77\" class=\"CitationRef\"\u003e77\u003c/span\u003e, \u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e, \u003cspan citationid=\"CR80\" class=\"CitationRef\"\u003e80\u003c/span\u003e, \u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e82\u003c/span\u003e, \u003cspan citationid=\"CR84\" class=\"CitationRef\"\u003e84\u003c/span\u003e, \u003cspan additionalcitationids=\"CR91\" citationid=\"CR90\" class=\"CitationRef\"\u003e90\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR92\" class=\"CitationRef\"\u003e92\u003c/span\u003e, \u003cspan citationid=\"CR96\" class=\"CitationRef\"\u003e96\u003c/span\u003e, \u003cspan citationid=\"CR97\" class=\"CitationRef\"\u003e97\u003c/span\u003e, \u003cspan citationid=\"CR101\" class=\"CitationRef\"\u003e101\u003c/span\u003e, \u003cspan citationid=\"CR103\" class=\"CitationRef\"\u003e103\u003c/span\u003e, \u003cspan citationid=\"CR110\" class=\"CitationRef\"\u003e110\u003c/span\u003e, \u003cspan citationid=\"CR111\" class=\"CitationRef\"\u003e111\u003c/span\u003e, \u003cspan citationid=\"CR114\" class=\"CitationRef\"\u003e114\u003c/span\u003e, \u003cspan citationid=\"CR118\" class=\"CitationRef\"\u003e118\u003c/span\u003e, \u003cspan citationid=\"CR119\" class=\"CitationRef\"\u003e119\u003c/span\u003e, \u003cspan additionalcitationids=\"CR122\" citationid=\"CR121\" class=\"CitationRef\"\u003e121\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR123\" class=\"CitationRef\"\u003e123\u003c/span\u003e, \u003cspan citationid=\"CR125\" class=\"CitationRef\"\u003e125\u003c/span\u003e, \u003cspan citationid=\"CR126\" class=\"CitationRef\"\u003e126\u003c/span\u003e, \u003cspan citationid=\"CR129\" class=\"CitationRef\"\u003e129\u003c/span\u003e, \u003cspan citationid=\"CR130\" class=\"CitationRef\"\u003e130\u003c/span\u003e], 12 on bipolar disorder (BD) [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e, \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e, \u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e, \u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e, \u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e, \u003cspan citationid=\"CR85\" class=\"CitationRef\"\u003e85\u003c/span\u003e, \u003cspan citationid=\"CR105\" class=\"CitationRef\"\u003e105\u003c/span\u003e, \u003cspan citationid=\"CR106\" class=\"CitationRef\"\u003e106\u003c/span\u003e, \u003cspan citationid=\"CR117\" class=\"CitationRef\"\u003e117\u003c/span\u003e], 42 on TRD [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan additionalcitationids=\"CR36 CR37 CR38\" citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e, \u003cspan additionalcitationids=\"CR58 CR59 CR60 CR61 CR62\" citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e, \u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e, \u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e, \u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e, \u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e, \u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e, \u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e, \u003cspan citationid=\"CR83\" class=\"CitationRef\"\u003e83\u003c/span\u003e, \u003cspan citationid=\"CR86\" class=\"CitationRef\"\u003e86\u003c/span\u003e, \u003cspan citationid=\"CR87\" class=\"CitationRef\"\u003e87\u003c/span\u003e, \u003cspan citationid=\"CR93\" class=\"CitationRef\"\u003e93\u003c/span\u003e, \u003cspan citationid=\"CR94\" class=\"CitationRef\"\u003e94\u003c/span\u003e, \u003cspan citationid=\"CR98\" class=\"CitationRef\"\u003e98\u003c/span\u003e, \u003cspan citationid=\"CR99\" class=\"CitationRef\"\u003e99\u003c/span\u003e, \u003cspan citationid=\"CR102\" class=\"CitationRef\"\u003e102\u003c/span\u003e, \u003cspan citationid=\"CR104\" class=\"CitationRef\"\u003e104\u003c/span\u003e, \u003cspan additionalcitationids=\"CR108\" citationid=\"CR107\" class=\"CitationRef\"\u003e107\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR109\" class=\"CitationRef\"\u003e109\u003c/span\u003e, \u003cspan citationid=\"CR112\" class=\"CitationRef\"\u003e112\u003c/span\u003e, \u003cspan citationid=\"CR113\" class=\"CitationRef\"\u003e113\u003c/span\u003e, \u003cspan citationid=\"CR116\" class=\"CitationRef\"\u003e116\u003c/span\u003e, \u003cspan citationid=\"CR128\" class=\"CitationRef\"\u003e128\u003c/span\u003e, \u003cspan citationid=\"CR131\" class=\"CitationRef\"\u003e131\u003c/span\u003e, \u003cspan citationid=\"CR132\" class=\"CitationRef\"\u003e132\u003c/span\u003e], and 16 included mixed MDD and BD populations [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e, \u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e, \u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e81\u003c/span\u003e, \u003cspan citationid=\"CR88\" class=\"CitationRef\"\u003e88\u003c/span\u003e, \u003cspan citationid=\"CR89\" class=\"CitationRef\"\u003e89\u003c/span\u003e, \u003cspan citationid=\"CR95\" class=\"CitationRef\"\u003e95\u003c/span\u003e, \u003cspan citationid=\"CR100\" class=\"CitationRef\"\u003e100\u003c/span\u003e, \u003cspan citationid=\"CR115\" class=\"CitationRef\"\u003e115\u003c/span\u003e, \u003cspan citationid=\"CR120\" class=\"CitationRef\"\u003e120\u003c/span\u003e, \u003cspan citationid=\"CR124\" class=\"CitationRef\"\u003e124\u003c/span\u003e, \u003cspan citationid=\"CR127\" class=\"CitationRef\"\u003e127\u003c/span\u003e]. Full study characteristics and demographics are presented in Supplementary \u003cb\u003eTable S1\u003c/b\u003e.\u003c/p\u003e \u003cp\u003eAcross the 134 active arms, 104 used conventional rTMS [\u003cspan additionalcitationids=\"CR26 CR27 CR28 CR29 CR30 CR31 CR32 CR33 CR34 CR35\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan additionalcitationids=\"CR41 CR42 CR43 CR44\" citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan additionalcitationids=\"CR48 CR49\" citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e, \u003cspan additionalcitationids=\"CR54\" citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e, \u003cspan additionalcitationids=\"CR58 CR59 CR60 CR61\" citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e, \u003cspan additionalcitationids=\"CR65 CR66\" citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e, \u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e, \u003cspan additionalcitationids=\"CR72 CR73\" citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e, \u003cspan additionalcitationids=\"CR77 CR78 CR79 CR80\" citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e81\u003c/span\u003e, \u003cspan additionalcitationids=\"CR84 CR85 CR86\" citationid=\"CR83\" class=\"CitationRef\"\u003e83\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR87\" class=\"CitationRef\"\u003e87\u003c/span\u003e, \u003cspan additionalcitationids=\"CR90\" citationid=\"CR89\" class=\"CitationRef\"\u003e89\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR91\" class=\"CitationRef\"\u003e91\u003c/span\u003e, \u003cspan citationid=\"CR94\" class=\"CitationRef\"\u003e94\u003c/span\u003e, \u003cspan additionalcitationids=\"CR97 CR98 CR99 CR100 CR101 CR102 CR103 CR104\" citationid=\"CR96\" class=\"CitationRef\"\u003e96\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR105\" class=\"CitationRef\"\u003e105\u003c/span\u003e, \u003cspan citationid=\"CR107\" class=\"CitationRef\"\u003e107\u003c/span\u003e, \u003cspan citationid=\"CR108\" class=\"CitationRef\"\u003e108\u003c/span\u003e, \u003cspan additionalcitationids=\"CR113 CR114 CR115 CR116 CR117 CR118 CR119 CR120 CR121 CR122 CR123 CR124\" citationid=\"CR112\" class=\"CitationRef\"\u003e112\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR125\" class=\"CitationRef\"\u003e125\u003c/span\u003e, \u003cspan additionalcitationids=\"CR129 CR130 CR131\" citationid=\"CR128\" class=\"CitationRef\"\u003e128\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR132\" class=\"CitationRef\"\u003e132\u003c/span\u003e] and 30 applied TBS (iTBS and cTBS) [\u003cspan additionalcitationids=\"CR38\" citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan additionalcitationids=\"CR51\" citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e, \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e, \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e, \u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e, \u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e, \u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e, \u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e, \u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e82\u003c/span\u003e, \u003cspan citationid=\"CR88\" class=\"CitationRef\"\u003e88\u003c/span\u003e, \u003cspan citationid=\"CR90\" class=\"CitationRef\"\u003e90\u003c/span\u003e, \u003cspan citationid=\"CR92\" class=\"CitationRef\"\u003e92\u003c/span\u003e, \u003cspan citationid=\"CR93\" class=\"CitationRef\"\u003e93\u003c/span\u003e, \u003cspan citationid=\"CR95\" class=\"CitationRef\"\u003e95\u003c/span\u003e, \u003cspan citationid=\"CR106\" class=\"CitationRef\"\u003e106\u003c/span\u003e, \u003cspan additionalcitationids=\"CR110\" citationid=\"CR109\" class=\"CitationRef\"\u003e109\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR111\" class=\"CitationRef\"\u003e111\u003c/span\u003e, \u003cspan citationid=\"CR113\" class=\"CitationRef\"\u003e113\u003c/span\u003e, \u003cspan citationid=\"CR119\" class=\"CitationRef\"\u003e119\u003c/span\u003e, \u003cspan citationid=\"CR126\" class=\"CitationRef\"\u003e126\u003c/span\u003e, \u003cspan citationid=\"CR127\" class=\"CitationRef\"\u003e127\u003c/span\u003e]. Most targeted the left dorsolateral prefrontal cortex (DLPFC; Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB, \u003cb\u003e69\u003c/b\u003e.4%) [\u003cspan additionalcitationids=\"CR26 CR27\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan additionalcitationids=\"CR32\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan additionalcitationids=\"CR37 CR38 CR39\" citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan additionalcitationids=\"CR43 CR44\" citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e, \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e, \u003cspan additionalcitationids=\"CR58\" citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e, \u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e, \u003cspan additionalcitationids=\"CR65 CR66 CR67 CR68 CR69 CR70 CR71 CR72 CR73\" citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e, \u003cspan additionalcitationids=\"CR78 CR79 CR80 CR81 CR82 CR83 CR84\" citationid=\"CR77\" class=\"CitationRef\"\u003e77\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR85\" class=\"CitationRef\"\u003e85\u003c/span\u003e, \u003cspan additionalcitationids=\"CR90\" citationid=\"CR89\" class=\"CitationRef\"\u003e89\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR91\" class=\"CitationRef\"\u003e91\u003c/span\u003e, \u003cspan citationid=\"CR94\" class=\"CitationRef\"\u003e94\u003c/span\u003e, \u003cspan additionalcitationids=\"CR97 CR98 CR99 CR100 CR101 CR102 CR103 CR104\" citationid=\"CR96\" class=\"CitationRef\"\u003e96\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR105\" class=\"CitationRef\"\u003e105\u003c/span\u003e, \u003cspan citationid=\"CR107\" class=\"CitationRef\"\u003e107\u003c/span\u003e, \u003cspan additionalcitationids=\"CR110 CR111 CR112 CR113 CR114 CR115 CR116 CR117 CR118 CR119 CR120 CR121 CR122 CR123 CR124\" citationid=\"CR109\" class=\"CitationRef\"\u003e109\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR125\" class=\"CitationRef\"\u003e125\u003c/span\u003e, \u003cspan additionalcitationids=\"CR129\" citationid=\"CR128\" class=\"CitationRef\"\u003e128\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR130\" class=\"CitationRef\"\u003e130\u003c/span\u003e]. The most frequent parameters were 110% of resting motor threshold (MT; Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC, \u003cb\u003e29\u003c/b\u003e.1%) [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan additionalcitationids=\"CR42 CR43 CR44\" citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan additionalcitationids=\"CR48 CR49\" citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e, \u003cspan additionalcitationids=\"CR55\" citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e, \u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e, \u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e, \u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e, \u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e, \u003cspan additionalcitationids=\"CR86\" citationid=\"CR85\" class=\"CitationRef\"\u003e85\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR87\" class=\"CitationRef\"\u003e87\u003c/span\u003e, \u003cspan citationid=\"CR107\" class=\"CitationRef\"\u003e107\u003c/span\u003e, \u003cspan citationid=\"CR108\" class=\"CitationRef\"\u003e108\u003c/span\u003e, \u003cspan citationid=\"CR110\" class=\"CitationRef\"\u003e110\u003c/span\u003e, \u003cspan citationid=\"CR111\" class=\"CitationRef\"\u003e111\u003c/span\u003e, \u003cspan additionalcitationids=\"CR116\" citationid=\"CR115\" class=\"CitationRef\"\u003e115\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR117\" class=\"CitationRef\"\u003e117\u003c/span\u003e, \u003cspan citationid=\"CR122\" class=\"CitationRef\"\u003e122\u003c/span\u003e, \u003cspan additionalcitationids=\"CR130\" citationid=\"CR129\" class=\"CitationRef\"\u003e129\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR131\" class=\"CitationRef\"\u003e131\u003c/span\u003e], 10 Hz frequency (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eD, 35.8%) [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan additionalcitationids=\"CR43 CR44\" citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e, \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e, \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e, \u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e, \u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e, \u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e, \u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e, \u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e, \u003cspan additionalcitationids=\"CR72 CR73\" citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e, \u003cspan citationid=\"CR77\" class=\"CitationRef\"\u003e77\u003c/span\u003e, \u003cspan citationid=\"CR80\" class=\"CitationRef\"\u003e80\u003c/span\u003e, \u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e81\u003c/span\u003e, \u003cspan citationid=\"CR84\" class=\"CitationRef\"\u003e84\u003c/span\u003e, \u003cspan citationid=\"CR90\" class=\"CitationRef\"\u003e90\u003c/span\u003e, \u003cspan citationid=\"CR91\" class=\"CitationRef\"\u003e91\u003c/span\u003e, \u003cspan citationid=\"CR96\" class=\"CitationRef\"\u003e96\u003c/span\u003e, \u003cspan citationid=\"CR97\" class=\"CitationRef\"\u003e97\u003c/span\u003e, \u003cspan citationid=\"CR99\" class=\"CitationRef\"\u003e99\u003c/span\u003e, \u003cspan additionalcitationids=\"CR102\" citationid=\"CR101\" class=\"CitationRef\"\u003e101\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR103\" class=\"CitationRef\"\u003e103\u003c/span\u003e, \u003cspan citationid=\"CR105\" class=\"CitationRef\"\u003e105\u003c/span\u003e, \u003cspan citationid=\"CR107\" class=\"CitationRef\"\u003e107\u003c/span\u003e, \u003cspan additionalcitationids=\"CR114\" citationid=\"CR113\" class=\"CitationRef\"\u003e113\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR115\" class=\"CitationRef\"\u003e115\u003c/span\u003e, \u003cspan citationid=\"CR117\" class=\"CitationRef\"\u003e117\u003c/span\u003e, \u003cspan citationid=\"CR119\" class=\"CitationRef\"\u003e119\u003c/span\u003e, \u003cspan citationid=\"CR121\" class=\"CitationRef\"\u003e121\u003c/span\u003e, \u003cspan citationid=\"CR122\" class=\"CitationRef\"\u003e122\u003c/span\u003e, \u003cspan citationid=\"CR124\" class=\"CitationRef\"\u003e124\u003c/span\u003e, \u003cspan citationid=\"CR132\" class=\"CitationRef\"\u003e132\u003c/span\u003e], 2-week treatment duration (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eE, 45.5%) [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan additionalcitationids=\"CR52\" citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e, \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e, \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e, \u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e, \u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e, \u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e, \u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e, \u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e, \u003cspan additionalcitationids=\"CR82\" citationid=\"CR81\" class=\"CitationRef\"\u003e81\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR83\" class=\"CitationRef\"\u003e83\u003c/span\u003e, \u003cspan additionalcitationids=\"CR86\" citationid=\"CR85\" class=\"CitationRef\"\u003e85\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR87\" class=\"CitationRef\"\u003e87\u003c/span\u003e, \u003cspan citationid=\"CR89\" class=\"CitationRef\"\u003e89\u003c/span\u003e, \u003cspan citationid=\"CR90\" class=\"CitationRef\"\u003e90\u003c/span\u003e, \u003cspan citationid=\"CR94\" class=\"CitationRef\"\u003e94\u003c/span\u003e, \u003cspan citationid=\"CR95\" class=\"CitationRef\"\u003e95\u003c/span\u003e, \u003cspan citationid=\"CR97\" class=\"CitationRef\"\u003e97\u003c/span\u003e, \u003cspan citationid=\"CR99\" class=\"CitationRef\"\u003e99\u003c/span\u003e, \u003cspan citationid=\"CR101\" class=\"CitationRef\"\u003e101\u003c/span\u003e, \u003cspan citationid=\"CR104\" class=\"CitationRef\"\u003e104\u003c/span\u003e, \u003cspan citationid=\"CR107\" class=\"CitationRef\"\u003e107\u003c/span\u003e, \u003cspan citationid=\"CR108\" class=\"CitationRef\"\u003e108\u003c/span\u003e, \u003cspan citationid=\"CR112\" class=\"CitationRef\"\u003e112\u003c/span\u003e, \u003cspan citationid=\"CR113\" class=\"CitationRef\"\u003e113\u003c/span\u003e, \u003cspan citationid=\"CR118\" class=\"CitationRef\"\u003e118\u003c/span\u003e, \u003cspan citationid=\"CR119\" class=\"CitationRef\"\u003e119\u003c/span\u003e, \u003cspan citationid=\"CR122\" class=\"CitationRef\"\u003e122\u003c/span\u003e, \u003cspan citationid=\"CR124\" class=\"CitationRef\"\u003e124\u003c/span\u003e, \u003cspan citationid=\"CR125\" class=\"CitationRef\"\u003e125\u003c/span\u003e], 10 total sessions (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eF, 38.8%) [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e, \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e, \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e, \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e, \u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e, \u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e, \u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e, \u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e, \u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e81\u003c/span\u003e, \u003cspan citationid=\"CR83\" class=\"CitationRef\"\u003e83\u003c/span\u003e, \u003cspan citationid=\"CR85\" class=\"CitationRef\"\u003e85\u003c/span\u003e, \u003cspan citationid=\"CR87\" class=\"CitationRef\"\u003e87\u003c/span\u003e, \u003cspan citationid=\"CR89\" class=\"CitationRef\"\u003e89\u003c/span\u003e, \u003cspan citationid=\"CR94\" class=\"CitationRef\"\u003e94\u003c/span\u003e, \u003cspan citationid=\"CR95\" class=\"CitationRef\"\u003e95\u003c/span\u003e, \u003cspan citationid=\"CR99\" class=\"CitationRef\"\u003e99\u003c/span\u003e, \u003cspan citationid=\"CR101\" class=\"CitationRef\"\u003e101\u003c/span\u003e, \u003cspan citationid=\"CR104\" class=\"CitationRef\"\u003e104\u003c/span\u003e, \u003cspan citationid=\"CR107\" class=\"CitationRef\"\u003e107\u003c/span\u003e, \u003cspan citationid=\"CR108\" class=\"CitationRef\"\u003e108\u003c/span\u003e, \u003cspan additionalcitationids=\"CR113\" citationid=\"CR112\" class=\"CitationRef\"\u003e112\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR114\" class=\"CitationRef\"\u003e114\u003c/span\u003e, \u003cspan citationid=\"CR118\" class=\"CitationRef\"\u003e118\u003c/span\u003e, \u003cspan citationid=\"CR122\" class=\"CitationRef\"\u003e122\u003c/span\u003e, \u003cspan citationid=\"CR124\" class=\"CitationRef\"\u003e124\u003c/span\u003e, \u003cspan citationid=\"CR125\" class=\"CitationRef\"\u003e125\u003c/span\u003e], 1,600 pulses per session (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eG, 17.6%) [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e, \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e, \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e, \u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e81\u003c/span\u003e, \u003cspan citationid=\"CR85\" class=\"CitationRef\"\u003e85\u003c/span\u003e, \u003cspan citationid=\"CR107\" class=\"CitationRef\"\u003e107\u003c/span\u003e, \u003cspan citationid=\"CR114\" class=\"CitationRef\"\u003e114\u003c/span\u003e, \u003cspan citationid=\"CR122\" class=\"CitationRef\"\u003e122\u003c/span\u003e, \u003cspan citationid=\"CR128\" class=\"CitationRef\"\u003e128\u003c/span\u003e], and 16,000 total pulses (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eH, 13.9%, ranged widely from 1,200 to 160,000 pulses) [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e, \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e, \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e, \u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e81\u003c/span\u003e, \u003cspan citationid=\"CR85\" class=\"CitationRef\"\u003e85\u003c/span\u003e, \u003cspan citationid=\"CR107\" class=\"CitationRef\"\u003e107\u003c/span\u003e, \u003cspan citationid=\"CR114\" class=\"CitationRef\"\u003e114\u003c/span\u003e, \u003cspan citationid=\"CR122\" class=\"CitationRef\"\u003e122\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003ePanel A Diagram of the preferred reporting items for systematic review and meta-analysis (PRISMA). B shows the flow of TMS treatment modalities and stimulation sites across different types of depressive episodes. Panels C\u0026ndash;F summarize stimulation intensity, frequency, treatment duration, and total number of sessions. Panels G\u0026ndash;H display the distributions of pulses per session and total pulses across all included trials. BD, bipolar disorder; MDD, major depressive disorder; TRD, treatment-resistant depression; TBS, theta-burst stimulation; rTMS, repetitive transcranial magnetic stimulation; R.PFC, right prefrontal cortex; L.PFC, left prefrontal cortex; R.DLPFC, right dorsolateral prefrontal cortex; L.DLPFC, left dorsolateral prefrontal cortex; DMPFC, dorsomedial prefrontal cortex.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eQuality of evidence\u003c/h3\u003e\n\u003cp\u003eRisk-of-bias assessments are summarized in Supplementary \u003cb\u003eTable S2\u003c/b\u003e and \u003cb\u003eFigure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e\u003c/b\u003e. Sequence generation was low risk in 65 trials (60.2%) and unclear in 43 (39.8%). Allocation concealment was low in 45 (41.7%), unclear in 60 (55.6%), and high in 3 (2.8%). Blinding of participants and personnel was low in 66 (61.1%) and unclear in 42 (38.9%). Blinding of outcome assessment was low in 103 (95.4%) and unclear in 5 (4.6%). Incomplete outcome data were low in 91 (84.3%), unclear in 11 (10.2%), and high in 6 (5.6%). Selective reporting was low in 104 (96.3%) and unclear in 4 (3.7%). Overall risk of bias was rated low in 54 trials (50.0%), unclear in 45 (41.7%), and high in 9 (8.3%).\u003c/p\u003e\n\u003ch3\u003eDose-response meta-analysis for total pulses\u003c/h3\u003e\n\u003cp\u003eThe dose-response associations for total pulses are shown in Fig. \u003cspan\u003e2\u003c/span\u003e and Supplementary \u003cstrong\u003eTable S3\u003c/strong\u003e. For depressive symptoms, a significant non-linear pattern emerged. In acute analyses (105 studies, 126 effect sizes), improvement peaked at 30,800 pulses (95% CI 16,100\u0026ndash;45,600), with a predicted SMD of 0.73 (95% CI 0.58\u0026ndash;0.88), after which the curve plateaued. At follow-up (30 studies; 35 effect sizes), the overall association remained significant but was approximately linear across the observed range, with no evidence of a distinct peak. For treatment response, the acute effect (87 studies, 100 effect sizes) peaked at 37,000 pulses (95% CI 30,700\u0026ndash;43,400), with a predicted RR of 2.61 (95% CI 2.18\u0026ndash;3.16), and decreased thereafter. At follow-up (14 studies, 16 effect sizes), the optimum was 32,300 pulses (95% CI 25,000\u0026ndash;39,700), with a predicted RR of 2.12 (95% CI 1.32\u0026ndash;3.35), but effects diminished at higher exposures. For remission, the acute optimum (58 studies, 72 effect sizes) was 39,100 pulses (95% CI 32,000\u0026ndash;46,100), with a predicted RR of 2.77 (95% CI 2.10\u0026ndash;3.67), followed by gradual decline. At follow-up (11 studies, 11 effect sizes), the curve was flatter, with no clear peak.\u003c/p\u003e\n\u003cdiv id=\"Sec11\"\u003e\n \u003ch2\u003eDose-response meta-analysis for pulses per session\u003c/h2\u003e\n \u003cp\u003eAssociations between pulses per session and outcomes are shown in Fig. \u003cspan\u003e3\u003c/span\u003e and Supplementary \u003cstrong\u003eTable S4\u003c/strong\u003e. In acute analyses, depressive symptoms indicated an optimum at 1,800 pulses/session (95% CI 870\u0026ndash;2,740), with a predicted SMD of 0.73 (95% CI 0.59\u0026ndash;0.87), then gradually declined. At follow-up, the optimum was 1,300 pulses/session (95% CI 870\u0026ndash;1,680), with a predicted SMD of 1.23 (95% CI 0.63\u0026ndash;1.83), followed by decline. Regarding treatment response, the acute effect peaked at 2,200 pulses/session (95% CI 1,830\u0026ndash;2,510), with a predicted RR of 2.56 (95% CI 2.14\u0026ndash;3.03), then decreased. At follow-up, the optimum was 1,600 pulses/session (95% CI 1,480\u0026ndash;1,760), with a predicted RR of 2.12 (95% CI 1.43\u0026ndash;3.16), again followed by decline. Similarly, for remission, the acute peak was 1,800 pulses/session (95% CI 1,610\u0026ndash;2,000), with a predicted RR of 2.83 (95% CI 2.27\u0026ndash;3.56), after which the effect tapered. At follow-up, the maximum was 1,840 pulses/session (95% CI 1,490\u0026ndash;2,190), with a predicted RR of 1.48 (95% CI 1.13\u0026ndash;1.92).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\"\u003e\n \u003ch2\u003eDose-response meta-analysis for total sessions\u003c/h2\u003e\n \u003cp\u003eThe associations for total number of sessions are shown in Fig. \u003cspan\u003e4\u003c/span\u003e and Supplementary \u003cstrong\u003eTable S5\u003c/strong\u003e. In terms of depressive symptoms, acute analyses peaked at 14 sessions (95% CI 11\u0026ndash;17), with a predicted SMD of 0.81 (95% CI 0.64\u0026ndash;0.98), followed by decline. At follow-up, the association appeared linear across the examined range, with no indication of a distinct peak. For treatment response, the acute optimum was 16 sessions (95% CI 12\u0026ndash;19), with a predicted RR of 2.29 (95% CI 1.90\u0026ndash;2.77). At follow-up, the dose\u0026ndash;response relation remained broadly linear without evidence of a peak or downturn. Regarding remission, acute effects peaked at 23 sessions (95% CI 17\u0026ndash;29), with a predicted RR of 2.59 (95% CI 1.99\u0026ndash;3.39), followed by gradual decline. At follow-up, no clear maximum was identified; the overall association was not statistically significant (\u0026chi;\u0026sup2;=5.09, df\u0026thinsp;=\u0026thinsp;2; p\u0026thinsp;=\u0026thinsp;0.078).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\"\u003e\n \u003ch2\u003eDose-response meta-analysis for treatment duration\u003c/h2\u003e\n \u003cp\u003eThe associations between treatment duration and outcomes are shown in Fig. \u003cspan\u003e5\u003c/span\u003e and Supplementary \u003cstrong\u003eTable S6\u003c/strong\u003e. Analysis of acute depressive symptoms revealed peak occurred at 2.9 weeks (95% CI 2.4\u0026ndash;3.5), with a predicted SMD of 0.84 (95% CI 0.67\u0026ndash;1.00). At follow-up, the test for non-linearity was not significant. Acute treatment response rose to a peak at 2.7 weeks (95% CI 2.2\u0026ndash;3.2; predicted RR 2.39, 95% CI 1.99\u0026ndash;2.89). This outcome at follow-up was maximized at 2.9 weeks (95% CI 2.4\u0026ndash;3.5; predicted RR 2.03, 95% CI 1.36\u0026ndash;3.00), after which it declined. Finally, the optimum for acute remission was 3.1 weeks (95% CI 2.5\u0026ndash;3.7; predicted RR 2.56, 95% CI 2.01\u0026ndash;3.32), while the follow-up maximum was 3.3 weeks (95% CI 2.6\u0026ndash;4.0; predicted RR 1.36, 95% CI 1.12\u0026ndash;1.66), with no further gains beyond this point.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\"\u003e\n \u003ch2\u003eSubgroup analysis\u003c/h2\u003e\n \u003cp\u003eEight prespecified subgroup models were examined (rTMS and TBS each assessed for total pulses, pulses per session, total sessions, and treatment duration). For conventional rTMS, acute outcomes consistently demonstrated non-linear associations with mid-range optima: 30,000 to 40,000 total pulses, 1,500 to 2,300 pulses per session, 15 to 17 sessions, and about 3 weeks of treatment. At follow-up, effects were weaker and largely linear; where peaks appeared, they were small and exploratory. For TBS, acute outcomes showed similar patterns but at lower dose levels, with optima around 2,000 pulses per session, 8 to 10 sessions, and 2 to 2.5 weeks of treatment. Total pulse analyses suggested peaks near 40,000 for response, but follow-up evidence was inconsistent, with sparse data (\u0026le;\u0026thinsp;5 studies in several strata) yielding unstable curves and wide uncertainty.\u003c/p\u003e\n \u003cp\u003eTaken together, the subgroup analyses indicate that moderate dosing regimens, rather than the highest exposures, are associated with the greatest acute benefit for both rTMS and TBS. Follow-up effects were smaller, often linear, and less precisely estimated, especially for TBS. We therefore highlight acute non-linearity and mid-range plateaus as the most reproducible findings, while treating apparent follow-up peaks as hypothesis-generating given limited data. Full subgroup outputs are reported in Supplementary \u003cstrong\u003eTables S7\u003c/strong\u003e\u0026ndash;\u003cstrong\u003eS14\u003c/strong\u003e and \u003cstrong\u003eFigs. S2\u003c/strong\u003e\u0026ndash;\u003cstrong\u003eS9\u003c/strong\u003e.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\"\u003e\n \u003ch2\u003eSensitivity analyses and publication bias\u003c/h2\u003e\n \u003cp\u003eThe robustness of our dose-response findings was supported by leave-one-out sensitivity analyses, which demonstrated stable EDmax estimates and linear slopes without sign reversals. Publication bias, evaluated using Egger\u0026rsquo;s test, was generally absent. Significant small-study effects were observed only in a few outcomes, particularly those assessing follow-up efficacy. Comprehensive results for these sensitivity and publication bias analyses are presented in the Supplementary material (see the Sensitivity analysis section), including detailed summaries (\u003cstrong\u003eTable S15\u003c/strong\u003e) and supporting visualizations (leave-one-out analyses in \u003cstrong\u003eFigures S10\u003c/strong\u003e\u0026ndash;\u003cstrong\u003eS13\u003c/strong\u003e; funnel plots in \u003cstrong\u003eFigures S14\u003c/strong\u003e\u0026ndash;\u003cstrong\u003eS17\u003c/strong\u003e).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this dose-response meta-analysis of 108 randomized, sham-controlled clinical trials, four rTMS dosing parameters (total pulses, pulses per session, number of sessions, and treatment duration) showed consistent non-linear associations with acute outcomes in MDE [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Across continuous and binary endpoints, benefits generally peaked at mid-range exposures and then plateaued or declined, indicating that more stimulation is not invariably better. For conventional rTMS, the dose ranges associated with the highest predicted acute benefit were 30,000\u0026ndash;40,000 total pulses, 1,500\u0026ndash;2,300 pulses per session, 15\u0026ndash;17 sessions, and approximately 3 weeks of treatment. Follow-up effects were smaller, often near-linear, and imprecisely estimated. TBS showed a qualitatively similar pattern, with optima at lower exposures of approximately 2 000 pulses per session, 8\u0026ndash;10 sessions, and about 2\u0026ndash;2.5 weeks of treatment. However, the evidence base was relatively sparse, particularly for follow-up outcomes.\u003c/p\u003e \u003cp\u003eA key observation is that estimated \u0026ldquo;best\u0026rdquo; doses differ across depressive-symptom change (continuous), response (\u0026ge;\u0026thinsp;50% reduction), and remission (scale-defined thresholds). This divergence is expected and clinically informative for three reasons. First, the endpoints capture progressively stricter clinical goals: continuous scores detect early, broad improvements; response requires surpassing a relative threshold; remission requires crossing an absolute low-symptom boundary. As targets become more stringent, curves tend to shift rightward or flatten because additional \u0026ldquo;consolidation\u0026rdquo; of benefit is needed to convert partial improvement into threshold-crossing events. Second, the endpoints are modeled on different statistical scales with distinct variance structures and inherent saturation: continuous outcomes summarize mean change on an approximately linear scale, whereas response and remission are estimated on the log-risk scale for Bernoulli outcomes with an implicit sigmoidal link. Even when underlying symptom improvement rises smoothly with increasing dose, probability curves derived from binary outcomes tend to flatten and saturate as they approach their 0\u0026ndash;1 limits. This produces different apparent slopes and internal peaks compared with standardized mean differences, reflecting differences in modeling scale rather than in subgroup composition. Third, the four dosing parameters correspond to different phases of clinical change. Pulses per session primarily represent within-session induction, whereas the number of sessions and overall duration reflect between-session consolidation. Total pulses combine these components and can be achieved through heterogeneous schedules with distinct neuroplastic and tolerability profiles. As a result, each endpoint-specific EDmax represents a different perspective on the same underlying dose\u0026ndash;response curve. Because many confidence intervals overlap, these differences should be viewed as indicative rather than prescriptive.\u003c/p\u003e \u003cp\u003eThese findings have clear clinical relevance. When the primary goal is to reduce symptoms, treatment regimens set at the moderate dose ranges identified above achieve most of the acute benefit with good efficiency [\u003cspan citationid=\"CR133\" class=\"CitationRef\"\u003e133\u003c/span\u003e, \u003cspan citationid=\"CR134\" class=\"CitationRef\"\u003e134\u003c/span\u003e]. Achieving remission depends more on adequate consolidation through sufficient sessions and treatment duration, but gains diminish at higher exposures. This pattern is consistent with metaplastic counter-regulation [\u003cspan citationid=\"CR135\" class=\"CitationRef\"\u003e135\u003c/span\u003e] and with practical limits on adherence and tolerability observed in real-world settings [\u003cspan citationid=\"CR136\" class=\"CitationRef\"\u003e136\u003c/span\u003e, \u003cspan citationid=\"CR137\" class=\"CitationRef\"\u003e137\u003c/span\u003e]. The modest and largely linear associations observed at follow-up suggest that sustaining treatment effects may require additional strategies beyond dose escalation. These include continuation or maintenance TMS [\u003cspan citationid=\"CR138\" class=\"CitationRef\"\u003e138\u003c/span\u003e, \u003cspan citationid=\"CR139\" class=\"CitationRef\"\u003e139\u003c/span\u003e], optimization of pharmacotherapy [\u003cspan citationid=\"CR140\" class=\"CitationRef\"\u003e140\u003c/span\u003e], and psychotherapy [\u003cspan citationid=\"CR141\" class=\"CitationRef\"\u003e141\u003c/span\u003e] tailored to individual risk profiles and early treatment response.\u003c/p\u003e \u003cp\u003eBeyond these clinical implications, our findings build on and help reconcile previous meta-analyses. Earlier studies reported bell-shaped or plateauing dose\u0026ndash;response patterns when total pulses were used to quantify exposure, with indications of a clinical plateau around 3\u0026ndash;4 weeks and possible moderation by stimulation frequency [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. By modelling the four dosing parameters separately and evaluating both acute and follow-up outcomes across continuous and binary measures, our analysis shows that the most consistent pattern is a mid-range plateau during the acute phase. The estimated maxima for total exposure and treatment duration align with findings from total-pulse\u0026ndash;based and trajectory analyses [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], but also suggest that increasing exposure beyond typical clinical regimens offers little additional benefit and, in some models, even a decline in efficacy. Several mechanisms may underlie these plateaus. rTMS involves neural plasticity mechanisms regulated by homeostatic or metaplastic processes [\u003cspan citationid=\"CR142\" class=\"CitationRef\"\u003e142\u003c/span\u003e], and excessive or prolonged stimulation can trigger counter-regulatory responses that reduce overall benefit [\u003cspan citationid=\"CR143\" class=\"CitationRef\"\u003e143\u003c/span\u003e]. Clinically, higher stimulation doses can lead to greater fatigue and scalp discomfort, which may limit tolerability. Higher dropout rates have been reported in TMS programmes and can, in turn, reduce the effective dose delivered and overall adherence [\u003cspan citationid=\"CR144\" class=\"CitationRef\"\u003e144\u003c/span\u003e]. Greater pulses per session also tend to co-vary with other parameters, such as inter-train interval, frequency, and intensity, which may alter the balance between facilitatory and inhibitory effects [\u003cspan citationid=\"CR145\" class=\"CitationRef\"\u003e145\u003c/span\u003e]. Although these dose-response analyses cannot fully separate such co-variations, the consistent shape of the curves across endpoints argues against a purely statistical explanation.\u003c/p\u003e \u003cp\u003eSeveral limitations should be acknowledged. Follow-up data, particularly for TBS, were limited, resulting in wide uncertainty at the extremes of the dose distribution. Although one-stage random-effects spline models help reduce ecological bias and capture non-linear trends, each dose parameter was analyzed separately. Residual confounding by unmeasured factors such as stimulation frequency, target site, intensity, coil type, or navigation method therefore remains possible, and total pulses are mathematically dependent on the other components [\u003cspan citationid=\"CR146\" class=\"CitationRef\"\u003e146\u003c/span\u003e]. Moreover, potential interactions among dose dimensions, including total pulses, pulses per session, number of sessions, and treatment duration, were not directly modeled [\u003cspan citationid=\"CR147\" class=\"CitationRef\"\u003e147\u003c/span\u003e]. Specific combinations of these parameters may exert synergistic or antagonistic influences on treatment outcomes (e.g., depressive-symptom change, treatment response, or remission) [\u003cspan citationid=\"CR147\" class=\"CitationRef\"\u003e147\u003c/span\u003e], which should be further explored in future research. In addition, most included trials targeted the left DLPFC using 10 Hz stimulation at about 110% of the motor threshold for 2\u0026ndash;3 weeks of treatment. Generalizability to other stimulation targets (e.g., dorsomedial or right prefrontal cortex) remains limited, and target-specific efficacy differences may exist [\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e]. Future research could employ network meta-analysis to systematically compare and rank target sites [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Finally, variation in sham procedures, concomitant treatments, definitions of treatment-resistant depression, and rating scales also contributes to heterogeneity across studies [\u003cspan citationid=\"CR148\" class=\"CitationRef\"\u003e148\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn summary, rTMS efficacy increases sharply at lower exposures, reaches its greatest effect at moderate doses, and then levels off or declines. The dose\u0026ndash;response maxima vary across endpoints, reflecting differences in clinical definition, statistical scale, and the relative roles of induction and consolidation. These findings support a dosing approach focused on well-calibrated, mid-range regimens that are matched to the therapeutic goal, such as symptom improvement, treatment response, or remission, and highlight the importance of maintenance strategies to sustain benefit over time.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eContributors\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eZXW and RMS contributed equally to this work. XYG and TFY contributed equally to this work and are joint senior authors. ZXW, RMS, XYG and TFY conceived and designed the study. XYG and TFY supervised the study. ZXW, RMS and ZLZ performed the statistical analysis. ZXW, RMS and RFS extracted the data. All authors contributed to the acquisition, analysis, or interpretation of data. ZXW, RMS, VRS, XYG and TFY drafted the manuscript. All authors revised the report and approved the final version before submission. XYG and TFY are the guarantors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors hereby attest that they do not have any conflicts of interest related to this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the National Key Research and Development Program of China (2023YFC2506202); Fundamental Research Funds for the Central Universities (project number YG2024ZD25); Zhejiang Key Laboratory of Precision Psychiatry (Grant No. 2025A4); Sichuan Science and Technology Program (2024NSFSC1564); Three-year action plan for Shanghai\u0026rsquo;s public health system construction (GWVI-2.1.4); National Institute on Mental Health (R01MH132044) and the National Institute on Drug Abuse (R21DA05871).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot required.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData sharing statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data used in this meta-analysis were extracted from previously published studies cited in the reference list. The data extraction and analytical code are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration\u0026nbsp;of generative\u0026nbsp;AI and\u0026nbsp;AI-assisted technologies\u0026nbsp;in\u0026nbsp;the\u0026nbsp;writing\u0026nbsp;process\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring the preparation of this work the authors used ChatGPT in order to language polishing. After using this tool/service, the authors reviewed and edited the content as needed and take full responsibility for the content of the published article.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGBD. 2019 Mental Disorders Collaborators. Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990\u0026ndash;2019: a systematic analysis for the Global Burden of Disease Study 2019. 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Clin Psychol Rev. 2023;100:102236.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmed","sideBox":"Learn more about [BMC Medicine](http://bmcmedicine.biomedcentral.com/)","snPcode":"12916","submissionUrl":"https://submission.nature.com/new-submission/12916/3","title":"BMC Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Transcranial magnetic stimulation, Major depressive episodes, Acute efficacy, Follow-up, Dose-response relationship","lastPublishedDoi":"10.21203/rs.3.rs-8648926/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8648926/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eTo characterize the dose-response relationships between key repetitive transcranial magnetic stimulation (rTMS) dosing parameters and clinical outcomes in major depressive episodes (MDE), and to identify optimal dosing ranges.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe performed a systematic review and one-stage dose-response meta-analysis of randomized sham-controlled trials investigating rTMS for adults with MDE. Outcomes were symptom severity, response, and remission, assessed acutely and in follow-up (\u0026gt;\u0026thinsp;7 days). Four key dosing dimensions (total pulses, pulses/session, sessions, duration) were modeled using restricted cubic spline models, and the maximum effective dose (EDmax) within the observed range was derived from the fitted model. Effect sizes were expressed as standardized mean differences and risk ratios with 95% confidence interval.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAcross 108 trials (134 active arms; n\u0026thinsp;=\u0026thinsp;5,621), total pulses, pulses per session, total sessions and treatment duration showed significant non-linear associations with acute efficacy. Peak efficacy for acute treatment was observed at 30,000\u0026ndash;39,000 total pulses, 1,800\u0026ndash;2,200 pulses per session, 14\u0026ndash;16 sessions, and 2.7\u0026ndash;3.1 weeks of treatment, with no additional benefit from higher doses across all parameters. Long-term analyses showed smaller and mostly linear associations: the best outcomes were generally observed at 26,000\u0026ndash;33,000 total pulses, 1,300\u0026ndash;1,800 pulses per session, 10\u0026ndash;14 sessions, and 2.8\u0026ndash;3.3 weeks of treatment. Sensitivity analyses confirmed the stability of these estimates, and publication bias was minimal.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003erTMS efficacy in MDE is maximized within a moderate dose range, beyond which additional stimulation yields minimal gain. Thus, sustained remission likely depends on maintenance strategies, not dose escalation.\u003c/p\u003e","manuscriptTitle":"Acute and long-term effects of repetitive transcranial magnetic stimulation in major depressive episodes: a systematic review and dose-response meta-analysis of randomized sham-controlled trials","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-02 14:14:05","doi":"10.21203/rs.3.rs-8648926/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-20T12:07:58+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-20T04:25:09+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-19T04:46:05+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-08T19:23:12+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"257327053592118121219399753065200763820","date":"2026-03-06T21:38:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"96198951502478773434593017753768512035","date":"2026-03-04T19:35:14+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"239203966386456934879514551256769822667","date":"2026-03-04T17:04:38+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-29T15:53:11+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-21T04:39:53+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-21T04:37:03+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Medicine","date":"2026-01-20T11:29:37+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmed","sideBox":"Learn more about [BMC Medicine](http://bmcmedicine.biomedcentral.com/)","snPcode":"12916","submissionUrl":"https://submission.nature.com/new-submission/12916/3","title":"BMC Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e7ee80a1-15ee-4827-a28d-6d7402e6cba5","owner":[],"postedDate":"February 2nd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-10T09:09:50+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-02 14:14:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8648926","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8648926","identity":"rs-8648926","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}