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Cited by 142Transcranial Magnetic Stimulation StudiesTreatment of Major DepressionElectroconvulsive Therapy Studies

Effectiveness of Standard Sequential Bilateral Repetitive Transcranial Magnetic Stimulation vs Bilateral Theta Burst Stimulation in Older Adults With Depression

Open access
Blumberger, Daniel M., Mulsant, Benoit H., Thorpe, Kevin E., McClintock, Shawn M., Konstantinou, Gerasimos N., Lee, Hyewon H., Nestor, Sean M., Noda, Yoshihiro +5 more·2022·JAMA Psychiatry
DOI 10.1001/jamapsychiatry.2022.2862PMC PMC9494264
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Abstract

Importance: Treatment-resistant depression (TRD) is common in older adults. Bilateral repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex for 48 minutes has demonstrated efficacy in TRD. Theta burst stimulation (TBS), a newer form of rTMS, can also be delivered bilaterally using left intermittent TBS and right continuous TBS for only 4 minutes. Objective: To establish the effectiveness and tolerability of TBS compared with standard rTMS in older adults with TRD. Design, Setting, and Participants: In this randomized noninferiority trial with open treatment and blinded assessors, recruitment occurred between December 2016 and March 2020. The trial was conducted at the Centre for Addiction and Mental Health in Toronto, Ontario, Canada and included outpatients 60 years and older with a diagnosis of depression, moderate severity, and nonresponse to 1 or more antidepressant trial of adequate dosage and duration or intolerance of 2 or more trials. Interventions: Participants were randomized to receive a course of 4 to 6 weeks of either bilateral standard rTMS or TBS. Main Outcomes and Measures: The primary outcome measure was change in Montgomery-Åsberg Depression Rating Scale; secondary outcome measures included the 17-item Hamilton Rating Scale for Depression, Quick Inventory of Depressive Symptomatology (16-item) (self-report), and dropout rates. A noninferiority margin of 2.75 points was used for the primary outcome. All participants who attained the primary completion point of 4 weeks were analyzed. Results: A total of 87 participants (mean [SD] age, 67.1 [6.7] years; 47 [54.0%] female) were randomized to standard bilateral rTMS and 85 (mean [SD] age, 66.3 [5.3] years; 45 [52.9%] female) to TBS, of whom 85 (98%) and 79 (93%) were assessed for the primary outcome, respectively, whereas tolerability was assessed in all randomized participants. In the rTMS group, 4 (4.6%) were American Indian, reported other, or preferred not to answer; 5 (5.8%) were Asian; and 78 (89.7%) were White. In the TBS group, 6 (7.1%) were Asian, 2 (2.4%) were Black or reported other, and 77 (90.3%) were White. Mean (SD) Montgomery-Åsberg Depression Rating Scale total scores improved from 25.6 (4.0) to 17.3 (8.9) for rTMS and 25.7 (4.7) to 15.8 (9.1) for TBS (adjusted difference, 1.55; lower 95% CI −0.67), establishing noninferiority for TBS. The all-cause dropout rates were relatively similar between groups (rTMS: 2 of 87 [2.3%]; TBS: 6 of 85 [7.1%]; P = .14; χ 2 = 2.2). Conclusions and Relevance: In older adults with TRD, bilateral TBS compared with standard bilateral rTMS achieved noninferior reduction in depression symptoms. Both treatments had low and similar dropout rates. Using TBS rather than rTMS could increase access to treatment several-fold for older adults with TRD. Trial Registration: ClinicalTrials.gov Identifier: NCT02998580

AI snapshot

Written from the paper’s full text.

TL;DR

In older adults with treatment-resistant depression, 4-minute bilateral theta burst stimulation (TBS) was noninferior to standard 47.5-minute sequential bilateral repetitive transcranial magnetic stimulation (rTMS) for reducing depressive symptoms. TBS had similar tolerability and cognitive safety, though pain ratings were higher with TBS.

Key findings

  • On the primary outcome, final MADRS score showed an estimated adjusted difference of 1.55 points favoring TBS, with a lower 95% CI of −0.67, below the noninferiority margin δ = 2.75 points.
  • MADRS response was 44.3% (35/79) with TBS vs 32.9% (28/85) with rTMS (adjusted difference 11.4% favoring TBS; lower 95% CI −1.1%, within δ < 15%); remission was 35.4% (28/79) vs 32.9% (28/85) (adjusted difference 2.5%; lower 95% CI −9.7%, within δ < 10%).
  • TBS was also noninferior on HRSD-17, QIDS-SR-16, and BSI-A, with no significant differences on cognitive measures; adverse events were similar, but pain scores were higher with TBS (right side mean [SD], 3.59 [2.45] vs 1.66 [1.79]; left side, 4.01 [2.55] vs 2.80 [1.99]).
  • Treatment discontinuation before the primary end point occurred in 2/87 (2.3%) rTMS participants and 6/85 (7.1%) TBS participants; during intervention, serious adverse events occurred in 0/87 rTMS and 1/85 TBS (1.2%).

Methods

  • Randomized noninferiority trial at a single academic health center (Centre for Addiction and Mental Health, Toronto) from December 2016 to March 2020; outpatients aged 60 years or older with major depressive disorder, MADRS score ≥18, and nonresponse/intolerance to antidepressants.
  • 172 participants were randomized; 164 completed the greater part of 4 weeks and were included in the primary analysis (85 standard bilateral rTMS, 79 bilateral TBS). Standard rTMS was right 1-Hz (600 pulses over 10 minutes) then left 10-Hz (3000 pulses over 37.5 minutes), total 47.5 minutes; bilateral TBS was right cTBS (40 seconds) then left iTBS (3 minutes 9 seconds), total 4 minutes, both at 120% resting motor threshold, for 20–30 sessions.
  • Primary analysis used ANCOVA with final MADRS score adjusted for baseline score and a noninferiority margin δ = 2.75; secondary outcomes included HRSD-17, QIDS-SR-16, response/remission rates, cognition, adverse effects, pain, and dropout.

Limitations

  • The paper states there was no sham group and participants were aware of treatment allocation; the trial was single-site; recruitment was halted by COVID-19 and the sample was smaller than planned; MRI neuronavigation may limit generalizability; there is no validated right-sided DLPFC target; and follow-up findings are limited by loss to follow-up.
  • The paper notes that longer standard rTMS sessions involved substantially more therapeutic contact with technicians, which could have introduced nonspecific bias favoring standard rTMS.
  • Evident from the text: technicians were unblinded because session durations differed, and the primary analysis excluded 8 randomized participants (172 randomized vs 164 analyzed), although intention-to-treat and other sensitivity analyses were conducted.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1001/jamapsychiatry.2022.2862

Cites

45 of 45 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

17 of 40 cited sources checked · 10 supported · 2 flagged · accuracy not yet measured

  • Premisecitation

    The recent trial enrolled mixed-age adults rather than only older adults.

    “However, the study enrolled mixed-age adults rather than only older adults, as we did.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [40] Chen L, Thomas EHX, Kaewpijit P,. Accelerated theta burst stimulation for the treatment of depression: a randomised controlled trial. Brain Stimul. 2021; 14(5): 1095- 1105. doi: 10.1016/j.brs.2021.07.018 34332155 source
  • Premisecitation

    Recent clinical registry data indicate no added benefit for bilateral over unilateral stimulation in a lifespan sample.

    “However, recent clinical registry data indicate no added benefit for bilateral over unilateral stimulation in a lifespan sample.37”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [37] Aaronson ST, Carpenter LL, Hutton TM,. Comparison of clinical outcomes with left unilateral and sequential bilateral transcranial magnetic stimulation (TMS) treatment of major depressive disorder in a large patient registry. Brain Stimul. 2022; 15(2): 326- 336. doi: 10.1016/j.brs.2022.01.006 35074549 source

      The Discussion reports that this registry study found no evidence that sequential bilateral TMS was superior to left unilateral TMS. The Methods define the analyzed sample as adults aged 18 or older, so the source does not establish the result across the full lifespan. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
  • Interpretationcitation

    The results of both the THREE-D study and the present FOUR-D study indicate that rTMS outcomes in older adults can be at least as good, and perhaps better, as in younger adults.

    “Although there is a pervasive assumption that rTMS in general is not well suited for older adults with TRD, the results of both the THREE-D study43 and the present FOUR-D study indicate that rTMS outcomes in older adults can be at least as good, and perhaps better, as in younger adults.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [43] Trevizol AP, Downar J, Vila-Rodriguez F, Thorpe KE, Daskalakis ZJ, Blumberger DM. Predictors of remission after repetitive transcranial magnetic stimulation for the treatment of major depressive disorder: an analysis from the randomised non-inferiority THREE-D trial. EClinicalMedicine. 2020; 22: 100349. doi: 10.1016/j.eclinm.2020.100349 32382720 PMC7200243 source

      The Results report a modest age-related pattern in remission odds, and the Discussion says that poorer rTMS outcomes with increasing age were not observed in this analysis. However, Methods > Participants limits the sample to ages 18–65, and the Discussion explicitly says the results cannot be generalized to people over 65. THREE-D therefore offers some support for the comparison within its age range, but not for older adults generally. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Findingown data

    During the intervention period, serious adverse events occurred in 0 of 87 participants undergoing rTMS and 1 of 85 participants undergoing TBS (1.2%) (psychiatric admission for depression).

    “During the intervention period, SAEs occurred in 0 of 87 participants undergoing rTMS and 1 of 85 participant undergoing TBS (1.2%) (psychiatric admission for depression);”
    Quote in the paperNot a substantial claim
  • Findingown data

    Noninferiority was demonstrated on all clinician-rated and self-report psychiatric symptom measures at all assessment points, including 12 weeks after treatment.

    “Noninferiority was demonstrated on all clinician-rated and self-report psychiatric symptom measures at all assessment points, including 12 weeks after treatment.”
    Quote in the paperSubstantial claim
  • May combine two claims. 35
  • Classified as probably not a substantial claim. 21

  • May combine two claims.

    Study design and conductcitation

    The use of MRI neuronavigation is a potential limitation to generalizability, although findings did not change with participants who received approximated treatment with the approximated scalp-based method.

    “The use of MRI neuronavigation is a potential limitation to generalizability, although findings did not change with participants who received approximated treatment with the approximated scalp-based method.18”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [18] Mir-Moghtadaei A, Caballero R, Fried P,. Concordance between BeamF3 and MRI-neuronavigated target sites for repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex. Brain Stimul. 2015; 8(5): 965- 973. doi: 10.1016/j.brs.2015.05.008 26115776 PMC4833442 source

      The Discussion says the trial employed neuronavigation for all subjects and did not test whether scalp-based targeting produced the same clinical outcomes. That contradicts the claim that findings were unchanged among participants who received scalp-based treatment. The paper does acknowledge limits to generalizing its image-based comparison to in vivo targeting. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    The remission rate of 35.4% in the bilateral TBS group is comparable to those in the authors' previous bilateral rTMS trial (33%) and deep rTMS trial (40%) and to aripiprazole augmentation in older adults with treatment-resistant depression.

    “This remission rate is comparable with those seen in our previous bilateral rTMS trial (33%)7 and deep rTMS trial (40%)32 and comparable with the remission rate seen with aripiprazole augmentation in older adults with TRD.33”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [7] Trevizol AP, Goldberger KW, Mulsant BH,. Unilateral and bilateral repetitive transcranial magnetic stimulation for treatment-resistant late-life depression. Int J Geriatr Psychiatry. 2019; 34(6): 822- 827. doi: 10.1002/gps.5091 30854751 PMC6488425 source

      Citation 7 is attached to the previous bilateral rTMS trial’s reported 33% remission rate. The cited paper’s Results section (page unavailable) instead reports remission in 8 of 20 bilateral rTMS participants, or 40%. The deep rTMS and aripiprazole comparisons have separate citations. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [32] Kaster TS, Daskalakis ZJ, Noda Y,. Efficacy, tolerability, and cognitive effects of deep transcranial magnetic stimulation for late-life depression: a prospective randomized controlled trial. Neuropsychopharmacology. 2018; 43(11): 2231- 2238. 29946106 PMC6135812 source
    • cites [33] Lenze EJ, Mulsant BH, Blumberger DM,. Efficacy, safety, and tolerability of augmentation pharmacotherapy with aripiprazole for treatment-resistant depression in late life: a randomised, double-blind, placebo-controlled trial. Lancet. 2015; 386(10011): 2404- 2412. doi: 10.1016/S0140-6736(15)00308-6 26423182 PMC4690746 source

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    A sample size of 200 participants was estimated to be required to determine if bilateral TBS was noninferior to bilateral rTMS with 80% power and a 1-sided alpha of 0.05, using a δ of 2.75 and a standard deviation of change of 7.8.

    “we used a δ of 2.75 and a standard deviation of change of 7.8 and estimated a sample size of 200 participants was required to determine if bilateral TBS was noninferior to bilateral rTMS with 80% power and a 1-sided alpha of 0.05.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [7] Trevizol AP, Goldberger KW, Mulsant BH,. Unilateral and bilateral repetitive transcranial magnetic stimulation for treatment-resistant late-life depression. Int J Geriatr Psychiatry. 2019; 34(6): 822- 827. doi: 10.1002/gps.5091 30854751 PMC6488425 source

      The Results section reports an analysis of 43 participants assigned to bilateral rTMS, unilateral rTMS, or sham; it does not report a bilateral TBS comparison. Searches for the 200-participant noninferiority calculation and the values 2.75 and 7.8 found no passage addressing that calculation. Page numbers were unavailable in our copy. (LLM, conf=0.78)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In 2 separate studies, our group found superior remission rates with bilateral stimulation (40%) compared with both left-unilateral (0%) and sham (0%) stimulation in older patients with treatment-resistant depression.

    “our group found in 2 separate studies superior remission rates with bilateral stimulation (40%) compared with both left-unilateral (0%) and sham (0%) stimulation in older patients with TRD.7”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [7] Trevizol AP, Goldberger KW, Mulsant BH,. Unilateral and bilateral repetitive transcranial magnetic stimulation for treatment-resistant late-life depression. Int J Geriatr Psychiatry. 2019; 34(6): 822- 827. doi: 10.1002/gps.5091 30854751 PMC6488425 source

      The Results (page unavailable) report remission rates of 40% with bilateral rTMS and 0% with both left-unilateral and sham rTMS in older adults with treatment-resistant depression. The Methods and Results describe a combined analysis of participants from two previous trials, not separate demonstrations of those rates in each study. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Based on raw mean difference between active and sham rTMS for response (21% difference) and remission (14% difference) from a previous meta-analysis, a noninferiority δ = 15% was used to compare response rates and a noninferiority δ = 10% was used to compare remission rates.

    “Based on raw mean difference between active and sham rTMS for response (21% difference) and remission (14% difference) from a previous meta-analysis,31 a noninferiority δ = 15% was used to compare response rates and a noninferiority δ = 10% was used to compare remission rates.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [31] Gaynes BN, Lloyd SW, Lux L,. Repetitive transcranial magnetic stimulation for treatment-resistant depression: a systematic review and meta-analysis. J Clin Psychiatry. 2014; 75(5): 477- 489. doi: 10.4088/JCP.13r08815 24922485 source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In older adults, most rTMS studies to date have been limited by suboptimal stimulation parameters, small sample sizes, and insufficient treatment durations.

    “However, in older adults, most rTMS studies to date have been limited by suboptimal stimulation parameters, small sample sizes, and insufficient treatment durations.6”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [6] Cappon D, den Boer T, Jordan C, Yu W, Metzger E, Pascual-Leone A. Transcranial magnetic stimulation (TMS) for geriatric depression. Ageing Res Rev. 2022; 74: 101531. doi: 10.1016/j.arr.2021.101531 34839043 PMC8996329 source

  • May combine two claims.

    Premisecitation

    The decision to compare TBS with standard bilateral TMS rather than sham was based on network meta-analytic findings supporting bilateral standard TMS over sham treatment and the widespread use of bilateral standard TMS in the community setting.

    “The decision to compare TBS with standard bilateral TMS rather than sham was a recognition of network meta-analytic findings supporting bilateral standard TMS over sham treatment34,35 as well as the widespread use of bilateral standard TMS in the community setting.37”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [34] Brunoni AR, Chaimani A, Moffa AH,. Repetitive transcranial magnetic stimulation for the acute treatment of major depressive episodes: a systematic review with network meta-analysis. JAMA Psychiatry. 2017; 74(2): 143- 152. doi: 10.1001/jamapsychiatry.2016.3644 28030740 source
    • cites [35] Mutz J, Vipulananthan V, Carter B, Hurlemann R, Fu CHY, Young AH. Comparative efficacy and acceptability of non-surgical brain stimulation for the acute treatment of major depressive episodes in adults: systematic review and network meta-analysis. BMJ. 2019; 364: l1079. doi: 10.1136/bmj.l1079 30917990 PMC6435996 source
    • cites [37] Aaronson ST, Carpenter LL, Hutton TM,. Comparison of clinical outcomes with left unilateral and sequential bilateral transcranial magnetic stimulation (TMS) treatment of major depressive disorder in a large patient registry. Brain Stimul. 2022; 15(2): 326- 336. doi: 10.1016/j.brs.2022.01.006 35074549 source

  • May combine two claims.

    Premisecitation

    The present study used bilateral stimulation rather than unilateral stimulation based on data suggesting better response to bilateral stimulation compared with sham in older adults and data demonstrating efficacy of bilateral cTBS/iTBS compared with sham in adults.

    “The present study used bilateral stimulation, rather than the unilateral stimulation in the THREE-D trial, based on data suggesting better response to bilateral stimulation compared with sham in older adults7 and data demonstrating efficacy of bilateral cTBS/iTBS compared with sham in adults.12,36”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [7] Trevizol AP, Goldberger KW, Mulsant BH,. Unilateral and bilateral repetitive transcranial magnetic stimulation for treatment-resistant late-life depression. Int J Geriatr Psychiatry. 2019; 34(6): 822- 827. doi: 10.1002/gps.5091 30854751 PMC6488425 source
    • cites [12] Li CT, Chen MH, Juan CH,. Efficacy of prefrontal theta-burst stimulation in refractory depression: a randomized sham-controlled study. Brain. 2014; 137(Pt 7): 2088- 2098. doi: 10.1093/brain/awu109 24817188 source
    • cites [36] Li CT, Chen MH, Juan CH,. Effects of prefrontal theta-burst stimulation on brain function in treatment-resistant depression: a randomized sham-controlled neuroimaging study. Brain Stimul. 2018; 11(5): 1054- 1062. doi: 10.1016/j.brs.2018.04.014 29730251 source

  • Classified as probably not a substantial claim.

    Premisecitation

    Previous work has suggested that older adults require higher stimulation intensities to ensure sufficient cortical stimulation.

    “Previous work has suggested that older adults require higher stimulation intensities39 to ensure sufficient cortical stimulation.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [39] Nahas Z, Li X, Kozel FA,. Safety and benefits of distance-adjusted prefrontal transcranial magnetic stimulation in depressed patients 55-75 years of age: a pilot study. Depress Anxiety. 2004; 19(4): 249- 256. doi: 10.1002/da.20015 15274174 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A recent trial suggested similar outcomes for TBS at 80% vs 120% RMT.

    “A recent trial suggested similar outcomes for TBS at 80% vs 120% RMT.40”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [40] Chen L, Thomas EHX, Kaewpijit P,. Accelerated theta burst stimulation for the treatment of depression: a randomised controlled trial. Brain Stimul. 2021; 14(5): 1095- 1105. doi: 10.1016/j.brs.2021.07.018 34332155 source

  • May combine two claims.

    Premisecitation

    Standard bilateral rTMS has been shown to be efficacious in multiple clinical trials and was one of the most effective rTMS protocols in 2 recent network meta-analyses.

    “Standard bilateral rTMS has been shown to be efficacious in multiple clinical trials and was one of the most effective rTMS protocols in 2 recent network meta-analyses.34,35”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [34] Brunoni AR, Chaimani A, Moffa AH,. Repetitive transcranial magnetic stimulation for the acute treatment of major depressive episodes: a systematic review with network meta-analysis. JAMA Psychiatry. 2017; 74(2): 143- 152. doi: 10.1001/jamapsychiatry.2016.3644 28030740 source
    • cites [35] Mutz J, Vipulananthan V, Carter B, Hurlemann R, Fu CHY, Young AH. Comparative efficacy and acceptability of non-surgical brain stimulation for the acute treatment of major depressive episodes in adults: systematic review and network meta-analysis. BMJ. 2019; 364: l1079. doi: 10.1136/bmj.l1079 30917990 PMC6435996 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    A total of 172 participants were randomized to receive treatment by the early stages of the COVID-19 pandemic in March 2020.

    “Table 1 summarizes the characteristics of the intention-to-treat sample of 172 participants randomized to receive treatment by the early stages of the COVID-19 pandemic in March 2020”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the primary analysis, final MADRS score change showed an estimated adjusted difference of 1.55 points favoring TBS, with a lower 95% CI of −0.67, which is lower than the a priori noninferiority δ = 2.75 points.

    “Final MADRS score change showed an estimated adjusted difference of 1.55 points favoring TBS, with a lower 95% CI of −0.67, lower than the a priori noninferiority δ = 2.75 points.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    On all secondary outcome measures, TBS demonstrated noninferiority to standard bilateral rTMS and at all follow-up time points.

    “On all secondary outcome measures, TBS also demonstrated noninferiority to standard bilateral rTMS (Table 2) and at all follow-up time points (eTable 1 in Supplement 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There were no substantial changes on any of the cognitive measures and no significant differences between standard rTMS and TBS on any of the cognitive measures.

    “There were no substantial changes on any of the cognitive measures and no significant differences between standard rTMS and TBS on any of the cognitive measures (eTable 3 in Supplement 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The MADRS response rate for TBS was 44.3% (35 of 79) compared with 32.9% (28 of 85) for standard bilateral rTMS, with an estimated adjusted difference of 11.4% favoring TBS and a lower 95% CI of −1.1%, smaller than the noninferiority δ < 15%.

    “The MADRS response rate for TBS was 44.3% (35 of 79) compared with 32.9% (28 of 85) for standard bilateral rTMS with an estimated adjusted difference of 11.4% favoring TBS, with a lower 95% CI of −1.1%, smaller than the noninferiority δ < 15%.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Noninferiority was demonstrated at all follow-up time points and in the sensitivity analysis sample (n = 157), with an estimated adjusted difference of 1.22 points favoring TBS and a lower 95% CI of −1.06 points.

    “Additional analyses demonstrated noninferiority at all follow-up time points (eTable 1 in Supplement 2) and in the sensitivity analysis sample (n = 157) (estimated adjusted difference of 1.22 points favoring TBS, with a lower 95% CI of −1.06 points).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The MADRS remission rate for TBS was 35.4% (28 of 79) compared with 32.9% (28 of 85) for standard bilateral rTMS, with an estimated adjusted difference of 2.5% favoring TBS and a lower 95% CI of −9.7%, smaller than the noninferiority δ < 10%.

    “Similarly, the MADRS remission rate for TBS was 35.4% (28 of 79) compared with 32.9% (28 of 85) for standard bilateral rTMS with an estimated adjusted difference of 2.5% favoring TBS, with a lower 95% CI of −9.7%, smaller than the noninferiority δ < 10%.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There were no differences in self-reported adverse effects or in serious adverse events between rTMS and TBS.

    “There were no differences in self-reported adverse effects or in SAEs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    The TBS arm demonstrated an ongoing improvement up to 4 weeks posttreatment that was superior to standard rTMS.

    “Indeed, the TBS arm demonstrated an ongoing improvement up to 4 weeks posttreatment that was superior to standard rTMS.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Repetitive transcranial magnetic stimulation (rTMS) of the left side of the dorsolateral prefrontal cortex at 10 Hz is a well-tolerated, evidence-based treatment for treatment-resistant depression.

    “rTMS of the left side of the dorsolateral prefrontal cortex (DLPFC) at 10 Hz is a well-tolerated, evidence-based treatment for TRD.5”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] McClintock SM, Reti IM, Carpenter LL,; National Network of Depression Centers rTMS Task Group; American Psychiatric Association Council on Research Task Force on Novel Biomarkers and Treatments. Consensus recommendations for the clinical application of repetitive transcranial magnetic stimulation (rTMS) in the treatment of depression. J Clin Psychiatry. 2018; 79(1): 16cs10905. doi: 10.4088/JCP.16cs10905 28541649 PMC5846193 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All participants provided written, informed consent to participate.

    “All participants provided written, informed consent to participate.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    A total of 164 participants completed the greater part of 4 weeks of treatment and were included in the primary analysis.

    “A total of 164 participants completed the greater part of 4 weeks of treatment and were included in the primary analysis (Figure 1).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Two sensitivity analyses were conducted: one excluded 7 participants who were not able to receive an MRI and the other used the intention-to-treat sample.

    “Two sensitivity analyses were conducted: one excluded 7 participants who were not able to receive an MRI and the other used the intention-to-treat sample.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Bilateral TBS protocols studied in major depressive disorder yield higher remission rates than sham TBS while still reducing session duration.

    “Bilateral TBS protocols have also been studied in major depressive disorder, and they yield higher remission rates than sham TBS12 while still reducing session duration.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] Li CT, Chen MH, Juan CH,. Efficacy of prefrontal theta-burst stimulation in refractory depression: a randomized sham-controlled study. Brain. 2014; 137(Pt 7): 2088- 2098. doi: 10.1093/brain/awu109 24817188 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Outcome raters were blinded to treatment assignment and located on another floor.

    “Outcome raters were blinded to treatment assignment and located on another floor.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    Outpatients were randomized by personnel external to the clinical team using a computer-based algorithm and allocated in a 1:1 ratio to the standard bilateral protocol or the bilateral TBS protocol.

    “Outpatients were randomized by personnel external to the clinical team using a computer-based algorithm and allocated in a 1:1 ratio to the standard bilateral protocol or the bilateral TBS protocol.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    In older adults with treatment-resistant depression, theta burst stimulation is effective and tolerable compared with standard repetitive transcranial magnetic stimulation, as established by this randomized noninferiority trial.

    “This randomized noninferiority trial establishes the effectiveness and tolerability of theta burst stimulation compared with standard repetitive transcranial magnetic stimulation in older adults with treatment-resistant depression.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The trial was conducted at an academic health center after research ethics board approval.

    “The trial was conducted at an academic health center (Centre for Addiction and Mental Health, Toronto, Ontario, Canada) after research ethics board approval.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Preclinical research suggests that theta burst stimulation can achieve similar or more potent effects on neural plasticity, with durable effects ensuing from 600 pulses of intermittent TBS over 3 minutes or 600 pulses of continuous TBS over 40 seconds.

    “Preclinical research suggests that TBS can achieve similar or more potent effects on neural plasticity, with durable effects ensuing from 600 pulses of intermittent TBS (iTBS) over 3 minutes or 600 pulses of continuous TBS (cTBS) over 40 seconds.10”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Di Lazzaro V, Dileone M, Pilato F,. Modulation of motor cortex neuronal networks by rTMS: comparison of local and remote effects of six different protocols of stimulation. J Neurophysiol. 2011; 105(5): 2150- 2156. doi: 10.1152/jn.00781.2010 21346213 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Randomization used randomly permuted blocks, with stratification by level of treatment resistance (0 or 1 vs >1 adequate trial).

    “Randomly permuted blocks, with stratification by level of treatment resistance (0 or 1 vs >1 adequate trial).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductreasoning

    Both technicians and participants were aware of the treatment condition.

    “Both technicians and participants (because of the different duration of sessions) were aware of the treatment condition.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Nontransparent, sealed envelopes with a randomization identification on the outside and treatment assignment on the inside were used for allocation.

    “Nontransparent, sealed envelopes with a randomization identification on the outside and treatment assignment on the inside were used for allocation.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    According to the National Institute of Clinical Health and Excellence, a clinically meaningful difference between drug and placebo is defined by 3 points or more on a depression rating scale.

    “According to the National Institute of Clinical Health and Excellence, a clinically meaningful difference between drug and placebo is defined by 3 points or more on a depression rating scale.29”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] National Collaborating Centre for Mental Health. Depression in adults with a chronic physical health problem: treatment and management. British Psychological Society and the Royal College of Psychiatrists; 2010. 22259826

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Stimulation at 120% RMT is consistent with current recommendations for standard rTMS.

    “While this intensity is consistent with current recommendations for standard rTMS,5 there is no current consensus on the optimal intensity for TBS and other studies have used lower intensities.12”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] McClintock SM, Reti IM, Carpenter LL,; National Network of Depression Centers rTMS Task Group; American Psychiatric Association Council on Research Task Force on Novel Biomarkers and Treatments. Consensus recommendations for the clinical application of repetitive transcranial magnetic stimulation (rTMS) in the treatment of depression. J Clin Psychiatry. 2018; 79(1): 16cs10905. doi: 10.4088/JCP.16cs10905 28541649 PMC5846193 source

  • May combine two claims.

    Premisecitation

    There is no current consensus on the optimal intensity for TBS, and other studies have used lower intensities.

    “While this intensity is consistent with current recommendations for standard rTMS,5 there is no current consensus on the optimal intensity for TBS and other studies have used lower intensities.12”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] Li CT, Chen MH, Juan CH,. Efficacy of prefrontal theta-burst stimulation in refractory depression: a randomized sham-controlled study. Brain. 2014; 137(Pt 7): 2088- 2098. doi: 10.1093/brain/awu109 24817188 source

  • May combine two claims.

    Interpretationreasoning

    The higher pain ratings with TBS did not translate into a higher dropout rate, possibly because of the much shorter duration of stimulation with TBS.

    “However, this did not translate into a higher dropout rate possibly because of the much shorter duration of stimulation with TBS.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The trial was conducted at a single site.

    “While the trial is one of the largest neurostimulation trials in older adults with TRD, it was nevertheless conducted at a single site.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The findings at the follow-up time points must be interpreted with caution since some participants were lost to follow-up.

    “Finally, the findings at the follow-up time points must be interpreted with caution since some participants were lost to follow-up.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The short-session duration lends itself to potentially accelerated response with multiple treatments per day, and the findings suggest that this may be possible using bilateral TBS with older adults with depression.

    “Furthermore, the short-session duration lends itself to potentially accelerated response with multiple treatments per day42 and the findings herein suggest that this may be possible using bilateral TBS with older adults with depression.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Cole EJ, Phillips AL, Bentzley BS,. Stanford neuromodulation therapy (SNT): a double-blind randomized controlled trial. Am J Psychiatry. 2022; 179(2): 132- 141. 34711062 source

  • May combine two claims.

    Interpretationown data

    Despite the relative disadvantage experienced by those in the TBS group, the overall outcomes demonstrated noninferiority and strengthen the overall findings.

    “Despite this relative disadvantage experienced by those in the TBS group, the overall outcomes demonstrated noninferiority and strengthen the overall findings.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Despite the truncated recruitment period and the smaller sample than planned, the findings strongly support the noninferiority of TBS and it is highly unlikely that these findings would change with an additional 20 or 30 participants.

    “Despite the truncated recruitment period and the smaller sample than planned, the findings strongly support the noninferiority of TBS and it is highly unlikely that these findings would change with an additional 20 or 30 participants.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Although the addition of 40 seconds of right-sided cTBS to 3 minutes of left-sided iTBS is a minimal increase in treatment time, it may also prove to yield minimal increase in clinical benefit over left-sided iTBS in the community setting.

    “Thus, although the addition of 40 seconds of right-sided cTBS to 3 minutes of left-sided iTBS is a minimal increase in treatment time, it may also prove to yield minimal increase in clinical benefit over left-sided iTBS in the community setting.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationown data

    The finding of sustained and progressive improvement is consistent with the possibility that TBS induces greater brain plasticity than standard rTMS protocols.

    “This finding of sustained and progressive improvement is consistent with the possibility that TBS induces greater brain plasticity than standard rTMS protocols.10”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Di Lazzaro V, Dileone M, Pilato F,. Modulation of motor cortex neuronal networks by rTMS: comparison of local and remote effects of six different protocols of stimulation. J Neurophysiol. 2011; 105(5): 2150- 2156. doi: 10.1152/jn.00781.2010 21346213 source

  • May combine two claims.

    Study design and conductown data

    Both the degree of improvement and the remission rate in the bilateral standard rTMS arm are consistent with results of previous randomized clinical trials and provide assay sensitivity.

    “Both the degree of improvement and the remission rate in our bilateral standard rTMS arm are consistent with results of previous randomized clinical trials and provides assay sensitivity.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    A sham arm would have allowed for an assessment of the contribution of nonspecific factors.

    “However, a sham arm would have allowed for an assessment of the contribution of nonspecific factors.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    Marked changes in the psychosocial and health care environment associated with the pandemic would have introduced confounding factors between pre- and post-COVID-19 cohorts.

    “Furthermore, marked changes in the psychosocial and health care environment associated with the pandemic would have introduced confounding factors between pre– and post–COVID-19 cohorts.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    While the analysis prespecified a 1-sided 95% CI, noninferiority findings remained on all measures with a more stringent 1-sided 97.5% CI.

    “Similarly, while we prespecified a 1-sided 95% CI for the analysis and more stringent recommendations suggest a 1-sided 97.5% CI, noninferiority findings remained on all measures with this more stringent criterion (eTable 2 in Supplement 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    There was no sham group and participants were aware of their treatment allocation.

    “As such, there was no sham group and participants were aware of their treatment allocation.”
    Quote in the paperSubstantial claim
49 of 49

  • The paper relies on this without support.

    Optimal parameters for rTMS are still in the process of being established.

    “While optimal parameters for rTMS are still in the process of being established, our group found in 2 separate studies superior remission rates with bilateral stimulation (40%) compared with both left-unilateral (0%) and sham (0%) stimulation in older patients with TRD.7”

  • The paper relies on this without support.

    There is no validated stereotaxic target for right-sided DLPFC-rTMS.

    “While the left-sided DLPFC target was based on previous work,17 there is an absence of any validated stereotaxic target for right-sided DLPFC-rTMS; as such, we mirrored the left stereotaxic coordinate to the right hemisphere following common clinical practice.”

  • The paper relies on this without support.

    The present study is the largest randomized clinical trial of nonconvulsive neuromodulation in older adults with treatment-resistant depression.

    “To our knowledge, we report on the largest randomized clinical trial of nonconvulsive neuromodulation in older adults with TRD.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

  • Incorrect percentage for antipsychotic augmentation in the rTMS group

    Minor

    Table 1 lists 21 participants receiving antipsychotic augmentation in the rTMS group of 87, which is 24.1%, not 32.1%.

    Reported 32.1 · recomputed 24.137931

1 of 1

Cited works that were retracted

Works this paper cites that were later retracted, from the retraction notices publishers deposit. Major when the notice came out before this paper was published.

  • Cites a retracted work: 10.1016/s0140-6736(20)30367-6

    Info

    The cited work was retracted on 2023-05-01 (notice 10.1016/s2468-2667(23)00083-x), not before this paper was published (2022-11-01).

    Cited work 10.1016/s0140-6736(20)30367-6 · retracted 2023-05-01 · notice 10.1016/s2468-2667(23)00083-x · this paper published 2022-11-01

1 of 1

Cites

1 retracted

Flagged first, then by citations

Research works printed but not linked: 1

  1. Delis, 2000, California Verbal Learning Test—Second Edition, Adult Version

Cited by

Sorted by citations

Related

Authors
Blumberger, D. M., Mulsant, B. H., Thorpe, K. E., McClintock, S. M., Konstantinou, G. N., Lee, H. H., Nestor, S. M., Noda, Y., Rajji, T. K., Trevizol, A. P., Vila-Rodriguez, F., Daskalakis, Z. J., & Downar, J.
Affiliations
  • Centre for Addiction and Mental Health (CA)
  • University of Toronto (CA)
  • St. Michael's Hospital (CA)
  • The University of Texas Southwestern Medical Center (US)
  • Sunnybrook Health Science Centre (CA)
  • Keio University (JP)
  • Non-Invasive Neurostimulation Therapies (NINET) Laboratory, University of British Columbia Hospital, Vancouver, British Columbia, Canada
  • University of California San Diego (US)
Corresponding author
Blumberger, Daniel M.
ORCID
Venue
JAMA Psychiatry
Publisher
American Medical Association (AMA)
Published
2022-11-01
Volume
79
Issue
11
Pages
1065
ISSN
2168-622X (ISSN-L)
DOI
10.1001/jamapsychiatry.2022.2862
PMC
PMC9494264
OpenAlex
W4297874913
Semantic Scholar
c2dea08ebd6709ea75824ab5d55c91088820fad3
Cited by
142
References
45
Citations by year
2026: 31 · 2025: 46 · 2024: 40 · 2023: 24 · 2022: 1
FWCI
9.78
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • JAMA Psychiatry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Klarman Family Foundation
  • Biogen
  • BrightFocus Foundation
  • Ontario Brain Institute
  • Fondation Brain Canada
  • Weston Brain Institute
  • BrainsWay
  • Miyuki Giken
  • Taiju Life Social Welfare Foundation
  • Michael Smith Health Research BC
  • Ontario Ministry of Health and Long-Term Care
  • Dainippon Sumitomo Pharma
  • Mochida Memorial Foundation for Medical and Pharmaceutical Research
  • Vancouver Coastal Health Research Institute
  • SENSHIN Medical Research Foundation
  • Teijin Pharma
  • H. Lundbeck A/S
  • National Institutes of Health
  • Allergan
  • Canadian Institutes of Health Research (148840_1)
  • Japan Society for the Promotion of Science (23K21398)
  • Ontario Ministry of Research and Innovation
  • Yoshitomiyakuhin Corporation
  • National Institute of Mental Health
  • Daiichi Sankyo Europe
Topics
  • Life Sciences › Neuroscience › Neurology › Transcranial Magnetic Stimulation Studies
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
Keywords
treatment-resistant depression, older adults, theta burst stimulation, dorsolateral prefrontal cortex, non-inferiority, tolerability, antidepressant non-response
MeSH terms
Aged, Depression, Major Depressive Disorder, Depressive Disorder, Major, Female, Humans, Male, Ontario, Treatment Outcome, Prefrontal Cortex, Transcranial Magnetic Stimulation, Depressive Disorder, Treatment-Resistant

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-28.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

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