Skip to main content
SpringerLink
Log in

Accelerated sequential bilateral theta-burst stimulation in major depression: an open trial

  • Original Paper
  • Published:
European Archives of Psychiatry and Clinical Neuroscience Aims and scope Submit manuscript

Abstract

Theta burst stimulation (TBS) is approved and widely used in the treatment of treatment resistant-major depression. More recently, accelerated protocols delivering multiple treatments per day have been shown to be efficacious and potentially enhance outcomes compared to once daily protocols. Meanwhile, bilateral treatment protocols have also been increasingly tested to enhance outcomes. Here, we examined the efficacy and safety of accelerated bilateral TBS in major depressive disorder (MDD). In this open label pilot study, 25 patients with MDD (60%: women; mean age (SD): 45.24 (12.22)) resistant to at least one antidepressant, received bilateral TBS, consisting of 5 sequential bilateral intermittent TBS (iTBS) (600 pulses) and continuous TBS (cTBS) (600 pulses) treatments delivered to the left and right dorsolateral prefrontal cortex (DLPFC), respectively, daily for 5 days at 120% resting motor threshold. Outcome measures were post-treat treatment changes at day 5 and 2-weeks in Hamilton Depression Rating Scale (HDRS-17) scores and response (≥ 50% reduction from the baseline scores) and remission (≤ 7) rates. There was a significant reduction in HDRS scores at day 5 (p < 0.001) and 2-weeks post treatment (p < 0.001). The response rates increased from 20% at day 5 to 32% at 2-weeks post treatment suggesting delayed clinical effects. However, reduction in symptom scores between two post treatment endpoints was non-significant. 60% of patients could not tolerate the high intensity stimulation. No major adverse events occurred. Open label uncontrolled study with small sample size. These preliminary findings suggest that accelerated bilateral TBS may be clinically effective and safe for treatment resistant depression. Randomized sham-controlled trials are needed to establish the therapeutic role of accelerated bilateral TBS in depression.

Trial registration: ClinicalTrials.gov, NCT10001858.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data availability

Data that support the findings of this study are available from the corresponding author upon reasonable request.

Code availability

No computer code or algorithm was used in this study.

References

  1. McClintock SM, Reti IM, Carpenter LL et al (2018) Consensus recommendations for the clinical application of repetitive transcranial magnetic stimulation (rTMS) in the treatment of depression. J Clin Psychiatry 79:3651. https://doi.org/10.4088/JCP.16cs10905

    Article  Google Scholar 

  2. Milev RV, Giacobbe P, Kennedy SH et al (2016) Canadian network for mood and anxiety treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder:. Neurostimulation treatments. Can J Psychiatry 61:561–575. https://doi.org/10.1177/0706743716660033

    Article  PubMed Central  PubMed  Google Scholar 

  3. Perera T, George MS, Grammer G, Janicak PG, Pascual-Leone A, Wirecki TS (2016) The clinical tms society consensus review and treatment recommendations for tms therapy for major depressive disorder. Brain Stimul 9:336–346. https://doi.org/10.1016/j.brs.2016.03.010

    Article  PubMed Central  PubMed  Google Scholar 

  4. Blumberger DM, Vila-Rodriguez F, Thorpe KE, Feffer K, Noda Y, Giacobbe P, Knyahnytska Y, Kennedy SH, Lam RW, Daskalakis ZJ, Downar J (2018) Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (Three-D): a randomised non-inferiority trial. Lancet 391:1683–1692. https://doi.org/10.1016/s0140-6736(18)30295-2

    Article  PubMed  Google Scholar 

  5. Voigt JD, Leuchter AF, Carpenter LL (2021) Theta burst stimulation for the acute treatment of major depressive disorder: a systematic review and meta-analysis. Transl Psychiatry 11:330. https://doi.org/10.1038/s41398-021-01441-4

    Article  PubMed Central  PubMed  Google Scholar 

  6. Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC (2005) Theta burst stimulation of the human motor cortex. Neuron 45:201–206. https://doi.org/10.1016/j.neuron.2004.12.033

    Article  CAS  PubMed  Google Scholar 

  7. Huang YZ, Chen RS, Rothwell JC, Wen HY (2007) The after-effect of human theta burst stimulation is nmda receptor dependent. Clin Neurophysiol 118:1028–1032. https://doi.org/10.1016/j.clinph.2007.01.021

    Article  CAS  PubMed  Google Scholar 

  8. Suppa A, Huang YZ, Funke K, Ridding MC, Cheeran B, Di Lazzaro V, Ziemann U, Rothwell JC (2016) Ten years of theta burst stimulation in humans: established knowledge, unknowns and prospects. Brain Stimul 9:323–335. https://doi.org/10.1016/j.brs.2016.01.006

    Article  CAS  PubMed  Google Scholar 

  9. Berlim MT, McGirr A, Rodrigues Dos Santos N, Tremblay S, Martins R (2017) Efficacy of theta burst stimulation (TBS) for major depression: an exploratory meta-analysis of randomized and sham-controlled trials. J Psychiatr Res 90:102–109. https://doi.org/10.1016/j.jpsychires.2017.02.015

    Article  PubMed  Google Scholar 

  10. Brunoni AR, Chaimani A, Moffa AH, Razza LB, Gattaz WF, Daskalakis ZJ, Carvalho AF (2017) Repetitive transcranial magnetic stimulation for the acute treatment of major depressive episodes: a systematic review with network meta-analysis. JAMA Psychiat 74(2):143–152. https://doi.org/10.1001/jamapsychiatry.2016.3644

    Article  Google Scholar 

  11. Li CT, Chen MH, Juan CH, Huang HH, Chen LF, Hsieh JC, Tu PC, Bai YM, Tsai SJ, Lee YC, Su TP (2014) Efficacy of prefrontal theta-burst stimulation in refractory depression: a randomized sham-controlled study. Brain 137:2088–2098. https://doi.org/10.1093/brain/awu109

    Article  PubMed  Google Scholar 

  12. Li CT, Cheng CM, Chen MH, Juan CH, Tu PC, Bai YM, Jeng JS, Lin WC, Tsai SJ, Su TP (2020) Antidepressant efficacy of prolonged intermittent theta burst stimulation monotherapy for recurrent depression and comparison of methods for coil positioning: a randomized, double-blind, sham-controlled study. Biol Psychiatry 87:443–450. https://doi.org/10.1016/j.biopsych.2019.07.031

    Article  CAS  PubMed  Google Scholar 

  13. Caulfield KA, Fleischmann HH, George MS, McTeague LM (2022) A transdiagnostic review of safety, efficacy, and parameter space in accelerated transcranial magnetic stimulation. J Psychiatr Res 152:384–396. https://doi.org/10.1016/j.jpsychires.2022.06.038

    Article  PubMed Central  PubMed  Google Scholar 

  14. Cole EJ, Phillips AL, Bentzley BS et al (2022) Stanford neuromodulation therapy (SNT): A double-blind randomized controlled trial. Am J Psychiatry 179:132–141. https://doi.org/10.1176/appi.ajp.2021.20101429

    Article  PubMed  Google Scholar 

  15. Sonmez AI, Camsari DD, Nandakumar AL, Voort JLV, Kung S, Lewis CP, Croarkin PE (2019) Accelerated TMS for depression: a systematic review and meta-analysis. J Psychiatry Res 273:770–781. https://doi.org/10.1016/j.psychres.2018.12.041

    Article  Google Scholar 

  16. Chen L, Thomas EHX, Kaewpijit P et al (2021) Accelerated theta burst stimulation for the treatment of depression: a randomised controlled trial. Brain Stimul 14:1095–1105. https://doi.org/10.1016/j.brs.2021.07.018

    Article  PubMed  Google Scholar 

  17. (2013) Diagnostic and statistical manual of mental disorders, 5th ed. American Psychiatric Association, Washington

  18. Hamilton M (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56–62. https://doi.org/10.1136/jnnp.23.1.56

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Fitzgerald PB, Daskalakis ZJ (2012) A practical guide to the use of repetitive transcranial magnetic stimulation in the treatment of depression. Brain Stimul 5(3):287–296. https://doi.org/10.1016/j.brs.2011.03.006

    Article  PubMed  Google Scholar 

  20. Duprat R, Desmyter S, de Rudi R et al (2016) Accelerated intermittent theta burst stimulation treatment in medication-resistant major depression: a fast road to remission? J Affect Disord 200:6–14. https://doi.org/10.1016/j.jad.2016.04.015

    Article  PubMed  Google Scholar 

  21. Fitzgerald PB, Hoy KE, Elliot D, Susan McQueen RN, Wambeek LE, Daskalakis ZJ (2018) Accelerated repetitive transcranial magnetic stimulation in the treatment of depression. Neuropsychopharmacology 43:1565–1572. https://doi.org/10.1038/s41386-018-0009-9

    Article  PubMed Central  PubMed  Google Scholar 

  22. Montgomery SA, Asberg M (1979) A new depression scale designed to be sensitive to change. Br J Psychiatry 134:382–389. https://doi.org/10.1192/bjp.134.4.382

    Article  CAS  PubMed  Google Scholar 

  23. Hamilton M (1959) The assessment of anxiety states by rating. Br J Med Psychol 32:50–55. https://doi.org/10.1111/j.2044-8341.1959.tb00467.x

    Article  CAS  PubMed  Google Scholar 

  24. Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, Melvin GA, Greenhill L, Shen S, Mann JJ (2011) The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry 168:1266–1277. https://doi.org/10.1176/appi.ajp.2011.10111704

    Article  PubMed Central  PubMed  Google Scholar 

  25. Snaith RP, Hamilton M, Morley S, Humayan A, Hargreaves D, Trigwell P (1995) A scale for the assessment of hedonic tone the Snaith–Hamilton pleasure scale. Br J Psychiatry 167:99–103. https://doi.org/10.1192/bjp.167.1.99

    Article  CAS  PubMed  Google Scholar 

  26. Ware JE Jr, Sherbourne CD (1992) The mos 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care 30:473–483. https://doi.org/10.1097/00005650-199206000-00002

    Article  PubMed  Google Scholar 

  27. American Psychiatric Association (2013) American psychiatric association releases DSM-5. APA, Washington. https://doi.org/10.1176/appi.books.9780890425596

    Book  Google Scholar 

  28. Thase ME, Rush AJ (1997) When at first you don’t succeed: sequential strategies for antidepressant nonresponders. J Clin Psychiatry 58:23–29

    PubMed  Google Scholar 

  29. Bech P, Boyer P, Germain JM, Padmanabhan K, Haudiquet V, Pitrosky B, Tourian KA (2010) HAMD-17 and HAMD-6 sensitivity to change in relation to desvenlafaxine dose and baseline depression severity in major depressive disorder. Pharmacopsychiatry 43:271–276. https://doi.org/10.1055/s-0030-1263173

    Article  CAS  PubMed  Google Scholar 

  30. Baeken C, Duprat R, Wu G-R, De Raedt R (2018) Accelerated intermittent theta burst stimulation rapidly attenuates depressive symptoms and suicide ideation in major depression: insights from brain perfusion and functional connectivity. Biol Psychiatry 83:S54. https://doi.org/10.1016/j.biopsych.2018.02.151

    Article  Google Scholar 

  31. Plewnia C, Pasqualetti P, Große S, Schlipf S, Wasserka B, Zwissler B, Fallgatter A (2014) Treatment of major depression with bilateral theta burst stimulation: a randomized controlled pilot trial. J Affect Disord 156:219–223. https://doi.org/10.1016/j.jad.2013.12.025

    Article  PubMed  Google Scholar 

  32. Prasser J, Schecklmann M, Poeppl TB, Frank E, Kreuzer PM, Hajak G, Rupprecht R, Landgrebe M, Langguth B (2015) Bilateral prefrontal rTMS and theta burst TMS as an add-on treatment for depression: a randomized placebo controlled trial. World J Biol Psychiatry 16:57–65. https://doi.org/10.3109/15622975.2014.964768

    Article  PubMed  Google Scholar 

  33. Blumberger DM, Vila-Rodriguez F, Wang W et al (2021) A randomized sham controlled comparison of once vs twice-daily intermittent theta burst stimulation in depression: a Canadian rTMS treatment and biomarker network in depression (CARTBIND) study. Brain Stimul 14:1447–1455. https://doi.org/10.1016/j.brs.2021.09.003

    Article  PubMed  Google Scholar 

  34. Caulfield KA, Brown JC (2022) The problem and potential of TMS’ infinite parameter space: a targeted review and road map forward. Front Psychiatry 13:867091. https://doi.org/10.3389/fpsyt.2022.867091

    Article  PubMed Central  PubMed  Google Scholar 

  35. McCalley DM, Lench DH, Doolittle JD, Imperatore JP, Hoffman M, Hanlon CA (2021) Determining the optimal pulse number for theta burst induced change in cortical excitability. Sci Rep 11:8726. https://doi.org/10.1038/s41598-021-87916-2

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Abraham WC, Bear MF (1996) Metaplasticity: the plasticity of synaptic plasticity. Trends Neurosci 19:126–130. https://doi.org/10.1016/s0166-2236(96)80018-x

    Article  CAS  PubMed  Google Scholar 

  37. Kramár EA, Babayan AH, Gavin CF, Cox CD, Jafari M, Gall CM, Rumbaugh G, Lynch G (2012) Synaptic evidence for the efficacy of spaced learning. Proc Natl Acad Sci USA 109:5121–5126. https://doi.org/10.1073/pnas.1120700109

    Article  PubMed Central  PubMed  Google Scholar 

  38. Thomson AC, de Graaf TA, Kenis G, Rutten BPF, Schuhmann T, Sack AT (2019) No additive meta plasticity effects of accelerated iTBS with short inter-session intervals. Brain Stimul 12:1301–1303. https://doi.org/10.1016/j.brs.2019.05.012

    Article  PubMed  Google Scholar 

  39. Fitzgerald PB, Hoy KE, Anderson RJ, Daskalakis ZJ (2016) A study of the pattern of response to rTMS treatment in depression. Depress Anxiety 33:746–753

    Article  PubMed  Google Scholar 

  40. Hunter AM, Minzenberg MJ, Cook IA, Krantz DE, Levitt JG, Rotstein NM et al (2019) Concomitant medication use and clinical outcome of repetitive transcranial magnetic stimulation (rTMS) treatment of major depressive disorder. Brain Behav 9:e01275

    Article  PubMed Central  PubMed  Google Scholar 

  41. Weigand A, Horn A, Caballero R, Cooke D, Stern AP, Taylor SF, Press D, Pascual-Leone A, Fox MD (2018) Prospective validation that subgenual connectivity predicts antidepressant efficacy of transcranial magnetic stimulation sites. Biol Psychiatry 84:28–37. https://doi.org/10.1016/j.biopsych.2017.10.028

    Article  CAS  PubMed  Google Scholar 

  42. Fox MD, Buckner RL, White MP, Greicius MD, Pascual-Leone A (2012) Efficacy of transcranial magnetic stimulation targets for depression is related to intrinsic functional connectivity with the subgenual cingulate. Biol Psychiatry 72(7):595–603. https://doi.org/10.1016/j.biopsych.2012.04.028

    Article  PubMed Central  PubMed  Google Scholar 

  43. Blumberger DM, Mulsant BH, Thorpe KE et al (2022) Effectiveness of standard sequential bilateral repetitive transcranial magnetic stimulation vs bilateral theta burst stimulation in older adults with depression: the FOUR-D randomized noninferiority clinical trial. JAMA Psychiat 79(11):1065–1073. https://doi.org/10.1001/jamapsychiatry.2022.2862

    Article  Google Scholar 

  44. Carrozzino D, Patierno C, Fava GA, Guidi J (2020) The Hamilton rating scales for depression: a critical review of clinimetric properties of different versions. Psychother Psychosom 89:133–150. https://doi.org/10.1159/000506879

    Article  PubMed  Google Scholar 

  45. Boucher PO, Ozdemir RA, Momi D, Burke MJ, Jannati A, Fried PJ, Pascual-Leone A, Shafi MM, Santarnecchi E (2021) Sham-derived effects and the minimal reliability of theta burst stimulation. Sci Rep 11:21170. https://doi.org/10.1038/s41598-021-98751-w

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Razza LB, Moffa AH, Moreno ML, Carvalho AF, Padberg F, Fregni F, Brunoni AR (2018) A systematic review and meta-analysis on placebo response to repetitive transcranial magnetic stimulation for depression trials. Prog Neuropsychopharmacol Biol Psychiatry 81:105–113. https://doi.org/10.1016/j.pnpbp.2017.10.016

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

Funding for the study was provided by a grant from Hotchkiss Brain Institute/ Mathison Centre Pilot Research Fund Program (PFUN), affiliated with Cumming School of Medicine (CSM), University of Calgary, Calgary, Alberta, Canada. The infra structure support was provided by Non-invasive Neurostimulation Network (N3) – Hotchkiss Brain Institute, University of Calgary. Partial data were presented as a poster at the Society of Biological Psychiatry April 2022 annual meeting.

Funding

Funding for the study was provided by a grant from Hotchkiss Brain Institute/Mathison Centre Pilot Research Fund Program (PFUN), affiliated with Cumming School of Medicine (CSM), University of Calgary, Calgary, Alberta, Canada. The infra structure support was provided by Non-invasive Neurostimulation Network (N3)—Hotchkiss Brain Institute, University of Calgary.

Author information

Authors and Affiliations

  1. Department of Psychiatry/Clinical Neurosciences Cumming School of Medicine, Mathison Centre for Mental Health Research and Education, Non-Invasive Neurostimulation Network, Hotchkiss Brain Institute, University of Calgary, TRW Building, Room 4D64, 3280 Hospital Drive NW, Calgary, AB, T2N4Z6, Canada

    Rajamannar Ramasubbu & Alexander McGirr

  2. School of Health and Care Management, Faculty of Business, Arden University, Berlin, Germany

    Elliot C. Brown

  3. Non-Invasive Neurostimulation Network, University of Calgary, Calgary, AB, Canada

    Ben Selby

  4. Mathison Centre for Mental Health Research & Education, Non-Invasive Neurostimulation Network, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada

    Jaeden Cole

  5. Mathison Centre for Mental Health Research and Education, University of Calgary, Calgary, AB, Canada

    Hadi Hassan

  6. Mathison Centre for Mental Health Research & Education Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada

    Laina McAusland

Authors
  1. Rajamannar Ramasubbu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elliot C. Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ben Selby
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alexander McGirr
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jaeden Cole
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hadi Hassan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Laina McAusland
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

RR and EB designed the study and wrote the grant. BS designed the TBS protocol. RR, LM recruited the patients, collected clinical data. BS and JC helped to perform TBS treatment. RR and HH planned the analysis. RR interpreted the results and wrote the manuscript. AM provided material support and critical review of the manuscript. All authors reviewed and approved the final manuscript.

Corresponding author

Correspondence to Rajamannar Ramasubbu.

Ethics declarations

Conflict of interest

Dr. Ramasubbu has received honorarium for serving in the advisory committee of Astra Zeneca, Lund beck, Janssen, and Otsuka. He also received investigator-initiated grant from Astra Zeneca and Pfizer. Dr. McGirr has received honorarium for serving on an advisory board for Allergan Canada and is a founder of MCGRx Corp. The funding agency had no influence on the design, and conduct of the study including collection, analysis and interpretation of the data, and preparation, review, or approval of the manuscript. Other authors declare no potential conflict of interest.

Ethical approval

The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008.

Consent to participate

Informed consent was obtained from all individual participants.

Consent to publish

All participants provided signed informed consent regarding publishing their data.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 20 KB)

Supplementary file2 (DOCX 13 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ramasubbu, R., Brown, E.C., Selby, B. et al. Accelerated sequential bilateral theta-burst stimulation in major depression: an open trial. Eur Arch Psychiatry Clin Neurosci 274, 697–707 (2024). https://doi.org/10.1007/s00406-023-01648-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00406-023-01648-0

Keywords

Search

Navigation