Decision-making for non-invasive neuromodulation prescription in the treatment of generalized anxiety disorder: a roadmap proposal

Authors

  • Igor Garcia Barreto Escola Bahiana de Medicina e Saúde Pública (Salvador). Bahia, Brazil. Núcleo de Assistência e Pesquisa em Neuromodulação - NAPeN network (Recife). Pernambuco, Brazil. https://orcid.org/0000-0003-3674-2826
  • Mateus Gonçalves Nogueira Clínica Neurama (São Bernardo do Campo). São Paulo, Brazil. Núcleo de Assistência e Pesquisa em Neuromodulação - NAPeN network (Recife). Pernambuco, Brazil. https://orcid.org/0000-0002-0285-6545
  • Júlia Thees Bortolotti Universidade Católica de Petrópolis (Petrópolis). Rio de Janeiro, Brazil. https://orcid.org/0009-0003-5105-4754
  • Marianita Ozorio Neubauer Faculdade de Medicina de Petrópolis (Petrópolis). Rio de Janeiro, Brazil. https://orcid.org/0009-0009-4018-205X
  • Kátia Monte-Silva Universidade Federal de Pernambuco (Pernambuco). Recife, Brazil. Núcleo de Assistência e Pesquisa em Neuromodulação - NAPeN network (Recife). Pernambuco, Brazil. https://orcid.org/0000-0001-7301-2553
  • Lívia Shirahige Universidade Federal de Pernambuco (Pernambuco). Recife, Brazil. Núcleo de Assistência e Pesquisa em Neuromodulação - NAPeN network (Recife). Pernambuco, Brazil. https://orcid.org/0000-0002-3331-0596
  • Abrahão Fontes Baptista Universidade Federal do Rio de Janeiro (Rio de Janeiro), Rio de Janeiro, Brazil. Núcleo de Assistência e Pesquisa em Neuromodulação - NAPeN network (Recife). Pernambuco, Brazil. https://orcid.org/0000-0001-7870-3820
  • Katia Nunes Sá Escola Bahiana de Medicina e Saúde Pública (Salvador). Bahia, Brazil. Núcleo de Assistência e Pesquisa em Neuromodulação - NAPeN network (Recife). Pernambuco, Brazil https://orcid.org/0000-0002-0255-4379

DOI:

https://doi.org/10.17267/2965-3738bis.2025.e6258

Keywords:

Neurosciences, Non-Invasive Brain Stimulation, Generalized Anxiety Disorder, Clinical Reasoning, Decision Making

Abstract

INTRODUCTION: Non-invasive brain stimulation (NIBS) has been used in the treatment of generalized anxiety disorder (GAD). However, the diversity of protocols, indications, and target populations requires careful standardization to ensure safety, efficacy, and uniformity in clinical practice based on the best available evidence, professional experience, and patient preferences. OBJECTIVE: To develop a clinical decision-making tree to standardize approaches and facilitate prescriptions by healthcare professionals regarding the use of NIBS to treat GAD. METHODOLOGY: Clinical reasoning study based on a roadmap for developing a decision-making tree. After reviewing the best evidence on the topic, five systematic reviews with meta-analyses were selected, from which randomized clinical trials with the largest effect sizes were extracted. From these trials, specific protocols were chosen and presented to researchers and clinical specialists in the field who, by consensus, constructed the clinical decision-making tree. The tools used to assess GAD symptoms in the studies were evaluated, identifying the most suitable ones for the Brazilian population, with recommendations on the best assessment instruments. The tree was presented to other specialists who validated the protocol recommendations. RESULTS: Four protocols were selected as interventions that could be recommended in clinical practice. The protocol with the largest effect size was not chosen as the first option due to the number of pulses exceeding the established safety criteria and the report of a tonic-clonic seizure as an adverse effect of stimulation. Three repetitive magnetic stimulation protocols presented equivalent effect sizes, but continuous Theta Burst stimulation to the right dorsolateral prefrontal cortex was chosen as the first indication because, in addition to having the largest effect size, it is an accelerated protocol, reducing application time, which impacts cost-effectiveness. CONCLUSION: The clinical reasoning process identified three instruments for outcome assessment and four transcranial magnetic stimulation protocol options for the treatment of GAD.

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References

1. World Health Organization. World mental health report: Transforming mental health for all [Internet]. Geneva: WHO; 2022. Available from: https://www.who.int/publications/i/item/9789240049338

2. Steel Z, Marnane C, Iranpour C, Chey T, Jackson JW, Patel V, et al. The global prevalence of common mental disorders: a systematic review and meta-analysis 1980-2013. Int J Epidemiol. 2014;43(2):476–93. https://doi.org/10.1093/ije/dyu038

3. Yang X, Fang Y, Chen H, Zhang T, Yin X, Man J, et al. Global, regional and national burden of anxiety disorders from 1990 to 2019: results from the Global Burden of Disease Study 2019. Epidemiol Psychiatr Sci. 2021;30:e36. http://dx.doi.org/10.1017/S2045796021000275

4. Santomauro DF, Herrera AMM, Shadid J, Zheng P, Ashbaugh C, Pigott DM, et al. Global prevalence and burden of depressive and anxiety disorders in 204 countries and territories in 2020 due to the COVID-19 pandemic. Lancet. 2021;398(10312):1700–12. http://dx.doi.org/10.1016/S0140-6736(21)02143-7

5. Darden M, Carl JR, Smits JAJ, Otto MW, Miller CB. Cost-effectiveness of automated digital CBT (Daylight) for generalized anxiety disorder: A Markov simulation model in the United States. PLOS Ment Health. 2024;1(3):e0000116. https://doi.org/10.1371/journal.pmen.0000116

6. Alonso J, Liu Z, Evans-Lacko S, Sadikova E, Sampson N, Chatterji S, et al. Treatment gap for anxiety disorders is global: Results of the World Mental Health Surveys in 21 countries. Depress Anxiety. 2018;35(3):195–208. http://dx.doi.org/10.1002/da.22711

7. Baldwin D, Woods R, Lawson R, Taylor D. Efficacy of drug treatments for generalised anxiety disorder: systematic review and meta-analysis. BMJ. 2011;342:d1199. http://dx.doi.org/10.1136/bmj.d1199

8. Springer KS, Levy HC, Tolin DF. Remission in CBT for adult anxiety disorders: A meta-analysis. Clin Psychol Rev. 2018;61:1–8. https://doi.org/10.1016/j.cpr.2018.03.002

9. Slee A, Nazareth I, Bondaronek P, Liu Y, Cheng Z, Freemantle N. Pharmacological treatments for generalised anxiety disorder: a systematic review and network meta-analysis. Lancet. 2019;393(10173):768–77. http://dx.doi.org/10.1016/S0140-6736(18)31793-8

10. Sá KN, Baptista RF, Shirahige L, Razza LB, Nogueira M, Coura MHF, et al. Evidence-based umbrella review of non-invasive brain stimulation in anxiety disorders. Eur J Psychiatry. 2023;37(3):167–81. https://doi.org/10.1016/j.ejpsy.2023.01.001

11. Qi L, Wang S, Li X, Yu Y, Wang W, Li Q, et al. Non-invasive brain stimulation in the treatment of generalized anxiety disorder: A systematic review and meta-analysis. J Psychiatr Res. 2024;178:378–87. http://dx.doi.org/10.1016/j.jpsychires.2024.07.046

12. Kan RLD, Padberg F, Giron CG, Lin TTZ, Zhang BBB, Brunoni AR, et al. Effects of repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex on symptom domains in neuropsychiatric disorders: a systematic review and cross-diagnostic meta-analysis. Lancet Psychiatry. 2023;10(4):252–9. http://dx.doi.org/10.1016/S2215-0366(23)00026-3

13. Yang X, Ma L, Fan C, Wang H, Zhang M, Du H, et al. Efficacy and acceptability of brain stimulation for anxiety disorders, OCD, and PTSD: A systematic review and network meta-analysis of randomized controlled trials. J Affect Disord. 2025;370:62–75. http://dx.doi.org/10.1016/j.jad.2024.10.071

14. Zheng EZ, Wong NML, Yang ASY, Lee TMC. Evaluating the effects of tDCS on depressive and anxiety symptoms from a transdiagnostic perspective: a systematic review and meta-analysis of randomized controlled trials. Transl Psychiatry. 2024;14(1):295. http://dx.doi.org/10.1038/s41398-024-03003-w

15. Rosson S, Filippis R, Croatto G, Collantoni E, Pallottino S, Guinart D, et al. Brain stimulation and other biological non-pharmacological interventions in mental disorders: An umbrella review. Neurosci Biobehav Rev. 2022;139:104743. http://dx.doi.org/10.1016/j.neubiorev.2022.104743

16. Cox J, Thakur B, Alvarado L, Shokar N, Thompson PM, Dwivedi AK. Repetitive transcranial magnetic stimulation for generalized anxiety and panic disorders: A systematic review and meta-analysis. Ann Clin Psychiatry. 2022;34(2):e2–24. Cited: PMID: 35550035

17. Parikh TK, Strawn JR, Walkup JT, Croarkin PE. Repetitive Transcranial Magnetic Stimulation for Generalized Anxiety Disorder: A Systematic Literature Review and Meta-Analysis. Int J Neuropsychopharmacol. 2022;25(2):144–6. http://dx.doi.org/10.1093/ijnp/pyab077

18. Hyde J, Carr H, Kelley N, Seneviratne R, Reed C, Parlatini V, et al. Efficacy of neurostimulation across mental disorders: systematic review and meta-analysis of 208 randomized controlled trials. Mol Psychiatry. 2022;27(6):2709–19. http://dx.doi.org/10.1038/s41380-022-01524-8

19. Li X, Zhang C, Tan J, Ding L, Wang C, Wang M, et al. Clinical effects of continuous theta burst stimulation for generalized anxiety disorder and a mechanism involving α oscillations: a randomized controlled trial. J Psychiatry Neurosci. 2022;47(2):E123–33. http://dx.doi.org/10.1503/jpn.210134

20. Dilkov D, Hawken ER, Kaludiev E, Milev R. Repetitive transcranial magnetic stimulation of the right dorsal lateral prefrontal cortex in the treatment of generalized anxiety disorder: A randomized, double-blind sham controlled clinical trial. Prog Neuropsychopharmacol Biol Psychiatry. 2017;78:61–5. http://dx.doi.org/10.1016/j.pnpbp.2017.05.018

21. Huang Z, Li Y, Bianchi MT, Zhan S, Jiang F, Li N, et al. Repetitive transcranial magnetic stimulation of the right parietal cortex for comorbid generalized anxiety disorder and insomnia: A randomized, double-blind, sham-controlled pilot study. Brain Stimul. 2018;11(5):1103–9. http://dx.doi.org/10.1016/j.brs.2018.05.016

22. Clarke E, Clarke P, Gill S, Paterson T, Hahn L, Galletly C. Efficacy of repetitive transcranial magnetic stimulation in the treatment of depression with comorbid anxiety disorders. J Affect Disord. 2019;252:435–9. http://dx.doi.org/10.1016/j.jad.2019.03.085

23. Maier W, Buller R, Philipp M, Heuser I. The Hamilton Anxiety Scale: reliability, validity and sensitivity to change in anxiety and depressive disorders. J Affect Disord. 1988;14(1):61–8. https://doi.org/10.1016/0165-0327(88)90072-9

24. Fydrich T, Dowdall DJ, Chambless DL. Reliability and validity of the beck anxiety inventory. Journal of Anxiety Disorders. 1992;6:55–61. https://doi.org/10.1016/0887-6185(92)90026-4

25. Plummer F, Manea L, Trepel D, McMillan D. Screening for anxiety disorders with the GAD-7 and GAD-2: a systematic review and diagnostic metaanalysis. General Hospital Psychiatry. 2016;39:24-31. http://dx.doi.org/10.1016/j.genhosppsych.2015.11.005

26. Chin EG, Buchanan EM, Ebesutani C, Young J. Depression, Anxiety, and stress: How should clinicians interpret the total and subscale scores of the 21-item Depression, Anxiety, and Stress Scales? Psychol Rep. 2018;122(4):1550–75. http://dx.doi.org/10.1177/0033294118783508

27. Vignola RCB, Tucci AM. Adaptation and validation of the depression, anxiety and stress scale (DASS) to Brazilian Portuguese. J Affect Disord. 2014;155:104–9. http://dx.doi.org/10.1016/j.jad.2013.10.031

28. Moreno AL, Sousa DA, Souza AMFLP, Manfro GG, Salum GA, Koller SH, et al. Factor structure, reliability, and item parameters of the Brazilian-Portuguese version of the GAD-7 questionnaire [Internet]. Temas Em Psicologia. 2016;24(1):367–76. Available from: https://repositorio.usp.br/item/002852644

29. Cunha JA. Manual da Versão Em Português das Escalas Beck. São Paulo: Casa do Psicólogo; 2001.

30. Rossi S, Antal A, Bestmann S, Bikson M, Brewer C, Brockmöller J, et al. Safety and recommendations for TMS use in healthy subjects and patient populations, with updates on training, ethical and regulatory issues: Expert Guidelines. Clin Neurophysiol. 2021;132(1):269–306. http://dx.doi.org/10.1016/j.clinph.2020.10.003

31. van Dun K, Manto M, Meesen R. Cerebellum and Neurorehabilitation in Emotion with a Focus on Neuromodulation. Adv Exp Med Biol. 2022;1378:285–99. https://doi.org/10.1007/978-3-030-99550-8_18

32. Elyamany O, Leicht G, Herrmann CS, Mulert C. Transcranial alternating current stimulation (tACS): from basic mechanisms towards first applications in psychiatry. Eur Arch Psychiatry Clin Neurosci. 2021;271(1):135–56. http://dx.doi.org/10.1007/s00406-020-01209-9

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Published

09/25/2025

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Original research

How to Cite

1.
Garcia Barreto I, Gonçalves Nogueira M, Thees Bortolotti J, Ozorio Neubauer M, Kátia Monte-Silva, Shirahige L, et al. Decision-making for non-invasive neuromodulation prescription in the treatment of generalized anxiety disorder: a roadmap proposal. Brain Imaging and Stimul. [Internet]. 2025 Sep. 25 [cited 2025 Dec. 5];4:e6258. Available from: https://www5.bahiana.edu.br/index.php/brain/article/view/6258