Clinical outcomes in adolescents undergoing sequential bilateral 1 Hz/20 Hz transcranial magnetic stimulation for treatment resistant depression

Major depressive disorder (MDD) is common in adolescents, with anxiety and suicidality as common comorbidities [[1]Ayvaci E.R. Croarkin P.E. Special populations: treatment-resistant depression in children and adolescents.Psychiatr Clin. 2023; 46: 359-370Google Scholar]. ≥30% of adolescents are unresponsive to conventional psychotherapies and antidepressants. For treatment-resistant depression in adults, transcranial magnetic stimulation (TMS) offers high remission rates, a benign side effect profile, and rapid improvement via accelerated regimens [[2]Cole E.J. Phillips A.L. Bentzley B.S. Stimpson K.H. Nejad R. Barmak F. et al.Stanford neuromodulation therapy (SNT): a double-blind randomized controlled trial.Am J Psychiatr. 2022; 179: 132-141Crossref PubMed Scopus (185) Google Scholar]. However, evidence for TMS in adolescent depression is more limited [[3]Cao P. Li Y. An B. Ye L. Xu Z. Efficacy and safety of repetitive transcranial magnetic stimulation combined with antidepressants in children and adolescents with depression: a systematic review and meta-analysis.J Affect Disord. 2023; 336: 25-34Crossref PubMed Scopus (2) Google Scholar]. A recent multi-center, randomized, sham-controlled study of 10 Hz TMS delivered to the left dorsolateral prefrontal cortex (DLPFC) failed to demonstrate superiority of active TMS [[4]Croarkin P.E. Elmaadawi A.Z. Aaronson S.T. Schrodt Jr., G.R. Holbert R.C. Verdoliva S. et al.Left prefrontal transcranial magnetic stimulation for treatment-resistant depression in adolescents: a double-blind, randomized, sham-controlled trial.Neuropsychopharmacology. 2021; 46: 462-469Crossref PubMed Scopus (37) Google Scholar]. However, recent electric-field modelling work suggests that the optimal TMS parameters may be different in adolescents versus adults [[5]Alawi M. Lee P.F. Deng Z.-D. Goh Y.K. Croarkin P.E. Modelling the differential effects of age on transcranial magnetic stimulation induced electric fields.J Neural Eng. 2023; 20https://doi.org/10.1088/1741-2552/ac9a76Crossref PubMed Scopus (4) Google Scholar]. Naturalistic studies may offer important contributions to optimizing TMS parameters for future clinical trials in adolescents and young adults with MDD [[6]Zhang T. Zhu J. Xu L. Tang X. Cui H. Wei Y. et al.Add-on rTMS for the acute treatment of depressive symptoms is probably more effective in adolescents than in adults: evidence from real-world clinical practice.Brain Stimul. 2019; 12: 103-109Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar]. Here we present a retrospective case series on treatment outcomes in 59 patients, ages 12–17, meeting DSM-5 criteria for MDD, who underwent a course of bilateral low-frequency right and high-frequency left DLPFC-TMS, between July 2017 and January 2022, at a large 14-site community practice in Texas (Salience TMS Neuro Solutions, Plano, TX). Patients were referred for treatment following a standard diagnostic clinical interview by their treating psychiatrist, and informed consent was obtained from patients and caregivers regarding off-label treatment in this age group and for the use of de-identified data for research purposes. Patients who did not provide assent or consent, or could not adhere to the treatment regimen, or had any standard contraindications to TMS, were excluded from treatment and data collection. This retrospective review was approved by the Western Institutional Review Board. Treatments were administered on a MagVita R30 pulse generator and Cool-B65 coil. Each treatment session delivered right DLPFC stimulation (120% of resting MT, 1 Hz, 60 s on/30 s off, 6 trains, 360 pulses total) as per Brunelin and colleagues [[7]Brunelin J. Jalenques I. Trojak B. Attal J. Szekely D. Gay A. et al.The efficacy and safety of low frequency repetitive transcranial magnetic stimulation for treatment-resistant depression: the results from a large multicenter French RCT.Brain Stimul. 2014; 7: 855-863Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar] followed by left DLPFC stimulation (120% of resting MT, 20 Hz, 2 s on/4 s off, 30 trains, 1200 pulses total) as per Cash and colleagues [[8]Cash R.F.H. Dar A. Hui J. De Ruiter L. Baarbé J. Fettes P. et al.Influence of inter-train interval on the plastic effects of rTMS.Brain Stimul. 2017; 10: 630-636Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar]. Treatment targets in the left and right DLPFC were localized using the Beam F3 method applied to the left and right side. Treatments were administered once daily on weekdays, 5 days a week. All patients were offered a course length of 36 sessions of treatment. The primary outcome measures were the Patient Health Questionnaire (PHQ-9) for depression severity and the 7-item Generalized Anxiety Disorder scale (GAD-7) for anxiety severity; tolerability was assessed as pain intensity ratings on a numerical rating scale from 0 (no pain) to 10 (intolerable pain), completed at baseline and 2 weeks. Demographic characteristics are presented in Supplementary Table 1. The series included 36 female, 22 male, and 1 sex-female/gender-male individuals, ages 12–17 (mean 15.8 ± SD1.1). 20/59 were 12–15 years old and 39/59 were 16–17 years old. 48/59 patients had a comorbid anxiety disorder, and 4/59 were medication naïve. 57/59 patients completed 30–36 sessions (mean 34.7 ± SD6.3); 2/59 discontinued for logistical reasons. There were no seizures, suicide attempts, completed suicides, or other serious adverse events. Depression treatment outcomes on PHQ-9 are presented in detail in Supplementary Table S2, and trajectories of improvement are shown in Fig. 1A. Overall, 32/57 treatment-completers (56.1%) met response criteria and 20/57 (35.1%) met remission criteria. Overall PHQ-9 scores improved by an average of 48.7%, from 15.2 ± SD6.1 to 7.8 ± SD6.1, indicating a large effect size (Cohen's d = 1.10). In the younger group (aged 12–15 years), 13/20 patients (65.0%) met response criteria and 6/20 (30.0%) met remission criteria; in the older group (aged 16–17 years), 19/39 (48.7%) met response criteria and 14/39 (35.9%) met remission criteria. There were no significant differences in PHQ-9 improvement between the older and younger groups (t55 = 0.88;p = 0.384), or between male and female patients (t54 = 0.10;p = 0.923). Anxiety outcomes on GAD-7 are presented in detail in Supplementary Table S3, and trajectories of improvement are shown in Fig. 1B. Overall, 32/57 treatment-completers (56.1%) met response criteria and 29/57 (50.9%) met remission criteria. Overall, GAD-7 scores improved by an average of 45.9%, from 11.8 ± SD5.9 to 5.9 ± SD5.2, indicating a large effect size (Cohen's d = 0.94). In the younger group (aged 12–15 years), 12/19 patients (63.2%) met GAD-7 response criteria and 9/19 (47.4%) met remission criteria; in the older group (aged 16–17 years), 20/38 (52.6%) met GAD-7 response criteria and 20/38 (52.6%) met remission criteria. There were no significant differences in GAD-7 improvement between the older and younger groups (t55 = 0.76;p = 0.453), or between male and female patients (t55 = 0.39;p = 0.702). Effects on suicidality were assessed via PHQ-9 item 9. Overall, 41/59 (69.4%) entered treatment with a baseline score ≥0 for suicidality on PHQ-9 item 9. Of these, 20/41 (48.7%) completed treatment with a post-treatment score of 0 (i.e., remission). The observations from this retrospective case series suggest that a bilateral 20 Hz left/1Hz right DLPFC protocol is safe, tolerable, and effective for both depressive symptoms and anxiety, with large effect sizes seen in this sample of adolescents. Safety and tolerability were strong, with 57/59 patients completing at least 30 sessions and no dropouts due to adverse effects. Treatment effectiveness appeared similar in male and female patients, and in younger (12–15) versus older (16–17) patients. Notably, the effect size of this bilateral DLPFC protocol for anxiety symptoms (d = 0.94) was nearly as large as for depression symptoms (d = 1.10), and among patients with nonzero suicidality at baseline, nearly half achieved remission from suicidality by the end of treatment. Superior effects of bilateral versus left unilateral DLPFC-TMS on anxiety and suicidality have previously been reported in adults [[9]Weissman C.R. Blumberger D.M. Brown P.E. Isserles M. Rajji T.K. Downar J. et al.Bilateral repetitive transcranial magnetic stimulation decreases suicidal ideation in depression.J Clin Psychiatry. 2018; 79https://doi.org/10.4088/JCP.17m11692Crossref PubMed Scopus (40) Google Scholar]. Limitations of this series include lack of sham or unilateral control arms, and absence of clinician-rated scales. The Beam F3 targeting approach has not been extensively validated in adolescents, requiring further neuroanatomical investigation. The number of adolescent bipolar patients in the retrospective timeframe (N = 3) was too few to allow meaningful comparison to unipolar MDD patients. These issues may be remedied in a future randomized sham-controlled trial. Following disappointing results with unilateral left treatment, bilateral DLPFC-TMS, or other protocols/targets, as we recently reported for dorsomedial prefrontal 1 Hz stimulation in this population [[10]Croarkin P.E. Dojnov A. Middleton V.J. Bowman J. Kriske J. Donachie N. et al.Accelerated 1 Hz dorsomedial prefrontal transcranial magnetic stimulation for generalized anxiety disorder in adolescents and young adults: a case series.Brain Stimul. 2024; 17: 269-271Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar], could offer effective novel pathways for younger patients with treatment-resistant MDD to achieve remission. The data set used and analyzed for this study is available from the corresponding author upon reasonable request. Paul E. Croarkin: Conceptualization, Formal analysis, Supervision, Writing – original draft, Writing – review & editing. Seth Zuckerman: Formal analysis, Conceptualization, Writing – original draft, Writing – review & editing. Victoria J. Middleton: Data curation, Formal analysis, Writing – original draft, Writing – review & editing. Naima Monira: Data curation, Writing – review & editing. Joseph Kriske: Data curation, Writing – review & editing. Jennifer Bowman: Data curation, Writing – review & editing. John Kriske: Data curation, Writing – review & editing. Nancy Donachie: Conceptualization, Supervision, Writing – original draft, Writing – review & editing. Jonathan Downar: Conceptualization, Formal analysis, Supervision, Writing – original draft, Writing – review & editing. Dr. Croarkin has received research support from the National Institutes of Health (NIH), National Science Foundation (NSF), Brain and Behavior Research Foundation and the Mayo ClinicFoundation. Dr. Croarkin has received research support from Pfizer, Inc. He has received grant-in-kind equipment support from Neuronetics, Inc., and MagVenture, Inc. He received grant-in-kind supplies and genotyping from Assurex Health, Inc. for an investigator-initiated study. He served as the principal investigator for a multicenter study funded by Neuronetics, Inc. and a site principal investigator for a study funded by NeoSync, Inc. Dr. Croarkin served on advisory boards for Engrail Therapeutics, Sunovion, Procter & Gamble Company, Meta Platforms, Inc, and Myriad Neuroscience. Dr. Croarkin is employed by Mayo Clinic. He receives compensation as the Editor-in-Chief for the Journal of Child and Adolescent Psychopharmacology. Dr. Downar has received research grants from the National Institute of Mental Health, Brain Canada, the Canadian Biomarker Integration Network in Depression, the Ontario Brain Institute, the Wilburforce Foundation, the Klarman Family Foundation, the Arrell Family Foundation and the Bowness Family Foundation, travel stipends from Lundbeck and ANT Neuro, in-kind equipment support for investigator-initiated trials from MagVenture, and is an advisor for Arc Health, TMS Neuro Solutions and Restorative Brain Clinics, and is a co-founder of Ampa Health. Mr. Zuckerman, Ms. Monira, Mr. Kriske, Mr. Kriske, and Dr. Donachie are employed by Salience Health. Ms. Bowman and Ms. Middleton are employed by Salience Timothy J. Kriske Research Institute and TMS Neuro Solutions. The other authors declare that they have no competing interests. Salience TMS Neuro Solutions internally funded the study. Dr. Croarkin is supported by National Institute of Mental Health Grants R01 MH113700 and R01 MH124655. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Health. The following is the Supplementary data to this article: Download .docx (.03 MB) Help with docx files Multimedia component 1

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