Deep TMS: A comprehensive summary of adverse events from five multicenter trials.

Deep repetitive transcranial magnetic stimulation, commonly known as Deep TMS, is a noninvasive neuromodulation tool which is now actively used throughout the world for the treatment of a variety of psychiatric diseases. Through electromagnetic induction Deep TMS coils lead to neural depolarization in a network of neural regions that are modulated by the specific conformation of the coil. Currently, there are three Deep TMS coils cleared for use in the United States by the Food and Drug Administration (FDA)- the H1, H4, and H7 coils. These coils have been studied in 5 multicenter double-blind, randomized, controlled studies [1Levkovitz Y. Isserles M. Padberg F. Lisanby S.H. Bystritsky A. Xia G. Tendler A. Daskalakis Z.J. Winston J.L. Dannon P. Hafez H.M. Reti I.M. Morales O.G. Schlaepfer T.E. Hollander E. Berman J.A. Husain M.M. Sofer U. Stein A. Adler S. Deutsch L. Deutsch F. Roth Y. George M.S. Zangen A. Efficacy and safety of deep transcranial magnetic stimulation for major depression: a prospective multicenter randomized controlled trial.World Psychiatr. 2015; 14: 64-73Crossref PubMed Scopus (242) Google Scholar, 2Zangen A. Zibman S. Tendler A. Barnea-Ygael N. Alyagon U. Blumberger D.M. Grammer G. Shalev H. Gulevsky T. Vapnik T. Bystritsky A. Filipčić I. Feifel D. Stein A. Deutsch F. Roth Y. George M.S. Pursuing personalized medicine for depression by targeting lateral or medial prefrontal cortex with deep TMS.JCI Insight. 2023; Crossref Scopus (0) Google Scholar, 3Isserles M. Tendler A. Roth Y. Bystritsky A. Blumberger D.M. Ward H. Feifel D. Viner L. Duffy W. Zohar J. Keller C.J. Bhati M.T. Etkin A. George M.S. Filipcic I. Lapidus K. Casuto L. Vaishnavi S. Stein A. Deutsch L. Deutsch F. Morales O. Daskalakis Z.J. Zangen A. Ressler K.J. Deep transcranial magnetic stimulation combined with brief exposure for posttraumatic stress disorder: a prospective multisite randomized trial.Biol Psychiatr. 2021; 90: 721-728Abstract Full Text Full Text PDF Scopus (0) Google Scholar, 4Carmi L. Tendler A. Bystritsky A. Hollander E. Blumberger D.M. Daskalakis J. Ward H. Lapidus K. Goodman W. Casuto L. Feifel D. Barnea-Ygael N. Roth Y. Zangen A. Zohar J. Efficacy and safety of deep transcranial magnetic stimulation for obsessive-compulsive disorder: a prospective multicenter randomized double-blind placebo-controlled trial.Am J Psychiatr. 2019; 176: 931-938Crossref PubMed Scopus (170) Google Scholar, 5Zangen A. Moshe H. Martinez D. Barnea-Ygael N. Vapnik T. Bystritsky A. Duffy W. Toder D. Casuto L. Grosz M.L. Nunes E.V. Ward H. Tendler A. Feifel D. Morales O. Roth Y. Iosifescu D.V. Winston J. Wirecki T. Stein A. Deutsch F. Li X. George M.S. Repetitive transcranial magnetic stimulation for smoking cessation: a pivotal multicenter double-blind randomized controlled trial.World Psychiatr. 2021; 20: 397-404Crossref PubMed Scopus (43) Google Scholar], 4 of which were sham controlled [[1]Levkovitz Y. Isserles M. Padberg F. Lisanby S.H. Bystritsky A. Xia G. Tendler A. Daskalakis Z.J. Winston J.L. Dannon P. Hafez H.M. Reti I.M. Morales O.G. Schlaepfer T.E. Hollander E. Berman J.A. Husain M.M. Sofer U. Stein A. Adler S. Deutsch L. Deutsch F. Roth Y. George M.S. Zangen A. Efficacy and safety of deep transcranial magnetic stimulation for major depression: a prospective multicenter randomized controlled trial.World Psychiatr. 2015; 14: 64-73Crossref PubMed Scopus (242) Google Scholar,3Isserles M. Tendler A. Roth Y. Bystritsky A. Blumberger D.M. Ward H. Feifel D. Viner L. Duffy W. Zohar J. Keller C.J. Bhati M.T. Etkin A. George M.S. Filipcic I. Lapidus K. Casuto L. Vaishnavi S. Stein A. Deutsch L. Deutsch F. Morales O. Daskalakis Z.J. Zangen A. Ressler K.J. Deep transcranial magnetic stimulation combined with brief exposure for posttraumatic stress disorder: a prospective multisite randomized trial.Biol Psychiatr. 2021; 90: 721-728Abstract Full Text Full Text PDF Scopus (0) Google Scholar, 4Carmi L. Tendler A. Bystritsky A. Hollander E. Blumberger D.M. Daskalakis J. Ward H. Lapidus K. Goodman W. Casuto L. Feifel D. Barnea-Ygael N. Roth Y. Zangen A. Zohar J. Efficacy and safety of deep transcranial magnetic stimulation for obsessive-compulsive disorder: a prospective multicenter randomized double-blind placebo-controlled trial.Am J Psychiatr. 2019; 176: 931-938Crossref PubMed Scopus (170) Google Scholar, 5Zangen A. Moshe H. Martinez D. Barnea-Ygael N. Vapnik T. Bystritsky A. Duffy W. Toder D. Casuto L. Grosz M.L. Nunes E.V. Ward H. Tendler A. Feifel D. Morales O. Roth Y. Iosifescu D.V. Winston J. Wirecki T. Stein A. Deutsch F. Li X. George M.S. Repetitive transcranial magnetic stimulation for smoking cessation: a pivotal multicenter double-blind randomized controlled trial.World Psychiatr. 2021; 20: 397-404Crossref PubMed Scopus (43) Google Scholar]. The H1 coil is indicated for major depression and anxious depression, the H7 is indicated for obsessive compulsive disorder, major depression, and anxious depression, and the H4 coil is indicated for short-term smoking cessation. Each coil has a distinct geometric configuration. While these unique configurations are important for modulating different neural networks, the unique coil configurations may also have unique adverse event profiles. Although the FDA labeling requires reporting only on adverse events that occur in ≥5% of subjects, to be even more transparent and comprehensive events present in at last 2% of the aggregate population are included. This Letter describes the aggregate adverse event frequency across five multicenter clinical trials utilizing the H1, H4, H7 and sham coils for the treatment of major depressive disorder, smoking addiction, obsessive compulsive disorder and post-traumatic stress disorder. Data Sources. Adverse event data was compiled from 884 individuals that participated in one of five multicenter, double-blind, randomized, sham-controlled clinical trials of Deep TMS, published from 2011-2023 (Supplementary Table 1). Adverse event reporting terminology was standardized using MedDRA coding. The relationship to the study device was determined by the site investigator. Data analysis. The data were analyzed using Pearson's chi-squared test on multiple factorial proportions followed by Z-test to compare between two proportions. A significance level (α) of p < 0.05 was set for all statistical analyses. The adverse event data associated with a given coil data was combined from all the multicenter studies that used that coil. Adverse event frequency. The adverse events reported by more than 2% of subjects are listed in Fig. 1. The most common events associated with active TMS were headache (35.43%), treatment site discomfort (29.92%), muscle spasm (5.91%), jaw pain (5.71%), neck pain (4.53%), mastication (2.76%), dental pain (2.56%), and general discomfort (2.56%) (Fig. 1A). These were all significantly more common following active TMS. Of these 8 symptoms, there was a significant difference in the distribution of the events across the coils as a whole (X = 61.05, df:30, P = 0.0007) with the H4 coil having lower rates of headache (X = 17.99, P < 0.0001), treatment site discomfort (X = 19.92, P < 0.0001), and jaw pain (X = 6.336, P = 0.0421), but higher rates of general discomfort (X = 8.013, p = 0.0182)(Fig. 1B). Secondary analysis by population. It is possible that adverse event sensitivity may vary based on the underlying disease state. While it is not possible to directly test that hypothesis with these data, an exploratory posthoc analysis for the H7 revealed no differnece in headache or treatment site discomfort among MDD, OCD, and PTSD patients (supplemental data). It is also possible that the likelihood of some of these adverse events is proportional to the absolute dose of TMS delivered (e.g. measured by machine output). While that level of detail is not current available to us for these studies, a future investigation in a large sample is warranted. Summary and recommendations. Initially cleared for the treatment of depression in 2013, there have now been five FDA-pivotal trials of various Deep TMS coils. Our analysis demonstrates that the most frequent adverse events were headaches and treatment site discomfort – observations which are consistent with decades of work in the TMS field. Perhaps more interesting is the comparatively low adverse event profile of the H4 coil relative to the H1 and H7 coil. The lower proportion of adverse events with the H4 coil may be related to the treatment position. It could also be related to the treatment population (tobacco cigarette smokers). From a practical perspective, most of the adverse events were transient and resolved within days and their severity was mild to moderate. No hearing loss cases were reported and hearing protection was used. Since the most common adverse event is application site discomfort or pain and headache, we recommend telling patients to premedicate for the first several days of TMS treatment with a non-steroidal anti-inflammatory or acetaminophen. Mastication symptoms or jaw pain may be caused by stimulation of the motor and sensory roots of the trigeminal nerve. Placing foam between the temple and the coil often improves tolerability with minimal effects on the total amplitude of the TMS dose [[6]Parazzini M. Fiocchi S. Chiaramello E. Roth Y. Zangen A. Ravazzani P. Electric field estimation of deep transcranial magnetic stimulation clinically used for the treatment of neuropsychiatric disorders in anatomical head models.Med Eng Phys. 2017; 43: 30-38Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar]. Neck pain can be ameliorated with a good chair, supporting neck cushion, patient posture, and proper TMS positioning techniques. Once the Deep TMS coils are placed, and the chin strap secured, the coil should be relatively weightless. The primary limitation for generalizing the result of this analysis to real-world patients is that data analysis was limited to prospective randomized trials, which often have lower efficacy rates than real-world practice. Additionally, the likelihood of the events was more common in the active versus sham groups when data from these 884 individuals are assessed in aggregate. While this is important to note for future development, it is it does not preclude the fact that the adverse event rate in the sham group was still sufficient in each of the multicenter studies to maintain the blinding based on the “forced choice” question subjects answered after the first treatment. There was also not sufficient power in the sample to assess for rare adverse events such as seizure (n = 1; active) [[7]Tendler A. Harmelech T. Gersner R. Roth Y. Seizures provoked by H-coils from 2010 to 2020.Brain Stimul. 2020; 14: 66-68Abstract Full Text Full Text PDF Scopus (5) Google Scholar], syncope (n = 2; both sham) [[8]Rouwhorst R. van Oostrom I. Dijkstra E. Zwienenberg L. van Dijk H. Arns M. Vasovagal syncope as a specific side effect of DLPFC-rTMS: a frontal-vagal dose-finding study.Brain Stimul. 2022; 15: 1233-1235Abstract Full Text Full Text PDF Scopus (2) Google Scholar], or hearing loss (n = 0) [[9]Tringali S. Perrot X. Collet L. Moulin A. [Related noise exposure and auditory consequence during transcranial magnetic stimulation: new insights and review of the literature].Neurophysiol Clin. 2013; 43: 19-33Crossref PubMed Scopus (0) Google Scholar] (See supplement for full list of reported adverse events). In summary, this paper presents the most comprehensive analysis of adverse events associated Deep TMS coils (relative to sham). We intend for this to be a resource to the TMS community at large. BrainsWay.