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Letter to the Editor: Failure of the VA TMS depression trial; Too Many Changes Leave Many Unanswered Questions

By: Aron Tendler, MD, Gaby Pell, PhD, & Yiftach Roth ,PhD

 

Why did the multi-centered VA double blinded controlled study of rTMS for treatment resistant depression fail1?

The authors note several factors that distinguish the trial from previous studies:

  • A disproportionate number of unemployed socially isolated older males (83%);
  • Significant levels of comorbidities such as substance abuse;
  • Large differences in active vs sham separation for subjects with and without PTSD;
  • Unique application of concomitant medication maintenance;
  • Rigorous evaluation of mental health and medication compliance resulting in long clinic visits having higher subject engagement.


All of these factors likely increased the placebo effect which may explain the extremely high remission rate and the failure to separate sham from active in the VA population. However, these issues should have also improved the active group as well, resulting in a separation between groups.

Hardware and Protocol Related issues: 

Other unique characteristics of the study that may contribute to the findings seem to relate to the hardware.  The Magventure device based on a standard figure-8 coil design is not identical to the Neurostar device based on an iron-core figure-8 which was used in the successful OPT-TMS study2 multi-center trial.

Unfortunately, so many treatment variables differ between this VA study and the civilian OPT-TMS study that one study alone cannot be considered to be conclusive: 

  • The VA TMS was administered in six blocks of five sessions over five to twelve days, which is not the same as thirty sessions over six weeks;
  • The Magventure device uses a unique blinding system, and the efficiency of that blinding from a multicenter study has not yet been published.  
  • The 4000 pulses per session with an inter-train interval (ITI) of 10 seconds used in the VA study is not equivalent to 3000 pulses with an ITI of 26 seconds used in the two Neurostar studies (the registration study and OPT-TMS).


In fact, the only two ITI values with proven multicenter-sham-controlled efficacy are 26 seconds with the Neurostar and 20 seconds with the Brainsway H-coil. Although shorter ITI are approved and safe, such as the dash protocol based on an ITI of 11 sec, they may be less efficacious, perhaps due to higher rates of conduction failure4.

 

The VA plans to continue their research: 

It seems unusual that the VA study was completed on December 31, 2016, yet on July 18, 2017 the VA posted VA119-17-R-0347, a request for proposal (RFP) for forty rTMS devices using the Magventure parameters. If the VA was aware the 9-center pilot study failed, why would they post an RFP for the same device? If the VA was unaware of the results, shouldn’t they have waited to analyze pilot study results before ordering 40 unproven (based on their pilot study) devices with taxpayer money to treat veterans with treatment resistant depression? 

 

Conclusion: 

The VA study for depression treatment with TMS had some confounding variables and methodological issues, with substantial differences which make comparison to other studies difficult.  However, the VA has plans to push on and expand their research.  It is hoped that in future studies, these issues will be corrected, to produce useful data and meaningful conclusions.

Disclosures: Dr. Tendler has a financial interest in Brainsway and a clinical and research TMS center. Dr. Pell is an employee of Brainsway. Dr. Roth has a financial interest in Brainsway.

 

Bibliography

  1. Yesavage JA, Fairchild JK, Mi Z, et al. Effect of Repetitive Transcranial Magnetic Stimulation on Treatment-Resistant Major Depression in US Veterans: A Randomized Clinical Trial. JAMA Psychiatry 2018. doi:10.1001/jamapsychiatry.2018.1483.
  2. George MS, Lisanby SH, Avery D, et al. Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: a sham-controlled randomized trial. Arch. Gen. Psychiatry 2010;67(5):507-516. doi:10.1001/archgenpsychiatry.2010.46.
  3. O’Reardon JP, Solvason HB, Janicak PG, et al. Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. Biol. Psychiatry 2007;62(11):1208-1216. doi:10.1016/j.biopsych.2007.01.018.
  4. Levkovitz Y, Isserles M, Padberg F, et al. Efficacy and safety of deep transcranial magnetic stimulation for major depression: a prospective multicenter randomized controlled trial. World Psychiatry 2015;14(1):64-73. doi:10.1002/wps.20199.
  5. Halawa I, Goldental A, Shirota Y, Kanter I, Paulus W. Less Might Be More: Conduction Failure as a Factor Possibly Limiting the Efficacy of Higher Frequencies in rTMS Protocols. Front. Neurosci. 2018;12:358. doi:10.3389/fnins.2018.00358.