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Posttraumatic stress disorder (PTSD) is highly prevalent among US Military Veterans and is often accompanied by major depressive disorder (MDD) (Magruder et al., 2005). These disorders can significantly impact the social functioning, employment, and even physical health of Veterans (Kessler, 2000; Shalev et al., 2017). While medications and therapies have proven efficacious for the treatment of PTSD, many who undergo these treatments continue to experience symptoms and side effects (Watts et al., 2013). Increasingly, repetitive transcranial magnetic stimulation (rTMS; hereafter TMS) is being used to augment standard treatment. 

TMS is a form of non-invasive brain often applied for its antidepressant effects, which may be induced by increasing neuronal depolarization in the dorsolateral prefrontal cortex, an area of the brain implicated in anxiety and mood disorders (Delgado, et al., 2008). The efficacy of TMS, which received FDA approval for treatment-resistant MDD in 2008, is well supported (Gaynes et al., 2014). Current research seeks to establish the most effective stimulation parameters for TMS treatment of PTSD and MDD.

We previously reported that 5Hz TMS reduces symptoms in both PTSD and MDD domains (Carpenter et al., 2018; Philip et al., 2016). Recently, a novel form of TMS, called intermittent theta burst stimulation (iTBS, hereafter TBS) has emerged, and appears noninferior to 10Hz TMS for treatment-resistant MDD (Blumberger et al., 2018), and is currently FDA cleared for this use. TBS delivers five 50Hz bursts per second and was designed to potentially mimic intrinsic hippocampal rhythms (Huang et al., 2005). TBS can be delivered in a fraction of the time, offering significant logistical advantages over standard 5Hz TMS treatment (3 vs. 37.5 minutes per daily session, reflecting 600 vs. 3000 pulses per daily session, respectively). 

We performed a retrospective chart review comparing the clinical outcomes of 10 Veterans with PTSD and MDD who received TBS (August 2019 - October, 2020) to those of 10 matched Veterans who received 5Hz TMS (September 2014- June 2016) at the Providence VA Medical Center in Providence, RI. In line with patient demographics at the Providence VA, veterans were mostly male, white, and had a variety of trauma exposures. Patients were referred to receive treatment if they demonstrated comorbid MDD and PTSD despite adequate treatment. Veterans in both groups received treatment daily (business days) for up to six weeks. Symptoms were evaluated using self-reported rating scales, including the PTSD checklist for DSM-5 (PCL-5) (Weathers et al., 2013) and the Inventory of Depressive Symptoms, Self-Report (IDS-SR) (Rush et al., 2003) at baseline, and every five treatments, up to thirty sessions. Both treatments were safe and well tolerated. 

We found that Veterans who received TBS reported significantly poorer outcomes (measured in effect size) compared to those who received 5Hz TMS treatment. Group differences were particularly striking when comparing PTSD outcomes. While prospective and controlled comparisons are required to confirm these findings, given the limitations of this small retrospective chart review, these results provide important information to clinicians providing TMS treatment for comorbid PTSD and MDD. Indeed, further analysis of previous works suggests that a greater cumulative TBS exposure number of delivered pulses (i.e., 1800 pulses daily) may be required to achieve optimal outcomes in this patient population (Petrosino et al. 2020, Philip et al., 2019). 

In summary, we found that the currently FDA-cleared TBS protocol produced inferior results compared to 5Hz TMS, whereas TBS protocols with a larger number of pulses yielded comparable outcomes with 5Hz. While it requires prospective replication, this report provides important potential guidance to clinicians when selecting an optimal stimulation protocol for patients with comorbid MDD and PTSD.

Reference/Target Article

Philip, N.S., Doherty, R.A., Faucher, C., Aiken, E., van ‘t Wout-Frank, M. (2021). Transcranial Magnetic Stimulation for Posttraumatic Stress Disorder and Major Depression: Comparing Commonly Used Clinical ProtocolsJournal of Traumatic Stress.

Discussion Questions

  1. What is intermittent theta burst stimulation (TBS)?
  2. How does intermittent theta burst stimulation (TBS) differ from other types of repetitive transcranial magnetic stimulation (TMS)?
  3. What factors should be considered when determining transcranial magnetic stimulation TMS treatment parameters?
  4. Which patients are best suited to receive intermittent theta burst stimulation (TBS) treatment?
  5. Would intermittent theta burst stimulation (TBS) along with other interventions result in better outcomes?

About the Authors

Christiana Faucher, B.S.
 is a Research Assistant at the VA RR&D Center for Neurorestoration and Neurotechnology at the Providence VA. Currently, Christiana’s research interests are focused on the novel ways that non-invasive brain stimulation (TMS, LIFU, tDCS, etc.) and other types of technology (MRI, EEG, etc.) can be leveraged to augment and or predict treatment outcomes for comorbid psychiatric disorders, such as major depressive disorder (MDD) and posttraumatic stress disorder (PTSD). 

Noah S. Philip, MD 
is the Lead for Affective and Cognitive Health at the VA RR&D Center for Neurorestoration and Neurotechnology, and Associate Professor of Psychiatry and Human Behavior at the Alpert Medical School of Brown University. His laboratory uses new and emerging technologies to understand and treat serious psychiatric disorders, such as posttraumatic stress disorder, major depression, and suicidality. He also serves as co-director for the Neuromodulation Core at the COBRE Center for Neuromodulation at Butler Hospital in Providence, RI. Clinically, he directs the Psychiatric Neuromodulation Clinic at the Providence VA, where he delivers TMS therapy to veterans with treatment-resistant psychiatric illnesses. Contactnoah_philip@brown.edu

References Cited

Blumberger, D. M., Vila-Rodriguez, F., Thorpe, K. E., Feffer, K., Noda, Y., Giacobbe, P., Knyahnytska, Y., Kennedy, S. H., Lam, R. W., Daskalakis, Z. J., & Downar, J. (2018). Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): A randomized non-inferiority trial. Lancet, 391(10131), 1683–1692. https://doi.org/10.1016/S0140-6736(18)30295-2

Delgado, M. R., Nearing, K. I., Ledoux, J. E., & Phelps, E. A. (2008). Neural circuitry underlying the regulation of conditioned fear and its relation to extinction. Neuron59(5), 829–838. https://doi.org/10.1016/j.neuron.2008.06.029

Gaynes, B., Lloyd, S. W., Lux, L., Gartlehner, G., Hansen, R. A., Brode, S., Jonas, D. E., Evans, T. S., Viswanathan, M., & Lohr, K. (2014). Repetitive transcranial magnetic stimulation for treatment-resistant depression: a systematic review and meta-analysis. Journal of Clinical Psychiatry, 75(5), 477-489. https://doi.org/10.4088/JCP.13r08815

Huang, Y. Z., Edwards, M. J., Rounis, E., Bhatia, K. P., & Rothwell, J. C. (2005). Theta burst stimulation of the human motor cortex. Neuron, 45(5), 201–206. https://doi.org/10.1016/j.neuron.2004.12.033 
Kessler, R.C. (2000). Posttraumatic stress disorder: the burden to the individual and to society. Journal of Clinical Psychiatry, 61(Suppl. 5), 4-12. 

Magruder, K.M. Frueh, B.C., Knapp, R.G., Davis, L., Hamner, M.B., Martin, R.H., Gold, P.B., Arana, G.W. (2005). Prevalence of posttraumatic stress disorder in Veterans Affairs primary care clinics. General Hospital Psychiatry, 27(3). https://doi.org/10.1016/j.genhosppsych.2004.11.001 

Petrosino, N. J., van’t Wout-Frank, M., Aiken, E., Swearingen, H. R., Barredo, J., Zandvakili, A., & Philip, N. S. (2020). One-year clinical outcomes following theta burst stimulation for post-traumatic stress disorder. Neuropsychopharmacology, 45(6), 940-946. https://doi.org/10.1038/s41386-019-0584-4

Philip, N. S., Aiken, E. E., Kelley, M. E., Burch, W., Waterman, L., & Holtzheimer, P. E. (2019). Synchronized transcranial magnetic stimulation for posttraumatic stress disorder and comorbid major depression. Brain Stimulation, 12(5), 1335–1337. https://doi.org/10.1016/j.brs.2019.06.010

Philip, N. S., Ridout, S. J., Albright, S. E., Sanchez, G., & Carpenter, L. L. (2016). 5-Hz Transcranial magnetic stimulation for comorbid posttraumatic stress disorder and major depression. Journal of Traumatic Stress, 29(1), 93–96. https://doi.org/10.1002/jts.22065

Rush, A. J., Gullion, C. M., Basco, M. R., Jarrett, R. B., & Trivedi, M. H. (1996). The Inventory of Depressive Symptomatology (IDS): Psychometric properties. Psychological Medicine, 26(3), 477-486. https://doi.org/10.1017/s0033291700035558  

Shalev, A., Liberzon, I., & Marmar, C. (2017). Post-traumatic stress disorder. New England Journal of Medicine, 376,2459–2469. https://doi.org/10.1056/NEJMra1612499

Watts, B. V., Schnurr, P. P., Mayo, L., Young-Xu, Y., Weeks, W. B., Friedman, M. J. (2013). Meta-analysis of the efficacy of treatments for posttraumatic stress disorder. Journal of Clinical Psychiatry, 74(6), e541-550. https://doi.org/10.4088/jcp.12r08225

Weathers, F. W., Litz, B. T., Keane, T. M., Palmieri, P. A., Marx, B. P., & Schnurr, P. P. (2013). The PTSD Checklist for DSM-5 (PCL-5)–Standard [Measure Instrument]. Washington, DC, US Dept of Veterans Affairs