Sir, We are grateful for the letter written by Williams et al. (2018) as they provide additional evidence to support the use of intermittent theta-burst stimulation (iTBS) as a safe and well-tolerated therapy for treatment-resistant depression. The evidence thus far seems to support the notion that stronger parameters of iTBS have better antidepressant efficacy. This is not unexpected, as a systemic review of traditional repetitive transcranial magnetic stimulation (rTMS) has shown that the stronger parameters of rTMS, including an intensity of stimulation higher than 100% of resting motor threshold (rMT) and >10 full days of treatment are associated with better antidepressant effectiveness (Dumas et al., 2012). Recent investigations have provided preliminary evidence that stronger iTBS parameters per course may have better antidepressant efficacy for treatment-resistant depression. Our randomized double-blind sham-controlled study confirmed the antidepressant efficacy of 10-day left prefrontal iTBS (i.e. a 2-s train of bursts repeated every 10 s for a total of 70 s in each session per day; a total of 18 000 pulses per course; Li et al., 2014). An intensive protocol of accelerated iTBS to the left prefrontal cortex was recently proposed (Desmyter et al., 2016; Duprat et al., 2016). Twenty iTBS sessions over 4 days (i.e. a total of 32 400 pulses per course) was well-tolerated and could be effective in decreasing suicide risk in treatment-resistant patients with depression (Desmyter et al., 2016). In their letter, Williams and colleagues propose a multiple spaced strategy of applying 10 iTBS sessions per day for five consecutive days (i.e. a total of 90 000 pulses per course) and the antidepressant efficacy was observed in five of six patients with highly refractory depression. Although stronger iTBS parameters may have better antidepressant efficacy, we would like to address a few concerns that may potentially bias the positive observations of an open-labelled, aggressive treatment trial for treatment-resistant depression. First, the placebo antidepressant effects could be high. In fact, a systemic review has indicated that placebo responses in antidepressant trials remain stable for decades in the range of 35 to 40% (Furukawa et al., 2016). The same may hold true for patients with persistent depression. For example, another recent systemic review analysed placebo reactions in 23 randomized controlled antidepressant trials for persistent depression and found a pooled placebo response rate of 31% and a placebo remission rate of 22%. The placebo responses were comparable to those in episodic depression. Several factors contribute to the occurrence of placebo responses and in studies with less chance of receiving a placebo (e.g. an open-labelled study), the placebo effects are more likely to be observed (Meister et al., 2017). In addition, the dosing schedule and visit frequency could be important contributors to placebo responses in antidepressant trials (Papakostas et al., 2015). That is, when patients perceive the present treatment to be stronger, the placebo effects would be higher. Therefore, treating patients 5–10 times per day may increase the possibility of placebo responses by the study design. Second, the therapeutic milieu effects may also be involved in the antidepressant responses of an aggressive treatment trial for treatment-resistant depression. That is, when patients receive several sessions in one day, the treatment environment in a hospital is therapeutic itself. To overcome these factors, a double-blind study design with a placebo control group is warranted. Moreover, stimulating bursts at or above an intensity of 80% rMT seems to be safe; however, it should be performed with caution. Regarding the intensity of a given burst, we adopted 80% of active motor threshold (aMT) (Li et al., 2014), which is the standard intensity of TBS, but is ∼20% weaker than rMT. In comparison, the spaced iTBS proposed by Williams and colleagues adopted 90% of rMT and the accelerated iTBS used 110% of rMT (Desmyter et al., 2016). Although the safety guideline for rTMS has been well defined (Rossi et al., 2009), the safety guideline for TBS remains to be determined. Theoretically, TBS effects are NDMA-dependent (Huang et al., 2007) and may have higher risks of seizure than other rTMS protocols. A review investigating adverse effects in studies published between May 2004 and December 2009 (Oberman et al., 2011) indicated only one seizure event and a resulting crude risk of seizure per subject of ∼0.1%. Notably, the reported seizure occurred in a 33-year-old healthy male subject without risk factors for epilepsy, following continuous bursts for 10 s to the primary motor cortex at a stimulating intensity of 100% rMT. Therefore, although a standard train of iTBS bursts takes only 2 s, one should still be cautious when iTBS bursts are repeatedly given at an intensity higher than 100% rMT. In conclusion, the evidence so far supports iTBS as safe and well-tolerated for treating treatment-resistant patients. Although some confounding factors that may contribute to the antidepressant response and the optimal parameters remain to be determined, fast antidepressant efficacy from the spaced or accelerated iTBS sessions may bring new hope for treating patients with treatment-resistant depression, even highly refractory ones. References Desmyter S, Duprat R, Baeken C, Van Autreve S, Audenaert K, van Heeringen K. Accelerated intermittent theta burst stimulation for suicide risk in therapy-resistant depressed patients: a randomized, sham-controlled trial. Front Hum Neurosci 2016; 10: 480. Google Scholar CrossRef Search ADS PubMed Dumas R, Padovani R, Richieri R, Lancon C. Repetitive transcranial magnetic stimulation in major depression: response factor. Encephale 2012; 38: 360– 8. Google Scholar CrossRef Search ADS PubMed Duprat R, Desmyter S, Rudi de R, van Heeringen K, Van den Abbeele D, et al. Accelerated intermittent theta burst stimulation treatment in medication-resistant major depression: a fast road to remission? J Affect Disord 2016; 200: 6– 14. Google Scholar CrossRef Search ADS PubMed Furukawa TA, Cipriani A, Atkinson LZ, Leucht S, Ogawa Y, Takeshima N, et al. Placebo response rates in antidepressant trials: a systematic review of published and unpublished double-blind randomised controlled studies. Lancet Psychiatry 2016; 3: 1059– 66. Google Scholar CrossRef Search ADS PubMed Huang YZ, Chen RS, Rothwell JC, Wen HY. The after-effect of human theta burst stimulation is NMDA receptor dependent. Clin Neurophysiol 2007; 118: 1028– 32. Google Scholar CrossRef Search ADS PubMed Li CT, Chen MH, Juan CH, Huang HH, Chen LF, Hsieh JC, et al. Efficacy of prefrontal theta-burst stimulation in refractory depression: a randomized sham-controlled study. Brain 2014; 137: 2088– 98. Google Scholar CrossRef Search ADS PubMed Meister R, Jansen A, Harter M, Nestoriuc Y, Kriston L. Placebo and nocebo reactions in randomized trials of pharmacological treatments for persistent depressive disorder. A meta-regression analysis. J Affect Disord 2017; 215: 288– 98. Google Scholar CrossRef Search ADS PubMed Oberman L, Edwards D, Eldaief M, Pascual-Leone A. Safety of theta burst transcranial magnetic stimulation: a systematic review of the literature. J Clin Neurophysiol 2011; 28: 67– 74. Google Scholar CrossRef Search ADS PubMed Papakostas GI, Ostergaard SD, Iovieno N. The nature of placebo response in clinical studies of major depressive disorder. J Clin Psychiatry 2015; 76: 456– 66. Google Scholar CrossRef Search ADS PubMed Rossi S, Hallett M, Rossini PM, Pascual-Leone A, Safety of TMSCG. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol 2009; 120: 2008– 39. Google Scholar CrossRef Search ADS PubMed Williams NR, Sudheimer KD, Bentzley BS, Pannu J, Stimpson KH, Duvio D, et al. High-dose spaced theta-burst TMS as a rapid-acting antidepressant in highly refractory depression. Brain 2018; 141: e18. Google Scholar CrossRef Search ADS © The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: firstname.lastname@example.org
Brain – Oxford University Press
Published: Mar 1, 2018
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