Research paper
Accelerated intermittent theta burst stimulation treatment in medication-resistant major depression: A fast road to remission?

https://doi.org/10.1016/j.jad.2016.04.015Get rights and content

Highlights

  • Accelerated iTBS treatment was found to be safe and well tolerated.

  • Given that all TRD patients experienced clinical improvement to some extent suggests that such accelerated iTBS protocols may be prone to stronger placebo effects.

  • Although only a modest part of our TRD patients responded immediate after the two-week iTBS treatment protocol, the follow-up assessment showed meaningful response increases, close to remission. These findings point to delayed positive clinical effects after accelerated iTBS treatment.

Abstract

Although accelerated repetitive Transcranial Magnetic Stimulation (rTMS) paradigms and intermittent Theta-burst Stimulation (iTBS) may have the potency to result in superior clinical outcomes in Treatment Resistant Depression (TRD), accelerated iTBS treatment has not yet been studied. In this registered randomized double-blind sham-controlled crossover study, spread over four successive days, 50 TRD patients received 20 iTBS sessions applied to the left dorsolateral prefrontal cortex (DLPFC). The accelerated iTBS treatment procedure was found to be safe and resulted in immediate statistically significant decreases in depressive symptoms regardless of order/type of stimulation (real/sham). While only 28% of the patients showed a 50% reduction of their initial Hamilton Depression Rating Scale score at the end of the two-week procedure, this response rate increased to 38% when assessed two weeks after the end of the sham-controlled iTBS protocol, indicating delayed clinical effects. Importantly, 30% of the responders were considered in clinical remission. We found no demographic predictors for response. Our findings indicate that only four days of accelerated iTBS treatment applied to the left DLPFC in TRD may lead to meaningful clinical responses within two weeks post stimulation.

Introduction

Repetitive transcranial magnetic stimulation (rTMS) is currently an evidence-based and accepted treatment option to treat patients suffering from Major Depressive Disorder (MDD) (Lefaucheur et al., 2014). Since two decades, evidence of supremacy of rTMS over placebo stimulation is accumulating, and the most compelling data have been provided by large, multisite, and randomized sham-controlled trials including pharmacotherapy resisting MDD patients (O’Reardon et al., 2007, George et al., 2010). On the other hand, the effects sizes are rather limited and remission rates are relatively small (De Raedt et al., 2015). Comparing classical HF-rTMS treatment to sham, applying daily rTMS sessions averagely over 2–4 weeks, shows moderate effect sizes on depressive symptoms of 0.39 (Schutter, 2009) or 0.55 (Slotema et al., 2010), depending on the meta-analysis. Generally, for left high frequency (HF) rTMS this yields an average rate of 29% responders in the active condition and 10% for sham (Berlim et al., 2014). Although the average rate of responders patients receiving active and sham right low frequency (LF) rTMS was respectively 38% and 15% in another meta-analysis (Berlim et al., 2013a), left HF-rTMS only received an A level of evidence in recent guidelines on the therapeutic use of rTMS (Lefaucheur et al., 2014). Notwithstanding that no meta-analyses have been carried out yet for accelerated designs (given the limited amount of available accelerated HF-rTMS data), in a recent open – label study response rate was 43%, with 29% remission immediately following treatment (15 sessions administered over 2 days) (Holtzheimer et al., 2010), and 35% response and 15% remission after a placebo-controlled HF-rTMS crossover study (Baeken et al., 2013). Of note, as treatment resistant depression (TRD) may not be the primary indication for rTMS treatment and may negatively influence the clinical outcome (George and Post, 2011), it is important to mention that these patients were not all treatment resistant.

The optimization in stimulation parameters, using more accurate methods to localize the stimulation area (Gershon et al., 2003, Fitzgerald et al., 2009, Levkovitz et al., 2015), and also introducing intensified or accelerated rTMS treatment algorithms have been evaluated to increase clinical responses, but seem to produce similar response rates (Baeken et al., 2013). For the latter, instead of the usually applied daily sessions, spread over two – to four weeks, accelerated stimulation protocols significantly reduce the time-period of stimulation. In sum, accelerated HF-rTMS treatment protocols in MDD may be able to yield clinical improvements similar to the classic treatment protocols, but within a significant shorter amount of time.

Recently, a new form of rTMS has been introduced, i.e. theta-burst stimulation (TBS), thought to produce similar if not greater effects on brain activity than standard rTMS protocols. Recent data indeed suggest that TBS has similar or superior clinical efficacy in treating MDD when compared to rTMS (Di Lazzaro et al., 2011; Chung et al., 2015, Prasser et al., 2015). Reduced administration duration may be a major advantage of TBS when compared to conventional rTMS procedures. Conventional TMS sessions may last between 20 and 45 min, while TBS paradigms may require less than 5 min of stimulation (Chung et al., 2015). Intermittent theta-burst stimulation (iTBS) uses bursts of high frequency stimulation at repeated intervals, usually on a 2 seconds on/8 seconds off cycle applying 50 Hz triplet bursts five times per second (Di Lazzaro et al., 2008; Bakker et al., 2015). Similar to HF-rTMS, iTBS may have excitatory effects on neurons, possibly matching or and exceeding the more classical HF-rTMS paradigms in antidepressant effectiveness (Di Lazzaro et al., 2011; Oberman et al., 2011, Bakker et al., 2015). Neurophysiological data suggest that iTBS affects cortical and subcortical neuroplasticity via long-term potentiation (Huang et al., 2005, Chistyakov et al., 2010). In theory, it may thus be possible that the strongest antidepressant effects may have a delayed onset. Interestingly, it has been suggested that TBS, at least the continuous form (cTBS), with effects comparable to the low frequency application of rTMS, may obey a dose-response function, suggesting that higher numbers of delivered stimuli may be needed to optimize clinical outcomes in MDD patients (Chistyakov et al., 2010). On the other hand, it has to be noted that the excitatory effects of iTBS may not be that straightforward, as prolonged iTBS sessions applied to the motor cortex in healthy individuals may result in inhibitory effects rather than excitation (Gamboa et al., 2010), although dose-dependent effects resulting in neuronal excitation have been reported as well (Nettekoven et al., 2014). Although at this stage no firm conclusion can be drawn, the effects of iTBS treatment may result in an even better clinical outcome than cTBS or rTMS (Li et al., 2014).

Building further on our previous studies of accelerated HF-rTMS (Baeken et al., 2013), the current crossover study aimed at investigating whether an accelerated iTBS treatment protocol (sham-controlled) could result in fast and meaningful beneficial clinical effects in a group of TRD patients. Because we wanted not only to include ‘last resort’ TRD patients, all patients were considered at least stage I treatment resistant (Rush et al., 2003). To evaluate the immediate influences of iTBS, mood was assessed daily. To evaluate delayed clinical effects, all patients were assessed two weeks after the end of the (two week) protocol. Patients were randomized to receive in the first week either 20 real or sham iTBS sessions (5 sessions/day), delivering a fixed amount of pulses amounting in total 32.400 stimuli over 4 days’ time (1620 pulses per session). The choice for the prolonged iTBS parameters within a stimulation session was based on the rationale of delivering a similar amount of pulses - as we performed in our former accelerated HF-rTMS study (Baeken et al., 2013)-in order to compare the two neurostimulation protocols for clinical outcome, rather than examining the inhibitory or excitatory effects of prolonged iTBS.

We hypothesized that the application of this accelerated iTBS protocol would result in fast and meaningful clinical outcomes, especially so after the real when compared to the sham iTBS treatment sessions. Secondly, during the real iTBS sessions, we expected to detect significant mood improvements even before the end of the 4-day stimulation protocol. Thirdly, given the possible large-scale neuroplasticity effects induced by iTBS, we expected that beneficial clinical changes brought about by iTBS would survive and possibly even increase two weeks after the end of the treatment.

Section snippets

Methods and materials

This registered study (http://clinicaltrials.gov/show/NCT01832805) was approved by the local Ghent University Hospital ethics committee and in accordance with the declaration of Helsinki (2004). All patients gave written informed consent. This study was part of a larger project investigating the influence of iTBS on neuro-cognitive markers.2

Statistical analyses

All collected data were analyzed with SPSS 22 (Statistical Package for the Social Sciences; IBM SPSS Statistics for Windows, Version 22.0, IBM Corp., Armonk, NY). Whenever the assumption of sphericity was violated, we applied the Greenhouse-Geisser correction. The significance level was set at p<0.05, two-tailed, for all analyses. Given the intention-to-treat protocol all analyses were completed by a last observation carry forward approach (LOCF) when applicable. See also Table 1.

First, to

Results

Although the iTBS treatment was found to be safe and generally well tolerated, a majority of patients, especially at the start of the first session, mentioned some discomfort such as superficial pain sensations at the stimulation site, or headache. These complaints spontaneously disappeared after a short period of time or shortly after the intake of a common analgesic such as paracetamol.

Given the three drop-out patients, we performed all analyses on the remaining 47 patients. Twenty-five

Discussion

Given that the majority of the iTBS studies typically use (sub)threshold stimulation intensities (% MT of 100% or less) (Oberman et al., 2011, Chung et al., 2015), this iTBS study shows that suprathreshold iTBS is safe, and it can even be applied several times a day with short time intervals between sessions. No seizures or any other major adverse events were observed. Minor transient complaints such as fatigue and headache were reported mainly after the first treatment sessions, but none

Author disclosure

None.

Role of funding source

There were no commercial or financial involvements relevant to this study (a full financial disclosure has been included with the submission, and is included in this document).

This work was supported by the Ghent University Multidisciplinary Research Partnership “The integrative neuroscience of behavioral control”. No other sponsors were included. Therefore, the authors report no conflict of interest.

Contributors

All authors contributed substantially to conception and design, or acquisition of data, or analysis and interpretation of data and drafted the article or revised it critically for important intellectual content and gave final approval of the version to be published.

Specifically,

Duprat Romain, Prof. Dr. De Raedt Rudi, and Prof. Dr. Baeken Chris

  • Designed the study, acquired, analyzed, and interpreted the data; and

  • drafted a first version of the article; and

  • gave final approval of the version to be

Acknowledgments

This work was supported by the Ghent University Multidisciplinary Research Partnership “The integrative neuroscience of behavioral control”. GP is supported in part by a 2015 NARSAD Independent Investigator Grant from the Brain & Behavior Research Foundation.

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