Elsevier

Journal of Affective Disorders

Volume 156, 1 March 2014, Pages 219-223
Journal of Affective Disorders

Preliminary communication
Treatment of major depression with bilateral theta burst stimulation: A randomized controlled pilot trial

https://doi.org/10.1016/j.jad.2013.12.025Get rights and content

Abstract

Background

Current efforts to improve clinical effectiveness and utility of repetitive transcranial magnetic stimulation (rTMS) in the treatment of major depression (MD) include theta burst stimulation (TBS), a patterned form of rTMS. Here, we investigated the efficacy of bilateral TBS to the dorsolateral prefrontal cortex (dlPFC) in patients with MD in additon to ongoing medication and psychotherapy.

Methods

In this randomized-controlled trial, thirty-two patients with MD were treated for six weeks (thirty sessions) with either successively intermittent, activity enhancing TBS (iTBS) to the left and continuous, inhibiting TBS (cTBS) to the right dlPFC or with bilateral sham stimulation. Primary outcome measure was the proportion of treatment response defined as a Montgomery–Åsberg Depression Rating Scale (MADRS)≤50% compared to baseline. Secondary outcomes comprised response and remission rates of the Hamilton Depression Rating Scale (HAMD) and the Beck Depression Inventory (BDI).

Results

A larger number of responders were found in the cTBS (n=9) compared to the sham-stimulation (n=4) group (odds ratio: 3.86; Wald χ2=3.9, p=0.048). On secondary endpoint analysis, patient-reported outcome as assessed by the BDI, pointed towards a higher rate of remitters in the cTBS (n=6) than in the sham (n=1) group (odds ratio: 9; Wald χ2=3.5, p=0.061).

Limitations

With regard to the pilot character of the study and the small sample size, the results have to be considered as preliminary.

Conclusions

These findings provide first evidence that six weeks treatment of MDD with iTBS to the left and cTBS to the right dlPFC for six weeks is safe, feasible and superior to sham stimulation applied add-on to pharmacological and psychotherapeutic treatment.

Introduction

High-frequency repetitive transcranial magnetic stimulation (rTMS) applied to the left dorsolateral prefrontal cortex (dlPFC) has been established as an effective treatment for major depressive disorder (Slotema et al., 2010, Fitzgerald and Daskalakis, 2012, Lee et al., 2012, George et al., 2013). It is currently recommended for moderately depressed patients when an initial treatment with antidepressant medication and psychotherapy failed (George and Post 2011). Nevertheless, considerable efforts are currently made to further enhance effectiveness and utility of rTMS as a treatment in major depression (Kammer and Spitzer, 2012).

Up to now, effects in larger controlled studies were predominantly shown in subjects treated with rTMS as monotherapy (O'Reardon et al., 2007, George et al., 2010, Herwig et al., 2007). Therefore, it is conceivable that improvements of effectiveness by optimizing stimulation protocols would considerably increase the number of patients eligible for rTMS treatment. In addition, the mode of action different from pharmacological and psychotherapeutic approaches points towards additive or even synergistic effects that most likely have not yet reached their full potential.

Recently, theta burst stimulation (TBS), a patterned form of rTMS with brief stimulation sessions has been put forward as a new option to induce a more effective modulation of cortical activity (Huang et al., 2005). The investigation of therapeutic effectiveness of this alternative stimulation paradigm for the treatment of various neuropsychiatric disorders has produced variable results (Eberle et al., 2010, Benninger et al., 2011, Plewnia et al., 2012). However, open studies have provided first preliminary evidence for an antidepressant effect of TBS (Chistyakov et al., 2010, Holzer and Padberg, 2010).

As regards the efforts to improve effectiveness of rTMS treatment, sequential bilateral stimulation and extended number of pulses per session have been put forward as potential methods to optimize existing unilateral stimulation protocols (Fitzgerald et al., 2006, Berlim et al., 2012) although recent studies have not found superior efficacy (Fitzgerald et al. 2012). Nevertheless, available data suggest that rTMS treatment courses up to 6 weeks or more may be suitable to enhance the effectiveness of rTMS treatment of MD (O'Reardon et al., 2007, George and Post, 2011).

In order to proceed on the development of effective rTMS treatment protocols of depression, we conducted a randomized, sham-controlled trial applying 6 weeks of sequential facilitatory intermittent TBS (iTBS) to the left and inhibitory continuous TBS (cTBS) to the right dlPFC as an add-on treatment. We hypothesized that this innovative protocol would yield a greater therapeutic effect than sham stimulation in patients on regular treatment with antidepressants and psychotherapy.

Section snippets

Subjects

Patients were recruited from the in-patient units of the department of Psychiatry and Psychotherapy at the University Hospital of Tübingen. Inclusion criteria were right-handedness, age 18–75 years, with a DSM-IV diagnosis of MD, single episode or recurrent. Exclusion criteria for study participation included inability to give informed consent, seizures in medical history, neurological disorders, previous brain injuries, ferromagnetic implants in the brain, deep brain stimulation, cardiac

Results

Baseline characteristics of the participants are summarized in Table 1. There were no significant differences between the groups. Twenty patients (sham: n=11; TBS: n=9) completed the entire protocol of 6 weeks rTMS. In 10 participants treatment was discontinued because of patient decision (TBS: n=5, [4 responder], sham: n=5 [2 responder]). In detail, one subjects (TBS) terminated participation in the trial after 1 week of treatment in remission. Another patient (sham) decided to discontinue

Discussion

This first randomized controlled pilot trial on the efficacy of TBS for the treatment of moderate to severe major depression found an augmentative therapeutic effect of sequential left excitatory and right inhibitory stimulation. A treatment response as quantified by a MADRS reduction of at least 50% (primary endpoint) was achieved in 56% and a remission (MADRS≤7) in 44% of the patients in the active group. This effect was significantly higher in the patients treated with bilateral TBS than in

Role of funding source

Dr. Plewnia is member of the Werner Reichardt Centre for Integrative Neuroscience, received research support and speakers honoraria by inomed Medizintechnik GmbH, Emmendingen, Germany and received funding not related to this research from the German Research Council (DFG; 525 PL1-1).

Dr. Zwissler received a research grant from the Werner Reichardt Centre for Integrative Neuroscience (PP 2011-11)

Dr. Fallgatter is member of the Werner Reichardt Centre for Integrative Neuroscience, received funding

Conflict of interest

The authors report no conflict of interest.

Acknowledgements

None.

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