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