Dutch-Depression Outcome trial comparing 5- day multi-daily neuronavigated Theta burst sessions with 6 weeks standard rTMS (D-DOTT study): Study Protocol for a Randomized Controlled Trial (Preprint)
Authors: Dols Annemiek , Biemans Tom , Coomans Coen , van Eijndhoven Philip , Dalhuisen Iris , van der Werf Ysbrand D , Vriend Chris , Gomes Elvira , Sack Alexander T , Schuhmann Teresa , Chaudry Mashood , Arns Martijn , Walters Bethany Hipple , Wijnen Ben , Zalesky Andrew , Cash Robin , Blumberger Daniel M , Scheepstra Karel WF , Hoogendoorn Adriaan W , van den Heuvel Odile A , van Exel Eric ,   The D-DOTT Consortium
Published: January 2025

BACKGROUND

Novel therapies are crucial for patients with major depressive disorder (MDD) since more than 33% of patients do not respond to first-line treatments. A promising novel treatment strategy is an intensive five-day course of Personalised functional connectivity guided Accelerated intermittent Theta burst stimulation (PAiT), modelled after the Stanford Neuromodulation Therapy (SNT) protocol . This new form of repetitive transcranial magnetic stimulation (rTMS) may lead to higher remission rates in patients with treatment-resistant depression (TRD). However, it remains unclear how this accelerated strategy compares to the standard once daily 10Hz rTMS at inducing remission of depression.

OBJECTIVE

To compare (cost-)effectiveness using the PAiT protocol and the standard 10Hz rTMS, in patients with TRD.

METHODS

108 patients will be enrolled in this multicentre randomized controlled trial. Patients will receive stimulation over the left dorsolateral prefrontal cortex using either the PAiT protocol (5 days of 10 sessions/day, resulting in 50 sessions in total, 90.000 pulses) or the standard 10 Hz rTMS, (once daily during 6 weeks, resulting in 30 sessions in total, 90.000 pulses). Personalised targets will be identified in the aiTBS condition based on negative functional coupling between the subgenual anterior cingulate cortex (sgACC) and the DLPFC. In the rTMS condition, DLPFC target locations are identified using the standard Beam-F3 method . In both conditions, coil placement is performed with neuronavigation, navigating either to the personalised functional connectivity target or the Beam-F3 location. Patients will undergo pre and post-treatment (f)MRI scans including cognitive and emotional tasks, and a behavioral task will be performed outside of the scanner. In addition, during stimulation, heart rate will be measured. There are four follow-up measurements, at 7, 12, 26 and 31 weeks post-baseline. We expect that the PAiT protocol is more (cost-)effective than standard 10 Hz rTMS.

RESULTS

The results of our study will provide professionals with an adequately powered trial answering whether the PAiT protocol is superior to standard HF-rTMS. In addition, this trial will provide further insights into the underlying mechanisms related to treatment effect, the effects of rTMS/aiTBS on cognitive domains such as executive functioning and emotion, possible differences in side-effects, long-term effects and (contributing factors to) possible relapse.

CONCLUSIONS

To our knowledge, the current study is the first clinical trial to compare the (cost-)effectiveness of PAiT to standard 10Hz rTMS as treatment for patients with TRD.

CLINICALTRIAL

This trial is registered at clinicaltrials.gov with code: NCT05900271, on June 12th 2023.