Comparison of 5-Day Multidaily Neuronavigated Theta-Burst Sessions With 6-Week Standard Repetitive Transcranial Magnetic Stimulation (the Dutch Depression Outcome Trial)

BACKGROUND: Novel therapies are crucial for patients with major depressive disorder, as more than 33% of patients do not respond to first-line treatments. A promising novel treatment strategy is an intensive 5-day course of personalized, functional connectivity-guided accelerated intermittent theta-burst stimulation (PAiT), modeled after the Stanford neuromodulation therapy 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 10 Hz rTMS at inducing remission of depression.

OBJECTIVE: This study aims to compare cost-effectiveness using the PAiT protocol and the standard 10 Hz rTMS in patients with TRD.

METHODS: A total of 108 patients will be enrolled in this multicenter randomized controlled trial. Patients will receive stimulation over the left dorsolateral prefrontal cortex using either the PAiT protocol (10 sessions per day over 5 days, resulting in 50 sessions in total and 90,000 pulses) or standard 10 Hz rTMS (once daily for 6 weeks, resulting in 30 sessions in total and 90,000 pulses). Personalized targets will be identified in the accelerated intermittent theta-burst stimulation condition based on negative functional coupling between the subgenual anterior cingulate cortex and the dorsolateral prefrontal cortex. In the rTMS condition, the dorsolateral prefrontal cortex target locations are identified using the standard Beam-F3 method. In both conditions, coil placement is performed with neuronavigation, navigating either to the personalized functional connectivity target or the Beam-F3 location. Patients will undergo pre- and posttreatment functional magnetic resonance imaging scans, including cognitive and emotional tasks. Four follow-up assessments are scheduled at 7, 12, 26, and 31 weeks after baseline. We expect that the PAiT protocol is more cost-effective than the standard 10 Hz rTMS.

RESULTS: Recruitment for this randomized controlled trial started in February 2024. As of December 2024, we had enrolled 31 patients; the last participant is expected to complete their posttreatment assessments in January 2027.

CONCLUSIONS: To our knowledge, this study is the first clinical trial to compare the cost- effectiveness of PAiT to standard 10 Hz rTMS as treatment for patients with TRD. The results of our study will offer professionals evidence from a sufficiently powered trial to determine whether the PAiT protocol is more effective than standard high-frequency rTMS. Specifically, it will assess whether PAiT leads to a shorter treatment duration for depression and greater societal or occupational participation among patients with TRD. In addition, this trial will provide further insights into the underlying mechanisms related to treatment effect, the effects of rTMS or accelerated intermittent theta-burst stimulation on cognitive domains such as executive functioning and emotion, possible differences in side effects, long-term effects, and factors contributing to possible relapse.

TRIAL REGISTRATION: ClinicalTrials.gov NCT05900271; https://clinicaltrials.gov/study/NCT05900271.

INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/70121.