# A sequential dual-site repetitive transcranial magnetic stimulation for major depressive disorder: A randomized clinical trial

## TL;DR

A new rTMS protocol targeting two brain regions shows rapid and lasting improvement in depression symptoms.

## Contribution

An accelerated dual-site rTMS protocol for MDD with rapid and sustained effects is introduced.

## Key findings

- Active group showed significantly greater depression reduction by day 4 compared to sham.
- Over 85% of responders remained in remission for 6 months.
- Symptom improvement linked to changes in dlPFC-frontoparietal and dmPFC-limbic connectivity.

## Abstract

Repetitive transcranial magnetic stimulation (rTMS) is approved for major depressive disorder (MDD), but it is limited by variable efficacy. Here, we examine antidepressant effects of our sequential dorsolateral prefrontal cortex (dlPFC)-dorsomedial prefrontal cortex (dmPFC) accelerated rTMS protocol, which includes a 4-day treatment with 4 sessions per day. At week 4, the Montgomery-Åsberg Depression Rating Scale (MADRS) reduction is significantly larger in the active group, and critical, significant differences were apparent on day 4. For active and sham-controlled groups, respectively, response rates are 57.69% and 23.08%, and remission rates are 38.46% and 15.38%. Of responders, over 85% remain in remission over 6 months. Resting-state fMRI shows dissociable symptom improvement associated with increased dlPFC-frontoparietal and decreased dmPFC-amygdalo-subcallosal cingulate functional connectivity. We highlight a cost-efficient generalizable rTMS approach targeting differential networks in MDD, which shows rapid and sustained antidepressant effects with a relatively small number of pulses and minimal treatment duration. The study is registered with ChiCTR (ChiCTR2100046042).

•The dlPFC-dmPFC dual-site accelerated rTMS protocol shows good treatment efficacy•The rTMS protocol demonstrates rapid and sustained antidepressant effects•Symptom improvement is linked to dlPFC-frontoparietal/dmPFC-limbic neural networks

The dlPFC-dmPFC dual-site accelerated rTMS protocol shows good treatment efficacy

The rTMS protocol demonstrates rapid and sustained antidepressant effects

Symptom improvement is linked to dlPFC-frontoparietal/dmPFC-limbic neural networks

Zhao et al. developed an accelerated dual-site rTMS protocol sequentially targeting the left dlPFC and dmPFC, demonstrating rapid and sustained antidepressant effects, possibly through normalizing functional connectivity in depression-related neural networks of the two targets. This cost-efficient intervention requires fewer pulses, no neuronavigation, and enables convenient patient engagement over 4 half-days.