Stanford neuromodulation therapy for treatment‐resistant depression: a randomized controlled trial confirming efficacy, and an <scp>EEG</scp> study providing insight into mechanism of action and a potentially predictive biomarker of efficacy

Stanford neuromodulation therapy (SNT) is a rapid-acting, high-dose, intermittent theta-burst stimulation protocol. Although it has previously demonstrated efficacy for treatment-resistant depression (TRD) in a randomized controlled trial (RCT), replication in a larger sample is needed. Additionally, the electrophysiological effects of SNT remain unknown. Here we report results from a new double-blind, sham-controlled RCT along with electroencephalography (EEG) findings from the initial and current trials. In the current RCT, 53 participants with TRD were enrolled, and 48 who continued to meet entry criteria were randomized to receive active (N=24) or sham (N=24) SNT. At 1-month, remission (primary outcome) was achieved in 50.0% of active vs. 20.8% of sham participants (χ² _1,48=4.5, p=0.035), and response (secondary outcome) similarly favored active treatment (54.2% vs. 25.0%; χ² _1,48=4.3, p=0.039). Beta band EEG findings converged across trials: frontal beta power decreased significantly following active but not sham SNT in both the initial pilot study and the current trial. Additionally, beta baseline activity and post-SNT changes related to treatment efficacy in the current study. Specifically, greater post-SNT reduction in left anterior cingulate cortex (L-ACC) beta power correlated with greater clinical improvement immediately (rho=0.48, p=0.019) and 1-month after (rho=0.51, p=0.012) active SNT. Moreover, higher pre-treatment L-ACC beta power predicted greater subsequent clinical benefit from active SNT (immediate-post: β=-10.26, p=0.0042; 1-month after: β=-9.00, p=0.024). Neither of these L-ACC beta power findings was observed with sham stimulation. In sum, this study replicates SNT's therapeutic efficacy, identifies left frontal beta suppression as a potential mechanism of action, and highlights baseline L-ACC beta power as a candidate scalable pre-treatment biomarker of efficacy.