New Neurostimulation Protocol Effective for Treatment-Resistant Depression

An accelerated protocol of intermittent theta-burst stimulation (iTBS) called Stanford neuromodulation therapy (SNT) was more effective than sham stimulation for treatment-resistant depression according to a recent study.

iTBS is approved by the FDA for treatment-resistant depression, but its effectiveness is limited by its 6-week protocol. Stanford researchers developed an accelerated protocol that is guided by functional connectivity MRI (fcMRI) and specific neurostimulation patterns. Their 5-day protocol involves multiple sessions per day, higher doses of stimulation, and personalized targeting of targets to the left dorsolateral prefrontal cortex.

Open-label trials of SNT have showed a 90% remission rate, which the researchers said is double that of the current gold standard, electroconvulsive therapy (ECT). Building on that data, the researchers wanted to investigate the efficacy of SNT in a randomized, double-blind sham-controlled trial. They conducted the trial at Stanford University’s Department of Psychiatry between March 2017 and December 2019. Participants (29) had moderate treatment resistance to major depressive disorder. Participants ranged from 22 to 80 years of age.

The researchers stopped the trial midway because the planned interim analysis showed a large effect size of active compared with sham treatment. The results were taken from participants who entered the trial up to the interim analysis.

Compared to iTBS, participants who underwent SNT reported more headaches — a common side effect of both. After 5 days of treatment, 79% of participants in the active SNT group (11 of 14 participants) achieved remission from depressive episodes during the 4-week followup. In the sham treatment group, 13% achieved remission. “The short treatment course and the high antidepressant efficacy of SNT present an opportunity to treat patients in emergency or inpatient settings where rapid-acting treatments are needed,” the researchers said.

The researchers attribute the results to the fact that they used neuroscience-informed stimulation parameters for optimal modulation. The length of intersession intervals and intensity of stimulation also played a role.

The small sample size, the single-site nature of the study, and the use of clinical outcome assessments were cited as limitations.

“Studies will be needed that compare the efficacy of SNT parameters with and without fcMRI-guided targeting to determine the importance of this targeting method,” the researchers conclude.


Cole EJ, Phillips AL, Bentzley BS, et al. Stanford Neuromodulation Therapy (SNT): A Double-Blind Randomized Controlled Trial. Am J Psychiatry. Published online ahead of print October 29, 2021. doi:10.1176/appi.ajp.2021.20101429