Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression (SAINT-TRD)

Abstract

Background: Current treatments for depression are limited by suboptimal efficacy, delayed response, and frequent side effects. Intermittent theta-burst stimulation (iTBS) is a non-invasive brain stimulation treatment which is FDA-approved for treatment-resistant depression. Recent studies suggest several improvements could be made to iTBS by 1) precision targeting of the left dorsolateral prefrontal cortex (L-DLPFC) to subgenual anterior cingulate cortex (sgACC) circuit, 2) treating with multiple sessions per day at spaced intervals and 3) applying a higher overall pulse dose of stimulation. Objective: Examine the feasibility, tolerability, and preliminary efficacy of an accelerated, highdose, fcMRI-guided iTBS protocol for treatment-resistant depression (TRD) termed 'Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT)'. Methods: Thirty-one participants with TRD received open-label SAINT. Resting-state functional connectivity MRI (fcMRI) was used to individually target the region of L-DLPFC most anticorrelated with sgACC. Fifty iTBS sessions (1800 pulses per session, 50-minute inter-session interval) were delivered as 10 daily sessions over 5 consecutive days at 90% resting motor threshold (adjusted for cortical depth). Neuropsychological testing was conducted before and after SAINT. Results: Twenty-eight of 31 participants (90.32%) met criteria for remission (≤10 on the MADRS) and all 31 were remitted on measures of suicidal ideation. Neuropsychological testing demonstrated no negative cognitive side-effects. There were no seizures or other severe adverse events. Discussion: Our highly accelerated, high-dose, iTBS protocol with fcMRI-guided targeting (SAINT) was well tolerated and safe. Efficacy was strikingly high, especially for this treatmentresistant population. Double-blinded sham-controlled trials are required to confirm the high remission rate found in this initial study.

Functional connectivity changes with rapid remission from moderate-to-severe major depressive disorder

“…Prior studies have reported significant reductions in FC between sgACC and 1 to 2 nodes of DMN (24, 37, 64-66); whereas, we observed significant reduction in FC in nearly all DMN nodes. Bearing in mind that SAINT induced remission in 90% of participants in 1-5 days (19), this question deserves careful consideration in future studies.…”

“…We hypothesized that individualized targeting and enhanced stimulation techniques could improve outcomes (20), and we developed Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT). In our initial open-label trial of SAINT in patients with severe, treatment-resistant depression, we observed a strikingly high remission rate of 90% with a mean of ~3 days of treatment to produce remision (19). Thus, FC changes that occur with SAINT may reflect generalized network-level changes associated with remission from depression.…”

“…Participants received a 5-day treatment course under the SAINT protocol. Stimulation location was depth-corrected (52) and chosen based on an algorithm that selected the area within the left dorsolateral prefrontal cortex (lDLPFC) with the most negative FC with sgACC (19). Ten sessions per day of intermittent theta-burst stimulation [iTBS, 60 cycles of 10 bursts of 3 pulses at 50Hz delivered in 2-second trains with an 8-second inter-train interval] were delivered hourly at 90% resting motor threshold for 5 consecutive days for a total of 90,000 pulses.…”

“…Detailed information regarding the participants, SAINT protocol, experimental design, and behavioral data analysis can be found in our prior report (19 score higher than 20 and not have responded to at least 1 antidepressant medication (minimum trial duration of 6 weeks) to be eligible for the study. Participants had no history of a psychotic disorder, substance use disorder, major systemic illness, current mania (assessed using the Young Mania Rating Scale), lesional neurological disorder, or any contraindications to rTMS or MRI (such as implanted metal or history of seizures).…”

“…Incipient investigations of potent 5-HT2a agonists demonstrate high rates of rapid remission (16,17); yet, the off-target effects are profound (18). We recently developed a form of repetitive transcranial magnetic stimulation (rTMS) that induces remission in 90% of individuals with severe, treatment-resistant MDD in a mean of ~3 days without off-target effects (19,20). This treatment provides a new opportunity to investigate the network alterations associated with remission from MDD.…”