Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression

Post by Stephanie Williams

What's the science?

Recently, the FDA approved an effective treatment for treatment-resistant depression called intermittent theta burst stimulation. The treatment involves noninvasively passing an electric current through a magnetic coil in order to excite areas of the brain and relieve symptoms associated with Major Depressive Disorder. In one study, when intermittent theta-burst stimulation was applied daily for 6 weeks, it was found to achieve a remission rate of 32%. However, questions still remain about how to optimize the stimulation protocol in order to maximize the treatment effect. Specifically, three aspects of the treatment protocol could be optimized 1) the timing and repetition of stimulation, 2) the intensity of the dose, and the 3) the process of tailoring the stimulation location to individual anatomy. This week in the American Journal of Psychiatry, Cole and colleagues developed and tested a new protocol for intermittent theta burst stimulation treatment aiming to treat depression symptoms. 

How did they do it?                             

The authors designed and tested a protocol to deliver high-dose intermittent theta burst stimulation using functional connectivity magnetic resonance imaging (MRI) -guided targeting to a group of individuals (N=21) who were currently experiencing an episode of severe or treatment-resistant depression. Some of the participants (N=6) had previously tried a 6-week cycle of conventional TMS stimulation and did not respond to that treatment. The authors delivered stimulation to participants across 5 days, in 10 sessions per day. Each session was spaced apart by 50 minutes. This intersession interval time was a key aspect of the protocol, as previous studies employing inter-session intervals of 40 minutes or less did not show a cumulative effect on synaptic strengthening. The dose that the authors used was five times the dose approved by the FDA for iTBS protocol, and it was used at a higher density than the previously approved method (90,000 pulses across 5 days compared to 18,000 pulses in 6 weeks). The authors chose the target region for stimulation by selecting the sub-region within the dorsolateral prefrontal cortex that was maximally anticorrelated (meaning, the two regions were active at opposite times and may inhibit each other) with the subgenual anterior cingulate cortex (a region implicated in depression). This step, which allowed the authors to target a functional subunit of the dorsolateral prefrontal cortex specific to each individual, distinguishes this protocol, coined Stanford Accelerated Intelligent Neuromodulation Therapy (“SAINT”), from other stimulation protocols that do not use individualized targeting methods. To track symptoms of depression across the course of the treatment, the authors administered several self-report and clinical assessments before the 5-day stimulation period, including the Montgomery-Asberg Depression Rating Scale, and 17-item Hamilton Depression Rating Scale and Beck Depression Inventory-II. Suicidality was addressed in one item on the 17-item Hamilton Depression Rating Scale, one item in the MADRS, and with the Columbia-Suicide Severity Rating Scale. Participants reported their depressive symptoms on a short 6-item Hamilton Depression Rating Scale at the end of each stimulation day. The authors also administered a neurocognitive battery to check for any cognitive side effects.

The primary outcome measure in the study was the change in participant depression symptom score immediately following the 5-day stimulation period, as measured by the Montgomery-Asberg Depression Rating Scale. The authors used the two other measures of depression severity – the Hamilton Depression Rating Scale and the Beck Depression Inventory—as their secondary outcomes. They used cutoff scores on the scales to define two outcome categories: 1) Response to treatment, which they defined as a reduction of fifty percent or more on the baseline Montgomery-Abserg Depression Rating Scale score and 2) Remission, which they defined as a score less than an accepted threshold adjusted for each of the scales. They used the daily 6-item Hamilton scores to calculate the number of stimulation days required for each subject to reach the two criteria, reduction and remission. 

What did they find?

The authors found that 90.48% of the subjects met remission criteria after the five-day period without any negative side effects. There was a significant effect of the testing day and week on the mean depression symptom score measure by the 6-item Hamilton Depression Rating Scale. The average number of stimulation days it took for participants to meet the response criterion was 2.3 days, and the average number of days it took for participants to meet the remission criterion was 2.6 days. The subgroup of participants who previously had not responded to TMS treatment showed an overall treatment effect that was similar to other participants, however, it took them longer to respond. On average, the previous TMS non-responders took 3 days to reach the response criterion, and 3.2 days to reach the remission criterion. 19 of the participants reported some degree of suicidality before the 5-day stimulation cycle began. The authors also found statistically significant reductions in suicidality scores after the treatment period.

What's the impact?

The authors demonstrate the efficacy and safety of accelerated, high-dose functional connectivity-guided intermittent theta burst stimulation treatment protocol, which they coin as “SAINT”, for alleviating symptoms of treatment-resistant depression. Their results suggest that high dose intermittent theta burst stimulation is safe and effective, and that other rTMS protocols may benefit from higher pulse doses. Their protocol could be used in larger, randomized control studies in the future to confirm the efficacy of this treatment. 

Cole et al. Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression. The American Journal of Psychiatry. (2020). Access the original scientific publication here.