Noninvasive device treatments for psychiatric disorders long have been investigated; however, they rarely have achieved substantial efficacy or implementation. To better tap into the potential of one such U.S. FDA-approved treatment, transcranial magnetic stimulation (TMS), Stanford University researchers developed a high-dose, precision-targeted protocol known as Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT).

They tested it in a 21-patient study of treatment-resistant severe depression, achieving a 90% remission rate for patients that put them into the nondepressed range. A double-blind, sham-controlled trial is up next to confirm these results, which were published in the April 7, 20 issue of the American Journal of Psychiatry.

Fast and effective

“We have tried to figure out how to solve a pragmatic, clinical issue, which is that we don't have any treatments that are designed for people who are hospitalized into psychiatric wards for suicidal depression,” Nolan Williams, assistant professor of psychiatry and behavioral sciences at Stanford and a senior author of the study, told BioWorld. “ECT (electroconvulsive therapy) is used. But if you look at the number of people that meet Medicare or Medicaid criteria to get ECT in the U.S., it's only about 1.5% of the whole group of folks that end up going into the inpatient unit for that problem.

“So, 98.5% of people don't have another option, and they end up getting access to the same medications that they have as an outpatient. ... But the highest risk for completed suicide and suicide attempts is in the first couple of months after you're discharged from a psychiatric hospitalization. So, this is a potential solution to that problem. We can do TMS over a short period of time and get a lot of people well; it looks relatively durable across the time period where that high risk is in place.”

ECT has an average remission rate of 48% for treatment-resistant depression, while no therapy has reported a higher than 55% remission rate in open-label testing, according to Williams. That makes these results highly unique.

Intermittent theta-burst stimulation was used in the study; it is a kind of TMS that is approved by the FDA. There hadn’t been large dose-ranging studies performed, but recent information suggested that multiple sessions within one day at short intervals, high pulse stimulation dose and precision targeting of the brain region would be more useful than the approved protocol.

There are several FDA-approved devices for the use of TMS to treat depression, some of which specifically have theta-burst approval. This study used the Magpro X100 device from Copenhagen, Denmark-based Magventure Inc.

How it works

The SAINT protocol involves more pulses per session, as well as more sessions closer together. The FDA-approved treatment is six weeks of once-daily sessions with 600 pulses per session. It offers improvement in roughly half of depression patients, with only about one-third experiencing remission.

By contrast, the newer protocol uses 1,800 pulses per session over 10 sessions per day of 10-minute treatments. There is a 50-minute break between each treatment. Continuation of treatment took up to five days of this regimen, with an average treatment of three days before patients reported depression relief.

SAINT also specifically targets a specific subregion within the left dorsolateral prefrontal cortex that is tied to the subgenual cingulate, which is a part of the brain that is overactive in depressed patients. In those individuals, the connection between the two regions is weak. Stimulating that subregion of the dorsolateral prefrontal cortex works by quieting the activity in the subgenual cingulate.

“The left dorsolateral prefrontal cortex, which is the area we stimulated with TMS, is really a large space,” said Williams. “It's about a 5 cm span; the diameter of the TMS pulse induced current is about 2 cm. So, the sizes proportionally allow for one to hit or miss a target.”

“There's also a bunch of new neuroscience about how to induce plasticity,” he continued. “That work is suggesting that there's an optimal spacing range, which is about an hour to an hour and a half to two hours where you stimulate and wait and stimulate again. You can build off the first stimulation with a second, and then a third stimulation onto the second, and so on and so forth.”

Steps to implementation

The researchers have completed a similar study – this time with a sham control arm. They are conducting follow-up via video chat as a result of the ongoing limitations of the COVID-19 pandemic. Still, they expect to publish these results next year. There is another paper under review that performs assessment in the posttreatment resting state to elucidate the changes induced in the state of brain activity.

The NIH has committed funding for a 100-patient trial that would start after the COVID-19 pandemic is firmly in hand. Williams hopes this could be enough to gain FDA approval for this protocol. The academics are exploring the best routes to commercialization and reimbursement. The protocol theoretically could be used off-label with existing equipment, but it presumably would not be reimbursable without an FDA nod.

Treatment-resistant depression is not the only potential indication that could be addressed with a similar approach, although one that targets another, specific region of the brain related to that disorder. Stanford has started or plans to soon start studies with high-dose, precision TMS treatment for additional psychiatric indications, including obsessive compulsive disorder, addiction and bipolar depression.

“All of the options on the table: licensing the technology to current device manufacturers, trying to talk to new companies – all of those things are within the range of possible routes,” summed up Williams on his future aims for this technological approach. “At the end of the day, it's about penetration; that's the part that's important. The goal in my head is to put several TMS devices in every in-patient psychiatric unit in the U.S.”