I started treating people with TMS for depression in 2015, using the first iteration of the BrainsWay H1 coil. It was rewarding to see people improve, without experiencing the common adverse side effects that people often get from taking daily antidepressant medications.
However, conventional, once-daily TMS still has a frustratingly slow onset of action. Most people notice subtle changes after 2-4 weeks of daily treatment, but the full benefit is not usually achieved until someone has completed 6 weeks of treatment; frequently, people notice no improvement after the initial 4 weeks of daily treatment. 72.7% of “acute phase non-responders" (people who show no benefit after the initial 4 weeks of daily treatment) go on to show a significant response during the twice weekly continuation phase.
The standard depression protocol with the H1 coil is once-daily TMS (5 days a week) for four weeks, followed by twice weekly TMS for twelve weeks, for 44 treatments. Waiting for four months for depression to fully remit is too long! There has been a recent shift in psychiatry to regard major depression as a “brain emergency,” that necessitates effective, rapid-acting treatments.
More recently, a new pattern of stimulation, referred to as intermittent theta burst stimulation (iTBS) has been studied in treatment-resistant depression. This pattern of stimulation is much more efficient than conventional TMS; studies have shown that approximately 3 minutes of iTBS, which delivers 600 pulses, is equivalent to 37.5 minutes of traditional TMS, which delivers 3000 pulses.
The FDA has cleared 3 minutes of once daily iTBS for the treatment of depression.
The pattern of pulses in iTBS more closely resembles neuronal firing patterns, or how our brain cells “talk” to each other. iTBS is a type of “patterned stimulus” and consists of a frequency within a frequency.
Specifically, iTBS delivers triplets, or “bursts” of three pulses delivered at 50Hz. These bursts are repeated at a frequency of 5Hz for approximately two seconds; the time that the coil is pulsing is referred to as “a train.”
The trains of stimulation are separated by a period when the coil is not pulsing, which allows for the underlying neurons to repolarize. This is referred to as “intermittent” theta burst stimulation because of the intertrain interval.
Continuous theta burst stimulation (cTBS) is also used, and consists of triplets (bursts) at 50Hz repeated at 5Hz, without any intertrain interval. cTBS is inhibitory to underlying neurons. cTBS stimulation is currently under investigation, but there are no current FDA-cleared TMS protocols that use cTBS.
With iTBS, the “intertrain interval” is 8 seconds. The following image shows the pulse patterns of conventional (10Hz) TMS compared to iTBS at 50Hz/5Hz:
Building upon the efficiency of iTBS, “accelerated” TMS protocols have been developed typically administering 9 minutes and 42s (1800 pulses) of iTBS multiple times per day. Research has shown that these stimulations are most effective if the sessions of 1800 pulses of iTBS are separated by an intersession interval of 45-90 minutes.
Most accelerated iTBS protocols therefore administer 9 minutes of iTBS, followed by a 50-minute rest, and this is repeated hourly up to 10 times in one day, for 5 or more consecutive days.
These accelerated protocols provide more rapid relief from depression. Although very promising and exciting, in that they can provide very rapid relief from depression, accelerated TMS protocols are not yet covered by insurance.
Our clinic offers an accelerated, 5-day TMS protocol, for private pay. In this protocol, the equivalent of 6 weeks' worth of once-daily TMS is delivered in one day and repeated over 5 consecutive days. So, the accelerated protocol is a much larger “pulse dose” compared to traditional TMS protocols, which likely accounts for the remarkably high response and remission rates achieved with accelerated iTBS protocols, for even very severe, long-standing, treatment-resistant depression.
There is an accelerated intermittent theta burst (a-iTBS) protocol that is FDA-cleared for treatment-resistant major depressive episodes. That protocol is known as the SNT or SAINT (Stanford Neuromodulation Therapy, or Stanford Accelerated Intelligent Neuromodulation Therapy) protocol and uses a proprietary TMS delivery system (a figure of eight coil manufactured by the company Magnus Medical), as well as functional MRI scanning (fcMRI) to more precisely target the area of the brain that is stimulated by the TMS coil to treat MDD (“functional neuronavigation”).
Using functional neuronavigation, rather than scalp-based targeting, the SAINT/SNT protocol avoids the pitfall of missing the intended target. The SNT system is only available through clinical trials; there are two clinics offering SNT/SAINT in the US as part of the “open-label optimization phase,” for the system, following it’s FDA-clearance in 2022.
SAINT/SNT is anticipated to come to the market as early as the spring of 2024, and we hope to offer it!
The clinical results achieved in the SAINT/SNT trials are unparalleled in depression treatment.
SAINT/SNT was granted “FDA fast track,” a designation intended to expedite the development and approval of therapies which may demonstrate substantial improvement over available therapy.
The first SAINT/SNT trial was “open label”,” meaning that there was no placebo or sham condition, and all patients received active SAINT/SNT. In that trial, 19 out of 21 patients (90.5%) reached full remission from depression after 5 days of treatment. These patients had suffered from treatment-resistant depression for an average of 22.95 years and had an average of 5.86 “failed” prior antidepressant trials. Six of the participants had a history of non-response to conventional “once daily,” TMS. This remission rate far exceeds the open-label response rates for the FDA-cleared conventional (once-daily) TMS protocols (37%), electroconvulsive therapy (48%), and intravenous ketamine infusions (31%).
A double-blind, sham-controlled trial of SAINT/SNT followed the open-label study. In this trial, a “randomized controlled trial” or RTC, patients were randomly assigned to receive either active SNT or sham treatment. The study was small with 29 patients randomized to either SNT or sham treatment; the small sample size was because the results of the planned interim analysis showed the active treatment to be far superior to sham treatment, so the study did not need to enroll a larger number of participants to determine the superiority of active SNT vs sham SNT. Of the 14 patients assigned to active SNT treatment, 12 participants (85.7%) met the criterion for response (a reduction ≥50% in depression), and 11 (78.6%) met the criterion for remission.
The accelerated TMS protocols at Clear Path Psychiatry use the BrainsWay machine and an H coil to effectively deliver the same type and pattern of intermittent theta burst stimulation used in the SNT/SAINT protocol. Because the geometric design of the H coil delivers a much wider and deeper stimulation, it is hypothesized that precise neuronavigation with fMRI is not essential with an H coil compared to the figure-of-eight TMS coil used with SAINT.
This hypothesis currently has no randomized, double-blind data to support it. However, the H coils have been used, and continue to be used, by many practitioners to effectively deliver accelerated intermittent theta burst stimulation to achieve similarly high response and remission rates.
