As we begin a new year, I thought it appropriate to do a brief highlight of the good and the bad in the world of FDA clearances and clinical protocols for TMS from the previous couple years. As I try to be an eternal optimist, I will start with the good! Though TMS has been FDA cleared for over a decade, for most of that time it was a single protocol, 10 Hz rTMS applied over left DLPFC for treatment-resistant depression. However, starting in 2017 several FDA clearances for new protocols and new indications for TMS have been cleared and are now clinically available. The bad involves FDA-regulated pivotal trials that simply failed to meet their primary end-points.
So, let’s start with the good, the approval of new and more efficient protocols for treatment-resistant MDD. Though many clinics still use the originally approved, 37-minute protocol, the FDA has now cleared much shorter protocols, which are available on most current models of TMS devices. Specifically, an “accelerated” high-frequency protocol that takes only 19 minutes due to a reduced inter-train interval (11 seconds rather than the original 26 seconds). As with the original clearance, Neurostar was the first to get this protocol through the FDA, with the other device companies including Magventure, Nexstim and Magstim close on their tails. The reduction from 37 minutes to 19 was definitely more convenient, making it possible to be in and out of a clinic visit in under half an hour. But, this is nothing compared to the game changer protocol, theta burst stimulation.
Theta burst stimulation was first introduced into the literature in 2005, but like other TMS protocols theta-burst stimulation remained in the research domain for over a decade before being clinically available. It was originally developed to mimic the natural pattern of firing rates of neurons when they are changing and adapting their connections and was originally used to study brain plasticity. Though the pattern of stimulation (with short bursts of 50 Hz (gamma band) stimulation applied 5 times per second (theta frequency)) was based on single-unit firing rates of individual neurons, it was thought that perhaps if TMS was applied at these same frequencies than the larger-scale networks would also be more apt to respond by changing and adapting their connections. It was also thought that this pattern of stimulation was more “natural” to the brain, compared to 10 Hz and so more likely to be effective. Whether theta-burst stimulation does actually lead to more change at the network level than 10 Hz has yet to be determined. Importantly though what was clearly demonstrated in late 2018, which lead to FDA clearance first for the Magventure device then shortly there-after the Magstim and Nexstim devices is that theta-burst stimulation is equally as effective in improving depressive symptoms as the standard 37-minute protocol. I haven’t even mentioned the clincher here, the theta-burst stimulation protocol that is equivalent in efficacy to the 37-minute protocol, takes only 3 minutes to put in. It will take longer to park the car and walk into the clinic than the treatment itself!
So what do we have to look forward to when it comes to protocols? Stay tuned! Now that duration of sessions have been shortened significantly, there are researchers and clinicians pushing the limits of number of sessions in a day. The most I’ve seen is 10 in a day (once an hour for 10 hours). In this protocol, the patient receives 50 sessions in one week. So, if you have a week “vacation”, in theory, you could get a full treatment regimen. Though early studies look quite promising, especially for severely depressed individuals, it has yet to be tested in a large-scale randomized trial. Thus, these “accelerated” protocols are not yet ready for prime time, but keep an eye out for FDA submissions related to multiple sessions in a day in the upcoming year.
The other good news in the TMS world came in late 2018 with the FDA clearance of the Brainsway “Deep TMS” device for the treatment of obsessive-compulsive disorder. This was notable both for the extension of TMS treatment to a disorder, but also because the protocol itself blended rTMS with a behavioral provocation. This was the first time that the treatment standardized the behavioral and brain state of the patient prior to the stimulation. Researchers have long known that the state of the brain will influence the effect of TMS. However, all other FDA cleared TMS protocols do not specify what the patient should be doing just before, during, or just after the stimulation session. An important note here is that unlike the Neurostar protocol that other devices quickly “piggybacked” onto. Brainsway’s device is significantly different than the other devices on the market, making it more difficult for other device companies to quickly and easily achieve the same clearance for the OCD protocol on their devices. Thus, for now, only the Brainsway device is FDA cleared for OCD. So, what is on the horizon for new indications? Anxiety? Addiction? Neuropathic Pain? I have no insider information, but I certainly believe that the upcoming years will see further extension of TMS treatments to additional neuropsychiatric disorders, so stay tuned!
Ok, so now to the bad. For every positive study and FDA clearance, there are many “negative” or “failed” trials. Trials that simply do not meet their primary endpoint. In other words, those that receive the active treatment do not do any better than those that receive the sham (placebo) version of the treatment. Some notable studies that missed their targets include the Neuronetics Adolescent Depression trial, the Neuronix Alzheimer’s trial, and the VA Depression Trial. These trials represent years of work and millions of dollars of investment and currently remain “off-label”. Each of these trials failed to show that the active versions of the treatment were superior to sham, but the fatal flaw in each may have been different.
For example, the Neuronetics Adolescent Depression Trial enrolled adolescents age 12-21 and applied the standard adult MDD protocol. Final results are not publicly available for this trial, however, it was announced in early 2019 that they did not reach their primary endpoint. In this case, is it possible that the brain of a 12-year-old does not respond the same as that of a 30-year-old and that a different protocol may be required. Or perhaps what we call “adolescent depression” is pathophysiologically different, requiring a different treatment approach than adult MDD.
At the other end of the age-span, we learned in early 2019 that the Neuronix Alzheimer’s trial also failed to reach the primary endpoint. In this case, the effect was simply not large enough. In this trial, perhaps the fatal flaw was the disease itself. Alzheimer’s is a Neurodegenerative Disease, meaning the brain loses neurons and loses plasticity across networks. Thus, is it possible that the brain of those in the study had degenerated and lost plasticity to the extent that TMS was not sufficient to modify the affected neural networks. In this case, could we perhaps try to intervene earlier in the disease process while the brain still has enough plasticity to make a difference? Again, stay tuned, there are those in the research domain working on this question as we speak!
The failed VA Depression Trial, published in 2018 failed for a totally different reason. In this case veterans with MDD were provided either the standard protocol or a sham (placebo) version of the same protocol. Notably, this trial failed due to a very large placebo effect (almost 50 percent). Thus is it possible that general aspects of the treatment (including compliance on meds, regular visits to the clinic, or providing hope for individuals who had perhaps lost some hope) may have been so therapeutic that it obscured any additional benefit of the TMS? In this case, should the failed trial prevent the clinical roll-out of TMS in the VA system? For what it is worth, it hasn’t, the VA system has invested millions of dollars into equipping multiple VAs with TMS devices and training providers.
The past few years have undoubtedly brought good news, in the form of FDA clearances for new TMS protocols and new indications, but those designing the next pivotal trials need to critically evaluate the fatal flaws of the negative trials, so that they do not repeat the same mistakes. I am excited to see what 2020 brings and will continue to provide insight into the latest news in the TMS world. I have no doubt 2020 will see TMS researchers and device companies continuing to push the envelope on new protocols and new indications. I continue to be humbled and honored to be a part of this life-changing (and sometimes life-saving) field.