This episode is dedicated to all the med studs and residents who cringe every time they have to go to journal club. I report the results of an initial trial of a special kind of Transcranial Magnetic Stimulation of the brain that might be the future of depression treatment, at least for the treatment resistant or severe varieties. I also use this as an opportunity to explain a little more about how repetitive TMS is usually performed (that is, its current FDA approved form), killing two dinosaurs with one asteroid.
Please leave feedback at https://www.psydactic.com.
References and readings (when available) are posted at the end of each episode transcript, located at psydactic.buzzsprout.com. All opinions expressed in this podcast are exclusively those of the person speaking and should not be confused with the opinions of anyone else. We reserve the right to be wrong. Nothing in this podcast should be treated as individual medical advice.
This episode is dedicated to all the med studs and residents who cringe every time they have to go to journal club. I report the results of an initial trial of a special kind of Transcranial Magnetic Stimulation of the brain that might be the future of depression treatment, at least for the treatment resistant or severe varieties. I also use this as an opportunity to explain a little more about how repetitive TMS is usually performed (that is, its current FDA approved form), killing two dinosaurs with one asteroid.
Please leave feedback at https://www.psydactic.com.
References and readings (when available) are posted at the end of each episode transcript, located at psydactic.buzzsprout.com. All opinions expressed in this podcast are exclusively those of the person speaking and should not be confused with the opinions of anyone else. We reserve the right to be wrong. Nothing in this podcast should be treated as individual medical advice.
Welcome to PsyDactic - Residency Edition - Your podcast resource to survive and thrive in your psych residency.
I am Dr. O’Leary, and as of this recording I am a 2nd Year Resident in the National Capital Consortium Psychiatry Residency Program. However, make no mistake, I do not speak for this program, nor do I speak for the Department of Defense or the Federal Government or anyone else for that matter. What I say is my opinion, and I reserve the right to be wrong, so trust me at your own risk. It’s a risk some are willing to take.
References and recommended readings can be found at the end of the show transcript, located at psydactic.buzzsprout.com.
This episode is dedicated to all the med studs and residents who cringe every time they have to go to journal club. I’m a skeptical dude, and I’m often that A-hole in Journal-Club that points out all of the weaknesses of a study, much to the chagrin of the presenter, but I’m trying to be more balanced in my approach and crush fewer souls.
I am going to report the results of an initial trial of a special kind of Transcranial Magnetic Stimulation of the brain that might be the future of depression treatment, at least for the treatment resistant or severe varieties. I’ll also use this as an opportunity to explain a little more about how repetitive TMS is usually performed (that is, its current FDA approved form), killing two dinosaurs with one asteroid.
The American Journal of Psychiatry in August 2020 reported the results of a potentially revolutionary new way to deliver magnetic stimulation to the brain. The paper was titled, Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression. They call this method SAINT.
As a completely extraneous and unnecessary aside, I decided to come up with alternative acronyms for this method, simply because I thought SAINT was a little self-congratulatory. My first suggestion is ANTS, or accelerated neuromodulation therapy from Stanford. The second is STAND, or Stanford Theta-burst Accelerated Neuromodulation Design. Finally, and most humbly I propose simply AINT: Accelerated Intermittent Neuromodulation using Theta-bursts. I’ll be the first to admit that none of these have the pazzazz of SAINT. None would inspire as much confidence, and though I find the term Intelligent to be a little excessive, this is likely just me being jealous.
Getting back to the point, the SAINT method takes TMS to the next level by delivering much more energy, much more quickly, and much more precisely than previous repetitive TMS protocols.
Let me start by reviewing a typical repetitive TMS protocol for depression and then compare it to the iTBS or intermittent theta burst model that SAINT uses. For rTMS, a patient normally may show up 5 days a week and get pulses at a rate of 10 Hz for a total of about 3000 pulses per day, given over the course of about a half an hour. A Hz is just a special way of giving a dead white guy immortality by making his name mean “per second,” so if something is 10 Hz and spaced out evenly, then it is given ten times per second, or every 100 milliseconds.
The SAINT protocol is described as a patient getting 60 cycles of 10 bursts of three pulses at 50 Hz delivered in 2-second trains (every 200 milliseconds) with an 8-second intertrain interval. This is delivered hourly for ten sessions per day (totaling 18,000 pulses/day, compared with the 3000 pulses for rTMS) for 5 consecutive days (90,000 pulses in total total), compared with about 90,000 pulses delivered over 30 days in rTMS.
If you're confused by all those cycles of bursts of pulses at frequencies in trains, let me read you Fox In Sox by Dr. Suess. Wait, that is copyrighted, so instead let me break this down quickly and then summarize the take-home point. Theta burst is named “theta burst” because one of the brain’s endogenous frequencies (called the theta rhythm) occurs at 3-7 Hz. In a iTBS protocol, 3-pulse 50 Hz bursts are applied with an interburst interval of 200 ms or 5 per second and this is smack in the middle of the of theta frequency range in the brain. rTMS on the other hand is not designed to imitate theta rhythms and the pulses are more spread out over time.
The take home point is that intermittent Theta Burst Stimulation (iTBS) is supposed to mimic the endogenous theta rhythms of the human brain. The desired outcome is to elicit excitatory effects, or cause a certain cortical brain region to be more active. This is thought to cause some downstream effects in the deeper brain regions. Also, the SAINT protocol isn’t smokin’ and jokin’ on their lunch break. They deliver a course of treatment over merely 5 days, 10 hours per day, compared to the rTMS protocols that can take 5 weeks of near daily office visits lasting on 30-45 minutes.
Stanford did not invent iTBS, but what they innovated was combining an accelerated iTBS protocol with precision focusing tools. They took both structural and functional MRI scans of their patient’s brains in order to locate the DLPFC. In normal rTMS protocols, the DLPFC is located by first placing the coils over the left motor cortex, turning it on and searching for the spot where the stimulation makes a patient’s right thumb twitch. This also involves titrating up the power to the coil to find the minimum amount of magnetic field needed to induce the motor response. This is called “the Motor Threshold.” Once that is accomplished, the tech simply moves the coil forward about 5 cm to where they guess the DLPFC is and presses the Go button. (I’m simplifying here. In my limited experience, they start below the motor threshold and slowly move up to about 120% of the MT.)
In the SAINT trial, they still needed to find the MT over the motor cortex, but they didn’t have to guestimate the location of the DLPFC. They had mapped it already. They also could precisely tell the depth of both the motor cortex and the DLPFC and adjust the energy accordingly. The take home point here is that the location of stimulation can be precisely calculated, instead of just assumed.
I suspect they used the word Intelligent in their acronym instead of Precision which would have resulted in Stanford Accelerated Precision Neuromodulation Therapy or SAPNT, which sounds like a secretive military special operations unit. Another completely useless aside on word shortening strategies, publishers still use the initialism TRD for treatment resistant depression, which as an acronym would be pronounced TERD.
Now, having swallowed that last bit of trivia, we can move on.
The SAINT trial was not a controlled trial. When studies with pills compare the test pill to a fake pill, they call it a placebo. When a procedural treatment is compared with a fake treatment, they call the fake treatment a sham. Both serve the same purpose and the effects of faked treatments in general can be called “placebo effects.” The original SAINT trial had no Sham treatment. It was open-label. All patients received the active protocol.
22 patients were included in an intention to treat analysis and one patient dropped out after the first session due to pre-existing anxiety. All the patients included had treatment resistant depression with an average of 6 adequate medication trials. 12 of the 22 patients were female and 7 of the patients had tried the FDA approved version of rTMS previously. None of the patients had tried ECT.
They used multiple scales including the Montgomery-Åsberg Depression Rating
Scale or MADRS, Hamilton Depression Rating Scale or HAM-D (6 and 17 item scale), the Beck Depression Inventory–II BDI-II scale and the Columbia-Suicide Severity Rating Scale or C-SSRS specifically for suicidal ideation, although this was also measured using the other scales. These are all normally used in research, so nothing strange here. The results of each scale, of course, are not independent of the other scales as they are simply different and similar ways of measuring the same thing: the symptom burden of depression.
They also used a battery of neuropsychological tests to test for cognitive side effects and the Young Mania Rating Scale to test for possible switching to hypomania.
The only side effects reported by participants other than the one who dropped out due to anxiety were fatigue and some discomfort at both the stimulation site and in facial muscles during stimulation. The only changes on the neurocognitive test was an improvement on one measure of cognitive inhibition, so the protocol does not seem to cause people thinking problems. What changed dramatically were the participants' depression scores. The remission rates on the different scales ranged from 80-93% on day 6 immediately after treatment and remained between 60-70% a month later. This is pretty impressive, even without a SHAM group. Also, rates of suicidality plummeted with a persistent significant reduction in suicidality of 80-100% on their various scales even a month after treatment.
If these responses are found to be typical of patients receiving this protocol and are found to be persistent, then this could be the best treatment available for depression. Now here is where I temper your expectations (I hope without crushing any souls).
New forms of treatment like this often appear transformative initially, but fail to perform in randomized, multicenter trials or when generalized to less controlled patient populations. In some sense, having done so well initially, they have nowhere to go but down, so mere regression to the mean could go a long way to reducing their effect sizes. Also, it is worth asking, “Is it possible that patients excited about a new treatment over-stated their initial symptom burden? Or overstated the results?”
The authors point out, and I’ll quote them here, “The remission rate we observed is higher than reported open-label remission rates for standard FDA-approved rTMSprotocols (37%), ECT (48%), and ketamine (31%) for treating treatment-resistant depression. However, they are comparing a single current study to some historical meta-analyses, so this might not be a fair comparison.
I should point out here, again without getting into too much detail, that many studies prior to this had suggested that iTBS could be an effective treatment. Stanford didn’t invent the treatment, they just innovated the intense delivery method.
Even if these results are treatment specific and durable, the authors point out that this study was not designed to see if the results were attributable to “the spaced stimulation sessions, accelerated delivery, high pulse dose, individualized targeting, higher sham effect, or a combination of these.” By “higher sham effect” I think they mean that the placebo effect of receiving 10 hours per day of treatment for your depression may have a large positive effect on mood, even if you fake it.
I am not sure what the cost of having two MRIs and five 10 hour days of iTBS treatment is, but I doubt it is cheap, so initial treatment of depression is likely to remain pharmacotherapy even if this protocol stands the test of time. However, depression has a huge burden on patients, families, the healthcare system, and the economy, so any effective treatments are likely to also be cost effective in the long run.
There are a couple other things I’d like to draw attention to. The first is kinda a bummer and the second is more encouraging. The authors of the SAINT trial reported that later (an average of 22 weeks later) 6 participants were treated again after relapse, but the re-treatment did not have an effect. It may be that this treatment can be given only a limited number of times, or it is just not for everybody. It’s hard to tell with such small samples.
To end on a high note, I found a registered 2020 study (you can find on ClinicalTrials.Gov) that did compare the SAINT protocol to a sham treatment. The results I was able to uncover were reported in abstract form in Brain Stimulation. The authors reported remission rates to be 78.57% in the active group and 13.33% in the SHAM treatment group of 29 total patients. This is more good news for depressed patients.
[Jingle Bells]
I know I have obsessed over acronyms and initialisms during this episode, and I will not apologize. In fact, I have one more for you. While producing this episode, I came across a new initialism of the SAINT acronym. It was in an online article in the Stanford Daily dated 02DEC2021 and titled “Stanford depression treatment nearly 80% effective.” I bring this up, because in this article, they don’t use the SAINT acronym, but instead report the treatment by the initialism SNT, short for Stanford Neuromodulation Therapy. I like this better than SAINT, not that my opinion matters. But, I still have a recommendation to improve it, not that anyone cares. I suggest TNT, short for Theta-burst Neuromodulation Therapy. I think it is a little more memorable, and a little less self-congratulatory.
In this episode, I discussed the SAINT trial and tried to use that as a way to compare iTBS with the current rTMS protocols. Hopefully in the future I’ll be able to give an updated report stating that SAINT or SNT or TNT will have proven its mettle.
Thank you for your time, and this has been an episode of PsyDactic - Residency Edition. 1–3