TMS for Treatment-Resistant Depression: A Clinical Guide with Dr. Owen Muir

Mark Mullen: [00:00:00] Welcome back to Psychiatry Bootcamp. Today we are talking to Dr. Owen Scott Muir, who is an expert in a lot of things. He's the author of the Frontier Psychiatrist Podcast, and he will give an extended introduction about the hundred thousand different industry-related things that he is involved with.

We're gonna talk about transcranial magnetic stimulation, which is a little bit like magic to me, to be honest with you, and I'm sure to many of you, which makes this an interview that I tried to approach with a very beginner's mindset because I have a very beginner's mindset. We talk about how TMS works, what TMS is indicated for.

We talk a lot about the FDA approval process or clearance process for this technology. We talk about what the future might hold for TMS. As you will hear, Dr. Meir is very high energy interview. He's a very fun person to listen to and he says a [00:01:00] lot of things where you feel like you wanna ask a follow up on that little thing, but you also know that then we would need another 10 hours.

And so we may have to have him back. Enjoy this episode on Transcranial Magnetic Stimulation, Dr. Owen Meer. Welcome to Psychiatry Bootcamp and I will ask you to introduce yourself to our audience. 

Owen Scott Muir, MD: I am, Owen Scott Muir. I am a child, adolescent and adult psychiatrist by training. I have those extra letters after my name 'cause I'm a distinguished fellow of the American Academy of Child and Adolescent Psychiatry, which means I did a lot of extra work, but it's fair 'cause I met my wife at the ACAP Conference a decade ago Now, maybe a little bit more.

I work with kids, adults. I'm also the chief medical officer and co-founder of a company called Radial, which is. A health technology and services company, AKA, we deliver care and build tech to make that better. I'm also fractionally the chief medical officer of a company called Neuro Leaf, which is an Israeli neurotechnology company which built, two [00:02:00] devices.

One is called ion, an at-home treatment for migraine, and the other will be Proli rx. And it's an at-home and in-clinic neurostimulator, using combined trigeminal and occipital afferent nerve stimulation for major depressive disorder that hasn't responded to treatment with other, oral medications.

And I'm an advisor to a number of companies. I'll mention those that are regulated and thus disclosures. I'm an advisor to Siren, which creates vocal biomarkers. I've been a principal investigator there. I have a small amount of equity in mind medicine where I've also been a principal investigator.

They're a psychedelic. Drug development company. I have, I think, like 10 shares of Compass, because I wanted to see it move around. and now Radial has a contract with them. They, creating the Comp 360 asset. I am an advisor to a company called, Viera, and was a principal investigator in an NIHR 44 funded grant for the development of [00:03:00] ai.

Identification of Tardive Dyskinesia, which is now in the world, is a product called TD screen.ai. I have some equity in a company called I Rx Reminder, which co-developed that software and, builds, medical devices for adherence to medications and I'm probably forgetting something. Oh, now Purple Gaze, which is gaze tracking.

I'm an, advisor, that's a medical device that's also regulated. I, work with my married to Carlene McMillan, who is an advisor to a company called Emo Bot, which is Passive Sensing, which also regulated medical device. And those are disclosable things that I can talk about. 

Mark Mullen: Okay. Thank you for getting ahead of us with those disclosures.

I think you're in, and I knew this before you went through all that. I think you're involved in more things generally speaking than anyone I've ever met. one of the ways that you. Well, we, the way we initially met was that you wrote some very kind words about psychiatry bootcamp in your Frontier Psychiatrist's newsletter, about a year and a half ago, and then reach out to me personally to [00:04:00] offer mentorship.

So it's been wonderful to, have that mentorship from you. I really appreciate it. But today we are here to talk about TMS. So let's dive right in. I wanna start with the history of TMS. Right? So this is one of the leading tools in our rapidly expanding field. I think there's a lot of future ahead and the future of psychiatry is the theme of our season.

But let's start in the past. Could you walk us through how TMS Transcranial magnetic Stimulation was discovered and how its applications in the field of psychiatry have evolved over time? 

Owen Scott Muir, MD: I'll start with how I discovered it. I was a psychiatry resident at the Hofstra Northwell Program at the Zucker Hillside Hospital, and in my third year of psychiatric residency training.

I got cripplingly depressed. I have bipolar disorder and I remembered when I was in my twenties, I was a research subject for J John [00:05:00] Mann, among others who gave me a lumbar puncture, in a study he was doing with Maria o Kendo around suicidality and bipolar disorder. And one of the other folks who I stayed on the schizophrenia unit 'cause they ran outta beds in the research unit, which is actually where I kind of got the idea to go become a psychiatrist.

And one of my other study participants in the schizophrenia research unit told me, well, I'm getting TMS. I'm like, what's that at age 20? fast forward many years later, it had been, approved in major depressive disorder, but it was not a mainstream treatment. And I've got bipolar disorder, which for at the time, and still it's not indicated for.

I went and saw my doctor, who I've been seeing since I was 20. Maria o Kendo referred me to him and, Mike Dolphin said, look, I don't do TMS, but if it works, it's easy to recreate. And I know this guy across town, Robert McMullen, who does TMS, I think you'd like him. He's kind of kooky, and I think he'd get [00:06:00] along.

And I was just like, whatever you say, Mike, I just, I'm like the most compliant patient on earth when I roll up into my doctor's office, I just do whatever they say no matter what the discipline, basically. And so I went and saw Dr. McMullen and he did an evaluation and he said, let's try it after my first treatment in, and this was in the spring of 2015, walked out and had the first full meal I'd had months.

Most TMS clinics are open five days a week, and we'll get back to that because it's important as a number. He had two different offices. So he had one in New York City, which was open five days a week, and one in Mount Kisco, New York, about hour and a half north. It was open on the weekends. So I got my five days of treatment in the city and then my now wife came to visit me and on Saturday I was fine.

And on Sunday I powered down like a robot and she's like, what is happening? Your depression [00:07:00] is back. Oh my God, let's drive you to Mount Kisco. I walked in like a zombie with psychomotor retardation, that's what we call it when you're walking slow and moving slow and thinking and talking slowly. And I got a treatment with transcranial magnetic stimulation and I walked out like a normal person, and my wife, who's also a psychiatrist, Carlene McMillan, who works at the same company I do now at Radial, said what happened?

This is,

we were like, I don't know what tell you, but I want, I wanna have brunch. It, was revelatory. And now obviously not everyone has the same experience. I've later learned, and the research shows that some individuals with bipolar depression actually get better faster than the traditional unipolar depression.

And TMS was the treatment for me, and I was able to get in the seven days of time I had left before, I couldn't complete training on time. I was well [00:08:00] enough to go back to work and I got the rest of the treatment in the evenings. And after that first course at TMSI graduated on time, was able to start fellowship on time and went, but I wasn't sold yet.

Like, I'm gonna be child psychiatrist. There's no data for this in kids. What does it even matter? so that was in my introduction to it. Now we'll rewind to the invention of TMS. So in the 1980s, Ted Barker in the UK was doing physiology research and there were a number of other, Neurophysiologist who, were doing work at that time.

And he realized that a magnetic field could induce an electrical field. And he designed a figure of eight coil. there are others involved, of course, no one's doing this in a vacuum, but, rothwell and others were, stimulating the brain. And he figured out that this magnetic coil could make the motor cortex fire.

And so you can find the thumb, which is [00:09:00] the biggest part of the ulus on the motor cortex, and you stimulate it magnetic field. So here's physics class thumb, the direction of the wire fingers curl and the direction of the magnetic field current induced in the wire. And so the axons in our brains are insulated with myelin.

They are functionally wires as far as a changing magnetic field is concerned. So you induced magnetic field, axons will fire and you can elicit a movement in the body. and this was crucial for the development of TMS 'cause there are a bunch of ways to modulate the brain that are hard to measure.

When we do psychotherapy, we're making neurons fire, but we're not watching your thumb move. So it's not as good of a motor probe, I guess you can yell boot and someone will jump. And that's a little bit of a right. You can measure startle response that way. But the ability to measure was crucial. So that was our motor probe version of TMS.

and there are some of us who are a bit more iconoclastic and one of them is Dr. Mark George, who I've had the pleasure of working with actually at the, I [00:10:00] mentioned at the beginning that company, neural leaf, which makes the proli device. Mark George was an investigator on that study as well. So he and I were just together, at the FDA recently.

So Mark gets the sense that this physiology probe might be able to do other things. 'cause by that time, they'd figured if you give a TMS pulse and you do it repeatedly, not transcranial magnetic stimulation, but repetitive transcranial magnetic stimulation, you could. Create an upregulation of neurons firing that would be durable.

You could create long-term potentiation, and he moved that figure of eight coil, a number of centimeters forward. There have been debates over the years about exactly how many centimeters and will get to that, but essentially the left front of the brain, left dorsal, lateral prefrontal cortex. If you stimulated that with a pattern, 10 hertz, pause, 20 seconds, 10 hertz for two seconds.

So that's called a train. [00:11:00] It's a bunch of pulses in a row at a certain pattern, intercession interval, and then another train. You would get increased motor firing over time, long-term potentiation. And just like you're using flashcards, right, you see a flashcard once, you'll forget it, you see it again, you might remember it, you see it 50 times, you'll remember it pretty well.

And so by doing this stimulation for 45 minutes at the time, which is about how long you could hold up the coil. Also there was no cooling systems yet, so you had to duck it in a bunk of ice water 'cause it got hot if you didn't have a cooling system at the time. But it turns out when that was eventually studied in an FDA, clearance trial in 2008 with, neurones the company as the study sponsor, it worked for depression for major depressive disorder in individuals who hadn't been helped by prior treatments.

Now there are a couple of, original sins in the development of TMS and [00:12:00] one of them was that we already had this motor probe around and the FDA had already said it was safe to measure human brains with this motor probe. So we had an initial de novo that's a brand new thing, approval for the motor probe.

So we had the option as a field and neurones the option as a study sponsor of having this treatment for depression be regulated as a FDA clearance, not an FDA approval. Those are different words and we can get into it more later or now if you want. Yeah. 

Mark Mullen: Clarify that for me. 

Owen Scott Muir, MD: Sure. So the FDA regulates drugs and devices.

It's actually different sides of the house, as it were. There are, it's different buildings. Literally at FDA for this, there is the Center for Devices and Radiologic Health, CDRH, and there is drugs. Every drug is considered a class three, risk, right? They, so you have to [00:13:00] study those in replicated, randomized controlled trials.

Historically that may be changing, to get an FDA approval and an FDA approval means this is safe and effective with medical devices. They recognized early on that if we've proven something as safe once, making someone prove it all over again doesn't make a ton of sense, and so safe and effective.

Safe may have already been demonstrated by another indication for the same device. And so for TMS, we already knew that this motor probe was safe to use on people. 

Mark Mullen: So you just needed the clearance, you didn't 

Owen Scott Muir, MD: need the full approval. We just need the clearance. 

Got 

Mark Mullen: it. 

Owen Scott Muir, MD: And that's great if you're the, if you're doing that sometimes.

But it also means anybody else can use that clearance to use your data to establish the safety of their thing. And Ted who invented this, did not patent the coil. 

Mark Mullen: Got it. Got it. 

Owen Scott Muir, MD: And so [00:14:00] we had an unpatented coil that anyone could make their own version of. 

Mark Mullen: And use. 

Owen Scott Muir, MD: And use. And that makes it really hard to get a defensible product in the market and protect your intellectual property that's not, and 

Mark Mullen: continue development and research.

Owen Scott Muir, MD: Right. Because it's expensive to do that. And so ironically, we invented this tremendously powerful technology with trillions of different ways to stimulate the brain, the parameter spaces around 7 trillion when you combine the number of targets, the number of, you know, possible patterns for stimulation, the powers at which we could do it, et cetera.

But very little return to any investor for fascinating for putting the money in to do that. And so that's one of the things that helped slow down TMS progress in 2012, the company Brainsway, licensed technology owned by the National Institutes of Health. 'cause that's where it was developed in the US and on what we call h [00:15:00] coils, which are a arrays of magnetic coils that add up.

A magnetic field that can stimulate a brain circuit. In 2020, I believe we had the H seven coil. So the H one for depression is actually bilateral. It's 12 coils on the left and six on the right. Basically no field strength in the middle. That was the first one. The second one was the H seven coil, which is 12 coils on the left and 12 on the right.

You look like Princess Leia when you take off the covering, but it creates a, stimulation right down the middle so we can target the. anti-correlated region with the dorsal anterior cingulate and treat OCD. Subsequent to that, we have anxious depression approval, clearances rather. We have, accelerated TMS with Saint, which is a combination product of FMRI guidance and AI algorithm to target the right spot in the brain to get around that tape measure problem and doing it 10 [00:16:00] times a day with a pattern called intermittent Theta birth stimulation, which Jonathan Downer in at the University of Toronto demonstrated was non-inferior to 10 hertz stimulation in a study.

But it's only three minutes. And, just in the past year, we've had the AMPA device, a company Jonathan Downer created, which has like a camera in the middle of it for ease of targeting, to which I'm also an advisor. That's a disclosure. And I've been a principal investor at Gator with Brainsway. That's another disclosure.

These. Series of technologies and there are a bunch of other manufacturers, but a bunch of people built a bunch of TMS machines, stimulated a bunch of brains that got a bunch of people, well from depression now OCD, smoking cessation. We now have studies in tons. Right. It's hard to keep up at this point in time, but we have approvals down to age 15, up to age 86.

It is a burgeoning field 

Mark Mullen: approvals, not just clearances, but approvals. 

Owen Scott Muir, MD: So these are all clearances because the original thing was the clearance. 

Mark Mullen: Gotcha. [00:17:00] 

Owen Scott Muir, MD: The only thing that is approved that I mentioned is that Prov Rx device, which is, went through a de novo and breakthrough approval process as a first in class therapeutic, similar to the flow device, which also got approved just a couple weeks ago.

Mark Mullen: So, I'm so excited about this episode because I am genuinely confused about TMS, like I and you should be, feel like I learned about it a little bit in residency and I vaguely, you know, I've had patients ask about it and I've seen people get better from it and I've read a lot of your stuff.

You're, you, do a. Enormous amount of writing and especially about TMS and I hated calculus. I hated physics with calculus, so it's not surprising to me that I didn't like, you know, I'm more of a kind of a mushy, hy kind of guy, but I didn't realize that it was not only scientifically complex, but all of this regulatory stuff is super important when thinking about.

What it's approved for, which by the way, is what the A BPN tests us on, our board exam is like, is it FDA approved for this? So I feel like I've [00:18:00] now learned that it's not just that I hate physics, it's also that there's all this regulatory bs, I shouldn't say BS because it's important stuff that physicians don't like to think about and that we don't teach about really in residency when we're practicing clinical medicine.

So I feel a little bit better with how confused I am. I'm really excited about this next question. So when we met for our brief mentorship meeting, you said something very nice to me. Well, first of all, you called me a baller in the article that you wrote about psychiatry bootcamp for starting, the podcast in residency.

And you noted that you started your own project, the Frontier Psychiatrist. Would it be in residency? 

Owen Scott Muir, MD: I mean, the, beginning of that? Yeah. Essentially 

Mark Mullen: it's the precursor to, and I, I. Rarely get called a baller. In fact, I don't know that it's ever happened to me. So that was really nice. But the second nice thing you said to me was, you do a really good job of getting really smart people and asking really stupid questions.

And I was like, that's exactly what I do. That's what psychiatry Bootcamp is all about, and I think [00:19:00] that's what most good interviews are all about. So here's the question. Explain to me like I am five years old how TMS works. 

Owen Scott Muir, MD: So the youngest I've treated is seven. I'll quote a 10-year-old when I say what he told me, which is, thanks for deleting my anxiety, dude.

Mark Mullen: Wow. 

Owen Scott Muir, MD: what does it do? It is a way to learn a lesson, which is how to be less depressed or how to be less anxious, except instead of reading a book or listening to a story or having someone tell you, you can close your eyes. And let it go straight into your brain. Whenever you hear someone tell a story, you're forming a memory what they said, and it might not be perfect, but if they tell you the story once, you'll remember it.

If they tell you the story every night when you go to bed, you'll remember it forever. TMS, depending on where it's pointed in, the brain is telling [00:20:00] your brain the story of how to feel better. And it's doing that with all the same mechanisms we have for learning. So if you can learn a story, you can learn how to feel better.

'cause your brain knows how to learn. I have a better metaphor for this, which requires being slightly older than five. 

Mark Mullen: Okay. Okay. I'll take the bait. how old do I have to be for the second metaphor? 

Owen Scott Muir, MD: I, did you take a music class? 

Mark Mullen: I would, in fact, yes. I'm a musician. Yes, 

Owen Scott Muir, MD: me too. What'd you play?

Mark Mullen: percussion. I'm a drummer. 

Owen Scott Muir, MD: You're a drummer? Okay. So if you have a set of drums, they're at tune. No matter how well you play in time, is it gonna sound good? 

Mark Mullen: Yeah. Drums are probably the worst, the worst thing for this analogy. But, no, it will not sound nearly as good as if they were tuned. 

Owen Scott Muir, MD: And imagine you gotta play drums, but in your ears is a metronome that's at the wrong tempo for the song.

Mark Mullen: That's not gonna work. 

Owen Scott Muir, MD: Not gonna work, right. You're out of time with the rest of the world. and so what is depression? It's being out of sync [00:21:00] with yourself and being out of sync with the rest of the world. And when I say outta sync, I actually mean that literally like your neurons are firing in a pattern that's not mirroring what other people are getting in their brains when you're, could the 

Mark Mullen: same be said for any mental disorder though?

Owen Scott Muir, MD: Yes. 

Mark Mullen: Okay. 

Owen Scott Muir, MD: And we'll get to it. 'cause it's not just mental disorders, it's all the brain circuit disorders, which include movement disorders and other neuropsychiatric illness. So if you imagine that when someone says we're on the same wavelength, they mean it literally, we have, you know, they, the.

Popular version of this is mirror neurons. But look, practice a piano all day long. If it's at tune, it'll sound like crap, but your piano is not gonna sound good. If you're not in time, you're not in tune and you're not playing with the rest of the band. So what is TMS? It's a way to tune the piano so that when you practice, it'll actually give you the feedback that sounds good.

So you can learn how to interact with yourself. You can learn how to interact with other people because you're now [00:22:00] finally in tune. And once you're in tune and able to get in time, you can get in the groove of your life. And so if you imagine there's something fundamentally off about your practice schedule, and it's like they handed you, you know, brushes when it's a rock song, like, and the metronome was, there's some latency there, right?

There are all these things that can go wrong, that can keep you out of sync, and depression is being out of sync. People will tell you, dude, you look off and we don't necessarily have the language to describe what's off, but if you were looking at the. both people are in A-F-M-R-I at the time, maybe fmri, EEG.

And we're looking at how those brain areas sync up or we look at heart brain coupling or whatever it happens to be physiology wise. When we connect with each other, our brains perform processes so that we're creating mental representations that have physical [00:23:00] encoding in neural firing, and our brains will fire in ways that are aligned.

So when you're really getting someone, what that means is your brains are firing in a way that is aligned. And when you're out of sync with yourself or with somebody else, you're not firing in the same circuits in the same way to represent each other accurately. 

Mark Mullen: I feel like a lot of what you're saying is what we describe as a field of interventional psychiatry, or maybe you could call it neuromodulation.

Owen Scott Muir, MD: Yeah. But it's actually all of psychiatry, like with therapy is neuromodulation. 

Mark Mullen: Yeah. 

Owen Scott Muir, MD: A walk. 

Mark Mullen: Yeah. it just feels more direct and immediate. Right. You're doing it right now as opposed to a top down approach where you're learning this. Yeah. I mean, I think it's more direct. Can we agree on that? 

Owen Scott Muir, MD: I mean, it's more directly targeted to the brain.

Mark Mullen: Yeah. 

Owen Scott Muir, MD: But it does help me understand why those other things might have been so potent. 

Mark Mullen: Yeah, for sure. So can you tease apart for me, at a high school reading level, the [00:24:00] differences between TMS and other neuromodulation therapies or therapies in interventional psychiatry, like electrical convulsive, the ECT or deep brain stimulation?

DBS, 

Owen Scott Muir, MD: so transcranial magnetic stimulation, TMS doesn't cut your head open and you don't go under anesthesia. It's non-invasive. It might sting a little at first, but most people don't actually consider it painful. 

Mark Mullen: I mean, typically a CT doesn't cut your head open, right? 

Owen Scott Muir, MD: Not yet. But you do go under anesthesia 

Mark Mullen: for sure.

Owen Scott Muir, MD: And you do have a seizure 

Mark Mullen: for sure. 

Owen Scott Muir, MD: The risk profile is different. 

Mark Mullen: Very, 

Owen Scott Muir, MD: I mean, it's also an awesome treatment for severe depression and all psychiatrists everywhere should rah, but it's hard to access just practically 'cause people don't want it. It takes two people to deliver ECT. You need anesthesiology, probably phlebotomist as well, unless the anesthesiologist is really good at it or has the time.

And you need a psychiatrist for transcranial magnetic stimulation. You just need one other human to [00:25:00] deliver it to you 

Mark Mullen: and you're awake. And it's a much more, you would say, targeted and well tolerated intervention with, significantly fewer side effects. Is that kind of fair to say? 

Owen Scott Muir, MD: That's fair. TMS sucks the least.

Mark Mullen: Although in, in terms of tolerability, in terms of efficacy, we are in agreement that ECT is highly effective pretty much across the spectrum. 

Owen Scott Muir, MD: No, ECT is effective in major depressive disorder. 

Mark Mullen: Mania. 

Owen Scott Muir, MD: Psychosis, mania, psychosis, epilepsy. Another non-psychiatric indication. 

Mark Mullen: I see. But maybe, no, not OCD. And we're not getting into the neuromuscular disorders, et cetera.

Correct. Or I should say movement disorders, et cetera. 

Owen Scott Muir, MD: And so we also have data on Saint treatment and FMRI guided treatment that in ECT failures, we can get patients to remission. With FMRI guided, accelerated transcranial magnetic stimulation. So there's a dose and targeting question. ECT is definitionally broad.

We put you under anesthesia so you don't shake, but we induce a [00:26:00] seizure with electrical stimulation. Historically we did that with insulin shock. In Europe we use magnetic seizure therapy, which is TMS turned up too high. 

Mark Mullen: Really? 

Owen Scott Muir, MD: Yeah. So inducing a seizure reliably resets the brain in some way, but it's not focal and we can't choose meaningfully.

Mark Mullen: Right. You place the electrode somewhere, but you are by definition inducing a generalized seizure. 

Owen Scott Muir, MD: Correct. 

Mark Mullen: Okay. 

Owen Scott Muir, MD: If you could only turn up or turn down the firing of a brain circuit, well that would be starting with transcranial magnetic stimulation. And if you have a functional neurosurgeon handy, you can implant an electrode deep into the brain, which is FDA, approved in Parkinson's disease and has yet more regulatory status.

FDA humanitarian device exemption, which means you can do it not in a study, but still not approved in dystonia and [00:27:00] essential tremor. Same lead we're using in Parkinson's disease or OCD with the same humanitarian device exemption. But if you wanna do it for depression, it's either off label or it's in a study and overwhelmingly it's in a clinical trial.

Mark Mullen: Fascinating. 

Owen Scott Muir, MD: And so what you're doing with deep brain stimulation is generally you're disrupting a circuit in a reversible way. So we've historically had, radio frequency ablation, AKA gamma knife. Where you can go in and lesion a tiny part of the brain such that a circuit is disrupted. Or you can use DBS to use an electrical field to disrupt the circuit, but you can turn it off.

Mark Mullen: I'm so excited about this episode. I feel like you, I feel like you're really distilling down these high level topics at a level that are gonna be understandable, even for patients, but certainly for, medical professionals. Let's, you've gone through a lot of this. I just wanna see if I can get a, maybe a more clear, list in state of [00:28:00] evidence.

Can you walk us through what TMS is currently being used for? So let's talk about, I think you mentioned there's maybe one FDA quote unquote approval. Well, there's one FDA approval and then there's additional FDA clearances. What, is the approval for? What are the clearances for? 

Owen Scott Muir, MD: So the, anytime you have a brand new device, and this is so long ago, I haven't even looked at this regulatory filing recently, so I don't wanna overspeak, but there are three different classes of device approval.

So there's only FDA approved for drugs, right? Or not. There's, an FDA clearance hierarchy for drugs. So, or devices rather. So a Class one device has very low risk band-aids, tongue depressors, stethoscopes medical use, but they're not gonna hurt you. Class two devices are colloquially slightly more dangerous, but not that much, right?

These are not things that are gonna impair your life or limb, especially if they go wrong. And Class three devices are either dangerous in and of [00:29:00] themselves, like extra corporeal membrane oxygenation, or if they are used in a life-threatening condition and go wrong, they could be risky. Like depression can cause suicide in and of itself.

And so you can regulate class three devices that have some risk, in the disorder in which they're treating them. When you go through the, good clinical practice training. For running a clinical trial or participating in clinical research, they hammer this into your brain if you're doing drug and device training.

So the regulatory status, how dangerous is the device, and if it's really dangerous, it's class three and that needs an approval. If it's not so dangerous, it's class two, and that can either be an FDA clearance using the five 10 K pathway where you're using a prior predicate devices approval as part of your submission.

I'll give you an example. If I'm looking at EEG and [00:30:00] using EEG to build a neuromodulation device, I can look at the risk profile of EEG. An EEG is a class two medical device. It's not particularly dangerous. Even below all of that, there's NSR non-significant risk. It's just not gonna hurt you. It's not more dangerous than walking down the street.

And the FDA is not looking to spend a ton of time on regulating the risk profile of walking down the street. Which it turns out like has non-trivial risk. Like you could drip, you could fall. Like if you're talking on the phone, it increases that risk. Like it's not nothing, but it's just not what they spend their time on.

But at the end of the day, the FDA is there to protect us from charlatan's, hucksters, and overenthusiastic healers because before the FDA drug companies would make a drug, send it to a doctor and say, Hey, tell me what this does. That's how Adderall came out, right? When Adderall first came out, there was no FDA.

So they'd send stimulants to doctors and tell us what this does for your patients. And they did [00:31:00] that. Was it 

Mark Mullen: pretty clear effects on that one? 

Owen Scott Muir, MD: Well, at the time they thought it was an antidepressant. At least initially it's not. But they didn't know. So TMS is a class two medical device. It has a well established risk profile, which is not high.

Can there be bad things? Yes, but not usually. ECT Serious Risks Drugs, serious risks. E CT could, does 

Mark Mullen: class three? 

Owen Scott Muir, MD: Yeah. 

Mark Mullen: So what does it, so what does it have clearance for? What does it have the class two approval for? 

Owen Scott Muir, MD: So the first clearance is, for major depressive disorder. You can have monotherapy trials where people want nothing else.

Or you can have adjunctive therapy trials where people are on something else at a time. So, great example. This is epilepsy, right? In epilepsy. It is no longer ethical to leave people with epilepsy untreated. So every new epilepsy drug [00:32:00] is studied as an adjunctive treatment to only partially effective epilepsy care, which means zero.

New epilepsy medications have a monotherapy indication. So they'll all say. Keppra is approved as an adjunctive treatment to standard of care treatment in the management of epilepsy. 

Mark Mullen: And when TMS was going for clearance, we already had SSRIs and so Correct. All of our patients were already on some treatment for depression, 

Owen Scott Muir, MD: but no.

Mark Mullen: Okay. 

Owen Scott Muir, MD: So you would think, right. So they did something with, when they, did that study, which is they took people who hadn't responded to their initial antidepressants and they took them off of them. So the initial pivotal trial where Mark George was the PI, was a monotherapy trial. And so they did that and got an FDA clearance for transcranial magnetic stimulation as a monotherapy for patients who are res resistant or have not responded to.

That's the language to prior [00:33:00] antidepressant treatment, 

Mark Mullen: meaning the FDA considers this effective, 

Owen Scott Muir, MD: the FDA considers it safe and effective for whom? With what problem, with what limitations. And this drug labeling or device labeling process is a whole to do because to say this is safe for the treatment of major depressive disorder and effective is different from saying this is safe as an adjunctive treatment to standard of care Treatment in major depressive disorder is different from this is safe for major depressive disorder and effective only in those who are not considered refractory to traditional treatment, which is, what, a version of what the flow label says.

So that's a whole negotiation, which is what happens before it's ever gotten to the market for most of these things. Large scale groups of people have not taken these drugs by the time these labels are in place. And so they're crucial for marketing because the FDA [00:34:00] is fundamentally with that label regulating what you can market your device for.

But then we go use our medical licenses for whatever the heck we want, and it's between us. Our patients, our God and our medical malpractice policies and subsequent lawsuits to determine what could or should have been done. But that FDA label prevents us from getting sued in some awful way if we do something truly off the rails.

Mark Mullen: So write it down for me in one sentence. TMS was FDA cleared for 

Owen Scott Muir, MD: FDA was cleared for major depressive disorder in patients who had not responded to standard of care treatment. 

Mark Mullen: Copy 

Owen Scott Muir, MD: that's, I'm not like reading that off the FDA website. I'm doing it outta my brain. It could be off a little bit.

Mark Mullen: Yeah. 

Owen Scott Muir, MD: Being this is why you have an intro 

Mark Mullen: and that's right. And okay. So that was the first, that was the first one. That was the first time yesterday said this is effective for X group. 

Owen Scott Muir, MD: Correct. And then Brainsway using the technology from NIH, got [00:35:00] another label on their H coil, which said the same thing basically.

So it said, we can treat major depressive disorder with our H coil, not just the figure of eight coil. And then the Cambrian explosion happened, and then we had four treatment resistant OCD, and then we had four smoking cessation that hasn't responded to traditional standard of care treatments. And then we had.

Anxious depression. And then we had depression in older adults and then we had depression in adolescence. And then we had this fancy accelerated version, which is a combination of an AI algorithm and doing it 10 times a day and doing it five days in a row and doing it a different pattern, which is Saint.

And then we had Swift, which is doing that same H one treatment in a different pattern five times a day, over six days with subsequent once a week getting two treatments over the next four weeks in, in that study. 

Mark Mullen: And is that they doing a specific device and protocol for each of these indications? It's not saying just TMS, right?

Owen Scott Muir, MD: No. So every [00:36:00] new device, the manufacturer has to go to FDA, but they don't have to do a new study anymore. So this is some of the horse trading. Brainsway the company as the study sponsor gets an FDA label on its TMS coil for OCD. And then Neurones turns around and says the initial brainsway approval.

They got their clearance rather they got their device cleared on was based on our data. Neurones did a trial. Brainsway said the H coil is substantially equivalent to our coil. And then they did a study that said that their coil did OCD. And since their coil was the same as our coil is the same as their coil.

And so our coil treats OCD. And then, you know, mag Venture makes them, mag Stim makes them cloud TMS makes them Ampa make all these companies make TMS coils and they say, Hey look, since thing, our thing is substantially equivalent to their thing and their thing has to label on this. And we do the thing.[00:37:00] 

They all have to go through this process of going to the FDA and getting an FDA clearance on their substantially equivalent device because there's not meaningful protection on the intellectual property when it comes to TMS, which is why this is such a terrible business for TMS device manufacturers compared to drugs.

A drug can make a bazillion dollars because it has very strong patent protection and nobody else can sell your drug for many years. When anyone can sell the thing. 

Mark Mullen: We have to go to break, but I need to make sure I'm understanding your answer to this first. So when these companies with their devices go to the FDA and say, we're substantially equivalent, and we have data that shows our, is it our device or our protocol?

Owen Scott Muir, MD: Our 

Mark Mullen: device 

Owen Scott Muir, MD: and our protocol, it's both 

Mark Mullen: and works in these particular indications for these 

Owen Scott Muir, MD: and, so I'll, summarize it. 

Mark Mullen: Yeah. 

Owen Scott Muir, MD: We have transcranial magnetic stimulation done with high frequency stimulation [00:38:00] and with intermittent theta birth stimulation. Both of those patterns have FDA labels from various manufacturers for the treatment of major depressive disorder that's resistant to current standard of care treatment.

We also have treatment refractory OCD number of manufacturers have. We also have smoking cessationist label. Anxious depression, and then up to 86, down, age 15 and more is coming, but we're not there yet. There's also the tweak that accelerated protocols are approved with two different devices. One of them is the Saint System by Magnus Medical, and the other is the, Brainsway Swift Protocol, which I an investigator on.

Mark Mullen: More is coming indeed. We're gonna take a quick break, and when we come back, we're gonna talk about the common side effects of TMS, how to talk about TMS with patients, as well as what we are thinking about for the future of TMS. 

Owen Scott Muir, MD: And we hope to understand why it made sense for anybody to go through that regulatory process.

So many times,[00:39:00] 

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Welcome back to Psychiatry Bootcamp. So you were saying before the break that these companies, basically the whole way that this system works in terms of the incentives for companies that make these devices, market these devices and are having to fund these studies, the whole incentive structure is different with regards to FDA approval because they don't have these ongoing intellectual property protections from the FDA like drug companies do.

So why are these companies in this space if they stand to make so much less money than if they had taken a different approach like drug companies? And maybe a more direct way to ask this is, you seem to have dedicated a major part of your life to this why. 

Owen Scott Muir, MD: I'm lucky to have been trained in mentalization based treatment by Peter Gie, Anthony Bateman and others.

[00:43:00] Mentalization based treatment teaches you to see the world not only as you see it, but to imagine what it might be like for somebody else. And so I think a lot about what's in people's minds and their incentives. It's the only psychotherapy modality that helps me think about my colleagues at a payer and why they might do what they do and why they might be more or less interested in what I'm up to.

One of the problems with psychiatry is we don't have a lot of procedural stuff, and some of us are, working industry, but most of us don't. When you're a surgeon and you're in the, or, there's a device rep in there like a lot of the time, like they know the screws better than the surgeon does, and so other medical specialties just have much closer relationships with industry in ways that are both, you know, plausibly pernicious, but can be helpful and collaborative.

Like device companies are making devices for surgeons. 'cause if they don't, no customer, right? It's gotta work for the surgeon. We [00:44:00] don't spend as much time with our pharma colleagues and when we do, they're selling us something. So here we have this range of medical devices that, for a quirk of history and a decision of basically one guy to not patent his initial thing meant that it was really hard to make traditional medical device money.

We also have a bunch of other stuff about psychiatry that makes it hard to make any money here. You know, any money, I mean like investors would consider that a real return if they could also choose Google or Apple or whatever. That's our competition for money is those companies. Money doesn't care, it wants more.

Our patients need treatments. What do we do? And so I decided to try to understand the incentives behind these things. And so I looked at TMS devices, which seemed like basically generic drugs. We have a real problem with supply chain and generic drugs because it's really hard to make any money there.

There are some fixes for [00:45:00] that. The Hatch Waxman Act, which created the generic drug industry as we have it 'cause we actually pay less for generic drugs in the US than the rest of the world, and vastly more. And on label drugs. That's a trade off we made in a legislative process, and we can feel the way we wanna feel about it.

We have generic TMS. That's a good way to think about it. TMS is a generic intervention, so all the money in TMS is in the delivery of the pro TMS itself, which is individual health providers and like you and I, physicians, nurse practitioners, et cetera. We get paid to deliver this treatment at some amount of money, decided by the A MA or at least some amount of money, decided by a calculation made by the A MA.

To split the baby around the fact that psychiatry has a really low rate card compared to other medical specialties, and yet this is a procedural treatment that requires a bunch of kit, and then insurance payers put a multiplier on that relative value unit calculation, which should be there. But is it [00:46:00] because TMS is carrier priced at the A MA?

Again, it's a whole thing, right? But at the end of the day, all medical procedures have math behind them. It's physician time multiplied by how expensive it is to be that kind of doctor. It's more expensive to be a surgeon than a psychiatrist, multiplied by the medical malpractice cost. How likely are you to be sued?

The psychiatrists don't get sued that much and multiplied by where you're in the country a little bit, and that's the math behind turning a amount of time you spend into a dollar amount calculation, a relative value unit. And I apologize for my. Slipping over my words sometimes, but that's gonna lead into explaining why I care about this so much.

I have tardive dyskinesia, and that's a movement disorder caused by long-term exposure to antipsychotic medicines, which I had to take for many years. And it's caused not only a problem with movements of my mouth, [00:47:00] sometimes dystonia in my foot, but I trip over my words now when I didn't used to. And so why do I care so much?

Because TMS doesn't hurt people in the same way. I mean, there are risks, and we'll get into it, but oral medications for depression, bipolar disorder, specifically psychotic disorders come with tremendous risks. Obesity, metabolic syndrome, permanent and disabling movement disorders, which I as the psychiatrist have.

Our patients die 20 years earlier with severe and persistent mental illness. And from an ethical stand. Our job is to make the money line up with the outcome we wanna see in the world. So if no one's making enough money on healing those patients, why not? And how do we fix it? 'cause until it's good for money, it's not good for our patients and it's not good for them if it comes outta their pocket.

These are vulnerable individuals and I am among [00:48:00] them, and that's why I care. It's an ethical stance. I wanna protect the health and safety of our patients by providing the most effective and safest treatment. At the same time that ratios gotta be right and I wanna feel good about what I'm getting informed consent four.

And that means building systems that align incentives. And so I had to look around in the world and find where was that possible. And TMS was a place where that could be possible. 'cause it's possible to drive down the cost of TMS if we want to, and it's necessary to capture the value if we're especially clever.

And it's certainly possible to make that argument to people who care about money, which I unfortunately don't. 

Mark Mullen: Right. And that's, and I think that's where it all comes back to us, is it's ethical, but it's also pragmatic. Right. You're taking this approach based on how the world actually works, not how.

Owen Scott Muir, MD: Yes. 

Mark Mullen: You know, and that's something that doctors are so bad at, right? We're terrible at, 

Owen Scott Muir, MD: yeah. 

Mark Mullen: Is thinking about how the world actually works because we prefer to kind of read a textbook and, you know, think about mechanisms. 

Owen Scott Muir, MD: But [00:49:00] it's not just how the world actually works, it's how the people moving through the world think about themselves.

Because there are people who do terrible things with their time. It turns out who don't think of themselves that way in the moment. Right. You could be working at a health insurance company and denying every single claim and tell yourself you're doing a wonderful thing for the world. You may be for justice, maybe less so for non maleficence, possibly for autonomy.

Definitely not, right? These ethical principles are in balance. We can't give everything to everybody. We can't give unlimited pizza and unicorns and rainbows to the whole world. That's not real. But if what we want is the best outcomes for the most people that are the safest and most effective, we have to make those arguments effectively.

And if we don't, we're abdicating our responsibility to our patients, and I'm not okay with that. 

Mark Mullen: I think the primary. Point that you drove. There was the [00:50:00] safety and tolerability of TMS relative to our other interventions for these for severe and persistent mental illness. So let's get granular again. Can you walk us through the most common side effect of TMS?

What are some contraindications to starting TMS treatment? 

Owen Scott Muir, MD: Contraindications are easy 'cause they're limited. Absolute contraindication. Iron containing metal in the head, like top of your head, not the bottom, like it's a magnetic field. The field strength falls off rather quickly. So if you have a cochlear implant, you're not getting TMS.

If you have iron containing bullet lodged in your forehead, you're not getting TMS. So have a titanium plate in the back of your head, that's probably fine. I've done that before, et cetera. Facilitatory treatment that increases the rate of firing with epilepsy. Absolute contraindication. It give some a seizure relative contraindication.

Well, we could do inhibitory treatment, which would reduce your risk of seizure. Plausibly be a treatment for your epilepsy, maybe. That'd work. Right. So there are a lot of relative contraindications, [00:51:00] risks. The only permanent risk that I worry about quite a bit is tinnitus or ringing in the ears, because that is also a brain circuit disorder.

Acoustic injury is part of the plausible mechanism here. I personally suspect there's a brain circuit component to it, but tinnitus is a risk in about one outta a thousand treatments. Seizure is a risk of TMS treatment, but it's actually less likely than oral medications are to cause a seizure. And if that seizure happens, it happens right in front of your face, in your office.

The order, the scale of this is at worst, one in a thousand, probably more on the order of one in 30,000, and it's about a hundred times the rate. Of that risk with Wellbutrin and maybe 10 times the rate, depending on the sample you're looking at for Prozac. But that happens on the street, not in your office.

Those numbers are constantly being updated, but it's at worst, just as [00:52:00] likely to cause a seizure as any of the other medicines we're administering for depression. There's a few more commonly headache, fatigue, scalp pain or tenderness, and that's about it. 

Mark Mullen: One of the things that I'm hoping is that people who listen to this podcast who are not going to be doing the TMS themselves, but who do see patients, will be able to explain this to their patients and understand what their patients are going through when they send them, maybe to someone like you for TMS treatment.

Can you tell me about what this actually looks like logistically speaking, how a typical treatment course progresses? What, I guess, what happens to the patient, right? They go to the first appointment and what happens there, and then what does it look like in the room? What does it feel like when this is being administered?

Owen Scott Muir, MD: So every psychiatrist should use TMS as one of the treatments they offer if they're treating patients with depression pretty soon that's gonna include psychosis [00:53:00] and other conditions of actually just about to submit a publication on auditory hallucinations, large fail phase three data. But I think there's a core tool of psychiatry.

So it's not if it's when get on board. Now, what do you need to notice to either refer to TMS or to do it yourself, but I would encourage learning how to do it yourself historically. Again, I, we talked about the development of TMS. Mark George's lab at MUSC was open five days a week, so how often was TMS done?

Mark Mullen: Makes sense. 

Owen Scott Muir, MD: Five days a week. And how many treatments did they need to do? Well, they had to pick and they did, they picked a number and the answer was 36 total treatments. Is that the right number? For some people it's great. For others, it could be 20. For others, it's 50. For others, it's more, I don't get to know.

I know what they did in that first study was 36, and then we did a bunch of that. [00:54:00] Subsequently, we have data that 44 is great in some people at blah, blah, blah, blah, blah. Brainsway showed efficacy at 20 stimulations. What's gonna happen is they're gonna come into the office and you're going to put that magnetic coil on their head, but you're not gonna put it where you're treating them first.

You're gonna put it over the motor cortex. 

Mark Mullen: When you say put it on their head, are you setting a metal object on their head? Are you holding it over their head? 

Owen Scott Muir, MD: Just like these, headphones around my hand. You have a band setting it on their head. You're 

Mark Mullen: setting it on their head uhhuh, 

Owen Scott Muir, MD: and you're moving it around and you're either eliciting a movement from the thumb or the foot if you're using the OCD coil, but you're, it's like a reflux hammer.

Tap it, fire, did the thumb move, yes or no? And then you get the thumb to move and you're moving it around and you wanna find the peak area where make thumb move the most with the same amount of energy. 

Mark Mullen: You generally know where that's gonna be, but for each person it's a little different. No, I mean, well, it's not gonna be in the back of your head for someone, the forehead, for others, 

Owen Scott Muir, MD: no, it's in the motor cortex.

Mark Mullen: Right. You know, [00:55:00] generally you have to feel that out. 

Owen Scott Muir, MD: Yeah, so you're finding where the hotspot is in the motor cortex, where you get the most movement for the same amount of energy, and then you find the motor threshold, which is defined as moving half the time. What's the energy at which you move half the time?

There's actually some complicated math you can do around, like you go up to 37, you go down to 33, it moved or it didn't, and you're doing this yes, no, yes, no algorithm. Or you can just do 1, 2, 3, 4, 5, 6 pulses and did it move half the time? And then you go down, and then you go down, and then you go down. And then when it stops moving, half the time it moves once.

Now you're below the motor threshold. It was one up, right? So you're moving a thing around to find the spot, doing a bunch of pulses in that spot, and now you know the energy to deliver. That's called brain mapping and motor threshold determination. The brain mapping spot does not change. So if you mark it down in [00:56:00] your electronic health record or in your machine, you can always go back to that same spot and elicit the motor threshold again.

However, the motor threshold does change, and I'm here to tell you it actually changes daily for some people. So when we developed this treatment, we measured once at the beginning and once a week thereafter. In my entire career of clinical practice, I've measured every single day. Sometimes multiple times a day and it changes.

Mark Mullen: That's fascinating. 

Owen Scott Muir, MD: And so it turns out like the, your, the dosage. Originally when Dr. George was treating individuals, with this, he started at a hundred percent of motor threshold. And that worked a lot, but not all the time. So he turned that number up to 120%. And lo and behold, it worked more often.

Usually in older individuals. Now we know their brains are somewhat further away. So we need more energy to get to the surface of the cortex. 'cause this is magnetism that falls in our squared law. I know you hated physics, but we're still algebra, we're not calculus. [00:57:00] 

Mark Mullen: No comment. 

Owen Scott Muir, MD: It's further away, it gets weak.

So there's again, some math around what the percentage is of the power that you do, but your doctor is gonna make the decision. Theta burst is more potent than high frequency stimulation. So we can use a lower percentage of motor threshold, but it might be more uncomfortable at first. So generally what happens is we find the spot and then we're finding the energy, and then we're using a percentage of that energy.

But in the beginning, it's less tolerable than it becomes because the brain is actually gradually editing out how nociceptive, how painful it's, and so we started a low power and we go up slowly, and that's within a train for some individuals or between them, depending on the device, but stimulate the brain with a pattern of stimulation.

Pause. There's an intercession interval that's either 24 hours. If you're doing it once a day, which by the way is kind of a waste of your time. Don't bother. I'm an acceleration [00:58:00] maxi. Or you're doing it multiple times in a day at an intercession interval, 

Mark Mullen: which is less frequently done in clinical practice at this particular juncture though.

Is that right? 

Owen Scott Muir, MD: yes. Less frequently done, but it's not uncommon. And we now have two FDA labeled versions of the treatment with 78 and 79% remission rates. So get on board people. 

Mark Mullen: Yeah. You're excited about this because it's coming, but your 

average 

Mark Mullen: person's, 

it's, 

here, but your average person going to get TMS might wind up with someone not getting that.

Okay. Just to 

Owen Scott Muir, MD: be 

Mark Mullen: clear. 

Owen Scott Muir, MD: Yeah. 

Mark Mullen: Yeah. Okay. Okay. '

Owen Scott Muir, MD: cause there's a medically unlikely edit on the code set because back in 2008, it was assumed it would only ever be done once in a day, and it was as unlikely as surgery on your right knee twice in the same day. That it would happen twice in the same day. And that is only recently changing, but that's what's in the way.

Mark Mullen: Okay, so then the, so a patient will come in, this is an outpatient procedure. Typically it's every day. Lately it's more than once a 

Owen Scott Muir, MD: day. So historically it's been an outpatient procedure. But why, [00:59:00] 

Mark Mullen: I guess people like to sleep in their own bed. I mean, 

Owen Scott Muir, MD: no. It's about money. 

Mark Mullen: Well, of course it's 

Owen Scott Muir, MD: about money Mark.

Mark Mullen: yeah, 

Owen Scott Muir, MD: Dr. Mullen, how is psychiatry inpatient paid for? 

Mark Mullen: Insurance reimbursement, generally? 

Owen Scott Muir, MD: Yeah. Two different ways though. How is regular medical care you're admitted to the hospital for something that's not psych. How do they get paid 

Mark Mullen: in a bundle, typically? 

Owen Scott Muir, MD: Correct. Right. It's called a diagnostic reference group.

And you're paid a multiplier based on the DRG. So if you get admitted for pneumonia, you get a chunk of money, you get admitted for heart failure, you get more. Why are you paid more for heart failure? 'cause we know we might have to implant a device. That's baked into the cost. Psychiatry historically has been paid on a completely different fee schedule, which is per diem or per day.

And there's no more money for you if you have depression or psychosis or anything 'cause we're not gonna do anything different. We're gonna have some nurses watch you. A Dr. May chats with you, we give you a pill and maybe we change the dose [01:00:00] of the pill. No technology there. There's nothing special.

Nothing costs more. It's all the same. So we pay the same. Do you ever wonder why we don't start LAIs in the hospital? 

Mark Mullen: Tell me 

Owen Scott Muir, MD: you don't get paid more. So we wait till you're an outpatient, then it's under the pharmacy benefit, not the inpatient behavioral health benefit, but do it with God. 

Mark Mullen: That's fascinating.

Owen Scott Muir, MD: We can do it with Haldol 'cause Haldol's generic and we can't do it with Concerta 'cause it's not blah, blah, blah. 

Mark Mullen: For the record, we do that where I work all the time. 

Owen Scott Muir, MD: Yeah. I, and well, you should, right? But I bet you do it with FL Drugs. I bet you don't do it with, 

Mark Mullen: no. Well, it's pr I don't know, I don't know how all it works, but we have some pretty good drugs that we give, 

Owen Scott Muir, MD: got a rebate.

Mark Mullen: I think our readmission risk is just so high that we have to do it inpatient, because it will never happen 

Owen Scott Muir, MD: outpatient. But then you're, there's all the reasons that might be the case. So in general medicine, we have what's called the new technology add-on Payment program. So in the ICU, you get admitted for a bundle, right?

But sometimes you can make more money on that bundle 'cause you use something new and better. And so when a new and better thing comes to market, you can apply to be part of this new technology add-on payment program, [01:01:00] which means there's some negotiated discount and instead of it costing a hundred percent of the price, it costs 60% of the price.

And Medicare covers it for the first three years, and then it just gets baked into the bundle. But biventricular, pacemakers, ecmo, every cool thing in medicine came through that pathway since 2000. 

Mark Mullen: Let's talk about T because I'm 

Owen Scott Muir, MD: afraid that, but that's why it's not inpatient. 

Mark Mullen: Right. Okay, sure. 

Owen Scott Muir, MD: Because you can't get it paid for.

There's a way to get paid for ECT and there's not for TMS until recently, and that's why nobody has it. So it is an outpatient procedure. We do map the brain, we do measure the motor threshold, and then we administer a train of treatments, stimulations, and that's it. Pattern stimulation of the brain, and then you wait either an hour or a day, 

Mark Mullen: depending on the protocol.

Owen Scott Muir, MD: Depending on the protocol. And maybe you get 10 in one day or you get one a day, but you get enough stimulation over time and your depression's over. More often than not. When I say more often than not, randomized control trial, [01:02:00] 79%. Remission with accelerated protocols, it's about 30% in traditional figure eight coil, TMS in populations who have a remission rate of around 5% with oral medications.

Mark Mullen: That's pretty impressive, especially for a, therapy that is, so well tolerated. Although I, will maintain, and obviously this is not a problem that you are liking to talk about, but it's not very accessible for people right now. Love, which is why you're doing what you're doing. Right. Love about, that's, your whole point.

That's why you're like, we need to spend time talking about incentives because, but, for our people who are just clinicians who are not, they may not be able to access these accelerated protocols right now. 

Owen Scott Muir, MD: Do you have any idea how cheap it is to go get a TMS machine? 

Mark Mullen: No. 

Owen Scott Muir, MD: The cheapest one that I know of is like 3000 bucks a month lease.

Not even lease a month to month contract. So can you find a way to break even when the whole thing costs you 3000 ish bucks in a month? 

Mark Mullen: I guess. I don't know. The reimbursement rate. 

Owen Scott Muir, MD: Do you even [01:03:00] care? 

Mark Mullen: Not really. 

Owen Scott Muir, MD: Yeah, at that price. 'cause you can treat everyone you want as much as you want in a month for 3000 bucks, let's say you treat a hundred people, boy that's 30 bucks a person like you can find a way to make that work.

That's probably less than their copay. 

Yeah, 

What do you get paid for a 9, 9 2, 1 5 visit? Right. It's more than that. They can just come in. I'm not saying, but that's what I'm saying is it's so cheap that the marginal cost of administering TMS is so low that we really should be doing it more broadly.

And if we are anchored to the existing reimbursement models, we accept the reality of we can only get paid the way we imagine, and not that we can go change it. Then we're stuck. 

Mark Mullen: Let's leave our systems level thinking for now. Let's go back 

Owen Scott Muir, MD: TM to TM forces you to think about the reality fair. The reality is TMS works.

You should do it. And if you don't do it yet, go with your patient, have the TMS doctor show you how they do it so you can learn. 

Mark Mullen: This is why I [01:04:00] invited you on the podcast 

Owen Scott Muir, MD: and I've done that by the way. I had my dear friend David Hirsh come down from, he sent me a patient to New York. I treated the kid, but he lives in Chicago.

He's not gonna keep coming to New York if he needs it again. The dad bought a device for his son to sit in the doctor's office. The son gets getting the treatment. He is doing great. David comes to New York for his next patient. I show him how to do it. He's treating tons of people in Chicago. Now, 

Mark Mullen: I think you're gonna get a lot of phone calls after this episode releases.

Owen Scott Muir, MD: I, this is what I'm here for. 

Mark Mullen: Back to clinical in indication. So in the, let's, think about, I want you to think about what you owe and me would consider to be the current standard of care. where are you thinking about TMS in your treatment algorithm? Are you thinking about it as an adjunctive treatment?

As a treatment alone? Are you thinking about it in strictly treatment resistant patients? Where does it fit into your algorithm? How are you thinking about that? 

Owen Scott Muir, MD: So I also live in the real [01:05:00] world, right? Happy to hear that. And so, part of what I've done is, at radial we have shaped our practice around what is reimbursed now, not just what we hope to be reimbursed in the future.

And so we focus on patients who are treatment refractory and sick. Now that having been said, I don't actually believe that oral medications, SSRIs should be used at all. They should not be first line treatments. We don't have the data to support TMS as first line treatments. So I can't say I believe in that.

I can't say psychotherapy exists. And that's a great first line treatment. We should probably use that as the FirstLine treatment and TMS should be adjunctive to that. Now, an adolescent, that's not true. An adolescent TMS is approved as a FirstLine adjunctive treatment, but adjunctive to standard of care, which might be just a nice visit with a psychiatrist who cares about you.

'cause don't underscore [01:06:00] or underrate the therapeutic nature of caring about somebody that having been said someone comes to you and they haven't responded to the prior thing. And in our practice. We just say we don't do drugs. It's not our thing. We'll manage your medications if you're getting neuromodulation with us, but not if you're just here for meds.

We're not interested in just meds. 

Mark Mullen: This is why this is kind of an interesting question, is that this is what you do, right? So when a patient comes to you, they, want this and you think they're right for it. Likely it's a self-selecting population that way. 

Owen Scott Muir, MD: so yes and no. I've also done a lot to change what exists in the world.

Like people aren't jumping up and down to get drugs. 

Mark Mullen: Right. Facts. 

Owen Scott Muir, MD: Right. They're, you know, we're, I've prescribed a lot of drugs in my life. I've taken a lot of drugs in my life. I'd rather not, and so would patients. 

Mark Mullen: Sure. 

Owen Scott Muir, MD: So we do have to decide to collect the evidence to support what we think is true.

But in good faith, can I either get paid or, represent this as an [01:07:00] appropriate first line treatment? I cannot, we have not studied it. 

Mark Mullen: Just 'cause the data's not there yet for the reasons that we've been talking about the sour. 

Owen Scott Muir, MD: When somebody asks me what's true, I can't tell them things that I wish were true.

Mark Mullen: Fair. 

Owen Scott Muir, MD: But to be really clear, you're a general practitioner. Someone comes to you with a problem you want and they're, let's just assume they're an adult. What's the first thing you're gonna do for depression therapy, let's say that doesn't work. How long of a drug trial are you gonna give it? And my answer would be until it's demonstrably effective and they're in remission.

And at that point, what do you do next? And here's where we have great data. Ascertained, TRD was completed last year. It's a really nice study. And they compared switch of oral antidepressants to augmentation with aripiprazole to adjunctive. TMS. 

Mark Mullen: Are you saying for patients who are partial responders. [01:08:00] 

Owen Scott Muir, MD: You were.

They are. They did not respond meaningfully. They're still depressed. 

Mark Mullen: They did not get into remission. 

Owen Scott Muir, MD: Correct. Not remission. 

Mark Mullen: Okay. 

Owen Scott Muir, MD: These are people with depression that's bad enough to get in a clinical trial. Maybe they got some benefit. I don't know. 

Mark Mullen: Okay. But whatever it was that wasn't remission. So they move 

Owen Scott Muir, MD: on.

That not good 

Mark Mullen: enough, right? Yep. Yep. 

Owen Scott Muir, MD: Right. And so part of this is we've satisfied ourselves in psychiatry with response as good enough. And that can also go choke on it. It's not good enough if your depression isn't over. We're not done. 

Mark Mullen: Yeah. 

Owen Scott Muir, MD: There's no amount of like cancer doctors like, well, great news.

You have half as much cancer. 

Mark Mullen: Yeah, we're 

Owen Scott Muir, MD: done here. 

Mark Mullen: And in this trial. 

Owen Scott Muir, MD: And in this trial, what they found was TMS blew everything else outta the water. Best treatment we had compared to switch and compared to augmentation. Augmentation was better than switch alone. But TMS was better than the other two.

Mark Mullen: And what protocol was that? 

Owen Scott Muir, MD: That was just standard once day treatment, 20 stimulations rather low dose TMS. 'cause again, we [01:09:00] designed studies year before, years and years before they're concluded. And so at the time they're like, oh, let's just do 20 treatments. And it was five or six or whatever years ago.

Mark Mullen: I think you answered the question that I asked, which is, what is your standard of care protocol for the treatment of major depressive disorder? At least that's the question that I meant to ask. I think we can agree that based on current clinical guidelines, your standard of care is pretty cutting edge and you absolutely would die on this hill and stand by it.

the take that 

Owen Scott Muir, MD: I raised $50 million, which is the most any mental health company has ever raised based on the thesis that this is the right care and the data has gotten better and better. And in kids, it is now a first line recommendation. 

Mark Mullen: Great. So what are you're excited about all of this.

What are you most excited about in the field of TMS over the next 10 years? 

Owen Scott Muir, MD: The thing I'm most excited about is the fact that we have a safe and effective treatment that can be [01:10:00] deployed rapidly and get people reliably to remission. And dun done not in definitive studies yet, but with early open label evidence, we have a, an open label clinical trial by Jonathan Downer and company, called the, 1D trial, which, demonstrated you could do d cyclo and ancient tuberculosis drug augmented transcranial magnetic stimulation, and you could do 20 stimulations in one day.

And it worked. 

Mark Mullen: Why? 

Owen Scott Muir, MD: Why? Well, it turns out de cycline potentiates neuroplasticity. And that allowed it to work. And just today, a preprint came out on a propensity matching study, which is some, you know, study design, not. Usually used in psychiatry. We actually use quite often cardiology and other fields of medicine.

But we're looking at, patients matched by a, series of factors. And we [01:11:00] compared this one one day TMS to once a day TMS, and it was better. So now we have to do a pivotal trial with good randomization and good controls. And so one of the innovations recently in the SWIFT trial, which I participated in with the Brainsway as a study sponsor, is it was comparing two active treatments.

We randomized people to once a day TMS in treatment resistant depression or five times a day treatment, resistant depression over six days with some taper. And that was important because what we learned in the saint trial that Nolan Williams designed was that if you do a powerful enough thing con compared to sham at the midpoint of the study, the IRB will shut it down because it's unethical to continue to give human subject sham when you know it's definitely better.

And so we can design the SWIFT trial to minimize the risk of that early discontinuation. 'cause everyone [01:12:00] was getting active treatment. My favorite story about being an investigator in that trial is one of the patients was too sick for the study. She was too suicidal to get into the trial. So what did I do?

I gave her off-label. TMS clinically. 

Mark Mullen: Yeah. 

Owen Scott Muir, MD: Because she was gonna die without it. 

Mark Mullen: Right? Right. 

Owen Scott Muir, MD: Can't be in the study, but definitely needs the treatment like, because it was already FDA labeled for people with depression. so what I'm so most excited about is one day TMS and the reason I'm so excited is that the device that company AMPA made, again, conflict of interest here, I'm an advisor to that company, but they made a light and cheap device that can go to the home, like fits in your luggage on a carry on.

I've flown with it 

Mark Mullen: and do a treatment in one day. 

Owen Scott Muir, MD: In one day. Yeah. It's pretty amazing. Put it trunk your camera. It's pretty amazing. Roll up to someone's house. It's got a camera in the coil so the tech can get it on the right spot without screwing it up. It's a design solution to the problem of not [01:13:00] enough TMS 

Mark Mullen: to state the obvious.

It sounds far too good to be true. So I'm very excited as well to see what comes of this 

Owen Scott Muir, MD: and, so the good news is we don't have to believe that it might be good. We have to prove that it will be. Now, is it you first have to design a thing that's technically possible. It's actually similar to psychotherapy, right?

Psychotherapy sounds crazy. You're gonna talk to someone and they're gonna not kill themself. Yeah. But you have to talk to 'em a couple times and you have to have read a book first. Right? And we have DBT, we have schema therapy, we have mentalization based treatment. We have the most effective treatments on earth are psychotherapies for suicidal people.

But you have to design the manual first. It has to be possible. You have to know it's possible. You have to know it's reliably replicable. TMS is the same. You have to have a device that can get to the patient, that can be reliably placed on their head and deliver the treatment. You think, and only then can you study whether it works 

Mark Mullen: in order to prove it.

You're not saying that you need manuals to have psychotherapy, you're saying [01:14:00] that you need manuals in order to prove that you're doing something reliably and that it has the effect that you think it has. 

Owen Scott Muir, MD: Exactly. Manual isn't necessary for effect. It's necessary to demonstrate what you thought did it is what did it.

Mark Mullen: Owen, we gotta wrap, but I know you, I know you're gonna wanna say a couple minutes more on what you're most excited about. Is there anything else you need to get out before we wrap? 

Owen Scott Muir, MD: That was just TMS. 

Mark Mullen: No, I, believe me. Believe a as so, as a reader of the Frontier Psychiatrist Newsletter. I know. Any final thoughts for our audience?

Owen Scott Muir, MD: Yeah. You have tremendous power to heal your patients, and it doesn't take TMS to do that. It doesn't take drugs to do that. It takes your curiosity, your compassion, your interest in them and their life, and that is enough. In fact, it's the most powerful part of anything we're [01:15:00] doing. The placebo effect is the effect that we're trying to build on with science.

But science only incrementally builds on the power of hope and the ability to sit there and really feel what someone is feeling tolerate it with them and stick with patients who are suffering is the superpower we have. My favorite patients are not often, not those who respond well to TMS, they're the ones who don't and who I have to stick with because if I don't, they're gonna lose hope.

So our ability to carry hope together with our patients when it's too heavy for them alone, that's what makes a doctor. It's not the technology, it's not the science. I do the science 'cause I wanna be able to offer hope. On top of that, I do the math so I can figure out what makes sense to my colleagues at payers and investment funds and all that stuff.

I don't care a lick about it. I care that I can stand there and say, let's give one more thing a try. I just read this [01:16:00] paper by a colleague and maybe it's worth it for you. And even if it doesn't work, I'm here with you. One of my greatest joys, I have to say, I work with a lot of patients who've been in clinical trials and it hasn't helped them.

And they're coming to me for what next? And when you're sitting there with somebody who was a participant in a brain surgery study and it didn't help and they're asking you, yeah, but what can you do? That's the moment I cherish. 'cause that person's contributed to our field with their life. I'm one of them.

Like I had J John Mann sticking a needle into my spine to measure serotonin precursors when I was 20 years old. 

Mark Mullen: This meaning that 

Owen Scott Muir, MD: became a psychiatrist Because of it. I respect the heck outta that. And I also think what was powerful about that study wasn't that it helped me. It was diagnostic, but I became a doctor because of my experience of someone just being curious, not even promising to do [01:17:00] anything.

What we do is profoundly human. If we lose that and think it's all science, we lose the threat. 

Mark Mullen: That's good. This is a really important note to end this particular episode on, a technology that I have not pretended to understand at a terribly high level. And I think it's tempting to look at a technology like this or to, let's say, accuse a profit like you of this technology of saying, this person is trying to sell this technology and say that's gonna solve all these problems and leaving the humanism behind.

And I really appreciate you giving us that disclaimer that says, that is not at all what you are trying to do. You're excited about this because you've seen the data and you've seen the people that it's helped. But bringing us down to the soul of psychiatry, I think is super, super important. 

Owen Scott Muir, MD: A million people a year are being treated in China with TMS every year here.

We treat a hundred thousand, we got the incentives wrong, but it's a problem of ethics and soul, not just practicality. 

Mark Mullen: Thanks for coming on the podcast, [01:18:00] Dr. I've really appreciated it.

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