207. Treatment-Resistant Depression: TMS, Ketamine, Spravato, and What Comes Next | Patrick Sullivan, DO

Welcome to Medicine Redefined. I'm Dr. Ultima Sharajah. And I'm Dr. Darsha. Let's put the health back in healthcare. If you're a high performer who wants a clear plan for longevity, performance, and staying active with fewer setbacks, I'm now seeing patients through my telemedicine practice who are finding health and performance. I'm opening a limited number of founding member spots at refininghealthrx.com. All right, let's jump in. If you've ever been told that your depression is treatment resistant, you've probably heard that as a verdict, as the final call. But our guest today wants to change that. In his words, treatment resistant doesn't mean untreatable. It just means that mechanisms that you've been trying aren't the one for you. And there are others. Our guest is Dr. Patrick Rocky Sullivan. He's an osteopathic physician who spent two decades in emergency medicine before opening Inishinova in Cherry Hill, New Jersey, where he now works full-time with people who've run out of standard options for depression, PTSD, and OCD. Initially, he started with ketamine, then built out one of the more comprehensive brain health practices around him. Ketamine-assisted psychotherapy, Spravato, and the focus of today's conversation, transcranial magnetic stimulation, or TMS for short. This is Rocky's second time on the show. Round one, back on episode 177, we went deep on ketamine. Today, we're getting into TMS, what magnetic stimulation is actually doing to the brain, how it differs from shock therapy reputation of ECT, why depression is probably several different conditions wearing the same name, and how accelerated protocols are compressing six weeks of treatment into a matter of days. We also get into where this is headed for pain, addiction, and beyond. If you or someone you care about has cycled through medication after medication without This one's worth your time. Dr. Patrick Rocky Sullivan. Welcome back, man. Thank you. Appreciate the invite. Excited. Round two here. I know we teed this up a little bit with all the things that we talked about the first time around. And for those who have not gotten a chance to listen to the first episode when you were here for round one with ketamine and everything, all its applications with the stuff that you do, episode 177. So we'll plug that in for folks to go listen, get a little bit more about your background. But For the new listeners who didn't get an opportunity to learn more about you, can you do a quick, brief 60 second of who you are and why it's important for us to listen to you about the topic that we're going to talk about today? Yeah, absolutely. So I'm an osteopathic physician. My background was in emergency medicine, which I did for 20 years, mostly focusing on psychiatry and neurology. And overlapping with that. I opened my practice in Ishii Nova in Cherry Hill in 2016. So I've been doing that for 10 years and I do that full time now. I no longer work in the hospital. Initially, our focus was on ketamine infusions for depression. And pretty quickly, we saw the application in a number of different diagnoses and conditions that people would have. So we developed ketamine assisted psychotherapy for PTSD and treatments for OCD. But I also quickly saw that there was a need for something else for some people that weren't hitting remission yet, even with powerful drugs like ketamine. So we added TMS in 2018 and it's continued to expand from there as we do a more comprehensive treatment for mental and physical health. And in the past year, we've added inspervato. So we have a full range of services. I love it. So magnetic stimulation, can you give a brief primer for the listener who's never heard of that? I think maybe those interested in brain health and neurology, this might be something that they're somewhat familiar with, but I think relatively speaking, this is novel, right? And there are a lot of questions on whether this is applicable in clinical medicine today for a variety of different things and how applicable it is. We'll get into that, but mechanistically speaking, what's actually happening at the level of the brain when people are exploring TMS or applying TMS? Yeah, great question. You know what the interesting thing is that it was actually FDA approved all the way back in 2008. So it's been around a long time. Almost 20 years. It took a while before it was catching on. And I think most people can find a TMS provider near them. But it's still surprising how many people don't know whether it's physicians or patients. They're not really familiar what it is or that it's an option out there. So I think it filled a void in creating a non-medication option for treatment-resistant depression. It's grown from there to a couple of other indications, but we're still mostly using it for depression. So TMS stands for transcranial magnetic stimulation. You can see my machine right behind me. So it's using targeted magnetic waves to stimulate circuits in the brain. Particularly, we use the prefrontal cortex where we stimulate for depression, some other areas of the brain for different conditions. in some of those circuits that are underactive when somebody has depressions or it's not communicating with other brain networks as well. So we're trying to strengthen those connections over time. Now, did you say prefrontal cortex? Is it exclusive to the prefrontal cortex? Depending on what we're treating. So no, I still think that TMS is in its infancy with how much we know. I think there's going to be tremendous applications for different conditions and stimulating different areas of the brain in different frequencies, whether it's an inhibitory frequency or a stimulatory frequency. The main application, the FDA approval is for depression or anxious depression. So we're targeting the dorsolateral prefrontal cortex. It's more like this area here. There's... dorsal medial prefrontal cortex in the midline for OCD. There's the motor cortex for pain. There was a more recent DA clearance for peripheral magnetic stimulation, where instead of putting the coil on your scalp, you can put it on the body to help disrupt some pain pathways. If you've had an injury, whether it was from trauma or surgery that caused an injury to that nerve and exaggerated sort of neuropathic pain, you can stimulate right on the periphery as well. Interesting. So you said anxious depression. I think you briefly touched on this last time. There are various types of depression. People just think that depression is all depression is created equal. All anxiety is created equal. Can you briefly reintroduce us to the concept of different types of depression and how they might present? Yeah, it's such an interesting fact because we say the word depression. I think we all tend to think of it as being one entity, but in reality, it's probably multiple conditions, different conditions that end up with certain features. But I think we can imagine some people who just have no energy at all. They have no motivation. They don't wanna do anything. They're laying around, they're sleeping all the time. They meet the criteria for depression. And somebody else who's super anxious, they're always worrying, their brain doesn't stop. They're not eating, they're not sleeping well. They also meet the criteria for depression, but clearly it seems like it's a different mechanism. And we should start thinking about it in different ways. Maybe there's different brain networks involved. But even if we expand outside of that, just because somebody ends up with depression, I like to think in my initial evaluation, what started it? What is contributing to it? Therefore, a lot of people, they might have had a traumatic event or a series of traumatic events first or OCD that developed first. and they get burnout over time, that then ends up with depression. So where I start with treatments, even though they all have depression, and by criteria, they might meet the standard to do one of these treatments, but they're going to have different outcomes depending on their underlying diagnoses. So we have so many different options. So you have good old psychotherapy. We've got a ton of different medications that we can play around for the various types of depression, anxiety, mental health disorders. We talked extensively about the role of ketamine on our last discussion. You have electroconvulsive therapy. I'm gonna ask you more about that. Where does this fit in into the treatment paradigm? You said you wanted to add to 2018 because you wanted to offer a different avenue for people. Where does this fit in amongst everything that we have? Yeah, that's a great question. And we should probably zoom out a little bit to think about what we're talking about because we're not necessarily just looking at people that have depression that they go right into doing TMS or one of these advanced treatments. We're generally referred to as treatment-resistant depression, which means you've developed the symptoms of depression and you've generally gone about the typical method of treating that. You tried an antidepressant. If that one didn't work, you went to the second antidepressant. If we look at data from a trial called STAR-D, It shows us that each time we add a new oral antidepressant, the chance of that one working is less and less. So the first medication might get you a third of the people feeling better. And then we add another one, you get a little bit more. And each time, by the time you get out to like the third or fourth medication, you're down to like five to 10% chance of that one working. because they're all similar. Of course, we want to add in psychotherapy and whatever other paradigms we can use, but each one of those new medications can be traumatizing for the patient because they get their hopes up, is it going to work? And then if it doesn't work, then they have side effects and withdrawal effects. And I think the key is treatment resistance sounds scary, but it's really more of a definition for the insurance company to say, if you meet this criteria, now I'll pay for one of these advanced treatments. And so treatment resistance depression doesn't mean you're not treatable. It just means that we need to look at a different mechanism. So then we have these other advanced treatments. We talked before about ketamine infusion therapy or ketamine assisted psychotherapy, which is more for a PTSD picture. Then we have the non-invasive TMS sort of treatment, which is for depression or the anxious depression. And then now we have in 2019, we got an indication for Spravato, which is an intranasal S-ketamine, a version of ketamine that is done in the office for treatment-resistant depression or depression with suicidal ideations, which is big because we don't really have many FDA-approved treatments for that. And then we have electroconvulsive therapy, which has been around for decades, which is also a very effective treatment. Each one of these comes with their own set of risks and benefits and different logistical and financial factors. So the question is not which one is best. It's which one is best for that individual patient and all the nuances that go around them as a person. How would you discern between ECT and TMS? They both have electricity. Our brain and our nervous system essentially runs on electricity. But for those listening, they might see one, think the other. They can't tell the difference. How do you explain that to the layperson? Yeah, they're both ways of stimulating the brain, but they're very different treatments. So electroconvulsive therapy is where it's generally done in a hospital setting. They put it in IV. You start off with treatment three days a week and probably going to do like 12 or 15 treatments overall. You get general anesthesia, so you're put to sleep and then an electrode is placed on your brain and it delivers electricity to induce a brief seizure. We don't really know exactly the mechanism of how it works. It is very effective. It's up there with IV ketamine. 70 to 75% of people are getting a good response to that. And it can be a bit durable. It's variable for everybody. Any one of these treatments are variable about how long they last and how effective they are. But it does have some very real side effects of some short-term memory loss and stigma that goes along with it. So it's a powerful treatment that might be the right option for some people, especially I particularly think of that one. I don't like to think about it as like last resort. It might be more for a psychotic depression or a catatonic depression where you really can't function well enough to come to a structured treatment program like TMS or Spravato. Whereas TMS, there's no electricity applied. There's no medications given to you. There's no memory loss. Electricity runs through the coil, through this black part here, which rests against your scalp. creating an alternating magnetic field, a magnetic pulse that comes out that then goes through your skin, through your bone, into your brain tissue, and stimulates electrical activity in the neurons in your brain cells, gets them to fire. And we do it repetitively. So it's RTMS is repetitive transcranial magnetic stimulation to train that circuit over time to strengthen it. You mentioned stigma with ECT. What's the stigma there? I'm not familiar. Yeah, stigma as it's referred to as shock therapy, not portrayed very favorably in movies like Nicholson and One Flew Over the Cuckoo's Nest and things like that, right? And so I think there's still a lot of people that are afraid of it. How young can a person be to be a candidate for TMS? So traditionally it was 18. In 2024, there was a new indication for adolescents. So I believe it goes to 15 years old. Okay. Other than depression, are there any other indications where we have studies to support its efficacy? There are. There's a lot of studies going on, but the FDA approval, meaning that insurance coverage is available, is for treatment-resistant depression or anxious depression, and then that clearance for peripheral magnetic stimulation, although that one's probably still going to be done as a cash pay and not covered by insurance. There is a decent amount of evidence for neuropathic pain. So some of these conditions like RSD or complex regional pain syndrome, some fibromyalgia and migraine headaches, things like that. We stimulate a different area on the motor cortex. And then there's exciting research in not only other mental health conditions, but addiction, neuromuscular diseases and things. These are not mainstream yet, but there is some excitement around that. Yeah, I certainly want to get into that from the pain perspective and see where you and I can collaborate. So I'm going to table that. We'll come back to that a little bit later. Let's just stay on what the main indication is. We talked a little bit about the ideal patient, right? So this is quote unquote treatment resistant depression. I know it's a bit of a loaded word. So somebody like me, other clinicians will say, Hey, can you failed the standard pathway? You might be somebody would benefit from this. When they come to you, walk us a little bit, just like you did last time, through your intake process. How are you integrating the conversation about other lifestyle factors, sleep, alcohol, because these are particularly substance use is going to be tools people are going to reach for to manage your depression. That's really popular. Is that a contraindication? Are you using TMS to help people avoid doing that? Walk us through that. Yeah, great question. I think it's such a nuanced answer there, but it's really important in the field as well as for patients when they're considering any of these options. I want to make sure that they know how to ask some questions about a provider that they're going to see and try to find out, is this the right place for me to get treatment? And is this the right treatment for me? The way I do it is I start out with a very thorough intake form where they tell me all aspects of their physical health, their medical conditions, their psychiatric conditions, substance abuse, lifestyle factors, diet, exercise, sleep, nutrition, all the medications they take, what they've tried before, what worked, what didn't work, supplements, everything, how much exercise, what are your main symptoms? What have you been diagnosed with? And then we'll meet and we'll tease through that and I'll help them clarify maybe what some of the, to make sure we have an accurate diagnosis. Based on that, from a medical perspective, here are your options. And it might be if there's a lot of depression, anxiety, PTSD, pain. We'll go through the pros and cons of each one of those treatments that we mentioned. And I can then say, based on these diagnosis you have, this treatment might be better for you. This one might be not as good. But then the next thing is, what are the logistical and financial considerations for that patient? If you're doing something like ketamine infusions or Spravato, you need to have a ride home. You can't drive until the next day. And depending on how far away they live and travel, that might be an issue for them. If they were looking at TMS, then we have to look at the schedule. And IV ketamine is an off-label TMS protocol, like an accelerated protocol is going to be people might choose them if it works best for them and they can afford that. If they need an insurance-based option, then sometimes it's not what's the best option for them, it's what's actually available. What can we really do and deliver from a practical perspective? So then we might look at Spravato or TMS and say, here's the pros and cons, the risk and benefit of each one. For traditional TMS treatment, the schedule is that you go to the office every day, five days a week for about six weeks. So somebody might say, I have four kids, I have my own business, there's no way I can come do that schedule. Let's look at one of the other options. Or if they're not working and they're able to do that, it might be great for them. Or they might want an accelerated protocol where the treatment is done in just a few days. but multiple treatments a day. I love it. So I want to dive a little bit more into these protocols is how would the person referring to the clinician, and I know very little about this. So what would be the point to even start to learn about this? So this idea of the accelerator protocol seems much more appealing. I think it's a matter of five days, you said, right? As opposed to the extended normal protocol is several weeks. There's a couple of different ways to do it. Let's talk about it then. Maybe where did we start the standard protocol and when and why did we decide that we needed an accelerator protocol? Yeah. The original approved protocol, like we said, was even in the older stimulation frequencies, if we go back to when it was first approved, it was more like a 40 minute treatment each time. So every day, five days a week for six weeks, usually the insurance approves. People usually do 36 treatments in total. Why do we do 36? Because that's what the insurance pays for. So that's what people are doing. Is that the optimal number for each patient? Probably not. There was some good studies showing that if you took all those people and put them through that protocol, maybe you got 50% of people that had a response. If you then took the non-responders and ran them through another 36, you got another 15% of people that responded. And if you took the non-responders and you did it again, you could pick up another 15%. So unlike some of these other treatments, something like ketamine, more is not necessarily better. TMS, more pulses tends to be better, but if we're We're only following a traditional protocol. We're limited at what we can do for what's going to be covered. In addition, some of the researchers say, how can I treat more patients, particularly if I need to get them better quicker, if they were in the hospital or something like that, or how can I get more people coming through the system? And so they looked at these accelerated protocols. A big one that people might be familiar with, they might have heard of the Stanford protocol development. at Stanford by Dr. Nolan Williams. And that was one that was done. They were 40 minute sessions and then it dropped down to 20 minute sessions a day. And then when I started in 2018, intermittent theta burst just came out. And that was a shorter, higher frequency treatment that was actually done in three minutes. And so I started out with just all accelerated theta burst protocols. And the beauty of that is because it was only three minutes and the patient could tolerate it much better, it allowed you to do more sessions in a day. So this is completely off label. It's not an FDA approval and it's not covered by insurance, but you could, we would generally do one an hour and you can do multiple in a day. So that's how the Saint protocol came out. They did a theta burst once an hour. They did 10 sessions in a day, five days in a row. And it had really impressive results at the end of that, that like 80 to 90% of people were hitting remission by the end of that first week, which is significantly better than anything else we had out there. So it created a lot of hype, but It wasn't really accessible because it was an fMRI guided neuro navigation process, which is what you really can only do with a big hospital system with a lot of funding. Not really something that can be done in an independent clinic. But there were some similar things. Dr. Jonathan Downer created some more like theta burst protocols, which is what I modeled after. And it didn't have to be that intense. It didn't have to be that frequent. So I was initially starting out doing like two or three days a week, multiple in a day. And then we've developed over there. There's a newer one that came out recently called a 1D program. protocol where we're trying to optimize the neuromodulation by using some medication. So similarly, the way we've combined ketamine and TMS over the years, sometimes a ketamine infusion during the TMS makes it more effective. This is a similar treatment where it's used. We're getting really into the weeds of the TMS world here that only some of the neuromodulation nerds even follow along with this. But for people who might be interested in this deeper dive, We use a medication called D-cycloserine where you take that in a one-time dose and we do like 15 or 20 TMS sessions in a day done about a half hour apart. Or sometimes I split that into two sessions. I don't think I've heard of that medication. What kind of medicine is that? Yeah, D-cycloserine. It was an old medication that if you look it up, it was used for like TB or it still has an indication for like treatment resistant UTI or something. It's an NMD partial agonist. The theory behind it as it makes the TMS more durable. and more effective. So ITBS, three minutes, 10 treatments a day, so basically 30 minutes of treatment per day. That sounds like the person would have to be at the clinic all day for five days. So technically is that inpatient administer? Not five days, we do it for one or two days. One or two days, okay. I have people that will travel three or four hours to come see me or they'll come stay in a hotel and be here for a couple of days. And so we start early in the morning, they take the medication in the morning, and then we do it through the course of the day. There's a bit of delayed response to that, that at the people are starting to feel benefit after a week, which just continues up to week four. But these are early. We haven't done a lot of them and there's only a handful of people actually doing these types of things. But this is not standard TMS treatment yet, but some of these options that are out there are nice to have some options. The standard protocol, the one that is FDA approved, the initial one, the 36 treatments that you mentioned, how long is each treatment about? If you're doing a standard protocol, it's about 20 minutes. A lot of times insurance nowadays, if the facility has the ability to do theta burst, then it's three minutes. So if you're coming in a couple of minutes of setup, three minutes of actual brain stimulation, and then you're on your way, and then you can drive yourself home. You said tolerated better. What about the treatment is intolerable? Does it hurt? It can be a little uncomfortable at first. A little scalp discomfort. I usually liken it to an electric woodpecker tapping on your head. We start off, we can control the intensity and ease you into it. And as you do it more than it tends to be, it's quite tolerable. It's quite well tolerated treatment. So I guess one way I'm thinking about it is, so I don't know if you know this, but I use a lot of peripheral nerve stimulation for pain, peripheral pain. And I think I always try to describe to people if like, if you ever had a TENS unit for any type of musculoskeletal ailment, I imagine this would be like putting those pads on your forehead or on the actual head, get a little tingling sensation, a little buzzing. Is that what they describe? Oh, you mean from the actual TMS treatment? Yeah. Do they describe any tingling, buzzing in their scalp? Um, no, it feels different than the tens where it's like that constant. This is a rhythmic sort of tapping sensation, depending on the protocol we're using. And like I said, it literally feels like an electric woodpecker. It's like a sharp little tap and it feels like a little bit electric and it stimulates the muscle to twitch. So usually with each tap, you get a little eyebrow twitch that goes along with it. When we first do it, they're like, well, that's interesting, a different sensation, but they usually forget it. Usually sitting there talking with us during, and the more you do it, the easier it gets. And And given that we're primarily targeting different parts of the frontal lobe, is it pretty focal, that sensation that they're having? Yes, exactly. It's right there. With the exception of, you might have heard of a deep TMS, which is done by a company called Brainsway. That's an actual, instead of just a coil that sits against, that's like an actual helmet that fits over the head. And that's a broader, deeper sort of stimulation. So it hits like a wider area of the brain at once. That gives a little bit more of a joke. When would you consider deep TMS for a patient? I think it's really just preference of the provider. I think there's different types of machines. There's a lot of different ones coming out now that try to do like some personalization, some EEG guided, try to hone in on the specific frequency that people talk about like a personalized. These are all still early. I don't find huge differences in them. I think the key to personalizing is make sure this is the right treatment for you if you're going to do TMS and that where you go, somebody pays close attention to the initial what we call brain mapping. They're doing some measurements and determining what is your motor threshold? Is the coil being placed in the correct location? And there's some user error where you have a person physically put it on you each time and to make sure that's in the right spot. But For personalization, I'll come back to your earlier question when you said, let's choose the right person based on their other lifestyle. And I didn't fully answer that question. It does make a difference. Sometimes it's better to fix those things first. I don't like to just look at, hey, what's the next medication or next treatment we can add? If we have some time, particularly if somebody is like, I have had this problem for 10 or 20 years, instead of spending money and time to go into one of these treatments, maybe we need to slow down and do a deeper dive. Do we have your diagnosis correct? What else can we find? A lot of times I'm finding doing some genomic testing, looking for some DNA mutations that maybe you don't transport B12 into your brain well enough. Like we see with some of our autistic patients or older patients with dementia, vitamin D receptor malfunctions. And then we look at some comprehensive lab work. I need to know is your omega-3 level, your vitamin D level, your inflammatory markers, your overall health. Are these in the optimal range that you can even make quality neurotransmitters? Maybe we can look at some targeted supplements and lifestyle changes first. If you're still heavily drinking alcohol, it all falls into the pattern of a lot of stress and then some trauma. And then I can't sleep and I'm anxious all the time. So then I'm using some marijuana or some alcohol to fall asleep. And then I'm tired during the day because it took away my REM sleep. And now I'm drinking caffeine all day. And now I need some stimulants to keep me awake because I can't think. I'm on my phone all the time. These different things develop. There's no one single pill or treatment that's going to fix that. We have to change the whole picture. And if you're really depressed, it's hard to make those lifestyle changes initially. So I'll look at one of these treatments as the catalyst, whether it's ketamine, Spravato, or TMS. Let me get you feeling better first. But then we have to look at, can we take away... the alcohol and the marijuana, get some quality sleep, stress management, diet, exercise, sleep and nutrition, all those play a crucial role. Because sometimes we can make metabolic psychiatry perspective, we can make massive changes by just improving somebody's metabolic health. You may have heard of some of these anecdotal stories when somebody takes the GLP-1 agonist for whether it's for diabetes or for weight loss, and then they have significant improvement in their mental health problems or their addiction problems. because they're really fixing their underlying metabolic physiology. So we can do that with diet, getting rid of processed foods and cutting down on sugar and lowering your insulin levels. A lot can be done. So if we can do that first and then introduce some of these other, or we might need to do that with a medication first and then make these lifestyle changes, but it all comes together for the big picture. Yeah, absolutely. In fact, we had a whole two-parter on metabolic psychiatry. I think Dr. Matt Bernstein, I'll find it and plug it in for people to listen to that and go deeper into that. All about that. You know, I really loved that you brought up this idea of questioning the diagnosis. Anytime... I try to at least when I'm working with my colleagues and I'm teaching. And if somebody comes back after we've done an intervention, and usually for me, that's an injection of some sort for some type of pain ailment, and they come back and they didn't get better. I try to tell them, hey, we have to ask a couple of questions. Question number one is, did we get the medication in the right spot? So for instance, if that was, you know, we're trying to inject a shoulder and trying to get to a rotator cuff tendon and sheath versus the bursa, did we do it precisely what we wanted? And with ultrasound guidance, we can confirm that. Okay, good. We check that box off. Question number two is, was the diagnosis correct? And that's a really important one. I think that because it's so hard for us in medicine to have humility and to say, hey, I'm wrong, right? Because that's the unsettling one to say, no, my diagnosis was incorrect. We're so quick to just say, oh, they didn't respond. They failed that part. Let's move on to the next step, which is... more advanced procedure, maybe it's PRP, maybe a surgical intervention, and they just go down this pathway. And at no point, somebody wants to just stop and say, hold on, am I wrong? Am I wrong with the whole thing? Are we going down the wrong pathway? And I love that you bring this up with depression, because there are so many medical issues, right? You could have hypothyroidism, hyperthyroidism, B12, you brought up, maybe somebody has unrecognized or undiagnosed sleep apnea, narcolepsy. And that's contributing to this. And so I think that just pausing and just asking yourself a question, not necessarily having imposter syndrome, but having imposter thoughts, those are healthy from time to time. That's so critical when it comes to that. And I think we could all probably stand to do more of that rather than just shuffling the patient along to the next person or the next treatment. I want to go to the decision-making pathway for you. So we spend a lot of time talking about ketamine in its role, ketamine-assisted psychotherapy as well. Now we got TMS first. Of course, we have the medication, the psychotherapy. Again, you are looking at the person, the whole picture. You've emphasized that multiple times. But if we can maybe just zoom in into these two treatments, because they are somewhat novel and that is your niche expertise, if I could. And especially given that Spravato is now insurance covered, you highlighted that. Now you're doing that routinely. What's your decision tree look like when somebody comes in? Who's the profile that you're saying, I think you would benefit from ketamine versus you would benefit from TMS? Yeah, that's great. There's a lot of different things that lead me towards, I think of TMS more for a nice clean case. They only have depression or depression with some anxiety and they want insurance based non-medication option. That's the perfect patient for that. They don't have any addiction issues and there's no trauma in the background. If I look a little further and there's multiple traumatic issues with or without a formal diagnosis of PTSD, or if we have a diagnosis of PTSD, I might try to expand on that and say, do you have certain things that bother you? Or there are certain thoughts that come up a lot in your depression that you ruminate on that you feel like unresolved that happens? heavily sways me. If the answer is yes, I heavily lean towards ketamine and ketamine-assisted psychotherapy on that. Addiction issues, particularly with alcohol, I'll lean more towards ketamine because it can really help us with that as well. If OCD was the primary driver. Now, there is an FDA indication for TMS for OCD as well. In my opinion, it doesn't work all that great. The response isn't as strong, but it could be a nice option. But I've developed a technique of using low dose ketamine and working with somebody to understand their OCD, to be able to change how they respond to the thoughts and the urges that they have to do some compulsive. So I think that's the most effective treatment for that. And then again, we go through the logistical and financial options of each one, but from a medical perspective, I think it depends on what the underlying etiologies are. Given that Spravato is now covered by insurance, does that change your calculus when it comes to ketamine, how you used to use it historically? It does. And I mean, the biggest thing I think about Spravato is an access point. It really increases access to this type of treatment for a lot of people, meaning they can get it in if they meet the definition of treatment-resistant depression. They don't have bipolar disorder. They have MDD with or without SI, and they've tried their oral antidepressants, and they want an insurance-based option. Then it really brings people in and has some similar qualities. Ketamine can be more powerful and we can fine tune it to the individual and I can use it for some of these off-label conditions. It works great for migraine headaches and addiction. If you use it in a certain way and OCD, things that you can't really use Spravato for outside of that. And I can fine tune the doses. So Spravato... It's such a great option for a number of reasons, but it only comes in two doses. So I can't really fine tune it. We do offer something called Spravato Assisted Psychotherapy, where if you get a little bit of dissociation from the Spravato treatment and our trauma therapist works with you to work on some of those. So it's not specifically indicated for PTSD, but it really can be helpful for some of those patients if you utilize it the right way. Whereas IV ketamine, I can fine tune the dose exactly what I want, the duration as long as I want. So it just gives me a little bit more control over the situation. When do you still send for ECT? Yeah, I think ECT is one of those ones where if I'm evaluating that person initially, and I don't find that they're really stable enough for the outpatient treatment, that if their suicidal ideation is so strong along with their depression that they need to be hospitalized and they're not really safe for outpatient treatment, then initiating that while they're in the hospital is a great option. And a good segue on that is we don't always have to look at each one of these in isolation. They can be complementary and they can be done in combination or they can be done sequentially. So maybe somebody needs ECT at first and then they stabilize and they improve and then they can look for one of these other ones down the line. Same thing with Spravata or IV ketamine. It doesn't have to be one or the other. We've had patients that started out with if they had a lot of severe PTSD, severe SI, right? And I really wanted to get them better as soon as possible or... The other thing is that you might have a delay before you could start Spravato because you have to take two antidepressants. What if they've only had one so far when they come for the evaluation? And I think they could be a good candidate for Spravato. They otherwise meet the criteria, but I prescribed them a new oral antidepressant. We have to be on it for eight weeks to see if it works or not. And we could prescribe that to see if they get enough benefit. We could start IV ketamine in the meantime to focus on their PTSD or get their suicidal ideations under control. If they have the money to pay that, but they didn't want to stay on that or they need to stay on that for maintenance, we could then maybe switch over to Spravato or vice versa. They want to start with Spravato initially. I've had patients that did Spravato first and they said it just wasn't effective for me. I didn't feel much from it. And then they came to me. and we added in IV ketamine at the right dose. They just needed a higher dose. We can keep looking at it. We talked in the beginning about why I decided to bring TMS in. I had a young guy that was doing IV ketamine, that severe depression, severe SI, was always in the hospital, did pretty well with ketamine. He got about a 50% response, right? So after about a year, he was in my office. He was crying and he said, I'm no longer suicidal. I'm no longer in the hospital all the time, but I'm never really happy. I'm 22 years old. I deserve to be happy sometime. And I was like, all right, you're absolutely right, because remission is the goal. So for people who aren't familiar, we talk about responses. If somebody has a 50 percent chance or a 70 percent chance of responding, that means that if you respond to it, your symptoms get about 50 percent better. But for remission, we're talking about that your symptoms pretty much go away. You're functioning back to normal. And that's really what we want to aim for. So you might have tried traditional antidepressants and you get a bit of a response, but you're still not really happy. Then one of these advanced treatments might be the right thing for you. Or your symptoms are severe. You're about to start a new antidepressant, but you can't wait the four to eight weeks because you're so depressed or you have suicidal ideations. Now you need to get better quickly. Maybe we start ketamine now while we're waiting for those medications to kick in. we have to meet the patient where they're at. So I told that patient, hang on, I'm getting TMS next month. We added in TMS. He started to get some benefit. And for him, we actually had to end up doing it combined where we did TMS during the ketamine infusions. And pretty quickly we got him to remission and it lasted. for years. And then we weaned off the TMS after several months and then just does a routine ketamine maintenance like once every six weeks. But he needed that additional brain network support initially to stabilize some things. And I think we're like eight years later and he's a very successful businessman and kicking ass in life. That's what it's about. That's what it's about. I love it. So I promised we'd come back to this. And I think this is the area that I'm most interested in. Over the last couple of years, I've had an increasing population of chronic pain. I think it's probably one of the most widespread disabilities, not just in the U.S., but worldwide. Osteoarthritis is the leading cause of disability, certainly worldwide. And the osteoarthritis, I think, specifically. And so chronic pain with the aging population, as we are getting better and better at extending lifespan, it's a very real thing. And probably pain. Yeah, I'm pretty sure I can say this. Pain is the most universal symptom that I was telling a student today that no matter what specialty you decide to get into, that you're going to experience some type of pain. So you got to know how to deal with it. And neuromodulation, you used the word earlier. So for those who don't know, it's just again, modulating the nervous system, right? You can do that centrally, which is what you're describing here today. What we're talking about from a pain perspective, if you've ever heard of a spinal cord simulator, that's what that is. A peripheral nerve simulator. A lot of what I do is that, and it works really, really well. And mechanistically, sometimes I was telling this to work with one of my residents yesterday's peripheral nerve stimulator. They're not supposed to have any central mediation. It doesn't work that way. But guess what? We see people proximally have pain that's improved. We people who have a central mediated pain like CRPS, it gets better. And so there are a lot of things that we just don't understand. And you touched on this, you hinted at how you're even having some success with neuropathic pain, some fibromyalgia, which is more of a central mediated pain. Talk a little bit about that, right? So you said the dorsolateral prefrontal cortex and the medial prefrontal cortex. How do you bias the protocol towards a little bit more of that? Does it really even matter that you have to? Is it that precise that you have to bias it? And anything else that you've noted in your experience? Yeah, it does matter. It depends on what we're treating. I love everything you said there. There's such an overlap between pain and mood. A lot of them are sharing the same brain circuitry as well, if there's some dysfunction in there. And plus, if somebody has chronic pain, they're more likely to develop depression. It's kind of hard, if you're in pain all the time, it's kind of hard not to become depressed over time or to have anxiety or develop sort of a PTSD. If you have chronic migraine... can I go to that wedding? Can I make dinner plans? Because I don't know if I'm going to have to cancel again because I get nine migraines a month that are debilitating and I can't do that. So you develop a sort of level of trauma and same with CRPS and all those types of things. So there's such an overlap. We generally think of neuromodulation with TMS as treating this neuropathic pain. Similar with ketamine, high doses of ketamine can treat some of these pain conditions like migraine, trigeminal neuralgia, CRPS type of thing. Neither one of them... should really benefit some of the nociceptive, we might refer to them, types of pain, your chronic back pain, neck pain, arthritis. But like you mentioned, I did have some patients where we were doing some ketamine infusions for depression. And they're like, yeah, I have this chronic low back pain and it gets a lot better after my infusions. I'm like, well, it's not supposed to, I don't know why. But so we certainly see things like that. Or if we get their depression better, their pain gets better. Or if we get their pain better, their depression gets better. Similarly, if we get their PTSD better, their depression tends to go away. Choosing a location or a type of treatment, if we were looking at neuromodulation, the first thing I would think about for a location to try is do they also have significant depression? If they have a sort of neuropathic pain syndrome and they meet the criteria for major depressive disorder, I think generally accepted approach is just to do standard depression-based TMS, dorsolateral prefrontal cortex, and many of those people will get improvement in both depression and pain. So whether it was migraine, CRPS, whatever else they have, fibromyalgia, start with the depression protocol first. If it's somebody like, yeah, maybe I have a little bit of depression, but it's really more of a pain syndrome, then I would think more to target the motor cortex, the M1 area, where we're trying to disrupt that pain. pain circuit. These are really sort of brand new avant-garde sort of treatments that are being studied, have a lot of excitement. They're not in general use yet, but I've used them all some, but it's very exciting and it's extremely rewarding when it works. Yeah. You said you don't know why it might help with somebody's chronic back pain. I think I do. Let me take a crack at it, right? And so for those listening, maybe you've used the term, we both have neuropathic pain. If you're not familiar, neuropathic pain is when we describe it in the medical field, pain related to nerves. So that's going to be, sometimes people have, we call it diabetic neuropathy. You have burning type tingling pins and needles. That's how people will describe it. At least that's how we learn in medical school. Sorry to cut you off. But except, you know, an acute musculoskeletal injury, not going to help. If they start to develop some central sensitization over time, that's where I'm going to see both EMS start to help. Understood. So I think then we're probably getting at the same thing. But this is the new term that I kind of want to introduce to the listener. I'm not sure if I've talked about this before, but historically, we would characterize again, two buckets neuropathic, you know this. And so this is more for the listener, Rocky, nociceptive pain is classic, I bruise my knee, I stub my toe. So it's more straightforward. It's a peripheral issue. This new concept of nociplastic or a better term, I think neuroplastic pain is what you're getting at where when you've been in pain, even though it's that stubbed toe, but if you were just walking on, I don't know, maybe nail is in your foot and you're just walking Over time, your brain and your nervous system are going to change. Your physiology is going to change. And so that's why I think neuroplastic is better because it's actually central level is what you're talking about. And so that makes sense to me. In fact, most people in chronic pain, I think it's more neuroplastic pain. Why do we know this? And again, for somebody who's had chronic back pain and doesn't have the nerve related stuff, maybe gabapentin shouldn't work or their shoulder pain, gabapentin shouldn't work, but it does. And the other way around, like NSAIDs, ibuprofen and stuff seem to work for something that should only be neuropathic in nature. And, you know, I have this phrase that I really love. I should probably coin it as I tell people, bodies don't read textbooks. They really don't. And so I love that you're doing this. I got to figure out and you're going to have to teach me how I can refer more patients over to you because I certainly have patients who have depression and chronic pain. Like you said, is when you are miserable all the time, it's also isolating, right? I talked about this recently with Dr. Marissa McCarthy, where when you have a disability like a brain injury and you have... this subsequent weakness or you're in a wheelchair because you had a spinal cord injury and or cerebral palsy or something. There are social groups you can connect with. People recognize your disabilities outwardly visible. Chronic pain, that's not the case. Migraines, that's not the case. And so you're in this miserable minority where you have difficulty connecting and finding your group where you can relate to people. And so it's also very isolating. Of course, you're going to be sad, you're going to be depressed. And yeah, these are comorbid conditions tightly coupled. I'm sure we can figure out how to get FDA approved payment for this so the patients can get the treatment. But yeah, this is playing the game, so to speak. Anything else to add to that where you think for pain, where it's promising, where it's premature, just for my payment, our pain physician colleagues who are listening? I think the thing that's most exciting to me that we need some more information on is neuromodulation, particularly stimulating the motor cortex for CRPS. For people who aren't as familiar with it, this is one of the most painful, debilitating conditions that somebody gets after an injury or a surgery where they just get this exaggerated pain response that becomes severe. It's really hard to treat. It seems like for a while, for at least a decade or two, where a lot of people were going for that was ketamine infusions. But it's not like the ketamine infusions we get from what we do for depression, where it's like 40 minutes and it's relatively affordable. It's a high-end high dose and usually a longer, a four hour infusion and sometimes multiple days in a row. And the dose is so high, you have to get some sedation along with it. So it's mentally and physically taxing for the patient. And you need to give, if you're in an office for five or six hours requiring a lot of critical care work, it's not something that's covered by insurance. And so most people with chronic pain are on disability, right? And they don't have a lot of money. So there's this really disconnect with people who need it, who probably can't afford it. I've only had one patient so far where I was able to try this on CRPS, who had already been on ketamine infusions for 13 years. but still only sort of brought it down temporarily into a manageable range, but was still pretty severe pain most of the time. And once we added on the TMS treatment, it brought her pain way down compared and much more effective than ketamine, much cheaper than what we can do with ketamine. I mean, it's one anecdote. It doesn't mean it works for everybody. And where I've done it for some fibromyalgia patients, some did well with a little bit. Some needed a lot more treatment more frequently, which gets more expensive because, again, it's not something covered by insurance. But I think there's excitement in the field. Once we get more published studies on this and some agreed upon protocols, then I think we can start expanding it. If there's some PM&R colleagues that are listening who want to get more involved in doing this, for themselves, they can look at the Clinical TMS Society. We actually just started last year was our first one. We have another training in TMS for pain at the annual TMS meeting, which is in Boston. I don't know when this, we probably won't be out in time with this podcast, but it's in June, but there'll be another one after that where you can go and do a training and using neuromodulation for pain if somebody wants to get more involved. We'll link that in. So eight years in, since you've been using TMS clinically, what have you changed your mind about regarding TMS? Yeah, I would say initially when I started, it was just like, hey, this is another tool and other treatments that can be used. Again, I like to slow down with it and think, what is the actual diagnosis and is it the right one for this patient and what is the best way to use it? It's not about just adding in another treatment or another medication. It's finding out what is best for each patient between all the different treatments and giving them some accurate information about the likelihood of responding. Awesome. I want to make sure that we do a little bit of field critique because I think anytime something novel comes, it's exciting. We all love the next thing. The problem with that is sometimes, especially in this patient population who is suffering, who is vulnerable, they can be oversold, right? And it can be a treatment that can also be overused. Right? for this vulnerable population. So two part question, what do you think clinics and manufacturers for TMS are overselling regarding what we actually know? I know we explored a lot of things where we don't have FDA approval, but the science makes sense. And maybe you can try off label. And the second part would be if patients are exploring this idea and they call a TMS clinic, what should they be asking to protect themselves to make sure that they're actually with candidates and they're not being oversold? Yeah, that's a great question. I think as far as the like overselling, I have seen on certain clinics, whether for TMS or Spoto, that they might say on their website that their success rates are like 80 or 90% for people. In my experience, clinically, I don't think that's where we're at, that we're getting. If we had any single treatment that worked 90% of the time, we wouldn't need the other treatments. And that applies to anything. And so I think if you were hearing something like that, 80 to 90% of people are improving, particularly if that's the only treatment they do, that should maybe be a red flag for somebody who's looking for a provider. Then I think it's fair to ask how long you've been doing this, who in the office does the actual brain mapping and determining the motor threshold. Who does the treatment day to day? How long have they been working with you? How long have they been doing this? What do you do if I'm not tolerating your will or if I have a dip in my mood or anxiety or if it doesn't work? What's your approach to that? And I think that would be some telling. Hopefully you have the opportunity to ask somebody those questions before just... Because one concern I have is if you're just speaking to a representative that just confirms you have diagnosis and looks at your insurance and says, yep, you qualify. You can do TMS, right? Without really doing a thorough evaluation of you and explaining, can they properly explain all the other treatments and the pros and cons of each? Even if they don't do them all, they should be able to tell you why TMS is the best option for you. I love that. Another thing that I always like to remind the residents that I work with is just because you can do something doesn't mean we should do something, right? And so, yeah, you might qualify, but you might be a horrible candidate for a variety of reasons. All the things that you so eloquently mentioned earlier on. All right, Rocky, let's land this plane, man. I think that this is good. I know we got a little nerdy for a little bit, but I think that it's complicated. Right. And it's physiology is complex. This treatment's complicated. And I think that it's exciting both from a Spravato perspective, but also this, I guess my last question for you would be with these advanced treatments for depression, OCD, addiction, where do you think this field is going to be in the next five years? Like, what are you most excited about? I mean, a lot has been done over the last 10 years where you've gotten a specific ketamine treatment approved FDA approved from an insurance perspective, TMS as well. What are you most excited about over the next five years as you look at this stuff? Yeah, great question. I'm most excited about ways to personalize this. We've talked about getting a thorough evaluation, right? Using clinical judgment to help a patient decide which one's best for me. But then I want more tools in there to help us decide also. So one of the things I mentioned doing genomic testing, we do this, we're a company called Intellix DNA, we do a cheek swab and it looks for certain gene mutations. And then, but the key to this one is it helps you, it has a clinical tool to say, what are the potential interventions that could help you? Maybe you need much higher levels of B12 or you need something to help decrease inflammation or, but there are some things in there that will say you're a better candidate for TMS or ketamine that can help us lead us there. And then particularly when I pair into some advanced diagnostics, either from a psychiatry or if I'm looking at. brain injury patients or the addiction stuff. I look at their lab work, more data sets that I can get together. That leads me to say, you have a better chance of responding to this particular treatment instead of the old trial and error methods. I think that's what's going to be most exciting going forward. So are they looking at single SNPs to see which treatments people will? Yeah. Is that covered by insurance or? It is not. Of course. I'm one of these brand new treatments that I'm excited about, and we're really incorporating that more for people. But again, one of those things we're looking at, it's an investment in your overall health to say, I've been dealing with this problem for 10 years. I don't want to keep doing trial and error method to figure out, like, help me totally. targeted. Just like if you're going to take supplements, you shouldn't be taking, I don't think anybody should be taking a supplement because somebody on YouTube told you it's good for that particular indication. You should take it because you have a genetic snip or an actual lab value that says you're low in that. And we're targeting a specific dose and a specific way of taking it. Absolutely. What does it run? Intellix, you said, right? Intellix DNA? Intellix DNA. Yeah. Ballpark. What's it run for? A mental health one, there's different ones. There's medical, there's neurocognitive, there's neurodevelopmental for our autistic patients. We most often are doing the mental wellness one, which is $1,300, which is the full evaluation. Plus that just gives you the raw data. Then we spend a lot of time analyzing the results and creating an action plan and then pairing. That might tell me you have a problem. with having an adequate level of zinc. Then I know I got to go check zinc and copper levels and some other things. I do some targeted lab work. And then I put that all together with your symptoms to say, let's fix these things first. And then we can look at one of these advanced treatments to give a higher chance of it working for you. So it's not something somebody could go online and order. They have to go to a practitioner and go through you. So I love that because it's not just about the data. It's about the interpretation of the data as well. Love it. Amazing. Rocky, what's the best way? Like you're doing such cool things, man. I'm so excited to keep talking to you about this stuff and also send you some amazing patients. I'm thinking of one, especially where I need your help. So we'll do that. How can people connect with you? You've got a couple of clinics, a couple of partners that you work with. Tell the people where to find you. Absolutely. The easiest way is just go on our website, MyInishinova. Just go on Google, type in Inishinova Cherry Hill. You'll find me here. We have a practice in Wilmington, Delaware. My partner, Dr. John Doherty works there. He's a sports psychiatrist. We handle more of our athletes and a lot of ketamine assisted psychotherapy and we're doing spravato there for the TMS and the pain treatments are more down in my Cherry Hill location. whether you're looking for a specific treatment with us, or you just want to sit down and have an evaluation with somebody, even if you go somewhere else, which we do for some people to say, I can help you understand what might be the best option for you, which is hard to get from some other places to find that type of unbiased answer. I love it. Rocky, thank you so much, man. Thank you. This was great. Thanks for listening to another episode of Medicine Redefined. If you enjoyed this episode, please be sure to check out some of the additional resources in the show notes. Please also check out our social media platforms where you can find more content like this. You can follow us on Instagram, Twitter, and TikTok at MedRedefined. 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