Welcome to Interventional Psychiatry, Advances, Acceptability, and Access. I'm Dr. Saedra Wilson from the University of Minnesota Twin Cities, and in this session you'll be given a foundation about the common procedures that make up the practice of interventional psychiatry along with updates on advancements in the field and some exposures to the current issues of access and acceptability of these tools. You're going to get a general survey here about electro-compulsive therapy, implantable vagus nerve stimulation, repetitive transcranial magnetic stimulation, and ketamine administration in the treatment of major depressive disorder, as well as other emerging techniques through the expertise of Drs. Sarah Lizenby, Christina Kuzan, and Dr. Laura Cabrera. Unfortunately Dr. Cabrera was not able to be with us today because of illness in her family so I will be presenting her data. And with that I'll hand things over to Dr. Lizenby. All right. Well good afternoon. And thank you so much for the opportunity to be here and present on new developments, access and acceptability of electro-compulsive therapy or ECT. These are my disclosures. So just so we're all on the same page, ECT, you've heard of it. It's our oldest somatic therapy in psychiatry. But we're going to look at it today through a fresh set of eyes to really try to understand the active ingredients of how this works. So it starts with the box, the ECT box, which is basically a pulse generator which delivers electrical pulses with alternating current through electrodes that are placed on the scalp. When you inject current through electrodes on the scalp, that induces an electrical current, a distribution of electrical field in the brain, which is illustrated in the center of the slide. That induced electric field in turn induces a seizure, a generalized tonic-clonic seizure that finally then changes functional connectivity in ways that have clinical benefits as well as cognitive side effects. So a typical course, two to three times per week, up to six to 12 treatments per week, highly effective for the treatment of depression, and in fact, not just depression when we think about ECT. ECT is unique among our therapeutic armamentarium because of its tremendously broad therapeutic spectrum. So all of the disorders listed on this slide, not just affective disorders, psychotic disorders, catatonia, repetitive self-injurious behaviors in autism, status epilepticus, neuroleptic malignant syndrome, even Parkinson's disease, it improves motor symptoms there. So extraordinarily broad therapeutic spectrum. Wouldn't it be really exciting if we could understand why, what makes ECT so powerfully effective across these disorders? So before we dive into some of the updates on what's new about ECT, let's get on the same page about how we define the dose of ECT, starting with the electroplacement. So there are three standard electroplacements, the bilateral temporal, the bifrontal, and the right unilateral, and each of these induce a different type of electrical field distribution in the brain. So this is realistic head modeling of the electric field induced in the brain with these three types of ECT. On the top is bilateral, on the middle row is bifrontal, and on the bottom row is right unilateral. So the first thing that jumps out at you is that they're different. When we move the electrodes on the scalp, we are shifting where the electrical current is going. Now we think about right unilateral as being right-sided and one-sided unilateral because indeed that's where the electrodes are placed, but in actuality the electric field induced by right unilateral spreads to the opposite hemisphere as well, although it is more intense on the right hemisphere. So those are the spatial aspects of dosing, where the electrical field is going in space. The other aspect of dosing for ECT are the temporal aspects, which is the change in the electrical current over time. Nowadays we give brief pulses, which are rectangular-shaped waves shown here, and there are two parameters that define them. There's the width of the wave, which is how long the pulse is in milliseconds, and then there's the height of the pulse, which is the current amplitude. These two have a relationship. If you plot on the x-axis the width of the pulse and on the y-axis the current, you can see that there's a relationship to how much current you have to give as a function of the pulse width in order to induce an action potential or neuronal depolarization. What this strength-duration curve tells us is that the knee of the curve is the most efficient pulse width. As you continue to lengthen the pulse width beyond 0.1 milliseconds, you're not gaining anything in terms of being able to lower your current amplitude. This is why ultra-brief pulse, when the pulse width is 0.25 or 0.3 milliseconds, is more efficient in inducing seizures than the conventional pulse width, which is 1-2 milliseconds long, which is also called brief pulse. So by optimizing these two aspects of dosing, dosing in space and in time, what we've learned over a series of clinical trials is that right unilateral ECT with ultra-brief pulse is a way of lowering the cognitive side effects of ECT. But it's important not just to lower the side effects, but you have to make sure it's as effective as conventional bilateral ECT. An important key to making sure that unilateral is as effective as bilateral is the next aspect of dosing, which is dose relative to the seizure threshold, seizure threshold being defined as the minimum amount of electrical stimulation required to induce a seizure. Now seizure threshold is titrated by giving trains of pulses with increasing number of pulses per train. We do this by lengthening the train and by increasing the frequency of the train until a seizure is induced. So once we titrate how much each patient needs to have a seizure induced, then we can stimulate it at a multiple above that, above their individually titrated seizure threshold. Doing this, we've found in randomized controlled trials that the combination of right unilateral ultra-brief pulse at six times the individual seizure threshold, which is the set of bars I've highlighted here, is the form of ECT that can match the antidepressant efficacy of bilateral ECT, but with cognitive savings. So on this bar graph, the green bars are the efficacy, and the red bars are cognitive side effects. So you can see with the far left set of bars, that's a low dose, and then a medium dose, and then the six times threshold unilateral. As we progressively increase the dose above the seizure threshold, we're increasing the efficacy of unilateral, but without as significant an increase in the cognitive side effects. You can see on the far right, that conventional bilateral ECT, highly effective, but also carrying more cognitive side effects than the ultra-brief right unilateral six times threshold ECT. We use that form of ECT, ultra-brief pulse, right unilateral, six times seizure threshold. I'm repeating it to sort of let that sink in. We use that form of ECT in a group of elderly patients with depression who were referred for ECT. This was the PRIDE study, which stands for Prolonging Remission in Depressed Elders. We had over 200 patients who were referred for ECT. And what I'm showing you on the orange bar graph is that with each successive ECT treatment, the number of treatments is on the x-axis, you see the cumulative percentage of patients achieving response. And that shows you that within the first two weeks of treatment, almost half of the patients had already responded. And by the third week of treatment, three quarters of the patients had responded. This study was important because there was skepticism at the time that ultra-brief right unilateral six times seizure threshold ECT would work in elderly patients and severely ill patients. This study showed that it did. We found in the study for completers a remission rate of 83%. So that is really excellent. When we think about the risks of suicide and the lethality of suicide attempts in the geriatric population who have very lethal suicide attempts, ECT can truly be lifesaving. And they can respond with a form of ECT that has the fewest cognitive side effects. The study also looked at maintenance of response. It's not enough to respond to ECT. We want people to stay well and to not relapse. Here you're looking at survival curves, which is the percentage of patients going without relapse after responding to the type of ECT which I just showed you. We compared two types of relapse prevention strategy. One was combining venlafaxine with lithium as a combination medication relapse prevention strategy. And that is in the green line. And in the orange line, we added on to that additional ECT treatments. We gave the treatments based on individual symptom expression. This was called symptom titrated longitudinally based ECT or stable. We used an algorithm. We assessed with high temporal frequency the depression symptoms and then treated, gave additional maintenance ECT treatments when patients had not actually already relapsed but were showing early signs of symptom reemergence. And this strategy was more effective in preventing relapse than the combination medications alone. Now that I've gotten you so excited about how effective ECT is and how it can be given safely and how we can sustain remission, why is utilization of ECT going down? It's actually going down. And I'm going to show you some of the data on that. So it's been estimated that just over seven people per 100,000 received ECT in the U.S. in 2009. Well, how many is that? It's actually almost half of the number that received ECT in 1993, which was 12.6. So the utilization per capita is going down. Depression is not going down. Suicide is not going down. ECT utilization is. Some studies suggest that some of this reduction in use is being driven by a number of factors, one of them being reduced utilization among the elderly, who are at increased risk of suicide, lethal means, and respond very well to ECT. The use in the elderly is going down. Now when you think about, well, how prevalent is depression? Some estimates put it as 16,000 per 100,000 people. And so when we contrast that number with the number per 100,000 who were getting ECT, and when we remember how common treatment resistance is among patients with depression, there's a real mismatch here. High rates of depression, but low rates of ECT utilization, and the rates are going down. The number of hospitals offering ECT is also going down. And so that's the first aspect of access. To access it, you have to be admitted to a hospital that has ECT. The number of hospitals that have ECT have gone down over the decades. It used to be about 75%, now it's closer to 40, or just over 40%. So here's some of the data on the declining availability of ECT in the United States. This study by Case et al. used a U.S. sample of discharges, patients who had been admitted for severe depression, recurrent depression, from 1993 to 2009. And you can see overall that there was a trend for reduction. The red line are those people who were 65 and older. That red line showing the most marked reduction. The study showed that the use of ECT fell from 12.6 to 7.2 per 100,000, and this reduction was mostly seen among the elderly. This dramatic decline driven by the decline in the probability that the hospital conducted ECT. So as I mentioned, it used to be around three-quarters of hospitals offering ECT, now it's less than half, less than half. And the decreased access is not uniformly distributed. There are disparities in who is having less access to ECT, specifically individuals from poorer neighborhoods, publicly insured, or uninsured, who are less likely to be treated in a hospital that performs ECT. So when we think about the social determinants of health and healthcare disparities, this is one of them. So when we think about what are some of the factors that are impacting access to ECT? Stigma is a big one. That's a major barrier. But there are others, provider shortages, shortages of ECT practitioners, lack of knowledge of and training in ECT among providers, especially among child and adolescent psychiatrists. I hope we've got some child and adolescent psychiatrists out here. We need you. Keep up the good work. There are also state laws that are restricting the use of ECT in certain age groups. So think about what state you practice in, and then consider what state laws impact your ability to use ECT in youth. So here we are, we're in California. The age cutoff is 12. And to use ECT in ages 12 to 16, there needs to be emergency and life-threatening treatment only with the involved procedures. And I won't read you the slide, but there are a number of restrictions across a number of states to accessing ECT because of laws restricting the medical practice. So you may know that the FDA changed the classification of ECT. ECT used to be class 3, which is a significant risk device. And the day after Christmas in 2018, they changed that order. They reclassified it to being class 2, meaning that there needed to be procedures to mitigate the safety risk, but it basically means that it's a safer procedure when you follow these procedures. And it also narrowed the label. So ECT is now on label for treating catatonia, or severe major depressive episode, and unipolar or bipolar disorder, in people who are 13 and over, and who are treatment resistant and require a rapid response. And so you notice there's some pertinent things missing from this slide, like treatment resistance, schizophrenia is not on there, other things that ECT is useful for, like self-adjusted behaviors and autism, not on that slide. So for the things that are not in the first bullet point, FDA requires a pre-market approval, or a notice of completion of a product development protocol would be required for those other indications to be on label. Of course, off-label practice is permitted. FDA does not regulate the practice of medicine. But it is important for everyone to know what ECT is classified for, and for your patients to know if you're treating them off-label, because they do need to be informed of that during the consent process. So I was talking about health care disparities and social determinants of health. There are racial differences in ability to access and the use of ECT. So in this study of almost half a million adult inpatients with a current major depression in the US who were admitted to community hospitals from 1993 to 2007, the red line shows the use of ECT for white versus black patients. And, well, it's higher. The utilization was higher in white patients compared to black patients. The purple line shows you that that disparity in utilization was not because they were admitted to hospitals that didn't have ECT. That's actually a one-to-one ratio. They were admitted at the same rate to hospitals that had ECT. It's simply that they were less likely to receive ECT, despite being admitted to a hospital that had access to ECT. Now, this study looked at a similar question, but went a little bit further to look not just at race, but also ethnicity and age on utilization of ECT. Across this time period, again, over half a million patients now looking at the elderly specifically. And that's the demographic I told you where there were more significant decreases. And what the study showed, so 45% of the patients were admitted to hospitals where ECT was available. However, Hispanics were 22% less likely than non-Hispanic whites. Non-Hispanic whites are the black line there, and Hispanic is the red line. The red line is lower, so the Hispanics were 20% less likely than the non-Hispanic whites to be admitted to an ECT-available hospital. So of course, they couldn't access it. And non-Hispanic blacks, which is the blue line, were nearly half as likely to receive ECT as non-Hispanic whites. So we have a number of factors that are influencing access to ECT on the basis of age, race, and ethnicity. Well, can we go a little deeper and understand what might be underlying these? Why is it that the patients are not being diagnosed with a disorder that is treatable by ECT? Is there some bias in diagnosis? Is there bias in a referral on the basis of the provider? This study looked at provider-level variables. The flow chart shows a variety of steps that need to happen for you to be, if you're a patient, for you to be prescribed ECT. First of all, you have to be diagnosed with something that is a major indication for ECT. And we know that there's racial bias in the likelihood of diagnosis and also in patterns of referral for different types of treatment. So there could be racially-influenced referral bias impacting whether you successfully go through this flow chart and at the bottom receive ECT. Another study concluded by McCall and Parker that work is needed to identify mechanisms by which systems level and provider-level racial bias perpetuates these disparities in real-time clinical encounters. And I'm not here to tell you what the solution is to this, but I am here to say that collectively, we need to develop solutions at the provider and systems level if we are going to move beyond simply showing you numbers that are concerning to being able to do something about it. And it is something at the systems level. So another aspect in terms of this flow chart of getting ECT is the informed consent process. And I was just having a discussion before this panel with an ECT provider about one of the patients that she had who was an African-American. And in thinking about the consent process, what she shared with me was that he had good reason to be skeptical about, what is it that you're trying to do to me? Should I trust you? When you consider the history of medicine, of medical research, and the history of our field with respect to differential treatment of people on the basis of race. And so this paper called for a culturally informed consent process in which it encourages clinicians to respect the unique experience, especially among our elders from minoritized communities, that they have legitimate reasons to be skeptical, to be concerned, to not trust, and that we have work to do to build trust so that the informed consent process can occur in a culturally informed way. And one of the conclusions of this article is that it places responsibility of creating racial equity in ECT upon clinicians' willingness to overcome our self-imposed stigma against validating mistrust and acknowledging the tangible impact of racial disparities. So that concludes my talk about ECT in terms of new updates, access, and acceptability. And now I'm going to hand the podium to our next speaker. And if there's time, I'll be back up at the end to talk about some future directions with new forms of neuromodulation and some exciting things coming down the pike from the BRAIN Initiative. Thank you. Thank you very much for being here. These are my disclosures, not related to this talk. And I will start my part of this presentation by talking about vagal nerve stimulation. Vagal nerve stimulation is a device that has been used on fewer, fewer patients compared to ECT, TMS, and other techniques, so we're talking about a few thousand. But we put it together in this talk to show how the novel neurotherapeutic interventions are really not available for patients with disparities in access to technology like vagal nerve stimulator. So you'll hear in a little bit are appalling. Let's start with what is it. It's a device composed by a battery, a generator, implanted in the chest, and a wire is tunneled to the vagal nerve. It delivers impulses throughout 24 hours, and it's very slow acting, it's not something you can implant in emergency. The consent process is extremely long to convince a patient that they do need a device implanted. By comparison, a pacemaker, which is very similar in terms of technology, is not that hard to convince a patient with arrhythmia. The cardiologists have a much easier life to convince them compared to what we do. A little bit of history. Since the 60s through the 80s, there were animal models showing that the cortical synchronization and desynchronization was modulated by the afferent fibers of the vagus nerve. In the 1980s, there were early clinical VNS studies. Again, VNS was developed for epilepsy, not for psychiatric disorders. And they were attempting to translate a new paradigm about treatment of epilepsy with this device. The studies were positive. In 1997, VNS was approved by the FDA for treatment of refractory epilepsy. And in this context, some astute clinicians started to observe that the patients, regardless of the control of the epilepsy, had marked improvement in their depression symptoms. And this led to a new series of studies to find a new indication for this device in patients with mood disorders. If we go back to the early 2000s, this is when the studies were published. We're talking over 20 years ago. There were studies starting in small samples, short duration, and the response rate was interesting. In patients with treatment-resistant depression, within 12 weeks, it was a 40%. The improvement was sustained over time, and the numbers continued to go up as the months go by with this device. There was a randomized control trial, including 124 patients treated with medication, treatment as usual, and 205 treated with the treatment as usual. They stay on their medication, psychotherapy, regimen, whatever they were on before, but it was at the VNS. This was three months, again, a relatively short period of time. We learned after the fact that the duration of the trial matters, and the amount of energy delivered by each pulse matters. The study was, unfortunately, not significant at three months, but the one-year response was 27% in patients with implanted VNS versus 13% in patients with treatment as usual at one year's sustained response. Again, we're talking about a population that have failed multiple treatments, and about 30% of these patients have failed electroconvulsive therapy, patients for whom we don't really have guidelines. Lately, in 2017, there was a five-year non-randomized study, including almost 800 patients, and they compared the outcome at five years, and this was shocking. The cumulative response rate for patients in the VNS group was 67% in patients with treatment-resistant depression at five years. Decreasing hospitalization, decreasing suicide attempt, decreasing all the outcome, solid outcome, is not just about symptom improvement. This saves money to the insurance company. This saves money in the system, and improved quality of life, reduced suicide versus treatment as usual. What are the side effects once you have this device? If you are to discuss with the patient, what are the pros and the cons of having this device implanted? There is some temporary hoarseness. The device goes off every five minutes, so for about 30 seconds, the voice changes. There's some cough, shortness of breath during this on phase. There is the risk associated with any surgery of infection if the appropriate procedures, the surgical procedures are not followed, and there is another surgery to replace the battery on averages after 10 years, and medical procedures requires special precautions if there are defibrillators, ultrasound can damage the VNS, and they need special precautions if they need to undergo MRIs. The cost was pretty high when it was originally approved, and is going up, so we can tell you a little bit about how expensive is the device, the surgery, the neurosurgeon, brief hospitalization or the stay in the hospital, all together is very expensive, and in the first three to six months, the programming is required, the device is activated, and then the impulse of the energy is gently increased every couple of weeks to reach the target dose. So this is a lot of visits with a specialist who is familiar with the programming of VNS. That is also pretty expensive. The story becomes a little more complicated because it was approved and covered without any particular problem by every insurance for epilepsy. In 2005, finally, VNS was approved by the FDA for treatment-resistant depression in patients over 18 who have failed four antidepressant trials, and in 2007, Medicare announced that they would not recover for VNS when used for depression, and most insurers followed through. So we have a device that is approved, effective, potentially saving life, and nobody pays for it. After the more recent studies, there was a memo that CMS would cover VNS device for Tier D after a CMS-approved double-blind randomized placebo-controlled trial with a follow-up of at least a year, and this is why Medicare partnered with the makers of the device to design this extremely long, complex study, recruiting a very large sample of patients in order to gain the coverage, the necessary support and data to obtain the coverage from insurers for this device. Again, the disparity for our psychiatric patients versus patients with epilepsy, there is exactly the same device, same surgery, same programming, same everything, covered for epilepsy, not covered for patients with treatment-resistant depression. I'll pass the baton. So we're now going to move on to transcranial magnetic stimulation, and I have no disclosures. And somehow our clicker got unhooked. Technical difficulties. Yep, pressing it. Oh, you got it. It's up. Wrong slide, though. There we go. Thank you. Making you get out of your seat is what made it work. No, it's. And there we go. All right. I have no financial disclosures for this topic. And we are talking about transcranial magnetic stimulation known as TMS. TMS is a non-invasive technology based on Faraday's law of electromagnetic induction. TMS induces high and low intensity magnetic fields in a specific brain region in order to modulate cortical excitability. These devices were cleared by the FDA since 2008 for the treatment of major depressive disorder that has failed to respond to at least one antidepressants in adults. The picture is showing example of only one of the FDA cleared devices, of which there are many. Just like Dr. Listenbee discussed, there are many things that make up the TMS, quote unquote, dose. TMS is a platform technology in which its effects depend on what TMS protocol is enacted. The parts of a protocol include the location of the treatment field, and in major depressive disorder, that's the dorsolateral prefrontal cortex, as well as the stimulus frequency, or the frequency at which pulses are delivered. The number of pulses are grouped together into a train, and the total number of trains determines the treatment session length. Just like with ECT, there's another dosing parameter of the stimulus intensity. In transcranial magnetic stimulation, the intensity is individualized based on what is called the motor threshold, or the amount of energy necessary to activate the motor cortex. It's believed that this same energy amount will activate other areas of the cortex for treatment. Finally, a protocol has a total number of treatment sessions that are delivered. And lastly, there is the context in which the sessions take place, whether they are once a day, or whether there is a concurrent therapeutic action that happens at the same time of the stimulation. Now, TMS was first cleared for MDD, but it has been explored in multiple disorders. And there is also FDA clearance for the treatment of obsessive compulsive disorder using a different protocol. And for smoking cessation using a different protocol. As you can see, there's many more conditions on this list in which there is moderate favorable evidence for TMS, even though there are only three FDA cleared protocols. Oh, excuse me. There's only three FDA cleared conditions at this time. If you take home any piece of information, something I want you to take home is the fact that TMS has a excellent safety profile. The common side effects associated with TMS are minor and easily managed, and include headache, scalp tenderness, and facial pain. Because the electromagnetic field is passing through the scalp muscles and causing physical contraction, that's the source of many of these side effects. The most serious potential side effect for TMS is seizure caused by over activation in cortical excitability, which is also extremely rare. There are very few contraindications to TMS, the most important being implanted ferromagnetic metal near the coil site. And this is a contraindication because the magnetic field is about the same strength as an MRI magnet, so it could cause heating or movement from ferromagnetic metal nearby. The efficacy of TMS has been established in a large non-industry sponsored clinical trial known as the Optimization of TMS, or OPT-TMS trial. This was a prospective multi-site sham controlled trial of TMS monotherapy, so what can TMS do on its own? They studied a protocol where they had three weeks of once a day treatments at the left prefrontal, dorsolateral prefrontal cortex, dorsolateral prefrontal cortex, and they delivered treatment at 10 pulses per second, or high frequency TMS for four second trains with a 26 second inter-train interval for a total of 3,000 pulses per session at supra threshold at 120% of the patient's individual motor threshold. This trial was very successful and there were no serious adverse events, so no seizures, deaths, or suicides were observed. And there was very high tolerability for this treatment with good retention and only 5.5% of patients treated with active TMS discontinued due to discomfort from side effects. In this very early trial, they were still having very remarkable effects and they had a rate of remission, complete resolution of depressive symptoms in 14.1% of the actively treated patients compared to only 5.1% of the sham-treated group, which was statistically significant, and they estimated a number needed to treat of about 12. Since these very early studies, we have continued to improve the response and remission rates for TMS by doing things like including concurrent oral medications and by greatly increasing the total number of treatment sessions from this three-week to closer to a six-week regimen, which is what's commonly used in clinical care at this point, which can make TMS a very labor-intensive and logistically challenging treatment to access. There's been a few important major advancements in the last few years for TMS, and one of those is intermittent theta burst stimulation. This involves the refinement of the stimulus frequency to a new type of stimulus that happens at 50 pulses per second, or 50 hertz. It occurs in triplet packets, and these packets are delivered every 200 milliseconds or at a five hertz carrier frequency. This type of theta burst stimulation has been shown in preclinical studies to induce excitability in the brain and long-term potentiation-type synaptic plasticity. A very important clinical trial in the TMS world is the 3D trial by Bloomberger and colleagues, where they directly compared 10 hertz regular TMS in red with intermittent theta burst TMS, and they showed that intermittent theta burst was non-inferior to 10 hertz, showing you could get similar clinical benefits from a three-minute protocol, reducing it down from the 10 hertz 37 and a half minute protocol. Another really important refinement to the field has been the Stanford Neuromodulation Therapy or the Stanford Accelerated Intelligent Neuromodulation Therapy, or SAINT. This is a refinement of the clinical TMS protocol because it includes changes in session frequency, so instead of one single session per day, we're talking about multiple sessions per day. They are also using theta burst stimulation, so they enhance the stimulation frequency, and their final modification was personalized, imaging-based functional MRI targeting to personalize the treatment location. This is data from Eleanor Cole's paper in the lab of Dr. Nolan Williams from their sham-controlled randomized trial, where their treatment protocol included only five consecutive days of treatment, but the patients had 10 sessions per day administered hourly, and they received 18,000 pulses in a day at a motor threshold range between 90 and 120%. As you can see, the HAM-17 score is decreasing with the light squares being active TMS and the dark circles being sham, that they were able to receive, they were able to achieve remission rates of 57.1% in the active group compared to 0% remission observed in the sham after only five days of treatment, and they were able to demonstrate some durability up to four weeks after that intensive protocol. This is going to be a really important development to follow in the world of TMS treatment. Now, I'm going to make a transition to talk a little bit more about issues of acceptability. I told you about some of the issues of acceptability in TMS being that a standard treatment protocol can take at least six weeks, and that brings up issues for working adults, for issues of caregiving, for issues of parenting, but I wanna spend a little bit more time talking specifically about an accessibility issue regarding research participation. It's important to look at disparities in research participation because research is how patients get exposed to the latest technology and techniques, and excluding people at this stage of the process can impact the acceptability and access of the treatment at the clinical stage. So what did we find? My colleagues and I examined the published scientific literature of US-based clinical trials whose primary outcome was major depressive disorder improvement. So we wanted to look at the clinical trials, not trials looking at biomarkers that were performed in the United States, the majority of which occurred after the FDA clearance of TMS. What we found was it's very hard to know who's participating in clinical trials because only 20% of the published work actually reported their racial demographics in their publication. Of those that did have reports, we compared the proportion of population groups to the US 2021 census. For example, white participants, white people make up 61.6% of the US population based on the 2020 census. But when we looked at the studies that had demographic information, white people were overrepresented in 96% of the studies, meaning they had a higher proportion. This overrepresentation was apparent across all regions of the United States, even though the demographic proportions may be different across the West, Northeast, South, or Midwest. This suggests that there is a research participation disparity specifically for transcranial magnetic stimulation that needs to be addressed. TMS is not alone in different ways TMS is not alone in demonstrating a research participation disparity. Here is a table from the RECOVER trial that Dr. Khazan was talking about, the Large Prospective Randomized Placebo Control Trial of Implantable Vagus Nerve Stimulation that's currently being co-sponsored by the Center for Medicare and Medicaid Services. So these are, again, US patients, federal insurance. This should be a diverse group of participants who are eligible. And if you look at that center column of the table, you'll see that, once again, white participants are overrepresented, making up 94.4% of the participants in the trial, and black or African American patients make up 2.4%, Asian Americans make up 1.8%, and other groups make up 0.7% of the trial participants, which is out of proportion to the US population and the people who should be eligible based on Medicare and Medicaid usage. So I don't wanna just talk about the disparity. I also want to try to offer some early solutions about what we can do to try to achieve equity in research participation for interventional psychiatry. Clark and colleagues did a literature evaluation and interviews with important clinical trial stakeholders, and they identified that there are five critical barriers that impact participation in research. The number one barrier stated was mistrust. Two was lack of comfort with the clinical trial process. Three is lack of information about clinical trials, and by information, they mean understanding their importance in treatment development and their importance for the good of public health and society. Number four was time and resource constraints. And number five was lack of clinical trial awareness, being not aware that there is a trial available for your illness. Of all of these, lack of clinical trial awareness has been where a lot of the focus has been in trying to improve equitable recruitment for clinical trials, but this was listed as the lowest priority by patient stakeholders of what we should be focusing on. So, Clark and colleagues did also recommend evidence-based messaging and clinical trial design recommendations to further improve trial participation. Number one, to reinforce to the patients that personal health is a priority in the study to increase sense of safety and trust. Number two, to practice what you preach and ensure that there is safety during the clinical trial process. Number three, to confirm that clear information is provided for decision-making, and this needs to be jargon-free, easy to understand, and maybe include frequently asked questions, and always have people available in the trial to answer ongoing questions. Number four, appreciate the participants' involvement. We're not just talking about compensating them for their time, you mean actively demonstrating to them that you appreciate the given time and their participation in the trial throughout the process. And number five, emphasize the available supports, whether that is research staff to answer questions, but also potentially incorporate family members or friends in the decision-making process if the patient desires, and keeping track and updating the patient's primary care provider as an important source of support for them throughout the trial. And then the very clear and normal logistical improvements like providing transportation and having flexible hours for working adults, and using mobile app communications, and sometimes even providing cell phones to encourage people to participate in clinical trials. With that, we come to the end of my section on research participation. But I will do Dr. Cabrera's slides next, and we can talk about stigma and acceptability. As I mentioned, Dr. Cabrera was not able to be with us today, but we're talking about neuromodulation acceptability and the role of stigma. She had no relevant financial disclosures for this talk. This talk is focusing on NIH-funded work, and specifically the paper, Is the Treatment Perceived to be Worse than the Disease? Ethical Considerations and Attitudes Towards Psychiatric Electroceutical Interventions. Dr. Cabrera defines psychiatric electroceutical interventions as electrical or magnetic stimulation to alter brain circuitry and function. In order to treat neuropsychiatric conditions, there were four types of PEIs studied, and those include electroconvulsive therapy, TMS, deep brain stimulation, and adaptive brain implants. She selected these four treatments because they have varied mechanisms of action and perceived amounts of invasiveness. As well as there's a solid mix of well-established techniques that are clinically available and FDA-cleared, as well as techniques that are still purely experimental. And she thought that'd be a good way to get understanding about the different degrees of public acceptance across these technologies. So what were the aims of the project? The aims were to determine the factors that are shaping psychiatrists, patients, and the public's ethical concerns, beliefs, and attitudes about these technologies. So she identified the stakeholder groups of psychiatrists, patients, and the public. Why is it important to understand these stakeholder barriers? Because understanding the barriers allows us to plan for mental health resource allocation and helps us set priorities in trying to identify and address misconceptions about the technologies. All right. So these were the key research questions. How do views about technologies vary by the treatment modality? How do views about these PEI technologies vary by TRD severity, either moderate or severe illness? And how do views about PEIs vary by stakeholder group? Psychiatrists, caregivers, people with depression, and the general public. So I'm only presenting partial data here for this study. There was lots and lots of areas of inquiry. But we are going to focus on the barrier information from this study. And there are two main groupings of barriers. And those are structural barriers, including availability of services, administrative challenges, limited resources, cost of equipment, and referral patterns of psychiatrists. And then there's attitudinal barriers, such as stigma, fear of the treatment, negative health beliefs, for example, concerns about memory loss with ECT, misinterpretations or uncertainty about treatment consequences, and perceived ethical issues will fall under attitudinal barriers. In this survey, there was a open response section. And this is just an example of some of the words that were used in the open response section when talking about all four of these different technologies. And you'll notice the larger, more prominently used words are generally negative. And while there's a few small words, such as good, easy, or helpful, the majority attitude is negative. Here's also some examples from the open response section of the survey. I think ECT sounds just plain scary, and I would never do it. Or it's sad that something reminiscent of barbaric treatment, TMS, is only slightly better than the sickness that you have no control over. It may be the lesser of two evils. And this shows that there is limited understanding and frequent comparison between technologies that may not be scientifically accurate. So let me tell you more about the survey that was performed. This was an extremely large national survey with 505 board-certified psychiatrists participating, and then over 1,000 participants in the general public group, the caregiver group, or patients who were experiencing depression themselves. In the survey, there was an embedded vignette in which they watched a simulated patient encounter where the patient describes either moderate or severe depression, and then the psychiatrist in the vignette recommends one of the four technology treatments. And this is how patients were given a baseline of information to make decisions about these treatments. It was administered via Qualtrics, and once again, there were lots of outcomes measured in this study, but I'm going to focus on the barrier data. The survey was successful in getting a reasonably representative sample. The psychiatrist group was more heavily male, college-educated, older, and of liberal politics, where the depressed patient group was overall younger, and there were less participants in that group who did have a college degree. Here is an example of the most important question from the survey. Below are potential factors that may limit the use of PEIs for addressing treatment-resistant depression in society generally. Please indicate what you think are the three most important practical barriers to this use. And these eight barriers were selected via previous focus group work as well as review of the literature, and you can see they have three big major groupings, grouping number one being logistical issues like out-of-pocket cost, insurance coverage, or geographic availability, attitudinal issues like low public trust and stigma, and informational issues like limited evidence of treatment effectiveness or lack of understanding about the technology. And they ranked these one through three. We're going to zoom down only on the patient's versus the psychiatrist's perceptions here, and you'll notice the darker stacked bars means that it was ranked as the first most critical barrier, and then it fades down second and third. One mismatch I really want to highlight is stigma about treatment. We're talking here about electroconvulsive therapy. It was the number one perceived barrier reported by psychiatrists with stigma, but it was nowhere near number one when it came to the attitude of the patients. This may reflect that patient's decision-making is not impacted by stigma, and they perhaps are thinking more about fear, and it's just not a stigmatizing process. Patient's number one perception was limited evidence of effectiveness, which was drastically different than what psychiatrists thought, because psychiatrists are better informed about the effectiveness of ECT. This shows that even though this treatment has been available for decades, there is not a good common understanding about the treatment's effectiveness, or that information has not been well accepted. Here, we'll talk about the perceived barriers in transcranial magnetic stimulation. You'll see, once again, a mismatch in limited evidence of effectiveness, but now there's a larger proportion of psychiatrists who also share this belief. This may represent that even though FDA approval has been there since 2008, this information hasn't disseminated across the field of psychiatry, or they feel that the evidence presented to the FDA was not convincing enough of effectiveness. The other really important mismatch is through logistical factors. Psychiatrists were more concerned about lack of insurance coverage and out-of-pocket costs, and patients did not highly value those particular barriers. This is another possible area of misinformation, because there is universal insurance coverage for TMS, and that has greatly reduced out-of-pocket costs since FDA approval was gained. And lastly, we'll talk here about deep brain stimulation, which, unsurprisingly, there's limited evidence of effectiveness, because this is still an experimental treatment for major depressive disorder, and there's lack of understanding of this technology, but you see there's less of a mismatch across the barriers for this particular technology, showing that the technology type matters. Last is some unpublished work, which used all of the survey data and focus group data that Dr. Cabrera's group collected, and they found that stigma is an important core component of the schema of coming up with ideas about depression and how you make decisions about your treatment. So targeting stigma is going to be a very important thing if we want to improve access to interventional psychiatry. I'm gonna acknowledge Dr. Cabrera's team at Michigan State University and Penn State University who provided this data. And then I'll hand you over for Ketamine. Thank you. Thank you for still being here at this time. Just for my understanding, how many of you have had direct experience with ketamine? Okay, fair number. Just didn't want to go too basic. Not that direct experience, a little less direct. So I will skip about the part, what is ketamine, old anesthetic, analgesic, it's been used, pre-anesthesia, ECT, combat in a variety of situation. And it's also a drug of abuse, or party drug, and a special K. Just a reminder, for depression, ketamine is off-label. What does it mean, off-label versus on-label? It means that somebody has conducted, and has obtained at least two randomized control trial that were positive, then they went to the FDA, and then they had the label put in the insert package. Now, a company will do that if there is a significant probability of getting a return for their investment, because two large randomized control trial cost millions. Nobody will ever do that for ketamine, because the patent expired in the 70s. So if there is no money to be made, ketamine, I get this question all the time, would probably never have a label for treatment-resistant depression. Just a reminder, oral ketamine has low bioavailability, between 17 and 25% of the dose, and there are a few studies, there is not much in depression. There is intranasal administration, it's 50% bioavailability, give or take, and intravenous, of course, has 100% bioavailability, and then there are other versions, oral or transdermal, that are being developed. But right now, we're talking about this modality. Does it work? I believe it is working. There are data from the early 2000s that a single low dose of ketamine had a positive effect on mood that was sustained. And then, after 2006, study coming from the Intramural Program of NIMH of Carlos Zarate, there were double-blind placebo-controlled studies, and those studies were replicated independently by many, many groups in major depressive disorder and bipolar depression. And there are several controlled studies that support its efficacy in major depressive disorder and suicidal ideation. The informed consent with these patients is another very long process because of cognitive difficulties in severe treatment-resistant depression and the hype from the media. The patients come with extremely high expectations of improvement with ketamine, as if it was a magic tool for us. The research study can show 65, 70% of response rate. At our site, we have patients who have failed a lot of other treatments, many more than four failed trials. About a third of them has failed electroconvulsive therapy, and on average, we're between 45 and 50% improvement, not remission. Post-ECT failure doesn't seem to be different, so these patients continue to respond to ketamine. The worst part of my job is that I have to come up with a plan B from the time of the informed consent. If ketamine does not work, this is what we're gonna do. You cannot really have a patient starting ketamine if you don't have a plan B ready because in the 50% or more cases of no improvement with ketamine, the patients can get really despondent and more suicidal, and if they're not appropriate for ketamine, they do not take the note very well. We have terrible numbers compared to the research studies, but for the patients, even if the numerical value of improvement is not impressive, it's sufficient for them to justify the maintenance and the cost associated with ketamine despite side effects, despite everything, transportation issues. So we explain the low level of response rate with our populations being extremely treatment refractory, being on complex medication regimen that often cannot be removed or decreased, and that the scales we apply probably don't really capture the improvement we see with ketamine in quality of life and other measurement, and then this population is very common to see fluctuation in depression and suicidal ideation related to life events. What we have seen in patients with extremely treatment refractory illness who have been chronically ill for five years or more, stopping the ketamine is almost invariably associated with relapse within a couple of months. So about half of our patients felt better with ketamine for the first time in years. This lasts for a very short period of time, sometimes one to two days in patients who are extremely treatment refractory, and then they're again severely depressed and suicidal. So unless you have the possibility to maintain the ketamine treatment, to sustain this over time, giving just an acute series or allowing a patient to have an acute series using their savings, using whatever money they can collect from family members who are willing to help, in reality would be detrimental because the patient at that point realizes that they do have some treatment that could be beneficial, it could help, and all of a sudden they have no access, and this has been some of the most heartbreaking situations we had at the clinic where the patients use all their savings and then they have to stop treatment because of lack of money. And then the problem with needing to include a good CBT team and access to psychotherapy because ketamine doesn't do all the work. Ketamine without the psychotherapy, without the functional, the rehabilitation, the vocational rehabilitation often doesn't help as much as we would like. How long is the treatment is the major problem. We don't have long-term data. We have case series and registry data, and it's likely like any other medical condition. Young patients with an intermittent type of disease where they have an episodic course of major depressive disorder, a cycle of ketamine or a brief treatment of ketamine will get them out of the episode and then the cycle of their illness will resume with whatever interval they were supposed to have. But patients who have been chronically ill for a long period of time, they do relapse. Just briefly, the patients allowed to get ketamine at our site, they have to have depression with significant functional consequences where ECT is being considered as failed or not tolerated or the patient is refusing it. Suicide risk in major depressive disorder and bipolar. They have other symptoms, depression, in the context of major access one disorder like PTSD or OCD. And for maintenance of patients who had a good treatment, patients who had a good therapeutic response. And then initially, we exclude patients with major acute medical illnesses and over the years, we have patients with terminal cancer, we have patients with all sorts of medical conditions and they were seeking relief from their severe depression so we're becoming much more flexible on medical complications. Major exclusion, substance use disorder, ongoing substance use disorder, probably not dangerous, but we know cannabis and other substances block the effect of ketamine so they make the treatment move. Psychosis because we don't have good data, we're not sure whether we could make patients worse over a long period of time. And then untreated medical illness, especially unstable blood pressure control. If the psychiatrist is not involved or the patient is self-referred, we will not take them. And if they have no transportation because MGH mandates an adult escort at the end of the procedure, no matter how small the dose of ketamine. The ethical dilemma of when is enough, when is ketamine the right next step? We don't have clear guidelines. In general, insurance, and I'll talk in a minute, will require four failed trials. In other cases, we have patients where we're trying to make sure they don't lose their job, they don't drop out of college or they're acutely suicidal and we need to figure out can we use ketamine in those conditions in sort of an emergency modality and can we convince the insurer that they should pay for ketamine in order to preserve functioning. I wanted to brief talk about the access issues at our site. Patients have been asking to try ketamine since 2012 when the first studies were just coming out. And we get five to 10 calls per week. We know that the patients who remain at the clinic in over three months after the initial series, they will probably require long-term maintenance for an indefinite period of time. So we primarily invested in expanding the IV clinic that allows to treat about 10 patients simultaneously and we do two cycles. Those patients are extremely complex. There are multiple psychiatric comorbidities have been hospitalized multiple times. They fluctuate, they relapse, they attempt suicide, hopefully rarely, but those patients require a team effort and it's a lot of work. It's not that we can just give the infusion and then forget about it until the next time. In the last, in four years of clinic, we have approached 15 insurers and only two out of 15 have agreed to cover IV ketamine. The same evidence convinced two insurers and did not convince the other that they say, nope, experimental, we don't wanna hear, we don't care. So ketamine remains for a lot of our patients self-pay and the acute series followed by maintenance infusion becomes pretty expensive. We have very limited coverage for inpatients. Most insurers even refuse to cover for patients who are hospitalized. Paradoxically, the insurer prefers to pay for longer hospitalization rather than pay for a treatment that could potentially get them out of the hospital bed. It's really hard to understand from my perspective. And that severely limits our space to accept new severely ill patients when they're acutely suicidal because we have a wait list of about 120 patients and we don't know what to tell them. We don't know when they're actually gonna be able to access the clinic. Thank you. I would like to pass to the next session. So we focus this panel on just a few of the many different neuromodulation modalities that are at various stages of research. On this slide, I'm showing you the landscape of the devices. On the x-axis is how invasive they are, from very non-invasive on the left part of the slide to surgery on the right part of the slide. On the y-axis, I'm showing you their spatial resolution, how focal they are, from being very focal at the bottom of the slide to being more non-focal at the top of the slide. So some of the technologies to point out to you that we didn't talk about, because they're still in development, try to maximize focusing at depth. And two of these that I'll mention are transcranial focus ultrasound and temporal interference. The first uses acoustic energy, and the second uses electrical stimulation to try to focus the stimulation at depth non-invasively. So that's a space to watch. But there are many more on this slide that we didn't have a chance to talk about. I'm going to highlight a few to highlight some of the research that our group is doing. So to tie these together, I'm gonna present to you a conceptual vision for precision in neuromodulation. We introduced the topic of dose. We talked about dose in space and in time, but we can also optimize dose in terms of the context, what the brain is doing at the time it's stimulated. So starting with spatial precision, we can improve this by using structural and functional image guidance as illustrated in the SAINT approach. We can also improve it by increasing our understanding of what we're actually stimulating with our coils or our electrodes. And that is now available with electric field simulation. So we can really understand where we're stimulating. But we can also design new transducers, new coils and new electrodes that are purpose-built to stimulate particular regions of the brain. In the temporal domain, we can modify the pulse shape, even with transcranial magnetic stimulation with new devices like the controllable pulse TMS device, for example. We can also optimize the spatial pattern or the temporal pattern of stimulation with nesting of frequencies as illustrated by theta burst stimulation, which was already mentioned, but there are other approaches as well. And we can also be clever about when we time the stimulation. We can gate the stimulation based on online recordings of neural oscillations, such as EEG gated TMS, to stimulate the brain when it's in the state that we want to target. In terms of context, we can manipulate what the brain is doing by having the person engaged in a cognitive task and stimulate during specific phases of that task performance. We can also synchronize to ongoing neural oscillations or biological rhythms or circadian rhythms and take advantage of those temporal changes. And we can optimize the both pharmacological regimen as well as what type of psychosocial intervention the person might be engaging in while they're getting the stimulation. And that is an approach we're using in one of our studies. And that study is called Concurrent TMS with Cognitive Therapy for Depression. This, what we're doing in this ongoing study in the Intramural Research Program at NIMH is the patient with depression performs a computer-assisted skills-based psychotherapy while they're receiving TMS. And so you can see the therapist is sitting assisting the patient. The patient's got the TMS coil on her head. We're using neuronavigation and individual MRI targeting. And our primary outcome measure is expression in a particular network of brain areas that are activated by certain skill acquisition. And what I'm showing you here from the dark blue from pre-treatment to the light blue post-treatment, we've seen increases in the bold response using fMRI in the ventromental prefrontal cortex as well as the hippocampus. And so that's our target engagement. And in this ongoing study, which you can learn more about by scanning this QVR code and it's also listed in clinicaltrials.gov, we're seeking to know if when we change expression in this task-related network, does depression improve? Another investigational approach I'd like to mention to you is magnetic seizure therapy or MST. What we did to develop MST is we redesigned TMS devices to be able to be adequately powered to induce seizures under anesthesia. Think ECT, but instead of grabbing the ECT electrodes, you put a TMS coil on the head and stimulate. The reason to do this is that TMS is more focal. And I'm showing you that here with the electric field modeling with ECT on the left and MST on the right, and they're both on the same scale. And this teaches you that even right unilateral ECT is whole brain stimulation, whereas MST is quite superficial stimulation. These more focal fields induce weaker and more focal seizures. I'm showing you here quantitative ictal EEGs, this EEG power during the seizure with ECT in the blue compared to MST in the purple for different frequency bands. So these seizures are weaker and more focal, and they induce less memory loss. I'm showing you here one measure, which is speed of reorientation with ECT in the black bars and MST in the gray bars. Other groups have replicated this, and I've also found similar efficacy between ECT and MST in treating depression. And a confirmatory non-inferiority trial is currently underway. It's an international trial called the CREST study, and when that study is completed, we will have more information to know whether MST is truly non-inferior to ECT. We already have pretty strong evidence that it's safer. So another approach we're taking to try to strip away from ECT, the adverse cognitive side effects, is called individualized low amplitude seizure therapy, or ILAST. What we're seeking to do here is achieve MST-like focality, but out of an ECT device. And how we do this is we individually titrate the pulse amplitude. So I talked to you about seizure threshold titration, where you give increasing number of pulses. Here what we're doing is we're starting with a lower amplitude and gradually increasing the amplitude. So we're individually titrating the amplitude. That's something that's done with TMS. That's called the motor threshold. It was not something that was done for ECT. ECT always used, even when you individually titrate seizure threshold, you're always using 800 or 900 milliamps. This is different. We do this individual titration because it's a way of adjusting for individual differences in head anatomy that influences how much electrical field gets into the brain. When we do this, we find that we can induce seizures with much lower current amplitudes. And here I'm showing you what that matters to the brain. So on the bottom is the electric field modeling with a 200 milliamp pulse versus on the top an 800 milliamp pulse. The hotter colors are stronger electric fields. What we can do with this lower amplitude, it's like a dimmer switch on the electric field, basically making it weaker and sparing deeper regions of the brain. I've highlighted in black outline the hippocampus, which is a key area that we're thinking is a non-target because we want to reduce cognitive side effects. And then we're coupling this with a multi-electrode array. So instead of just using two large electrodes, we're using five electrodes to better focus the electric field. And on the left, I'm showing you a conventional bright unilateral ECT, and on the far right is the eyelast electrode configuration where we can really have a more focal, tighter area of stimulation. This is an approach that's used with transcranial direct current stimulation. You may have heard of high-definition TDCS. This is high-definition for ECT. No reason that we couldn't do it for ECT, it just had not been tried yet. And we're doing it now in a first-in-human study. And if you scan this QVR code, if you have patients that you'd like to refer to be among the first to evaluate whether this approach is feasible and safe. Now the flip side, so I've talked about MST and eyelast, which seek to induce seizures without very much electricity in the brain, testing the hypothesis that it's the seizure and not the electric field that's responsible for therapeutic benefit. But what if the opposite were true? What if it was the electricity that drove efficacy and the seizure drove the side effects? This study is going to test that hypothesis. It's called a transcranial electrical stimulation therapy or TEST. With TEST, we give ECT-like amplitude. So we're giving 800 or 900 milliamps, but we stop the pulse train before the seizure is induced. And so you can see in the middle part of this slide what the TEST train looks like. High amplitude, but fewer pulses compared to conventional ECT on the bottom. And we're doing a randomized controlled trial right now on TEST. And if you scan that QVR code, you can learn more about it. So I'm gonna conclude, seizure therapy can be made safer without sacrificing efficacy by improving the focality of the electric field induced in the brain and the seizure induced. Non-convulsive brain stimulation like TMS can be made more effective by optimizing spatial and temporal tuning as well as by optimizing the context. And I showed you an example of coupling TMS with precisely targeted and timed cognitive intervention may show promise in selectively enhancing circuit function with the potential for therapeutic benefit. And next generation brain technologies offer hope for discovering neural circuit dynamics underlying depression with the goal of one day targeting these more precisely through closed loop interventions. Now, just when you think I might be finished, but wait, there's more. The BRAIN Initiative. The BRAIN Initiative stands for Brain Research Through Advancing Innovative Technologies. One of the best acronyms, and I can't take credit for coming up with the acronym, but I can take credit for being part of the BRAIN Initiative. It's one of the most fun things I get to do at NIH. And the reason why it's exciting is the mission of the BRAIN Initiative is to revolutionize our understanding of the human brain by accelerating the development and application of innovative technologies. So you saw what I showed you on that landscape of neuromodulation. We want more. We want more focal, we want safer, we want higher resolution. BRAIN Initiative is funding such work. And to learn more about it, we invite all of you to come to DC or just tune in online for free to the BRAIN Initiative meeting, which is on June 12th to 13th. You can learn more about it at this website where you'll hear all of the latest research. And by the way, Dr. Cabrera's research on acceptability of brain stimulation was funded by the BRAIN Initiative. So we're supporting not just tech, tech, tech development, but we're also supporting programs on neuroethics and societal and legal impact of these novel technologies. These are the members of my lab at NIMH and we're recruiting. So thank you very much again for your invitation. And now I guess questions. Thank you. being recorded, so we do ask that questions go into the central microphone so they can be recorded and everybody can hear what you have to ask. And while people make their way to the microphone, I also would like to thank Rebecca Brindell, the APA president, who proposed this session and put together this team on the panel for you today. Hi. Go ahead. Hi. My name is Patrick Brindell. I'm going into my third year of residency at Bronx Care Health System. Thank you so much. This is an incredible talk. I'm in the process of getting a deep TMS machine over at Bronx Care, by Brain's Way. We've had a three-month stall in trying to get our main payers, who are Health First and MetroPlus Medicaid, to tell us whether they'll cover it, how they'll cover it, what coverage, you know, policies they have, any advice on that. Maybe it's just our financial department, but maybe it's them. I don't know. Persistence. Yes. I got that, but I mean, like, is there... Absolutely, persistence and to know that maybe you start with Medicare-covered patients who generally do not require a prior authorization while you continue to build your relationships and look for local site contracts for Medicaid coverage, because it's hardest to start with the Medicaid population. Okay. I have more questions, but I'll let... We'll trade off. Hello. My name is Nick. I'm from the Cambridge Health Alliance. My question is about ketamine versus ECT for major depression. In particular, I hear sort of a lot of criticism about this risk of relapse with ketamine, and I wonder how that risk of relapse of a depressive episode compares for risk of relapse from ECT, and whether or not there's similarities in sort of the maintenance scheduling and the expected relapse, or if it's, you know, more susceptible for ketamine patients. We don't have much in terms of direct comparison of relapse rate with ECT. I worked for 10 years in the ECT service at Mass General, and patients do relapse. The sickest they are, the more treatment factor they are, the sooner they relapse, so it's a reality. And the patients enrolling clinical trials now with either ketamine or ECT are usually sicker than the patients enrolling clinical trials in the 70s or the 80s, so it's really hard to draw a comparison. We have many more antidepressants, many more augmentation with atypicals that we didn't have 30 years ago. So it's until somebody funds a study to have a direct comparison about relapse rate, it's really hard to figure it out. I have to say, so far, ketamine has shown to be really benign, even in younger patients. We haven't seen much in terms of cognitive side effects, and the patient's preference also plays a huge role in the choices that they make. Can I also respond? So on Wednesday, Amit Anand will be presenting the results of the ELECT-D study, which was funded by PCORI with over 400 patients randomly assigned to ECT and ketamine. We're really looking forward to hearing those results, and I believe that study has a follow-up period, so that will be a really great question to ask Dr. Anand on Wednesday when he presents that here at the APA. Great, thank you. Go ahead and jump in, Randy, or were you next? I'll come next. You were next, sorry. I'm Ruben from Chicago. Great talk. I was wondering if you could speak a little bit, with the data on right unilateral versus bilateral ACT, do you still feel there are patients suffering from depression where it's reasonable to start with bilateral ACT, and then also just comment on right unilateral versus bilateral and other indications like mania, psychosis, and catatonia? So I'm happy to take that. So, you know, it's a clinical judgment call. I think that if you have a patient who had failed right unilateral in the past and responded well to bilateral, you might consider, well, let's start you with bilateral because of your treatment response history. You know, in terms of other indications, I think that we know less. So the randomized controlled trials, the larger ones focused on depression. We don't have that same level of evidence in the treatment of other conditions with the head-to-head comparison of right unilateral versus bilateral. I know that practice varies. And there is a thought that for some conditions like catatonia, that bilateral might be better given that's a life-threatening situation. However, there's certainly experience of success using even unilateral even for catatonia. So I think it really depends. But I'd love to hear, do you have thoughts on that? And is that something you think we should study further? Oh, I guess I'm thinking just from what I've read in textbooks that, you know, some practitioners talk about the idea that in patient populations that, you know, might not fit into clinical trials, people still use bilateral ACT or right unilateral. And I just appreciate your opinion on that. Yeah, I think that's a very good point. When we talk about evidence-based practice, you don't want to overgeneralize the evidence. And so if the patient you're treating doesn't match the population that was studied, then overgeneralizing might not be the right thing to do. Thanks so much. Thank you. This was a really lovely and wonderful talk, all of you. Thank you. Just want to give a personal perspective. I want to thank Holly, actually you, because it was back in 2006, my journey in TMS and the stimulation world started when you spent a good 25 minutes on a phone when I was referring one of my patients to the original neuronetics trials. So thank you. And, you know, I'm Randy Pardell, and I'm past president of the Clinical TMS Society. I also am president of the Foundation for the Advancement of Clinical TMS. So I guess I'm putting myself out there. But one of the things that happened this morning, Roger McIntyre gave a lecture on TRD, treatment-resistant depression, this morning, and there was one slide on TMS and one slide on ECT. Lots of talk about meds and what meds you can do. For those of us in the world of brain stimulation, what should be the treatment algorithm for treatment-resistant depression? How soon do you move to one of the stimulation treatments rather than adding on another medication? Or it could be ketamine too. You know, I've often thought we need a STAR-D for devices as well as for the novel medications. We don't really know. I think the PCORI-funded ECT versus ketamine trial is a step in that direction. That's a really important question. Which should you give first? And are there any clinical predictors of who's likely to respond to one or the other? You know, when STAR-D was being designed and conducted, I did wonder why wasn't ECT anywhere in the algorithm when you consider treatment-resistant depression? And if you fail, how many trials do you have to make the person fail before they can get ECT? I think, well, this is the APA, isn't it? And the APA puts out practice guidelines for depression that do include ECT and TMS. And so I would say, at least for this organization, and those guidelines are updated on the basis of new evidence. And so I think that's where we would want to position. And of course, those guidelines are evidence-based. And there might be gaps in the evidence. There might be studies that need to be done to address where those gaps are so that those guidelines can be comprehensive and incorporate all of these new developments. Okay. So to be seen, to be determined. Okay. Yes. Yes, hi. My name is Karina Stone. I live in Portland, Oregon. Oregon, the laws do not specify, the laws are very confusing around ECT, and practitioners require a judicial order if someone's not able to consent, even if they have a guardian. So I often wonder where are things at with MST in terms of it being FDA approved? I know there's several randomized trials, and I'm just curious how, if there's been specific studies to compare stigma around magnetic-type treatments versus electrical-type treatments. Great. Well, thank you for that question. So I mentioned there's a confirmatory efficacy trial underway right now that NIMH is sponsoring. It was powered to be a non-inferiority trial. And so when that study is finished, we will know more about whether there's a level of evidence that the FDA would find acceptable to find MST substantially equivalent to ECT, which would be the regulatory pathway. So in addition to that trial, I actually recently submitted a manuscript on a trial that I did on ECT versus MST, in which we found no difference between the efficacy of the two, and also no difference in maintenance of benefit at longer-term follow-up, but improved cognitive outcomes with MST. And we're not the only ones. Other groups have published this. The way that things get FDA approved is that an industry partner would want to have a product put forward for substantial equivalency. And so it really is a question for the industry about the interest in bringing technologies like MST or some of the other technologies we talked about to the stage of FDA approval. And as we saw in the case of VNS, getting FDA approval is not the end of the story. You have to get CMS approval. You have to get the insurance reimbursement as well. But in terms of the acceptability, I really like your idea. There's room for studying the lived experience and the patient perspectives on what it's like to get ECT versus MST. That's a really great idea. So thank you for raising that. Next. And we are going over time, so feel free if anybody needs to walk out. But I'm not going anywhere. We're the last session. So thank you very much, Danielle Kushner from New York City. I work in forensics and correctional settings. So I wanted to go back to the discussion about the disparities and access to care to these treatments. And from the varying systems I've been with, just seeing the varying levels of access to ECT, I think we can all agree ECT is probably the best option that we have in correctional settings. And my system is lucky to have that, but not all do. So I'm kind of curious to your guys' experience in advocating for that access, any particular challenges in your areas. And one side question with that is also involuntary treatment for these settings. And any thoughts you have. Thank you. So I actually don't have any experience advocating for neuromodulation access in the correction facilities. My best friend from residency works at Folsom State Prison, and I'm sure she would love to be able to use her skills in transcranial magnetic stimulation and ECT. But I do not know of anybody who is spearheading that advocacy right now. Do you want to say anything about court involuntary treatment in corrections? No? Okay. Dr. B? Hi, I'm Mate Beiser, University of Minnesota. I was curious about your thought. I appreciated that you had bifrontal on there. It's a little bit of the redheaded stepchild even within the ECT community, and I just wanted to probe your thoughts on what you see as the role of bifrontal treatment. Yeah, so it's an example of how much the way we practice is based on how we're trained. I've never given bifrontal. I was trained to give unilateral or bilateral, but I'm also influenced by data, and the consortium for research on ECT randomly assigned patients to right unilateral, bilateral, and bifrontal and found similar efficacy among them. You know, if you've got more experience with bifrontal, I'd be interested in hearing that. I think the attempt for bifrontal was to try to make it safer than bilateral, but I'm not sure that we know enough about where is it more effective, because the studies that were showing on antidepressant efficacy were unilateral and bilateral. Bifrontal wasn't anywhere in those studies, so I think we know less about that. I trained at Zucker Hillside, where actually the majority of our treatments were bifrontal, and, you know, so I guess where I think about it is for patients who, you know, have been treated, you know, and are, you know, we're doing bilateral treatments, and the cognitive side effects are really accumulating, and the evidence for unilateral in, you know, whether it's catatonia or psychosis is less robust in that population, where, you know, I guess my impression is that it splits the difference between the two other placements, but in terms of efficacy and side effects, but in my current practice, I actually haven't, I don't do that much ECT, although recently I've been doing a lot more, but I haven't used it, so, yeah, I was glad to see it mentioned. Thank you. Thank you for sharing that. Next. Hi, my name is Bianca Day. I'm a medical student at UCSF. Thank you so much for this talk. A question that came up for me, especially thinking about, like, racial disparities in, like, access to care and also patient perceptions of barriers to care, I was wondering if there have been any studies on, like, demographics of the patients offering neuromodulation treatments, just thinking about, like, cultural concordance and how that can, like, improve the therapeutic alliance. So, all the racial concordance studies that I have read have been in the area of electroconvulsive therapy, and unfortunately, even in relationships of racial concordance between the provider and the patient, there are still no ECT recommendation and still persevering difficulties in correct diagnosis and referral for ECT-qualifying diagnoses. So, that's where I would look if you want to read in that area, but otherwise, I think for other technologies, the field is really open. Yeah. Thank you so much. I'm just saying thanks and bringing a Scientology perspective into the room. Hey, hey, APA, how many kids did you shock today? And the answer is not enough, and we need to be accountable for that. So, thank you for bringing us this education. I will note that the odds ratio with which youth are under prescribed ECT is identical to the fall-off in Scientologists between 1991 and now, because there's a .3 odds ratio for youth getting prescribed ECT, and there are many, many fewer Scientologists in the exact same ratio than there were back in the day. So, we should not fail like they have failed as an organization, and they're right to criticize us for our underutilization of neuromodulation in youth, and thank you for bringing it up and how crucial it is, because these are life-saving treatments, and on the stigma point, for me personally, I'd be dead without it. So, thank you for the work that led to my doctor saying, let's try this, and we all need to get as many of our colleagues who look as varied as humans are to have these conversations with our patients and really mean it. Thank you. Thank you. Thank you, Owen, and I absolutely agree that ECT is an essential part of the mental health treatment infrastructure, and everybody should encourage all the trainees they know to gain that skill set so they can continue to expand ECT access across the country. One more, Rich? I just had a question on the ECT access and going down. Anybody look at reimbursement rates? I've been doing ECT for the last 10 to 15 years, and where I've seen trouble with us recruiting more doctors onto the service is, you know, as reimbursement rates have gone up for E&M, which I'm very thankful for, frankly, they can make more money per hour seeing two or three medication patients versus doing two or three ECT patients an hour. So, where the rubber meets the road, you know, in clinical practice sometimes is everybody has to pay their mortgages, put their kids through college. So, I've seen more than one program go down because we can't recruit people to staff. Yeah, I'll comment on that, and thank you for raising that. So, when we consider the cost effectiveness of a treatment in psychiatry, I think it's important to consider that in the context of the larger health system. And it's not just about psychiatry reimbursement rates, but about anesthesiology, the OR, the PACU or whatever, you know, hospital-based system. And there are models where, on balance, actually it's financially feasible. It depends on how you parse it out between the professional fees across the departments and the hospital fees. So, I think it's to sustain financially, it does require a partnership with the other disciplines as well as with the healthcare system. Yeah, yeah. The facility has made a lot of money, and the anesthesiologists have a really good case rate. But in our system, it's really been challenging. I do believe that there is, yeah, I have one more for Michelle. I do believe that there's an open comment period, because there is a current movement to petition for additional codes for procedures to be used in the inpatient setting, specifically to provide for the SAINT TMS protocol. If they are successful in petitioning for codes, they can add on to that billing to the regular day weight of inpatient care, and ECT may be included in that process. Hi. Bring us on home. Y'all did a great job. I'm so impressed. It was so much fun to listen to y'all, and I'm sorry that your fourth could not be here. I thought it was curious how we talked about ketamine and not the FDA-cleared version of it. Any comments? What do you want to hear about it? I'm just curious. Do you use it in your lab? Esketamine is a very small cohort, because also the insurance was a nightmare at the beginning, and then once it became more widely covered, we didn't have any room, because those are two-hour visits every week. That would prevent us from treating more patients who are acutely suicidal. So at this point, we're trying to figure out, and we are pursuing expansion of the space for esketamine patients, but because we have this large cohort of patients on IV ketamine to maintain and to continue to treat, the space for esketamine was extremely limited. On that same note, do you have patients that now that have been using ketamine that you offer them to convert to esketamine since it's covered now? Why would you do a treatment two hours once a week if you can do an hour and a half once a month? They're not happy about it. It's just the induction month. It doesn't mean you actually have to. We've done it in our office. We've converted them, just hard convert. It's a space issue. At most general space, real estate is really expensive and not available. Okay. Thanks.

interventional psychiatry

electroconvulsive therapy

vagal nerve stimulation

transcranial magnetic stimulation

ketamine administration

major depressive disorder

psychiatric conditions

treatment efficacy

treatment side effects

treatment accessibility

treatment stigma

neuromodulation

racial disparities

socioeconomic disparities