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Treatment-Resistant Depression: An Update on Manag ...
Presentation and Q&A
Presentation and Q&A
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Hello, everyone, and welcome. I'm Dr. Rob Cotez, Associate Professor at Emory University School of Medicine, Director of the Clinical and Research Program for Psychosis at Grady Health System, and SMI Advisor Physician Expert. I am so pleased that you are joining us for today's SMI Advisor webinar, Treatment-Resistant Depression, an update on management strategies. SMI Advisor, also known as the Clinical Support System for Serious Mental Illness, is an APA and SAMHSA initiative devoted to helping clinicians implement evidence-based care for those living with serious mental illness. Working with experts from across the SMI clinician community, our interdisciplinary effort has been designed to help you get the answers you need to care for your patients. Today's webinar has been designated for one AMA-PRA Category 1 Credit for Physicians and one Nursing Continuing Professional Development Contact Hour. Credit for participating in today's webinar will be available until July 17, 2021. Slides from the presentation today are available in the handouts area found in the lower portion of your control panel. Select the link to download the PDF. Please feel free to submit your questions throughout the presentation by typing them into the question area found in the lower portion of your control panel. We'll reserve 10 to 15 minutes at the end of the presentation for Q&A. Now I'd like to introduce you to the faculty for today's webinar, Dr. Brayden Kamig. Dr. Brayden Kamig currently serves as an Assistant Professor of Nursing in the Department of Health and Community Systems, where she has the opportunity to blend her passion for teaching, clinical practice, scholarship, and service. She teaches across the undergraduate and graduate programs where her teaching responsibilities include mental health nursing, advanced practice psychiatric nursing, psychotherapy for advanced practice psychiatric nurses, and psychiatric management for primary care providers. She is also involved in various health education training programs, most recently and currently serving as faculty expert on a SAMHSA-funded program that is integrating substance use training and specific content on buprenorphine prescribing across advanced practice registered nursing curricula. Dr. Kamig, thank you so much for leading today's webinar. Thank you so much. I am really excited to be here and I want to thank everyone in advance for their time and attention today. So the learning objectives for this afternoon at the end of the presentation, you should be able to identify risk factors for treatment resistant depression, describe pharmacological and interventional psychiatric treatment strategies, and describe strategies for implementation of interventional psychiatric treatment strategies in clinical practice. I am certain that it is no surprise to anyone here this afternoon that depressive disorders remain really a very significant public health problem, perhaps now more than ever in the context of COVID-19. One of the more recent large epidemiological studies that included well over 600,000 individuals used data from the National Survey on Drug Use and Health, really looking at the prevalence of depressive disorders within the past year in people over the age of 12 across the United States. So over a 10-year period, ranging from about 2005 to 2015, we saw an increase in depressive disorders from about 6.6% to about 7.3. And that's fairly comparable to what is reported in the DSM-5. While maybe not a huge percentage increase, we can see this as less than 1%. When you think about the sheer number of people in the United States, it impacts a large segment of the population. When we look more broadly, that is at lifetime rates of depressive disorders across the world, a recent meta-analysis looked at 90 studies, they were conducted over 30 countries, spanning over a million adults. And interestingly, one-year prevalence rates were fairly stable from the previous US study that we just talked about, but lifetime rates reached nearly 13%. So moving forward, looking at these risk factors, I'm fairly confident that this is probably what many of you have encountered in clinical practice. And as you can see, a lot of these risk factors may have become more pronounced in the context of the COVID-19 pandemic. Women consistently have an increased risk for depressive disorders, suicide attempts, other risk factors like social isolation, educational status, financial instability, and veteran status remain fairly significant risk factors for the development of depressive disorders and depressive symptoms. Interestingly enough, while not included in today's presentation, I did come across a recent study looking at risk factors for COVID-19 infection and mental health comorbidities following COVID-19 survivorship, and veteran status was one of the strongest risk factors for COVID-19 and associated mental health problems. Unfortunately, we know that for many individuals, we know there's high rates of depression prevalence across the United States, and for many people, symptoms can be refractory or treatment resistant. Since the STAR-D studies well over a decade ago, it's been fairly well known that first-line medication interventions, first med that you try, be that an SSRI or an SNRI, have a remission rate of only about 30% or less than one in three people. So with these high rates of treatment-resistant disorders, come high rates of disability, healthcare, social costs. When prevalence rates were compared with average direct costs, so that would be things like medical services, prescription drug costs, costs related to death by suicide, so looking at things like lifetime earnings lost, workplace costs, the annual costs related to major depressive disorder alone exceed $200 billion annually. So in this context, we know that depression can be difficult to treat. We know that prevalence is high, associated morbidity, mortality, and costs are high. Nonetheless, there remains really a lack of consensus about what exactly constitutes treatment-resistant depression. Some have delineated treatment-resistant depression as a failure to achieve remission with two to three med trials from different classes. I think it's important just to reiterate when we think about medication trials, thinking about the adequacy of the trial. So what was the dose? What was the duration? I'm sure many here have had patients come in, they have a very lengthy extensive med list, and then you drill down and you find out, you know, these people have never really been on higher than the minimum dose. They've never had a trial longer than a month. So really thinking about was the trial adequate? When you think about this definition, rates of treatment resistance are really estimated as high as 30%. And I think that data alone speaks to the importance of being familiar with second, third-line interventions to treat depression. I'm sure that everyone here has their own experience as to why this really hits home, why this is so important. Thinking back, I think all of us have cases of people that were really quite refractory and difficult to treat. So we reviewed that depression can be difficult to treat. We reviewed that there are high rates of refractory symptoms. All of that considered, it is not hopeless. As providers, we have a lot of tools in our back pocket. There are multiple interventions that we can use to address refractory depression beyond first-line antidepressants. And we'll talk about some of these options today. So some are more tried and true pharmacological augmentation strategies, augmenting with atypical antipsychotics, lithium. We'll briefly review that today. And then other things, ECT, while that falls under that interventional psychiatry domain, we certainly know that ECT is not new. We do have some more emerging interventions like TMS. And then we will briefly go over things like ketamine and esketamine. So thinking about pharmacological strategies, we obviously have more traditional antidepressants, things like TCAs, MAOIs. As I'm sure we're all aware of, of these strategies, to some extent have fallen out of favor definitely as a first-line intervention due to their side effect profile. But we know they can be effective as an augmentation strategy for more refractory depression. You can think of TCAs as being more of a true augmentation through which we're maybe augmenting at lower doses, maybe more addressing sleep, pain. Certainly MAOIs are prescribed as monotherapy after that washout period. We know rates of MAOIs prescriptions dropped really considerably after better tolerated medications became available like SSRIs, SNRIs. We know there is concern with MAOIs for medication interactions, serotonin syndrome, hypertensive crisis, the list goes on. But there are some cases when those types of medications as a later line approach can be appropriate to address refractory symptoms. More recently, multiple atypical antipsychotics that are FDA approved for depressive augmentation, Seroquel, Abilify, Rexaltine, Symbiax, Olanzapine in combination with fluoxetine. Unfortunately, we know these meds can be really effective as an augmentation strategy, but they're not without the potential for some considerable adverse effects. Certainly, risks related to EPS and tardive dyskinesia are lower compared to typical antipsychotics, but those risks are not absent. And in fact, as we see that these medications are prescribed more frequently for some of these augmentation purposes, we still see rates of EPS and TD in the community that are fairly high. Certainly significant metabolic concerns with these medications. When we think about patients with depression, we know they may be more likely to present with systemic inflammation, chronic comorbidities. They may be less likely to engage in primary care because of the symptoms of their depression. So the risks related to metabolic syndrome with these medications are not insignificant. And then lastly, from a medication standpoint, we'll talk about lithium. Certainly not a novel med, but there is some more recent evidence that we can use this off-label to reduce suicidality and to improve depressive symptoms. So as I mentioned on the previous slide, we know that a few of the atypical antipsychotics are FDA approved to treat depression. We are also aware of the significant adverse effects with atypicals, including the risk of metabolic syndrome. Interestingly, we have this recent study that examined safety of augmentation with atypical antipsychotics. So the authors used claims data, primarily from the U.S. Medicaid program, over a period of about 10 years and linked that data with National Death Index data. Included in this study, adults, non-elderly adults, so people between the ages of 25 and 64 years were included that held the diagnosis of depression and that were augmented with either an antipsychotic or a second antidepressant. So the study included about 40,000 individuals. Of this group, half were augmented with an antipsychotic. The other half were augmented with a second antidepressant. And when we look at all cause mortality, there was a hazard ratio when we look at mortality, about 1.5 times the risk of mortality for those augmented with an antipsychotic. Breaking this down in a little bit more detail, about 22,000 people were augmented with an atypical. During the follow-up period, about 105 died. And when you look at person years in that follow-up period, it was about 7,600. The other group, a little bit less than 20,000, they were augmented with a second antidepressant. And in the follow-up period of about 5,700 person years, 48 died. Obviously, this study needs to be considered in the context of a generally low number of deaths during the follow-up. And the other interesting factor is it really was unclear whether people who were augmented with a second antidepressant were truly augmented or if this was a switch. So just thinking about this in the context of perhaps there are certainly increased risks with atypical antipsychotics. The other consideration when we think about atypicals is cost. And there's wide variability in cost. One study looked at out-of-pocket costs for certain medications using cost estimates from the medical expenditure survey. And if you look at this table, out-of-pocket costs are considered as is number needed to treat for depressive symptom response. These data points were used to really estimate the cost to achieve response in one patient and then compared that to cost specifically with Abilify and Rexalti. As you can see here, significant differences among atypical antipsychotics compared to some of the other augmentation strategies, which included lithium, BuSpar, to highlight some of these key findings. I think this is really interesting. It's estimated that about 320 patients could be treated to response with lithium compared to one patient with Rexalti. Now, obviously, these numbers are going to change as medications lose their patent, as they become generic. And this is something, as you'll see on the next slide, when we think about costs, it really depends on how we're defining cost. But nonetheless, this may become more important depending on the patient population you're working with and access to resources, insurance coverage, among other things. As I mentioned, we also have some conflicting data in this regard. So another study looked at costs related to atypicals, including expenditures, and also including rates of hospitalization. So a variety of claims databases were used, and the sample included about 10,000 patients, looked at costs and rates of psychiatric hospitalizations, as I mentioned. As I mentioned, it's a bit divergent in the findings compared to the data that we previously discussed, and that lorazodone, catepine were associated with overall higher costs compared to Rexalti. What is really interesting is this study did not only look at medication costs alone, but also looked at inpatient and outpatient services costs. So it broadened kind of the definition a little bit. What also I think is really interesting is when we look at risk of hospitalization, Seroquel was associated with higher rates of hospitalizations. So these are just two kind of snapshots that really highlight, I think, the importance of considering the variety of factors when we're thinking about augmenting, thinking about safety, efficacy, cost, patient preference, all things to consider when we're talking about augmentation. And then lastly, as I mentioned, we know lithium is FDA approved for bipolar mania. There is emerging evidence really supporting its use off-label in unipolar depression as an augmentation strategy, with some evidence supporting these anti-suicidality properties. Important to remember that when we think about this in the context of unipolar depression, we're thinking about off-label use. And just like we talked about with some of the atypical antipsychotics, certainly not without safety risks, you know, renal, thyroid monitoring, close monitoring of lithium toxicity. Switching gears into some of the neuromodulation or interventional psychiatry techniques, I'm going to highlight ECT briefly. We'll go into TMS in a little bit more detail for a few reasons. Number one, ECT has been around. Longer than TMS, certainly. So, as providers, you may have a little bit more familiarity with ECT. The other thing to consider is when we're thinking about interventions that we can implement in outpatient settings, TMS can be done with a little bit more ease compared to ECT. So, we'll briefly cover ECT and then kind of look at some comparisons between that and TMS. So, we know ECT induces generalized seizure activity. We know it's extraordinarily effective. Still considered the gold standard for refractory depression. But unfortunately, use of general anesthesia, neuromuscular blocking agents have kind of limited its use from a practicality perspective. And we'll talk about some other barriers that we see. So, interestingly, as I mentioned, we know ECT is considered the gold standard for treatment resistant depression, especially in patients who may be pregnant or presenting with catatonia or acute suicidality. Nonetheless, it has been established in the literature, I am sure many of you see this in your clinical practice, that ECT really does remain very underutilized. So, what are the barriers to ECT? Again, I've encountered them in clinical practice. I'm sure many of you have encountered them in clinical practice. And they've been well described in the literature and actually pretty stable over time. One of the biggest barriers that I see personally when I'm considering referring someone for ECT is stigma. And this can permeate from patients themselves or from their family members. I have a fair amount of patients that have I have a fair amount of patients that I think about that have, you know, really strong family histories of mental health problems, who perhaps had grandparents, aunts, uncles, even great grandparents treated with ECT who describe hearing horror stories about this type of treatment and are very resistant to considering it. Despite, you know, when you provide education about how far ECT has come over the past 30, 40, 50 years. I feel like this is especially problematic because when you think about patients who have stronger family histories of mental health problems, particularly depression, they themselves may be at increased risk of being refractory or difficult to treat. One other barrier that I think comes up, you know, we have patient stigma, but we also have our own biases as mental health providers. I think a lot of people working in the community may lack perhaps resources in the community as far as referrals. Perhaps some people may have a hard time like really providing education around ECT or initiating that referral process. And then lastly, you know, the most practical barrier that I think comes up is, you know, use of general anesthesia and associated recovery time. Yes, ECT is safe, but some patients may have transportation problems. The commitment to ECT as far as, you know, downtime or recovery time can be one barrier. That is one benefit to TMS treatment that we'll talk about shortly is then it's a little bit easier to implement on an outpatient basis and patients can get TMS treatments with very, very little downtime. So if you're using ECT in your clinical practice settings or if you're referring to ECT, I do think it's important to be familiar with the pre-ECT evaluation. Depending on where you're working, this can be a very streamlined process or an arduous one. I don't think I mentioned, but just for context, I work at the Veterans Administration Hospital in Pittsburgh, and then I work on an outpatient basis at a community practice that's not affiliated with the healthcare system. And I always say, when I'm referring patients for ECT, it is night and day as far as ease and the streamline of the process. When I'm at the VA, it's a simple process. It's done without a lot of fuss. We do the pre-ECT evaluation in-house, and then we contract with a local hospital who administers the ECT. At my outpatient practice, we're not affiliated with the healthcare system, so I refer a lot of patients to a local, small community hospital for ECT. They do not do any of the pre-ECT evaluation. They want it done all before the patient is even seen for the first time. So if I have patients who are established with primary care, this is usually not all that big of a deal, but some of my patients that I see really don't have a primary care provider, so I'm tasked with facilitating a lot of this pre-ECT workup before I'm even able to initiate a referral. So again, you may be involved in this in more of a degree than others, depending on your practice setting. I think most of this is routine, although the oral exams can be difficult if the patient doesn't have a relationship with a dentist, and it's one of the things in my experience and supported in the literature that's often missed during the pre-ECT evaluation. We know it's important as far as assuring safety from a patient airway perspective, can a bite block be inserted, etc. So as I mentioned, we will go over repetitive transcranial magnetic stimulation, TMS is how I will refer to it moving forward, in a bit more detail. I mentioned this is not a new intervention per se, but its use is becoming far more popular and far more widespread over the past five years or so. But again, it's not new, the first TMS machine was actually developed around 1985. So this is something that can be implemented on an outpatient basis with a little bit more ease as compared to ECT. So as I mentioned, we'll review this in a fair amount of detail for those of you here today that might be interested. When we think about ECT, we're using electrical stimulation to induce seizure activity. With TMS, we're using a magnetic field to facilitate electrical pulses into neuronal tissue. This does not induce a seizure, and we'll talk about later, it can increase risk of seizure, but that's not the intended outcome as is the case with ECT. When we're using TMS, we're really using this magnetic field and the downstream effect is this synchronous activation of neurons in particular target areas in the brain. We're talking about this today in the context of depression. So when we think about the target area, it's primarily the dorsolateral prefrontal cortex, but you may see TMS used for a variety of other either on-label or off-label indications like OCD, post-stroke, substance use, and in those instances, the location of the target area might vary. So we have this stimulation of neurons in the brain, and this is thought to modulate neural networks. Subsequently, we see behavioral changes, maybe improvement in some of those depressive symptoms, and we also see brain network changes, and that will be depicted in a few slides. So we have these magnetic fields generating electrical currents, and this forms the basis of TMS mechanism of action. One question that patients often ask from a safety perspective, what is the strength of this magnetic field? I get asked this question a fair amount, too, from people interested in TMS, especially younger people, maybe of childbearing age, like, is it safe for me to be a TMS administrator? The magnetic field, the strength is pretty comparable, even a little bit lower than what you would expect for a clinical MRI scanner. There hasn't been any evidence of harm to brain tissue in patients exposed to TMS, so we think of this as really a safe intervention. A few safety things to consider, the coil itself, and I have not an image of the coil, but something to kind of give you a visual of that later, will react to any metal-containing iron. So when we think about absolute contraindications, we think about iron-containing metal primarily in the head, cochlear implants, implanted brain stimulators. If the metal is more than about 30 centimeters from the coil itself, it can be safe to use. So metal elsewhere in the body is not necessarily a complete exclusion. We have this coil, the electrical current is conducted along this wire that's wound into the shape of the coil. If you've ever been in a place where people are receiving TMS, you've probably heard that loud clicking. That's associated with the coil itself heating and cooling. We hear a really loud sound. In fact, patients and facilitators need to wear hearing protection. So we'll talk about FDA clearances in a few slides, but I initially brought up TMS in the context of kind of comparing it to ECT. Interestingly, there has yet to be a randomized study comparing ECT to TMS. There are some more observational studies. Generally speaking, it is thought that ECT has higher rates of remission and a quicker response, which speaks to the fact that it does, like I said, remain the gold standard. That being said, TMS is associated with fewer side effects and is generally better tolerated. So it can be prudent if you are working with somebody that you feel like would benefit from some of these interventional treatment options. Starting with ECT, it's more convenient, it's better tolerated. And then if they don't do well, you can kind of use like a step-up approach and move forward with TMS. The nice thing, we'll talk about convenience as far as treatment goes, but probably the biggest side effect I hear about with ECT is cognitive symptoms. And those are minimal with TMS. So this is a really simple diagram demonstrating kind of the mechanism of action related to TMS and logistically how this looks. So we have the TMS or that electromagnetic coil that's placed on the patient's scalp in a targeted area. As I mentioned, typically for depression, we think of the left dorsolateral prefrontal cortex. The machine's turned on, we see this magnetic field passing through the skull, passing through the connective tissue and inducing electrical currents on the surface of the brain for depression in the prefrontal cortex. Subsequent effects, we see neuronal activity locally on the surface of the brain. And then we see downstream activity that really speaks to some of the longer-term benefit we see with TMS. The magnetic fields themselves are what induces that secondary electrical current. We see ionic shifts, we see depolarization of neurons within the cortex of the brain. And really what we're doing is we're modifying neuronal excitability through this mechanism. What I think is really interesting is that the effects of TMS persist following termination of treatment. So you may have somebody who has a six-week course of TMS and they continue to see improvement after treatment has ended. The mechanism behind this is really related to neuroplasticity. It's thought that synaptic strength is enhanced using TMS, and then that persists following termination of treatment. And we have intracellular changes that result in improved kind of interneuronal communication. This is thought to perhaps be modulated in part through receptor upregulation in subsequent release of the monoamines. The coil itself, as you can see here, touches the patient's head directly. You know, if there's a gap, the magnetic field may not effectively pass through skull or connective tissue. The other thing that's really important is the angle. The angle of the coil has to be positioned at a 45-degree angle for treatment efficacy. So there are various types of TMS treatment, bilateral TMS, right or left prefrontal TMS, and deep TMS. When we think about depression, we're really thinking about left prefrontal or deep TMS, and we'll go over some nuances between the two. Traditionally, you'll see on the next slide, what we call a figure of eight coil was used. Although there are newer models that use what we call deep TMS, the coil was shaped like an H, and that does what it sounds like, stimulates deeper areas of the brain, but it is less focal. One other thing that we'll briefly cover is what we call accelerated forms of TMS. There's one treatment called theta burst, in which we implement therapy over a shorter period of time. So this diagram depicts the two most common types of TMS coils. There are others, but they're really only used in research. We don't use them in clinical practice, so they're not depicted here. But as you can see from these images, we have the figure of a coil, and it has shallower depth, but it's more focal, whereas the H coil stimulates neurons deeper in the brain, but it's less focal. Deep TMS, the one machine that uses deep TMS therapy, is newer. It was approved, FDA approved for depression in 2013, so it's a little bit newer of a paradigm, if you will, compared to the figure of eight coil. Both of these are used in clinical practice, and they're pretty comparable in safety, efficacy, perhaps a marginally increased risk of seizures with deep TMS, although that has not been soundly concluded. So this image, for those of you who maybe are more visual learners, shows network level alterations following TMS stimulation. The regions depicted here are heavily implicated in patients suffering with depression, and so we see, following TMS, increased activity in these regions. That is thought to modulate the improvement in behavior, mood, psychosocial functioning that we see following TMS treatment. So from a pragmatic standpoint, when you're thinking about implementing this into like an outpatient or inpatient practice setting, what is really the step-by-step process? So first, after someone has been referred for TMS, you know, there's been an intake, history, based on that information, they have been deemed appropriate, and they agree to move forward with treatment. What is the first step in starting treatment? And that is really locating and identifying the motor threshold or the motor hotspot. When you think about the motor threshold, you can think about it as being one sensitivity to TMS stimulation, a measure of cortical excitability, or figuring out where somebody lies during the mapping process. It's important to remember, we'll talk about mapping, and we'll talk throughout this presentation, somebody's motor threshold can change over time. Number one, it varies person to person, and it can vary over time based on external factors, based on internal factors, sleep, medication use. It also may depend on whether somebody has an active muscle or a resting muscle, so are they physically tense? That might influence what we know about their motor threshold. So again, thinking about this step-by-step process, we find the motor hotspot, that's a part, we're moving a coil around somebody's, the top of somebody's head, and we're finding a spot where we stimulate, and we see this isolated thumb twitch. All of this is done during the mapping process, and we'll break that down in a little bit more detail. When we do the mapping, we want to use the minimum amount of stimulation needed to activate neurons, so that's why we're finding that motor hotspot, and then we're finding the motor threshold. We wanna use stimulation that's intense enough to have activation of neurons, but not so intense that we're increasing risk of seizure. You really can think of this as a safety measure. You're doing the mapping before starting treatment, but it's not like a one and done thing. It's something that can and really should be done routinely to evaluate any changes in motor threshold. So how do we find the motor hotspot? That's step one. I don't know if any of you have seen this, but we place a cap, it's like a treatment cap, it looks kind of like a swim cap on somebody's head, and we take a variety of measurements. We measure from the front of the head to the back of the head. We measure from the tragus, part of the ear, to the other tragus. We see a point where those lines cross, that's called the vertex, and then we mark some other measurements until we get a point of the brain where we start evaluating the motor hotspot. We put the coil, TMS coil there, and we're moving it in a systematic way until we find what we call the best motor hotspot. When you think about that, you're finding the point where the coil is stimulating the brain and we see an isolated thumb twitch. When we think about the best motor hotspot, you want to consider, okay, is it an isolated thumb twitch or are other fingers moving? How intense is the thumb twitch? When you're doing this process, we usually start the machine at a certain threshold, 65% intensity. Some people have a higher motor threshold and they need higher degrees of intensity to even find the motor hotspot, but we do this really carefully, increasing in small intervals. Once you find that spot where you're stimulating and you have this thumb twitch, you mark it on their cap and then you find the minimum motor threshold. We know they had a twitch at 65%, which is generally where we start the machine, but maybe all they needed is 57%. We find the minimum intensity to reduce risk for seizures. After we do this and we find the motor hotspot and we determine the threshold, we find the treatment location. Really how that's done, it's a computerized process where we're entering measurements that we took during the mapping process. Then it gives you certain measurements to consider where are we putting the actual oil for treatment. We're doing this before treatment, obviously, but after informed consent is really recommended because you are using some of the magnetic fields during this process. I think it's important to think about during informed consent, addressing patient expectations. This might be a treatment that helps them, but it may not, they may still require medication after the fact. Also, while there's little downtime, we have patients who do this before work. We have patients who have their TMS treatment on their lunch break. It is a big commitment and that they generally are coming to the clinic five days a week over a period of six weeks. If they're traveling, thinking about that, if they're going out of town for two weeks, maybe it's not the best time to start this. Maybe we want to initiate it when they get home. Maybe that has not been terribly relevant in light of COVID, but I think it's something that we want to consider as restrictions lesson. It's important to do this mapping process cautiously because we want to find the correct target area. If the treatment location is inaccurate, treatment might not be as effective. That's why some people may prefer deep TMS where it is a little bit less focal. If you've seen people who have referred to TMS and they have not done as well as you would have expected, perhaps it was a treatment problem. There are TMS parameters that we think about from a safety and efficacy perspective. We have what we call the train duration and the inter-train interval, what they sound like. The train duration is how long are the pulses delivered. That's usually in seconds. Then the inter-train interval refers to the time in between pulsations. Greater duration or shorter intervals are associated with higher risks related to adverse effects seizures, which makes sense because somebody may be getting, you can think of it as a higher dose. The intensity is based on the machine output itself. You can think about that as being conceptualized as like the strength of the pulse that's delivered. How this is determined, you get that motor threshold number. You do that during the mapping process. Then you multiply it by this prescribed value of 1.2. That's the setting, generally speaking, that you utilize during the treatment. We tend to treat in about four seconds, for about four seconds. The train duration is usually four seconds. For deep TMS, it can be a little bit shorter, more like two. Then we like pretty long intervals, 10 to 20 seconds. Usually we deliver about like 75 trains total. When you add this all together, we can have treatment ranging from about 20 to 40 minutes. As I mentioned, when we think about TMS, we're really thinking about patients coming five days a week over a period of six weeks. Interestingly, for deep TMS, it can be a little bit abbreviated, where we have five days a week for four weeks. Then patients can do bi-weekly sessions for another three months or so. Lastly, when we think about these parameters, frequency. How fast are the pulse delivered? What is the frequency in the pattern? The pattern refers to how the pulses are delivered in a repetitive manner. When we think about a typical pattern, as I mentioned, frequency five days a week over six weeks, it's a little bit abbreviated for deep TMS. Then there's one mechanism called theta burst stimulation, where the bursts are delivered more quickly over a shorter period of time. Some patients will have multiple treatments within the course of a day, over a period of one week. When we think about these parameters, they're defined per device guidelines. There may be some variability, but they speak to safety. We know the parameters that's recommended by the device are safe, but increasing those parameters or going beyond what is recommended can increase risk for seizures or adverse effects. The other thing that I think is really amazing about TMS is perhaps there is some evidence that continued treatment can result in improvement in outcomes. Some patients at six weeks, there's some improvement, but they've yet to achieve remission. They can continue going. There are some, we'll talk about maintenance treatment shortly. It's also recommended that, you know, if you have a patient that remits in two, three weeks, that they continue for six weeks. There's really no evidence in the literature that continuing treatment is associated with adverse effects. And in fact, continuing treatment up into that six weeks reduces risk related to relapse. I think of this personally as analogous to continuing antidepressant therapy for nine to 12 months after stabilization. So to that point, what about maintenance treatment? There's a lot of variability in clinical practice. Recent clinical practice guidelines address this variability, and there's really no clear guidance on maintenance treatment. I've seen patients do one treatment a month indefinitely, or maybe a few treatments a month. I've seen people do shorter courses, you know, a couple of times a year. Some patients may require like a full additional course after recurrence. They tend to do well. If you've had a patient who has achieved, you know, remission once with TMS, it's likely that they will again. So this diagram, in my opinion, I think it's a nice visual in relation to the mechanism of TMS. So we see this stimulation in the dorsolateral prefrontal cortex. That area is reachable by TMS, right? Some of the deeper areas of the brain can't be reached by even the H-coil. So then we have these downstream effects in the medial prefrontal cortex, in the anterior cingulate cortex, and the frontal cortex. We see this feedback between these areas in the amygdala, and overall improvement in emotional processing, emotional regulation, mood, and behavior. So as I had mentioned, TMS is FDA approved for major depressive disorder. I believe the first machine in the United States was approved in 2008, and then there are varying devices, and deep TMS was first approved in 2013. Other indications, obsessive compulsive disorder, neuropathic pain, migraine pain. The one deep TMS machine as of 2020 was approved for smoking cessation. There is some off-label use for TMS related to anxiety, PTSD, Parkinson's, post-TBI, or post-stroke. One thing to consider, and we will talk about this briefly, is bipolar depression. That remains kind of controversial, and we'll go over that when we talk about safety and monitoring for mania or hypomania. So probably the number one question that we get asked when referring somebody for any type of treatment is side effects. We know TMS is safe. They may have less of a side effect burden than even SSRIs or SNRIs. Most of the side effects are pretty self-limited and transient. Headaches, neck pain occur in about one in three people, but typically they're amenable to tweaking the treatment a little bit or PRN medications. The benefit, as you can see, is most of these side effects are localized related to the stimulation site. We don't see those systematic adverse effects that we see with antidepressants. Sexual side effects, weight gain. Two of the more rare but high-risk side effects with TMS include seizures and mania. Very uncommon, especially when the settings are within FDA-indicated parameters. As I mentioned, the click of the coil makes a pretty loud sound, so we use adequate hearing protection up to about 30 decibels. And then most people continue with their prescribed psychotropic medications. This is important because if we're changing medications during treatment, we can be inadvertently changing seizure threshold and predisposing somebody to seizures. So I typically tell patients, if they're insistent that they wanna stop all of their medications, they should do so prior to TMS, but it can be safe to allow patients to continue and then after the course is done, tweak them as it's appropriate. TMS-induced mania, rare. Occurring in less than 1% of patients, probably comparable to placebo. And there is some evidence, like I said, while controversial that we can use TMS for bipolar suppression. Seizures are rare, also less than 1%. When you compare seizure risk with immediate release Welbutrin, seizures with TMS are less common. What's also interesting is when you look at the literature, any TMS-induced seizures did spontaneously resolve. So when we think about assessment data, absolute contraindication includes medical devices in the head that contain ferrous metal, cochlear implants, absolute contraindications. Generally speaking, a history of seizures or epilepsy, generally contraindicated, and really if you're treating those types of patients, you wanna use exceeding caution. Meds, any meds that lower the seizure threshold, typical antipsychotics, Plazapine, Welbutrin, stimulants, we wanna use with caution. One other thing just to consider, patients with neurological disorders, it may be difficult to find that motor hotspot and motor threshold, sometimes we'll have to do nerve conduction tests. So thinking from a safety perspective, once you have somebody who's engaged in TMS, we wanna monitor throughout treatment. Medication changes, behavioral changes, sleep, substance use, can increase risk related to seizures. So we wanna ask this before every treatment. As I mentioned, we do the mapping, we find the motor hotspot and motor threshold at the start of treatment, but it can be prudent to reassess, even as often as weekly, because we know this can change over time. And from a safety perspective, if we're reassessing the motor hotspot regularly, or the motor threshold regularly, we can reduce the risk of seizures. Obviously, just like with any intervention from a mental health perspective, we're assessing for suicidality, mania, hypomania. There's some evidence if patients do develop hypomanic symptoms, we can discontinue TMS and we can re-challenge at a later time with a lower intensity. Syncope, really common with patients receiving TMS, especially for those who are heightened with anxiety. So differentiating that from a seizure, was there confusion? Was there a postictal state? Was there incontinence? So thinking about that. Lastly, just thinking about efficacy, considering comorbidities. This table shows data from RCT that looked at veterans specifically without PTSD and with PTSD. As you can see, patients with comorbid PTSD really did not do as well from a remission standpoint. So they may be inherently more difficult to treat. This study looked at, I think, nine DAs, there were 150 veterans, and then follow-up treatment was at about 24 weeks. And then this data looks at active TMS versus sham TMS using quite a few rating scales. So as we can see here, pretty clinically significant drops with active TMS. And this was an RCT, I think, including about 300 people. And the treatment was TMS five days a week for six weeks. One thing I just briefly wanna talk about is tapering people. There's some evidence that, really not from an efficacy standpoint, but just from a psychosocial standpoint, that tapering people can kind of transition them from the routine of coming somewhere five days a week. And then lastly, ketamine, we know is an IV infusion. It's sub-anesthetic doses can be used off-label for treatment-resistant depression. And then more recently, 2019, we have S-ketamine as a nasal spray, FDA approved for augmentation specifically. Ketamine, the IV infusion is a racemic mixture, and S-ketamine is the S enantiomer, and is about four times as potent comparatively. It's rapidly absorbed across nasal mucosa, crosses the blood-brain barrier. Both work as NMDA receptor antagonists, and the benefit to ketamine is it can really rapidly improve depressive symptoms and suicidality. Generally well-tolerated when dosed appropriately, the common adverse effects mainly include CNS effects, obviously risk of dissociative or psychosomatic symptoms. So we use this really carefully in patients with, say, bipolar or psychotic symptoms. We also know there's a concern for misuse, so patients with a history of substance use disorders may need closer monitoring. But given that this is done in a controlled environment, that can minimize risk. Two doses for the nasal spray, 56 and 84 milligrams. Generally speaking, for the first month, we dose about twice a week, and then weekly thereafter. We talked about adverse effects, but for the S-ketamine, there's boxed warnings for sedation, dissociative reactions, suicidality, and misuse. And if you're implementing this on an outpatient basis, REMS registration's required. Monitoring two hours post-treatment is what is recommended. For the IV infusions, the dosing can really vary. If patients have underlying cardiovascular disease, this can be kind of risky. If you are implementing this in a practice setting, it's recommended that we have somebody who's well-versed in mood disorders, but also somebody who is ACLS certified in case of a medical emergency. In facilities that are using ketamine infusion, have to be equipped really for EKG monitoring, blood pressure monitoring, is there a crash card on site? So prior to referring for ketamine, or S-ketamine, confirming the diagnosis, making sure we're rolling out bipolar, psychotic disorders, physical exam is recommended, again, just to assess cardiovascular risk. I think really a unique setting is needed, because we need somebody, like I mentioned, who's an expert in mood disorder management, and who may be able to respond in the case of like a cardiorespiratory emergency. Inpatient hospital settings are likely well-equipped for this, but both the S-ketamine and the ketamine infusions can be administered outpatient, but obviously considerable planning and REMS registration is needed. We know patients need to be monitored, assessing for things like psychotic symptoms, suicidality, and then one downside, especially compared to RTMS, which like I said, there's little downtime, patients can drive there, they can have their TMS treatment, and they can leave, with ketamine, they need transportation after the treatment. So at any rate, I greatly appreciate everybody's time, attention this afternoon, it really was a pleasure to be here. And with that, I'm happy to answer any questions that you may have. Okay, terrific, thank you so much for that excellent presentation, Dr. Kamik. Before we switch into the Q&A, I just wanna take a moment and let you know that SMI Advisor is accessible from your mobile device. Use the SMI Advisor app to access resources, education, and upcoming events, complete your mental health rating scales, and even submit questions directly to our team of SMI experts. Download the app now, smiadvisor.org slash app. All right, and now onto the Q&A. The first question I have is I'm sort of wondering if you have any clinical pearls for when you're working through the differential diagnosis and you're evaluating someone who may have TRD, what are you thinking about? And also as a sort of a related question, how do you think about personality disorders if they come up in the context of depression? Absolutely, that's a great question. And I have to chuckle at that because unfortunately TMS is fabulous for treatment-resistant depression, but not so much for personality disorders. And I actually hear a lot of providers bring that up where they say, you know, I've referred people and I haven't seen much of an improvement, and that's often my first question, well, have you rolled out or considered a personality disorder? When we're thinking about kind of evaluating somebody for treatment-resistant depression, I think considering is this treatment resistant? So number one, have they been adherent with meds? Thinking about the adequacy of a trial is really critical. And then, you know, if they're taking their meds, you're not seeing an improvement. Exploring, is there an underlying medical problem? How's their thyroid? I live in Pittsburgh, it's always cloudy here. So how's their vitamin D? Are they deficient? Working through some of those medical or substance-related concerns and rolling those out. But you do get to a point with refractory cases that you do wanna be mindful of, is there a comorbid either substance use? Is this bipolar disorder? Is this a personality disorder? Because we know for personality disorders, some of these interventional treatment strategies, as I said, may not be so effective. And then you have providers frustrated, why isn't this working? So does that answer your question? Yes, that's great. Next question I have for you is, can you talk a little bit about how you incorporate measurement-based care, especially like within TMS? Are there specific rating scales that you prefer to use? How often are you getting them? Great question. So actually with TMS and just for people who I'm doing like routine outpatient med management for, I do use the PHQ-9 and the GAD-7 at every visit. I think that's pretty standard for TMS, but in my experience, most of the time with TMS, we're getting a little bit more additional objective data, maybe the Hamilton. I think it's really, really important because oftentimes with TMS, just like we see with medications, we sometimes see the improvement quicker than the patient does. And especially when it's an intervention that you have somebody coming five days a week, if they're not seeing an improvement within those first two, three weeks, which oftentimes they don't, they may kind of become disheartened and say, you know what, forget this. So in my experience, it's been helpful to have that objective data and say, I know you don't feel great. Maybe your PHQ-9 score is, maybe you have a patient, their score is still 15. We haven't got them to remission, but maybe it's dropped from a 25. So using that data I think can enhance buy-in and adherence. As far as the frequency, typically weekly or bi-weekly for TMS, I don't think you have to give somebody the rating scales every day, but I would say at least once a week, maybe twice a week is sufficient. But yeah, that's an important component, especially early in treatment before somebody has really seen a response or remitted. All right, excellent. I wholeheartedly agree. Next question is, can you talk a little bit about people who are taking other medications while they're getting TMS? Do you typically have them stay on SSRIs, SNRIs, lithium augmentation, their current pharmacological regimen, or are you making adjustments prior to TMS or even during TMS? Right. So when we think about this, one thing I think is important to consider is using a patient-centered approach and thinking about patient preferences. In that context, also setting up realistic expectations. Have I had patients who have had a course of TMS and have gotten off all their meds and been fine? Yes, but that is the ideal, and in my experience, not the norm. So I sometimes tell patients, I have some people come in and they're interested in TMS and they say, I don't wanna take any medications. And I tell them, okay, well, that may be an option, but it's not guaranteed. I would say the majority of patients, TMS gets them to a point of response or remission where their medications either work better. So I try to set the expectation that, look, you may continue to need antidepressants after this. Sure, maybe we can consolidate your regimen after this, maybe we can lower the dose, but most people do continue to take something. Have I had some patients who have been very insistent that they don't wanna take medications? Yes, but I try to tell them that's fine. I'll work with what you wanna do, but if you wanna stop meds, we really need to do that either before TMS or after, because we try not to make really significant medication adjustments, be it increases or decreases during the treatment itself. If it's critical, if somebody develops an adverse reaction to a medication during TMS treatment, certainly we'll address that. But just your routine adjustments, we really try not to do during the active six weeks of treatment. Okay, thank you. That's really helpful. And I think that that's all the time we have in the Q&A section. So Dr. Kamberg, I wanna thank you again. That was really, really terrific. Thank you all so much. Thank you for having me. It was really a pleasure to be here this afternoon. All right, great. Thanks again. So if you have follow-up questions about this or any topic related to evidence-based care for SMI, our clinical experts are now available for online consultations. Any mental health clinicians can submit a question and receive a response from one of our SMI experts. Consultations are free and confidential. SMI Advisor is just one of the many SAMHSA initiatives that are designed to help clinicians implement evidence-based care. We encourage you to explore the resources available on the Mental Health Addiction and Prevention TTCs, as well as the National Center of Excellence for Eating Disorders and the Suicide Prevention Resource Center. These initiatives cover a broad range of topics from school-based mental health through the opioid epidemic. To claim credit for participating in today's webinar, you'll need to have met the requisite attendance threshold for your profession. Verification of attendance may take up to five minutes. You'll then be able to select Next to advance and complete the program evaluation before claiming your credit. And finally, please join us next week on June 25th, 2021 as Dr. John B. Roseman with McLean Hospital presents Electroconvulsive Therapy, a Comprehensive Review, which I think will really nicely follow this talk. Again, this free webinar will be June 25th, 2021 from noon to 1 p.m. Eastern Standard Time. Thank you so much for joining us. Until next time, take care.
Video Summary
In this webinar, Dr. Brayden Kamig discusses treatment-resistant depression and updates on management strategies. She provides an overview of the Clinical and Research Program for Psychosis and the SMI Advisor initiative, which aims to provide evidence-based care for serious mental illnesses. The webinar is eligible for AMA-PRA Category 1 credit for physicians and Nursing Continuing Professional Development Contact Hour. Dr. Kamig talks about the prevalence of depressive disorders and the risk factors associated with them, such as social isolation, educational status, and financial instability. She highlights the high rates of treatment-resistant depression and the associated costs and disability. Dr. Kamig discusses various pharmacological strategies for treatment-resistant depression, including atypical antipsychotics and lithium. She also explores neuromodulation or interventional psychiatry techniques such as electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS). Dr. Kamig explains the mechanisms of action and safety considerations for TMS and discusses the use of ketamine as an off-label treatment for treatment-resistant depression. She emphasizes the importance of monitoring and measurement-based care throughout the treatment process. In conclusion, Dr. Kamig provides clinical pearls for evaluating patients with treatment-resistant depression and managing comorbidities such as personality disorders.
Keywords
webinar
treatment-resistant depression
management strategies
evidence-based care
pharmacological strategies
neuromodulation
electroconvulsive therapy
transcranial magnetic stimulation
ketamine
comorbidities
Funding for SMI Adviser was made possible by Grant No. SM080818 from SAMHSA of the U.S. Department of Health and Human Services (HHS). The contents are those of the author(s) and do not necessarily represent the official views of, nor an endorsement by, SAMHSA/HHS or the U.S. Government.
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