Thank you for attending today's webinar, Recognizing and Managing Mental Health Comorbidities in Children and Adults with Epilepsy. Please note that this webinar does offer continuing education credit after completing the evaluation. You will be taken to the evaluation immediately after the webinar. You will receive an email when the on-demand version is available. Before we get started, I would like to take a moment to acquaint you with a few features of this web event technology. At any time, you may adjust your audio using any computer volume settings that you may have. Should you encounter any audio issues, refer to the meeting information pod for further instruction. On the right-hand side of your screen, you will see the text Q&A window. There is a large window which holds all of your sent messages and a smaller text box at the bottom where you will type in your questions. To send a question, click in the text box and type your text. When finished, click the Send button. All questions that you submit are only seen by today's presenters. Your questions will be responded to in the order in which they were received and will be addressed at the end of the presentation. I'd now like to introduce today's moderator, Dr. Elaine Kyriacopoulos from the Geisel School of Medicine, Dartmouth Health and AES Online Education Committee member. Thanks very much. I'd like to welcome everyone to today's webinar, Recognizing and Managing Mental Health Comorbidities in Children and Adults with Epilepsy. And today's webinar will focus on psychiatric disorders including depression, anxiety and attention deficit disorders which commonly occur in people with epilepsy and often present as complex and challenging comorbidities for clinicians to recognize and manage. It's my great pleasure to introduce our speaker for today's webinar, Dr. Jay Salpiker who is the Director of the Pediatric Neuropsychiatry Center at the Kennedy Krieger Institute and is an Associate Professor of Psychiatry and Neurology at Johns Hopkins University Medical School. He received bachelor's and medical degrees from Washington University in St. Louis and continued at Barnes Hospital for General Psychiatry and then did a Child and Adolescent Psychiatry Fellowship at Yale University Child Study Center. He has been an academic clinician overlapping psychiatry and neurology for over 25 years and he has distinguished fellow status in the American Epilepsy Society, the American Neuropsychiatric Association and in the American Academy of Child and Adolescent Psychiatry. The American Epilepsy Society recently honored him with the Rebecca Goldman Kauffman Award for Ethical Neuropsychiatry. He serves on the editorial board for several journals and is internationally renowned with clinical consultation and lectures that span the globe. His current projects highlight the overlap of anxiety with epilepsy and explore novel treatments that may address both conditions simultaneously. This educational opportunity is supported from a grant from the Centers for Disease Control and Prevention and AES webinar in conjunction with the Managed Epilepsy Well Network and Dartmouth Health. Disclosures for today's presentation are listed here. And learning objectives for today include identifying the overlap of psychiatric and neurologic symptoms from both a pathologic and phenomenologic perspective, describing the range and severity of behavioral issues that may be present in epilepsy and learning to utilize strategies for managing symptoms of psychiatric illness that may reflect pathophysiologic processes present in neurologic disease. And with that, I'm going to turn things over to Dr. Salpekar. Thanks so much for sharing your time and your expertise with us today, Jay. Thank you, Elaine. Thanks very much for the introduction and thanks for everybody here for joining in. This is a subject that is near and dear to my heart and what I've been spending my academic career doing, the overlap between psychiatry and neurology is a fascinating space to be in. And I'll try to prove that to you. I'll try to give you some information and some perspectives, particularly as it pertains to epilepsy and the complexities of epilepsy when it comes to mental health comorbidities. So just to kind of level set and introduce us, here are two different EEGs for epilepsy. This is our disease, our condition of focus at this point. Focus is, of course, on purpose because the left side of the EEG is a focal seizure and the right side is a generalized seizure. The common thread, of course, is that these are hyper excitable neurons. And I would posit that this is the prototype for what we think about the overlap between psychiatry and neurology. And what we think of when we think of brain behavior relationships and comorbid conditions. Note that for many focal seizures, awareness is not impaired. Certainly it can be impaired and if it develops into a generalized seizure, then awareness is universally impaired. But for many focal events, the awareness is preserved. And that brings us to a whole different kind of territory about phenomenology and what we think of when we have hyper excitable neurons. And I think it explains some of the overlap that we see with psychiatric conditions as well. Sometimes it's not so simple. And what I hope to prove to you also today is that it's not going to be so clear cut that this is a seizure or not a seizure or this is where the seizure begins and ends and the comorbid conditions continue or take over, if you will. We see a lot of common ground between epilepsy and psychiatric symptoms. Specific symptoms might overlap quite significantly. Just in terms of a seizure aura for a focal unaware seizure, sometimes there's a prodrome of several seconds that can be an aura of feeling unusual or feeling unsettled, maybe even feeling anxious or nervous. Sometimes you can have frank anxiety attacks or panic feelings in the early stages of a focal unaware seizure. That's what we used to call complex partial. Well, in the early stages of a panic attack, a focal unaware seizure can look exactly the same. Sometimes they're indistinguishable. A panic attack, of course, is a sudden onset of anxiety where someone has fear. They will have physical symptoms as well. Their heart will beat fast. They'll have shortness of breath. They might be sweating. They might have a fear of foreboding or a sense that something very bad is going to happen. Sometimes that they'll even have a heart attack or they could die any second. Well, that's a panic attack. And sometimes we have a prodrome or a seizure aura that can look the same. So right away, we've got common ground between epilepsy and psychiatric symptoms. The common ground continues. And one very interesting phenomenon is that for people, and this has been replicated and verified with a couple of different epidemiologic studies, there are many confounds, of course, because these are heterogeneous conditions. But we do see that generalized seizures seem to be associated with less mood disorder. That's a fascinating conundrum at first. But if you think about it a little bit more, we do all kinds of procedures in psychiatry, such as electroconvulsive therapy or transcranial magnetic stimulation. And the goal is to actually produce a generalized seizure. There's something curative about a generalized seizure in terms of mood, especially when mood is not well-treated by existing medicines. So there might actually be some relationship with generalized seizures and treating mood disorder of some sort. So that fact can't be denied. Now, we also know that early on in the course of epilepsy, we see evidence of brain changes. White matter growth is not quite the same. If you have even the very early onset of seizures and then the bidirectional relationship, and I'm gonna talk a little bit more about that in some detail. We already know that there's something different about epilepsy. We know that psychiatric problems are well overrepresented. And one of the 50-year-old studies that was done by Sir Michael Rudder by the Isle of Wight Epidemiology Study showed that, in fact, if you have epilepsy, it's worse in terms of psychiatric illness than it is for other chronic medical conditions. Significantly worse, even for conditions like asthma, which can have a sudden onset and be very terrifying, or diabetes, which has significant lifestyle changes. Now, this data is from pediatrics, but it's also true for adults in terms of chronic medical illness, certainly with diabetes or other cardiac conditions or other immunologic conditions. The comorbidity is worse with epilepsy. In pediatrics, it's three times worse for epilepsy than for asthma or diabetes. That's a significant increase that we just can't explain very well. I'll talk a little bit more about autism spectrum, but we think that epilepsy might be present in up to a third of those individuals. And then anxiety and depression. The numbers are not well set because of the way that we count them up in studies. It's very difficult to do these studies and to know what you're looking at. But up to a third of people with epilepsy also have anxiety or depression. That's remarkable. That tells us that epilepsy is as much a psychiatric condition as anything else, certainly as anything else in the medical world. And it tells me, certainly as an academician and as a clinician in this space, that there's something about this illness that overlaps. So we might be treating the same things when we look at seizure counts or comorbid conditions like depression or anxiety. In any case, the autism spectrum overlap is very interesting and we know that with autism spectrum, we have anomalous connectivity. A lot of these connections are fraught with migrational problems or overgrowth. And there are a lot of people who once thought that overgrowth had to do with head circumferences and other types of details that might be present with autism spectrum disorder. But we also know now that there may be excess glutamate transmission. And of course, glutamate is an excitatory transmitter. If you have excess glutamate, well, then you've got hyper excitable nerves. That's the whole problem with seizures is we have hyper excitable nerves. And we do know that there is hyper excitability with autism spectrum disorder. We think that the interneurons, particularly the GABAergic interneurons, might be faulty, not only in epilepsy, but also with autism spectrum disorder. So the problem is in actually shutting down these hyper excitable conditions. And you've got nerves that are firing when we don't want them to fire. And if you build these circuits that are anomalous to begin with, especially if you're in between cortical and subcortical regions, where the connectivity might result in oscillations or reverberating circuits of some sort, there are a lot of people who think that that's how seizures are actually propagated because you've got different brain regions that have these resonances that overlap. Well, the same thing might be happening in a micro level with autism spectrum disorder. So it's no accident that we see an overlap in these conditions. So that at least in some manner could explain it. Now, that brings us to another phenomenologic condition here. And if you think about which comes first, chicken or the egg, epilepsy, psychiatric symptoms, well, then you have to think about bidirectionality a little bit. And this is a quote that I love putting up here from Lancet Neurology, dated at this point, although not terribly dated, it's only about 10 years old. Andy Kanner, who of course has been in this space for a very long time, prominent neurologist and psychiatrist who has been brilliant about so many of these overlaps. Well, he wrote a very controversial statement some time ago, although it's less controversial now. This idea that there might be an overlap between pathology and pathologic mechanisms between depression and seizures. This was very controversial at the time, but more and more bidirectionality is proving to be the case. Now, we might think that it's intuitive to believe that if you have epilepsy, if you have seizures, you're more likely to develop depression. Okay, fine. You know, it can be stressful, it can be difficult. Maybe even some of these neural networks are entangled in some manner, fine. You can have epilepsy, you're more likely to have depression. Well, it turns out that very careful epidemiologic studies have shown, done by Dale Hausdorfer and others, that if you have depression, you're more likely to develop epilepsy. So stop and think about that for a moment. That's a huge change in how we think about comorbidity and development of comorbid conditions with medical illness. We're saying that depression can develop into medical illness. Now, that's what the numbers are showing us. That's what the epidemiologic studies are saying. And not only is it true for depression, but it's also true for autism. We have these very large population registries from Sweden, from Denmark, that show that in fact, you will have increased prevalence of autism, increased hazard ratios if you start with epilepsy. We see the same thing for ADHD, that if you initially are identified as having ADHD, attention deficit hyperactivity disorder, that you may eventually be developing epilepsy. So that's a fascinating thing, and it turns everything around in terms of what we think about the brain and about comorbidity and comorbid conditions. And I'm gonna come back to stress and epilepsy too, because that's a huge overlap that tells us a lot about what we need to understand better about epilepsy. Now, I do wanna talk a little bit more about depression and about temporal lobe seizures, temporal lobe foci for seizures. Classic data suggests that if you have a temporal lobe focus, especially on the left side, you might be more likely to have depression. We've done a study showing that the same thing is the case, especially in pediatrics, where you've got medically refractory epilepsy, and that is where the medicines don't do such a great job of curing the seizures. Well, if you have a temporal lobe focus for your seizures, you're much more likely to have depressive symptoms on several different measures, different rating scales. And we also have learned a lot more about depressogenic circuits or pathologic circuits in the brain. This doesn't just come out of nowhere. There seems to be some reverberating circuit between subcortical regions like the caudate nucleus, the amygdala, which is of course the mesial temporal lobe, and the orbital frontal prefrontal cortex. These seem to be key regions that are involved in depression symptoms. And if there's a seizure foci or a seizure focus at any point or multiple foci at several points, well, there's gonna be no accident that you might have depressive symptoms that are co-occurring with your epilepsy. So these are very important overlaps. And knowing more about the pathologic process for depression and seeing how it might interact and interplay with different epileptogenic circuits, well, that's gonna be significant. And of course, the limbic system. Everybody gets excited about talking about the limbic systems. It's about emotion and intensity and everything else, anxiety. So of course, it's intrinsically interesting. Well, it just turns out that it happens to be a common focus for seizures and the amygdala especially. And this is classic from Pierre Glore 20, 30 years ago, where there were a couple of different procedures that were done with neurosurgery and stimulating seizure foci in the amygdala. And it turns out that the amygdala's job is actually to monitor and identify fear and anxiety in incoming stimuli. So a lot of this mesial temporal lobe is intrinsically integrated into how we perceive emotion and how emotion is managed and how anxiety and fear especially seems to be tagged to different things that we see, touch, hear, taste, everything else. All the amygdala's involved. So if it's overactive in any kind of way, either with some sort of endogenous depression or intrinsic depression, or with a seizure focus that happens to be located where you've got hyper excitable nerves in that region, then there's no accident that we're gonna see fear symptoms. Now, what do we call this? Do we call this depression? Do we call this epilepsy? Do we call it both? It's a tough question, but fortunately for me, of course, I've been able to study this for 20 plus years and it's been a fascinating journey to think about phenomenology and epidemiology and how these things have developed and the field has developed too. So anyway, I'll talk a little bit more about this and try to show you some more details about where we're going. Now, just in terms of seizures, we know the seizure threshold can be affected by multiple conditions and multiple circumstances. Decreased oxygen will lower the seizure threshold. Decreased sleep, that's the whole reason why we want people to be sleep deprived for their EEGs is because we wanna hire a yield to actually identify a seizure and get some information about it during the EEG. So sleep deprivation will certainly lower the seizure threshold, make seizures more likely to occur. Different medications, dehydration, different points of the menstrual cycle will impart differing vulnerabilities for seizures to occur too. And certainly fevers, infections, we know all these things and that's why the epilepsy specialists will ask questions about, have you had a fever? Have you been sick? If seizures seem to pop up. Stress. It used to be when I was early in my career, I couldn't convince anybody that stress was related to seizure threshold. Now everybody believes it. I think everybody believes it. Or a lot more people believe it than early in my career. The overlap is just incredible. And you can look at people who are exposed to stressful circumstances. Now these are pretty extreme things. These are natural disasters, as in the Netherlands nearly 30 years ago. Well, it just turns out if you have seizures and you're exposed to some stressful environment, your seizures will get worse. And certainly that was true in other types of stressful situations. If you were in a war affected region, then you were gonna have seizures more often. And these are in kids, of course, but it's also true for adults. And then Israel, where it's very common for young adults to serve in the military. Well, it turns out that if you were in the military and you were assigned to a combat unit, presumably more stressful, then you had a much higher incidence of seizures. These are people without preexisting epilepsy. Exposed to stressful circumstances, they could develop epilepsy. Stress begetting epilepsy. And that's just a concept that has been shown so many times now, we have to pay attention to it. We have to accept that there is a relationship between stress and anxiety and developing seizures. So the overlap, the bidirectionality, the information is just so convincing at that point that we have to accept it. Now, we've always known this in terms of big engines of the brain, the HPA axis, hypothalamo-pituitary-adrenal axis. A lot of our medications affect this axis, certainly. And from the old textbooks, when I went to medical school, there was this big arrow called stress, and that led to the HPA axis. Well, that has something to do with it. Maybe it's cortisol. Maybe it's other glucocorticoids. Maybe it's throwing a wrench in the cascade or at least a homeostasis for this area, this region, this process. Well, it turns out that you can have a lot of vulnerability when the HPA axis is dysregulated. We already know that it's dysregulated in epilepsy, and overactivity is a hallmark for mood disorders and for anxiety states as well. We have a lot of people who come in with sort of ambiguous conditions like dysautonomia or postural tachycardia syndrome, and maybe they have overlaps with epilepsy, sometimes not. But we do know that this axis is critical, and we know that shared pathological features of the HPA axis hyperactivity could contribute to affective states or affective disorders within epilepsy. And we also know that there's greater vulnerability for epilepsy based upon what happens acutely and chronically with stress and with upregulation of the HPA axis. So this is probably where it's happening, and we haven't worked it out fully yet, at least in humans in vivo, but we have a lot of information in vitro and with animal studies about how this axis can change and how seizure threshold can also change if there's dysregulation of this axis. So the bottom line is that we have so much information about the overlap between epilepsy and behavioral conditions and psychiatric symptoms like mood disorder, like depression, like anxiety, like panic, and we have to find a way to treat it. And I do think that epilepsy specialists have to at least find a way to identify it and then find a way to address it. Lucky for us, it turns out that anticonvulsants, what we call antiseizure medicines now, antiseizure medicines are spectacular medications, spectacular treatments in neuropsychiatry, and we can have a lot of neuropsychiatric benefit with these medicines, not only seizures, but they're spectacular medicines for impulsivity, for rage outbursts, for mood swings, for mood lability. Antiseizure medicines are first-line treatments for bipolar disorder and very effective to put a cap on explosive irritability or rage outbursts, anything like that. And just like for epilepsy, sometimes it doesn't take a full amount, just a low dose can serve as a good adjunct. The same thing happens with bipolar disorder or for mood disorder. Sometimes an antiseizure medicine is an adjunctive treatment for depression and can be very effective. We use a lot of antiseizure medicines for that purpose. We can use them for epilepsy too. We can use adjuncts that can enhance mood stability in addition to enhancing seizure stability or seizure control. So we have access to quite a number of antiseizure medicines that could play a dual role, and we did a study on this too, a very simple study looking back and thinking about epilepsy and particularly people who seem to have comorbid conditions. We stuck with bipolar spectrum just to see if we could actually treat both conditions with a single medicine. And it turns out that even way back when, when we did this review going on 15, 16 years ago, that we treated both conditions. And since that time, we've done clinical trials with anxiety and epilepsy with Clobazam. Clobazam, of course, is a uniquely structured benzodiazepine that has the nitrogen in a different spot than other benzodiazepines. It's a 1,5 versus a 1,4. And it turns out that we can actually treat anxiety and epilepsy with both conditions. There's a lot of talk about cannabidiol at this point, and I think it's because we have had pivotal trials showing significant efficacy for seizure control. Well, it turns out that we might actually improve anxiety and mood with cannabidiol too. Now, we can't prove it yet, but we're studying it, and we're hoping that it can be proven, especially when we have comorbid conditions like epilepsy, maybe certain seizure subtypes. But the bottom line here is that we have medicines available to us that can be excellent for treating comorbid conditions. So we should get used to that. We should become accustomed to using those medicines, if not as primary heavy lifters, at least as adjuncts, that can be add-ons, that can add to polytherapy and essentially yield good results in multiple different ways. Now I'm just going to go through what our options might be. And most of you, I'm sure, on this webinar know the details here and are very familiar with these medicines. I'm just going to divide it up in terms of GABAergic drugs. If you enhance GABA, then you're enhancing inhibition. Inhibition is great if you're trying to stop a seizure, you're trying to reduce hyperexcitability. That's what we want. So we want to enhance GABA. Most of our benzodiazepines do a very good job with that. Well, it turns out that most of them are pretty good for panic attacks or for anxiety as well. We use things like alprazolam in psychiatry very commonly, and alprazolam is a very common benzodiazepine. In a pinch, we use clonazepam, we use diazepam, we use lorazepam for acute treatment of anxiety. We also use gabapentin. Sometimes there's some data showing that it improves social phobia and certainly for pain control. Pregabalin may also be anti-anxiety. It doesn't mean that others won't work for that. There are benefits, there are pros and cons, certainly. With any type of GABAergic drug, you might get sedation, you might get fatigued, and sometimes you can even get frank depression in some ways. But GABAergic drugs might have a benefit. This is just a rough way to define it. I recognize that this is an oversimplification, but anti-glutamatergic drugs, if we reduce more directly the hyperexcitability, then we might have some benefit, not only for seizure control but also for comorbid psychiatric symptoms. Our go-to often here is lamotrigine. Lamotrigine is a very good medicine in the psychiatry world for bipolar depression, for maintenance for bipolar depression is the actual indication. But the utility certainly has been explored in many other aspects as well. Of all of our anti-seizure medicines, it might have the most robust antidepressant effect. Sometimes people can have responsivity for depressive symptoms, even for frank major depression or major depressive episode by using lamotrigine. That can be a go-to if we have someone with depression comorbidity along with epilepsy, and it's often used as an adjunct for people without epilepsy. So an anti-glutamatergic drug might be a go-to for us. And then, of course, the largest group of medicines is going to be mixed, multiple, unknown mechanisms. We're not really sure how all these things work, but that's okay. We can still use them. Our dibenzazepines are very common, carbamazepine, eslacarbazepine, noxcarbazepine. We use those quite frequently. They can be effective mood stabilizers. We also have some anecdotes with medicines like glucosamine, even levotiracetam, which can do a little bit of both. It can improve mood sometimes. It can worsen mood, sometimes markedly sometimes. Briviracetam, other medicines in that space can be very useful. And then valproate has been a go-to for bipolar disorder for a very long time, especially when the bipolar disorder is mixed, when you don't have frank manic episode, but if you're kind of up and down or a little bit variable, mixed episode is often very responsive to valproate. So those are all different types of medicines that can be useful for mood disorder, for any types of conditions that could become more, but especially when we have mood lability, so certainly. And, of course, the reference here is from FOCUS 2016. Please look it up. We go into a deep dive for all of those things. Anyway, I don't want to superficially go over anxiety and mood disorder. I am a psychiatrist, a pediatric psychiatrist by training, a neuropsychiatrist, a pediatric neuropsychiatrist by practice and by experience, and that's what I've been doing for 20 years. So I want to give some insight because a lot of people are very intimidated by anxiety and mood disorders. And, of course, they're scary, but, geez, a whole lot of things in medicine are scary. I mean, a lot of people are scared by epilepsy. And certainly we know the stigma still exists, and that's because people are scared about it. So let's make us all less scared that we can actually manage these things and address these things boldly and often with good success. So just a cursory look and an overview. Depression is a significant departure from typical function. There's a decreased interest, energy, enjoyment of usual activities. And there's usually some sense of hopelessness about the future. These people are in a rut. They're in a down phase. They're not thinking hopefully. They have a negative outlook. They're not enjoying the things that they usually enjoy, and they have a negative outlook for the future. And often there are physical symptoms to go along with it. They don't sleep as well. They don't eat as well. Their energy fluctuates. Sometimes they can't concentrate as well either. They have something physiologic. Think back to the HPA axis. Think to the mesial temporal lobe, the amygdala, the hippocampus. Those regions of the brain are not working as efficiently as possible. And it's affecting them in terms of big function, sleep, appetite, energy. And then anxiety itself. Sometimes anxiety becomes the problem, and a lot of people who are worriers are worried. They sometimes forget what they're worrying about. They're looking for something to worry about. Worry about worrying is kind of the sine qua non for that kind of thing. They also have sleep problems. They have troubles falling asleep. And then they can be so anxious and nervous that they get irritable or they get restless, or sometimes they have physical symptoms, headaches, stomach aches, something else. And the main thing is that they cannot control the worry it takes over them. And for any of these things, we go by function. And, you know, nobody's trying to make up problems for anyone, but it's just how someone is functioning. If you're not functioning, and this is the reason why, well then we have to do something about it. And oftentimes this is a significant departure from their typical levels of function. So just as an overview, it's a spectrum, but that is a way that we can understand that type of thing. And clinically they may not come up with problems like I'm depressed or I'm nervous or I'm anxious or I'm worried. It might be I have headaches or I've got stomach upset or I can't sleep. And certainly people might, in pediatrics, we see a lot of disruptive behavior or irritability. And that might be, especially in adolescence, that might be the equivalent to being depressed. They might just be irritable. There's a lot of self-medication that happens in adolescence or in young adults, and then sometimes social isolation or social phobia. That can be a big problem to help or to prevent someone from getting out of their doldrums or their ruts. If they're isolated, then that can be a big task, especially if they have social phobia, if their anxiety carries over into interactivity with others. So anyway, that's what we'll see clinically. So if you've got epilepsy, the first thing that you want to think about is let's not make it worse. If there are high-risk medicines that can yield depression, and the highest risk probably is phenobarbital, and sometimes it can be sustained. You can make someone depressed for a while, and sure, you can treat the seizures. And we know that phenobarbital works often when nothing else works, but we've got to watch out. There are moderate risks for other medicines, topiramate, felbamate, levotiracetam. Sometimes people who take benzodiazepines as standing doses, especially high doses, if you abruptly withdraw them, not only can you have a withdrawal seizure, but you can also have withdrawal depression or anxiety or panic attacks. Then you can get mood reactions from other medicines too. You can get mood reactions or depression with any anti-seizure medicine. Just because it's not on the list doesn't mean that it's impossible for it to occur. It could still occur, so keep that in mind too. And then let's treat it, address it. Now, psychotherapy can be very helpful. Just having another person to be a sounding board, to be someone who can build a relationship, to build trust, that can be very helpful. Look, a lot of our patients don't have anyone to talk to about this. They don't really want to talk to their families or friends about it because it just puts a burden on them and it makes them worry. So having a therapist is a neutral person who can actually talk about these things and help them sort it out. A lot of people say, well, we should have cognitive behavior. That's fine. There are some very skilled modalities of treatment, but the most important thing is does the patient like the therapist? And you have to keep looking until you find a therapist that has a good relationship or a therapeutic alliance. Then the modality doesn't really matter so much. Sure. Okay, so that's good if it's mild to moderate, but if we have high risk, then we're going to need to have a psychiatric specialist or at least somebody that's experienced by using antidepressant medicines. And most of the times it's going to be with an SSRI. I mentioned most of this already. Relationship building is the key and support. But most of the time, if you're going to use a medicine, we're going to use an SSRI. There are a lot of things that are acceptable for adults. For pediatrics, the world is a little bit smaller. We do have some FDA indications with fluoxetine, sertraline, fluvoxamine. I could also add escitalopram for adolescents. Those are very good medicines to use, very easy to use. The main thing about it is you want to know, does someone need more energy or less energy? That is your main decision point. If they're just in a rut, they have low energy, then give them something a little bit activating. That is going to be fluoxetine, sertraline, or duloxetine. Duloxetine is actually an SNRI, also includes norepinephrine. But if they need less activation, if they can't sleep, they're too wound up, they need to be relaxed a little bit, well then it's going to be escitalopram, escitalopram, ritazapine, something like that. If you're a primary care doctor or a neurologist, you want to get used to a couple of these that can be your go-tos, that you have a lot of experience with. Then if you refer to a specialist, then they're going to be able to fine-tune and tailor-make symptoms that correlate with different theoretical treatments anyway. For anybody, you have to see how it works out. For any antidepressant, and note that, of course, there's a scary precaution, a strong precaution, a warning, black box warning, may cause suicidality for any antidepressant, which is still a conundrum. It's an absurdist thing, quite frankly. But the grain of truth is that you get side effects in the first couple of weeks. It takes a long time for these medicines to work. If someone is suicidal or has suicidal ideas, they're still going to be suicidal for a few weeks after you take the medicine. Most of the time they have not gotten better. But they can be energized, they can be more activated, and that is often what we see. So the improved mood effects take longer, but the energy increases happen sooner. So that's what we have to pay attention to. It takes a while to wait it out. So that means you have to have very consistent follow-up, weekly visits even. A lot of the world is telehealth now. Do a telehealth check-in. How are you doing? How's your energy? Are you sleeping? Any side effects? Even the contact with the clinician can go a long way to build a safety agreement, a therapeutic alliance. And then monitor. If anybody becomes too agitated, too activated, too restless, stop the medicine. Just stop it. Start low. Don't, by rote, automatically increase the dose after a week or two. The energy still is going to be increasing then, so you don't want to increase it that quickly. It takes a while, so a month, maybe two months even, for this stuff to work. So you have to have a close relationship. Now I'll talk a little bit about nuances, and then I'll end this and I'll take as many questions as we can here. Anyway, when you have epilepsy, this is a life-changing thing, certainly. And for families, for parents, for kids, for adolescents, for adults, how you interact with people, what kind of restrictions you have on work activity, on driving, that makes a big difference. A lot of kids with epilepsy have arrested development to some degree because they've not been allowed to socially mature. A lot of them have lost time in terms of social development because of requiring medical treatments or being out of normal development for a long time. Sometimes they have delayed cognitive development or academic development because of inattention or executive functioning difficulties. And, of course, they might be more isolated. Parents. Look, part of the territory is being very fearful that your child could have a seizure and die. I mean, suit-up is a real thing, and it's a scary thing. And living with the fear is stressful. It's a very consistent thing. Kids know it, parents know it, and often they can unwittingly prevent social development. That's what that's supposed to say. Unwittingly prevent independence or social development or expanding their orbit or social interactions. And that's just part of the territory. You have to work through that a little bit. School. I could also include work activities. There might be limiting things that you can do, and you're not going to be one that can be without hydration for a long time, or meals, or something like that. You've gotta be careful about strenuous physical activity until you get used to being able to do it. Schools, you do often require some sort of supported educational curriculum, an individualized educational plan. And then addressing the stigma, of course, is gonna be a problem, too. There's still, it still exists. And I hear heartbreaking stories all the time about kids being ridiculed, or tormented in different ways, and having to come to terms with that, or at least reconcile it. So that's still an issue, and I think that stigma continues until our treatments and acknowledgements increases. But hey, this webinar is a step in the right direction. We have hundreds of people on, which is terrific. So that's the way we identify and address it. Anyway, I'll tie this all together here. So a neuropsychiatric paradigm. That might cover everything. That might actually be what we're thinking about here. This may not be two different illnesses. If you're an epileptologist, you might actually be good at, or need to be good at, and certainly get good at treating depression, treating anxiety, treating ADHD, because those things might co-occur. Connectivity, hyperexcitability might be the way that this is. Comorbidity might not be accurate. Co-occurring, or even better, anxiety might be a part of epilepsy. Depression might be a part of epilepsy, especially if you have a seizure focus in the temporal lobe. If you have a seizure focus in the amygdala, or the mesial temporal lobe, then depression and anxiety might be part of your symptoms. That might be part of what needs to be treated. We might need to select medications, or treatment, or psychotherapy, or whatever adjunct treatments are available based on what your seizure focus may be, and using a medicine that could cover a few different bases here. And certainly, seizure control and behavioral improvement might go hand-in-hand, and we know that some medicines are better at this than others. We already know that, and we're doing studies to find out more about medicines like Clobazam, and cannabidiol, and thinking about newer medicines, even, that have the potential to treat multiple conditions simultaneously. Those might be our go-tos if you've got co-occurring psychiatric symptoms, or even frank conditions, diagnosable conditions. And the most important thing, certainly for all of us, if you've got up to a third of our patients with epilepsy, that could also have depression, well, then we're gonna have to identify and treat depression. There's just no excuse to avoid that anymore. You know, we have to take it on, we have to be proactive about it. It's gonna be there, whether we treat it or not. So you might as well treat it, and there's some evidence, anecdotes at this point, but some evidence that outcomes for seizures are better if we treat the depression. Certainly, we know that quality of life is better if we treat the depression. So we might as well just take this head-on, tackle it head-on, and treat the depression, have a healthy index of suspicion that someone might be more likely to have depression, depending on different seizure characteristics, or subtypes, or foci. And we're working pretty hard, trying to figure out which conditions might have a higher yield for some of this, so we can at least provide information about that. So far, this is what we know. And I have to thank all of you for being here, and for joining in. And I think I will turn this back over to Dr. Kyriacopoulos and discuss questions. Great, thanks so much, Jay. Let's see if I can come back and join you all. Here we go. Thanks for a wonderful talk, Jay. Really, so much content, and you put it together for us in a way that made it really understandable, and helped us to appreciate the relationships between psychiatric disorders and epilepsy. I'm wondering, because we have a lot of clinicians on with us who aren't specialists, who are primary care providers, and out in the community, if you could just talk a little bit practically about coordinated care, and how you work with primary care providers to help care for your patients that have these types of difficulties. I think coordination is critical. I think that we have to communicate. Patients complain about us a lot, rightly so, that we don't communicate. What I often do is I will say, okay, number one, I want to get permission to talk to a primary care doctor or a neurologist. So we do that immediately. We set up the lines of communication. I think that we can send secure emails, or even insecure emails, leave voice messages, and I think it's important for a doctor to be able to do that, and leave a message like, just giving information. I think so-and-so in a person has depression. I think it's important to treat at this point. I'm seriously considering an antidepressant, but would like to have the conversation with you. It might make sense to stop prescribing this anti-seizure medicine and continue a different one, if that's possible at all. And 90% of the time, especially nowadays, I get very good feedback, very good response. 20 years ago, I would hear things like, well, the seizures are stable, so forget it. We're not changing anything. And that would be a difficult circumstance, but nowadays, especially the younger people, I have high hopes for the younger generation, and they're proving me correct. They are thinking about seizure medicines to treat comorbid symptoms and co-occurring symptoms proactively. So anyway, I think it's fine to say, well, I think it's time to start an antidepressant, or I think I would like to add an adjunct anti-seizure medicine, something like Lamotrigine, just as an example. Does that make sense from a seizure standpoint to do, or will that rock the boat too much to do that? So that's the kind of dialogue that you have to have. And I think for anybody with active epilepsy, especially if it's unstable epilepsy, you wanna have a conversation with a neurologist and with the epilepsy specialist, if possible, and just think it through a little bit and to say, should we do the antidepressant first? Should we do a different seizure medicine first? Often, if the seizures are unstable, that would be your go-to. You wanna try to do that. And I would say, let's use a seizure medicine that might have some mood benefit. Great. Thanks so much for that insight. There's a question around, a specific question asking about, can any of these medications, so those that treat anxiety and depression, be used while using epidiolex for seizures? Can you address that one? Okay, so that's using medicines for anxiety and depression versus seizures? Nope. So while someone is on epidiolex for seizures, is there any contraindication to treating the anxiety and depression with some of the other medicines that you've mentioned? Oh, okay, okay. No, there is no contraindication that I know of. Now, you still have to be reasonable and check other things. I mean, people worry about liver enzymes. Especially if they're taking other adjunctive or concomitant medicines. I think that you wanna have reasonable measures, reasonable targets, at least, so that you can have a baseline. I mean, there are a lot of people who think that pharmaceutical-grade cannabidiol has some benefit for anxiety and depression. Whether it does or whether it doesn't is hard to say, at least today. I think there's some encouraging indications. I personally don't feel strong hesitation in using other seizure medicines along with pharmaceutical-grade cannabidiol. I am a little bit more hesitant about antidepressants only because I wanna make sure that a patient is in antidepressant territory and we can't address it with a seizure medicine or a psychotherapy or something like that. Great. There's a question asking for you to comment on how acute versus chronic stress might differentially affect someone who has epilepsy. Sure, yeah. You know, it's a fascinating thing to think about. Acute stress actually switches on neurogenesis. So if someone is acutely stressed, you think about it, you're on alert. Your HPA axis is alerted, it's energized, and the brain growth and neurogenesis can be significant. So you actually turn things on. The problem is with chronic stress because then with chronic stress, the brain shifts into survival mode. You're not really growing new connections or synaptogenesis is significantly reduced in chronic stress because your HPA axis is so ultra-alert. It's so highly tuned that you're not really efficiently learning new things. Your cognitive functions are less efficient, memory, attention, concentration, because the chronic stress usurps the brain power and it makes you be in survival mode versus actually processing, relaxing, growing brain, managing, consolidating, all those types of things. Now the same thing will occur for seizures as well. Sometimes if you're acutely stressed, the mechanisms are a little bit more stable, but the chronic stress kind of taxes the organism and taxes brain function and development such that you can't recruit those mechanisms or those resources anymore. It's a complicated business, but I would refer you to one of our publications, a lot of basic science. There's some terrific people. I'll give a shout out to Jamie McGuire, who's done some of this work and just done some brilliant work to outline the basic science pathways in which this happens. Great. There is a question about more recent or novel forms of treatment for treatment-resistant depression. And the question revolves around ketamine and transcranial magnetic stimulation. And what are your thoughts on using them in a person who has intractable epilepsy and depression? Well, I can be very controversial about this, but hey, I'm up for that. I think that transcranial magnetic stimulation, now there are different methods of it, and I'm not an expert on it, but there are some people who think it has to be bilateral versus unilateral. The same arguments were made for electroconvulsive therapy. When the end point is a generalized seizure, and with each subsequent treatment of transcranial magnetic stimulation or electroconvulsive therapy has to have a higher charge dose per se, what you're actually doing is increasing the seizure threshold. Now think about what that means. Intuitively, it means you could actually treat epilepsy with ECT or with TMS, because what you're doing is increasing the seizure threshold. That's the whole point. We want the seizure threshold to increase. Now, this has been thought about for many, many years, 30 years, and of course, for any epileptologist, and I don't blame anyone. I mean, it's a little, it's like I can't give somebody a seizure. I'm trying to prevent seizures, but for any of these treatments, the seizures are muscles are paralyzed, fully oxygenated, fully monitored. So at least initial evidence that was done back in the 90s, pretty much, was that the brain doesn't suffer from it. There's no lingering damage from that, as much as we could tell. I actually believe it. I don't think, I think if there was something that could be controversial in that way, we would have seen it, and not just paranoia or fear about this. I mean, we have to be open to different treatments. That's the whole reason CBD is on the market now, is because parents and families insisted upon it. And then we have to be open to different types of treatments. So anyway, TMS and ECT for treating refractory epilepsy with depression makes sense to me. It absolutely makes sense to me. Now, ketamine is a little bit of a different animal. And ketamine, the reason why ketamine sort of hit the market is because people were tired of waiting, you know, a month and a half for an antidepressant to work. So they wanted something that was gonna work quickly. And that's the appeal of ketamine. Ketamine is kind of a mixed bag. You can get, you know, pretty frank psychosis with ketamine. So that's a big downside. I'm not a bold enough person to wanna give ketamine to someone with unstable epilepsy. Great. That's just my opinion though. Yep. And I'll be honest, that is just my opinion. Yeah, okay. So sort of along those lines with sort of other treatment modalities, what about neurostimulation? Are there devices, things like VNS or RNS or neurostimulation devices that can help as far as targeting both seizures and psychiatric conditions? VNS is fascinating. And I think, you know, the same argument for seizure control as a result of VNS is probably also true for depression and mood. The reality is that there probably is a benefit from it. Nobody knows how long it's supposed to take. And that's the hard part of it. Is it gonna take six months? It takes a long time for VNS to treat epilepsy even. And it probably takes a long time for mood also. Six months, eight months, 10 months, 12 months. That's the hard part for VNS, but I have seen it work. And I am convinced that it can work. As far as RNS, I think it's a little too soon to tell, but I have seen RNS be very effective in a handful of cases with refractory seizures plus depression. And I think it's encouraging in that way. Now it might have a little bit to do with seizure subtypes or seizure foci. If you've got mesial temporal sclerosis and you wanna have an RNS, I think that probably makes a lot of sense because you're gonna have depression along with that. You're gonna have medically refractory seizures. So it makes a lot of sense to go there and think about it for those types of conditions, especially if it can't be better treated any other way. Depression is very hard to treat for people with refractory seizures with a focus in the temporal lobe. Sometimes the medicines just don't work. So I think an RNS or a VNS certainly is worth considering. Great. There's a question here. Should neurologists be using depression scales at visits like pediatricians do? And I guess this question is alluding to screening and maybe just a few words from you on screening and regular screening and where that can happen as far as out in community practices, as well as at big medical centers. I think screening is great. I think it can be very effective. I don't think it's required. The only thing that's really required is you talk to the person in front of you and you just say, are you depressed? Or a lot of people with epilepsy, especially your type of epilepsy can have depression. Have you been depressed? Some people have anxiety attacks or panic attacks with your kind of epilepsy. Has that ever happened to you? If you can do that and the answer is yes, I really am unconcerned what the screening tests show. That's more important to me. But at the same time, you can sometimes track treatment response with some good screening tools. There are a lot of great screening tools out there, but none of them are as good as a relationship with a clinician and being able to have that conversation and be proactive about addressing it. Great. There's also a question that came in about assessing suicidality. And maybe you could give a little perspective on what that's like, say the difference between a youth or young adult or an older adult, what that process is like for people who are trying to do this, maybe out in their primary care practice or what are your thoughts around that, some guidance? Well, it's a difficult thing to talk about for anybody. It's difficult for psychiatrists to talk about. I would suggest a stepwise approach. Start by just saying, are you depressed? Then some people say some people get so depressed that they don't have much hope for the future. You can say some people get to such a hopeless point that they question whether they even wanna be alive or not. And then you kind of build from there. Some people will say things like, I wish I were dead. Have you ever felt like that? And then some people have actively considered taking their own life or not living anymore. And if you're in that territory, well, then you know, okay. And then you can even just say, well, that's pretty serious. Maybe we should find somebody for you to talk to about that, or maybe we should do something to treat it because often treatment can be very effective. And we can be realistic and just say, look, it's not gonna solve all the problems that you have, but it can make you feel better. It can make you feel a little bit better so that at least you can solve the other problems. And being very realistic, very frank like that is usually a good starting point. We'll do one more from a practicing child neurologist who shares that the majority of their practice is treating epilepsy. Are there significant drug-drug interactions to be aware of when prescribing SSRIs or SNRIs to patients with epilepsy on anti-seizure medicines? Well, the best information that we have is that if you've got pretty stable epilepsy, like one seizure a month or less, that the medicines do not seem to worsen seizures. So you can be pretty confident in those circumstances that the antidepressants will not worsen the epilepsy. Now, even if you're not that stable, it's hard to make a causal argument. We have shared pathogenic mechanisms lots of times, and I think that's an important point to keep in mind. So treating the depression that is co-occurring with the epilepsy might actually improve both conditions. Now, we can't prove that quite yet, and maybe it's still a chicken-and-egg thing, but the reality is, I would, for somebody that has moderate to severe depression, and certainly for any type of suicidality, I think you're mostly going to have to err on the side of treating. Great. Well, I want to thank you once again, Dr. Salpaker. It was a wonderful talk, and thank you for addressing these questions. I'd like to thank everyone for your attention and your engagement for being here with us today. Some online resources are presented here as well. I'd like to thank the team, everyone at AES, for making the webinar possible, and wish you all a good rest of your afternoon. Thanks again. Thank you.

epilepsy

mental health

comorbidities

psychiatric disorders

depression

anxiety

seizure conditions

anti-seizure medications

multidisciplinary approach

patient care