Good morning, everyone. My name is Vishal Madan. I'm the Chief of Education and Deputy Medical Director at the American Psychiatric Association. Thank you all for joining us today for our virtual immersive on clinical updates and sleep disorders. We've carefully curated a comprehensive program today that highlights the latest advances in sleep psychiatry. Today's agenda covers the diagnosis, treatment, and management of various sleep disorders in a broad range of ages, ranging from children, teens, to adults, of course. We are delighted to present seven talks from distinguished experts in sleep psychiatry. I'm also thankful to APA staff, especially Ms. Shazia Khan for keeping us all on track for this event. Now throughout the day, we'll have two short coffee breaks and lunch break. As a participant, you'll have access to recordings of all the sessions available in the APA Learning Center for up to three years. Now it's my pleasure to introduce our first speaker, Dr. Karl Dagramji, Professor of Psychiatry, Neurology, and Medicine, and Medical Director of the Jefferson Sleep Disorder Center, as well as the Program Director of the Fellowship in Sleep Medicine there. Dr. Dagramji will kick us off with his first lecture. Dr. Dagramji, the floor is yours. Thank you, Dr. Madan. It's a pleasure to be here with you early in the morning as we speak about waking up to insomnia. I'd like to also thank the APA and certainly you, Dr. Madan and Shazia Khan for planning this conference on sleep disorders. I'll be discussing insomnia today, and we'll start out by discussing the prevalence and impact of insomnia in clinical settings. We'll also try to review an evidence-based approach for the detection and evaluation of insomnia in our psychiatric practices. Finally, and most importantly, we'll try to construct an individualized treatment plan for insomnia patients, considering all the safety and efficacy concerns of the medications and treatment approaches for insomnia. Now, let's start off with talking about the prevalence of insomnia. This is one of the most common maladies in clinical medicine. About 30% of the general population has a complaint of insomnia over the course of a year and even a higher prevalence over the course of one's lifetime. About 10% of the population qualifies loosely for having insomnia disorder by virtue of the daytime functional impairments that they have in association with insomnia. As I said before, 50% of our clinical practices feature the complaint of insomnia, so this is a very, very common concern. In terms of insomnia disorder, the DSM-5 outlines clearly insomnia as a disorder, not just as a symptomatic problem or as a complaint, but as a disorder if it meets certain criteria. Number one, dissatisfaction with the quality and quantity of sleep with difficulty in initiating sleep, maintaining sleep, or waking up early in the morning. But number two, there has to be some significant distress or impairment, and I'll go over the nature of those impairments in a couple of minutes. Frequency of three nights or more per night and a duration criterion of more than three months. And of course, individuals should have an adequate opportunity for sleep. People who deprive themselves of sleep because of work reasons or shift work and whatnot, those people technically do not have insomnia disorder. Let's go over the impairments associated with insomnia that people may have. There are many of them, but the classic and most common ones are fatigue, malaise, attentional concentration issues. Insomniacs often have decrements in family and social occupational relationships and performance, mood disturbances, certainly daytime sleepiness. It's not uncommon for insomniacs to have this daytime abnormality in functioning because of sleepiness. Behavioral problems, hyperactivity, impulsivity, motivation issues, accidents, and of course, concerns and dissatisfaction. It's always a question, which of these are caused by insomnia, which of these are a result of other factors which may in turn also cause these problems. So it's always a problem, it's always a concern or the question is what came first, the chicken or the egg? And we'll talk a bit about this potential bidirectional relationship between insomnia and its comorbidities in a couple of minutes. In terms of health abnormalities that insomniacs might have and long-term consequences, these are on the bottom of the slide, insomniacs have a much higher predilection for the future development of various psychiatric disorders and particularly major depression and even medical disorders, hypertension, myocardial infarction, believe it or not, increased absenteeism from work, quality of life issues, and insomnia poses an increased economic burden. Patients have insomnia later on develop abnormalities which in turn cause economic issues by virtue of not being able to work as productively, taking up healthcare resources, and so on. Let's just talk a bit about the depression aspect of insomnia because a greater concern for our particular audience here. Before I do that, let me just mention hypertension real quickly. These are long-term studies with insomniacs over the course of four years and showing that people who have insomnia at 0.1 without any evidence of high blood pressure have a greater predilection for development of hypertension, high blood pressure, four years down the line by virtue of having insomnia, compared to individuals who do not have insomnia. So, insomnia, whether it's initiation problems or maintenance problems, confers a higher risk for future development of hypertension, and some of this might be due to the very nature of insomnia. Insomnia is a disorder we think of hyperarousal, where the entire brain and body are activated, aroused, by the autonomic nervous system is on hyperdrive, if you will, and it could be that this hyperactivation of the body over the long term leads to the persistence of high blood pressure abnormalities and cardiovascular abnormalities as well, and then the development of morbidity and mortality, even being higher with insomniacs. I mentioned the major depression feature. These are long-term longitudinal studies spanning many, many years, in some cases up to 10 or 15 years, showing that insomniacs, or rather people who have insomnia, have a higher rate of future development of major depressive disorder, where at 0.1 they may not have had that. So, the question again becomes, is there a bidirectional relationship between insomnia and underlying psychiatric disorders and major depression? We know that depression can cause insomnia, obviously, but is it possible that insomnia can also cause the future development of major depression? Again, this bidirectional type of relationship. Interestingly, after the resolution of depression, achievement of remission, the patients who continue to have insomnia have a higher risk of the redevelopment of depression or the recurrence of depression. So, it may be very relevant for us to pay attention in our depressed patients to insomnia, because it might be an independent predictor of the future development of more depressive episodes, and it's possible that the treatment of insomnia may confer a diminished risk, although those data yet have not emerged in a consistent fashion. But we do have, certainly, data from CBT, as well as some hypnotic agents, showing that treatment of insomnia may confer a diminished risk. I apologize. Treatment of insomnia may actually confer a positive benefit in terms of a more rapid resolution of depressive episodes. The insomnia is also associated with suicidal ideation. We know that the insomniacs have a higher rate of suicidal ideation, even after controlling for other co-factors, like hopelessness and diminished, and even depression. We also know, interestingly, the treatment of the, of insomnia itself in patients who are already being, who are depressed and have major depression, treatment of insomnia in this population confers, or rather, diminishes suicidal ideation. So, these are patients who are being treated for depression with antidepressants, and who continue to have insomnia, and during the course of the antidepressant treatment, patients have the introduction of a hypnotic agent or a placebo. The patients who have been treated with the hypnotic agent have a diminished rate of suicidal ideation compared to those who are just treated with placebo. Again, highlighting the possibility that insomnia is an independent risk factor for many psychiatric symptoms and syndromes, including early major depression, but even suicidal ideation itself. Now, despite the impact of insomnia, it's interesting that in clinical settings, many clinicians do not ask about insomnia. Only 30% of patients report that their practitioner actually asked about insomnia, whereas 70% do not. And the whys of this are, it's a long story, but it could be that we need to have more education involved in medical settings to confer to physicians and practitioners the importance of looking at insomnia as a predictor of so many other impairments, both psychiatric and medical. But once insomnia is detected, the question becomes, where do we go to next? What do we do in the evaluation of this problem? Well, certainly obtaining details about the pattern of insomnia, and I'll talk about this in a couple of minutes, and then determining whether insomnia is in fact contributing to daytime impairment. If it's not, then these patients might not be at risk for any major problems and may just need some reassurance. But if insomnia is a contributor to daytime impairments and is a significant concern for patients, then the first job, I think, is to outline the comorbidities and then manage those. Certainly, sometimes it's important to treat the insomnia together with the comorbidity, and it's an open question as to whether or not we should be treating the insomnia directly as we treat the comorbidity, or whether we should treat the comorbidity first, and then if the insomnia persists, treat the insomnia. And of course, in terms of treatments, there are many ways to skim this cake. But the two major categories of treatments are cognitive behavioral therapy and pharmacotherapy. We'll be going over that in detail. Let's talk a little bit about the pattern of insomnia. What is the relevance of that? Well, if it's an initial insomnia, middle, or terminal, it may be important to determine, because this may have relevance in terms of diagnosis or what the comorbidity might be. So if we have initial insomnia, this may be restlessness syndrome that may be causing it. If insomnia is a terminal problem, depression may be more likely or advanced sleep disorder. The pattern of sleep and insomnia may also be relevant in terms of our choice of hypnotic agents. Agents of our proof are the initial insomnia, the maintenance insomnia, or the combination of those two agents. So the pattern of insomnia may have relevance in terms of both diagnosis as well as therapy. The comorbidities of insomnia I mentioned before are important to treat in order for us to have a better resolution of the insomnia complaint. Well, what are those comorbidities? Well, there are many, many of them. And it's a good idea to do a thorough history and physical and psychiatric examination. Mood anxiety disorders, substance use problems, circadian rhythm problems, breathing difficulties, like sleep apnea, restless legs, all these examples of some of these. Medical disorders, such as heart disease, cancer, urinary problems, GI problems, and so on. So it's important to do a comprehensive evaluation to determine why the patient cannot sleep and determine whether these are causally related to the insomnia or not, or whether they're independent of the insomnia. How do we do this evaluation? Well, that's a very lengthy lecture, but I think in terms of looking at the various methods of the evaluation, history, physical exam, Epworth sleepiness score for daytime sleepiness, insomnia severity scale. I'd like to encourage many of you here to look into the insomnia severity scale. Here it is, the insomnia severity index. It's a self-administered scale which insomniacs rate themselves on a scale of none to very severe, zero to four, whether they're having difficulty with these various problems, whether insomnia interferes with daytime functioning, how noticeable it is, how worried or distressed they are. And a score of seven and above indicates clinically significant insomnia, and a 15 and above moderate, and a 22 and above severe insomnia. So this can guide us as to whether or not our treatment approach is working or not by sequentially administering the scale all the time. And also, if we have questions about whether or not this patient meets the criteria for insomnia disorder, this may be a helpful one to use. Sleep testing may be relevant as well to detect underlying reading disturbances of sleep and other disorders. Now, in terms of treatment, I mentioned that it's important to manage both the comorbidity as well as the insomnia itself. And let's talk a bit about direct management of the insomnia with either CBT or pharmacologic agents. What is CBT? Well, cognitive behavioral therapy in insomnia has multiple techniques and modalities. Stimulus control therapy is basically a treatment which asks the patient to not stay in bed for long periods of time, but once the insomnia occurs, while the patient is in bed, to basically get out of bed after a certain period of time and sit in a different room. And after the concern about sleeplessness diminishes, to come back to bed and try the process again. Relaxation therapy, biofeedback, progressive muscle relaxation are very helpful as well. Restricting time in bed for patients of multiple awakenings, especially elderly, may actually be more helpful. Many patients mistake that we spend a lot of time in bed trying to make up for lost sleep, which has the negative impact of making sleeplessness even worse. Cognitive therapy, dispelling patients' misperceptions and exaggerations about the impact of sleep and what notions that they have that are skewed. So, for example, telling patients that, you know, you don't have to get nine hours of sleep every night, you can get less sleep certain nights, and that sleeplessness on a couple of nights is not necessarily harmful for one's body, especially when considering the long-term effects. So, dispelling unwarranted misperceptions and so on. We'll talk a bit about sleep hygiene education as well. So, cognitive behavioral therapy may be a very helpful way of treating insomnia. You all know about the principles of sleep hygiene, but it's important, I think, to go over these with every patient. Getting up out of bed at the same time every morning, regularly is so critical. Insomnia violates this principle so often. Routines that are in sleep and wakefulness that are imposed on a regular basis. Setting aside worry times and making sure that we worry at times which are not close to bedtime and establishing a comfortable sleep environment. Not having alcohol stimulants during the day. Exercising not too close to bedtime. Avoiding napping as much as possible. And brief short naps are not a bad idea, especially if done at the same time, but avoiding regular napping and lengthy napping and certainly avoiding watching the clock at bedtime. So important principles of sleep hygiene, which I would strongly recommend we all go over systematically with each patient. And now, what about cognitive behavioral therapies? Well, there are many different kinds. And I mentioned before that some of these are useful for insomnia patients in every category, but cognitive behavioral therapy, six to eight sessions in person over eight weeks is really the gold standard. The problem with CBT is that there's a paucity of trained therapists. So a number of online and other techniques have been developed to accommodate for this problem. And the most common and one that's commonly available, very much available now is called SHUTI. It's a validated durability for 18 months. It was created by the FDA and is available online. And one is now being developed called the Brief Behavioral Therapy for Insomnia, BBTI. It's a two in-person visit with two telephone sessions over four weeks validated with nurse practitioners. So more and more online sessions are being developed for the treatment of insomnia to accommodate with a paucity of trained therapists. And if we look at the meta analytic data with cognitive behavioral therapy, we notice that there are data that show that it certainly does work. Sleep onset latency diminished by 20 minutes in this meta analysis, wake after sleep onset improved by 26 minutes and total sleep time by about seven minutes. So we know it works and it's a good idea to try it. The question becomes, if you have the luxury to try either CBT or pharmacotherapy, which should you try first? Which should you prioritize? And there are certain factors which determine one versus the other. Certainly if patients have no specific cognitive or behavioral factors and not violating any sleep hygiene issues, they don't have mental spinning, they don't have necessarily specific behavioral issues, then pharmacotherapy may make more sense. Pharmacotherapy also works more quickly and is more appealing if therapists have time limitations and certainly limited finances on the part of patients. In this era of shortage of trained therapists, I think we tend to gravitate towards pharmacotherapy. But CBT-I makes more sense if we're considering sustained clinical improvement as an important factor. So if patients want to develop something which works and works for long periods of time, pharmacotherapy is not the answer. CBT-I maybe is better and this has been shown in many studies. Patients have a substance abuse history, certainly gravitating towards CBT-I makes sense and if they have a lot of comorbid disorders. People who want to discontinue hypnotics, CBT-I makes more sense. Now let's talk a little bit about the medications that have been developed for insomnia. They fall into four different categories. Dietary supplements, which are not prescribed and have no formal indication. Over-the-counter sleep aids, which are indicated for insomnia but are not prescription agents. Assortment of off-label prescribed agents that are both prescribed and indicated by the FDA for insomnia. Excuse me. The first category, these complementary agents which are not necessarily not prescribed and certainly not indicated for insomnia. There's some general supportive evidence for a few of them, including Tai Chi, yoga and acupressure. These are non-pharmacologic agents, obviously. There's a mixed evidence for acupuncture, acupressure and L-tryptophan. L-tryptophan has fallen into disuse because of the development of something called eosinophilia myalgia syndrome many years ago. So it's not used that much anymore, even though the more recent preparations don't have this problem. There's really weaker unsupportive evidence for some of the more commonly used pharmacologic agents like valerian and herbal medications. So valerian is commonly used but it may have some side effects including hepatotoxicity and the evidence for it is somewhat weak at this point. What about cannabis? I certainly know that many of you know this patients tend to gravitate to cannabis for many different disorders, including pain, anxiety. Unfortunately, evidence for the use of cannabis is weak at this point, but the evidence seems to suggest that maybe some benefit for sleep problems in terms of sleep onset latency and wake after sleep onset. THC may have some short-term benefits but chronic use unfortunately can lead to habituation and to the sleep effects and the lower dose of CBD may be stimulating. So higher doses tend to be somewhat sedating. This is an area that is being actively looked at. And I think we have some data that suggests its usefulness. Although at this point, I don't think we can wholeheartedly say that cannabis works for sleep disorders, especially insomnia. What about the antihistamines? These are H1 antagonists like diphenhydramine and doxamine. The evidence is poor at this point with these agents, but certainly there's some evidence that diphenhydramine may be helpful for both sleep initiation as well as total sleep time and is used by many patients for sleep disorders. Diphenhydramine may have some anticholinergic effects and other effects which may lead to side effects such as confusion, urinary retention, dry mouth and blurred vision. It's a greater risk for elderly patients and patients who are taking other anticholinergic agents such as antidepressants. So it's a good idea to watch out for side effects for these compounds. What about low-dose antidepressants such as trazodone, I should say, doxepin or mirtazapine used at low doses for treatment of insomnia, sometimes used with other antidepressants? Certainly the disadvantage here is that they have not been well-established. There's one study showing that trazodone at low doses at 25 to 50 milligrams may work after a week or so for increasing the amount of continuity of sleep, but then there's rapid development of tolerance. These agents also have some disadvantages in terms of daytime sedation, and you might want to watch out for that. Certainly the one advantage is that there are many doses that we can go to with these agents, that one dose doesn't work and the abuse risk is very low at all. What about antipsychotic agents, cotiapine and olanzapine used again at low doses for insomnia? Again, these agents have not been well looked at. They may have some problems with daytime sedation and extraparanormal symptoms might occur. Some glucose and lipid abnormalities could occur with cotiapine over long-term use, but from a positive standpoint, they have low abuse potential and they could be effective, especially useful for patients with comorbid psychotic disorders. What about melatonin? Melatonin is a naturally occurring compound in our bodies. It's secreted from the pineal gland at night. Its secretion is suppressed during the day and with life. It acts as two sets of receptors, the MT1 and MT2 receptor. Its major function in animals is the control of circadian rhythms and production of sleep, although it may have other functions as well. There've been a number of placebo-controlled studies with melatonin. This is a meta-analysis of just a few of them showing that it may have some modest effects in patients with insomnia, reducing sleep latency and increasing total sleep time and improving sleep quality. Concerns have been raised about the use of melatonin with the various potential side effects, including lipid abnormalities. I apologize, glucose abnormalities. It may decrease in care over glucose tolerance in the morning and in the afternoon. It may also affect the sensitivity of various receptors throughout the body to various drugs. So it may be a good idea to use melatonin if it's used only for shorter periods of time and at lower doses, lowest doses possible. Now, there are more data with the use of melatonin in circadian rhythm disorders, which may actually be associated with insomnia. Most notably, delayed sleep-based syndrome and non-24-hour sleep-based syndrome. Delayed sleep-based syndrome is a problem which occurs primarily in youngsters where there's a constant delay or clockwise motion of the sleep-wake rhythm so that they cannot wake up. They cannot fall asleep until two or three in the morning or late hours of the morning. And it's hard for them to wake up at the end of the morning. They always wake up later. And this delay is constant. That is, it's not varying over time. There's another disorder called non-24-hour sleep-wake syndrome, which is more common in blind and visually impaired people where there's also a delay in the sleep-wake rhythm, but that delay is sequential over time. It's variable. So that is, they fall asleep later in the night and wake up later in the morning. But that delay is magnified over time so that maybe weeks and weeks later, now they may have a completely distorted sleep-wake rhythm so that now they're falling asleep at noon as opposed to at nighttime. The reason is that their sleep-wake rhythm is more than 24 hours long. That's why it's called the non-24-hour sleep-wake syndrome. Let's go back to delayed sleep-based for a second. This is more common in adolescents and young adults, as I said before. And its etiology is not clear, but the studies done with melatonin in this disorder indicate that administration of melatonin prior to bedtime, a few hours prior to bedtime, these are the number of hours before a DILMO, a dim-light melatonin onset, that this drug, melatonin, is administered. So giving the drug a few hours before the onset of melatonin increase, that onset of melatonin increase tends to be close to bedtime, many hours before, four or five, six hours before, is actually useful for this disorder, not at bedtime. And in terms of the disorder we talked about, the non-24-hour disorder, in this particular disorder, which is more common in blind individuals, there's a drug that's been approved. It's a melatonin receptor agonist called Tazimeltion, which is administered with 20 milligrams at bedtime. So melatonin may be useful, very useful for these chronobiologic disorders, circadian rhythm disorders, but melatonin administered at bedtime for regular insomnia may have only modest effects, and we should be careful about its use over long periods of time. Let's talk a little bit about the prescription agents for insomnia, benzodiazepine receptor agonists, the non-benzodiazepines, which are benzodiazepine receptor agonists, but are non-benzodiazepines in their compounds, the exposed BZRAs, melatonin agonists, histamine agonists, and dual orexin receptor antagonists. First of all, just a quick review of sleep physiology. As you all know, there are two major receptor systems governing arousal and sleep. The arousal system is governed by various underlying neurotransmitters, including histamine, dopamine, acetylcholine, norepinephrine, and another major area called the hypocretins. The sleep system is governed by primarily GABA, gamma-amino butyric acid, whose nucleus is primarily in ventrolateral preoptic area. Now, regarding the hypocretins, these are also called orexins. These are also arousal neurotransmitters, and they actually seem to also have a controlling mechanism over the other wake neurotransmitters, which we talked about earlier. They're localized to the dorsolateral hypothalamus, and they control not only arousal, but various other things like metabolism and blood pressure and so on. But for our purposes here, they're arousing neurotransmitters. So many of the compounds that we'll be talking about either antagonize these arousing systems or agonize or augment the activity of the GABA, which is the sedating area of the brain. Excuse me. Now, let's talk a little bit about the GABAergic neuron. GABA, as you know, is the major negative or inhibitory neurotransmitter of the brain. And the benzodiazepine agonists essentially hook onto the benzodiazepine receptor recognition site and augment or enhance the activity of GABA, and by doing so, promote sleep. Now, here are all of the hypnotic agents noted that we just talked about earlier. First of all, the benzodiazepine receptor agonists noted on the top of the slide. The non-benzodiazepine agonists, which they're not benzos in their chemical structure, but they also work at the benzodiazepine recognition site noted here. The alternative delivery benzo-BZRAs, such as the sublingual oral sprays and so on, oral sprays. And then finally, the melatonin receptor agonists, remeltion, selective histamine receptor agonists, like doxepin, low-dose doxepin, and the dual orexin receptor antagonists, a suborexin, lemorexin, or a GABA-orexin. These are the agents which we have available to us. The question becomes, you know, which agent do we use and for what reason? And there are two major decision points, decisions and deciding factors, I should say, which help us understand which of these agents which should we use in this particular case. And those two major factors are, does the drug work for sleep onset insomnia primarily or sleep maintenance in early morning awakening? So is it a sleep onset drug or is it a sleep maintenance drug or is it both? The older benzodiazepine receptor agonists, like eszopiclone, I apologize, like xalopron and zolpone, tend to have defects primarily for sleep onset insomnia. So if a patient has difficulty falling asleep only, these are two drugs which would be useful. On the other hand, some of the other benzodiazepine receptor agonists, such as eszopiclone and zolpone, extended with these, tend to work both for initiation insomnia, onset insomnia, as well as sleep maintenance insomnia. So they're more sort of panacea drugs. And these are useful in patients complaining about difficulty falling asleep and staying asleep in bed. Rameltion is useful only for the initiation insomnia. Middle of the night sublingual zolpidem is an agent given to patients after they fall asleep. If they fall asleep and cannot stay asleep, it's an agent which is given sublingually after they wake up in the middle of the night. And they may be able to fall back to sleep and wake up and not have any residual impairment. So sublingual zolpidem in the middle of the night is available and useful for sleep maintenance insomnia. What about low-dose doxepin? This is 3 milligrams, 6 milligrams. This is useful for maintenance insomnia if given in the beginning of the night, but not for initiation insomnia. And finally, the orexin receptor antagonists, such as lemborexin, suborexin, and daretorexin, these are useful for both initiation and maintenance insomnia. So the maintenance and initiation question is the main question to ask for in determining which of these drugs might be your first choice agent. Now, there are many other factors as well, which we'll talk about in a couple of minutes. By the way, the agents that have been actually studied for psychiatric syndrome along with insomnia are zolpidem, zolpidem-extended release, and eszopiclone. In the case of eszopiclone, interestingly, 3 milligrams was used in conjunction with fluoxetine for patients who were depressed. And interestingly, this showed that the use of eszopiclone improved not only sleep measures, but also provided a higher rate for major depression remission over time and improved quality of life. So, again, showing us the treatment of sleep problems in our psychiatric patients may actually benefit patients not just for sleep, but also for other psychiatric comorbidities. Again, these are not FDA indications as such, but research data, which are preliminary and which need to be substantiated in future studies. What about adverse effects? Well, here they are. I encourage all of you to look at these. Some of the major problems that we worry about with these symptomatics are their impairment of respiration, of course, addiction, and habituation, and so on and so forth. We'll talk about these in a couple of minutes. Now, vulnerable populations include the elderly, women especially, because they metabolize these drugs in a slower fashion sometimes. So it's important to decrease the dose in these populations. People with drug and alcohol and substance use disorders, there are a couple of drugs which are not FDA, which are not DEA-scheduled. Rimalteon and the low-dose doxyquin. So these agents might be especially useful for patients who have drug and alcohol use issues. Of course, you want to be careful of pregnancy, hepatic impairment, and depression. All of these agents can be used concomitantly with patients who have depression. They're used only without antidepressants and without depression treatments with patients who have depression and insomnia, as I'm going to tell you. The underlying depression must be treated. These agents are not indicated for pediatric patients, obviously. Let me talk a little bit about the most recently introduced agents, the dual orexin receptor antagonists. The first of these was suvorexant introduced in 2014 for both sleep onset and maintenance insomnia. Side effects are indicated here, but I wanted to emphasize the fact that this was also studied for mild to moderate sleep apnea without the use of CPAP or other treatments for apnea and demonstrated some safety and also with mild to moderate COPD. There were two trials for insomnia, a three-month study and another study, which was in the elderly. And there was another study which was used for specifically for Alzheimer's population. And in both of these cases, there was certainly improvement in sleep. So these agents have been studied extensively for various populations of insomniacs, but importantly with minimal respiratory suppression in these mild to moderate cases. Another agent, lemborexant, was approved in 2019 and its side effects are noted here, but this was studied with mild sleep apnea and there was no increase in frequency of apneic episodes. And there were two trials for insomnia, a one-month trial and a six-month placebo-controlled phase as well. And again, showing improvement. And in this particular case, this study showed superiority. The zolpidem-extended release will wake up to sleep onset in the second half of the night. This was one of the few studies which agents, I should say, which actually showed superiority to another agent, in this case, zolpidem-extended release. And finally, daridorexin, the most recently introduced agent for insomnia of the daridorexin antagonist class. Safety-wise study for moderate COPD and mild to moderate obstructive sleep apnea showing minimal impairment. And two trials for insomnia, a three-month study and the first study that was at 25 and 50 milligrams, showing improvement in objective and subjective measures of sleep. And the second study, interesting, showing improvement in daytime measures of impairment from insomnia. So these are patients which actually improved in terms of their daytime sleepiness domain on something called the IDZIC, which is a questionnaire looking at daytime impairment for insomnia. This is something which has been not shown with many hypnotics, and interestingly, was shown improvement as a secondary measure with this particular drug. So again, many agents available to us, each of them having various pros and cons. The orexin receptor antagonists, by the way, have also been looked at in terms of next day morning driving performance, no impairment in these three drugs, but impairment in some subjects, next day memory abnormalities, middle of the night administration if the patient takes the drug middle of the night, are they impaired? Again, showing some impairment. So these drugs should not be used for patients who need to get up in the middle of the night to walk around and do complex things, but if they are used for whatever reason, showing that there may be some advantage to these agents over and above some of these older drugs, which have not been looked at for this particular purpose. Long-term use, no rebound, no withdrawal symptoms after long-term use with these two agents. So given all of these factors, which agents do we use for which particular purpose? Certainly age is a factor. The older patients are the less we should be reliant on this, the more sedating agents. If patients have sleep onset insomnia, initiation insomnia, difficulty falling asleep, rumeltion, zolpidem, and xaloplan are specifically indicated in this practice. If the patients have sleep maintenance problems, doxepin low-dose or zolpidem low-dose, sublingual, as needed in the middle of the night may be appropriate. If patients have both onset and maintenance problems, eszopicol, zolpidem extended release, sumorexin, lemborexin, and deriverexin, they're specifically indicated for these difficulties. If patients need to wake up in the middle of the night after an auditory stimulus, like a baby wakes up or they need to, they're over on call at night, they need to answer a phone call, doxepin low-dose lemborexin and suborexin have been studied for this purpose. If patients have comorbid mild to moderate sleep apnea, rumeltion, suborexin, deriverexin have been specifically studied for these purposes, or mild to moderate COPD as well, these rumeltion, suborexin, and deriverexin. If patients have a history of substance abuse, rumeltion and doxepin are not scheduled agents and may be specifically going to, and so the cost in patient companies issues as well. Well, parasomnias or movement disorders in the middle of the night have been noted when patients get up in the middle of the night to perform complex activity, sometimes dangerous activity, have been reported with the use of some of these hypnotic agents, most commonly with zolpidem. These, unfortunately, have not been well studied, but one of the determiners of whether patients have these disturbances or not might be the comorbid use of other hypnotic agents, other sedative agents, and the use of alcohol. So patients should be specifically warned, do not drink, do not have alcohol when you use hypnotic agents, do not take other hypnotics, and of course, take your hypnotics as prescribed, at bedtime, at the dose you were prescribed. The American Academy of Sleep Medicine and other agencies recommend regular follow-ups for patients who have been using hypnotics and also using the lowest effective dosage. Long-term use, well, yes, these agents could be used long-term. Is it a good idea? Well, if the hypnotics work and are not producing unwanted side effects, then the patient needs them. How do you know if they need them? Well, episodic reduction in dosage may be a good idea. Every few months, reducing the dose slightly to see if the hypnotic is needed. Further or not, may not be a good idea. And certainly recommending that patients engage in cognitive behavioral therapy as a way of introducing a non-drug strategy which might work and which may be able to supplant the use of the hypnotic agent over time. So in conclusion, insomnia is a highly prevalent problem in community and in clinical settings. It's associated with functional consequences, negative health outcomes. To evaluate insomnia, it's important to perform a systematic evaluation, manage the comorbidities whenever possible, and considering combination strategies. Cognitive behavioral strategies, pharmacologic strategies, either in isolation or in combination. And it's important to develop a personalized approach for each patient that takes into consideration the characteristics of each pharmacologic drug, the pros and the cons, and the tail of the drug for the specific needs of the patient based on the patient's clinical presentation. I want to thank you for your attention today. And I will be staying for a few minutes for questions and answers, but I want to encourage you to stay for the 8.30 session, I'm sorry, the 9.30 session with Dr. Carlos Schenck on the parasomnias, a fascinating lecture on things that go bump in the night. Now I'd like to address any questions that you may have when we go to the chat session, and then we can encourage again, all of you to be able to ask questions as they come up. Let's see now. By the way, I also want to mention that the slides of this presentation will be made available to you in the APA Learning Center if you want to look at them afterwards. Now, those of you who have questions, please submit them in the Zoom panel. We'll address the questions in the last 10 to 15 minutes of the session, right now. One question that kind of comes up and came up in this session is the use of gabapentin. Does this work for sleep or not? Gabapentin was looked at in a couple of studies with comorbid insomnias, with patients who have comorbid substance use issues. And was shown to be useful in terms of improving sleep continuity in patients who have drug and alcohol use issues. So it may be useful in this specific population, especially since we do not want to use scheduled agents with this population. And then we need to do more work with gabapentin, but it might be useful agents in increasing sleep depth and being able to reduce more sleep continuity in patients who have sleep and maintenance issues and who have substance use issues. Question on the use of hypnotic agents in the pediatric population. What do we do with children? Yeah, and none of the hypnotic agents are indicated with children, as you know. In ADD, this is specifically a problem because most ADD patients have problems with sleep. They either wake up a lot during the night or they have morning fatigue. They also have difficulties unless falling asleep. I think in ADD, it makes a great deal of sense to consider cognitive behavioral therapies. Many of our CBT strategies are specifically, have been specifically looked at with children. In addition, sleep hygiene issues are very critically important in children. It's so common with the youngsters to be eating chocolate chip cookies or eating chocolate close to bedtime or being not only active close to bedtime but having lots of light sources introduced into their lives such as with these televisions or with these handheld devices or games that are on tablets. It's really important to be able to take these away from children as bedtime approaches and to have the nighttime become a winding downtime for children to be able to help them sleep better as opposed to using pharmacologic agents. If we must use pharmacologic agents, I would suggest melatonin for short periods of time at low doses with children. Some of those might be a good strategy. Now, the other question that comes up is in the other end of the spectrum in terms of the elderly. What are some strategies with the elderly? Well, I certainly would recommend, again, use of cognitive behavioral strategies. The American Academy of Geriatrics, American Academy of Family Physicians have both recommended that hypnotic agents not be used in some cases with older patients and that CBT, cognitive behavioral therapy, be the only method used with older patients. And I think that certainly makes sense to look at these recommendations. The one strategy that works well with older patients is limiting the time in bed because older patients have such a discontinuous night's sleep that limiting the time that they spend in bed may actually make sleep much more continuous. So if, for example, the patient is spending 8, 9, 10 hours in bed and this pattern is scattered throughout the course of the night and the day, then to tell patients to now spend maybe 6 hours or 6 1⁄2 hours in bed only and to not nap during the day. And as the efficiency of their sleep increases, their sleep becomes more productive, even to increase that limitation in bed. And in the lecture that I provided, you'll see some more specific guidelines about how to do this. So limiting time in bed may be more productive for older people than basically spending more time in bed, which can be counterproductive. Yeah, the use of natural compounds comes up as a question. Yeah, many patients are using things like valerian, cavacava, skullcap, and so on and so forth. I would strongly recommend that we, whenever we see a patient with insomnia, that we look very carefully at what non-prescription items they're using. Number one, these could interact with the agents that we're going to be prescribing. And number two, these may have actually negative impact on the patient. For example, some of these agents could be hepatotoxic, and therefore it's important to look at these and maybe even discontinue these agents in patients. The average patient has actually taken at least two or three of these agents before they see a physician for insomnia. So carefully look at these agents and make sure that patients are not using them when you introduce your medication, your therapy, for patients who are insomniac. Well, it looks like we've reached the end of our questions. I'd like to thank you again all for joining me today, and I'd like to encourage you to stay on for the next discussion, which will be on parasomnias.

insomnia

sleep disorders

cognitive behavioral therapy

pharmacotherapy

American Psychiatric Association

DSM-5

personalized treatment

Dr. Vishal Madan

Dr. Karl Dagramji