The Pathophysiology of Sleep-Wake Disorders Transcript PDF

The Pathophysiology of Sleep-Wake Disorders Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2533795-dt-... The Pathophysiology of Sleep-Wake Disorders So this slide set is about the physiology, the etiology, and characterizatio...

The Pathophysiology of Sleep-Wake Disorders Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2533795-dt-... The Pathophysiology of Sleep-Wake Disorders So this slide set is about the physiology, the etiology, and characterization I guess of sleep-wake disorders, aka, insomnia. Sleep wake disorders are certainly something that will be part of your everyday world in mental health, whether it's the primary reason that the patient comes to see you or an ancillary reason, or maybe it's just a symptom of an underlying phenomenon, but you're de!nitely going to have to manage people that are having trouble sleeping. And so in this slide set-- and it might be a bit of a review of 6026 now that I think about it, but that's OK. I always say, the more you hear it, you get-- it can only be to your advantage to hear something more than once. People that have insomnia or a sleep disorder, to use proper terminology these days, there's a whole slew of things that can cause it. One treatment does de!nitely not !t all. So that's why !rst we talk about the underlying pathophysiology. That helps you !gure out what type of sleep disorder or what type of insomnia you're having to manage. And that will tell you, A, if a medication is appropriate, number one. And then B, if so, maybe give you some idea of what to choose. So let's take a look at sleep-wake disorders. All righty. As I look through this slide set, I do think, in retrospect, quite a bit of it was presented to you in Nursing 6026. So if this is a repeat, my apologies. You can not listen to it. You can move ahead to your other learning activities. That's entirely up to you. But for those of you that don't remember or 6026 has been a while ago, here it is again. So sleep-wake disorder really is the more contemporary terminology for what we used to call insomnia. I mean, we do have disorders of wakefulness. We have things like narcolepsy. And we will allude to them in other lectures, but the real topic of conversation here is the patient who has what we typically call insomnia. I can't sleep. In some way, I can't sleep. Insomnia is a generic term. Classically, it is associated with the inability to fall asleep, 1 of 21 12/8/24, 4:29 PM The Pathophysiology of Sleep-Wake Disorders Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2533795-dt-... but it could mean many things. More accurately, more appropriately, insomnia is any circumstance in which a person experiences inadequate restorative sleep. And that may not seem like so much of a di"erence to you, but it really is. Insomnia can have many forms. And there are several stages of sleep, and they really are all necessary for physiologic restoration. Di"erent stages of sleep restore di"erent processes. And so that's why insomnia can be such a challenge. Some people have de!ciencies in one stage of sleep, and so that causes one set of problems or symptoms. Other patients will have problems with another stage of sleep, and so their primary symptom presentation is quite di"erent. So we really do need to take a little bit closer look at what it means to have trouble sleeping, what it really is when somebody has insomnia. And that is, of course, the purpose of this slide set. So one of the great debates in the world of academic medicine is whether insomnia is a diagnosis to be treated in its own right or is it a symptom of something else, not entirely unlike headache. Is headache-- when patients have a headache, is the headache the problem, like in migraine or tension headaches, or is it a symptom of something else like a subarachnoid hemorrhage or a bleed or meningitis, or whatever? So insomnia, diagnosis or symptom? And it has been often debated. And if you do like a real deep dive, do like a Google Scholar search and read what all the really smart people say about it. People argue, they have their opinion. In the !nal analysis, it really doesn't matter so much whether it's a diagnosis in its own right or a symptom of something else. We're going to !gure it out if we work it up appropriately. But one thing we do want to be clear on is that the word insomnia can mean di"erent things to di"erent people, and these di"erent things typically have di"erent causation. So patient A might say they have insomnia and what they have is problems falling asleep. Once they fall asleep, they can stay asleep. This poor soul might go to bed at 9:00 or 10:00 p.m. because they have to get up at 6:00 a.m. And they go to bed at 10:00 and they lay there awake until 1:00. But when they fall asleep, they sleep like a brick. And then when the alarm goes o" at 6:00 a.m., they're pulled out of the deepest sleep, and that stinks and they don't feel great. So that's trouble falling asleep. But once they fall asleep, they can stay there. There are those people who fall asleep just like that. You will have patients who tell you, the minute my head hits the pillow, I am out. I don't even remember turning o" 2 of 21 12/8/24, 4:29 PM The Pathophysiology of Sleep-Wake Disorders Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2533795-dt-... the TV or whatever the case may be. But 1:00 a.m., 2:00 a.m., wide awake. Eyes open and it's like-- and some of you listening, you probably experience this too and you know exactly what I'm talking about. You open your eyes and you're like, oh God. It's still dark out. I know. Here it is again, like 1:00 a.m. So this might be the person that goes to bed at 10:00 because they have to get up at 6:00. They fall right asleep. By 10:02, they're out. And then bam, those eyes are wide open and they just know before they even look at the clock, it's going to be like 1:00 or 2:00 or something like that. So then you very grudgingly roll over and look at the clock and go, why does this keep happening to me? That's di"erent sleep disorder and it's di"erent etiologies and di"erent interventions. And then we have patients who have trouble with early morning awakening. So this is the person who they wake up too early but by the time they wake up, they just can't go back to sleep or there is no point. This might be the person who goes to bed at 10:00, has the alarm set for 6:00, but at 4:30, bam, eyes wide open like, oh brother, what I wouldn't give to be able to sleep for another hour and a half. But of course now, it's done. Now they're awake. These are di"erent things. Di#culty falling asleep, DFA, di#culty remaining asleep, aka, nocturnal awakening, and then early morning awakening, or EMA. They are all di"erent issues and they have di"erent causation. So the !rst thing you want to do when somebody tells you that they can't sleep, they have insomnia, they have trouble sleeping, you really want to quantify exactly what they're talking about. And then, of course, you have the patient who tells you that they haven't slept all night, that they lay there all night long and haven't slept at all. They wake up in the morning-- or they might say they fell asleep !ve minutes before the alarm went o". And then when the alarm went o", they got pulled out of a very sound sleep. But there are those who just maintain they do not sleep all night long. These are the people who in the morning just feel like they haven't slept. They probably have. They just have-- in fact, they certainly have. When they have a sleep study, it is clear that they fall into certain stages of sleep, but they don't stay in the necessary stages of sleep long enough to experience physiologic restoration. So we refer to that as nonrestorative sleep. And they all are di"erent and they all have potentially di"erent etiologies. And you know how this goes, the best approach to treating a problem is to getting a 3 of 21 12/8/24, 4:29 PM The Pathophysiology of Sleep-Wake Disorders Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2533795-dt-... real handle on what's causing it. And there are di"erences, there are di"erent causations between trouble falling asleep, trouble staying asleep, waking up too early, or just feeling like you haven't slept all night. So there are those who advocate for referring to insomnia as a diagnosis. Insomnia is the problem and insomnia is the primary treatment target. This would imply that trouble sleeping is independent of other factors. These patients don't have any medical diagnoses, no psychiatric diagnoses. They're not on many medications that would keep them awake. There's nothing else going on in their world that would keep them awake. They just have one of those problems that we just described. And so there's lots of things that can cause this. One of them, one of the more common ones is psychophysiologic arousal. In other words, there is something on their mind keeping them awake even if they don't necessarily realize it. And I know that sounds a little bit ambiguous, but hold on to that idea. We'll get there. Arousal. And hyperarousal is a common theme in people that have trouble sleeping. And so sometimes they experience physiologic arousal, cortical arousal because of some sort of underlying target of their worry, perseveration, depression, racing thoughts or something like that. And then we do have patients who have what is now called non-24 circadian rhythm disorder. It's become a fairly popular diagnosis in recent history. There's a couple of medications on the market that have a particular indication for this problem. And it really refers to the patient whose sleep disorder is related to circadian problems, to an imbalance of sleep and wake hormones, which is the primary problem for most people-- or not most. That's not what I meant to say. For some people. There are those who genuinely have an imbalance in their sleep-wake hormones, and it could be for any variety of reasons. Obviously, one of them is exposure to light. The whole-- if you just take this back to-- way back in the old, old, old, old days, we are supposed to be awake during the day when it's light out so that we can get up and work hard so that we can eat and do the things we need to do to sustain life. And then at the end of the day, when the light goes down, when the sun goes down and it's dark out, we sleep. And there's de!nitely a relationship here between light and the production of wake- producing hormones and dark and the production of sleep-producing hormones. So obviously in patients who are not sighted, there is the potential for an imbalance here. 4 of 21 12/8/24, 4:29 PM The Pathophysiology of Sleep-Wake Disorders Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2533795-dt-... Patients that do not have sight, don't have the light stimulus that is part of that circadian rhythm of sleep-wake hormones. So in blind patients, yes, that makes perfect sense. But there are patients with vision who still, independent of light and dark stimuli, have an imbalance of those circadian hormones, and so they genuinely have trouble falling asleep and staying asleep when they're supposed to. So in circumstances like that, insomnia may in itself be the primary diagnosis. There isn't another underlying problem causing di#culty sleeping. On the $ip side, insomnia as a symptom of something else is generally believed to be the more common phenomenon. This is the traditional view of insomnia, and this suggests that trouble sleeping is the consequence of something else. There's a lot of something elses that can do it. A number of medical disorders can give you trouble sleeping. The obvious ones, the classic ones are those that are characterized by accelerated metabolism: hypothyroidism, hypercortisolism, hyperadrenalism, just o" the top of my head. But there are certainly-- there are certainly others. Psychiatric disorders, the manic patient, not only can't sleep but doesn't feel a need to sleep. And the depressed patient. When you look at the physiology of depression, there's abnormal stimulation right there in your reticular formation. And so it's not unusual that patients that have depression have trouble sleeping. Anxiety disorders are related to trouble sleeping. So it could be an underlying psychiatric problem. Of course, any medication that serves as a sympathetic nervous system stimulant, beta adrenergic agonists, like medications that we use for, what do you call it, asthma. Psychostimulants that we use for ADD, stimulants that we use for appetite suppression, just to name a few. So insomnia logically can be a consequence of any of those. And as always, we do have to rule out substance abuse as the etiology of the problem. Alcohol in the evening is a really common cause of nocturnal awakening. To you and me, it seems very obvious, but patients just don't make this connection. But remember that alcohol is a sympathetic nervous system suppressant, depressant. If you drink alcohol, it does slow down your sympathetic nervous system. It blocks excitation. And so if you have even just a glass of wine or two with dinner, or a cocktail after dinner to relax in the evening, you are suppressing your sympathetic nervous system that will promote sleep. 5 of 21 12/8/24, 4:29 PM The Pathophysiology of Sleep-Wake Disorders Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2533795-dt-... But alcohol metabolizes fairly quickly. I mean, unless you drink way too much of it, it's half-life is comparatively short. And so it may-- this is one of the !rst things you should consider in the patient who has no trouble falling asleep but then eyes wide open at 1:00 a.m. for no obvious reason. Because what happens is, you drink early in the evening-- and it doesn't have to be a lot. In fact, it usually isn't a lot. Just, in fact, it may be such minimal alcohol consumption that the patient doesn't even think to mention it to you. You don't even know that they're drinking on a regular evening basis. But they have a drink or two in the evening, they go to bed at 9:00 or 10:00, and then at 1:00 a.m., wide awake. And it's because they have then metabolized the alcohol. And without the alcohol on board, their sympathetic nervous system is suddenly not suppressed and then they are wide awake. So if you don't remember anything else about this conversation, do remember the patient that tells you they're just waking up in the middle of night and they don't know why, really do pursue what they are drinking in the evening. Chances are, they are having maybe just a cocktail or two that didn't even seem relevant. In any event, whether a symptom or a diagnosis, it really doesn't matter. Number one, sleep disorders are totally undertreated. And sleep dysfunction or sleep insomnia of any form really is a contributor to a wide variety of problems, both psychiatric diagnoses and medical diagnoses. It's like a positive feedback cycle. There are conditions that can cause di#culty sleeping. And then if you can't sleep, it exacerbates those conditions and it just gets worse and worse and worse. So identi!cation of underlying causes really is an important part of the history of present illness, which is why it doesn't even matter if you consider it a diagnosis or you consider it a symptom because either way, when the patient comes to you with a chief complaint of "I'm having trouble sleeping," the !rst thing you're going to do is !nd out exactly what they're talking about. Are they having trouble falling asleep, staying asleep? Are they waking up too early or do they feel like they don't sleep all night long? And once you've got that down, then you're going to consider all the potential underlying causes. And your history of present illness is designed to rule them in or out. If you !nd a cause, treat it. If you don't !nd a cause, then that suggests that the insomnia is the primary diagnosis, and then you really do need to consider whether or not there is a circadian rhythm disorder, whether it is truly a sleep-wake hormone imbalance. And what's the last thing here? Yes, of course. I mean, any underlying comorbidities, of 6 of 21 12/8/24, 4:29 PM The Pathophysiology of Sleep-Wake Disorders Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2533795-dt-... course, we're going to treat them. And sometimes you might readily identify what the problem is. You know, it's not unusual for this to be cortical arousal because of some major change in their lives, some concern, a job change or a !nancial concern or upcoming wedding, new baby, just lost their job, whatever the case may be. It may be easy enough to !gure out why the patient is having trouble sleeping, but the treatment part of it, not so easy. So then you may have to medicate the patient while you're working on treatment, but treatment of the underlying problem is the priority there. Also, keep in mind that we do have to consider the di"erent types of insomnia because they do give us a clue as to what's going on. So acute insomnia is one of the easier ones. In the patient with acute insomnia, they've never had it before. This is something new. It is time-limited according to the DSM. It is shorter, like shorter than a four- month duration. There is a readily identi!able trigger, whether it's a medical condition, a new medication, a new source of worry or hyperarousal. But in that circumstance then, obviously the primary treatment target is the insomnia. Treat the issue at hand. Whatever emerges as the trigger, that's the thing you're going to treat. So that's easy. Well, easier. Then we have what's referred to as associated insomnia. And so this is when the patient is experiencing some sleep di#culty as a consequence of something else. And so it's not always that cut and dried. I mean, I know on a slide it looks very cut and dried, but it's not always that straightforward. OK, the patient's having trouble sleeping and they have a diagnosis of depression. But maybe they've had a diagnosis of depression for decades and they never had trouble sleeping before. Well, who knows if that's the impression, if that's the memory, if that's actually the case? But once you go through your history of present illness and rule out all of your underlying potential causes, if what you're left with is the patient is being treated for depression and they have not achieved a good remission or a dysthymia or a bipolar or anything else that's listed here, well, then you do have to try to get a better handle on the other underlying psychiatric diagnoses and hope that that will help them sleep better. In the interim, you may have to give them something to help them sleep. I mean, not sleeping just makes depression, bipolar, et cetera, worse, right? So they are sometimes interrelated and it's not that straightforward. We also have to consider, well, substance of abuse at the bottom here. That's a given. But poor sleep hygiene, this really is a thing-- a thing with a capital T, especially in this modern world of everything is instantaneous and everything is immediately available on a device and you can just watch anything on some device whenever you want to or 7 of 21 12/8/24, 4:29 PM The Pathophysiology of Sleep-Wake Disorders Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2533795-dt-... pick up your phone in the middle of night and see what's up on Facebook. There is a tendency for its poor sleep hygiene. And you do want to make sure that your patients know what you're talking about when you say this. I kid you not, I was evaluating a patient who was referred to mental health because of her trouble sleeping. And she was telling me in the !rst visit that, yes, she's been through all this, the sleep hygiene, and she washes her face and brushes her teeth before bed. And that's not what we're talking about with respect to hygiene. We're talking about making sleep the activity that goes on in the bedroom in bed. I mean, yes, occasionally it might be another activity that goes on, but that will put you to sleep if you do it right, and most of the time you don't do it after a certain point. But sleep hygiene is really more about the room is dark, the TV is o", the devices are o". There's not a lot of noise. You don't wake up, realize you can't sleep and then pick up your iPad and start looking at stu" or turn on your TV or go grab a soda and something to eat. Like when you do things in bed that are not associated with sleeping, your brain does start to make associations. And so when you-- some of this is conditioned arousal. If you go to bed at night and you are having trouble sleeping, if you just then sit up, grab your iPad and start reading, or whatever, you grab something to snack or to drink or whatever and you're laying in bed, your brain begins to associate those activities with being in bed. So it starts to associate wakeful activities with being in bed, and it really does become harder to sleep there. And that's what we're talking about with sleep hygiene. If you're having trouble sleeping, you can't lay there with your iPad on all night. You can't lay there with the TV on or the lights on or all that kind of stu". That's what we're talking about there. And then !nally, there is the patient with primary chronic insomnia, where insomnia does become your primary diagnosis. Chronic insomnia usually is multimodal in its etiology, which means it's going to be multimodal in its treatment strategies. There are a number of factors that can predispose to this kind of insomnia, which really explains why some people do very well with one class of drug and others it doesn't touch them at all. And you know this is one of my biases, so I'm sure I mentioned in Nursing 626. And forgive me if I'm beating the horse here, but we just live in such an anti-controlled 8 of 21 12/8/24, 4:29 PM The Pathophysiology of Sleep-Wake Disorders Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2533795-dt-... substance world that some of our peers will feel that if a patient tries a noncontrolled approach to sleep and says it doesn't help, they're really just looking for a controlled substance prescription. And I'm not suggesting that that's not true, sometimes. I mean, that's part of what we get the big bucks for, is to tell the di"erence. But there are those people who will not respond to noncontrolled agents because the mechanism of their insomnia just doesn't lend themselves to that. So I think the primary bene!t in understanding the underlying etiology and the multimodal of the underlying etiology is understanding that not everybody will respond to the same treatment modalities. And it's not that they're not trying and it's not that they don't want it and it's not that they just want drugs, it's that in some patients, the underlying problem is primarily a thing that does not lend itself to a nonpharmacologic or a noncontrolled intervention. By de!nition, chronic insomnia is insomnia of at least four months duration. Usually a lot longer, and it is harder to manage. Another thing that we need to consider when evaluating the patient with sleep-wake disorders is the sleep cycle. So this is its whole own study. If you're interested, I think there's some links in your learning unit this week that link you to more information about it. But the sleep cycle is a predictable one. And each stage of sleep has a job and missing any of them is going to lead to sleep dysfunction and varying levels of either perception of-- abnormal perception about sleep or just not feeling well and not being physiologically-- easy for me to say. Not being physiologically restored in the morning. So depending on whose book you read, you might see slightly di"erent tweaks on this, but generally speaking, we have multiple stages of non-REM sleep and then we have the stage of REM sleep. And they all serve a di"erent purpose. Non-REM stage one. This only typically lasts a few minutes. This is that transition state between being awake and being asleep. This is the transition between being awake and getting down to that deep sleep where you do experience physiologic restoration. In this early stage of sleep, the muscles in your body are active, the patient can be very easily awakened and can move. This is almost like your startle. Like somebody comes in to wake you up and you're like, oh, I wasn't sleeping. I wasn't sleeping. And you were, but just barely. You were just beginning that transition. Non-REM stage two. Notice that you spend half the night in non-REM two. That's because as you transition and cycle through the stages, you will spend half of your 9 of 21 12/8/24, 4:29 PM The Pathophysiology of Sleep-Wake Disorders Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2533795-dt-... night in non-REM two. This is the stage that we refer to as light sleep. There is de!nitely a di"erence in your brainwaves. If you happen to be having an EEG performed, you can see the di"erence in this stage. This is the time of beginning muscle relaxation. This really is the transition to restorative sleep. Towards the end of non-REM stage two, you become prepared for the truly restorative stages of deep sleep. Your heart rate slows, your respirations slow. You really enter a state that is driven primarily by your parasympathetic nervous system. And this state is the transition between deeper REM and lighter REM. You just go through these stages multiple times during the night. But in this stage, there are genuinely physiologic changes that prepare you for the restorative phase of sleep. And then the next stage is non-REM three. And some authors break this down into two, like there's a three and a four. Really, at the end of the road, it doesn't really matter. What does matter is that this is your deeper non-REM sleep. It is not rapid eye movement. Your brain isn't moving in the way that it will when you get to REM sleep. So notice that we spend up to 40 minutes a night in non-REM three, and it does decline with age. So this is the time of slow wave deep sleep. This is the time of physiologic muscle repair. This is the time of physical restoration. Like really, if you go to bed bone tired, like you're just so weary. You've been working hard all day digging ditches or chopping down trees or doing whatever it is that you do that is really physically active and like every muscle in your body hurts. Non-REM three is the time when that repair goes on. So you need this stage of sleep to make you feel physically rejuvenated and restored for the morning. People that have di#culty with deep non-REM sleep are those who wake up feeling physically tired, who don't have as much energy during the next day. Whereas REM sleep, rapid eye movement sleep, this is very di"erent. This represents up to 25% of your total sleep cycle. So if you sleep eight hours a night, if you're lucky, two of them are spent in the REM stage. So this, of course, is the stage of dreaming. This is the stage that's so famous and everybody is familiar with. While you are in REM sleep, you are paralyzed. If you are suddenly awakened in the middle of a dream, you won't be able to move. It's pretty fast. I mean, you might not even realize it. By the time you actually transition to the wakeful state, then you can move again. But this is a stage of muscle paralysis. And it is your body protecting you. You need REM sleep because this is the time of brain restoration, so the brain is very active here. So you have to be paralyzed because 10 of 21 12/8/24, 4:29 PM The Pathophysiology of Sleep-Wake Disorders Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2533795-dt-... if you weren't, you might act out some of the things that you're dreaming about. And of course, there are people that have dysfunctional REM sleep. And one of the manifestations of dysfunctional REM sleep is that you're not paralyzed. And these are the people that sleepwalk. These are the people that get up and engage in whatever activity it is that they are dreaming about. This is like-- and the textbook version occurs every 90 minutes. So of course, there's a fair amount of variability here. And the longer the night goes on, the greater periods of REM that you have. So if you are in a circumstance where you don't fall asleep until 3:00 and you have to get up at 5:00, you're going to cheat yourself out of REM sleep, and the next day you're going to feel it. You might have a couple of good hours of deep non-REM sleep there so you might feel physically refreshed and restored. But if you haven't had the opportunity for REM sleep, your brain is going to su"er the next day because REM sleep is the time of brain restoration. This is where really, your neurons, your neuronal connections, they truly correct themselves. Decreases in REM sleep are linked to cognitive dysfunction. You can see your handout on depression. But cognitive function is a big one. People that don't get enough REM sleep, they're the ones whose brains don't work right the next day. Their memory is o". They can't recall things. One of the concerns about benzodiazepine receptor agonist mediated sleep aids is that they actually depress REM sleep. So you do sleep all night and you sleep deeply and you wake up in the morning going, dang, I slept. I physically feel good. But if your REM sleep is suppressed by way of benzodiazepines, your brain function doesn't get the chance to recover. And this really is-- if you actually spend some time with your patients, query them, ask the questions, you might !nd that patients who take a benzo or a benzo agonists like Ambien or something to help them sleep, they'll tell you they slept all night, they wake up in the morning and they feel great. They feel strong. Like physically, they feel great because they did have some awesome non-REM sleep, but they !nd themselves being forgetful. They're just not quite as cognitively sharp. And that's believed to be because those medications can actually suppress REM sleep a little bit. So is it true or not? I don't know. In !ve years, I'm sure somebody will have a totally di"erent impression of this, but that is the current impression of the science, is that with those agents, the benzodiazepine receptor agonist agents, you do get wonderful non-REM sleep and so you wake up feeling physically restored, but that there is a 11 of 21 12/8/24, 4:29 PM The Pathophysiology of Sleep-Wake Disorders Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2533795-dt-... suppression of REM sleep and so you are not as brain restored as you should be. Notice too, REM deprivation can rebound when sleep occurs, and this may increase from normal. So you may spend more of your time in REM sleep. So this is the patient who, for whatever reason, hasn't had enough sleep in the last, I don't know, a day or two or something. Like maybe you were traveling, really long plane ride, just didn't really get a chance to sleep at all. When you !nally get to bed, like really get to go to sleep for the !rst time in like 36 hours, you immediately $unk into REM sleep. Like it's a rebound. You go into REM sleep quickly and in an exaggerated state. And this is the time when all of those like funky realistic dreams occur and stu" like that. Very interesting, the whole study of sleep. I wish I was a lot younger and had years to study this kind of stu", but I don't so I just !nd the super!cial things interesting. So non-REM sleep, like I mentioned, it is the time of physical restoration and there is-- I mean, there is-- I mean, these do overlap. I always tend to speak in extremes. And I know I do that and I probably shouldn't. Of course, there is some cognitive restoration during non-REM sleep. So you can't go wrong with some good non-REM sleep. It's just that for optimal function the next day, you have the appropriate balance of non-REM and REM sleep so that you are both physically restored and brain restored. And let's see, the less time we spend in non-REM sleep, the less capable of learning new skills, which is true, which is why the younger you are, the longer you sleep. Babies sleep all the time. Infant sleep really long. And little kids, toddlers, little kids, school age kids, they need to sleep longer and longer because they're in that time of sensory motor learning. And then, of course, as we get to the other side of the lifecycle, we don't spend as much time in any stage of sleep, including non-REM sleep and our ability to learn really is diminished because of it. All right. So getting back to the actual underlying problems and how we treat insomnia, this is the pathophysiologic mechanism of insomnia that has been asserted by an author named Levenson, I think. I don't remember the citation o" the top of my head. I'm sure I should, but if you Google pathophysiologic model of insomnia, it will take you to a more detailed description of this process, but this is the gist of it. This is what they assert, that there are three primary considerations in the patient with insomnia. First one in green are the risk factors. There are risk factors that just predispose someone. There is a gene apparently linked to di#culty sleeping. And so if insomnia is prominent in the family history, any given patient is at greater risk. There's that. The 12 of 21 12/8/24, 4:29 PM The Pathophysiology of Sleep-Wake Disorders Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2533795-dt-... older we are, the greater the risk of insomnia. Women report greater di#culty sleeping than men all across the spectrum-- trouble falling asleep, trouble staying asleep, et cetera. Insomnia is reported more commonly in persons of African and non-Caucasian race. Substance use and medications, we've beat that one up pretty good. Obviously, that's always among our leading di"erential, as well as medical conditions. So that has to be part of anybody's history of present illness, all of those things. But then we look at the physiologic processes and the behavioral processes. The physiologic processes really are about homeostasis and the circadian rhythm. This is referred to as process C and S. So for some patients, there really is a hormonal imbalance. For other patients, there is dysfunction in homeostasis. And these are di"erent things. Don't worry, slides coming here. And then there are those who experience hyperarousal of the cerebral cortex. So the cerebral cortex is that part of the brain of which we are aware. We are aware of what's going on there. Most of what goes on in the brain, we never have conscious awareness of, but that most-- like outermost, so 1 to 2 millimeter layer, the cerebral cortex, that is the area where we know what's going on. So there are people that have-- that are just hyperaroused. It might be a"ective arousal like they're worried about something. It's an emotional thing. It might be cognitive arousal. They are problem-solving. It might be autonomic arousal, dysfunctional autonomic nervous system. In fact, I know I'm getting ahead of myself here. I can see the next slide and I see that I'm already going too far, so let me just abort that part of the conversation right now and say physiologic processes and behavioral processes. For some patients, it's all of the above. For some, one is clearly more dominant than the other. And so it's our job to try to !gure out what's going on so that we can o"er the best intervention. OK, here's the hyperarousal thing that I got all excited and started talking about too soon. So the cortical nervous system, yep, it might be something of which we are aware. We are worried. We are having emotion. We just had a big breakup. Or it might be autonomic nervous system dysfunction but there may be some phenomenon that is contributing to accelerated arousal of the cerebral cortex. And so that being the case, we need to ask people-- I mean, it might seem obvious, but are they worried about something? Has something changed in their lives? Is there something that's producing a new emotion? Are they having other phenomenon of autonomic nervous system dysfunction like syncopal or near syncopal episodes, new 13 of 21 12/8/24, 4:29 PM The Pathophysiology of Sleep-Wake Disorders Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2533795-dt-... onset anxiety attacks, or panic attacks. So hyper arousal is de!nitely something to be considered. The autonomic nervous system really does relate very closely to the sleep state. When we were talking about the stages of sleep, the stages of non-REM sleep a few slides ago, I mentioned that as you get deep into non-REM two, you start to experience decreased heart rate, decreased respirations. This is where the parasympathetic nervous system takes over. You need to have a functional and appropriate autonomic nervous system to move through the appropriate stages of sleep because the parasympathetics dominates non-REM sleep and the sympathetic nervous system then kicks back into gear for REM sleep. So there clearly is an autonomic nervous system- sleep relationship. And sleep dysfunction might be to autonomic nervous system instability. Or the classic stu". So yep, I said it all too fast. My apologies. It's just here again for your reading pleasure in case it slipped your mind when I said it two slides ago. It might seem really obvious or a no-brainer to you and me, but some people just can't sleep because they're worried about something or they are subject to an emotion that is particularly intense and they just can't shut down their brain. Now process S and C. So if you get into the sleep literature and start reading a lot about sleep, you will read about process S and C. This, like your slide says, it was really described in the '80s. The same person who described this theoretical approach to sleep and insomnia updated it a little bit, I don't know, like 10 or 15 years ago or something. But what he really keeps coming back to is that there are two processes that are the primary drivers to sleep. Process S is the homeostatic one. I don't know why he calls homeostasis process S. I understand why circadian is referred to as process C, but there must be some other word in some language where homeostatic, the word, actually begins with an S. Anyway process S and C, these are believed to be the primary physiologic contributors to insomnia. So process S. This is about homeostasis. This is about the steady state. And so the bottom line is that the process S approach to sleep is that you get up in the morning, so you've only been awake for a few minutes, right? And then the longer you are awake, the greater your sleep drive will become. I mean, it really-- it is theorized to just go back to way, way olden times where when it 14 of 21 12/8/24, 4:29 PM The Pathophysiology of Sleep-Wake Disorders Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2533795-dt-... got light out, we woke up because it was light. We got up, we hunted, we gathered, we did whatever we did at those prehistoric periods to stay alive. We gathered, we took care of family, we farmed, we !shed, we got water. We did all the work of staying alive. And then when the sun went down, coincidentally, we had been awake for 12 or 14 or 16 hours, and now we're tired. So process S really refers to the fact that the longer you're awake, the greater your drive to sleep will become. And then that drive only goes away when you get sleep. The process S drive is relieved by deep slow wave non-REM sleep. So it really is like, to visualize it, slowly and steadily climbing a mountain all day long and then you just get to that point where you can't climb anymore and you fall asleep. Then you tumble down. And all night long, you tumble down. And then in the morning when you get to the bottom of that hill, you're awake again. And then after eight or nine hours of sleep, your homeostatic drive will wake you up and it starts all over again. So process S refers to the fact that the longer you are awake, the greater your drive to sleep because everything is a balance when it comes to the human body. On the $ip side, process C is about the circadian clock. This is driven largely by the light- dark cycle. Remember that the light is an enormous trigger to the pineal gland, which will stimulate all of those things that we need to do to be awake, to feed ourselves so we can stay alive. This really is a very primitive explanation for why we wake up and why we go to sleep. Process C, the circadian rhythm, regulates sleep and feeding patterns. In other words, when we're awake, we should be trying to eat because when we go to sleep, we won't be able to eat. We won't be able to consume fuel. And so some of the markers of process C are those markers of homeostatic patterns or circadian patterns, like core body temperature, melatonin rhythms, and a series of hormones that help either suppress wakefulness or encourage it. So the molecular mechanisms that promote wakefulness and suppress sleep are some of the things listed on your slide. Catecholamines: dopamine, epinephrine, norepinephrine, serotonin. Sound familiar? These are wake-promoting molecules. They actually make it hard to sleep and promote wakefulness. Orexin is another hormone that has several roles, but one of them is promoting the wakeful state. And histamine is a wake-promoting hormone. 15 of 21 12/8/24, 4:29 PM The Pathophysiology of Sleep-Wake Disorders Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2533795-dt-... So these hormones-- very often, hormones that promote wakefulness also drive hunger because when we're awake, we should be eating so that we can store enough fuel to survive while we're sleeping, right? So we have wake-promoting, sleep- suppressing hormones. And then conversely, we have sleep-promoting and wake-suppressing hormones. So adenosine, serotonin in numerous dominant areas of the brain, and melatonin are all sleep-promoting, wake-suppressing. So in the healthy steady state, the cycle of our sleep-promoting, wake-suppressing hormones matches our homeostatic driver to sleep. And then the release of our wake-promoting, sleep-suppressing hormones will match the homeostatic driver to be awake. One of the theories of insomnia or sleep-wake disorders is that there is a process S or C, process S and C rather, mismatch-- that our homeostatic driver to be awake or to be asleep is not in alignment with our wake-promoting and/or sleep-promoting hormones. Like in other words, if you work the night shift-- if you work night shift, you're trying to sleep all day and be awake all night, except that your body is releasing sleep-promoting hormones at night and wake-promoting hormones during the day. It doesn't care what your shift is. Remember, this is largely related to very inherent mechanisms and light and dark as driven by the sun. Some people adapt very well and they are your classic night shift people for life and other people never adapt very well. They work a night shift. They have all good intentions of going home during the day and sleeping all day, but somehow it just never works out. And then they wake up and then they do stu" and then they go to work on the night shift, and they try really hard to stay awake and drink a lot of co"ee, or whatever the case may be, but there does come a time when it becomes exceedingly di#cult and that's because their sleep- promoting hormones are in high gear. So one of the theories of insomnia is that there is a process S and C misalignment, that they're not well matched, that you have a deviation from that pattern of the homeostatic driver for sleep peaks at the same time that your sleep-promoting hormones are released. Complicated, isn't it? And that's just scratching the surface. And so what we do about it-- I mean, what we do is, of course, we counsel about sleep hygiene and we advise people not to lay there with your iPad on if you're trying to go to sleep. I mean, all the obvious stu". Like we tell people, if you are awake and you can't go to sleep, get out of bed. Go into another room. Go be somewhere else so that your brain doesn't associate 16 of 21 12/8/24, 4:29 PM The Pathophysiology of Sleep-Wake Disorders Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2533795-dt-... being awake with being in bed. That conditioned arousal can be very hard to reverse. So if a patient really cannot sleep, bed is not the place for them. But mostly what we do in our place in the world is prescribe medications. And so this is where I know it's a real repeat from nursing 6026 and so I'm going to be very quick on this review here. We have lots of medications that we can use to treat sleep disorders. Some of them are controlled substances. Some of them are not. And the success of them for any given patient is really going to depend on what their primary underlying problem is. The benzodiazepine receptor agonists-- well, there are slides that describe these, so let me wait until we get there. With this slide, su#ce it to say, there are numerous medications that we can use to try to promote sleep, and they all impact di"erent pieces of those drivers that we just talked about. A benzodiazepine receptor agonist is really going to calm down the cerebral cortex. It will suppress arousal. Melatonin agonists augment melatonin. They act like melatonin, the sleep-producing hormone. Short-or-intermediate-acting benzodiazepine receptor agonist, it really depends on what the problem is. The patient who can't fall asleep, short acting is the one for them. The patient who can't stay asleep or who has persistent early morning awakening, then an intermediate acting agent is better for them. We also use antidepressants and capitalize on the adverse e"ects of sedation. Same thing with second-generation antipsychotics. And if you remember that histamine is a wake-promoting hormone, well, people that really do have an imbalance of that hormone will bene!t hugely from antihistamines. And so any combination of these. I mean, how you start, that's really up to you. Classically, we have always started with a benzo or a benzodiazepine receptor agonist. It's just that now because they are controlled substances, prescribers are becoming more and more uncomfortable with them. They will put you to sleep no matter what. No matter what your underlying problem is, the benzo agonist will put you to sleep. Whereas a melatonin agonist is only going to really help if your problem genuinely is a melatonin imbalance. Some of the antiepileptics are things that calm people down, ditto the second-generation antipsychotic. So we have lots of di"erent drug classes. We just have to decide which one is most appropriate for the patient. With the benzodiazepine receptor agonist, we do have some benzos that actually are indicated for sleep. Triazolam is marketed as Halcion. Estazolam is marketed as 17 of 21 12/8/24, 4:29 PM The Pathophysiology of Sleep-Wake Disorders Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2533795-dt-... Prosom. Temazepam is marketed as Restoril. Flurazepam is an old school one. It's got a long half-life. And I don't think anybody uses it anymore, but it was known as Dalmane and back in the day, it was the sleeper of choice. But there are benzos that were not intended for anxiety. They were intended for sleep. And these are some examples of them. But because the benzos can be habit-forming and physiologically addictive and dangerous in the withdrawal, there was, of course, a move, a drive to !nd a way to do the same thing but have a safer medication. And that's where the Z drugs were born-- zolpidem, zaleplon, and eszopiclone-- Ambien, Sonata, and Lunesta. They are benzo-- they are nonbenzodiazepine benzodiazepine receptor agonists. They are controlled substances, but they are believed to have a lesser abuse pro!le and a more favorable safety issue as compared to the benzos. For a very long time, I mean for years, these were the drugs of choice for insomnia. But even now, because they are controlled substances, you do see a general tendency to move away from them, not because they're not appropriate and not because they don't work but because prescribers don't want to give people controlled substances. The melatonin agonist, these are becoming a favorite because they're not controlled. And I mean, I really don't-- I know I sound like I'm saying, oh, give everybody a controlled substance. Life is beautiful. No problem. And I'm really not saying that. I totally advocate for the judicious use of controlled substances, but we do need to remember that sometimes patients do need them. So we don't want to never ever use something people need just out of fear. We just want to be judicious about it. So consider that sometimes patients do need a benzo receptor agonist. However, the melatonin agonist, for people that have a true circadian hormonal disorder, these can be enormously e"ective. There are two in the market right now. Rozerem is indicated primarily for di#culty falling asleep because it augments a sleep- producing hormone. It is not-- unlike the benzo agents, it is not associated with next day impairment or fall risk. So it's very safe. It is a substrate of two cytochrome P450 enzymes so you do have to be careful of that, be watchful of that. But these generally are indicated. Rozerem is believed to be nonhabit-forming, not addictive, not a drug of abuse, ergo very safe, and so a favorite among prescribers. It is not cheap. I will tell you that. And when it works, it works great. But it primarily works for people that have a true melatonin imbalance, which isn't everybody. 18 of 21 12/8/24, 4:29 PM The Pathophysiology of Sleep-Wake Disorders Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2533795-dt-... Hetlioz is another melatonin agonist. This one is actually indicated for non-24 circadian rhythm disorder. That's like kind of its claim to fame. This one is believed to have a little bit of a harder hitting-- what's the word I want-- homeostatic impact. It is believed to synchronize melatonin and cortisol levels. Of course, melatonin being sleep-promoting and cortisol as a stress hormone being wake-promoting. And Hetlioz is believed to actually help balance those in a way that Rozerem doesn't. So that's one option, but just remember that it's going to have its greatest e#cacy for people that really do have a melatonin problem. The tricyclics really aren't targeted toward any speci!c process C problem. It's really just capitalizing on the sedation adverse e"ects of some antidepressants. So some of them are indicated for it. The thing about using tricyclic antidepressants is that the doses we use to promote sleep are much lower than the doses we use to treat mood disorders. So they do tend to be quite safe and not have a signi!cant adverse e"ect pro!le. But the one thing to keep in mind about them is that food enormously impacts absorption, and absorption impacts half-life. So the way to avoid the next day hangover is that if you're going to use a tricyclic for sleep, really it's got to be taken on an empty stomach. Patients should not take it with food. That makes a big di"erence. Don't take it with your evening snack because then it's not even going to be absorbed and distributed till the middle of the night, and then you are going to have a next day hangover. When people tell you that things like, what do you call it, trazodone, they have a hangover the next day, chances are they're taking it with dinner or they're taking it right after dinner when their stomach is still full. You really want them to do it on an empty stomach. The orexin receptor antagonist. So this should look familiar because remember that orexin is a wake-promoting hormone. And so orexin antagonists block the action of the naturally occurring wake-promoting hormone, and that's how it works. And so there are some parameters here for prescribing. This is not a drug of abuse. This is not something that people use to alter their nervous system awareness or responsiveness. So it's not something that people use as a drug of abuse. I mean, do keep in mind that any time anything helps somebody sleep, the patient with chronic insomnia, if they !nd a medication that helps them sleep, there is de!nitely the potential for a psychological dependence. But in terms of abuse, this drug class, the risk of abuse is much lower and there are a few in class now. I feel like-- I must have 19 of 21 12/8/24, 4:29 PM The Pathophysiology of Sleep-Wake Disorders Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2533795-dt-... missed one. The !rst one, it was marketed as Belsomra. It was called suvorexant. Yeah, there we go. Many of the same considerations as suvorexant. That was the !rst one. Dayvigo is a newer drug in class. There are concerns about cytochrome P450 interactions that you might remember from Nursing 6026. But reportedly, this is better at inducing sleep. So I don't know. All of these drugs do block the wake-promoting hormone orexin, so it really comes down to what the patient's insurance will pay for. Although, they are reported-- this drug is reportedly better at inducing sleep. There also appears to be a signi!cant incidence of hypnogogic hallucinations and cataplexy. So this is the patient who is having those really, really vivid hallucinations as they transition from wakefulness to sleep and vice versa. And then we have a very new drug in this class. It's called Quviviq. And it just got approved in the United States in May of 2022. So it reportedly is better than the other orexin antagonist in that it is very selective. And this reportedly decreases the wake drive without interfering with those non-REM stages of sleep. So it remains to be seen if that's really clinically signi!cant or not. Many times, and I've probably said this to you before, there is a real motivation to be the !rst company to have a drug in a new class. So whenever you see a new drug class on the market, the !rst one-- I mean, it makes billions of dollars and everybody's very happy, except that it often like just met safety and e#cacy standards of the FDA to get on the market. And so there are often adverse e"ects or problems that are not unsafe, but not always desirable. And then other pharmaceutical houses will try to !nd a way to take that molecule and make it better, easier, safer, less adverse e"ects, or whatever. And then they'll market a new version of it. And it might be that this is that, or maybe this one really does help you progress more normally through the sleep stages. I don't know. Remains to be seen because it just became available in the U.S. market a few months ago. And then, of course, we have a whole line of medications that we capitalize on adverse e"ects by using them o"-label. Some of the antidepressants we already mentioned, like trazodone and mirtazapine, and even antipsychotics, quetiapine, olanzapine, and risperidone are all used in patients who have treatment refractory sleep disorders. And then there are those-- I mean, even good old fashioned antihistamines over the counter. All of the things like Tylenol PM and Excedrin PM and any other PM, the PM part is diphenhydramine. It's the antihistamine. And it makes sense because histamine is a wake-promoting hormone. So giving an antihistamine logically would help you sleep. Some people take them and feel like they're great. Others feel like they don't 20 of 21 12/8/24, 4:29 PM The Pathophysiology of Sleep-Wake Disorders Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2533795-dt-... help at all, except to give them a dry mouth. So you know what that means, the patients in whom antihistamines are really e"ective, well, a big part of their problem probably is a histamine imbalance. Same thing with melatonin. And the herbal options. I only feel compelled to mention them here because they do exist. Full disclosure, I know very little about nutraceuticals and herbal remedies. I have a hard enough time keeping on top of your garden variety prescription FDA-approved medications. So I don't know much about the herbal options, but I do know that there is a reasonable body of evidence for some of these things to support their ability to help patients sleep. So that's all I know about that. Now you have an entire learning unit to explore more deeply all of this stu". Print this page 21 of 21 12/8/24, 4:29 PM