Novel Treatments for Patients with Excessive Daytime Sleeping and Associated Sleep Disorders
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Charles Raison:
I'm Chuck Raison. I'm one of the co-chairs this year, and it's my pleasure to welcome you all to our in-person and virtual attendees. Hello people out in computer land. This session is entitled: Novel Treatments for Patients with Excessive Daytime Sleepiness and Associated Sleep Disorders: Clinical Considerations for Patients with Comorbid Psychiatric Conditions.
Okay, so this activity has been supported through an independent educational grant from Jazz Pharmaceuticals. We thank them for this learning opportunity. While I introduce the speakers for this session, please take a moment, and I'll actually stop for a second, to answer our polling questions. I think you point your phones at the QR code and it'll pull up the polling questions. We'll ask these again at the end, and it's a very important way by which the efficacy of these sorts of learning engagements is assessed. So I'll give you guys a couple of secs here to get that pulled up. And for virtual attendees, you should be able to see the relevant stuff to the right of your live stream. As I said, these questions will be asked again at the end of the program and thanks for answering them, the polling questions.
All right, so it is my pleasure to introduce our presenters for today's session. My colleague, Dr. Karl Doghramji, who is an associate professor and professor of psychiatry, neurology and medicine at Thomas Jefferson University and runs a sleep program there. And Dr. David Neubauer, who's an associate professor, Johns Hopkins University School of Medicine in Baltimore. And please be sure to submit your questions by using that same QR code for our attendees in the audience. For virtual folks, you can type in your question in the Q&A box to the right of the screen. And it always depends on how long these gentlemen talk, but we'll try to answer as many questions as we can at the end and we'll try to address the most popular questions first. So without further delay, gentlemen, please come up.
David Neubauer, MD:
Good morning, everybody. Welcome. Thank you for coming to the hall and those of you who are tuning in virtually as well. Anybody sleepy? We all get sleepy sometimes and maybe some of you at least of those who were here live might've been out watching the boat parade last night and the rest of you maybe saw it on TV. It's kind of fun for the day of the dead celebrations here.
Any case, sleepiness, general topic today, and we'll be talking about the problem that's so pervasive among psychiatric patients, but also those particular disorders that involve hypersomnolence. So we should give you a pretty good review of this. As you've heard already, we are David Neubauer, me. Karl Doghramji coming up about halfway through. We have various disclosures here that you can see listed. Consultations with an assortment of companies. This is the general disclosure. I'll note in particular that Dr. Doghramji is going to be talking about pharmacologic aspects of treatment and will be discussing off-label investigation or use of drugs in the presentation and he will make sure that those are identified. If you didn't catch it earlier, now is your opportunity to scan the QR code, which you can use for both the polling and also for Q&A.
Here are our learning objectives for today's program. Describe the prevalence and impact of excessive daytime sleepiness and the burden that it places on patients suffering from psychiatric disorders. Incorporate clinical strategies and diagnostic tools for the identification and assessment of EDS in patients with psychiatric disorders. Develop an evidence-based strategy to manage EDS in the context of psychiatric practice, utilizing general medical, cognitive behavioral, pharmacologic techniques and evaluate the safety and efficacy of current and emerging pharmacologic agents for the treatment of EDS, particularly in patients with psychiatric disorders.
I'm doing the first session here about evaluating sleepiness. And so obviously sleepiness itself is universal and we all experience at one time or another. Ideally not too often, but a lot of times when we're getting around to bedtime we're feeling kind of sleepy. It's really a very natural experience. We define it here as this increased likelihood of falling asleep. Normal biologic drive. And sleeping is satisfying for sleepiness in an analogous sense with eating satisfies their hunger. And some of you may think of other analogies that might be representing satisfaction of different desires.
So hypersomnia. This is a prolonged sleep time. It can be a subjective complaint. It can also be measured objectively with laboratory testing and other sorts of monitoring. Here we have excessive daytime sleepiness. Clearly that suggests that there is a problem. It's a sleepiness that occurs in a situation when an individual would usually be expected to be awake and alert. And then finally there were this realm of people complaining of feeling so tired and fatigued. And it's important to tease that apart because sometimes tiredness means physically, mentally exhausted, and sometimes it means sleepy.
When somebody comes in complaining or feeling so tired all day long, you need to try to assess whether or not that really represents a greater tendency to sleep. Is the person napping? Are they nodding off sleepiness or is it that they just feel very sluggish and rundown? So we define it here sort of as a sensation of weariness, exhaustion, loss of energy, the desire to rest. It is not necessarily sleepiness, but some people of course use it that way. While there's a huge impact of excessive sleepiness, you can imagine this in so many domains. There's evidence from a lot of research with results listed here. So slower response time, instability of attention, cognitive slowing with rapid deterioration of performance, increased cognitive errors, increased time pressure, decline in short-term recall, working memory performance, reduced learning on cognitive tasks. And all of us when we've been sleep-deprived for whatever reason, may experience all of these.
There's a whole nother realm to the problems that go along with excessive sleepiness, sometimes quite tragic. Drowsy driving, diminished motivation, increased depression and anxiety symptoms. There can be elevated sympathetic activity. And depending upon the underlying causes and association with sleep deprivation, there may be insulin resistance, impaired immune function, hypoxemia, impaired quality of life, and of course, in the very worst increased mortality. So all of these are part of a bigger picture and again, may have a variety of different underlying causes.
So what leads to excessive daytime sleepiness and what should we all be thinking about when a patient comes in saying, "I'm so sleepy, I have trouble staying awake, I'm getting enough sleep at nighttime, but I'm still nodding off and I'm worried about my driving." The top of the list, of course is the most common. Insufficient sleep. A lot of people who are chronically sleep-deprived. Either because of their work or school schedules or various lifestyle choices, just staying up to late in the habit of watching the 11 o'clock news to see what the weather's going to be, to see what to wear the next day, and then having to get up too early. And instead of getting a nice seven to eight hours, maybe they're just allowing themselves six to seven hours in bed. This can be acute. So if you're up all night because of work or other might be factors undermining your schedule, or for a whole lot of people it is this chronic problem, not quite enough sleep every night and that really adds up over time. But the differential diagnosis needs to include lots of other things. Circadian rhythm, sleep wake disorders, the really obvious cases of the severe night owls and the severe early birds are kind of obvious, but there are a lot of other people who have less obvious predilections in their circadian system that leads to difficulty falling asleep and then lingering sleepiness in the morning or the opposite, excessive sleepiness early in the evening and then problems sustaining sleep through the night. And then there are other patterns with the non-24. The shift work problems can occur here as well. Sleep disordered breathing really should be on your radar for 100% of patients who are coming in complaining of feeling sleepy in the daytime. It is a huge problem in our society and you sure don't want to miss that as an underlying cause.
There are a variety of disorders of central hypersomnia that also would be important to identify so that you can be treating that primary underlying cause. We list here idiopathic hypersomnia and narcolepsy. I've got a longer list coming up in a few slides. Don't want to miss it if it's a medication. A lot of medications we prescribe are sedating and some people are more sensitive to those. That should be in the differential diagnosis. And even the use of abused substances.
Hypersomnia associated with psychiatric disorders, really a very common complaint. And so many people, for whatever reason, it might be the medication they're on, but the underlying disorders as well oftentimes have a component of sleepiness. And finally I put down here insomnia. We would think that when somebody's complaining of insomnia getting four or five hours of sleep out of seven or eight hours in bed, well naturally they would be sleepy the next day. But the fact is that most people with insomnia disorder are not sleepy.
They have lots of complaints about how they feel and function the next day, a lot of fatigue, but most of them are not sleepy. It seems as though for the insomnia disorder population, whatever it is that has them aroused through the night and unable to sleep very well, it's occurring in the daytime as well. And many of them will say that they used to be able to enjoy a nap sometimes, and since they've had the insomnia, they're no longer able to nap. And in fact, they may even talk about craving sleep but not being able to achieve that. Still, should be a consideration in the broader differential diagnosis.
I want to share this paper with you because it just got published. This is from the Journal of Clinical Sleep Medicine. This is the American Academy of Sleep Medicine Clinical Practice Guidelines. It's hot off the press. And I want to share it with you mainly because it gives a list of these central disorders of hypersomnolence. So there's narcolepsy, which is very well-defined disorder at this point and relatively homogeneous. There's idiopathic hypersomnia and we've come a long way in better understanding this disorder, although not quite so well as narcolepsy. There's Kleine-Levin syndrome, it's a recurrent hypersomnia. The hypersomnia can be very profound and yet can go on for days and weeks and then in between people can be functioning normally.
There's hypersomnia due to medical conditions, there's post-traumatic hypersomnia from, perhaps, traumatic brain injury. There are some genetic disorders associated with a primary central nervous system somnolence. And also, this broader category secondary to brain tumors, infections, other central nervous lesions. This article talks about the data supporting treatments for all of these, but I really wanted to just make sure you're familiar with these categorizations.
I want to talk now about the identification of excessive daytime sleepiness and particularly with the more common disorders. So the evaluation and management in a psychiatric setting. There are some very good screening strategies. Sleep logs are really very helpful actually for most sleep disorder patients. And so if somebody's coming in complaining of excessive sleepiness, having people keep track of when they're sleeping is a really good first step. There also are some scales that can be very helpful in quantifying the severity of sleepiness. The STOP-BANG, as we'll see in a moment relates to looking at risk factors for obstructive sleep. Apnea, of course, a comprehensive health history is really important. We are always going to advise if people follow good sleep hygiene measures.
A lot of these are behavioral strategies. Obviously, we want to make sure that the psychiatric disorder is treated optimally. That may involve pharmacologic agents. But in some cases with these disorders, we will recommend direct management and there are very good medications now are available. And fortunately, increasing in number and indications as well. This area of treatment has evolved quite a bit in the last few years.
Sleep logs. One way to do it is with this example from the National Sleep Foundation. And this type of diary allows a whole lot of different information. You can see on the left is the part that the individual fills out in the morning, and on the right it's in the evening, and you can put a whole lot of detail in that, and that's the value of it. On the other hand, there are these kinds of sleep logs which are much simpler to fill out. They don't have all that other information, but you can sort of see patterns at a glance very quickly about when people are sleeping and if they're phased, delayed or phase advanced or sleeping a long time or having a lot of naps throughout the day or if they're really not getting much sleep at all.
I mentioned that there are different sleepiness scales. The Epworth Sleepiness Scale is very popular. It's pretty widespread. It's very useful and it's very simple to fill out. There are these eight different conditions where people will estimate the likelihood of falling asleep during those situations and you can rate it zero to three. And so with these eight items, it would add up to a total of 24. And the nice thing about this is its recent times. Its recent weeks over the last month or so. That's a good reflection historically of the degree to which somebody's experiencing sleepiness. Very simple to do and very useful and it's a nice way to estimate the severity. And you can see that adding up the numbers, if somebody's got a score above 10, then that's suggests perhaps a clinically significant hypersomnolence. And most of the people with the disorders like narcolepsy, obstructive sleep apnea with residual sleepiness, idiopathic hypersomnolence, they're going to be pretty high numbers.
On the right-hand side is the Stanford Sleepiness Scale. This is very nice and it really relates to that immediate experience of sleepiness, but it is something that you do right now as opposed to looking back historically. It's kind of nice from a research perspective to see throughout the day the degree to which somebody is describing this degree of sleepiness, but it's less valuable historically, say compared to the Epworth Sleepiness scale.
So where do we see sleepiness or sleep problems in general in psychiatric disorders? Appropriately, depression is at the top. And so this slide suggests that sleep difficulty occurs and 90% of those with major depressive disorder during acute episodes. In between, it's still a problem, but primarily during acute episodes. And also people complain when they have major depression of excessive sleepiness described as hypersomnia and that roughly 30% of individuals. And among that subpopulation with seasonal affective disorder, the percentage is much higher and we're sort of getting into that season right now.
Bipolar disorder, people who are manic oftentimes say they don't need to sleep, but it doesn't mean they don't have impairment associated with sleep insufficiency. During depressive phase, very commonly there is this description of hypersomnolence. Anxiety disorders, sleep difficulties of course are very common and oftentimes there is daytime fatigue associated with it. Similarly, with the post-traumatic stress disorder, there's difficulty falling asleep and staying asleep and the nightmares and the panic awakenings, and these may be associated with fatigue and some degree of sleepiness during the daytime. Our patients with schizophrenia, and I'm sure you see this as well, very frequently have irregularities in their sleep/wake cycle. Many of them fall into this pattern of reversal of day and night. Up all night, sleeping much of the daytime.
And there's the added problem of sleep disorder breathing clearly many of the medications we use contribute to weight gain and therefore increasing there a risk for obstructive sleep apnea. Alcohol use disorder, of course this can be a problem undermining sleep at nighttime, causing some sleepiness in the daytime as well. Broadly speaking, we can actually describe this population including people with a lot of different psychiatric disorders. There is this hypersomnia associated with psychiatric disorder. It's a diagnostic category and it's pretty simple. The daytime sleepiness lasting for at least three months with a concurrent psychiatric disorder and sleepiness that's not better explained by an underlying sleep disorder, some neurologic disorder, or medication effects.
And if you look at the total population of people coming in complaining of excessive sleepiness, in the general population, it's estimated that maybe 5% to 7% of them are fall into this category of being related to a primary psychiatric disorder. The study suggests that it's more common in women, tends to come about in the middle years from maybe twenties and into the fifties. It's mostly people with major depression by far more than other psychiatric diagnoses. Also we see that severe sleep disturbances often occur prior to episodes of acute psychotic decompensation when it does occur in schizophrenia. It's certainly what I've seen with several patients looking at longitudinally at the course of their illness.
Key learning point here is sleep difficulties are encountered in up to 90% of patients with major depressive disorder and 30% of patients with major depressive disorder report hypersomnia. We want to transition into looking more closely at these primary disorders of excessive sleepiness. This is right out of the DSM- 5. There are diagnostic criteria for narcolepsy. So it's recurrent irrepressible sleep at least three times a week for at least three months. Usually by the time we see people, it's three years or longer. And there needs to be the presence of at least one, either cataplexy a few times a month, hypocretin or orexin deficiency, and that's going to be determined from a lumbar puncture, or sleep testing that identifies during multiple sleep latency testing.
You look at nighttime sleep and then daytime naps, and it's a matter of there being short enough sleep onset on those daytime naps and the presence of REM episodes occurring during those naps as well. Now, if you're actually trying to diagnose somebody with narcolepsy based upon these, there were various combinations of how quickly somebody goes into REM sleep during the nighttime study and how many REM episodes they might have during naps during the daytime. But basically the diagnosis is made with those daytime naps, documenting the excessive sleepiness, documenting the presence of REM sleep, which would be unusual more than one time during those naps.
I want to say a little bit about the cataplexy because it's such an unusual symptom and you don't see it with other disorders and it's kind of easy to confuse it with other things. Cataplexy is essentially a muscle weakness that occurs while somebody's awake, but in the context of heightened emotions and laughter. Somebody telling a joke has the greatest association, but it can be a lot of different things. It can be laughing at somebody else telling a joke. It can be excitement. It can be being startled. It can be just a heightened sense of emotion in any way, can bring about an episode. And essentially, it is the intrusion of the normal paralysis that we all experience at nighttime when we're asleep, when we're in REM sleep. So the motor areas in our brains are activated when we're dreaming in REM sleep. And fortunately, there's a cutoff mechanism in the brain stem that prevents all of those stimuli from being transmitted to our muscles. So usually unless you have another disorder, we're able to be quiet physically during REM sleep when our brain is very active. But what happens with cataplexy is that normal paralysis intrudes into our waking during these episodes of heightened emotion.
Now, there's a whole spectrum of how that can occur. So for some people it can be very subtle, and I've seen the space last as many times in our sleep clinic. Talking to patients, talking about their experience, feeling a little bit more emotional about it, and getting to the point where they're not able to talk and their jaw can sag a little bit and their head may slump over a little bit and then within about a minute, they're back to their normal self again. And so this is the more subtle end of the spectrum. And for some people, it might just be that their knees are weak and maybe they have to grab onto something. The other end of the spectrum is those people who end up on the floor unable to move.
Now, it's not like fainting, it's not syncope. People feel it coming on, so it's rare for them to have any injury. So usually, they know this happens and they can grab onto something. They can usually ease themselves down and they can be on the ground for a minute or so, unable to move, usually fully awake, sometimes frustrated about people gathering around them and wanting to call 911 because whatever, but they come back around and then they're absolutely fine after that. So that's a full-blown generalized cataplexy episode. The other ones are partial episodes. And when somebody's got a very clear history of this cataplexy, that pretty much makes the diagnosis clearly in the right context of the individual having a persistent sleepiness.
So much has been done to understand the pathophysiology of narcolepsy over the past few decades, and we know that there is a decrease in orexin or hypocretin, two words, same molecules in narcolepsy. And so you see normal stained cells where there is orexin on the left and on the right-hand side, narcolepsy, there's a deficiency. So I mentioned that this multiple sleep latency test was an important part of diagnosing narcolepsy. And so it's a daytime test. Usually, there are four or five naps separated by two hours, and the measurement is how long it takes for the individual to fall asleep in bed in a nice, comfortable, dark room. And most of us would fall asleep. The test goes on for 20 minutes, so you have that option, and if somebody's really wide awake, then maybe they're not going to fall asleep at all during those nap opportunities.
Not unusual for people to fall asleep eventually. So if you see on the chart where it says sleep latency in the green at the top and the estimate of this average of 13.4 minutes, and that might be the case for any of us, but lower down in the red, you see the individual with narcolepsy and the average for their sleep onset under these circumstances is about three minutes. And this is very typically what we see. The criteria goes up to eight minutes and below representing narcolepsy, but a lot of times, it's much obviously a lot shorter than that. On the right-hand side, we see REM periods. So it's abnormal when people have two REM periods or more. Clinical presentation. Obviously there is the excessive daytime sleepiness. So these individuals may be sleeping a lot during the daytime. They may voluntarily be taking naps. There may be involuntary sleep episodes, there may be these micro sleeps. Sometimes people exhibit automatic behaviors. Then there are these REM related phenomena. So cataplexy, maybe 60% of individuals, hypnagogic hallucinations. So these are the sleep onset. Drifting off to sleep feeling as though there are things happening in the room, might be visual, might be auditory, sometimes kinetic. And sleep paralysis, most diagnostic if it's sleep onset, but perhaps later during the night as well. And ironically, these people who are too sleepy in the daytime tend not to sleep that well at nighttime. So it's as though the governing mechanism for the regulation of the sleep-wake cycle just isn't working very well. So people with narcolepsy tend not to stay awake that well. They tend not to sleep that well either.
Sometimes these symptoms can be a little confusing. So cataplexy could be a TIA, probably the history would pretty readily differentiate that. Syncope, that's a very reasonable thing to consider a kinetic seizure. The hypnagogic hallucinations could be dreaming nightmares, psychotic hallucinations. It's not uncommon for a lot of people drifting off to sleep to have some sort of dream-like mentation that doesn't really represent REM sleep. But usually, these hypnagogic hallucinations among narcolepsy patients are really pretty vivid and dramatic. Sleep paralysis could be nocturnal panic, TIA. Recurrent sleep paralysis. So a lot of people have sleep paralysis. So cataplexy is pretty specific narcolepsy, sleep paralysis, there's a whole idiopathic group or familial. And so just because you have that doesn't suggest that you have narcolepsy. Sleep disruption. Well, of course a lot of people have insomnia, so you wouldn't diagnose narcolepsy just based on that.
I do want to emphasize the fact that there is a whole lot of comorbidity and narcolepsy with psychiatric disorders. And you can see here, odds ratios for people with narcolepsy having anxiety disorders. So you can see the control group and the percentage of people in the narcolepsy group ending up with this odds ratio of 2.5 and for mood disorders, even greater of 4.0. I want to share with you the questions that are in the narcolepsy severity scale. And I want to do this just to give you a sense of the kinds of issues that people do experience and ways to try to determine the severity. So during the past month, the questions here were, did you experience an irresistible need to sleep during the day? And how many episodes? Are you worried about falling asleep without noticing it suddenly during the daytime? How important is the disruption of your work and activities caused by these daytime sleep attacks? How important is the disruption of your social and family life by these daytime sleep attacks? And how do you feel generally after one such daytime sleep attack.
After a daytime sleep attack, how much time will pass before the next daytime sleep attack occurs? To what extent do these sudden daytime sleep attacks affect your ability to drive a car? How frequently do you have episodes of generalized cataplexy when experiencing emotion? So it says here, laughter, intense pleasure or surprise. And defining here, this generalized cataplexy, the loss of muscle tone all over, collapse, cannot move. And how frequently do you have episodes of partial cataplexy, only face or neck, arms or knees when experiencing emotions? How much is your work, social, family life affected by these episodes of cataplexy? How frequently do you have hallucinations when falling asleep or waking up? To what extent are you bothered by these hallucinations? How frequently do you experience sleep paralysis when falling asleep or waking up? To what extent are you bothered by these sleep paralysis episodes? And currently, how disturbed is your nighttime sleep?
So this is a quick one, the Swiss Narcolepsy Scale, screening for narcolepsy with cataplexy. How often are you unable to fall asleep? How often do you feel bad or not rested in the morning? How often do you take a nap during the day? How often have you experienced weak knees? Buckling of the knees during emotions like laughing, happiness or anger? How often have you experienced sagging of the jaw during emotions like laughing, happiness, or anger? So quick way of looking at those.
So the next major disorder we want to talk about is hypersomnolence disorder. This is right out of the DSM-6. So you can see here it's excessive sleepiness at least three times a week over three months with the main sleep period lasting at least seven hours. And then you need to have one of the following. And right in the middle, it says prolonged main episode greater than nine hours that is non-restorative. So that alone is going to qualify you for the diagnosis. But on the left, we see recurrent episodes of sleep within the same day and on the right, difficulty being fully awake after abrupt awakenings. And this is sleep inertia. And then of course it's the DSM-5. So there needs to be significant distress or impairment. And then down to the bottom, of course, not attributable to some other disorder of medication or use of a substance.
So we have more screening questions. Actually, these are more severity questions. There are 14 of these. So what for you is the ideal duration of nighttime sleep? And this is assuming you have the opportunity to get that sleep on a weekend or holiday. And so when somebody's saying it's, "Oh, I sleep nine or 10 hours or 11 hours, when nothing's getting in the way." That's going to be a clue. When circumstances require that you get up at a particular time in the morning, do you feel that you have not had enough sleep? Is it extremely difficult for you or even impossible to wake up in the morning without several alarm clocks or the help of someone else? After a night's sleep, how long does it take you to feel like you are functioning properly after you get up? In the minutes after waking up, do you ever do irrational things, and/or say irrational things, or are you very clumsy? And during the day when circumstances allow, do you ever take a nap?
What for you is the ideal length of your naps at the weekends or on holidays? Again, assuming you have the opportunity to. And if you take several naps, add them all together. In general, how do you feel after a nap? And during the day while carrying out activities that are not very stimulating, do you ever struggle to stay awake? Do you consider that your hypersomnolence has an impact on your general health? Lack of energy, no motivation to do things, physical fatigue on exertion, decrease in physical fitness? And do you consider that your hypersomnolence is a problem in terms of your proper intellectual functioning, concentration, memory, decrease in intellectual performance? Do you consider your hypersomnolence affects your mood? Sadness, anxiety, hypersensitivity, irritability? Do you consider that hypersomnolence prevents you from carrying out daily tasks properly? School, job-related tasks? Do you consider that your hypersomnolence is a problem in terms of your driving a car?
So want to move on to another disorder? I mentioned earlier, obstructive sleep apnea. And again, if somebody's complaining of sleepiness, you want to assess to see if this is the underlying cause. So excessive daytime sleepiness, fatigue, restless sleep, insomnia, snoring are common complaints. There also may be memory impairment, altered attention, irritability, depression, morning headache, decreased libido, obesity, very common but not necessary. Refractory hypertension, gastroesophageal reflux, nocturia, cardiac dysrhythmias, nocturnal angina, and really nice screen here with the stop-bang. So these are risk factors. The S is for snoring and the T is for feeling tired or sleepy. And the O is observed cessation of breathing or choking or gasping. Pressure for elevated blood pressure. Then the bang part, BMI greater than 35, age over 50, and for neck size being greater than these values here. And then G for gender, you get a point for just being male.
And so you can see right here, the range of zero to two is low and anything above that is either intermediate or high. We've got a few cases to share with you. Here's Gary. 50-year-old male, slightly overweight, married, two children. Appears subdued but not lethargic. Symptoms evolving over the past few years. Works as an office manager, mostly sedentary. Complains of lack of energy. Struggles to remain alert, especially in the afternoon. May nod off while at his computer. Naps on weekends. Doesn't feel as productive as in past year. His mood is low. Wife complains he's less engaging, avoiding interaction with family members. Has gained 15 pounds over the last five years. Picks up a carryout on the way home from work. Goes to bed about 10:00. Watches TV, falls asleep within an hour, gets up at 6:00 on work days, 8:00 on weekends, drinks coffee in the morning, noon and into the mid-afternoon.
Wife notes he's an active sleeper. Snoring on occasion. Says he sleeps okay, but gets up to urinate two or three times most nights. Diagnosed with hypertension, pre-diabetes. Physical's pretty much okay except his BMI, 33. Blood pressure is up a bit. Poor eye contact, slow speech, affect, mildly depressed, otherwise normal. And let's visit Gary.
Gary:
I didn't want to admit it, but after my coworker caught me falling asleep at my desk the other day, there's no avoiding it now. I'm just so darn tired all the time. It's been getting worse over the past couple of years, but now I can barely stay awake in the afternoon at work. I drink about three cups of coffee in the morning, usually one right after lunch, but it doesn't keep me awake and alert anymore in the afternoon. So then I start nodding off at my desk and it's starting to affect my weekends and family time too. I have to take a nap in the afternoon, so I miss out on my kids' games. I can see how much that hurts them.
David Neubauer, MD:
So are you thinking when he's sitting in your office, "Oh, this guy's really depressed." Are you also thinking sleep apnea? So what's the most relevant next step? Want to check his TSH, do a home sleep study. Do a multiple sleep latency test to check for narcolepsy. Check his vitamin B-12, serum orexin levels. We think a home sleep study is probably a good thing to do. Home sleep studies are good for people at high risk for obstructive sleep apnea. Not really that good for screening in the general population.
Let's visit with Emily. So she's in her late 20s, normal weight. Appears alert. Presents after receiving poor grades in college. Difficulty staying alert and attentive for long as she can remember, at least since high school. Intensified after starting college. Constant mental fog. Can't focus on homework and in class. Mind drifts during lectures. Hard to stay awake during lectures, drinks diet sodas all day. Mostly on her feet all day at work. Naps during her lunch break. Feels like she's zoned out at work sometimes. Lives with roommate. Goes to bed about 11:00. Gets up at 5:30 for work and about 8:00 on other days. Sleep is restless. Lots of tossing and turning and awakenings. Some with disturbing dreams. Takes two to three unintended naps during the day, which are very refreshing yet the effects are transient. Reports of vivid dreaming during naps.
Occasional feelings of being stuck during a dream, following a sudden awakening with palpitations and anxiety, but no snoring. Uses Diphenhydramine for occasional insomnia symptoms with inconsistent results. Medications include Fluoxetine in the morning and an oral contraceptive. Wants to go to the gym more, but often too tired when off work. So her Epworth Sleepiness Scale is pretty high at 16. Denies recreational drug use. You might have four or five alcoholic beverages on weekends. Periods of intense anxiety and occasional panic with low mood with daytime symptoms considerably mitigated by the Fluoxetine and psychotherapy. Normal appearance, mild psychomotor activation, sensorium clear. And let's see what she has to say.
Emily:
Where to start. Since high school, my mom always had to bang on my bedroom door and yell at me every day to get me to wake in time for school. I thought I just wasn't a morning person, but it just got worse in college. I was tired all day, even during the weekends when I did nothing. I had to take a nap after each class. My junior year, I made sure I had enough time between classes to nap, but I was still falling asleep during my lectures. I somehow made it through college with decent enough grades to get into medical school. I knew I had to change things though before I started medical school. So I talked to my doctor and he prescribed me Zoloft for depression and sleep problems. And I was taking it for like three months and it didn't help me at all. Still exhausted all day and it's not like I'm up all night either. I sleep for like 10 hours a night and it's still not enough.
I don't have the energy to go to my Zumba classes, so I've gained even more weight and I can't even rely on coffee to keep me up. I'm only three months into medical school and my professors are giving me warnings that I need to do better or they'll fail me. So I went back to my psychiatrist because this is getting out of control. He gave me a list of things that I should try to improve my sleep. He calls it sleep hygiene. I'm going to stick with it, but I honestly don't know if it'll actually work.
David Neubauer, MD:
Yes. Well, we'll see. Most relevant step, a nocturnal sleep study. Increase your fluoxetine, anxiety inventory, history of periods of muscle weakness following emotional arousal, urine drug screen. Probably try to get a little bit more history real quickly about whether or not you might have cataplexy, and the other things would be reasonable as well. One last picture of excessive sleep, and this is a 40-year-old woman married, eight-year-old daughter. Concerned about lack of energy, feeling too tired all day, stays in bed as late as possible every day. Daytime fatigue, dragging through the day, naps in the late afternoon some days. Naps are lengthy and refreshing, not associated with dreaming.
Pushes herself to go to work, but has called out a few days recently. Avoids usual household chores as much as possible. Typically bedtime with 10:30, but now going to bed about 9:00. She'd falls asleep quickly, maybe up once during the night for a bathroom visit. Alarm is set for 6:00 AM workdays. May awake by 8:00 AM one day she's not working. Stays in bed for another hour, never feels refreshed when she gets up for the day. Husband says she snores a little. No hypnagogic hallucinations, sleep paralysis, cataplexy. Has seen a therapist when she was in college. Primary care provider treats depression and anxiety over the past three years. Hypothyroid, but the TSH is within normal limits on treatment. So she's on the Fluoxetine, Levothyroxine. BMI 28, low mood, some psychomotor slowing. Her Epworth is a little borderline, slightly above the cutoff at 11.
Donna:
I can usually fall asleep pretty quickly at night and I only get up maybe once or twice a night. But I wake up and never feel refreshed. I have zero energy throughout the day, which is hard to imagine when you have a second-grader. On the weekends, I lay in bed as long as possible. My husband has been wonderful at picking up my slack when it comes to the household chores, but he can't keep doing that forever. I'm still tired on the weekends and after work, that I can't even bring myself to clean up around the house. Is this just how it is when you get older? Is there anything we can do about this?
David Neubauer, MD:
And what might explain it? Idiopathic hypersomnia, definitely a possibility. Hypothyroid, major depression, medication induced hypersomnia, all of the above. The first choice is a good consideration that again, we would round out with a bit more history. At this point, I'm going to welcome Dr. Doghramji to the stage and he's going to talk about the management of excessive daytime sleepiness, especially in the psychiatric setting. Karl.
Karl Doghramji, MD:
Morning, everybody. So just want to let you know last night my flight arrived at 12:30 AM. I woke up at 5:30 this morning to make this talk. So you'll be experiencing the effects of sleep deprivation on one's lecture, but seriously, that's one of the things I'd like to talk about today and sleep deprivation as a cause of daytime sleepiness.
One other sort of commentary, when I was a resident, I asked one of my professors, I said, "How commonly do you see sleepy people," a psychiatrist, "... sleepy people in your practice?" And he said, "I don't have any sleepy people in my practice. All my patients are alert, I don't have any sleepiness in my practice. So I did a little survey.
I sent around a survey to all of my professors who, psychiatrists who were seeing patients and asked them, how commonly do you see sleepy people? Zero. Nobody answered, yes. Finally, I did a little Epworth Sleepiness scale that Dr. Neubauer gave us on an unselected population within our psychiatric clinic. Same patient seen by my professors.
80% had high Epworth scores, 80% were sleepy, but nobody had detected sleepiness in these psychiatric patients. My point being that as psychiatrists, mental health professionals, we see a lot of sleepy people. They're all over the place. We just don't monitor that part of the people's sleep wakefulness.
We usually look at insomnia, but I'd also like to suggest that sleepiness is a very important factor in terms of affecting psychiatric comorbidity in a negative way. People's affect deteriorates, as Dr. Neubauer mentioned, David mentioned, their underlying psychiatric syndromes worsen. And by treating and monitoring and treating sleepiness during the day, we can really impart a lot of positive benefit to these patients in terms of the things we're interested in, which is affect, mood, daytime functioning, and all sorts of other psychosocial areas.
So that's my commentary. Now let's go back to the first slide. Let's talk about daily sleep requirements. How much sleep do we need? Well, one of the questions of course is how old is the person you're talking about? And newborns, of course, they get a lot of sleep. Infants, 12, 16 hours of sleep as many of you know. But as we age, the sleep requirements diminish and as adults, interestingly, teenagers, about eight to 10 hours of sleep per day. They need a lot of sleep, teenagers, and they deprive themselves obviously very frequently.
Adults, people in this group presumably are about seven or eight hours of sleep. So if somebody is in front of you, patients that are in front of you say I'm sleepy, one of the things you need to ask is how much sleep are you getting, right? How many hours do you sleep?
If they're only sleeping four hours a day like I just did last night, they're going to be sleepy. And one of the ways to identify sleep deprivation in your patient as a cause of sleepiness of course, is to ask them to spend a couple of hours more in bed per day and see if that improves matters.
And these are patients, of course, who are setting their alarms to wake up early. So sleep deprivation should be isolated and identified before you embark on treatment of daytime sleepiness in pharmacologic and other ways. Now, let's talk a little bit about daytime sleepiness management pharmacologically.
Dr. Neubauer mentioned narcolepsy, idiopathic hypersomnia, sleep apnea and SWSD is shift work sleep disorder. These are some of the medications that are indicated for these syndromes. Caffeine, I have some right here. Caffeine is a very important drug. It's probably the most commonly used psychoactive compound in the world.
Caffeine is an adenosine receptor antagonist. Adenosine is what we call a homeostatic factor. When adenosine increases in our central nervous system, we get sleepier and sleepier and antagonizing adenosine receptors can help alert us, diminish sleepiness. It's not FDA approved obviously, but it's commonly used. Very few side effects if done in moderation.
Caffeine is actually a very good choice for many of our patients if they don't drink it too close to bedtime. People metabolize caffeine variably. Some people, even if they have an afternoon, one cup of coffee, they won't sleep well that evening. But most people, by and large, if they have coffee no later than noontime will not have too many sleep issues.
Methylphenidate amphetamines, these are used for narcolepsy. They enhance neurotransmission of dopamine and serotonin to some extent, but mainly dopamine and norepinephrine. Modafinil armodafinil, also called wake promoting agents, they're indicative for excessive sleepiness with narcolepsy, sleep apnea, we'll talk about that in a couple of minutes and shift work sleep disorder in patients who are adult patients, sodium oxybate and recently introduced low sodium oxybate.
We'll talk about that in a couple of minutes. These are GABA B receptor agonists and they're indicative for cataplexy or sleepiness in patients more than seven years of age with narcolepsy. Now, LXB or low sodium oxybate, low sodium oxybate is also indicated for idiopathic hypersomnia. That's just got an indication for that disorder just a few months ago and we'll talk just a bit more about that in detail.
So solriamfetol, this is a dopamine norepinephrine reuptake inhibitor, also a relatively new drug. It's indicated for sleepiness associated with narcolepsy or with obstructive sleep apnea in adult patients. And finally, pitolisant. This is a histamine H three antagonist and inverse agonist. It's kind little sort of an interesting sort of twist there, but basically it enhances histamine neurotransmission.
Many of you remember histamine is an activating neurotransmitter within the central nervous system and through a histaminergic mechanism, antagonizes sleepiness, and even cataplexy in patients who have narcolepsy and who are adults. So those are the medications we'll talk about. Just a couple of details on some of these medications.
The cataplexy medication, remember cataplexy is that loss of muscle tone. So patients can either collapse or more commonly they have a partial loss of muscle tone in their hands or in their maybe lips, lip sag, something along those lines. Sodium oxybate is indicated for that as well as low sodium oxybate, which just came out, which has instead of sodium, has calcium, magnesium, potassium as the cation.
Pitolisant and some antidepressants, which many of us use for other reasons are also not indicated, but can be used for cataplexy in the case of narcolepsy. Tricyclics, SSRIs, norepinephrine uptake inhibitors. Interesting, you don't have to use a full dose, full antidepressant dose. A small dose which may not be that great for depression is often enough to treat cataplexy in these patients.
And many narcoleptics also have depression. So many of us who are psychiatrists and sleep specialists actually will treat narcoleptics with an antidepressant for both their depression as well as for cataplexy. These agents can also positively impact hypnogogic hallucinations and sleep paralysis. Remember, those are all REM phenomena. These are rapid eye movements, sleep phenomena occurring when they shouldn't be. If you have REM right now collapse, you'll start hallucinating if you REM at the wrong time. If that happens at nighttime at the wrong time, you'll do the same thing. You'll be paralyzed. Well, these agents are anti REM in a way, they're anti-catalytic but also can diminish things like hypnogogic hallucinations and sleep paralysis, which are manifestations of abnormal REM.
They're not FDA indicated for that, but they can help. Now what about idiopathic hypersomnia? Remember IH or idiopathic hypersomnia is this sort of, some people call non REM narcolepsy. It's sleepiness, long periods of sleep and sleepiness, but none of the REM findings, they don't have hypnogogic hallucinations. They don't have cataplexy, but they sleep for long, long, long periods of time, 12, 14 hours.
Some of you maybe have seen bipolar patients who are like that during the depressed phase. They sleep for long periods of time and questions, are they really sleeping or are they simply withdrawn and lying in bed and not truly asleep? And of course the latter is probably more likely in many bipolars, but these are agents which are useful for idiopathic hypersomnia according to a recent paper that came out that David mentioned initially, and that was the American Academy of Sleep Medicine practice parameters for the treatment of central nervous system, hypersomnia.
Modafinil, there's strong evidence for that and clarithromycin, it's an antibiotic. There are a couple of different studies on this interestingly showing might be helpful. Not FDA indicated for this, but interestingly may actually diminish sleepiness in some of these IH patients. Studies are weak. I just warn you, they're not that great, but there it is.
And by the way, it works we think by modulating that GABA receptor, allosteric modulation of the GABA receptor and that's how it diminishes sleepiness, methylphenidate, pitolisant and sodium oxybate. The only one that's actually indicated by the FDA for IH is not even on the slide. And the slide was made before that indication came out. And that's low sodium oxybate, low sodium oxybate, it's indicated for IH just received that indication.
Here it is. It's a GABA B agonist, it's schedule three. It's approved for cataplexy or daytime sleepiness in patients more than seven years of age, obviously with narcolepsy and idiopathic hypersomnia. Its dose is a little bit tricky. It's a liquid and patients actually ingest it not during the day when you would expect sleepiness drugs to be given, but at nighttime before they go to bed.
4.5 grams, and not milligrams, and they divide the 4.5 grams into two doses. So they actually take 2.25 grams and they go to bed and two or three hours later they wake up, most wake up spontaneously, they take the second dose of 2. 25 grams and go back to sleep and then wake up about three or four hours later.
They should stay in bed for four hours after that second dose because if that drug lasts in the CNS too long, they can be sleep or dopey when they wake up in the morning. Interesting drug. By actually enhancing the quality of sleep at night and in some other way that we're not sure, some other mechanism, it actually enhances alertness during the day, but it works at night and that effect is lasting during the course of the day.
You titrate upwards until you get to a maximum dose of nine grams if you need it. Main side effects, headache, nausea, dizziness, some appetite issues. Parasomnia, a small number of patients on this drug in the clinical trials had sleepwalking. Now remember, what stage of sleep does sleepwalking occur in? Stage three, slow wave sleep. This drug enhances slow wave sleep and so it enhances the stage where parasomnias can occur, where at least non-REM parasomnias can occur. So it's an interesting mechanism. Hyperhidrosis or sweating anxiety. I've actually had some anxiety increase in some psychiatric patients, so you've got to be a little bit careful about these drugs. Not that they're contraindicated if there's a comorbidity of psychiatric comorbidity, but you've got to be a bit more careful and monitor these patients a bit more regularly. Low sodium. Why low sodium? Why is that so you should have low sodium? Well, these narcoleptic patients are exposed to these drugs for many years, right? Narcolepsy is an incurable disorder. Lifelong incurable disorder. Sodium exposure for long periods of time may have negative consequences on heart function, renal function, high blood pressure, may diminish lifespan, believe it or not, long, many, many years of sodium exposure.
I try to make sure I get very low sodium myself. And so because of that it's probably preferable in the long run to sodium oxybate if you can get people on this in terms of their general overall health, especially if they have heart conditions or kidney disease, blood pressure increase and that sort of thing.
Pitolisant, that's that histamine drug that I mentioned. It's not a scheduled medicine unlike many of the medicines we've been speaking about today that enhance alertness during the day. It's non-scheduled. So it's a drug that may be desirable for people who have histories of drug misuse. It's approved for excessive sleepiness and cataplexy both in patients with narcolepsy.
Dosing range, the dosing is a little bit unusual in terms of the decimal points and so on, and that's because the drug was initially studied in Europe and then brought to the US and the same dosing in Europe did not translate into the US FDA's dosing strategy.
But the active amount of drug in both the US and Europe are exactly identical. So you start out with 8.9 milligrams once a day in the morning, obviously week one and it's available in 4.45 milligram tablets. So you can give them one or two in the morning and then you increase it every week until you reach a maximum if you have to of 35.6 milligrams once a day.
It's long enough lasting so that it lasts pretty much throughout the course of the day for the management of sleepiness. You've got to be a little bit careful about the QT interval. Do an EKG first and after you treat patients for a few doses worth, maybe five doses, get another EKG just to make sure you haven't prolonged that QT interval, especially in people that are on many other drugs that can affect QT segment length and renal impairment as well in some.
Just make sure patients have a kidney function tests that are normal. The adverse effects, insomnia as you would expect if it lasts too long. Anxiety, it's an activating drug, some nausea and it may reduce the effectiveness of some non-steroidal hormonal contraceptives. I apologize, non-hormonal contraceptives because of its activity of the CYP3A4 liver enzyme system, it actually enhances that enzyme, diminishing amounts of other drugs that are metabolized by that enzyme.
So you've got to be a bit careful about that. Use other methods of birth control possibly. Solriamfetol, it's a dopamine norepinephrine reuptake inhibitor. It is scheduled, scheduled four, available in 75 milligrams and typically patients will start with 37.5, half of that dose if they have obstructive sleep apnea and that full dose if they have narcolepsy in the morning and then you can increase it to 150 if you have to.
Obviously contraindicated with MAOIs. Renal excretion is the way in which it's excreted renally rather. So if people have high renal disease, you may want to think about decreasing dose. Blood pressure increase is one of the things you've got to watch out a little bit. So I tell my patients, monitor your blood pressure daily for the next week or two until I see you again. And if you have blood pressures above 120 over 80, let me know and we can talk about what to do.
Unstable cardiovascular disease, get a cardiac consult you might want to avoid and no effect on oral contraceptives, which is nice. And there are no data on breast milk, unfortunately. It does not have a positive effect on cataplexy. So if a patient has narcolepsy with cataplexy, you'll help them with their sleepiness with this drug but not with the cataplexy. So you've got to introduce an anti-cataplectic agent in addition to this, like those antidepressants that we talked about or possibly switch them to pitolisant, the prior drug which is active both for sleepiness and for cataplexy. These are some long-term studies I just want to make you aware of. I'm not going to go into the details very much, but for Solriamfetol, the point that I would like to make is that it was studied for 12 weeks. So these are long-term treatment drugs and in this particular case it was a 12-week double-blind placebo controlled study, which showed that it did work and continued to work for excessive daytime sleepiness in these narcoleptic agents.
Pitolisant, the second one down there was studied in an open label fashion that is non-controlled in a regular clinical setting, multi-site clinical setting for up to one year. And this was primarily a safety study and the data which are obviously not definitive, showed continued improvement over the course of that one year compared to baseline.
And there was another 12 week study with low sodium oxybate again showing efficacy, but this was an unusual study. Design was a bit complex where they actually took people off of it after a certain period of treatment to see if sleepiness returned and again, it was effective. Now let's go over obstructive sleep apnea. David, Dr. Neubauer, David, do you mind if I call you David? Awesome. You can call me Karl. So daytime obstructive apnea. So obstructive apnea as David mentioned is a disorder, which is very common and it is common in our psychiatric patients to look for, ask for snoring and stoppages of breathing during sleep, call a bed partner, so on and so forth.
I've had so many patients improve in terms of their mental status just by treating underlying obstructive apnea. Many treatments, continuous positive airway pressure, the most commonly used treatment, air, it's just nothing but air, introducing it to the upper airway, keeping the pharynx open. Upper airway surgery in milder cases. Oral appliances, those are the ones you see on the second diagram on the left. These oral appliances. Do I have a pointer? Maybe not.
There it is right there. Oral appliances actually protrude the jaw forward just a little bit opening up the pharynx a little bit. Body positioning devices in patients who actually have positional apnea. You can see that on the sleep study. So you prescribe a positioning device which keeps them on their side.
Nasal expiratory PAP devices. These are small nasal plugs which actually trap air in the upper airway. Upper airway muscle strengthening, not very effective, but in milder cases could be helpful. Medications, again, you don't rely on them very much because they're in refractory cases, may want to think about them. Certainly in patients who have morbid obesity, bariatric surgery has been extremely helpful.
It's revolutionized the treatment of sleep apnea in the morbidly obese patients. And hypoglossal nerve stimulators, this is a sort of a newer treatment which is an implanted pacemaker and stimulates or paces the upper airway muscles through its effect on the hypoglossal nerve. Every time the patient breathes, there's a signal to the hypoglossal, the airway stretches and it's been a highly effective treatment for obstructive apnea.
Here's the problem. After you treat obstructive apnea effectively, patients are using their devices and so on and so forth, about 20% still remain sleepy and we don't know why, but we think that it might have something to do with maybe a long-term hypoxia on the brain before treatments started.
Many of these people are identified 30 years after they've had symptoms, so sometimes sleepiness does not go away. And the question is what do you do? You're treating the apnea but they're still sleepy. Well, one of the strategies is to manage them pharmacologically on the very bottom with one of these three drugs, modafinil, armodafinil or Solriamfetol.
These are indicated for obstructive apnea related sleepiness where you've treated the apnea but they're still sleepy. You may also, by the way, before you jump to drugs, think about other alternative treatments. I mean, if a patient's on CPAP, for example, and still sleepy, it might just be that their apnea is not controlled on the CPAP or maybe they're not using it right, especially if they're kind of noncompliant with it or poorly compliant, you might want to switch them to an oral appliance or something along those lines.
And if there may be other causes of sleepiness, not every person who has apnea is sleepy because of the apnea. They could have bipolar disorder, they might have short sleep, I mean the sleep deprivation or all sorts of other things. Sleepiness is caused by many things, not just apnea, if patients have apnea. So treat the comorbidities as well.
But when you've done all of that and they're still sleepy, you might want to think about some medications and they're indicated. I'm not going to go over this at all in detail, but this was a study showing meta-analyses with modafinil and arm modafinil and also with Solriamfetol essentially showing that these agents were effective in the treatment of excessive daytime sleepiness.
So novel wake promoting agents are available for the treatment of excessive daytime sleepiness, and these include low sodium oxybate, pitolisant and Solriamfetol. And the mechanisms are given on this slide. Now let's talk about the cases that David mentioned. These are Gary, remember Gary was the guy who was ... Well, here he is.
Gary:
My sleep, it's okay, not great, but I think it could be worse. I'm sure my wife would have a different answer. She says I snore, but that doesn't bother her as much as me waking up several times a night to use the restroom. I just don't have any energy anymore.
I can't stay focused during calls and meetings at work. When I get home, the kids usually want to play or go outside, but I'm just too tired. So I have to tell them no. My primary care doc told me I have high blood pressure and I'm pre-diabetic. I don't know, maybe that has something to do with all this.
Karl Doghramji, MD:
You've all seen Gary in your practices, right? He's not an unfamiliar person. He's withdrawn, he's sleepy, he's tired, and could be depressed. Maybe he's depressed, but the point being that sleepiness can manifest itself in many ways, including mood decrement. Is this... Yeah. In Gary's case, we do a sleep study. As many of you said or thought or maybe we're thinking, a sleep study isn't such a bad idea, and his AHI is 45. He has 45 apneas and hypopneas per hour of sleep. That's severe apnea, anything above 30 is severe. That's his problem right there. You talk to him, you start him on CPAP, it's a most commonly used method of treating apnea. Comes back and you see he's really using it. His residual apnea, which you can monitor from his machine. His machine, it's what's called a smart card, will show you how much apnea he has. Nor is normal, less than five, less than four.
You follow up with him and his sleep has improved, Gary's saying he's sleeping better, he's feeling better during the day, but like many of these patients, he's still having some sleepiness. You give him a month, two months, he's doing what he's supposed to be doing, but he's still a little bit on the sleepy side. He's better, but not well. You remember that phrase, right? "Better, but not well." You may want to talk to him about some pharmacologic therapies, they may help. In this case, he does obviously use one and his energy level increases, no longer falling asleep, mood shows normal undulation, his wife is pleased. That's not an uncommon scenario for patients who have sleep apnea and who remain sleepy. These are the agents, of course, just to refresh your memories that are potentially used for patients with sleep apnea and who have sleepiness in a residual fashion after treatment. Solriamfetol and modafinil and armodafinil. Emily, remember? Emily was that person who was a medical student, remember? She was falling asleep in lectures. Let's take another look at her.
Emily:
Okay, so I actually did everything my psychiatrist told me to do. I had a strict sleep routine that I even kept during the weekends, I put my phone and my computer away two hours before bedtime, stopped drinking, and I even stopped drinking coffee after 1:00 PM, but guess what? It didn't make a single difference. After a month of this, I went back to my psychiatrist and he made me do a couple of different tests and diagnosed me with narcolepsy, type two. Narcolepsy, I was shocked. All I knew about narcolepsy was from that character in Spaceballs, but my doctor explained everything to me and then prescribed me a new medication. I've been taking that for about two months now, and I can't even begin to describe how much better my life is now.
I can stay awake during my lectures and actually stay focused while doing my assignments. My friends notice the difference, too. They said I was like a zombie before my diagnosis. I'm only napping once a day, but I still feel awake throughout the day. For the first time in years, I'm actually in the moment now, and I'm loving my life again.
Karl Doghramji, MD:
That's great. Want to see that in your patients, don't you? Narcolepsy type two, which she was diagnosed with, it's not a diagnosis, which you'll see in the DSM-5, it's an ICSD-diagnosed, International Classification of Sleep Disorders. Basically, what it means is narcolepsy without the cataplexy, sleepiness and so on. You put them in the sleep lab, you see those findings on the MSLT, the daytime study that David mentioned, the two sleep onset REM episodes and all that, but they do not have cataplexy. That's narcolepsy type two. Mean sleep latency that is on the daytime... Yeah. Yeah, on the MSLT, right? She has a mean sleep latency of 2.5 minutes, so on this daytime nap test, five naps, she's put in the sleep lab and has to fall asleep. She falls asleep in two and a half minutes. You and I, maybe not me, but you would fall asleep in like 10, 20, maybe 10, 15 minutes.
You would stay awake and fall asleep in 10, 15 minutes, but she's falling asleep in two minutes, that's extremely sleepy. Very sleepy. She also has REM sleep in her naps. If you and I took a brief nap, we would not have REM sleep, maybe one REM, but not four REMs on our nap test. That's abnormal. She has narcolepsy. Discussion of treatments and behavioral strategies. Of course, narcoleptics need to make sure that they're getting plenty of sleep. Napping is good for narcoleptics, a nap or two a day. It refreshes them and makes the need for medications less prominent, and medications of the mainstay of treatment. We already talked about the medications that are indicated for narcolepsy, they're modafinil, armodafinil, pitolisant for various types of narcolepsy, so we have a large number of medications available, potentially, for the treatment of this disorder. Finally, let's talk about Donna.
Donna:
When I worked from home, I was able to hide how exhausted I was. If I didn't have any meetings in the afternoon, I would sneak in a nap, so that I could be awake enough later on to finish up my work for the day, but that never worked. I would nap for a couple of hours and never feel better, and by that point, I called it quits on working for the day. Now that I have to go back into the office a couple of days a week, it's noticeable to my colleagues, and it's worse. It feels like I'm dragging myself through the day and I can't stop yawning. I called out of work a couple of times last month, because I just couldn't pull myself together to get out of bed and go into the office. I've been on an antidepressant now for a while, maybe my depression is getting worse.
Karl Doghramji, MD:
Donna is an interesting case, because it's a mixture of things. One of the things that we think that she might have is idiopathic hypersomnia, right? Because once she gets to PSG, MSLT, so she has long periods of sleep. Remember history, she's getting about 10, 12 hours of sleep per night and still feels sleepy during the day, and there's no other... Anything else that could explain her levels of sleepiness, daytime hypersomnia. If she gets more sleep, she still feels sleepy during the day. We ruled out other things with her. One of the things with these IH patients is you really have to be careful about subtle depressions. In this particular case, thinking about maybe modulating her antidepressant isn't such a bad idea.
We all know some antidepressants are activating helpful in this population, but if not, if it's not the depression, again, as I mentioned before, there are medications that are indicated. These are not indicated, but certainly mentioned in this review paper that I mentioned to you before. The one that is indicated is low sodium oxybate, which received its indication for this disorder after this slide was made. In conclusion, excessive daytime sleepiness hypersomnia, which is long sleep, fatigue, common and encountered in psychiatric disorders are associated with significant impairment, including impairing their psychiatric comorbidities. A systematic evaluation is not a bad idea to uncover sleep disorders that may be treated directly, so that the patient doesn't remain sleepy despite what you're doing for them. Novel wake-promoting agents for the achievement of excessive sleep in narcolepsy with or without cataplexy and obstructive sleep apnea are available, and mental health professionals have the opportunity to uncover and address excessive sleepiness associated with narcolepsy and OSA and IH in their patients. Thanks, everybody. Very much appreciate your attention.
Charles Raison, MD:
All right, so we've got some time for questions. Yeah, don't leave, gentlemen. I've told you this, Karl, I actually have excessive daytime sleepiness. Oh, my goodness gracious. Yeah, fall asleep at meetings. It's a real problem, so I appreciated your talk.
Karl Doghramji, MD:
I'll do an interview next time, just check it out and see what your history is.
Charles Raison, MD:
Yeah. People kick me under the table. I have literally fallen asleep when people are talking to me directly.
Karl Doghramji, MD:
Yes, yes.
Charles Raison, MD:
Not as bad now as it was in the past, but it's really an irritating thing. I have inherited this question, it says, "A few patients from other providers who take Adderall for energy, not ADHD. I would never start Adderall for that, but I feel pressure to continue it, though I have doubts. What are your thoughts about that?"
Karl Doghramji, MD:
Go ahead, David.
David Neubauer, MD:
Yeah, I've got some people taking Adderall for excessive sleepiness. For some people, it is overlap and they were originally put on it for ADHD symptoms, but realized that their excessive sleepiness was improved dramatically. It is indicated for narcolepsy, so it's got a role. Methylphenidate as well.
Karl Doghramji, MD:
If the question is long-term management, unfortunately these disorders don't go away, and these are symptomatic management techniques, so long-term management is common with this entire group of drugs.
David Neubauer, MD:
Yeah.
Karl Doghramji, MD:
Maybe being careful and getting EKGs every once in a while, cardiac exam, looking carefully for affective abnormalities in this population. That would be my thought after long-term management.
David Neubauer, MD:
Yeah, sometimes people ended up on pretty high doses that may be worrisome. I have seen people develop some paranoia, maybe some hallucinations, but usually, long-term high dose.
Karl Doghramji, MD:
It's also a practical issue, because you've got to refill the medications once a month. That's one of the...
Charles Raison, MD:
Yeah, we were doing an ADHD talk in here the other day, and that's one of the thing I talked about, how people that really make a life of that have to have a whole system in place for all the... Am I correct, though, in understanding that it's not a crazy idea? It's not a... No, that it actually could be defensible.
David Neubauer, MD:
I've got quite a few.
Charles Raison, MD:
All right. By the way, while we're doing this, if you don't mind, please fill out the polling questions. Again, same thing with the QR code, so we can capture the measure of your assessment afterwards. Do you have concerns for modafinil abuse, particularly in those with the history of meth addiction?
Karl Doghramji, MD:
Meth addiction?
Charles Raison, MD:
Yeah.
Karl Doghramji, MD:
Meth. The data with modafinil don't really bear out a lot of misuse or abuse. It's not really sold out there on the streets, doesn't seem to have a very high potential for misuse and abuse. Now, on the other hand, if a person has an addiction to begin with, this is a scheduled agent, I'd be a little bit concerned about intensifying their host addiction, the meth abuse itself, as opposed to misusing the modafinil. Yes, I would be careful before I started somebody on modafinil, yes.
David Neubauer, MD:
I haven't seen an issue with any of my patients.
Charles Raison, MD:
With modafinil?
David Neubauer, MD:
Yeah.
Charles Raison, MD:
Yeah. Any data on the use of low sodium oxybate for those with non-24-hour or delayed sleep phase disorder?
Karl Doghramji, MD:
Not me. I have no experience with that whatsoever. How about you, David?
David Neubauer, MD:
No, not yet. With those populations, there are a lot of other things that we would do first, with a circadian rhythm disorder, rather than turning to something as potent as the sodium oxybate or the low sodium oxybate.
Karl Doghramji, MD:
Right.
Charles Raison, MD:
Okay, very good. "Depending on insurance, sometimes it can take clients months to have a sleep study done, or some of my patients with high deductible private insurance cannot afford a sleep study. Any recommendations for their daytime," this says "Sleeplessness," but I bet they mean "Sleepiness," "Other than stimulants, Wellbutrin, or exercise, something like that?"
David Neubauer, MD:
That's a tough one, you need the sleep study. If it really is somebody high risk of... A home sleep study are relatively inexpensive, and that's usually what a lot of insurance companies will require, unless there's some special health problem that warrants actually doing the in-lab study.
Charles Raison, MD:
Is there a difference? Anybody ever looked to see our in-home studies as reliable as lab studies?
David Neubauer, MD:
Here's the big problem that I see. If you have somebody that is very high risk, a guy who's 40 and his BMI is 40 and he's snoring really loudly and a spouse says, "He stops breathing." Clearly, that person has it, but it has to be documented, so a home sleep study is ideal for those circumstances, but most home sleep studies are not measuring the EEG, so they're not measuring when somebody is actually asleep. If you've got somebody with insomnia, and a lot of people with obstructive sleep apnea do have awakenings and are complaining of insomnia symptoms, if you're doing the standard home sleep study, you're looking at the recording period as your denominator in measuring the frequency of disordered breathing events. If that person is awake a lot of the time and they've got insomnia, so they probably are, and you are underestimating the apnea-hypopnea index for that person. That's a real weakness for most of the home sleep studies.
There are a few that actually do monitor the EEG, you can know when somebody's in REM sleep, non-REM, you actually know when they're asleep, so you actually know what that denominator is when you're trying to calculate the number of events per hours of sleep. Clearly, there are weaknesses with the home sleep studies.
Karl Doghramji, MD:
Basically, if a home study is negative, doesn't show apnea-
Charles Raison, MD:
Doesn't rule it out.
Karl Doghramji, MD:
... you're not done, you're not done.
Charles Raison, MD:
If you're waking up, say, 27 times an hour like I was, odds are it's even worse than that, is that...
Karl Doghramji, MD:
Yeah. Yes, yes.
David Neubauer, MD:
At least the home sleep studies are also... When they're not looking at the EEG, at least they're monitoring your oxygen level and they can calculate how many significant drops in oxygen you have. That's a pretty good clue.
Karl Doghramji, MD:
Direct answer to that question, almost anybody can order home sleep studies, so if the labs are booked and backed up, get an HST or home sleep study, see what you're dealing with, that might be all you need.
David Neubauer, MD:
A few hundred dollars compared to a few thousand dollars.
Charles Raison, MD:
Yeah, so significant difference and very nice, pragmatic advice. All right. "How long after patients have stopped substance use of meth or opioids," I suppose cocaine, "Would you wait to recommend workup of hypersomnolence?"
Karl Doghramji, MD:
That's a bit of a tough one. There was a study which actually looked at patients who had stopped using alcohol for one whole year and their symptoms remained. Actually, they got better, but then didn't go away. Both insomnia, poor sleep, as well as daytime sleepiness. The question, of course, always is, did the problem start before they started using alcohol or did the alcohol produce the problem? We don't know. As far as we know, these patients who were misusing drugs for long periods of time will have long-lasting symptoms, either because they had them to begin with or because the drugs did it. The question is, how long would you wait until you treated them with another agent? I wouldn't wait indefinitely, they're going to have these symptoms for a long time, and I would be judicious about which ones to use. We mentioned a couple, for example, that were not scheduled, wake-promoting agents not scheduled, I want to think about some of those. Yeah.
Charles Raison, MD:
Okay, fair enough. This is interesting, these questions come around with stimulant talks too. "How would you treat narcolepsy in a patient with a history of meth addiction?"
David Neubauer, MD:
Cautiously.
Karl Doghramji, MD:
Yeah. Yeah. No differently, but more carefully.
David Neubauer, MD:
Yeah.
Karl Doghramji, MD:
You've got to use these medications, unless there's an unstable addiction that... I have a couple of patients, you as well, where their addiction is still ongoing and dealing with a psychiatrist collaboratively to make sure that the patients are using the drugs responsibly, but still treating them.
David Neubauer, MD:
We'd have to think about mechanism of action. Maybe the pitolisant would be interesting. Although, the gamma hydroxybutyrate, the sodium oxybate, is an abused substance, it's very different from somebody with a meth addiction. With careful monitoring, maybe that would've a role.
Karl Doghramji, MD:
Another good question is related, and I have patients like this, how would you treat an narcoleptic who's also a schizophrenic? A number of those as well. Again, carefully, but you do treat them. Yeah.
Charles Raison, MD:
Yeah, all right. "I have had some patients who recognize that they sleep excessively." This is an interesting question, "I've had some patients who recognize that they sleep excessively, but that they use it as an escape and sometimes feel that they're addicted to sleeping. Have you seen many patients like this? What do you think about it?"
Karl Doghramji, MD:
Absolutely. Most of the ones I've seen are physicians, believe it or not.
Charles Raison, MD:
I believe it, yeah.
Karl Doghramji, MD:
This is true. Yeah. I've had patients like that and they say they're sleepy, they can't stay awake, no signs of depression, whatever. Bring them into the sleep lab, their sleep is fine at night, they wake up in the morning, the multiple sleep latency tests is completely normal, yet they claim they're very sleepy. You talk to them for a while, this is on the days when I used to do a lot of therapy, insight-oriented psychotherapy. Anyways, you talk to them for a while and you begin to find out that sleepiness can be used in a defensive fashion, absolutely. Yeah. I think the answer is yes, it can happen, but to assume that that's what it is without careful introspection, I think, is not a good idea.
David Neubauer, MD:
I think, a lot of the time, there's going to be an element of depression and just lack of motivation.
Charles Raison, MD:
It offers an escape from the pain of consciousness, if you're really feeling... This then would highlight the importance of getting testing, because if somebody's complaining of that, but they're completely normal, it would point that direction.
Karl Doghramji, MD:
Good point.
Charles Raison, MD:
Of course, it's interesting, in COVID, I think a lot of people... This has been written about, that people began to take afternoon naps and felt like that one of the things they were going to miss when they went back to work was taking an afternoon nap. Of course, there's cultures that take afternoon naps. It's a pleasant thing to do.
Karl Doghramji, MD:
Siesta.
Charles Raison, MD:
Yeah, I can understand that one, too, but that's interesting. Again, the idea, I think that it really is important and to do the testing, so that if that is what's going on, you're not going to medicate them with a bunch of medicines, you're going to talk to them. "I have several patients who seem to have three to four day cycle of hypo, then hypersomnia, but don't nap or complain of EDS. Any thoughts about this?"
Karl Doghramji, MD:
[inaudible]...possibly. You mentioned that, David, in your talk. Yeah, cyclic hypersomnia, two or three days of hypersomnia with... Maybe a few weeks, then normality. These people, during the hypersomnia periods, also sometimes have hyperphasia, enhanced sexuality. I don't know if the etiology is known, but some of these stimulants, they're recommended for that group of patients off-label. Yeah.
David Neubauer, MD:
It's a pretty dramatic presentation, because those people are like night and day, going on for many days at a time in one phase or the other.
Karl Doghramji, MD:
Right.
David Neubauer, MD:
On the other hand, they are just people with their everyday lives who are pushing themselves so much for a few days and then they crash, and then they go through this cycle back and forth as well. There's probably a little bit of normality to it as well.
Karl Doghramji, MD:
Another possibility is non-24 sleep-wake disorder, and that's a cyclic... When you think of some cyclic hypersomnias, you think of that.
David Neubauer, MD:
That ought to be weeks at a time for most people, to go through the whole phase.
Karl Doghramji, MD:
Yep.
Charles Raison, MD:
Yep. Okay, we're out of time. Thank you, all. Thank you, gentlemen. That was a great talk.
David Neubauer, MD:
Thanks.