Stephen Stahl, MD, PhD

Let me ask you this as we’re closing. What do you think the role is in treating narcolepsy for psychiatrists and neurologists?

 If you’re part of the team, we have the opportunity to see these patients and screen and look for these questions. Then if you’re not comfortable with managing narcolepsy, find you a sleep doctor who is, but work with them because psychiatry and neurology needs to be involved. Psychiatrists really need to help. Once you have the diagnosis of narcolepsy, there’s some grieving about the 10 years that you didn’t know when you had all these failures. There are also some changes in the family. Suddenly these people with narcolepsy wake up and say, “Here I am,” and they want to change the routines and schedules for everybody, and that’s different. The dynamics are different. There are lots of reasons for psychiatrists to be involved, even if they don’t want to be the frontline person. But proper screening by the neurologists and psychiatrists would be a huge advancement for the disorder of narcolepsy. What do you think?

 Often you can stabilize this situation if you’re a sleep specialist. And the other role that can happen is psychiatrists should get enough comfort so that they continue the prescription. They may not want to initiate the prescription, and they may not want to decide among the options, but they should be able to move and accept referral back. Maybe they’re treating an underlying depression, as you said, or some other disorder, but they can facilitate the access to medicines by re-prescribing.

 Right, and diagnosing and treating the anxiety too. This has been a great discussion. It’s my pleasure to be working with you. I feel honored. I’m a superfan of yours. This has been great for me. I hope we’ve helped to educate some people about narcolepsy, and treatment options, and some of the behavioral things you have to consider with narcolepsy.

I would like to thank you all for watching this 

Dr Stephen Stahl is clinical professor of psychiatry and neuroscience at the University of California Riverside, adjunct professor of psychiatry at the University of California San Diego, and honorary fellow in psychiatry at the University of Cambridge. Over the past 12 months (January 2020 - December 2020), Dr Stahl has served as a consultant to Acadia, Alkermes, Allergan, AbbVie, Arbor Pharmaceuticals, Axovant, Axsome, Celgene, Concert, Clearview, EMD Serono, Eisai Pharmaceuticals, Ferring , Impel NeuroPharma, Intra-Cellular Therapies, Ironshore Pharmaceuticals, Janssen, Karuna, Lilly, Lundbeck, Merck, Otsuka, Pfizer, Relmada, Sage Therapeutics, Servier, Shire, Sunovion, Takeda, Taliaz, Teva, Tonix, Tris Pharma, and Viforpharma; he is a board member of Genomind; he has served on speakers bureaus for Acadia, Lundbeck, Otsuka, Perrigo, Servier, Sunovion, Takeda, Teva, and Vertex; and he has received research and/or grant support from Acadia, Avanir, Braeburn Pharmaceuticals, Eli Lilly, Intra-Cellular Therapies, Ironshore, ISSWSH, Neurocrine, Otsuka, Shire, Sunovion, and TMS NeuroHealth Centers.

Dr Debra Stultz is the Director and Owner of Stultz Sleep and Behavioral Health in Barboursville, West Virginia. Dr Stultz earned her medical degree from Marshall University School of Medicine in Huntington, West Virginia. She completed a residency in psychiatry and a fellowship in child and adolescent psychiatry through West Virginia University at their Charleston Division through Charleston Area Medical Center in Charleston, West Virginia. She is board certified in psychiatry, sleep medicine, and behavioral sleep medicine. With a special interest in Narcolepsy, she treats a variety of sleep disorders and psychiatric issues. She is also the editor for the Clinical TMS Society newsletter, on their Board of Directors, and the chairman of the TMS and Sleep Disorders Affinity Group. Dr Stultz is on the advisory committee for Harmony Biosciences and is a speaker for Harmony Biosciences and Jazz Pharmaceuticals.

Videos

In this custom video series, experts in sleep and neuroscience discuss the role of neurologists, psychiatrists, and sleep specialists in the treatment of narcolepsy and comorbid conditions.

Role of Neurologists and Psychiatrists in Narcolepsy Management

 Let’s move on and talk about pitolisant, or Wakix.

This is an interesting drug that has a unique mechanism of action, different from anything that has ever been used before. It is pro histamine. Usually I say it’s histaminergic, but every audience I’ve had since I started talking about this hears 

. No, it’s the opposite of an antihistamine. The so-called antihistamines are H1 postsynaptic antagonists, and you must know that histamine is a neurotransmitter in the brain. It doesn’t just make you itch. It’s an arousal neurotransmitter. It comes from an important part of the sleep-wake switch in your hypothalamus. These neurons go into the brain and arouse you and normally make you attentive and are even involved in cognition. You want to boost histamine in your brain, and you can do that by a couple of different mechanisms. Did you know that the presynaptic nerve has an auto receptor on it? It’s called an H3 receptor, and it’s there to be a brake and shut off histamine release. If you cut the brake cable, guess what? Histamine comes out, and the histamine comes out and wakes you up.

 It’s going to be dancing on those postsynaptic H1 receptors—histamine itself, but the drug releases histamine.

 This is an exciting medication. It’s been FDA approved for excessive daytime sleepiness and cataplexy. There have been some studies on it helping with sleep paralysis and hypnagogic hallucinations. The other main advantage of it is it’s not a controlled substance, so that’s a major advantage given a lot of the other medicines we have to deal with in narcolepsy.

 We’re late to the party. The United States got this, but overseas in Europe it’s been available for longer. My colleagues in Europe had much more experience with it than we did. They like it because it’s not overstimulating, it’s not a controlled substance, it’s not abusable, and it’s effective. It wakes you up and it has a refreshing effect, not like when you use too many stimulants; you’re way too much awake and people don’t like that. It’s almost better to not take the drug sometimes. This is not an adverse effect of pitolisant.

In this custom video series, experts discuss the uniqueness of pitolisant as a treatment option within the setting of narcolepsy and the role histamine plays in wakefulness.

Pitolisant and the Role of Histamine in Narcolepsy

 Let’s talk about some medicines that we’ve used for narcolepsy. Do you want to start with modafinil and armodafinil?

 Those are agents that would probably be best characterized as dopamine reuptake blockers. They’re mild stimulants. They’re weak stimulants in the sense that they probably don’t rapidly block the transporter and don’t completely block the transporter. Almost all the medicines are dedicated to boosting arousal. If you don’t have orexins to boost arousal, you have to have medicines to boost arousal. You remember the old reticular activating system—dopamine, norepinephrine, not so much serotonin, but histamine, acetylcholine. These are the more arousal neurotransmitters.

It turns out that you can be in trouble if you block any of the arousal neurotransmitters. That puts you to sleep. That’s the last thing you want to do. In treating people with modafinil, 1 of the first things you want to do is to say, “Am I blocking dopamine or any of these other neurotransmitters,” and stop those drugs if you can. But modafinil and its active enantiomer or armodafinil boost dopamine, but not norepinephrine transporters; it doesn’t look like it. In so doing, they have a mild stimulant effect and boost the arousal neurotransmitter dopamine. By doing that, they wake you up.

 Yes. These medications, I believe, have helped change the medicines when they came out—a new way to treat the success of daytime sleepiness. They do not have the same significant adverse effects on heart rate, blood pressure, and abuse potential that the stimulants have. One of the only things we had for several years for that was stimulants. They’ve been very beneficial medicines.

 The stimulants work sometimes too well because they work rapidly. They go up too high a dose; they overstimulate. It’s hard to adjust the dose. They often must be taken more than once a day, although there are some new ones that don’t. It’s hard to get a dose-response curve with stimulants that have the right amount of efficacy without the adverse effects. They tend to happen, but it’s much easier to do that with modafinil and armodafinil because they don’t have the overstimulating effects, and they don’t have the rapid onset and the big peaks. Sometimes you have to give them twice a day, sometimes just once a day. Because stimulants, unless you give the controlled release, must all be given more than once a day.

 Stimulants certainly have their place, and they add on, but they have more of an abuse potential and more cardiac effects. It’s interesting how you must dose them. Sometimes we have to add a sprinkle of it to some other medicines.

Let’s talk for just a minute about sodium oxybate. That medicine changed the face of narcolepsy for sure.

 It’s got a checkered history, but boy does it work to make narcolepsy better. It’s probably the most powerful drug to make you have slow-wave sleep.

 That’s a really good point. It helps with the disrupted nocturnal sleep. It’s FDA approved for excessive daytime sleepiness and cataplexy. There have also been some studies on it helping the sleep paralysis and hypnagogic hallucinations.

 The main problem is that it causes you to have to take it twice. It’s so short acting that it’s a pain to take sometimes. It’s a liquid. It’s also highly controlled. The access problems can be somewhat problematic or a hassle, but the good news is that it works so well that people are coming up with once-a-day formulations.

 Patients get used to it after a while. Now they have the new form with less sodium.

 It’s a heck of a sodium load, isn’t it?

 For people who have sodium, it can be a problem.

 But the new formulation has 92% less sodium and the same effectiveness, and it’s also been approved for sleepiness and cataplexy

 But most of what you want to do is make sure you’re stopping the medicines that cause the activation to be blocked, and you want to start medications that boost activating neurotransmitters.

 Right. We did leave 1, solriamfetol. We may talk about that, Sunosi. That’s interesting. I’m sure you will think from a neurotransmitter.

 It’s like a stimulant in a certain sense because stimulants are norepinephrine and dopamine reuptake inhibitors. Remember, I told you that bupropion is a norepinephrine reuptake inhibitor. Modafinil is a dopamine reuptake inhibitor. All these are good for different things on a theme, different variations of a theme. What’s interesting is that there are some good things that stimulants do without having the overstimulation.

 Right. One of the advantages of this medicine is it doesn’t have an effect on birth control pills, so that’s important for some young women. There can be effects on the birth control pill, like Provigil, or modafinil. One advantage of this medicine is it doesn’t have the effect on the birth control pill.

 Yes. That makes it attractive. It’s also been approved for the excessive daytime sleepiness of sleep apnea, as well as for the excessive daytime sleepiness of narcolepsy but not cataplexy. I haven’t seen any studies on its effect with the sleep paralysis or hypnagogic hallucinations.

In this custom video series, experts discuss the advantages and disadvantages of stimulating agents in the treatment of narcolepsy in addition to other notable pharmacological options.

Pharmacological Treatment Options for Narcolepsy

 We’re going to talk in a minute about what medications we would use, but there are also behavioral therapies we need to use with these patients. We need to talk to them about naps and how refreshing a 20-minute nap can be and keeping their sleep schedule regular. With the naps, 1 of the important things is to time their daily naps when they have their sleepiest period. If 2 o’clock is when they get really sleepy, then you plan the naps at 1 o’clock. Having a nap is necessary for patients with narcolepsy. In my mind, it’s the same as a person with who has to have frequent small snacks and has to keep something with them. The narcolepsy patient must plan on the naps and try to keep their sleep schedule regular.

 One of my old professors of biochemistry, who I worked with when I was in medical school, eventually was diagnosed with having narcolepsy because he was taking naps at work. But he was older, so maybe people thought he had it. He probably had a mild case his whole life, but what he would do is he’d have in his hand a big stack of keys that had a big metal name on it, and he was on this very hard floor that had a drain next to his chair, which was metal. He would take a nap as long as it took for him to lose the tone in his hand and drop the keys and wake up, and then he would go back to work.

 I don’t know [how long it was]—about 20 minutes—but he used that as his own alarm clock. That was a form of excessive daytime sleepiness. You’d find all sorts of odd stories like this if you actually look for them, and people find adaptive ways to try to deal with it and not get treatment.

 They’ve had to live with it forever. They go to their car at lunchtime and take a nap or know which restaurants have a place where they can safely take a little nap after they get.

In this custom video series, Debra Stultz, MD, leads a discussion on behavioral interventions for the treatment of narcolepsy and adaptation of patients in lieu of seeking treatment.

Behavioral Interventions and Adaptations in Narcolepsy

 There are different medical and psychiatric illnesses that can be confused during your work-up with narcolepsy. What do you think about that?

 The big 1, of course is OSA, obstructive sleep apnea. As you say, you can have it with narcolepsy, but you need to do that sleep EEG [electroencephalogram] to see if people are having apneic periods at night to make that diagnosis. That’s the big 1.

 Right. Or for any other sleep disorder, like restless leg or circadian rhythm.

 How about those acting out at night during sleep episodes, which you get with the onset of Parkinson disease. Or some hypnotic agents that make you act out weird stuff—you go down and eat from the refrigerator, come back to bed, and don’t know it.

 REM [rapid eye movement] behavior disorder. Other psychiatric disorders are also part of the differential if it’s depression, anxiety, bipolar depressed fatigue, anxiety, thyroid problems. There are a lot of things to consider. Medications that cause excessive sleepiness and timing. Are they taking their blood pressure medicine in the morning? Is it causing extreme sedation or substance abuse, or other substances?

 Absolutely. Antipsychotics are a big 1. A lot of people fall asleep with these agents that we give them in the daytime. They think, “Oh, I got narcolepsy because I’m falling asleep in the daytime all the time.”

 It could be just the medicines. But it’s common for people with narcolepsy to have psychiatric disorders, especially depression and social anxiety. But patients with narcolepsy are 16 times more likely to have anxiety. Just because they have those symptoms, it’s not 1 or the other. I had a provider say, “I’m going to treat the depression before I start working on the narcolepsy.” That, to me, doesn’t make sense. If you had a patient who had high blood pressure, diabetes, or COPD [chronic obstructive pulmonary disease] you would go in and treat their blood sugar, give them a medicine for their blood pressure and an inhaler. You would treat all 3. You wouldn’t say, I’ll just treat the diabetes, and we’ll see what happens with the rest. Having depression in narcolepsy, you’ve got to treat them both and treat them aggressively. The ongoing frustration with narcolepsy—having job problems, relationship problems, problems with your children—can lead to depression.

One other important point I’d like to make is sometimes people with severe cataplexy are trying hard to suppress their symptoms that they look flat and emotionless and seem depressed, but they’re not. I had a patient just like that, and I kept asking her about depression. I kept asking her, and she had significant cataplexy. She knew that if she got angry, or looked depressed, or suddenly got sad, then she was going to have this severe cataplexy. She was really blank and flat. And her kids knew that, so they knew they could get her frustrated and manipulate her. That was a really sad situation because you think of a mother trying to raise kids being completely flat.

 Yes. It may not be depression. It may just be they’re trying to suppress their symptoms. But there’s certainly coexisting depression just because you have the narcolepsy.

 Yes. If you think they have narcolepsy and they have depression, then 1 treatment alternative would be to use 1 of the antidepressants we’ve used to help cataplexy to treat the depression. We would use something like an SSRI [selective serotonin-reuptake inhibitors] or SNRI [serotonin-norepinephrine reuptake inhibitors] that could help with cataplexy and treat their depression.

In this custom video series, experts discuss medical and psychiatric illnesses that can be confused with narcolepsy as well as the presence and treatment of psychiatric comorbidities.

Psychiatric Comorbidities & Differential Diagnosis in Narcolepsy

 Well, there’s the rich man’s way and the poor man’s way. I’m not sure I can diagnose narcolepsy, but I can diagnose sleep onset and possibly even sleep-onset REM [rapid eye movement] in an airplane. This is my anecdote. If you get on an airplane, you’ll be on the runway and very quiet because you’re ready to take off. You can take 20 or 30 minutes in the quiet room. If you’re very observant, you’ll see this [his head falls forward]—all these heads breaking down and a lot of people going to sleep. They may or may not have excessive daytime sleepiness. I’m teasing. That’s very much how I diagnose narcolepsy. Put somebody in a room that’s dark and quiet and see how long it takes them to fall asleep. You can measure the latency to fall asleep. If it’s very quickly, then that’s not normal. There are a number of causes of excessive daytime sleepiness other than narcolepsy, but that diagnosis EDS, excessive daytime sleepiness.

 However, if you have an EEG [electroencephalogram] on at the same time, it’s not normal to go to sleep right into REM. That’s highly suspicious that you have narcolepsy. Some sleep deprivation can cause that as well; it’s not 100%. But sleep-onset REM, excessive daytime sleepiness, and latency to go to sleep very fast are all a diagnosis of narcolepsy.

 Right. To get the diagnosis, we do an overnight sleep study followed by MSLT, multiple sleep latency test, which is having the patient try to go to sleep 4 times every 2 hours, and we measure how quickly they go to sleep and what kind of sleep they have, and how quickly they get into REM sleep if they have REM sleep at all. We know we can use even an early REM sleep onset latency in their overnight setting, the PSG [polysomnography]. But by the strictest definition of narcolepsy, you must have 2 sleep-onset REM periods during the MSLT [multiple sleep latency test] or you could have 1 in the MSLT and 1 in the PSG.

 You don’t think these are often confirmatory? The way you get somebody to go through the hassle and expense of getting the test is different, which is to say that they fall asleep as a passenger in a car. Because if they have some of these problems, then they figure out to stop driving. If you’re at a traffic signal and that’s another way to say it, if you’re at a red light and you fall asleep, you’d better look into this a little. Does Grandpa fall asleep or does Mom fall asleep at the light? A lot of us do, but there are hints that people are sleeping too much, and they go rapidly into sleep. The other thing is they often wake up refreshed. It’s very funny how not all the time when I take a nap do I wake up refreshed, but that’s what these very brief episodes—you say, “Maybe we better investigate that,” then you do these fancy MSLTs and sleep EEGs.

 Those are good points about the history, about the naps being refreshing and how quickly they can fall asleep. The MSLTs can also be influenced once again if they’re on antidepressants or any REM-suppressant medications when they have the MSLT. It can make the MSLT negative. The other point I’d like to make is 1 MSLT does not exclude this diagnosis. Even having a negative MSLT at all does not exclude the diagnosis.

In this custom video series, Debra Stultz, MD, and Stephen Stahl, MD, PhD, share insights into diagnosing narcolepsy, including signs to monitor for, testing, and the potential for false negatives.