Phyllis C. Zee, MD, PhD

Many narcolepsy patients are managed by psychiatrists, and what do you see as some of the big take home messages here? Dr. Moawad?

 I’m going to say these two patients were typical in many ways, and they're both fairly complicated. Things don't stay the same and consistent throughout the whole disease course. I think that expectation of symptomatic change over the years and morbid psychiatric issues is something that is pretty common with people who have narcolepsy.

 I think with any patient that presents with excessive daytime sleepiness in practice, that narcolepsy should be in a differential diagnosis. It's not common necessarily, but it should be in a differential diagnosis. Also look at how medications may be masking some of the symptoms of cataplexy for example, as we saw in this patient. I think to ask questions beyond that about cataplexy, perhaps about sleep paralysis and hypnagogic hallucinations, just to consider it. It doesn’t take that much time. Just consider it.

It's a few more questions to ask and it's worth drilling in. Dr. Benca?

 So, again, another take home, particularly for psychiatrists is a lot of our patients complain about sleepiness and tiredness. Some of them are going to have narcolepsy, very few, but it's like finding the needle in the haystack. It's so critical to make the right diagnosis. We have a whole range of sleepy patients where we must tailor the treatment to their disease. And again, we want to neither over diagnosed nor under diagnosed narcolepsy.

That's well put. I think we're starting to run short on time here. But I want to thank all three of you for your great opinions. Appreciate lots of good ideas here. Thanks to the listeners for joining us for this Around the Practice program.

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An expert panel concludes the discussion by reviewing factors to consider when diagnosing and treating narcolepsy.

Key Takeaways and the Future of Narcolepsy Treatment

So, she's coming in because she's not happy with her medications. She's having these weird episodes. Dr. Benca, what do you think about goals of treatment here? And how would you approach this? Clearly, there's a lot of room for good tuning up in this woman.

 First and foremost, if you have a patient with excessive daytime sleepiness and anxiety, I'm not sure giving them a combination of alprazolam and buspirone is the best option because those can also contribute to daytime sleepiness. You need to clear that out and figure out how you can improve her anxiety. I think a lot of education is necessary for this patient on what narcolepsy is and how we treat it. I think also some guidance about the fact that many of the drugs that we would prescribe for the sleepiness could worsen her anxiety. We might need to try different things to see how she does with them. Probably the amphetamines are a little bit more notorious for worsening anxiety, and some of the other ones might work better. But again, you have to try and see. Again, setting reasonable goals of what we can expect and how treatment is going to need to be chronic and she can't stop and start medications.

It sounds like this is somebody who was on medication for a while and is probably going to be consistent. Dr. Moawad, let me turn to you. If this was somebody that you saw in your clinic, what would you be thinking of in terms of medications for starters?

 I think that medication side effects or medication just not working anymore is something to consider. But this case in particular highlights the idea that the disease can change, that the symptoms can change, and that it's always important to reassess what the symptoms are. When a person is diagnosed with a certain type of narcolepsy, that doesn't mean  it is not going to change. The main thing I take from this case is to back up a little bit and have to this holistic view of what could potentially be going on with her narcolepsy. As well as has she developed another condition independently? Anxiety, for example, an anxiety disorder. So, it's always important to reevaluate the diagnosis.

So, do you find the story compelling for narcolepsy?

 Oh, yeah. I think a lot of people will describe their history over the years as having changed throughout the years. That the symptoms they initially presented with were under control for a while and that things evolved. I think it's a very typical thing that I've heard from patients, especially people who have been diagnosed way in the past and are giving that brief snippet of what's happened.

 I agree with Dr. Benca, that the antidepressant may well have been masking some cataplexy. But of course, people can develop cataplexy months or years after the onset of sleepiness. And so, it's possible as you say, that this is just simply part of a disease evolution over time. I want to try to pin you down on this. So, she's not happy with her amphetamine type medication. She's having these episodes of weakness. What would what do you think would be a good medicine for her?

 I'm thinking she has anxiety, and we don't think the alprazolam and buspirone combination is the right thing. Fluoxetine certainly has some alerting effects and can also treat her cataplexy. I wonder if that seems reasonable. But it maybe is not the best one as an SSRI for the anxiety. I'm thinking, can we switch to another SSRI type of medication that could help both with the cataplexy as well as with the anxiety and for depression? I'm going to leave it to the psychiatrists to tell me what that would be. And avoid, of course, anything that's going to cause more cataplexy, like mirtazapine or something of that sort. I would think about doing that as at least as part of the thinking. I would certainly be talking to the psychiatrists and the colleagues and co-manage that with all of them.

I think it's in your court, Dr. Benca. What do you think as far as a fitting antidepressant here?

 I think with the anti-anxiety effects of antidepressants of the SSRIs, sometimes they work, but sometimes they don't. Paroxetine sometimes can make people more sleepy. So, I might either try fluoxetine or maybe sertraline. Sertraline is one of the ones I like to start with if I want to minimize side effects because she does need some treatment for her depression, and it might help her anxiety. If she needs a medication for anxiety, she could potentially stay on the buspirone. – I’d to get rid of the alprazolam because we'd have to know how much she's using. Is she using it just once in a while? Or is she on it regularly? Because you can sort of see how these peaks and then these withdrawal effects where anxiety can be worsened sometimes with alprazolam, so I might try to get rid of that. And then in terms of stimulants, you're asking -?

Yeah, because I think we focused on the antidepressant aspects.

 Again, I would first of all taper her off of the amphetamine with no driving and somebody keeping an eye on her, because it's hard to cross-taper a stimulant. I might start her on modafinil/armodafinil and see how she does with that to see if she has some benefit from it. Clearly the amphetamine is making her very anxious. You can always work your way up and advise her, because we are going to have to try things until we find what is the most helpful to her.

Anybody else have thoughts on weight promoting agents here?

 I agree with Dr. Benca. That probably would be my initial thinking as well. You could think about as you're tapering or decreasing the amphetamines, could you at the same time be adding something else to smooth that out a little bit with something like pitolisant, which has both weight promoting effects as well as anti-cataplexy effects. That may be something I would think about as a potential one as I'm tapering them off the amphetamines because it would do both.

: Many of the weight promoting agents don't really do much for cataplexy. But you might get a two for one with that. The oxybates can also help both, but do you have any concerns about oxybates in somebody like this?

 Well, she also has little kids, and she might need to get up at night to take care of them. So that would be a concern, plus with her history of depression, is it going to worsen that?

We are going to have to watch out for that. If you could just expand on that a little bit more, would you give an oxybate to somebody who has a little bit of depression, that is not bothering too much?

But if somebody had just been hospitalized for suicidality?

 Then I'd be a little bit more cautious or if they had any kinds of more significant history. I think for her, my bigger concern would be does she have to wake up at night with small children?

Yeah. Because the sedation from the oxybates can be quite intense.

A group of specialists discuss treatment options for patients experiencing daytime sleepiness and anxiety.

Goals of Therapy and Factors That Shape Narcolepsy Treatment

Dr. Benca, what do you think of this story?

 Well, it sounds awfully suspicious for narcolepsy with cataplexy. Not only the episodes that sound like cataplexy, but also that they really were exacerbated with the discontinuation of the paroxetine. On the other hand, I've also had psychiatric patients come in and complain to me of weakness or falling episodes that are not cataplexy. So, in a psychiatric patient, you want to be very careful about understanding what are the triggers that brings these on? Do they come on suddenly? To make sure that they really are classic cataplectic episodes.

You raise a really good point because diagnosing cataplexy is all about the history. It's the kind of questions you ask and how the patient responds. So, what is it about this particular story that we just described that makes you think cataplexy is likely?

 I think it's the paroxetine withdrawal and the episodes increasing afterwards to me the most suspicious. And certainly, with the combination of the excessive sleepiness.

Doother people have thoughts of what is compelling with that story?

 I think it's cataplexy. It is triggered by a strong emotion. I think she was telling a joke. The antigravity muscles, the slumping, I mean, this is as classic as you can get of a description and certainly not hidden, certainly not a mild form. I think this should make people suspicious of that.

Emotionally triggered, brief, and I would add a real functional impact because this touches on what Dr. Benca was saying a second ago about episodes of weakness or general feelings of weakness in people who all have concomitant psych problems. Sometimes we refer to those feelings of weakness as pseudo cataplexy. How do you tease those apart?

 I think one of the issues, of course, is what is triggering them? Do they come on suddenly? Do they have the classic presentation as Phyllis described, like the head drooping, the antigravity muscles, the slurred speech, versus just “I feel like I'm going to fall.” The psychiatric or the pseudo cataplexy are a lot vaguer, I think, and don't have the clean immediate onset and then of course, the offset.

And the duration can be longer. Triggers can be typical negative emotions, like grief or just feeling overwhelmed with anxiety.

Yes, “I'm feeling weak with stress,” would certainly point me in a different direction.

 Yes. That sounds like anxiety. Sometimes anxiety presents with “I'm feeling weakness with stress. I feel weak all over. I can't move.” It's really a lot of stress.

Thought leaders discuss what elements to consider when distinguishing between cataplexy and pseudo cataplexy. 

Clinical Impressions From Patient Case #2

Let's move on to another case, because it'll touch on some of the other facets of narcolepsy management. This is a 27-year-old woman, who was previously diagnosed with depression and daytime sleepiness. Now she is coming in to talk to her psychiatrist because she is having episodes of whole-body weakness, which has actually caused her to fall. She has been treated with paroxetine since she was about 24 years old. She also takes amphetamines/dextroamphetamine, extended release 30 milligrams each day. She has been on that for the last couple of years for her sleepiness. In the last couple of months, she says her mood has improved and the paroxetine was stopped three weeks ago. Since then, she's had three episodes of weakness which are really very striking. She says each one lasts about 30 to 60 seconds. With the first couple episodes her head slumped forwards, her speech was slurred, and with the third episode, she was joking with a friend, and she got so weak that she actually had to slump into a chair and she could not even stand up for a minute. She found these extremely bizarre and frightening. She is also not terribly happy with the amphetamine/dextroamphetamine because she thinks it makes her lose her appetite. She has had some weight loss with it. She also thinks it's causing headaches, a racing heart, and irritability. She also has anxiety and she's taking alprazolam and buspirone for that. As far as her past history I mentioned she's had depression for the last three years or so, she has got anxiety and she has daytime sleepiness. No illicit drugs, no alcohol, she's married, she has a couple of kids, her labs are all fine.

Thomas E. Scammell, MD reviews the history and current symptoms of a patient with narcolepsy.

Patient Case #2: 27-Year-Old Woman With Cataplexy

Let's talk about some of the newer medications in the last couple of years; solriamfetol and pitolisant have been approved by the FDA as well as a lower sodium version of oxybates. Any thoughts on how these slot in amongst these other medicines?

 what is interesting about pitolisant is that some of their studies have also been done as a medication that's been used with others such armodafinil and even, I believe, sodium oxybate. I personally have added pitolisant on to some of these other medications such as modafinil rather than an amphetamine, for example. Maybe I would try that first, depending on cost and availability. I think same for solriamfetol. I usually don't use it together with another stimulant, but that may be my next one up for modafinil, maybe solriamfetol rather than amphetamine.

Is there advantages of solriamfetol in that regard?

 Well, I think that being more of a reuptake inhibitor, it is supposedly less, although there are cardiovascular side effects versus, there is this issue with blood pressure, but at least in my head, I think it may be less. Just based on that there may be advantages, but I don't know about the long-term data with solriamfetol. Maybe somebody else can comment on that, the abuse liability, etcetera. I'm not as clear, I would imagine it will be similar.

My impression is the abuse liability with solriamfetol is pretty low.

And I agree with you. At higher doses, especially, it can increase blood pressure a few points. But as a reuptake blocker of dopamine and norepinephrine, I think it is a bit less prone towards the somewhat large increases in blood pressure that you can sometimes see with amphetamines.

 That's probably why I would just use that as the second line after Modafinil. It's cost that is another issue, it is being able to prescribe that to your patients. Sometimes they make you try all these other things first.

Dr. Moawad, you have some thoughts? Yes, go ahead, Dr. Benca?

 Well, as I mentioned earlier too in patients where you're concerned about substance abuse potential, and you want to stay away from amphetamines, these are also things to consider.

Have any of you encountered actual drug abuse with pitolisant, solriamfetol, or oxybate?

 I have not with the pitolisant or sodium oxybate. Not sure about solriamfetol, I just don't have enough of an experience with that, but not really. I've had patients say, “well, maybe it doesn't work even at higher doses,” and then go to the next thing. I have not seen them abuse it or go to higher doses. I have not seen that.

Thought leaders consider the role of newer medications in the therapeutic landscape. 

New Directions in Treatment

Dr. Moawad, what do you see are some of the challenges with these traditional medicines regarding abuse or side effects and so forth? What are the biggest pitfalls and concerns in your mind?

 I have, unfortunately, heard patients talking about sharing medications with friends or family members who are not given those prescriptions. Sometimes, also diagnosing friends or family members and saying. I have heard from people who have said, “I tried it, because my roommate took it or a family member took it, and it worked. So maybe this condition is what I have,” and working backwards. That is one problem. Also, potentially inconsistent use is another thing; someone might be feeling better one week so they stop taking it or do not take as much. Self-regulating can end up being problematic. Some people will report that they self-regulated or shared but some people do not necessarily share that information as willingly.

I think that once somebody gets on a good regimen, they appreciate the benefits of those promoting medicines enough that they are motivated to take it consistently every day. But certainly stopping some medicines or taking them intermittently—such as if somebody is taking an antidepressant for their cataplexy –can be a catastrophe with rebound cataplexy. Dr. Benca, Dr. Zee, what do you think? More comments on abuse or side effect issues that come up?

 Well, I think one thing to keep in mind, since we are talking to a psychiatric audience, is that many psychiatrists are very comfortable prescribing large doses of amphetamines for things like attention deficit disorders and hyperactivity disorders. We are cautioning to be a little bit more careful with these medications. Keep that in mind as well.

 I think that cardiovascular side effects potentially from the amphetamines are foremost in my mind, especially if it is a chronic disease, a chronic disorder. We are going to be taking care of these patients for a long time as they get older, middle aged and so forth. That is something that weighs on me when I start somebody on one of these types of medications. Not so much with sodium oxybate. We're talking about the amphetamines.

You are probably familiar with the papers by Yves Dauvilliers showing that just having narcolepsy itself predisposes people to hypertension. When you add on some of these sympathomimetic medicines, I think you can get into some pretty good concerns there.

Thomas E. Scammell, MD; Heidi Moawad, MD; Phyllis C. Zee, MD, PhD; and Ruth Benca, MD, PhD, discuss abuse, side effects, and other obstacles associated with traditional medications.