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Antidepressant augmentation is a common practice, and there are many strategies from which to choose. The 

 recommends a menu approach that encourages patients to collaboratively choose an option that best fits their needs.

 In addition to psychotherapy and lifestyle approaches like aerobic exercise, they recommend augmentation with:

1. Natural treatments: omega-3 fatty acids, L-methylfolate, or light therapy

2. Antipsychotics: aripiprazole, risperidone, or quetiapine

3. Antidepressants: bupropion, imipramine, or mirtazapine

When rapid relief is the priority, an antipsychotic might be the best choice. For favorable tolerability, there is bupropion or a natural therapy, and lithium has strong antisuicide effects, if that is a concern. But what if insomnia is the chief complaint? Mirtazapine is tempting here, but this medication carries a risk of weight gain and did not perform well in several recent, well-designed augmentation trials.

 Instead, a standard hypnotic may be a good option when patients continue to have depression and insomnia on an antidepressant, but not just any hypnotic.

Eszopiclone: The Science Behind Its Potential Effect on Depression

In the early 2000s, a group of sleep researchers set out to investigate whether hypnotics could improve mood in patients with depression and insomnia. The results did not pan out exactly as expected, but they point the way toward a medication with unique potential in depression.

But first, investigators had to overcome a hurdle. At the time, it was thought that hypnotics might cause depression through their sedative effects. That concern was partly put to rest in a 1999 study that tested whether zolpidem could relieve selective serotonin reuptake inhibitor [SSRI]-induced insomnia in patients who had otherwise recovered on the antidepressant. The sleep problems improved with zolpidem and, to the investigators’ relief, the sedating medication did not worsen depression.

Buoyed by this result, the manufacturer of eszopiclone funded a large trial to see if depression might actually improve with their hypnotic. Five hundred and forty-five patients with depression and insomnia were randomized to receive either eszopiclone 3mg or placebo while simultaneously starting a trial of fluoxetine. As expected, the hypnotic improved sleep, but it also improved mood symptoms that were unrelated to sleep. Compared to placebo, those who received eszopiclone experienced a more rapid and complete recovery from depression.

The same group repeated the study with zolpidem ER in a large trial of similar design. Once again, the hypnotic improved sleep, but this time there was no change in mood.

 Replication in China brought the same negative results, and last year zolpidem failed again to lift mood or reduce suicidality when added to an SSRI in a randomized trial of patients with depression, insomnia, and suicidality.

Meanwhile, eszopiclone repeated its success, improving mood and insomnia in 2 additional trials, 1 of which involved peri- and postmenopausal women with insomnia and depressive symptoms.

 Generalized anxiety disorder also improved when eszopiclone was added to an SSRI in a large manufacturer-supported trial that replicated the design of eszopiclone’s pivotal depression trial.

Both the zolpidem and eszopiclone studies involved many of the same investigators, who had pursued this work with the idea that any hypnotic that improved sleep would indirectly improve mood. But to this day eszopiclone remains the only hypnotic with distinct antidepressant effects (ramelteon has mild preventative benefits in bipolar disorder but is not known to treat depression).

 Whether this is a statistical fluke or a true difference is difficult to say, as eszopiclone has not gone head-to-head against other hypnotics in depression. However, eszopiclone does have a unique mechanism of action that might explain its antidepressant effects. To understand that we need to turn to the GABAA receptor.

Compared to the benzodiazepines, the z-hypnotics have more limited effects on GABAA, which is thought to explain why they treat sleep but not anxiety. Specifically, the z-hypnotics are selective for the sleep-inducing GABAA α-1 subunit, while benzodiazepines have additional effects on the α-2 and -3 subunits that are involved in anxiety and depression. But eszopiclone is an exception. It acts at all of the α subunits, and may actually be a little more selective for the anxiolytic α-2 and-3.

 This effect is furthered by eszopiclone’s active metabolite, desmethylzopiclone, which is a selective partial agonist at α-2 and -3 with very little α-1 activity (that is a good thing, as it would otherwise cause a lot of daytime sedation).

 In animal models, desmethylzopiclone reduced anxiety without causing sedation or motor impairment.

 Its effects in humans are not well described, but the trials above give us a hint, and the company that launched eszopiclone has patented this metabolite as a potential anxiolytic.

In this way, eszopiclone resembles the benzodiazepines, which have been used to treat depression and hasten the response to antidepressants in over 3 dozen controlled trials.

 In most of those trials, their antidepressant effects were independent of their anxiolytic effects, just as eszopiclone treated symptoms of depression that were unrelated to sleep.

Despite this research, benzodiazepines are not used routinely for depression because of their risk of tolerance and abuse. Those risks may also apply to eszopiclone, but the trials above provide some reassurance. In several of them, eszopiclone was replaced with a placebo after 2 months of treatment without any loss of the antidepressant and anxiolytic gains. Nor was there any rebound insomnia and, in some studies, it stabilized sleep patterns in a way that continued after the hypnotic was stopped.

Does all this elevate eszopiclone to the level of antidepressant augmentation? Possibly. It does have more positive results than some the augmentation strategies that are endorsed by evidence-based guidelines.1 But there are 2 caveats. First, eszopiclone was only studied in patients with comorbid insomnia, but this is not a major hurdle as it is the rare patient with depression who does not struggle with sleep (about 15%).

 More significantly, eszopiclone was started in tandem with an antidepressant in these augmentation trials, so we do not know if it could turn things around when added later, after a few antidepressant failures.

When selecting a hypnotic in depression or generalized anxiety disorder, eszopiclone should be on the list. The treatment need not be long-term. Most patients were able to taper off the hypnotic after recovery. To bolster those odds, start out with the expectation of short-term use and guide the patient toward 

is the Mood Disorders Section Editor for 

 He has written several books on mood disorders, most recently

 with his cohost Kellie Newsome, PMH-NP. The author does not accept honoraria from pharmaceutical companies but receives royalties from PESI for

The psychopharmacology algorithm project at the Harvard South Shore Program: an update on unipolar nonpsychotic depression.

Mirtazapine augmentation: Running low on rocket fuel.

. September 2019. Accessed August 27, 2021.

3. Asnis GM, Chakraburtty A, DuBoff EA, et al. 

Zolpidem for persistent insomnia in SSRI-treated depressed patients.

Efficacy and tolerability of Z-drug adjunction to antidepressant treatment for major depressive disorder: a systematic review and meta-analysis of randomized controlled trials.

5. McCall WV, Benca RM, Rosenquist PB, et al. 

Reducing suicidal ideation through insomnia treatment (rest-it): a randomized clinical trial.

6. McCall WV, Blocker JN, D'Agostino R Jr, et al. 

Treatment of insomnia in depressed insomniacs: effects on health-related quality of life, objective and self-reported sleep, and depression.

7. Joffe H, Petrillo L, Viguera A, et al. 

Eszopiclone improves insomnia and depressive and anxious symptoms in perimenopausal and postmenopausal women with hot flashes: a randomized, double-blinded, placebo-controlled crossover trial.

. Eszopiclone coadministered with escitalopram in patients with insomnia and comorbid generalized anxiety disorder.

Melatonin receptor agonists-ramelteon and melatonin-for bipolar disorder: a systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials.

. Searching for perfect sleep: the continuing evolution of GABAA receptor modulators as hypnotics.

Molecular actions of (S)-desmethylzopiclone (SEP-174559), an anxiolytic metabolite of zopiclone.

12. Carlson JN, Haskew R, Wacker J, et al. 

Sedative and anxiolytic effects of zopiclone's enantiomers and metabolite.

13. Benasi G, Guidi J, Offidani E, et al. 

Benzodiazepines as a monotherapy in depressive disorders: a systematic review.

Wisniewski SR, et al. Insomnia in patients with depression: a STAR*D report.

A hypnotic might be a good option for augmenting depression treatment, but which hypnotic has the best evidence for efficacy? 

An Overlooked Strategy for Antidepressant Augmentation?

 What advice do you have for community-based psychiatrists treating patients with narcolepsy? What would you tell them? How should they interact with sleep specialists?

 They need to find 1 they’re comfortable with. They need to start thinking about sleep issues on any of their resistant psychiatric patients, whether it’s depression, anxiety, or schizophrenia. The studies on people who have schizophrenia and narcolepsy have shown that those patients often don’t respond well to antipsychotics. But if you diagnose the narcolepsy and you treat them with a little stimulant and an antipsychotic, they get better. When they’re seeing resistant anything, they should be thinking sleep disorders.

It’s important to not assume that it’s probably their medicines or that they’re way better than they used to be. How much better is better enough for these patients? If they come in and you think they’re schizophrenic and you’ve gotten them to this point and they’re doing better, is that as good as it gets if they’re sleepy every day or they sleep 12 or 13 hours a day? They may not be hallucinating, but they’re still sleeping a lot and napping every day. It could be the medicines, but could we get them better?

It’s the same thing with depression and treating depressed patients. You’re often treating their cataplexy whether you know it or not. They may not come and say, “I have sleepiness, I have cataplexy,” because they’ve been on antidepressants for a long time. The only symptom you may get in a depressed patient at a psychiatric office is the excessive daytime sleepiness. Educating all the providers, even the therapist, about this excessive daytime sleepiness or whatever they call it—I’m tired, I can’t wake up, I can’t get going in the morning—is important. This symptom needs to be a serious symptom that we address, and we look for sleep apnea, narcolepsy, and what medicines we’re using.

 One hundred percent yes. Exactly. Not everyone is going to be doing an Epworth Sleepiness Scale in their office—not a psychiatrist, not a neurologist. But if you can identify a patient, they’re not going to say, “I’m sleepy,” but they may say, “I’m tired, I’m fatigued, I’m unmotivated.” They have inertia. That’s your chance to step in and look for something else that might be going on. It doesn’t mean narcolepsy. You could have sleep apnea that’s impacting you to a degree. But the point is to make an intervention at that point with our resistant patients. You can really make a difference in their lives.

 Yes. Restless leg syndrome is a huge 1 in the psychiatric world. Not only do the patients have it, but a lot of our medicines increase it. When they take the medicine is so important. Psychiatrists at community-based facilities need to be looking at that, what medicines you’re giving them, and when you’re giving them. Are they taking any vitamins? Is there magnesium? There are a lot of behavioral treatments for every 1 of our sleep disorders.

 Absolutely. It’s important to work together with psychiatrists, neurologists, and primary care physicians in the community. As you said, this is why I love doing these programs. We’re educating and getting the word out there to keep an eye out for patients in your practice who likely have sleep disorders. We know that probably 1 of 2 people walking on the street has a sleep issue of some sort.

 They’re prevalent, and in today’s day and age and our society that we live in with screens and our lifestyle, it’s gotten worse.

 Absolutely. And insomnia. I do a lot of insomnia. But it’s not just a medicine—an Ambien or Lunesta treatment. There are usually so many other reasons. Even the patients with narcolepsy have a lot of insomnia and disrupted sleep. I’ve had a sleep physician tell a patient, “You can’t have narcolepsy, because you have insomnia,” and I’m like, “That’s not true. You have disrupted sleep and disrupted wake. What you have with narcolepsy is a disruption.”

 It’s not just your daytime sleepiness. It happens at night too, because your brain is confused about sleep and wake. Absolutely. Great points.

We’re at the end, and I want to thank you for participating in this program. I really appreciate the dialogue we’ve had. Hopefully this will help our psychiatrist colleagues and other doctors in identifying narcolepsy and psychiatric comorbidities and getting these patients adequately treated. Thank you for watching this 

 program. It’s been an excellent discussion. Hopefully you’ll find it useful to your clinical practice. Thank you so much.

Dr Stultz has disclosed that she serves as a consultant on the advisory board for Harmony Biosciences and that she receives support in her role with the speaker’s bureau for Harmony Biosciences and Jazz Pharmaceuticals.

Dr Singh has disclosed that he serves as a consultant and receives support in his role with the speaker's bureau for Jazz Pharmaceuticals and Harmony Biosciences. 

In this custom video series, Debra Stultz, MD, and Haramandeep Singh, MD, share advice for community-based psychiatrists on the management of narcolepsy.

Narcolepsy Treatment Advice

 What are some of the common challenges and unmet needs you face when treating patients with narcolepsy?

 Education is the key. We need more resources for the families and patients that are written on their level, because the family members really don’t understand it. The patients will come to the office, and they may get the diagnosis. They get excited and start looking it up online. The family members may not always do that. Just the other day, a patient I’ve treated for some time for narcolepsy kept saying, “My husband doesn’t understand it.” I said, “Bring him in. This is perfect, we’ll do a little family therapy thing.” It was helpful, but it’s going to take time. We need more education and support for the other people involved in the narcolepsy world.

We need more education for primary care providers and even sleep doctors about when to order tests for narcolepsy, the symptoms to look for, and what to order. We need to start with the patient, look at their family, and look at their providers. We need a lot for this diagnosis to keep moving forward.

 No doubt. I like that point about primary care providers and even sleep specialists, who just say, “When can we think about making the diagnosis, getting the MSLT [multiple sleep latency test] done, and even looking at ancillary symptoms of narcolepsy—sleep paralysis, hallucinations, automatic behaviors, cataplexy—and documenting that in your chart?” It’s the little things like how long you’ve been sleepy. It doesn’t take a lot. It just takes that extra few minutes to explore a little more of your patient and what’s happening for them. Those are the unmet needs.

We talked about how we definitely have options in terms of treatment, and those are going to continue to expand, which is great. We’re looking at other options coming out in the future as well that may be useful.

 Yes. We should be screening for all sleep disorders when the patient first comes in the sleep laboratory, and not just snoring. We need to carefully look at restless leg syndrome, whether you’re kicking in your sleep, whether you have sleep paralysis and the hypnagogic hallucinations. We should have a good sleep screener, and the sleep history should be an important part of dictating even a regular sleep study. Oftentimes, the primary care doctor says it’s excessive daytime sleepiness, and the patient thinks they’re getting an extensive sleep review. If they just get back a piece of paper that says they don’t have sleep apnea, then where do they go?

Or maybe they’ve had an MSLT before and they say, “I had that test, I don’t have narcolepsy.” That’s not true either. MSLTs are like EKGs [electrocardiogram]; it’s not 1 and you’re done. You wouldn’t say, “I had an EKG about 10 years ago. My heart is fine.” You’d say, “You need to do another EKG.” The same is true of you needing another MSLT. We need to look at this again. We need to make sure we study you during the MSLT off certain medicines, or considering certain medicines if you’re still on them, and that may not have been done when they had an MSLT before.

 Great points. I often comment that we’re doctors, so we should be looking at the patient holistically and not just following 1 test. You come back with a negative test, and that’s where our patients get lost. They’re like, “I’m still tired. It’s 10 years later, and now I’m depressed and unmotivated, and I can’t focus.” This is where we miss the boat. We have to holistically look at the patient and use the test as a guidance. Maybe we need to repeat the test and think about other options. I appreciate those points.

In this custom video series, sleep specialists discuss common unmet needs and challenges when treating patients with narcolepsy.

Unmet Needs in the Treatment of Narcolepsy

 In terms of the roles and responsibilities of the neurologists and psychiatrists in narcolepsy treatment, what are some of the challenges that arise in having multiple perspectives on 1 patient? If the psychiatrist sees a patient for comorbid depression, what are some challenges that come with that?

 I’m sorry, did you mean challenges with different providers?

 Yes, with a neurologist and psychiatrists who may have different perspectives on the same patient.

 Sometimes there are some issues. You have to have somebody who’s the captain of the ship when you’re treating narcolepsy. That’s probably the person who diagnoses it if they’re comfortable with treating that and using the medicines. Some of my colleagues who are sleep doctors or pulmonary doctors don’t do a lot of narcolepsy and are more than happy to send the patient with narcolepsy or insomnia to me because I’m used to these medicines and how we prescribe them. In that case, they’re saying, “You do this, and if you need me, let me know.”

I’ve also had sleep doctors refer to me and say, “I want you to treat the depression before I treat the narcolepsy,” I say, “We probably should go in with both at the same time. I’ll treat the depression, and I’ll treat with something that might help some of these symptoms, but we need to treat the narcolepsy too.” Sometimes there’s thinking, “What can we do to get this patient better faster?” In my opinion, it’s usually treating both.

If there’s cataplexy and other hints of neurological things, then we need a neurologist to help us look for secondary causes of narcolepsy that we might not be thinking about. Do they have MS [multiple sclerosis] or Parkinson’s disease? One of my other favorite things to monitor for is head injuries. A lot of our patients with narcolepsy have a past history of some head injuries. Did that play in? Having a neurologist on board is very helpful. We have to decide who’s going to treat what so that we’re not doubling up on medications, or even with the primary care provider.

One of the things I’d mention about pitolisant, when we were talking about the first case, is that we always have to tell the patients, “You need to tell me if you change any medicines, and you need to tell your primary care providers that you’re on this medicine.” I had a patient who was on an antidepressant and was on the lower dose of pitolisant. She was doing great, so I didn’t see her for 6 months. When she came back in, I asked, “How are you doing?” She said, “I’m doing pretty well, but I had some depression, so my primary care provider started Wellbutrin.” Then we had the patient on 2 antidepressants and pitolisant that could affect the 2D6. It’s also important to let the primary care doctor know what you’re doing and who’s doing what so that we’re not all throwing things in there.

 Great point. That communication among other providers is so important. I like the comment about the captain of the ship. If you’re the expert in treating this, then it’s your responsibility to take the reins and say, “I’m going to treat the narcolepsy.” I have a lot of doctors who I work with who are psychiatrists and neurologists. When they’re treating something else, whether it’s depression, anxiety, or whatever else is going on for the patient, they should continue that role, but let me be the 1 who’s treating the narcolepsy. The education, communication, and dialogue among doctors is so important.

 We need psychiatrists and therapists involved in treating narcolepsy because we often have a patient who’s had symptoms and excessive daytime sleepiness or cataplexy for years, and it’s greatly affected their life, failures, disappointments, and not understanding. They may get the diagnosis of narcolepsy and be all excited that somebody figured it out. Initially, it’s relief. But then they start looking at the way life could have been better had somebody caught it 10 years ago. They look at their relationships and the ballgames they missed for 8 to 10 years of their kids’ childhood. There’s a grieving process that happens with narcolepsy. They may have depression for years for a variety of reasons, but then there’s some stuff that goes on once you get the diagnosis and you start treating. Having a psychiatrist or therapist on board for treating narcolepsy is invaluable for the sleep physician or neurologist who’s treating a patient with narcolepsy with just the medicines.

 Absolutely, I agree 100%. The more you get in terms of mental health providers who can help in managing a chronic condition in general is a huge benefit.

 That’s right. These patients with narcolepsy will wake up and suddenly have more energy, and they’re excited about life. They start trying to make some changes and will do this and do that. Everybody else in their world is like, “We’ve been doing fine on our own here.” The change and relationship issues are often hard. There’s a whole dynamic to the diagnosis of narcolepsy for not only the patient, but also the significant other, children, and even work.

 Good point. Many times, I’ve heard the patient with narcolepsy get branded as being lazy or not motivated. That branding gets put into the family member and the spouse. They have to have the education. Therapy is such a useful part of that process as well in helping them with the family situation.

 Right. The self-esteem stuff starts at a very young age. These sleepy kids go to school and have trouble with grades, get to school late, miss school a lot, or get in trouble because they’re fussy and irritable. The self-esteem stuff starts then.

 Exactly. As we know, that’s when it starts. We know that the amount of time it takes for the diagnosis of narcolepsy is often 15 to 20 years before the patients are recognized. Their symptoms started way back when. We know with sleep disorders it takes a long time in general, but with narcolepsy especially it takes a long time.

In this custom video series, Haramandeep Singh, MD, and Debra Stultz, MD, discuss the roles and responsibilities of sleep specialists, neurologists, and psychiatrists in the management of narcolepsy.

Role of Specialists in Narcolepsy Management

 When you’re considering choosing a treatment regimen, what patient factors and symptoms come into play? How is the patient involved in that process in terms of choosing a treatment for them?

 That’s very important. The way I choose a lot of times is based on what the coexisting thing is. If they use alcohol, then I’m going to stay away from sodium oxybate, unless they’re drinking once or twice a month. Then you can hold your Xyrem that night and still be OK. But if they’re drinking pretty regularly, that’s not a medicine I’m going to use.

If they have a lot of anxiety, then I’m going to try to steer away from the stimulants that might cause more anxiety. If they have coexisting depression and cataplexy, I may go with more of the traditional antidepressants that might treat the symptoms. If they have trouble remembering to take medicines, then I’m going to use something that’s once a day in the morning. If they say, “I’m so rushed when I get out, I probably wouldn’t remember a morning medicine,” then I’m going to start looking to use 1 of the bedtime medicines that could treat the sleepiness and cataplexy. If they have cataplexy, as we talked about earlier, pitolisant or sodium oxybate would be a good choice because that would kill 2 birds with 1 stone. My decision is often based on what else is there.

 Absolutely. Having that conversation with a patient in terms of their other symptoms and their lifestyle is really important.

 It’s exactly as we saw in that 20-year-old college-age student who is probably going out a few times a week, so it makes it clear for us that we want to try to use something that’s got less of a controlled substance. We want to avoid sodium oxybate. But then there’s the patient who has had a multitude of trials with modafinil, with stimulants. They tolerate them; they’re still sleepy. We know that with some of our narcoleptics, they need to be on 2 or 3 medications to get relief. Sometimes we’ll add pitolisant, or Wakix, on top of that, or add sodium oxybate, or taper them off 1 and get them on that. I appreciate that, in terms of the conversation you’re having with them.

 Yes. The majority of our patients with significant narcolepsy end up on a combination of medicines. When you think about it, we’re looking at different neurotransmitters and symptoms. We mentioned the birth control pill earlier. You can have trouble with the birth control pill with not only pitolisant but also modafinil and armodafinil. So maybe Sunosi is the choice there. If it’s a young woman of reproductive age, I’ll have the talk about that. They may be fine with taking that medicine while practicing safe sex, so we’re fine. But I have that discussion.

It depends on age, sex, who’s taking care of it, and who else lives in the family. I have patients who have narcolepsy, but also have a substance abusing child living at home. In those situations, I don’t want anything else. Even though they’re going to try to lock it up, I don’t want anything else there that can contribute. Even if my patient isn’t a substance abuser, I usually ask who’s at home. I want to make sure we’re not leaving medicines around. That could play into the decision as well.

 Absolutely. That conversation is so important in terms of delineating your therapy. Another area is Sunosi is cleared by the kidney, so if you’ve got a patient who’s on multiple other medications catalyzed by the liver, that’s another area where you could think about Sunosi. I’ve had young women with young children at home who may not want to take so much sodium oxybate at night, [to the point that] they feel as if they can’t wake up in the mornings. All these things, and having that conversation, are really important.

The good thing we find in today’s day and age, and what we’ve lacked in the past, is that we have options. This is an area in which we’ve finally gotten more standard of care. The AASM, the American Academy of Sleep Medicine, has made it clear that these are standards of care we should consider when we’re treating our patient.

 Yes. We’ve been so lucky in the field of narcolepsy. I’ve been doing sleep medicine for years, and narcolepsy has been my favorite disorder to treat. But for years, nobody was talking about it, and we didn’t have a lot of options. Then it just exploded with options. The wonderful thing about that is we’re getting the word out about narcolepsy to patients. Even if the providers are not as informed about narcolepsy, the patients are coming in saying, “I might have this,” or “Can we try this medicine?”

 I love what it’s done to education of society.

In this custom video series, experts in sleep medicine discuss patient factors and symptoms they consider when selecting optimal treatment regimens for patients with narcolepsy.

Approaching Treatment of Narcolepsy

 What are the other main common psychiatric comorbidities that you find with patients who have narcolepsy?

 Depression and anxiety for sure, along with panic and PTSD [post-traumatic stress disorder]. A lot of the psychiatric disorders can have narcolepsy or narcolepsy-like signs and symptoms. One of our landmark studies over the years has been the Burden of Narcolepsy Disease study by Dr [Jed] Black and associates. They looked at what kinds of illnesses are associated with narcolepsy, and psychiatric illness was at the top of the list at 31%, followed by GI [gastrointestinal] disturbances and then neurological things. At least a third of the patients with narcolepsy had some kind of psychiatric illness, whether it was depression or anxiety or panic attacks.

There’s a lot of social anxiety in patients with narcolepsy, especially if they have a large component of cataplexy, because they’re fearful that they might get out and have an episode and would be embarrassed, or they go out to eat and get extremely sleepy, like can’t-hold-their-head-up sleepy. They have a lot of anxiety about going to certain restaurants and around a lot of crowds or people they don’t know very well. There’s a lot of depression and anxiety.

 I absolutely agree. One other one I’d mention here is ADHD [attention-deficit/hyperactivity disorder]. Sometimes patients who have sleep disorders in general and narcolepsy because they’re not sleeping well, they can’t focus, they can’t concentrate, and they can’t remember. We often find that they come to us already on stimulants for ADHD, when they actually have a sleep disorder.

 Right, it’s not treated. When we look at the medical disorders, it’s associated with all our sleep disorders too, like sleep apnea, periodic limb movement disorder, and restless leg syndrome. Sleep apnea is another place where we need to be sure and address if there are any narcolepsy symptoms present, because it’s estimated that about 30% of patients with narcolepsy can have coexisting sleep apnea, and 5%— some of the later studies say up to 30%—of patients with sleep apnea can have narcolepsy. Once they’ve had 1 sleep study, it’s not 1 and done with your diagnosis or treatment.

 Thank you for bringing that up, because even in that Burden of Narcolepsy Disease study, we find that outside psychiatric comorbidities, the highest was sleep apnea.

 With our patients who have sleep apnea, we often get tuned in to treating them with a CPAP [continuous positive airway pressure] machine and adjusting pressures, and we miss the fact that they’re not responding to treatment or they’re partially responding and they pull more to narcolepsy, which is so common.

 I absolutely love modafinil, armodafinil, and Sunosi in the treatment of excessive daytime sleepiness of sleep apnea. Modafinil and armodafinil have especially moved us in the sleep world an incredible amount in helping people out. But I also think we’ve half-treated narcolepsy. With some of these people who have coexisting disorders, we’ve treated a lot of their sleepiness. Now we have patients presenting to us who have narcolepsy, and their sleepiness is fairly well controlled, but they have cataplexy. They may go to the neurologist or psychiatrist because they have these weird symptoms. They think it must be psychiatric, and that it’s something in their head, and it may be that the other medicines have helped with the excessive daytime sleepiness, but now the cataplexy is the most prominent thing.

 Great point. I saw a patient the other day who was treated with modafinil and armodafinil for daytime sleepiness from OSA [obstructive sleep apnea]. But they were just missing the cataplexy that she had. It was subtle, it wasn’t happening, and eventually those medicines wore out and she really needed to get on something that was more tuned in to her cataplexy as well as her CPAP. She continued to use her CPAP, and then getting on something like sodium oxybate or pitolisant made a big difference for her.

 Right. I’m pretty fixated on looking for sleep and psychiatric stuff from the very beginning. That’s what I tell the students who rotate with me. You can’t tease them out in the world that we live in. Usually there’s a screener where patients fill out an extensive questionnaire, but I ask every psychiatric patient about sleep stuff and every sleep patient about psychiatric stuff. I do because I don’t think you can exclude those 2.

In this custom video series, Debra Stultz, MD, comments on common psychiatric comorbidities seen with narcolepsy and the impact on a patient’s quality of life.

Psychiatric Comorbidities Common in Narcolepsy

 Let’s go on to our next case. This is a little more complicated, but it’s a real-world scenario. I’ll describe the case to you. This is a 23-year-old man with a diagnosis of schizoaffective disorder. He was diagnosed a few years back. He had hypnagogic hallucinations while falling asleep and getting up from sleep, in addition to possible delusions. At that point, the diagnosis of schizoaffective disorder was made, and he was started on olanzapine, which improved his psychotic symptoms, but he continued to be sleepy and have sleep fragmentation at night. He continued to wake up a lot and have a hard time going back to sleep. He had frequent awakenings. He was then referred for additional medical evaluation and testing, and at that point, they made a diagnosis of narcolepsy. He had a PSG [polysomnography] and MSLT [multiple sleep latency test], and then diagnosis was made.

We’ve heard this type of case before, in which people have psychiatric symptoms, comorbidities, depression, anxiety, and sometimes hallucinations and are diagnosed with psychiatric disorder. But is narcolepsy comorbid with that psychiatric disorder? Is it the main diagnosis? That’s what we’re trying to figure out in this particular patient. I’d love to hear your overall impressions about this case as well.

 Right. It’s interesting. Narcolepsy is often misdiagnosed as schizophrenia, especially in the younger kids, because you’re hearing voices and stuff. But those 2 can co-occur, and you may have symptoms of both disorders, like in this case. It’s very interesting. It’s important to get the history of when the symptoms started and what was going on with the patient, along with family history to help you make the differential of whether it’s truly a psychiatric disorder or narcolepsy.

Narcolepsy runs hand-in-hand with multiple psychiatric disorders. The studies on schizophrenia and narcolepsy are pretty varied. Most of the studies say anywhere from 4% to 8% of people with schizophrenia can have narcolepsy. Some studies have said up to 14%. It’s important for us to start thinking about that and look for those symptoms in our patients with schizophrenia. I don’t treat a lot of schizophrenia in my office because of the nature of the practice that I have, but that’s a great point for us to make to the mental health centers and to be educating them about what to look for.

 I can’t say it enough in terms of the misdiagnosis. What happens is a lot of these patients present with psychiatric symptoms like hallucinations and then get funneled, and that’s all we think about. We forget about the daytime sleepiness and the fatigue that’s happening over the years. We need to try to focus in on that part of our history too, and figure out if this person has a sleep disorder and if that’s what we need to target. If we can educate practitioners and say, “Let’s look at getting sleep evaluated as well,” it will be beneficial for patient diagnosis and long-term outcomes.

 Absolutely. That’s why I love doing these teaching talks, because we really have to educate people about all sleep disorders. Especially narcolepsy—in our own practices and in our own psychology and neurology fields—because it’s missed. It’s sometimes hard. If you look at schizophrenia and narcolepsy, they both can have sleepiness. Schizophrenics can be very sleepy just from the medicines they’re on or the illness they have. It may be that they have other sleep disorders, because patients with schizophrenia can have restless leg syndrome and periodic limb movement disorder, just like patients with narcolepsy can have. Some of the medications that they’re on can cause restless leg syndrome and periodic limb movement disorder, so there may be other sleep disorders.

The hallucinations can be different and help you decide which 1 it is. If the hallucinations are more with going to sleep or coming from sleep, then you need to start thinking of narcolepsy. It wouldn’t just be at night, because patients with narcolepsy have naps during the day and fall asleep unintentionally, so they can have some hallucinations that occur during the day. You can’t just say hallucinations at night might be narcolepsy. But if it’s associated with a sleep period, then you might be thinking more narcolepsy.

When patients with schizophrenia hallucinate, they’re more auditory and associated with delusions. There are some other psychiatric symptoms. With patients with narcolepsy who have hypnagogic or hypnopompic hallucinations, they’re often visual or tactile. Patients will tell me they feel something, or they’re floating, or there’s a sense of rushing or looking from above. The narcolepsy hallucinations are often of a different type from the auditory condemning hallucinations of schizophrenia, and that may help you look toward if it’s 1 or the other.

 Excellent points. I really appreciate that, because it can absolutely help in clarifying the diagnosis and appropriate treatment.

In this custom video series, Haramandeep Singh, MD, and Debra Stultz, MD, discuss a case involving a 23-year-old man with schizoaffective disorder and newly diagnosed narcolepsy.

Case Presentation: Schizoaffective Disorder with Narcolepsy

 This patient was started on pitolisant. What are your thoughts on starting this patient on pitolisant?

 It’s a great option. You have a young patient who probably doesn’t have any other medical problems you can be concerned about. Also, pitolisant is a noncontrolled substance, so you’re not starting them on a stimulant or something you have to be concerned about. It’s a good choice in the long term. It’s easy to use, the patient doesn’t have to go to the pharmacy every month, and the doctor doesn’t have to write the script every month. It’s a good choice. The other thing is that the patient has excessive daytime sleepiness and cataplexy. With pitolisant and Xyrem, both medications can treat both symptoms, so you’re hopefully not going to have to use a combination to treat both symptoms.

 Later on down the road, if you do have to use a combination, pitolisant is OK to use with modafinil, sodium oxybate, or 1 of those other medicines. It’s a good choice.

 Yes, I agree with you, especially because this is a young patient. It’s so easy to use in terms of no-controlled. It’s the only FDA noncontrolled medication that’s indicated for sleepiness and cataplexy. Of course, a lot of these patients down the line may need combination, and we always have that option. Those are great points on using pitolisant.

After you start patients on pitolisant, how often do you monitor them, in terms of follow-up, adjusting the dose, and that sort of thing?

 At first, pretty frequently. One other thing I should have mentioned about this patient, is that because this is a young female patient, I would want to tell them early on that it could affect the birth control pill, even for 21 days after they stop it. I’d want to tell them up front, and then when I see them again shortly thereafter, I’d be sure to remind them that this is something we need to look for.

I’d see them back in 2 to 4 weeks to make sure they’re doing OK because we’re increasing the dose. After they get to the ultimate dose, I’d want to see them a few weeks after that, and then we can start extending the treatments.

 Yes, very good points about the oral contraceptive. There’s a theoretical impact there for sure, so it’s important to warn them about that. In general, do most of your patients on pitolisant get to a certain dose that you find effective?

 Yes. If I can, I push them to the higher dose and then warn them up front that this is a medicine that has to build up in your system. It’s like an antidepressant. It can take 4, 6, or even 8 weeks to build up in your system. A lot of my patients—and I’m sure yours too—are on antidepressants. They’re 2D6 medicines, so maybe we have to stop at the lower dose, wait there, and see how they’re doing.

 Yes. With some of the 2D6 inhibitors, we’ve got to be careful. Paxil, Prozac, and Wellbutrin are the most common in terms of that. Get up to 17.8 mg first, then see how they’re doing before making a change.

 Great. Thank you for your comments on that case. It’s a great case to talk about because it’s not common. A patient with narcolepsy with cataplexy is very typical and 1 we definitely don’t want to miss.

In this custom video series, Debra Stultz, MD, leads the discussion on the use of pitolisant as initial therapy for a patient newly diagnosed with narcolepsy and cataplexy.

Pitolisant in Newly Diagnosed Narcolepsy With Cataplexy

 When we talk about classic cataplexy, we know that cataplexy generally doesn’t present in this manner. I’d love to hear your thoughts on how cataplexy generally presents in your practice, how you recognize it, and how you differentiate from other diagnoses often given to these patients who may have partial cataplexy.

 I remember a very similar case from when I was in medical school. The patient had narcolepsy and fell on the floor. It was very dramatic. In my mind, I thought, “When I see that, I’ll know that’s cataplexy.” I’ve worked in sleep medicine for many years now, so I realize that cataplexy can present in a variety of ways and is often very subtle. The other thing that’s important to note is patients sometimes aren’t the best historians about cataplexy. They may not even realize that when they laugh or have a strong emotion, they’re doing something unusual with their face or they’re having a muscle collapse or something. Cataplexy is a symptom where if they say no, then I say, “I want you to think about this. I want you to ask the people around you.” Sometimes you’ve got to get third-party history to get the symptom of cataplexy.

Cataplexy is any muscle weakness with a strong emotion. It can occur with laughter and anger, which are the most common. But it can also occur with frustration, sexual excitation, disgust, being surprised. I’ve read that if somebody meets up with an old friend and they’re surprised and emotional at the same time, that can cause it. For other people, listening to music that’s very moving to them can cause some cataplexy. Music can move them. Any strong emotion that causes the muscle weakness is cataplexy.

The presentation is different for everybody. When I talk to my patients, I’ll ask them about cataplexy starting from the head and working my way down. Some have a strong emotion and have their head drop; that’s pretty common. But you can have drooping eyelids, blurred vision, or weakness in the tongue muscles. Sometimes patients will stutter. Weakness in the jaw is especially common in pediatric cases of narcolepsy, where the jaw thrusts forward and the tongue may protrude a little. It almost looks like Down syndrome. Other presentations can be shoulder weakness, arm weakness, weakness of the hand, buckling of the knees, and ankles getting weak. It can be very subtle or more dramatic. It can almost look like a tic. I call it a reverse of a tic, because they get the muscle weakness and then it comes back, so there’s almost a jerky quality. With any kind of unusual muscle movement, you should start thinking cataplexy.

 I appreciate that detailed response. I concur 100%. I’ve seen it all through the years. I had a patient the other day who told me that she was diagnosed with depression, but she told me that when she felt sad, she would have weakness in her trunk muscles of her abdomen and she’d keel over. You can see it in any manner. That’s where your radars have to be up. This is associated with any emotion that can cause weakness in any part of your body.

 If you’re very suspicious of it and you’re working on this diagnosis with the patient and they talk to their family, the family members can actually video with their phone. I’ve had patients bring it in, and I say, “Looks like that to me.” We’re really lucky with the electronics we have available that might be able to even see it, because it’s not often seen in your office.

 We’re lucky with today’s technology to be able to catch those things. It’s rare that you’re going to catch it in your office. It’s really important to get that history and document, with a detailed idea of what your patients are going through on a day-to-day basis in whatever aspect of their life that they’re focused on, whether it’s work or they have an incident of cataplexy at home. I appreciate your comments on that.

In this custom video series, experts in sleep medicine provide insight on ways cataplexy can present in patients with narcolepsy.

Presentation of Cataplexy in Patients With Narcolepsy

 program titled “Narcolepsy Management and the Roles Neurologists and Psychiatrists Play.” I’m Dr Haramandeep Singh. I’m a board-certified psychiatrist and a sleep specialist, as well as the founder of Sleep Medicine Specialists of California in San Ramon. Joining me is Dr Debra Stultz. She’s a board-certified psychiatrist and sleep specialist, as well as the founder of Stultz Sleep and Behavioral Health in Barboursville, West Virginia.

The goal of our discussion is to share insights regarding the management of narcolepsy, as well as offer recommendations on how neurologists and psychiatrists can work with sleep specialists in the management of this disorder. Welcome, Dr Stultz.

 It’s good to see you too. We’re going to start by reviewing a couple of case scenarios. I’ll describe the first case to you, and then we can discuss it.

 This is a case of a 20-year-old woman who was referred for excessive daytime sleepiness and sleep attacks. Her excessive daytime sleepiness began in her later teens. She continued to have difficulty staying awake while she was in class and during exams, and then she recently got into a minor car accident due to a sleep attack. She then began experiencing sudden physical collapse when she got angry or when she laughed. Her knees would suddenly buckle. Then she underwent a medical evaluation and some testing, and narcolepsy with cataplexy was diagnosed. She was started on pitolisant, which reduced both her excessive daytime sleepiness and her cataplexy symptoms.

This is a scenario of a young adult who struggled with chronic daytime sleepiness and presents with pretty classic cataplexy, and then is eventually diagnosed with narcolepsy with cataplexy. We don’t often see that to be the case. But that’s what happened, and she started on pitolisant. What are your overall impressions on this case?

 There are some pretty typical findings for narcolepsy. The excessive daytime sleepiness started, and several years later the cataplexy started, which is very common. As you said, she had some pretty classic cataplexy symptoms, which isn’t always the case. But the strong emotions of laughter or anger and buckling of the knees are the common symptoms of narcolepsy that we would love to see on a day-to-day basis, but that’s not always the case.

 Absolutely. I appreciate you saying that because this is a case that we’d love to have step in our office. Like, “You’ve got narcolepsy and we know it,” right? But the general doctor out there who evaluates this patient may be questioning what’s going on with this patient and may have some other ideas. At this point, generally speaking, who would a general doctor refer this patient to: a sleep specialist, a psychiatrist, a neurologist?

 It would be wonderful if they referred them to a sleep specialist. Typically, these symptoms will help them know that this is a sleep disorder and that you need to go to a sleep specialist. But not all sleep specialists are even comfortable with narcolepsy. A lot of sleep laboratories primarily treat obstructive sleep apnea and pulmonary issues, so you need to make sure you have a sleep specialist who’s comfortable talking about narcolepsy and looking at the other things. A sleep specialist would be a great place to refer the patient to, but someone who specializes in sleep in psychiatry or neurology would also be a wonderful place to refer the patients to. Regardless, somebody is going to need to order a sleep study.

To look at the symptoms and make sure you’re evaluating both the sleepiness and the cataplexy, you need someone who’s comfortable with sleep disorders in general, and the patient to describe all the symptoms to whoever the provider is going to be. For instance, if they show up to a pulmonologist and say, “I’m sleepy,” but don’t give the other history about cataplexy, then they may be going down the path of looking at obstructive sleep apnea. If they go to a psychiatrist and talk about the sleepiness, and then they say, “Do you have insomnia? That must be depression,” then they could go off in another direction for depression. It’s the same thing with neurology. If they just focus on the cataplexy, we might get lost. We’ve got to make sure to tell our patients that if primary care or a psychiatry practice doesn’t do a lot of sleep medicine, to make sure the patients present both of their symptoms so they can clearly get diagnosed and treated.

 Those are some great points. I appreciate you bringing those up, because when the evaluating doctor sees this patient, who they refer them to is going to make a huge impact in their outcome. It would be great if doctors can recognize sleepiness and say, “This is a patient who should have a sleep evaluation before anything else,” because then we can target them in the right direction and get them on the right treatment. It makes a huge difference, so I appreciate your comments on that.

In this custom video series, Haramandeep Singh, MD, and Debra Stultz, MD, discuss a case involving a 20-year-old woman newly diagnosed with narcolepsy and cataplexy, initial impressions, and appropriate provider referral.

Sleep Disorders