Separating Depression From Hypersomnia: David T. Plante, MD, PhD

Telling primary hypersomnia from sleepiness driven by depression often depends on the course of both illnesses and, when history is not enough, on sleep testing, said David T. Plante, MD, PhD, associate professor of psychiatry and medical director of the Wisconsin Institute for Sleep and Consciousness at the University of Wisconsin–Madison School of Medicine and Public Health.

In this interview with The American Journal of Managed Care^® (AJMC^®), Plante discusses which symptoms matter most to patients with idiopathic hypersomnia and narcolepsy, how he sequences oxybate and wake-promoting therapies when insurance requirements and comorbidities come into play, and what randomized withdrawal and open-label phase 4 data can show about efficacy.

This interview has been edited for clarity.

AJMC: Your research discusses both sleep medicine and psychiatry, specifically hypersomnolence in patients with depression. When a patient presents with both, how do you decide how much of the sleepiness reflects the mood disorder and how much reflects a primary disorder, such as idiopathic hypersomnia (IH) or narcolepsy, that needs its own treatment?

Plante: It's very challenging. There's a lot of overlap between what we call central nervous system disorders of hypersomnolence, like narcolepsy and IH, and mood disorders like depression that can also present with hypersomnolence. It is certainly a clinical conundrum. The things that I will often ask about are typical symptoms that may not be reflective of purely a depressive episode if someone's presenting with both sleepiness and depression. Certainly, things like cataplexy, which is the loss of muscle tone in response to emotional stimuli, can be much more suggestive of narcolepsy type 1 with co-occurring depression, but oftentimes that is not something that's as easily identifiable.

The things that I will often ask in history are about the course of illness. When I say that, I mean both the course of depressive symptoms and the course of sleepiness. If people have clear periods where they weren't sleepy and they weren't depressed, that is more suggestive of hypersomnolence associated with a mood disorder. On the other hand, if people have had chronic, unremitting daytime sleepiness and then episodic periods of depression mixed in, that, to me, suggests it may be more of a central nervous system hypersomnia. However, in reality, it's oftentimes very difficult to tease these things apart just by history alone because patients aren’t sure or don’t remember.

In those cases, we'll often use sleep testing to try to get a sense of how fast people fall asleep on the multiple sleep latency test, or MSLT, which is a nap paradigm. That helps us to distinguish between, or at least identify, things like IH and narcolepsy, and we are less likely to see as abnormal results in depression. However, the MSLT is far from a perfect test, and persons with depression can and do have abnormal MSLT findings, and in those cases, it's even harder to disentangle.

AJMC: In IH, excessive daytime sleepiness is only part of the picture, alongside sleep inertia, cognitive fog, fatigue, and longer sleep time. Which outcomes matter most to your patients, in both IH and narcolepsy, and how are they measured?

Plante: It's really hard to say what the most important symptom is across all patients because every patient is going to experience things a little bit differently. Daytime sleepiness occurs in everyone with IH, whereas some of the symptoms you've described, like excessive sleep inertia or prolonged sleep time, don't necessarily occur in every person. That said, when they do occur, they can be quite disabling and problematic.

If people can't wake up for several hours in the morning, it often leads to problems with the inability to get to work on time, missing work entirely, or even accidents on the way to work. Long sleep times can be really challenging as well. If people are sleeping 11 hours a day, it's really hard to get anything else done in your life, so that can be quite debilitating. When those things occur, they can be equally, if not more, debilitating than daytime sleepiness, but they don't occur in every single person with IH.

AJMC: Narcolepsy treatment now spans oxybates, such as Xywav (calcium, magnesium, potassium, and sodium oxybates), Xyrem (sodium oxybate), and Lumryz (sodium oxybate extended-release), as well as pitolisant (Wakix) and solriamfetol (Sunosi), but Xywav is the only one approved by the FDA for IH.¹ How do you go through these options, and what role do off-label agents play?

Plante: One class of agents you left out, which are also approved to treat narcolepsy and used quite commonly for both conditions, are modafinil and armodafinil. In terms of how I think about treatment, I look at what data are available and also try to have a pragmatic treatment plan for patients, because even if a drug is FDA approved, it doesn't necessarily mean that it's the right drug for someone, especially to go to right off the bat. There are certainly insurance requirements that oftentimes come up and substantially affect treatment planning. I also think about comorbidities that people may have that may guide us toward one agent or another.

In someone with narcolepsy, there are many different options available. Oftentimes, if we're targeting daytime sleepiness, separate from cataplexy, I will think about a wake-promoting medication like modafinil or armodafinil as a first-line option because they're usually reasonably accessible, they're generic, and they can be effective for some patients. One of the challenges with those medications is that they can have a drug-drug interaction with hormonal contraceptives, so they may not be a good option for women of childbearing age on hormonal contraceptives. It's not dangerous to take them concurrently, but modafinil and armodafinil can enhance the metabolism of the hormonal contraceptive, potentially making it functionally less effective, which obviously can have pretty significant impacts on people's lives.

I'll also sometimes use standard stimulant medications if needed, although some of that is driven not by clinical desire but, to be honest, insurance companies steering me toward those medications. They've been around for a long time. They certainly do have a place in the treatment of narcolepsy, but oftentimes, because there are several generic options available in that sphere, we may try those sooner rather than later, and occasionally as a supplemental agent taken as needed for breakthrough sleepiness.

Another branching point, besides whether people have cataplexy in the context of narcolepsy, is what their nighttime sleep is like. You mentioned the oxybates as a class. They tend to be compounds that can improve fragmented sleep, which can commonly occur in narcolepsy, whereas most of the other drugs are focused more on keeping people awake and alert during the day with minimal impacts on sleep, per se. Oxybates have some challenges, in that they're not the perfect medication for everyone, but they certainly can be helpful in the treatment of narcolepsy, and they help not just with daytime sleepiness but also with cataplexy. They're a quite robust anticataplectic agent, so if we can't get control of cataplexy with other options, like antidepressants, we certainly will consider oxybates.

Pitolisant, or Wakix, is also a very reasonable option. It's a unique compound because it's not a scheduled agent, and it seems to have no significant abuse liability. For patients who may have a history of substance use problems or a family history of addictions and are nervous about trying a stimulant medication or oxybate, it may be a really good choice. It's also approved to treat both daytime sleepiness and cataplexy. It can often be added on to therapy as well, because it tends to be prescribable with stimulants and oxybates, but it has a drug-drug interaction with hormonal contraceptives, similar to modafinil and armodafinil, that we have to be mindful of.

Solriamfetol, or Sunosi, is also a very useful wake-promoting medication that's not a stimulant, but it works on some of the same neurotransmitter systems. It can be more effective for some, and more tolerable than some of these other medications. In short, there are many options for treating narcolepsy that can be tailored to the individual patient.

For IH, it's less complicated because we have only 1 approved drug. However, it's more complicated because oftentimes insurance requires that we try different things for IH that may not be indicated. There is good data for the use of modafinil in IH. There are a couple of randomized controlled trials that have been done, so the evidence for its use is reasonable.² Oftentimes, as is the case for narcolepsy, we will use traditional stimulants, particularly if required to by insurance.

I think there's also some hesitancy among many providers to use oxybates for IH, even though Xywav is now approved to treat the disorder. I think some people are nervous, or they don't understand why you would give a nighttime, potentially sedating medication to people who sleep long amounts of time and are, if anything, maybe “too good” at sleeping. But the reality is, when you use it, it seems to be quite helpful with daytime sleepiness, and it also seems to help with sleep inertia, and it can even shorten the amount of sleep that people with IH are getting.³ It seems to improve the quality of sleep in people who have IH in ways that we don't fully understand at this point, but I think it is effective for several symptom domains. In my practice, I tend to use oxybates sooner in the treatment course now that there is an approved agent that shows sizeable efficacy in patients.

AJMC: The pivotal trials in both conditions used a randomized withdrawal design. In IH, the Epworth Sleepiness Scale and the IH Severity Scale scores stayed stable with Xywav and worsened with placebo,⁴ and in narcolepsy, cataplexy and sleepiness worsened with placebo.⁵ What does this design show you about these conditions?

Plante: Randomized withdrawal trials are a particular research design that allows you to try everyone who qualifies or enrolls on the active medication, and then, once people are stable, they are randomized to either placebo or to stay on the active medication, and they don't know which. What you're looking for is separation, or rebound worsening, of people randomized to placebo compared with staying on the drug. In the results of the studies you describe that's how efficacy is judged. People who stay on the study drug stay the same, but people who are randomized to placebo get worse on these different outcome measures, like the Epworth Sleepiness Scale and the IH Severity Scale. That's what you'd expect if the drug were effective.

There are nice benefits to a randomized withdrawal trial, including the fact that everyone gets to try the medication, and people who don't respond to the medication in an open-label phase don't have to continue with the trial, so oftentimes there are fewer patients needed in these rare conditions to understand if the medication is effective. One of the downsides is that it's sometimes hard to translate the findings directly to clinical practice, because it's a different design than might be typical for a standard double-blind, randomized, placebo-controlled trial.

AJMC: In the DUET study, patients with IH had a mean 8.4-point improvement on the Epworth Sleepiness Scale, and there were also improvements in sleep inertia and fatigue. In narcolepsy, the Epworth score fell 7.7 points, and 93% of the people who completed the study improved.6 The samples were small, with 46 patients for IH and 34 for narcolepsy. How do you weigh these data against the pivotal trials?

Plante: The DUET study is a phase 4 trial, so it occurred after the FDA indications for narcolepsy and IH, and it was open label. In other words, all the participants knew what they were getting while they were in the study. When you look at effects on things like the Epworth Sleepiness Scale and other measures, it's hard to compare them to randomized trials where there's a placebo. It's just a slightly different situation.

That said, in the DUET study, the changes that were observed in the magnitude of the effect, both for IH and narcolepsy, in terms of improvement in daytime sleepiness, were quite good. Usually, people will say that a clinically significant change in the Epworth Sleepiness Scale is about 3 points.6 Here, it's clearly a pretty sizable improvement on the Epworth in the DUET study. I think it suggests that these medications can be effective, which, to some degree, is expected based on the previous phase 3 trials.

REFERENCES

1. Jazz Pharmaceuticals announces US FDA approval of Xywav (calcium, magnesium, potassium, and sodium oxybates) oral solution for idiopathic hypersomnia in adults. News release. Jazz Pharmaceuticals. August 12, 2021. Accessed October 27, 2026. https://investor.jazzpharma.com/news-releases/news-release-details/jazz-pharmaceuticals-announces-us-fda-approval-xywavr-calcium/
2. Inoue Y, Tabata T, Tsukimori N. Efficacy and safety of modafinil in patients with idiopathic hypersomnia without long sleep time: a multicenter, randomized, double-blind, placebo-controlled, parallel-group comparison study. Sleep Med. 2021;80:315-321. doi:10.1016/j.sleep.2021.01.018
3. Grossi G. Low-Sodium Oxybate Reduces Excessive Sleep Time in Idiopathic Hypersomnia. AJMC. February 11, 2026. Accessed October 27, 2026. https://www.ajmc.com/view/low-sodium-oxybate-reduces-excessive-sleep-time-in-idiopathic-hypersomnia
4. Jazz Pharmaceuticals Presents Phase 3 Study Results of Xywav™ (calcium, magnesium, potassium, and sodium oxybates) Oral Solution in Adult Patients with Idiopathic Hypersomnia at 2021 American Academy of Neurology Annual Meeting. News release. Jazz Pharmaceuticals. August 20, 2021. Accessed October 27, 2026. https://investor.jazzpharma.com/news-releases/news-release-details/jazz-pharmaceuticals-announces-us-fda-approval-xywavr-calcium/
5. Bogan RK, Foldvary-Schaefer N, Skowronski R, Chen A, Thorpy MJ. Long-Term Safety and Tolerability During a Clinical Trial and Open-Label Extension of Low-Sodium Oxybate in Participants with Narcolepsy with Cataplexy. CNS Drugs. 2023;37(4):323-335. doi:10.1007/s40263-023-00992-y
6. Plante DT, Cairns A, Schneider LD, et al. Effectiveness and Safety of Low-Sodium Oxybate in Participants with Idiopathic Hypersomnia: Primary Results from the DUET Study. CNS Drugs. 2026;40(6):803-822. doi:10.1007/s40263-025-01262-9Telling primary hypersomnia from sleepiness driven by depression often depends on the course of both illnesses and, when history is not enough, on sleep testing, said David T. Plante, MD, PhD, associate professor of psychiatry and medical director of the Wisconsin Institute for Sleep and Consciousness at the University of Wisconsin–Madison School of Medicine and Public Health.