Sleep Neurotherapeutics: Identifying the Challenges and Opportunities

High angle shot of a beautiful young woman sleeping in her bed at home during the night
In an interview, sleep medicine experts Milena K Pavlova, MD, and Rachel Ziegler, MD, discuss the latest developments in sleep disorder therapies and the existing gaps in sleep medicine.

Sleep disorders are associated with a range of comorbidities and a substantial impairment in quality of life. Sleep disorders may result from or affect the progression of neurologic diseases, such as Parkinson disease, and they can also exacerbate or increase the risk for other comorbid conditions.1 For example, impaired sleep may worsen the severity of headache and epilepsy and increase the risk for depression and cardiovascular disease.2-4

Conversely, the adequate treatment of sleep disorders may improve outcomes of comorbid conditions and reduce the risk for secondary diseases, underscoring the need for effective treatment strategies.2,5

In the past 2 decades, there has been significant progress in understanding sleep and its impact on health, as well as potential mechanisms underlying sleep disorders, including narcolepsy and restless legs syndrome. “Yet only recently have these seminal advances in sleep clinical and translational neuroscience begun directly to enable new therapeutic possibilities and rational and specific therapies,” wrote the authors of a review published in Neurotherapeutics in February 2021.6

To discuss the latest developments and existing gaps in sleep medicine, we interviewed Milena K. Pavlova, MD, associate professor of neurology at Harvard Medical School, Boston, neurologist in the Division of Sleep and Circadian Disorders at Brigham and Women’s (BW) Hospital, Boston, and medical director of the BW Faulkner Sleep Laboratory; and Rachel Ziegler, MD, a specialist in the sleep medicine department at Mayo Clinic Health System in Fairmont, Minnesota.

What are some noteworthy recent developments in neurotherapeutics for sleep disorders?

Milena K. Pavlova, MD: Several new developments have occurred in the field of sleep, and these span across different disorders. For patients with insomnia, a new medication called lemborexant, which targets the orexin system, became available last year. It is the second drug of this class, following the development of suvorexant several years ago.6

For patients with narcolepsy, there have been several developments, including the ability to measure cerebrospinal fluid hypocretin in patients to confirm narcolepsy type 1. Several new therapies became available, including [gammahydroxybutyrate or] Xywav, a low-sodium version of the night-time treatment sodium oxybate (trade name Xyrem); there was also the introduction of daytime wake-promoting medications pitolisant and solriamfetol.7,8

In addition, new groups were formed to focus on the evaluation and treatment of complex sleep disorders that require multiple specialties. I have been involved in the establishment of 2 such groups recently. The International Association of Circadian Clinics is an association for experts, in circadian rhythm disorders – some with a primary research background and some who are predominantly clinicians – that aims to improve treatment using novel methods for testing (such as dim light melatonin onset time) and treatment. 

Another group is the Sleep and Epilepsy Workgroup, which we developed with the counsel of the American Epilepsy Society, aimed at optimizing treatment of sleep disorders among patients with epilepsy.9

Additionally, the International RBD Study Group continues to be very active, with new multinational trials seeking a better understanding of the risks for neurodegeneration in these patients.

Rachel Ziegler, MD: In my opinion, the most noteworthy recent developments for sleep disorders include wake-promoting agents for treatment of disorders of hypersomnolence, including narcolepsy with and without cataplexy and hypersomnia secondary to obstructive sleep apnea (OSA).

Solriamfetol is an oral selective dopamine and norepinephrine reuptake inhibitor that may be initiated as monotherapy, both for daytime sleepiness in narcolepsy and for patients with hypersomnia despite adequately treated OSA. 

Pitolisant is an oral histamine H3 receptor inverse agonist, which may be used as monotherapy to treat the daytime sleepiness associated with narcolepsy and may also be used to treat cataplexy.

For both [solriamfetol and pitolisant], consideration may be given as first-line therapy and for patients [in whom treatment with] other agents [has failed].

Can you describe any specific recommendations and caveats for clinicians regarding the use of these therapies?

Dr Ziegler: Solriamfetol for narcolepsy is started at 75 mg once-daily in the morning and titrated to 150 mg once-daily in the morning, based on clinical response and tolerability. Smaller doses may be used in patients with OSA and patients with renal insufficiency. Headache is the most common side effect, and other common side effects include nausea, diarrhea, and appetite loss.

[Solriamfetol] is contraindicated in patients [receiving] monoamine oxidase inhibitors and should be avoided in pregnancy. It has not been approved for use in children. Solriamfetol should be used with caution in patients with a history of drug abuse. 

Pitolisant is started at 8.9 mg once-daily in the morning and titrated to 17.8 mg once-daily in the morning after 1 week, based on clinical response and tolerability. The maximum dose is 35.6 mg once-daily in the morning. Headache is the most common side effect, with other side effects including insomnia, nausea, and anxiety.

Pitolisant may prolong the QT interval and should be avoided in patients with known QT prolongation. This medication should also be avoided in combination with other medications that prolong the QT interval.

Pitolisant should be used with caution in patients with hepatic or renal impairment and in patients [with inadequate metabolism of] CYP2D6. Pitolisant may reduce the effectiveness of hormonal contraception and should be avoided in pregnancy.

What are some of the other exciting discoveries applicable to sleep science?

Dr Pavlova: There have been some major discoveries in neurodegenerative disorders. Many of these discoveries concern the newly defined glymphatic system, which functions as an intermediary from the dense brain parenchyma through to within the brain parenchyma to the venous circulation. This system has a major role in the clearance of biproducts that can otherwise accumulate, including apolipoprotein. In animal studies, the function of the glymphatic system is active during sleep and 90% suppressed during wakefulness.10

What are some of the most common barriers in the treatment of patients with sleep disorders?

Dr Pavlova: The biggest obstacle for me as a clinician is when health insurance companies refuse coverage for medications and tests that the patient’s doctor has prescribed. Such denials may delay care because doctors have to go through a lengthy appeal process, and they can sometimes even result in loss of care because the patient may become discouraged and not seek further care. This sometimes changes the treatment from what is appropriate based on the individual patient’s symptoms, health risks, and comorbidities, to a treatment plan that is not personalized and may be suboptimal.

What are other important gaps that warrant attention in sleep medicine?

Dr Ziegler: Further studies are needed for comparison of these newer agents to modafinil and traditional stimulants, and to determine the safety of these medications in combination with modafinil and/or traditional stimulants. Further research is also needed in women who are pregnant or nursing, in children, and in older adults.

Dr Pavlova: Further educating health professionals about sleep remains important and is sometimes underrecognized. I feel that I am making some contribution towards this because I lead an annual CME course on sleep. There is still much variability in how well signs of sleep disorders are recognized. For example, diagnosis of narcolepsy is notoriously delayed by years, often decades, and I have patients who have faced much social pressure to ignore sleep symptoms. Health care disparities are prevalent in our field, as in other neurology subspecialties.   


1. Vila-Chã N, Cavaco S, Mendes A, et al. Sleep disturbances in Parkinson’s disease are associated with central parkinsonian pain. J Pain Res. 2019;12:2137-2144. doi:10.2147/JPR.S206182

2. Ju YS, Videnovic A, Vaughn BV. Comorbid sleep disturbances in neurologic disorders. Continuum (Minneap Minn). 2017;23(4):1117-1131. doi:10.1212/CON.0000000000000501

3. Fang H, Tu S, Sheng J, Shao A. Depression in sleep disturbance: A review on a bidirectional relationship, mechanisms and treatment. J Cell Mol Med. 2019;23(4):2324-2332. doi:10.1111/jcmm.14170

4. Choi Y, Choi JW. Association of sleep disturbance with risk of cardiovascular disease and all-cause mortality in patients with new-onset type 2 diabetes: data from the Korean NHIS-HEALS. Cardiovasc Diabetol. 2020;19(1):61. doi:10.1186/s12933-020-01032-5

5. Rémi J, Pollmächer T, Spiegelhalder K, et al. Sleep-related disorders in neurology and psychiatry. Dtsch Arztebl Int. 2019;116(41):681-688. doi:10.3238/arztebl.2019.0681

6. St Louis EK, Videnovic A. Sleep neurology’s toolkit at the crossroads: challenges and opportunities in neurotherapeutics lost and found in translation. Neurotherapeutics. 2021;18(1):1-5. doi:10.1007/s13311-021-01032-7

7. American Academy of Sleep Medicine. FDA approves Xywav to treat narcolepsy. Updated October 21, 2020. Accessed September 29, 2021.

8. Thorpy MJ. Recently approved and upcoming treatments for narcolepsy. CNS Drugs. 2020;34(1):9-27. doi:10.1007/s40263-019-00689-1

9. Quigg M, Bazil CW, Boly M, et al. Proceedings of the Sleep and Epilepsy Workshop: section 1 decreasing seizures-improving sleep and seizures, themes for future research. Epilepsy Curr. Published online March 31, 2021. doi:10.1177/15357597211004566

10. Reddy OC, van der Werf YD. The sleeping brain: harnessing the power of the glymphatic system through lifestyle choices. Brain Sci. 2020;10(11):868. doi:10.3390/brainsci10110868