Year in Review: Key Developments in Sleep Medicine

In this podcast, Neurology Learning Network's Sleep Medicine Section Editor Joseph Diamond, MD, discusses new drug approvals, phase 3 clinical trial data, "COVID-somnia," and more developments from 2020. A full transcript is provided below.

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Joseph Diamond, MD, is an assistant professor of neurology at the Icahn School of Medicine at Mount Sinai in New York, NY.

References:

1. Daridorexant phase 3 results in insomnia presented at SLEEP 2020. News release. Idorsia Pharmaceuticals LTD. August 28, 2020. https://www.idorsia.com/media/news-details?newsId=2359821
2. Jazz Pharmaceuticals announces U.S. FDA approval of Xywav™ (calcium, magnesium, potassium, and sodium oxybates) oral solution for cataplexy or excessive daytime sleepiness associated with narcolepsy. News release. Jazz Pharmaceuticals; July 22, 2020. Accessed July 22, 2020. https://investor.jazzpharma.com/news-releases/news-release-details/jazz-pharmaceuticals-announces-us-fda-approval-xywavtm-calcium
3. Miller MA, Cappuccio FP. A systematic review of COVID-19 and obstructive sleep apnoea. Sleep Med Rev. 2021;55:101382. doi:10.1016/j.smrv.2020.101382
4. Rishi MA, Ahmed O, Barrantes Perez JH, et al. Daylight saving time: an American Academy of Sleep Medicine position statement. J Clin Sleep Med. Published online August 26, 2020. doi:10.5664/jcsm.8780

Transcript:

Christina Vogt: Hello, everyone, and welcome back to another podcast. I'm Christina Vogt, managing editor of Neurology Learning Network. Today, I'm joined by Dr Joseph Diamond, who is an assistant professor of neurology at the Icahn School of Medicine at Mount Sinai in New York City. Today, we are going to have a year-in-review discussion of key developments in the field of sleep medicine.

Thank you for joining me today, Dr Diamond. First, could you talk a little bit about some of the new pharmaceutical therapies that have been FDA-approved in the sleep medicine space this year?

Dr Joseph Diamond: Yeah. The biggest one that's been improved is Xywav, which is a calcium, magnesium, potassium, and sodium oxybates which is used to treat narcolepsy with cataplexy.

As a refresher, narcolepsy is a chronic and debilitating neurologic disorder, which is defined by excessive daytime sleepiness and inability to normally regulate sleep-wake cycles. It affects 1 out of 2000 people. The symptoms usually manifest in childhood or adolescence, but it can take 10 years or even longer for a formal diagnosis to be made.

The 5 main symptoms of narcolepsy are excessive daytime sleepiness, cataplexy, disrupted nighttime sleep, sleep-related hallucinations which are either hypnagogic, when someone has fallen asleep, or hypnopompic, when you're waking up, and sleep paralysis.

Everyone with narcolepsy experiences excessive sleepiness, which is the inability to stay awake and alert during the day, with resultant drowsiness and unplanned sleep lapses, but not necessarily the other 4. Narcolepsy is also associated with a higher prevalence of cardiometabolic abnormality, such as obesity, hypertension, diabetes, and hyperlipidemia.

Cataplexy is the most specific, however not the most prevalent symptom of narcolepsy. I like to think of it as a line in the sand in which it divides type 1 narcolepsy, which is that with cataplexy, affecting about 70% of those with narcolepsy, from type 2 narcolepsy, which is that without the cataplexy.

Cataplexy is the sudden, generally brief, lasting less than 2 minutes—can even be seconds—loss of muscle tone with retained consciousness, often triggered by strong emotions such as laughter, which is actually one of the strongest ones causing cataplexy, surprise, or anger.

There's more often partial attacks, meaning specific muscle groups affected, such as your arms, legs, face, eyelids, than a complete collapse of somebody's entire body.

Xywav was developed by Jazz Pharmaceuticals and has been approved by the FDA for the treatment of cataplexy or excessive daytime sleepiness in patients 7 years of age and older with narcolepsy. It's also currently being studied and developed for the treatment of idiopathic hypersomnia in adults.

Xywav is comprised of a unique composition of cations resulting in 92% less sodium, or approximately 1000 to 1500 mg per night less than sodium oxybate, which actually aims to put patients more in line with the American Heart Association guidelines for daily sodium intake as it's less than sodium oxybate. It's given at a recommended dosage range of 6 to 9 g.

Xywav has the same oxybate concentration of sodium oxybate and includes a mix of calcium, magnesium, potassium, and sodium cations.

While the exact mechanism of action of Xywav is unknown, it's thought that the therapeutic effects of Xywav on cataplexy and excessive daytime sleepiness are mediated through the GABAB actions during sleep at noradrenergic and dopaminergic neurons, as well as at thalamocortical neurons.

There was a study that enrolled 201 participants and randomized 134 of those. That included those previously treated with sodium oxybate as well as those naïve to sodium oxybate with or without other anti-cataplectic treatments.

There was a 2-week double-blind randomized withdrawal period. During that period, there was a significant increase in the median weekly number of cataplexy attacks in participants randomized to take placebo compared with those randomized to continue Xywav treatment.

Those that were switched to placebo were about 2.3 times more likely to experience a cataplexy attack compared to those that were continuing on Xywav treatment.

At the end of the double-blind randomized withdrawal period, there was also a significant increase in the median Epworth Sleepiness Scale scores in participants randomized to take placebo compared with participants randomized to continue Xywav by about 2 points on that scale.

The most common adverse reactions in adults were headache, nausea, dizziness, decreased appetite, parasomnia, diarrhea, hyperhidrosis, anxiety, and vomiting. The most common adverse reactions in children were bedwetting, nausea, headache, vomiting, decrease in weight, decreased appetite, and dizziness.

Christina Vogt: Could you discuss the phase 3 clinical trial findings for daridorexant that came out this year?

Dr Diamond: Daridorexant is a new dual orexin receptor antagonist used to treat insomnia. Insomnia is a condition of overactive wake signaling. Studies have actually shown that areas of the brain impacted with wakefulness do not actually quiet down in patients with insomnia when they are trying to or even actually sleeping.

The orexin neurons are located in the lateral hypothalamus and operate as the pivotal regulator of wakefulness, signaling the other wake-promoting neurons to be active, thus maintaining the wake state and our normal levels of consciousness. Blocking the orexin activity reduces the downstream activity of other wake-promoting neurotransmitters, facilitating sleep.

The phase 3 clinical trial information was actually presented at the annual Associated Professional Sleep Societies virtual meeting this year, which was known as SLEEP 2020. It's the world's largest meeting entirely devoted to clinical sleep medicine, as well as sleep and circadian rhythm research.

Daridorexant is developed by Idorsia, Ltd. In their phase 3 clinical trial, they demonstrated efficacy of treatment with daridorexant on objective and subjective sleep parameters, as well as daytime functioning. Important to note there was no next-morning residual effect, no red flag concerning for rebound insomnia, and no withdrawal effects.

Daridorexant significantly improved sleep maintenance, as seen with a larger decrease in wake after sleep onset from baseline as compared to placebo. Wake after sleep onset means those little awakenings we get throughout the night.

We get up. We toss and turn, use the restroom. Those all add up over time. There was about 18 minutes decrease in WASO on the 25-mg dose and 29 minutes on the 50-mg dose following 1 month of use.

There was also significantly improved sleep onset, as seen with a larger decrease in latency—that's the time from when you get to bed and you fall asleep—from baseline as compared to placebo, with 28 minutes on the 25-mg dose and 31 minutes on the 50-mg dose at 1 month and then 30 minutes and 34 minutes, respectively, at 3 months of use.

Subjective total sleep time also increased by 34 minutes on the 25-mg dose and 44 minutes on the 50-mg dose at 1 month, and then 38 minutes on the 25-mg dose and 58 minutes on the 50-mg dose at 3 months.

There was also noted to be improved daytime functioning according to a specific sleepiness/tiredness domain of a newly developed insomnia questionnaire. The most frequent adverse effects were nasopharyngitis and headache, followed by somnolence.

This is so important, as insomnia is the most commonly reported sleep disorder worldwide. Its prevalence and especially impact are often underestimated. Sleepless nights can leave people irritable, unable to adequately and satisfactorily perform a number of crucial daily activities, such as studying, employment work opportunities, social activities, and relationships.

It also has economic impact. People with insomnia have higher risk of accident injury, such as when driving or performing their duties in the workplace, as well as reduced productivity at work and higher absenteeism.

It is also associated with higher rates of depression, decreased concentration, and lower energy levels during the day. Chronic insomnia is associated with cardiovascular and cerebrovascular disease and increased mortality.

The current treatment before the dual orexin receptor antagonist, which also includes previously released suvorexant, also known as Belsomra, and lemborexant, also known as Dayvigo, are cognitive behavioral therapy, sleep hygiene and sleep restriction, and pharmacotherapy, particularly those that enhance γ-aminobutyric acid, also known as GABA effects, which is a main inhibitory neurotransmitter of the central nervous system.

The GABA-enhancing medications are only maximally effective in the short term and have a myriad of side effects, such as anterograde amnesia, which means forgetting things that have happened after you take the medication at one point, abnormal behaviors, specific parasomnias that you might have heard of, such as sleep eating, sleep driving even, when patients are not aware that they're doing this during their sleep, and risk of tolerance and dependence. A new medication would hopefully circumvent all these issues.

Christina Vogt: Recent data have shown that the risks associated with COVID-19 are increased among patients with obstructive sleep apnea. What points are important for clinicians to know about this?

Dr Diamond: According to a systematic review of the literature in Sleep Medicine Reviews, many of the risk factors and comorbidities associated with obstructive sleep apnea, known as OSA, are also culpable with poor COVID-19 outcomes.

Diabetes, obesity, and hypertension, which are all comorbidities of OSA, are often associated with poor COVID-19 outcomes. Patients with OSA experience repetitive complete or partial blockages of the upper airway while sleeping, resulting in blood oxygen desaturation and apneas, which are interruptions in breathing.

It is hypothesized that many of the same mechanistic pathways that are activated in COVID-19 infection are also activated in OSA patients, such as activated inflammatory pathways, increased cytokine production, and activation of the renin-angiotensin and bradykinin pathways.

Vitamin D has a role in suppressing harmful reactive oxygen species and lowering levels of inflammation. It was noted that vitamin D levels were lower in both OSA patients and those with poor COVID-19 outcomes.

A study published in Diabetologia in May of this year found that people with diabetes hospitalized with COVID-19 who had treated OSA were almost 3 times as likely to die by day 7 of the hospital admission, particularly if the OSA was severe.

A Life Sciences study from March also thought that melatonin could be protective against COVID-19. It could reduce the activated pathways in patients with the virus, such as inflammation, oxidative stress, and the immune response that could result in progression of the acute respiratory distress syndrome and lung injury and the cytokine storm from COVID-19.

A study in the British Journal of Anesthesia in May found that COVID-19 patients who were not in the ICU had a lower prevalence of OSA compared to those in the ICU, so 6.3% vs 8.3%, respectively.

CPAP use has actually also become controversial and may be a potential means of spreading viral droplets, but its continued use in this setting needs to be weighed against all the other problems of stopping therapy.

The consensus now is that if an individual suspects or has actually been diagnosed with COVID, they should continue to use CPAP, but in a well-ventilated room and isolated from others to prevent transmission and further spread.

Despite all the above, there isn't enough evidence to establish a direct relationship between having OSA and getting COVID-19. However, study has shown that patients with OSA and COVID-19 were more likely to need hospitalization and had double the risk of developing respiratory failure as compared to those without OSA.

Christina Vogt: Speaking of COVID-19, what's important to know about the “COVID-somnia” phenomenon that's been seen during the pandemic?

Dr Diamond: The lockdown and quarantine has changed the routine of many people, and I think that's a bit of an understatement, as it pertains to the levels of physical activity, socialization parameters. Social distancing wasn't even a thing before this, so it's increased use of telecommunications, changes in eating habits and sleep habits, including the schedule.

These changes have led to sleep disturbances with reduced quality and varying quantities. During this time, the term "COVID-somnia" has emerged, which has been used to refer to the above sleep changes and to promote communication amongst patients as well as providers to further explain and allow research into this phenomenon.

The most widely identified characteristics of this include delay in bedtime and wake time, meaning individuals are going to bed later and waking up later. There is a reduction in total time spent in sleep at night, and an increase in daytime napping, which could possibly be used to offset the deprivation of nighttime sleep, resulting in excessive daytime sleepiness.

It's thought that the lack of social zeitgebers , also known as time cues, during the lockdown are to blame, but there could actually be other factors, such as a chronotype or circadian typology. Think if someone is a morning lark, more tend to waking up earlier and going to bed earlier, or a night owl, waking up later and going to bed later, as well as age.

For example, shifting to a later bedtime and wake time was most prevalent in the evening chronotypes, those night owls, those with a younger age, even teenagers, compared to adults and older adults and women.

Why is this? As many have experienced, lockdowns have unfortunately led to emotional and psychological distress, uncertainties, and unemployment. However, different people respond differently to stressful situations—a concept which is called sleep reactivity.

Those with high sleep reactivity are more prone to develop sleep disturbances. Life stress, sleep reactivity, and dysfunctional beliefs are not causative but merely risk factors for the development of insomnia.

Interestingly, the COVID-19 infection itself causes systemic inflammation, leading to a surge in inflammatory pathways in the body that are known to influence sleep and vice versa. This can increase the amount of non-REM sleep and increase the duration of sleep, possibly an attempt to conserve energy and combat the infection.

However, different infections have varying effects on sleep, with some increasing it and others reducing it. Unfortunately, COVID-19 seems to fall in the latter category. For example, a case report suggested that COVID- 19 infection led to insomnia and restless leg syndrome, which improved with resolution of the infection.

Systemic inflammation and hypoxemia, or low oxygen levels, contributed to these symptoms. Sleep often remains disturbed even after recovery from COVID-19 in a significant number of people.

When it actually is allowed to enter the brain and makes its way there, the SARS-CoV-2 virus preferentially affects the prefrontal cortex, basal ganglia, and hypothalamus, which are areas that are very important for sleep regulation.

These changes, even among those with asymptomatic infections, could also lead to the surge in sleep disturbances, as opposed to only the well-thought-of-and-studied social and emotional factors. However, more research is needed in this area.

Other evidence suggests there is a bidirectional relationship between sleep and SARS-CoV-2 infection. Sleep plays an important role in regulation of cellular and humoral immunity, and this sleep deprivation can reduce the immune response to any challenges it encounters.

As previously discussed, people with OSA are at increased risk of contracting SARS-CoV-2 infection, becoming hospitalized, and developing respiratory failure. Therefore, adequate amount of optimal-quality sleep is thought to be an important tool in combating infection, hopefully. You can try to sleep the virus and infection away.

There is no association as yet reported between morbidity or mortality from SARS-CoV-2 and insomnia or poor sleep quality.

Overall, there is not a lot of current research and literature identifying an association between COVID-19 and sleep disorders. This is a major area for research opportunity, as the relationship appears bidirectional, with improvement in sleep possibly being utilized to reduce the impact of COVID-19 and vice versa.

The long-term effects of COVID-19 infection on sleep need to be further investigated to assess the incidence and prevalence of sleep disorders in these patients.

Christina Vogt: Earlier this year, the American Academy of Sleep Medicine recommended eliminating daylight savings time. Could you discuss this in more detail?

Dr Diamond: Daylight saving time is the period of the year between spring and fall when clocks in most of the United States are set 1 hour ahead of standard time. It's the time that we "spring forward," we call it. The remaining period, between fall and spring of the following year, is called standard time.

The light-dark cycle of the day is key to the circadian entrainment. The acute changes in timing due to transitions to and from daylight saving time lead to misalignment between the circadian biological clock and the light-dark cycle of photoperiods resulting in personal disruption and significant public health and safety risk.

The Congressional Research Service identified dozens of states that have introduced legislation that would support changes to the observance of daylight saving time. A lot of support exists for the elimination of the spring and fall time changes, but proposed solutions are conflicting this.

Some states have introduced legislation proposing variations of permanent daylight saving time, and a near equal number of states have introduced legislation to establish permanent standard time. One are doing one thing, one are proposing another.

US statute does allow state-level exemption from daylight saving time. The 2 states that are well known to do this are Hawaii and Arizona. Moving to permanent daylight saving time nationwide will require legislative approval by Congress.

The American Academy of Sleep Medicine (AASM's) position is that the US should eliminate sleeping time changes in favor of a national fixed year round time. Current evidence best supports the adoption of year-round standard time as opposed to year-round daylight saving time, which better aligns with human circadian biology and provides explicit benefit to the public health and safety.

Light is the most powerful exogenous zeitgeber time cue to the regulation of the endogenous circadian rhythm. When exposed to light, the human circadian phase responds by delaying or shifting the endogenous biological sleep onset and offset, or otherwise known as wake time, to a later clock time. Circadian rhythm moves away from light and becomes later.

The recommendation in support of permanent standard time is based on the adverse acute and chronic effects of shifting between standard time and daylight saving time twice yearly, as well as being in daylight saving time during the middle part of the year.

The acute effects of switching between standard time and daylight saving time is that it's been associated with increased cardiovascular and cerebrovascular morbidity, such as myocardial infarction or heart attack, stroke, and hospital admission secondary to atrial fibrillation.

Also, it's noted there's missed medical appointments and higher emergency department visits and return visits to the hospital in the spring, particularly during the transition from standard time to daylight saving time.

Due to less light exposure in the morning and greater exposure to evening light in the spring, there is often sleepwalk and resulting sleep death as there is continued social occupational demands in the early morning hours. People are just going about as business as usual despite the light changing outside.

As a result, a number of cellular derangements emerge, including altered myocyte gene expression which are in the heart, epigenetic, and transcriptional profile of core clock genes. The clock genes are components of the circadian clock comparable to the cogwheels of a mechanical watch. They interact with each other in an intricate matter generating oscillations of gene expression.

Also noted is increased production of inflammatory markers, lower vagal tone, which is a key component of the rest and digest system, which leads to higher heart rate and blood pressure and reduced sleep.

More of these adverse effects are seen when transitioning from standard time to daylight saving time. The transition into and out of both have been linked to sleep disruption, mood disturbances, and suicide.

Traffic accidents in the US increase in the first few days after the change from standard time to daylight saving time. An uptick in fatal crashes of up to 6%, pretty significant. There are also economic effects. On the Monday after transition to daylight saving time, there's higher volatility in the US stock market.

The reasons are not explicitly clear, but it could be proposed that the deleterious impact of sleep deprivation on frontal lobe functioning may result in impaired decision-making capacity as well as judgment almost akin to these people being under the influence of substances such as alcohol.

The chronic effects of daylight saving time are not as well delineated as most studies have either been retrospective or address the issue indirectly.

Some good points of daylight saving time is that it's been associated with a decrease in crime rate and may be associated with a modest overall decrease in risk to motor vehicle crashes, possibly due to hour of daylight lasting into the evening when most accidents occur.

However, when year-round daylight saving time has been implemented, there was an increase in fatalities among school-aged children in the morning between January and April. This might be due to darkness lasting longer in the morning when children are traveling to school.

Daylight saving time is less well-aligned with the intrinsic human circadian physiology and it disrupts the natural seasonal adjustment of the human clock due to the effect of late-evening light on the circadian rhythm. Those early-morning darkness and light in the evening have a similar effect on the circadian phase causing the endogenous rhythm to shift to later in the day.

The human body clock does not adjust to daylight saving time even after several months. Permanent daylight saving time could, therefore, result in permanent phase delay, a condition that could also lead to perpetual misalignment or discrepancy between the innate biological clock and the extreme environmental clock, as well as chronic sleep loss due to early morning social demands that cut off the opportunity to sleep.

This chronic misalignment between the time and the demands of work, school, other obligations against the innate circadian rhythm has been termed social jetlag. Studies show that social jetlag is associated with an increase risk of obesity, metabolic syndrome, cardiovascular disease, and depression.

One study found that in the fall, during the shift from daylight saving time back to standard time, there actually was a reduction in the rate of cardiovascular events, suggesting that the risk of myocardial infarction may be elevated because of chronic effects of daylight saving time.

Social jetlag associated with daylight saving time may be worse in the westernmost areas within a given time zone where sunset occurs relatively later than those in the eastern area part of a time zone. Adopting permanent daylight saving time also would undo the benefits of delaying the start times for middle schools and high schools, as those students tend to do better with a day that starts later and ends later.

Future studies are needed to evaluate the chronic effects of daylight saving time on physiology, performance, health, economics, and safety. This especially should aim to tease out the confounding seasonal effects, including length of the photo period, which is hours of daylight over 24-hour periods.

More studies are also needed to ascertain how eastward, those that are earlier in time zone, or westward, those that are later in a time zone position, influences health and safety. Finally, studies comparing the impacts of permanent standard time to a permanent daylight saving time are needed.

The existing data is outlined in the American Academy of Sleep Medicine position statement to support the elimination of seasonal time changes in favor of fixed, year-round time. Daylight saving time can cause misalignment between the biological clock and environmental clock, resulting in significant health and public safety-related consequences, especially in the days immediately following the annual change to daylight saving time.

A change to permanent standard time is best aligned with human circadian biology and has the potential to produce beneficial effects for public health and safety.

Christina Vogt: Thanks again for joining me today, Dr Diamond. For more podcasts like this, visit neurologylearningnetwork.com.