Breakthroughs in Narcolepsy Research and Treatment

Introduction

Narcolepsy is a chronic neurological disorder characterized by the brain’s impaired ability to regulate a normal sleep-wake cycle. Narcolepsy affects roughly 40-50 people per 100,000 worldwide, but these numbers are estimated to be underinflated due to the difficulty of properly diagnosing this disorder. With the average time between symptom onset and diagnosis being seven years, estimates place up to 60% of patients being initially misdiagnosed with conditions such as depression, insomnia, or obstructive sleep apnea (“Narcolepsy Fast Facts”, 2015). Narcolepsy is not only characterized by excessive daytime sleepiness (EDS); associated symptoms include sudden loss of muscle tone and cataplexy (weakness), sleep paralysis, hallucinations, fragmented sleep, and insomnia. Narcolepsy is further classified into Type 1–narcolepsy with cataplexy–or Type 2–narcolepsy without cataplexy–as well as secondary narcolepsy, which is caused by damage to the brain’s hypothalamus, responsible for regulating sleep. Narcolepsy is known to add significant difficulties to ordinary daily-life functioning, with affected patients falling asleep unexpectedly and often in the middle of tasks like driving, eating, or engaging in conversation (Fletcher, 2023).

The causes of narcolepsy are not completely understood and ongoing research in the field is focused on uncovering the underlying genetic, autoimmune, and neurobiological factors thatcontribute to the development of this complex sleep disorder. It has been noted that nearly all patients with Type 1 narcolepsy (with cataplexy) display abnormally low levels of hypocretin or orexin, neuropeptide hormones produced in the hypothalamus that promote wakefulness and regulate the sleep cycle. The causes for this hypocretin deficiency remain a topic of intense research but are likely the result of a myriad of factors, including autoimmune disorders, family history, and past brain injury. Researchers have also identified human leukocyte antigen (HLA) gene markers to be present in most patients with narcolepsy; however, these variants are common in the general population, and only a small number of people within this subpopulation will develop narcolepsy (“Narcolepsy,” n.d.).

Current Treatments

Since there is currently no cure for narcolepsy, treatments center on managing symptoms through lifestyle changes and medication. Lifestyle interventions include sticking to a strict sleep schedule, taking short naps, avoiding nicotine and alcohol, and regular exercise. Drug therapies fall into several classifications, including stimulants, antidepressants, central nervous system depressants, and histamine H3 receptor (H3R) antagonists (Mayo Clinic, 2023).

Stimulants are often considered the first-line treatment for narcolepsy due to their effectiveness in managing the condition's most prevalent symptom–excessive daytime sleepiness. Patient regimens commonly include medications such as Modafinil (Provigil), Armodafinil (Nuvigil), and Solriamfetol (Sunosi). These act by inhibiting the breakdown of catecholamines, mainly dopamine, adrenaline, and noradrenaline, to help individuals with narcolepsy stay awake and alert throughout the day (Gowda, 2014). In patients where these are not effective, physicians will prescribe stronger stimulants as their second-line treatment, as these medications have a less favorable safety profile and greater potential for abuse and negative side effects. These stimulants, including methylphenidate (Ritalin, Concerta) and amphetamines (Adderall XR 10, Dexedrine), while stronger, increase the risk of dependency and habituation (habit-formation). These stimulants work by increasing alertness and reducing the overwhelming urge to fall asleep during the day, by once again increasing the levels of catecholamines in the brain and blocking their reuptake, allowing individuals with narcolepsy to maintain a closer to normal daily routine. However, it's important to note that stimulant medications do not address all aspects of narcolepsy, and their long-term use may come with potential side effects, including tolerance and dependency.

While stimulants are the first-line treatment for combating excessive daytime sleepiness (EDS), antidepressants can be prescribed to combat the associated cataplexy and muscle weakness. These are further categorized into two segments: tricyclics (Imipramine, Desipramine, Clomipramine, and Protriptyline) and selective serotonin reuptake inhibitors (Venlafaxine, Fluoxetine, and Atomoxetine). These medications help patients modulate their own moods by reducing the triggers for cataplexy, empowering/giving patients more control over their symptoms (“Narcolepsy,” n.d.). Sodium oxybate and related oxybate salts are central nervous system depressants that are likewise prescribed to treat cataplexy and daytime sleepiness. While our understanding of these medications’ complete mechanisms is not comprehensive, they have been shown to increase slow-wave sleep duration, delta power, and improve sleep quality overall in narcoleptic patients. It is theorized that these therapeutic effects are a result of GABA-B agonist activity, which enhances inhibitory signals in the brain, stabilizes sleep patterns, and reduces the frequency and severity of cataplectic episodes, ultimately leading to better symptom management in narcolepsy patients (Dominguez, 2023).

With the FDA approval of Pitolisant in 2020, histamine-3 receptor (H3R) antagonists are now recognized as an effective treatment for both T1N and T12 (narcolepsy with and without cataplexy, respectively). By antagonizing the H3 receptor, Pitolisant blocks calcium channels, thereby increasing synthesis and release of neurotransmitters histamine, dopamine, acetylcholine, and others. The increased release of histamine enables better patient management of EDS symptoms, as well as improved cognitive function. These medications are recognized as having less potential for abuse and show similar efficacy to Modafinil for EDS, and superior efficacy for cataplexy control. As a result, research into other H3R antagonists is ongoing and has much potential to transform narcolepsy treatment, with the possibility of such medications replacing stimulants as the first-line therapy (Harwell, 2020).

Limitations with Current Treatment Options

Narcolepsy remains a chronic, life-long condition with no known cure. While physicians may recommend behavioural changes, over 90% of patients still require some form of pharmacotherapy to combat their symptoms. Stimulants, which are commonly used to manage excessive daytime sleepiness, come with their own set of limitations and negative side effects. For instance, they may cause an increase in heart rate, insomnia, and dependency, which can make long-term use challenging for some individuals. Antidepressants used for cataplexy management also come with their own set of side effects including weight gain and sexual dysfunction and may also not be effective for everyone. Lastly, while some newer medications like sodium oxybate offer promising therapeutic effects, access to them remains limited by high costs and associated insurance reimbursement policies along with prescribing guidelines. There are also risks associated with taking these medications during pregnancy and breastfeeding. Even though medications have not been shown to be teratogenic when used in therapeutic doses, concerns exist from animal studies regarding potential embryotoxicity; therefore, most clinicians advocate for the cessation of drug therapy during conception, pregnancy, and breastfeeding (Wozniak, 2015). Ongoing research into treatments for narcolepsy aims to overcome these challenges and develop more effective, easily tolerated options for individuals affected by this complex sleep disorder.

Recent Breakthroughs

A recent study published in May 2023 by Ali Seifinejad et al. revealed new insights into the underlying causes of narcolepsy. The traditional theory of auto-immune destruction of hypocretin/orexin neurons has been challenged by the researchers’ discovery that a large umber of these neurons are preserved in narcoleptic patients. However, the genes responsible for producing hypocretin/orexin were silenced and therefore not actively producing the neurotransmitter. Upon further investigation, they found that the protein-coding gene was in fact intact, but epigenetically silenced as represented by abnormal methylation patterns. These findings are extremely significant as it provides evidence opposing the traditional theory of auto-immune destruction of these neurons, suggesting that it is possible to reverse these changes in affected patients and open new avenues for narcolepsy treatments (Seifinejad,2023). These findings were further supported by a publication from researchers in Tokyo inJune, who found similar abnormal methylation in genes associated with Narcolepsy Type I (Yoshida-Tanaka, 2023).

Also announced in May 2023, Avadel Pharmaceuticals achieved FDA approval for their new medication Lumryz. This extended-release sodium-oxybate therapeutic is the first of its kind as it only requires a single dose to be taken at bedtime. Traditionally, sodium oxybate must be administered twice, with the first dose at bedtime and a repeat dose 2-4 hours later. This requires patients to rise in the middle of the night in order to experience the maximum therapeutic effects of a full dose. As explained by Dr. Michael J. Thorpy, M.D, Director at theSleep-Wake Disorders Center at Montefiore Medical Center and Professor of Neurology at theAlbert Einstein College of Medicine, “This long-awaited therapy for people living with narcolepsy fills a critical unmet need by avoiding the burden of a second middle-of-the-night dose that immediate-release oxybate products require. The once-at-bedtime dosing regimen of Lumryzmay help restore a more natural sleep-wake cycle” (Avadel Pharmaceuticals, 2023).

Recent discoveries in narcolepsy research are challenging traditional approaches and paving the way for more targeted interventions. One area of promising research is the use of OX2Ragonists, which have the potential to address the root causes of narcolepsy rather than just managing its symptoms. By targeting orexin receptors, these agonists offer a unique opportunity to restore disrupted neurochemical pathways, providing long-lasting relief. However, despite the impressive effectiveness of Takeda's OX2R agonist TAK-994 in treating key narcolepsy symptoms, concerns have been raised about its association with hepatotoxicity. The early termination of the Phase 2 and extension trials highlights the need for novel and well-toleratedOX2R agonists in the field of narcolepsy research (Takeda, 2023).

Researchers are working to uncover new biomarkers to differentiate narcolepsy due to the difficulty of diagnosing the disease. In a study published in Sleep in early 2023, researchers identified mean REM sleep duration as a particularly promising neurophysiological biomarker for identifying narcoleptic patients with hypocretin deficiencies. This groundbreaking finding challenges conventional diagnostic criteria and suggests that assessing REM sleep duration during the Multiple Sleep Latency Test (MSLT) could significantly enhance the accuracy of narcolepsy diagnosis. The study revealed that a mean REM sleep duration of ≥5.7 minutes in narcoleptic patients exhibited robust discriminatory power, with an AUC accuracy, sensitivity ,and specificity values all nearing 0.80. Mean REM sleep duration has been identified as a promising biomarker of narcolepsy, and additional research is underway to explore other reliable markers that will accelerate diagnoses and reveal underlying components of this complex disorder (Lopez, 2023). In addition to sleep metrics, biomarkers of an electrophysiological nature are being discovered. In a recent study done in Italy, researchers explored the efficacy of muscle tone in determining narcolepsy. Measured by the atonia index during wakefulness(WAI), these researchers found significant changes in this metric between narcoleptic (both typeI and type II) and control patients with other hypersomnias (Romigi, 2023). As researchers continue to unveil innovative biomarkers, the path toward more accurate and timely diagnosis of narcolepsy becomes increasingly illuminated, offering hope for enhanced patient care and a deeper understanding of this intricate disorder.

Ongoing Clinical Trials Currently Recruiting: