Narcolepsy and NIH Women's Health Research

Signs, Symptoms, and Risk Factors

Narcolepsy is a chronic neurological disorder that affects how the brain controls sleep and wakefulness.^{1 , 2} The main symptom is excessive daytime sleepiness. People with narcolepsy experience an overwhelming need to sleep that can strike while sitting quietly or during activities such as having a meal or conversation.¹ Other common features include sleep paralysis, vivid or frightening dream-like experiences when falling asleep or waking up, and poor nighttime sleep (i.e., sleep fragmentation, frequent awakenings). Beyond these core symptoms, people with narcolepsy have higher rates of depression, obesity, and cardiovascular risk than the general population.^{2 - 4} The disorder is classified into two main types. Type 1 includes sudden, brief muscle weakness that is triggered by strong emotions like laughter or excitement (cataplexy) or a low level of orexin, a chemical that helps regulate the sleep-wake cycle, in the cerebrospinal fluid. Type 2 involves neither cataplexy nor low orexin levels. In some people, narcolepsy may result from an injury to the hypothalamus and may include other neurological symptoms and unusually long periods of nighttime sleep.²

Narcolepsy is estimated to affect between 1 in 2,000 and 1 in 3,000 people in the United States, and it most often begins in adolescence, although it can appear at any age.^{1 , 5} The causes are not fully understood, but research points to a combination of genetic and environmental factors.^{1 , 2} In most cases of narcolepsy type 1, symptoms stem from the loss of neurons in the hypothalamus that produce orexin, and evidence increasingly points to an autoimmune process being behind this neuronal loss.^{1 , 2 , 6} A variation in a gene called HLA-DQB1, part of the immune system's human leukocyte antigen (HLA) complex, is strongly associated with narcolepsy, and certain bacterial or viral infections may trigger the disorder in people who are genetically susceptible.^{1 , 2}

Impact on Women's Health

Although narcolepsy affects men and women equally, women tend to carry a greater disease burden.^{7 - 9} Women with narcolepsy tend to experience more daytime sleepiness and depression than men, and they are more likely to be recognized as having a disability.⁷ Female sex has also been identified as a risk factor for longer diagnostic delay, and women are more frequently misdiagnosed.⁸ During pregnancy, women with narcolepsy must make difficult treatment decisions, because most narcolepsy medications carry uncertain or known risks to the fetus. Many patients and providers choose to discontinue treatment, and management through pregnancy and lactation can be challenging.¹⁰

Diagnosis and Treatment

Narcolepsy is diagnosed using two specialized sleep tests: a polysomnogram, which monitors sleep overnight, and a multiple sleep latency test (MSLT), which measures daytime sleepiness the following day.² A spinal fluid test that measures orexin levels can confirm narcolepsy type 1. No equivalent biological marker currently exists for type 2, and its diagnosis relies on the clinical evaluation, polysomnogram, and MSLT results. Despite these tools, an estimated half of people with narcolepsy never receive a formal diagnosis, and many wait years before getting one.¹¹

The medications that are used to treat narcolepsy include wake-promoting agents for daytime sleepiness, such as modafinil, armodafinil, solriamfetol, and stimulants.² Pitolisant and oxybates address both sleepiness and cataplexy but do not restore the orexin that is lost.^{2 , 12} A new class of drugs, known as orexin agonists, directly restores orexin signaling, and early results show meaningful gains in wakefulness and fewer cataplexy episodes in people with narcolepsy who are taking orexin agonists.¹³ One such drug, oveporexton, has recently received approval from the Food and Drug Administration for the treatment of narcolepsy type 1 in adults.²

Ongoing Research

Oveporexton is the first orexin agonist that is approved to treat narcolepsy type 1, and studies of other drugs in the class are ongoing.¹⁴ Researchers are also studying whether these drugs help people with narcolepsy type 2 and idiopathic hypersomnia, related conditions that cause excessive daytime sleepiness but in which orexin levels are typically normal.¹⁵ Early results have been mixed, and it is not yet clear whether restoring orexin signaling will help when orexin is not deficient.¹⁴

NIH funds research on narcolepsy across a range of areas. For example, the recently completed Clarithromycin Mechanisms in Hypersomnia Syndromes trial built on earlier findings that showed that clarithromycin, a common antibiotic, can reduce daytime sleepiness in people with narcolepsy. The trial investigated the biological mechanisms behind this effect by examining brain activity, inflammation, gut bacteria, and cerebrospinal fluid. In another NIH-funded feasibility trial, the Awareness and Self-Compassion Enhancing Narcolepsy Treatment (ASCENT) study, researchers adapted a mindfulness-based program for people with narcolepsy and delivered it via telehealth alongside standard care. Early results showed promising improvements in mood, self-compassion, and mental health.¹⁶

The National Institute of Neurological Disorders and Stroke (NINDS) is the primary NIH institute that supports narcolepsy research. NINDS funds research into the genetic and immune factors behind orexin neuron loss, the basic biology of sleep, and the development of orexin-based therapies.