Idiopathic hypersomnia (IH) is a

neurological disorder A neurological disorder is any disorder of the nervous system. Structural, biochemical or electrical abnormalities in the brain, spinal cord or other nerves can result in a range of symptoms. Examples of symptoms include paralysis, muscle weakn ...

which is characterized primarily by excessive sleep and

excessive daytime sleepiness Excessive daytime sleepiness (EDS) is characterized by persistent sleepiness and often a general lack of energy, even during the day after apparently adequate or even prolonged nighttime sleep. EDS can be considered as a broad condition encompass ...

(EDS). The condition typically becomes evident in early adulthood and most patients diagnosed with IH will have had the disorder for many years prior to their diagnosis. , an FDA-approved medication exists for IH, in addition to several off-label treatments (primarily FDA-approved narcolepsy medications). Idiopathic hypersomnia may also be referred to as IH, IHS, or primary hypersomnia and belongs to a group of sleeping disorders known as central hypersomnias, central disorders of hypersomnolence, or hypersomnia of brain origin. ''

Diagnostic and Statistical Manual of Mental Disorders The ''Diagnostic and Statistical Manual of Mental Disorders'' (DSM; latest edition: DSM-5-TR, published in March 2022) is a publication by the American Psychiatric Association (APA) for the classification of mental disorders using a common langu ...

'', Fourth Edition (DSM-IV) defines idiopathic hypersomnia as EDS without

narcolepsy Narcolepsy is a long-term neurological disorder that involves a decreased ability to regulate sleep–wake cycles. Symptoms often include periods of excessive daytime sleepiness and brief involuntary sleep episodes. About 70% of those affect ...

or the associated features of other sleep disorders. It occurs in the absence of medical problems or sleep disruptions, such as

sleep apnea Sleep apnea, also spelled sleep apnoea, is a sleep disorder in which pauses in breathing or periods of shallow breathing during sleep occur more often than normal. Each pause can last for a few seconds to a few minutes and they happen many tim ...

, that can cause secondary

hypersomnia Hypersomnia is a neurological disorder of excessive time spent sleeping or excessive sleepiness. It can have many possible causes (such as seasonal affective disorder) and can cause distress and problems with functioning. In the fifth edition ...

Signs and symptoms

Individuals with IH share common symptoms like

, sleep inertia, brain fog, long sleep periods, and others. *

Excessive daytime sleepiness Excessive daytime sleepiness (EDS) is characterized by persistent sleepiness and often a general lack of energy, even during the day after apparently adequate or even prolonged nighttime sleep. EDS can be considered as a broad condition encompass ...

, characterized by persistent sleepiness throughout the day and often a general lack of energy—even during the day after apparently adequate or even prolonged nighttime sleep. People with EDS nap repeatedly throughout the day and have strong urges to sleep while driving, working, eating, or conversing with others. * Sleep inertia (also known as sleep drunkenness), characterized by having extreme difficulty waking up and feeling an uncontrollable desire to go back to sleep. * Clouding of consciousness characterized by inattention, thought process abnormalities, comprehension abnormalities, and language abnormalities. These symptoms may affect performance on perception, memory, learning, executive functions, language, constructive abilities, voluntary motor control, attention, and mental speed. Affected individuals can complain of forgetfulness, confusion, or inability to think clearly. * Excessive sleep (9 hours or more over a full 24-hour period), without feeling refreshed after waking. Daytime naps can be up to several hours and are also unrefreshing. Some studies have shown increased frequencies of palpitations, digestive problems, difficulty with body temperature regulation, and other symptoms in patients with IH. Anxiety and depression are frequent, likely as a response to chronic illness. A case series in 2010 found that peripheral vascular symptoms, such as cold hands and feet (e.g.,

Raynaud Syndrome Raynaud syndrome, also known as Raynaud's phenomenon, eponymously named after the physician Auguste Gabriel Maurice Raynaud, who first described it in his doctoral thesis in 1862, is a medical condition in which the spasm of small arteries ca ...

), were more common in people with IH than in controls. Other autonomic dysfunctional symptoms, such as fainting episodes, dizziness upon arising, headaches (possibly migrainous in quality), food cravings, and impotence may also be correlated with IH. Researchers have found that people reporting IH symptoms report high levels of autonomic dysfunction on par with other conditions of autonomic failure (i.e., MSA and

diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...

). , there is no evidence to suggest such symptoms are related to IH in any way.

Causes

Unlike

with cataplexy, which has a known cause (

autoimmune In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". ...

destruction of hypocretin-producing neurons), the cause of IH is largely unknown. , researchers have identified a few abnormalities associated with IH, which with further study may help to clarify the etiology. Destruction of noradrenergic neurons has produced hypersomnia in experimental animal studies, and injury to adrenergic neurons has also been shown to lead to hypersomnia. IH has also been associated with a malfunction of the

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad ...

system and decreased

cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates. CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the ...

(CSF)

histamine Histamine is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Since histamine was discover ...

levels. Researchers have recently found an abnormal hypersensitivity to GABA (the major brain chemical responsible for

sedation Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure. Examples of drugs which can be used for sedation include isoflurane, diethyl ether, ...

) in a subset of patients with central hypersomnia i.e.: IH, narcolepsy without cataplexy and long sleepers. They have identified a small (500 to 3000 daltons) naturally occurring bioactive substance (most likely a

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. ...

as it is

trypsin Trypsin is an enzyme in the first section of the small intestine that starts the digestion of protein molecules by cutting these long chains of amino acids into smaller pieces. It is a serine protease from the PA clan superfamily, found in the d ...

-sensitive) in the CSF of affected patients. Although this substance requires further identification of its chemical structure, it is currently referred to as a "somnogen" because it has been shown to cause hyper-reactivity of GABA_A receptors, which leads to increased sedation or somnolence. In essence, it is as though these patients are chronically sedated with a

benzodiazepine Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, ...

(medication which acts through the GABA system) such as Versed or Xanax, even though they do not take these medications.

Diagnosis

Idiopathic hypersomnia lacks a clearly defining biological marker (i.e.

HLA-DQB1 Major histocompatibility complex, class II, DQ beta 1, also known as HLA-DQB1, is a human gene and also denotes the genetic locus that contains this gene. The protein encoded by this gene is one of two proteins that are required to form the DQ he ...

*0602

genotype The genotype of an organism is its complete set of genetic material. Genotype can also be used to refer to the alleles or variants an individual carries in a particular gene or genetic location. The number of alleles an individual can have in a ...

in narcolepsy). Doctors can more carefully exclude these causes of EDS in order to more correctly diagnose IH. However, "even in the presence of other specific causes of hypersomnia, one should carefully assess the contribution of these etiological factors to the complaint of EDS and when specific treatments of these conditions fail to suppress EDS, the additional diagnosis of IH should be considered." The severity of EDS can be quantified by subjective scales, such as the

Epworth Sleepiness Scale The Epworth Sleepiness Scale (ESS) is a scale intended to measure daytime sleepiness that is measured by use of a very short questionnaire. This can be helpful in diagnosing sleep disorders. It was introduced in 1991 by Dr Murray Johns of Epwor ...

and the

Stanford Sleepiness Scale The Stanford Sleepiness Scale (SSS), developed by William C. Dement and colleagues in 1972, is a one-item self-report questionnaire measuring levels of sleepiness throughout the day. The scale, which can be administered in 1–2 minutes, is gen ...

, and also by objective tests, like

actigraphy Actigraphy is a non-invasive method of monitoring human rest/activity cycles. A small actigraph unit, also called an actimetry sensor, is worn for a week or more to measure gross motor activity. The unit is usually in a wristwatch-like package wo ...

psychomotor vigilance task A psychomotor vigilance task (PVT) is a sustained-attention, reaction-timed task that measures the consistency with which subjects respond to a visual stimulus. Research indicates increased sleep debt or sleep deficit correlates with deteriorat ...

, maintenance of wakefulness test (MWT), multiple sleep latency test (MSLT) although as per latest research studies, the effectiveness of MSLT has been called into question. Several groups of researchers have found normal MSLT results in patients who otherwise seem to have IH. Therefore, when IH is suspected, researchers suggest appending a 24-hour continuous polysomnography to the standard overnight/MSLT study in order to record total sleep time. The recent studies have also found that reports of sleepiness in IH relate more to mental fatigue rather than physiological sleepiness per se and the subjective scales like ESS, IH symptom diary (IHSD) and PGIC better captures the severity of symptoms consistently. It is also important to note that whereas narcolepsy is strongly associated with the

*0602

, "HLA typing is of no help in the positive diagnosis of idiopathic hypersomnia." This is "despite some reports that suggest an increase 'sic''frequency of HLA Cw2 and DRS in idiopathic hypersomnia subjects." In patients with IH, polysomnography typically shows short sleep latency, increased mean slow wave sleep, and a high mean sleep efficiency. "Latency to REM sleep and percentages of light sleep and REM sleep were normal, compared with normal ranges." Despite this, one study has found increased sleep fragmentation in patients with IH without long sleep time, suggesting multiple possible presentations. Per ICSD-3, five criteria must be met for a diagnosis of IH: # Daytime lapses into sleep or an irrepressible need to sleep on a daily basis, for at least 3 months # Absence of insufficient sleep syndrome # Absence of cataplexy # Absence of other causes of hypersomnia # The presence of positive MSLT tests. The latest ICD 10 defines IH with long sleep time as a neurological disorder that is a rare sleep disorder characterized by prolonged sleep at night and extreme sleepiness during the day. There are no apparent causes. This disorder affects the ability to function. It is of

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

origin characterized by prolonged nocturnal sleep and periods of daytime drowsiness. Affected individuals experience difficulty with awakening in the morning and may have associated sleep drunkenness, automatic behaviors, and memory disturbances. This condition differs from narcolepsy in that daytime sleep periods are longer, there is no association with cataplexy, and the multiple sleep latency onset test does not record sleep-onset rapid eye movement sleep.

Management

Since the underlying mechanism is not yet fully understood, treatment efforts have usually focused on symptom management. In August 2021, low-sodium oxybate (Xywav) became the first U.S. FDA-approved treatment for idiopathic hypersomnia. Wake-promoting medications used in narcolepsy are also commonly used

off-label Off-label use is the use of pharmaceutical drugs for an unapproved indication or in an unapproved age group, dosage, or route of administration. Both prescription drugs and over-the-counter drugs (OTCs) can be used in off-label ways, although ...

to help manage the excessive daytime sleepiness of IH. CNS stimulants tend to be less effective for IH than they are for narcolepsy and may be less well tolerated.

Stimulants

The main treatment of excessive daytime sleepiness is done through central nervous system stimulants.

Methylphenidate Methylphenidate, sold under the brand names Ritalin and Concerta among others, is the most widely prescribed central nervous system (CNS) stimulant medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent ...

and Dextroamphetamine are most used stimulants to controlled EDS. Increased dopamine release is felt to be the main property explaining wake-promotion from these medications.

Insomnia Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...

is another common side effect and may require additional treatment.

Non-stimulant wake-promoting medications

Solriamfetol is the first and only dual-acting dopamine and norepinephrine reuptake inhibitor approved by the FDA to improve wakefulness in adults living with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea. Pitolisant, a selective histamine 3 (H3) receptor antagonist/inverse agonist, was approved by FDA during August 2019. It works by increasing the synthesis and release of histamine, a wake-promoting neurotransmitter in the brain.

Modafinil Modafinil, sold under the brand name Provigil among others, is a central nervous system (CNS) stimulant medication used to treat sleepiness due to narcolepsy, shift work sleep disorder, and obstructive sleep apnea. While it has seen off-la ...

and Armodafinil elevate hypothalamic

levels, and they are known to bind to the dopamine transporter, thereby inhibiting dopamine reuptake. Modafinil can cause uncomfortable side effects, including nausea, headache, and a dry mouth for some patients, while other patients report no noticeable improvement even on relatively high dosages. They may also "interact with low-dose contraceptives, potentially reducing efficacy, although the scientific data supporting this claim is weak and rests on poorly documented anecdotes."

Sleep promoting medications

Sodium oxybate is an

orphan drug An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases. The assignment of ...

which was designed specifically for the treatment of narcolepsy. Common side effects include nausea, dizziness, and hallucinations. A 2016 study by Leu-Semenescu et al. found sodium oxybate reduced daytime sleepiness in IH to the same degree as in patients with narcolepsy type 1, and the drug improved severe sleep inertia in 71% of the hypersomnia patients. In July 2020, the FDA approved Xywav™ (calcium, magnesium, potassium, and sodium oxybates), an oral solution for the treatment of cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age and older with narcolepsy.

Cognitive Behavioral Therapy

Although behavioral approaches have not been demonstrated to improve clinical markers of IH, cognitive behavioral therapy has been found to potentially reduce depressive symptoms and improve

self-efficacy In psychology, self-efficacy is an individual's belief in their capacity to act in the ways necessary to reach specific goals. The concept was originally proposed by the psychologist Albert Bandura. Self-efficacy affects every area of human end ...

in people with central disorders of hypersomnolence.

Prognosis

IH can profoundly affect work, education, and quality of life due to excessive daytime somnolence. Patients will often need to adapt their lifestyle to avoid situations that might be dangerous while sleepy, such as high risk work, or driving. The risks associated with these activities have been found to be higher for patients with hypersomnias than for those with sleep apnea or severe insomnia.

Epidemiology

Typically, the symptoms of IH begin in adolescence or young adulthood, although they can begin at a later age. After onset, hypersomnia often worsens over several years, but it is often stable by the time of diagnosis and appears to be a lifelong condition. Spontaneous remission is only seen in 10–15% of patients. According to the limited epidemiological data that exists, IH "has more of a female preponderance (1.8/1)." Family cases are frequent, in a range from 25% to 66% without any clear mode of inheritance." IH has long been considered a rare disease, believed to be 10 times less frequent than narcolepsy. The prevalence of narcolepsy (with cataplexy) is estimated between 1/3,300 and 1/5,000. Although the true prevalence of IH is unknown, it is estimated at 1/10,000 to 1/25,000 for the long sleep form and 1/11,000 to 1/100,000 without long sleep. A more precise estimate "is complicated by a lack of clear biologic markers" and a lack of "unambiguous diagnostic criteria." Because of the rarity of IH, research into the condition is limited "Patients are rare, researchers and scientists involved in the field are few and research findings are therefore scarce." "In Europe and in North America there is now a public health concern about helping patients and families affected by these rare diseases. Due to the complexity of the disease, they often experience difficulties to be diagnosed and often face social and professional consequences."

Research

GABA-directed medications

There is ongoing research into the efficacy of gamma aminobutyric acid A (GABA_A) receptor antagonists for the treatment of IH. Research findings suggest that the GABA neurotransmitter system plays a significant role in the etiology of primary hypersomnias, such as IH and Narcolepsy Type 2. Given the possible role of hyperactive GABA_A receptors in IH, medications that could counteract this activity are being studied to test their potential to improve sleepiness. These currently include clarithromycin and flumazenil. Flumazenil, a GABA_A receptor antagonist is approved by the FDA for use in anesthesia reversal and

benzodiazepine overdose Benzodiazepine overdose describes the ingestion of one of the drugs in the benzodiazepine class in quantities greater than are recommended or generally practiced. The most common symptoms of overdose include central nervous system (CNS) depressio ...

. Research has shown that flumazenil provides relief for most patients whose CSF contains the unknown "somnogen" that enhances the function of GABA_A receptors, making them more susceptible to the sleep-inducing effect of GABA. For one patient, daily administration of flumazenil by sublingual lozenge and topical cream has proven effective for several years. A 2014 case report also showed improvement in IH symptoms after treatment with a continuous subcutaneous flumazenil administration. The patient was treated with a short-term subcutaneous administration through 96-hour continuous low dose (4 mg/day) infusion of flumazenil, followed by a slow-release long term subcutaneous administration through flumazenil implant. Clarithromycin, an antibiotic approved by the FDA for the treatment of infections, was found to return the function of the GABA system to normal in patients with IH. In the pilot study, clarithromycin improved subjective sleepiness in GABA-related hypersomnia. In 2013, a retrospective review evaluating longer-term clarithromycin use showed efficacy in a large percentage of patients with GABA-related hypersomnia.

Transcranial direct-current stimulation (tDCS)

Dr. Ferini-Strambi and his colleagues in Milan, Italy, performed neurologic examinations by applying anodal tDCS by placing one electrode over the left dorsolateral prefrontal cortex, with the cathode over the contralateral orbit over 3 weeks period and found that seven of the eight participants (87.5%) reported improvement in their daytime sleepiness, including for up to two weeks after the end of the study.

Transcranial magnetic stimulation (TMS)

Neural networks that regulate arousal and sleep comprise a bottom-up (from the brainstem to the cortex) pathway and a top-down (corticothalamic) pathway. The bottom-up pathway emerges from the ascending reticular arousal system (ARAS) and activates the cortex via well-characterized thalamic and nonthalamic pathways through cholinergic and aminergic neurotransmission. The bottom-up pathway represents the leverage point for pharmaceutical interventions. It is complemented by a corticothalamic top-down pathway, which appears to be modifiable through noninvasive brain stimulation (NIBS) techniques. A single case report study indicates that high-frequency repetitive transcranial magnetic stimulation (HF rTMS) over the left dorsolateral prefrontal cortex (DLPFC) might represent an alternative choice for symptom control in narcoleptic patients with cataplexy. rTMS may also exert intrinsic effects on hypersomnia in depressed adolescents.

Mazindol

Mazindol is a stimulant similar to amphetamines that "has been shown to be effective in treating hypersomnia in narcoleptics." However, it is not currently approved in the US.

Selegiline

Selegiline Selegiline, also known as L-deprenyl and sold under the brand names Eldepryl and Emsam among others, is a medication which is used in the treatment of Parkinson's disease and major depressive disorder. It is provided in the form of a capsule or ...

, monoamine oxidase type B (MAO-B) inhibitor works by slowing the breakdown of certain substances in the brain (mostly dopamine, but also serotonin and norepinephrine). It may also be useful, as it is also a metabolic precursor of amphetamine and exerts most of its therapeutic effects through amphetamine metabolism. It is not commonly prescribed for people with narcolepsy because of the high dosage required and potential for severe side effects.

Atomoxetine

Atomoxetine Atomoxetine, sold under the brand name Strattera, among others, is a medication used to treat attention deficit hyperactivity disorder (ADHD). It may be used alone or along with psychostimulants. It is also used as a cognitive enhancer to imp ...

(or

reboxetine Reboxetine, sold under the brand name Edronax among others, is a drug of the norepinephrine reuptake inhibitor (NRI) class, marketed as an antidepressant by Pfizer for use in the treatment of major depression, although it has also been used of ...

in Europe) is an adrenergic reuptake inhibitor which increases wakefulness (generally less strongly than the medications which act on dopamine) and which has been argued to have a "clear use in the therapeutic arsenal against narcolepsy and hypersomnia although undocumented by clinical trials."

Ritanserin

Ritanserin Ritanserin, also known by its developmental code name R-55667, is a serotonin antagonist medication described as an anxiolytic, antidepressant, antiparkinsonian agent, and antihypertensive agent. It was never marketed for medical use due to saf ...

is a

serotonin antagonist A serotonin antagonist, or serotonin receptor antagonist, is a drug used to inhibit the action at serotonin (5-HT) receptors. Types 5-HT2A antagonists Antagonists of the 5-HT2A receptor are sometimes used as atypical antipsychotics (contrast wi ...

that has "been shown to improve daytime alertness and subjective sleep quality in patients on their usual narcolepsy medications." It is intended as an adjunct (supplement to another main therapeutic agent), and although it is not available in the US, it is available in Europe.

Antidepressants

Antidepressants seems to have some therapeutic effects as they enhance synaptic levels of noradrenaline and serotonin. Further, different medicines are known to augment the activity of one another like as seen in the case of

Fluoxetine Fluoxetine, sold under the brand names Prozac and Sarafem, among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used for the treatment of major depressive disorder, obsessive–compulsive diso ...

which augmented the activity of methylphenidate when taken together.

Bupropion Bupropion, sold under the brand names Wellbutrin and Zyban among others, is an atypical antidepressant primarily used to treat major depressive disorder and to support smoking cessation. It is also popular as an add-on medication in the cas ...

, a norepinephrine-dopamine reuptake inhibitor (NDRI), which works by inhibiting the reabsorption of two important brain chemicals – norepinephrine and dopamine, is known to have wake-promoting effects.

, an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class is also known to have mild stimulating effects. It is also known to augment the activity of methylphenidate.

Caffeine

Caffeine Caffeine is a central nervous system (CNS) stimulant of the methylxanthine chemical classification, class. It is mainly recreational drug use, used recreationally as a Nootropic, cognitive enhancer, increasing alertness and attentional perfor ...

is one of the safer nondopaminergic wake-promoting compounds. It is widely used but "has intolerable side effects at high doses (including cardiovascular), and it is generally not efficient enough for patients with hypersomnia or narcolepsy." Although it is commonly used by people with IH or narcolepsy, many people with these disorders report that it has only limited benefit on their sleepiness.

Melatonin

Melatonin Melatonin is a natural product found in plants and animals. It is primarily known in animals as a hormone released by the pineal gland in the brain at night, and has long been associated with control of the sleep–wake cycle. In vertebrat ...

is a hormone that the body produces to help regulate sleep. One small study, which used a dose of 2 mg slow-release melatonin at bedtime, found that 50% of participants had “shortened nocturnal sleep duration, decreased sleep drunkenness and relieved daytime sleepiness.” Other studies have shown that melatonin synchronizes the circadian rhythms, and improves the “onset, duration and quality of sleep.”

Levothyroxine

There have been some studies suggesting levothyroxine as a possible treatment for IH, especially for patients with

subclinical hypothyroidism Hypothyroidism (also called ''underactive thyroid'', ''low thyroid'' or ''hypothyreosis'') is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormone. It can cause a number of symptoms, such as po ...

.H. Shinno et al. (June 2011). "Effect of levothyroxine on prolonged nocturnal sleep time and excessive daytime somnolence in patients with idiopathic hypersomnia." Sleep Medicine Vol. 12 6: 578–583 This treatment does carry potential risks (especially for patients without

hypothyroidism Hypothyroidism (also called ''underactive thyroid'', ''low thyroid'' or ''hypothyreosis'') is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormone. It can cause a number of symptoms, such as ...

or subclinical hypothroidism), which include cardiac arrhythmia.

Hypocretin agonists

Hypocretin-1 has been shown to be strongly wake-promoting in animal models, but it does not cross the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable border of endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of the central nervous system where ne ...

Suvorexant Suvorexant, sold under the brand name Belsomra, is an orexin antagonist medication which is used in the treatment of insomnia. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset and/or mainte ...

, a hypocretin receptor antagonist, has been developed to limit the natural effects of hypocretin in patients with insomnia. It is therefore possible that a hypocretin

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ag ...

may be similarly developed for the treatment of hypersomnia.

Acetylcholinesterase inhibitor

Antidepressants seems to have some therapeutic effects as they enhance synaptic levels of noradrenaline and serotonin and for same reason enhancing the levels of acetylcholine may have some therapeutic effect. Donepezil showed improvement in one patient by decreasing ESS score from 20 up to 14. Memantine has also shown some positive effect on a patient with narcolepsy.

Levodopa

Levodopa -DOPA, also known as levodopa and -3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize -DOPA ...

is an amino acid and is the precursor to the neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline). As per a study of six narcoleptic patients it was found that L-dopa improved vigilance and performance as evaluated by the AVS and the FCRTT, while the capacity to fall asleep rapidly remained unchanged as evaluated by the MSLT. It raises the hypothesis that dopamine may play a role in the physiopathology of excessive daytime sleepiness of this condition.

Carnitine

Carnitine Carnitine is a quaternary ammonium compound involved in metabolism in most mammals, plants, and some bacteria. In support of energy metabolism, carnitine transports long-chain fatty acids into mitochondria to be oxidized for energy production, an ...

, has also been shown to improve narcolepsy symptoms (including daytime sleepiness) by increasing fatty-acid oxidation. Abnormally low levels of acylcarnitine have been observed in patients with narcolepsy. These same low levels have been associated with primary hypersomnia in general in mouse studies. "Mice with systemic carnitine deficiency exhibit a higher frequency of fragmented wakefulness and rapid eye movement (REM) sleep, and reduced locomotor activity." Administration of acetyl-L-carnitine was shown to improve these symptoms in mice. A subsequent human trial found that narcolepsy patients given

L-carnitine Carnitine is a quaternary ammonium compound involved in metabolism in most mammals, plants, and some bacteria. In support of energy metabolism, carnitine transports long-chain fatty acids into mitochondria to be oxidized for energy production, an ...

spent less total time in daytime sleep than patients who were given placebo.

References

External links

{{SleepSeries2 Sleep disorders