RARE DISEASE
Idiopathic hypersomnia
Idiopathic hypersomnia
Idiopathic hypersomnia
Synonyms: Idiopathic excessive sleepiness
Synonyms: Idiopathic excessive sleepiness
Synonyms: Idiopathic excessive sleepiness
Drug discovery
13
drugs
With orphan designations
Overview
Idiopathic hypersomnia (IH) is a chronic neurologic sleep disorder characterized by excessive daytime sleepiness unrelieved by adequate or prolonged sleep, accompanied by sleep inertia, prolonged nonrestorative naps, and cognitive dysfunction [1][3][7]. Diagnosis requires exclusion of other hypersomnolence causes via polysomnography and multiple sleep latency testing, with absence of cataplexy or sleep-onset REM periods [1][4][8]. While similar to narcolepsy type 2, IH lacks specific biomarkers and demonstrates distinct sleep architecture patterns [5][6].
Burden
Functional: 47% work productivity loss, 12% absenteeism, 64% daily activity impairment [9][17].
Cognitive/psychiatric: 63% with moderate-severe cognitive complaints; 36% depression prevalence (vs 5% general population) [2][5][6].
Diagnostic delays: 7-9 years average, contributing to increased healthcare utilization [5][13][15].
Therapies
Pharmacologic: Low-sodium oxybate (FDA-approved), modafinil (first-line), and pitolisant (off-label) [3][8][12]. Stimulants (methylphenidate/amphetamine) for refractory cases [1][8].
Nonpharmacologic: Sleep hygiene optimization, cognitive behavioral therapy, and activity accommodations [12][16].
58-73% require multiple therapies; 20-30% report inadequate symptom control [9][14].
Categories: rare neurological diseases
Research Papers
284 drug discovery papers about Idiopathic hypersomnia, with 1 first-in-class and 19 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
284 drug discovery papers about Idiopathic hypersomnia, with 1 first-in-class and 19 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-31 | Therapeutic potential of targeting the orexin (hypocretin) system in sleep disorders.
Sleep is emerging as a key health topic in modern society. The prevalence of and focus on sleep-wake disorders is increasing, which has led to a large interest from the pharmaceutical industry to develop new treatments targeting sleep biology (that is, drugs that have the potential to mimic normal sleep-wake physiology). The orexin (also known as hypocretin) system is one of the key targets and regulators of sleep and wakefulness. In this Review, we will discuss the mechanisms by which loss of orexin signalling is involved in narcolepsy type 1 and whether loss and/or disruption of orexin signalling might have a role in other sleep disorders such as narcolepsy type 2, idiopathic hypersomnia and obstructive sleep apnoea. We will also describe current and emerging therapies for sleep disorders involving orexin, such as orexin receptor antagonists for insomnia and orexin receptor agonists for narcolepsy.
2026-07-20 | Development of Narcolepsy Type 1 Following COVID-19 Infection in a Patient Previously Diagnosed With Idiopathic Hypersomnia: A Case Report
Narcolepsy type 1 is a rare sleep disorder characterized by excessive daytime sleepiness (EDS) and cataplexy, thought to result from the immune-mediated destruction of hypocretin-producing neurons in genetically susceptible individuals. Viral infections have been implicated as potential environmental triggers. We present the case of a 17-year-old female National Collegiate Athletic Association (NCAA) Division I student-athlete with a prior diagnosis of idiopathic hypersomnia who developed new-onset cataplexy following COVID-19 infection. Initial polysomnography and multiple sleep latency testing demonstrated severe hypersomnolence without sleep-onset rapid eye movement periods. Several months later, she developed emotionally triggered episodes of muscle weakness consistent with cataplexy. Repeat multiple sleep latency testing demonstrated only one sleep-onset rapid eye movement period; however, given the development of typical cataplexy and the overall clinical presentation, a clinical diagnosis of narcolepsy type 1 was made. Cerebrospinal fluid hypocretin testing was not performed. Symptoms were refractory to multiple stimulant and antidepressant regimens but responded well to sodium oxybate in combination with solriamfetol, resulting in the resolution of EDS and cataplexy. This case highlights a possible temporal association between COVID-19 infection and the subsequent development of narcolepsy type 1 and underscores the importance of clinical judgment when objective diagnostic testing is inconclusive.
2026-06-16 | Redefining hypersomnia disorders in the context of psychiatry.
Daytime sleepiness and excessive sleep are frequent symptoms. When these symptoms are recognized, they are often attributed to comorbid depression or, following ambulatory screening, to obstructive sleep apnea (OSA). While OSA affects 20-50% of the population, more frequently in men, its contribution to sleepiness in the general population is modest, and subjective sleepiness shows stronger associations with depression, insufficient sleep, and shift work. As a result, mild OSA in the presence of sleepiness is often overtreated. Further, stimulants are used as adjunct therapy in depression despite limited evidence. When referred to sleep disorder specialists, after exclusion of OSA, these patients are typically evaluated using a daytime nap test, the Multiple Sleep Latency Test (MSLT). The MSLT is used to diagnose Narcolepsy or Idiopathic Hypersomnia. Problematically, the MSLT performs well only to confirm narcolepsy type 1, a disorder with cataplexy and caused by orexin deficiency. A high false positive rate occurs in the absence of cataplexy, leading to questionable diagnoses of narcolepsy type 2 and idiopathic hypersomnia. A return to four historical subtypes of central nervous system hypersomnolence independent of MSLT testing is proposed. Narcolepsy Type 1: cataplexy, refreshing naps, sleep-onset REM periods. It is caused by orexin deficiency, responds to oxybate, antidepressants, stimulants, and low dose orexin receptor 2 agonists (in development). Narcolepsy-like hypersomnolence: Irresistible sleep attacks with short, refreshing naps. Insufficient Sleep must be excluded. It is often responsive to modafinil. Idiopathic Hypersomnia with sleep inertia and unrefreshing sleep: Excessive sleep amounts, severe sleep inertia, and long, unrefreshing naps. Association with psychiatric comorbidities, notably resolved depression, is frequent. Sodium oxybate can be transformative. Kleine-Levin Syndrome: periodic extreme hypersomnia with apathy and derealization. Responds to lithium in ∼50% of cases. A pathophysiological overlap with bipolar disorder is likely. A greater collaboration between psychiatry and sleep medicine is needed considering the emergence of orexin receptor agonists as potential therapies for hypersomnia.
2026-05-30 | Slow Wave Activity During Nocturnal Sleep in Hypersomnolence Disorder.
Slow waves during non-rapid eye movement (NREM) sleep are associated with the restorative aspects of sleep. Previous research has suggested reduced normalized slow wave activity (SWA), particularly in the first cycle of NREM sleep, as a feature of hypersomnolence disorder (HD); however, the scarcity of existing research highlights the need for replication studies. Thus, the aim of this investigation was to evaluate normalized SWA in patients with HD, relative to healthy sleeper controls (HSC). Nocturnal polysomnography from 37 unmedicated HD clinical patients were compared against 29 HSC. Six-channel electroencephalographic data from polysomnography was processed according to consensus standards. Normalized SWA (0.5-4.5hz) was calculated from artefact-free NREM epochs for all-night data, as well as sleep cycle 1, 2, and 3. Normalized SWA was compared across groups, with adjusted analyses accounting for age, sex, body mass index, and depressive symptomatology. Post hoc analyses compared HD who met objective criteria for idiopathic hypersomnia (HD/IH+), those who did not (HD/IH-), and HSC. HD demonstrated significantly reduced all-night, normalized SWA in unadjusted analyses across all channels, without significant differences observed in fully adjusted analyses. In cycle 1, HD displayed significantly reduced normalized SWA across all channels in both unadjusted and adjusted analyses. HD/IH+ and HD/IH- were statistically comparable in normalized SWA across all analyses. This study provides further evidence of reduced SWA, particularly during cycle 1 of NREM sleep, as a core feature of HD. Future studies that investigate the causal role of slow waves in the pathophysiology of HD are warranted.
2026-05-29 | Management of Central Disorders of Hypersomnolence in Pregnancy and Lactation.
Over 37% of pregnant women report excessive daytime sleepiness or hypersomnia during the first trimester, and commonly throughout the remaining trimesters of pregnancy and the postpartum period. The clinical presentation and symptoms of central disorders of hypersomnolence (CDH) such as narcolepsy, idiopathic hypersomnia, or excessive daytime sleepiness secondary to shift work or obstructive sleep apnea may be confounded by physiological changes in sleep architecture and hormonal fluctuations occurring during pregnancy. These overlapping features may cause delays in diagnosis and treatment, impacting quality of life, maternal functioning, and overall health. Management of CDH during pregnancy and lactation requires careful consideration of maternal benefits, potential side effects of medications and fetal and neonatal safety. Here, we present a case of idiopathic hypersomnia and detail management and outcomes during pregnancy and lactation. We briefly review the existing literature on prevalence, pathophysiological mechanisms, diagnostic challenges, objective findings, and risks posed by CDH in pregnancy and lactation. In this narrative review for primary care clinicians, we also summarize currently available evidence regarding the efficacy, teratogenic and other risks of pharmacologic agents used in the treatment of CDH in pregnancy and lactation. Lastly, we provide a clinical algorithm for management of CDH during pregnancy and lactation.
2026-07-31 | Therapeutic potential of targeting the orexin (hypocretin) system in sleep disorders.
Sleep is emerging as a key health topic in modern society. The prevalence of and focus on sleep-wake disorders is increasing, which has led to a large interest from the pharmaceutical industry to develop new treatments targeting sleep biology (that is, drugs that have the potential to mimic normal sleep-wake physiology). The orexin (also known as hypocretin) system is one of the key targets and regulators of sleep and wakefulness. In this Review, we will discuss the mechanisms by which loss of orexin signalling is involved in narcolepsy type 1 and whether loss and/or disruption of orexin signalling might have a role in other sleep disorders such as narcolepsy type 2, idiopathic hypersomnia and obstructive sleep apnoea. We will also describe current and emerging therapies for sleep disorders involving orexin, such as orexin receptor antagonists for insomnia and orexin receptor agonists for narcolepsy.
2026-07-20 | Development of Narcolepsy Type 1 Following COVID-19 Infection in a Patient Previously Diagnosed With Idiopathic Hypersomnia: A Case Report
Narcolepsy type 1 is a rare sleep disorder characterized by excessive daytime sleepiness (EDS) and cataplexy, thought to result from the immune-mediated destruction of hypocretin-producing neurons in genetically susceptible individuals. Viral infections have been implicated as potential environmental triggers. We present the case of a 17-year-old female National Collegiate Athletic Association (NCAA) Division I student-athlete with a prior diagnosis of idiopathic hypersomnia who developed new-onset cataplexy following COVID-19 infection. Initial polysomnography and multiple sleep latency testing demonstrated severe hypersomnolence without sleep-onset rapid eye movement periods. Several months later, she developed emotionally triggered episodes of muscle weakness consistent with cataplexy. Repeat multiple sleep latency testing demonstrated only one sleep-onset rapid eye movement period; however, given the development of typical cataplexy and the overall clinical presentation, a clinical diagnosis of narcolepsy type 1 was made. Cerebrospinal fluid hypocretin testing was not performed. Symptoms were refractory to multiple stimulant and antidepressant regimens but responded well to sodium oxybate in combination with solriamfetol, resulting in the resolution of EDS and cataplexy. This case highlights a possible temporal association between COVID-19 infection and the subsequent development of narcolepsy type 1 and underscores the importance of clinical judgment when objective diagnostic testing is inconclusive.
2026-06-16 | Redefining hypersomnia disorders in the context of psychiatry.
Daytime sleepiness and excessive sleep are frequent symptoms. When these symptoms are recognized, they are often attributed to comorbid depression or, following ambulatory screening, to obstructive sleep apnea (OSA). While OSA affects 20-50% of the population, more frequently in men, its contribution to sleepiness in the general population is modest, and subjective sleepiness shows stronger associations with depression, insufficient sleep, and shift work. As a result, mild OSA in the presence of sleepiness is often overtreated. Further, stimulants are used as adjunct therapy in depression despite limited evidence. When referred to sleep disorder specialists, after exclusion of OSA, these patients are typically evaluated using a daytime nap test, the Multiple Sleep Latency Test (MSLT). The MSLT is used to diagnose Narcolepsy or Idiopathic Hypersomnia. Problematically, the MSLT performs well only to confirm narcolepsy type 1, a disorder with cataplexy and caused by orexin deficiency. A high false positive rate occurs in the absence of cataplexy, leading to questionable diagnoses of narcolepsy type 2 and idiopathic hypersomnia. A return to four historical subtypes of central nervous system hypersomnolence independent of MSLT testing is proposed. Narcolepsy Type 1: cataplexy, refreshing naps, sleep-onset REM periods. It is caused by orexin deficiency, responds to oxybate, antidepressants, stimulants, and low dose orexin receptor 2 agonists (in development). Narcolepsy-like hypersomnolence: Irresistible sleep attacks with short, refreshing naps. Insufficient Sleep must be excluded. It is often responsive to modafinil. Idiopathic Hypersomnia with sleep inertia and unrefreshing sleep: Excessive sleep amounts, severe sleep inertia, and long, unrefreshing naps. Association with psychiatric comorbidities, notably resolved depression, is frequent. Sodium oxybate can be transformative. Kleine-Levin Syndrome: periodic extreme hypersomnia with apathy and derealization. Responds to lithium in ∼50% of cases. A pathophysiological overlap with bipolar disorder is likely. A greater collaboration between psychiatry and sleep medicine is needed considering the emergence of orexin receptor agonists as potential therapies for hypersomnia.
2026-05-30 | Slow Wave Activity During Nocturnal Sleep in Hypersomnolence Disorder.
Slow waves during non-rapid eye movement (NREM) sleep are associated with the restorative aspects of sleep. Previous research has suggested reduced normalized slow wave activity (SWA), particularly in the first cycle of NREM sleep, as a feature of hypersomnolence disorder (HD); however, the scarcity of existing research highlights the need for replication studies. Thus, the aim of this investigation was to evaluate normalized SWA in patients with HD, relative to healthy sleeper controls (HSC). Nocturnal polysomnography from 37 unmedicated HD clinical patients were compared against 29 HSC. Six-channel electroencephalographic data from polysomnography was processed according to consensus standards. Normalized SWA (0.5-4.5hz) was calculated from artefact-free NREM epochs for all-night data, as well as sleep cycle 1, 2, and 3. Normalized SWA was compared across groups, with adjusted analyses accounting for age, sex, body mass index, and depressive symptomatology. Post hoc analyses compared HD who met objective criteria for idiopathic hypersomnia (HD/IH+), those who did not (HD/IH-), and HSC. HD demonstrated significantly reduced all-night, normalized SWA in unadjusted analyses across all channels, without significant differences observed in fully adjusted analyses. In cycle 1, HD displayed significantly reduced normalized SWA across all channels in both unadjusted and adjusted analyses. HD/IH+ and HD/IH- were statistically comparable in normalized SWA across all analyses. This study provides further evidence of reduced SWA, particularly during cycle 1 of NREM sleep, as a core feature of HD. Future studies that investigate the causal role of slow waves in the pathophysiology of HD are warranted.
2026-05-29 | Management of Central Disorders of Hypersomnolence in Pregnancy and Lactation.
Over 37% of pregnant women report excessive daytime sleepiness or hypersomnia during the first trimester, and commonly throughout the remaining trimesters of pregnancy and the postpartum period. The clinical presentation and symptoms of central disorders of hypersomnolence (CDH) such as narcolepsy, idiopathic hypersomnia, or excessive daytime sleepiness secondary to shift work or obstructive sleep apnea may be confounded by physiological changes in sleep architecture and hormonal fluctuations occurring during pregnancy. These overlapping features may cause delays in diagnosis and treatment, impacting quality of life, maternal functioning, and overall health. Management of CDH during pregnancy and lactation requires careful consideration of maternal benefits, potential side effects of medications and fetal and neonatal safety. Here, we present a case of idiopathic hypersomnia and detail management and outcomes during pregnancy and lactation. We briefly review the existing literature on prevalence, pathophysiological mechanisms, diagnostic challenges, objective findings, and risks posed by CDH in pregnancy and lactation. In this narrative review for primary care clinicians, we also summarize currently available evidence regarding the efficacy, teratogenic and other risks of pharmacologic agents used in the treatment of CDH in pregnancy and lactation. Lastly, we provide a clinical algorithm for management of CDH during pregnancy and lactation.
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Drug Discovery Landscape
13 orphan drug designations for Idiopathic hypersomnia, including 1 approved therapy.
13 orphan drug designations for Idiopathic hypersomnia, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
alixorexton | small molecules | FDA | 2026-06-11 | — | Alkermes, Inc. |
oxybate | small molecules | FDA | 2026-06-04 | — | Tris Pharma, Inc. |
11-Fluoro-N-[(42S, 43S)-13,15,22--trifluoro-5-oxo-8-oxa-4(2,1)-piperidina-1(1,2),2(1,3)-dibenzenacyclooctaphane-43-yl] cyclopropane-1-sulfonamide | small molecules | FDA | 2026-06-04 | — | Centessa Pharmaceuticals (UK) Limited |
sodium oxybate | small molecules | FDA | 2025-06-04 | — | Avadel CNS Pharmaceuticals, LLC |
Serdexmethylphenidate | small molecules | EMA | 2024-05-24 | — | Zevra Denmark A/S |
pitolisant | small molecules | FDA | 2023-09-05 | — | Harmony Biosciences Management, Inc. |
serdexmethylphenidate | small molecules | FDA | 2022-11-17 | — | Collegium Pharmaceutical Inc. |
mazindol | small molecules | FDA | 2022-10-31 | — | NLS Pharmaceutics AG |
Mazindol | small molecules | EMA | 2022-08-10 | — | Propharma Group The Netherlands B.V. |
Calcium oxybate, magnesium oxybate, potassium oxybate, sodium oxybate | small molecules | EMA | 2021-01-06 | — | Jazz Pharmaceuticals Ireland Limited |
calcium, magnesium, potassium, and sodium oxybates [Xywav] | small molecules | FDA | 2019-07-31 | 2021-08-12 | Jazz Pharmaceuticals Ireland Limited |
Pentetrazol | small molecules | EMA | 2015-11-11 | — | Pharma Gateway AB |
pentetrazol | small molecules | FDA | 2015-09-09 | — | Balance Therapeutics, Inc. |
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