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PubMed2026

Safety, tolerability, and efficacy of alixorexton, a selective orexin 2 receptor agonist for narcolepsy type 1 (Vibrance-1): a randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: The clinical potential of orexin 2 receptor (OX2R) agonism for improving measures of wakefulness and cataplexy in patients with narcolepsy type 1 has been described in a phase 2 study. Here, we aimed to evaluate the safety, tolerability, and efficacy of alixorexton, another oral OX2R agonist, in narcolepsy type 1. METHODS: In this randomised, double-blind, placebo-controlled, phase 2 trial, adult participants (aged 18-70 years) with narcolepsy type 1 were recruited from 46 hospitals and private research centres across the USA, Europe, and Australia. Participants were centrally randomly assigned (1:1:1:1) in blocks of four via an interactive response technology system stratified by region and baseline weekly cataplexy rate (WCR) to receive 4 mg, 6 mg, or 8 mg tablets of alixorexton or placebo once daily for 6 weeks, followed by an optional 7-week open-label extension. Participants had narcolepsy type 1, diagnosed per the International Classification of Sleep Disorders, Third Edition, and confirmed by overnight polysomnography and the Multiple Sleep Latency Test or cerebrospinal hypocretin-1 concentrations. The sponsor, assessors, investigators, and participants were masked during the randomised double-blind treatment period. Efficacy and safety assessments were conducted in participants who received at least one dose of study drug. The primary endpoint was change from baseline to week 6 in mean sleep latency (MSL) on the Maintenance of Wakefulness Test (MWT). Safety endpoints included treatment-emergent adverse events. This trial was registered with ClinicalTrials.gov (NCT06358950) and is completed. FINDINGS: Between May 24, 2024, and May 5, 2025, 153 individuals were screened and 92 participants were randomly assigned to receive alixorexton 4 mg (n=23), 6 mg (n=22), 8 mg (n=24), or placebo (n=23). Mean age was 33·5 years (SD 12·1), 57 (62%) were women, and 35 (38%) were men. At week 6, the observed MSL on the MWT was 2·3 min (SD 2·7) for placebo, 24·0 min (8·7) for alixorexton 4 mg, 25·9 min (9·4) for 6 mg, and 28·2 min (11·4) for 8 mg. Alixorexton improved MSL on the MWT, with a least-squares mean placebo-corrected change from baseline of 22·2 min (95% CI 17·2-27·2) for alixorexton 4 mg, 24·1 min (19·0-29·1) for 6 mg, and 26·0 min (21·0-31·0) for 8 mg (adjusted p=0·0099 for 4 mg, adjusted p<0·0001 for 6 mg and 8 mg). Treatment-emergent adverse events occurring in at least 5% of participants given alixorexton and more frequently than those given placebo up to week 6 were pollakiuria (38 [55%]), insomnia (19 [28%]), salivary hypersecretion (17 [25%]), micturition urgency (ten [14%]), blurred vision (ten [14%]), and hyperhidrosis (five [7%]). INTERPRETATION: In this phase 2 trial, once-daily oral alixorexton provided clinically meaningful improvements at 6 weeks for participants with narcolepsy type 1, including in wakefulness, excessive daytime sleepiness, and cataplexy. The treatment was generally well tolerated, with adverse events consistent with the known on-target effects of OX2R agonists. Together, these findings support the further phase 3 evaluation of alixorexton as a potential therapeutic option for people with narcolepsy type 1. FUNDING: Alkermes.

Humans↗

PubMed1975

Depresssion in narcolepsy and hypersommia.

The authors studied the occurrence of depression in 100 randomly selected patients with narcolepsy and in 30 patients with hypersomnia. In the isolated form of idiopathic narcolepsy (without signs of cataplexy, sleep paralysis or hypnagogic hallucinations) depression occurred 28.6 per cent of cases. In idiopathic narcolepsy with cataplexy or other symptoms of sleep dissociation, depression was found in 17.2 per cent of cases. In idiopathic hypersomnia the occurrence of depression was 26.1 per cent. In the majority of cases the endogenous form of depression was observed. In the symptomatic form of narcolepsy and hypersomnia the occurence of depression has not been noted in any case. In most cases a parallel clincial course has been observed between the manifestation of depression and narcolepsy or hypersomnia. During a remission of the depressive state the hypersomniac symptoms decreased or disappeared totally. The authors furter discuss the possible pathophysiological mechanisms of the above mentioned symptoms. They are of the opinion that an important role is played by the secretion and metabolism of the cerebral monamines.

Cataplexy↗

PubMed1979

Narcolepsy: regional cerebral blood flow during sleep and wakefulness.

Serial measurements of regional cerebral blood flow were made by the 135Xe inhalation method during the early stages of sleep and wakefulness in eight normal volunteers and 12 patients with narcolepsy. Electroencephalogram, electro-oculogram, and submental electromyogram were recorded simultaneously. In normals, mean hemispheric gray matter blood flow (Fg) during stages I and II sleep was significantly less (-9.2 percent) than waking values (84.3 +/- 13 ml per 100 gm brain per minute). Maximum regional blood flow decreases during sleep occurred in the brainstem-cerebellar (-25.1 percent), right inferior temporal (-23.1 percent) and bilateral frontal (-18.9 percent) regions (p less than 0.05). In patients with narcolepsy, mean hemispheric Fg while awake was 80.5 +/- 13 ml per 100 gm brain per minute. During REM sleep (n = 2), mean hemispheric Fg increased by 9.8 percent concurrently with large increases (+34.6 percent) in brainstem-cerebellar region flow. During stages I and II sleep without REM (n = 6), there were significant increases in mean hemispheric Fg of +/-20.2 percent (p less than 0.01) and brainstem-cerebellar Fg of 38.0 percent (p less than 0.01), just the opposite of changes in normals. In narcolepsy, there appears to be a reversal of normal cerebral deactivation patterns, particularly involving the brainstem, during stages I and II sleep.

Adult↗

PubMed1976

Narcolepsy. Diagnosis and treatment.

Narcolepsy may affect as many as 200,000 Americans. The illness involves a neurologic defect in the regulation of sleep and wakefulness. The chief symptoms are sleepiness, inappropriate sleep episodes, and cataplexy. A characteristic history of cataplexy establishes the diagnosis. Narcoleptic patients also frequently complain of hypnagogic hallucinations, sleep paralysis, blackouts (or automatic behavior), and disturbed nocturnal sleep. Narcolepsy usually develops in adolescence and is a life-long illness. Symptoms may also appear in young children who may be misdiagnosed as hyperactive or psychotic. No completely satisfactory treatment is available at the present time. The current treatments of choice are methylphenidate (for sleepiness and sleep episodes) and imipramine (for cataplexy). Medication dosages must be adjusted for individual patients. A careful history of the illness can rule out hypothyroidism, hypoglycemia, and epilepsy. Sleep apnea is a serious complication of narcolepsy and may be life threatening.

Adolescent↗

PubMed1979

Narcolepsy: a family study.

We obtained medical and psychological assessments and 48-hr polysomnographic recordings on five sisters, three of whom had narcolepsy. Of the three, two were identical twins. All three narcoleptic sisters cited emotional stress and environmental demands for sustained performance as the major factors which aggravated their symptoms, and corresponding to this, the illness followed a different life course in each of the three. Most striking were the differences between the twin sisters in clinical symptoms and polysomnographic signs. One sister suffered from all the symptoms of narcolepsy and her sleep recording showed the typical sleep onset REM periods of the disease. Her twin suffered only from excessive daytime drowsiness and her sleep recording was normal--at least by the usual criteria. The sleep of all three narcoleptic sisters, however, was significantly more fragmented than that of their normal siblings. Our data suggested that excessive sleep fragmentation was a basic feature of narcolepsy and that it betrayed a constitutional predisposition for sleep to dissociate into its components and to become distributed around the nycthemeron. This process could be aggravated by emotional stress and by environmental demands for sustained vigilance, and this in turn, created the differences in symptoms and signs between individuals with identical genetic predispositions.

Aged↗

PubMed1979

Narcolepsy and automatic behavior: a case report.

Narcolepsy is characterized by excessive daytime sleepiness and cataplexy, which may be accompanied by hypnogogic or hypnopompic hallucinations and sleep paralysis. Automatic behavior is a relatively newly recognized symptom of the narcolepsy syndrome. This case report describes a particularly troublesome sort of automatic behavior--shoplifting--in a narcoleptic patient. It illustrates how a sleep-laboratory evaluation was used to confirm the diagnosis of narcolepsy and considers aspects of the treatment of the problem.

Automatism↗

PubMed1976

Narcolepsy and hypersomnia: review and classification of 642 personally observed cases.

In this paper the author gives a survey and a classification of 642 cases of narcolepsy and hypersomnia which he himself studied in the course of 26 years. 368 cases were classified as narcolepsy, 274 as hypersomnia. The author further classifies narcolepsies according to their etiology, clinical form and pathophysiological mechanisms of origin. Hypersomnias are divided by the author into the symptomatic and the functional groups. According to the author it is useful to distinguish "short cycle hypersomnia", i.e. those with short duration of sleep attacks (hours) and intervals, from "long cycle hypersomnia", i.e. those with long attacks (days or weeks) and intervals. The author goes on to describe different forms of symptomatic and functional hypersomnias, such as idiopathic hypersomnia, neurotic hypersomnia, the Pickwickian syndrome" and its variants as well as different varieties of periodic long cycle hypersomnias. Finally the author makes a brief mention of the syndrome of insufficiency of wakefulness.

Age Factors↗

PubMed1979

Mazindol in the treatment of narcolepsy.

Thirty-four subjects with the narcoleptic syndrome were treated with mazindol 3--8 mg daily for 1 year. Treatment cuased a sustained improvement in narcolepsy, but had no effect on cataplexy or sleep paralysis. The response to mazindol was excellent in six subjects, good in 14, moderate in 12 and poor in two. No cardiovascular effects, haematological toxicity, tolerance or dependence occurred. Mazindol 6 mg had the same effect on narcolepsy as d-amphetamine 50 mg, but caused less side effects.

Adolescent↗

PubMed1976

Problems in the differential diagnosis of narcolepsy versus schizophrenia.

The authors discuss the problems of accurately diagnosing narcolepsy when patients manifest the auxiliary symptoms of this disorder, i.e., cataplexy, hypnagogic hallucinations, and sleep paralysis, which conclude that misdiagnosis of narcolepsy can be avoided if clinicians are aware that this illness can simulate a psychiatric disorder and if they give careful attention to the histroy of the patient's illness.

Adult↗

PubMed1976

A genetic model of narcolepsy.

An analysis of recently published family history data on rapid eye movement (REM) narcolepsy was undertaken to determine the goodness-of-fit of a multifactorial (MF) model of inheritance. The analysis revealed that a two-threshold MF model can successfully account for the prevalence of REM narcolepsy and other disorders of excessive sleep (DES) observed in the first-degree relatives of the REM narcoleptic probands studied.

Humans↗

PubMed1979

Twenty-four-hour secretory patterns of growth hormone, prolactin, and cortisol in narcolepsy.

Twenth-four-hour patterns of plasma GH, PRL, and cortisol concentrations concomitant with sleep stages were studied in four male patients with typical narcolepsy, aged 30--34 yr, and four normal subjects. All medications were withdrawn 2 weeks before the study. Blood was drawn every 20 min during a 24-h fasting period, except for the first sleep cycle of nocturnal sleep when samples were drawn at 5-min intevals. In all of the narcoleptics, a plasma GH peak associated with slow wave sleep at the nocturnal sleep onset was absent (n = 2) or markedly decreased (n = 2). The normal rise of PRL during sleep was present only in a narcoleptic, whereas a significant fall in plasma PRL concentrations occurred immediately after the sleep-onset rapid eye movement period and lasted 1--1.5 h in the remaining three patients. A sleep-onset rapid eye movement period occurred in all of the patients, and this abnormal phenomenon characteristic of narcolepsy was considered to be related to the suppression of GH release at the sleep onset and to the decrease of plasma PRL levels during the early part of sleep. In contrast, the normal circadian periodicity of cortisol secretion was evident in all of the narcoleptics.

Adult↗

PubMed1976

[Premature and usual periods of "rapid" sleep during attacks of diurnal narcolepsy].

The authors studied some psychophysiological characteristics of precocious and usual periods of rapid sleep in 17 patients with polysymptomatic narcolepsy during 92 attacks of day sleep. Precocious rapid sleep duffers from usual one in an inclusion into the dream content the experimental situations and their emotional saturation. The patients underestimated the duration of sleep and were unsatisfied by its quality. These differences indicate to a functional interconnection of rapid sleep with delta-sleep in the process of brain integration of information and assist to understand the pathogenesis of some traits of narcolepsy.

Humans↗

PubMed2025

DNA methylation and multi-omics profiling of T cells uncovers chemotactic pathways and proliferation-linked hypomethylation in narcolepsy type 1.

Narcolepsy type 1 (NT1) is a chronic sleep disorder caused by a loss of orexin-producing cells in the brain and involves autoimmune mechanisms, including the presence of autoreactive T cells. In this study, we performed genome-wide DNA methylation analysis using both CD4+/CD8+ T cells from 42 NT1 patients and 42 controls across discovery and replication cohorts. To identify methylation changes more robustly associated with the disease, we prioritized differentially methylated regions (DMRs) over single-site differentially methylated positions (DMPs). Furthermore, to validate and interpret DMP-level associations, we integrated genome-wide genotype and gene expression data obtained from the same individuals. As a result, the DMR analysis identified 15 reproducible DMRs in CD4+ T cells and 5 in CD8+ T cells, with most DMRs shared between the two cell types. Shared DMRs included regions associated with CCL5 (p = 2.1E-02) and CCR4 (p = 8.3E-03). Integrative analysis with genotype and gene expression data also showed that the DMP related to S100A4, which promotes lymphocyte migration through CCR5 and CXCR3 receptors, was associated with the disease in CD4+ T cells. Pathway analysis of genes identified through both the DMR and integrative analyses indicated enrichment in cell chemotaxis-related pathways, suggesting that aberrant chemokine-mediated cell migration plays a central role in NT1 pathogenesis. Further, NT1-associated methylation changes were predominantly hypomethylation events, significantly enriched in non-promoter, non-CpG island regions (p = 1.74E-102). We further observed that global hypomethylation levels were correlated with hypoSC, a mitotic index estimated from methylation data, highlighting increased T cell proliferation in NT1.

Humans↗

PubMed1975

Methysergide in the treatment of narcolepsy.

Five patients with narcolepsy (four with the allied symptom of cataplexy) were treated with the serotonin antagonist methysergide. All patients had as good control of their sleep attacks while on methysergide therapy as on a control period of dextroamphetamine therapy. The cataplexy was less well controlled by methysergide than by dextroamphetamine, but improved when compared to a period without medication. Two patients developed severe calf claudication while on methysergide.

Adult↗

PubMed1979

Successful treatment of narcolepsy with propranolol: a case report.

A patient with severe narcolepsy and cataplexy had been treated with a high dosage of methylphenidate hydrochloride, but the drug was not effective. To relieve the patient's cardiac arrhythmia, which was assumed to be secondary to drug therapy, we withdrew methylphenidate therapy and started propranolol hydrochloride therapy. When the dosage of propranolol was increased to a level consistent with maximum beta-adrenergic receptor blockade, the attacks were eliminated.

Female↗

PubMed1979

Acromegaly and narcolepsy.

7 of 372 acromegalic patients had troublesome episodes of paroxysmal daytime sleep. Although 3 patients had complete remission of symptoms within a few days of pituitary implantation of isotopes, the cause of this increased frequency of narcolepsy among acromegalic patients is not known.

Acromegaly↗

PubMed1979

The treatment of narcolepsy-cataplexy with nocturnal gamma-hydroxybutyrate.

Sixteen patients with narcolepsy and cataplexy were treated with gamma-hydroxybutyrate (GHB) given at night and tailored to achieve as continuous a night's sleep as possible. The dosage usually consisted of 1.5-2.25 gm orally at bedtime and then one or two further 1.0-1.5 gm doses with awakenings during the night, and totaled about 50 mg/kg. Apart from one patient who took only the bedtime dose, the subjective quality of night sleep improved in all patients and the number of irresistible daytime attacks of sleep and cataplexy substantially diminished. Some residual daytime drowsiness remained and this usually responded well to low doses of methylphenidate. Improvement has been maintained for up to 20 months without the development of tolerance. Two patients experienced adverse side effects necessitating withdrawal of GHB treatment, but no serious toxic effects have occurred.

Adult↗

PubMed1977

Narcolepsy, paranoid psychosis, and tardive dyskinesia: a pharmacological dilemma.

The case history of a 54-year-old man with concomitant narcolepsy, paranoid psychosis, and tardive dyskinesia is presented. These disorders may all result from alteration in catecholamines, serotonin, and/or acetylcholine in the central nervous system. The interactions of the various psychopharmacological agents usually used to treat the disorders when they occur separately are considered in terms of current neurotransmitter hypotheses. The management of this case creates a pharmacological dilemma; the agents used for treatment of each of the disorders separately exacerbate one or both of the other two syndromes.

Chlorpromazine↗