暂无摘要。

OBJECTIVE: Idiopathic hypersomnia (IH) is characterized by excessive sleepiness during the day, prolonged sleep at night, and difficulty waking up. The true prevalence of IH is uncertain. ICSD provides criteria for diagnosing IH; however, the definition has evolved. Managing IH involves using pharmacologic and non-pharmacologic approaches, although the most effective strategies are still unclear. The objective of this scoping review was to identify the extent, range, and nature of the available evidence, identify research gaps, and discuss the implications for clinical practice and policy.
METHODS: To conduct this review, a comprehensive search was conducted across scientific databases, without any restrictions on the date or study type. Eligible studies examined the effectiveness of pharmacologic and non-pharmacologic treatments for IH and reported the outcomes of these interventions. Data from the studies were screened, analyzed, and synthesized to provide an overview of the available literature landscape.
RESULTS: 51 studies were included in this review, which used various methods and interventions. Pharmacological treatments, particularly modafinil, have been frequently studied and have yielded positive results. There is also emerging evidence for alternative medications such as low-sodium oxybate and pitolisant. Non-pharmacological approaches, such as CBT-H and tDCS have also shown promise in managing IH.
CONCLUSIONS: This review highlights the complexity of managing IH management and emphasizes the need for personalized multidisciplinary approaches. Pharmacological interventions are important in managing IH and can be complemented by non-medication strategies. Larger-scale studies are necessary to advance our understanding of IH and to improve treatment outcomes.

Mental health disorders are among the top leading causes of disease burden worldwide and many patients have high levels of treatment resistance. Even though medications offer improvement to some patients, antidepressants are only effective in about half of those treated, and schizophrenia is treatment-refractory in about one-third of patients. One way to combat this disparity is to improve medication development and discovery for psychiatric disorders through evidence-based research. Recently, most psychiatric medications approved by the United States Food and Drug Administration (FDA) are for increased tolerability or extended release. Because of the slow, incremental progress, there is a pressing need to explore novel medications with new indications or mechanisms of action to treat the expanding population with mental disorders, especially in those who are fully or partially recalcitrant to first-line medication options. This review aims to present the newest FDA medications with new indications, establish the clinical need for each, and discuss future directions in drug development. We searched and reviewed novel psychiatric medications approved by the FDA from 2018 to 2022. We then analyzed each medication in the United States Clinical Trials Registry and gathered updated results for efficacy and safety information. We also searched PubMed/MEDLINE (Medical Literature Analysis and Retrieval System Online), Scopus, Web of Science, Elsevier, and Google Scholar to understand how these new indications met current clinical needs. Finally, we inquired about related technological implications that will lead the field of psychopharmacology now and in the years to come. We found 12 novel psychiatric medications approved by the FDA from 2018 to 2022, representing a very small percentage of the total FDA approvals during that period. These psychiatric medications with novel mechanisms or improved efficacy and safety  are expected to provide further options for treating mental health disorders; promising results will lead to new patterns of research.

Pitolisant, a novel histamine H3-receptor antagonist, holds significant promise for treating narcolepsy. However, a petition, which highlighted that pitolisant was associated with deaths during clinical trials, has propelled it into the spotlight of widespread societal attention on April 3, 2023. Till now, the clinical safety of pitolisant remains a heatedly debated topic. This study aimed to offer a comprehensive assessment of the safety profile of pitolisant in real-world clinical settings. Adverse event reports where pitolisant was the primary suspect drug were extracted from the FDA Adverse Event Reporting System database. The clinical characteristics and concomitant drugs of the pitolisant-associated adverse events were analyzed. The potential adverse event signals of pitolisant were explored using four disproportionality analysis methods. Furthermore, the difference in pitolisant-associated adverse event signals was investigated concerning sex, age, weight, and dose. A total of 526 reports and 1695 adverse events with pitolisant as the primary suspected drug were identified. The most significant adverse event signals were generally mild and of short duration. The concomitant drugs of pitolisant were highly intricate, mainly included drugs for treating narcolepsy as well as antidepressants. Seven new significant adverse event signals emerged. The safety profile of pitolisant exhibited no significant differences across age and dose groups, although slight variations were observed in relation to sex and weight. The findings from reports of death and life-threatening outcomes underscore the importance of enhanced monitoring for cardiac and respiratory adverse reactions when utilizing pitolisant. This study provided a broader understanding of the safety profile of pitolisant.

The histamine H3 receptor, prominently expressed in neurons with a minor presence in glial cells, acts as both an autoreceptor and an alloreceptor, controlling the release of histamine and other neurotransmitters. The receptor impacts various essential physiological processes. Our team\'s initial investigations had demonstrated that the histamine H3 receptor antagonists could facilitate nerve regeneration by promoting the histamine H1 receptors on primary neural stem cells (NSCs) in the traumatic brain injury mouse, which suggested the potential of histamine H3 receptor as a promising target for treating neurological disorders and promoting nerve regeneration. Pitolisant (PITO) is the only histamine H3 receptor antagonist approved by the Food and Drug Administration (FDA) for treating narcolepsy. However, there is no report on Pitolisant in neural development or regeneration, and it is urgent to be further studied in strong biological activity models in vitro. The embryonic stem (ES) cells were differentiated into neural cells in vitro, which replicated the neurodevelopmental processes that occur in vivo. It also provided an alternative model for studying neurodevelopmental processes and testing drugs for neurological conditions. Therefore, we aimed to elucidate the regulatory role of Pitolisant in the early differentiation of ES cells into neural cells. Our results demonstrated that Pitolisant could promote the differentiation of ES cells toward NSCs and stimulated the formation of growth cones. Furthermore, Pitolisant was capable of inducing the polarization of NSCs through the cAMP-LKB1-SAD/MARK2 pathway, but had no significant effect on later neuronal maturation. Pitolisant altered mitochondrial morphology and upregulated the levels of mitochondrion-related proteins TOM20, Drp1, and p-Drp1, and reversed the inhibitory effect of Mdivi-1 on mitochondrial fission during the early neural differentiation of ES cells. In addition, Pitolisant induced the increase in cytosolic Ca2+. Our study provided an experimental foundation for the potential application of histamine H3 receptor-targeted modulators in the field of neuroregeneration.

Modafinil is a common treatment for excessive daytime sleepiness (EDS) in narcolepsy. The long-term use of modafinil can lead to tolerance with the loss of efficacy and the continuous increase of its dose. Pharmacological strategies to deal with the tolerance to modafinil are lacking. We investigated the efficacy and safety of pitolisant-supported bridging during drug holidays in patients with tolerance to modafinil.
Narcolepsy patients on monotherapy with modafinil who developed symptoms of tolerance were eligible. The following alternating therapy regimen was established: Monday to Friday patients continued on modafinil whereas Saturday and Sunday they switched to pitolisant to \"bridge\" the EDS symptoms. Patients were assessed at baseline and after three months with the Epworth Sleepiness Scale (ESS) and the Ullanlinna Narcolepsy Scale (UNS). Health-related quality of life (HrQol) was evaluated by EuroQol5D. Adverse events were documented in the patients\' diaries.
41 patients aged 30.9 ± 5.6 years were included. After three months of the alternating therapy regimen, the symptoms of tolerance decreased and the modafinil dose could be reduced by 41% (p < 0.01) resulting in better safety. The EDS improved on ESS (baseline: 18.2 ± 4.2, follow-up: 12.6 ± 4.0, p < 0.0001) and UNS (baseline: 25.8 ± 7.9, follow-up: 18.9 ± 5.9, p < 0.0001). The HrQol increased significantly.
Patients with tolerance to modafinil could benefit from pitolisant-supported bridging during drug holidays. This alternating pharmacological strategy proved to be safe and helped to reduce EDS and to decrease the modafinil dose. Further randomized controlled studies are required to evaluate the different strategies to deal with the tolerance to modafinil.
Clinical Trials.gov Identifier NCT05321355.

暂无摘要。

BACKGROUND: First symptoms of narcolepsy mostly present during childhood. Pharmacological management options in children are limited, also due to approval status. Pitolisant is an inverse histamine 3 receptor agonist and has been approved for the treatment of adult narcolepsy with or without cataplexy by EMA and FDA. Clinical experience indicates for a beneficial use also in children and adolescents. Our goal was to evaluate the effects and tolerability of pitolisant in narcolepsy children/adolescents in a real-world setting.
METHODS: This multicentre retrospective observational study included 55 patients with narcolepsy from three international narcolepsy centers (Germany, France and Italy) who were treated with pitolisant. Patients were eligible if they were at least 6 years old and diagnosed with narcolepsy type 1 or 2. Demographic and clinical characteristics, questionnaires, sleep medicine and laboratory data were collected.
RESULTS: 55 children/adolescents (25 girls, 45.45%, 30 boys, 54.55%) aged 6-18 years, with narcolepsy (type 1 = 92.7%, type 2 = 7.3%), were treated with pitolisant. The mean pitolisant dose was 34.1 mg/d. Treatment was effective for excessive daytime sleepiness (EDS) and cataplexy: the pediatric Epworth Sleepiness Scale (ESS) score decreased from 19 to 13.5 (p < 0.001) and the weekly cataplexy frequency improved from 7.9 at baseline to 5.2 (p < 0.001). Treatment with pitolisant was well tolerated. Side effects were mild and mostly short-term. Insomnia was reported most frequently (5.5%).
CONCLUSIONS: First real-world results suggest that pitolisant treatment is effective in improving EDS and cataplexy in children with narcolepsy, and also is well tolerated.

The clinical symptoms of Parkinson’s disease (PD) appear when dopamine (DA) concentrations in the striatum drops to around 20%. Simultaneous inhibitory effects on histamine H3 receptor (H3R) and MAO B can increase DA levels in the brain. A series of compounds was designed and tested in vitro for human H3R (hH3R) affinity and inhibitory activity to human MAO B (hMAO B). Results showed different activity of the compounds towards the two biological targets. Most compounds had poor affinity for hH3R (Ki > 500 nM), but very good inhibitory potency for hMAO B (IC50 < 50 nM). After further in vitro testing (modality of MAO B inhibition, permeability in PAMPA assay, cytotoxicity on human astrocyte cell lines), the most promising dual-acting ligand, 1-(3-(4-(tert-butyl)phenoxy)propyl)-2-methylpyrrolidine (13: hH3R: Ki = 25 nM; hMAO B IC50 = 4 nM) was selected for in vivo evaluation. Studies in rats of compound 13, in a dose of 3 mg/kg of body mass, confirmed its antagonistic effects for H3R (decline in food and a water consumption), decline in MAO B activity (>90%) in rat cerebral cortex (CTX), and an increase in DA content in CTX and striatum. Moreover, compound 13 caused a slight increase in noradrenaline, but a reduction in serotonin concentration in CTX. Thus, compound 13 is a promising dual-active ligand for the potential treatment of PD although further studies are needed to confirm this.

Excessive daytime sleepiness (EDS) is defined as \"irresistible sleepiness in a situation when an individual would be expected to be awake, and alert.\" EDS has been a big concern not only from a medical but also from a public health point of view. Patients with EDS have the possibility of falling asleep even when they should wake up and concentrate, for example, when they drive, play sports, or walk outside. In this article, clinical characteristics of common hypersomnia and pharmacologic treatments of each hypersomnia are described.