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American Family Physician Feb 2024Insomnia affects 30% of the U.S. population, with 5% to 15% meeting criteria for chronic insomnia. It can negatively impact quality of life, decrease productivity,...
Insomnia affects 30% of the U.S. population, with 5% to 15% meeting criteria for chronic insomnia. It can negatively impact quality of life, decrease productivity, increase fatigue and drowsiness, and put patients at higher risk of developing other health problems. Initial treatment focuses on nonpharmacologic therapies such as cognitive behavior therapy, which improves negative thought patterns and behaviors through sleep restriction, stimulus control, and relaxation techniques. Other nonpharmacologic treatments include exercise, mindfulness, and acupuncture. If these approaches are ineffective, pharmacologic agents may be considered. Medications such as benzodiazepines and Z-drugs are often prescribed for insomnia but should be avoided, if possible, due to short- and long-term risks associated with their use. Melatonin receptor agonists are safer and well tolerated but have limited effectiveness. Dual orexin receptor antagonists are effective in patients who have sleep maintenance insomnia or difficulty with sleep onset. Evidence for the use of antihistamines to treat insomnia is generally lacking, but doxylamine is effective for up to four weeks.
Topics: Adult; Humans; Sleep Initiation and Maintenance Disorders; Quality of Life; Benzodiazepines; Hypnotics and Sedatives; Sleep
PubMed: 38393799
DOI: No ID Found -
Revista de Neurologia Jul 2023Narcolepsy type 1 is a focal degenerative disease of the hypothalamus that selectively affects orexin (hypocretin)-producing neurons. It presents multiple clinical...
INTRODUCTION
Narcolepsy type 1 is a focal degenerative disease of the hypothalamus that selectively affects orexin (hypocretin)-producing neurons. It presents multiple clinical manifestations, both in wakefulness and in sleep. The symptoms are often so disruptive that they cause enormous suffering and impair patients' quality of life. Although a non-pharmacological approach is sometimes sufficient, the vast majority of patients need medication for adequate clinical management.
CASE REPORT
A male who, at 43 years of age, began to present acutely with excessive daytime sleepiness and episodes of cataplexy. After a thorough examination, he was diagnosed with narcolepsy type 1. Throughout the course of the disease, he was prescribed antidepressants, neurostimulants and sodium oxybate, in monotherapy or in combination. The response to pharmacological treatment was insufficient and accompanied by numerous side effects. Following the introduction of pitolisant, there was a marked improvement in his symptoms and a reduction in the dose of the other drugs and their adverse effects was achieved.
CONCLUSION
A number of measures are now available to address the cardinal symptoms of the disease, although there are still cases that are resistant to anti-narcoleptic treatment. Drugs with mechanisms of action that act upon receptors in the histaminergic system can be very useful in these cases.
Topics: Humans; Male; Antidepressive Agents; Cataplexy; Central Nervous System Stimulants; Narcolepsy; Quality of Life; Sodium Oxybate; Adult; Drug Resistance, Multiple; Sleepiness
PubMed: 37477029
DOI: 10.33588/rn.77s01.2023198 -
Frontiers in Cellular Neuroscience 2023Cortical layer 6b is considered by many to be a remnant of the subplate that forms during early stages of neocortical development, but its role in the adult is not well... (Review)
Review
Cortical layer 6b is considered by many to be a remnant of the subplate that forms during early stages of neocortical development, but its role in the adult is not well understood. Its neuronal complement has only recently become the subject of systematic studies, and its axonal projections and synaptic input structures have remained largely unexplored despite decades of research into neocortical function. In recent years, however, layer 6b (L6b) has attracted increasing attention and its functional role is beginning to be elucidated. In this review, I will attempt to provide an overview of what is currently known about the excitatory and inhibitory neurons in this layer, their pre- and postsynaptic connectivity, and their functional implications. Similarities and differences between different cortical areas will be highlighted. Finally, layer 6b neurons are highly responsive to several neuropeptides such as orexin/hypocretin, neurotensin and cholecystokinin, in some cases exclusively. They are also strongly controlled by neurotransmitters such as acetylcholine and norepinephrine. The interaction of these neuromodulators with L6b microcircuitry and its functional consequences will also be discussed.
PubMed: 37744882
DOI: 10.3389/fncel.2023.1257803 -
Sleep Feb 2024Dual orexin receptor antagonists (DORAs) are emerging treatments for insomnia. This meta-analysis study aimed to assess the safety of FDA-approved DORAs (suvorexant,... (Meta-Analysis)
Meta-Analysis
STUDY OBJECTIVES
Dual orexin receptor antagonists (DORAs) are emerging treatments for insomnia. This meta-analysis study aimed to assess the safety of FDA-approved DORAs (suvorexant, lemborexant, and daridorexant), focusing on narcolepsy-like symptoms associated with these drugs.
METHODS
Five prominent databases were searched to identify randomized controlled trials (RCTs) on this topic. Primary safety outcomes included treatment-emergent adverse events (TEAEs), treatment-related TEAEs, TEAEs leading to discontinuation, and serious TEAEs. Excessive daytime sleepiness (EDS), sleep paralysis, and hallucinations were categorized as adverse events (AEs)-related narcolepsy-like symptoms.
RESULTS
Eleven RCTs with 7703 patients were included. DORAs were associated with a higher risk of TEAEs (risk ratio [RR], 1.09; 95% confidence interval [CI], 1.03 to 1.15) and treatment-related TEAEs (RR, 1.69; 95% CI: 1.49 to 1.92) when compared to placebo. The DORA group exhibited a significantly higher risk of EDS (RR, 2.15; 95% CI: 1.02 to 4.52) and sleep paralysis (RR, 3.40; 95% CI: 1.18 to 9.80) compared to the placebo group.
CONCLUSION
This meta-analysis achieved a comparative evaluation of the clinical safety and tolerability of FDA-approved DORAs for primary insomnia, specifically focusing on AEs-related narcolepsy-like symptoms. This study contributes to understanding the safety profile of FDA-approved DORAs for treating insomnia.
Topics: Humans; Sleep Initiation and Maintenance Disorders; Orexin Receptor Antagonists; Sleep Paralysis; Narcolepsy
PubMed: 37950346
DOI: 10.1093/sleep/zsad293 -
BioRxiv : the Preprint Server For... Sep 2023Sleep and circadian rhythm disruption (SCRD) is commonly observed in aging, especially in individuals who experience progressive cognitive decline to mild cognitive...
Sleep and circadian rhythm disruption (SCRD) is commonly observed in aging, especially in individuals who experience progressive cognitive decline to mild cognitive impairment (MCI) and Alzheimer's disease (AD). However, precise molecular mechanisms underlying the association between SCRD and aging are not fully understood. Orexin A is a well-characterized "sleep neuropeptide" that is expressed in hypothalamic neurons and evokes wake behavior. The importance of Orexin is exemplified in narcolepsy where it is profoundly down-regulated. Interestingly, the synaptic immediate early gene NPTX2 is co-expressed in Orexin neurons and is similarly reduced in narcolepsy. NPTX2 is also down-regulated in CSF of some cognitively normal older individuals and predicts the time of transition from normal cognition to MCI. The association between Orexin and NPTX2 is further evinced here where we observe that Orexin A and NPTX2 are highly correlated in CSF of cognitively normal aged individuals and raises the question of whether SCRD that are typically attributed to Orexin A loss of function may be modified by concomitant NPTX2 down-regulation. Is NPTX2 an effector of sleep or simply a reporter of orexin-dependent SCRD? To address this question, we examined NPTX2 KO mice and found they retain Orexin expression in the brain and so provide an opportunity to examine the specific contribution of NPTX2 to SCRD. Our results reveal that NPTX2 KO mice exhibit a disrupted circadian onset time, coupled with increased activity during the sleep phase, suggesting difficulties in maintaining states. Sleep EEG indicates distinct temporal allocation shifts across vigilance states, characterized by reduced wake and increased NREM time. Evident sleep fragmentation manifests through alterations of event occurrences during Wake and NREM, notably during light transition periods, in conjunction with an increased frequency of sleep transitions in NPTX2 KO mice, particularly between Wake and NREM. EEG spectral analysis indicated significant shifts in power across various frequency bands in the wake, NREM, and REM states, suggestive of disrupted neuronal synchronicity. An intriguing observation is the diminished occurrence of sleep spindles, one of the earliest measures of human sleep disruption, in NPTX2 KO mice. These findings highlight the effector role of NPTX2 loss of function as an instigator of SCRD and a potential mediator of sleep disruption in aging.
PubMed: 37808783
DOI: 10.1101/2023.09.26.559408 -
Annual Review of Pharmacology and... Jan 2024Sleep is essential for human well-being, yet the quality and quantity of sleep reduce as age advances. Older persons (>65 years old) are more at risk of disorders... (Review)
Review
Sleep is essential for human well-being, yet the quality and quantity of sleep reduce as age advances. Older persons (>65 years old) are more at risk of disorders accompanied and/or exacerbated by poor sleep. Furthermore, evidence supports a bidirectional relationship between disrupted sleep and Alzheimer's disease (AD) or related dementias. Orexin/hypocretin neuropeptides stabilize wakefulness, and several orexin receptor antagonists (ORAs) are approved for the treatment of insomnia in adults. Dysregulation of the orexin system occurs in aging and AD, positioning ORAs as advantageous for these populations. Indeed, several clinical studies indicate that ORAs are efficacious hypnotics in older persons and dementia patients and, as in adults, are generally well tolerated. ORAs are likely to be more effective when administered early in sleep/wake dysregulation to reestablish good sleep/wake-related behaviors and reduce the accumulation of dementia-associated proteinopathic substrates. Improving sleep in aging and dementia represents a tremendous opportunity to benefit patients, caregivers, and health systems.
Topics: Humans; Aged; Aged, 80 and over; Orexins; Orexin Receptor Antagonists; Orexin Receptors; Sleep; Alzheimer Disease
PubMed: 37708433
DOI: 10.1146/annurev-pharmtox-040323-031929 -
Therapie 2024The psychiatric risks associated with drugs are sometimes one of the few restrictions on the use of certain drug classes, such as corticosteroids in patients with a...
The psychiatric risks associated with drugs are sometimes one of the few restrictions on the use of certain drug classes, such as corticosteroids in patients with a history of severe psychotic episodes associated with this drug class. In this non-exhaustive review, we propose to deal with the most recent issues concerning psychiatric disorders induced by drugs and encountered in doctors' clinical practice. Firstly, we look at depressive disorders and suicide risks, secondly at psychotic and manic disorders and thirdly at anxiety and sleep disorders. While lot of drugs are associated with psychiatric disorders, the confounding by indication represents an important methodological gap since information on the psychiatric profile of patients is not always available. This is particularly the case for serotonin reuptake inhibitors and esketamine used as antidepressants. Recent pharmacovigilance concerns of psychiatric disorders emerged with montelukast, orexin receptor antagonists or cystic fibrosis transmembrane regulator (CFTR) modulators.
Topics: Humans; Pharmacovigilance; Mental Disorders; Antidepressive Agents; Selective Serotonin Reuptake Inhibitors
PubMed: 37957053
DOI: 10.1016/j.therap.2023.09.007 -
Neurobiology of Disease Jan 2024Sleep-wake disturbances are common in neurodegenerative diseases and may occur years before the clinical diagnosis, potentially either representing an early stage of the... (Review)
Review
Sleep-wake disturbances are common in neurodegenerative diseases and may occur years before the clinical diagnosis, potentially either representing an early stage of the disease itself or acting as a pathophysiological driver. Therefore, discovering biomarkers that identify individuals with sleep-wake disturbances who are at risk of developing neurodegenerative diseases will allow early diagnosis and intervention. Given the association between sleep and neurodegeneration, the most frequently analyzed fluid biomarkers in people with sleep-wake disturbances to date include those directly associated with neurodegeneration itself, such as neurofilament light chain, phosphorylated tau, amyloid-beta and alpha-synuclein. Abnormalities in these biomarkers in patients with sleep-wake disturbances are considered as evidence of an underlying neurodegenerative process. Levels of hormonal sleep-related biomarkers such as melatonin, cortisol and orexin are often abnormal in patients with clinical neurodegenerative diseases, but their relationships with the more standard neurodegenerative biomarkers remain unclear. Similarly, it is unclear whether other chronobiological/circadian biomarkers, such as disrupted clock gene expression, are causal factors or a consequence of neurodegeneration. Current data would suggest that a combination of fluid biomarkers may identify sleep-wake disturbances that are most predictive for the risk of developing neurodegenerative disease with more optimal sensitivity and specificity.
Topics: Humans; Neurodegenerative Diseases; Sleep; Amyloid beta-Peptides; Sleep Wake Disorders; Biomarkers
PubMed: 38049012
DOI: 10.1016/j.nbd.2023.106369 -
Molecular Metabolism Oct 2023The present study tests the hypothesis that changes in the glucose sensitivity of lateral hypothalamus (LH) hypocretin/orexin glucose-inhibited (GI) neurons following...
OBJECTIVE
The present study tests the hypothesis that changes in the glucose sensitivity of lateral hypothalamus (LH) hypocretin/orexin glucose-inhibited (GI) neurons following weight loss leads to glutamate plasticity on ventral tegmental area (VTA) dopamine neurons and drives food seeking behavior.
METHODS
C57BL/6J mice were calorie restricted to a 15% body weight loss and maintained at that body weight for 1 week. The glucose sensitivity of LH hypocretin/orexin GI and VTA dopamine neurons was measured using whole cell patch clamp recordings in brain slices. Food seeking behavior was assessed using conditioned place preference (CPP).
RESULTS
1-week maintenance of calorie restricted 15% body weight loss reduced glucose inhibition of hypocretin/orexin GI neurons resulting in increased neuronal activation with reduced glycemia. The effect of decreased glucose on hypocretin/orexin GI neuronal activation was blocked by pertussis toxin (inhibitor of G-protein coupled receptor subunit Gα) and Rp-cAMP (inhibitor of protein kinase A, PKA). This suggests that glucose sensitivity is mediated by the Gα-adenylyl cyclase-cAMP-PKA signaling pathway. The excitatory effect of the hunger hormone, ghrelin, on hcrt/ox neurons was also blocked by Rp-cAMP suggesting that hormonal signals of metabolic status may converge on the glucose sensing pathway. Food restriction and weight loss increased glutamate synaptic strength (indexed by increased AMPA/NMDA receptor current ratio) on VTA dopamine neurons and the motivation to seek food (indexed by CPP). Chemogenetic inhibition of hypocretin/orexin neurons during caloric restriction and weight loss prevented these changes in glutamate plasticity and food seeking behavior.
CONCLUSIONS
We hypothesize that this change in the glucose sensitivity of hypocretin/orexin GI neurons may drive, in part, food seeking behavior following caloric restriction.
Topics: Mice; Animals; Orexins; Hypothalamic Area, Lateral; Neuropeptides; Caloric Restriction; Glucose; Mice, Inbred C57BL; Dopaminergic Neurons; Glutamates
PubMed: 37536499
DOI: 10.1016/j.molmet.2023.101788 -
Neuron Jun 2024Pupil size is a widely used metric of brain state. It is one of the few signals originating from the brain that can be readily monitored with low-cost devices in basic... (Review)
Review
Pupil size is a widely used metric of brain state. It is one of the few signals originating from the brain that can be readily monitored with low-cost devices in basic science, clinical, and home settings. It is, therefore, important to investigate and generate well-defined theories related to specific interpretations of this metric. What exactly does it tell us about the brain? Pupils constrict in response to light and dilate during darkness, but the brain also controls pupil size irrespective of luminosity. Pupil size fluctuations resulting from ongoing "brain states" are used as a metric of arousal, but what is pupil-linked arousal and how should it be interpreted in neural, cognitive, and computational terms? Here, we discuss some recent findings related to these issues. We identify open questions and propose how to answer them through a combination of well-defined tasks, neurocomputational models, and neurophysiological probing of the interconnected loops of causes and consequences of pupil size.
PubMed: 38925124
DOI: 10.1016/j.neuron.2024.05.029