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The Journal of Family Practice Jul 2023Insomnia is a distinct disorder that is common, yet underrecognized and undertreated in primary care. Treating insomnia has been shown to improve outcomes, including... (Review)
Review
Insomnia is a distinct disorder that is common, yet underrecognized and undertreated in primary care. Treating insomnia has been shown to improve outcomes, including reduced risk of developing cardiovascular and mental health disorders. Insomnia is influenced by the brain's regulation of sleep and wake, which are mutually exclusive events. Insomnia should be treated as a distinct condition, even when occurring with a comorbid diagnosis such as depression or anxiety. Clinicians should implement a multimodal approach to insomnia management, including nonpharmacologic interventions and pharmacologic therapy (when indicated). Pharmacologic agents that are approved by the US Food and Drug Administration for insomnia include benzodiazepine receptor agonists (zolpidem, eszopiclone, and zaleplon), low-dose doxepin (tricyclic antidepressant), ramelteon (melatonin receptor agonist), and dual orexin receptor agonists (DORAs, daridorexant, lemborexant, and suvorexant). Unlike other pharmacologic agents, DORAs inhibit wakefulness rather than induce sedation. Additionally, these medications have no evidence of rebound insomnia or withdrawal, and little to no abuse potential. Daridorexant is the newest DORA, has an ideal half-life of 8 hours, and has demonstrated continued efficacy over a 12-month period. Selection of pharmacologic agent should be based on the patient's comorbid conditions, treatment goals and preferences, and other clinical characteristics.
Topics: Humans; Sleep Initiation and Maintenance Disorders; Sleep; Zolpidem; Doxepin
PubMed: 37549414
DOI: 10.12788/jfp.0620 -
Journal of Sleep Research Dec 2023Progress in the field of insomnia since 2017 necessitated this update of the European Insomnia Guideline. Recommendations for the diagnostic procedure for insomnia and... (Review)
Review
Progress in the field of insomnia since 2017 necessitated this update of the European Insomnia Guideline. Recommendations for the diagnostic procedure for insomnia and its comorbidities are: clinical interview (encompassing sleep and medical history); the use of sleep questionnaires and diaries (and physical examination and additional measures where indicated) (A). Actigraphy is not recommended for the routine evaluation of insomnia (C), but may be useful for differential-diagnostic purposes (A). Polysomnography should be used to evaluate other sleep disorders if suspected (i.e. periodic limb movement disorder, sleep-related breathing disorders, etc.), treatment-resistant insomnia (A) and for other indications (B). Cognitive-behavioural therapy for insomnia is recommended as the first-line treatment for chronic insomnia in adults of any age (including patients with comorbidities), either applied in-person or digitally (A). When cognitive-behavioural therapy for insomnia is not sufficiently effective, a pharmacological intervention can be offered (A). Benzodiazepines (A), benzodiazepine receptor agonists (A), daridorexant (A) and low-dose sedating antidepressants (B) can be used for the short-term treatment of insomnia (≤ 4 weeks). Longer-term treatment with these substances may be initiated in some cases, considering advantages and disadvantages (B). Orexin receptor antagonists can be used for periods of up to 3 months or longer in some cases (A). Prolonged-release melatonin can be used for up to 3 months in patients ≥ 55 years (B). Antihistaminergic drugs, antipsychotics, fast-release melatonin, ramelteon and phytotherapeutics are not recommended for insomnia treatment (A). Light therapy and exercise interventions may be useful as adjunct therapies to cognitive-behavioural therapy for insomnia (B).
Topics: Adult; Humans; Sleep Initiation and Maintenance Disorders; Melatonin; Sleep; Benzodiazepines; Antidepressive Agents
PubMed: 38016484
DOI: 10.1111/jsr.14035 -
Journal of Neurosciences in Rural... 2023The growing prevalence of dementia makes it important for us to better understand its pathophysiology and treatment modalities, to improve the quality of life of... (Review)
Review
The growing prevalence of dementia makes it important for us to better understand its pathophysiology and treatment modalities, to improve the quality of life of patients and caregivers. Alzheimer's disease (AD), a neurodegenerative disease, is the most common form of amnestic dementia in the geriatric population. Pathophysiology of AD is widely attributed to aggregation of amyloid-beta (Aβ) plaques and hyperphosphorylation of tau proteins. Initial treatment modalities aimed to increase brain perfusion in a non-specific manner. Subsequent therapy focused on rectifying neurotransmitter imbalance in the brain. Newer drugs modify the progression of the disease by acting against aggregated Aβ plaques. However, not all drugs used in therapy of AD have been granted approval by the United States Food and Drug Administration (FDA). This review categorizes and summarizes the FDA-approved drugs in the treatment of AD in a manner that would make it a convenient reference for researchers and practicing physicians alike. Drugs that mitigate symptoms of dementia may be categorized into mitigators of Behavioral and Psychological Symptoms of Dementia (BPSD), and mitigators of cognitive decline. BPSD mitigators include brexpiprazole, an atypical antipsychotic with a once-daily dosage suited to treat agitation in dementia patients, and suvorexant, an orexin receptor antagonist used to treat sleep disturbances. Cognitive decline mitigators include cholinesterase inhibitors such as donepezil, rivastigmine, and galantamine and glutamate inhibitors such as memantine. Donepezil is the most commonly prescribed drug. It is cheap, well-tolerated, and may be prescribed orally once daily, or as a transdermal patch once weekly. It increases ACh levels, enhances oligodendrocyte differentiation and also protects against Aβ toxicity. However, regular cardiac monitoring is required due to reports of cardiac conduction side effects. Rivastigmine requires a twice-daily oral dosage or once-daily replacement of transdermal patch. It has fewer cardiac side effects than donepezil, but local application-site reactions have been noted. Galantamine, in addition to improving cognitive symptoms in a short span of time, also delays the development of BPSDs and has minimal drug-drug interactions by virtue of having multiple metabolic pathways. However, cardiac conduction disturbances must be closely monitored for. Memantine, a glutamate regulator, acts as an anti-Parkinsonian agent and an antidepressant, in addition to improving cognition and neuroprotection, and requires a once-daily dosage in the form of immediate-release or sustained-release oral tablets. Disease-modifying drugs such as aducanumab and lecanemab reduce the Aβ burden. Both act by binding with fibrillary conformations of Aβ plaques in the brain. These drugs have a risk of causing amyloid-related imaging abnormalities, especially in persons with ApoE4 gene. Aducanumab is administered once every 4 weeks and lecanemab once every 2 weeks. The decision on the choice of the drug must be made after considering the availability of drug, compliance of patient (once-daily vs. multiple doses daily), cost, specific comorbidities, and the risk-benefit ratio for the particular patient. Other non-pharmacological treatment modalities must also be adopted to have a holistic approach toward the treatment of AD.
PubMed: 38059250
DOI: 10.25259/JNRP_356_2023 -
Nature Sep 2023Only recently have more specific circuit-probing techniques become available to inform previous reports implicating the rodent hippocampus in orexigenic appetitive...
Only recently have more specific circuit-probing techniques become available to inform previous reports implicating the rodent hippocampus in orexigenic appetitive processing. This function has been reported to be mediated at least in part by lateral hypothalamic inputs, including those involving orexigenic lateral hypothalamic neuropeptides, such as melanin-concentrating hormone. This circuit, however, remains elusive in humans. Here we combine tractography, intracranial electrophysiology, cortico-subcortical evoked potentials, and brain-clearing 3D histology to identify an orexigenic circuit involving the lateral hypothalamus and converging in a hippocampal subregion. We found that low-frequency power is modulated by sweet-fat food cues, and this modulation was specific to the dorsolateral hippocampus. Structural and functional analyses of this circuit in a human cohort exhibiting dysregulated eating behaviour revealed connectivity that was inversely related to body mass index. Collectively, this multimodal approach describes an orexigenic subnetwork within the human hippocampus implicated in obesity and related eating disorders.
Topics: Humans; Body Mass Index; Cohort Studies; Cues; Electrophysiology; Evoked Potentials; Feeding and Eating Disorders; Feeding Behavior; Food; Hippocampus; Obesity; Orexins; Neural Pathways
PubMed: 37648849
DOI: 10.1038/s41586-023-06459-w -
Frontiers in Neuroscience 2023Sleep-wake and fasting-feeding are tightly coupled behavioral states that require coordination between several brain regions. The mammalian lateral hypothalamus (LH) is... (Review)
Review
Sleep-wake and fasting-feeding are tightly coupled behavioral states that require coordination between several brain regions. The mammalian lateral hypothalamus (LH) is a functionally and anatomically complex brain region harboring heterogeneous cell populations that regulate sleep, feeding, and energy metabolism. Significant attempts were made to understand the cellular and circuit bases of LH actions. Rapid advancements in genetic and electrophysiological manipulation help to understand the role of discrete LH cell populations. The opposing action of LH orexin/hypocretin and melanin-concentrating hormone (MCH) neurons on metabolic sensing and sleep-wake regulation make them the candidate to explore in detail. This review surveys the molecular, genetic, and neuronal components of orexin and MCH signaling in the regulation of sleep and metabolism.
PubMed: 37674517
DOI: 10.3389/fnins.2023.1230428 -
Neuron Apr 2024Physical exercise is known to reduce anxiety, but the underlying brain mechanisms remain unclear. Here, we explore a hypothalamo-cerebello-amygdalar circuit that may...
Physical exercise is known to reduce anxiety, but the underlying brain mechanisms remain unclear. Here, we explore a hypothalamo-cerebello-amygdalar circuit that may mediate motor-dependent alleviation of anxiety. This three-neuron loop, in which the cerebellar dentate nucleus takes center stage, bridges the motor system with the emotional system. Subjecting animals to a constant rotarod engages glutamatergic cerebellar dentate neurons that drive PKCδ amygdalar neurons to elicit an anxiolytic effect. Moreover, challenging animals on an accelerated rather than a constant rotarod engages hypothalamic neurons that provide a superimposed anxiolytic effect via an orexinergic projection to the dentate neurons that activate the amygdala. Our findings reveal a cerebello-limbic pathway that may contribute to motor-triggered alleviation of anxiety and that may be optimally exploited during challenging physical exercise.
Topics: Animals; Anti-Anxiety Agents; Anxiety; Hypothalamus; Cerebellum; Anxiety Disorders
PubMed: 38301648
DOI: 10.1016/j.neuron.2024.01.007 -
International Clinical... Sep 2023Mood disorders are recurrent/chronic diseases with variable clinical remission rates. Available antidepressants are not effective in all patients and often show a... (Review)
Review
Mood disorders are recurrent/chronic diseases with variable clinical remission rates. Available antidepressants are not effective in all patients and often show a relevant response latency, with a range of adverse events, including weight gain and sexual dysfunction. Novel rapid agents were developed with the aim of overcoming at least in part these issues. Novel drugs target glutamate, gamma-aminobutyric acid, orexin, and other receptors, providing a broader range of pharmacodynamic mechanisms, that is, expected to increase the possibility of personalizing treatments on the individual clinical profile. These new drugs were developed with the aim of combining a rapid action, a tolerable profile, and higher effectiveness on specific symptoms, which were relatively poorly targeted by standard antidepressants, such as anhedonia and response to reward, suicidal ideation/behaviours, insomnia, cognitive deficits, and irritability. This review discusses the clinical specificity profile of new antidepressants, namely 4-chlorokynurenine (AV-101), dextromethorphan-bupropion, pregn-4-en-20-yn-3-one (PH-10), pimavanserin, PRAX-114, psilocybin, esmethadone (REL-1017/dextromethadone), seltorexant (JNJ-42847922/MIN-202), and zuranolone (SAGE-217). The main aim is to provide an overview of the efficacy/tolerability of these compounds in patients with mood disorders having different symptom/comorbidity patterns, to help clinicians in the optimization of the risk/benefit ratio when prescribing these drugs.
Topics: Humans; Depressive Disorder, Major; Antidepressive Agents; Bupropion; Sleep Initiation and Maintenance Disorders; Comorbidity
PubMed: 37381161
DOI: 10.1097/YIC.0000000000000488 -
Nutrients Aug 2023Orexin plays a significant role in the modulation of REM sleep, as well as in the regulation of appetite and feeding. This review explores, first, the current evidence... (Review)
Review
Orexin plays a significant role in the modulation of REM sleep, as well as in the regulation of appetite and feeding. This review explores, first, the current evidence on the role of orexin in the modulation of sleep and wakefulness and highlights that orexin should be considered essentially as a neurotransmitter inhibiting REM sleep and, to a much lesser extent, a wake promoting agent. Subsequently, the relationship between orexin, REM sleep, and appetite regulation is examined in detail, shedding light on their interconnected nature in both physiological conditions and diseases (such as narcolepsy, sleep-related eating disorder, idiopathic hypersomnia, and night eating syndrome). Understanding the intricate relationship between orexin, REM sleep, and appetite regulation is vital for unraveling the complex mechanisms underlying sleep-wake patterns and metabolic control. Further research in this field is encouraged in order to pave the way for novel therapeutic approaches to sleep disorders and metabolic conditions associated with orexin dysregulation.
Topics: Appetite; Sleep, REM; Orexins; Appetite Regulation; Sleep
PubMed: 37686711
DOI: 10.3390/nu15173679 -
Brain Structure & Function Jul 2023The mammillary body (MB) is a component of the extended hippocampal system and many studies have shown that its functions are vital for mnemonic processes. Together with... (Review)
Review
The mammillary body (MB) is a component of the extended hippocampal system and many studies have shown that its functions are vital for mnemonic processes. Together with other subcortical structures, such as the anterior thalamic nuclei and tegmental nuclei of Gudden, the MB plays a crucial role in the processing of spatial and working memory, as well as navigation in rats. The aim of this paper is to review the distribution of various substances in the MB of the rat, with a description of their possible physiological roles. The following groups of substances are reviewed: (1) classical neurotransmitters (glutamate and other excitatory transmitters, gamma-aminobutyric acid, acetylcholine, serotonin, and dopamine), (2) neuropeptides (enkephalins, substance P, cocaine- and amphetamine-regulated transcript, neurotensin, neuropeptide Y, somatostatin, orexins, and galanin), and (3) other substances (calcium-binding proteins and calcium sensor proteins). This detailed description of the chemical parcellation may facilitate a better understanding of the MB functions and its complex relations with other structures of the extended hippocampal system.
Topics: Rats; Animals; Mammillary Bodies; Neurochemistry; Anterior Thalamic Nuclei; Amino Acids; Memory, Short-Term
PubMed: 37378855
DOI: 10.1007/s00429-023-02673-4