Clinical Management of Insomnia

2017 ◽  
Author(s):  
Timothy Roehrs ◽  
Thomas Roth
Keyword(s):  
Relaxation Training ◽  
Behavioral Therapy ◽  
Receptor Site ◽  
Benzodiazepine Receptor ◽  
Female Gender ◽  
Consensus Conference ◽  
Receptor Subtype ◽  
Behavioral Treatments ◽  
Hypnotic Efficacy ◽  
Electroencephalographic Activity

Insomnia is the most common sleep disorder, with a prevalence of around 20%. The clearest risk factors are female gender and the presence of a psychiatric or medical disorder. The most important conceptual change in our understanding of insomnia, defined in the National Institutes of Health 2005 consensus conference, is that insomnia is a disorder itself rather than a symptom of another disorder. Specifically, insomnia is a disorder of hyperarousal. Insomniacs do not have an abnormal sleep homeostat or circadian system but rather an overactivated wake system. Cognitively, patients often complain they cannot “shut [their] brain down.” Physiologic correlates include elevated brain metabolism, increased fast electroencephalographic activity, and increased autonomic, metabolic, and hypothalamic-pituitary-adrenal axis activity. Treatment for insomnia can be divided into two categories, behavioral and pharmacologic. Another important categorization relates to self-treatment (sleep hygiene and over-the-counter drugs) versus clinician-directed therapy (cognitive-behavioral therapy for insomnia [CBT-I] and prescribed hypnotics). Among behavioral treatments are sleep restriction, stimulus control, relaxation training, and cognitive therapy. The most widely used behavioral therapy is a combination of the four treatment components referred to collectively as CBT-I. The majority of Food and Drug Administration (FDA)-approved hypnotics are drugs that occupy the benzodiazepine receptor site, which is part of the GABAA receptor complex. The hypnotic efficacy of the FDA-approved benzodiazepine receptor agonists (BzRAs) has been well documented using objective polysomnography and subjective measures of sleep induction and duration. Many BzRA side effects are associated with the desired sedative effects of the drug and relate to the pharmacokinetics, receptor subtype affinities, and dose of the drug. Key words: behavioral therapy, GABA, histamine, insomnia disorder, melatonin, orexin, pathophysiology, pharmacotherapy

Models and Treatment of Panic: Behavioral Therapy of Panic

1991 ◽  
Vol 5 (3) ◽  
pp. 199-214 ◽  
Author(s):  
Michelle G. Craske
Keyword(s):  
Panic Disorder ◽  
Relaxation Training ◽  
Behavioral Therapy ◽  
Post Treatment ◽  
Panic Attacks ◽  
Wait List ◽  
Global Functioning ◽  
Wait List Control ◽  
End Of Treatment ◽  
Behavioral Treatments

In this presentation, the results from two studies examining the effectiveness of behavioral treatments for panic disorder are presented. In the first study, a dismantling treatment study design was used to compare relaxation training, exposure and cognitive procedures, the combination of relaxation plus expoosure and cognitive procedures, and a Wait-List control. Subjects with panic disorder and mild or no agoraphobic avoidance were compared immediately after the 15-week treatment program and 6 months and 24 months later. Overall, exposure and cognitive procedures were found to be more effective than relaxation for the control of panic attacks in the short term and over the long term. In the second study, the combination of relaxation plus exposure and cognitive procedures was compared to Alprazolam, Placedbo, and Wait-List control conditions. Overall, the Cognitive-Behavioral therapy condition showed strongest improvements by the end of treatment in terms of panic, general enxiety and global functioning. Finally, it was noted that although exposure and cognitive procedures effectively controlled panic attacks in approximately 80% of subjects (immediately post treatment and 24-months post treatment), only 50% of the subjects were no longer distressed in general.

Cardiovascular Complications of Sleep Disorders: A Better Night’s Sleep for a Healthier Heart / From Bench to Bedside

2020 ◽  
Vol 19 (2) ◽  
pp. 210-232 ◽  
Author(s):  
Theodora A. Manolis ◽  
Antonis A. Manolis ◽  
Evdoxia J. Apostolopoulos ◽  
Helen Melita ◽  
Antonis S. Manolis
Keyword(s):  
Sleep Disorders ◽  
Disease Risk ◽  
Behavioral Therapy ◽  
Benzodiazepine Receptor ◽  
Cardiovascular Complications ◽  
Gamma Aminobutyric Acid ◽  
Acid Type ◽  
Increased Risk ◽  
Cv Disease ◽  
Meta Analyses

: Sleep is essential to and an integral part of life and when lacking or disrupted, a multitude of mental and physical pathologies ensue, including cardiovascular (CV) disease, which increases health care costs. Several prospective studies and meta-analyses show that insomnia, short (<7h) or long (>9h) sleep and other sleep disorders are associated with an increased risk of hypertension, metabolic syndrome, myocardial infarction, heart failure, arrhythmias, CV disease risk and/or mortality. The mechanisms by which insomnia and other sleep disorders lead to increased CV risk may encompass inflammatory, immunological, neuro-autonomic, endocrinological, genetic and microbiome perturbations. Guidelines are emerging that recommend a target of >7 h of sleep for all adults >18 years for optimal CV health. Treatment of sleep disorders includes cognitive-behavioral therapy considered the mainstay of non-pharmacologic management of chronic insomnia, and drug treatment with benzodiazepine receptor agonists binding to gamma aminobutyric acid type A (benzodiazepine and non-benzodiazepine agents) and some antidepressants. However, observational studies and meta-analyses indicate an increased mortality risk of anxiolytics and hypnotics, although bias may be involved due to confounding and high heterogeneity in these studies. Nevertheless, it seems that the risk incurred by the non-benzodiazepine hypnotic agents (Z drugs) may be relatively less than the risk of anxiolytics, with evidence indicating that at least one of these agents, zolpidem, may even confer a lower risk of mortality in adjusted models. All these issues are herein reviewed.

scholarly journals Characterisation of the Contribution of the GABA-Benzodiazepine α1 Receptor Subtype to [11C]Ro15-4513 PET Images

2012 ◽  
Vol 32 (4) ◽  
pp. 731-744 ◽  
Author(s):  
James FM Myers ◽  
Lula Rosso ◽  
Ben J Watson ◽  
Sue J Wilson ◽  
Nicola J Kalk ◽  
...  
Keyword(s):  
Spectral Analysis ◽  
A Priori ◽  
Benzodiazepine Receptor ◽  
Brain Regions ◽  
Complex Model ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Time Activity ◽  
Positron Emission ◽  
The Impact

This positron emission tomography (PET) study aimed to further define selectivity of [11C]Ro15-4513 binding to the GABARα5 relative to the GABARα1 benzodiazepine receptor subtype. The impact of zolpidem, a GABARα1-selective agonist, on [11C]Ro15-4513, which shows selectivity for GABARα5, and the nonselective benzodiazepine ligand [11C]flumazenil binding was assessed in humans. Compartmental modelling of the kinetics of [11C]Ro15-4513 time-activity curves was used to describe distribution volume ( VT) differences in regions populated by different GABA receptor subtypes. Those with low α5 were best fitted by one-tissue compartment models; and those with high α5 required a more complex model. The heterogeneity between brain regions suggested spectral analysis as a more appropriate method to quantify binding as it does not a priori specify compartments. Spectral analysis revealed that Zolpidem caused a significant VT decrease (~10%) in [11C]flumazenil, but no decrease in [11C]Ro15-4513 binding. Further analysis of [11C]Ro15-4513 kinetics revealed additional frequency components present in regions containing both α1 and α5 subtypes compared with those containing only α1. Zolpidem reduced one component (mean ± s.d.: 71% ± 41%), presumed to reflect α1-subtype binding, but not another (13% ± 22%), presumed to reflect α5. The proposed method for [11C]Ro15-4513 analysis may allow more accurate selective binding assays and estimation of drug occupancy for other nonselective ligands.

scholarly journals Rewriting One Patient’s Story of Disrupted Sleep

2019 ◽  
pp. 161-172
Author(s):  
Samantha Domingo ◽  
Michelle L. Drerup
Keyword(s):  
Social Support ◽  
Treatment Adherence ◽  
Relaxation Training ◽  
Behavioral Therapy ◽  
Treatment Options ◽  
Cognitive Restructuring ◽  
Sleep Hygiene ◽  
Sleep Restriction ◽  
Insomnia Disorder

This chapter covers treatment options for individuals with chronic insomnia disorder. We describe the effectiveness of cognitive behavioral therapy for insomnia (CBT-i) and various modalities of delivery of the treatment. CBT-i is an alternative treatment for insomnia that has been demonstrated to be as successful as pharmacological therapies in the short term, and more effective in the long term. CBT-i comprises sleep restriction, stimulus control, relaxation training, sleep hygiene, and cognitive restructuring. The authors examine group CBT-i as a way to increase social support and enhance treatment adherence. Computerized CBT-i is a newer option to provide increased access to this treatment.

scholarly journals Structure and allosteric activity of a single-disulfide conopeptide from Conus zonatus at human α3β4 and α7 nicotinic acetylcholine receptors

2020 ◽  
Vol 295 (20) ◽  
pp. 7096-7112
Author(s):  
Madhan Kumar Mohan ◽  
Nikita Abraham ◽  
Rajesh R P ◽  
Benjamin Franklin Jayaseelan ◽  
Lotten Ragnarsson ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Therapeutic Potential ◽  
Receptor Site ◽  
Peptide Bond ◽  
Rational Drug Design ◽  
Receptor Subtype ◽  
Design Strategies ◽  
New Paradigm ◽  
Nicotinic Acetylcholine ◽  
Subtype Selectivity

Conopeptides are neurotoxic peptides in the venom of marine cone snails and have broad therapeutic potential for managing pain and other conditions. Here, we identified the single-disulfide peptides Czon1107 and Cca1669 from the venoms of Conus zonatus and Conus caracteristicus, respectively. We observed that Czon1107 strongly inhibits the human α3β4 (IC50 15.7 ± 3.0 μm) and α7 (IC50 77.1 ± 0.05 μm) nicotinic acetylcholine receptor (nAChR) subtypes, but the activity of Cca1669 remains to be identified. Czon1107 acted at a site distinct from the orthosteric receptor site. Solution NMR experiments revealed that Czon1107 exists in equilibrium between conformational states that are the result of a key Ser4–Pro5cis-trans isomerization. Moreover, we found that the X-Pro amide bonds in the inter-cysteine loop are rigidly constrained to cis conformations. Structure-activity experiments of Czon1107 and its variants at positions P5 and P7 revealed that the conformation around the X-Pro bonds (cis-trans) plays an important role in receptor subtype selectivity. The cis conformation at the Cys6–Pro7 peptide bond was essential for α3β4 nAChR subtype allosteric selectivity. In summary, we have identified a unique single-disulfide conopeptide with a noncompetitive, potentially allosteric inhibitory mechanism at the nAChRs. The small size and rigidity of the Czon1107 peptide could provide a scaffold for rational drug design strategies for allosteric nAChR modulation. This new paradigm in the “conotoxinomic” structure-function space provides an impetus to screen venom from other Conus species for similar, short bioactive peptides that allosterically modulate ligand-gated receptor function.

ChemInform Abstract: Synthesis of Novel Imidazobenzodiazepines Selective for the α5. beta.2γ2 (Bz5) GABAA/Benzodiazepine Receptor Subtype.

ChemInform ◽  
2010 ◽  
Vol 27 (21) ◽  
pp. no-no
Author(s):  
R. LIU ◽  
P. ZHANG ◽  
R. M. MCKERNAN ◽  
K. WAFFORD ◽  
J. M. COOK
Keyword(s):  
Benzodiazepine Receptor ◽  
Receptor Subtype

scholarly journals Angiotensin-(1–7) can interact with the rat proximal tubule AT4 receptor system

1999 ◽  
Vol 277 (1) ◽  
pp. F75-F83 ◽  
Author(s):  
Rajash K. Handa
Keyword(s):  
Proximal Tubule ◽  
Rat Kidney ◽  
Receptor Site ◽  
Transport Processes ◽  
Proximal Tubules ◽  
Receptor Subtype ◽  
Angiotensin Receptor ◽  
Peptide Fragments ◽  
Receptor System ◽  
Rat Proximal Tubule

This study was undertaken to identify the non-AT1, non-AT2 angiotensin receptor that mediates the ANG-(1–7) inhibitory action on rat proximal tubule transport processes. ANG-(1–7) inhibited nystatin-stimulated, ouabain-suppressible O2consumption (Qo 2) rates in freshly isolated rat proximal tubules (reflecting reduced basolateral Na+-K+-ATPase activity). Selective angiotensin-receptor subtype antagonists revealed that AT1 and AT4 receptors mediated the response of ANG-(1–7). Receptor autoradiography of the rat kidney demonstrated a high density of AT1and AT4 receptors and no specific125I-ANG(1–7) binding sites. Competition assays in rat kidney sections indicated that ANG-(1–7) competed predominantly for the AT1 receptor site, whereas its NH2-terminal-deleted metabolite, ANG-(3–7), competed primarily for the AT4-receptor site. Metabolism of125I-ANG-(1–7) in rat proximal tubules generated peptide fragments that included ANG-(3–7), with the pentapeptide producing a concentration-dependent inhibition of nystatin-stimulated proximal tubule Qo 2that was abolished by AT4-receptor blockade. These results suggest that the generation of ANG-(3–7) from the NH2-terminal metabolism of ANG-(1–7) caused the interaction of the parent peptide with the proximal tubule AT4 receptor, which elicited a decrease in energy-dependent solute transport.

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