Sleep disorder studies

Originally, Rohypnol was developed as a sleeping pill. It has been used successfully for that purpose in many countries outside the United States (It is the most frequently prescribed sleeping pill in Europe.) When used as prescribed, it is an effective short-term therapy for severe sleep disorders. Studies show that Rohypnol increases the total amount of time spent sleeping and lessens the difference between the amount of time spent in bed and the amount of time asleep. Both factors are significant to people who suffer from severe sleep problems that leave them sleep-deprived and anxious. Therapeutic doses of Rohypnol vary from 0.5 mg to 1 mg. 

Assess patient sleep complaints, conduct sleep histories, and evaluate sleep studies to recognize day- and nighttime symptoms and characteristics of common sleep disorders. 

Peppard P, Young T, Palta M, et al. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000 342 1378-1384. 

Melatonin secretion is synchronized to the light/dark (LD) cycle, with a nocturnal maximum (in young humans, about 200 pg/ml plasma) and low diurnal baseline levels (about 10 pg/ml plasma). Studies have supported the value of the exogenous administration of melatonin in circadian rhythm sleep disorders, insomnia, cancer, neurodegenerative diseases, disorders of the immune function, and oxidative damage (Karasek et al. 2002 Pandi-Perumal et al. 2005, 2006 Srinivasan et al. 2005a,b, 2006 Hardeland et al. 2006). 

Gillin J. C., Smith-Vaniz A., Schnierow B. et al. (2001). An open-label, 12-week clinical and sleep EEG study of nefazodone in chronic combat-related posttraumatic stress disorder. J. Clin. Psychiatry 62, 789-96. 

As part of the study of potential sleep disorder therapeutics referred to above (cf. Scheme 100), the thienoquinolizines 461 and 462 have been synthesized as shown in Scheme 103 <1997TL8475>. 

Compiled from US. Modafinil in Narcolepsy Multicenter Study Group and Standard of Practice Committee of the American Sleep Disorders Association. Pradice parameters for the use of stimulants in the treatment of narcolepsy. Seep 1994 17 348-351. 

Tricyclic antidepressants have been used for decades to treat depression and anxiety in the general population, and clomipramine has been used to treat OCD. Clomipramine has been studied with respect to treating school phobia or school refusal (Berney et ah, 1981). Gittleman-Klein and Klein (1971) found imipramine to be superior to placebo in treating school refusal. As the TCAs may improve other disorders such as nocturnal enuresis, ADHD, and sleep disorders, they may be attractive for children with any of these comorbid conditions and anxiety disorder. 

Kastner et al. (1993) evaluated valproic acid in 18 children and adults (mean age, 19.7 years) with self-injury or aggression, irritability, sleep disorder, and evidence of cycling. Fourteen (78%) responded positively as assessed by the CGI in this uncontrolled study. The authors found that 11 subjects with established or suspected epilepsy responded significantly better than participants with no evidence of epilepsy. 

Antihistamines such as diphenhydramine, a mainstay of OTC sleep preparations, are also used widely by parents for their children at doses of 1 mg/kg. Most of the reports of the use of clonidine for sleep disorders are clinical and anecdotal case reports of use in children with ADFFD (Wilens et ah, 1994 Prince et ah, 1996). There are some safety concerns about using clonidine once a day at bedtime, especially in patients who take a daytime stimulant. Melatonin was studied using a double-blind, placebo-controlled, crossover design (Jan et ah, 1994) on a mixed group of 15 children with sleep disturbances, with some improvement reported. However, caution is warranted in using this agent because melatonin is unregulated, and there are concerns about the purity and safety of some commercially available preparations (Werry and Aman, 1999). 

Soldatos CR, Sakkas P, Bergiannaki JD, et al Sleep laboratory studies in the evaluation of antidepressants methodological considerations, in Psychiatry A World Perspective, Vol 2 Neuroscience in Psychiatry Biological Correlates of Mental Disorders. Edited by Stefanis CN, Soldatos CR, Rabavilas AD. New York, Excerpta Medica, 1990, pp 636-642... 

Modafinil is a stimulant medication used to improve wakefulness in patients with narcolepsy, obstructive sleep apnea/hypopnea syndrome (as adjunct to standard treatments for the underlying disorder), and shift work sleep disorder. Controlled and open trials provided data on the efficacy and safety of modafinil in patients with narcolepsy (Besset et al. 1996 Billiard et al. 1994 Broughton et al. 1997 Mitler et al. 2000 U.S. Modafinil in Narcolepsy Multicenter Study Group 1998, 2000). Modafinil has a long duration of action and low potential for dependence and may be a reasonable first choice in the treatment of mild to moderate narcolepsy (Silber 2001). There is also considerable interest in the potential use of modafinil in the treatment of ADHD, and studies are in progress. 

Nieto FJ, Young TB, Link BK, et al. Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. JAMA 2000 283 1829-1836. 

Melatonin has been studied in the treatment of various sleep disorders, including insomnia and delayed sleep-phase syndrome. It has been reported to improve sleep onset, duration, and quality when administered to healthy volunteers, suggesting a pharmacologic hypnotic effect. Melatonin has also been shown to increase rapid-eye-movement (REM) sleep. These observations have been applied to the development of ramel-teon, a prescription hypnotic, which is an agonist at melatonin receptors (see Chapter 22). 

Clinical studies in patients with sleep disorders have shown that oral melatonin supplementation may alter sleep architecture. Subjective improvements in sleep quality and improvements in sleep onset and sleep duration have been reported. However, the significance of these findings is impaired by many study limitations. 

Since animals sleep, this begs the question—do animals have sleep disorders Well, we may never know if animals suffer from insomnia because we can t ask them, Are you getting enough sleep But in fact, there are several species of animals that display behaviors remarkably similar to symptoms of human sleep disorders. For example, pigs can show signs of sleep apnea and have been used to study potential treatments for the disorder. 

Melatonin may be an effective treatment for several conditions. Studies suggest that it may be helpful in treating sleep disorders, jet lag, and even cancer. However, research on this topic is still very limited and experts have warned consumers that very little is known about the effectiveness or long-term safety of taking melatonin supplements. 

While the effectiveness of melatonin in treating sleep disorders in most people remains unclear, research shows that it can be helpful for certain individuals. For example, many blind people have sleep disorders, and melatonin has been shown to help promote sleep in this population. Studies have also shown that it is helpful in treating sleep disorders in disabled children. 

Howard and colleagues (31) suggested a reform of residents work and duty hours based on a study that assessed the levels of physiological and subjective sleepiness in 11 anesthesia residents in three conditions (1) during a normal (baseline) work schedule, (2) after an in-hospital 24-hr on-call period, and (3) after a period of extended sleep. MSLT scores were shorter in the baseline (6.7 min) and postcall (4.9 min) conditions, compared with the extended-sleep condition (12 min), and there was no significant difference between the baseline and postcall conditions. Residents daytime sleepiness on the MSLT in both baseline and postcall conditions was near or below levels associated with clinical sleep disorders, and residents were subjectively inaccurate determining EEG-defined sleep onset. 

We are using the term inadequate sleep instead of sleep deprivation in our title for a number of reasons. First, few studies have aimed specifically to deprive children or adolescents of sleep. We describe some research on experimental sleep restriction in children but most of these studies fall far short of common deprivation paradigms in animals or even adult humans. Instead, most research in younger humans has assessed outcome measures such as school grades, self-reported sleepiness, and so forth as a function of variations in self-selected or usual sleep patterns with the expectation that children and adolescents who obtain lower than normal amounts of sleep will manifest deficits. Thus, inadequate sleep is defined by sleep characteristics of a sample. We also wanted to note some of the literature on sleep that is disturbed or disrupted due to disease processes such as apnea or periodic leg movements the duration of sleep in sleep disorders may or may not be shortened or restricted although it is likely fragmented and otherwise abnormal. We decided on the term inadequate sleep with the hope that it would encompass these different areas of concern. 

Infants, school-age children, and adolescents have been studied in the laboratory, hospital nurseries, schools, institutions, and their homes with polysomnography, time-lapse video monitors, activity monitors, diaries, and self- and parent-report instruments. Children both with and without sleep disorders have been evaluated with these various assessment procedures, and researchers have used a wide range of study designs to investigate the impact of inadequate sleep. For example, in laboratory studies children and adolescents have been assessed on their usual (often arguably inadequate) schedules as well as on study-defined optimized and restricted... 

Moreover, there is evidence for increased rates of ADHD symptoms in clinical populations of children with sleep disorders, including children with the obstructive sleep apnea syndrome (OSAS), periodic limb movements of sleep (PLMS), narcolepsy, and sleep-wake schedule disorders. Studies indicate that treating the primary sleep disorder can produce significant improvement in ADHD symptoms (103). 

Sleep disorders such as sleep apnea, narcolepsy, delayed sleep-phase syndrome (DSPS), and insomnia can cause problem sleepiness and difficulty functioning during the day for adolescents (103). Over the course of several studies, Roberts and colleagues have shown that insomnia and related sleep problems have adverse consequences for the future functioning of adolescents (107,108). In particular, insomnia symptoms such as nonrestorative sleep, difficulty initiating sleep, and daytime sleepiness predicted self-esteem difficulties, interpersonal relationship problems, and symptoms of depression, along with somatic complaints (108). 

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