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A compendium of placebo-controlled trials of the risks/benefits of pharmacological treatments for insomnia: The empirical basis for U.S. clinical practice
Abstract
For many years practitioners have had limited data from double-blind, placebo-controlled studies to guide the types of decision-making needed to optimally manage patients with insomnia in clinical practice. However, in recent years there has been a great increase in insomnia research studies that address issues of clinical importance. This body of work represents an increasingly useful empirical basis for making clinical practice decisions. The purpose of this article is to compile the body of work on the pharmacological management of insomnia to make it available in as accessible form as possible for optimal application in clinical practice with the hopes that doing so will decrease the gap separating the available research and the clinical management of insomnia and, thereby, improve the care of the many individuals who suffer from this condition. The review of studies consists of the following sections: 1) basic pharmacology; 2) double-blind, placebo-controlled trials in adults with primary insomnia; 3) double-blind, placebo-controlled trials in elderly patients with primary insomnia; 4) adverse effects reported in placebo-controlled trials in elderly primary insomnia patients; 5) double-blind, placebo-controlled trials in adults and the elderly as a function of treatment duration; 6) double-blind, placebo-controlled trials of the treatment of comorbid insomnia. Issues related to the application of these data to clinical practice are discussed in the text.
... It has been estimated that 300,000 adults in England have received a prescription for benzodiazepines for one year or more, above the recommended 4-week use of these medications (Davies et al., 2017). Z-drugs (imidazopyridines, pyrazolopyrimidines, and cyclopyrrolones) are also licensed for use in insomnia and act similarly through allosteric modulation of GABA A (Krystal, 2009). ...
... However, there is a significant concern for the risk of abuse with these classes of medication (Krystal, 2009). Melatonin, which is involved in the regulation of the sleep-wake cycle and promotion of sleep (Karasek & Winczyk, 1997), is approved for the treatment of insomnia in patients over 55 years of age by the European Medicines Agency (Clay et al., 2013). ...
... Despite the availability of pharmacological therapies for insomnia, the rates of remission for chronic insomnia are poor and there are concerns regarding the risks of dependency with long-term prescribing of benzodiazepines and Z-drugs, demonstrating a need to identify emerging therapies (Davies et al., 2017;Janson et al., 2001;Krystal, 2009). The endocannabinoid system (ECS) has been suggested as a target for such therapies due to the evidence of its role in regulating the sleep-wake cycle. ...
Introduction
The primary aim of this study was to assess changes in sleep‐specific health‐related quality of life (HRQoL) for those prescribed cannabis‐based medicinal products (CBMPs) for insomnia.
Methods
A case series of UK patients with insomnia was analyzed. Primary outcomes were changes in the Single‐Item Sleep‐Quality Scale (SQS), Generalized Anxiety Disorder‐7 (GAD‐7), and EQ‐5D‐5L at up to 6 months from baseline. Statistical significance was identified as a p value < .050.
Results
61 patients were included in the analysis. There was an improvement in the SQS from baseline at 1, 3, and 6 months (p < .001). There were also improvements in the EQ‐5D‐5L Index value and GAD‐7 at 1, 3, and 6 months (p < .050). There were 28 (45.9%) adverse events recorded by 8 patients (13.1%). There were no life‐threatening/disabling adverse events.
Conclusion
Patients with insomnia experienced an improvement in sleep quality following the initiation of CBMPs in this medium‐term analysis. Fewer than 15% of participants reported one or more adverse events. However, due to the limitations of the study design, further investigation is required before definitive conclusions can be drawn on the efficacy of CBMPs in treating insomnia.
... Некоторые антидепрессанты, первоначально использовавшиеся для терапии большой депрессии, в настоящее время используются для лечения бессонницы. Эта категория препаратов так же вызывает улучшение сна, воздействуя на определенные нейромедиаторные системы [96]. Наиболее часто рекомендуемыми антидепрессантами для лечения бессонницы являются 15 мг миртазапина, 10-75 мг доксепина, 50-150 мг тразодона и 10-100 мг амитриптилина [96]. ...
... Эта категория препаратов так же вызывает улучшение сна, воздействуя на определенные нейромедиаторные системы [96]. Наиболее часто рекомендуемыми антидепрессантами для лечения бессонницы являются 15 мг миртазапина, 10-75 мг доксепина, 50-150 мг тразодона и 10-100 мг амитриптилина [96]. Побочные эффекты, вызванные антидепрессантами для лечения бессонницы, могут варьироваться. ...
... Антипсихотики, в основном используемые для лечения психотических состояний, иногда также используются для лечения бессонницы, но в дозе ниже той, которая обычно используется при лечении психотических расстройств [96]. Эти препараты могут быть рекомендованы пациентам со склонностью к злоупотреблению наркотиками. ...
Insomnia is a common disorder among the general population, which has a chronic course and a heavy burden on patients and the health care system. Epidemiological papers on sleep disorders show that a large number of people complain of sleep disorders. Today, there are several classifications and definitions for sleep disorders, and first of all for insomnia. Insufficient sleep can contribute to the occurrence of rapid fatigue during the daytime, reduced activity, attention and efficiency. Studies have shown that long-term and severe sleep disorders can lead to and/or exacerbate various somatic, neurological and mental diseases. Insomnia can contribute to cognitive impairment. Although both non-pharmacological and pharmacological interventions are available, drugs are more often prescribed due to greater availability. Cognitive behavioural therapy for insomnia is recommended as the first line treatment for adults of any age. Pharmacological intervention may be offered, if cognitive behavioural therapy for insomnia is not enough effective or not available. At the same time, the pharmacotherapy for sleep disorders remains problematic despite a large number of sleeping pills. Sleeping agents that are widely used in medical practice both in terms of their mechanisms of action and final results such as their effect on sleep do not always contribute to the development of natural (or at least close to physiological) sleep. Benzodiazepines, benzodiazepine receptor agonists, antidepressants, antihistamines, antipsychotics, melatonin, and phytotherapeutic medicines can be used to treat insomnia.
... Non-benzodiazepine hypnotics, often referred to as Z-drugs, include agents such as zolpidem and zaleplon. They act on the GABA-A receptor complex to promote sedation and are characterized by their short half-lives and reduced residual sedation compared to benzodiazepines [53,54]. ...
... However, the use of Z-drugs is associated with risks, including tolerance, dependence, cognitive impairment, and next-day drowsiness, which may impair athletic performance or increase injury risk [53,57,58]. Because of these risks, their use in athletes should be cautious and limited to short durations under medical supervision. ...
Sleep is a critical determinant of recovery, performance, and overall well-being in athletes. Despite its importance, sleep disturbances—including insomnia, delayed sleep onset, and circadian rhythm disruption—are common in athletic populations, driven by both primary factors (e.g., overtraining, evening workouts, jet lag) and secondary factors (e.g., stress, injury, metabolic conditions). These disturbances can impair physical restoration, hormonal balance, and cognitive functioning. This review explores the physiological foundations of sleep in athletes, outlines the multifactorial causes of insomnia, and evaluates pharmacological strategies—including melatonin, non-benzodiazepine hypnotics, cannabidiol (CBD), and certain antidepressants—for managing sleep disorders. While pharmacotherapy may provide short-term benefits in select situations, non-pharmacological approaches such as Cognitive Behavioral Therapy for Insomnia (CBT-I) remain the gold standard due to their long-term efficacy and minimal side effects. An integrated, personalized approach that combines behavioral, physiological, and pharmacological strategies offers the greatest potential for optimizing sleep and supporting sustainable athletic performance.
... Two notable exceptions to this are zolpidem, for which we found 22 RCTs, possibly explained by the diversity of commercial presentations available, and DORAs, which are a more recent pharmacological class. The lack of RCTs is not only restricted to the drug categories being assessed, but also to the population being studied in these trials; for example, there are few RCTs for insomnia treatments in specific populations, such as children, older adults, and people with comorbidities, as has been reported in previous studies 32 . In addition, there is a lack of longer-term RCTs that look at the side effects of the concomitant use of these drugs with other drugs, such as antidepressants and antipsychotics 32 . ...
... The lack of RCTs is not only restricted to the drug categories being assessed, but also to the population being studied in these trials; for example, there are few RCTs for insomnia treatments in specific populations, such as children, older adults, and people with comorbidities, as has been reported in previous studies 32 . In addition, there is a lack of longer-term RCTs that look at the side effects of the concomitant use of these drugs with other drugs, such as antidepressants and antipsychotics 32 . A number of other issues have been raised regarding the methods employed in RCTs for pharmacological treatments for insomnia. ...
... [5][6][7][8] Because of this reason and also because of association of insomnia with deterioration in quality of life and increase in risk of falls and accident, it has been suggested that pharmacotherapy should be targeted to address insomnia specifically if it is present along with other psychiatric or physical disorders. 9,10 For the patients meeting the diagnostic criteria for insomnia, many treatments option that is empirically supported are available. There are also nonpharmacological interventions in addition to pharmacotherapies. ...
... There are also nonpharmacological interventions in addition to pharmacotherapies. 10,11 In addition to improve sleep hygiene through non-pharmacologic approaches, pharmacological agents for sleep are often prescribed for the management of hospital-related insomnia. 12 One of the most used groups of pharmacological agents for sleep aids in the hospital setting are non-benzodiazepine agonists of GABA receptors because of strong evidence of their efficacy in insomnia particularly in the outpatient setting. ...
... 8 In fact, this belief is not based on existing data, since, after the long-term use, only 15 to 40% of patients show withdrawal symptoms, rebound insomnia, and increased anxiety, and it has even been established that addiction is also due to biological factors of certain patients that are related to specific subtypes of the GABA neurotransmitter. 16,55,56 Another possible explanation about why psychiatrists seem to dislike benzodiazepines is that their patients are likely to have a chronic/persistent form of the disorder or comorbidity with other psychiatric disorders and have already tried other treatments without success, so psychiatrists choose antidepressants or antipsychotics, which appear to be more effective in these cases. 26,33,34 In the current survey, physicians evaluated Z-drugs as the most efficient regimen for the treatment of insomnia. ...
Objective To explore the preferences of medical practitioners concerning various medications and other remedies to manage insomnia, and to ascertain whether these preferences are associated with their respective medical specialties.
Materials and Methods Employing the snowball sampling technique, we administered two versions of a questionnaire to an international group of medical professionals, including trainees and specialists from diverse medical backgrounds.
Results Zopiclone, zolpidem, and mirtazapine were evaluated as the most effective treatments for insomnia, while physicians would typically avoid using other tricyclic antidepressants, dual orexin receptor antagonists, and tryptophan for insomnia treatment. Noteworthy statistical correlations between physicians' specialty and preferred drug therapy, were observed in three out of five cases: 1) first-line drug treatment for short-term intervention against insomnia; (2) second-line treatment for long-term intervention; and 3) cases involving the elderly.
Discussion Psychiatrists demonstrated a greater preference for antipsychotics and antidepressants for the treatment of insomnia compared with other physicians. Conversely, other medical professionals exhibited a preference for benzodiazepines and Z-drugs (zopiclone and zolpidem). Although Z-drugs were evaluated as the most effective in the treatment of insomnia, in the clinical practice, physicians administer or would administer antidepressant or antipsychotic drugs more often (mirtazapine and quetiapine respectively). Regarding Dual Orexin Receptor Antagonists (DORAs), the high prevalence of “Do not know/No opinion” answers implies that our sample was not familiar with this innovative treatment.
... For instance, it was reported that sleep disorders multiply the risk of having episodes of psychiatric disorders [26]. Further, it is now becoming evident that many pharmacological agents can be commonly used for the treatment of both groups of illnesses [27,28]. Interestingly, it has been shown that sleep deprivation, which is known to correlate with an increase in MPO plasma levels and the risk of cardiovascular diseases [29,30], may aggravate numerous psychiatric disorders [31]. ...
Atherosclerosis is a chronic inflammatory disease that involves modified low-density lipoproteins (LDL) which play a pivotal role in the initiation and progression of the disease. Myeloperoxidase oxidized LDL (Mox-LDL) is considered to be the most patho-physiologically relevant type of modified LDL and has been reported to be ubiquitously present in atheroma plaques of patients with atherosclerosis. Besides its involvement in the latter disease state, Mox-LDL has also been shown to be implicated in the pathogenesis of various illnesses including sleep disorders, which are in turn associated with heart disease and depression in many intricate ways. Meanwhile, we have recently shown that lox-1-mediated Mox-LDL signaling modulates neuroserpin activity in endothelial cells, which could have major implications that go beyond the pathophysiology of stroke and cerebrovascular disease (CD). Of note is that tissue plasminogen activator (tPA), which is the main target of neuroserpin in the brain, has a crucial function in the processing of brain-derived neurotrophic factor (BDNF) into its mature form. This factor is known to be involved in major depressive disorder (MDD) development and pathogenesis. Since tPA is more conventionally recognized as being involved in fibrinolytic mechanisms, and its effect on the BDNF system in the context of MDD is still not extensively studied, we speculate that any Mox-LDL-driven change in the activity of tPA in patients with atherosclerosis may lead to a decrease in the production of mature BDNF, resulting in impaired neural plasticity and depression. Deciphering the mechanisms of interaction between those factors could help in better understanding the potentially overlapping pathological mechanisms that regulate disease processes in CD and MDD, supporting the possibility of novel and common therapeutic opportunities for millions of patients worldwide.
... [14][15][16][17][18][19] All these factors make insomnia an important pathology that should be diagnosed appropriately and treated accordingly. 20,21 Several treatment options are available for Insomnia. This paper reviews the various studies on insomnia with special emphasis on diagnosis and various non-pharmacological treatments like cognitive behavior therapy in insomnia (CBT-I). ...
... These agents are most effective for treating sleep problems and many of them are approved by the FDA for the treatment of insomnia, such as diazepam (Morin et al., 2015). However, these agents might be problematic for drug dependence and drug abuse (Krystal, 2009), and alternative treatments are needed. ...
Huanglian Wendan Decoction (HWD) is a traditional Chinese medicine (TCM) prescribed to patients diagnosed with insomnia, which can achieve excellent therapeutic outcomes. As positively modulating the γ-aminobutyric acid (GABA) type A receptors (GABAARs) is the most effective strategy to manage insomnia, this study aimed to investigate whether the activation of GABAARs is involved in the anti-insomnia effect of HWD. We assessed the metabolites of HWD using LC/MS and the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and tested the pharmacological activity in vitro and in vivo using whole-cell patch clamp and insomnia zebrafish model. In HEK293 cells expressing α1β3γ2L GABAARs, HWD effectively increased the GABA-induced currents and could induce GABAAR-mediated currents independent of the application of GABA. In the LC-MS (QToF) assay, 31 metabolites were discovered in negative ion modes and 37 metabolites were found in positive ion modes, but neither three selected active metabolites, Danshensu, Coptisine, or Dihydromyricetin, showed potentiating effects on GABA currents. 62 active metabolites of the seven botanical drugs were collected based on the TCMSP database and 19 of them were selected for patch-clamp verification according to the virtual docking simulations and other parameters. At a concentration of 100 μM, GABA-induced currents were increased by (+)-Cuparene (278.80% ± 19.13%), Ethyl glucoside (225.40% ± 21.77%), and β-Caryophyllene (290.11% ± 17.71%). In addition, (+)-Cuparene, Ethyl glucoside, and β-Caryophyllene could also serve as positive allosteric modulators (PAMs) and shifted the GABA dose-response curve (DRC) leftward significantly. In the PCPA-induced zebrafish model, Ethyl glucoside showed anti-insomnia effects at concentrations of 100 μM. In this research, we demonstrated that the activation of GABAARs was involved in the anti-insomnia effect of HWD, and Ethyl glucoside might be a key metabolite in treating insomnia.
... Antidepressants Several medications were originally developed for the treatment of major depressive disorder and are commonly used for treating sleep disorders. These agents may enhance sleep effects by blocking the receptors for neurotransmitters that are wake enhancing [60]. Mirtazapine is one of the antidepressants that is most commonly used to treat sleep disorders. ...
Angelman syndrome (AS) is a neurodevelopmental disorder caused by abnormal expression of the maternal ubiquitin protein ligase E3A gene ( UBE3A ). As one of the most challenging symptoms and important focuses of new treatment, sleep disturbance is reported to occur in 70–80% of patients with AS and has a serious impact on the lives of patients and their families. Although clinical studies and animal model studies have provided some clues, recent research into sleep disorders in the context of AS is still very limited. It is generally accepted that there is an interaction between neurodevelopment and sleep; however, there is no recognized mechanism for sleep disorders in AS patients. Accordingly, there are no aetiologically specific clinical treatments for AS-related sleep disorders. The most common approaches involve ameliorating symptoms through methods such as behavioural therapy and symptomatic pharmacotherapy. In recent years, preclinical and clinical studies on the targeted treatment of AS have emerged. Although precision therapy for restoring the UBE3A level and the function of its signalling pathways is inevitably hindered by many remaining obstacles, this approach has the potential to address AS-related sleep disturbance.
... When insomnia is brought to the attention of a primary care physician, treatment is typically restricted to pharmacotherapy. Although hypnotic medications are effective for the short-term management of insomnia only and there is limited evidence about their sustained efficacy in long-term use [7]. Recognition of the psychological factors that play an important role in maintaining sleep disturbances has led to increased interest in the use of nonpharmacological treatments for insomnia. ...
Introduction: Insomnia is the most prevalent of all sleep disorders. Non-pharmacological interventions in recent years have
been established as first-line treatment for nonorganic insomnia. Studies have shown Cognitive Behavior Therapy for Insomnia
(CBT-I) to be effective for primary insomnia. Paradoxical intention is a Logo-therapeutic technique based on the existential
origins of the founder, Viktor E. Frankl. Past researches into the effectiveness of paradoxical Intention interventions have been
inconsistent. There is a lack of evidence that Paradoxical Intention Therapy is differentially effective in insomnia when compared
with CBT-I.
Aim: To evaluate and compare the effectiveness of CBT-I and PIT and to study their effects on mental health in Non-Organic
Insomnia in young adults.
Method: Participants: A mixed-gender group of 20 young adults with a mean age of 25.35 years.
Procedure: Participants were recruited via an online survey with the help of the Insomnia Severity Index. 100 participants
responded to the online survey on Insomnia Severity Index out of which 24 met the inclusion criteria and finally 20 participants
gave their consent to undergo the intervention modules. Participants were randomly assigned to two intervention groups namely
CBT-I (n=10) and PIT group (n=10). Both the interventions were given for two months. Scores of Insomnia Severity Index,
Pittsburg Sleep Quality Index, and Mental Health Inventory were taken as outcome measures at baseline (Pre-Intervention), at
the end of the intervention (Post Intervention), and in a follow-up assessment after 45 days, assessment of Insomnia Severity
and Sleep Quality was done to study the maintenance of the therapeutic effect and relapse. An informed consent was taken from
participants before the intervention results: It was found that both CBT-I and PIT are effective. Although CBT-I was associated
with greater improvements than PIT. Both the groups showed significant improvements in the scores of outcome measures. The
overall patterns of change with treatment demonstrated statistically and clinically significant improvements in the severity of
insomnia symptoms as well as statistically significant differences in sleep quality and mental health.
Conclusion: Both CBT and PIT are effective in non-organic insomnia but CBT-I might be a substantial treatment of choice with a
more sustained and high effect for CBT-I when compared to Paradoxical Intention Therapy.
Aim
Suvorexant is an orexin receptor antagonist (ORA) for the treatment of insomnia. The antagonistic action of suvorexant on orexin receptors is associated with an increase in rapid eye movement (REM) sleep, which can potentially lead to nightmares depending on the patient's condition. However, the precise risk factors for nightmares among patients taking ORAs, such as suvorexant, have yet to be identified. In this retrospective study, we aimed to identify the risk factors for the development of nightmares in patients treated with suvorexant.
Methods
The risk factors were determined by comparing parameters between the nightmare group and the nonnightmare group. This study included 440 patients who received suvorexant at the University of Miyazaki Hospital from April 2014 to January 2021.
Results
We found that 9.1% (n = 40) of the patients experienced suvorexant‐induced nightmares. There was a significant difference in the median age, which was lower in the nightmare group than in the nonnightmare group (p < 0.01). Furthermore, both multiple logistic regression analysis and Cox proportional hazards regression analysis revealed increased odds ratios for nightmares for individuals aged 20–39 years.
Conclusions
This study revealed that elderly patients taking suvorexant had fewer nightmares than nonelderly patients did.
This article reviews the history of insomnia pharmacotherapy, documenting the evolution that has occurred over time in the increasing availability of medications with novel mechanisms of action that more specifically target the neural systems that modulate sleep/wake function. This evolution provides an increasing capacity to improve the effectiveness of insomnia pharmacotherapy by allowing the selection of medications that specifically target the particular type of sleep difficulty present in each patient. As a result, they can achieve a therapeutic effect with fewer effects on aspects of brain function other than those needed to achieve benefit, thereby minimising adverse effects. The accumulated evidence‐base is such that it can serve as the basis for a personalised insomnia pharmacotherapy paradigm. Here we outline a set of best‐practice recommendations for how to carry out optimised personalised insomnia pharmacotherapy based on that evidence base in the hope that it will improve the treatment delivered to the many individuals suffering from insomnia.
Chronic insomnia is one of the most common sleep disorders in the world. The representation of chronic insomnia in the general population reaches 10-20% according to various sources. The most effective method of treating chronic insomnia with a sustained effect is cognitive behavioral therapy of insomnia (CBT-I). Among the disadvantages of CBT-I is its low availability (due to the lack of specialists) and high cost. Methods of delivered CBT-I are becoming increasingly relevant. The advantage of such type of CBT-I is the possibility of its use by a wide group of people. There are different ways of conducting delivered CBT, including those that do not require the direct participation of a specialist. The effectiveness of this method of treatment is comparable to full-time CBT-I.
Anxiety disorders are prevalent conditions in the world population, whose standard approaches include pharmacotherapy, psychotherapy, and combinations of these interventions. Different classes of psychopharmaceuticals are recommended as the first line of drugs to treat these disorders, which can have several adverse effects, treatment resistance, dependence, and drug–drug interactions making it necessary to search for new therapeutic agents. In particular, diazepam (DZP), a prototype drug from the group of benzodiazepines, has been commonly used and evaluated for its efficacy and safety in different anxiety disorders in clinical trials. DZP is also the most widely used reference standard in in vivo pharmacological assays of natural compounds. However, translating the results obtained in different rodent species and physiological anxiety tests instead of psychopathological animal models that can be of clinical application remains challenging. A systematic review of scientific articles published between 2010 and 2020 that included in vivo pre-clinical tests to define the anxiolytic, sedative and/or hypnotic effect of flower extracts is proposed. PRISMA and Rayyan were used for the selection of studies using four databases (Pubmed, Scopus, Web of Science, and QInsight), using the keywords: “Animals,” “Anxiolytic,” “Diazepam,” “Elevated Plus Maze,” “Flower Extracts,” “Insomnia,” “In vivo,” “Mice,” “Open Field Test,” “Pre clinical” and “Sedative.” The characteristics of anxiety studies in animal models, other studies related to locomotor activity, and the hypnotic effect of the extracts were compiled. Twenty-four articles were included, 21 of them performed the animal model of anxiety-like behavior of the elevated plus maze, seven the open field test, and six the light–dark box test. The locomotor activity was evaluated in 10 studies after the administration of the extracts to the animals to define their sedative effect, where only one defined that the extract (Matricaria chamomilla) had a sedative effect. The plants declared with this type of activity were Achyranthes aspera, Alcea aucheri, Brassica nigra, Cananga odorata, Carthamus tinctorius, Chrysanthemum indicum, Citrus aurantium, Couroupita guianensis, Echium amoenum, Erythrina berteroana, Gardenia jasminoides, Hibiscus tilliaceus, Lavandula officinalis, Lawsonia inermis, Matricaria chamomilla, Melia azedarach, Nerium oleander, Passiflora incarnata, Plumeria rubra, Salix aegyptiaca, Syzygium aromaticum, Tagetes erecta, Tilia americana. Although this review showed that some flower extracts have an anxiolytic effect as effective as diazepam, their therapeutic utility in anxiety disorders remains to be extensively demonstrated. Hence, more reliable and predictive behavioral tests and appropriate strategies for the experimental designs are needed to obtain more conclusive evidence with clinical significance.
Previous studies have shown that modulating neural activity can affect rapid eye movement (REM) and non-rapid eye movement (NREM) sleep. Low-intensity transcranial ultrasound stimulation (TUS) can effectively modulate neural activity. However, the modulation effect of TUS on REM and NREM sleep is still unclear. In this study, we used ultrasound to stimulate motor cortex and hippocampus, respectively, and found the following: (i) In healthy mice, TUS increased the NREM sleep ratio and decreased the REM sleep ratio, and altered the relative power and sample entropy of the delta band and spindle in NREM sleep and that of the theta and gamma bands in REM sleep. (ii) In sleep-deprived mice, TUS decreased the ratio of REM sleep or the relative power of the theta band during REM sleep. (iii) In sleep-disordered Alzheimer’s disease (AD) mice, TUS increased the total sleep time and the ratio of NREM sleep and modulated the relative power and the sample entropy of the delta and spindle bands during NREM and that of the theta band during REM sleep. These results demonstrated that TUS can effectively modulate REM and NREM sleep and that modulation effect depends on the sleep state of the samples, and can improve sleep in sleep-disordered AD mice.
Unrecognized sleep disorders can shorten lives, promote hypertension, augment risk for diabetes, exacerbate metabolic syndrome, increase overall medical care costs, impair cognition, cause motor vehicle crashes, reduce workplace productivity, and greatly diminish quality of life. Sleep problems are among the most common complaints that patients bring to their clinicians, but little medical training is devoted to the field and so sleep disorders tend to remain undiagnosed for many years. The case-based chapters in this book highlight key points and pitfalls in a readable, easily assimilated, and memorable format that should improve a clinician's ability to address, investigate, and manage common sleep disorders. The cases illustrate how clinical skill and occasional wisdom can complement data obtained from laboratory testing. Common Pitfalls in Sleep Medicine will be of particular interest to clinicians and trainees in sleep medicine, neurology, internal medicine, family medicine, pulmonary medicine, otolaryngology, psychiatry, and psychology.
Unrecognized sleep disorders can shorten lives, promote hypertension, augment risk for diabetes, exacerbate metabolic syndrome, increase overall medical care costs, impair cognition, cause motor vehicle crashes, reduce workplace productivity, and greatly diminish quality of life. Sleep problems are among the most common complaints that patients bring to their clinicians, but little medical training is devoted to the field and so sleep disorders tend to remain undiagnosed for many years. The case-based chapters in this book highlight key points and pitfalls in a readable, easily assimilated, and memorable format that should improve a clinician's ability to address, investigate, and manage common sleep disorders. The cases illustrate how clinical skill and occasional wisdom can complement data obtained from laboratory testing. Common Pitfalls in Sleep Medicine will be of particular interest to clinicians and trainees in sleep medicine, neurology, internal medicine, family medicine, pulmonary medicine, otolaryngology, psychiatry, and psychology.
Unrecognized sleep disorders can shorten lives, promote hypertension, augment risk for diabetes, exacerbate metabolic syndrome, increase overall medical care costs, impair cognition, cause motor vehicle crashes, reduce workplace productivity, and greatly diminish quality of life. Sleep problems are among the most common complaints that patients bring to their clinicians, but little medical training is devoted to the field and so sleep disorders tend to remain undiagnosed for many years. The case-based chapters in this book highlight key points and pitfalls in a readable, easily assimilated, and memorable format that should improve a clinician's ability to address, investigate, and manage common sleep disorders. The cases illustrate how clinical skill and occasional wisdom can complement data obtained from laboratory testing. Common Pitfalls in Sleep Medicine will be of particular interest to clinicians and trainees in sleep medicine, neurology, internal medicine, family medicine, pulmonary medicine, otolaryngology, psychiatry, and psychology.
Unrecognized sleep disorders can shorten lives, promote hypertension, augment risk for diabetes, exacerbate metabolic syndrome, increase overall medical care costs, impair cognition, cause motor vehicle crashes, reduce workplace productivity, and greatly diminish quality of life. Sleep problems are among the most common complaints that patients bring to their clinicians, but little medical training is devoted to the field and so sleep disorders tend to remain undiagnosed for many years. The case-based chapters in this book highlight key points and pitfalls in a readable, easily assimilated, and memorable format that should improve a clinician's ability to address, investigate, and manage common sleep disorders. The cases illustrate how clinical skill and occasional wisdom can complement data obtained from laboratory testing. Common Pitfalls in Sleep Medicine will be of particular interest to clinicians and trainees in sleep medicine, neurology, internal medicine, family medicine, pulmonary medicine, otolaryngology, psychiatry, and psychology.
Unrecognized sleep disorders can shorten lives, promote hypertension, augment risk for diabetes, exacerbate metabolic syndrome, increase overall medical care costs, impair cognition, cause motor vehicle crashes, reduce workplace productivity, and greatly diminish quality of life. Sleep problems are among the most common complaints that patients bring to their clinicians, but little medical training is devoted to the field and so sleep disorders tend to remain undiagnosed for many years. The case-based chapters in this book highlight key points and pitfalls in a readable, easily assimilated, and memorable format that should improve a clinician's ability to address, investigate, and manage common sleep disorders. The cases illustrate how clinical skill and occasional wisdom can complement data obtained from laboratory testing. Common Pitfalls in Sleep Medicine will be of particular interest to clinicians and trainees in sleep medicine, neurology, internal medicine, family medicine, pulmonary medicine, otolaryngology, psychiatry, and psychology.
Unrecognized sleep disorders can shorten lives, promote hypertension, augment risk for diabetes, exacerbate metabolic syndrome, increase overall medical care costs, impair cognition, cause motor vehicle crashes, reduce workplace productivity, and greatly diminish quality of life. Sleep problems are among the most common complaints that patients bring to their clinicians, but little medical training is devoted to the field and so sleep disorders tend to remain undiagnosed for many years. The case-based chapters in this book highlight key points and pitfalls in a readable, easily assimilated, and memorable format that should improve a clinician's ability to address, investigate, and manage common sleep disorders. The cases illustrate how clinical skill and occasional wisdom can complement data obtained from laboratory testing. Common Pitfalls in Sleep Medicine will be of particular interest to clinicians and trainees in sleep medicine, neurology, internal medicine, family medicine, pulmonary medicine, otolaryngology, psychiatry, and psychology.
Unrecognized sleep disorders can shorten lives, promote hypertension, augment risk for diabetes, exacerbate metabolic syndrome, increase overall medical care costs, impair cognition, cause motor vehicle crashes, reduce workplace productivity, and greatly diminish quality of life. Sleep problems are among the most common complaints that patients bring to their clinicians, but little medical training is devoted to the field and so sleep disorders tend to remain undiagnosed for many years. The case-based chapters in this book highlight key points and pitfalls in a readable, easily assimilated, and memorable format that should improve a clinician's ability to address, investigate, and manage common sleep disorders. The cases illustrate how clinical skill and occasional wisdom can complement data obtained from laboratory testing. Common Pitfalls in Sleep Medicine will be of particular interest to clinicians and trainees in sleep medicine, neurology, internal medicine, family medicine, pulmonary medicine, otolaryngology, psychiatry, and psychology.
Unrecognized sleep disorders can shorten lives, promote hypertension, augment risk for diabetes, exacerbate metabolic syndrome, increase overall medical care costs, impair cognition, cause motor vehicle crashes, reduce workplace productivity, and greatly diminish quality of life. Sleep problems are among the most common complaints that patients bring to their clinicians, but little medical training is devoted to the field and so sleep disorders tend to remain undiagnosed for many years. The case-based chapters in this book highlight key points and pitfalls in a readable, easily assimilated, and memorable format that should improve a clinician's ability to address, investigate, and manage common sleep disorders. The cases illustrate how clinical skill and occasional wisdom can complement data obtained from laboratory testing. Common Pitfalls in Sleep Medicine will be of particular interest to clinicians and trainees in sleep medicine, neurology, internal medicine, family medicine, pulmonary medicine, otolaryngology, psychiatry, and psychology.
Unrecognized sleep disorders can shorten lives, promote hypertension, augment risk for diabetes, exacerbate metabolic syndrome, increase overall medical care costs, impair cognition, cause motor vehicle crashes, reduce workplace productivity, and greatly diminish quality of life. Sleep problems are among the most common complaints that patients bring to their clinicians, but little medical training is devoted to the field and so sleep disorders tend to remain undiagnosed for many years. The case-based chapters in this book highlight key points and pitfalls in a readable, easily assimilated, and memorable format that should improve a clinician's ability to address, investigate, and manage common sleep disorders. The cases illustrate how clinical skill and occasional wisdom can complement data obtained from laboratory testing. Common Pitfalls in Sleep Medicine will be of particular interest to clinicians and trainees in sleep medicine, neurology, internal medicine, family medicine, pulmonary medicine, otolaryngology, psychiatry, and psychology.
Unrecognized sleep disorders can shorten lives, promote hypertension, augment risk for diabetes, exacerbate metabolic syndrome, increase overall medical care costs, impair cognition, cause motor vehicle crashes, reduce workplace productivity, and greatly diminish quality of life. Sleep problems are among the most common complaints that patients bring to their clinicians, but little medical training is devoted to the field and so sleep disorders tend to remain undiagnosed for many years. The case-based chapters in this book highlight key points and pitfalls in a readable, easily assimilated, and memorable format that should improve a clinician's ability to address, investigate, and manage common sleep disorders. The cases illustrate how clinical skill and occasional wisdom can complement data obtained from laboratory testing. Common Pitfalls in Sleep Medicine will be of particular interest to clinicians and trainees in sleep medicine, neurology, internal medicine, family medicine, pulmonary medicine, otolaryngology, psychiatry, and psychology.
Unrecognized sleep disorders can shorten lives, promote hypertension, augment risk for diabetes, exacerbate metabolic syndrome, increase overall medical care costs, impair cognition, cause motor vehicle crashes, reduce workplace productivity, and greatly diminish quality of life. Sleep problems are among the most common complaints that patients bring to their clinicians, but little medical training is devoted to the field and so sleep disorders tend to remain undiagnosed for many years. The case-based chapters in this book highlight key points and pitfalls in a readable, easily assimilated, and memorable format that should improve a clinician's ability to address, investigate, and manage common sleep disorders. The cases illustrate how clinical skill and occasional wisdom can complement data obtained from laboratory testing. Common Pitfalls in Sleep Medicine will be of particular interest to clinicians and trainees in sleep medicine, neurology, internal medicine, family medicine, pulmonary medicine, otolaryngology, psychiatry, and psychology.
Unrecognized sleep disorders can shorten lives, promote hypertension, augment risk for diabetes, exacerbate metabolic syndrome, increase overall medical care costs, impair cognition, cause motor vehicle crashes, reduce workplace productivity, and greatly diminish quality of life. Sleep problems are among the most common complaints that patients bring to their clinicians, but little medical training is devoted to the field and so sleep disorders tend to remain undiagnosed for many years. The case-based chapters in this book highlight key points and pitfalls in a readable, easily assimilated, and memorable format that should improve a clinician's ability to address, investigate, and manage common sleep disorders. The cases illustrate how clinical skill and occasional wisdom can complement data obtained from laboratory testing. Common Pitfalls in Sleep Medicine will be of particular interest to clinicians and trainees in sleep medicine, neurology, internal medicine, family medicine, pulmonary medicine, otolaryngology, psychiatry, and psychology.
Unrecognized sleep disorders can shorten lives, promote hypertension, augment risk for diabetes, exacerbate metabolic syndrome, increase overall medical care costs, impair cognition, cause motor vehicle crashes, reduce workplace productivity, and greatly diminish quality of life. Sleep problems are among the most common complaints that patients bring to their clinicians, but little medical training is devoted to the field and so sleep disorders tend to remain undiagnosed for many years. The case-based chapters in this book highlight key points and pitfalls in a readable, easily assimilated, and memorable format that should improve a clinician's ability to address, investigate, and manage common sleep disorders. The cases illustrate how clinical skill and occasional wisdom can complement data obtained from laboratory testing. Common Pitfalls in Sleep Medicine will be of particular interest to clinicians and trainees in sleep medicine, neurology, internal medicine, family medicine, pulmonary medicine, otolaryngology, psychiatry, and psychology.
Unrecognized sleep disorders can shorten lives, promote hypertension, augment risk for diabetes, exacerbate metabolic syndrome, increase overall medical care costs, impair cognition, cause motor vehicle crashes, reduce workplace productivity, and greatly diminish quality of life. Sleep problems are among the most common complaints that patients bring to their clinicians, but little medical training is devoted to the field and so sleep disorders tend to remain undiagnosed for many years. The case-based chapters in this book highlight key points and pitfalls in a readable, easily assimilated, and memorable format that should improve a clinician's ability to address, investigate, and manage common sleep disorders. The cases illustrate how clinical skill and occasional wisdom can complement data obtained from laboratory testing. Common Pitfalls in Sleep Medicine will be of particular interest to clinicians and trainees in sleep medicine, neurology, internal medicine, family medicine, pulmonary medicine, otolaryngology, psychiatry, and psychology.
Unrecognized sleep disorders can shorten lives, promote hypertension, augment risk for diabetes, exacerbate metabolic syndrome, increase overall medical care costs, impair cognition, cause motor vehicle crashes, reduce workplace productivity, and greatly diminish quality of life. Sleep problems are among the most common complaints that patients bring to their clinicians, but little medical training is devoted to the field and so sleep disorders tend to remain undiagnosed for many years. The case-based chapters in this book highlight key points and pitfalls in a readable, easily assimilated, and memorable format that should improve a clinician's ability to address, investigate, and manage common sleep disorders. The cases illustrate how clinical skill and occasional wisdom can complement data obtained from laboratory testing. Common Pitfalls in Sleep Medicine will be of particular interest to clinicians and trainees in sleep medicine, neurology, internal medicine, family medicine, pulmonary medicine, otolaryngology, psychiatry, and psychology.
Unrecognized sleep disorders can shorten lives, promote hypertension, augment risk for diabetes, exacerbate metabolic syndrome, increase overall medical care costs, impair cognition, cause motor vehicle crashes, reduce workplace productivity, and greatly diminish quality of life. Sleep problems are among the most common complaints that patients bring to their clinicians, but little medical training is devoted to the field and so sleep disorders tend to remain undiagnosed for many years. The case-based chapters in this book highlight key points and pitfalls in a readable, easily assimilated, and memorable format that should improve a clinician's ability to address, investigate, and manage common sleep disorders. The cases illustrate how clinical skill and occasional wisdom can complement data obtained from laboratory testing. Common Pitfalls in Sleep Medicine will be of particular interest to clinicians and trainees in sleep medicine, neurology, internal medicine, family medicine, pulmonary medicine, otolaryngology, psychiatry, and psychology.
Unrecognized sleep disorders can shorten lives, promote hypertension, augment risk for diabetes, exacerbate metabolic syndrome, increase overall medical care costs, impair cognition, cause motor vehicle crashes, reduce workplace productivity, and greatly diminish quality of life. Sleep problems are among the most common complaints that patients bring to their clinicians, but little medical training is devoted to the field and so sleep disorders tend to remain undiagnosed for many years. The case-based chapters in this book highlight key points and pitfalls in a readable, easily assimilated, and memorable format that should improve a clinician's ability to address, investigate, and manage common sleep disorders. The cases illustrate how clinical skill and occasional wisdom can complement data obtained from laboratory testing. Common Pitfalls in Sleep Medicine will be of particular interest to clinicians and trainees in sleep medicine, neurology, internal medicine, family medicine, pulmonary medicine, otolaryngology, psychiatry, and psychology.
Unrecognized sleep disorders can shorten lives, promote hypertension, augment risk for diabetes, exacerbate metabolic syndrome, increase overall medical care costs, impair cognition, cause motor vehicle crashes, reduce workplace productivity, and greatly diminish quality of life. Sleep problems are among the most common complaints that patients bring to their clinicians, but little medical training is devoted to the field and so sleep disorders tend to remain undiagnosed for many years. The case-based chapters in this book highlight key points and pitfalls in a readable, easily assimilated, and memorable format that should improve a clinician's ability to address, investigate, and manage common sleep disorders. The cases illustrate how clinical skill and occasional wisdom can complement data obtained from laboratory testing. Common Pitfalls in Sleep Medicine will be of particular interest to clinicians and trainees in sleep medicine, neurology, internal medicine, family medicine, pulmonary medicine, otolaryngology, psychiatry, and psychology.
Unrecognized sleep disorders can shorten lives, promote hypertension, augment risk for diabetes, exacerbate metabolic syndrome, increase overall medical care costs, impair cognition, cause motor vehicle crashes, reduce workplace productivity, and greatly diminish quality of life. Sleep problems are among the most common complaints that patients bring to their clinicians, but little medical training is devoted to the field and so sleep disorders tend to remain undiagnosed for many years. The case-based chapters in this book highlight key points and pitfalls in a readable, easily assimilated, and memorable format that should improve a clinician's ability to address, investigate, and manage common sleep disorders. The cases illustrate how clinical skill and occasional wisdom can complement data obtained from laboratory testing. Common Pitfalls in Sleep Medicine will be of particular interest to clinicians and trainees in sleep medicine, neurology, internal medicine, family medicine, pulmonary medicine, otolaryngology, psychiatry, and psychology.
Unrecognized sleep disorders can shorten lives, promote hypertension, augment risk for diabetes, exacerbate metabolic syndrome, increase overall medical care costs, impair cognition, cause motor vehicle crashes, reduce workplace productivity, and greatly diminish quality of life. Sleep problems are among the most common complaints that patients bring to their clinicians, but little medical training is devoted to the field and so sleep disorders tend to remain undiagnosed for many years. The case-based chapters in this book highlight key points and pitfalls in a readable, easily assimilated, and memorable format that should improve a clinician's ability to address, investigate, and manage common sleep disorders. The cases illustrate how clinical skill and occasional wisdom can complement data obtained from laboratory testing. Common Pitfalls in Sleep Medicine will be of particular interest to clinicians and trainees in sleep medicine, neurology, internal medicine, family medicine, pulmonary medicine, otolaryngology, psychiatry, and psychology.
Unrecognized sleep disorders can shorten lives, promote hypertension, augment risk for diabetes, exacerbate metabolic syndrome, increase overall medical care costs, impair cognition, cause motor vehicle crashes, reduce workplace productivity, and greatly diminish quality of life. Sleep problems are among the most common complaints that patients bring to their clinicians, but little medical training is devoted to the field and so sleep disorders tend to remain undiagnosed for many years. The case-based chapters in this book highlight key points and pitfalls in a readable, easily assimilated, and memorable format that should improve a clinician's ability to address, investigate, and manage common sleep disorders. The cases illustrate how clinical skill and occasional wisdom can complement data obtained from laboratory testing. Common Pitfalls in Sleep Medicine will be of particular interest to clinicians and trainees in sleep medicine, neurology, internal medicine, family medicine, pulmonary medicine, otolaryngology, psychiatry, and psychology.
Unrecognized sleep disorders can shorten lives, promote hypertension, augment risk for diabetes, exacerbate metabolic syndrome, increase overall medical care costs, impair cognition, cause motor vehicle crashes, reduce workplace productivity, and greatly diminish quality of life. Sleep problems are among the most common complaints that patients bring to their clinicians, but little medical training is devoted to the field and so sleep disorders tend to remain undiagnosed for many years. The case-based chapters in this book highlight key points and pitfalls in a readable, easily assimilated, and memorable format that should improve a clinician's ability to address, investigate, and manage common sleep disorders. The cases illustrate how clinical skill and occasional wisdom can complement data obtained from laboratory testing. Common Pitfalls in Sleep Medicine will be of particular interest to clinicians and trainees in sleep medicine, neurology, internal medicine, family medicine, pulmonary medicine, otolaryngology, psychiatry, and psychology.
Unrecognized sleep disorders can shorten lives, promote hypertension, augment risk for diabetes, exacerbate metabolic syndrome, increase overall medical care costs, impair cognition, cause motor vehicle crashes, reduce workplace productivity, and greatly diminish quality of life. Sleep problems are among the most common complaints that patients bring to their clinicians, but little medical training is devoted to the field and so sleep disorders tend to remain undiagnosed for many years. The case-based chapters in this book highlight key points and pitfalls in a readable, easily assimilated, and memorable format that should improve a clinician's ability to address, investigate, and manage common sleep disorders. The cases illustrate how clinical skill and occasional wisdom can complement data obtained from laboratory testing. Common Pitfalls in Sleep Medicine will be of particular interest to clinicians and trainees in sleep medicine, neurology, internal medicine, family medicine, pulmonary medicine, otolaryngology, psychiatry, and psychology.
Unrecognized sleep disorders can shorten lives, promote hypertension, augment risk for diabetes, exacerbate metabolic syndrome, increase overall medical care costs, impair cognition, cause motor vehicle crashes, reduce workplace productivity, and greatly diminish quality of life. Sleep problems are among the most common complaints that patients bring to their clinicians, but little medical training is devoted to the field and so sleep disorders tend to remain undiagnosed for many years. The case-based chapters in this book highlight key points and pitfalls in a readable, easily assimilated, and memorable format that should improve a clinician's ability to address, investigate, and manage common sleep disorders. The cases illustrate how clinical skill and occasional wisdom can complement data obtained from laboratory testing. Common Pitfalls in Sleep Medicine will be of particular interest to clinicians and trainees in sleep medicine, neurology, internal medicine, family medicine, pulmonary medicine, otolaryngology, psychiatry, and psychology.
Unrecognized sleep disorders can shorten lives, promote hypertension, augment risk for diabetes, exacerbate metabolic syndrome, increase overall medical care costs, impair cognition, cause motor vehicle crashes, reduce workplace productivity, and greatly diminish quality of life. Sleep problems are among the most common complaints that patients bring to their clinicians, but little medical training is devoted to the field and so sleep disorders tend to remain undiagnosed for many years. The case-based chapters in this book highlight key points and pitfalls in a readable, easily assimilated, and memorable format that should improve a clinician's ability to address, investigate, and manage common sleep disorders. The cases illustrate how clinical skill and occasional wisdom can complement data obtained from laboratory testing. Common Pitfalls in Sleep Medicine will be of particular interest to clinicians and trainees in sleep medicine, neurology, internal medicine, family medicine, pulmonary medicine, otolaryngology, psychiatry, and psychology.
Unrecognized sleep disorders can shorten lives, promote hypertension, augment risk for diabetes, exacerbate metabolic syndrome, increase overall medical care costs, impair cognition, cause motor vehicle crashes, reduce workplace productivity, and greatly diminish quality of life. Sleep problems are among the most common complaints that patients bring to their clinicians, but little medical training is devoted to the field and so sleep disorders tend to remain undiagnosed for many years. The case-based chapters in this book highlight key points and pitfalls in a readable, easily assimilated, and memorable format that should improve a clinician's ability to address, investigate, and manage common sleep disorders. The cases illustrate how clinical skill and occasional wisdom can complement data obtained from laboratory testing. Common Pitfalls in Sleep Medicine will be of particular interest to clinicians and trainees in sleep medicine, neurology, internal medicine, family medicine, pulmonary medicine, otolaryngology, psychiatry, and psychology.
Unrecognized sleep disorders can shorten lives, promote hypertension, augment risk for diabetes, exacerbate metabolic syndrome, increase overall medical care costs, impair cognition, cause motor vehicle crashes, reduce workplace productivity, and greatly diminish quality of life. Sleep problems are among the most common complaints that patients bring to their clinicians, but little medical training is devoted to the field and so sleep disorders tend to remain undiagnosed for many years. The case-based chapters in this book highlight key points and pitfalls in a readable, easily assimilated, and memorable format that should improve a clinician's ability to address, investigate, and manage common sleep disorders. The cases illustrate how clinical skill and occasional wisdom can complement data obtained from laboratory testing. Common Pitfalls in Sleep Medicine will be of particular interest to clinicians and trainees in sleep medicine, neurology, internal medicine, family medicine, pulmonary medicine, otolaryngology, psychiatry, and psychology.
Single 25 mg intravenous and 50 mg oral doses of trazodone were given to 43 healthy subjects, divided into young men and women (aged 18 to 40 years) and elderly men and women (aged 60 to 76 years). Among men, trazodone volume of distribution (Varea) was increased in elderly vs. young subjects (1.15 vs. 0.89 L/kg; P < 0.05), and clearance decreased (1.65 vs. 2.31 ml/min/kg; P < 0.05), thereby increasing elimination half-life (t½) in elderly men (8.2 vs. 4.7 hours; P < 0.001). Varea in women was also increased in the elderly (1.5 vs. 1.27 L/kg; P < 0.02), causing increased t½ (7.6 vs. 5.9 hours; P < 0.05), but clearance was unrelated to age. Absolute bioavailability of oral trazodone averaged 70% to 90% and was unrelated to age or sex. In 23 obese subjects (mean weight 112 kg) vs. 23 matched control subjects of normal weight (mean 65 kg), Varea was greatly increased (162 vs. 67 L; 1.43 vs. 1.04 L/kg; P < 0.001) and was highly correlated with body weight (r = 0.91). Clearance was unchanged between groups (146 vs. 136 ml/min), but the increased Varea caused prolonged t½ in obese subjects (13.3 vs. 5.9 hours; P < 0.001). Reduced clearance of trazodone among elderly men may indicate a need for dosage reduction during chronic therapy. In obese individuals, choice of dosage during chronic treatment should be based on ideal rather than total body weight.
A double-blind crossover study was performed to evaluate the efficacy of hypnotics in geriatric insomniacs. Twenty-seven patients with a mean age of 70 years (range 60-94 years) received each of five treatments on 5 consecutive nights. The treatment conditions, consisting of chloral hydrate 250 and 500 mg, triazolam 0.25 and 0.50 mg, and placebo, were administered using a Latin Square design. Subjective estimates of sleep were collected in the morning following each treatment night. The patients' global evaluation of effectiveness indicated that triazolam 0.25 mg and 0.50 mg improved sleep more than placebo, while chloral hydrate 250 and 500 mg were not better than placebo. Triazolam 0.50 mg was felt to be significantly better than either dose of chloral hydrate. In addition, triazolam 0.50 mg was found to significantly decrease the patients' estimates of their sleep latency. Patients estimated their total sleep time to be longer following the use of triazolam 0.25 mg as compared to choral hydrate 500 mg, and their estimates of the number of awakenings was significantly lower on triazolam 0.50 mg than it was on chloral hydrate 500 mg or placebo.
The aim of the study was to assess prevalence and treatment modalities of insomnia in general practice. To investigate the course of insomnia, a longitudinal study design was adopted. Two thousand five hundred and twelve patients (age 18-65 years) were investigated with a questionnaire in general practice (T1). Four months later (T2) and again 2 years later (T3) a questionnaire was sent to all patients who had complained about severe insomnia at the time of the first inquiry. To assess insomnia, operationalized diagnostic criteria were applied (DSM-III-R). Eighteen point seven percent suffered from severe, 12.2% suffered from moderate and 15% suffered from mild insomnia. In the course of 2 years insomnia appeared as a chronic health problem. A high comorbidity of severe insomnia was found with chronic somatic and psychiatric disorders, especially with depression. Of the severely insomniac patients, 23.9% used prescribed hypnotics habitually, mainly benzodiazepines. The use of prescribed hypnotics remained rather stable during the whole study period. More than half of the patients reported a daily use of the hypnotics for 1-5 years or longer, but only 22% of the severely insomniac patients reported at the time of the third inquiry a significant improvement of insomnia due to the administration of sleeping pills. Thus, the long-term administration of benzodiazepine hypnotics seems to be an inadequate treatment strategy in chronic insomnia. Whether the occurrence of rebound insomnia after benzodiazepine withdrawal may be one of the main factors for chronic hypnotic use requires discussion.(ABSTRACT TRUNCATED AT 250 WORDS)
Sleep disturbances are an integral part of depressive disorder. As such, they are a pare of all contemporary sets of diagnostic criteria for major depression and of all major symptom-based rating scales for depression. Insomnia is a particularly frequent complaint, and it is reported by more than 90% of depressed patients. Although the "kindling" or "illness transduction" model of depression remains hypothetical, there is evidence that people with recurrent depression have more pronounced abnormalities of sleep neurophysiology than those experiencing a single or initial episode. Therefore, early relief of insomnia in a depressed patient, in addition to alleviating other symptoms, may increase adherence to treatment and increase daytime performance and overall functioning, while complete relief of insomnia may improve prognosis. Stimulation of serotonin-2 (5-HT2) receptors is thought to underlie insomnia and changes in sleep architecture seen with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). This is the reason why hypnotics or low-dose trazodone are commonly coprescribed at the initiation of the treatment with either the SSRIs or SNRIs. On the other hand, antidepressant drugs with 5-HT2 blocking properties, such as mirtazapine or nefazodone, alleviate insomnia and improve sleep architecture. In depressed patients, mirtazapine produces a significant shortening of sleep-onset latency, increases a total sleep time, and leads to a marked improvement in sleep efficiency. Antidepressants with preferential 5-HT2 blocking properties are therefore a good treatment option for depressed patients with marked insomnia.
Two doses of estazolam (1 mg and 2 mg) were compared with placebo in a double-blind multi-center clinical investigation of short-term efficacy and safety. Three-hundred sixty-seven chronic insomnia patients (mean age 41.1 years, range 19-65) were randomly assigned to one of three parallel-treatment conditions: placebo, 1 mg or 2 mg estazolam. Patients completed daily questionnaires while sleeping at home for the seven days of drug or placebo ingestion. In general, both doses of estazolam were found to have significant hypnotic effects. Estimated sleep latency and the reported number of awakenings were decreased for both 1 mg and 2 mg doses of estazolam relative to placebo. Reported total sleep time, depth of sleep and sleep quality were increased for both doses as compared to placebo. All measures except reported total sleep time showed significant dose effects. Investigator judgments of clinical efficacy also suggested significant hypnotic efficacy for both doses of estazolam. Mild adverse experiences were reported as frequently in the placebo group as in the active compound groups. Estazolam appears to be a safe and effective hypnotic compound in the dosages examined.
• Healthy adult volunteers (n = 52) received single oral doses of flurazepam hydrochloride (15 mg), temazepam (15 mg), triazolam (0.25 mg), or placebo in a parallel, double-blind study. Sedative effects were greatest with triazolam, followed next by temazepam; peak effects closely coincided with peak plasma concentrations. Differential recovery from sedation corresponded in part to differences in mean elimination halflife, although sedative effects returned to baseline before plasma drug concentrations became undetectable. Sedation following flurazepam administration was less intense than with triazolam and temazepam. When tested at three hours after dosing, none of the active treatments impaired learning of a 16-item word list. However, at 24 hours, triazolam recipients could not recall a significant fraction of what was learned. Thus, dynamic differences among three benzodiazepine hypnotics may be partly explained by kinetic differences, as well as, we should caution, by possible "clinical inequivalence" in dosage.
At any age hypnotic drug use can give rise to 3 major problems: unwanted effects on daytime mood and behaviour associated with drug consumption; rebound effects associated with drug withdrawal; and dependency associated with long term drug use. For 2 reasons elderly hypnotic users are both more vulnerable and more exposed to each of these problems. Firstly, age-related changes in pharmacodynamic and pharmacokinetic processes amplify the behavioural impact of many hypnotics; and secondly, age-related changes in the structure and quality of sleep tend to increase the demand for, and the long term use of, sedative hypnotic compounds in old age. The existence of physical illness, cognitive impairment, or daytime behaviour already compromised by normal aging processes further increases the likelihood of hypnotic drugs detrimentally affecting well-being in later life.
These important causes for concern emphasise the need for 2 separate clinical responses: the need for greater circumspection in the choice and use of hypnotic drugs among elderly patients, and the need for a more broadly based clinical approach to the management of sleep problems in old age.
As part of the National Institute of Mental Health Epidemiologic Catchment Area study, 7954 respondents were questioned at baseline and 1 year later about sleep complaints and psychiatric symptoms using the Diagnostic Interview Schedule. Of this community sample, 10.2% and 3.2% noted insomnia and hypersomnia, respectively, at the first interview. Forty percent of those with insomnia and 46.5% of those with hypersomnia had a psychiatric disorder compared with 16.4% of those with no sleep complaints. The risk of developing new major depression was much higher in those who had insomnia at both interviews compared with those without insomnia (odds ratio, 39.8; 95% confidence interval, 19.8 to 80.0). The risk of developing new major depression was much less for those who had insomnia that had resolved by the second visit (odds ratio, 1.6; 95% confidence interval, 0.5 to 5.3). Further research is needed to determine if early recognition and treatment of sleep disturbances can prevent future psychiatric disorders.
(JAMA. 1989;262:1479-1484)
PurposeThis study evaluated the relationship of dose, plasma concentration, and time to the pharmaco-dynamics of zaleplon and zolpidem, 2 structurally distinct benzodiazepine receptor agonists.Method
Ten healthy male volunteers received single oral doses of placebo, 10 mg zaleplon, 20 mg zaleplon, 10 mg zolpidem, and 20 mg zolpidem in a double-blind, 5-condition crossover study, with 48 hours elapsing between trials. Plasma drug concentrations and pharmacodynamic effects were measured during the 8 to 24 hours after administration.ResultsKinetics of zaleplon and zolpidem were not significantly related to dose. However, zaleplon had more rapid elimination (apparent elimination half-life [t½] of 1 hour) and higher apparent oral clearance (approximately 4300 mL/min) than zolpidem (t½, 2.0 to 2.2 hours; apparent oral clearance, 340 to 380 mL/min). Active treatments produced pharmacodynamic effects consistent with benzodiazepine agonist activity: self- and observer-rated sedation, impairment of digit symbol substitution test (DSST) performance, impaired memory, and increased electroencephalographic activity in the beta frequency range. The overall order of agonist potency was as follows: placebo < 10 mg zaleplon < 20 mg zaleplon < 10 mg zolpidem < 20 mg zolpidem; on a number of measures, 20 mg zaleplon was comparable to 10 mg zolpidem. Quantitative effects of zolpidem 20 mg far exceeded those of other treatments. Dynamic effects of both drugs were significantly related to plasma concentration.Conclusions
Benzodiazepine agonist effects of zaleplon and zolpidem were dose and concentration dependent. At the usual clinically effective hypnotic dose (10 mg of either drug), agonist effects of zolpidem exceeded those of zaleplon.Clinical Pharmacology & Therapeutics (1998) 64, 553-561; doi:
344 21–65 yr old chronic insomnia patients received either estazolam (1 or 2 mg/day) or placebo for 1 wk, in addition to completing a daily 5-item sleep questionnaire, to examine the short-term efficacy and safety of estazolam. Ss' estimated sleep latency and reported number of awakenings decreased, and reported total sleep time, depth of sleep, and sleep quality increased for both doses of estazolam as compared to placebo. It is concluded that estazolam is a safe and effective hypnotic compound in the dosages examined. (5 ref) (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Trazodone is an antidepressant which is used at low doses as a hypnotic. The hypnotic efficacy of trazodone in non-depressed insomniacs is unknown, especially in comparison to hypnotic medications such as zolpidem. Following a placebo screening week, DSM-IIIR defined primary insomniacs were randomized into a parallel-group, double-blind, 14-day comparison of trazodone 50 mg, zolpidem 10 mg and placebo. Patients completed daily morning questionnaires and weekly office visits. Self-reported sleep latencies were compared by the Cox proportional hazards regression technique; self-reported sleep duration by ANOVA. During treatment Week 1, both drugs produced significantly shorter self-reported sleep latencies and longer self-reported sleep durations than placebo. Self-reported sleep latency was significantly shorter with zolpidem than with trazodone. During Week 2, only the zolpidem group maintained a significantly shorter sleep latency than the placebo group, and self-reported sleep duration did not vary significantly among groups. The incidence of adverse events was low in all groups. Both trazodone and zolpidem improved self-reported sleep latency and duration of non-depressed, primary insomniacs; zolpidem was somewhat more efficacious at the doses studied. © 1998 John Wiley & Sons, Ltd.
Insomnia is a frequent complaint in the elderly population. Hypnotic agents, including benzodiazepines, with longer pharmacological half-lives have been associated with side effects, including residual sedation, memory impairment, and discontinuation effects. Zaleplon is a short-acting (elimination half-life of 1 hour), non-benzodiazepine hypnotic that acts on the benzodiazepine type 1 site of the gamma-aminobutyric acid type A (GABAA) receptor complex. The pharmacology and pharmacokinetics of Zaleplon suggest a safety profile that is improved over other hypnotics. The objective of this placebo-controlled study was to evaluate the efficacy and safety of Zaleplon (5 and 10 mg) in elderly (⩾65 years) outpatients with primary insomnia. This was a multicenter, double-blind, randomised, placebo-controlled 2-week outpatient study. Postsleep questionnaires were used to record subjective sleep variables: sleep latency, sleep duration, number of awakenings, and sleep quality. Zaleplon significantly reduced subjective sleep latency during both weeks of the study with both 5- and 10-mg doses. Subjective sleep quality was improved for significantly more patients treated with zaleplon 10 mg than those treated with placebo during both weeks of treatment. There was a weak indication of rebound insomnia after discontinuation of treatment with the 10-mg dose, but no significant difference in common treatment–emergent adverse events across treatment groups. Zaleplon is an effective and safe hypnotic for the treatment of insomnia in the elderly. Copyright © 2000 John Wiley & Sons, Ltd.
Effects of age and gender on the pharmacokinetics and pharmacodynamics of ramelteon, a hypnotic acting via binding to melatonin MT(1) and MT(2) receptors, were evaluated in healthy young (18-34 years) and elderly (63-79 years) volunteers. Part 1 evaluated the pharmacokinetics of open-label oral ramelteon, 16 mg. Part 2 was a double-blind, randomized, 2-trial crossover pharmacodynamic study of 16-mg ramelteon and matching placebo. Ramelteon clearance was significantly reduced in elderly vs young volunteers (384 vs 883 mL/min/kg, P<.01) and half-life significantly increased (1.9 vs 1.3 h, P<.001). Gender did not significantly influence clearance or half-life. Ramelteon was extensively transformed to its hydroxylated M-II metabolite, with serum AUC values averaging about 30 times those of the parent drug. Compared to placebo, ramelteon increased self- and observer-rated sedation, but age and gender did not influence the magnitude of the ramelteon-placebo difference. Ramelteon did not significantly impair digit-symbol substitution test performance or impair information acquisition and recall. Thus, the reduced clearance and higher serum levels of ramelteon in elderly subjects were not associated with enhanced pharmacodynamic effects. The usually recommended clinical dose of ramelteon (8 mg) does not require modification based on age or gender.
The human cytochromes P450 (CYPs) mediating amitriptyline N-demethylation have been identified using a combination of enzyme kinetic and chemical inhibition studies. Amitriptyline was N-demethylated to nortriptyline by microsomes from cDNA transfected human lymphoblastoid cells expressing human CYPs 1A2, 2C9, 2C19, 2D6, and 3A4. CYP 2E1 showed no detectable activity. While CYP 2C19 and CYP 2D6 showed high affinity, CYP 3A4 showed low affinity; CYP 2C9 and 1A2 showed intermediate affinities. Based on these kinetic parameters and estimated relative abundance of the different CYPs in human liver, CYP 2C19 was identified as the major amitriptyline N-demethylase at low (therapeutically relevant) amitriptyline concentrations, whereas CYP 3A4 may be more important at higher amitriptyline concentrations. Chemical inhibition studies with ketoconazole and omeprazole indicate that CYP 3A4 is the major amitriptyline N-demethylase at 100 mumol/L amitriptyline, while CYP 2C19 is equally important at a substrate concentration of 5 mumol/L. The CYP 1A2 inhibitor alpha-naphthoflavone and the CYP 2C9 inhibitor sulfaphenazole produced much less inhibition of amitriptyline N-demethylation at both substrate concentrations. Quinidine produced no detectable inhibition. The kinetics of amitriptyline N-demethylation by human liver microsomes were consistent with a two enzyme model, with the high affinity component exhibiting Michaelis Menten kinetics and the low affinity component exhibiting Hill enzyme kinetics. No difference was apparent in the kinetics of amitriptyline N-demethylation in two liver samples with low levels of CYP 2C19 activity compared with two other samples with relatively normal 2C19 activity. This may reflect the importance of higher substrate concentration values in estimation of kinetic parameters in vitro.
The safety and efficacy of 0.25 mg triazolam were compared to those of 15 mg flurazepam and placebo in 41 geriatric outpatients suffering from insomnia. The patients were randomly assigned to one of the three treatment groups. The medication was taken at bedtime for 28 days. Tolerance development was also studied. Triazolam was found to be significantly better than placebo in how much the medication helped the patients sleep, in sleep onset, in duration of sleep, number of nighttime awakenings, in quality (depth) of sleep, and in feeling of restfulness in the morning. Triazolam was significantly better than flurazepam in duration of sleep and was rated higher than flurazepam in all other variables. Flurazepam was significantly better than placebo in only two variables--onset of sleep and quality (depth) of sleep. Side effects were reported in each treatment group, and one patient on placebo discontinued because of side effects. There was no decrease in hypnotic effect over this four-week period, therefore, no evidence of tolerance development on either of the active compounds. Both active compounds provided the same amount of relief from insomnia after four weeks as they had after one week. Laboratory analyses and poststudy physical examinations showed no deleterious effects over the four-week period.
In this multi-clinic double-blind study, patients suffering from insomnia were treated with triazolam 0.5 mg (Halcion) or placebo for 14 days. Four investigators treated 239 patients, 122 on triazolam and 117 on placebo. Thirty-nine patients, 10 on triazolam and 29 on placebo, dropped out for ineffectiveness of the medication and 32 patients, 16 in each group, dropped out for side effects. Analysis of pooled efficacy data showed that triazolam was significantly better than placebo on all efficacy parameters measured, including how much the medication helped the patients sleep, onset of sleep, duration of sleep, duration compared to usual, number of nocturnal awakenings, and feeling of restfulness in the morning. Triazolam did not produce evidence of tolerance development after 2 weeks of treatment. The same variety of side effects occurred on each treatment and primarily included drowsiness, grogginess, headaches, impaired coordination nausea, and dizziness.
Lorazepam is a 3-hydroxy-1,4-benzodiazepine derivative biotransformed by glucuronide conjugation, followed by urinary excretion of the glucuronide metabolite. The kinetic properties of single 1.5- to 3.0-mg doses of intravenous lorazepam were assessed in 15 healthy elderly subjects, 60 to 84 yr of age, and in 15 healthy young subjects, 19 to 38 yr of age. Volumes of distribution for lorazepam in the elderly group (mean, 0.99 1/kg), were slightly but significantly smaller than in the young group (1.11 1/kg), suggesting less extensive drug distribution in the elderly. Values of elimination half-life (t1/2beta) in the elderly (15.9 hr) did not differ significantly from those in the young group (14.1 hr), but total clearance in the elderly (0.77 ml/min/kg) was 22% less (p less than 0.05) than in the young subjects (0.99 ml/min/kg). Age differences in lorazepam clearance were partly explained by more frequent cigarette smoking in the young subjects. Gender had no apparent relationship to kinetics. The rate and completeness of absorption of intramuscular (IM) and oral loraxepam was assessed in 10 of the elderly subjects. Deltoid IM injection and oral administration of tablets in the fasting state led to rapid absorption of lorazepam into the systemic circulation. Peak plasma lorazepam concentrations were always reached within 2.5 hr, and values of absorption half-life (t1/2a) did not exceed 45 min. Absorption of IM and oral lorazepam was 80% to 100% complete. Thus, the aging process is associated with small changes in the kinetics of lorazepam. IM and oral administration of lorazepam in elderly persons, as in the case of young individuals, leads to rapid and nearly complete absorption into the systemic circulation.
The efficacy and safety of temazepam 30 mg, compared with glutethimide 500 mg and placebo, were evaluated in double‐blind conditions in a 4‐day study in 75 outpatients with a history of insomnia.
Temazepam and glutethimide were rated by the patients as effective and significantly superior to placebo for general quality of sleep, time requiredto fall asleep, frequency of nocturnal and early morning awakenings, and duration of sleep.
Residual effects reported for temazepam and glutethimide immediately after awakening and during the day were similar to or less than those reported for placebo.
Triazolam, 0.4 and 0.8 mg, flurazepam, 15 and 30 mg, and placebo were compared in a double-blind, randomized 5-night crossover study in 25 inpatient insomniacs. These patients all complained difficulty falling asleep; all said they usually slept less than 5 hr a nigh and woke up too early in the morning. Results of the patients' global evaluation of the medications shows that all of the treatments were rated significantly higher than placebo, with the exception of triazolam, 0.4 mg, which was not significantly different from flurazepam, 15 or 30 mg, or from placebo. In subjective evaluation of sleep onset, only triazolam, 0.4 and 0.8 mg, was rated faster than placebo. All 4 active medications increased duration of sleep. Triazolam, 0.8 mg, and flurazepam, 30 mg, were rated as providing deeper sleep than placebo while all treatments except flurazepam, 15 mg, decreased the number of awakenings below that on placebo. A significant dose-response curve was obtained with triazolam and flurazepam for some of the parameters. Very few adverse effects were reported. One patient reported feeling groggy and drowsy on 0.4 mg triazolam while 2 reported nightmares on placebo.
The clinical pharmacokinetics of amitriptyline were studied in four volunteers after the oral administration of 75 mg. Peak amitriptyline plasma concentrations ranged from 10.8 to 43.7 ng/ml. The disappearance was biphasic and followed first-order kinetics. The mean elimination half-life was 36.1 hours. The mean estimated first-pass metabolism of amitriptyline was 60 per cent. Significant quantities of the metabolite, nortriptyline, were produced although peak concentrations ranged from only 5.9 to 12.3 ng/ml. The relationship between these findings to clinical practice and earlier reports is discussed.
Eight healthy subjects were administered trazodone-HCl orally (100 mg) with and without food and by infusion in a three way cross-over study. Unchanged trazodone was determined in serum and urine by high performance liquid chromatography after an alkaline extraction. Absorption of trazodone was irregular in fasting subjects and improved after food intake. Food intake significantly decreased the maximum serum concentrations of trazodone from 1.88 +/- 0.42 to 1.47 +/- 0.16 micrograms/ml, and increased the time for reaching maximum concentration from 1.3 +/- 0.8 hr to 2.0 +/- 1.5 hr. No differences were observed in the total amount of trazodone absorbed with or without food with bioavailability values of 65 +/- 6 and 63 +/- 4 per cent, respectively. The apparent volume of distribution and total body clearance for trazodone were estimated to 0.84 +/- 0.16 l/kg and 5.3 +/- 0.9 l/hr, respectively. The terminal elimination half-life of 7.3 +/- 0.8 hr showed no significant differences between the different ways of administration. Urinary excretion of unchanged trazodone during 26 hr was less than 0.13 per cent of the administered dose, suggesting a high degree of trazodone metabolism. Earlier statements of enterohepatic circulation of trazodone and pharmacokinetic differences between males and females were not confirmed by the present study. Due to the irregular absorption in fasting subjects, trazodone should preferably be administered after food.
The comparative pharmacokinetics of alprazolam and lorazepam were evaluated in African Green Monkeys and in healthy male human volunteers. Six monkeys received a single 250 micrograms/kg oral dose of alprazolam and of lorazepam on two separate occasions. Mean kinetic values for the two drugs, respectively, were: elimination half-life, 5.7 and 1.7 h; oral clearance, 5.5 and 40.2 ml/min/kg. Healthy male volunteers (n = 22) received a single 1 mg oral dose of alprazolam; another group (n = 24) received a single 2 mg oral dose of lorazepam. Mean values of elimination half-life in humans (11.5 and 12.4 h, for alprazolam and lorazepam, respectively) were substantially longer than corresponding values in the primate animal model, and human values of clearance (0.85 and 1.40 ml/min/kg) likewise were much lower. However, in humans, kinetic differences between the two drugs were much smaller than in the primate animals. Thus comparative studies of the behavioral effects of these two drugs in African Green Monkeys should utilize relative dosages that reflect the pharmacokinetic properties of the drugs in that species. Use of dosage ratios analogous to those used in humans may lead to results that cannot be extrapolated to humans.
The pharmacokinetics of estazolam were examined in 17 healthy male subjects. Plasma concentration-time profiles were compared following the oral administration of one 1-mg tablet, two 1-mg tablets, and one 2-mg tablet. No statistically significant differences were detected among the mean time of maximal plasma concentration (Tmax), maximal plasma concentration (Cmax), area under the plasma concentration-time curve from zero to 72 hours (AUC), or half-life values for the 2-mg doses. Mean Cmax was 97.7 and 98.6 ng/ml and mean Tmax was 1.9 and 1.6 hours for two 1-mg tablets and one 2-mg tablet, respectively. Proportionately decreased Cmax and AUC were observed following the 1-mg dose. Mean Cmax was 54.7 ng/ml for the 1-mg dose. Mean Tmax and elimination half-life values were similar to those observed after the 2-mg doses. The overall harmonic mean half-life was 14.4 hours.
A multicenter, double-blind placebo-controlled clinical trial was designed to compare the safety and efficacy of estazolam compared with flurazepam as hypnotics. Outpatients complaining of insomnia were randomized to receive either estazolam 2 mg, flurazepam 30 mg or placebo for 7 consecutive nights. The analysis of efficacy was based on the patients' daily assessments of sleep and the investigators' global evaluations. Adverse events which were considered by the investigator to be attributable to, or of unknown relationship to the test medication were analyzed. The patient subjective questionnaire indicated that estazolam and flurazepam significantly improved all parameters (P less than .05) as compared to placebo. A marked or moderate improvement in sleep was reported by 81% (58/72), 78% (63/81) and 36% (27/76) of estazolam, flurazepam, and placebo recipients, respectively. There were no significant differences in hypnotic effect between estazolam and flurazepam. All efficacy parameters of the investigators' global evaluation improved significantly more (P less than .05) for patients receiving estazolam or flurazepam (except quality of sleep) than for those receiving placebo. The percentage of patients reporting any adverse experience was greatest for flurazepam (72%), followed by estazolam (59%), and placebo (43%). Somnolence and hypokinesia were the most commonly reported adverse events. An analysis of the global evaluation of side effects showed that flurazepam had a significantly worse side effect profile than estazolam (P less than .05) or placebo (P = .001). Estazolam and flurazepam effectively, and comparably, relieved insomnia when administered for 7 nights in adult patients complaining of insomnia. Estazolam demonstrated a more favorable side effect profile than flurazepam.
Most studies with zopiclone, a cyclopyrrolone derivative with a short elimination half life (5 h) have compared its hypnotic activity with that of long elimination half life molecules. In this double-blind study in geriatric patients, drugs were administered during 3 weeks and the therapeutic effects of zopiclone at optimal dosage (5 or 7.5 mg) were compared to those of triazolam (0.125 or 0.25 mg). After a 3 day single-blind washout period, placebo responders were excluded and 48 patients were thereafter treated with either placebo (Tétreault et al., 1965), zopiclone or triazolam (Pegram et al., 1980). The initial dosage was increased when indicated at the end of the first week and kept constant thereafter. At the end of the third week of double-blind treatment, a 4 day single-blind placebo washout was performed to assess drug withdrawal effects. Results confirmed the safety and efficacy of both drugs over placebo during active administration. Hypnotic activity was maximal at 7.5 mg of zopiclone and 0.25 mg of triazolam. Drug efficacy was found constant over the 3 week administration both for triazolam and zopiclone. During withdrawal, no true rebound effect was demonstrated but the active drugs were significantly worse than placebo during the first day for sleep onset duration, sleep soundness and quality of sleep. With triazolam some effects persisted up to the third day of withdrawal.
Sixty insomniac patients participated in a controlled double-blind parallel group study designed to investigate the dose-response relationship of zopiclone. Following 1 day of treatment with placebo, patients were randomly assigned to 1 of 6 groups and received treatment for 7 days with either placebo, or flurazepam 30 mg, or zopiclone, 3.75 mg, 7.5 mg, 11.25 mg or 15 mg. Four patients were dropped from the study; two from the placebo group due to ineffectiveness and one each in zopiclone 11.25 mg and 15 mg groups due to side-effects. Flurazepam 30 mg significantly improved sleep induction and maintenance by comparison to placebo and was indistinguishable from zopiclone 7.5 mg or higher. Results of a self-administered sleep questionnaire found a predominantly linear relationship between the dose of zopiclone administered and the degree of sleep improvement. The greatest increment in improvement was generally obtained with 3.5 mg and 7.5 mg of zopiclone, with some additional benefit occurring with zopiclone 11.25 mg. Clinicians' global impressions showed that the severity of illness clearly decreased in a dose related manner up to zopiclone 11.25 mg. Although zopiclone was well tolerated at 3.75 mg and 7.5 mg, an increase in side-effects occurred at 11.25 mg and 15 mg, which favours the use of 7.5 mg zopiclone as the optimum dose for most patients, although certain patients may benefit from a higher dose of the drug when well tolerated.
Twenty-four healthy volunteers, aged 21-59 years, received single 30 mg oral doses of the benzodiazepine hypnotic temazepam. Levels of intact temazepam were determined in multiple plasma samples drawn during 48 h after dosage. Intact temazepam, its direct glucuronide conjugate, and the conjugate of its demethylated (oxidized) metabolite oxazepam were measured in two consecutive 24-h urine collections. Mean kinetic variables for temazepam in plasma were: peak plasma level (Cmax), 873 ng ml-1; time of peak, 1.36 h after dosage; volume of distribution, 0.961 kg-1; elimination half-life 9.9 h; clearance, 1.16 ml min-1 kg-1. Volume of distribution increased significantly with body weight (r = 0.67, p less than 0.001), and Cmax decreased with weight (r = -0.58, p less than 0.01). Only 0.2 per cent of the dose was excreted as intact temazepam, and negligible amounts as intact oxazepam. However, 39 per cent of the dose was recovered as temazepam glucuronide, and oxazepam glucuronide accounted for another 4.7 per cent of the dose. The remainder was not accounted for. Thus, a significant fraction of temazepam clearance occurs by direct glucuronide conjugation, with the conjugate temazepam glucuronide excreted in urine. A much smaller fraction undergoes parallel oxidation to form oxazepam, which is subsequently conjugated to oxazepam glucuronide and excreted in urine.
At any age hypnotic drug use can give rise to 3 major problems: unwanted effects on daytime mood and behaviour associated with drug consumption; rebound effects associated with drug withdrawal; and dependency associated with long term drug use. For 2 reasons elderly hypnotic users are both more vulnerable and more exposed to each of these problems. Firstly, age-related changes in pharmacodynamic and pharmacokinetic processes amplify the behavioural impact of many hypnotics; and secondly, age-related changes in the structure and quality of sleep tend to increase the demand for, and the long term use of, sedative hypnotic compounds in old age. The existence of physical illness, cognitive impairment, or daytime behaviour already compromised by normal aging processes further increases the likelihood of hypnotic drugs detrimentally affecting well-being in later life. These important causes for concern emphasise the need for 2 separate clinical responses: the need for greater circumspection in the choice and use of hypnotic drugs among elderly patients, and the need for a more broadly based clinical approach to the management of sleep problems in old age.
Healthy adult volunteers (n = 52) received single oral doses of flurazepam hydrochloride (15 mg), temazepam (15 mg), triazolam (0.25 mg), or placebo in a parallel, double-blind study. Sedative effects were greatest with triazolam, followed next by temazepam; peak effects closely coincided with peak plasma concentrations. Differential recovery from sedation corresponded in part to differences in mean elimination halflife, although sedative effects returned to baseline before plasma drug concentrations became undetectable. Sedation following flurazepam administration was less intense than with triazolam and temazepam. When tested at three hours after dosing, none of the active treatments impaired learning of a 16-item word list. However, at 24 hours, triazolam recipients could not recall a significant fraction of what was learned. Thus, dynamic differences among three benzodiazepine hypnotics may be partly explained by kinetic differences, as well as, we should caution, by possible "clinical inequivalence" in dosage.
Thirteen women chronically using low-dose estrogen-containing oral contraceptives (50 micrograms or less of ethinyl estradiol or its equivalent for a minimum of 3 months) and 12 age-matched drug-free control women received a single 25 mg oral dose of doxylamine succinate in the fasting state. Ten women taking oral contraceptives and ten controls received a single 50 mg oral dose of diphenhydramine hydrochloride. Multiple plasma samples drawn during 30 hours following the dose of doxylamine, and 12 hours after diphenhydramine dosage, were analyzed by gas chromatography using nitrogen-phosphorus detection. Mean pharmacokinetic variables for doxylamine in control and oral contraceptive groups were: peak plasma concentration, 103 vs 100 ng/ml; time of peak, 2.40 vs 1.87 hours after dosage, elimination half-life, 10.1 vs 10.2 hours; and total clearance, 3.70 vs 3.88 ml/min/kg. Mean pharmacokinetic variables for diphenhydramine in control and oral contraceptive groups were: peak plasma concentration, 63.7 vs 73.8 ng/ml; time of peak, 2.7 vs 2.2 hours after dosage; elimination half-life, 6.0 vs 5.1 hours; and total clearance, 21.8 vs 25.5 ml/min/kg. None of these differences were statistically significant. Thus, low-dose estrogen-containing oral contraceptives do not significantly influence the pharmacokinetics of the antihistamines doxylamine or diphenhydramine.
Twelve normal subjects aged 24-41 years, and 12 subjects aged 62-79 years, received single 50-mg doses of chlordiazepoxide hydrochloride by mouth and by intravenous injection on two occasions. Chlordiazepoxide volume of distribution was significantly correlated with body weight (r = 0.63, p less than 0.001), but was not related to age or sex. Among male subjects, elimination half-life was prolonged (20 vs. 8 h, p less than 0.025) and clearance reduced (20 vs. 43 ml/min, p less than 0.05) in elderly as opposed to young volunteers. Among women, there was no significant difference between elderly and young subjects in elimination half-life (12 vs. 13 h) or clearance (29 vs. 22 ml/min). Absolute bioavailability of oral chlordiazepoxide was not less than 100%, and was unrelated to age or sex. Among 20 subjects who received a single 1.0- to 1.2-gram intravenous dose of antipyrine on another occasion, clearance of chlordiazepoxide and of antipyrine were significantly correlated (r = 0.62, p less than 0.01). Like many other low-clearance oxidatively metabolized compounds, chlordiazepoxide clearance is reduced and half-life prolonged in elderly men, but not elderly women. Individual variations in chlordiazepoxide clearance are significantly correlated with those of antipyrine, a drug commonly used as an index of hepatic oxidizing capacity.
As part of the National Institute of Mental Health Epidemiologic Catchment Area study, 7954 respondents were questioned at baseline and 1 year later about sleep complaints and psychiatric symptoms using the Diagnostic Interview Schedule. Of this community sample, 10.2% and 3.2% noted insomnia and hypersomnia, respectively, at the first interview. Forty percent of those with insomnia and 46.5% of those with hypersomnia had a psychiatric disorder compared with 16.4% of those with no sleep complaints. The risk of developing new major depression was much higher in those who had insomnia at both interviews compared with those without insomnia (odds ratio, 39.8; 95% confidence interval, 19.8 to 80.0). The risk of developing new major depression was much less for those who had insomnia that had resolved by the second visit (odds ratio, 1.6; 95% confidence interval, 0.5 to 5.3). Further research is needed to determine if early recognition and treatment of sleep disturbances can prevent future psychiatric disorders.
The benzodiazepine derivative flurazepam (FLZ) is widely used as a hypnotic, but the relative contributions of FLZ and its metabolites desalkylflurazepam (DA-FLZ), hydroxyethylflurazepam (ETOH-FLZ), and flurazepam aldehyde (CHO-FLZ) to overall clinical activity remain uncertain. A single 20 mg/kg dose of FLZ.HCl was administered to mice, with plasma and brain concentrations of FLZ and metabolites determined during 5 h after dosage. Brain and plasma concentrations of FLZ were maximal at 0.5 h after dosage, then declined rapidly in parallel, whereas those of DAFLZ were maximal at 2 h, then declined slowly. Concentrations of ETOH-FLZ, the most polar metabolite, were maximal at 0.5 h, and were undetectable after 3 h. Little CHO-FLZ was detected in either brain or plasma. A single 30-mg oral dose of FLZ.HCl was given to 18 human volunteers, with plasma levels determined over 9 days. FLZ was detected in plasma at low concentrations for no more than 3 h after dosage. ETOH-FLZ concentrations were higher and persisted for 8 h after dosage. CHO-FLZ reached intermediate peak levels and was present longer than FLZ or ETOH-FLZ. In contrast, DA-FLZ achieved the greatest peak concentrations, occurring at 10 h after dosage. Levels declined very slowly, with a mean half-life of 71.4 h, and were still detectable 9 days after FLZ dosage. Plasma free fractions (percent unbound) in mice were 40.3, 51.4, and 25.0% for FLZ, ETOH-FLZ and DA-FLZ, respectively; in humans, values were 17.2, 35.2, and 3.5%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Details of consumption of hypnotic drugs derived from a nationally representative sample of elderly people were analysed in terms of the prevalence, duration, and likely frequency of use. Of 1020 randomly selected subjects aged 65 and over 16% (166) reported using (mainly benzodiazepine) hypnotic drugs, and of these 89% reported having taken such a drug the night before the interview. Most of these users (73%) had been taking hypnotic drugs for more than one year, with 25% reporting drug use for more than 10 years.
These results suggest that for most elderly users of hypnotic drugs, patterns of consumption encourage the development of cumulative effects and benzodiazepine dependence.
Serotonin can induce analgesia when injected directly into the brain, but analgesia after peripheral administration has been more difficult to show. The pentobarbital anesthetized mouse (PAM) model, developed to alleviate some of the problems involved in the measurement of tail flick latency, was used to assess the action of peripherally administered serotonin. Mice were anesthetized with about 65 mg/kg of sodium pentobarbital IP and their tail flick latencies measured while they were in stage III anesthesia. In these anesthetized mice, IP serotonin induced a significant analgesia that was much more robust than that found in awake mice. The analgesic effect was dose-dependent from 0.25 mg/kg to 10 mg/kg but was not blocked by the antiopiate naltrexone. Of several psychotropic agents tested, only amitriptyline, mianserin, and trazodone had significant effects on analgesia in the PAM model. The analgesic effect of serotonin was reproduced by the 5HT2 agonist DOI and totally blocked by the 5HT2 antagonist NPP. These results show the utility of the PAM model in studying nonopiate analgesia and suggest that the analgesic action of serotonin is mediated primarily through the 5HT2 receptor.
Elderly persons with insomnia are unique because the cause of their insomnia differs from that of younger people and their metabolism of benzodiazepine hypnotics differs as well. This study used nocturnal polysomnography and daytime sleep/wake tendency measures (Multiple Sleep Latency Test, MSLT) to assess the efficacy and safety of a reduced triazolam dosage (0.125 mg) in elderly subjects with insomnia. After 2 nights and an intervening day of screening each subject received triazolam and placebo for 2 consecutive nights presented in a counter-balanced design. Compared to placebo the reduced triazolam dose induced and maintained sleep thereby increasing total sleep time. Sleep stage distribution and the frequency of apneas and periodic leg movements was not altered. The improved sleep was associated with a restoration of the normal pattern of daytime alertness. The correspondence of this clinical data to known pharmacokinetic data is discussed.
Using radioligand binding techniques, we determined the equilibrium dissociation constants (KDS) for a series of antidepressants at the histamine H1, muscarinic acetylcholine, alpha-1 and alpha-2 adrenergic and dopamine (D-2) receptors of normal human brain tissue obtained at autopsy. Twenty-five different antidepressants were studied at all but the D-2 receptor at which the number was 13 (including a metabolite of an antidepressant). Of all the receptor interactions studied, that at the histamine H1 receptor was in general the most potent interaction of this class of compounds, corresponding to results from studies using animal tissue as the source of receptors. At the human brain histamine H1 receptor, antidepressants remained among the most potent histamine H1 antagonists known, although their affinities for human receptors were lower than those for animal receptors. The most potent and the least potent compounds at the receptors were doxepin (KD = 0.24 nM) and fluvoxamine (KD = 109 microM) at the histamine H1 receptor, amitriptyline (KD = 18 nM) and trazodone (KD = 324 microM) at the muscarinic receptor, doxepin (KD = 24 nM) and viloxazine (KD = 14 microM) at the alpha-1 receptor, mianserin (KD = 73 nM) and bupropion (KD = 81 microM) at the alpha-2 receptor and amoxapine (KD = 160 nM) and trazodone (KD = 3800 nM) at the D-2 receptor, respectively. In general, compared to older drugs, the newer compounds tended to have lower affinities for these receptors.
The hypnotic and residual sedative effects of the first and seventh of seven regular night-time doses of nitrazepam 5 mg, temazepam 20 mg, and placebo were studied in 58 elderly inpatients. Plasma temazepam and nitrazepam concentrations rose by about 50% and 113% respectively between the mornings of day 1 and day 7. Patients reported sleeping well more often after the first dose of either hypnotic (p less than 0.05), but there was no difference after the seventh dose. Reaction time was unchanged on the morning after the first dose but was significantly prolonged after the seventh dose of both hypnotics (p less than 0.01). The time taken to eliminate the letter E from a page of prose tended to be prolonged after the first dose of both drugs (temazepam v placebo, p less than 0.05; nitrazepam v placebo, not significant) and was further prolonged on the morning after the seventh dose of nitrazepam (nitrazepam v placebo, p less than 0.05). Thus plasma accumulation of the drug was associated with a deterioration in daytime performance. This change in performance did not correlate with age, cerebral blood flow, or plasma concentration, but patients of low intelligence tended to be more severely affected.
The dose range of estazolam for hypnotic effects was studied in seven men and eight women (mean age 30.3 +/- 8.6 years) who complained of insomnia and had polysomnographic evidence of disturbed sleep. Patients slept in the laboratory and were monitored using standard polysomnographic techniques. Four consecutive nights in the laboratory with placebo, which served as baseline and screening nights, were followed by five 2-night drug administration periods separated by 5-day drug washout periods spent at home. Each of the patients received a sequence of four doses (0.25, 0.5, 1.0, and 2.0 mg) of estazolam and placebo administered according to a Latin square design and in a double-blind manner. Estazolam significantly increased total sleep time and reduced time awake during sleep in a dose-dependent manner. Sleep latency parameters were reduced systematically with increasing doses of estazolam, but these effects on sleep latency were not statistically significant. Increasing doses of estazolam had systematic and statistically significant effects on sleep stages. Subjective estimations of sleep were consistent with the polysomnographic findings bur were not statistically significant.
The safety and hypnotic efficacy of quazepam 30 mg vs placebo in 57 insomniac outpatients were assessed in a randomized, controlled comparison. Patients received placebo during a 3-night, single-blind baseline period, and then quazepam 30 mg or placebo during a 5-night, double-blind treatment period. Quazepam-treated patients reported significantly better sleep quantity and quality on the first treatment night and for the overall treatment period than did placebo patients. No clinically significant change was seen in pre- and posttreatment physical examinations, electrocardiograms, or routine laboratory tests. Of the 57 subjects, 20 (16 quazepam, 4 placebo) reported adverse experiences. All 20 reported daytime somnolence (drowsiness, lethargy, or sleepiness), and one quazepam-treated patient also had hypokinesia. Overall, quazepam 30 mg was a safe and effective hypnotic, with significant hypnotic activity on the first night of administration.
The pharmacokinetics of orally administered doxepin (50 mg) was studied in 8 healthy volunteers. Doxepin (DOX) and desmethyldoxepin (DDOX) concentrations in serum (or plasma) and red blood cells (RBCs) were measured by radioimmunoassay. Peak serum concentrations of DOX were observed at 1-2 hours and they ranged between 59.1-107.4 nmol/1. DOX disappearance was biphasic with a mean distribution half-life of 2.0 hrs and elimination half-life of 17.9 hrs. The mean total apparent volume of distribution was 22.7 l/kg and plasma clearance 0.93 l/hr/kg. The estimated mean first-pass metabolism of DOX was 71% assuming complete absorption. Peak DDOX concentrations were observed at 1-6 hours and they ranged between 35.0-117.8 nmol/l. DDOX elimination was monophasic with a mean apparent half-life of 28.5 hours. Equilibrium dialysis gave a mean protein binding of 75.5% for DOX and 76.0% for DDOX. A highly time dependent and interindividually variable RBC/plasma concentration ratio was observed for both substances. Initially the plasma concentrations were 3-4 times higher than the respective RBC concentrations, but at later time points more DOX and DDOX could be found from the RBCs than from plasma. The major reason for this seemed to be a slower elimination of both drugs from the erythrocytes than from plasma.
Risperidone is a benzisoxazole derivative with antipsychotic activity that is chemically unrelated to other currently available antipsychotic agents. Its neuropharmacological properties, characterized by potent central antagonism of both serotonin 5-HT2 and dopamine D2 receptors, also differ from those of most other antipsychotic drugs. The pharmacokinetics of risperidone are well understood, having been studied in healthy subjects as well as in psychotic patients. The absolute oral bioavailability of risperidone is nearly 70%, and after oral administration, it is rapidly absorbed with the plasma level reaching a peak at about 1 h. 9-Hydroxyrisperidone, one of the metabolites of risperidone, is equally active with the parent compound and so the clinical activity of a dose of risperidone is due to the combined actions of both moieties. The plasma concentrations of risperidone and its active metabolite remain dose proportional even at doses exceeding the therapeutic range. In clinical trials with chronic schizophrenia patients, risperidone has an overall therapeutic activity comparable with that of haloperidol, but at doses that produce similar improvements in the positive symptoms of schizophrenia, risperidone has a greater effect on the negative symptoms and produces less extrapyramidal side effects than does haloperidol. However, additional controlled clinical studies are needed before the claims that risperidone is therapeutically superior to haloperidol can be considered to be established firmly. Although risperidone is effective in acute schizophrenia and in non-treatment-resistant schizophrenics, studies adequately comparing risperidone with clozapine in treatment-resistant schizophrenic patients remain to be published. In addition, risperidone has been reported to be of value in patients with schizodepressive disorders. The clinical success of risperidone suggests that the development of compounds with selective affinity for 5-HT2 or other serotonin receptors may result in even further improvements in the pharmacotherapy of psychiatric disorders.
In a randomized, double-blind, parallel group study in private practice, zopiclone given for 28 days was compared with flunitrazepam, triazolam and placebo in its effect on quality of sleep and daytime well-being in 1507 patients suffering from insomnia. For quantitative assessment, patients were defined as responders according to either a shortening of sleep latency by at least 15 min, or prolongation of total sleep time by at least 20%, or reduction of the number of nocturnal awakenings to three or less and a fresh feeling in the morning, as well as lack of impairment in daytime well-being as a result of tiredness or anxiety. The responder rate tended to be higher with zopiclone (37.4%) than with flunitrazepam (30%) and triazolam (32.2%) and was significantly greater (p = 0.0017) than with placebo (26.8%). Daytime well-being was particularly responsive to zopiclone and most responsive in severe insomniacs. With the exception of those to triazolam, rates of response were most pronounced in patients with insomnia of a short duration (< or = 1 year) than in those with insomnia of a longer duration (> or = 1 year). Following discontinuation of treatment, all groups showed a moderate reduction in therapeutic effect, but no rebound insomnia occurred.
The disposition of the enantiomers of zopiclone and its two chiral metabolites was investigated after oral administration of a single dose of 15 mg of a racemic mixture (twice the usual therapeutic regimen) in 12 adult Caucasian volunteers. Determination of concentrations of zopiclone enantiomers in plasma showed that zopiclone pharmacokinetics is stereoselective with AUC0-->infinity values of 691.3 and 209.5 ng.ml-1.hr (p < 0.001), Cmax values of 87.3 and 44.0 ng.ml-1 (p < 0.001), oral CLtot/F values of 195.5 and 659.8 ml.min-1 (p < 0.001), Vd/F values of 98.6 and 192.8 liters (p < 0.01) and elimination half-life of 399.2 and 225.6 min (p < 0.01) for (+)-zopiclone and (-)-zopiclone, respectively. On the contrary, absorption half-life and Tmax values were not significantly different. In 48-hr urine, 3.6% of unchanged zopiclone was excreted, whereas 14.2% and 13.8% of both metabolites, N-desmethylzopiclone and N-oxidezopiclone, respectively, were found. Quantities of (+)-zopiclone excreted in urine were always higher compared with its antipode (-)-zopiclone for the 12 volunteers (p < 0.001). For the metabolites, quantities of both enantiomers were either equal or different and when different, it was always in favor of the (+)-enantiomer.
This study aimed to assess the prevalence and treatment modalities of elderly practice attenders. A total of 330 patients aged over 65 years were investigated with a questionnaire in general practice. To assess insomnia, operationalized diagnostic criteria according to DSM-III-R were applied. Twenty-three percent of the elderly patients suffered from severe, 17% from moderate and 17% from mild insomnia. More than 80% of the patients reported suffering from insomnia for 1-5 years or longer, which indicates a chronic course. Elderly patients showed unrealistic expectations concerning duration of sleep and spend more time in bed than they realistically can expect to sleep. More than half of the elderly patients reported habitual daytime napping. Sleep-disturbed elderly patients did not differ significantly from good sleepers in their habit of taking daytime naps, but even when taking daytime naps, good sleepers slept significantly longer than the sleep-disturbed patients. A significant association was found between insomnia and mental disorders, i.e., depression and organic brain syndrome according to the diagnosis of the general physician. In about half of the cases the primary care physician was not aware that the elderly patient suffered from severe insomnia. More than half of the elderly severe insomniacs took prescribed hypnotics habitually, mainly benzodiazepines.
The authors investigated trazodone as a hypnotic for depressed patients who had persistent, exacerbated, or new insomnia while taking either fluoxetine or bupropion.
Seventeen depressed patients who had insomnia while taking fluoxetine or bupropion were given either trazodone or placebo in a double-blind crossover trial. Sleep was assessed by self-report with the Pittsburgh Sleep Quality Index and the sleep items of the Yale-New Haven Hospital Depressive Symptom Inventory.
Improvement with trazodone, but not with placebo, was shown by the total Pittsburgh index scores and Yale-New Haven inventory total sleep scores and by the Pittsburgh index measures of sleep duration and Yale-New Haven inventory measures of early morning awakening, and there was a trend toward improvement in the Yale-New Haven inventory item regarding middle of the night awakenings. Subjective sleep quality and sleep latency also showed a trend toward improvement, but the Pittsburgh index measures of sleep efficiency and disturbances and the Yale-New Haven inventory item regarding difficulty falling asleep were unaffected by trazodone. One patient dropped out because of excessive daytime sedation with trazodone, and another dropped out because of nonresponse to placebo. Of the completers, 67% experienced overall improvement in sleep with trazodone according to a priori criteria, whereas only 13% experienced improvement with placebo.
Trazodone is an effective hypnotic for patients with antidepressant-associated insomnia.
Zolpidem is a short-acting, nonbenzodiazepine hypnotic with rapid onset of action. Even though it is not a benzodiazepine, it binds to one of three types of central benzodiazepine receptors, showing selective binding to the type 1 benzodiazepine receptor subtype. Therapeutic hypnotic dosages do not disturb normal sleep patterns (sleep architecture).
A randomized, double-blind, placebo-controlled, parallel group multicenter trial was conducted to determine the effectiveness of 10 mg and 15 mg of zolpidem in the long-term (35 nights) treatment of chronic insomnia in 75 patients. Sleep stage effects and motor and cognitive effects during the 35-night treatment period and the 3-night posttreatment period were also investigated.
Within the first week of treatment, 10 mg of zolpidem had a significant effect on latency to persistent sleep and sleep efficiency. Efficacy was maintained throughout the 35 nights of drug administration. There was no evidence of residual effect with 10 mg of zolpidem. Stage 3-4 sleep was preserved at both the 10-mg and 15-mg zolpidem dosages. There was no evidence of tolerance at either dose and no significant treatment differences between the 10-mg zolpidem group and placebo in latency to persistent sleep or sleep efficiency during the posttreatment period. Also, the 10-mg zolpidem dosage was judged by the patients to have helped them fall asleep. Similar results were observed with the 15-mg zolpidem dosage. However, there were significant decreases in REM sleep at Weeks 3 and 4 with 15 mg of zolpidem compared with placebo. Overall, incidence rates of treatment-emergent adverse events in the zolpidem groups were similar to those in the placebo group.
This is the first sleep laboratory study using a parallel placebo group to demonstrate efficacy for longer than 4 weeks with a hypnotic agent. In this study 10 mg of zolpidem was found to be safe and effective for the long-term treatment of chronic insomnia, demonstrating hypnotic efficacy without affecting sleep stages or producing tolerance effects, rebound effects, or detrimental effects on psychomotor performance. The 15-mg zolpidem dosage provided no clinical advantage over the 10-mg zolpidem dosage.
The addition of benzodiazepine hypnotics to a treatment with tricyclic antidepressants has received little systematic study. In a double-blind placebo-controlled design, the effects on mood and on sleep of two benzodiazepine hypnotics (lormetazepam and flunitrazepam) were studied in patients with major depression who were also treated with maprotiline or nortriptyline. After 4 weeks of combined treatment, lormetazepam resulted in a significantly greater decrease in the score on the Hamilton Depression Subscale than placebo, while there was a non-significant trend in favour of lormetazepam in comparison with flunitrazepam. With respect to sleep EEGs, lormetazepam resulted in a significantly greater suppression of REM sleep. The differences between lormetazepam and flunitrazepam may be partly explained by the shorter half-live of lormetazepam.