Transient Insomnia Research Articles

Melatonin Agonist Tasimelteon (VEC-162) for Transient Insomnia After Sleep-Time Shift: Two Randomized Controlled Multicentre Trials

Substantial evidence suggests that exogenous melatonin and melatonin agonists promote sleep and entrain endogenous circadian rhythms. Two previous meta-analyses evaluated the efficacy of melatonin treatment in patients with secondary sleep disorders or circadian rhythm sleep disorders and reached opposite conclusions on efficacy. This study presents the results of 2 randomized, double-blind, placebo-controlled, parallel-group trials, which evaluated tasimelteon (VEC-162), a novel melatonin agonist, in a model of transient insomnia induced by a 5-hour advance in the sleep-wake schedule. The investigators hypothesized that the melatonin agonist would reduce the sleep disruption produced by transient insomnia and readjust circadian rhythms. The study subjects in the phase II study were 39 healthy individuals who were randomized to receive either tasimelteon (in doses of 10 [n = 9], 20 [n = 8], 50 [n = 7], or 100 mg [n = 7]) or placebo (n = 8) 30 minute before bedtime. The plasma melatonin concentration was measured for circadian phase assessment. The study subjects in the phase III study were 411 healthy individuals who were randomized to receive either tasimelteon (20 [n = 100], 50 [n = 102], or 100 mg [n = 106]) or placebo (n = 103) 30 minute before bedtime. Changes in sleep patterns were assessed by polysomnography in the phase II and III studies with prespecified primary efficacy outcomes. Safety was assessed by daily queries about adverse events and physical examinations. In the phase II study, compared with placebo, tasimelteon increased sleep efficiency and duration, and reduced sleep latency and latency to persistent sleep. There was a dose-dependent shift in plasma melatonin to an earlier hour associated with treatment. In addition to improvements in sleep latency, efficiency, duration, and latency to persistent sleep, treated-individuals in the phase III study had reduced wake after sleep onset (improved sleep maintenance). The frequency and severity of adverse events were low and similar among all treatment groups. These findings indicate that tasimelteon improves sleep initiation and maintenance simultaneously with a shift in endogenous circadian rhythms and has therapeutic potential for transient insomnia associated with circadian rhythm sleep disorders.

E.04.02 The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines

This chapter discusses current drug therapy for insomnia, which includes γ-aminobutyric acid A (GABAA) receptor agonists, melatonin receptor agonists, over-the-counter (OTC) products, antidepressants and antihistamines. GABAA receptor agonists used for insomnia fall into two classes: ‘Z-drugs' and benzodiazepines. Zolpidem, a ‘Z-drug’, is the market leading compound in this therapeutic group. ‘Z-drugs' are the most frequent treatment for insomnia with the compounds zolpidem, zaleplon and zopiclone marketed for transient insomnia and eszopiclone (S-isomer of zopiclone) for both transient and chronic insomnia. Imidazo[1,2-a]pyridine, the central scaffold in Zolpidem, has been extensively explored in the search for insomnia drugs. Melatonin receptor agonists and their relevance for the treatment of sleep disorders and major depression have been previously reviewed. Since then, ramelteon has been approved, representing an important milestone for the proof of concept of this target, and has opened new possibilities for research. Compound LY-156735/PD-6735 is a melatonin MT1 and MT2 agonist currently undergoing phase II trials for the improvement of sleep onset latency in patients with primary insomnia. The chapter also discusses orexin receptor antagonists such as N-quinolinyl-N0-phenyl ureas and N-quinolinyl cynamamides; 1,2,3,4-tetrahydroisoquinolines, piperazines and morpholines; and pyrrolo- and pyrido[2,1-b]quinazolinones and 3,4-dihydroquinoxalin-3-ones followed by histaminergic and serotoninergic modulators.

Sex differences and the effect of gaboxadol and zolpidem on EEG power spectra in NREM and REM sleep

Hypnotics that interact with the GABA(A) receptor have marked effects on the electroencephalogram (EEG) during sleep. It is not known whether the effects of hypnotics on EEG power spectra differ between the sexes. The effects of 5, 10 and 15 mg of gaboxadol (GBX) and 10 mg of zolpidem (ZOL) on EEG power spectra were assessed in a randomized, double-blind, placebo-controlled, 5-way cross-over design study using a phase-advance model of transient insomnia. Sleep stage specific EEG power spectra were computed in 36 men and 45 women. GBX enhanced power density in delta and theta activity in non-rapid eye movement (NREM) and rapid eye movement (REM) sleep, and suppressed sleep spindle activity in NREM sleep. The increase of delta and theta activity in NREM and REM sleep was significantly larger for women than for men but the suppression of spindle activity did not differ between the sexes. After ZOL administration, no sex differences were observed in the reduction of delta and theta activity in NREM sleep, but the increase in sleep spindle activity in NREM sleep was greater in women than in men. These sex dependent and differential effects of GBX and ZOL may be related to their differential affinity for GABA(A) receptor subtypes and their modulation by neurosteroids.

Insomnia: A Review of the Use of Eszopiclone

The present paper presents a review of the literature examining the efficacy of eszopiclone for treating insomnia. The purpose of the paper was to evaluate both the statistical and clinical efficacy of eszopiclone for treating insomnia. Both subjective and objective assessments of insomnia were evaluated across various sleep variables. Additionally, the efficacy of eszopiclone for treating insomnia comorbid with other conditions (sleep disordered breathing, psychiatric diagnoses, peri/post-menopause, rheumatoid arthritis), transient insomnia, and across diverse samples (adults, older adults, and samples pooled by race) was reviewed. Finally, the impact of eszopiclone use on daytime functioning was examined.

Melatonin agonist tasimelteon (VEC-162) for transient insomnia after sleep-time shift: two randomised controlled multicentre trials

Circadian rhythm sleep disorders are common causes of insomnia for millions of individuals. We did a phase II study to establish efficacy and physiological mechanism, and a phase III study to confirm efficacy of the melatonin agonist tasimelteon (VEC-162) for treatment of transient insomnia associated with shifted sleep and wake time. We undertook phase II and phase III randomised, double-blind, placebo-controlled, parallel-group studies. In a phase II study, 39 healthy individuals from two US sites were randomly assigned to tasimelteon (10 [n=9], 20 [n=8], 50 [n=7], or 100 mg [n=7]) or placebo (n=8). We monitored individuals for 7 nights: 3 at baseline, 3 after a 5-h advance of sleep-wake schedule with treatment before sleep, and 1 after treatment; we measured plasma melatonin concentration for circadian phase assessment. In a phase III study, 411 healthy individuals from 19 US sites, who had transient insomnia induced in a sleep clinic by a 5-h advance of the sleep-wake schedule and a first-night effect in a sleep clinic, were given tasimelteon (20 [n=100], 50 [n=102], or 100 mg [n=106]) or placebo (n=103) 30 min before bedtime. Prespecified primary efficacy outcomes were polysomnographic sleep efficiency (phase II study), latency to persistent sleep (phase III study), and circadian phase shifting (phase II study). Analysis was by intention to treat. Safety was assessed in both studies. These trials are registered with ClinicalTrials.gov, numbers NCT00490945 and NCT00291187. In the phase II study, tasimelteon reduced sleep latency and increased sleep efficiency compared with placebo. The shift in plasma melatonin rhythm to an earlier hour was dose dependent. In the phase III study, tasimelteon improved sleep latency, sleep efficiency, and wake after sleep onset (ie, sleep maintenance). The frequency of adverse events was similar between tasimelteon and placebo. After an abrupt advance in sleep time, tasimelteon improved sleep initiation and maintenance concurrently with a shift in endogenous circadian rhythms. Tasimelteon may have therapeutic potential for transient insomnia in circadian rhythm sleep disorders.

Sublingual zolpidem is more effective than oral zolpidem in initiating early onset of sleep in the post-nap model of transient insomnia: A polysomnographic study

Objective OX22 is zolpidem formulated for sublingual administration. The primary objective of the present study was to evaluate the efficacy of single doses of sublingual zolpidem (5 and 10 mg) versus oral zolpidem (10 mg), with regard to latency to persistent sleep (LPS), in a post-nap model of insomnia. Methods Twenty-one healthy volunteers included in this study were recorded by polysomnography during 2 consecutive nights and, on the day in between, during a 2 h nap. Eighteen out of these 21 subjects were finally analyzed. Treatment was randomly administered before the second recording night to subjects demonstrating at least 30 min of sleep during the nap recording. Results Contrast analyses show that 10 mg OX22 significantly shortened LPS compared to oral zolpidem administration of 10 mg (12.8 ± 9.9 and 18.4 ± 11.3 min, respectively; p < .05). No treatment effects could be evidenced on total sleep time, time awake after sleep onset and sleep architecture parameters for OX22 compared to oral zolpidem. All treatments were well tolerated and did not induce next-day residual effects. Conclusion The present results show that OX22, a sublingual formulation of zolpidem, has a significant earlier sleep initiation as compared to an equivalent dose of oral zolpidem in healthy volunteers in a post-nap model of insomnia.

Clinical Guideline for the Evaluation and Management of Chronic Insomnia in Adults

Insomnia is the most prevalent sleep disorder in the general population, and is commonly encountered in medical practices. Insomnia is defined as the subjective perception of difficulty with sleep initiation, duration, consolidation, or quality that occurs despite adequate opportunity for sleep, and that results in some form of daytime impairment.1 Insomnia may present with a variety of specific complaints and etiologies, making the evaluation and management of chronic insomnia demanding on a clinician's time. The purpose of this clinical guideline is to provide clinicians with a practical framework for the assessment and disease management of chronic adult insomnia, using existing evidence-based insomnia practice parameters where available, and consensus-based recommendations to bridge areas where such parameters do not exist. Unless otherwise stated, "insomnia" refers to chronic insomnia, which is present for at least a month, as opposed to acute or transient insomnia, which may last days to weeks.

The effects of ramelteon in a first-night model of transient insomnia

Objective To evaluate the efficacy and safety of ramelteon, a highly selective MT 1/MT 2 melatonin receptor agonist, for the treatment of transient insomnia in adults. Methods In a randomized, double-blind, placebo-controlled, multi-center study, 289 adults naive to a sleep laboratory environment were randomized to receive a single nighttime dose of ramelteon 8 mg, 16 mg, or placebo. The primary variable was latency to persistent sleep measured by polysomnography. Additional objective and subjective sleep parameters as well as next-morning residual effects were assessed. Results Ramelteon 8 mg treatment significantly reduced latency to persistent sleep compared with placebo (12.2 min vs. 19.7 min, P = 0.004). Total sleep time was significantly increased with both ramelteon 8 mg (436.8 min, P = 0.009) and ramelteon 16 mg (433.1 min, P = 0.043) compared with placebo (419.7 min). Ramelteon did not alter sleep architecture, and no significant next-morning residual effects were detected. The incidence of adverse events was similar for the ramelteon and placebo groups and most were considered mild or moderate. Conclusion Ramelteon 8 mg significantly decreased latency to persistent sleep and increased total sleep time, with no significant next-morning psychomotor, memory, or cognitive effects in this first-night model of transient insomnia.

P.6.a.004 The use of sensibilizing medicines in the therapy of alcohol dependence

Zolpidem is a short-acting non-benzodiazepine hypnotic drug that belongs to the imidazopyridine class. In addition to immediate-release (IR) and extended-release (ER) formulations, the new delivery forms including two sublingual tablets [standard dose (SD) and low dose (LD)], and an oral spray form have been recently developed which bypass the gastrointestinal tract. So far, Zolpidem has been studied in several clinical populations: cases poor sleepers, transient insomnia, elderly and non-elderly patients with chronic primary insomnia, and in comorbid insomnia.Peak plasma concentration (Tmax) of zolpidem-IR occurs in 45 to 60 min, with the terminal elimination half-life (t½) equating to 2.4 h. The extended-release formulation results in a higher concentration over a period of more than 6 h. Peak plasma concentration is somewhat shorter for the sublingual forms and the oral spray, while their t½ is comparable to that of zolpidem-IR. Zolpidem-IR reduces sleep latency (SL) at recommended doses of 5 mg and 10 mg in elderly and non-elderly patients, respectively. Zolpidem-ER at doses of 6.25 mg and 12.5 mg, improves sleep maintenance in elderly and non-elderly patients, respectively, 4 h after its administration. Sublingual zolpidem-LD (5 mg) and zolpidem oral spray are indicated for middle-of-the-night (MOTN) wakefulness and difficulty returning to sleep, while sublingual zolpidem-SD (10 mg) is marketed for difficulty falling asleep.With their array of therapeutic uses and their popularity among physicians and patients; this review describes the clinical pharmacology, indications and uses, identifying withdrawal symptoms, abuse and dependence potentials, and adverse drug reactions are discussed.

P.6.a.005 Comparative sleep improving effects of zolpidem vs. nitrazepam at alcoholics

Zolpidem is a short-acting non-benzodiazepine hypnotic drug that belongs to the imidazopyridine class. In addition to immediate-release (IR) and extended-release (ER) formulations, the new delivery forms including two sublingual tablets [standard dose (SD) and low dose (LD)], and an oral spray form have been recently developed which bypass the gastrointestinal tract. So far, Zolpidem has been studied in several clinical populations: cases poor sleepers, transient insomnia, elderly and non-elderly patients with chronic primary insomnia, and in comorbid insomnia.Peak plasma concentration (Tmax) of zolpidem-IR occurs in 45 to 60 min, with the terminal elimination half-life (t½) equating to 2.4 h. The extended-release formulation results in a higher concentration over a period of more than 6 h. Peak plasma concentration is somewhat shorter for the sublingual forms and the oral spray, while their t½ is comparable to that of zolpidem-IR. Zolpidem-IR reduces sleep latency (SL) at recommended doses of 5 mg and 10 mg in elderly and non-elderly patients, respectively. Zolpidem-ER at doses of 6.25 mg and 12.5 mg, improves sleep maintenance in elderly and non-elderly patients, respectively, 4 h after its administration. Sublingual zolpidem-LD (5 mg) and zolpidem oral spray are indicated for middle-of-the-night (MOTN) wakefulness and difficulty returning to sleep, while sublingual zolpidem-SD (10 mg) is marketed for difficulty falling asleep.With their array of therapeutic uses and their popularity among physicians and patients; this review describes the clinical pharmacology, indications and uses, identifying withdrawal symptoms, abuse and dependence potentials, and adverse drug reactions are discussed.

Indiplon: A Nonbenzodiazepine Sedative–Hypnotic for the Treatment of Insomnia

To review the pharmacology, pharmacokinetics, pharmacodynamics, efficacy data, and adverse effects of indiplon in the treatment of transient and chronic insomnia in adult and geriatric patients. A literature search was conducted using MEDLINE (1966-May 2008), International Pharmaceutical Abstracts (1970-May 2008), and Cochrane database (2007) for the key words indiplon or NBI-34060. References cited in the articles were reviewed for additional information. Abstract data were included only in the absence of significant published data. English-language literature reporting animal and human clinical studies was reviewed to evaluate data on the pharmacology, pharmacokinetics, pharmacodynamics, efficacy, and adverse effects of indiplon. Clinical trials selected for inclusion were limited to those with human subjects, with the accepted inclusion of pharmacology data in animals. Indiplon is a nonbenzodiazepine sedative-hypnotic that exhibits its sedating activity through its interaction with the gamma-aminobutyric acid alpha receptor complex. Indiplon immediate-release (IR) as well as modified-release (MR) forms have shown improvement compared with placebo in patients with DSM-IV-TR primary insomnia in various areas of subjective and objective sleep measurements. Specifically, improvements in total sleep time, latency to persistent sleep, latency to sleep onset, wake after sleep onset, and sleep quality have been noted in clinical trials. Trials evaluating both indiplon IR and MR have so far not identified any major serious adverse effects. Limited clinical trial data exist on use of indiplon in a "true" transient insomnia patient population. Based on recent Food and Drug Administration requests, clinical trial data assessing direct comparisons of indiplon IR with other approved nonbenzodiazepine sedative-hypnotics are needed to clearly define the differences among these agents.

Treating transient insomnia cause by substance abuse

Treating transient insomnia cause by substance abuse

Effect of microdialysis perfusion of 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridine-3-ol in the perifornical hypothalamus on sleep–wakefulness: Role of δ-subunit containing extrasynaptic GABA A receptors

Gaboxadol or 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridine-3-ol (THIP) is a selective agonist for the δ-subunit containing extrasynaptic GABA A receptors that will soon enter the U.S. market as a sleep aid [Winsky-Sommerer R, Vyazovskiy VV, Homanics GE, Tobler I (2007) The EEG effects of THIP (gaboxadol) on sleep and waking are mediated by the GABA(A)delta-subunit-containing receptors. Eur J Neurosci 25:1893–1899]. Numerous studies have shown that systemic administration of THIP reduces wakefulness and increases sleep both in humans and rats [ Lancel M, Langebartels A (2000) Gamma-aminobutyric acid(A) (GABA(A)) agonist 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol persistently increases sleep maintenance and intensity during chronic administration to rats. J Pharmacol Exp Ther 293:1084–1090; Walsh JK, Deacon S, Dijk DJ, Lundahl J (2007) The selective extrasynaptic GABAA agonist, gaboxadol, improves traditional hypnotic efficacy measures and enhances slow wave activity in a model of transient insomnia. Sleep 30:593–602]. However, it is yet unclear where in the brain THIP acts to promote sleep. Since the perifornical lateral hypothalamus (PFH) contains orexin neurons and orexin neurons are critical for maintenance of arousal [McCarley RW (2007) Neurobiology of rapid eye movement (REM) and NREM sleep. Sleep Med 8:302–330], we hypothesized that THIP may act on PFH neurons to promote sleep. To test our hypothesis, we used reverse microdialysis to perfuse THIP unilaterally into the PFH and studied its effects on sleep–wakefulness during the light period in freely behaving rats. Microdialysis perfusion of THIP (100 μM) into the PFH produced a significant reduction in wakefulness with a concomitant increase in non-rapid eye movement or slow wave sleep as compared with artificial cerebrospinal fluid perfusion. REM sleep was unaffected. This is the first study implicating the δ-subunit containing extrasynaptic GABA A receptors in PFH in control of sleep–wakefulness in freely behaving rats.

Herbal medicine for cancer patients: An evidence based review

Insomnia is a common disorder in both clinical and general populations. Treatment is complicated various methods of classification and confounding co-morbidity. Conventional pharmaceutical managements tends to focus on short term relief of symptoms rather than managing the underlying cause of insomnia. Moreover, conventional pharmaceuticals have unwanted side effects, tolerance and dependence. Herbal medicine provides safe, effective and reliable treatment strategies aimed at addressing both symptoms and aetiology of insomnia. Herbal treatments for insomnia tend to offer a cost effective alternative with no associated issues relating to tolerance and dependence. This article provides a summary of herbal treatment options in insomnia, and a brief analysis of supporting evidence. INTRODUCTION It is important to distinguish insomnia from other sleeping disorders. Indeed, a patient may themselves not know sufficient information about their sleep disorder and history to differentiate. Often it is information from parents or a bed partner that provides the clues to differentiate insomnia from, for example, hypersomnia and parasomnia. Moreover, one must differentiate insomnia symptoms from clinical insomnia (genuine dissatisfaction with sleep) highlighted perhaps by a recent study that indicated 36% of people reported insomnia but only 25% of those (9% overall) experienced genuine dissatisfaction with sleep (1). Insomnia relates to problem initiating or maintaining sleep (2,3) and tends to result in day time fatigue (3). Hypersomnia is excessive day time sleepiness with a tendency to fall asleep during the day and is generally associated with respiratory disorders (sleep apnea, narcolepsy) (3). Parasomnia are sleep aberrations like sleep walking, night tremors, nightmares and sleep paralysis (3). Other sleep disorders include restless leg syndrome and circadian rhythm disorder (3). Insomnia can be classified in terms of either its duration (acute or chronic) or its aetiology (primary or secondary) (4). Acute insomnia (also known as transient insomnia) generally results from a significant event in ones daily life (eg. trauma, long distance travel, change in sleep/awake pattern) and can be treated directly or preventative measures might be adopted (4). Chronic insomnia tends to be longer lasting with an association with medical aetiology and requires a more rigorous assessment to determine treatment options (4). Primary insomnia are those where there is no mental or physical cause requiring more direct treatment while secondary insomnia results as co-morbidity associated with other mental or physical illness requiring a more considered treatment approach (4). It must be noted, however, that any classification of insomnia can be confounded by the presence of a multitude of contributory factors (2). In general practice, the prevalence of clinical insomnia (causing day time dysfunction) range from 10% to 34% and is typically higher in older persons, women, those with less education, the unemployed and in those separated or divorced (1,5). Prevalence of insomnia is also higher in clinical populations than the general population (5) which reflects both secondary insomnia and the skewed age distribution in the clinical population. Ebert, Wafford and Deacon (2) report that 25% of adults experience insomnia at some point while 10% of the population consider insomnia to be a chronic problem. PATIENT HISTORY The goal of the patient history is to elicit sufficient information to classify the sleep disorder; to confirm indeed that the patient is suffering insomnia and not another sleep disorder. If insomnia is the correct sleep disorder, the information will also provide some scope to classify the type of insomnia; chronic versus acute, primary versus secondary, and an insight into the cause, although one recognises that Insomnia: An Overview Of Herbal Treatments 2 of 5 causal relationships are extraordinarily difficult to establish. Only after establishing this history can an intervention be considered; the correct treatment will depend on accurate classification and reatments should reflect the aetiology of insomnia and, thus, be individualised for each patient. HISTORY (,): Onset of insomnia Severity of insomnia Duration of insomnia Progression of insomnia Impact on awake activities Family history of sleep disorders Sleeping habits (sleep hygiene) and perhaps a ‘sleep diary'.

Evaluation of Automated and Semi-Automated Scoring of Polysomnographic Recordings from a Clinical Trial Using Zolpidem in the Treatment of Insomnia

To evaluate the performance of 2 automated systems, Morpheus and Somnolyzer24X7, with various levels of human review/editing, in scoring polysomnographic (PSG) recordings from a clinical trial using zolpidem in a model of transient insomnia. 164 all-night PSG recordings from 82 subjects collected during 2 nights of sleep, one under placebo and one under zolpidem (10 mg) treatment were used. For each recording, 6 different methods were used to provide sleep stage scores based on Rechtschaffen & Kales criteria: 1) full manual scoring, 2) automated scoring by Morpheus 3) automated scoring by Somnolyzer24X7, 4) automated scoring by Morpheus with full manual review, 5) automated scoring by Morpheus with partial manual review, 6) automated scoring by Somnolyzer24X7 with partial manual review. Ten traditional clinical efficacy measures of sleep initiation, maintenance, and architecture were calculated. Pair-wise epoch-by-epoch agreements between fully automated and manual scores were in the range of intersite manual scoring agreements reported in the literature (70%-72%). Pair-wise epoch-by-epoch agreements between automated scores manually reviewed were higher (73%-76%). The direction and statistical significance of treatment effect sizes using traditional efficacy endpoints were essentially the same whichever method was used. As the degree of manual review increased, the magnitude of the effect size approached those estimated with fully manual scoring. Automated or semi-automated sleep PSG scoring offers valuable alternatives to costly, time consuming, and intrasite and intersite variable manual scoring, especially in large multicenter clinical trials. Reduction in scoring variability may also reduce the sample size of a clinical trial.

Efficacy of the selective extrasynaptic GABA A agonist, gaboxadol, in a model of transient insomnia: A randomized, controlled clinical trial

Objective The hypnotic efficacy of gaboxadol, a selective extrasynaptic GABA A agonist (SEGA), was evaluated in a phase-advance model of transient insomnia. Methods Healthy subjects (18–64 years) completed a randomized, double-blind, parallel group study in which the sleep period was advanced 4 h from habitual sleep time. Polysomnographic (PSG) and self-reported sleep measures were used to compare gaboxadol 10 mg ( N = 271) and 15 mg ( N = 274) versus placebo ( N = 277). Results In the placebo group, the phase-advance procedure disrupted sleep maintenance as measured by PSG wakefulness after sleep onset (WASO) and self-reported WASO (sWASO), and also, to a lesser extent, disrupted sleep onset as measured by PSG latency to persistent sleep (LPS) and self-reported time to sleep onset (sTSO). Both doses of gaboxadol decreased WASO and sWASO versus placebo ( p ⩽ 0.05). Gaboxadol 15 mg also reduced LPS versus placebo ( p ⩽ 0.01) and both doses reduced sTSO versus placebo ( p ⩽ 0.01). PSG and self-reported total sleep time as well as ratings of sleep quality were improved with both gaboxadol doses relative to placebo (all p ⩽ 0.01 or better). The amount of slow wave sleep (SWS) was greater with both doses of gaboxadol than with placebo ( p ⩽ 0.001). No group differences in the amount of rapid eye movement sleep were found. Most PSG and self-report measures indicated a mild dose response. The percentage of subjects with adverse events was low (<10% in any treatment group) and all were mild or moderate; none were serious and gaboxadol did not impact morning gait or coordination. Conclusions Gaboxadol 10 and 15 mg were efficacious in significantly reducing the sleep maintenance and sleep onset disruption produced by this model of transient insomnia, with effects generally being most pronounced for the 15 mg dose. Gaboxadol also enhanced SWS.

Efficacy and Tolerability of Indiplon in Transient Insomnia

The efficacy of indiplon was evaluated by polysomnography (PSG) in an experimental model of transient insomnia consisting of the first night effect combined with a 2-hour phase advance. Healthy volunteers age 21-64 years (N=593; 62% female; mean +/- SEM) years, 32 +/- 0.39) were randomized to double-blind treatment with a single nighttime dose of indiplon (10 mg or 20 mg) or placebo. PSG assessments included latency to persistent sleep (LPS, primary endpoint) and total sleep time (TST); self-report assessments included sleep quality (SQ); next day residual effects were evaluated by the Digit Symbol Substitution Test (DSST), Symbol Copying Test (SCT), and a Visual Analog Scale of sleepiness (VAS). LPS mean (+/- SEM) values were significantly reduced on indiplon 10 mg (21.2 +/- 1.5 minutes) and indiplon 20 mg (16.8 +/- 1.1 minutes) compared to placebo (33.1 +/- 2.5 minutes; p < 0.0001 for both comparisons to placebo). TST mean (+/- SEM) values were significantly increased on indiplon 10 mg (414.5 +/- 3.9 minutes) and indiplon 20 mg (423.5 +/- 3.1 minutes) compared to placebo (402.9 +/- 3.9 minutes; p <0.005 for the 10 mg dose; p < 0.0001 for the 20 mg dose). SQ was also significantly improved on both doses. There were no differences between indiplon and placebo on next day DSST, SCT, or VAS. Indiplon was effective in inducing sleep, increasing sleep duration, and improving overall sleep quality without next day residual effects in healthy volunteers in a model of transient insomnia.

The Selective Extrasynaptic GABAA Agonist, Gaboxadol, Improves Traditional Hypnotic Efficacy Measures and Enhances Slow Wave Activity in a Model of Transient Insomnia

Evaluate the hypnotic efficacy of gaboxadol, a selective extrasynaptic GABAA agonist (SEGA), in a phase advance model of transient insomnia. A randomized, double-blind, cross-over study in which habitual sleep time was advanced by 4 h. Sleep research laboratories. 109 healthy subjects (18-58 y). Gaboxadol 5 mg, 10 mg, and 15 mg (GBX5, GBX10, GBX15) versus placebo (PBO). Zolpidem 10 mg (ZOL10) was used as an active reference. Polysomnographic (PSG) and self-reported (s) sleep measures Wakefulness after sleep onset (WASO) decreased (P < 0.05) and total sleep time (TST) increased (P < 0.001) in all treatments versus PBO. Latency to persistent sleep was shorter (P < 0.05) than PBO for all treatments except GBX5. GBX10 and GBX15 increased slow wave activity (SWA; 0.75-4.5 Hz, P < 0.001) and theta activity (4.75-7.75Hz; P < 0.001) and reduced sigma activity (12.25-15.0 Hz; significant for GBX15 only, P < 0.001) compared to PBO in NREM sleep EEG, in a dose-response manner. Zolpidem suppressed power density over a broad low frequency range including delta and theta frequencies (2.25-8.0 Hz, P < 0.05) and also enhanced sigma activity (P < 0.001). Self-reported sWASO and sTST improved for all treatments versus PBO (P < 0.05). Self-reported sleep latency was reduced following GBX10 (P < 0.05) and ZOL10 (P < 0.001). Neither drug treatment was associated with residual effects the morning after treatment. Gaboxadol and zolpidem improved objective and subjective efficacy measures in this model of transient insomnia. The gaboxadol-induced enhancement of SWA and theta activity and the reduction of sigma activity contrasts with zolpidem's effects on the spectral EEG. These differences may reflect the different mechanisms of action of the two drugs.

The effect of placebo administration on the first-night effect in healthy young volunteers

The first-night effect is a well-known phenomenon that is considered to result from a subject's lack of adaptation to the unfamiliar environment of a sleep laboratory and to the technical equipment used for polysomnography. The effect has been explored as a laboratory model for transient insomnia. The main characteristics of this effect are short total sleep time (TST) and rapid eye movement (REM) sleep, a lower sleep efficiency index, and longer REM sleep latency. Previous studies have reported that personality traits (such as trait anxiety) are a potential cause of the first-night effect and that the placebo effect is closely related to the anxiety levels of the subjects. To the best of our knowledge, there are no reports regarding the effects of a placebo on first-night sleep. This omission can be explained by the fact that the polysomnographic recordings obtained during the first night of a study are generally excluded from the analysis in order to avoid the inclusion of the first-night effect. In the present study, 8 male university students were subjected to polysomnographic examinations during drug-free, placebo-administration, and benzodiazepine-administration conditions in order to clarify the placebo effect on sleep during consecutive nights, particularly on the first night. The recordings for each condition were conducted for 4 consecutive nights. A placebo or 5 mg nitrazepam was administered at 2230 h using a double-blind crossover design, while no drug was administered during the drug-free condition. There was a 10-day interval between the examination of each condition. Polysomnographic recording was started at 2300 h and continued until the natural awakening of the subjects on the next morning. Subsequently, the subjects were requested to fill in a rating scale that is used to evaluate the subjective perception of sleep. An increase in stage-2 sleep associated with the first-night effect was observed on the first night during the drug-free and placebo-administration conditions. However, REM sleep reduction associated with the first-night effect was detected on the first night during the drug-free condition; this decrease in REM sleep was counteracted by the placebo during the placebo-administration condition. The nitrazepam, but not the placebo, decreased both slow-wave sleep (SWS) and REM sleep. The values for the tendency to fall asleep, feeling refreshed upon awakening in the morning, and the tension upon awakening in the morning were improved to a greater extent by the placebo and nitrazepam administrations than when no drug was administered. These results demonstrate the possibility that placebo administration may have a hypnotic/anxiolytic effect and may improve transient insomnia without causing SWS and REM sleep reductions.

HY 10275* shows potential in the treatment of transient insomnia,

HY 10275* shows potential in the treatment of transient insomnia,