Sleep after intranasal progesterone vs. zolpidem and placebo in postmenopausal women - A randomized, double-blind cross over study.

CONTEXT: The loss of progesterone during menopause is linked to sleep complaints of the affected women. Previously we demonstrated sleep promoting effects of oral progesterone replacement in postmenopausal women. The oral administration of progesterone, however, is compromised by individual differences in bioavailability and metabolism of the steroid. OBJECTIVE: We compared the sleep-endocrine effects after intranasal progesterone (MPP22), zolpidem and placebo in healthy postmenopausal women. DESIGN: This was a randomized double-blind cross-over study. SETTING: German monocentric study PARTICIPANTS: Participants were 12 healthy postmenopausal women. INTERVENTIONS: Subjects received in randomized order four treatments, 2 doses of intranasal progesterone (4.5 mg and 9 mg of MPP22), 10 mg of zolpidem and placebo. OUTCOME MEASURES: Main outcome were conventional and quantitative sleep-EEG variables. Secondary outcomes were the subjective sleep variables and the sleep related concentrations of cortisol, growth hormone (GH), melatonin and progesterone. RESULTS: Sleep promoting effects were found after the higher dosage of MPP22 and after zolpidem. Zolpidem prompted benzodiazepine-like effects on quantitative sleep EEG as expected, whereas no such changes were found after the two dosages of MP22. Nocturnal progesterone levels increased after 9.0 mg MPP22. No other changes of hormone secretion were found. CONCLUSIONS: Our study shows sleep promoting effects after intranasal progesterone. The spectral signature of intranasal progesterone did not resemble the sleep-EEG alterations induced by GABA active compounds. Progesterone levels were elevated after 9.0 mg MPP22. No other endocrine effects were observed.

Limited Efficacy of Caffeine and Recovery Costs During and Following 5 Days of Chronic Sleep Restriction.

Objectives: To investigate the effects of caffeine on psychomotor vigilance and sleepiness during sleep restriction and following subsequent recovery sleep. Methods: Participants were N = 48 healthy good sleepers. All participants underwent five nights of sleep satiation (time-in-bed [TIB]: 10 hours), followed by five nights of sleep restriction (TIB: 5 hours), and three nights of recovery sleep (TIB: 8 hours) in a sleep laboratory. Caffeine (200 mg) or placebo was administered in the form of chewing gum at 08:00 am and 12:00 pm each day during the sleep restriction phase. Participants completed hourly 10-minute psychomotor vigilance tests and a modified Maintenance of Wakefulness Test approximately every 4 hours during the sleep restriction and recovery phases. Results: Caffeine maintained objective alertness compared to placebo across the first 3 days of sleep restriction, but this effect was no longer evident by the fourth day. A similar pattern of results was found for Maintenance of Wakefulness Test sleep latencies, such that those in the caffeine group (compared to placebo) did not show maintenance of wakefulness relative to baseline after the second night of restriction. Compared to placebo, participants in the caffeine condition displayed slower return to baseline in alertness and wakefulness across the recovery sleep period. Finally, the caffeine group showed greater N3 sleep duration during recovery. Conclusions: Caffeine appears to have limited efficacy for maintaining alertness and wakefulness across 5 days of sleep restriction. Perhaps more importantly, there may be recovery costs associated with caffeine use following conditions of prolonged sleep loss.

Distinct Cortical Signatures Associated with Sedation and Respiratory Rate Depression by Morphine in a Pediatric Population.

BACKGROUND: Opioid analgesia is an essential component of perioperative care, but effective analgesia can be limited by excessive sedation and respiratory depression. The cortical signatures associated with sedation by opioids and the relationship between changes in cortical activity and respiratory function are not well understood. The objectives of this study were to identify the electroencephalogram signatures of sedation and respiratory changes induced by morphine in a pediatric population after elective surgery. METHODS: After otologic surgery, patients (14.8 ± 2.8 yr, n = 10) stayed overnight for pain relief with morphine (3 to 10 mg), hydration, and clinical observation. Electroencephalogram activity and polysomnography were performed before and after morphine, and electroencephalogram spectral properties and cardiorespiratory activities were analyzed. RESULTS: Compared to wakefulness and non-rapid eye movement sleep, morphine reduced high-frequency ß1 (13.5 to 20 Hz) and ß2 (20 to 30Hz) electroencephalogram powers (n = 10) and decreased coherence between frontal and occipital ß2 electroencephalogram activities (n = 9), therefore indicating that morphine induced a deep sedative state. Morphine also reduced respiratory rate by 8.3% (n = 10). Interestingly, there was a significant correlation between the reduction in ß1 electroencephalogram activity and the depression in respiratory rate induced by morphine (R = 0.715, n = 10). With significant reduction in ß1 power, respiratory rate was decreased by more than 25%, suggesting that reduction in cortical arousal is associated with the severity of respiratory rate depression. CONCLUSIONS: Analgesic doses of morphine are associated with reduction in respiratory rate when accompanied by reduction in ß1 electroencephalogram power, indicating a powerful effect of cortical arousal state per se in respiratory rate depression by morphine.

Home-use servo-ventilation therapy in chronic pain patients with central sleep apnea: initial and 3-month follow-up.

PURPOSE: Opioid treatment of non-malignant chronic pain can result in hypoxemia, hypercarbia, and central sleep apnea. The aim of this study was to determine the initial efficacy of auto servo-ventilation (ASV) and after 3 months of home use. METHODS: This prospective multicenter interventional study recruited chronic pain patients prescribed ≥100 morphine equivalents for at least 4 months. PARTICIPANTS: Following full-night polysomnography (PSG) to confirm the presence of sleep-disordered breathing, patients were randomized to three additional full-night-attended PSGs with continuous positive airway pressure (CPAP), ASV, and servo-ventilation with an initial mandatory pressure support of 6 cm H2O (ASV manual PSmin 6). Following the PSGs, patients were sent home with EncoreAnywhere and ASV with or without mandatory pressure support. RESULTS: Based on the initial PSG studies, CPAP improved but did not normalize the apnea-hypopnea index (AHI), central apnea index (CAI), or hypopnea index (HI), as all remained elevated. Clinically significant reductions were noted after just one night of ASV and ASV manual (PSmin 6). After 3 months of ASV home use, the AHI, CAI, and obstructive apnea index (OAI) were significantly reduced when compared to baseline diagnostic levels and even when compared to respiratory disturbance indices with CPAP treatment. CONCLUSIONS: Initial and home use of ASV for 3 months resulted in significantly lower AHI, CAI, and OAI. This reduction attests to the efficacy of ASV treatment in chronic pain patients on high doses of opioids.

Impact of medications on cognitive function in obstructive sleep apnea syndrome.

PURPOSE: Medications can impact cognitive function. Obstructive sleep apnea syndrome (OSAS) is associated with cognitive impairment. There is currently a paucity of data evaluating the impact of medications on sleep architecture and cognition in untreated OSAS. Our objective was to evaluate the impact of obstructive sleep apnea syndrome (OSAS) and medications on cognition by a screening questionnaire called the Mail-In Cognitive Function Screening Instrument (MCFSI). METHODS: We conducted a retrospective chart review on consecutive adults (age > 18 years) with OSAS seen in Medical University of South Carolina Sleep Clinic between January 1, 2012 and May 8, 2013, for whom the Mail-In Cognitive Function Screening Instrument (MCFSI) score was available and who were not on continuous positive airway pressure (CPAP). The correlation between different medications, sleep study variables, and MCFSI scores was studied. RESULTS: Univariate analysis revealed that many medications had significant correlations with MCFSI scores, including antidepressants (p = 0.05), antipsychotics (p = 0.01), anxiolytics (p = 0.005), statins (p = 0.077) and narcotics (p = 0.006). The mean percentage of rapid eye movement (REM) sleep (p = 0.04) and Epworth Sleepiness Scale (p = 0.01) were also significantly correlated with MCFSI scores. Multivariate analysis revealed that Epworth Sleepiness Scale and use of antipsychotics, narcotics, and anxiolytics correlated with higher MCFSI scores (worse cognition) and conversely that statin use was associated with improved cognition. CONCLUSIONS: Medications have a significant impact on cognitive function in OSAS. Thus, medication use should be considered in future studies of cognitive function in patients with OSAS.

The effect of nightly nasal CPAP treatment on nocturnal hypoxemia and sleep disorders in mustard gas-injured patients.

INTRODUCTION: Sleep-related breathing disorders are associated with unusual respiratory pattern or an abnormal reduction in gas exchange during sleep that is common in sulfur mustard (SM) exposure. METHODS: We compared 57 Iranian male patients injured with SM and had any complaints of sleep problems with an age-matched group of 21 Iranian male patients who had complaints of sleep problems and were not chemically injured; this group had Epworth Sleepiness Scale (ESS) above 10 and whom referred for polysomnography. Split-night studies were performed for patients with diagnostic polysomnography for obstructive sleep apnea (OSA) and respiratory events. We then studied respiratory events including episodes of OSA, apnea-hypopnea index (AHI) and respiratory disturbance index (RDI). RESULTS: The mean age in mustard-exposed patients was 48.14±8.04 years and in age-matched group, 48.19±8.39 years. In mustard exposed patients, there were statistical differences for the episodes of OSA (p=0.001), AHI (p=0.001), and RDI (p=0.001) between two segments of split-night studies. In the age-matched group, there were statistically differences for each parameter (episodes of OSA (p=0.001), AHI (p=0.001), and RDI (p=0.001)). There were no significant differences between two groups. CONCLUSION: This study indicated that the incidence of respiratory events and nocturnal hypoxemia during sleep in mustard-exposed patients were high and treatment with CPAP significantly reduced all these events.

A review of the effects of pregabalin on sleep disturbance across multiple clinical conditions.

Pregabalin is approved for the treatment of a variety of clinical conditions and its analgesic, anxiolytic and anticonvulsant properties are well documented. Pregabalin's effects on sleep, however, are less well known. This review summarizes the published data on the effects of pregabalin on sleep disturbance associated with neuropathic pain, fibromyalgia, restless legs syndrome, partial onset seizures and general anxiety disorder. The data demonstrate that pregabalin has a positive benefit on sleep disturbance associated with several different clinical conditions. Polysomnographic data reveal that pregabalin primarily affects sleep maintenance. The evidence indicates that pregabalin has a direct effect on sleep that is distinct from its analgesic, anxiolytic and anticonvulsant effects.

Ovarian hormones promote recovery from sleep deprivation by increasing sleep intensity in middle-aged ovariectomized rats.

Sleep disturbances are commonly associated with menopause. Hormone replacement therapy is often used to treat various menopausal symptoms, but its efficacy for improving sleep is a matter of debate. We addressed this question by using a rodent model of ovarian hormone loss and replacement in midlife. Middle-aged female rats were ovariectomized and implanted with capsules containing estradiol with or without progesterone, or oil. After two weeks, sleep/wake states were recorded polygraphically during a 24-h baseline period, followed by 6h of sleep deprivation in the second half of the light phase, and a 24-h recovery period. During the baseline dark phase, hormone treatments increased wakefulness, and decreased non-rapid eye movement sleep (NREMS) by shortening NREMS episodes; however, NREMS EEG delta power or energy (cumulative power) was unaffected by combined hormones. Following sleep deprivation, all the groups showed NREMS and rapid eye movement sleep (REMS) rebounds, with similar relative increases from respective baseline levels. The increases in NREMS EEG delta power/energy during recovery were enhanced by combined hormones. These results from middle-aged ovariectomized rats indicate that replacement with estrogen with or without progesterone reduces baseline NREMS without affecting sleep intensity, particularly during the dark (active) phase, whereas following sleep deprivation the same hormone treatments do not affect the ability to increase NREMS or REMS, but treatment with both hormones, in particular, enhances the intensity of recovery sleep. These results support the usefulness of ovariectomized middle-aged rats as a model system to study the biological effects of hormone replacement on sleep regulation.

New pathways and data on rapid eye movement sleep behaviour disorder in a rat model.

OBJECTIVE: An abnormality in auditory evoked responses localised to the inferior colliculus (IC) has been reported in rapid eye movement (REM) sleep behaviour disorder (RBD) patients. The external cortex of the inferior colliculus (ICX) has been demonstrated not only to be involved in auditory processing, but also to participate in the modulation of motor activity. METHODS: Rats were surgically implanted with electrodes for electroencephalography (EEG) and electromyography (EMG) recording and guide cannulae aimed at the ICX for drug infusions. Drug infusions were conducted after the animals recovered from surgery. Polysomnographic recordings with video were analysed to detect normal and abnormal sleep states. RESULTS: Baclofen, a gamma-aminobutyric acid B (GABAB) receptor agonist, infused into the ICX increased phasic motor activity in slow-wave sleep (SWS) and REM sleep and tonic muscle activity in REM sleep; it also elicited RBD-like activity during the infusion and post-infusion period. In contrast, saclofen, a GABAB receptor antagonist, did not produce significant changes in motor activities in sleep. Baclofen infusions in ICX also significantly increased REM sleep during the post-infusion period, while saclofen infusions did not change the amount of any sleep-waking states. CONCLUSIONS: This study suggests that GABAB receptor mechanisms in the ICX may be implicated in the pathology of RBD.

Correlations of sleep disorders with severity of obstructive airway disease in mustard gas-injured patients.

INTRODUCTION: Mustard gas has serious adverse effects on several organs and functions in humans. In this study, we analyzed potential correlations between obstructive airway disease and sleep disorders in Iranian mustard gas-injured patients. METHODS: We enrolled 30 male mustard gas-injured veterans and civilians from the Chemical Warfare Exposure Clinic at Baqiyatallah Hospital, Tehran. All the subjects underwent comprehensive polysomnographic and spirometric evaluations for diagnosis of sleep disorders. Patients were categorized into three groups according to the severity of their obstructive airway disease based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria: group 1 (GOLD I and II), group 2 (GOLD III), and group 3 (GOLD IV). RESULTS: Patients with less severe obstructive airway disease had significantly higher rate of hypopnea (p = 0.05) and AHI (p = 0.05). The number of REM events was significantly higher in patients with less severe airway disease (p = 0.028). Stage 1 sleep among patients with higher FEV1 significantly constituted a higher proportion of sleep, and stage 4 sleep was significantly longer in patients with higher DLCO (p = 0.043, both). CONCLUSION: We found that sleep parameters in SM-exposed patients have some relations with spirometric parameters. Future studies with large patient populations are needed for confirmation of our results, and therapeutic interventions are needed to evaluate endeavors we can do to enhance health and quality of life in our mustard gas-injured population.

Buprenorphine disrupts sleep and decreases adenosine concentrations in sleep-regulating brain regions of Sprague Dawley rat.

BACKGROUND: Buprenorphine, a partial µ-opioid receptor agonist and κ-opioid receptor antagonist, is an effective analgesic. The effects of buprenorphine on sleep have not been well characterized. This study tested the hypothesis that an antinociceptive dose of buprenorphine decreases sleep and decreases adenosine concentrations in regions of the basal forebrain and pontine brainstem that regulate sleep. METHODS: Male Sprague Dawley rats were implanted with intravenous catheters and electrodes for recording states of wakefulness and sleep. Buprenorphine (1 mg/kg) was administered systemically via an indwelling catheter and sleep-wake states were recorded for 24 h. In additional rats, buprenorphine was delivered by microdialysis to the pontine reticular formation and substantia innominata of the basal forebrain while adenosine was simultaneously measured. RESULTS: An antinociceptive dose of buprenorphine caused a significant increase in wakefulness (25.2%) and a decrease in nonrapid eye movement sleep (-22.1%) and rapid eye movement sleep (-3.1%). Buprenorphine also increased electroencephalographic delta power during nonrapid eye movement sleep. Coadministration of the sedative-hypnotic eszopiclone diminished the buprenorphine-induced decrease in sleep. Dialysis delivery of buprenorphine significantly decreased adenosine concentrations in the pontine reticular formation (-14.6%) and substantia innominata (-36.7%). Intravenous administration of buprenorphine significantly decreased (-20%) adenosine in the substantia innominata. CONCLUSIONS: Buprenorphine significantly increased time spent awake, decreased nonrapid eye movement sleep, and increased latency to sleep onset. These disruptions in sleep architecture were mitigated by coadministration of the nonbenzodiazepine sedative-hypnotic eszopiclone. The buprenorphine-induced decrease in adenosine concentrations in basal forebrain and pontine reticular formation is consistent with the interpretation that decreasing adenosine in sleep-regulating brain regions is one mechanism by which opioids disrupt sleep.

D(1)/D(2) receptor-targeting L-stepholidine, an active ingredient of the Chinese herb Stephonia, induces non-rapid eye movement sleep in mice.

L-stepholidine, an active ingredient of the Chinese herb Stephonia, is the first compound known to have mixed dopamine D(1) receptor agonist/D(2) antagonist properties and to be a potential treatment medication for schizophrenia. In schizophrenic patients insomnia is a common symptom and could be partly related to the presumed over-activity of the dopaminergic system. To elucidate whether stepholidine modulates sleep behaviors, we observed its effects on sleep-wake profiles in mice. The results showed that stepholidine administered i.p. at doses of 20, 40 or 80 mg/kg significantly shortened the sleep latency to non-rapid eye movement (non-REM, NREM) sleep, increased the amount of NREM sleep, and prolonged the duration of NREM sleep episodes, with a concomitant reduction in the amount of wakefulness. Stepholidine at doses of 40 and 80 mg/kg increased the number of state transitions from wakefulness to NREM sleep and subsequently from NREM sleep to wakefulness. However, stepholidine had no effect on either the amount of REM sleep or electroencephalogram power density of either NREM or REM sleep. Immunohistochemistry study showed that stepholidine dose-dependently increased c-Fos expression in neurons of the ventrolateral preoptic area, a sleep center in the anterior hypothalamus, as compared with the vehicle control. These results indicate that stepholidine initiates and maintains NREM sleep with activation of the sleep center in mice, suggesting its potential application for the treatment of insomnia.

Effects of anabolic androgenic steroids on sleep patterns of individuals practicing resistance exercise.

Anabolic androgenic steroid (AAS) abuse has become a public health problem in many countries, and is associated with many psychiatric disorders. Epidemiological studies have also found increasing numbers of sleep disorders reported by individuals using AASs. The purpose of this study was to evaluate sleep patterns and disorders in anabolic androgenic users who practice resistance exercise. The sample comprised 58 males divided into three groups: (1) 20 current AAS users aged 26 +/- 1.2, (2) 21 controls with no history of AAS use, aged 26 +/- 1 and (3) 17 sedentary men with no sleep disorders aged 27.2 +/- 0.34. The volunteers spent a night in the sleep laboratory for polysomnography. Comparing the three groups, the user group showed reduced sleep efficiency and more wakings after sleep onset than the sedentary group (P = 0.001). The sedentary group showed a higher percentage of stage 4 than the non-users group. We suggest that using of anabolic steroids reduced sleep efficiency and alters sleep architecture.

A genetic variation in the adenosine A2A receptor gene (ADORA2A) contributes to individual sensitivity to caffeine effects on sleep.

Caffeine is the most widely used stimulant in Western countries. Some people voluntarily reduce caffeine consumption because it impairs the quality of their sleep. Studies in mice revealed that the disruption of sleep after caffeine is mediated by blockade of adenosine A2A receptors. Here we show in humans that (1) habitual caffeine consumption is associated with reduced sleep quality in self-rated caffeine-sensitive individuals, but not in caffeine-insensitive individuals; (2) the distribution of distinct c.1083T>C genotypes of the adenosine A2A receptor gene (ADORA2A) differs between caffeine-sensitive and -insensitive adults; and (3) the ADORA2A c.1083T>C genotype determines how closely the caffeine-induced changes in brain electrical activity during sleep resemble the alterations observed in patients with insomnia. These data demonstrate a role of adenosine A2A receptors for sleep in humans, and suggest that a common variation in ADORA2A contributes to subjective and objective responses to caffeine on sleep.

A double-blind comparison of the effect of the antipsychotics haloperidol and olanzapine on sleep in mania

The effects of haloperidol and olanzapine on polysomnographic measures made in bipolar patients during manic episodes were compared. Twelve DSM-IV mania patients were randomly assigned to receive either haloperidol (mean ± SD final dosage: 5.8 ± 3.8 mg) or olanzapine (mean ± SD final dosage: 13.6 ± 6.9 mg) in a 6-week, double-blind, randomized, controlled clinical trial. One-night polysomnographic evaluation was performed before and after the haloperidol or olanzapine treatment. Psychopathology and illness severity were rated respectively with the Young Mania Rating Scale (YMRS) and the Clinical Global Impressions - Bipolar version (CGI-BP). There was a significant improvement in the YMRS and CGI-BP scores at the end of the study for both groups. Mixed ANOVA used to compare the polysomnographic measures of both drugs demonstrated significant improvement in sleep measures with olanzapine. In the olanzapine group, statistically significant time-drug interaction effects on sleep continuity measures were observed: sleep efficiency (mean ± SEM pre-treatment value: 6.7 ± 20.3 percent; after-treatment: 85.7 ± 10.9 percent), total wake time (pre-treatment: 140.0 ± 92.5 min; after-treatment: 55.2 ± 44.2 min), and wake time after sleep onset (pre-treatment: 109.7 ± 70.8 min; after-treatment: 32.2 ± 20.7 min). Conversely, improvement of polysomnographic measures was not observed for the haloperidol group (P > 0.05). These results suggest that olanzapine is more effective than haloperidol in terms of sleep-promoting effects, although olanzapine is comparatively as effective as haloperidol in treating mania. Polysomnography records should provide useful information on how manic states can be affected by psychopharmacological agents.

[Methadone and sleep apnea syndrome]. / Méthadone et syndrome d'apnées du sommeil.

BACKGROUND: Sleep apnea syndrome occurs when, during sleep, breathing stops for 10 seconds or longer, with an index of 5 times or more an hour. It is clinically characterized by loud snoring at night, continuous or interrupted by pauses followed by loud breathing. Sleep is fitful, broken by arousals, and yields little rest. There is daytime excessive sleepiness with repeated involuntary falling asleep, often unknown by the subject. CLINICAL DESCRIPTION: In this article, we describe an observation of central sleep apnea syndrome in a female patient receiving an opiate replacement therapy. METHOD: An analysis of the before and after methadone withdrawal polysomnograhic tracing was done for this patient. RESULTS: This diagnosis etiology and physiopathology are critically approached. Clinicians should be careful in treating induced sleep disorders in such patients. CONCLUSION: Prescribing benzodiazepines during an opiate withdrawal of the methadone type is not recommended when central apnea occurs.

Night sleep EEG and daytime sleep propensity in adult hypopituitary patients with growth hormone deficiency before and after six months of growth hormone replacement.

BACKGROUND: Hypopituitary patients with growth hormone deficiency (GHD) complain of reduced vitality, general fatigue, lack of concentration, irritability and reduced alertness during daytime. It is unclear whether these symptoms are primarily due to GH-deficiency and/or secondary to GHD related sleep impairments. Bi-directional interactions between the somatotropic system and human sleep patterns are well established. However, data on the effect of GH either in subjects without GHD or in patients with GHD under GH replacement therapy on the sleep electroencephalogram (EEG) are controversial. No reports exist about objective measures of daytime sleepiness in GH deficient patients before and during GH-therapy. OBJECTIVE: To assess the effects of GH on nocturnal and daytime sleep in adult patients with GHD before and during recombinant human GH (rhGH, Somatropin) replacement therapy. METHODS: Eighteen adult patients with GHD (4 women and 14 men) participated in the study. Mean age at the beginning of the study was 48.5 years (range 27-64 years). Ten patients were recruited from a double-blind, randomized placebo controlled trial over 6 months, followed by an open treatment period of 6 additional months (Group I). In all patients from this group, only the effects of the first 6 months of GH treatment were assessed. Eight additional patients were treated in an open study design for 6 months (Group II). Nocturnal sleep recordings and daytime sleep EEGs with a multiple sleep latency test were performed at baseline and after 6 months of additional GH replacement therapy. RESULTS: One patient dropped out due to side effects and was not included in sleep analysis. IGF-1 levels were increased in all patients, partially in a supraphysiologic range. Side effects were mainly mild but in one patient (from group II), general muscle pain led to interruption of the study. Therefore sleep analysis was only done in 17 patients. Sleep parameters were comparable to healthy control groups from the literature. GH substitution over 6 months did neither affect total sleep time nor times spent in different sleep stages. REM sleep density was also not changed. Daytime sleep propensity as measured by the multiple sleep latency test was not influenced by GH treatment. CONCLUSIONS: GH replacement does neither affect night sleep nor daytime sleep propensity in GH deficient hypopituitary adults. GH substitution has no sleep disturbing effect.

Caffeine attenuates waking and sleep electroencephalographic markers of sleep homeostasis in humans.

Prolonged wakefulness increases electroencephalogram (EEG) low-frequency activity (< 10 Hz) in waking and sleep, and reduces spindle frequency activity (approximately 12-16 Hz) in non-rapid-eye-movement (nonREM) sleep. These physiologic markers of enhanced sleep propensity reflect a sleep-wake-dependent process referred to as sleep homeostasis. We hypothesized that caffeine, an adenosine receptor antagonist, reduces the increase of sleep propensity during waking. To test this hypothesis, we compared the effects of caffeine and placebo on EEG power spectra during and after 40 h of wakefulness. A total of 12 young men underwent two periods of sleep deprivation. According to a randomized, double-blind, crossover design, they received two doses of caffeine (200 mg) or placebo after 11 and 23 h of wakefulness. Sleep propensity was estimated at 3-h intervals by measuring subjective sleepiness and EEG theta (5-8 Hz) activity, and polysomnographic recordings of baseline and recovery nights. Saliva caffeine concentration decreased from 15.7 micromol/l 16 h before the recovery night, to 1.8 micromol/l 1 h before the recovery night. Compared with placebo, caffeine reduced sleepiness and theta activity during wakefulness. Compared with sleep under baseline conditions, sleep deprivation increased 0.75-8.0 Hz activity and reduced spindle frequency activity in nonREM sleep of the recovery nights. Although caffeine approached undetectable saliva concentrations before recovery sleep, it significantly reduced EEG power in the 0.75-2.0 Hz band and enhanced power in the 11.25-20.0 Hz range relative to placebo. These findings suggest that caffeine attenuated the build-up of sleep propensity associated with wakefulness, and support an important role of adenosine and adenosine receptors in the homeostatic regulation of sleep.

Effect of bupropion-SR on REM sleep: relationship to antidepressant response.

RATIONALE: The effects of antidepressant (AD) drugs on sleep in depressed patients and their relationship to AD response have been investigated previously. However, newer AD agents, which appear to have different effects on sleep, have not been evaluated systematically for their usefulness in predicting treatment response. OBJECTIVES: To examine the effect of bupropion sustained release (SR) (Wellbutrin SR) on sleep macroarchitecture, and to assess whether the observed electroencephalographic (EEG) sleep changes in response to a single dose of bupropion are associated with treatment response to the AD. METHODS: Twenty patients with unipolar major depressive disorder received EEG sleep assessments prior to treatment. Subjects were studied twice for 2 consecutive nights, with each 2-night session approximately 1 week apart. Baseline EEG sleep and the EEG sleep responses to placebo (baseline sleep) and a single dose of bupropion SR (150 mg, PO) were measured using a randomized, double-blind, crossover design. The participants then received open-label treatment with bupropion SR for about 8 weeks. RESULTS: No relationship was observed between baseline EEG sleep measures and response to treatment with bupropion. However, a statistically significant relationship was found between latency to the onset of rapid eye movement (REM) sleep following a single dose of bupropion and clinical response to treatment with bupropion. Responders showed an increase in REM latency following bupropion challenge, whereas non-responders showed a decrease. Moreover, the REM latency change in response to bupropion challenge correlated with change in depression ratings as a result of treatment. CONCLUSIONS: These findings suggest that bupropion's effect on REM latency and its AD action might be linked, possibly via dopamine (D(2)) receptor-mediated effects, or by noradrenergic mechanism(s).