A single dose of melatonin prevents the phase delay associated with a delayed weekend sleep pattern

STUDY OBJECTIVES: This study was designed to test the hypotheses that a delayed weekend sleep pattern may lead to a phase delay of the endogenous circadian rhythm, and that melatonin administration can counteract the phase delay and prevent the sleep and functional impairments associated with this sleep pattern. DESIGN: A within-subject, counterbalanced design was used in which each subject participated in both placebo and melatonin conditions. Subjects' sleep-wake schedules were delayed by two hours on Friday and Saturday to simulate the delayed weekend sleep pattern. Six mg of melatonin or a placebo pill was administered double blind on Sunday late afternoon. SETTING: N/A. PARTICIPANTS: Ten healthy volunteers (mean age = 22.1 years old). MEASUREMENTS and RESULTS: Salivary dim-light melatonin onset (DLMO) was measured on Friday and Monday nights. Subject's sleep was recorded with polysomnography on Sunday night and their levels of sleepiness, cognitive functioning and mood were assessed on Sunday night and Monday morning. Results show that the delayed weekend sleep pattern caused a 31.6 min delay of the endogenous melatonin rhythm. Melatonin administration counteracted the phase delay of endogenous melatonin onset. On Sunday, melatonin administration increased the sleepiness throughout the evening and reduced sleep onset latency at bedtime. On Monday morning, subjective sleepiness was decreased in the melatonin condition. CONCLUSION: A delayed weekend sleep pattern did show a mild phase-delay effect on the endogenous circadian rhythm. A single dose of melatonin can acutely reverse the weekend drift.     

Day-time melatonin administration: Effects on core temperature and sleep onset latency

Significant hypothermic and hypnotic effects have been reported for melatonin at a wide range of doses. It has been suggested that this decrease in core temperature (Tc) following melatonin administration may mediate the observed increase in sleepiness. To test this, melatonin was administered to young adults during the day, and the concurrent effects on Tc and sleep onset latency (SOL) were recorded. Sixteen healthy males received either a 5 mg oral formulation of melatonin or placebo at 14.00 hours. Core temperature was recorded continuously. Sleep onset latency to stage 1 (SOL1) and stage 2 (SOL2) were recorded using an hourly multiple sleep latency test (MSLT). Compared with placebo, melatonin significantly decreased Tc 1.5 h after administration for 6 h. Between 15.00 and 18.00 hours, the drop in Tc was associated with a concurrent decrease in SOL1 and SOL2. Following administration mean SOL1 and SOL2 were reduced by 40 and 25%, respectively. In this study, daytime melatonin administration produced a significant decrease in Tc with a corresponding decrease in SOL. Taken together, these data are not inconsistent with the suggestion that melatonin may facilitate sleep onset via a hypothermic effect. In addition, this study provides support for the idea that melatonin may play a role in regulating circadian and/or age-related variations in sleep/wake propensity. From a practical perspective, exogenous melatonin may be useful in the treatment of sleep disorders associated with increased nocturnal Tc.     

Ramelteon (TAK-375), a selective MT1/MT2-receptor agonist, reduces latency to persistent sleep in a model of transient insomnia related to a novel sleep environment

OBJECTIVE: Evaluate the efficacy of ramelteon, an MT/1MT2-receptor agonist, for the treatment of transient insomnia in healthy adults. DESIGN: Randomized, double-blind, placebo-controlled design using a model of transient insomnia related to sleeping in a novel environment. SETTING: Fourteen sleep research centers. PARTICIPANTS: Healthy adults (N=375; 228 women), aged 35 to 60 years, who had never previously slept in a sleep laboratory and had a reported usual sleep duration of 6.5 to 8.5 hours and usual bedtime between 8:30 PM and midnight. INTERVENTIONS: Single administration of ramelteon (16 or 64 mg) or placebo 30 minutes before bedtime. OUTCOME MEASURES: Primary efficacy measure was latency to persistent sleep. Also evaluated were total sleep time, wake after sleep onset, percentage of each sleep stage, subjective estimates of sleep from postsleep questionnaire, number of awakenings, and subjective number of awakenings. Residual effects were assessed via Digit Symbol Substitution Test and postsleep questionnaire. RESULTS: Participants in ramelteon-treated groups had significantly shorter latency to persistent sleep relative to placebo. They also were associated with significantly longer total sleep time. Wake after sleep onset and time spent in each sleep stage were not significantly different from placebo. The use of ramelteon (16 mg) was associated with a shorter subjective sleep latency compared to placebo. Other subjective measures of sleep did not differ significantly from placebo. Digit Symbol Substitution Test scores did not differ significantly among the 3 groups, but the use of the 64-mg [corrected] dose was associated with subjective reports of impairment in the morning. CONCLUSIONS: Ramelteon significantly improved latency to persistent sleep and total sleep time in this model of transient insomnia in healthy adults. No dose-related differences in latency to persistent sleep were observed, and both doses were well tolerated.     

The effects of mirtazapine on sleep: a placebo controlled,double-blind study in young healthy volunteers

STUDY OBJECTIVES: Mirtazapine is classified as a noradrenergic and specific serotonergic antidepressant. This study aims at objectively investigating the effects of single-dose mirtazapine on sleep of healthy volunteers. DESIGN AND SETTING: We studied the effect of acute administration of mirtazapine (30 mg) on the sleep polysomnogram, using a double-blind, placebo-controlled design. Subjects spent 3 consecutive nights in the laboratory. First night allowed for adaptation to the laboratory and application of electroencephalogram electrodes, while the second and third nights were reserved for recording baseline sleep and studying the effects of drug treatment, respectively. PARTICIPANTS: Young healthy volunteers (n=20), with a mean age of 24 years, were randomly separated into two groups: placebo (n=10) and mirtazapine (n=10). INTERVENTIONS: On the third night, subjects received either placebo or mirtazapine. Comparisons were made between sleep variables from baseline values in both groups. Independent samples t-test was utilized to evaluate the differences between the two groups. MEASUREMENT AND RESULTS: Mirtazapine improved the variables related to sleep continuity when compared with placebo. It increased the sleep efficiency index, while decreasing the number of awakenings and their duration. The slow wave sleep time was increased, while the stage 1 sleep time was decreased significantly. There was no significant effect on rapid eye movement sleep variables. CONCLUSION: Our findings suggest that mirtazapine has considerable effects on slow wave sleep. Further studies are recommended to investigate the efficiency of antidepressants, in respect to the effects of 5-HT2 blockade on slow wave sleep.     

Hypnotic activity of melatonin

OBJECTIVE: To establish the effect of melatonin upon nocturnal and evening sleep. METHODS: Experiment I: The effect of melatonin (0.1, 0.5, 1.0, 5.0, and 10 mg), ingested at 23:30, was studied on nocturnal sleep (23:30-07:30) and core body temperature in 8 healthy volunteers. Performance was measured 8.5 h post-ingestion. On completion of the experiment dim light melatonin onsets (DLMO) were determined. Experiment II: The effect of melatonin (0.5, 1.0, 5.0, and 10 mg), ingested at 18:00, was studied on evening sleep (18:00-24:00) and core body temperature in 6 healthy volunteers. Performance was measured 6.5 h post-ingestion. Each experiment was placebo-controlled and double-blind with a cross-over design with temazepam (20 mg) as an active control. RESULTS: Experiment I: Melatonin (5 mg) reduced the duration of stage 3 in the first 100 min of sleep. Melatonin (0.1 mg) reduced body temperature 6.5 to 7 h post-ingestion. Temazepam increased stage 2, reduced wakefulness and stage 1, and increased the latency to REM sleep. Temazepam reduced body temperature 4.5 to 6.5 h post-ingestion. There were no changes in performance compared with placebo. DLMO occurred between 20:40 and 23:15. Experiment II: Melatonin (all doses) increased total sleep time (TST), sleep efficiency index (SEI) and stage 2, and reduced wakefulness. Temazepam increased TST, SEI, stage 2 and slow-wave sleep, and reduced wakefulness. There were no changes in body temperature or performance compared with placebo. CONCLUSION: Melatonin given at 23:30 has no significant clinical effect on nocturnal sleep in healthy individuals. Hypnotic activity of melatonin when given in the early evening (presumably in the absence of endogenous melatonin) is similar to 20 mg temazepam.     

Melatonin and zopiclone: the relationship between sleep propensity and body temperature

STUDY OBJECTIVES: The sleep promoting effects of the sedative-hypnotics, melatonin and temazepam, have been associated with a decline in core body temperature (Tc). To determine whether changes in body temperature are a general feature of sedative-hypnotics, the present study compared the sleep inducing, core and peripheral temperature effects of melatonin, with those of zopiclone. DESIGN: Subjects were supine from 08:00-21:30 h and received melatonin, zopiclone or placebo at 14:00 h. SETTING: Individual, light and temperature controlled bedrooms. PARTICIPANTS: 12 healthy, young, adults (7m, 5f; 20.3 +/- 0.6 years). INTERVENTIONS: Melatonin (5mg), zopiclone (Imovane; 7.5 mg) and placebo were administered in a double-blind, crossover design. MEASUREMENTS AND RESULTS: From 11:00-20:00 h, modified hourly multiple sleep onset latency tests (MSLT) of a 20-min duration were conducted and heart rate (HR) was recorded. Tc and foot temperature (T(Ft)) were recorded continuously using thermistors. Compared with placebo, melatonin and zopiclone significantly reduced sleep onset latency (SOL) to stage 1 (by 3.50 +/- 0.73 min and 6.80 +/- 0.61 min, respectively) and reduced Tc (by 0.22 +/- 0.02C and 0.14 +/- 0.02C, respectively). For melatonin, Tc declined as the result of an increase in peripheral heat loss (increase in T(Ft) of 1.65 +/- 0.43 degrees C), and possibly a reduction in heat production as indicated by a decrease in HR (4.56 +/- 0.94 bpm). Zopiclone increased heat loss (increase in T(Ft) of 1.43 +/- 0.68C) and had no cardiac effects. For melatonin, a negative association was found between Tc (mean r=-0.43), however, this association was only weak for zopiclone (mean r=-0.23). CONCLUSIONS: These results suggest that body temperature changes may be a general feature of sedative-hypnotics. The potential role of this effect in the promotion of sleep appears to vary between agents.     

Effect of gradual withdrawal on the rebound sleep disorder after discontinuation of triazolam

Sixty volunteers with insomnia participated in a randomized, double-blind, controlled clinical trial. After an initial six nights of placebo, 30 subjects (the abrupt-withdrawal group) received 0.5 mg of triazolam nightly for 7 to 10 nights, after which they received placebo. The other 30 subjects (the tapered-dosage group) received the same initial placebo treatment, then triazolam at 0.5 mg for seven nights, at 0.25 mg for two nights, and at 0.125 mg for two nights, and then placebo. As compared with the initial placebo period, the triazolam period significantly reduced the interval before the onset of sleep (sleep latency), and it prolonged sleep duration, reduced the number of awakenings, and improved the self-rated soundness of sleep in all cohorts. In the abrupt-withdrawal group, plasma levels of triazolam were undetectable the morning after the first night of placebo substitution, and subjects reported prolongation of sleep latency (57 minutes longer than base line), reduction in sleep duration (1.4 hours less than base line), and increased awakenings (1.2 per night above base line). The symptoms of rebound sleep disorder lasted one or possibly two nights, and there was a reversion toward base line on subsequent placebo nights. In the tapered-dosage group, however, plasma triazolam levels fell gradually to zero, and rebound symptoms were decreased or eliminated. Thus, rebound sleep disorder following abrupt discontinuation of triazolam can be attenuated by a regimen of tapering.     

A randomized, double-blind, placebo-controlled crossover study of the effect of exogenous melatonin on delayed sleep phase syndrome

OBJECTIVE: The effects of exogenous melatonin on sleep, daytime sleepiness, fatigue, and alertness were investigated in 22 patients with delayed sleep phase syndrome whose nocturnal sleep was restricted to the interval from 24:00 to 08:00 hours. This study was a randomized, double-blind, placebo-controlled crossover trial. Subjects received either placebo or melatonin (5 mg) daily for 4 weeks, underwent a 1-week washout period, and then were given the other treatment for an additional 4 weeks. Patients could take the melatonin between 19:00 and 21:00 hours, which allowed them to select the time they felt to be most beneficial for the phase-setting effects of the medication. METHODS: Two consecutive overnight polysomnographic recordings were performed on three occasions: at baseline (before treatment), after 4 weeks of melatonin treatment, and after 4 weeks of placebo treatment. RESULTS: In the 20 patients who completed the study, sleep onset latency was significantly reduced while subjects were taking melatonin as compared with both placebo and baseline. There was no evidence that melatonin altered total sleep time (as compared with baseline total sleep time), but there was a significant decrease in total sleep time while patients were taking placebo. Melatonin did not result in altered scores on subjective measures of sleepiness, fatigue, and alertness, which were administered at different times of the day. After an imposed conventional sleep period (from 24:00 to 08:00), subjects taking melatonin reported being less sleepy and fatigued than they did while taking placebo. CONCLUSIONS: Melatonin ameliorated some symptoms of delayed sleep phase syndrome, as confirmed by both objective and subjective measures. No adverse effects of melatonin were noted during the 4-week treatment period.     

Prediction of melatonin efficacy by pretreatment dim light melatonin onset in children with idiopathic chronic sleep onset insomnia

Research has shown efficacy of melatonin treatment to advance sleep-wake rhythms in insomnia. In healthy adults, direction and magnitude of the phase shift depends on the timing of administration relative to the phase position of the circadian system. Therefore, in the present study we investigated whether in children with chronic sleep onset insomnia (SOI) efficacy of melatonin treatment in the early evening could be predicted from dim light melatonin onset (DLMO), a phase marker of the circadian system. We combined data of two previously published double blind, randomized, placebo-controlled trials in 110 participants, aged 6-12 years. Sleep was actigraphically estimated, and saliva collected, at baseline and in the third week of a 4-week treatment period with 5 mg melatonin or placebo at 18:00 or 19:00 hours. Primary outcome measures were pre- to post-treatment changes in dim light melatonin onset (DeltaDLMO), sleep onset (DeltaSO), sleep latency (DeltaSL), and total sleep duration (DeltaTSD). Melatonin advanced DLMO with +1:12 h (P < 0.001), SO with +0:42 h (P = 0.004), SL decreased with 25 min (P = 0.019), and TSD did not change significantly, as compared with placebo. In the melatonin-treated group, but not in the placebo-treated group, pretreatment DLMO was significantly related to DeltaDLMO [F(1, 29) = 7.28, P = 0.012] and DeltaSO [F(1, 25) = 7.72, P = 0.010]. The time interval between treatment administration and pretreatment DLMO (INT) was only significantly related to DeltaSO [F(1,26) = 5.40, P = 0.028]. The results suggest that in children with SOI, the efficacy of early evening melatonin to advance sleep onset and endogenous melatonin onset increases the later the pretreatment DLMO is.     

The use of exogenous melatonin in delayed sleep phase disorder: a meta-analysis

Study Objectives:

To perform a meta-analysis of the efficacy and safety of exogenous melatonin in advancing sleep-wake rhythm in patients with delayed sleep phase disorder.

Design:

Meta analysis of papers indexed for PubMed, Embase, and the abstracts of sleep and chronobiologic societies (1990–2009).

Patients:

Individuals with delayed sleep phase disorder.

Interventions:

Administration of melatonin.

Measurements and Results:

A meta-analysis of data of randomized controlled trials involving individuals with delayed sleep phase disorder that were published in English, compared melatonin with placebo, and reported 1 or more of the following: endogenous melatonin onset, clock hour of sleep onset, wake-up time, sleep-onset latency, and total sleep time. The 5 trials including 91 adults and 4 trials including 226 children showed that melatonin treatment advanced mean endogenous melatonin onset by 1.18 hours (95% confidence interval [CI]: 0.89–1.48 h) and clock hour of sleep onset by 0.67 hours (95% CI: 0.45–0.89 h). Melatonin decreased sleep-onset latency by 23.27 minutes (95% CI: 4.83 –41.72 min). The wake-up time and total sleep time did not change significantly.

Conclusions:

Melatonin is effective in advancing sleep-wake rhythm and endogenous melatonin rhythm in delayed sleep phase disorder.

Citation:

van Geijlswijk IM; Korzilius HPLM; Smits MG. The use of exogenous melatonin in delayed sleep phase disorder: a meta-analysis. SLEEP 2010;33(12):1605-1614.     

Evening administration of melatonin and bright light: Interactions on the EEG during sleep and wakefulness

Both the pineal hormone melatonin and light exposure are considered to play a major role in the circadian regulation of sleep. In a placebo- controlled balanced cross-over design, we investigated the acute effects of exogenous melatonin (5 mg p.o. at 20.40 hours) with or without a 3-h bright light exposure (5000 lux from 21.00 hours–24.00 hours) on subjective sleepiness, internal sleep structure and EEG power density during sleep and wakefulness in healthy young men. The acute effects of melatonin, bright light and their interaction were measured on the first day (treatment day), possible circadian phase shifts were assessed on the post-treatment day. On the treatment day, the evening rise in subjective sleepiness was accelerated after melatonin and protracted during bright light exposure. These effects were also reflected in specific changes of EEG power density in the theta/alpha range during wakefulness. Melatonin shortened and bright light increased sleep latency. REMS latency was reduced after melatonin administration but bright light had no effect. Slow-wave sleep and slow-wave activity during the first non-rapid eye movement (NREMS) episode were suppressed after melatonin administration and rebounded in the second NREMS episode, independent of whether light was co-administered or not. Self rated sleep quality was better after melatonin administration whereas the awakening process was rated as more difficult after bright light. On the post-treatment day after evening bright light, the rise in sleepiness and the onset of sleep were delayed, independent of whether melatonin was co-administered or not. Thus, although acute bright light and melatonin administration affected subjective sleepiness, internal sleep structure and EEG power density during sleep and wakefulness in a additive manner, the phase shifting effect of a single evening bright light exposure could not be blocked by exogenous melatonin     

Recovery sleep and performance following sleep deprivation with dextroamphetamine

Twelve subjects were studied to determine the after-effects of using three 10-mg doses of dextroamphetamine to sustain alertness during sleep deprivation. Sleep architecture during recovery sleep was evaluated by comparing post-deprivation sleep beginning 15 h after the last dextroamphetamine dose to post-deprivation sleep after placebo. Performance and mood recovery were assessed by comparing volunteers who received dextroamphetamine first (during sleep deprivation) to those who received placebo first. Stages 1 and 2 sleep, movement time, REM latency, and sleep latency increased on the night after sleep deprivation with dextroamphetamine vs. placebo. Stage 4 was unaffected. Comparisons to baseline revealed more stage 1 during baseline than during either post-deprivation sleep period and more stage 2 during baseline than during sleep following placebo. Stage 4 sleep was lower during baseline than it was after either dose, and REM sleep was lower during baseline and after dextroamphetamine than after placebo. Sleep onset was slowest on the baseline night. Next-day performance and mood were not different as a function of whether subjects received dextroamphetamine or placebo during deprivation. These data suggest dextroamphetamine alters post-deprivation sleep architecture when used to sustain alertness during acute sleep loss, but next-day performance and subjective mood ratings are not substantially affected. A recovery sleep period of only 8 h appears to be adequate to regain baseline performance levels after short-term sleep deprivation.     

A multicenter, placebo-controlled trial of melatonin for sleep disturbance in Alzheimer's disease

OBJECTIVES: To determine the safety and efficacy of 2 dose formulations of melatonin for the treatment of insomnia in patients with Alzheimer's disease. DESIGN: A multicenter, randomized, placebo-controlled clinical trial of 2 dose formulations of oral melatonin coordinated by the National Institute of Aging-funded Alzheimer's Disease Cooperative Study. Subjects with Alzheimer's disease and nighttime sleep disturbance were randomly assigned to 1 of 3 treatment groups: placebo, 2.5-mg slow-release melatonin, or 10-mg melatonin. SETTING: Private homes and long-term care facilities. PARTICIPANTS: 157 individuals were recruited by 36 Alzheimer's disease research centers. Subjects with a diagnosis of Alzheimer's disease were eligible if they averaged less than 7 hours of sleep per night (as documented by wrist actigraphy) and had 2 or more episodes per week of nighttime awakenings reported by the caregiver. MEASUREMENTS: Nocturnal total sleep time, sleep efficiency, wake-time after sleep onset, and day-night sleep ratio during 2- to 3-week baseline and 2-month treatment periods. Sleep was defined by an automated algorithmic analysis of wrist actigraph data. RESULTS: No statistically significant differences in objective sleep measures were seen between baseline and treatment periods for the any of the 3 groups. Nonsignificant trends for increased nocturnal total sleep time and decreased wake after sleep onset were observed in the melatonin groups relative to placebo. Trends for a greater percentage of subjects having more than a 30-minute increase in nocturnal total sleep time in the 10-mg melatonin group and for a decline in the day-night sleep ratio in the 2.5-mg sustained-release melatonin group, compared to placebo, were also seen. On subjective measures, caregiver ratings of sleep quality showed improvement in the 2.5-mg sustained-release melatonin group relative to placebo. There were no significant differences in the number or seriousness of adverse events between the placebo and melatonin groups. CONCLUSIONS: Based on actigraphy as an objective measure of sleep time, melatonin is not an effective soporific agent in people with Alzheimer's disease.     

Controlled‐release melatonin,singly and combined with cognitive behavioural therapy,for persistent insomnia in children with autism spectrum disorders: a randomized placebo‐controlled trial

Although melatonin and cognitive–behavioural therapy have shown efficacy in treating sleep disorders in children with autism spectrum disorders, little is known about their relative or combined efficacy. One hundred and sixty children with autism spectrum disorders, aged 4–10 years, suffering from sleep onset insomnia and impaired sleep maintenance, were assigned randomly to either (1) combination of controlled‐release melatonin and cognitive–behavioural therapy; (2) controlled‐release melatonin; (3) four sessions of cognitive–behavioural therapy; or (4) placebo drug treatment condition for 12 weeks in a 1 : 1 : 1 : 1 ratio. Children were studied at baseline and after 12 weeks of treatment. Treatment response was assessed with 1‐week actigraphic monitoring, sleep diary and sleep questionnaire. Main outcome measures, derived actigraphically, were sleep latency, total sleep time, wake after sleep onset and number of awakenings. The active treatment groups all resulted in improvements across all outcome measures, with moderate‐to‐large effect sizes from baseline to a 12‐week assessment. Melatonin treatment was mainly effective in reducing insomnia symptoms, while cognitive–behavioural therapy had a light positive impact mainly on sleep latency, suggesting that some behavioural aspects might play a role in determining initial insomnia. The combination treatment group showed a trend to outperform other active treatment groups, with fewer dropouts and a greater proportion of treatment responders achieving clinically significant changes (63.38% normative sleep efficiency criterion of >85% and 84.62%, sleep onset latency <30 min). This study demonstrates that adding behavioural intervention to melatonin treatment seems to result in a better treatment response, at least in the short term.     

The effects of gamma-hydroxybutyrate on the sleep of narcolepsy patients: a double-blind study

The effects of gamma-hydroxybutyrate (GHB: 25 mg/kg h.s. and 3 h later) vs. placebo on objectively evaluated nighttime sleep and daytime sleepiness in narcolepsy were evaluated in a double-blind, counterbalanced crossover design. Twenty narcolepsy patients were given an overnight polysomnogram (PSG), followed by a daytime multiple sleep latency test (MSLT) at baseline and on the 1st and 29th days of GHB and placebo treatment. The overnight PSGs indicated that the narcolepsy patients had the following significant results during GHB versus placebo treatment: decreased stage 1 (p = 0.012), increased stage 3 (p = 0.008), increased delta (stage 3 and 4 combined) sleep (p = 0.049), fewer stage shifts (p = 0.002), and fewer awakenings (p = 0.006). Minutes of wakefulness were significantly increased only for the last 2 h of the 8 h sleep period on GHB versus placebo (p = 0.019), which is beyond the time of GHB's direct influence. The MSLTs indicated that the narcolepsy patients had a marginally increased sleep latency mean during GHB versus placebo treatment (p = 0.074) and significantly increased total stage 0 (wakefulness) on day 29 of GHB versus day 29 of placebo treatment (p = 0.038). Female narcolepsy patients had significantly fewer naps with REM sleep (REM naps) on day 29 of GHB vs. day 29 of placebo treatment (p = 0.020). The therapeutic effect of GHB in narcolepsy patients, i.e., decreases cataplexy, appears to be due to its improving nocturnal sleep quality, since its half-life is only 1.5 to 2 h. It is conjectured that GHB, an endogenous neurochemical, may be a sleep neurotransmitter or neuromodulator, since GHB rapidly induces sleep, and increases sleep continuity and delta sleep without suppressing REM sleep in both normals and narcolepsy patients.     

Effects of sleep loss on waking actigraphy

STUDY OBJECTIVES: To assess the effect of sleep loss and the effect of a sedating drug on waking actigraphy DESIGN: N/A SETTING: N/A PARTICIPANTS: Seventeen healthy volunteers, aged 19-35 yrs Interventions: Four night-day treatments presented in a Latin Square Design: placebo-8 hr time-in-bed (TIB), placebo-4 hr TIB, placebo-0 hr TIB, and diphenhydramine 50 mg-8 hr TIB. MEASUREMENTS AND RESULTS: After the appropriate TIB, medication was administered at 09:00 hr, the Multiple Sleep Latency Test at 09:30, 11:30, 13:30, 15:30, and 17:30 hr, and a 45 min performance battery at 10:30, 14:30, and 16:30 hr. Each day the volunteers wore actigraphs from 0700-1800 hrs. Decreasing TIB was associated with decreased daily mean sleep latency on the MSLT with 4 and 0 hrs differing from 8 hrs and each other. Daytime activity also was reduced by the reduced prior TIB. Increased inactivity relative to the 8 hr TIB developed between the 4 hr and 0 hr TIBs, with 4 hrs differing from 0 hrs, but not 8 hrs. Diphenhydramine 50 mg reduced mean daily sleep latency and increased percent inactive time relative to placebo. On the MSLT diphenhydramine was intermediate to 4 hr and 0 hr TIB and on actigraphy it was similar to 0 hr TIB. CONCLUSIONS: The difference in the effect of diphenhydramine on these actigraphy and MSLT may reflect the different sensitivities of the measures.     

What is the moment of sleep onset for insomniacs?

Subjective estimates of sleep latency were compared with three EEG-assessed measures of sleep onset: (a) the traditional one, i.e., the first epoch that is scored as stage 2 sleep; (b) the beginning of the first 15 min of uninterrupted stage 2 sleep; and (c) the beginning of the first 30 min of uninterrupted stage 2 sleep. A total of 56 insomniacs and 10 good sleepers were studied for 3 nights each in the laboratory. The traditional measure of sleep latency agreed best with the subjective estimates of good sleepers. Most insomniacs, however, were best able to estimate their sleep latency when the 15-min criterion was used. We suggest that for most insomniacs the subjective experience of being asleep occurs later in the EEG-defined transition from waking to sleeping than it does for good sleepers.     

Melatonin advances the circadian timing of EEG sleep and directly facilitates sleep without altering its duration in extended sleep opportunities in humans

The rhythm of plasma melatonin originating from the pineal gland and driven by the circadian pacemaker located in the suprachiasmatic nucleus is closely associated with the circadian (approximately 24 h) variation in sleep propensity and sleep spindle activity in humans. We investigated the contribution of melatonin to variation in sleep propensity, structure, duration and EEG activity in a protocol in which sleep was scheduled to begin during the biological day, i.e. when endogenous melatonin concentrations are low. The two 14 day trials were conducted in an environmental scheduling facility. Each trial included two circadian phase assessments, baseline sleep and nine 16 h sleep opportunities (16.00–08.00 h) in near darkness. Eight healthy male volunteers (24.4 ± 4.4 years) without sleep complaints were recruited, and melatonin (1.5 mg) or placebo was administered at the start of the first eight 16 h sleep opportunities. During melatonin treatment, sleep in the first 8 h of the 16 h sleep opportunities was increased by 2 h. Sleep per 16 h was not significantly different and approached asymptotic values of 8.7 h in both conditions. The percentage of rapid eye movement (REM) sleep was not affected by melatonin, but the percentage of stage 2 sleep and sleep spindle activity increased, and the percentage of stage 3 sleep decreased. During the washout night, the melatonin-induced advance in sleep timing persisted, but was smaller than on the preceding treatment night and was consistent with the advance in the endogenous melatonin rhythm. These data demonstrate robust, direct sleep-facilitating and circadian effects of melatonin without concomitant changes in sleep duration, and support the use of melatonin in the treatment of sleep disorders in which the circadian melatonin rhythm is delayed relative to desired sleep time.     

Interindividual variation in sleep duration and its association with sleep debt in young adults

STUDY OBJECTIVE: To determine whether variation in sleep duration reflects variation in sleep need or self-imposed sleep restriction. DESIGN: After habitual bedrest duration of participants was assessed during a 2-week outpatient protocol, volunteers were scheduled to sleep according to this schedule for 1 week prior to and the first night after admission to a general clinical research center. The inpatient protocol included multiple sleep latency testing on the second day and sleep recordings during a bedrest extension protocol that included 16 hours of sleep opportunity (12 hours at night and 4 hours at midday) for 3 consecutive days. SETTING: Outpatient monitoring followed by inpatient assessment of sleep. PARTICIPANTS: Seventeen healthy volunteers (10 women) aged 18-32 years without clinical sleep disorders. INTERVENTIONS: Extension of sleep opportunity. MEASUREMENTS AND RESULTS: The habitual bedrest duration varied from 6.1 to 10.3 hours. Individuals with shorter habitual bedrest duration fell asleep more quickly and frequently during the multiple sleep latency test than did those with longer habitual bedrest duration. On the first day of extended sleep opportunity, the total sleep time of all individuals was greater than their habitual bedrest duration; the average increase in total sleep time was 4.9 hours (P = 0.001). The increase in total sleep time declined across the 3 day bedrest-extension protocol (P = 0.003 for trend). During the third day of increased sleep opportunity, the total sleep time was negatively associated with habitual bedrest duration (P = 0.005); individuals with shorter habitual bedrest duration continued to sleep more than those with longer habitual bedrest duration. CONCLUSION: Those individuals with shorter habitual sleep durations carry a higher sleep debt than do those with longer habitual sleep duration. Interindividual variation in sleep duration may primarily reflect variation in self-selected sleep restriction or wake extension.     

A double-blind study in healthy volunteers to assess the effects on sleep of pregabalin compared with alprazolam and placebo

STUDY OBJECTIVES: To assess the effects of pregabalin compared with alprazolam and placebo on aspects of sleep in healthy volunteers. DESIGN: Randomized, double-blind, placebo- and active-controlled, 3-way crossover. SETTING: Single research center. PARTICIPANTS AND INTERVENTIONS: Healthy adult (12 men) volunteers (N=24) received oral pregabalin 150 mg t.i.d., alprazolam 1 mg t.i.d., and placebo t.i.d. for 3 days. MEASUREMENTS AND RESULTS: Objective sleep was measured by an 8-channel polysomnograph; subjective sleep was measured using the Leeds Sleep Evaluation Questionnaire. Compared with placebo, pregabalin significantly increased slow-wave sleep both as a proportion of the total sleep period and the duration of stage 4 sleep. Alprazolam significantly reduced slow-wave sleep. Pregabalin and alprazolam produced modest, but significant, reductions in sleep-onset latency compared with placebo. Rapid eye movement sleep latency after pregabalin was no different than placebo but was significantly shorter than that found with alprazolam. Although there were no differences between the active treatments, both pregabalin and alprazolam reduced rapid eye movement sleep as a proportion of the total sleep period compared with placebo. Pregabalin also significantly reduced the number of awakenings of more than 1 minute in duration. Leeds Sleep Evaluation Questionnaire ratings of the ease of getting to sleep and the perceived quality of sleep were significantly improved following both active treatments, and ratings of behavior following awakening were significantly impaired by both drug treatments. CONCLUSIONS: Pregabalin appears to have an effect on sleep and sleep architecture that distinguishes it from benzodiazepines. Enhancement of slow-wave sleep is intriguing, since reductions in slow-wave sleep have frequently been reported in fibromyalgia and general anxiety disorder.