Polysomnography during withdrawal with clomethiazole or placebo in alcohol dependent patients--a double-blind and randomized study

INTRODUCTION: The present study was designed to assess if the routine application of clomethiazole to ameliorate withdrawal symptoms in chronic alcohol dependent patients perpetuates sleep disturbances. METHODS: Twenty inpatients with alcohol dependence according to DSM-IV criteria received clomethiazole or placebo in a double-blind, randomized design upon admission. 11 patients were randomized to the clomethiazole group and 9 patients to the placebo group. During the first 5 days of treatment the patients received either clomethiazole (1st day: 3 x 384 mg, 2nd day: 4 x 384 mg, 3rd day: 3 x 384 mg, 4th day: 2 x 384 mg and 5th day: 1 x 384 mg) or placebo capsules at constant intervals. The patients spent two consecutive nights in the sleep laboratory at each of three assessment times: the first time at the beginning of abstinence (night 1 and 2, T0), the second time 6 days later (i. e. after 5 days of treatment and one day of discontinuation of clomethiazole or placebo: nights 6 and 7, T1) and the third time after 13 days (nights 13 and 14, T2). The first night at each of the three assessment times was an adaptation night. RESULTS: During the first two weeks of abstinence, the analysis of variance demonstrated a significant variation of Rapid Eye Movement (REM) sleep variables in the clomethiazole group. The placebo group showed no such variation. Clomethiazole evidently had a pronounced REM sleep suppressing effect, whereas the discontinuation of clomethiazole led to a REM sleep rebound. Furthermore, analysis of sleep continuity and sleep architecture variables showed that the clomethiazole group had significantly disturbed sleep at T1 in comparison to the placebo group. Simultaneous statistical testing with alcohol intake as covariate reduced the test power so that contrasts between the groups became nonsignificant. CONCLUSIONS: The REM sleep results are in line with earlier findings that REM sleep disinhibition in primary alcohol dependency is partly due to a REM sleep rebound after withdrawal from medication. Differences in the polysomnographic variables of sleep continuitiy and sleep architecture at T0 and T1 found between the clomethiazole and the placebo patients correspond to rebound insomnia following discontinuation of clomethiazole. Our findings indicate that drugs enforcing GABAergic neurotransmission may perpetuate the neuroadaptative effects caused by chronic alcohol consumption.     

The Sleep Pattern of Chronic Alcoholics During the Alcohol Withdrawal Period

Abstract: The sleep pattern of 13 alcoholics was recorded for five consecutive nights after the cessation of alcohol intake. In six of the 13 patients, delirium tremens occurred after hospitalization. A decrease of total sleep time and slow wave sleep was more pronounced in the patients with delirium tremens than in those without. REM sleep had slightly decreased in both groups. Rebound increase in REM sleep had not been observed in all the patients with delirium tremens. Stage 1-REM with tonic EMG was observed in these two groups.
From these results we are inclined to hypothesize that a deficiency of cerebral 5-HT in alcoholics may lead to a pronounced decrease in slow wave sleep, with rapid eye movements appearing in stage 1 sleep.     

Dose response effects of zolpidem in normal geriatric subjects

The dose-related hypnotic effects and effects on memory, performance, and daytime alertness of zolpidem 5, 10, 15, and 20 mg were compared with those of placebo in 30 elderly non-insomniac volunteers in a randomized, placebo-controlled, three-period crossover study. Subjects were randomized into two groups and received either placebo, zolpidem 5 mg, or zolpidem 15 mg or placebo, zolpidem 10 mg, or zolpidem 20 mg for 2 consecutive nights followed by 1 night of placebo during the same 3 nights of 3 consecutive weeks. Polysomnographic results showed statistically significant decreases in sleep latency and increases in sleep efficiency at all doses. Subjective reports also showed improved sleep latency, total sleep time, and sleep quality. REM percent was slightly decreased at doses of 10 and 20 mg. No consistent effects on memory or performance were observed, and the Multiple Sleep Latency Test showed no effects on daytime sleepines. There was no objective evidence of rebound insomnia upon drug discontinuation.     

A psychophysiological investigation of the short-term effects of clozapine upon sleep parameters of normal young adults.

A nine consecutive night, double-blind design was used to assess the effects of a psychotropic agent (clozapine) upon sleep parameters as well as measures of mood and performance in a group of seven normal, young adults. Placebo was administered to a control group of seven subjects. EEGs and EOGs were monitored throughout the night in a laboratory environment and were scored according to standardized criteria. The administration of 25 mg clozapine/night for three consecutive nights significantly reduced stage 4 sleep on the second and third nights. Whereas stage REM sleep was not affected, a variety of REM indices were significantly increased on the third night of clozapine administration and/or on the first night of clozapine withdrawal. The number of body movements and the number of body movements/minute of sleep were significantly reduced on the three nights of clozapine administration. Numerous psychophysiological side effects were reported. These results indicate that clozapine may be a useful medication in the treatment of sleep disorders. However, the incidence of adverse side effects of represents a major limitation in the use of clozapine as an hypnotic agent at the dose-rate employed.     

Rapid eye movement sleep,non-rapid eye movement sleep,dreams, and hallucinations

After the discovery of rapid eye movement (REM) sleep in 1953, oneiric activity was long thought to be associated uniquely with REM sleep. Subsequent evaluation of sleep in humans combining neurophysiologic, psychophysiologic, and, more recently, functional neuroimaging investigations, has instead shown that dreaming also occurs during non-REM (NREM) sleep. It has been documented that hallucinatory activity during sleep is a normal phenomenon that is not constant throughout the night but increases toward morning when it tends to become present to the same extent in REM and NREM sleep. The role of sleep mechanisms in the generation of visual hallucinations is well-recognized in narcolepsy in the case of hypnagogic hallucinations, which are thought to derive from a REM-dissociation state in which dream imagery intrudes into wakefulness. Similar mechanisms have been hypothesized to play a role in the physiopathogenesis of visual hallucinations in various neuropsychiatric disorders. Furthermore, a growing body of evidence indicates that not only REM but also NREM processes, such as arousal-related processes, may play a role in the physiopathogenesis of hallucinations in the aforementioned disorders. The role of these processes has been most extensively documented in visual hallucinations occurring in the context of delirium tremens and Parkinson’s disease.     

Sleep analysis during drug-free weekends in chronic schizophrenic patients.

The authors made a polygraphic registration of the night sleep in a sample of 14 chronic schizophrenic patients who for several months (mean 8 months) have been on a stable, relatively low maintenance dosage of neuroleptics administered according to the drug-free weekend schedule (two consecutive drug-free days at the weekend). During this treatment none of them showed a relapse or deterioration (BPRS, CGI, and NOSIE rating scales were applied periodically). Their only complaint was of sleep deterioration during the drugfree weekend nights, especially during the second night. The polygraphic night-sleep pattern of each patient was studied during two consecutive weeks. No difference was found between the adaptation night on medication and the consecutive night on medication during the first week, and between the adaptation and readaptation nights on medication during two consecutive weeks. There was no difference in any sleep parameters between the nights on medication and the first drug-free nights. There was a signifcant difference in the total sleep time between the nights on medications and the second drug-free nights. No difference was found in any other sleep parameters in nights analysed as a blocks and in the distribution of NREM and REM stages in the first vs. the second half of the night when B3 was compared with A2. The practical implication is, that to avoid any change in nocturnal behavior it is preferable to withdraw the medication on two nonconsecutive days in the week. The evaluation of both daily and nocturnal behavior seems to be a useful tool in evaluating the first sign of the drug-withdrawal syndrome.     

A five week, polysomnographic assessment of zaleplon 10 mg for the treatment of primary insomnia

Objective: To examine the hypnotic efficacy of zaleplon 10 mg, a selective benzodiazepine receptor agonist, over a period of 35 nights in primary insomniacs.Methods: A double-blind, parallel-group, placebo-controlled design was employed. Subjects were 113 men and women, ages 18 to 65 years. Polysomnographic and subjective sleep data were collected during baseline, on two nights during each of five treatment weeks, and on the first two nights after discontinuation of active medication.Results: Sleep latency was significantly shortened with zaleplon 10 mg for all 5 weeks of treatment as assessed by polysomnography and by subjective sleep measures. Total sleep time, whether evaluated with polysomnography or with subjective estimates, was inconsistently affected. Sleep architecture was similar with zaleplon and placebo. There was no evidence of tolerance to the sleep promoting effects of zaleplon during the five weeks of administration, and there was no rebound insomnia upon discontinuation. Adverse events occurred with equal frequency in the zaleplon and placebo groups.Conclusions: Zaleplon 10 mg is effective in the treatment of sleep onset insomnia over a period of 35 nights, with minimal evidence of undesired effects.     

REM phase deprivation and schizophrenia II.

Nine schizophrenic patients with active symptomatology were compared with seven patient controls in their response to two nights of rapid eye movement (REM) sleep deprivation. The control subjects demonstrate "normal" increases in total REM and percentage REM time increase on recovery nights compared to base line nights. The schizophrenic subjects differ substantially from the control subjects in both these measurements and show no perceptible change from base line nights on recovery nights. The effects of medication, anxiety, sleep loss, ceiling effects, and intensity change were not considered adequate to account for the above results. However, many questions, such as the specificity of this rebound failure to the schizophrenic patients and the possibility of a sleep disturbance factor operating independently of psychiatric diagnosis, remain to be answered.     

The effects of gamma-hydroxybutyrate on sleep.

Sodium gamma-hydroxybutyrate (GHB) is a remarkably safe and nontoxic hypnotic agent which is reported to be free of addicting properties. It is also a normal metabolite of the mammalian nervous system. We examined its effects on the sleep-EEG of eight patients with histories of impaired sleep, as a prelude to a more detailed study of its clinical potential. Sleep induced with GHB was indistinguishable subjectively from natural sleep as well as by behavioral and electroencephalographic criteria. Unlike most synthetic hypnotics, GHB increased delta sleep and did not suppress REM sleep. It shortened the REM sleep latency and shifted REM sleep into the first third of the night. On one occasion it induced a sleep onset REM period which was experienced as an attack of sleep paralysis. Withdrawal was simple; there was no REM sleep rebound and sleep patterns immediately returned to their pre-drug form. Its major clinical drawback was its short duration of action: its hypnotic effect lasting only 2 to 3 hr. We suggest that GHB may serve as the prototype for a new class of hypnotic compounds derived from natural sources and capable of activating the neurological mechanisms of normal human sleep.     

Effects of L-DOPA on Natural Night Sleep and on Rebound of REM Sleep

To investigate the relationship between REM sleep and the central catecholamine in man, L-DOPA 1,000 mg was orally ad ministered to five normal young adults and its effects were investigated on their REM sleep. No effect of L-DOPA 1,000 mg was found on the natural night sleep. Then, the effects of the same dose of L-DOPA were investigated on the rebound elevation of REM sleep in the recovery night after partial differential REM sleep deprivation, and its rebound was not only in the 1st recovery night but also in the 2nd. From these results, it is supposed that the central noradrenaline is more easily and rapidly synthesized from exogenous L-DOPA in the recovery night sleep than in the natural night sleep, and that the rebound elevation of REM sleep disappears as a consequence of rapid restoration of the central noradrenaline. Therefore, one of the functions of REM sleep in man may be sup posed to be participation in the maintenance of the central noradrenaline, and the re bound elevation of REM sleep may be a phenomenon which is caused by a brain mechanism to maintain the central noradre naline.     

Immediate effects of intravenous clomipramine on sleep and sleep-related secretion in depressed patients

An i.v. challenge dose of clomipramine (12.5 mg) was given to eight outpatients with major depression. The procedure facilitated the examination of all-night sleep and sleep-related neuroendocrine changes (cortisol, growth hormone, and prolactin). In comparison to baseline saline nights, the patients experienced a profound suppression of rapid eye movement (REM) sleep throughout the night with no rebound recovery in the second half of the night. Furthermore, REM-suppressing effects were noted on the following no-drug night. In contrast, little effect on delta wave sleep was found, except for increased consolidation of delta waves within stage 3 and 4 sleep. Delta sleep measures were significantly correlated with levels of cortisol and growth hormone.     

The effects of scopolamine on sleep and mood in depressed patients with a history of alcoholism and a normal comparison group.

In order to determine the effect of an anticholinergic agent on mood and sleep, scopolamine (0.4 mg IM) was administered before bedtime for three consecutive nights to 10 depressed patients (8 with a history of alcohol abuse) and 10 normal comparison subjects. The patients had a small, statistically significant antidepressant response on the second morning of treatment. Scopolamine inhibited rapid eye movement (REM) sleep and prolonged REM latency equally in depressed patients and the normal comparison group. Partial tolerance to the REM inhibiting effect of scopolamine developed between the first and third night of treatment. A REM rebound occurred during recovery nights. These results are consistent with concepts relating central cholinergic mechanisms to the control of REM sleep. Compared with controls, patients showed a greater increase in Stage 2 and Stage 2% and a lesser and increase in Delta (Stage 3 and 4) sleep % and Stage 4% on the first night of treatment. Further, well-controlled studies are needed to determine whether anticholinergic drugs possess clinically significant antidepressant effects.     

Study on the Partial Differential REM Deprivation (PDRD)

With an aim to make observations on the rebound elevation of REM sleep, we have devised the partial differential REM deprivation (PDRD) method whereby the subjects are awakened forcibly at a fixed time early in the morning. By this method, REM sleep is deprivated by about a half and stage 2 sleep by about one third of the baseline value; but stage SWS is not deprivated. When the test set of PDRD is performed repeatedly on an identical subject, the REM sleep time during PDRD night and recovery night is almost always constant. Our PDRD, we believe, is an excellent method that relieves the discomfort of the subject and the physical burden of research workers and yet is capable of measuring almost accurately the magnitude of rebound elevation of REM sleep in each subject.     

Study on the partial differential REM deprivation (PDRD).

With an aim to make observations on the rebound elevation of REM sleep, we have devised the partial differential REM deprivation (PDRD) method whereby the subjects are awakened forciby at a fixed time early in the morning. By this method, REM sleep is deprivated by about a half and stage 2 sleep by about one third of the baseline value; but stage SWS is not deprivated. When the test set of PDRD is performed repeatedly on an identical subject, the REM sleep time during PDRD night and recovery night is almost always constant. Our PDRD, we believe, is an excellent method that relieves the disconfort of the subject and the physical burden of research workers and yet is capable of measuring almost accurately the magnitude of rebound elevation of REM sleep in each subject.     

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.     

Individual variations in response of human REM sleep to amitriptyline and haloperidol.

The effect of amitriptyline and haloperidol on REM sleep was investigated in healthy human adults, with special attention to individual variations in these drugs' effects. In addition, an investigation was made of the rebound elevation of REM sleep occurring on the following night of partial differential REM deprivation (PDRD), again with emphasis being placed on individual variations in that effect. The administration of amitriptyline in a single oral dose of 25 mg was followed by an inhibition of REM sleep in all subjects. The per cent decrease in REM sleep was found to have a significant negative correlation with the per cent increase in REM sleep following PDRD in individual subjects. The amount of REM sleep during the recovery night following the night of amitriptyline medication tended to correlate with the per cent increase in REM sleep following PDRD in individual subjects. Haloperidol in a single oral dose of 1.5 mg caused REM sleep to augment in some subjects but inhibit in others. A significant correlation was noted to exist between drug-induced change in REM sleep and the per cent increase in REM sleep following PDRD.     

Comparison of the effects of zolpidem and triazolam on nocturnal sleep and sleep latency in the morning: a cross-over study in healthy young volunteers

1. Zolpidem (ZPD, 10 mg) was directly compared with triazolam (TRZ, 0.25 mg), a benzodiazepine hypnotic of a short action comparable to ZPD. The compounds were given to healthy young subjects for three nights, in a crossover design. 2. Polysomnographic data of three 150-min sections of the nights as well as the whole nights were analyzed, to clearly detect the proper effects of the very short acting hypnotics, which might be missed in the analysis of whole night. 3. Time courses were significantly different between the two compounds in the ratios (%) of stage wake (SW), stage 2 (S2), slow wave sleep (SWS) and stage REM (SR). 4. Compared to the baseline, SWS was increased by ZPD on the first night, not by TRZ. The separate analysis of the three 150-min sections revealed an increase of SWS during the first 150-min of the ZPD night, suggesting a proper action of ZPD to augment SWS. An increase of S2 and a decrease of SR were caused by TRZ, not by ZPD. However, the separate analysis indicated that ZPD might reduce SR during the first 150-min, which was cancelled by a subsequent rebound increase in the whole night analysis. 5. During the withdrawal period, TRZ, not ZPD, increased SW and SR with worsening of mood in the morning. ZPD did not affect sleep latency in the morning, while TRZ caused a trend of the reduction.     

Zaleplon, A Novel Nonbenzodiazepine Hypnotic, Effectively Treats Insomnia in Elderly Patients Without Causing Rebound Effects

BACKGROUND: Insomnia is a very common symptom, particularly in the elderly. Thus, all hypnotic medications should be carefully evaluated in the elderly population. Zaleplon, a new nonbenzodiazepine hypnotic with a short elimination half-life (approximately 1 hour), was evaluated in the current study. METHOD: This multicenter, randomized, placebo-controlled outpatient study evaluated the efficacy and safety of zaleplon, 5 and 10 mg, in elderly patients with insomnia (as defined by DSM-IV); zolpidem, 5 mg, was the active comparator. Sleep was assessed in 549 elderly patients (>/= 65 years old) by using morning questionnaires completed after each of 7 baseline nights during which placebo was given, 14 nights of double-blind treatment, and 7 nights of placebo after discontinuation of active treatment. RESULTS: Zaleplon, 10 mg, and zolpidem, 5 mg, significantly reduced sleep latency during both weeks of the study. Zaleplon, 5 mg, reduced sleep latency only during week 2. Sleep duration was increased with zolpidem, 5 mg, during weeks 1 and 2 and with zaleplon, 10 mg, during week 1. No clinically significant rebound insomnia was observed after discontinuation of treatment with zaleplon, whereas evidence of rebound effects was seen with zolpidem. There was no significant difference between either zaleplon dose and placebo in the frequency of any central nervous system adverse events. CONCLUSION: Zaleplon is effective in reducing latency to sleep without evidence of undesired effects in elderly patients with insomnia.     

A sleep laboratory evaluation of the long-term efficacy of zopiclone

Six patients between the ages of 25 and 59, with chronic, primary insomnia received the new, non-benzodiazepine, hypnotic zopiclone continuously for 17 weeks after a drug free interval of 12 nights. To qualify for the study, sleep efficiency, determined by a sleep study on two, consecutive, placebo-controlled nights, had to be less than 75%. Patients evaluated their sleep by questionnaire and had sleep studies completed throughout active treatment. Zopiclone (7.5 mg) increased sleep efficiency by decreasing sleep latency, wakefulness after sleep onset and increasing total sleep time. Sleep architecture was minimally affected by zopiclone treatment; no significant changes in delta or REM sleep were observed. The commonest side effect was a bitter or metallic taste. No significant changes in biological functioning were noted throughout the study period. These findings indicate that zopiclone is a safe and effective hypnotic medication which maintains its effectiveness with protracted use.     

Individual differences in compensatory rebound of REM sleep, with particular reference to their relationship to personality and behavioral characteristics.

In subjecting 14 healthy university students to partial differential rapid eye movement (REM) sleep deprivation (PDRD), the compensatory rebound of REM sleep during the next night was determined, and showed fairly substantial individual differences in the increased percentage of REM sleep time. This rate was approximately the same for the same individual for two sleep recordings. These individual differences had no positive correlation with the decreased rate of REM time in the PDRD nights or with the percentage of REM time in the baseline night. Therefore, the individual differences in the increased percentage of REM time can be presumed to reflect individual differences in need for deprived REM sleep. Next, we looked into the relationship between the individual subject's personality and behavior characteristics, and his increased percentage of REM time. This revealed that the individuals who were extrovertive, active, optimistic, showy, and who had many friends had significantly higher increases in the percentage of REM time than the individuals who were introvertive, neurotic, inactive, nervous, modest, and who had few friends. Also discussed was the neurophysiological and biochemical basis of the central nervous system as the background for the relationship between the personality and behavioral characteristics and the increased percentage of REM sleep time.