Somno-Art Software identifies pathology-induced changes in sleep parameters similarly to polysomnography.

Polysomnographic sleep architecture parameters are commonly used to diagnose or evaluate treatment of sleep disorders. Polysomnography (PSG) having practical constraints, the development of wearable devices and algorithms to monitor and stage sleep is rising. Beside pure validation studies, it is necessary for a clinician to ensure that the conclusions drawn with a new generation wearable sleep scoring device are consistent to the ones of gold standard PSG, leading to similar interpretation and diagnosis. This paper reports on the performance of Somno-Art Software for the detection of differences in sleep parameters between patients suffering from obstructive sleep apnea (OSA), insomniac or major depressive disorder (MDD) compared to healthy subjects. On 244 subjects (n = 26 healthy, n = 28 OSA, n = 66 insomniacs, n = 124 MDD), sleep staging was obtained from PSG and Somno-Art analysis on synchronized electrocardiogram and actimetry signals. Mixed model analysis of variance was performed for each sleep parameter. Possible differences in sleep parameters were further assessed with Mann-Whitney U-test between the healthy subjects and each pathology group. All sleep parameters, except N1+N2, showed significant differences between the healthy and the pathology group. No significant differences were observed between Somno-Art Software and PSG, except a 3.6±2.2 min overestimation of REM sleep. No significant interaction 'group'*'technology' was observed, suggesting that the differences in pathologies are independent of the technology used. Overall, comparable differences between healthy subjects and pathology groups were observed when using Somno-Art Software or polysomnography. Somno-Art proposes an interesting valid tool as an aid for diagnosis and treatment follow-up in ambulatory settings.

Performance of Somno-Art Software compared to polysomnography interscorer variability: A multi-center study.

The visual scoring of gold standard polysomnography (PSG) is known to present inter- and intra-scorer variability. Previously, Somno-Art Software, a cardiac based sleep scoring algorithm, has been validated in comparison to 2 expert visual PSG scorers. The goal of this research is to evaluate the performances of the algorithm against a pool of scorers. Sixty PSG and actimetry recording nights, representative of clinical practice (healthy subjects and patients suffering from obstructive sleep apnea [OSA], insomnia or major depressive disorder), were scored by 5 different sleep scoring centers and by the Somno-Art Software. Intra-class correlation coefficient (ICC) and Wilcoxon Signed-Rank Test were calculated between each scorer and the average value of the 6 scorers, including Somno-Art Software. In addition, epoch-by-epoch agreement between scorers were analyzed. Somno-Art Software estimation of sleep efficiency, wake, N1+N2, N3 and REM sleep fit within the interscorer range for the full dataset and the subgroups, except for underestimating N3 sleep in OSA patients. Additionally, Somno-Art Software overestimated sleep latency compared to the average scoring for insomniacs (+4.7 ± 1.6min). On the full dataset, Somno-Art Software had good (0.75 < ICC<0.90) or excellent (ICC>0.90) ICC scores for all sleep parameters except N3 sleep (moderate score, 0.50 < ICC<0.75). For the 4-stages epoch-by-epoch agreement, Somno-Art Software was slightly below that of the visual scorers except for the healthy sub-group where an overlap was demonstrated. Somno-Art Software sleep scoring shows a good interscorer reliability in the range of the 5 visual polysomnography scorers.

Validation of Somno-Art Software, a novel approach of sleep staging, compared with polysomnography in disturbed sleep profiles.

Study Objectives: Integrated analysis of heart rate (electrocardiogram [ECG]) and body movements (actimetry) during sleep in healthy subjects have previously been shown to generate similar evaluation of sleep architecture and continuity with Somno-Art Software compared to polysomnography (PSG), the gold standard. However, the performance of this new approach of sleep staging has not yet been evaluated on patients with disturbed sleep. Methods: Sleep staging from 458 sleep recordings from multiple studies comprising healthy and patient population (obstructive sleep apnea [OSA], insomnia, major depressive disorder [MDD]) was obtained from PSG visual scoring using the American Academy of Sleep Medicine rules and from Somno-Art Software analysis on synchronized ECG and actimetry. Results: Inter-rater reliability (IRR), evaluated with 95% absolute agreement intra-class correlation coefficient, was rated as "excellent" (ICCAAAvg95% ≥ 0.75) or "good" (ICCAAAvg95% ≥ 0.60) for all sleep parameters assessed, except non-REM (NREM) and N3 sleep in healthy participants (ICCAAAvg95% = 0.43, ICCAAAvg95% = 0.56) and N3 sleep in OSA patients (ICCAAAvg95% = 0.59) rated as "fair" IRR. Overall sensitivity, specificity, accuracy, and Cohen's kappa coefficient of agreement (κ) on the entire sample were respectively of 93.3%, 69.5%, 87.8%, and 0.65 for wake/sleep classification and accuracy and κ were of 68.5% and 0.55 for W/N1+N2/N3/rapid eye movement (REM) classification. These performances were similar in healthy and patient population. Conclusions: The present results suggest that Somno-Art can be a valid sleep-staging tool in both healthy subjects and patients with OSA, insomnia, or MDD. It could complement existing non-attended techniques measuring sleep-related breathing patterns or be a useful alternative to laboratory-based PSG when this latter is not available.

Guidelines for the recording and evaluation of pharmaco-sleep studies in man: the International Pharmaco-EEG Society (IPEG).

The International Pharmaco-EEG Society (IPEG) presents guidelines summarising the requirements for the recording and computerised evaluation of pharmaco-sleep data in man. Over the past years, technical and data-processing methods have advanced steadily, thus enhancing data quality and expanding the palette of sleep assessment tools that can be used to investigate the activity of drugs on the central nervous system (CNS), determine the time course of effects and pharmacodynamic properties of novel therapeutics, hence enabling the study of the pharmacokinetic/pharmacodynamic relationship, and evaluate the CNS penetration or toxicity of compounds. However, despite the presence of robust guidelines on the scoring of polysomnography -recordings, a review of the literature reveals inconsistent -aspects in the operating procedures from one study to another. While this fact does not invalidate results, the lack of standardisation constitutes a regrettable shortcoming, especially in the context of drug development programmes. The present guidelines are intended to assist investigators, who are using pharmaco-sleep measures in clinical research, in an effort to provide clear and concise recommendations and thereby to standardise methodology and facilitate comparability of data across laboratories.

A new sublingual formulation of zolpidem for the treatment of sleep-onset insomnia.

Insomnia is a very frequent complaint that periodically or permanently affects up to 60% of the general population. Valuable therapeutic options rely on pharmacological and nonpharmacological management of insomnia complaints. Zolpidem is one of the most popular hypnotic drugs used to treat insomnia. The drug was synthesized by Synthélabo Recherche in the early 1980s and has proved to be a suitable and well-tolerated drug, especially with regard to efficacy in sleep initiation. The present review focuses on an alternate delivery form of zolpidem, Edluar™, a new sublingual formulation of zolpidem that has been developed for the treatment of sleep-onset insomnia. Studies have shown that Edluar has a faster sleep-induction effect, whereas it did not differ from the oral formulation in terms of sleep maintenance or side effects. This review also discusses the mechanism of action of zolpidem and its pharmacokinetic profile in comparison to Edluar. Efficacy studies in specific settings (such as non-nightly use or use in combination with cognitive behavioral therapy) and particular safety issues encountered with zolpidem use are also discussed.

EEG spectral power density profiles during NREM sleep for gaboxadol and zolpidem in patients with primary insomnia.

There is significant interest in the functional significance and the therapeutic value of slow-wave sleep (SWS)-enhancing drugs. A prerequisite for studies of the functional differences is characterization of the electroencephalography (EEG) spectra following treatment in relevant patients. We evaluate for the first time gaboxadol and zolpidem treatments in insomniac patients using power spectra analysis. We carried out two randomized, double-blind, crossover studies. Study 1, 38 patients received gaboxadol 10 mg and 20 mg and zolpidem 10 mg; study 2, 23 patients received gaboxadol 5 mg and 15 mg. Treatments were administered during two nights and compared with placebo. Gaboxadol 10, 15 and 20 mg enhanced slow-wave activity (SWA) and theta power. In 1 Hz bins gaboxadol 10 and 20 mg enhanced power up to 9 Hz. In study 2, 15 mg gaboxadol showed a similar effect pattern. Zolpidem suppressed theta and alpha power, and increased sigma power, with no effect on SWA. In the 1 Hz bins zolpidem suppressed power between 5-10 Hz. Gaboxadol dose-dependently increased SWA and theta power in insomniac patients. In contrast, zolpidem did not affect SWA, reduced theta and alpha activity and enhanced sigma power. EEG spectral power differences may be consequences of the different mechanisms of action for zolpidem and the SWS-enhancing agent, gaboxadol.

Pharmacokinetic profile of SKP-1041, a modified release formulation of zaleplon.

OBJECTIVES: Two investigations aimed to define the pharmacokinetic profile of a modified-release preparation of zaleplon (SKP-1041). METHODS: Protocol SOM001 was a 5-way crossover, double-blind, randomized trial comparing three novel modified-release formulations of zaleplon 15 mg (SKP-1041A, SKP-1041B, SKP-1041C) to placebo and immediate-release zaleplon 10 mg. Protocol SOM002 was a randomized, crossover, open-label trial to compare the pharmacokinetics of SKP-1041B after day and night administration. In SOM001, study drug was administered at 9:00 a.m. (fasted); blood samples were obtained beginning 1 h predose through 12 h postdose. In study SOM002, study drug was administered at 9:00 a.m. or 10:30 p.m.; blood samples were obtained beginning 1 h predose through 12 h postdose. Subjects were 19 (SOM001) and 23 (SOM002) healthy adults between ages 20-46. RESULTS: Dose-normalized total AUCs for modified-release preparations A, B, C and immediate-release zaleplon were not significantly different; peak plasma concentrations were similar for A and B, and both were significantly higher than C. Time to peak plasma concentration for A, B, and C were 4-5 h compared to 1.5 h for immediate-release zaleplon; mean terminal phase half-life was in the range 1-2 h for A, B and immediate-release zaleplon. No significant differences were noted between day and night administration in the SOM002 study. CONCLUSIONS: Zaleplon, 15 mg, in a novel, modified-release formulation (SKP-1041) had a time to peak plasma concentrations at 4-5 h postdose compared to 1.5 h for immediate-release zaleplon, 10 mg. The pharmacokinetic profile suggests this formulation may be useful for treating middle-of-the-night awakening.

Citalopram may reduce sympathoadrenal hyperactivity in elderly depressed patients: an open multicenter study in Belgium and Luxembourg.

INTRODUCTION: Through effects of catecholamines upon the heart, blood vessels and platelets, sympathoadrenal hyperactivity contributes to the development of cardiovascular diseases in elderly depressed patients. To assess the cardiovascular effect of Citalopram in elderly depressed patients, data from an open multicenter study in Belgium and Luxembourg, in which a total of 811 patients were evaluated, was retrospectively analysed. Although the aim of the study was to assess the efficacy and safety of Citalopram, blood pressure and heart rate were also monitored. SUBJECT AND METHODS: Patients included in the study were referred either by psychiatrists, geriatricians or general practitioners. Clinical assessment included ratings on the Hamilton Rating Depression Scale, the Clinical Global Impression Scale, the UKU Side effect rating scale and the assessment of side effects spontaneously reported. RESULTS: With few side effects, Citalopram significantly improves the clinical condition of elderly patients suffering from depressive symptoms. A series of repeated multivariate analyses of covariance were performed on heart rate and blood pressure controlling for the effect of age. Interestingly, a sustained decrease of these parameters was shown during the whole study period reaching significance for systolic blood pressure (p<0.05). These effects were observed both in responding as well as non-responding patients, and were somewhat more marked in responders for heart rate (p=0.058). CONCLUSION: The slight but significant decrease in systolic blood pressure and heart rate suggests that citalopram may reduce sympathoadrenal hyperactivity and the related increased cardiovascular morbidity and mortality associated with depression.

Structured multiplicity and confirmatory statistical analyses in pharmacodynamic studies using the quantitative electroencephalogram.

Pharmacodynamic (PD) clinical studies are characterised by a high degree of multiplicity. This multiplicity is the result of the design of these studies that typically investigate effects of a number of biomarkers at various doses and multiple time points. Measurements are taken at many or all points of a "hyper-grid" that can be understood as the cross-product of a number of dimensions each of which has typically 3-30 discrete values. This exploratory design helps understanding the phenomena under investigation, but has made a confirmatory statistical analysis of these studies difficult, so that such an analysis is often missing in this type of studies. In this contribution we show that the cross-product structure of PD studies allows to combine several well-known techniques to address multiplicity in an effective way, so that a confirmatory analysis of these studies becomes feasible without unrealistic loss of power. We demonstrate the application of this technique in two studies that use the quantitative EEG (qEEG) as biomarker for drug activity at the GABA-A receptor. QEEG studies suffer particularly from the curse of multiplicity, since, in addition to the common dimensions like dose and time, the qEEG is measured at many locations over the scalp and in a number of frequency bands which inflate the multiplicity by a factor of about 250.

Sublingual zolpidem in early onset of sleep compared to oral zolpidem: polysomnographic study in patients with primary insomnia.

OBJECTIVE: To compare the hypnotic effects of a single dose of a sublingual formulation of zolpidem (Edluar*) 10 mg vs oral formulation (Ambien dagger ) 10 mg by polysomnography (PSG) in DSM-IV primary insomnia patients. Primary objective was to compare the two formulations on sleep induction, measured by latency to persistent sleep (LPS), sleep onset latency (SOL) and latency to stage 1 (ST1L). RESEARCH AND METHODS: This was a randomized, double-blind, two-period, cross-over multi-centre study in which each period comprised two successive PSG recording nights. Treatment was administered when PSG recordings started. Subjective sleep and residual effects were assessed the next morning. RESULTS: Seventy female and male patients aged 19-64 were analysed. Sublingual zolpidem significantly shortened LPS by 34% or 10.3 minutes as compared to oral zolpidem (95% CI: -4.3 min to -16.2 min, p = 0.001). SOL and ST1L were also significantly shortened (p < 0.01). Furthermore the two formulations were comparable in terms of sleep maintenance properties based on total sleep time (TST). The improvement in subjective sleep and next-day residual effects did not differ between the two treatments. Both routes of administration were well tolerated. CONCLUSIONS: The results demonstrate that sublingual zolpidem is superior to an equivalent dose of oral zolpidem in terms of sleep inducing properties in a carefully selected sample of primary insomnia patients.

Comorbidity of insomnia and depression.

During the last decade, several studies have shown that insomnia, rather than a symptom of depression, could be a medical condition on its own, showing high comorbidity with depression. Epidemiological research indicates that insomnia could lead to depression and/or that common causalities underlie the two disorders. Neurobiological and sleep EEG studies suggest that a heightened level of arousal may play a common role in both conditions and that signs of REM sleep disinhibition may appear in individuals prone to depression. The effects of antidepressant drugs on non-REM and REM sleep are discussed in relation to their use in insomnia comorbid with depression. Empirical treatment approaches are behavioral management of sleep combined with prescription of a sedative antidepressant alone, co-prescription of two antidepressants, or of an antidepressant with a hypnotic drug.

The effect of prolonged-release melatonin on sleep measures and psychomotor performance in elderly patients with insomnia.

Objectives of this study were to investigate the effects of prolonged-release melatonin 2 mg (PRM) on sleep and subsequent daytime psychomotor performance in patients aged > or =55 years with primary insomnia, as defined by fourth revision of the Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association. Patients (N = 40) were treated nightly single-blind with placebo (2 weeks), randomized double-blind to PRM or placebo (3 weeks) followed by withdrawal period (3 weeks). Sleep was assessed by polysomnography, all-night sleep electroencephalography spectral analysis and questionnaires. Psychomotor performance was assessed by the Leeds Psychomotor Test battery. By the end of the double-blind treatment, the PRM group had significantly shorter sleep onset latency (9 min; P = 0.02) compared with the placebo group and scored significantly better in the Critical Flicker Fusion Test (P = 0.008) without negatively affecting sleep structure and architecture. Half of the patients reported substantial improvement in sleep quality at home with PRM compared with 15% with placebo (P = 0.018). No rebound effects were observed during withdrawal. In conclusion, nightly treatment with PRM effectively induced sleep and improved perceived quality of sleep in patients with primary insomnia aged > or =55 years. Daytime psychomotor performance was not impaired and was consistently better with PRM compared with placebo. PRM was well tolerated with no evidence of rebound effects.

Relationships between the number of ultradian cycles and key sleep variables in outpatients with major depressive disorder.

The regulation of the alternation between rapid eye movement sleep (REMS) and non-rapid eye movement sleep (NREMS) is still a matter of much debate. It is also an important topic for psychiatric research, since both sleep components show anomalies in Major Depressive Disorders (MDD) and related syndromes. In previous studies on healthy controls, we showed preferential links of the number of ultradian cycles with REMS-related variables rather than with NREMS-related variables. REMS Latency (RL), for example, was shown to be inversely related to the number of cycles. The present study replicates these analyses in a group of 29 patients with MDD (age range: 23-56; 16 females), after two adaptation nights. Results showed significant correlations between the number of cycles and REMS, and between the number of cycles and RL, whereas correlations with NREMS were not significant. This indirectly supports regulation hypotheses considering REMS as the main focus of the oscillation, inhibiting and interrupting NREMS. Also, when the RL is shorter, there are more ultradian cycles than when the RL is long. This adds an interesting element in the elucidation of the physiological meaning of anomalies of RL.

Suicidality in opioid-dependent subjects.

We determined suicide attempt characteristics in 160 opioid-dependent subjects. Three aspects of suicide vulnerability were also examined: familial aggregation of suicidal behaviors, degree of aggression/impulsivity, and smoking. Forty-eight percent of subjects had a personal history of suicide attempt. A personal history of suicide attempt was associated with an early onset of heroin use, but not with gender differences. A family history of suicide was a progressive risk factor for suicide attempt. Subjects with a personal history of suicide attempt had a higher degree of aggression/impulsivity and smoked more cigarettes. In conclusion, opioid-dependent subjects who attempt suicide show familial aggregation and clinical expressions of suicidal liability similar to those described in other psychiatric groups.

Insomnia treatment assessment based on physiological data analysis.

For the purposes of insomnia treatment, pharmacotherapy is widely used, despite the possibility for the use of behavioural treatment of insomnia. Thus, the assessment and treatment of patients with insomnia needs further investigation. This work addresses insomnia treatment evaluation and medication side-effect assessment based on continuous physiological signals such as EEG and ECG monitoring and analysis. EEG and ECG measurements regarding drug medication (verum/placebo cases) have been used in a series of experiments, where spectral and non-linear features have been calculated, for assessing a possible distinct behaviour between the verum/placebo condition and furthermore the relation of features to a physiological conditions. Results show that a combination of EEG and ECG based characteristics, both spectral and non-linear, can be used to reveal the differences introduced with insomnia medication treatment, either being improvement in the hyperarousal state, or undesired side effects.

A double-blind, placebo-controlled, randomized study evaluating the effect of paliperidone extended-release tablets on sleep architecture in patients with schizophrenia.

The effects of paliperidone extended-release on sleep architecture in patients with schizophrenia-related insomnia were evaluated in this multicenter, double-blind, randomized, placebo-controlled study. Patients received paliperidone extended-release 9 mg/day or matching placebo during the 14-day double-blind phase. Sleep architecture and sleep continuity were evaluated using polysomnograms. Subjective sleep measures were evaluated daily using the Leeds Sleep Evaluation Questionnaire. Efficacy and safety were also assessed. Thirty-six patients (17 on paliperidone extended-release, 19 on placebo; mean age 32.2 years) completed the study. Paliperidone extended-release treatment vs. placebo resulted in clinically and statistically significant differences in sleep measurements from baseline to endpoint including a reduction in: persistent sleep latency (41 min), sleep onset latency (35 min), number of awakenings after sleep onset (7), time awake in bed (50 min), and stage 1 sleep duration (12 min); prolongation in: total sleep time (53 min), sleep period time (42 min), stage 2 sleep duration (51 min), and rapid eye movement sleep duration (18 min); and an increase in sleep efficiency index (11%). Paliperidone extended-release, compared with placebo, did not exacerbate daytime somnolence and improved symptoms of schizophrenia. Paliperidone extended-release was well tolerated and improved sleep architecture and sleep continuity in patients diagnosed with schizophrenia and concomitant insomnia.

Effect of short-term treatment with gaboxadol on sleep maintenance and initiation in patients with primary insomnia.

STUDY OBJECTIVE: To perform an early evaluation of the efficacy and safety of gaboxadol in the treatment of primary insomnia. METHODS: 26 adults (18-65 years) with DSM-IV criteria for primary insomnia were randomly assigned gaboxadol (5 mg, 15 mg) or placebo in a double-blind, crossover study. After a 3-night polysomnographic (PSG) screen, treatment was administered 30 min before bedtime on 2 consecutive nights during 3 separate sessions including PSG. Efficacy analyses (n = 23) were based on the average of Nights 1 and 2, and compared gaboxadol versus placebo. Baseline was the average of Nights 2 and 3 of the screening session. Both gaboxadol doses significantly (P < 0.05) improved mean total sleep time (mean +/- SD: baseline = 368.0 +/- 51.1 min, 15 mg = 420.3 +/- 24.5 min, 5 mg = 419.8 +/- 20.4 min, placebo = 408.7 +/- 30.4 min). Both gaboxadol doses reduced mean wake after sleep onset, although statistical significance was only achieved with 5 mg (baseline = 61.6 +/- 35.4 min, 15 mg = 38.0 +/- 21.1 min, 5 mg = 34.6 +/- 14.3 min, placebo = 43.4 +/- 22.9 min). Gaboxadol 15 mg also significantly reduced mean latency to persistent sleep (baseline = 55.6 +/- 27.0 min, 15 mg = 23.6 +/- 15.1 min, placebo = 30.0 +/- 19.1 min) and enhanced slow wave duration (baseline = 72.4 +/- 20.8 min, 15 mg = 114.0 +/- 37.5 min, placebo = 93.9 +/- 31.3 min) with no significant effects on REM sleep duration. Patient reports (Leeds Sleep Evaluation Questionnaire) of reduced time to sleep and increased sleep quality showed significant improvement with gaboxadol 15 mg. No next-day residual effects were observed with either dose of gaboxadol (assessed 2 h and 9 h after lights on). All adverse events were mild or moderate. CONCLUSION: Gaboxadol 15 mg was effective and generally well tolerated in the short-term treatment of patients with primary insomnia. Gaboxadol also enhanced slow wave sleep duration and had no significant effects on REM sleep duration. These findings suggest that gaboxadol may be a useful treatment for insomnia.

Surrogate outcomes in neurology, psychiatry, and psychopharmacology.

A surrogate outcome can be defined as an outcome that can be observed sooner, at lower cost, or less invasively than the true outcome, and that enables valid inferences about the effect of intervention on the true outcome. There is increasing interest in the use of surrogate outcomes of treatment efficacy measurement in investigational drug trials. However, the significance of surrogate markers of treatment outcome in neurology and psychiatry has not yet been sufficiently demonstrated. Few such markers have been adequately "validated, " that is, shown to predict the effect of the treatment on the clinical outcome of interest. In this article, evidence that would support the validation of such markers is discussed. Biomarkers used during early clinical development programs of new psychotropic compounds are considered in the contexts of Parkinson's disease, affective disorder, and schizophrenia. The particular case of neuroprotective trials is exemplified by Parkinson's disease, where a biomarker substituting for a clinical measure of progression could be considered as a surrogate treatment outcome.

Effects of acamprosate on sleep during alcohol withdrawal: A double-blind placebo-controlled polysomnographic study in alcohol-dependent subjects.

BACKGROUND: Sleep disturbances are frequently encountered in alcohol-dependent patients. Drugs improving sleep during abstinence from alcohol may play an important role in the recovery process. METHODS: In the present study, the effects of acamprosate, a drug successfully used in maintaining abstinence following alcohol withdrawal, were assessed by polysomnographic recordings. A parallel double-blind placebo-controlled study was conducted in 24 male DSM-IV alcohol-dependent subjects aged 35.9+/-1.2 years. Treatments (2 tablets of 333 mg acamprosate vs placebo t.i.d.) were initiated 8 days before alcohol withdrawal and continued during the 15 days following alcohol withdrawal. Polysomnographic assessments were recorded during acute withdrawal (the first 2 nights following withdrawal) and during postwithdrawal abstinence (the last 2 nights of the trial). RESULTS: Results show that, compared with placebo, acamprosate decreased wake time after sleep onset and increased stage 3 and REM sleep latency (all treatment effects with a p < 0.05 significance). Withdrawal effects themselves were also demonstrated as sleep efficiency (p < 0.01) and total sleep time (p < 0.05) were lower in abstinence nights versus withdrawal nights, whereas no significant treatment x withdrawal effect could be evidenced. Acamprosate was well tolerated during the entire course of the study. CONCLUSIONS: The present study shows that acamprosate ameliorates both sleep continuity and sleep architecture parameters classically described as disturbed in alcohol-dependent patients. From a clinical perspective, it suggests that an 8-day acamprosate prewithdrawal treatment is well tolerated and can attenuate the sleep disturbances engendered by alcohol withdrawal in alcohol-dependent subjects.

Next-day residual effects of hypnotics in DSM-IV primary insomnia: a driving simulator study with simultaneous electroencephalogram monitoring.

RATIONALE: Most studies that investigated the next-day residual effects of hypnotic drugs on daytime driving performances were performed on healthy subjects and after a single drug administration. OBJECTIVES: In the present study, we further examine whether the results of these studies could be generalised to insomniac patients and after repeated drug administration. METHOD: Single and repeated (7 day) doses of zolpidem (10 mg), zopiclone (7.5 mg), lormetazepam (1 mg) or placebo were administered at bedtime in a crossover design to 23 patients (9 men and 14 women aged 38.8+/-2.0 years) with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) primary insomnia. Driving tests were performed 9-11 h post-dose. RESULTS: Results showed that treatment effects were evidenced for subjective sleep, for driving abilities, and for electroencephalogram (EEG) recorded before (resting EEG) and during the driving simulation test (driving EEG). Compared to placebo, zopiclone increased the number of collisions and lormetazepam increased deviation from speed limit and deviation from absolute speed, whereas zolpidem did not differentiate from placebo on these analyses. EEG recordings showed that in contrast to zolpidem, lormetazepam and zopiclone induced typical benzodiazepine-like alterations, suggesting that next-day poor driving performance could relate to a prolonged central nervous system effect of these two hypnotics. CONCLUSION: The present results corroborate studies on healthy volunteers showing that residual effects of hypnotics increase with their half-lives. The results further suggest that drugs preserving physiological EEG rhythms before and during the driving simulation test 9-11 h post-dose, such as zolpidem, do not influence next-day driving abilities.