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

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

Effects of prolonged-release melatonin, zolpidem, and their combination on psychomotor functions, memory recall, and driving skills in healthy middle aged and elderly volunteers.

BACKGROUND: Melatonin is an important regulator of the sleep-wake cycle. A prolonged-release formulation of melatonin (PR-M) that essentially mimics the profile of the endogenous production of the hormone is effective in the treatment of insomnia in patients aged 55 years and older. Because hypnotics result in impairments of various cognitive skills, it is important to examine the cognitive effects associated with the use of PR-M. OBJECTIVES AND METHODS: The effects of therapeutic oral doses of PR-M (2 mg), zolpidem (10 mg) and their combination administered at bedtime on cognitive functions in healthy subjects aged 55 years and older (12 males + 4 females, age 59.4 +/- 3.2 years) were assessed in a randomized, double-blind, placebo-controlled, and four-way crossover study. Psychomotor functions, memory recall, and driving skills were assessed at 1 and 4 h following administration and the next morning. RESULTS: Compared to placebo, PR-M alone did not impaired performances on any cognitive tasks. Zolpidem significantly impaired psychomotor and driving performance 1 h and 4 h post-dosing, and early memory recall; these impairment were exacerbated with PR-M co-administration. No effects on next morning psychomotor or driving performance were observed except that the decline in memory recall after zolpidem was more pronounced in the next day. No pharmacokinetic interactions were found. CONCLUSIONS: This study extends previous researches showing impairment of cognitive functions by zolpidem within 5 h post-administration. Further, PR-M use was not found associated with impairment of psychomotor functions, memory recall, and driving skills, and point to a pharmacodynamic interaction between melatonin and GABA-A modulators.

Short-term treatment with gaboxadol improves sleep maintenance and enhances slow wave sleep in adult patients with primary insomnia.

RATIONALE: Gaboxadol is a selective extrasynaptic GABA(A) agonist, previously in development for the treatment of insomniac patients. OBJECTIVE: To evaluate the acute efficacy and safety of gaboxadol in primary insomnia (PI). METHODS: This was a randomised, double-blind, four-way crossover, polysomnograph study comparing gaboxadol 10 and 20 mg (GBX20) to placebo in 40 adults with the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, criteria for PI. Zolpidem 10 mg was used as an active reference. Treatment was administered on two consecutive nights in each treatment session. Next-day residual effects were evaluated 2 and 9 h after lights on. RESULTS: Efficacy analysis included the per-protocol population (n = 38) from night 2. GBX20 reduced wake after sleep onset (p < 0.01). Both doses of gaboxadol, but not zolpidem, reduced the number of night awakenings (p < 0.001). GBX20 and zolpidem increased total sleep time (p < 0.05). Neither dose of gaboxadol nor zolpidem significantly reduced sleep onset latency, although a trend was seen for zolpidem. Gaboxadol enhanced slow wave sleep (SWS) dose-dependently (gaboxadol 10 mg: p < 0.01, GBX20: p < 0.001). Patients reported improved sleep quality following GBX20 (p < 0.05). Both doses of gaboxadol were generally well tolerated with almost exclusively mild to moderately severe adverse events (AEs). More frequent and severe AEs followed GBX20. No serious AEs were reported. No drug treatment was associated with next-day residual effects. CONCLUSION: Acute administration of gaboxadol improves sleep maintenance and enhances SWS in a dose-dependent manner in adult patients with PI. Gaboxadol was not associated with next-day residual effects. Gaboxadol was generally well tolerated, although gaboxadol showed a dose-dependent increase in incidence and severity of AEs.

Sleep effects of a 24-h versus a 16-h nicotine patch: a polysomnographic study during smoking cessation.

BACKGROUND AND PURPOSE: Sleep disturbance is a common symptom of tobacco withdrawal and might contribute to early relapse vulnerability in abstinent smokers. This study was designed to compare the effects on sleep of nicotine patches applied either for 24 h (Nicopatch) or 16 h (Nicorette). PATIENTS AND METHODS: During a short smoking cessation period (48 h), this open-label, randomised, two-period crossover study compared the effects on sleep of the two nicotine patches in 20 heavy smokers (9 women, 11 men). During each period, polysomnographic recordings were performed from 12 pm to 7 am for two consecutive nights (baseline and treatment nights). Smoking cessation started from 8 pm the day of the baseline sleep recordings, and treatments were applied around 8 am the following morning. RESULTS: Compared to the 16-h nicotine patch, smokers who received the 24-h nicotine patch experienced significantly less microarousals, a greater proportion of slow wave sleep, a higher REM density and higher rapid eye movement (REM) beta activities. CONCLUSIONS: The results of this study suggest that a 24-h nicotine patch is more efficient than a 16-h nicotine patch to alleviate tobacco withdrawal-induced sleep disturbances.

Restless legs syndrome and low brain iron levels in patients with haemochromatosis.

Regional brain iron levels of two patients with haemochromatosis and severe restless legs syndrome (RLS) were assessed using R2' magnetic resonance imaging (MRI) sequences in both patients and in nine healthy controls. R2' relaxation rates in the patients were decreased in the substantia nigra, red nucleus, and pallidum when compared with the controls. These results indicate that local brain iron deficiency may occur in patients with haemochromatosis and suggest a role for brain iron metabolism in the pathophysiology of RLS.

[Development of compounds active in insomnia: recent developments and methodological aspects]. / Développement de molécules actives dans l'insomnie: actualités et aspects méthodologiques.

Most pharmacotherapeutic treatments designed to treat insomnia target GABAergic activity globally in the brain. Development of new molecules having a more specific activity pathway should improve treatment efficacy and acceptance. Both subjective and objective criteria are needed to study drug efficacy. Data regarding drug effects on polysomnographic recordings are mandatory for the development of hypnotics. Whether the drug-induced sleep is comparable to normal sleep is tackled with the spectral analysis of the sleep EEG. Residual drug effects are assessed with a package of psychomotor and neurocognitive tests, and with the driving simulator test Clinical studies investigating drug efficacy and tolerability have to be conducted on large groups of patients carefully selected using polysomnographic recordings. Our knowledge about sleep will undoubtedly soon become available for treatment of insomnia.

Characterization of the CNS effects of naftidrofuryl (Praxilène) by quantitative EEG and functional MRI: a study in healthy elderly subjects.

In the present study, we investigated the effects of a single and a repeated (5 days) administration of naftidrofuryl, a serotonin 5-HT2 receptor inhibitor having neuroprotective properties, on functional brain physiology in male healthy elderly subjects, using quantitative electroencephalography (EEG) and functional magnetic resonance imaging (fMRI). Twelve subjects aged 60 +/- 3.8 years completed the quantitative EEG study, where the effects of 400 and 600 mg were assessed, and 12 other subjects (aged 56 +/- 4.7 years) completed the fMRI study, where the effect of 400 mg was assessed on the brain activation induced by the continuous performance test (CPT). Naftidrofuryl induced a transient reduction in alpha activity followed by a specific synchronisation of the 9.5- to 11-Hz EEG activity most pronounced after repeated administration. Such regimen also increased the CPT-induced brain activation visualized by way of fMRI. The results of the present study can be interpreted at the functional level that naftidrofuryl induced an improved level of vigilance or an increased capacity of alertness in healthy elderly subjects.

Disturbances in hypothalamo pituitary adrenal and thyroid axis identify different sleep EEG patterns in major depressed patients.

This study was aimed at investigating the relationships between sleep EEG abnormalities and hypothalamo pituitary adrenal (HPA) and hypothalamo pituitary thyroid (HPT) disturbances in major depressive disorder. Post dexamethasone (DXM) cortisol levels and the dual TSH response to 08:00 h and 23:00 h TRH administration were determined after a 2 weeks wash-out period in a group of 113 DSM-IV major depressed patients (72 females aged 44.3+/-13.0 and 41 males aged 45.7+/-11) who were consecutively admitted to undergo sleep EEG recordings. Post-DXM cortisolemia, 08:00 and 23:00 post-TRH TSH values, time spent in rapid eye movement sleep (REMS), in slow wave sleep (SWS), and in stage 2 as well as time awake after sleep onset were introduced in a principal component (PC) analysis. The four 3 PC scores explaining up to 74% of the data set were further calculated for each patients and used in a cluster analysis. A three-cluster solution was retained. Controlling for the effects of age and gender, patients belonging to these three clusters could clearly be differentiated on the basis of their neuroendocrine responses and on their sleep EEG profiles. Compared to the two other clusters, cluster I (n=26) patients showed the most severe sleep continuity disturbances. Post-DXM cortisol escape and sleep architecture disturbances (consisting of a shortening of REMS latency and a decreased SWS) identified patients belonging to cluster II (n=39). Patients in cluster III (n=48) had the lowest TSH response to TRH and the less marked sleep EEG alteration. Clinical or demographic variables were unable to differentiate the three clusters. Our results suggest that different biological dysfunctions could each underlie particular neuroendocrine and sleep EEG disturbances in major depression.

Psychiatric disorders and social characteristics among second-generation Moroccan migrants in Belgium: an age-and gender-controlled study conducted in a psychiatric emergency department.

PURPOSE: Clinically, one of the most consistent clinical findings among migrant patients is an increase in the rate of psychosis. The aim of the present study was to confirm this finding in Belgium by comparing second-generation Moroccan migrant patients with Belgian patients, matched for the variables of age and gender. SUBJECTS AND METHOD: We conducted a cross-sectional survey on 272 patients admitted in a psychiatric emergency unit during the year 1998. We used univariate and multivariate analyses to compare the two subgroups. RESULTS: Multivariate analyses showed that migrant patients lived more often with their parental family and that they presented a higher rate of admission for psychotic disorders and a lower rate of employment. DISCUSSION: Our findings add to the growing body of results showing increased incidence of psychosis among immigrants to European countries, but several factors have to be taken into account, particularly with regard to selection biases and differences in help-seeking behaviour and in family perception of the mental illness. CONCLUSION: Our results are compatible with the hypothesis that unemployment is a contributing factor in the risk for psychosis among migrant groups. Further studies would be needed to better explain some of our results, particularly the role played by the families of migrant patients.

Correlations using the NREM-REM sleep cycle frequency support distinct regulation mechanisms for REM and NREM sleep.

Polysomnograms of most homeothermic species distinguish two states, rapid eye movement (REM) and non-REM (NREM) sleep. These alternate several times during the night for reasons and following rules that remain poorly understood. It is unknown whether each state has its own function and regulation or whether they represent two facets of the same process. The present study compared the mean REM/NREM sleep ratio and the mean number of NREM-REM sleep cycles across 3 consecutive nights. The rationale was that, if REM and NREM sleep are tightly associated, their ratio should be comparable whatever the cycle frequency in the night. Twenty-six healthy subjects of both sexes were recorded at their home for 4 consecutive nights. The correlation between the REM/NREM sleep ratio and the number of cycles was highly significant. Of the two sleep components, REM sleep was associated to the number of cycles, whereas NREM sleep was not. This suggests that the relationship between REM sleep and NREM sleep is rather weak within cycles, does not support the concept of NREM-REM sleep cycles as miniature units of the sleep process, and favors the concept of distinct mechanisms of regulation for the two components.

[Mania, parkinson disease and risperidone. Case report]. / Eficacia de risperidona en un caso de manía y enfermedad de Parkinson.

Risperidone is an atypical antipsychotic with a low prevalence of extrapyramidal side-effects. The use of this antipsychotic in Parkinson's disease is still controversial. We describe a 59 year-old bipolar patient with Parkinson's disease non-responding to conventional antimanic drugs successfully treated with risperidone.

Shorter REM latency associated with more sleep cycles of a shorter duration in healthy humans.

A significant association between rapid eye movement (REM) sleep latency and the number of non-REM/REM sleep cycles was found 15 years ago in a large retrospective study. The present prospective study further explored this intra-sleep relationship and analyzed the links between these two variables and the mean cycle duration. It was based on a carefully selected group of healthy control subjects whose sleep was polysomnographically recorded at home for 4 sequential nights. The latency of REM sleep was inversely correlated with the number of cycles and positively correlated with the mean cycle duration, both in individual nights and on means of 4 nights. The present study demonstrated that variations in the number of cycles or the mean cycle duration between the nights are far less important than the substantial differences observed between subjects. Present outcomes support the study of sleep cycle periods and frequencies in those psychiatric disorders where REM sleep latencies have been found to be shorter, and they suggest that these variables be included in sleep studies in which cycles are compared with each other.

Effects of the selective activation of 5-HT3 receptors on sleep: a polysomnographic study in healthy volunteers.

The respective role of various classes of central serotonin (5-HT) receptors in the regulation of sleep-wakefulness cycles has been the subject of many studies. Notably, it has been reported that 5-HT1A/B receptors are involved in the regulation of rapid eye movement sleep (REMS) and that 5-HT2A/C receptors participate in the control of slow wave sleep (SWS), but the role of 5-HT3 receptors is less well characterised. In this study we investigated the effects of SR 57227A, a potent and selective 5-HT3 agonist, on the sleep EEG of normal young male volunteers. SR 57227A (2.5, 5, 10, 20, 40 mg o.d. and 20 mg b.i.d.) or placebo were administered during 7 consecutive days in seven groups of ten subjects using a parallel group design. Sleep EEG recordings were performed on days 6 and 7 after an habituation session. SR 57227A produced a dose-dependent shift of REMS toward the end of the night without changing REMS and SWS duration nor altering sleep continuity. It suggests a role for the 5-HT3 receptor in the human sleep-wakefulness cycle and particularly in REMS regulation.

The first-night effect may last more than one night.

The first-night effect in sleep polysomnographic studies is usually considered to last for one night. However, a few observations have indicated that variables associated to rapid eye movement sleep take longer to stabilize. Notwithstanding, current opinion holds that second nights of recording can be used without restriction for research and clinical purposes. The goal of this study was to describe the dynamics of habituation to polysomnography in optimal conditions. Twenty-six young, carefully screened, healthy subjects were recorded in their home for four consecutive full polysomnographies. Repeated measures ANOVA were applied. Between the two first nights, while there were no differences in sleep duration in non-rapid eye movement sleep, marked modifications in corresponding spectral power were observed. The dynamics of adaptation of rapid eye movement sleep appeared to be a process extending up to the fourth night. Similar dynamics in NREMS and REMS homeostasis have been observed in sleep deprivation studies, and it appears that the same mechanisms may be responsible for the FNE. The longer habituation process of REMS in particular has important implications for sleep research in psychiatry.

Morning and evening TSH response to TRH and sleep EEG disturbances in major depressive disorder.

1. The aim of this study was to investigate hypothalamo-pituitary-thyroid axis (HPTA) functioning and sleep EEG disturbances in major depressive disorder. 2. Thyroid function was evaluated by determination of TSH levels before and after 8 AM and 11 PM TRH administration on the same day in a sample of 113 consecutively-admitted DSM-IV major depressed inpatients (72 females aged 44.3 +/- 13.0 and 41 males aged 45.7 +/- 10.7) that underwent sleep EEG recordings. 3. A blunted TSH response occurred in 15.9% for 8 AM deltaTSH (maximum increment above baseline at the 8 AM TRH challenge), in 39.8% for 11 PM deltaTSH and in 77% for deltadeltaTSH (difference between 11 PM deltaTSH and 8 AM deltaTSH). A negative correlation between deltadeltaTSH and duration of awakenings after sleep onset, and a shorter sleep onset latency in patients with a blunted 11 PM deltaTSH were found, but these two significant relationships disappeared after controlling for the effects of gender and age. 4. The present findings do not support the hypothesis that, in major depression, HPTA dysfunctioning, as reflected in TSH response to TRH, may be related to sleep EEG disturbances.

Mild to moderate sleep respiratory events: one negative night may not be enough.

STUDY OBJECTIVES: Reports on the reproducibility of apnea-hypopnea indexes (AHIs) across sequential polysomnography (PSG) sessions are conflicting, leading to a lack of clear recommendations on the optimal use of this technique: is one night of monitoring sufficient or is a second night required in order to safely reject the diagnosis? DESIGN: Retrospective comparison of two consecutive nights. SETTING: Sleep unit of a tertiary-care facility. PATIENTS: Two hundred forty-three subjects with suspected sleep apneas. INTERVENTIONS: Two sequential PSG sessions in a sleep unit. MEASUREMENTS AND RESULTS: Using analysis of covariance for repeated measures, with age and body mass index as covariates and gender as a cofactor, a classic first-night effect was found for sleep variables. In addition, a night effect was demonstrated for sleep respiratory variables. Moreover, the high variability of AHIs showed that many patients had their condition diagnosed on only one of the two nights, and more often on the second night than on the first. The gain in detection by adding a second night when the results of testing on the first were negative was between 15% and 25%, according to the AHI obtained on night 1. CONCLUSIONS: Considering the disability associated with sleep apnea/hypopnea syndrome, as well as its global cost for society, the present study shows that it is worth performing two consecutive PSG sessions or at least a second one when the result of the first one is negative in all patients admitted for apnea detection.

5-HT2a receptor polymorphism gene in bipolar disorder and harm avoidance personality trait.

The purpose [corrected] of this study was to investigate the relationship between bipolar disorder and the harm avoidance personality trait (HA), and the genetic contribution of the polymorphic DNA variation T102C in exon 1 of 5-HTR2a (chromosome 13q14-21) in bipolar disorder and HA personality trait. Forty bipolar patients and 89 normal subjects completed the TPQ questionnaire and were genotyped for 5-HT2a. Bipolar patients scored higher than normal subjects on the HA dimension. However, no contribution of the 5-HTR2a polymorphism on the bipolar disorder or on the HA personality trait emerged. Despite the limited sample size, these results exclude a major effect of the 5-HTR2a polymorphism on bipolar disorder and HA personality trait but not a minor effect.

A European multicenter association study of HTR2A receptor polymorphism in bipolar affective disorder.

The available data on the role of 5-HT in a variety of behaviors support the hypothesis that a dysfunction in brain serotoninergic system activity contributes to vulnerability to major depression. The diversity in the electrophysiological actions of 5-HT in the central nervous system can now be categorized according to receptor subtypes and their respective effector mechanisms. In particular, the implication of central postsynaptic 5-HT2A receptor in affective disorders has been supported by findings consistent with the hypothesis of 5-HT2A receptor up-regulation in depression. For these reasons, the 5-HT2A receptor (HTR2A) gene can be considered as a candidate gene in bipolar affective disorder (BPAD). We tested the possible genetic contribution of the polymorphic DNA variation T102C in exon 1 of HTR2A (chromosome 13q14-21) gene in a large European multicentric case-control sample. Allele and genotype frequencies, as well as homo-heterozygote distributions were compared between the two groups of 309 bipolar affective disorder patients and 309 matched controls. No significant differences were observed in the allelic and genotypic (also for homo-heterozygote) distribution between BPAD and controls. These results indicate that, in our sample, the 5-HT2A receptor polymorphism studied is unlikely to play a major role in the genetic susceptibility to BPAD. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:136-140, 2000.

Changes in EEG power density during sleep laboratory adaptation in depressed inpatients.

BACKGROUND: The aim of the present study was to evaluate the first-night effect in depressed inpatients, using standard sleep measures as well as all-night spectral analysis of the sleep electroencephalogram (EEG). METHODS: Eighteen drug-free, depressed inpatients were studied for 3 consecutive nights in the hospital sleep laboratory. RESULTS: Visual sleep scoring results showed a slight but measurable first-night effect, characterized by a reduction of rapid eye movement (REM) sleep amount and increased wakefulness. Sleep EEG spectral analysis showed significantly reduced delta (p <.01) and theta (p <.05) power density in non-REM (NREM) sleep of the first night compared with that of the second and third nights. These differences were limited to the early part of the sleep period, a time during the night that is particularly vulnerable to the effects of depressive disorder. In contrast to the NREM sleep findings, spectral REM variables studied did not significantly vary across the three nights. CONCLUSIONS: The results obtained suggest that first-night data should not be simply discarded but could be used in subsequent analyses and could be considered useful in the evaluation of the sleep of depressed patients.