Reduction Of Slow Wave Sleep Research Articles

Sleep and depression — results from psychobiological studies: an overview

Disturbances of sleep are typical for most depressed patients and belong to the core symptoms of the disorder. Polysomnographic sleep research has demonstrated that besides disturbances of sleep continuity, in depression sleep is characterized by a reduction of slow wave sleep and a disinhibition of REM sleep, with a shortening of REM latency, a prolongation of the first REM period and increased REM density. These findings have stimulated many sleep studies in depressive patients and patients with other psychiatric disorders. In the meantime, several theoretical models, originating from basic research, have been developed to explain sleep abnormalities of depression, like the two-process-model of sleep and sleep regulation, the GRF/CRF imbalance model and the reciprocal interaction model of non-REM and REM sleep regulation. Interestingly, most of the effective antidepressant agents suppress REM sleep. Furthermore, manipulations of the sleep–wake cycle, like sleep deprivation or a phase advance of the sleep period, alleviate depressive symptoms. These data indicate a strong bi-directional relationship between sleep, sleep alterations and depression.

Increase of waking and reduction of NREM and REM sleep after nitric oxide synthase inhibition: prevention with GABA A or adenosine A 1 receptor agonists

The effect of N G-nitro- l-arginine methyl ester ( l-NAME), a competitive inhibitor of enzyme nitric oxide synthase (NOS), on spontaneous sleep during the light period, was studied in adult rats implanted for chronic sleep recordings. l-NAME was injected by subcutaneous (s.c.) route or was infused directly into the dorsal raphe nucleus (DRN). Subcutaneous (46.0–185.0 μmol/kg) administration of l-NAME increased waking (W), slow wave sleep (SWS) and rapid-eye-movement sleep (REMS) latency, whereas SWS, REMS and the number of REM periods were reduced. Direct application of l-NAME into the DRN (0.37–1.1 μmol) induced an increment of W and a reduction of SWS and REMS. Values corresponding to SWS and REMS latency, and the number of REM periods remained within control levels. Subcutaneous administration of the GABA A receptor agonist muscimol (1.7–3.5 μmol/kg) or the adenosine A 1 receptor agonist l-PIA [L(-)N 6-(2-phenylisopropyl)adenosine] (0.1–0.3 μmol/kg) induced slight but inconsistent changes of W, light sleep (LS), SWS and REMS that did not attain significance. Pretreatment with muscimol (1.7–3.5 μmol/kg, s.c.) or l-PIA (0.1–0.3 μmol/kg, s.c.) antagonized the increase of W and reduction of SWS and REMS induced by s.c. (92.0 μmol/kg) or intra-DRN (0.74 μmol) administration of l-NAME. However, neither muscimol nor l-PIA prevented the increase of REMS latency induced by l-NAME 92.0 μmol/kg, s.c. Our findings tend to indicate that the change of behavioral state observed after systemic or intra-DRN administration of l-NAME is partly related to the reduction of GABA and adenosine at critical sites in the CNS.

Effects of prolonged wakefulness on c-fos and AP1 activity in young and old rats

Recent studies have demonstrated that the immediate-early gene c-fos is induced in neuronal populations responsible for specific sleep–wake states. The induction of this gene may be functionally relevant to sleep homeostasis since without the gene mice (c-fos null) take longer to fall asleep and have a selective reduction in slow-wave sleep. This suggests that a build-up of c-fos during wakefulness increases the drive to sleep and lack of c-fos is associated with reduced sleep. Sleep also has an effect on c-Fos serving to eliminate the protein rapidly. Waxing and waning of transcription factors such as c-Fos may influence slow, oscillating events such as sleep and wakefulness. To further examine what role c-Fos may play in regulating sleep, the present study examined the effects of prolonged wakefulness on c-Fos and AP-1 activity in young (3.5 months old) and old (21.5 months old) Sprague–Dawley rats. Previously we found that old rats slept less even after prolonged wakefulness, and other investigators have found that aging is also associated with a decline in c-Fos. In the present study, we reasoned that prolonged wakefulness would also fail to increase c-Fos in old versus young rats. The baseline levels of c-Fos and AP-1 activity were not different between young and old rats. However, in response to 6 or 12 h of prolonged wakefulness, old rats demonstrated significantly less c-Fos and AP-1 activity compared to young rats. These findings suggest that in old rats the mechanism responsible for c-Fos induction in response to wakefulness is deficient. Such a decline at the molecular level could contribute to the decline in sleep that typically occurs with age.

Sleep apnea in childhood migraine

In our previous study we found a high prevalence of disordered sleep breathing in migraine children vs. controls. Since no quantitative studies about sleep respiratory disorders have been carried out in migraine children, we performed a polysomnographic (PSG) study in 10 migraine patients (7 boys, 3 girls; mean age 8.11 years, range, 5.8–14.5) attending the Headache Center of our department, to evaluate the presence of sleep apnea. Mothers completed a headache diary and a sleep diary for at least 1 month and filled out a sleep questionnaire. PSG data showed a normal sleep architecture in 3 cases, an insomnia pattern in 2, a reduction of slow wave sleep in 3 and a reduction of REM sleep in 2. Respiratory analysis revealed that 2 of 10 patients had obstructive sleep apnea. These 2 patients presented habitual snoring and associated sleep disturbances such as restless sleep and hypnic jerks. Sleep apnea may be a subtle and often undiagnosed symptom in several migraine patients. The report of habitual snoring associated with other sleep disturbances such as restless sleep and other parasomnias may be a sign of sleep apnea in migraine children.

Sleep and wakefulness in c-fos and fos B gene knockout mice

G-protein coupled receptor (GPCR) stimulation has been implicated in the regulation of sleep. Upon stimulation of a GPCR an intracellular cascade involving second and third messengers is initiated. The latter include the fos-family of immediate early genes (IEGs). Although there is considerable evidence indicating that IEGs are expressed in response to sleep, the effects of their deletion on sleep is not known. The present study examined sleep–wakefulness in mice lacking the c-fos or fos B genes. Null c-fos mice compared to their wildtype (WT) and heterozygote (het) siblings had more wakefulness and less slow wave sleep (SWS); REM sleep was not affected. The null c-fos mice also had increased delta activity (0.3–4 Hz). In contrast, the null and heterozygote fos B mice had less REM sleep, but the time spent in SWS or wakefulness was not different from their wild-type (WT) siblings. In the null c-fos mice, the increased wakefulness and the reduction in SWS could not be due to a systemic alteration in temperature since the core temperature was similar in all mice. By demonstrating that these IEGs are involved in sleep, we suggest that the deletion of specific genes, even within a family of genes, can have a specific effect on sleep.

Effects of chronic ethanol exposure on sleep in rats

Sleep disturbance is a common complaint in alcoholics. When polysomnographic studies are performed in alcoholics, reductions in slow wave sleep are a common finding; however, few studies have evaluated the effects of chronic alcohol exposure on sleep in animal models. In the present study, the sleep EEG was evaluated in 40 Wistar rats who were exposed to chronic alcohol or control conditions in vapor chambers. Rats were exposed to ethanol vapors or control chambers for 6 weeks and then withdrawn. Sleep EEG was recorded before exposure (baseline), immediately following exposure, and 5 weeks after withdrawal from the ethanol/control chambers. In the ethanol-exposed animals, blood ethanol levels averaged 192 mg/dL over 6 weeks of exposure. Chronic ethanol exposure and withdrawal was not found to affect either slow wave sleep latency or slow wave sleep duration; however, overall spectral power as well as power in the delta, theta, and beta frequencies were significantly reduced following chronic exposure (2–4 Hz, [ F(1, 17) = 18.11, p = 0.001], 4–6 Hz, [ F(1, 17) = 15.98, p = 0.001], 6–8 Hz [ F(1, 17) = 15.52, p = 0.001], 8–16 Hz band [ F(1, 17) = 18.73, p < 0.0001], 16–32 Hz [ F(1, 17) = 10.13, p = 0.005], and 1–50 Hz [ F(1, 17) = 17.03, p = 0.001]. After 5 weeks of withdrawal, significant decreases still persisted in the delta and theta frequencies (2–4 Hz [ F(1, 16) = 6.21, 0.024], 4–6 Hz [ F(1, 16) = 6.26, 0.024], and 6–8 Hz [ F(1, 16) = 4.84, p = 0.043]). These findings suggest that spectral analysis of the EEG is a highly sensitive measure of the effects of ethanol on sleep. These findings additionally demonstrate that chronic ethanol exposure can produce persistent diminution in the systems that generate cortical slow waves in the rat and thus may provide a model for understanding the mechanisms underlying sleep disturbances associated with alcoholism.

Aging does not affect the sleep endocrine response to total sleep deprivation in humans

Aging is associated with decreased sleep continuity, slow wave sleep (SWS), growth hormone (GH) release and an increased hypothalamo-pituitary-adrenocortical (HPA) system activity. Total sleep deprivation (TSD) is a strong stimulus for sleep. To determine if aging affects the response to TSD, for the first time the combined effects of TSD on conventional and spectral sleep electroencephalographic (EEG) parameters and GH, cortisol and prolactin secretion were compared in elderly (60–80 years; n = 7) vs. younger subjects (20–30 years; n = 7). MANOVA revealed a reduction of SWS in the elderly. TSD led to an increase in SWS, a decrease in sleep onset latency, rapid eye movement (REM) density and by trend REM-latency without a global group difference. GH was reduced, whereas prolactin was enhanced in the elderly. After TSD GH was unchanged and prolactin secretion was enhanced without group difference. Thus, the plasticity of the sleep-endocrine system in response to TSD is sustained during aging. The possible involvement of the GABAergic system, that seems not to be severely impaired with age, is proposed.

Interleukin-1 β and calcitonin, but not corticotropin-releasing factor, alter sleep cycles when injected into the rat hypothalamic lateral paraventricular area

Interleukin-1 β (Il-1 β) is a cytokine known to have somnogenic properties. We have previously shown that Il-1 β decreases food intake when injected into the lateral part of the paraventricular nucleus of the hypothalamus (PVH), and, because food intake and sleep are closely related behaviors, we tested the hypothesis that Il-1 β could alter sleep when injected into the lateral PVH area. We compared the effects of Il-1 β with those of two other peptides involved in feeding behavior and known to act in the PVH area, the corticotropin-releasing factor (CRF) and salmon calcitonin (sCT). The EEG of rats was recorded for 48 h after the injection. The results showed that CRF had no effects, Il-1 β reduced significantly sleep duration during the first 5 h following the injection, and sCT profoundly affected sleep cycles, producing an almost 30-h long insomnia, with a major reduction of slow wave sleep and a long period of alternation of REM sleep and wakening. It is concluded that (i) the area between the lateral part of the PVH and the fornix is a brain site involved in sleep regulation, (ii) Il-1 β, a peptide generally considered as somnogenic, decreases sleep when administered in this area, and (iii) sCT is an extremely potent suppressor of slow wave sleep.

Role of nitric oxide in sleep regulation: effects of l-NAME, an inhibitor of nitric oxide synthase, on sleep in rats

The effect of N G-nitro- l-arginine methyl ester ( l-NAME), a competitive inhibitor of enzyme nitric oxide synthase (NOS), on spontaneous sleep during the light period, was studied in adult rats implanted for chronic sleep recordings. l-NAME was injected by subcutaneous (s.c.) or intracerebroventricular (i.c.v.) routes or was infused directly into the dorsal raphe nuclei (DRN). Subcutaneous (1.25–5.0 mg/kg) or i.c.v. (0.25–1.0 mg) administration of l-NAME increased waking (W) and reduced slow wave sleep (SWS) and rapid-eye-movement sleep (REMS) during the first 3 h of recording. On the other hand, direct application of l-NAME into the DRN (50.0–150.0 μg) induced an increment of W and a reduction of SWS without suppressing REMS. Values of W and SWS were significantly different compared with those of controls during the 6-h recording period. The effects of l-NAME observed after s.c. or i.c.v. administration confirm previous studies in rabbits and rats, in which the NOS inhibitor reduced sleep and increased W in a dose-dependent manner. It is possible that REMS suppression after l-NAME could be related to a reduction of acetylcholine release in areas critical for REMS promotion. A decrease in γ-aminobutyric acid (GABA) release after nitric oxide synthesis inhibition could play a role in the reduction of SWS.

Effects of accumbens m-chlorophenylbiguanide microinjections on sleep and waking in intact and 6-hydroxydopamine-treated rats

Effects of the 5-HT 3 receptor agonist, m-chlorophenylbiguanide (10.0–40.0 μg), on sleep and waking were studied in control, vehicle-treated and 6-hydroxydopamine-injected rats. Bilateral injections of m-chlorophenylbiguanide into the nucleus accumbens of the control and the vehicle-infused animals significantly increased waking and reduced slow wave sleep. Rapid eye movement sleep (REM sleep) remained unchanged. Pretreatment with the selective 5-HT 3 receptor antagonist, MDL 72222 (1a H,3a,5a, H-tropan-3-yl-3,5-dichloro-benzoate) (0.5 mg/kg, s.c.), reversed the effects of m-chlorophenylbiguanide (10.0–20.0 μg) on sleep and waking in the control group. Administration of the 5-HT 3 receptor agonist to the 6-hydroxydopamine-treated animals modified only slightly the time spent in wakefulness and slow wave sleep, while REM sleep was significantly and dose dependently reduced. Our findings further support the proposal that increase of wakefulness and reduction of slow wave sleep after activation of 5-HT 3 receptors, is partly related to the release of endogenous dopamine.

Circadian regulation of human sleep and age-related changes in its timing, consolidation and EEG characteristics

The light-entrainable circadian pacemaker located in the suprachiasmatic nucleus of the hypothalamus regulates the timing and consolidation of sleep by generating a paradoxical rhythm of sleep propensity; the circadian drive for wakefulness peaks at the end of the day spent awake, ie close to the onset of melatonin secretion at 21.00-22.00 h and the circadian drive for sleep crests shortly before habitual waking-up time. With advancing age, ie after early adulthood, sleep consolidation declines, and time of awakening and the rhythms of body temperature, plasma melatonin and Cortisol shift to an earlier clock hour. The variability of the phase relationship between the sleep-wake cycle and circadian rhythms increases, and in old age sleep is more susceptible to internal arousing stimuli associated with circadian misalignment. The propensity to awaken from sleep advances relative to the body temperature nadir in older people, a change that is opposite to the phase delay of awakening relative to internal circadian rhythms associated with morningness in young people. Age-related changes do not appear to be associated with a shortening of the circadian period or a reduction of the circadian drive for wake maintenance. These changes may be related to changes in the sleep process itself, such as reductions in slow-wave sleep and sleep spindles as well as a reduced strength of the circadian signal promoting sleep in the early morning hours. Putative mediators and modulators of circadian sleep regulation are discussed.

Effects of the D 3 preferring dopamine agonist pramipexole on sleep and waking, locomotor activity and striatal dopamine release in rats

Quantitation of 2 h sessions after administration of the D 3 preferring dopamine (DA) agonist pramipexole (10–500 μg/kg) showed dose-related effects on wakefulness (W), slow wave sleep (SWS) and REM sleep in rats. The 30 μg/kg dose of the DA agonist increased SWS and REM sleep and reduced W during the first recording hour, while the 500 μg/kg dose augmented W. On the other hand, W was increased while SWS and REMS were decreased after the 500 μg/kg dose during the second recording hour. The mixed D 2- and D 3 receptor antagonist YM-09151-2 (30–500 μg/kg), which per se affected sleep variables prevented the increase of REMS induced by pramipexole. Furthermore, the highest doses (500–1000 μg/kg) of the DA antagonist effectively antagonized the increase of W and reduction of SWS induced by the 500 μg/kg dose of the DA agonist. Pramipexole (30–100 μg/kg) induced a decrease of locomotor activity during the 2 h recording period. In addition, the 500 μg/kg dose gave rise to an initial reduction of motor behavior which was reverted 2 h later. Pramipexole (30 and 500 μg/kg) did not significantly affect striatal DA release during the first two hours following drug administration, as measured by microdialysis. It is tentatively suggested that D 3 receptor could be involved in the pramipexole-induced increase of sleep and reduction of locomotor activity. On the other hand, the increase of W and of motor behavior after relatively high doses could be related to activation of postsynaptic D 2 receptor.

S-16-3 - GABA mechanisms in sleep deprivation and their relevance to depression

The mechanism of action and the pharmacokinetics of hypnotic drugs are key determinants of their clinical effects in patients with primary or comorbid insomnia. Accordingly, the sedation and sleep-promoting properties of drugs acting as positive allosteric modulators of the GABAA receptor depend upon their selective binding to the α1 receptor subtype. The additional binding to other receptor subtypes conditions the occurrence of adverse events. The absorption rate has been emphasized as a determinant of onset of action, and the elimination half-life (t1/2) and distribution as key factors of duration of action of hypnotic drugs in clinical use. Benzodiazepine and nonbenzodiazepine hypnotics improve sleep induction, and depending on their t1/2 and presence of active metabolites, they improve sleep maintenance. In this respect, the pyrazolopyrimidine derivative zaleplon does not affect total sleep time. On the other hand, the increase of total sleep time that follows the administration of the benzodiazepine and imidazopyridine derivatives midazolam, triazolam, and zolpidem immediate-release, is limited to the first half of the night. In order to circumvent this limitation, a zolpidem extended-release preparation has been made available. The benzodiazepine hypnotics, temazepam, flunitrazepam, and flurazepam, and the cyclopyrrolone derivatives, zopiclone and eszopiclone, increase total sleep time beyond the first half of the night. The effect of the melatonin agonist ramelteon on sleep variables is limited to a decrease of the latency to sleep onset. The benzodiazepine derivatives induce a further reduction of slow-wave sleep (SWS) and rapid eye movement (REM) sleep in patients with an insomnia complaint. Furthermore, during the administration of the nonbenzodiazepine derivatives, zaleplon, zolpidem, zopiclone, and eszopiclone, and the melatonin agonist ramelteon, SWS and REM sleep do not regain normal levels or can even be further suppressed.

Caffeine-induced sleep disruption: effects on waking the following day and its reversal with an hypnotic

The effects of 4 mg/kg and 8 mg/kg caffeine nocte as a model of insomnia, and its potential for reversal with an hypnotic (temazepam 20 mg) were investigated in two double-blind placebo controlled crossover studies, each with six healthy volunteers. Following an adaption night and day, two nights per treatment were assessed with multiple sleep latency tests (MSLTs), performance measures and subjective questionnaires undertaken the following day. In comparison to placebo significant (P < 0.05) increases in sleep onset latency of 30 and 40 min were seen for low and high doses respectively. Significant reductions in sleep duration were limited to the higher dose (total sleep time 80 min, sleep efficiency 17 per cent), as were reductions in slow wave sleep and non-REM sleep which contrasted with increased waking. However, contrast analysis revealed significant dose-related effects for these measures, whilst the lower dose produced more stable effects across nights, suggesting it as more suitable for a model of insomnia in healthy sleepers. Significant decrements in critical flicker fusion (CFF) performance and reduced MSLT latencies reflected increased daytime sleepiness following both doses; although significant subjective changes to sleep and sleep tendency next day were limited to the higher dose. Co-administration of temazepam elixir successfully reversed increased sleep latency seen with the lower caffeine dose and improved subjective sleep, but significant effects on other sleep measures were more limited despite improved mean trends. Similarly, improvements in CFF performance and MSLT latencies failed to achieve significance, suggesting a possible limitation of the hypnotic in overcoming the effects of sleep disturbance and consequences for waking function next day.

Increased waking after intra-accumbens injection of m-chlorophenylbiguanide: prevention with serotonin or dopamine receptor antagonists

Bilateral injection of the selective 5-HT 3 receptor agonist m-chlorophenylbiguanide (5.0–40.0 μg) into the nucleus accumbens of the rat significantly increased waking and decreased slow wave sleep. Rapid eye movement (REM) sleep remained unchanged. Pretreatment with the 5-HT 3 receptor antagonist MDL 72222 (1 aH,3 a,5 a,H-tropan-3-yl-3,5-dichloro-benzoate) (0.5 mg/kg s.c.) reversed the effects of m-chlorophenylbiguanide (10.0–20.0 μg) on sleep and waking. Blockade of the dopamine D 1 or D 2 receptor with (+)-SCH 23390 (0.25 mg/kg s.c.) or YM-09151-2 ( cis-N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-methylaminobenzamide) (0.5 mg/kg s.c.), respectively antagonized the increase of waking and reduction of slow wave sleep induced by m-chloro-phenylbiguanide (10.0 μg). Our results tend to indicate that the increase of wakefulness after injection of the selective 5-HT 3 receptor agonist m-chlorophenylbiguanide into the nucleus accumbens is partly related to the release of endogenous dopamine. In addition, they suggest that concomitant stimulation of both accumbens dopamine D 1 and D 2 receptor-related mechanisms is a necessary prerequisite to increase wakefulness.

A quantitative sleep-EEG study on the effects of benzodiazepine and zopiclone in schizophrenic patients

Polysomnographic examinations (PSG) were performed on 6 male schizophrenic outpatients who were being treated with benzodiazepine (BZD) hypnotics in combination with neuroleptics and 6 healthy male volunteers. In schizophrenic subjects, zopiclone (ZPC), 15 mg/day, was substituted for the BZD hypnotics, and PSGs were recorded again during ZPC therapy. All-night sleep stage scoring was carried out by visual analysis, and computerized period-amplitude analysis of sleep EEG was also performed. The schizophrenics showed marked reduction in the amount of slow-wave sleep (SWS) and in the number of delta half-waves during all-night sleep, especially those with higher amplitude, as compared to the normals. The number of delta half-waves in the patients was markedly reduced during the first sleep cycle. The average amplitude of delta half-waves during all-night sleep in the schizophrenics was significantly lower than that in the normals. The half-wave count of total delta waves in the schizophrenics was higher during treatment with ZPC than with BZDs, although no significant differences were observed in the amount of SWS between the two treatments. Soundness of sleep in the subjective sleep assessment was better evaluated during treatment with ZPC than BZDs. These results suggest that reduction of SWS in schizophrenia may be attributable mainly to the decrease in the number of delta waves with higher amplitude and that ZPC may induce deeper sleep in schizophrenics than BZDs.

The effects of fenfluramine on sleep and prolactin in depressed inpatients: A comparison of potential indices of brain serotonergic responsivity

The effects of fenfluramine, an indirect serotonergic agonist, on electroencephalographic sleep and prolactin secretion were assessed in 12 unmedicated inpatients with a primary diagnosis of major depressive episode. Compared to prefenfluramine profiles, sleep studies performed following fenfluramine administration showed a statistically significant reduction of slow-wave sleep (SWS) ( p < 0.001) and a corresponding increase in percentage of stage-2 sleep ( p < 0.007). Automated delta wave counts per min decreased significantly during the first nonrapid eye movement (NREM) period ( p = 0.04), and automated rapid-eye movement (REM) counts were also decreased in the second REM period ( p = 0.02). These effects on sleep electroencephalogram (EEG) did not correlate significantly with another measure of serotonergic responsivity, namely peak prolactin level following fenflurramine, nor with the severity of depression. The reductions in SWS and REM counts are proposed to be the result of time-dependent changes in serotonergic neurotransmission following the administration of fenfluramine. These findings are consistent with earlier work suggesting a role for serotonin in initiation and regulation of SWS and REM sleep.

Automatic Detection of K-Complexes: Validation in Normals and Dysthymic Patients

A model-based automatic K-complex (Kc) detector was applied to all-night single-channel sleep electroencephalographic (EEG) recordings from normal and dysthymic patients. The performance of the detector was analyzed in the two groups, and the differences obtained were discussed. The results showed that the detection rate of Kc in the normal group was around 92% through all stages of non-rapid eye movement (NREM) sleep, but with high numbers of "false" positives in stage 4 NREM, which reached 57%. In the dysthymic patients "true" detection included 85% of the Kc, but the percentage of "false" positives dropped to 25% in stage 4 NREM. Most of the "false" detections in the normal group were due to sharp delta activity during slow wave sleep (SWS). The results in the patient group were expected, because sleep in dysthymics showed a reduction in SWS when compared to normals. The behavior and automatic artifact rejection mechanisms of the detector are briefly presented. The model-based Kc detector performed significantly better than other automatic detectors described in the literature; it was found to be a useful tool for routine sleep EEG studies.

Pharmaco-EEG profile of intravenous zolpidem in healthy volunteers

The mechanism of action and the pharmacokinetics of hypnotic drugs are key determinants of their clinical effects in patients with primary or comorbid insomnia. Accordingly, the sedation and sleep-promoting properties of drugs acting as positive allosteric modulators of the GABAA receptor depend upon their selective binding to the α1 receptor subtype. The additional binding to other receptor subtypes conditions the occurrence of adverse events. The absorption rate has been emphasized as a determinant of onset of action, and the elimination half-life (t1/2) and distribution as key factors of duration of action of hypnotic drugs in clinical use. Benzodiazepine and nonbenzodiazepine hypnotics improve sleep induction, and depending on their t1/2 and presence of active metabolites, they improve sleep maintenance. In this respect, the pyrazolopyrimidine derivative zaleplon does not affect total sleep time. On the other hand, the increase of total sleep time that follows the administration of the benzodiazepine and imidazopyridine derivatives midazolam, triazolam, and zolpidem immediate-release, is limited to the first half of the night. In order to circumvent this limitation, a zolpidem extended-release preparation has been made available. The benzodiazepine hypnotics, temazepam, flunitrazepam, and flurazepam, and the cyclopyrrolone derivatives, zopiclone and eszopiclone, increase total sleep time beyond the first half of the night. The effect of the melatonin agonist ramelteon on sleep variables is limited to a decrease of the latency to sleep onset. The benzodiazepine derivatives induce a further reduction of slow-wave sleep (SWS) and rapid eye movement (REM) sleep in patients with an insomnia complaint. Furthermore, during the administration of the nonbenzodiazepine derivatives, zaleplon, zolpidem, zopiclone, and eszopiclone, and the melatonin agonist ramelteon, SWS and REM sleep do not regain normal levels or can even be further suppressed.

Sleep disturbances in patients with generalized anxiety: a clinical and EEG sleep study

All night EEG sleep recordings and clinical evaluations of sleep were performed in order to compare patients with generalized anxiety and normal controls. Patients were selected according to DSM III-R criteria and went through a two weeks phase treatment with placebo before the sleep evaluation. As compared to normals, anxious patients showed a fragmented and superficial sleep with no changes of REM sleep features. Further to disturbances of sleep continuity and duration, they had a higher percentage of wake and stage 2, as well as a reduction of slow wave sleep (SWS) mainly due to a diminished percentage of stage 4. Several EEG sleep measures--related both with the amounts of SWS and sleep duration and continuity--are significantly correlated with symptoms severity. The pathogenic significance of sleep disturbances in generalized anxiety is discussed.