Drug Nights Research Articles

Mirtazapine Provokes Periodic Leg Movements during Sleep in Young Healthy Men

Recent evidence suggests that certain antidepressants are associated with an increase of periodic leg movements (PLMS) that may disturb sleep. So far, this has been shown in patients clinically treated for depression and in cross-sectional studies for various substances, but not mirtazapine. It is unclear whether antidepressants induce the new onset of PLMS or only increase preexisting PLMS, and whether this is a general property of the antidepressant or only seen in depressed patients. We report here the effect of mirtazapine on PLMS in young healthy men. Open-labeled clinical trial (NCT00878540) including a 3-week preparatory phase with standardized food, physical activity, and sleep-wake behavior, and a 10-day experimental inpatient phase with an adaptation day, 2 baseline days, and 7 days with mirtazapine. Research institute. Twelve healthy young (20-25 years) men. Seven days of nightly intake (22:00) of 30 mg mirtazapine. Sleep was recorded on 2 drug-free baseline nights, the first 2 drug nights, and the last 2 drug nights. Eight of the 12 subjects showed increased PLMS after the first dose of mirtazapine. Frequency of PLMS was highest on the first drug night and attenuated over the course of the next 6 days. Three subjects reported transient restless legs symptoms. Mirtazapine provoked PLMS in 67% of young healthy males. The effect was most pronounced in the first days. The possible role of serotonergic, noradrenergic and histaminergic mechanisms in mirtazapine-induced PLMS is discussed.

Effects of a Mandibular Repositioning Appliance on Sleep Structure, Morning Behavior and Clinical Symptomatology in Patients with Snoring and Sleep-Disordered Breathing

Background: Mandibular repositioning appliances (MRAs) have become an established treatment for snoring and sleep-disordered breathing – though most studies only focused on the evaluation of respiratory variables. Methods: This single-blind, placebo-controlled case-series study investigated the effects of an individually adjustable MRA on psychopathology, macro-/microstructure of sleep, periodic leg movements, morning performance, mood/affect and psychophysiology. Fifty patients (37 males) aged 59.7 ± 10.3 years, suffering from primary snoring (7), mild (22), moderate (15) and severe apnea (6), spent 4 nights in the sleep laboratory (adaptation, placebo, drug and MRA night). The drug night is not subject of the present paper. Results: Confirmatory statistics showed an improvement of the snoring index by 72%. Descriptively, the apnea index and the apnea-hypopnea index normalized. A clinical improvement was seen in the Pittsburgh Sleep Quality Index, the Zung Anxiety/Depression Scales and the Epworth Sleepiness Scale. The restless legs syndrome also improved. Polysomnographically, sleep stages REM and 4 as well as REM latency increased, stage 3, movement time, stage shifts and periodic leg movements decreased, as did all arousal measures. Subjectively, morning well-being, drive, affectivity and wakefulness improved. Objectively, attention, motor and reaction time performance, critical flicker frequency as well as muscular strength increased, diastolic blood pressure and the pulse rate decreased. Conclusion: Apart from its good therapeutic effects on snoring and respiratory variables (snoring showed complete or partial response in 68%, the apnea-hypopnea index in 67% of the apnea patients), the MRA also improved psychopathology, objective and subjective sleep and awakening quality.

Benzodiazepine effects on human sleep eeg spectra: A comparison of triazolam and flunitrazepam

The effects of 0.5 mg triazolam (TRI) and 4 mg flunitrazepam (FNZ) on the sleep electroencephalogram (EEG) were studied in eleven (six for TRI, and five for FNZ) healthy young male subjects. C3 EEG channel data of one baseline night, three drug nights and two withdrawal nights were recorded and their analyzed using a fast Fourier transformation (FFT) method. Changes in the 0.5 Hz to 40 Hz power spectrum showed that: 1) both TRI and FNZ increased higher frequency activity and reduced lower frequency activity on the drug nights; 2) on drug nights, NREM sigma frequency power was more strongly enhanced by TRI than FNZ, while the beta power of both NREM and REM was more strongly enhanced by FNZ than TRI; 3) NREM alpha power increased on the second night of withdrawal from both TRI and FNZ; 4) the power spectra for both NREM and REM sleep returned to baseline levels by the fourth night of withdrawal from either TRI or FNZ. These findings suggest that 0.5 mg TRI and 4 mg FNZ have both common and differing pharmacological effects on the central nervous system. Such differences could be caused by differences in the dose, half-life or systemic distribution of these two drugs.

Flunitrazepam effects on human sleep eeg spectra II: Sigma and beta alterations during NREM sleep

Flumtrazepam (FNZ) is known to enhance the higher EEG frequencies, including sigma (10–15 Hz) and beta (20–28 Hz). Both sigma and beta frequency bands show an inverse relationship with delta (0.3–3 Hz) during NREM periods, as we have previously reported. It is not known whether generation of these two EEG frequencies is mediated by the same or different neuronal mechanisms. In this report, we compare alterations of delta, sigma and beta EEG induced by FNZ (4 mg) orally administered to five healthy male subjects for seven consecutive nights. Sleep EEG on the baseline night (BLN), and the fourth and seventh drug nights (4DN, 7DN) was subjected to fast Fourier transform (FFT) analysis. On drug nights, sigma was enhanced without regard to delta amount, but beta was enhanced only during epochs containing low delta. Thus, sigma and beta EEG were altered differently by the same pharmacological agent. These results suggest that sigma and beta EEG are mediated by different neuronal mechanisms.

P-8-5 - Effects of zopiclone, zolpidem and flunitrazepam on nocturnal psychomotor and cognitive functions in normal young subjects

1987) was completed daily each morning. Sleep lab studies were carried out on 7 nights (pre-drug placebo nights 6, 7; drug nights I, 27, 28; post-drug placebo nights 1,7) and included polysomnography, evaluation of subjective sleep quality, subjective and objective awakening quality measured by psychometry. An activity monitor was worn by the patients throughout the 6 weeks to investigate the sleep-wake cycle. Preliminary evaluations demonstrated significant improvement of the anxiety syndrome and the sleep quality during both active compounds, as compared with placebo, with a worsening of symptoms on the I st night of placebo substitution, levelling off until the 7th night. Differential drug effects will be discussed.

Flunitrazepam effects on human sleep EEG spectra: Differences in NREM, REM and individual responses

Flunitrazepam (FNZ) (4 mg), an intermediate type benzodiazepine (BDZ) hypnotic, was administered orally to five healthy male subjects (Ss) for seven consecutive nights. Sleep EEG from the baseline night (BLN), the initial drug night (IDN), the fourth and the seventh drug nights (4DN, 7DN) was subjected to fast Fourier transform (FFT) analysis. During NREM sleep of 4DN and 7DN sigma band (11.0–12.5 Hz) activity was similarly enhanced in every S. In REM of 4DN and 7DN the beta band (23.0–29.0 Hz) was enhanced, but with larger variations among Ss. High intra-individual consistency of the relative EEG power patterns on 4DN and 7DN was observed. These results suggest that 1) EEG responses to FNZ are different in sleep states; explorations of these differences may provide better understandings of sleep mechanisms, and 2) individual variations in EEG responses may reflect individual variations of the BDZ receptor system. These methods may be useful for exploring receptor changes in neuropsychiatric disorders.

Cyclic alternating pattern (CAP) rate in the polygraphic investigation of classic and novel hypnotic drugs

SummaryThe difficulty to recruit homogeneous samples of insomniacs requires alternative approaches for sleep studies. Acoustic perturbation in healthy volunteers made it possible to determine an experimental model of acute situational insomnia in order to investigate the effects of classic and novel hypnotic compounds. Unfortunately, the traditional scoring parameters of sleep are inadequate to provide reliable information for defining the neurophysiological bases of insomnia and for evaluating the efficacy of hypnotic drugs. Recent studies on the microstructure of sleep have permitted to identify a specific EEG feature, the cyclic alternating pattern (CAP), correlated with the subjective appreciation of sleep quality. Comparing placebo, zolpidem, zopiclone, lorazepam and triazolam, given at equivalent therapeutic doses in middle-aged healthy volunteer subjects under basal conditions and under acute situational insomnia, provided non-significant information when using classical sleep parameters whereas CAP rate (the percentage ratio of CAP time to non-REM sleep time) permitted to discriminate the basal nights from the perturbed nights and the drug nights from the placebo nights. These data have been confirmed in clinical studies using zolpidem versus placebo in chronic insomniacs.

Analysis of sleep EEGs by the interval histogram method--validity of the baseline night as a control and the effect of ethyl loflazepate (CM6912).

The effects of an anxiolytic drug, ethyl loflazepate (CM6912) on sleep EEGs were investigated by the interval histogram method originally developed. EEGs were classified into each of the delta 2-beta 2 and sigma 1 wave-form parameters, and the individual frequencies were determined on the third baseline, second drug and the first recovery nights in each sleep stage. In comparison with the second baseline night, the sigma 1 waves in stage 2 sleep and the delta 1 waves in REM sleep were decreased and the alpha and sigma 1 waves in stage 3 sleep were increased on the third baseline night. In consideration of the 5% significance level and the remarkable influence of drug administration, described below, no major problems were encountered in the use of the night as a control in this experimental schedule. The main characteristics of administration of CM6912 manifested as decreases in the slow wave, increases in the fast wave, and an increase in the sigma 1 wave in sleep stages other than stage 1. These tendencies were remarkable on the second drug night and were still evident even on the recovery night. Increases in sigma 1 wave were related to increases in sleep spindles. The increases in the beta 2 wave were particularly remarkable in REM sleep.

Temazepam 7.5 mg

Temazepam, 7.5 mg was evaluated in the sleep laboratory in 8 elderly insomniacs, using a 14-night protocol (4 placebo-baseline nights, 7 drug nights, and 3 placebo-withdrawal nights). With short-term use temazepam was found to be effective, producing a significant improvement in total wake time from baseline (100 vs. 145 min). With continued drug administration, total wake time remained below baseline but not significantly so (125 vs. 145 min). During drug administration, there were no major CNS and behavioral adverse effects reported such as daytime sedation, memory impairment or hyperexcitability (daytime anxiety). Following drug withdrawal, there was no significant increase in wakefulness, i.e., no rebound insomnia (150 vs. 145 min). In summary, temazepam, 7.5 mg is effective in elderly subjects with short-term use and has a minimum of adverse effects. Use of hypnotic drugs is an adjunctive therapy which should be for a short-term period with subsequent short-term intermittent use as needed. Because of its low propensity for producing rebound insomnia, temazepam can be effectively used in this manner.

Temazepam 7.5 mg: effects on sleep in elderly insomniacs.

Temazepam, 7.5 mg was evaluated in the sleep laboratory in 8 elderly insomniacs, using a 14-night protocol (4 placebo-baseline nights, 7 drug nights, and 3 placebo-withdrawal nights). With short-term use temazepam was found to be effective, producing a significant improvement in total wake time from baseline (100 vs. 145 min). With continued drug administration, total wake time remained below baseline but not significantly so (125 vs. 145 min). During drug administration, there were no major CNS and behavioral adverse effects reported such as daytime sedation, memory impairment or hyperexcitability (daytime anxiety). Following drug withdrawal, there was no significant increase in wakefulness, i.e., no rebound insomnia (150 vs. 145 min). In summary, temazepam, 7.5 mg is effective in elderly subjects with short-term use and has a minimum of adverse effects. Use of hypnotic drugs is an adjunctive therapy which should be for a short-term period with subsequent short-term intermittent use as needed. Because of its low propensity for producing rebound insomnia, temazepam can be effectively used in this manner.

Comparison of the Effect of Zopiclone and Brotizolam on Sleep EEG by Quantitative Evaluation in Healthy Young Women

We studied the effect of brotizolam (BRO) (0.25 mg) and zopiclone (ZPC) (7.5 mg) on the sleep electroencephalograms (EEG) of seven healthy young women (ages 20-21 years). In addition to conventional sleep scoring, we performed spectral analysis of EEG wave forms using the Fast Fourier Transformation (FFT) method. Four weeks following two consecutive polysomnographic recordings with placebo administration (for baseline data), polysomnography with BRO or ZPC administration was performed on the subjects who were then crossed over to polysomnography with ZPC or BRO, respectively, 1 week later. Total rapid eye movement (REM) time was decreased on the ZPC and BRO nights and REM latency was prolonged on the ZPC night compared with baseline (BL) night. Other parameters, however, were not significantly different between the drug nights and the BL night. There were also no differences in standard scoring results between both drug nights. FFT analysis revealed significant differences in total power density percentage and mean power density percentage in both nonrapid eye movement (NREM) and REM sleep between ZPC and BRO nights and between both drug nights compared to the BL night. Total power density and mean power density per epoch showed significant decreases in the theta band (6.0-8.0 Hz) and sigma band (12.0-14.0 Hz) on the ZPC night versus the BRO night or BL night during specific NREM periods. The results of this study corroborate previous reports that suggest computer-aided quantitative electroencephalography aids in differentiating specific effects of hypnotics and other central-nervous-system-acting agents on the sleep EEG.(ABSTRACT TRUNCATED AT 250 WORDS)

Cortical reactivity in REM sleep with tonic mentalis EMG activity induced by clomipramine: an evaluation by slow vertex response

Slow vertex response (SVR) to sound stimuli was used as an index to assess whether cortical reactivity in REM sleep with tonic mentalis EMG activity (stage 1-REM) corresponds to that in REM sleep or rather to that in stage 1 of NREM sleep. In 11 young adult subjects 3 night polygraphic records were made after administration of 25 or 50 mg of clomipramine or non-active placebo. Stage 1-REM was observed in the drug night in 8 of the 11 subjects. N 1-P 2 and P 2-N 2 amplitudes of SVR were markedly smaller in stage 1-REM than in stage 1, but were virtually of the same height in stage 1-REM and in stage REM. This indicates that cortical reactivity in stage 1-REM closely resembles the counterpart in stage REM. This findings corresponds well with the frequent emergence of vivid dreams in stage 1-REM, indicating that stage 1-REM observed in the present subjects probably represents REM sleep without muscle atonia.

Sleep Laboratory Studies on the Single-Dose Effects of Serotonin Reuptake Inhibitors Paroxetine and Fluoxetine on Human Sleep and Awakening Qualities

Paroxetine is a novel antidepressant drug with selective serotonin (5-HT) reuptake inhibitory properties. In a double-blind placebo-controlled crossover sleep laboratory study the single-dose effects on objective and subjective sleep and awakening qualities were investigated after paroxetine 20, 30 and 40 mg morning doses (PX 20, 30, 40), paroxetine 30 mg evening dose, fluoxetine 40 mg morning dose (FX 40) and placebo in 18 healthy young volunteers. The drugs were orally administered in 2-wk intervals. In addition to each drug night, the adaptation night and washout night were recorded. Polysomnographic investigations (10:30 p.m. to 6:00 a.m.) showed a delayed sleep onset only after the morning intake of paroxetine, PX 40 being statistically different from placebo. Total sleep time and sleep efficiency deteriorated under morning PX 30, PX 40 and evening PX 30 as compared to placebo. The nocturnal wake time and sleep stage 1 increased under the paroxetine. Rapid eye movement (REM) reduction (min and %) occurred dose dependently after all paroxetine doses, but the REM latency was lengthened only after the morning intake. The suppressant effect on REM sleep is characteristic for antidepressants and was still significant in the washout nights following PX 40 and evening PX 30. The only statistically relevant finding under 40 mg fluoxetine referred to the increase of REM latency in both drug and washout nights. In contrast to objective results, subjective sleep quality remained generally unchanged. Attention, concentration and reaction performance improved under paroxetine as compared to baseline. The deterioration of well-being under PX 40 might be related to the appearance of drowsiness and nausea. Blood pressure and pulse rate were unaffected.

Ultradian dynamics of sleep after a single dose of benzodiazepine hypnotics

A single bedtime dose of the benzodiazepine hypnotics, flunitrazepam (2 mg), triazolam (0.5 mg) or flurazepam (30 mg), was administered to young, healthy subjects. Abortive first rapid eye movement sleep (REMS) episodes, characterized by a low level of EEG slow-wave activity (spectral power density in the 0.75–4.5 Hz band) without rapid eye movements and/or muscle atonia, were more frequent in the drug night than in the placebo night or in the drug-free night following upon the drug night. The benzodiazepine hypnotics depressed slow-wave activity in non-REM sleep (NREMS) in the drug night and the subsequent drug-free night. However, the typical declining trend of slow-wave activity over the first three NREMS-REMS cycles, and the cyclic ultradian pattern of slow-wave activity were little affected by the hypnotics. The results indicate that benzodiazepine hypnotics depress the generation of slow EEG waves without disrupting the homeostatic and ultradian processes of sleep regulation.

Sleep laboratory studies on single dose effects of suriclone.

1. In a double-blind, placebo-controlled sleep laboratory study single doses of suriclone, a new non-benzodiazepine anxiolytic binding to benzodiazepine receptors, were investigated with respect to sleep and awakening. 2. Sixteen healthy young volunteers spent 10 nights in the sleep laboratory: 1 adaptation night, 1 baseline night and 4 drug nights (placebo; 0.2 mg, 0.4 mg suriclone; 2 mg lorazepam as reference drug) and 4 subsequent wash-out nights (drug-interval: 1 week). Somnopolygraphic investigations (22.30 h to 06.00 h) were commenced 0.5 h after drug-intake. A self-rating scale for sleep and awakening quality as well as psychometric tests were completed in the morning. 3. Hypnotic effects were most pronounced after lorazepam in regard to total sleep time and sleep efficiency. After lorazepam as well as after 0.4 mg suriclone nocturnal awakenings decreased significantly as compared with placebo, which was reflected in an improved subjective sleep quality after both dosages. Suriclone 0.2 mg did not induce any alterations in all night sleep. 4. In the morning, well-being, drowsiness and reaction time performance deteriorated after lorazepam as compared with placebo but not after suriclone. The latter was significantly superior to lorazepam with respect to subjective awakening quality, well-being, emotional rapport, drowsiness and attention. 5. Blood pressure and pulse remained unchanged after all of the drugs. Critical flicker frequency and muscle strength decreased only after lorazepam as compared with placebo.

Effects of moclobemide on sleep in healthy human subjects

Ten healthy, normal subjects (5 male and 5 female) aged 20-28 years participated in this experimental study of the effect of moclobemide on sleep. The design consisted of 2 sessions of 5 nights each, comprising 1 adaptation night, 2 nights on placebo and 2 inputs of moclobemide 4 mg/kg (session B). The 2 sessions were separated by at least 15 days and their order was balanced and randomized. During the last 4 nights of each session, sleep parameters were recorded throughout the night according to standard procedures. Moclobemide at a dose of 4 mg/kg induced moderate changes in the sleep-wake balance: a significant increase in stage 1 on the second drug night, a slight increase in stage 2 and a significant decrease in paradoxical sleep on the 2 drug nights. There was also a moderate reduction in the number of rapid eye movements (REM) during paradoxical sleep, but the number of cycles and latency to paradoxical sleep were unchanged, as well as all other sleep parameters measured. With 6.5 mg/kg, the changes were more pronounced: total sleep time was diminished, but this was significant only on the second and third nights. Transient awakenings increased significantly on the first drug night, and wakening latency decreased. The only modification of orthodox sleep was an increase in the percentage of stage 2 on the first drug night, whereas slow-wave sleep was unchanged. Paradoxical sleep was reduced on the first 2 drug nights, but tolerance appeared on the third night. The decrease in paradoxical sleep was exacerbated in the last part of the night. REM were decreased during paradoxical sleep.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of Triazolam on the Perception of Sleep and Wakefulness in Insomniacs

AbstractAlthough the short-acting benzodiazepines are the most widely used hypnotics in the world, the mechanism by which they induce a sense of improved sleep remains obscure. In order to determine whether triazolam alters the perception of being asleep, we have performed auditory arousal threshold measures on chronic insomniacs during waking and sleeping at five points through the night, and then questioned them regarding their subjective experience prior to each forced arousal. As expected, triazolam 0.25 mg resulted in increased EEG or behavioral arousal thresholds 5 minutes after “lights out,” during stage 2 sleep 10 minutes after the first sleep spindle, and during spontaneous waking time. As with other benzodiazepine hypnotics, the arousal thresholds in stage 2 on active drug nights exceeded the amplitude of common commercial smoke alarms. Patients reported having been awake during the stage 4 trial in 50% of the cases after placebo, but only 8% after 0.25 mg triazolam (p < 0.02). After triazolam, ...

Effects of Mianserin on Human Sleep

Sleep EEG and nocturnal penile tumescence (NPT) were investigated in 6 healthy men during placebo and mianserin administration and after mianserin withdrawal. The results were assessed in a historical comparison with those previously obtained with clomipramine. With mianserin, REM sleep was suppressed slightly. However, the suppressive effect of mianserin on REM sleep--based on the historical comparison--was significantly weaker than that of clomipramine throughout all the drug nights. Accordingly, a rebound increase in REM sleep was not observed after withdrawal. Less suppressive effects on NPT and disturbance of sexual function with mianserin than with clomipramine were observed. We suggest that a correlation between the prolonging effect on REM latency and the clinical antidepressant effect is limited to some antidepressants.

Effects of repeated ritanserin on middle-aged poor sleepers

Nine subjects who believed themselves to be poor sleepers, of mean age 58 years, took a placebo for 7 days, then ritanserin 5 mg for 20 days, followed by 3 days on placebo. Sleep was recorded electrophysiologically on 2 nights during baseline, 2 early drug nights, 2 late drug nights and the 2nd and 3rd withdrawal nights. Ratings of sleep quality were collected each morning. Ritanserin, a 5HT2 antagonist, caused a persistent doubling of the amount of EEG slow wave sleep, without altering the total duration of sleep. Ritanserin decreased the frequencies of awakening and after about a week it appeared to improve the subjective quality of sleep. Sleep was then impaired during withdrawal, as indicated by decreased duration and poorer subjective quality, being worst on the 3rd withdrawal night.

Differential Effects of Flunitrazepam on Human Sleep in Combination with Flumazenil

The experiments reported here were designed to characterize in detail the spectrum of activity of flunitrazepam in human sleep. The direct and residual effects of flunitrazepam, as well as the antagonism by flumazenil, an antagonist of benzodiazepine receptors, were studied in 28 normal subjects recorded in the sleep laboratory. The five categories of variables--sleep-wake balance, sleep organization, orthodox sleep, phasic events in sleep, and sleep waveforms--were all modified by flunitrazepam. Some of these modifications were observed only on the drug night and were antagonized by flumazenil, whereas others persisted in the placebo postdrug night and were not antagonized by flumazenil. A few variables showed changes intermediate between these two types of reactivity. The results do not fit well with the multiple benzodiazepine receptors theory, but instead support the concept of spare receptors. Along these lines, the study of the reactivity of sleep components to ligands of benzodiazepine receptors can contribute to the better understanding of the neuronal systems involved in their control.