S Deacon

Sex differences and the effect of gaboxadol and zolpidem on EEG power spectra in NREM and REM sleep

Hypnotics that interact with the GABAA receptor have marked effects on the electroencephalogram (EEG) during sleep. It is not known whether the effects of hypnotics on EEG power spectra differ between the sexes. The effects of 5, 10 and 15 mg of gaboxadol (GBX) and 10 mg of zolpidem (ZOL) on EEG power spectra were assessed in a randomized, double-blind, placebo-controlled, 5-way cross-over design study using a phase-advance model of transient insomnia. Sleep stage specific EEG power spectra were computed in 36 men and 45 women. GBX enhanced power density in delta and theta activity in non-rapid eye movement (NREM) and rapid eye movement (REM) sleep, and suppressed sleep spindle activity in NREM sleep. The increase of delta and theta activity in NREM and REM sleep was significantly larger for women than for men but the suppression of spindle activity did not differ between the sexes. After ZOL administration, no sex differences were observed in the reduction of delta and theta activity in NREM sleep, but the increase in sleep spindle activity in NREM sleep was greater in women than in men. These sex dependent and differential effects of GBX and ZOL may be related to their differential affinity for GABA A receptor subtypes and their modulation by neurosteroids.

Dissociating Effects of Global SWS Disruption and Healthy Aging on Waking Performance and Daytime Sleepiness

STUDY OBJECTIVE To contrast the effects of slow wave sleep (SWS) disruption and age on daytime functioning. DESIGN Daytime functioning was contrasted in three age cohorts, across two parallel 4-night randomized groups (baseline, two nights of SWS disruption or control, recovery sleep). SETTING Sleep research laboratory. PARTICIPANTS 44 healthy young (20-30 y), 35 middle-aged (40-55 y), and 31 older (66-83 y) men and women. INTERVENTIONS Acoustic stimulation contingent on appearance of slow waves. MEASUREMENTS AND RESULTS Cognitive performance was assessed before sleep latency tests at five daily time-points. SWS disruption resulted in less positive affect, slower or impaired information processing and sustained attention, less precise motor control, and erroneous implementation, rather than inhibition, of well-practiced actions. These performance impairments had far smaller effect sizes than the increase in daytime sleepiness and differed from baseline to the same extent for each age group. At baseline, younger participants performed better than older participants across many cognitive domains, with largest effects on executive function, response time, sustained attention, and motor control. At baseline, the young were sleepier than other age groups. CONCLUSIONS SWS has been considered a potential mediator of age-related decline in performance, although the effects of SWS disruption on daytime functioning have not been quantified across different cognitive domains nor directly compared to age-related changes in performance. The data imply that two nights of SWS disruption primarily leads to an increase in sleepiness with minor effects on other aspects of daytime functioning, which are different from the substantial effects of age.

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.

Enhanced slow wave sleep and improved sleep maintenance after gaboxadol administration during seven nights of exposure to a traffic noise model of transient insomnia

Slow wave sleep (SWS) has been reported to correlate with sleep maintenance, but whether pharmacological enhancement of SWS also leads to improved sleep maintenance is not known. Here we evaluate the time-course of the effects of gaboxadol, an extra-synaptic gamma-aminobutyric acid (GABA) agonist, on SWS, sleep maintenance, and other sleep measures in a traffic noise model of transient insomnia. After a placebo run-in, 101 healthy subjects (20–78 y) were randomized to gaboxadol (n = 50; 15 mg in subjects <65 y and 10 mg in subjects ≥65 y) or placebo (n = 51) for 7 nights (N1–N7). The model caused some disruption of sleep initiation and maintenance, with greatest effects on N1. Compared with placebo, gaboxadol increased SWS and slow wave activity throughout N1 to N7 (p < 0.05). Gaboxadol reduced latency to persistent sleep overall (N1–N7) by 4.5 min and on N1 by 11 min (both p < 0.05). Gaboxadol increased total sleep time (TST) overall by 16 min (p < 0.001) and on N1 by 38 min (p < 0.0001). Under gaboxadol, wakefulness after sleep onset was reduced by 11 min overall (p < 0.01) and by 29 min on N1 (p < 0.0001), and poly-somnographic awakenings were reduced on N1 (p < 0.05). Gaboxadol reduced self-reported sleep onset latency overall and on N1 (both p < 0.05) and increased self-reported TST overall (p < 0.05) and on N1 (p < 0.01). Subjective sleep quality improved overall (p < 0.01) and on N1 (p < 0.0001). Increases in SWS correlated with objective and subjective measures of sleep maintenance and subjective sleep quality under placebo and gaboxadol (p < 0.05). Gaboxadol enhanced SWS and reduced the disruptive effects of noise on sleep initiation and maintenance.

EEG Power Spectra Response to a 4-h Phase Advance and Gaboxadol Treatment in 822 Men and Women

STUDY OBJECTIVE To explore the effect of gaboxadol on NREM EEG in transient insomnia using power spectral analysis and evaluate the response between men and women. METHODS This was a randomized, double-blind, 3-way, parallel-group transient insomnia study in 22 sleep laboratories. After a baseline night (N1), subjects underwent a 4-h phase-advance of their habitual sleep time the following night (N2). Healthy subjects aged 18-64 y were given single-blind placebo on N1 followed by double-blind treatment on N2 (gaboxadol 10 mg [n = 271], 15 mg [n = 274], or placebo [n = 277]) RESULTS At baseline, women showed significantly greater values in low frequency activity (< 10 Hz) and in high spindle/low beta frequency activity (14-18 Hz) compared to men. During the phase advance (placebo N2-baseline N1), there was a significant increase in power within the high spindle/low beta frequency range (15-17 Hz) and a significant reduction in beta activity (20-32 Hz), which was greater in women than men. Gaboxadol induced a significant (dose-related) increase in low frequencies (< 8 Hz) and a significant (dose-related) decrease within the alpha/spindle range (11-12 Hz). The effect was dependent upon sex, with a greater magnitude of effect observed in women than men. CONCLUSION Gaboxadol shows a characteristic NREM EEG spectral profile in a model of transient insomnia. Men and women show clear differences in NREM EEG activity at baseline, to gaboxadol treatment and to phase-shifts in habitual sleep/wake times. The exact mechanisms underlying the sex differences remain unclear, but sex is an important variable in studies evaluating sleep and gaboxadol. TRIAL REGISTRY INFORMATION: TRIAL REGISTRY www.clinicaltrials.gov, study identifier: NCT00102167.

Morning vs evening dosing of the cathepsin K inhibitor ONO-5334: effects on bone resorption in postmenopausal women in a randomized, phase 1 trial.

SummaryThe cathepsin K inhibitor, ONO-5334, improves bone mineral density in postmenopausal women with osteoporosis. The effects of morning versus evening administration of ONO-5334 were investigated by measuring bone turnover marker levels in healthy postmenopausal women. Morning administration of ONO-5334 showed a more consistent suppressive effect on bone resorption than evening administration.IntroductionBone turnover is thought to be subject to circadian variation, and the efficacy of osteoporosis treatments may be optimized by regulating the time of dosing. This study assessed whether evening administration of the cathepsin K inhibitor, ONO-5334, had a differential effect on the bone turnover marker, C-terminal telopeptide of type I collagen (CTX-I), compared with morning administration.MethodsThis was a single-center, single blind crossover study. Fourteen healthy postmenopausal women were assigned to receive ONO-5334 150 mg once daily for 5 days in each period; they were randomized to receive either evening doses in the first period and morning doses in the second or vice versa. Serum and urinary levels of CTX-I were measured throughout the study.ResultsBoth regimens showed similar patterns of reduction in serum and urinary CTX-I; however, CTX-I suppression was more consistently >60% over 24 h following morning administration. Morning administration led to 6% greater suppression of 24-h serum CTX-I area under the effect curve (AUE; 69 vs 63%; P < .05) and 7% greater suppression of urinary CTX-I/creatinine AUE (93 vs 86%; P < .01) than evening administration. Higher plasma ONO-5334 concentrations were observed between 12 and 24 h postdose following morning administration, with mean trough concentrations for the morning and evening regimens at 9.4 and 4.0 ng/mL, respectively. There were no safety findings of concern.ConclusionMorning dosing of ONO-5334 is more efficacious at reducing markers of bone turnover in healthy postmenopausal women than evening dosing.Trial registrationClinicalTrials.gov: NCT01384188, registered on June 27, 2011EudraCT: 2008-006284-37