Effect of the GABAA agonist gaboxadol
on nocturnal sleep and hormone secretion in healthy elderly
subjects
Marike
Lancel,
Thomas C.
Wetter,
Axel
Steiger, and
Stefan
Mathias
Max Planck Institute of Psychiatry, 80804 Munich, Germany
 |
ABSTRACT |
Aging is
associated with a dramatic decrease in sleep intensity and continuity.
The selective GABAA receptor agonist gaboxadol has been
shown to increase non-REM sleep and the duration of the non-REM
episodes in rats and sleep efficiency in young subjects and to enhance
low-frequency activity in the electroencephalogram (EEG) within non-REM
sleep in both rats and humans. In this double-blind, placebo-controlled
study, we investigated the influence of an oral dose of 15 mg of
gaboxadol on nocturnal sleep and hormone secretion (ACTH, cortisol,
prolactin, growth hormone) in 10 healthy elderly subjects (6 women).
Compared with placebo, gaboxadol did not affect endocrine activity but
significantly reduced perceived sleep latency, elevated self-estimated
total sleep time, and increased sleep efficiency by decreasing
intermittent wakefulness and powerfully augmented low-frequency
activity in the EEG within non-REM sleep. These findings indicate that
gaboxadol is able to increase sleep consolidation and non-REM sleep
intensity, without disrupting REM sleep, in elderly individuals and
that these effects are not mediated by a modulation of hormone secretion.
-aminobutyric acidA receptor; growth hormone; hypothalamic-pituitary-adrenocortical axis; sleep-electroencephalogram
spectral analysis; aging
 |
INTRODUCTION |
INSOMNIA, WHICH
COMPRISES a dissatisfaction with the quantity or quality of
sleep, is particularly common in the elderly (9, 19, 26).
Polysomnographic studies demonstrated that sleep quality deteriorates
as a function of age. With advancing age, sleep intensity decreases, as
indexed by progressive reductions in the amount of slow-wave sleep
(SWS; stages 3 and 4) and in low-frequency activity in the
electroencephalogram (EEG) during non-rapid-eye-movement (non-REM)
sleep, which are most pronounced during the first half of the night.
Moreover, sleep efficiency (total sleep time relative to time in bed)
declines due to an increase in the number and duration of nocturnal
awakenings, especially during the second half of the night (reviewed in
Refs. 1, 20). These age-related sleep changes
are associated with alterations in neuroendocrine activity. It is
assumed that the efficacy of the sleep-promoting growth hormone
(GH)-releasing hormone (GHRH) is reduced in the aged (reviewed in Ref.
28). Compared with young individuals, the nocturnal
release of GH is drastically blunted (30), and pulsatile
GHRH infusions evoke a diminished increase in the amount of SWS and GH
concentrations and a decrease in cortisol plasma levels in elderly
subjects (11). Furthermore, there is a lot of evidence
indicating that the hypothalamic-pituitary-adrenocortical (HPA) system
changes with age (reviewed in Ref. 29). In the young,
plasma concentrations of the wake-related corticotropic hormones are
minimal during the first half of the night and steadily increase during
the rest of the sleep period. In elderly individuals, cortisol levels
are relatively high during the beginning of the night, start to rise at
an earlier time point, and display dampened diurnal fluctuations.
To improve their sleep, many elderly insomniacs use hypnotics
occasionally or habitually. Most hypnotics, such as benzodiazepines, are so-called agonistic modulators of
-aminobutyric
acidA (GABAA) receptors in that they
allosterically potentiate the response of GABAA receptors
to GABA (reviewed in Ref. 25). These compounds reliably
shorten sleep onset latency and increase sleep continuity, but they
suppress REM sleep and deep sleep, as reflected by a decrease in SWS
and/or an attenuation of low-frequency activity in the EEG within
non-REM sleep (reviewed in Ref. 15). Although the data are
inconsistent, benzodiazepine hypnotics seem to affect hormonal
secretions. Various studies have found a suppression of cortisol or,
less desirable, of GH and a stimulation of prolactin (4, 12,
27).
Recent experiments have demonstrated that the selective
GABAA receptor agonist gaboxadol
[4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol; THIP], which is
currently developed by H. Lundbeck for the treatment of insomnia,
exerts effects on sleep that differ markedly from those of agonistic
modulators of GABAA receptors. In rats, gaboxadol dose
dependently increases time in non-REM sleep, lengthens the duration of
the non-REM episodes, and elevates the slow-frequency components (<9
Hz) in the EEG within non-REM sleep (14, 16). In contrast
to hypnotic benzodiazepines, these effects are sustained during a 5-day
chronic treatment (17). In young men, a single oral dose
of 20 mg of gaboxadol taken at bedtime appeared to significantly increase sleep efficiency and the amount of SWS and to augment low-frequency activity (<8 Hz), while depressing activity in the frequency range of sleep spindles in the EEG within non-REM sleep (7). Intriguingly, these findings indicate that gaboxadol
is able to increase sleep consolidation as well as sleep intensity without inhibiting REM sleep. If gaboxadol exerts comparable effects in
older people, it counteracts the typical age-related changes in sleep
and possibly also in nocturnal hormone secretion.
In the present double-blind and placebo-controlled study, we
investigated the influence of gaboxadol, taken orally shortly before
retiring during two consecutive nights, on undisturbed sleep during the
first night and on sleep-related hormonal profiles during the second
night in 10 healthy elderly subjects without sleep complaints.
 |
MATERIALS AND METHODS |
Subjects.
Ten healthy volunteers (age range 61-78 yr), six women (mean age
68.0 ± 6.7 yr) and four men (mean age 68.3 ± 2.8 yr),
participated in the study after being subjected to extensive
psychiatric, physical, and laboratory examinations. Criteria for
exclusion from the study were subjective sleep disturbances, substance
abuse, medical illness, aberrancies in blood chemistry, waking EEG or
electrocardiogram, a personal or family history of psychiatric
disorders, recent stressful life events, a transmeridian flight during
the previous 3 mo, and shift work. Additionally, the subjects underwent
a two-night polysomnographic examination in the sleep laboratory to
rule out specific sleep disorders such as sleep-associated breathing
disorders or periodic leg movement disorder. Written informed consent
was obtained from all subjects after procedures and possible side effects were explained to them. The subjects were requested to maintain
regular bedtimes and to abstain from alcohol before and during the study.
Study design.
The experiment was approved by the local ethics committee. The subjects
participated in two experimental sessions that were separated by at
least 1 wk. Each session consisted of three consecutive nights in our
sleep laboratory beginning at 2100. Night 1 served for
adaptation to the laboratory conditions. On nights 2 and 3, the subjects took a gelatin capsule at 2230 containing a placebo (lactose) in one session and 15 mg of gaboxadol
(Lundbeck, Copenhagen, Denmark) in the other session, according to a
randomized double-blind schedule (5 subjects started with placebo). On
night 2, electrodes were placed to record EEGs (C3-A2 and
C4-A1), the submental electromyogram (EMG), and a vertical and
horizontal electrooculogram (EOG). On night 3, an indwelling
forearm catheter was inserted, which was connected to a plastic tube
that ran through a soundproof lock to a neighboring laboratory. To
measure the circulating levels of adrenocorticotropic hormone (ACTH),
cortisol, GH, and prolactin, blood samples were taken from the
intravenous cannula every 30 min between 2100 and 0700, except at 2230. On all nights, the subjects went to bed at 2300 (lights off). They were
allowed to sleep until 0700 during the adaptation night. To assess
possible effects on total sleep time, bedtime was unrestricted during
nights 2 and 3. On the morning after night
2, 15-30 min after rising, the subjects completed a
questionnaire consisting of open and multiple choice questions
assessing subjective sleep quality and monitoring whether, and if so
which, physical or psychological side effects they had noticed. The
rationale for measuring sleep and hormone levels during separate nights
is that blood sampling is well known to disrupt sleep.
Sleep-EEG analysis.
Throughout night 2 (from 2300 until the subject wanted to
rise), EEGs (time constant 0.3 s, amplification 70 µV/cm, high- and low-pass filtering 0.53 and 70 Hz,
3 dB, and
12 dB/octave), EMG, and EOGs were recorded on a Schwartzer ED 24 polygraph. Sleep stages were visually scored per 30-s epoch according to conventional criteria (22) by experienced raters who were unaware of
the treatment. The variables computed included total time in bed, total
sleep time, sleep efficiency (total sleep time/time in bed), sleep
onset latency (time between lights off and the first occurrence of
stage 2), the latency to REM sleep (time between sleep onset latency
and the first epoch of REM sleep), absolute time spent in each sleep
stage, intermittent wakefulness (wakefulness between sleep onset
latency and the last sleep epoch), and the number of awakenings (
30-s
epoch and
1 min).
By use of a personal computer, the signals were sampled at 100 Hz by an
8-bit analog-digital converter and stored on disk. The C3-A2 EEG
derivation was submitted to a fast Fourier transformation. EEG power
spectra were computed for consecutive rectangular windows of 256 samples (
2.56 s), resulting in a frequency resolution of
0.39 Hz
between 0 and 50 Hz. EEG spectra were averaged over epochs of 12 consecutive windows (
30.72 s). For the following epoch, the
procedure stepped back 72 samples (0.72 s) to permit synchronization
with the 30-s epochs of the visual scores. Epochs containing visually
identified EEG artifacts, as well as epochs scored as movement time,
were eliminated. Average power in 49 frequency bins (0.39-19.14
Hz, 0.39-Hz bins), slow-wave activity (SWA; 0.78-4.29 Hz), and
-activity (12.5-14.84 Hz) within non-REM sleep (stages 2, 3, and 4) were computed for the first four 2-h intervals. To avoid missing
values, average power in each of the 49 frequency bins was computed per
4-h interval for REM sleep. Because of large interindividual
differences in absolute power, EEG power densities within non-REM and
REM sleep were normalized by their being expressed as a percentage of
the average power in the same frequency band and sleep state during the
entire placebo night.
Hormone analysis.
After heparinization and centrifugal separation, the plasma samples
taken during night 3 were immediately frozen at
25°C (cortisol, GH, and prolactin) or
80°C (ACTH). For technical
reasons, the blood samples of only nine subjects could be analyzed. The plasma levels of ACTH and cortisol were determined by commercial radioimmunoassay kits (Nichols Institute, San Juan Capistrano, CA
and ICN Biomedicals, Carson, CA, respectively). The detection limits
were 3 pg/ml for ACTH and 1.5 ng/ml for cortisol. GH was measured using
Nichols Luma Tag human GH and chemiluminescence immunometric assay
(Nichols Institute), which has a sensitivity limit of 0.2 ng/ml.
Prolactin concentrations were detected with a two-site
immunoluminometric assay (Liaison, Prolactin, Byk-Sangtec Diagnostica,
Dietzenbach, Germany) with a detection limit of 0.5 ng/ml. Intra- and
interassay coefficients of variation were <10% for all hormones. For
each hormone, all samples were analyzed in the same assay. Average
plasma levels were determined, and area under the curve was calculated
using Simpson's rule (trapezoidal integration) for the presleep period
(samples taken between 2100 and 2200) and for the first and second
halves of the sleep period (samples taken between 2300 and 0230 and
from 0300 to 0700, respectively).
Statistical evaluation.
Because of the ordinal data structure of the subjective sleep
parameters and endocrine variables, differences between the treatments
were analyzed with the nonparametric Wilcoxon matched-pairs signed-rank
test. To approach normality in the visually scored sleep parameters,
the data were log transformed [y = log10(x + 1)]. Differences in visually
scored sleep parameters and in EEG power density measures were
identified by a one- or two-factorial repeated-measures analysis of
variance (ANOVA; Greenhouse-Geisser correction), with treatment (2 levels) and time (2 or 4 levels) as within-subjects factors. Where
appropriate, ANOVA was followed by two-sided paired t-tests.
 |
RESULTS |
Subjective sleep quality.
Compared with placebo, gaboxadol significantly reduced self-estimated
sleep onset latency and increased the subjective assessment of total
sleep time (Table 1). It did not
influence the other aspects of subjective sleep quality or the
perceived state upon awakening.
With regard to the question of whether the subjects had experienced
physical or psychological side effects, one subject reported "unpleasant dreams" during the night of placebo treatment.
Visually scored sleep parameters.
Gaboxadol significantly increased sleep efficiency (Table
2; see legend for results of ANOVA) on
average by 4.5%, which was caused mainly by a tendential increase in
total sleep time. Although gaboxadol did not affect sleep onset
latency, it significantly decreased intermittent wakefulness and
reduced the number of awakenings. Although gaboxadol increased stage 2 and SWS in 8 of the 10 subjects, none of the non-REM sleep stages was
significantly affected by it. Gaboxadol neither altered the latency to
REM sleep nor total time in REM sleep.
Accumulation of the stages over 2-h intervals shows that gaboxadol
decreased wakefulness throughout the night (Fig.
1). This seems to be related to a
nonsignificant increase in SWS during the first half and to an increase
in stage 2 during the second half of the night. In contrast, the
temporal evolution of REM sleep was practically identical during the
placebo and gaboxadol nights.

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Fig. 1.
Cumulation of intermittent wakefulness, stage 2, slow-wave sleep and rapid eye movement (REM) sleep after administration
of placebo and gaboxadol. Values are means ± SE
(n = 10) and are plotted at the upper limit of each 2-h
interval. *P 0.05 (two-sided paired
t-tests).
|
|
EEG power spectra within non-REM and
REM sleep.
Analysis of SWA within non-REM sleep yielded a significant effect of
treatment (F1,9 = 16.9, P = 0.003) and of time (F3,27 = 59.6, P < 0.0001). Compared with placebo, gaboxadol
powerfully elevated SWA during the entire night, most prominently
during the first 4 h (Fig. 2).
Irrespective of the treatment, SWA declined monotonically over
consecutive 2-h intervals. For
-activity, ANOVA found only a
significant time effect (F3,27 = 7.4, P = 0.004), which was due to a treatment-independent
decline across the first two 2-h intervals (Fig. 2).

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Fig. 2.
Time course of slow-wave and -activity within non-REM
sleep (stages 2, 3, and 4) after administration of placebo and
gaboxadol. Values are means ± SE (n = 10) and are
plotted in the middle of the 2-h intervals. For each subject, data were
expressed as a percentage of the average SWA and -activity within
non-REM sleep during the entire placebo night. *P < 0.05 (two-sided paired t-tests).
|
|
Analysis of EEG power densities in each of the 0.39-Hz bins yielded a
significant (P < 0.05) treatment effect for all
frequencies <7.5 Hz. Over the first 8 h of the sleep period,
gaboxadol prominently enhanced power in all affected frequency bands
(Fig. 3), which was evident throughout
the recording period (Fig. 4).
Furthermore, ANOVA found a significant time effect for all frequency
bands <8 Hz and between 9 and 17 Hz, reflecting a steady decline in low-frequency activity and a transient decrease in high-frequency activity that were not affected by the treatment.

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Fig. 3.
Effect of gaboxadol on electroencephalogram (EEG) power
densities within non-REM sleep (stages 2, 3, and 4) and REM sleep
during the first 8 h of the sleep period. Values are means ± SE (n = 10). For plotting purposes, data of each
subject were expressed as a percentage of the corresponding placebo
value. Lines at the bottom of the graphs indicate frequency bands for
which ANOVA yielded a significant (P < 0.05) effect of
treatment.
|
|

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Fig. 4.
EEG power densities in the frequencies between 0.39 and
19.14 Hz within non-REM sleep (stages 2, 3, and 4) per 2-h interval
after administration of placebo and gaboxadol. Values are means ± SE (n = 10). For plotting purposes, data of each
subject were expressed as a percentage of the average power in the same
frequency band within non-REM sleep during the entire placebo night.
Lines at the bottom of the graphs indicate frequency bands in which
power differed significantly between the treatments (P < 0.05, two-sided paired t-tests).
|
|
For EEG power densities within REM sleep, ANOVA found a significant
effect of treatment for all frequency bands <12 Hz and of time for
nearly all frequencies >3 Hz. Gaboxadol augmented power in the lower
frequencies, most prominently in the frequency bands between 5 and 9 Hz
(Fig. 3), which subsided during the course of the sleep period (Fig.
5). Irrespective of the treatment, power in most frequency bands declined over the night.

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Fig. 5.
EEG power densities in the frequencies between 0.39 and 19.14 Hz
within REM sleep per 4-h interval after administration of placebo and
gaboxadol. Values are means ± SE (n = 10). For
plotting purposes, data of each subject were expressed as a percentage
of the average power in the same frequency band within REM sleep during
the entire placebo night. Lines at the bottom of the graphs indicate
frequency bands in which power differed significantly between the
treatments (P < 0.05, two-sided paired
t-tests).
|
|
Endocrine variables.
Plasma concentrations of ACTH, cortisol, prolactin, and GH did not
differ significantly between the placebo and gaboxadol conditions
(Table 3 and Fig.
6).

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Fig. 6.
Time course of the levels of ACTH, cortisol, prolactin,
and growth hormone. Values are means ± SE (n = 9).
|
|
 |
DISCUSSION |
Placebo night.
The questionnaire revealed that the subjects were satisfied with their
sleep during the placebo condition. Nevertheless, the polysomnographically derived parameters showed that sleep quality was
in general rather poor. In agreement with most previous reports on
nocturnal sleep in the elderly (1, 20), sleep efficiency was low, on average 81.5%, caused by frequent and partially
long-lasting arousals. Moreover, the subjects displayed little SWS,
which was due to a relatively low amount of stage 3 and the complete
absence of stage 4. Other studies demonstrated that the age-related
decline of SWS is associated with a reduction in the amplitude
(8) and density (6) of slow waves and,
consequently, with a decrease of spectral power density in the lower
frequency bands (5, 6, 18). Conforming with these reports,
the temporal changes in SWS and SWA across the night were qualitatively
identical to the patterns in young subjects: SWS was concentrated in
the first part of the night, and SWA decayed monotonically in the
course of the sleep period. Coupled with the fact that extended
previous wakefulness increases SWS (3, 23, 31) and SWA
(21) in older as in younger subjects, sleep intensity
clearly remains a function of sleep-wake-dependent processes.
Reportedly, age-related decreases in EEG power are not confined to SWA
but also encompass
- as well as
-frequency bands (5,
18), whereby the latter is related to a reduction in the number,
duration, and amplitude of sleep spindles (10, 32). In
contrast to slow-frequency components, the time course of
-activity
changes profoundly with age. Whereas
-activity tends to increase
over consecutive non-REM episodes in the young, it hardly fluctuates in
middle-aged individuals (5, 18) and even declines across
the first half of the night in our senior subjects.
Gaboxadol night.
The employed dose of 15 mg of gaboxadol was well tolerated; none of the
subjects reported negative side effects. As earlier observed in young
subjects (7), gaboxadol did not affect sleep onset
latency. Because this substance is absorbed rapidly after oral
administration (24), this finding indicates that gaboxadol does not influence sleep initiation in subjects without difficulties in
falling asleep; yet gaboxadol significantly shortened self-estimated sleep latency. Intriguingly, subjective sleep latency exceeded objective sleep onset latency during placebo, whereas they matched closely during the gaboxadol night. It is well established that elderly
individuals tend to perceive sleep latency as being of longer duration
(reviewed in Ref. 30). The gaboxadol-evoked reduction may
be explained by its known weak anxiolytic properties (13).
Moreover, gaboxadol significantly increased subjectively assessed total
sleep time and tended to increase objective total sleep time. Although
time in bed was unchanged, gaboxadol reduced the number of awakenings
and persistently decreased intermittent wakefulness. Consequently,
sleep efficiency was increased by
4.5%. The decrease in wakefulness
was associated with a tendential increase in SWS during the first half
and with an increase in stage 2 during the second half of the night.
Gaboxadol did not promote SWS to the extent that it does in younger
subjects. It is well established that many manipulations that
increase SWS in young individuals, including sleep deprivation and the
pulsatile administration of GHRH or cortisol, evoke only minor changes
in SWS in aged subjects (2, 11, 21). These findings
suggest that the flexibility to change the sleep pattern decreases with
age. However, analysis of the EEG within non-REM sleep revealed that
gaboxadol powerfully elevated SWA as well as the activity in the
-frequency bands. The elevations were most prominent during the
first part of the sleep period but were still evident at the end of the
night. Qualitatively similar yet shorter-lasting effects have been
observed in young subjects (7). Thus the elimination
half-life of gaboxadol, which is 1.5-2 h in young individuals
(24), may increase as a function of age. Although it is at
present unclear whether the augmented power in the lower-frequency
bands is caused by increases in the number and/or amplitude of slow
waves, these observations indicate that gaboxadol increases non-REM
sleep intensity. Unlike its influence in young subjects, gaboxadol did
not depress
-activity, which may be a consequence of age-related
changes in the neuronal processes underlying the generation and
synchronization of sleep spindles. Concurrent with previous findings in
young subjects, gaboxadol did not alter the distribution of REM sleep
but persistently enhanced power in all frequency bands <12 Hz, most
prominently in high
, in the EEG within this stage. Because an
earlier study found that middle-aged subjects exhibit less power in the
-,
-, and
-frequencies during REM sleep than young people
(5), the present observation suggests that gaboxadol
reverses most age-related EEG alterations in both non-REM and REM
sleep. Finally, gaboxadol did not affect the hormone levels, which
demonstrates that the sleep changes evoked by it are not mediated by or
associated with altered activity of the
hypothalamic-somatotrophic or HPA systems. Thus the GABAA
agonist gaboxadol and benzodiazepine-agonistic modulators of
GABAA receptors not only differ in their effects on the
sleep EEG but also on sleep-related endocrine activity. With regard to
the observation that various compounds that increase SWS or SWA, such
as GHRH and
-hydroxybutyrate, also increase GH secretion (reviewed
in Ref. 29), the absence of such an effect of gaboxadol
may be unexpected. However, it has recently been shown that sleep
deprivation does not elevate GH levels in elderly subjects either
(21), which indicates that increases in SWS and/or SWA are
not necessarily associated with concomitant changes in GH.
Previous reports demonstrated that the sleep profile evoked by
gaboxadol in rats and young subjects largely resembles recovery sleep
after prolonged wakefulness. A recent study examined the influence of a
40-h sleep deprivation on sleep, EEG power densities within non-REM
sleep, and hormonal secretion in a group of subjects >60 yr old.
Unlike gaboxadol, sleep deprivation slightly elevated the levels of
prolactin, prominently reduced sleep onset latency, and attenuated EEG
activity in some frequency bands in the range of sleep spindles.
Similar to gaboxadol, it did not influence GH and cortisol
concentrations, decreased intermittent wakefulness, moderately
increased SWS, and augmented EEG activity in the frequency bands <8 Hz
(21). Thus gaboxadol pharmacologically mimics various aspects of sleep homeostatic processes in elderly as well as in young individuals.
In conclusion, the present pilot study demonstrates that, upon acute
administration, gaboxadol has marked effects on nocturnal sleep in
elderly subjects (it increases sleep efficiency, by decreasing intermittent wakefulness, and robustly enhances low-frequency activity
in the EEG within non-REM sleep, which suggests an increase in sleep
intensity) that counteract typical age-related sleep changes. Coupled
with the finding that tolerance to its sleep effects does not seem to
develop rapidly in rats (17), gaboxadol shows promise as a
treatment strategy for the chronic sleep disturbances that are most
common in the elderly population.
 |
ACKNOWLEDGEMENTS |
We thank Dr. Manfred Uhr and Alexandra Rippl for the hormone analyses.
 |
FOOTNOTES |
This study was supported by H. Lundbeck A/S, Copenhagen, Denmark.
Address for reprint requests and other correspondence: M. Lancel, Max Planck Institute of Psychiatry, Kraepelinstrasse 2, 80804 Munich, Germany (E-mail: lancel{at}mpipsykl.mpg.de)
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 18 October 2000; accepted in final form 15 February 2001.
 |
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