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Contributed by Masashi Yanagisawa, September 14, 2019 (sent for review April 29, 2019; reviewed by Seiji Nishino and Kenneth P. Wright, Jr.)
Significance
Insomnia is a common symptom representing an important health burden. Widely prescribed hypnotic agents enhance the function of γ-aminobutyric acid (GABA), a major inhibitory neurotransmitter. The ability to arouse and respond to unexpected stimuli is a feature of normal sleep, and one of the concerns of this class of hypnotic agents is that patients may become physically and/or cognitively impaired while the drug is in effect. As a new approach for the treatment of insomnia, orexin receptor antagonists have been recently approved, which specifically inhibit the orexin-mediated wake-promoting system, supposedly without affecting the whole brain. We found that, compared with the GABA receptor agonist brotizolam, the orexin receptor antagonist suvorexant induced less impairment in body balance after taking the medicine.
Abstract
The majority of patients with insomnia are treated with hypnotic agents. In the present study, we evaluated the side-effect profile of an orexin receptor antagonist and γ-aminobutyric acid A (GABAA) receptor agonist on physical/cognitive functions upon forced awakening. This double-blind, randomized, placebo-controlled, cross-over study was conducted on 30 healthy male subjects. Fifteen minutes before bedtime, the subjects took a pill of suvorexant (20 mg), brotizolam (0.25 mg), or placebo and were forced awake 90 min thereafter. Physical- and cognitive-function tests were performed before taking the pill, after forced awakening, and the next morning. Polysomnographic recordings revealed that the efficacies of the hypnotic agents in prolonging total sleep time (∼30 min) and increasing sleep efficiency (∼6%) were comparable. When the subjects were allowed to go back to sleep after the forced awakening, the sleep latency was shorter under the influence of hypnotic agents (∼2 min) compared to the placebo trial (24 min), and the rapid eye movement latency was significantly shorter under suvorexant (98.8, 81.7, and 48.8 min for placebo, brotizolam, and suvorexant, respectively). Although brotizolam significantly impaired the overall physical/cognitive performance (sum of z score) compared with placebo upon forced awakening, there was no significant difference in the total z score of performance between suvorexant and placebo. Notably, the score for static balance with the eyes open was higher under suvorexant compared to brotizolam administration. The energy expenditure was lower under suvorexant and brotizolam compared with the placebo. The effect size of brotizolam (d = 0.24) to reduce the energy expenditure was larger than that of suvorexant (d < 0.01).
Insomnia is a common symptom in the general population, and various studies worldwide have shown its prevalence in 10 to 30% of the population, some even as high as 50 to 60% (1⇓⇓–4). Chronic insomnia occurs in 9 to 33% of the adult population (5, 6), and nearly half (45.6%) of the patients with insomnia take hypnotic agents (7). Currently, the most commonly prescribed hypnotic agents are γ-aminobutyric acid (GABA) agonists, which enhance the function of the major inhibitory neurotransmitter GABA by binding to the allosteric benzodiazepine site on GABAA receptors. Electroencephalographic (EEG) power spectral analyses have revealed a decrease in low-frequency (0.25 to 7.02 Hz) activity and an increase in high-frequency activity (14.04 to 21.84 Hz) in non-rapid eye movement (NREM) sleep with the administration of these GABAA receptor agonists (8, 9). As a consequence of the widespread expression of GABAA receptors in the central nervous system, GABAA receptor agonists can inhibit neurons throughout the brain and spinal cord, including those not involved in the induction and maintenance of sleep (10, 11).
Suvorexant is a recently approved orexin receptor antagonist representing an alternative mechanistic approach for the treatment of insomnia, which specifically inhibits the orexin-mediated wake-promoting system (12). Unlike GABAA agonists, orexin receptor antagonists promote both NREM and rapid eye movement (REM) sleep, do not disrupt sleep-stage-specific quantitative EEG spectral profiles, and allow somnolence indistinct from normal sleep (12). In animal studies, sleep induced by an orexin receptor antagonist did not impair the ability to selectively respond and arouse to emotionally salient auditory stimuli, similar to natural sleep (13, 14). Interestingly, after awakening, the animals returned to sleep in a dose-proportional manner.
The potential side effects of GABAA agonists include impaired cognitive and physical functions upon awakening from sleep (15, 16). Animal studies have suggested distinct effects of GABAA agonists and orexin receptor antagonists on motor and cognitive functions (17⇓–19). Motor coordination assessed 30 min after the administration of hypnotic drugs was impaired by the GABAA agonists zolpidem, eszopiclone, and diazepam in a dose-dependent manner, but not following the administration of the orexin receptor antagonist DORA-22 (17). However, the effect of orexin receptor antagonists on human cognitive and physical functions upon awakening from sleep remains untested. In addition, orexin receptor antagonists may modulate energy metabolism during sleep (20), as orexin infusion into the hypothalamus increases the oxygen consumption of freely behaving and anesthetized rats (21, 22). Moreover, orexin receptor antagonists and GABAA agonists could modify energy metabolism during sleeping through their effects on the sleep architecture, as the sleeping energy expenditure is related to the sleep stages (23). The primary objective of the present study was to compare the pharmacological effects of an orexin receptor antagonist and a GABAA agonist on physical and cognitive functions upon forced awakening when the drug effect was maximal. We also assessed the effects of hypnotic agents on the metabolic rate while sleeping.
Results
Subject Characteristics.
The characteristics of the subjects are presented in SI Appendix, Table S1. All subjects fulfilled the inclusion/exclusion criteria (SI Appendix, SI Materials and Methods). The time in bed, total sleep time, sleep latency, and sleep efficiency of the adaptation night were 515 min, 460.4 ± 46.0 min, 6.0 ± 7.5 min, and 89.4 ± 8.9%, respectively. Due to some technical problems, there were missing data for 1 Stroop color-word test, 1 eyes-opened body-sway test, and 2 indirect calorimetry measurements.
Sleep Parameters.
The total sleep time during the total time in bed was increased by brotizolam and suvorexant compared with the placebo (Table 1). Brotizolam and suvorexant decreased the awake time and increased sleep efficiency. Suvorexant increased stage REM (R) compared with brotizolam and placebo. Brotizolam increased stage NREM 2 (N2) compared with suvorexant and placebo (Fig. 1 and Table 1).
View this table:
Table 1.
Total sleep time during total time in bed (23:00 to 00:15 and 00:40 to 08:00)
Fig. 1.
Cumulative display of sleep architecture in all 30 subjects. The percentage of subjects in each sleep stage is shown. The subjects were forced awake at 00:15 and went back to sleep at 00:40.
When the sleep architecture was separately analyzed before and after forced awakening, there were no statistically significant differences during the 75-min period before forced awakening (SI Appendix, Table S2). The sleep stages immediately before the forced awakening were comparable among the 3 trials (SI Appendix, Table S3); this was important because the sleep stage from which the subject is forced awake affects subsequent performance.
The sleep latency after forced awakening was significantly longer compared with that before forced awakening in placebo trials (SI Appendix, Tables S2 and S4 and Fig. 1; P = 0.026). However, in the brotizolam and suvorexant trials, the sleep latencies after forced awakening were significantly shorter than that before forced awakening (SI Appendix, Tables S2 and S4 and Fig. 1; P = 0.017 and 0.015, respectively).
The comparison of sleep architecture showed that the effects of hypnotic compounds were manifested during the 1st quarter of sleep time after forced awakening (posttest), with increases in stages N3 and R by suvorexant and increases in stages N2 and N3 by brotizolam. A substantial decrease in wake was observed under both hypnotic agents during the 1st quarter of sleep. An increase in stage R by suvorexant was also observed during the 3rd quarter, and an increase in stage N2 by brotizolam was observed during the 2nd quarter of sleep time (SI Appendix, Table S5). When the subjects were allowed to go back to sleep after forced awakening, suvorexant significantly decreased the REM latency and prolonged stage R compared with the other 2 trials. In 40% of the subjects, stage R occurred with a short REM latency (<15 min) under the influence of suvorexant (SI Appendix, Table S4 and Fig. S1 and Fig. 1).
Physical and Cognitive Functions.
Total z score.
The sum of z scores (24) from all physical- and cognitive-function tests performed before bedtime (pretest), after forced awakening (posttest), and on the next morning (follow-test) is shown in Table 2. The time effect and the interaction of group and time effects were significant. Compared with the pretest, the posttest total z score was significantly decreased in all trials, including placebo. The total posttest z score was lower than that of the follow-test (P = 0.033) under the influence of brotizolam. The total posttest z score under brotizolam was also lower compared to the placebo (P = 0.001), whereas the difference between suvorexant and placebo was not significant (P = 0.264). This was also reflected in the fact that, although there were no significant posttest differences in the sum of z scores between suvorexant and brotizolam (P = 0.167), the effect size of suvorexant was smaller than that of brotizolam (SI Appendix, Table S6). There were significant order effects observed in the total z score (P = 0.001) (i.e., the total z scores were improved as the subjects repeated the trials).
View this table:
Table 2.
Comparison of physical- and cognitive-functions test by trial
Stroop color-word test.
A time effect was observed on the neutral task score, which deteriorated in the posttest condition. For the incongruent task, there were significant time effects and interactions. The score of the incongruent task deteriorated in the posttest condition with brotizolam and suvorexant administration. In Stroop interference, there was no significant effect of group, time, or interaction.
Purdue pegboard test.
There were significant group and time effects. The scores deteriorated in the posttest condition. In the follow-test condition, the scores returned to levels similar to those of the pretest condition in the 3 trials. The Purdue pegboard test score was lower with brotizolam and suvorexant administration compared with the placebo.
Body sway.
The rectangular area of the center of foot pressure during 30 s of test with the eyes opened showed significant effects of time, group, and interaction. With the eyes closed, there were significant effects of time, but there were no statistically significant effects of group or interaction. When the center of foot-pressure trajectory length was evaluated during the test, there were no significant effects of time, group, or interaction (Table 2 and SI Appendix, Fig. S2).
Agility and dynamic balance test.
Significant effects of time and interaction were observed. After forced awakening, agility and dynamic balance significantly deteriorated with brotizolam and suvorexant administration, but not placebo.
Choice stepping reaction time.
There was a significant time effect. The reaction deteriorated in the posttest condition, but returned to a level similar to the pretest results.
Energy Metabolism.
The energy expenditure showed significant effects of time (P = 0.001), group (P = 0.005), and interaction (P = 0.001). The post hoc test revealed significant differences among average energy expenditure during the 20 min from 00:40 to 01:00 and subsequent hourly averages (Fig. 2). The cumulative energy expenditure over the entire sleeping period was smaller with brotizolam (532 ± 53 kcal during sleep) than with suvorexant (544 ± 52 kcal during sleep, P = 0.027) and placebo (544 ± 49 kcal during sleep, P = 0.013) administration.
Fig. 2.
Time course of energy expenditure. The hourly average, average of 15 min between 00:00 and 00:15, and average of 20 min between 00:40 and 01:00 are shown with the SEM. Physical- and cognitive-function tests were performed outside the metabolic chamber. §Significant differences between suvorexant and brotizolam; #significant differences between suvorexant and placebo; ¶significant differences between brotizolam and placebo.
Discussion
In the present study, to enhance the assay sensitivity, forced awakening was targeted when the plasma concentration of hypnotic drugs presumably peaked 90 min after suvorexant ingestion (25). Among the GABAA agonists currently prescribed, brotizolam was selected as a positive control because its plasma concentration peaked 60 to 120 min after ingestion (26). During the first 75 min, the sleep architecture was comparable among the 3 trials. After the forced awakening, all subjects maintained a wakeful state to complete the tests. When the subjects were allowed to go back to sleep, the sleep latency of the placebo trial was prolonged (P = 0.026), presumably because of the strong psychological arousal induced by the physical- and cognitive-assessment tasks (27, 28). In contrast, the sleep latency under suvorexant (P = 0.015) and brotizolam (P = 0.017) was shortened compared with the first sleep latency of the night. The effects of the hypnotic drugs were manifested until late at night (SI Appendix, Table S5), and both hypnotics were similarly effective in increasing sleep efficiency after forced awakening.
The observed order effect on the total z score underscores the earnest attempt of the subjects at each trial. In order to offset the order effect, we adopted a randomized cross-over study design. The poor performance after forced awakening may have been partly due to the influence of sleep inertia, the transitional state of lowered arousal occurring immediately after awakening from sleep. Indeed, the total z score of the posttest condition was significantly decreased, even with placebo (Table 2). As significant differences in the sleep architecture were observed immediately after the subjects were allowed to go back to sleep, it was assumed that the physical- and cognitive-function tasks were performed under the influence of the hypnotic agents. Compared with the placebo, the sum of z scores was further decreased at the posttest condition by brotizolam. The sum of z scores under suvorexant was not significantly different from that of the placebo or brotizolam (Table 2). When the effect size was evaluated, it was found to be smaller under suvorexant than under brotizolam (SI Appendix, Table S6).
The distinct effect of suvorexant and brotizolam on body sway was observed when it was evaluated as the circumscribed rectangular area of foot pressure trajectory with the eyes open (SI Appendix, Fig. S2). In theory, the outer circumference of the area of the center of foot pressure during the sway test is determined by big sways. Compared with trajectory length, the sway area of the center of foot pressure is more sensitive to alcohol consumption (29). Because visual information is essential for maintaining body balance (30), the level of difficulty increased when the same balance task was performed with the eyes closed, and this might mask the differences in body sway among the experimental trials (SI Appendix, Fig. S2). Suvorexant had little effect on body sway, evaluated as the rectangular area of the center of pressure with the eyes open, suggesting a lower risk of falls (15, 16, 31⇓⇓–34).
Our present findings were consistent with previous animal studies comparing the effects of orexin receptor antagonists and GABAA agonists on the time spent on an accelerating rotating rod (rotarod). The rotarod performance was impaired by the GABAA agonists zolpidem, eszopiclone, and diazepam, but not by the orexin receptor antagonist DORA-22 (17, 18). The differential effects of suvorexant and brotizolam are likely related to the fundamental differences in their mechanisms of action. Balance is coordinated by the cerebellum (35), in which benzodiazepine receptors are abundantly expressed (36). In contrast, the cerebellum is free from the direct effects of orexin; orexin-producing neurons essentially send no projections to the cerebellum (37), where very little expression of orexin receptors has been documented (38). The effect size on the Stroop incongruent task and the agility and dynamic balance test under suvorexant were smaller compared to brotizolam (SI Appendix, Table S6). However, the performance of the Stroop incongruent task and agility and dynamic balance test was impaired by both suvorexant and brotizolam at the posttest compared with the pretest condition. Thus, further clinical studies on incidents of falling under suvorexant are warranted.
The suppressive effect of hypnotic agents on energy expenditure was detected in the present study, although indirect calorimetry was interrupted for 25 min when the plasma concentration of hypnotic compounds presumably peaked. The reduction of energy expenditure might be due to the drug’s direct effects on energy metabolism (39). Alternatively, hypnotic agents might suppress the energy expenditure by inducing sleep. Applying a semiparametric regression analysis on the time course of energy expenditure after forced awakening, the effect of hypnotic agents was decomposed into the effect through changes in sleep stages and the effect independent of sleep stages (23). However, the relative importance of these 2 factors remained inconclusive (SI Appendix, Figs. S3 and S4). Additionally, the energy metabolism measured after the subjects reentered the metabolic chamber might be affected by the residual effect of physical activity during the test, known as excess postexercise oxygen consumption (40). Further study is warranted to assess the effects of hypnotic agents on energy metabolism during the entire sleeping period.
Consistent with previous studies (41⇓–43), the effects of suvorexant and brotizolam on the sleep architecture were different. When the subjects were allowed to go back to sleep under the influence of suvorexant, stage R with a short REM latency was observed in 12 of 30 subjects (with a mean latency of 4.7 min in the 12 subjects). This was substantially more frequent than the sleep-onset REM periods (SOREMPs) observed in clinical trials of suvorexant; in 1 such study (41), SOREMPs were observed in 4.1% of subjects taking 20 mg (15 mg for elderly subjects) of suvorexant at bedtime compared with 1.0% of subjects taking a placebo. This was likely due to the fact that, in the present study, the subjects were allowed to go back to sleep when suvorexant was already exerting maximal effects. The subsequent peak in the percentage of subjects in REM sleep was observed at ∼190 min after the initial bedtime in the trial with suvorexant (Fig. 1). In the placebo and brotizolam trials, the peak increase in the percentage of subjects in REM sleep was also observed at ∼190 min after the first bedtime, without the initial R stage shortly after going back to bed. We speculated that the NREM–REM cycle might be discontinued and reset by sleep interruption as previously observed (44, 45) in the placebo and brotizolam trials, whereas suvorexant might have partially suppressed this resetting of the NREM–REM cycle.
The ability to arouse and respond to unexpected environmental stimuli is a feature of normal sleep, which is crucial when people are faced with urgent situations. There is a general concern that hypnotic agents may impair physical and cognitive functions, eliciting muscle atonia, ataxia, loss of balance, retrospective amnesia, attention deficits, and slower response time, and patients might become temporarily incapacitated and unable to appropriately respond under the effect of hypnotic agents. When patients need to be awake under the influence of a hypnotic agent, the impairment of physical and cognitive functions might manifest as a fall or serious misjudgment. The use of GABAA receptor agonists has been associated with an increased risk of falling and traffic accidents (10, 46⇓⇓–49). In the present study, to maximize the assay sensitivity, physical and cognitive functions were assessed when the plasma concentration of the hypnotic agent peaked. However, this protocol may not be optimal with respect to real-world clinical significance, as falls and other incidents related to leaving the bed, such as urination, occur at later hours (15).
Next-day sedation and cognitive dysfunction have been reported after the use of GABAA receptor agonists (50), but the z score in the follow-test condition returned to a level similar to that of the pretest in all experimental trials in our present study. This lack of residual effects of hypnotic agents 9.75 h after dosing suggested that the dose of the hypnotic agents was within a reasonable range. Consistently, it has been reported that, after single and repeated doses of suvorexant, its residual effects on driving performance in the morning were negligible (35, 36). As this was an initial study with forced awakening under the maximal influence of suvorexant, a new class of hypnotics, we enrolled relatively young, healthy individuals in consideration of their safety. Thus, further study with patients with insomnia, particularly elderly subjects, is necessary.
Materials and Methods
Subjects.
We used advertisements to recruit 30 healthy male subjects. The study concepts were explained to all of the subjects, and they all provided signed informed consent. This study was approved by the Ethics Committee of the University of Tsukuba (reference no. Tai 27-143). The study protocol (UMIN000022752) was registered with the University Hospital Medical Information Network Center (https://www.umin.ac.jp/english/).
Study Design and Procedure.
This double-blind, randomized, placebo-controlled, 3-way cross-over study was conducted from July 2016 to January 2018. The washout period was more than 2 d, and the 3 trials were completed within 8 wk. The experiment was preceded by an adaptation night in a metabolic chamber, during which the sensors and electrodes of a polysomnographic recording system were attached to the subjects. Prior to the physical- and cognitive-function tests, the subjects ate dinner 5 h before bedtime, and the electrodes were attached. A series of physical- and cognitive-function tests before sleep (pretest) were performed 3.5 h before bedtime. Subsequently, the subjects entered the metabolic chamber and assumed a sitting position. Then, they took a pill of either suvorexant (20 mg), brotizolam (0.25 mg), or placebo 15 min before bedtime. Brotizolam was selected as a positive control to demonstrate the assay sensitivity versus placebo, as in other studies (51, 52). At 23:00, polysomnography recording commenced with the lights out. At 00:15, 90 min after taking the pill, the subjects were forced awake to repeat the same physical- and cognitive-function tests (posttest). Thereafter, they returned to the metabolic chamber and were allowed to sleep from 00:40 to 08:00. At 08:30, after maintaining a sitting position for 30 min, the subjects repeated the physical- and cognitive-function tests (follow-test) (Fig. 3).
Fig. 3.
Experimental protocol. Physiological- and cognitive-function tests were performed in the evening (19:30), after forced awakening (00:15), and on the next morning (08:30). PSG, polysomnography.
Measurements.
Indirect calorimetry using a whole-room metabolic chamber.
The subjects slept in a whole-room indirect calorimeter (Fuji Medical Science) (23), and the energy equivalence of the measured O2 uptake and CO2 production was calculated according to Weir’s equation (53). The effects of sleep stages and time after going back to bed on the energy expenditure were analyzed by semiparametric regression analysis, as described (23).
Polysomnography.
Sleep was recorded polysomnographically by using a PSG-1100 system (Nihon Kohden) (23). The records were scored every 30 s to stages wakefulness (W), N1, N2, N3, and R. Measurements during sleep-onset latency were classified as stage W. Wake after sleep onset (WASO) was defined according to standard criteria (54).
Physical- and cognitive-assessment tasks.
Physical- and cognitive-assessment tasks were performed in the following order: Stroop color-word, Purdue pegboard test, body sway, agility and dynamic balance, and choice stepping reaction time test.
Statistical Analyses.
We used the sum of z scores for all of the physical- and cognitive-assessment tasks. Each score of the physical- and cognitive-function tasks was analyzed by using 2-way ANOVA with repeated measures and post hoc tests with Bonferroni’s correction for changes at different time points between treatments. In order to assess differences in sleep parameters and energy expenditure between treatments, 2-way ANOVA and Bonferroni’s correction as post hoc tests were used. The comparison of the sleep stage before forced awakening was performed by using χ2 statistics. Statistical significance was established at P < 0.05 (2-tailed). All analyses were carried out by using IBM SPSS statistics software (Version 25.0; IBM Corporation) for Windows.
Acknowledgments
We thank Naruki Kitano for hard work on the pilot study and Momoko Kayaba for helping keep polysomnography electrodes attached. This work was supported by Ministry of Education, Culture, Sports, Science and Technology–Japan (MEXT) Grant-in-Aid for Scientific Research on Innovative Areas Grant JP15H05942 (to M.Y.); the MEXT World Premier International Research Center Initiative “Living in Space” (to M.Y.); Japan Society for the Promotion of Science (JSPS) KAKENHI Grant 17H06095 (to M.Y.); MEXT CREST Grant A3A28043 (to M.Y.); the JSPS Funding Program for World-Leading Innovative R&D on Science and Technology (M.Y.); a Uehara Memorial Foundation research grant (to M.Y.); a Takeda Science Foundation research grant (to M.Y.); and the Japan Sports Agency Sports Research Innovation Project (K.T.). Also, J.S. is a recipient of a scholarship from the Otsuka Toshimi Scholarship Foundation.
Footnotes
↵1J.S. and Y.F. contributed equally to this work.
- ↵2To whom correspondence may be addressed. Email: yanagisawa.masa.fu{at}u.tsukuba.ac.jp.
Author contributions: S.F., T.K., and M.Y. designed research; J.S., Y.F., I.P., Y.S., F.K., T.O., M.S., and K.T. performed research; J.S., Y.F., I.P., Y.S., F.K., K.Y., T.O., and K.T. analyzed data; and J.S., Y.F., K.T., and M.Y. wrote the paper.
Reviewers: S.N., Stanford University School of Medicine; and K.P.W., University of Colorado Boulder.
The authors declare no competing interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1907354116/-/DCSupplemental.
Published under the PNAS license.
References
Distinct effects of orexin receptor antagonist and GABAA agonist on sleep and physical/cognitive functions after forced awakening
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