Comparative efficacy and safety of hypnotics for insomnia in older adults: a systematic review and network meta-analysis.

STUDY OBJECTIVES: To compare the efficacy and safety of various hypnotics for identifying the best treatments for insomnia in older adults. METHODS: We searched the EMBASE, PubMed, ClinicalTrials.gov, and ProQuest Dissertations and Theses A&I databases from the inception to September 12, 2020. Only randomized controlled trials comparing hypnotics with either another hypnotic or placebo for insomnia treatment in elderly people were included. Sleep outcomes, including total sleep time, sleep onset latency, wake after sleep onset, sleep efficiency, were derived from polysomnography, valid questionnaires, or sleep diaries. RESULTS: We identified 24 articles with 5917 older adults. Eszopiclone and low-dose doxepin were ranked the optimal therapy for prolonging objective and subjective total sleep time (26.69 and 28.19 min), respectively, compared to placebo. Zaleplon was the most effective therapy in reducing objective and subjective sleep onset latency (-21.63 and -15.86 min) compared with control. Temazepam was the best treatment for objective and subjective wake after sleep onset (-25.29 and -22.25 min) compared with control. Low-dose doxepin appeared to be the effective treatment for increasing objective sleep efficiency (6.08%) Triazolam showed the higher risk of overall adverse events (odds ratio, 1.96, 95% confidence interval 1.03-3.74) when compared to zaleplon. CONCLUSIONS: Considering study quality and the potential adverse effects of benzodiazepines and nonbenzodiazepines, low-dose doxepin seems to be the optimal pharmacotherapy for the improvements in total sleep time and sleep efficiency. Future RCTs investigating the treatment effects of hypnotics, particularly low-dose doxepin, on insomnia in older adults are warranted. PROSPERO Registration number: CRD42016046301.

Zolpidem and Eszopiclone Pre-medication for PSG: Effects on Staging, Titration, and Adherence.

Introduction: The non-benzodiazepine sedative hypnotic (NBSH) eszopiclone improves polysomnography (PSG) quality and continuous positive airway pressure (CPAP) adherence. It is unclear whether zolpidem has the same effect and neither NBSH has been studied in populations with milder forms of obstructive sleep apnea. Materials and Methods: We performed a retrospective analysis on patients undergoing level I PSG at our institution. Patients are pre-medicated with NBSHs at the discretion of the sleep physician. We compared PSG/CPAP titration quality and subsequent CPAP adherence for patients receiving NBSHs or no pre-study medication. We adjusted for obstructive sleep apnea pre-test probability (PTP), arousal threshold, and other factors showing differences at baseline. Results: Data on 560 patients were analyzed. Mean age and body mass index were 42.2 ± 10.1 and 28.8 ± 4.5, respectively. Median apnea hypopnea index was 12.9 (6.4-25.3), 100 (18.0%) patients had normal studies, 97 (17.3%) were split, and 457 (81.6%) had a respiratory low-arousal threshold. After adjusting for differences at baseline, neither NBSH was associated with sleep efficiency, wake after sleep onset, or total sleep time on PSG. After adjustment, patients receiving eszopiclone had a higher apnea hypopnea index at the final CPAP pressure (ß = 14.2; 95% confidence intervals (CI) 7.2-21.2; p < 0.001) and were more likely to have an unacceptable titration (odds ratio (OR) = 6.6; 95% CI 2.0-21.0; p = 0.002). When only split-night studies were examined, there were no differences in any adherence variables across or between categories. Conclusions: In a population with predominantly mild obstructive sleep apnea, NBSHs did not improve PSG or CPAP titration quality and did not increase CPAP adherence. There was no difference in effect between eszopiclone and zolpidem.

Plasticity-Related Gene Expression During Eszopiclone-Induced Sleep.

Study Objectives: Experimental evidence suggests that restorative processes depend on synaptic plasticity changes in the brain during sleep. We used the expression of plasticity-related genes to assess synaptic plasticity changes during drug-induced sleep. Methods: We first characterized sleep induced by eszopiclone in mice during baseline conditions and during the recovery from sleep deprivation. We then compared the expression of 18 genes and two miRNAs critically involved in synaptic plasticity in these mice. Gene expression was assessed in the cerebral cortex and hippocampus by the TaqMan reverse transcription polymerase chain reaction and correlated with sleep parameters. Results: Eszopiclone reduced the latency to nonrapid eye movement (NREM) sleep and increased NREM sleep amounts. Eszopiclone had no effect on slow wave activity (SWA) during baseline conditions but reduced the SWA increase during recovery sleep (RS) after sleep deprivation. Gene expression analyses revealed three distinct patterns: (1) four genes had higher expression either in the cortex or hippocampus in the group of mice with increased amounts of wakefulness; (2) a large proportion of plasticity-related genes (7 out of 18 genes) had higher expression during RS in the cortex but not in the hippocampus; and (3) six genes and the two miRNAs showed no significant changes across conditions. Even at a relatively high dose (20 mg/kg), eszopiclone did not reduce the expression of plasticity-related genes during RS period in the cortex. Conclusions: These results indicate that gene expression associated with synaptic plasticity occurs in the cortex in the presence of a hypnotic medication.

GABAA receptor positive allosteric modulators modify the abuse-related behavioral and neurochemical effects of methamphetamine in rhesus monkeys.

GABAA receptor positive allosteric modulators (GABAA receptor modulators) are commonly used for the treatment of insomnia. Nevertheless, the effects of these compounds on psychostimulant-induced sleep impairment are poorly understood. Because GABAA receptor modulators have been shown to decrease the abuse-related effects of psychostimulants, the aim of the present study was to evaluate the effects of temazepam (0.3, 1.0 or 3.0 mg/kg) and eszopiclone (0.3, 1.0 or 3.0 mg/kg), two GABAA receptor modulators, on the behavioral neuropharmacology of methamphetamine in adult rhesus macaques (n = 5). Sleep-like measures and general daytime activity were evaluated with Actiwatch monitors. Methamphetamine self-administration (0.03 mg/kg/inf) was evaluated during morning sessions. Methamphetamine-induced dopamine overflow was assessed through in vivo microdialysis targeting the nucleus accumbens. Nighttime treatment with either temazepam or eszopiclone was ineffective in improving sleep-like measures disrupted by methamphetamine self-administration. Acute pretreatment with a low dose of temazepam before self-administration sessions increased methamphetamine self-administration without affecting normal daytime home-cage activity. At a high dose, acute temazepam pretreatment decreased methamphetamine self-administration and attenuated methamphetamine-induced increases in dopamine in the nucleus accumbens, without decreasing general daytime activity. Acute eszopiclone treatment exerted no effects on methamphetamine intake or drug-induced increases in dopamine. Our study suggests that treatments based on GABAA receptor modulators are not effective for the treatment of sleep disruption in the context of psychostimulant use. In addition, distinct GABAA receptor modulators differentially modulated the abuse-related effects of methamphetamine, with acute treatment with the high efficacy GABAA receptor modulator temazepam decreasing the behavioral and neurochemical effects of methamphetamine.

Eszopiclone and Zolpidem Do Not Affect the Prevalence of the Low Arousal Threshold Phenotype.

STUDY OBJECTIVES: We sought to determine whether non benzodiazepine sedative hypnotics (NBSH) reduce the occurrence of the low arousal threshold (LAT) phenotype. METHODS: Consecutive patients with suspected obstructive sleep apnea (OSA) referred for polysomnography (PSG) had demographic and PSG data abstracted. LAT was estimated using PSG criteria. After adjusting for pretest probability (PTP) for OSA, we calculated the effect that premedication with NBSHs has on LAT prevalence. RESULTS: Five hundred seventy-nine patients with a mean age and body mass index of 42.2 ± 10.1 y and 28.9 ± 4.5 kg/m2, respectively, had data available for analysis. Most patients (444, or 80.9%) had a LAT, and administering a NBSH (zolpidem or eszopiclone) on the same night as the PSG did not change LAT prevalence (NBSH: 339 (83.3%) versus no drug: 100 (80.6%); p = 0.50). Adjusting for PTP, neither administration of eszopiclone (odds ratio 0.80 (95% confidence interval: 0.33-2.0); 0.69) nor zolpidem (odds ratio 1.65 (95% confidence interval: 0.8-3.5); p = 0.19) reduced the odds that a patient had a LAT. NBSHs did not change the mean SpO2 nadir, percentage hypopneas, or apnea-hypopnea index. There was no association between zolpidem or eszopiclone dosing and SpO2 nadir (zolpidem: ß = -0.69, p = 0.80; eszopiclone: ß = -1.53, p = 0.68), percentage hypopneas (zolpidem: ß = 2.2, p = 0.43; eszopiclone ß = -6.2, p = 0.46), or apnea-hypopnea index (zolpidem: ß = 3.1, p = 0.22; eszopiclone: ß = 2.6, p = 0.39). CONCLUSIONS: The LAT is common in our population and NBSH premedication does not alter its occurrence. Further studies are needed to determine how the LAT can be optimally managed to improve OSA treatment.

Inhibition of Orexin Signaling Promotes Sleep Yet Preserves Salient Arousability in Monkeys.

STUDY OBJECTIVES: In addition to enhancing sleep onset and maintenance, a desirable insomnia therapeutic agent would preserve healthy sleep's ability to wake and respond to salient situations while maintaining sleep during irrelevant noise. Dual orexin receptor antagonists (DORAs) promote sleep by selectively inhibiting wake-promoting neuropeptide signaling, unlike global inhibition of central nervous system excitation by gamma-aminobutyric acid (GABA)-A receptor (GABAaR) modulators. We evaluated the effect of DORA versus GABAaR modulators on underlying sleep architecture, ability to waken to emotionally relevant stimuli versus neutral auditory cues, and performance on a sleepiness-sensitive cognitive task upon awakening. METHODS: DORA-22 and GABAaR modulators (eszopiclone, diazepam) were evaluated in adult male rhesus monkeys (n = 34) with continuous polysomnography recordings in crossover studies of sleep architecture, arousability to a classically conditioned salient versus neutral acoustical stimulus, and psychomotor vigilance task (PVT) performance if awakened. RESULTS: All compounds decreased wakefulness, but only DORA-22 sleep resembled unmedicated sleep in terms of underlying sleep architecture, preserved ability to awaken to salient-conditioned acoustic stimuli while maintaining sleep during neutral acoustic stimuli, and no congnitive impairment in PVT performance. Although GABAaR modulators induced lighter sleep, monkeys rarely woke to salient stimuli and PVT performance was impaired if monkeys were awakened. CONCLUSIONS: In nonhuman primates, DORAs' targeted mechanism for promoting sleep protects the ability to selectively arouse to salient stimuli and perform attentional tasks unimpaired, suggesting meaningful differentiation between a hypnotic agent that works through antagonizing orexin wake signaling versus the sedative hypnotic effects of the GABAaR modulator mechanism of action.

Zolpidem and eszopiclone prime α1ß2γ2 GABAA receptors for longer duration of activity.

BACKGROUND AND PURPOSE: GABAA receptors mediate neuronal inhibition in the brain. They are the primary targets for benzodiazepines, which are widely used to treat neurological disorders including anxiety, epilepsy and insomnia. The mechanism by which benzodiazepines enhance GABAA receptor activity has been extensively studied, but there is little mechanistic information on how non-benzodiazepine drugs that bind to the same site exert their effects. Eszopiclone and zolpidem are two non-benzodiazepine drugs for which no mechanism of action has yet been proposed, despite their clinical importance as sleeping aids. Here we investigate how both drugs enhance the activity of α1ß2γ2 GABAA receptors. EXPERIMENTAL APPROACH: We used rapid ligand application onto macropatches and single-channel kinetic analysis to assess rates of current deactivation. We also studied synaptic currents in primary neuronal cultures and in heterosynapses, whereby native GABAergic nerve terminals form synapses with HEK293 cells expressing α1ß2γ2 GABAA receptors. Drug binding and modulation was quantified with the aid of an activation mechanism. KEY RESULTS: At the single-channel level, the drugs prolonged the duration of receptor activation, with similar KD values of ∼80 nM. Channel activation was prolonged primarily by increasing the equilibrium constant between two connected shut states that precede channel opening. CONCLUSIONS AND IMPLICATIONS: As the derived mechanism successfully simulated the effects of eszopiclone and zolpidem on ensemble currents, we propose it as the definitive mechanism accounting for the effects of both drugs. Importantly, eszopiclone and zolpidem enhanced GABAA receptor currents via a mechanism that differs from that proposed for benzodiazepines.