Pharmacologic Sleep Aids in the Intensive Care Unit: A Systematic Review.

Background: Patients in the intensive care unit (ICU) often experience poor sleep quality. Pharmacologic sleep aids are frequently used as primary or adjunctive therapy to improve sleep, although their benefits in the ICU remain uncertain. This review aims to provide a comprehensive assessment of the objective and subjective effects of medications used for sleep in the ICU, as well as their adverse effects. Methods: PubMed, Web of Science, Scopus, Embase, and Cochrane Central Register of Controlled Trials were systematically searched from their inception until June 2023 for comparative studies assessing the effects of pharmacologic sleep aids on objective and subjective metrics of sleep. Results: Thirty-four studies with 3498 participants were included. Medications evaluated were melatonin, ramelteon, suvorexant, propofol, and dexmedetomidine. The majority of studies were randomized controlled trials. Melatonin and dexmedetomidine were the best studied agents. Objective sleep metrics included polysomnography (PSG), electroencephalography (EEG), bispectral index, and actigraphy. Subjective outcome measures included patient questionnaires and nursing observations. Evidence for melatonin as a sleep aid in the ICU was mixed but largely not supportive for improving sleep. Evidence for ramelteon, suvorexant, and propofol was too limited to offer definitive recommendations. Both objective and subjective data supported dexmedetomidine as an effective sleep aid in the ICU, with PSG/EEG in 303 ICU patients demonstrating increased sleep duration and efficiency, decreased arousal index, decreased percentage of stage N1 sleep, and increased absolute and percentage of stage N2 sleep. Mild bradycardia and hypotension were reported as side effects of dexmedetomidine, whereas the other medications were reported to be safe. Several ongoing studies have not yet been published, mostly on melatonin and dexmedetomidine. Conclusions: While definitive conclusions cannot be made for most medications, dexmedetomidine improved sleep quantity and quality in the ICU. These benefits need to be balanced with possible hemodynamic side effects.

Association between the use of orexin receptor antagonists and falls or fractures: A meta-analysis.

Evidence indicates that the use of sedative-hypnotics, including benzodiazepines and z-drugs, is linked to an increased risk of falls and fractures. Nonetheless, the potential exacerbation of this risk by orexin receptor antagonists, which are novel therapeutic agents for treating insomnia, remains uncertain despite their escalating prevalence in clinical practice. We systematically searched four electronic databases from inception to April 17, 2024. In addition, we performed a quality assessment; calculated pooled odds ratios (ORs) to assess the relationship between the use of orexin receptor antagonists and the occurrence of falls or fractures; evaluated heterogeneity across the included studies; and conducted sensitivity analyses. The meta-analysis encompassed eight papers, comprising a total of 46,636 subjects. These papers included 5 case-control studies and 3 randomized controlled trials (RCTs), collectively encompassing ten studies. Analysis of the included case-control studies (pooled adjusted OR = 0.75, 95% confidence interval [CI] = 0.00-1.50, I2 = 66.2%, k = 3) and RCTs (OR = 0.68, 95% CI = 0.31-1.50, I2 = 45.9%, k = 5) indicated that the use of orexin receptor antagonists did not elevate the risk of falls. Similarly, analysis of the included case-control studies revealed no significant increase in the risk of fractures associated with the use of orexin receptor antagonists (pooled adjusted OR = 1.01, 95% CI = 0.82-1.20, I2 = 40.1%, k = 2). This meta-analysis suggests that the use of orexin receptor antagonists for treating insomnia does not escalate the risk of falls or fractures, although the data for lemborexant and daridorexant are limited.

The dual orexin receptor antagonist suvorexant in alcohol use disorder and comorbid insomnia: A case report.

Key Clinical Message: This case suggests using dual orexin receptor antagonists to treat alcohol use disorder and comorbid sleep disorders may be effective, commencing treatment in withdrawal and continuing it to prevent relapse. Abstract: Effective medications for the treatment of alcohol use disorder are limited. This is partially due to the heterogenous nature of the symptomatology associated with alcohol use disorder and the abundance of presenting comorbidities. One common, and often overlooked, symptom that occurs during withdrawal of alcohol use is sleep disruption. Here, we report a case study of a participant with comorbid alcohol use disorder and insomnia. This participant was treated with a dual orexin receptor antagonist, suvorexant (Belsomra®), currently approved to treat insomnia. We demonstrate improvements in alcohol cravings, physical and psychological health, and sleep outcomes with treatment. These data support abundant preclinical and emerging clinical data in this space. The findings from this case report highlight the potential for suvorexant to treat comorbid alcohol use disorder and insomnia with fully powered, randomized controlled trials moving forward.

Association between dual orexin receptor antagonists (DORAs) and suicidality: reports to the United States Food and Drug Administration Adverse Event Reporting System (FAERS).

BACKGROUND: Package inserts for the FDA-approved dual orexin receptor antagonists (DORAs) suvorexant, lemborexant and daridorexant state that suicide risk should be monitored. It remains unknown whether suicidality is attributed to DORAs. We aim to evaluate suicidality associated with DORAs reported to the FDA Adverse Event Reporting System (FAERS). METHODS: The reporting odds ratio (ROR) was determined with trazodone as the control. Significant disproportionate reporting was determined when 95% confidence intervals (CIs) did not encompass 1.0. We used information components (ICs) to calculate the lower limit of the 95% CI (IC025). IC was significantly increased when the IC025 ≥0. RESULTS: Suvorexant (0.025 ROR), lemborexant (0.019 ROR) and daridorexant (0.002 ROR) were significantly associated with lower odds of reported completed suicides compared to trazodone (p < 0.05). There was no significantly increased RORs for the DORAs regarding suicidal ideation, depression suicidal, suicidal behavior and suicide attempts. Nonsignificant associations between all parameters of suicidality were observed for each DORA using IC025. CONCLUSION: We did not find a significant association between any parameter of suicidality captured in the FAERS for each DORA. All persons treated for insomnia pharmacologically/non-pharmacologically should be evaluated for emergence/worsening of any suicidality aspect.

Effects of methamphetamine on actigraphy-based sleep parameters in female rhesus monkeys: Orexin receptor mechanisms.

BACKGROUND: The orexin system has been implicated as a mechanism underlying insomnia and methamphetamine-induced sleep disruptions, with a potential role for OX2 receptors in the sleep-modulating effects of orexin. The aim of the present study was to investigate the extent to which orexin receptors mediate the effects of acute methamphetamine administration on actigraphy-based sleep in female rhesus monkeys. METHODS: Actigraphy-based sleep measures were obtained in female rhesus monkeys (n=5) under baseline and acute test conditions. First, morning (10h) i.m. injections of methamphetamine (0.03 - 0.56mg/kg) were administered to determine the effects of methamphetamine alone. Then, saline or methamphetamine (0.3mg/kg) were administered at 10h, and evening (17h30) oral treatments with vehicle, the non-selective orexin receptor antagonist suvorexant (1 - 10mg/kg, p.o.), or the OX2-selective orexin receptor antagonist MK-1064 (1 - 10mg/kg, p.o.) were given. The ability of suvorexant and MK-1064 (10mg/kg, p.o.) to improve actigraphy-based sleep was also assessed in a group of female monkeys quantitatively identified with "short-duration sleep" (n=4). RESULTS: Methamphetamine dose-dependently disrupted actigraphy-based sleep parameters. Treatment with either suvorexant or MK-1064 dose-dependently improved actigraphy-based sleep in monkeys treated with methamphetamine. Additionally, both suvorexant and MK-1064 promoted actigraphy-based sleep in a group of monkeys with baseline short actigraphy-based sleep. CONCLUSIONS: These findings suggest that orexin-mediated mechanisms play a role in the effects of methamphetamine on actigraphy-based sleep in female monkeys. Targeting the orexin system, in particular OX2 receptors, could be an effective option for treating sleep disruptions observed in individuals with methamphetamine use disorder.

Orexin Receptor Antagonists as Adjunct Drugs for the Treatment of Depression: A Mini Meta-Analysis.

Introduction: There is growing interest in the efficacy of orexin receptor antagonists (ORA), one of the new psychopharmacological agents used in the treatment of insomnia, in other psychiatric disorders such as depression. Methods: This meta-analysis was conducted in accordance with PRISMA requirements. Literature searches were conducted using PubMed, Scopus and EBSCO (Medline) databases. Search words were (depression OR mood disorder OR affective disorder) AND (orexin OR orx OR hypocretin OR orx1 OR orx2 OR orexin receptor antagonist OR almorexant OR suvorexant OR lemborexant OR daridorexant OR seltorexant OR vornorexant OR filorexant). No date restrictions were used. The random effects model was used for analyses with I2 values above 50% and fixed effects model was used for analyses with I2 values below 50%. Results: In the acute phase, ORAs had no significant effect on core, sleep-adjusted and total symptoms of depression respectively; Standardized Mean Difference (SMD) for random effect -0.422, 95% CI [-0.90; 0.06], p=0.089, I2=62.4%; SMD for random effect -0.375, 95% CI [-1.24; 0.49], p=0.400; I2=66.6% and SMD for random effect -0.477, 95% CI [-0.97; 0.01], p=0.059; I2=83.1%). However, they had a significant effect on core and total symptoms of depression in the early period respectively; SMD for fixed effect=-0.228, 95% CI [-0.44; -0.01], p=0.036, I2=9.1%; and SMD for fixed effect=-0.186, 95% CI [-0.37; -0.001], p=0.048, I2=0.0%, respectively). Conclusion: The results of this meta-analysis suggest that ORAs may provide direct antidepressant efficacy when added to existing antidepressant treatment and may also have indirect antidepressant effects through improvement in sleep symptoms. Considering the physiological effects of orexin on behaviors, ORAs may be promising new treatment modalities in the treatment of many psychiatric disorders other than insomnia. However, these results are preliminary and further studies with different ORAs at different doses and with different samples are needed.

Efficacy and Safety of Transitioning to Lemborexant from Z-drug, Suvorexant, and Ramelteon in Japanese Insomnia Patients: An Open-label, Multicenter Study.

INTRODUCTION: For patients with chronic insomnia, conventional therapy may not always provide satisfactory efficacy and safety. Thus, switching to an alternative therapeutic agent can be explored. However, there is a lack of prospective studies evaluating the effectiveness of such changes. This prospective, non-randomized, open-label, interventional, multicenter study assessed whether Japanese patients with chronic insomnia dissatisfied with treatment could transition directly to lemborexant (LEM) from four cohorts-non-benzodiazepine sedative-hypnotic (zolpidem, zopiclone, or eszopiclone) monotherapy, dual orexin receptor antagonist (suvorexant) monotherapy, suvorexant + benzodiazepine receptor agonists (BZRAs), and melatonin receptor agonist (ramelteon) combination. We evaluated whether transitioning to LEM improved patient satisfaction based on efficacy and safety. METHODS: The primary endpoint was the proportion of successful transitions to LEM at 2 weeks (titration phase end), defined as the proportion of patients on LEM by the end of the 2-week titration phase who were willing to continue on LEM during the maintenance phase (Weeks 2-14). Patient satisfaction and safety (the incidence of treatment-emergent adverse events [TEAEs]) were assessed at 14 weeks (end of titration and maintenance phases). RESULTS: Among the 90 patients enrolled, 95.6% (95% confidence interval: 89.0-98.8%) successfully transitioned to LEM at 2 weeks. The proportions of patients who successfully continued on LEM were 97.8% and 82.2% at the end of the titration and maintenance phases (Weeks 2 and 14), respectively. The overall incidence of TEAEs was 47.8%; no serious TEAEs occurred. In all cohorts, the proportions of patients with positive responses were higher than the proportions with negative responses on the three scales of the Patient Global Impression-Insomnia version. During the maintenance phase, Insomnia Severity Index scores generally improved at Weeks 2, 6, and 14 of LEM transition. CONCLUSIONS: Direct transition to LEM may be a valid treatment option for patients with insomnia who are dissatisfied with current treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04742699.

Interaction modes of human orexin 2 receptor with selective and nonselective antagonists studied by NMR spectroscopy.

Orexin neuropeptides have many physiological roles in the sleep-wake cycle, feeding behavior, reward demands, and stress responses by activating cognitive receptors, the orexin receptors (OX1R and OX2R), distributed in the brain. There are only subtle differences between OX1R and OX2R in the orthosteric site, which has hindered the rational development of subtype-selective antagonists. In this study, we utilized solution-state NMR to capture the structural plasticity of OX2R labeled with 13CH3-ε-methionine in complex with antagonists. Mutations in the orthosteric site allosterically affected the intracellular tip of TM6. Ligand exchange experiments with the subtype-selective EMPA and the nonselective suvorexant identified three methionine residues that were substantially perturbed. The NMR spectra suggested that the suvorexant-bound state exhibited more structural plasticity than the EMPA-bound state, which has not been foreseen from the close similarity of their crystal structures, providing insights into dynamic features to be considered in understanding the ligand recognition mode.

Is schedule IV suvorexant an appropriate reference drug of abuse to use in preclinical abuse liability testing in the rat?

The abuse potential of novel CNS-active drug candidates with low specificity for known receptors involved in abuse might be complex to test preclinically relative to an appropriate reference drug of abuse. Suvorexant, a Schedule IV dual orexin receptor antagonist was investigated for its potential use as a reference drug in Drug Discrimination Learning (DDL) studies. Firstly, toxicokinetic properties of suvorexant were determined in male and female rats after single oral doses of 160 and 325 mg/kg in MC and PEG400. Thereafter the subjective effects of suvorexant at 325 mg/kg versus vehicle were evaluated in a DDL paradigm and plasma exposures were measured. Mean maximum plasma exposures in male rats after a single dose of 325 mg/kg suvorexant were 2.5- (MC) to 10.5-fold (PEG400) the human exposure at supratherapeutic doses of 40 mg q.d. (Cmax:1.1 µM), and 4.9- (MC) to 20.8-fold (PEG400) the approved maximum human efficacious dose (20 mg q.d.; 0.557 µM). Training male rats at 325 mg/kg in the DDL study however did not result in discriminative stimulus generalisation versus respective vehicles. Suvorexant, a Schedule IV dual orexin receptor antagonist failed to serve as a robust reference drug of abuse in the DDL paradigm in rats despite appropriate exposures.

Suvorexant alters dynamics of the sleep-electroencephalography-power spectrum and depressive-symptom trajectories during inpatient opioid withdrawal.

STUDY OBJECTIVES: Opioid withdrawal is an aversive experience that often exacerbates depressive symptoms and poor sleep. The aims of the present study were to examine the effects of suvorexant on oscillatory sleep-electroencephalography (EEG) band power during medically managed opioid withdrawal, and to examine their association with withdrawal severity and depressive symptoms. METHODS: Participants with opioid use disorder (N = 38: age-range:21-63, 87% male, 45% white) underwent an 11-day buprenorphine taper, in which they were randomly assigned to suvorexant (20 mg [n = 14] or 40 mg [n = 12]), or placebo [n = 12], while ambulatory sleep-EEG data was collected. Linear mixed-effect models were used to explore: (1) main and interactive effects of drug group, and time on sleep-EEG band power, and (2) associations between sleep-EEG band power change, depressive symptoms, and withdrawal severity. RESULTS: Oscillatory spectral power tended to be greater in the suvorexant groups. Over the course of the study, decreases in delta power were observed in all study groups (ß = -189.082, d = -0.522, p = <0.005), increases in beta power (20 mg: ß = 2.579, d = 0.413, p = 0.009 | 40 mg ß = 5.265, d = 0.847, p < 0.001) alpha power (20 mg: ß = 158.304, d = 0.397, p = 0.009 | 40 mg: ß = 250.212, d = 0.601, p = 0.001) and sigma power (20 mg: ß = 48.97, d = 0.410, p < 0.001 | 40 mg: ß = 71.54, d = 0.568, p < 0.001) were observed in the two suvorexant groups. During the four-night taper, decreases in delta power were associated with decreases in depressive symptoms (20 mg: ß = 190.90, d = 0.308, p = 0.99 | 40 mg: ß = 433.33, d = 0.889 p = <0.001), and withdrawal severity (20 mg: ß = 215.55, d = 0.034, p = 0.006 | 40 mg: ß = 192.64, d = -0.854, p = <0.001), in both suvorexant groups and increases in sigma power were associated with decreases in withdrawal severity (20 mg: ß = -357.84, d = -0.659, p = 0.004 | 40 mg: ß = -906.35, d = -1.053, p = <0.001). Post-taper decreases in delta (20 mg: ß = 740.58, d = 0.964 p = <0.001 | 40 mg: ß = 662.23, d = 0.882, p = <0.001) and sigma power (20 mg only: ß = 335.54, d = 0.560, p = 0.023) were associated with reduced depressive symptoms in the placebo group. CONCLUSIONS: Results highlight a complex and nuanced relationship between sleep-EEG power and symptoms of depression and withdrawal. Changes in delta power may represent a mechanism influencing depressive symptoms and withdrawal.

Effect of lemborexant on pharmacokinetics of clozapine: A potential drug-drug interaction mediated by time-dependent inhibition of CYP3A4.

Clozapine (CLZ) is extensively used for treatment-resistant schizophrenia (TRS) with caution to avoid serious adverse events such as agranulocytosis and drug-drug interactions (DDIs). In the current report, we present a case of a 35-year-old male non-smoking TRS patient whose steady-state plasma trough concentrations (Ctrough ) of CLZ and its active metabolite, N-desmethylclozapine (NDMC), were significantly increased after initiating oral administration of lemborexant (LEM), a dual orexin receptor antagonist, for the treatment of insomnia. The patient experienced oversedation with sleepiness and fatigue while maintaining high levels of Ctrough of CLZ. The increased concentrations of CLZ returned to normal ranges after the discontinuation of LEM dosing, implying a pharmacokinetic DDI between CLZ and LEM. To gain insight into possible mechanisms, we performed in vitro assays of CYP1A2- and CYP3A4-mediated CLZ metabolism by measuring the formations of NDMC and clozapine N-oxide (CNO). In accordance with previous studies, the incubation of CLZ with each enzyme resulted in the production of both metabolites. LEM had only a weak inhibitory effect on CYP1A2- and CYP3A4-mediated CLZ metabolism. However, the preincubation of LEM with CYP3A4 in the presence of NADPH showed a significant enhancement of inhibitory effects on CLZ metabolism with IC50 values for the formations of CNO and NDMC of 2.8 µM and 4.1 µM, respectively, suggesting that LEM exerts as a potent time-dependent inhibitor for CYP3A4. Taken together, the results of the current study indicate that co-medication of CLZ with LEM may lead to increase in exposure to CLZ and risks of CLZ-related adverse events.

Orexin Receptor Antagonism: Normalizing Sleep Architecture in Old Age and Disease.

Sleep is essential for human well-being, yet the quality and quantity of sleep reduce as age advances. Older persons (>65 years old) are more at risk of disorders accompanied and/or exacerbated by poor sleep. Furthermore, evidence supports a bidirectional relationship between disrupted sleep and Alzheimer's disease (AD) or related dementias. Orexin/hypocretin neuropeptides stabilize wakefulness, and several orexin receptor antagonists (ORAs) are approved for the treatment of insomnia in adults. Dysregulation of the orexin system occurs in aging and AD, positioning ORAs as advantageous for these populations. Indeed, several clinical studies indicate that ORAs are efficacious hypnotics in older persons and dementia patients and, as in adults, are generally well tolerated. ORAs are likely to be more effective when administered early in sleep/wake dysregulation to reestablish good sleep/wake-related behaviors and reduce the accumulation of dementia-associated proteinopathic substrates. Improving sleep in aging and dementia represents a tremendous opportunity to benefit patients, caregivers, and health systems.

Clinical safety and narcolepsy-like symptoms of dual orexin receptor antagonists in patients with insomnia: a systematic review and meta-analysis.

STUDY OBJECTIVES: Dual orexin receptor antagonists (DORAs) are emerging treatments for insomnia. This meta-analysis study aimed to assess the safety of FDA-approved DORAs (suvorexant, lemborexant, and daridorexant), focusing on narcolepsy-like symptoms associated with these drugs. METHODS: Five prominent databases were searched to identify randomized controlled trials (RCTs) on this topic. Primary safety outcomes included treatment-emergent adverse events (TEAEs), treatment-related TEAEs, TEAEs leading to discontinuation, and serious TEAEs. Excessive daytime sleepiness (EDS), sleep paralysis, and hallucinations were categorized as adverse events (AEs)-related narcolepsy-like symptoms. RESULTS: Eleven RCTs with 7703 patients were included. DORAs were associated with a higher risk of TEAEs (risk ratio [RR], 1.09; 95% confidence interval [CI], 1.03 to 1.15) and treatment-related TEAEs (RR, 1.69; 95% CI: 1.49 to 1.92) when compared to placebo. The DORA group exhibited a significantly higher risk of EDS (RR, 2.15; 95% CI: 1.02 to 4.52) and sleep paralysis (RR, 3.40; 95% CI: 1.18 to 9.80) compared to the placebo group. CONCLUSION: This meta-analysis achieved a comparative evaluation of the clinical safety and tolerability of FDA-approved DORAs for primary insomnia, specifically focusing on AEs-related narcolepsy-like symptoms. This study contributes to understanding the safety profile of FDA-approved DORAs for treating insomnia.

Sleep loss, caffeine, sleep aids and sedation modify brain abnormalities of mild traumatic brain injury.

Little evidence exists about how mild traumatic brain injury (mTBI) is affected by commonly encountered exposures of sleep loss, sleep aids, and caffeine that might be potential therapeutic opportunities. In addition, while propofol sedation is administered in severe TBI, its potential utility in mild TBI is unclear. Each of these exposures is known to have pronounced effects on cerebral metabolism and blood flow and neurochemistry. We hypothesized that they each interact with cerebral metabolic dynamics post-injury and change the subclinical characteristics of mTBI. MTBI in rats was produced by head rotational acceleration injury that mimics the biomechanics of human mTBI. Three mTBIs spaced 48 h apart were used to increase the likelihood that vulnerabilities induced by repeated mTBI would be manifested without clinically relevant structural damage. After the third mTBI, rats were immediately sleep deprived or administered caffeine or suvorexant (an orexin antagonist and sleep aid) for the next 24 h or administered propofol for 5 h. Resting state functional magnetic resonance imaging (rs-fMRI) and diffusion tensor imaging (DTI) were performed 24 h after the third mTBI and again after 30 days to determine changes to the brain mTBI phenotype. Multi-modal analyses on brain regions of interest included measures of functional connectivity and regional homogeneity from rs-fMRI, and mean diffusivity (MD) and fractional anisotropy (FA) from DTI. Each intervention changed the mTBI profile of subclinical effects that presumably underlie healing, compensation, damage, and plasticity. Sleep loss during the acute post-injury period resulted in dramatic changes to functional connectivity. Caffeine, propofol sedation and suvorexant were especially noteworthy for differential effects on microstructure in gray and white matter regions after mTBI. The present results indicate that commonplace exposures and short-term sedation alter the subclinical manifestations of repeated mTBI and therefore likely play roles in symptomatology and vulnerability to damage by repeated mTBI.

Orexin 2 receptor antagonism sex-dependently improves sleep/wakefulness and cognitive performance in tau transgenic mice.

BACKGROUND AND PURPOSE: Tau pathology contributes to a bidirectional relationship between sleep disruption and neurodegenerative disease. Tau transgenic rTg4510 mice model tauopathy symptoms, including sleep/wake disturbances, which manifest as marked hyperarousal. This phenotype can be prevented by early transgene suppression; however, whether hyperarousal can be rescued after onset is unknown. EXPERIMENTAL APPROACH: Three 8-week experiments were conducted with wild-type and rTg4510 mice after age of onset of hyperarousal (4.5 months): (1) Tau transgene suppression with doxycycline (200 ppm); (2) inactive phase rapid eye movement (REM) sleep enhancement with the dual orexin receptor antagonist suvorexant (50 mg·kg-1 ·day-1 ); or (3) Active phase non-NREM (NREM) and REM sleep enhancement using the selective orexin 2 (OX2 ) receptor antagonist MK-1064 (40 mg·kg-1 ·day-1 ). Sleep was assessed using polysomnography, cognition using the Barnes maze, and tau pathology using immunoblotting and/or immunohistochemistry. KEY RESULTS: Tau transgene suppression improved tauopathy and hippocampal-dependent spatial memory, but did not modify hyperarousal. Pharmacological rescue of REM sleep deficits did not improve spatial memory or tau pathology. In contrast, normalising hyperarousal by increasing both NREM and REM sleep via OX2 receptor antagonism restored spatial memory, independently of tauopathy, but only in male rTg4510 mice. OX2 receptor antagonism induced only short-lived hypnotic responses in female rTg4510 mice and did not improve spatial memory, indicating a tau- and sex-dependent disruption of OX2 receptor signalling. CONCLUSIONS AND IMPLICATIONS: Pharmacologically reducing hyperarousal corrects tau-induced sleep/wake and cognitive deficits. Tauopathy causes sex-dependent disruptions of OX2 receptor signalling/function, which may have implications for choice of hypnotic therapeutics in tauopathies.

The effects of a dual orexin receptor antagonist on fear extinction memory and sleep in mice: Implications for exposure therapy.

Extinction of conditioned fear is considered a fundamental process in the recovery from posttraumatic stress disorder and anxiety disorders. Sleep, especially rapid-eye-movement (REM) sleep, has been implicated in promoting extinction memory. The orexin system contributes to the regulation of sleep and wakefulness and emotional behaviors. In rodents, administrations of an orexin receptor antagonist following fear extinction training enhanced consolidation of extinction memory. Although orexin antagonists increase sleep, including REM sleep, the possible contribution of sleep to the effects of orexin antagonists on extinction memory has not been examined. Therefore, this study examined the effects of suvorexant, a dual orexin receptor antagonist, on extinction memory and sleep and their associations in mice. C57BL/6 mice underwent sleep recording for 24 h before and after contextual fear conditioning with footshocks and extinction learning during the early light phase or early dark phase. Mice were systemically injected with either 25 mg/kg of suvorexant or vehicle immediately after the extinction session. We found that suvorexant neither altered sleep nor improved extinction memory recall compared with vehicle. The higher percentages of REM sleep during the post-extinction dark phase were associated with lower extinction memory recall and greater freezing responses to the fear context. Results also indicate that animals did not reach complete extinction of fear with the fear extinction training protocol used in this study. These findings suggest that promoting REM sleep may not enhance fear extinction memory when extinction of fear is incomplete.

Efficacy of combined use of Suvorexant and Ramelteon in preventing postoperative delirium: a retrospective comparative study.

BACKGROUND: Suvorexant and ramelteon have been presented as useful for preventing postoperative delirium. Previous studies reported on the comparison with benzodiazepine hypnotics which have been known for the risk for inducing delirium, but the comparison with patients not taking any hypnotics has not been reported yet. Therefore, we assessed the incidence rates for postoperative delirium comparing cancer patients who received preoperative combined administration with suvorexant and ramelteon and those not taking any hypnotics. METHODS: Among 110 cancer patients who underwent surgeries at the Division of Hepato-Biliary-Pancreatic Surgery at the Shizuoka Cancer Center between April 1, 2017 and June 30, 2020, 50 patients who received combined administration with suvorexant and ramelteon from 7 days prior to their surgeries and 60 patients who did not take any hypnotics including suvorexant and ramelteon were classified. They were retrospectively observed during the 7 days from their surgeries onward to compare the cumulative incidence rates for postoperative delirium. RESULTS: The cumulative incidence rate for postoperative delirium during the 7 days in the combined-administration group was 14.0% (7/50), while that for the no-hypnotic group was 36.7% (22/60), which proved that the incidence rate for the former was significantly low (OR: 0.28, 95%CI: 0.11-0.73, P = 0.009). CONCLUSIONS: The present study suggests that the preventive combined administration with suvorexant and ramelteon starting from the preoperative period for cancer patients can be effective in lowering the incidence rate for postoperative delirium. TRIAL REGISTRATION: Retrospectively registered.

Efficacy and safety of pharmacotherapy in chronic insomnia: A review of clinical guidelines and case reports.

Introduction: Chronic insomnia affects 5% to 10% of the US population, increasing the demand for treatment options and the corresponding research to prove their validity.1 This review compares recommendations from 3 clinical guidelines and summarizes hypnotic medications, including their newly reported side effects not mentioned in the guidelines. In addition, we aim to provide an overview of what pharmacotherapies are available for prescribers and patients. Methods: A literature search was conducted for articles published prior to January 10, 2022, and case reports and clinical studies were retrieved from PubMed and Google Scholar. Results: Definitive conclusions cannot be drawn regarding the safety and efficacy of medications reviewed; however, trends are apparent. All 3 guidelines included in this review remarked most treatment recommendations as weak except for cognitive behavioral therapy for insomnia, which is effective but not readily available. Furthermore, based on the 15 case reports and 13 clinical studies presented in this review, many of the medications used for treatment of insomnia present safety concerns. Discussion: Benzodiazepines and benzodiazepine receptor agonists are commonly used hypnotic agents with the "Z-drugs" having robust data establishing their efficacy for the short-term treatment of chronic insomnia. However, significant adverse effects related to the central nervous system (CNS), including developing tolerance, addiction, CNS depression, and amnesia, remain barriers to their long-term use. In comparison, newer agents present more favorable side-effect profiles although with less established efficacy. Additionally, off-label agents, including antidepressants, antihistamines, and natural supplements, are discussed due to their prominent use.

Lack of Efficacy of Suvorexant in People with Insomnia and Poorly Controlled Type 2 Diabetes.

Objective/Background: Sleep disturbance is a common and underappreciated feature of diabetes and sleep may contribute to glycemic control in people with type 2 diabetes (T2D). We conducted a 3-month trial to examine the efficacy of suvorexant in improving sleep and health outcomes in people with suboptimally controlled T2D and insomnia. Participants/Methods: This parallel, double-blind, randomized placebo-controlled trial was conducted using the sequential parallel comparison design (SPCD). Sixty-nine people with poorly controlled T2D (HbA1c ≥ 6.5) were randomized to placebo and/or suvorexant (10-20 mg). The primary outcome was subjective total sleep time (sTST), and secondary outcomes were Insomnia Severity Index (ISI) score and wake time after sleep onset (WASO). Exploratory outcomes included sleep efficiency, hemoglobin A1c (HbA1c), and C-reactive protein (CRP). Exploratory analyses were conducted on relationships between sleep and diabetes outcomes. Results: There were no significant improvements in sTST (p = 0.27), ISI (p = 0.86), or WASO (p = 0.94) among participants taking suvorexant compared to placebo. There were also no significant changes in any of the exploratory endpoints. Improvements in sleep were associated with improvements in both objective (ie, HbA1c) and subjective (ie, Diabetes Distress Scale) measures of diabetes, as well as reductions in depressive symptoms, independent of treatment assignment. Conclusion: The study did not find evidence that suvorexant is efficacious for insomnia in people with poorly controlled T2D. The associations of improved sleep with improvements in both diabetes-related metrics and depressive symptoms across groups highlight the importance of identifying and treating sleeping difficulties in this population. CT Registration #: Nct03818581.