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.

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.

A double-blind, randomized, placebo-controlled plus open trial of adjunctive suvorexant for treatment-resistant insomnia in patients with bipolar disorder.

BACKGROUND: Sleep pattern alteration is a core feature of bipolar disorder (BD), often challenging to treat and affecting clinical outcomes. Suvorexant, a hypnotic agent that decreases wakefulness, has shown promising results in treating primary insomnia. To date, data on its use in BD are lacking. This study evaluated the efficacy and tolerability of adjunctive suvorexant for treatment-resistant insomnia in BD patients. METHODS: Thirty-six BD outpatients (19 BDI, 69.4% female, 48.9 [±15.2] years) were randomized for 1 week to double-blind suvorexant (10-20 mg/day) versus placebo. Then, all subjects who completed the randomized phase were offered open suvorexant for 3 months. Subjective total sleep time (sTST) and objective total sleep time (oTST) were assessed. RESULTS: During the randomized control trial (RCT) phase, an overall increase in the oTST emerged, which was statistically significant for the Cole-Kripke algorithm (p = 0.035). The comparison between the suvorexant and placebo groups was limited by significant differences between measurements at baseline. During the open phase, no significant improvement was detected relative to either sTST and oTST. No adverse events nor major intolerances were reported. DISCUSSION: Efficacy results are inconsistent. During the RCT phase, only a small increase in the objective oTST emerged, while during the open phase, no significant improvement was detected. While this is the first ever study of suvorexant in BD-related insomnia, the limitation of the small sample and the high rate of dropouts limits the generalizability of these findings. Larger studies are needed to assess suvorexant in treating BD-related insomnia.

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.

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.

The orexin story and orexin receptor antagonists for the treatment of insomnia.

Insomnia is present in up to one third of the adult population worldwide, and it can present independently or with other medical conditions such as mental, metabolic, or cardiovascular diseases, which highlights the importance of treating this multifaceted disorder. Insomnia is associated with an abnormal state of hyperarousal (increased somatic, cognitive, and cortical activation) and orexin has been identified as a key promotor of arousal and vigilance. The current standards of care for the treatment of insomnia recommend non-pharmacological interventions (cognitive behavioural therapy) as first-line treatment and, if behavioural interventions are not effective or available, pharmacotherapy. In contrast to most sleep medications used for decades (benzodiazepines and 'Z-drugs'), the new orexin receptor antagonists do not modulate the activity of γ-aminobutyric acid receptors, the main inhibitory mechanism of the central nervous system. Instead, they temporarily block the orexin pathway, causing a different pattern of effects, e.g., less morning or next-day effects, motor dyscoordination, and cognitive impairment. The pharmacokinetic/pharmacodynamic properties of these drugs are the basis of the different characteristics explained in the package inserts, including the recommended starting dose. Orexin receptor antagonists seem to be devoid of any dependence and tolerance-inducing effects, rendering them a viable option for longer-term treatment. Safety studies did not show exacerbation of existing respiratory problems, but more real-world safety and pharmacovigilance experience is needed. This review provides an overview of the orexin history, the mechanism of action, the relation to insomnia, and key features of available drugs mediating orexin signalling.

Efficacy and safety of lemborexant as an alternative drug for patients with insomnia taking gamma-aminobutyric acid-benzodiazepine receptor agonists or suvorexant.

BACKGROUND: Although gamma-aminobutyric acid-benzodiazepine (GABA-BZ) receptor agonists are used to treat insomnia, their long-term or high-dosage use causes adverse events. Nevertheless, evidence regarding the discontinuation and replacement of GABA-BZ receptor agonists with alternative agents is lacking. Suvorexant (SUX), an existing orexin receptor antagonist, is effective in preventing nocturnal awakening in 70%-75% of patients with insomnia. METHODS: The novel dual orexin receptor antagonist lemborexant (LEM) has fewer adverse effects than GABA-BZ receptor agonists. Therefore, in this retrospective study, we categorised patients taking GABA-BZ receptor agonists and SUX into LEM-treated (switched) and non-treated (non-switched) groups and compared their outcomes over a 12-week period. RESULTS: The GABA-BZ group (N = 59) comprised 34 'switched' and 25 'non-switched' and the SUX group (N = 14) comprised 6 'switched' and 8 'non-switched' patients. A mixed model showed a significant diazepam equivalence reduction in patients taking GABA-BZ receptor agonists and improved Athens Insomnia Scale score in those taking SUX. The safety and tolerability of GABA-BZ receptor agonists and SUX were high, and no serious adverse effects were observed after switching to LEM. CONCLUSIONS: Lemborexant may be a useful alternative for long-term GABA-BZ receptor agonist users. For SUX, the number of cases (N = 6) was insufficient to draw definite conclusions.

Hypocretins (orexins): The ultimate translational neuropeptides.

The hypocretins (Hcrts), also known as orexins, are two neuropeptides produced exclusively in the lateral hypothalamus. They act on two specific receptors that are widely distributed across the brain and involved in a myriad of neurophysiological functions that include sleep, arousal, feeding, reward, fear, anxiety and cognition. Hcrt cell loss in humans leads to narcolepsy with cataplexy (narcolepsy type 1), a disorder characterized by intrusions of sleep into wakefulness, demonstrating that the Hcrt system is nonredundant and essential for sleep/wake stability. The causal link between Hcrts and arousal/wakefulness stabilisation has led to the development of a new class of drugs, Hcrt receptor antagonists to treat insomnia, based on the assumption that blocking orexin-induced arousal will facilitate sleep. This has been clinically validated: currently, two Hcrt receptor antagonists are approved to treat insomnia (suvorexant and lemborexant), with a New Drug Application recently submitted to the US Food and Drug Administration for a third drug (daridorexant). Other therapeutic applications under investigation include reduction of cravings in substance-use disorders and prevention of neurodegenerative disorders such as Alzheimer's disease, given the apparent bidirectional relationship between poor sleep and worsening of the disease. Circuit neuroscience findings suggest that the Hcrt system is a hub that integrates diverse inputs modulating arousal (e.g., circadian rhythms, metabolic status, positive and negative emotions) and conveys this information to multiple output regions. This neuronal architecture explains the wealth of physiological functions associated with Hcrts and highlights the potential of the Hcrt system as a therapeutic target for a number of disorders. We discuss present and future possible applications of drugs targeting the Hcrt system for the treatment of circuit-related neuropsychiatric and neurodegenerative conditions.

Cost-effectiveness analysis of lemborexant for treating insomnia in Japan: a model-based projection, incorporating the risk of falls, motor vehicle collisions, and workplace accidents.

BACKGROUND: Lemborexant has demonstrated statistically significant improvements in sleep onset and sleep maintenance compared with placebo and zolpidem tartrate extended release, measured both objectively using polysomnography and subjectively using sleep diaries, in the phase 3 clinical trial SUNRISE 1. This study evaluated the cost-effectiveness of lemborexant compared with suvorexant, zolpidem immediate release (IR), and untreated insomnia. METHODS: A decision-tree model was developed for falls, motor vehicle collisions, and workplace accidents associated with insomnia and insomnia treatments from a Japanese healthcare perspective and with a 6-month time horizon. The model extracted subjective sleep onset latency treatment responses and disutility values for non-responders from SUNRISE 1. Cost-effectiveness was assessed using incremental cost per quality-adjusted life year (QALY) gained. One-way and probabilistic sensitivity analyses were conducted to evaluate the impact of parameter uncertainty on the results. RESULTS: In the base-case analysis, the mean estimated QALYs for lemborexant, suvorexant, zolpidem-IR, and untreated insomnia were 0.4220, 0.4204, 0.4113, and 0.4163, and expected medical costs were JPY 34 034, JPY 38 371, JPY 38 139, and JPY 15 383, respectively. Lemborexant saved JPY 4337 and JPY 4105 compared with suvorexant or zolpidem-IR, respectively, while conferring QALY benefits. The incremental cost-effectiveness ratio (ICER) of lemborexant compared with that of untreated insomnia was JPY 3 220 975 /QALY. Lemborexant was dominant over suvorexant and zolpidem-IR and was cost-effective when compared with untreated insomnia. Sensitivity analyses supported the results' robustness. CONCLUSIONS: In a Japanese clinical practice setting, lemborexant may represent a better investment for treating insomnia in the healthcare system in Japan.

Orexin Receptor Antagonists and Insomnia.

PURPOSE OF REVIEW: We review recent evidence on the use of orexin receptor antagonists (ORAs) for treating insomnia. We evaluate studies on five dual ORAs and one selective ORA. RECENT FINDINGS: Research on suvorexant in recent years gradually focus on comorbid insomnia, while lemborexant and daridorexant were still being validated in primary insomnia. Almorexant is now mainly used as a commercial specific inhibitor of the orexin system in animal studies due to safety issues. Although filorexant has also shown a certain sleep-promoting effect, there are few clinical or experimental studies on sleep-related aspects of filorexant in recent years. As for selective ORAs, orexin receptor 2 antagonist seltorexant still has not yet reached phase 3. High-quality clinical trials in insomnia populations are needed which directly compare authorized ORAs and investigate non-approved ORAs, the use of ORAs in comorbid insomnia, and the orexin signaling system pathophysiology in insomnia.

Effectiveness of change from suvorexant to lemborexant drug in the treatment of sleep disorders.

BACKGROUND: This study aimed to examine the effects of a change in medication from suvorexant to lemborexant among patients with insomnia. METHODS: Patients with chronic insomnia who had persistent insomnia for 3 months or longer and who had been taking suvorexant for 3 months or longer were selected. The participants were divided into two groups: the 'modified' group and the 'non-modified' group. Four sub-types of insomnia (i.e., difficulty initiating sleep, difficulty maintaining sleep, early-morning awakening, and non-restorative sleep) were investigated. Logistic regression was used to investigate improvements in both the groups after 12 weeks. RESULTS: Among the 77 participants, 43 and 34 patients were in the modified drug group and the non-modified drug group, respectively. Comparing sleep disorders between the two groups, we found significant improvement after 12 weeks in the modified drug group in terms of difficulty initiating sleep, compared with the non-modified drug group (odds ratio = 0.036, P = 0.008, 95% CI = 0.003-0.415). However, no significant differences were found between the two groups in terms of difficulty maintaining sleep, early-morning awakening, and non-restorative sleep. CONCLUSIONS: Sleep disorders can be treated by alleviating difficulties in initiating sleep by changing from suvorexant to lemborexant. In addition, it was confirmed that the drug change caused no serious side effects and that it was highly safe and tolerated.

Suvorexant with or without ramelteon to prevent delirium: a systematic review and meta-analysis.

Delirium is a common and serious neurobehavioral syndrome, associated with prolonged hospital stays, and increased morbidity and mortality. As it remains unclear whether suvorexant with or without ramelteon prevents delirium in elderly hospitalized patients, we conducted a systematic review and meta-analysis to evaluate, searching the PubMed, Cochrane Library, Web of Science, EMBASE, and EBSCOhost databases for all randomized controlled trials (RCTs), case-control studies, and cohort studies that investigated the effects of suvorexant with or without ramelteon on delirium in adult hospitalized patients. The primary outcome was the incidence of delirium. Two randomized controlled trials, 7 cohort studies and 2 case-control studies involving 2594 patients were included in this meta-analysis. The results showed that both suvorexant alone (odds ratio (OR) = 0.30, 95% confidence interval (CI): 0.14-0.65, P = 0.002) and suvorexant with ramelteon (OR = 0.39, 95% CI 0.23-0.65, P = 0.0003) reduced the incidence of delirium in adult hospitalized patients. Six studies involved the use of benzodiazepines; subgroup analysis performed separately in the suvorexant alone and suvorexant with ramelteon groups indicated that when benzodiazepine was administered, suvorexant with ramelteon was effective at reducing the incidence of delirium (OR = 0.53, 95% CI 0.37-0.74, P = 0.0002), but no significant difference was observed for suvorexant alone (OR = 0.40, 95% CI 0.11-1.53, P = 0.18). The current literature thus supports the effectiveness of suvorexant with or without ramelteon for delirium prevention, although suvorexant alone failed to significantly reduce the incidence of delirium when benzodiazepine was administered. The present study was limited by the significant heterogeneity among the included studies, and caution should be exercised when interpreting the results. This study was registered in the PROSPERO database (CRD4202017964).

Pilot evaluation of a consumer wearable device to assess sleep in a clinical polysomnography trial of suvorexant for treating insomnia in patients with Alzheimer's disease.

The orexin receptor antagonist suvorexant was previously reported to significantly improve total sleep time (TST), by 28 min per night versus placebo after 4 weeks, in a sleep laboratory polysomnography (PSG) study of patients with Alzheimer's disease and insomnia. The study included an exploratory evaluation of a consumer-grade wearable "watch" device for assessing sleep that we report on here. Participants who met diagnostic criteria for both probable Alzheimer's disease dementia and insomnia were randomized to suvorexant 10-20 mg (N = 142) or placebo (N = 143) in a double-blind, 4-week trial. Patients were provided with a consumer-grade wearable watch device (Garmin vívosmart® HR) to be worn continuously. Overnight sleep laboratory PSG was performed on three nights: screening, baseline and Night 29 (last dose). Watch treatment effects were assessed by change-from-baseline in watch TST at Week 4 (average TST per night). We also analysed Night 29 data only, with watch data restricted to the PSG recording time. In the 193 participants included in the Week 4 watch analysis (suvorexant = 97, placebo = 96), the suvorexant-placebo difference in watch TST was 4 min (p = .622). In patients with usable data for both assessments at the baseline and Night 29 PSG (suvorexant = 57, placebo = 50), the watch overestimated TST compared to PSG (e.g., placebo baseline = 412 min for watch and 265 min for PSG) and underestimated change-from-baseline treatment effects: the suvorexant-placebo difference was 20 min for watch TST (p = .405) and 35 min for PSG TST (p = .057). These findings show that the watch was less sensitive than PSG for evaluating treatment effects on TST.

Significant decrease in delirium referrals after changing hypnotic from benzodiazepine to suvorexant.

BACKGROUND: The use of benzodiazepines (BZDs) causes delirium, especially in elderly people. For this reason, suvorexant has been recommended as the first-line hypnotic in elderly patients. The aim of this study was to determine whether the first-line use of suvorexant, instead of BZDs, decreases referrals for delirium in elderly patients. METHODS: Since May 2016 at Nagoya Ekisaikai Hospital, suvorexant has been recommended as the first-line hypnotic instead of BZDs. In May 2017, suvorexant was adopted as the first-line hypnotic. The number of delirium cases referred to psychiatry was compared among three consecutive periods: period A (May 2015-April 2016), during which BZDs were mainly used for insomnia; period B (May 2016-April 2017), during which the use of suvorexant was recommended instead of BZDs; and period C (May 2017-April 2018), during which suvorexant was principally adopted as the first-line hypnotic for insomnia. Potential confounding factors that may affect the development of delirium were also examined during the three periods. RESULTS: The number of delirium referral cases in elderly patients in each period decreased, from 133 in period A to 86 in period B and 53 in period C. The rate of delirium referral cases decreased significantly every year (P = 9.02 × 10-10 ). Almost no significant confounding factors other than hypnotics were detected during the three periods. CONCLUSION: The referrals for delirium in elderly patients decreased significantly after the hypnotic was changed from BZDs to suvorexant.

The Discovery of Suvorexant, the First Orexin Receptor Drug for Insomnia.

Historically, pharmacological therapies have used mechanisms such as γ-aminobutyric acid A (GABAA) receptor potentiation to drive sleep through broad suppression of central nervous system activity. With the discovery of orexin signaling loss as the etiology underlying narcolepsy, a disorder associated with hypersomnolence, orexin antagonism emerged as an alternative approach to attenuate orexin-induced wakefulness more selectively. Dual orexin receptor antagonists (DORAs) block the activity of orexin 1 and 2 receptors to both reduce the threshold to transition into sleep and attenuate orexin-mediated arousal. Among DORAs evaluated clinically, suvorexant has pharmacokinetic properties engineered for a plasma half-life appropriate for rapid sleep onset and maintenance at low to moderate doses. Unlike GABAA receptor modulators, DORAs promote both non-rapid eye movement (NREM) and REM sleep, do not disrupt sleep stage-specific quantitative electroencephalogram spectral profiles, and allow somnolence indistinct from normal sleep. The preservation of cognitive performance and the ability to arouse to salient stimuli after DORA administration suggest further advantages over historical therapies.

Hypnotics with novel modes of action.

Insomnia and, more generally, lack of sleep are on the rise. Traditionally treated by classical hypnotics, such as benzodiazepines and Z drugs, which both act on the GABAA receptor, and other modalities, including nondrug therapies, such as cognitive behavioural therapy, there is a range of new hypnotics which are being developed or have recently received market approval. Suvorexant and the like target the orexin/hypocretin system: they should have less side effects in terms of drug-drug interactions with e.g. alcohol, less memory impairment and dependence potential compared to classical hypnotics.

From orexin receptor agonist YNT-185 to novel antagonists with drug-like properties for the treatment of insomnia.

YNT-185 is the first known small molecule acting as orexin 2 receptor (OX2R) agonist with implication to narcolepsy treatment, served as a template scaffold in generating a small set of seven compounds with predictive affinity to OX2R. The design of the new small molecules was driven mostly by improving physicochemical properties of the parent drug YNT-185 in parallel with in silico studies, later suggesting their favorable binding modes within the active site of OX2R. We obtained seven new potential OX2R binders that were evaluated in vitro for their CNS availability, cytotoxicity, and behavior pattern on OX2R. Out of them, 15 emerged as the most potent modulator of OX2R, which, contrary to YNT-185, displayed inverse mode of action, i.e. antagonist profile. 15 was also submitted to an in vivo experiment revealing its ability to permeate through BBB into the brain with a short half-life.

Association of Hypnotic Drug Use with Fall Incidents in Hospitalized Elderly Patients: A Case-Crossover Study.

We investigated whether use of hypnotic drugs, including benzodiazepine receptor agonists, as well as ramelteon and suvorexant are associated with fall incidents in elderly inpatients aged no less than 75 years, who were hospitalized at an acute care general hospital in Japan, between November 1st, 2016 and October 31st, 2017. Multivariate analysis results were reported as odds ratio (OR) with 95% confidence interval (CI). Following to a case-crossover study protocol, the time windows of the case and the control days were assigned to the day or the days, which are one day or 2-8 d before the fall incidents, respectively. In the enrolled 111 patients, the accumulated total available numbers of the cases and the control days were 111 and 554 patient days, respectively. Hypnotic drug use was significantly associated with fall incidents (OR: 2.85, 95% CI: 1.03-7.90, p = 0.04). Especially benzodiazepine receptor agonists (OR: 5.79, 95% CI: 1.52-22.1, p = 0.01) showed statistically significant association with fall incidents. In contrast, neither ramelteon (OR: 7.95, 95% CI: 0.72-87.9, p = 0.09) nor suvorexant (OR: 0.25, 95% CI: 0.06-1.06, p = 0.06) were significantly associated with fall incidents. Thus, benzodiazepine receptor agonists, but not ramelteon or suvorexant, showed significant association with fall incidents. Therefore, special care should be taken especially when benzodiazepine receptor agonists are administrated to elderly subjects. In contrast, fall risk may be much less in patients treated with ramelteon or suvorexant. These results could help us to conduct safer drug treatment for insomnia patients aged no less than 75 years.

Polysomnographic assessment of suvorexant in patients with probable Alzheimer's disease dementia and insomnia: a randomized trial.

INTRODUCTION: We evaluated the clinical profile of the orexin receptor antagonist suvorexant for treating insomnia in patients with mild-to-moderate probable Alzheimer's disease (AD) dementia. METHODS: Randomized, double-blind, 4-week trial of suvorexant 10 mg (could be increased to 20 mg based on clinical response) or placebo in patients who met clinical diagnostic criteria for both probable AD dementia and insomnia. Sleep was assessed by overnight polysomnography in a sleep laboratory. The primary endpoint was change-from-baseline in polysomnography-derived total sleep time (TST) at week 4. RESULTS: Of 285 participants randomized (suvorexant, N = 142; placebo, N = 143), 277 (97%) completed the trial (suvorexant, N = 136; placebo, N = 141). At week 4, the model-based least squares mean improvement-from-baseline in TST was 73 minutes for suvorexant and 45 minutes for placebo; (difference = 28 minutes [95% confidence interval 11-45], p < 0.01). Somnolence was reported in 4.2% of suvorexant-treated patients and 1.4% of placebo-treated patients. DISCUSSION: Suvorexant improved TST in patients with probable AD dementia and insomnia.

Orexin receptor antagonists for the treatment of insomnia and potential treatment of other neuropsychiatric indications.

In this review, we outline the role of orexin receptor antagonists in disorders of sleep/wake and other potential neuropsychiatric conditions, with a focus on suvorexant, which is currently the only approved agent in this class. The efficacy of suvorexant was established in Phase 2-3 trials with treatment durations ranging from 1 to 12 months in patients with insomnia. Suvorexant is effective at improving sleep assessed by patient self-report and by polysomnography, with generally little effect on underlying sleep architecture. The main side-effect is next day somnolence. With the growing realization of the important connections between sleep and other disorders, studies are ongoing to explore this novel mechanism in other disorders such as Alzheimer's disease and depression.