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Effects of Suvorexant on the Insomnia Severity Index in Patients with Insomnia: Analysis of Pooled Phase 3 Data
Abstract
Objective:
Suvorexant is an orexin receptor antagonist that is approved in the US, Japan and Australia for the treatment of insomnia. Using outcomes from the Insomnia Severity Index (ISI) in the core registration studies, we explored suvorexant effects on sleep problems and their impact on daytime function.
Methods:
Data were pooled from two similar Phase 3, randomized, double-blind, placebo-controlled, parallel-group, three-month trials in elderly (≥65 years) and non-elderly (18-64 years old) insomnia patients. Age-adjusted (non-elderly/elderly) dose-regimes of 40/30 mg and 20/15 mg were evaluated. The ISI, a 7-item self-rated questionnaire with each item rated on 0-4 scale (higher score corresponds to increasing severity), was administered to patients as an exploratory assessment in both studies at baseline and one and three months after randomization.
Results:
The analysis included 1824 patients. Suvorexant improved change-from-baseline ISI total scores to a greater extent than placebo (Month three: 20/15 mg = -6.2, 40/30 mg = -6.7, placebo = -4.9, p-values for both active arms vs. placebo <0.001) and resulted in a greater proportion of responders than placebo using a variety of definitions (eg, ≥6-point improvement from baseline at Month three: 20/15 mg = 55.5%, 40/30 mg = 54.9%, placebo = 42.2%, p-values for both active arms vs. placebo <0.001). Additionally, the "impact of insomnia" component, which assesses the impact of insomnia on daytime function/quality-of-life, was improved to a greater extent by suvorexant than placebo.
Conclusions:
Suvorexant 20/15 mg and 40/30 mg improved sleep to a greater extent than placebo as assessed by the ISI in patients with insomnia. Improvement in sleep onset/maintenance as well as a reduction of the impact of sleep problems on daytime function contributed to the overall improvement observed in ISI total score. CLINICALTRIALS.
Gov identifier:
NCT01097616, NCT01097629.
... Analysis of suvorexant in elderly populations through phase 3 clinical trials has indicated its safety and efficacy, and this drug is well tolerated after multiple doses 108 . However, in instances where patients have been on another medication for insomnia previously, higher incidences of adverse drug reactions and dependence were reported 109 . ...
... Comparison of the currently available sleep aids for use in the older adults that are FDA approved for treating sleep disorders Dual orexin receptor antagonists (DORAs) are the only class of drugs with high benefit and low risk22,90,103,108,128,[131][132][133][134][135][143][144][145][146] . Further, studies have directly compared DORAs to several other sleep drugs and the general pattern of results is that DORAs do a better job of reducing time spent awake in the middle of the sleeping period, and have less adverse effect on balance[147][148][149][150][151] . ...
We examine the relationship between sleep, glymphatics and Alzheimer’s disease (AD), and recent work questioning glymphatic clearance during sleep. We highlight a need for understanding glymphatic and/or other mechanism of clearance during sleep, and review glymphatic flow measurement methods. Further, we explore dual orexin receptor antagonists (DORAs) potential to mitigate AD sleep disturbances and enhance clearance. Further research could elucidate a linkage between DORAs, improved sleep and reducing AD pathophysiology.
... The orexin receptor antagonist was developed as an insomnia treatment drug, and many studies reported that the orexin receptor antagonist was effective for insomnia. 11,12) Suvorexant is one of the orexin receptor antagonists, and is reported to improve sleep in patients with insomnia. 11) Recently, some studies presented that suvorexant prevented delirium during acute hospitalization and ICU stay. ...
... 11,12) Suvorexant is one of the orexin receptor antagonists, and is reported to improve sleep in patients with insomnia. 11) Recently, some studies presented that suvorexant prevented delirium during acute hospitalization and ICU stay. 13,14) A few reports reported the postoperative effect of suvorexant in patients who underwent cardiovascular surgery. ...
Purpose: We retrospectively evaluated the postoperative efficacy of an orexin receptor antagonist for patients who underwent off-pump coronary artery bypass grafting (OPCAB).
Materials and Methods: We invested 108 patients who underwent cardiovascular surgery at our hospital. Patients were categorized as those received orexin receptor antagonist after surgery (S group, n = 64) or without orexin receptor antagonist (N group, n = 44), and the following data were analyzed between both groups.
Results: The incidence of postoperative delirium (POD) was significantly less in the S group than in the N group (N vs. S = 36.4 vs. 6.3%, p <0.001). Postoperative new atrial fibrillation (POAF) was significantly less in the S group compared with the N group (N vs. S = 36.4% vs. 12.5%, p = 0.003). Intensive care unit stay (N vs. S = 5.0 ± 1.5 vs. 3.8 ± 0.9 days, p <0.001) and hospitalization (N vs. S = 20.5 ± 9.2 vs. 17.1 ± 7.2 days, p = 0.037) were significantly shorter in the S group compared with the N group.
Conclusion: Orexin receptor antagonists might reduce POD and POAF, and this effect could introduce the shortness of intensive care unit stay and hospitalization. Orexin receptor antagonist could be useful for patients who undergo OPCAB.
... DORA treatment results in significant and dose-related improvements in both subjective and objective sleep [26, 60,61]. A meta-analysis and several clinical trials found that suvorexant is associated with significant improvements in subjective time to sleep onset, subjective total sleep time, and subjective sleep quality [24, [62][63][64]. Statistically significant sleep-promoting effects on both REM and NREM sleep have been reported, and sleep architecture and the power spectral profile are not disrupted in patients with primary insomnia or healthy people who are treated with suvorexant [23, 60,65,66]. The DORA SB-649868 has been shown to increase total sleep time and REM sleep duration and reduce waking after sleep onset, the latency to persistent sleep, and the latency to REM sleep in healthy men in a model of situational insomnia and men with primary insomnia [67,68]. ...
... Herring et al. [63] Insomnia patients Reduced WASO by reducing the number and time spent in long wake bouts. ...
Orexins comprise two neuropeptides produced by orexin neurons in the lateral hypothalamus and are released by extensive projections of these neurons throughout the central nervous system. Orexins bind and activate their associated G protein-coupled orexin type 1 receptors (OX1Rs) and OX2Rs and act on numerous physiological processes, such as sleep-wake regulation, feeding, reward, emotion, and motivation. Research on the development of orexin receptor antagonists has dramatically increased with the approval of suvorexant for the treatment of primary insomnia. In the present review, we discuss recent findings on the involvement of the orexin system in the pathophysiology of psychiatric disorders, including sleep disorders, depression, anxiety, and drug addiction. We discuss the actions of orexin receptor antagonists, including selective OX1R antagonists (SORA1s), selective OX2R antagonists (SORA2s), and dual OX1/2R antagonists (DORAs), in the treatment of these disorders based on both preclinical and clinical evidence. SORA2s and DORAs have more pronounced efficacy in the treatment of sleep disorders, whereas SORA1s may be promising for the treatment of anxiety and drug addiction. We also discuss potential challenges and opportunities for the application of orexin receptor antagonists to clinical interventions.
... Suvorexant Two clinical studies on suvorexant treatment support the focus statement. One publication presented data pooled from two similar Phase 3, randomized, double blind, placebo-controlled, parallel group, 3-month trials of the DORA drug suvorexant [14]. Study participants received suvorexant administered at dose regimes of either 20/15 mg, 40/30 mg, or placebo. ...
A scientific advisory panel of seven U.S. and Canadian sleep experts performed a clinical appraisal by comparing general medical opinion, assessed via a survey of practicing clinicians, regarding insomnia treatment, with the available scientific evidence. This clinical appraisal focuses on the specific statement, “Treatments for insomnia have uniformly been shown to significantly improve the associated daytime impairment seen with insomnia.” The advisory panel reviewed and discussed the available body of evidence within the published medical literature to determine what discrepancies may exist between the currently published evidence base and general medical opinion. The advisory panels’ evaluation of this statement was also compared with the results of a national survey of primary care physicians, psychiatrists, nurse practitioners, physician assistants, and sleep specialists in the United States. Contrary to general medical opinion, the expert advisory panel concluded that the medical literature did not support the statement. This gap highlights the need to educate the general medical community regarding insomnia treatment efficacy in pursuit of improved treatment outcomes.
... The impact of insomnia on the daily life portion of the subject-reported insomnia severity index was significantly improved in the group of subjects taking suvorexant compared to placebo; suvorexant improves sleep in insomniac patients and reduces the impact of insomnia on patients' daytime function. 57,58 ELDERLY AND ADOLESCENTS Sub-group analysis of a phase 3 trial demonstrates that suvorexant is safe and efficacious in elderly patients with insomnia. Three groups of elderly patients were observed, those under 65 years of age, those 65to 75, and those above 75 years of age. ...
Purpose of Review
The present investigation is a comprehensive review regarding the use of Suvorexant for insomnia treatment. It covers the background, pathophysiology, and significance of addressing insomnia, the pharmaceutical details of Suvorexant, and its safety, efficacy, and implications in treating insomnia. We further discuss Suvorexant’s role in targeting insomnia with other comorbidities.
Recent Findings
Insomnia refers to poor quality and/or quantity of sleep. While there are many existing treatments such as benzodiazepines, melatonin agonists, TCAs, and atypical antipsychotics used to target various receptors involved in normal induction and maintenance of sleep, Suvorexant is an antagonist that specifically targets orexin receptors. Recent clinical studies suggest that Suvorexant is both clinically safe and effective. Quantity and quality of sleep are measured in various ways, yet the consensus points towards Suvorexant’s effectiveness in improving sleep time, onset, latency, and quality compared to placebo. In addition to helping improve isolated insomnia, Suvorexant helps improve sleep in patients that have other comorbidities such as obstructive sleep apnea, Alzheimer’s disease, dementia, acute stroke, and delirium. While Suvorexant is safe, there are still adverse effects associated with the drug that needs to be considered. The most common adverse effects include dizziness, somnolence, headaches, and cognitive impairment.
Summary
Insomnia is a major public health concern that affects many people worldwide and has been linked to many adverse health outcomes. While there are existing treatments that target different receptors and pathways of normal sleep induction and maintenance, Suvorexant is a novel drug that targets dual orexin receptors. Its safety and efficacy, mechanism of action, pharmacokinetic parameters, and relative lack of rebound and withdrawal effects render suvorexant a reliable choice for the treatment of insomnia.
... 151 According to a recent suvorexant trial in both young and older patients with insomnia, dosing for three months of 20/15 mg and 40/30 mg improved sleep to a greater extent than placebo, as shown by the Insomnia Severity Index. 152 A good therapeutic efficacy was also demonstrated with objective sleep measures, such as polysomnography (PSG)-derived indexes, with improvement of sleep latency, sleep efficiency, and sleep maintenance, both after the first night of administration and after 4 weeks, with a dose dependent effect, 153,154 in a 50-to-100 mg study. 155 Relative to placebo, suvorexant was found to decrease substantially the time spent in long wake bouts (> 2 minutes) and to increase slightly the time spent in short wake bouts (≤ 2 minutes) in patients with insomnia. ...
After a detailed description of orexins and their roles in sleep and other medical disorders, we discuss here the current clinical evidence on the effects of dual (DORAs) or selective (SORAs) orexin receptor antagonists on insomnia with the aim to provide recommendations for their further assessment in a context of personalized and precision medicine. In the last decade, many trials have been conducted with orexin receptor antagonists, which represent an innovative and valid therapeutic option based on the multiple mechanisms of action of orexins on different biological circuits, both centrally and peripherally, and their role in a wide range of medical conditions which are often associated with insomnia. A very interesting aspect of this new category of drugs is that they have limited abuse liability and their discontinuation does not seem associated with significant rebound effects. Further studies on the efficacy of DORAs are required, especially on children and adolescents and in particular conditions, such as menopause. Which DORA is most suitable for each patient, based on comorbidities and/or concomitant treatments, should be the focus of further careful research. On the contrary, studies on SORAs, some of which seem to be appropriate also in insomnia in patients with psychiatric diseases, are still at an early stage and, therefore, do not allow to draw definite conclusions.
... In contrast to quetiapine and clozapine, which were found to be ineffective, the novel neuroleptic agent pimavanserine demonstrated positive effects on insomnia symptoms in PD [105]. Other potential treatment options, such as orexin antagonists, have not yet been investigated in neurodegenerative diseases [109]. This lack of evidence is further complicated by case reports noting specific side effects of these new drugs such as the occurrence of troublesome RBD symptoms [110]. ...
Parkinson’s disease (PD) is defined by its motor symptoms rigidity, tremor, and akinesia. However, non-motor symptoms, particularly autonomic disorders and sleep disturbances, occur frequently in PD causing equivalent or even greater discomfort than motor symptoms effectively decreasing quality of life in patients and caregivers. Most common sleep disturbances in PD are insomnia, sleep disordered breathing, excessive daytime sleepiness, REM sleep behavior disorder, and sleep-related movement disorders such as restless legs syndrome. Despite their high prevalence, therapeutic options in the in- and outpatient setting are limited, partly due to lack of scientific evidence. The importance of sleep disturbances in neurodegenerative diseases has been further emphasized by recent evidence indicating a bidirectional relationship between neurodegeneration and sleep. A more profound insight into the underlying pathophysiological mechanisms intertwining sleep and neurodegeneration might lead to unique and individually tailored disease modifying or even neuroprotective therapeutic options in the long run. Therefore, current evidence concerning the management of sleep disturbances in PD will be discussed with the aim of providing a substantiated scaffolding for clinical decisions in long-term PD therapy.
... Suvorexant is a dual orexin receptor antagonist approved to treat sleep onset and sleep maintenance insomnia. 113 An RCT of 10 to 20 mg in 285 patients with probable AD showed TST increased 73 minutes for suvorexant versus 45 minutes for placebo. 114 Somnolence, the most common adverse effect, was reported inb 4% treated with suvorexant versus 1.4% placebo. ...
In this narrative review, we summarize recent research on the prognostic significance of biomarkers of sleep in continuous EEG and polysomnographic recordings in intensive care unit patients. Recent studies show the EEG biosignatures of non-rapid eye movement 2 sleep (sleep spindles and K-complexes) on continuous EEG in critically ill patients better predict functional outcomes and mortality than the ictal-interictal continuum patterns. Emergence of more complex and better organized sleep architecture has been shown to parallel neurocognitive recovery and correlate with functional outcomes in traumatic brain injury and strokes. Particularly interesting are studies which suggest intravenous dexmedetomidine may induce a more biomimetic non-rapid eye movement sleep state than intravenous propofol, potentially providing more restorative sleep and lessening delirium. Protocols to improve intensive care unit sleep and neurophysiological studies evaluating the effect of these on sleep and sleep architecture are here reviewed.
... Taken together, these data potentially implicate orexin's mechanistic role underlying the emergence of VMS and related sleep disturbance and thereby provide a rationale for testing the efficacy of orexin receptor antagonists in the treatment of VMS-related insomnia disorder. While previous clinical trials [30][31][32] in young and older men and women have demonstrated suvorexant's efficacy in reducing insomnia severity, heterogeneity by menopause status, and/or VMS was not reported. Given the high prevalence of VMSassociated insomnia disorder and the potential role of orexin in this prevalent insomnia disorder phenotype, we tested the efficacy of suvorexant for chronic insomnia disorder related to nighttime VMS in peri-and postmenopausal women in a randomized double-blind placebo-controlled trial. ...
Study Objectives
The neuropeptide orexin promotes wakefulness, modulates thermoregulation, increases after menopause, and is normalized in women receiving estrogen therapy, suggesting a role for orexin antagonism as a treatment for vasomotor symptom (VMS)-associated insomnia disorder. We tested the efficacy of the dual orexin receptor antagonist suvorexant for chronic insomnia related to nighttime VMS.
Methods
In a double-blind, placebo-controlled trial, 56 women with chronic insomnia associated with nighttime VMS, Insomnia Severity Index (ISI) scores ≥15, and >30 minutes of diary-rated wake after sleep-onset (WASO) were randomized to receive oral suvorexant 10-20 mg (n=27) or placebo (n=29) nightly for 4 weeks. Analysis of within-person change in ISI was adjusted for baseline ISI and race.
Results
Mean baseline ISI scores were 18.1 (95% CI, 16.8-19.4) and 18.3 (95% CI, 17.2-19.5) in the suvorexant and placebo groups, respectively (p=0.81). The average 4-week ISI within-person decrease from baseline was greater on suvorexant [-8.1 (95% CI, -10.2 to -6.0)] compared to placebo [-5.6 (95% CI, -7.4 to -3.9), p=0.04]. Compared to placebo, nighttime diary-rated VMS frequency was significantly reduced with suvorexant (p<0.01). While diary-rated WASO and total sleep time trended toward improvement on suvorexant, findings were not significant after adjustment for multiple comparison. Daytime VMS and other sleep-related outcomes did not differ between groups. Suvorexant was well tolerated.
Conclusion
These results suggest that suvorexant is likely a well-tolerated and efficacious treatment for VMS-associated insomnia disorder and reduces nighttime VMS. Antagonism of orexin receptors could provide a novel therapeutic option for midlife women with VMS-associated chronic insomnia.
... Exposure was enteral SPM administration during mechanical ventilation through an oral endotracheal tube. This study defined the following medications as SPM: trazodone, mianserin, quetiapine, and suvorexant [21][22][23]. Exposure was considered as present if these drugs were administered after enteral nutrition in the evening or before sleep. We divided the patients into the following three groups: "administration within 48 hours of ICU admission (early administration [EA])," "administration after 48 hours of ICU admission (late administration [LA])," and "no administration [NA])." ...
Background
The clinical effect of enteral administration of sleep-promoting medication (SPM) in mechanically ventilated patients remains unclear. This study aimed to investigate the relationship between enteral SPM administration and the intravenous sedative dose and examine the safety and cost of enteral SPM administration.
Methods
This single-center retrospective cohort study was conducted in a Japanese tertiary hospital intensive care unit (ICU). The exposure was enteral SPM administration during mechanical ventilation. The outcome was the average daily propofol dose per body weight administered as a continuous sedative during mechanical ventilation. Patients were divided into three groups based on the timing of SPM administration at ICU admission: “administration within 48 hours (early administration [EA]),” “administration after 48 hours (late administration [LA]),” and “no administration (NA).” We used multiple linear regression models.
Results
Of 123 included patients, 37, 50, and 36 patients were assigned to the EA, LA, and NA groups, respectively. The average daily propofol dose per body weight was significantly lower in the EA group than in the LA and NA groups (β -5.13 [95% confidence interval (CI) -8.93 to -1.33] and β -4.51 [95% CI -8.59 to -0.43], respectively). Regarding safety, enteral SPM administration did not increase adverse events, including self-extubation. The total cost of neuroactive drugs tended to be lower in the EA group than in the LA and NA groups.
Conclusions
Early enteral SPM administration reduced the average daily propofol dose per body weight without increasing adverse events.
... Dual orexin receptor antagonists, suvorexant and lemborexant, have been approved for the treatment of insomnia disorder in the United States, characterized by difficulties with sleep onset and/ or sleep maintenance in adults based on the results of pivotal phase 3 studies. However, these agents have not been shown to be effective or approved for MDD (Herring et al., 2019;Rosenberg et al., 2019;Kärppä et al., 2020). Filorexant, also a dual orexin antagonist, was tested as augmentation therapy in patients with MDD and showed no difference in efficacy from placebo (Connor et al., 2017). ...
Background
Seltorexant, a selective antagonist of human orexin-2 receptors, demonstrated antidepressant effects in a previous exploratory study in patients with major depressive disorder (MDD).
Methods
To replicate and extend this observation, a double-blind, adaptive dose-finding study was performed in patients with MDD who had an inadequate response to 1-3 selective serotonin/serotonin-norepinephrine reuptake inhibitors in the current episode. Patients were randomized (2:1:1) to placebo or seltorexant (20 mg or 40 mg) once-daily, administered adjunctively to the antidepressant which the patient had been receiving at screening. After an interim analysis (6 weeks post-randomization of 160 th patient), newly recruited patients randomly received (3:3:1) placebo or seltorexant 10 mg or 20 mg; the 40 mg dose was no longer assigned. Patients were stratified by baseline Insomnia Severity Index scores (ISI ≥15 vs ISI <15). Primary endpoint was change from baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score at week 6.
Results
Mixed-Model for Repeated Measures (MMRM) analysis showed a greater improvement in MADRS total score in the seltorexant 20 mg group vs placebo at weeks 3 and 6; least-square means (LSM) difference (90% CI): -4.5 (-6.96;-2.07), p=0.003 and -3.1 (-6.13; -0.16), p=0.083, respectively. The improvement in MADRS score at week 6 for seltorexant 20 mg was greater in patients with baseline ISI ≥15 vs those with ISI <15; LSM difference (90% CI) vs placebo: -4.9 (-8.98;-0.80) and -0.7 (-5.16;3.76), respectively. The most common (≥5%) adverse events with seltorexant were somnolence, headache, and nausea.
Conclusions
A clinically meaningful reduction of depressive symptoms was observed for seltorexant 20 mg. In the subset of patients with sleep disturbance (ISI ≥15), a larger treatment difference between seltorexant 20 mg and placebo was observed, warranting further investigation. No new safety signal was identified.
... This inhibition of orexin receptor signaling promotes sleep by attenuating the wake-promoting effect of the hypocretin/orexin system, resulting in an increase in the number of transitions to non-rapid eye movement (NREM) and REM sleep in laboratory rodents whose sleep is polyphasic (Table 1) [19]. Like almorexant, suvorexant reduces the latency to persistent sleep (LPS), decreases WASO, and increases total sleep time (TST; Table 2) in humans [20][21][22]. The DORA lemborexant [23,24] was approved by the FDA for insomnia in 2019 (Table 2). ...
The hypocretins/orexins are two excitatory neuropeptides, alternately called HCRT1 or orexin-A and HCRT2 or orexin-B, that are the endogenous ligands for two G-protein-coupled receptors, HCRTR1/OX1R and HCRTR2/OX2R. Shortly after the discovery of this system, degeneration of hypocretin/orexin-producing neurons was implicated in the etiology of the sleep disorder narcolepsy. The involvement of this system in a disorder characterized by the loss of control over arousal state boundaries also suggested its role as a critical component of endogenous sleep-wake regulatory circuitry. The broad projections of the hypocretin/orexin-producing neurons, along with differential expression of the two receptors in the projection fields of these neurons, suggest distinct roles for these receptors. While HCRTR1/OX1R is associated with regulation of motivation, reward, and autonomic functions, HCRTR2/OX2R is strongly linked to sleep-wake control. The association of hypocretin/orexin with these physiological processes has led to intense interest in the therapeutic potential of compounds targeting these receptors. Agonists and antagonists for the hypocretin/orexin receptors have shown potential for the treatment of disorders of excessive daytime somnolence and nocturnal hyperarousal, respectively, with the first antagonists approved by the US Food and Drug Administration (FDA) in 2014 and 2019 for the treatment of insomnia. These and related compounds have also been useful tools to advance hypocretin/orexin neurobiology.
... Suvorexant also improved subjective measures of total sleep time (TST) and sleep onset latency. 40 Additionally, no withdrawal symptoms have been observed after the long-term use of suvorexant, suggesting a low potential for physical dependence. 41 Somnolence, fatigue and dry mouth are common side effects and suvorexant is also associated with abnormal dreams. ...
Introduction
Insomnia frequently occurs in patients admitted to an intensive care unit (ICU). Sleep-promoting agents may reduce rapid eye movement sleep and have deliriogenic effects. Suvorexant (Belsomra) is an orexin receptor antagonist with Food and Drug Administration (FDA) approval for the treatment of adult insomnia, which improves sleep onset and maintenance as well as subjective measures of quality of sleep. This trial will evaluate the efficacy of postoperative oral suvorexant treatment on night-time wakefulness after persistent sleep onset as well as the incidence and duration of delirium among adult cardiac surgical patients.
Methods and analysis
In this single-centre, randomised, double-blind, placebo-controlled trial, we will enrol 120 patients, aged 60 years or older, undergoing elective cardiac surgery with planned postoperative admission to the ICU. Participants will be randomised to receive oral suvorexant (20 mg) or placebo one time a day starting the night after extubation. The primary outcome will be wakefulness after persistent sleep onset. The secondary outcome will be total sleep time. Exploratory outcomes will include time to sleep onset, incidence of postoperative in-hospital delirium, number of delirium-free days and subjective sleep quality.
Ethics and dissemination
Ethics approval was obtained through the ‘Committee on Clinical Investigations’ at Beth Israel Deaconess Medical Center (protocol number 2019P000759). The findings will be published in peer-reviewed journals.
Trial registration number
This trial has been registered at clinicaltrials.gov on 17 September 2019 ( NCT04092894 ).
... Early high-throughput screen (HTS) hit Diazepane, 1, and more optimized molecule Diazepane In Vivo Tool, 2, which was appropriate for initial in vivo testing. 26 Characterization of suvorexant pharmacokinetics at clinically meaningful doses established that peak concentrations occur at ∼2 h under fasted conditions, which can be prolonged by ∼1.5 h if administered with consumption of a high-fat meal. Suvorexant's mean absolute bioavailability is ∼80%, and it is largely eliminated via CYP3A-mediated metabolism. ...
The development of therapeutics for central nervous system (CNS) disorders has many challenges that result in low probability of success and longer-than-typical development timelines. Suvorexant (Belsomra), the first dual orexin receptor antagonist used for insomnia, was approved by the United States Food and Drug Administration ∼10 years after the initial high-throughput screen was conducted to identify orexin receptor antagonists. What accounted for this success and speed? Here we suggest that this program was unique and set up for success by (1) having a robust and high-throughput pharmacodynamic readout that was translatable across species, including humans, (2) a well-validated target with a defined product profile, resulting in a highly energized team with a can-do attitude, and (3) a highly executable and streamlined clinical strategy. The utility of Belsomra for insomnia, as well as other neurological and psychiatric diseases, continues to be explored, most recently for insomnia associated with Alzheimer’s disease.
Background
Mirtazapine promotes sleep by blocking serotonin and histaminergic receptors and is often used off-label to treat chronic insomnia. However, its efficacy remains to be demonstrated in a clinical trial. The MIRAGE study aims to determine the efficacy and safety of mirtazapine in older patients with chronic insomnia.
Methods
This was a double-blind, randomised, placebo-controlled trial in a geriatric outpatient clinic of a teaching hospital. Adults aged 65 years and older with chronic insomnia were included. Sixty participants were randomised in a 1:1 ratio to receive mirtazapine 7.5 mg or a matching placebo for 28 days. The primary efficacy endpoint was the mean change in the Insomnia Severity Index (ISI) score from baseline to 28 days post-treatment. The primary safety endpoints included any adverse events reported during the clinical trial and all adverse events leading to premature discontinuation.
Results
Mirtazapine was superior to placebo on the primary outcome measure, subjective wake after sleep onset, total sleep time and sleep efficiency. After 28 days, the mean change in ISI score was significantly greater in the mirtazapine group (−6.5 [95%CI; −8.3 to −4.8]) compared to the placebo group (−2.9 [95%CI; −4.4 to −1.4]), with a p-value of 0.003. No participant experienced severe adverse events. A total of 6 participants in the mirtazapine group and 1 participant in the placebo group discontinued their treatment due to adverse events.
Conclusion
Mirtazapine reduces chronic insomnia symptoms in older people. However, its use may be limited by mild but clinically relevant adverse events. (clinicaltrials.gov NCT05247697).
Impact statement
This is the first randomised, double-blind, placebo-controlled trial on the efficacy and safety of Mirtazapine in older adults with chronic insomnia. Our findings show that a 28-day treatment with mirtazapine, compared to placebo, significantly reduces insomnia severity, as measured by the Insomnia Severity Index. Despite the current lack of robust evidence, mirtazapine is widely prescribed by clinicians to treat insomnia in older adults with chronic insomnia. Publishing our study will facilitate the broad dissemination of this critical information, helping clinicians more effectively treat their older patients.
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.
Chronic insomnia disorder (simplified in this document as insomnia) is an increasingly common clinical condition in society and a frequent complaint at the offices of different areas of health practice (particularly Medicine and Psychology). This scenario has been accompanied by a significant evolution in treatment, as well as challenges in approaching patients in an appropriately way. This clinical guideline, coordinated by the Brazilian Sleep Association and the Brazilian Association of Sleep Medicine and counting on the active participation of various specialists in the area, encompasses an update on the diagnosis and treatment of insomnia in adults. To this end, it followed a structured methodology. Topics of interest related to diagnosis were written based on theoretical framework, evidence in the literature, and professional experience. As for the topics related to the treatment of insomnia, a series of questions were developed based on the PICO acronym (P – Patient, problem, or population; I – Intervention; C – Comparison, control, or comparator; O – Outcome). The work groups defined the eligible options within each of these parameters. Regarding pharmacological interventions, only the ones currently available in Brazil or possibly becoming available in the upcoming years were considered eligible. Systematic reviews were conducted to help prepare the texts and define the level of evidence for each intervention. The final result is an objective and practical document providing recommendations with the best scientific support available to professionals involved in the management of insomnia.
Study objectives
Recent treatment guidelines for chronic insomnia recommend pharmacological and non-pharmacological therapies. One of the contemporary drug options for insomnia includes dual orexin receptor antagonist (DORA), such as suvorexant and lemborexant. We conducted a systematic review and meta-analysis for the treatment of insomnia with suvorexant and lemborexant based on randomized, double-blind, placebo-controlled Trials.
Methods
We conducted a comprehensive search on three databases (PubMed/Medline, Web of Science, and Cochrane Library) till August 14, 2021, without any restrictions to retrieve the relevant articles. The effect sizes were computed presenting the pooled mean difference or risk ratio along with 95% confidence interval of each outcome.
Results
Our search showed eight articles (five for suvorexant and three for lemborexant). Results of diary measures, rating scales, polysomnography results, treatment discontinuation, and adverse events were measured. All efficacy outcome measures favorably and significantly differed in the suvorexant compared to placebo. Safety profile did not differ significantly except for somnolence, excessive daytime sleepiness/sedation, fatigue, back pain, dry mouth, and abnormal dreams. Important adverse events including hallucinations, suicidal ideation/behavior and motor vehicle accidents did not differ between suvorexant and placebo. All the efficacy outcomes significantly differed between lemborexant 5 and lemborexant 10 compared to placebo. Somnolence rate for lemborexant 5 and lemborexant 10 and nightmare for lemborexant 10 were significantly higher than placebo.
Conclusion
The present meta-analysis reported that suvorexant and lemborexant are efficacious and safe agents for the patients with insomnia. Further data in patients with insomnia and various comorbid conditions are needed.
Sleep can be influenced and impaired in countless ways. Sleep disorders often severely impair quality of life and lead to high morbidity, as well as increased mortality. The indication for pharmacological treatment is based on the diagnosis of a sleep disorder, which often varies in symptoms, intensity, and duration. This chapter discusses medications for the treatment of sleep disorders and related symptoms. For more detailed information about sleep medicine diagnostics, as well as for nonpharmacological therapy modalities, please refer to the relevant sleep medical literature. We herein propose a new classification and terminology for medicines for the treatment of sleep disorders: Somnologics (lat. somnologica). With a focus on insomnia disorders, trouble falling and staying asleep, we review substances that promote sleep (anti-insomnics), either by increasing sleep pressure (somnics) or by reducing wake pressure (antivigilantics). With regards to circadian rhythm disorders, we discuss substances for the realignment of the sleep phase (chronotherapeutics). After that, medications for the treatment of hypersomnia disorders, associated with an increased need for sleep, are reviewed (antihypersomnics). Herein, we include medications for the reduction of the sleep drive (vigilantics), as well as for the treatment of cataplexy (anticataplectics).
Purpose of review:
Insomnia affects more than 10% of the population and causes significant discomfort and disability. Suvorexant is an orexin receptor antagonist that specifically targets the wake-sleep cycle. This review summarizes recent and seminal evidence in the biological and physiological evidence of insomnia, the mechanism of action of suvorexant in treating insomnia, and clinical evidence regarding its use.
Recent findings:
There is no single clear diagnosis for insomnia, and thus prevalence is not entirely clear, but it is estimated to affect 10%-30% of the adult population. Comorbidities include obesity, diabetes, and various psychiatric conditions, and insomnia likely has a contributing role in these conditions. Insomnia, by definition, impacts sleep quality and also wakefulness, including academic success and work efficiency. Insomnia is likely related to genetic susceptibility and a triggering event, leading to hyper-arousal states and functional brain disturbances. This leads to hyperactivity of the hypothalamic-pituitary-adrenal axis, over-secretion of corticotropin-releasing factor, and aberrancy in neurotransmitter release. Though several pharmacological options exist for the treatment of insomnia, there is equivocal data regarding their efficacy or limits to their use due to side effects and contraindications. Suvorexant is a novel dual orexin receptor antagonist, which is shown to improve sleep by reducing arousals. Unlike classical therapeutics, suvorexant does not alter the sleep profile; it prolongs the time spent in each sleep state. Though it may cause some somnolence, it is milder than reported with other drugs.
Summary:
Multiple clinical studies support the use of suvorexant in insomnia. In primary insomnia, suvorexant is effective (over placebo), as measured by polysomnography and reported by patients, in both attaining and maintaining sleep. Similar, albeit to a smaller degree, results were found in secondary insomnia. Suvorexant carries two significant advantages over existing therapies; it has a much better safety profile in approved doses, and it preserves natural sleep architecture, thus promoting more restful sleep and recovery. Unfortunately, data exists mostly for suvorexant versus placebo, and head-to-head trials with common hypnotics are needed to assess the true efficacy of suvorexant over the alternatives. And while tolerance is less likely to develop, close monitoring of post-marketing data is required to evaluate for long term adverse events and efficacy.
Objective/background
Evaluate changes in insomnia severity in subjects with moderate to severe insomnia (Insomnia Severity Index [ISI] score ≥15) treated for 12 months nightly with lemborexant.
Patients/methods
This phase 3 randomized study comprised two 6-month treatment periods. In Period 1, 949 subjects were randomized to placebo, lemborexant 5 mg (LEM5) or 10 mg (LEM10). In Period 2, placebo subjects were rerandomized to LEM5 or LEM10; subjects initially randomized to lemborexant continued their assigned treatment. Insomnia severity was assessed using baseline ISI and 1-, 3-, 6-, 9-, and 12-month post-treatment scores.
Results
Mean ISI scores improved significantly across treatment groups and disease severities, with greater decreases from baseline in the LEM5 and LEM10 versus placebo groups at months 1 (−7.1, −7.2, −5.2, respectively), 3 (−8.6, −8.9, −6.1, respectively), and 6 (−9.9, −9.8, −7.2 respectively); ISI score improvements were maintained with LEM5 and LEM10 at months 9 (−11.1 and −11.2, respectively) and 12 (−11.5 and −11.2, respectively). At months 1, 3, and 6, significantly more treatment responders (≥7-point ISI score decrease from baseline) were observed with LEM5 (44%–57%) and LEM10 (44%–52%) versus placebo (30%–41%). At months 1, 3, and 6, more remitters (ISI total score <10 and <8) were observed with LEM5 (30%–44% and 22%–34%, respectively) and LEM10 (31%–41% and 22%–31%, respectively) versus placebo (18%–28% and 11%–21%, respectively).
Conclusions
Lemborexant significantly reduced insomnia severity for 12 months and increased clinically meaningful response and remission rates versus placebo.
Clinical trial registration
ClinicalTrials.gov, NCT02952820; ClinicalTrialsRegister.eu, EudraCT Number 2015-001463-39.
There is a large unmet need for effective treatment of major depressive disorder (MDD), an often chronic/recurrent disorder that affects 1 in 5 adults during their lifetime in the United States. Clinicians and individuals with MDD often rely on augmentation approaches given the low rate of remission with the initial antidepressant treatment. Therefore, the report by Savitz and colleagues on the safety and efficacy of seltorexant is of great interest as it provides initial evidence for the antidepressant potential of drugs targeting orexin neurotransmission. Findings of this study suggest that seltorexant 20 mg is more effective than placebo, especially in individuals with moderate or insomnia symptoms at baseline. Given that insomnia is a common feature of depression, orexin 2 receptor antagonists may serve as important new treatment alternatives for people with MDD.
Objective: We assessed the safety of Suvorexant, an orexin receptor antagonist, on cardiac and respiratory function in patients who underwent off-pump coronary artery bypass grafting (OPCAB) retrospectively. Materials and methods: We investigated 66 patients including 16 women (mean age 71.6 ± 8.1 years) who underwent OPCAB alone at our hospital. Patients were categorized as those received orexin receptor antagonist after OPCAB (S-group, n=35) or without orexin receptor antagonist (N-group, n=31), and the following data were analyzed between both groups. Results: The incidence of postoperative delirium was significantly lesser in the S-group than in the N-group (N vs. S =32.3% vs. 8.6%, p=0.004). Intensive care unit stay was also significantly shorter in the S-group compared with the N-group (N vs. S=4.6 ± 1.1 vs. 4.1 ± 0.8 days, p=0.040). No significant intergroup difference was observed in arterial blood gas measurement (mean the potential of hydrogen, partial pressure of oxygen, the partial pressure of carbon dioxide, base excess, and respiratory rate) and circulation statement (systolic arterial blood pressure, pulmonary artery wedge pressure, heart rate, cardiac index, and mixed venous oxygen saturation) before and after the administration of Suvorexant. Conclusion: Orexin receptor antagonists didn’t worsen the cardiac function and the respiratory function in patients who underwent OPCAB.
We evaluated a single‐item Patient Global Impression‐Severity (PGI‐S) scale for assessing insomnia severity during the clinical development programme for suvorexant. The analyses used data from two randomised, double‐blind, placebo‐controlled, 3‐month, Phase III clinical trials of suvorexant in patients with Diagnostic and Statistical Manual of Mental Disorders IV criteria insomnia. Patients assessed insomnia severity during the previous week using the PGI‐S, a one‐item questionnaire containing six response options ranging from 0 (none) to 5 (very severe), at baseline and at Week 2, and Months 1, 2, and 3 after randomisation. The seven‐item Insomnia Severity Index (ISI) and other subjective and objective assessments were also completed by patients. PGI‐S responses were compared primarily with the ISI using descriptive statistics and correlations. The PGI‐S demonstrated favourable measurement characteristics (validity, reliability, responsiveness and sensitivity). PGI‐S scores decreased from baseline to Month 3 in a similar pattern to the ISI total score, and the Spearman correlation coefficient between PGI‐S and the ISI was .73. An improvement of ≥2 points on the PGI‐S defined a treatment responder, based on comparison to the ISI definition of a responder (improvement of ≥6 points). Our present findings suggest that the PGI‐S is a simple but valid, reliable, responsive, sensitive, and meaningful patient‐reported assessment of insomnia severity. The PGI‐S may be particularly useful as a companion outcome to sleep monitoring using wearable sleep devices or smartphones in at‐home settings.
Background
Sleep disturbances are frequently reported in patients with major depressive disorder. We aimed to investigate the effects of vortioxetine on sleep quality and association between changes in sleep and treatment response.
Methods
This study is a post-hoc analysis of a clinical trial that sought to evaluate the sensitivity to cognitive change of THINC-integrated tool in patients with major depressive disorder. In total, 92 patients (aged 18 to 65) meeting Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for moderate or severe major depressive disorder and 54 healthy controls were included. All patients received open-label vortioxetine (10–20 mg/day, flexibly dosed) for 8 weeks. Herein, the primary outcomes of interest were changes in sleep, as measured by the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale and Insomnia Severity Index, between weeks 0, 2, and 8. The association between changes in sleep and depressive symptom severity was secondarily assessed.
Results
We observed that sleep, as indicated by scores of Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale and Insomnia Severity Index, was significantly poorer in patients with major depressive disorder compared to healthy controls at weeks 0, 2, and 8 ( p < 0.05). Among patients with major depressive disorder, we observed significant improvements on the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale and Insomnia Severity Index between weeks 0 and 8 ( p < 0.05). We observed a significant association between improvements on the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, and Insomnia Severity Index and improvement of depressive symptoms.
Conclusion
Improvement of depressive symptoms in major depressive disorder patients treated with vortioxetine was associated with significant improvements in sleep. Furthermore, improvements in sleep were predictive of antidepressant response and were linearly correlated with improvement in overall depressive symptom severity.
Sleep abnormalities have widespread and costly public health consequences, yet we have only a rudimentary understanding of the events occurring at the cellular level in the brain that regulate sleep. Several key signaling molecules that regulate sleep across taxa come from the family of neuropeptide transmitters. For example, in Drosophila melanogaster, the neuropeptide Y (NPY)-related transmitter short neuropeptide F (sNPF) appears to promote sleep. In this study, we utilized optogenetic activation of neuronal populations expressing sNPF to determine the causal effects of precisely timed activity in these cells on sleep behavior. Combining sNPF-GAL4 and UAS-Chrimson transgenes allowed us to activate sNPF neurons using red light. We found that activating sNPF neurons for as little as 3 s at a time of day when most flies were awake caused a rapid transition to sleep that persisted for another 2+ hours following the stimulation. Changing the timing of red light stimulation to times of day when flies were already asleep caused the control flies to wake up (due to the pulse of light), but the flies in which sNPF neurons were activated stayed asleep through the light pulse, and then showed further increases in sleep at later points when they would have normally been waking up. Video recording of individual fly responses to short-term (0.5–20 s) activation of sNPF neurons demonstrated a clear light duration-dependent decrease in movement during the subsequent 4-min period. These results provide supportive evidence that sNPF-producing neurons promote long-lasting increases in sleep, and show for the first time that even brief periods of activation of these neurons can cause changes in behavior that persist after cessation of activation. We have also presented evidence that sNPF neuron activation produces a homeostatic sleep drive that can be dissipated at times long after the neurons were stimulated. Future studies will determine the specific roles of sub-populations of sNPF-producing neurons, and will also assess how sNPF neurons act in concert with other neuronal circuits to control sleep.
Orexins/hypocretins are key neuropeptides responsible for regulating central arousal and reward circuits. Two receptors respond to orexin signaling, orexin 1 receptor (OX(1)R) and orexin 2 receptor (OX(2)R) with partially overlapping nervous system distributions. Genetic studies suggest orexin receptor antagonists could be therapeutic for insomnia and other disorders with disruptions of sleep and wake. Suvorexant (MK-4305) is a potent, selective, and orally bioavailable antagonist of OX(1)R and OX(2)R currently under clinical investigation as a novel therapy for insomnia. Examination of Suvorexant in radioligand binding assays using tissue from transgenic rats expressing the human OX(2)R found nearly full receptor occupancy (>90%) at plasma exposures of 1.1 μM. Dosed orally Suvorexant significantly and dose-dependently reduced locomotor activity and promoted sleep in rats (10, 30, and 100 mg/kg), dogs (1 and 3 mg/kg), and rhesus monkeys (10 mg/kg). Consistent cross-species sleep/wake architecture changes produced by Suvorexant highlight a unique opportunity to develop dual orexin antagonists as a novel therapy for insomnia.