0405 Randomized Controlled Clinical Polysomnography Trial of Suvorexant for Treating Insomnia in Patients with Alzheimer’s Disease

Herring, W. Joseph; Ceesay, Paulette; Snyder, Ellen; Bliwise, Donald L.; Budd, Kerry; Hutzelmann, Jill; Stevens, Joanne; Michelson, David

doi:10.1093/sleep/zsz067.404

Cited by 4 publications

(5 citation statements)

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“…Based on the observation that the orexin system is involved in sleep and dementia, orexin receptor antagonists are studied as a new promising treatment for insomnia with less adverse outcomes than hypnotics. In a double-blind RCT including a large number of patients with probable AD and insomnia, 4 weeks treatment with suvorexant, a dual orexin receptor antagonist, significantly increased total sleep time and sleep efficiency and decreased wake after sleep onset in PSG, but had no significant effect on the underlying sleep architecture profile and on cognition compared to placebo (Herring et al, 2020). In a small RCT with cognitively unimpaired volunteers, suvorexant treatment acutely decreased tau phosphorylation and amyloid-β in CSF by 10-20% starting 5 h after administration compared to placebo (Lucey et al, 2023).…”

Section: The Influence Of Therapies Of Sleep Disorders On the Course ...mentioning

confidence: 99%

Associations of sleep disorders with all-cause MCI/dementia and different types of dementia – clinical evidence, potential pathomechanisms and treatment options: A narrative review

Mayer,

Frohnhofen,

Jokisch

et al. 2024

Front. Neurosci.

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Due to worldwide demographic change, the number of older persons in the population is increasing. Aging is accompanied by changes of sleep structure, deposition of beta-amyloid (Aß) and tau proteins and vascular changes and can turn into mild cognitive impairment (MCI) as well as dementia. Sleep disorders are discussed both as a risk factor for and as a consequence of MCI/dementia. Cross-sectional and longitudinal population-based as well as case–control studies revealed sleep disorders, especially sleep-disorderded breathing (SDB) and excessive or insufficient sleep durations, as risk factors for all-cause MCI/dementia. Regarding different dementia types, SDB was especially associated with vascular dementia while insomnia/insufficient sleep was related to an increased risk of Alzheimer’s disease (AD). Scarce and still inconsistent evidence suggests that therapy of sleep disorders, especially continuous positive airway pressure (CPAP) in SDB, can improve cognition in patients with sleep disorders with and without comorbid dementia and delay onset of MCI/dementia in patients with sleep disorders without previous cognitive impairment. Regarding potential pathomechanisms via which sleep disorders lead to MCI/dementia, disturbed sleep, chronic sleep deficit and SDB can impair glymphatic clearance of beta-amyloid (Aß) and tau which lead to amyloid deposition and tau aggregation resulting in changes of brain structures responsible for cognition. Orexins are discussed to modulate sleep and Aß pathology. Their diurnal fluctuation is suppressed by sleep fragmentation and the expression suppressed at the point of hippocampal atrophy, contributing to the progression of dementia. Additionally, sleep disorders can lead to an increased vascular risk profile and vascular changes such as inflammation, endothelial dysfunction and atherosclerosis which can foster neurodegenerative pathology. There is ample evidence indicating that changes of sleep structure in aging persons can lead to dementia and also evidence that therapy of sleep disorder can improve cognition. Therefore, sleep disorders should be identified and treated early.

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Section: The Influence Of Therapies Of Sleep Disorders On the Course ...mentioning

confidence: 99%

Associations of sleep disorders with all-cause MCI/dementia and different types of dementia – clinical evidence, potential pathomechanisms and treatment options: A narrative review

Mayer,

Frohnhofen,

Jokisch

et al. 2024

Front. Neurosci.

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“…Altogether, this is supportive of orexin dysfunction as a viable target for AD intervention. In this regard, a phase III clinical trial (NCT02750306) to treat insomnia in patients with AD using the orexin receptor antagonist (Suvorexant) was effective and generally well-tolerated (Herring et al, 2019).…”

Section: The Molecular Mechanisms Of Sleepmentioning

confidence: 99%

Steps Towards Developing Effective Treatments for Neuropsychiatric Disturbances in Alzheimer’s Disease: Insights From Preclinical Models, Clinical Data, and Future Directions

Clement

Wiborg

Asuni

2020

Front. Aging Neurosci.

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Alzheimer's disease (AD) is the most common form of dementia worldwide. It is mostly known for its devastating effect on memory and learning but behavioral alterations commonly known as neuropsychiatric disturbances (NPDs) are also characteristics of the disease. These include apathy, depression-like behavior, and sleep disturbances, and they all contribute to an increased caregiver burden and earlier institutionalization. The interaction between NPDs and AD pathology is not well understood, but the consensus is that they contribute to disease progression and faster decline. Consequently, recognizing and treating NPDs might improve AD pathology and increase the quality of life for both patients and caregivers. In this review article, we examine previous and current literature on apathy, depressive symptoms, and sleep disturbances in AD patients and preclinical AD mechanistic models. We hypothesize that tau accumulation, beta-amyloid (Aβ) aggregation, neuroinflammation, mitochondrial damage, and loss of the locus coeruleus (LC)-norepinephrine (NE) system all collectively impact the development of NPDs and contribute synergistically to AD pathology. Targeting more than one of these processes might provide the most optimal strategy for treating NPDs and AD. The development of such clinical approaches would be preceded by preclinical studies, for which robust and reliable mechanistic models of NPD-like behavior are needed. Thus, developing effective preclinical research models represents an important step towards a better understanding of NPDs in AD.

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“…In this four-week study, 142 patients with both probable mild-to-moderate AD dementia and DSM-V insomnia received suvorexant (10 or 20 mg, dose adjusted based on clinical response), and 143 patients received placebo. Similar to what has been reported in other populations with insomnia, suvorexant increased TST in AD patients by 28 min compared to placebo, an improvement corresponding to a 73 min increase from a baseline of 278 min . Patients taking suvorexant were also twice as likely to experience an improvement of ≥60 min relative to those taking placebo.…”

Section: The Value Of Translatable End-points and An Executable And S...mentioning

confidence: 99%

“…Similar to what has been reported in other populations with insomnia, suvorexant increased TST in AD patients by 28 min compared to placebo, an improvement corresponding to a 73 min increase from a baseline of 278 min. 58 Patients taking suvorexant were also twice as likely to experience an improvement of ≥60 min relative to those taking placebo. Suvorexant also reduced WASO relative to placebo, consistent with observations in prior insomnia studies.…”

mentioning

confidence: 99%

The Discovery of Suvorexant: Lessons Learned That Can Be Applied to Other CNS Drug Development Efforts

Uslaner

Herring

Coleman

2020

ACS Pharmacol. Transl. Sci.

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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 highthroughput 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.

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0405 Randomized Controlled Clinical Polysomnography Trial of Suvorexant for Treating Insomnia in Patients with Alzheimer’s Disease

Cited by 4 publications

References 0 publications

Associations of sleep disorders with all-cause MCI/dementia and different types of dementia – clinical evidence, potential pathomechanisms and treatment options: A narrative review

Associations of sleep disorders with all-cause MCI/dementia and different types of dementia – clinical evidence, potential pathomechanisms and treatment options: A narrative review

Steps Towards Developing Effective Treatments for Neuropsychiatric Disturbances in Alzheimer’s Disease: Insights From Preclinical Models, Clinical Data, and Future Directions

The Discovery of Suvorexant: Lessons Learned That Can Be Applied to Other CNS Drug Development Efforts

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