Annals of Neurology and Neuroscience | Volume 1, Issue 1 | Review Article | Open Access
Qasim Zia*
Muhammad Umar Rasheed1, Muhammad Hamza Khan2, Omer Ismail Khalid3, Qasim Zia4*, Amjad Ismail5, Jyoti Kella6, Muhammad Atif Ijaz7 1Hearts International Hospital, Rawalpindi, Pakistan 2Nishtar Medical University, Multan, Pakistan
3Arrahma Mental Hospital, Multan, Pakistan
4Multan Medical & Dental College, Multan, Pakistan
5Sharif Medical and Dental College, Lahore, Pakistan
6People's University of Medical and Health Sciences, Nawabshah, Pakistan
7Bakhtawar Amin Trust Hospital, Multan, Pakistan
Fulltext PDFNocturnal agitation in Lewy body dementia is a poorly defined syndrome arising from prolonged wakefulness, rapid eye movement sleep behavior disorder, hallucinations, cognitive fluctuation, pain, autonomic symptoms, sleep-disordered breathing, circadian disruption, medication effects, or superimposed delirium. This heterogeneity makes nonspecific sedation potentially hazardous. Dual orexin receptor antagonists reduce wake-promoting orexin signaling without directly enhancing gamma-aminobutyric acid transmission and therefore offer a biologically plausible treatment for an agitated-wake phenotype. This review evaluates the mechanistic rationale, clinical evidence, LBD-specific safety concerns, and trial-design requirements. Direct evidence is limited to a small uncontrolled study of lemborexant in 13 patients with dementia with Lewy bodies, which found no significant change in actigraphic sleep, rapid eye movement sleep behavior symptoms, or cognition. Randomized trials in Alzheimer dementia demonstrate that suvorexant can increase total sleep time and that lemborexant can improve selected rest-activity measures, but these findings do not establish efficacy for nocturnal agitation or safety in a synucleinopathy population. The principal risks in Lewy body dementia include next-day somnolence, falls, orthostatic symptoms, worsening cognitive fluctuation, hallucination-like experiences, and dream enactment. A definitive trial should enroll patients only after structured nocturnal phenotyping, use caregiver-verified minutes of agitated wakefulness corroborated by actigraphy as the primary endpoint, and require benefit without deterioration in prespecified neurological and functional safety domains. Dual orexin receptor antagonists should currently be considered investigational for nocturnal agitation in Lewy body dementia, with future use guided by phenotype rather than by insomnia symptoms alone.
Lewy body dementia; Nocturnal agitation; Orexin antagonists; Insomnia; REM sleep behavior disorder; Actigraphy; Neuropsychiatric symptoms
Muhammad Umar Rasheed, Muhammad Hamza Khan, Omer Ismail Khalid, Qasim Zia, Amjad Ismail, Jyoti Kella, et al. Dual Orexin Receptor Antagonists for Nocturnal Agitation in Lewy Body Dementia: A Narrative Review and Clinical Trial Framework. Anna Neur & Neurosci. 2026;1(1):1-11.