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July 22, 2019

Factors Hampering the Discovery of New Therapeutics for Rapid Eye Movement Sleep Behavior Disorder

Author Affiliations
  • 1Stanford Center for Sleep Sciences and Medicine, Department of Psychiatry and Behavioral Sciences, Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, California
  • 2Minnesota Regional Sleep Disorders Center, Department of Psychiatry, Medical School, University of Minnesota, Minneapolis
  • 3Hennepin County Medical Center, Minneapolis, Minnesota
JAMA Neurol. 2019;76(10):1137-1138. doi:10.1001/jamaneurol.2019.2062

First formally described more than 30 years ago, rapid eye movement (REM) sleep behavior disorder (RBD) results from loss of normal muscle atonia during REM sleep, which can lead to disruptive and potentially injurious dream-enactment behaviors.1 This disorder affects more than 1% of adults older than 40 years, and in middle-aged and older adults, it is a prodromal symptom of neurodegeneration until proven otherwise.2 It offers a unique window for prognostication and disease-modifying interventions years before progression to Parkinson disease or dementia with Lewy bodies. Research efforts have grown at an increasing pace, providing deeper insights into the pathophysiology and natural history of RBD, setting the ground for neuroprotective trials.3 In comparison, little progress has been made in the area of symptomatic therapeutics for RBD. Most patients are treated with the same drugs used for more than 2 decades: clonazepam and melatonin. Based on the literature and clinical experience, though, more than 30% of patients may not achieve adequate symptom control. Furthermore, with symptoms reduction at a mean of 30% to 40% with either drug, according to patients,4 the actual benefits of these drugs could be modest. This was illustrated by 2 recent, long-awaited randomized clinical trials5,6 that tested melatonin and clonazepam against placebo and showed disappointing results. Although clonazepam is more effective at higher dosages, many patients cannot tolerate its adverse effects. As a consequence, a considerable proportion of individuals and their bed partners remain at risk for sleep disruption and sleep-associated injuries. In 2010, the best-practice guide issued by the American Academy of Sleep Medicine7 could only make a weak recommendation (level B [ie, intervention is suggested]) for these 2 drugs, based on insufficient quality evidence. While we await new American Academy of Sleep Medicine guidelines, the current state of knowledge on RBD therapy is unlikely to result in stronger or markedly different recommendations. In the last decade, only 3 randomized clinical trials8 using alternative agents have been published: 1 testing memantine and 2 using transdermal rivastigmine. What could be some of the challenges in conducting more and better designed trials on this potentially life-threatening condition?