A Single Center, Open Label Prospective Observational Pilot Study to Evaluate the Effects of Tasimelteon in Participants With REM Behavior Disorder (RBD)

REM behavior disorder (RBD) is characterized by abnormal behaviors that emerge from REM sleep and can lead to injury and disturbed sleep. Most patients have frequent events - typically more than once per week. Abnormalities can be seen almost nightly and consist of intermittent loss of the normal atonia of REM sleep. This phenomenon is used as diagnostic criterion even in the absence of an overt clinical event during the night.

RBD has serious consequences for the health of the patient. Besides risk of sometimes severe injury, a direct consequence of a violent nocturnal movement, it often leads to sleep disruption. Furthermore, it is commonly seen in association with Parkinson's disease and many experts in the field consider it a prodrome of neurodegenerative conditions. Other comorbidities may include a higher risk of cerebral hemorrhage as well as stroke. Multiple factors may contribute to the risk of RBD. Aside from neurodegenerative conditions, RBD is seen in association with disorders of REM sleep regulations: narcolepsy, post-traumatic stress disorder, or with use of selective serotonin reuptake inhibitors (SSRIs).

In healthy individuals, REM sleep is closely linked to circadian phase, with a peak a little after the nadir of the core body temperature, and thus also around the time when melatonin secretion is maximal. Studies using a forced desynchrony protocol suggest that the circadian system has a primary effect of REM sleep regulation with a modifying effect from the homeostatic factors. Various other factors affect REM sleep, including complex interactions with the serotonergic system, primarily from the raphe nuclei in the medulla, which inhibit the REM generating pontine tegmentum nuclei. Clinically, patients treated with antidepressants, particularly with serotononergic properties (particularly SSRIs), tend to suppress REM sleep and may also lead to REM without atonia and/or trigger RBD events.

The melatonin MT1 and MT2 receptors likely both affect the NREM/REM ratio with activation of the MT2 leading to earlier and more abundant NREM sleep, while MT1 receptors favoring REM sleep. Furthermore, RBD is common in patients with Parkinson's disease, and a reduced number of melatonin receptors have been found in the areas involved in the neurodegeneration: a recent study found a reduced number of MT1 receptor expression in the striatum and amygdala, and a reduced MT2 receptor expression in the substantia nigra and amygdala. In addition to circadian phase shift, activation of melatonin MT1 and MT2 receptors has been implicated as a potential protective mechanism against multiple other progressive neurodegenerative disorders, while MT2 receptors have been implicated in neurogenesis. Thus, REM suppression and/or disruption, as a result of the neurodegenerative process, that also involves impaired MT1 and MT2 receptor function may be a key mechanism for RBD pathophysiology and potential therapeutic target.

Treatment options for RBD are limited. The most commonly used agent is clonazepam, which has to be used in caution in patient with dementia symptoms and has many potentially serious side effects. Due to the strong association with neurodegenerative conditions, RBD patients are likely to have contraindications for benzodiazepine treatment. This creates a need for other medications that can be safely used in patients who are elderly and/or have neurodegenerative comorbid conditions. If the mechanism for RBD include REM sleep disruption, can improved REM sleep regulation lead to a better treatment? Melatonin is the most common therapeutic alternative to clonazepam for RBD. Initial studies may have been partially prompted by its high clinical convenience: a very favorable side effect profile, and availability in the US. It was first reported as effective in a case report in 1997, of a 64 year old man who experienced improvement of his RBD symptoms after treatment with 3 mg melatonin, without any change in his REM proportion on polysomnography. Further studies have included open label case series. In one recent study, melatonin was found to be equally effective as clonazepam for RBD treatment. However, studies have been small, open label, sometimes retrospective, and generally the timing of melatonin is not consistently reported.