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.

Use of melatonin has a number of clinical challenges, since the medication is over the counter, not regulated, and dose and bioavailability can vary widely. Can melatonin agonists, which have a higher affinity to melatonin receptors also be used for treatment? Indeed, ramelteon has been reported successful in some cases. In 2013, Nomura et al used ramelteon, 8 mg in two patients who had polysomnographically confirmed RBD in association with parkinsonian syndromes. One of them had multisystem atrophy, and could not tolerate clonazepam due to the lability of her blood pressure, and the other had persistent symptoms despite clonazepam treatment. Both individuals had improvement of their RBD symptoms, including the RBD severity scale (RBDSS). Later Esaki et al treated 12 consecutive patients with idiopathic RBD in an open label trial, using 8 mg ramelteon given 30 minutes before bedtime and reported a trend towards improvement. Yet another study examined the effect of ramelteon on motor and non-motor symptoms in patients with Parkinson's disease, with or without RBD, and reported improvement in a variety of measures after treatment, including a statistically significant RBD improvement.

Novel data has emerged in the past two years regarding the chronotherapeutic aspects of RBD, suggesting that a potential not only for improved symptom control, but also long-term benefit in terms of decreasing neurodegeneration.

However, due to a large first pass effect, the mean systemic availability of ramelteon following an oral dose is less than 2%, and there is a large degree of inter-subject variability in plasma concentration after exposure. Thus, another melatonin agonist could be very helpful for patients with REM behavior disorder, potentially providing a more effective treatment option for this disease, and allowing safer control of the symptoms for those who cannot use benzodiazepines. A potent activator of the MT1 receptors, such as tasimelteon, could be an ideal RBD treatment. To better evaluate this important clinical question, I propose to evaluate the efficacy of tasimelteon as a potential treatment for RBD.