Minimal effect of long-term clonazepam on cognitive function in patients with isolated rapid eye movement sleep behavior disorder.

STUDY OBJECTIVES: Despite its widespread use in patients with isolated rapid eye movement sleep behavior disorder (iRBD), the cognitive effect of clonazepam is uncertain. This study aimed to investigate the effect of cumulative clonazepam on cognitive function in patients with iRBD. METHODS: Demographic characteristics, baseline cognitive test, and most recent cognitive test information were collected retrospectively. Based on cumulative clonazepam doses, patients were classified into 4 subgroups: group 1, < 365 mg (1 mg × 1 year); group 2, 365 mg to < 1,095 mg (1 mg × 3 years); group 3, 1,095 mg to < 2,190 mg (1 mg × 6 years); and group 4, 2,190 mg or more. Cognitive test scores were calculated as z scores adjusted for age, education, and sex. RESULTS: This study included 101 patients with iRBD (63 males). Groups 1, 2, 3, and 4 had 14, 20, 32, and 35 patients, respectively. In within-group comparisons, follow-up Digit Span Backward test and the Trail Making Test A scores decreased in group 3, and follow-up Trail Making Test A and the Trail Making Test B scores decreased significantly in group 4. In the multiple regression analysis to determine influential factors on cognitive decline, cumulative clonazepam dose did not show a significant correlation with any cognitive domain. Follow-up cognitive function showed significant correlation only with baseline cognitive function. CONCLUSIONS: Memory and executive functions tended to decline in patients with iRBD. However, there was no significant effect of cumulative clonazepam. There was no evidence that long-term use of clonazepam was related to cognitive decline in patients with iRBD. CITATION: Lee M, Kim TK, Hong JK, Yoon I-Y. Minimal effect of long-term clonazepam on cognitive function in patients with isolated rapid eye movement sleep behavior disorder. J Clin Sleep Med. 2024;20(7):1173-1182.

Polysomnographic features associated with clonazepam and melatonin treatment in isolated REM sleep behavior disorder: Time for new therapeutic approaches?

AIMS: Although clonazepam (CLO) and melatonin (MLT) are the most frequently used treatments for REM sleep behavior disorder, the polysomnographic features associated with their use are little known. The aim of this study was to evaluate polysomnographic and clinical parameters of patients with idiopathic/isolated REM sleep behavior disorder (iRBD) treated chronically with CLO, sustained-release MLT, alone or in combination, and in a group of drug-free iRBD patients. METHODS: A total of 96 patients were enrolled: 43 drug-free, 21 with CLO (0.5-2 mg), 20 with sustained-release MLT (1-4 mg), and 12 taking a combination of them (same doses). Clinical variables and polysomnography were collected. RESULTS: Although clinical improvement was reported in all groups, MLT impacted sleep architecture more than the other treatments, with significant and large increase in N3 stage, moderate reduction in N2 and REM sleep, and moderate increase in REM latency. CLO moderately increased the percentage of both REM sleep and especially N2, while reducing N1 and wakefulness. Patients treated with both CLO and MLT did not show major changes in sleep architecture. CONCLUSION: These results suggest that the administration of MLT or CLO impacts (positively) on sleep parameters of iRBD patients. However, there is a need to better stratify patients, in order to treat them in a targeted manner, depending on the patient's individual sleep architecture and expected differential effects of these agents.

Rapid Eye Movement Sleep Behavior Disorder: Management and Prognostic Counseling.

Management of rapid eye movement sleep behavior disorder (RBD) includes reducing injurious dream-enactment behaviors, risk of injury to self and bedpartner, and vivid or disruptive dreams and improving sleep quality and bedpartner sleep disruption. Safety precautions should be reviewed at each visit. Medications to reduce RBD symptoms such as melatonin, clonazepam, pramipexole, and rivastigmine should be considered for most patients. Isolated RBD confers a high lifetime risk of neurodegenerative diseases with a latency often spanning many years. A patient-centered shared decision-making approach to risk disclosure is recommended. Knowledge of the risk allows for life planning and participation in research.

A case of prazosin in treatment of rapid eye movement sleep behavior disorder.

Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by dream-enactment behaviors that emerge during a loss of REM sleep atonia. Untreated RBD carries risks for physical injury from falls or other traumatic events during dream enactment as well as risk of injury to the bed partner. Currently, melatonin and clonazepam are the mainstay pharmacological therapies for RBD. However, therapeutic response to these medications is variable. While older adults are most vulnerable to RBD, they are also particularly vulnerable to the adverse effects of benzodiazepines, including increased risk of falls, cognitive impairment, and increased risk of Alzheimer disease. Prazosin is a centrally active alpha-1 adrenergic receptor antagonist often prescribed for trauma nightmares characterized by REM sleep without atonia in patients with posttraumatic stress disorder. We report a case of successful RBD management with prazosin in a patient in whom high-dose melatonin was ineffective. Although there was no observable reduction in dream-enactment behaviors with high-dose melatonin, the possibility of a synergistic effect of prazosin combined with melatonin cannot be ruled out. This case report supports further evaluation of prazosin as a potential therapeutic for RBD. CITATION: Cho Y, Iliff JJ, Lim MM, Raskind M, Peskind E. A case of prazosin in treatment of rapid eye movement sleep behavior disorder. J Clin Sleep Med. 2024;20(2):319-321.

Treatment of REM sleep behavior disorder with trazodone: report of 3 cases.

Rapid eye movement sleep behavior disorder is a sleep disturbance characterized by the absence of regular paralysis during rapid eye movement sleep, accompanied by dream enactment behavior. The available pharmacotherapy options for treating rapid eye movement sleep behavior disorder are limited, and the utilization of antidepressants has yielded mixed results. We report 3 cases of isolated rapid eye movement sleep behavior disorder improved with trazodone. Doses of 50-100 mg of trazodone at bedtime over 4-6 months resulted in significant clinical improvement. These cases highlight that trazodone could serve as a treatment for isolated rapid eye movement sleep behavior disorder that does not respond to traditional treatments at submaximal dosages. CITATION: Barrow J, Vendrame M. Treatment of REM sleep behavior disorder with trazodone: report of 3 cases. J Clin Sleep Med. 2024;20(5):821-823.

REM Behavior Disorder: Implications for PD Therapeutics.

PURPOSE: Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia that occurs during REM sleep, characterized by REM sleep without atonia (RSWA) and dream enactment behavior (DEB). RBD is associated with several diseases and medications but most notably is a prodromal feature of synucleinopathies, including Parkinson's disease (PD). This article reviews RBD, its treatments, and implications for PD therapeutics. RECENT FINDINGS: Recent research recognizes RBD as a prodromal marker of PD, resulting in expansion of basic science and clinical investigations of RBD. Current basic science research investigates the pathophysiology of RBD and explores animal models to allow therapeutic development. Clinical research has focused on natural history observation, as well as potential RBD treatments and their impact on sleep and phenoconversion to neurodegenerative disease. RBD serves as a fresh access point to develop both neuroprotective and symptomatic therapies in PD. These types of investigations are novel and will benefit from the more established basic science infrastructure to develop new interventions.

Pharmacological interventions targeting α-synuclein aggregation triggered REM sleep behavior disorder and early development of Parkinson's disease.

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by elevated motor behaviors and dream enactments in REM sleep, often preceding the diagnosis of Parkinson's disease (PD). As RBD could serve as a biomarker for early PD developments, pharmacological interventions targeting α-synuclein aggregation triggered RBD could be applied toward early PD progression. However, robust therapeutic guidelines toward PD-induced RBD are lacking, owing in part to a historical paucity of effective treatments and trials. We reviewed the bidirectional links between α-synuclein neurodegeneration, progressive sleep disorders, and RBD. We highlighted the correlation between RBD development, α-synuclein aggregation, and neuronal apoptosis in key brainstem regions involved in REM sleep atonia maintenance. The current pharmacological intervention strategies targeting RBD and their effects on progressive PD are discussed, as well as current treatments for progressive neurodegeneration and their effects on RBD. We also evaluated emerging and potential pharmacological solutions to sleep disorders and developing synucleinopathies. This review provides insights into the mechanisms and therapeutic targets underlying RBD and PD, and explores bidirectional treatment effects for both diseases, underscoring the need for further research in this area.

Quantitative measurement of motor activity during sleep in isolated REM sleep behavior disorder patients using actigraphy before and after treatment with clonazepam.

STUDY OBJECTIVES: We conducted a prospective study to quantify motor activity during sleep measured by actigraphy before and after 3 months of treatment with clonazepam in patients with video-polysomnography (vPSG) confirmed isolated rapid eye movement (REM) sleep behavior disorder (iRBD). METHODS: The motor activity amount (MAA) and the motor activity block (MAB) during sleep were obtained from actigraphy. Then, we compared quantitative actigraphic measures with the results of the REM sleep behavior disorder questionnaire for the previous 3-month period (RBDQ-3M) and of the Clinical Global Impression-Improvement scale (CGI-I), and analyzed correlations between baseline vPSG measures and actigraphic measures. RESULTS: Twenty-three iRBD patients were included in the study. After medication treatment, large activity MAA dropped in 39% of patients, and the number of MABs decreased in 30% of patients when applying 50% reduction criteria. 52% of patients showed more than 50% improvement in either one. On the other hand, 43% of patients answered "much or very much improved" on the CGI-I, and RBDQ-3M was reduced by more than half in 35% of patients. However, there was no significant association between the subjective and objective measures. Phasic submental muscle activity during REM sleep was highly correlated with small activity MAA (Spearman's rho = 0.78, p < .001) while proximal and axial movements during REM sleep correlated with large activity MAA (rho = 0.47, p = .030 for proximal movements, rho = 0.47, p = .032 for axial movements). CONCLUSIONS: Our findings imply that quantifying motor activity during sleep using actigraphy can objectively assess therapeutic response in drug trials in patients with iRBD.

Sodium oxybate in treatment-resistant rapid-eye-movement sleep behavior disorder.

STUDY OBJECTIVES: Symptomatic therapies for rapid-eye-movement (REM) sleep behavior disorder (RBD) are limited. Sodium oxybate (SXB), a gamma-aminobutyric acid (GABA)-B agonist, could be effective but has not been evaluated against placebo. METHODS: This double-blind, parallel-group, randomized, placebo-controlled trial in 24 participants was conducted at the Stanford Sleep Center. Patients were adults with definite iRBD or Parkinson's disease and probable RBD (PD-RBD), and persistence of ≥ 2 weekly episodes despite standard therapy. Patients were randomized 1:1 to receive SXB during a 4-week titration followed by a 4-week stable dosing period. Primary outcome was number of monthly RBD episodes according to a diary filled by patients and partners. Secondary outcomes were severity, number of severe RBD episodes, and objective RBD activity on video polysomnography. RESULTS: Twelve iRBD and 12 PD-RBD participated (mean 65.8 years), and 22 (n = 10 SXB, 12 placebo) completed the study. Although no significant between-group difference was found, SXB showed reduction of monthly RBD episodes by 23.1 (95% CI -36.0, -10.2; p = 0.001) versus 10.5 with placebo (95% CI, -22.6, 1.6; p = 0.087). Improvement from baseline was similarly observed for RBD overall severity burden (each episode weighted for severity), number of severe episodes, and objective RBD activity per video-polysomnography. Two participants receiving SXB withdrew due to anxiety and dizziness. The majority of adverse events are otherwise resolved with dose adjustment. CONCLUSION: SXB could reduce RBD symptoms; however, response was inconsistent and a large placebo effect was observed across patient-reported outcomes. Larger studies using objective endpoints are needed. CLINICAL TRIAL: Treatment of REM Sleep Behavior Disorder (RBD) With Sodium Oxybate https://clinicaltrials.gov/ct2/show/NCT04006925 ClinicalTrials.gov identifier: NCT04006925.

Sleep and circadian rhythms in α-synucleinopathies-Perspectives for disease modification.

The global north is facing an unprecedented rise in the prevalence of neurodegenerative diseases. The increasing incidence of Parkinson's disease is being referred to as a pandemic. The reason for the enormous increase is only partly understood. Lifestyle factors are known to play a role, but they alone cannot account for the surge. One factor that-although being recognized as important-has not been explored in detail so far is the influence of circadian rhythms. Sleep and circadian rhythm disruption are known as key factors in neurodegeneration, and their occurrence during early disease stages suggests a causal role in the pathogenesis. Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) has been identified as a prodromal state of α-synucleinopathies, such as Parkinson's disease, Lewy body dementia, and multiple system atrophy offering a window for insights into the early development of these diseases. Even though REM sleep is the sleep state most pronounced, driven and modulated by the circadian timing system, specific circadian abnormalities have not been described in iRBD. Novel experimental and clinical approaches exploiting the molecular circuitry underlying circadian timekeeping hold promise to disentangle some of the pathophysiologic mechanisms of α-synucleinopathies. In this review, we summarize current knowledge on sleep and circadian rhythm disruptions in α-synucleinopathies with an emphasis on molecular aspects and therapeutic potentials. These insights might contribute to our understanding of the pathogenesis of neurodegenerative diseases and may allow therapeutic interventions addressing the disturbed circadian system at the early stage of disease.

Management of REM sleep behavior disorder: an American Academy of Sleep Medicine clinical practice guideline.

INTRODUCTION: This guideline establishes clinical practice recommendations for the management of rapid eye movement sleep behavior disorder (RBD) in adults. METHODS: The American Academy of Sleep Medicine (AASM) commissioned a task force of experts in sleep medicine to develop recommendations and assign strengths based on a systematic review of the literature and an assessment of the evidence using Grading of Recommendations, Assessment, Development and Evaluation methodology. The task force provided a summary of the relevant literature and the certainty of evidence, the balance of benefits and harms, patient values and preferences, and resource use considerations that support the recommendations. The AASM Board of Directors approved the final recommendations. GOOD PRACTICE STATEMENT: The following good practice statement is based on expert consensus, and its implementation is necessary for the appropriate and effective management of patients with RBD: It is critically important to help patients maintain a safe sleeping environment to prevent potentially injurious nocturnal behaviors. In particular, the removal of bedside weapons, or objects that could inflict injury if thrown or wielded against a bed partner, is of paramount importance. Sharp furniture like nightstands should be moved away or their edges and headboard should be padded. To reduce the risk of injurious falls, a soft carpet, rug, or mat should be placed next to the bed. Patients with severe, uncontrolled RBD should be recommended to sleep separately from their partners, or at the minimum, to place a pillow between themselves and their partners. RECOMMENDATIONS: The following recommendations, with medications listed in alphabetical order, are a guide for clinicians in choosing a specific treatment for RBD in adults. Each recommendation statement is assigned a strength ("strong" or "conditional"). A "strong" recommendation (ie, "We recommend…") is one that clinicians should follow under most circumstances. A "conditional" recommendation (ie, "We suggest…") is one that requires that the clinician use clinical knowledge and experience and strongly consider the patient's values and preferences to determine the best course of action.Adult patients with isolated RBD.1. The AASM suggests that clinicians use clonazepam (vs no treatment) for the treatment of isolated RBD in adults. (CONDITIONAL).2. * The AASM suggests that clinicians use immediate-release melatonin (vs no treatment) for the treatment of isolated RBD in adults. (CONDITIONAL).3. * The AASM suggests that clinicians use pramipexole (vs no treatment) for the treatment of isolated RBD in adults. (CONDITIONAL).4. The AASM suggests that clinicians use transdermal rivastigmine (vs no treatment) for the treatment of isolated RBD in adults with mild cognitive impairment. (CONDITIONAL).Adult patients with secondary RBD due to medical condition.5. * The AASM suggests that clinicians use clonazepam (vs no treatment) for the treatment of secondary RBD due to medical condition in adults. (CONDITIONAL).6. * The AASM suggests that clinicians use immediate-release melatonin (vs no treatment) for the treatment of secondary RBD due to medical condition in adults. (CONDITIONAL).7. The AASM suggests that clinicians use transdermal rivastigmine (vs no treatment) for the treatment of secondary RBD due to medical condition (Parkinson disease) in adults. (CONDITIONAL).8. * The AASM suggests that clinicians not use deep brain stimulation (DBS; vs no treatment) for the treatment of secondary RBD due to medical condition in adults. (CONDITIONAL).Adult patients with drug-induced RBD.9. * The AASM suggests that clinicians use drug discontinuation (vs drug continuation) for the treatment of drug-induced RBD in adults. (CONDITIONAL).* The Recommendations section of this paper includes remarks that provide additional context to guide clinicians with implementation of this recommendation. CITATION: Howell M, Avidan AY, Foldvary-Schaefer N, et al. Management of REM sleep behavior disorder: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2023;19(4):759-768.

The Effect of Cannabidiol for Restless Legs Syndrome/Willis-Ekbom Disease in Parkinson's Disease Patients with REM Sleep Behavior Disorder: A Post Hoc Exploratory Analysis of Phase 2/3 Clinical Trial.

Background: Cannabidiol (CBD) is one of the main nonpsychoactive components of Cannabis sativa and may represent an alternative treatment for Restless Legs Syndrome/Willis-Ekbom Disease (RLS/WED) in patients with Parkinson's disease (PD) and REM (Rapid Eye Movement) sleep behavior disorder (RBD). Objective: Our purpose was a post hoc exploratory analysis to evaluate the CBD's efficacy to improve the severity of RLS/WED symptoms in patients with PD and RBD. Methods: A post hoc exploratory analysis of a phase II/III, a parallel, double-blind, placebo-controlled clinical trial was conducted in 18 patients with RLS/WED and PD plus RBD associated. Six patients were randomized to the CBD group in doses of 75-300 mg, and twelve received placebo capsules. They were followed up for 14 weeks. The primary outcome was the severity of RLS/WED by Restless Legs Syndrome Rating Scale of the International Restless Legs Syndrome Study Group (IRLSSG). Results: CBD showed no difference in relationship to placebo for primary and secondary outcomes. Conclusion: CBD showed no reduction in the severity of RLS/WED manifestation in patients with PD and RBD.

Comparative efficacy of prolonged-release melatonin versus clonazepam for isolated rapid eye movement sleep behavior disorder.

PURPOSE: Clonazepam and melatonin are recommended as first-line treatments for isolated rapid eye movement (REM) sleep behavior disorder (iRBD). This study aimed to compare their efficacy and safety in REM sleep without atonia (RWA) and RBD-related symptoms. METHODS: This prospective, open-label, randomized trial included patients with video-polysomnography-confirmed iRBD. The patients were randomly assigned to receive either clonazepam 0.5 mg or prolonged-release (PR) melatonin 2 mg 30 min before bedtime for 4 weeks. The primary outcome was changes in RWA on follow-up polysomnography (PSG). Secondary endpoints were changes in other PSG parameters, clinical global improvement-impression scale (CGI-I) scores, and sleep questionnaire scores. The safety endpoint was adverse events. RESULTS: Of 40 patients with probable RBD considered, 34 were enrolled in the study and randomized. Visual scoring parameters of RWA indices were reduced, and automatic scoring parameters tended to be improved after clonazepam treatment but not after PR melatonin treatment. The proportion of N2 sleep was increased, and N3 and REM sleep were decreased only in the clonazepam group. The clonazepam group tended to answer "much or very much improvement" on the CGI-I more frequently than the PR melatonin group (p = 0.068). Daytime sleepiness and insomnia symptoms were reduced after PR melatonin but not after clonazepam. Depressive symptoms increased after clonazepam. Four of the patients (13.3%) reported mild to moderate adverse events, which were similar between the two groups. CONCLUSION: Four weeks of clonazepam, but not PR melatonin, improved RWA. RBD symptom improvement tended to be better after clonazepam than PR melatonin in exchange for increased depressive symptoms and daytime sleepiness. CLINICALTRIALS: gov identifier: NCT03255642 (first submitted August 21, 2017).

Neuroprotective Trials in REM Sleep Behavior Disorder: The Way Forward Becomes Clearer.

As neuroprotective therapies continue to be advanced against neurodegenerative synucleinopathies, such as Parkinson disease (PD), dementia with Lewy bodies (DLBs), and multiple system atrophy, increasing attention is turning to the prodromal stages of disease. Treatments at the prodromal stage have the compelling advantages of being applied early enough to make a meaningful difference and can be tested without confounding by symptomatic therapies used for clinical PD/DLB. As it currently stands, patients with idiopathic/isolated REM sleep behavior disorder (iRBD) represent the only large existing cohort of untreated prodromal PD/DLB that would be ready to start a clinical trial now. Several thousand patients with RBD are currently being followed in research-based clinics, and more than 80% of them will develop a full neurodegenerative synucleinopathy. Research into RBD phenoconversion rates and predictors has advanced considerably, and we are now able to generate increasingly precise estimates of progression rates, can select stratification markers to enrich trials, and are able to understand the progression and sample size implications of different primary outcome measures. This review will outline the potential for neuroprotective trials in iRBD, including the pathophysiologic mechanisms with the most promise to target in iRBD, selection criteria for inclusion, and the optimal primary trial outcome measures to choose.

What Is the Prognostic Significance of Rapid Eye Movement Sleep Without Atonia in a Polysomnogram?

SUMMARY: Freud said we are lucky to be paralyzed during sleep, so we cannot act out our dreams. Atonia of skeletal muscles normally present during rapid eye movement sleep prevents us from acting out our dreams. Observing rapid eye movement sleep without atonia in a polysomnogram in older adults first and foremost warrants consideration of rapid eye movement behavior disorder. Seventy-five to 90% of older adults with isolated rapid eye movement behavior disorder will develop a neurodegenerative disease within 15 years, most often a synucleinopathy. Rapid eye movement sleep without atonia in those younger than 50 years is commonly found in individuals with narcolepsy and those taking antidepressant medications.

[Sleep disorders in patients with a neurocognitive disorder]. / Les troubles du sommeil chez les patients atteints d'un trouble neurocognitif.

INTRODUCTION: Sleep disorders are prevalent in patients with a neurocognitive disorder, and diagnosis and treatment in these patients remain challenging in clinical practice. METHODS: This narrative review offers a systematic approach to diagnose and treat sleep disorders in neurocognitive disorders. RESULTS: Alzheimer's disease is often associated with circadian rhythm disorders, chronic insomnia, and sleep apnea-hypopnea syndrome. Alpha-synucleinopathies (e.g., Parkinson's disease and Lewy body dementia) are often associated with a rapid eye movement sleep behavior disorder, restless legs syndrome, chronic insomnia, and sleep apnea-hypopnea syndrome. A focused history allows to diagnose most sleep disorders. Clinicians should ensure to gather the following information in all patients with a neurocognitive disorder: (1) the presence of difficulties falling asleep or staying asleep, (2) the impact of sleep disturbances on daily functioning (fatigue, sleepiness and other daytime consequences), and (3) abnormal movements in sleep. Sleep diaries and questionnaires can assist clinicians in screening for specific sleep disorders. Polysomnography is recommended if a rapid eye movement sleep behavior disorder or a sleep apnea-hypopnea syndrome are suspected. Sleep complaints should prompt clinicians to ensure that comorbidities interfering with sleep are properly managed. The main treatment for moderate to severe obstructive sleep apnea-hypopnea syndrome remains continuous positive airway pressure, as its efficacy has been demonstrated in patients with neurocognitive disorders. Medications should also be reviewed, and time of administration should be optimized (diuretics and stimulating medications in the morning, sedating medications in the evening). Importantly, cholinesterase inhibitors (especially donepezil) may trigger insomnia. Switching to morning dosing or to an alternative drug may help. Cognitive-behavioral therapy for insomnia is indicated to treat chronic insomnia in neurocognitive disorders. False beliefs regarding sleep should be addressed with the patient and their caregiver. The sleep environment should be optimized (decrease light exposure at night, minimize noise, avoid taking vital signs, etc.). Sleep restriction can be considered as patients with a neurocognitive disorder often spend too much time in bed. The need for naps should be assessed case by case as naps may contribute to insomnia in some patients but allow others to complete their diurnal activities. Trazodone (50mg) may also be used under certain circumstances in chronic insomnia. Recent evidence does not support a role for exogenous melatonin in patients with a neucognitive disorder and insomnia. Patients in long-term care facilities are often deprived of an adequate diurnal exposure to light. Increasing daytime exposure to light may improve sleep and mood. Patients with circadian rhythm disorders can also benefit from light therapy (morning bright light therapy in case of phase delay and evening bright light therapy in case of phase advance). Rapid eye movement sleep behavior disorder can lead to violent behaviors, and the sleeping environment should be secured (e.g., mattress on the floor, remove surrounding objects). Medication exacerbating this disorder should be stopped if possible. High dose melatonin (6 to 18mg) or low dose clonazepam (0.125-0.25mg) at bedtime may be used to reduce symptoms. Melatonin is preferred in first-line as it is generally well tolerated with few side effects. Patients with restless legs syndrome should be investigated for iron deficiency. Medication decreasing dopaminergic activity should be reduced or stopped if possible. Behavioral strategies such as exercise and leg massages may be beneficial. Low-dose dopamine agonists (such as pramipexole 0.125mg two hours before bedtime) can be used to treat the condition, but a prolonged treatment may paradoxically worsen the symptoms. Alpha-2-delta calcium channel ligands can also be used while monitoring for the risk of falls. CONCLUSION: Multiple and sustained nonpharmacological approaches are recommended for the treatment of sleep disturbances in patients with neurocognitive disorder. Pharmacological indications remain limited, and further randomized clinical trials integrating a multimodal approach are warranted to evaluate the treatment of sleep disorders in specific neurocognitive disorders.

A critical review of the pharmacological treatment of REM sleep behavior disorder in adults: time for more and larger randomized placebo-controlled trials.

Rapid Eye Movement sleep behavior disorder (RBD) is a parasomnia causing sufferers to physically act out their dreams. These behaviors can disrupt sleep and sometimes lead to injuries in patients and their bed-partners. Clonazepam and melatonin are the first-line pharmacological treatment options for RBD based on direct uncontrolled clinical observations and very limited double-blind placebo-controlled trials. Given the risk for adverse outcomes, especially in older adults, it is of great importance to assess the existing level of evidence for the use of these treatments. In this update, we therefore critically review the clinical and scientific evidence on the pharmacological management of RBD in people aged over 50. We focus on the first-line treatments, and provide an overview of all other alternative pharmacological agents trialed for RBD we could locate as supplementary materials. By amalgamating all clinical observations, our update shows that 66.7% of 1,026 RBD patients reported improvements from clonazepam and 32.9% of 137 RBD patients reported improvements from melatonin treatment on various outcome measures in published accounts. Recently, however, three relatively small randomized placebo-controlled trials did not find these agents to be superior to placebo. Given clonazepam and melatonin are clinically assumed to majorly modify or eliminate RBD in nearly all patients-there is an urgent need to test whether this magnitude of treatment effect remains intact in larger placebo-controlled trials.

Efficacy and safety of treatments for REM sleep behaviour disorder in Parkinson's disease: a systematic review and Bayesian network meta-analysis protocol.

INTRODUCTION: Sleep disorders are the main non-motor characteristics of Parkinson's disease (PD). The quality of life is significantly impacted by rapid eye movement sleep behaviour disorder (RBD). It is not clearly evidenced in the literature that some medications can reduce the dream activities of patients with PD and RBD and improve sleep quality. And, they have side effects that may increase the severity of this disease. To further understand which medication has better efficacy and fewer adverse effects for patients with PD and RBD, it is necessary to perform a network meta-analysis. METHODS AND ANALYSIS: This protocol is performed accordingly to the guidelines of the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols and the Cochrane Collaboration Handbook.A thorough literature selection will be conducted up to September 2021 using PubMed, Cochrane Library (The Cochrane Database of Systematic Reviews) and Embase. We will not only include randomised controlled trials, but prospective, retrospective cohort, case-control, nested case-control, case-cohort, cross-sectional and case series. We will use the Cochrane Collaboration tool to assess the risk of bias. Pairwise and network meta-analyses will be conducted using the R netmeta package and Stata V.14.0. The relative ranking probability of the best intervention will be estimated using the surface under the cumulative ranking curve. Additionally, sensitivity analysis, subgroup analysis, quality assessment and publication bias analysis will be performed. ETHICS AND DISSEMINATION: No research ethics approval is required for this systematic review, as no confidential patient data will be used. We will disseminate our findings through publication in a peer-reviewed journal and conference presentations, and our review will support development of a BMJ Rapid Recommendations providing contextualised clinical guidance based on this body of evidence. PROSPERO REGISTRATION NUMBER: CRD42020206958.

Effects of safinamide on REM sleep behavior disorder in Parkinson disease: A randomized, longitudinal, cross-over pilot study.

BACKGROUND: Rapid Eye Movement sleep behavior disorder (RBD) is characterized by dream enactment and loss of muscle atonia during REM-sleep. RBD as a premotor feature occurred souvent in patients who develop Parkinson's disease. The glutamatergic, glycinergic, and GABA-ergic systems appear to play a crucial role in the pathogenesis of RBD. METHODS: The present exploratory longitudinal cross-over study aimed to observe the effect of safinamide on RBD symptoms. Thirty patients with PD and RBD were randomized into two groups (15 subjects each), those that received for a period of 3-months safinamide (50 mg/die) in addition (Group A + ) or in absence (Group B - ) to the usual antiparkinsonian therapy. Patients exploring the clinical and video-polysomnographic changes occurred during this pharmacological therapy. RESULTS: Twenty-two of 30 patients reported clear improvement in symptoms during safinamide treatment, and 16 were absolutely free from clinical RBD-symptoms at the end of the treatment. Eight patients reported slight improvement in RBD-symptoms. In 6/30 patients no substantial improvement was recorded about clinical RBD-symptoms had frightening dreams or from the bed after 1-week of treatment. In addition, after safinamide, the mean UPDRS-II and III scores decreased, while PDSS-2 score indicating an improvement in both motor symptoms and nocturnal sleep features. A significant reduction of sleep behavior disorder by questionnaire-Hong Kong-score (RBDQ-HS), mainly for two individual RBDQ-HK-items (dream related movements and failing out of bed) was registered. CONCLUSIONS: This pilot study indicated that safinamide is well tolerated and improves RBD-symptom in parkinsonian.

Treatment of isolated REM sleep behavior disorder using melatonin as a chronobiotic.

Melatonin is recommended as a first-line treatment in isolated REM sleep behavior disorder (iRBD), although no large patient group has been reported. To assess effects, time course and confounding factors in the treatment of patients with iRBD using melatonin, 209 consecutive patients were included in this single-center, observational cohort study. A total of 171 patients had taken melatonin according to our chronobiotic protocol (2 mg, ≥6 months, always-at-the-same-clock time, 10-11pm, corrected for chronotype), 13 had applied melatonin for about 1-3 months, and 25 underwent mixed treatments. In total, 1529 clinical evaluations were performed, including Clinical Global Impression (CGI) and a newly developed RBD symptom severity scale (Ikelos-RS), analyzed using linear mixed models. Validation of Ikelos-RS showed excellent inter-rater reliability (ρ = 0.9, P < .001), test-retest reliability (ρ = 0.9, P < .001) and convergent validity (ρ = 0.9, P < .001). With melatonin, RBD symptom severity gradually improved over the first 4 weeks of treatment (Ikelos-RS: 6.1 vs. 2.5; CGI Severity: 5.7 vs. 3.2) and remained stably improved (mean follow-up 4.2 ± 3.1years; range: 0.6-21.7years). Initial response was slowed to up to 3 months with melatonin-suppressing (betablockers) or REM sleep spoiling co-medication (antidepressants) and failed with inadequately timed melatonin intake. When melatonin was discontinued after 6 months, symptoms remained stably improved (mean follow-up after discontinuation of 4.9 ± 2.5years; range: 0.6-9.2). When administered only 1-3 months, RBD symptoms gradually returned. Without any melatonin, RBD symptoms persisted and did not wear off over time. Clock-timed, low-dose, long-term melatonin treatment in patients with iRBD appears to be associated with the improvement of symptoms. The outlasting improvement over years questions a pure symptomatic effect. Clock-time dependency challenges existing prescription guidelines for melatonin.