Clonazepam for probable REM sleep behavior disorder in Parkinson's disease: A randomized placebo-controlled trial

Shin, Chaewon; Park, Hye-Young; Lee, Woong-Woo; Kim, Hyun Jeong; Kim, Han Joon; Jeon, Beomseok

doi:10.1016/j.jns.2019.04.029

Cited by 53 publications

(46 citation statements)

References 23 publications

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“…Patient and partner reported dream enactment events were collected every day in weeklong diary reports and then averaged in 4-week epochs that represent the four phases of the study (pretreatment, early and late treatment, and follow-up). The primary endpoint of the study was the late treatment epoch (weeks [5][6][7][8]. Panel (A) shows that there was no significant difference between melatonin (in blue) and placebo (in red) on the number of RBD events (primary outcome; P for difference = 0.92).…”

Section: Discussionmentioning

confidence: 99%

“…2,3 These visual symptoms can be observed from the very early stages of the disease. [4][5][6] The retina is similar to the brain in terms of cell composition, structure, and inflammatory and immunologic reactions to insults. 7,8 It also has dopaminergic cells that express α-synuclein, and loss of retinal dopamine Relevant conflicts of interests/financial disclosures: Nothing to report.…”

Section: Supporting Datamentioning

confidence: 99%

“…3,4 Clonazepam is a long-acting benzodiazepine linked to adverse outcomes, 3,4 whereas its efficacy for reducing RBD in PD was recently challenged. 5 Melatonin has a safer profile with milder side effects, such as headache and morning sleepiness. 2,4,[6][7][8][9] Melatonin has a 30-to 50-minute elimination half-life.…”

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confidence: 99%

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Melatonin for Rapid Eye Movement Sleep Behavior Disorder in Parkinson's disease: A Randomised Controlled Trial

et al. 2019

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A B S T R AC TBackground: Melatonin may reduce REM-sleep behavior disorder (RBD) symptoms in Parkinson's disease (PD), though robust clinical trials are lacking. Objective: To assess the efficacy of prolonged-release (PR) melatonin for RBD in PD. Methods: Randomized, double-blind, placebocontrolled, parallel-group trial with an 8-week intervention and 4-week observation pre-and postintervention (ACTRN12613000648729). Thirty PD patients with rapid eye movement sleep behavior disorder were randomized to 4 mg of prolonged-release melatonin (Circadin) or matched placebo, ingested orally once-daily before bedtime. Primary outcome was the aggregate of rapid eye movement sleep behavior disorder incidents averaged over weeks 5 to 8 of treatment captured by a weekly diary. Data were included in a mixed-model analysis of variance (n = 15 per group). Results: No differences between groups at the primary endpoint (3.4 events/week melatonin vs. 3.6 placebo; difference, 0.2; 95% confidence interval = −3.2 to 3.6; P = 0.92). Adverse events included mild headaches, fatigue, and morning sleepiness (n = 4 melatonin; n = 5 placebo). Conclusion: Prolonged-release melatonin 4 mg did not reduce rapid eye movement sleep behavior disorder in PD.

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Section: Discussionmentioning

confidence: 99%

Section: Supporting Datamentioning

confidence: 99%

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Melatonin for Rapid Eye Movement Sleep Behavior Disorder in Parkinson's disease: A Randomised Controlled Trial

et al. 2019

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“…22 However, lowdose clonazepam at 0.5 mg per night also resulted in a response rate of 76.5% in Parkinson's disease with probable RBD, although with no significant difference between the clonazepam and placebo groups. 37 The most commonly used dose for melatonin therapy in clinical trials involving RBD is 3 mg, although higher doses up to 12 mg have been found in retrospective studies. 38 Therefore, although the doses of clonazepam and melatonin during the follow-up period were slightly higher than the initial doses in our study, further increases in the dose could have led to additional improvements in some patients.…”

Section: Discussionmentioning

confidence: 99%

Comorbid Depression Is Associated with a Negative Treatment Response in Idiopathic REM Sleep Behavior Disorder

et al. 2020

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Background and Purpose The first-line medications for the symptomatic treatment of rapid eye movement sleep behavior disorder (RBD) are clonazepam and melatonin taken at bedtime. We aimed to identify the association between depression and treatment response in patients with idiopathic RBD (iRBD). Methods We reviewed the medical records of 123 consecutive patients (76 males; age, 66.0± 7.7 years; and symptom duration, 4.1±4.0 years) with iRBD who were treated with clonazepam and/or melatonin. Clonazepam and melatonin were initially administered at 0.25-0.50 and 2 mg/day, respectively, at bedtime, and the doses were subsequently titrated according to the response of individual patients. Treatment response was defined according to the presence or absence of any improvement in dream-enacting behaviors or unpleasant dreams after treatment. Results Forty (32.5%) patients were treated with clonazepam, 56 (45.5%) with melatonin, and 27 (22.0%) with combination therapy. The doses of clonazepam and melatonin at followup were 0.5±0.3 and 2.3±0.7 mg, respectively. Ninety-six (78.0%) patients reported improvement in their RBD symptoms during a mean follow-up period of 17.7 months. After adjusting for potential confounders, depression was significantly associated with a negative treatment response (odds ratio=3.76, 95% confidence interval=1.15-12.32, p=0.029). Conclusions We found that comorbid depression is significantly associated with a negative response to clonazepam and/or melatonin in patients with iRBD. Further research with larger numbers of patients is needed to verify our observations and to determine the clinical implications of comorbid depression in the pathophysiology of iRBD.

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“…13 Unfortunately, a recent placebo-controlled trial in RBD occurring with PD was negative, with only a trend of RBD symptom improvement with clonazepam compared with placebo, as measured by clinical global impression of change (CGI). 14 Melatonin, for its more favourable side effect profile, is frequently preferred as initial therapy for RBD. 15 16 In higher doses (6 to 18 mg at bedtime) melatonin improved frequency and severity of RBD symptoms in up to 70% of patients, as documented in several observational studies.…”

Section: Symptomatic Treatments For Rbdmentioning

confidence: 99%

Clinical trials in REM sleep behavioural disorder: challenges and opportunities

Videnović

Arnulf

et al. 2020

J Neurol Neurosurg Psychiatry

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The rapid eye movement sleep behavioural disorder (RBD) population is an ideal study population for testing disease-modifying treatments for synucleinopathies, since RBD represents an early prodromal stage of synucleinopathy when neuropathology may be more responsive to treatment. While clonazepam and melatonin are most commonly used as symptomatic treatments for RBD, clinical trials of symptomatic treatments are also needed to identify evidence-based treatments. A comprehensive framework for both disease-modifying and symptomatic treatment trials in RBD is described, including potential treatments in the pipeline, cost-effective participant recruitment and selection, study design, outcomes and dissemination of results. For disease-modifying treatment clinical trials, the recommended primary outcome is phenoconversion to an overt synucleinopathy, and stratification features should be used to select a study population at high risk of phenoconversion, to enable more rapid clinical trials. For symptomatic treatment clinical trials, objective polysomnogram-based measurement of RBD-related movements and vocalisations should be the primary outcome measure, rather than subjective scales or diaries. Mobile technology to enable objective measurement of RBD episodes in the ambulatory setting, and advances in imaging, biofluid, tissue, and neurophysiological biomarkers of synucleinopathies, will enable more efficient clinical trials but are still in development. Increasing awareness of RBD among the general public and medical community coupled with timely diagnosis of these diseases will facilitate progress in the development of therapeutics for RBD and associated neurodegenerative disorders.

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Clonazepam for probable REM sleep behavior disorder in Parkinson's disease: A randomized placebo-controlled trial

Cited by 53 publications

References 23 publications

Melatonin for Rapid Eye Movement Sleep Behavior Disorder in Parkinson's disease: A Randomised Controlled Trial

Melatonin for Rapid Eye Movement Sleep Behavior Disorder in Parkinson's disease: A Randomised Controlled Trial

Comorbid Depression Is Associated with a Negative Treatment Response in Idiopathic REM Sleep Behavior Disorder

Clinical trials in REM sleep behavioural disorder: challenges and opportunities

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