Table 4.

Studies describing effects of levodopa and dopamine agonists in patients with RBD.

Authors, Year [Ref]	Study Setting/Design	Type of Study	Main Findings	Level of Evidence (Quality Score)
Tan et al., 1996 [49]	3 patients with iRBD preceding PD treated with levodopa (doses not stated)	Case report series	Dramatic clinical improvement of RBD symptoms in 2 patients and moderate improvement in 1 patient.	III (NA)
Yamauchi et al., 2003 [50]	1 patient with RBD as the initial symptom of DLB	Single case report	Clinical improvement of RBD symptoms, reduction of night time activity measured by actigraphy; a lack of muscle atonia and intermittent appearance of augmented muscle tone during REM sleep by PSG after treatment with levodopa, starting at 100 mg daily and increased to 500 mg daily	III (NA)
Fantini et al., 2003 [51]	8 patients diagnosed with iRBD were treated with 0.5–1 mg of pramipexole 1 h before bedtime. Clinical, video recording, and PSG assessment	Open-label study	Sustained reduction in the frequency or intensity of sleep motor behaviours (confirmed by video recording) in 5 patients. Lack of changes for the percentage of phasic EMG activity during REM sleep. Surprisingly, a decrease in the percentage of time spent with REM sleep muscle atonia	II (NA)
Schmidt et al., 2006 [52]	10 patients with PSG confirmed iRBD (6 of them with concomitant RLS or PLMS) treated with pramipexole (a single dose before bedtime or a divided dose regimen with the first dose given in the early evening and the second dose at bedtime). Clinical assessment with a mean follow-up of 13.1 months.	Open-label study	The average total evening dose of pramipexole at the end of the study was 0.89 + 0.31 mg. A divided dose regimen of pramipexole was used in 56% of patients remaining on pramipexole. 89% of patients experienced either a moderate or complete reduction in the frequency of RBD symptoms. 67% reported at least a moderate reduction in the severity of RBD symptoms.	II (NA)
Kumru et al., 2008 [53]	11 PD patients with RBD under stable dose of levodopa. Evaluation of the effect of pramipexole at an initial dose of 0.18 mg 3 times daily on RBD symptoms with bed partner interviews and blind assessment of video-PSG measures	Prospective open-label study	Lack of improvement of RBD-related symptoms and objective video-PSG abnormalities	II (NA)
Sasai et al., 2012 [54]	15 patients with iRBD with a PLMS index > 15 events/h shown. Treatment with 0.125–0.375 mg of pramipexole. PSG measures before and after 1 month of treatment.	Open-label study	Symptomatic improvement in 14 patients (80%) Reduction of REM density and PLMS index during non-REM sleep despite the unchanged amount of REM sleep without atonia. Positive correlation between the rate of change in RBD symptoms and the rate of REM density reduction.	II (NA)
Sasai et al., 2013 [55]	98 patients with iRBD treated with pramipexol (n = 81; in 31 non-responders, clonazepam was added) and/or clonazepam (n = 17; in 2 non-responders, pramipexol was added) during >3 months. Examination of PSG factors associated with pramipexole effectiveness	Retrospective cohort study	Efficacy of pramipexole in 61.7% (50/81) of patients Association of the ratio of REM sleep without atonia with total REM sleep with pramipexole effectiveness (with a cut-off rate of 16.8%). Responders to combined treatment with pramipexole and clonazepam showed significantly more REM sleep without atonia, total REM sleep, and frequency of vocalization or dream enactment behaviour than responders to monotherapy with pramipexole of with clonazepam	II (NA)
Wang et al., 2016 [56]	11 PD patients with untreated RBD. Administration of rotigotine at increasing doses (12.36 ± 4.27 mg at the end of the study; 24.7 ± 2.41 weeks). Evaluation of RBD symptoms through patient and bed partner interviews, RBDQ-HK, and blinded assessments of video-PSG measures	Prospective open-label study	Improvement of Parkinsonism and subjective sleep quality. Decrease in the RBDQ-HK total score, especially in the frequency and severity of abnormal RBD-related motor behaviours. Increase of total sleep time and stage 1 and decrease in PLMS index in the video-PSG without significant differences in RBD-related sleep measures	II (NA)
Plastino et al., 2021 [57]	30 patients with PD and RBD under stable antiparkinsonian therapy. Addition or no addition of safinamide 50 mg/day during 3 months, 15 days of washout, and switch of safinamide during other 3 months. Clinical (including PDSS-2 and RBDQ-HK scores) and PSG assessment	Longitudinal randomized cross-over study	Symptomatic improvement in 22 (73.3%) of patients (16 of them free from RBD symptoms at the end of treatment) Significant reduction in PDSS-2 and RBDQ-HK scale scores with safinamide. Significant increase of total sleep time and improvement in tonic submental electromyography activity, phasic submental electromyography activity, and REM density in the PSG study	I (>50%)

DLB, dementia with Lewy bodies; EMG, electromyography; iRBD, idiopathic or isolated REM sleep behaviour disorder; PD, Parkinson’s disease; PDSS-2, Parkinson’s disease Sleep Scale-2; PSG, polysomnography; PLMS, periodic leg movements during sleep; RBD, REM sleep behaviour disorder; RBDQ-HK, RBD Questionnaire-Hong-Kong version; REM, rapid eye movements; RLS, restless legs syndrome.