Table 1.

Systematic overview of all prospective observational studies on the pharmacological management of RBD

Study Design	Study (First author, year)		Clinical population	Treatment (Daily dosage)	Groups (n subjects) [Age in years]	RBD screening method	RBD outcome measure(s)	Main results on RBD	Level of evidence (Box 1)
Clonazepam
DB-RCT	Shin, 2019 [36]		Parkinson	(A) Clonazepam (0.5 mg) daily for 4 weeks (B) Matched placebo (0.5 mg) daily for 4 weeks	(A) Active (n = 19) [66, 48–73]* (B) Placebo (n = 20) [70, 56–77]	RBD single screening question	(1) CGI	Non-effective No other outcomes of RBD assessed	I-B
POS	Li, 2016 [37]		iRBD	Clonazepam (0.125–1.0 mg) at baseline and (0.125–3.0 mg) at follow up 28.8 ± 13.3 months later Treatment duration not fixed	Active (n = 39) [68.3 ± 7.8] -27 remained on therapy -10 had prescription changed -2 were not on therapy at follow-up No control group	PSG	(1) RWA on PSG (2) Movements during sleep on PSG (3) RBDQ-HK modified to cover past 3 months	Worse RWA and no reduction in movements during sleep on PSG. Subjective improvement reported in 66.7% of subjects	II-B
POS	Iranzo, 2005 [39]		iRBD, Parkinson, and MSA	If clinically required, clonazepam (0.25–0.5 mg) was started at diagnosis and titrated up in 0.25–0.5 mg increments to clinical response and tolerability. Mean follow-up across all subjects was 26.9 ± 21.3 months later Treatment duration not fixed	Active -iRBD (n = 39) taking mean dose of 0.89 (0.55) mg/day [68.4 ± 5.9] -Parkinson (n = 45) taking mean dose of 0.72 (0.42) mg/day [64.8 ± 7.8] -MSA (n = 26) taking mean dose of 0.63 (0.22) mg/day [62.0 ± 7.1] No control group	PSG	(1) Clinical response to clonazepam (Substantial, partial, no response, in %)	Subjective improvement (substantial or partial) reported in almost all subjects, except 3.1% of the iRBD cases. No side effects in Parkinson, whereas 11.1% of MSA and 25% of iRBD reported side effects, mainly somnolence	II-B
POS	Lappiere, 1992 [38]		iRBD, with one case presenting soft cerebellar signs on MRI	Clonazepam (0.5–2.0 mg) for a duration of 2 months	-Active (n = 5) [58.6, 44–65]* No control group	PSG	(1) RBD episodes on PSG (2) Phasic EMG density on PSG at REM (3) RSWA on PSG	(1) Subjective improvements reported though occasional sleep-talking and limb-jerking observed (2) Reduction in phasic EMG density at REM (3) No reduction in RSWA	II-B
Melatonin
DB-RCT	Gilat, 2020 [42]		Parkinson	(A) PR-melatonin (Circadin, 2 × 2 mg) for 8 weeks (B) Matched placebo (2 × 2 mg) for 8 weeks	(A) Active (n = 15) [65.3 ± 6.9] (B) Placebo (n = 15) [67.9 ± 5.3]	PSG	(1) Frequency of RBD in 2nd month of treatment based on self-report diary entries (2) RWA on PSG in a subset of n = 8 on melatonin and n = 6 on placebo (3) Several RBD questionnaires (4) CGI-I	Non-effective Also no group differences seen for RWA on PSG, the CGI, or any of the RBD Questionnaires	I-B
DB-RCT	Jun, 2019 [41]		i-RBD	(A) PR-melatonin (Circadin, 1 × 2 mg) + matched placebo (2 × 2 mg) for 4 weeks (B) PR-melatonin (Circadin, 3 × 2 mg) for 4 weeks (C) Matched placebo (3 × 2 mg) for 4 weeks	(A) Active 1 (n = 7) [68.1 ± 9.1] (B) Active 2 (n = 9) [64.7 ± 8.3] (C) Placebo (n = 9) [66.4 ± 8.5]	PSG	(1) CGI-I (2) RBDQ-KR questionnaire after 4 weeks of treatment (3) DEB frequency recorded by patients on daily diary	Non-effective on either primary- or any secondary outcomes on RBD, including diary entries. RWA on PSG not assessed post-treatment	I-B
DB-RCT	Kunz, 2010 [16]		Mixed diagnoses (5 iRBD, 1 Parkinson, 2 Narcolepsy + PLMS)	(A) Melatonin (3 mg) for 4 weeks (B) Placebo for 4 weeks	Subjects (n = 8) entered in cross-over study and randomized to first receive melatonin or placebo therapy for 4 weeks and switch treatments after 3–5 days of washout period [53.8, 26–67]* Two subjects were 26 and 37 years old, respectively	PSG	(1) Number of REM epochs without RWA on PSG (2) CGI severity	Compared to baseline, melatonin significantly reduced number of REM epochs with RWA and improved CGI, whereas the improvement seen during placebo did not reach significance. No differences were found for RWA or CGI severity scores when comparing melatonin to placebo	I-B
POS	Takeuchi, 2001 [46]		RBD, idiopathic or with unknown concomitant diagnoses (not reported)	Melatonin (3 mg) that in some subjects was titrated up to 9 mg according to degree of clinical RBD symptoms Treatment duration not fixed and not reported	Total of 15 subjects with RBD assessed at baseline and at a non-specified point in time during therapy ‘when their clinical symptoms were improved or stable’ [63.5, SD or range not reported]	PSG	(1) Clinical opinion (2) % Tonic/Phasic REM activity on PSG (3) Melatonin blood concentration levels at 3hour intervals	Remarkable improvement noted in 3/15 and partial improvement in 10/15 patients. Significant reduction in tonic REM EMG activity on PSG. Melatonin concentration increased in a subset of patients with low baseline melatonin levels	II-B
POS	Kunz, 1999 [15]		Mixed diagnoses (2PD, 2 iRBD, 1 RBD with hypertension, 1 RBD with sympathetic dysautonomia)	Melatonin (3 mg) for 6 weeks	Total of 6 subjects assessed before and after therapy [54, 26–71]*	PSG	(1) Clinical opinion (2) Number of REM epochs without RWA on PSG (3) Movement time in bed based on actigraphy data	Subjective improvements in 5/6 patients with presumed long-term effects lasting weeks or even up to 22 months in one subject. Reduced REM epochs without muscle atonia on PSG seen after 6 weeks of melatonin compared to baseline	II-B
Ramelteon
POS	Esaki, 2016 [48]		iRBD	Ramelteon (8 mg) for 8.3 ± 6.8 weeks Treatment duration not fixed	Active (n = 12) [70.9, 52–81] No control group	PSG	(A) RWA on PSG (B) RBDSS on PSG (C) VAS-scale for subjective RBD severity rated by partner	Non-effective on PSG or VAS-scale, though subjective severity trended towards a significant improvement. Some subjects with worsening RWA reported subjective improvements	II-B
POS	Kashihara, 2016 [49]		Parkinson	Ramelteon (8 mg) for 12 weeks	Active (n = 35) -24 screened positive for probable RBD -6 stopped therapy due to adverse events -3 were lost to follow-up [69.1 ± 11.1] No control group	RBDSQ (Japanese version)	RBDSQ (Japanese version)	Significant improvement in 13 patients with probable RBD, but also in 11 patients without probable RBD	II-B
Dopamine-agonists
POS	Sasai, 2012 [51]		iRBD with PLMS	Pramipexole (0.21 ± 0.09 mg) for 9.1 ± 7.1 months Treatment duration not fixed	Total of 15 subjects assessed before and after treatment period [66.5, 57–75]	PSG	(1) Four-point severity scale based on clinical opinion (2) Subjective frequency of nightmares (3) RSWA on PSG	Subjective partial improvements were noted for 12/15 patients	II-B
POS	Kumru, 2008 [53]		Parkinson	Pramipexole (0.54 mg) divided in 3 dosages with last dosage taken one hour before bedtime, for 3 months	Total of 11 PD with untreated RBD on levodopa monotherapy at study entry assessed before and after 3 months of pramipexole therapy [62.1 ± 8.0]	PSG	(1) Three point severity scale on subjective frequency of RBD by patient and bed-partner (2) Subjective frequency of unpleasant dreams by patients and bed-partners (3) RWA on PSG 4) % of time spent with DEB during REM sleep (4) Three point severity scale of DEB on PSG by blinded assessors	Non-effective on both subjective and objective PSG measures	II-B
POS	Fantini, 2003 [54]		iRBD	Pramipexole (0.125 mg/24 hr) titrated up by 0.125 mg every 3 days until a mean final dosage of 0.78 ± 25 mg/24 hr, 1–9 months later Treatment duration not fixed	Total of 8 subjects with iRBD assessed before and after 4.5 (range 1–9.5) months of therapy [66 ± 6.8]	PSG	(1) Four point subjective severity rating based on patient and bed partner self-report of RBD severity on (2) RWA on PSG (3) DEB on PSG	Subjective sustained improvement in 5/8 patients and reduced simple DEB on PSG, though RWA on PSG worsened on therapy compared to baseline	II-B
POS	Wang, 2016 [50]		Parkinson	Rotigotine (2 mg/24 hr) titrated up to 16 mg over 8 weeks followed by 12–20 weeks of dose-maintenance Treatment duration not fixed	Active (n = 11) [66.27 ± 8.47]	PSG	(A) RWA on PSG (B) DEB on PSG (C) RBDQ-HK	Non-effective on PSG measures. Subjective improvement reported in 63.64% of subjects	II-B
POS	Dušek, 2010 [52]		Parkinson	PR-ropinirole for 5–13 weeks at the dosage closest to the dosage of immediate release ropinorole already taken by the subjects at study entry for past 3.4 ± 1 years Treatment duration not fixed	Total of 35 PD, of whom only 5 had RBD, taking immediate release ropinorole 2–5 times daily at study entry who were switched to a similar dose (17.2 ± 6 mg) of PR-ropinorole and followed-up 5–13 weeks later [62.5, 44–75]*	PSG	RBDSQ	Non-effective in subset of 5 PD with RBD at study entry	II-B
Acetylcholinesterase inhibitors
SB-RCT	Brunetti, 2014 [28]		iRBD with MCI	(A) Rivastigmine patch (4.6 mg/24 hr) for 30 days (B) Placebo patch for 30 days	Subjects (n = 25) deemed refractory to melatonin or clonazepam therapy entered in cross-over study and randomized to first receive rivastigmine or placebo therapy for 30 days and switch treatments after 7 days of washout period [63.0, 49–81]*	PSG	(A) RBD frequency recorded on diary by bed-partners PSG not performed post-therapy	Improvement in subjective RBD frequency on rivastigmine compared to placebo	I-B
DB-RCT	Di Giacopo, 2012 [27]		Parkinson	(A) Rivastigmine patch (4.6 mg/24 hr) for 3 weeks (B) Placebo patch for 3 weeks	Subjects (n = 12) deemed refractory to melatonin or clonazepam therapy entered in cross-over study and randomized to first receive rivastigmine or placebo therapy for 3 weeks and switch treatments after 7 days of washout period. Two dropped out [66.7 ± 7.3]	PSG	(A) RBD frequency recorded on diary by bed-partners (B) RWA on PSG in subset of 4 subjects	Significantly lower frequency of RBD on diary during rivastigmine, but not placebo. No change on PSG in subset of 4 subjects	I-B
NMDA antagonist
DB-RCT	Larsson, 2010 [47]		Parkinson with dementia (PDD) or DLB	(A) Memantine (5 mg) for 24 weeks titrated up to 20 mg at week 4 of therapy (B) Placebo Secondary analysis from previously published DB-RCT, which was not focused on RBD	(A) Active (n = 25) [76.4 ± 6.5] (B) Placebo (n = 22) [76.3 ± 5.0]	Probable RBD based on subjective rating on a single item of the Stavanger Sleep Questionnaire (SSQ): “Is the patient physically active during sleep?”	Four-point subjective severity rating on a single item of the SSQ regarding physical activity during sleep, which may or may not have occurred during REM sleep. The baseline frequency of patients with probably RBD was 54% and equally distributed between the two groups	Probable RBD severity decreased significantly following memantine compared to placebo, though careful interpretation is warranted due to possible non-RBD specificity of outcome measure	I-B
SSRI
POS		Yamamoto, 2006 [33]	IRBD	Paroxetine (10-40 mg) for an unknown duration Treatment duration and dosage not fixed	(A) Active (n = 19) [64.7 ± 7.8] No control group	PSG	(A) Subjective RBD severity rating (Mild, Moderate, Severe)	Subjective RBD improved to a mild state in 11 and to a moderate state in 5 patients, while in 3 patients severe RBD persisted. Treatment was ceased in 2 due to side-effects	III-B

Daily dose presented as mean ± SD mg/day; Age in years presented as [mean ± SD], or [mean, range]; * = one or more subjects could be < 50 years of age

CGI = Clinical Global Impression scale; DB-RCT = Double-blinded randomized controlled trial; DEB = Dream Enactment Behaviors; (I)RBD = (Idiopathic) REM sleep Behavior Disorder; Parkinson = Parkinson’s disease; PLMS = Periodic Limb Movements; POS = Prospective open-label study (i.e., no control intervention); PR = Prolonged Release; PSG = Polysomnography; QA = Quality Assessment; RBDQ-HK = RBD Questionnaire Hong Kong; RBDSQ = RBD Screening Questionnaire; RBDSS = RBD Severity Scale based on PSG; RWA = REM sleep without atonia; SB-RCT = Single-blinded RCT; SSRI = Selective Serotonin Reuptake Inhibitor; VAS = Visual Analogue Scale