Table 6.

Description of the effect of other drugs in the treatment of RBD.

Drug	Authors Year, [Ref]	Study Setting	Type of Study	Main Findings	Level of Evidence (Quality Score)
Drugs used in Alzheimer’s disease
Donepezil	Ringman and Simmons, 2001 [66]	3 patients with RBD treated with 10–15 mg/day of donepezil (one of them diagnosed with Alzheimer’s disease)	Case series	Marked improvement of RBD symptoms with donepezil (in two cases maintained for at least one year)	III (NA)
Rivastigmine	Di Giacopo et al., 2021 [67]	12 patients with PD (non-demented) and RBD confirmed by PSG resistant to clonazepam and melatonin, treated with 4.6 mg/day of rivastigmine or placebo	3-week, double-blind placebo-controlled, crossover pilot trial	Significant decrease of RBD episodes with rivastigmine compared to basal evaluation and placebo	I (>50%)
	Brunetti et al., 2014 [68]	25 patients with mild cognitive impairment and RBD confirmed by PSG resistant to clonazepam and melatonin treated with 4.6 mg/day of rivastigmine or placebo	30 days, placebo-controlled, cross-over pilot trial	Marked decrease of RBD episodes with rivastigmine compared to basal evaluation and placebo. 72% of patients treated with rivastigmine vs 20% with placebo showed at least 50% of reduction of RBD episodes.	I (>50%)
Memantine	Larsson et al., 2010 [69]	42 patients with DLB or PDD (probable RBD was assessed by a single question in the Stavanger Sleep Questionnaire). Treatment with 20 mg/day of memantine (n = 25) or placebo (n = 22)	24-week, double-blinded, placebo-controlled randomizedmulticentre trial	Frequency of moderate/severe probable RBD decrease from 44% to 13% in patients treated with memantine; this increased from 25% to 32% in the placebo group.	I (>50%)
Antidepressant and/or serotonergic drugs
Desipramine	Schenck et al., 1986 [1]	The first description of 4 RBD patients	Case series	Considerable improvement of RBD symptoms with desipramine in 1 patient	III (NA)
Imipramine	Patterson et al., 1989 [70]	One patient with RBD treated with 75 mg of imipramine at bedtime (no improvement with 0.5 mg of clonazepam)	Single case report	Considerable improvement of RBD symptoms with imipramine maintained for at least 6 months	III (NA)
Fluvoxamine/paroxetine	Takahashi et al., 2008 [71]	One patient with RBD treated with 50 mg of fluvoxamine or 10 mg of paroxetine at bedtime	Single case report	Marked improvement of RBD symptoms with both fluvoxamine (withdraw because of bad tolerance) and paroxetine	III (NA)
Agomelatine	Bonakis et al., 2012 [45]	3 patients with iRBD treated with 25–50 mg of agomelatine (MT1 and MT2 melatonin receptor agonist and a 5-HT2 antagonist) 1 h before bedtime	Case series	Significant improvement in 1 patient and partial improvement in 2 patients with 25 mg of agomelatine (these patients considerably improved with increasing dose to 50 mg) A trend for improvement in sleep efficiency with decreased WASO, a slight increase in the percentage of REM epochs with muscle atonia, and a decrease in 2 patients of the percentage of REM epochs with high tonic density No adverse effects were reported.	III (NA)
Trazodone	Chica-Urzola, 2015 [72]	One patient with iRBD resistant to clonazepam treated with 50 mg/day of trazodone	Single case report	Marked improvement of RBD symptoms maintained for at least 3 months.	III (NA)
Vortioxetine	Du et al., 2020 [73]	One patient with RBD resistant to paroxetine and melatonin treated with 10 mg of vortioxetine.	Single case report	Marked improvement of RBD symptoms maintained for at least 3 months.	III (NA)
Nelotanserin	Stefani et al., 2021 [74]	26 patients with DLB and 8 with PDD with PSG-confirmed RBD. Treatment with 80 mg of nelotanserin or placebo (1:1 ratio). Assessment with video-PSG	4-week double-blind placebo-controlled randomizedmulticentre trial treatment period	Non-significant differences between nelotanserin and placebo in RBD behaviours.	I (>50%)
5-hydroxy-tryptophan (5-HTP)	Meloni et al., 2021 [75]	18 patients with PD and PSG confirmed RBD treated with of 50 mg/day 5-HTP or placebo	4-week, single-centre, randomized, double-blind placebo-controlled crossover trial	CGI and self-reported clinical status improved similarly with 5-HTP and with placebo. 5-HTP improved UPDRS part 2 score. 5-HTP produced an increase in the total percentage of stage REM sleep without a related increase of RBD episodes and with a trend toward reduction in arousal index and wake after sleep onset.	I (>50%)
Antiepileptic drugs
Carbamazepine	Bamford, 2003 [76]	One patient with iRBD treated with 100 mg of carbamazepine twice daily	Single case report	75% improvement of RBD symptoms maintained for at least 14 months.	III (NA)
Levetiracetam	Batalini et al., 2016 [77]	One patient with RBD associated with probable LBD treated with 1000 mg of levetiracetam twice daily	Single case report	Reduction of RBD episodes by 50% and worsening to basal level after withdrawal of levetiracetam	III (NA)
Cannabinoids
Cannabidiol	Chagas et al., 2014 [78]	4 patients with PD and RBD symptoms (n = 2) or PSG-confirmed RBD (n = 2). Treatment with 75 mg/day of cannabidiol (1 with 300 mg/day)	Case series	Marked (1) or complete (3) improvement in RBD symptoms during a 6-week treatment	III (NA)
	De Almeida et al., 2021 [79]	33 patients with PD and PSG-confirmed RBD. Treatment with 75 mg/day of cannabidiol, 300 mg/day of cannabidiol, or placebo. Assessment of the frequency of nights with RBD, CGI-I, and CGI-S.	14-week, phase II/III, double-blind, randomized, placebo-controlled clinical trial	Non-significant differences between cannabidiol and placebo in the frequency of nights with RBD, CGI-S, and CGI-I scale scores. Improvement in average sleep satisfaction from the 4th to 8th week	I (>50%)
Herbals
Yokukansan (Yi-Gan San)	Shinno et al., 2008 [80]	3 patients with PSG-confirmed RBD treated with 2.5–7.5 g/day of yokukansan in 2 cases as add-on therapy to clonazepam	Case series	Complete or significant improvement of RBD symptoms in 3 patients, with relapsing in 2 patients after yokukansan withdrawal and new improvement after its reintroduction	III (NA)
	Matsui et al., 2019 [81]	36 patients with PSG-confirmed iRBD treated with yokukansan alone (n = 17) or as add-on therapy (n = 19). Assessment with CGI-I, and CGI-S.	Retrospective analysis of clinical records	70.6% of patients with yokukansan in monotherapy and 21.1% of them receiving yokukansan as add-on therapy were “responders” (“very much improved” and “much improved”). Mean reductions in CGI-S and CGI-I scores were significantly higher in patients on monotherapy.	II (NA)
	Ozone et al., 2020 [82]	23 patients with RBD treated with yokukansan (n = 11) or clonazepam (n = 12) for at least 3 months. Assessment with RBDQ-JP and SF-8 scales	Retrospective analysis of clinical records	Significant and similar improvement of RBDQ-JP score after treatment with both yokukansan (3.0 + 1.0 g/day) and with clonazepam (0.9 + 0.5 g/day) Non-significant changes in SF-8 scores with yokukansan and with clonazepam.	II (NA)

CGI-I, clinical global impression-improvement; CGI-S, clinical global impression-severity; DLB, dementia with Lewy bodies; 5-HT, 5-hydroxytryptamine (serotonin); 5-HTP, 5-hydroxytryptophan; iRBD, idiopathic or isolated REM sleep behaviour disorder; MT, melatonin; PD, Parkinson’s disease; PDD, Parkinson’s disease dementia; PSG, polysomnography; RBD, REM sleep behaviour disorder; RBDQ-JP, RBD Questionnaire Japanese version; REM, rapid eye movements; SF-8, Short-Form Health Survey; UPDRS, Unified Parkinson’s Disease Rating Scale; WASO, wake after sleep onset.