Table 5.

Studies including treatment of PD and RBD patients with melatonin.

Subjects	Design	Study's duration	Treatment	Measured	Results	References
40 PD patients	Open-label, placebo-controlled trial	2 weeks	5–50 mg melatonin p.o./daily at bed time. All subjects were taking stable doses of antiparkinsonian medications	Actigraphy	Relative to placebo, treatment with 50 mg of melatonin significantly increased night time sleep, as revealed by actigraphy. As compared to 50 mg or placebo, administration of 5 mg of melatonin was associated with significant improvement of sleep in the subjective reports	(196)
18 PD patients	Open-label, placebo-controlled trial	4 weeks	3 mg melatonin p.o./daily at bed time	Polysomnography (PSG). Subjective evaluation by the Pittsburgh Sleep Quality Index and Epworth Sleepiness Scale	On initial assessment, 14 patients showed poor quality sleep EDS. Increased sleep latency (50%), REM sleep without atonia (66%), and reduced sleep efficiency (72%) were found in PSG. Melatonin significantly improved subjective quality of sleep. Motor dysfunction was not improved using melatonin	(179)
38 patients with PD without dementia and with complaints on sleep disorders	Open-label trial	6 weeks	Group 1 (n = 20) received 3 mg melatonin in addition to the previous dopaminergic group 2 (n = 18) received clonazepam 2 mg at night	Polysomnography (PSG) at baseline and at the end of the trial. Subjective evaluation by the PD sleep scale (PDSS) and the Epworth Sleepiness Scale (ESS). Neuropsychological testing using MMSE, five-word test, digit span and the Hamilton scale	Compared to baseline, melatonin and clonazepam reduced sleep disorders in patients. The daytime sleepiness (ESS) was significantly increased in the clonazepam group. Patients treated with melatonin had better scores on the MMSE, five-word test, Hamilton scale at the end of the study period as compared with the clonazepam group. Changes in total point scores on the PSG at the end of week 6 were in favor of the group treated with melatonin	(197)
1 RBD patient	Case report	5 months	3 mg melatonin p.o./daily at bed time	Actigraphy, PSG	Significant reduction of motor activity during sleep, as measured by actigraphy. After 2 months' treatment, PSG showed no major changes except an increase of REM sleep	(198)
6 consecutive RBD patients	Open-label prospective case series	6 weeks	3 mg melatonin p.o./daily at bed time	PSG	Significant PSG improvement in 5 patients within a week which extended beyond the end of treatment for weeks or months	(199)
14 RBD patients	Open-label prospective case series	Variable	3–9 mg melatonin p.o./daily at bed time	PSG	Thirteen patients and their partners noticed a suppressing effect on problem sleep behaviors after melatonin administration. % tonic REM activity in PSG findings was decreased after melatonin administration. Melatonin concentrations in 10 RBD patients were under 30 pg/mL at maximal values, their mean 33.5 pg/mL RBD patients with low melatonin secretion tended to respond to melatonin therapy	(200)
14 RBD patients	Retrospective case series	14 months	3–12 mg melatonin p.o./daily at bed time	PSG	8 patients experienced continued benefit with melatonin beyond 12 months of therapy	(201)
45 RBD patients	Retrospective case series		All initially treated with clonazepam. When melatonin was used, it was given at a 10 mg p.o./daily at bed time		21 patients continued to take clonazepam, 8 used another medication, and 4 required a combination of medications to control symptoms adequately	(202)
25 RBD patients	Retrospective case series	27–53 months	6 mg melatonin p.o./daily at bed time		As compared to clonazepam-treated RBD patients (n = 18) patients receiving melatonin reported significantly reduced injuries and fewer adverse effects	(203)
8 RBD patients	Double blind, placebo-controlled trial	4 weeks	3 mg melatonin p.o./daily at bed time.	PSG	Reduced number of 30-s epochs of REM without atonia and reduced frequency of RBD episodes	(204)
1 RBD patient	Case report	5 years	2 mg prolonged release melatonin p.o./daily at bed time	PSG and DA transporter scintigraphy (DaTSCAN)	A then 72-year-old man was clinically suspected to suffer from PD in 2011. DaTSCAN revealed reduced DA transporter density and PSG confirmed the diagnosis of RBD. After 6 months of melatonin treatment, clinical signs of RBD were absent. Control PSG in 2014 confirmed normalized REM sleep with atonia. Additional DaTSCANs were performed in 2013 and 2015 indicated normalization of DA transporter density	(205)
4 RBD patients with concomitant obstructive sleep apnea	Open label	4 weeks	2 mg prolonged release melatonin p.o./daily at bed time	PSG	Treatment led to a relevant clinical improvement of RBD symptoms in all patients, so far untreated for the sleep related breathing disorder. REM without atonia incidence was high probably because of the untreated comorbid condition	(206)