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Keywords:

  • chronobiotic;
  • circadian rhythms;
  • Lewy body dementia;
  • melatonin;
  • neurodegenerative disorder;
  • REM sleep behaviour disorder;
  • RBD;
  • sleep disorders

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Rapid eye movement (REM) sleep behaviour disorder (RBD) has been suggested to predict the development of neurodegenerative disorders. Patients with RBD are acting out dream behaviour associated with loss of normal muscle atonia of REM sleep. The aim of the present study was to confirm that exogenous melatonin improves RBD. Eight consecutively recruited males (mean age 54 years) with a polysomnographically (PSG) confirmed diagnosis of RBD were included in a two-part, randomized, double-blind, placebo-controlled cross-over study. Patients received placebo and 3 mg of melatonin daily in a cross-over design, administered between 22:00 h and 23:00 h over a period of 4 weeks. PSG recordings were performed in all patients at baseline, at the end of Part I of the trial and at the end of Part II of the trial. Compared to baseline, melatonin significantly reduced the number of 30-s REM sleep epochs without muscle atonia (39% versus 27%; = 0.012), and led to a significant improvement in clinical global impression (CGI: 6.1 versus 4.6; = 0.024). Interestingly, the number of REM sleep epochs without muscle atonia remained lower in patients who took placebo during Part II after having received melatonin in Part I (–16% compared to baseline; = 0.043). In contrast, patients who took placebo during Part I showed improvements in REM sleep muscle atonia only during Part II (i.e. during melatonin treatment). The data suggest that melatonin might be a second useful agent besides clonazepam in the treatment of RBD.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Rapid eye movement (REM) sleep behaviour disorder (RBD) is clinically impressive by virtue of its vigorous sleep behaviours, which are usually accompanied by vivid dreams and often result in injuries to the patients themselves or to bed partners (AASM, 2006; Gagnon et al., 2006b; Schenck and Mahowald, 2002). Even though the neurophysiological correlate of RBD, loss of muscle atonia during REM sleep, was described in the mid-1970s, the complete clinical syndrome was not defined until 1986 (Schenck and Mahowald, 2002).

Although its aetiology is virtually unknown, RBD is far from rare (Gagnon et al., 2006b; Schenck and Mahowald, 2002). Approximately one-third of patients with Parkinson’s disease experience RBD prior to the onset of Parkinson’s disease symptoms (Olson et al., 2000; Schenck et al., 1996) and more than 90% of patients with multiple system atrophy (MSA) have RBD (Iranzo et al., 2006; Plazzi et al., 1997). There is also a strong association between RBD and neurodegenerative diseases, especially Lewy body dementia (Boeve et al., 1998; Iranzo et al., 2006). An increasing number of psychoactive drugs are being recognized as inducing a loss of muscle atonia – the neurophysiological basis of RBD – during REM sleep (Gagnon et al., 2006c). Recently, RBD was even proposed to be a predictor and early marker of the development of neurodegenerative diseases (Gagnon et al., 2006b; Iranzo et al., 2006; Turek and Dugovic, 2005).

Because the origin of RBD is unknown, therapeutic approaches to date have been limited to symptomatic treatment. Clonazepam was reported to be highly effective in two cohort studies and is widely accepted among clinicians as a treatment for RBD (Gagnon et al., 2006b; Schenck and Mahowald, 2002). Nevertheless, there are patients who do not respond to clonazepam, and the drug can cause side effects such as daytime somnolence, muscle relaxation in the elderly, reduced sleep quality, cognitive impairment and worsening of sleep apnoea.

Previously, we and others have reported improvement of RBD symptoms in open-labelled studies with melatonin (Boeve, 2001; Kunz and Bes, 1997, 1999; Takeuchi et al., 2001). The aim of the present study was to confirm this finding in a placebo-controlled clinical trial.

Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Subjects

The study protocol was approved by the ethics committee of the Freie Universität Berlin. All participants provided written, informed consent.

All patients included in the study had contacted our interdisciplinary sleep clinic voluntarily and were seeking treatment for neuropsychiatric sleep-related disturbances. Polysomnography (PSG) was performed in cases meeting the American Academy of Sleep Medicine (AASM) indications for diagnostic polysomnography (AASM, 2006), and patients were included in the study if International Classification for Sleep Disorders (ICSD) criteria for RBD were met (1997). Exclusion criteria were current or recent shiftwork (during the past year), poor sleep hygiene (sleep log or actigraphic proof of a more than 2-h variation in bedtime during a 14-day recruitment period), habitual bedtime outside the 22:00–24:00 h range, transmeridian travel (during or within 1 month of the study), psychiatric disorders (DSM-IV), pathological findings in brain imaging, recent changes in medication (within 1 month of the study) and the intake of any medication that might interfere with melatonin production/secretion or REM sleep (Arendt, 1995; Gagnon et al., 2006c; Kunz and Bes, 1999).

In total, eight consecutive male outpatients were included in the study (mean age 54 years, range 26–67). Concomitant diagnoses were narcolepsy accompanied by periodic limb movement disorder (n = 2) and Parkinson’s disease (n = 1). Five patients were diagnosed with idiopathic RBD, two of whom had concomitant idiopathic insomnia (n = 2).

Of the eight patients participating in the study, three had suffered from their respective disorders for more than 10 years, and five had suffered from their respective disorders for between 5 and 10 years. The patient with Parkinson’s disease received 375 mg l-dopa per day. His medication remained unchanged during the 4 weeks preceding the diagnostic PSG, as well as during all the study procedures. The seven remaining patients did not receive any concomitant medication.

Study design

The melatonin used in the study was obtained from Helsinn Chemicals SA in Switzerland and analysed for purity by the Department of Pharmaceutics at Freie Universität Berlin. The melatonin and placebo (mannitol filler) were administered orally to patients as hard-gelatine capsules, which were indistinguishable from one another in terms of appearance, taste and smell. The capsules provided for bioavailability within 30 min of ingestion. All capsules were dispensed using identical, light-resistant bottles labelled ‘Part I’ or ‘Part II’. The Department of Pharmaceutics supplied a computer-generated randomization list and sealed data regarding patient allocation in envelopes separately for each subject. The study code was broken only after all study procedures had been terminated.

After diagnostic PSG, patients were assigned randomly to one of two groups: a treatment group receiving 3 mg of melatonin daily for 4 weeks or a placebo group. We referred to this part of our study as ‘Part I’. After a 3- to 5-day washout period, patients treated with melatonin during Part I received placebo, and patients treated with placebo during Part I received melatonin for 4 weeks. We referred to this second part of our study as ‘Part II’. Throughout the entire study, patients remained in their natural environment and were asked not to change their daily routines. Patients were instructed to take melatonin between 22:00 h and 23:00 h and to go to bed within 30 min of melatonin administration. However, because adherence to such a strict schedule is not always feasible in a naturalistic setting, patients were also allowed to take melatonin as late as 23:30 h, but only if absolutely necessary. If they were unable to meet these intake requirements on any particular evening, patients were instructed to skip their dose of study medication on that evening. Poor sleep hygiene (an exclusion criterion) was defined as not going to bed at the instructed time for more than three nights within one treatment period, or once within 5 days of PSG. Sleep hygiene was monitored during Parts I and II of the study by actigraphy (ZAK, Kirchdorf/Inn, Germany) and a patient sleep log.

An adaptation night and a PSG recording night were performed three times in all patients: once at baseline, once at the end (i.e. the last two nights) of Part I and once at the end (i.e. the last two nights) of Part II. Between the adaptation and recording nights, participants left the clinical research centre to attend to their normal activities. Patients were asked to refrain from napping (controlled for by actigraphy), exercise and alcohol consumption. On the same day, they returned to the clinical research centre at 20:00 h and remained there until 08:30 h.

Study procedures

Study procedures were identical for the adaptation and recording nights, with the exception that no electroencephalogram (EEG), electro-oculogram (EOG) or electromyogram (EMG) recordings were made during the adaptation nights. Patients slept in windowless, completely dark, sound attenuated, air-conditioned single bedrooms. PSG included a standard 19-channel montage for scoring sleep stages: horizontal and vertical EOG, five central and occipital EEG leads, four EMG leads (mental, submental, tibiales left and right), ECG, snore microphone, bed actometry, nasal/oral airflow and thoracic respiratory effort. Signals were digitized and recorded using the Walter Graphtek paperless PL-EEG (Lübeck, Germany). Rectal temperature was measured continuously using a disposable thermistor (Yellow Springs Instrument,Yellow springs, OH, USA) and recorded at 30-s intervals. Prior to the adaptation night, clinical global impression (CGI) (National Institute of Mental Health, 1970) was assessed. Starting before the adaptation night and concluding at the end of the last PSG night, urine samples were collected after each of five time-periods (for protocol, see Mahlberg et al., 2006a). The urinary concentrations of 6-sulphatoxymelatonin (aMT6s) were measured in duplicate using a highly sensitive, competitive enzyme-linked immunosorbent assay (ELISA) kit (IBL Hamburg, Germany; sensitivity: 1.7 ng mL−1; intra-assay variation: 4–9%; interassay variation: 9–12%).

All PSGs were scored visually (30-s epochs) (Rechtschaffen and Kales, 1968) by the same highly experienced scorer. The scorer was blinded to all patient data (e.g. age, gender, disease, and in which part of the study patients received melatonin or placebo. Because muscle atonia is deficient in RBD patients, REM sleep was scored according to the rules of Rechtschaffen and Kales, but without the instructions regarding submental EMG. REM sleep without atonia and phasic REM sleep muscle activity were assessed using the criteria of Lapierre and Montplaisir (1992).

Outcome measures

Our primary outcome measures with respect to efficacy were: (i) percentage of REM sleep epochs without muscle atonia; and (ii) clinical relevance as measured by CGI.

Statistical analysis

Based on data from a pilot study (Kunz and Bes, 1999), the sample size required to prove the significance of a reduction in the percentage of REM sleep epochs without muscle atonia was calculated to be five for each group (α-power: 0.05, β-error: 0.2). Because of the low toxicity of melatonin the dropout rate was expected to be low, and the total sample size was determined to be 12.

Because the effects of melatonin on REM sleep have been shown to persist beyond the period of melatonin administration (Kunz et al. 2004), the effects of melatonin from both parts of the study were pooled and compared to baseline. Data are expressed as means ± standard deviation (SD). Data were analysed for statistical significance using the Wilcoxon test. The level of significance was set at < 0.05.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Because of administrative changes in our psychiatric department, the study was terminated before all 12 patients had been randomized. At the time of study termination, a total of eight patients had been randomized and had completed all study procedures. Three patients had been assigned randomly to placebo in Part I, and five patients had been assigned randomly to placebo in Part II. Data are given in Table 1 for baseline, melatonin and placebo for all subjects. To evaluate the enduring effects of melatonin (i.e. beyond the period of melatonin administration itself), changes from baseline to placebo are given separately for the placebo group in Part I (i.e. prior to melatonin) and the placebo group in Part II (i.e. after melatonin).

Table 1.   Demographics and clinical results of eight RBD patients with melatonin
PatientAgeGenderDuration of RBD (years)Clinical improvement of RBDConcomittant disorder
  1. PLMD, periodic limb movement disorder.

159Male20MuchNarcolepsy, PLMD (30 years)
226Male6No dream outactingNarcolepsy, PLMD (9 years)
337Male6MuchIdiopathic insomnia (20 years)
455Male10MuchIdiopathic insomnia (30 years)
559Male5LittleNone
663Male5No dream outactingParkinson’s (4 years)
764Male5No dream outactingNone
867Male8No dream outactingNone

None of the eight patients evaluated in our study failed to take their medication more than once during any one treatment period. Patients maintained good sleep hygiene as indicated by the low SD in bedtimes recorded by means of individual sleep logs and actigraphy. The 24-h excretion of aMT6s in urine at baseline was 28 μg on average (range 15–42 μg), which is similar to the 24-h excretion observed in patient groups in our earlier studies (Kunz and Bes, 1999, 2001; Kunz et al. 1999, 2004).

Except for a reduction in sleep-onset latency, placebo in Part I did not affect sleep significantly (Table 2: baseline versus placebo). Compared to baseline (Table 2: baseline versus melatonin), melatonin reduced sleep-onset latency significantly and the percentage of REM sleep epochs without muscle atonia. We were unable to observe significant changes in any of the other sleep variables evaluated in our study. Melatonin did not change REM density or phasic muscle activity during REM sleep, but did improve the CGI score significantly. Melatonin did not change REM latency consistently or time of temperature minimum [baseline: 04:30 h (SD = 2 h 40 min); melatonin: 04:32 h (SD = 2 h 44 min); placebo: 04:39 h (SD = 2 h 45 min)], indicating that the circadian phase also remained unchanged. When the results of placebo in Part II are compared to baseline (Table 2: placebo II), the effects on REM sleep epochs without muscle atonia still remained significantly different (= 0.043). This would seem to indicate that melatonin has an enduring effect that outlasts the actual period of melatonin administration.

Table 2.   Effects of melatonin on sleep in patients with RBD
 BaselineMelatoninPlaceboPlacebo I – Baseline*Placebo II – Baseline*Baseline vs. MelatoninBaseline vs. PlaceboMelatonin vs. Placebo
n = 8n = 8n = 8n = 3n = 5n = 8n = 8n = 8
Mean SDZ (Wilcoxon test) P
  1. Numbers refer to means ± SD; CGI numbers: median and inter-quartile range (value of 25–75% range of raw data numbers on a continuous scale); numbers refer to means ± SD of difference between baseline- and placebo-values; ‘%’ are expressed as percentage of SPT; SOL – sleep onset latency, interval between lights off and first epoch sleep other than stage NREM 1; REM-Lat – REM onset latency, interval between SOL and first epoch stage REM; SPT – sleep period time, interval between first and last epoch stage NREM 2, 3, 4 or REM; TST – total sleep time, sum of all epochs NREM 1, 2, 3, 4, REM; SE – sleep efficiency, percentage of TST on SPT; WASO – wake after sleep onset; SWS – slow-wave sleep (NREM 3 + 4); REM-density – percentage of 3-s mini-epochs REM with at least one REM; Phasic Muscle Twitches – percentage of 3-s mini-epochs REM with at least one muscle twitch; REMwM – percentage of REM-epochs with more than 50 percent of the epoch with muscletone; CGI – clinical global impression; bold numbers represent significant results.

SOL (min)26.615.017.3−6.5−10.91.962.03−0.56
19.114.39.710.111.60.0500.0430.58
REM-Lat (min)77.086.184.6−18.323.1−0.70−0.676−0.11
48.344.665.627.326.90.4830.4990.917
SPT (min)500.0479.9493.0−5.7−7.8−0.98−0.14−1.26
53.6917.039.582.529.80.3270.8990.207
TST (min)402.2417.0378.87.5−41.9−0.42−0.70−1.40
76.763.485.129.765.40.6740.4840.161
SE (%)79.586.476.43.4−7.1−1.40−0.701.96
12.011.816.112.215.40.1610.4840.050
WASO (%)19.513.323.0−3.27.5−1.26−0.70−1.54
12.811.816.612.116.20.2080.4840.123
NREM1 (%)16.017.616.01.1−0.8−0.56−0.28−0.70
5.34.45.64.43.10.5750.7790.484
NREM2 (%)36.237.632.8−1.7−4.6−0.42−0.84−1.26
14.416.413.411.49.10.6740.4010.208
SWS (%)8.17.610.23.61.2−0.14−1.12−1.68
5.55.76.85.96.00.8890.2630.093+
REM (%)19.019.316.7−1.0−3.2−0.42−0.70−1.54
4.05.54.40.47.80.6740.4840.123
REM-Density (%)50.252.352.5−1.54.5−1.26−0.84−0.14
11.515.111.412.88.20.2080.4010.889
Phasic muscle twitches (%)48.648.349.81.890.83−0.42−0.28−0.98
26.225.425.57.858.310.6740.7790.327
REMwM (%)39.226.830.64.0−16.22.52−1.26−0.84
23.520.915.615.017.60.0120.2080.401
CGI-Severity6.14.65.6−0.3−0.62.264−1.63−1.54
0.81.20.90.60.90.0240.1020.123
CGI-Change3.34.52.157
1.20.80.031

A total of seven of eight patients reported clear improvements in symptoms during melatonin treatment, and four of these seven were free of clinical RBD symptoms at the end of the treatment period according to their own and their bed partner’s reports. One patient reported slight improvements in RBD symptoms, but felt unchanged with regard to daytime symptoms. Improvements started during the first week of active treatment and increased gradually during the 4-week treatment period. None of the responders reported having frightening dreams, nor did any of them fall or jump out of bed after 4 days of treatment had passed. No adverse events or side effects were reported. All patients were able to distinguish placebo from verum based on a reduction in dream mentation and/or the fact that they felt more refreshed in the morning. The most frequently cited subjective changes during melatonin treatment were a reduction in daytime fatigue (n = 3), a stronger sense of feeling refreshed after awakening (n = 5) and increased sleepiness in the evening (n = 3).

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Our data represent the first placebo-controlled clinical treatment study of RBD. Clonazepam, the most widely accepted therapy in the treatment of RBD today, reduces phasic muscle activity (Lapierre and Montplaisir, 1992). In contrast, melatonin increases the number of epochs scored as REM sleep without muscle atonia. Thus, melatonin seems to have a different mode of action in patients suffering from RBD than clonazepam.

Although generated in an ultradian manner, expressions of REM sleep such as REM sleep latency, REM sleep episode length and REM continuity are under strong circadian control (Bes et al., 1996; Dijk and Czeisler, 1995; Wurts and Edgar, 2000). However, melatonin clearly influences REM sleep. Melatonin administered during the early evening hours to healthy subjects changes REM latency and lengthens the first REM sleep episode (Cajochen et al., 1997). Low endogenous melatonin is accompanied with reduced REM sleep duration (Mahlberg et al., 2008). Exogenous melatonin also increases REM sleep percentage to normal levels in patients with reduced REM sleep duration and re-organizes REM sleep episode length during night-time sleep (Kunz et al. 2004). Beta-blockers decrease melatonin excretion and reduce the number of REM sleep epochs simultaneously, which can be reversed by exogenous melatonin (van den Heuvel et al., 1997).

One striking finding in patients treated with melatonin in comparison to those treated with clonazepam is the enduring effect of melatonin. The symptoms of RBD re-occur immediately after clonazepam is discontinued (Schenck and Mahowald, 2002). In the present study, the positive clinical and neurophysiological effects in the five patients treated with melatonin in Part I extended into Part II (i.e. the placebo part) of the trial; in other words, the effects of melatonin lasted for at least 5 weeks. We and others have reported a resolution of clinical RBD symptoms lasting for up to 3 years after discontinuation of melatonin treatment (Boeve, 2001; Kunz and Bes, 1999).

RBD occurs frequently in dementia (Gagnon et al., 2006a, 2006b; Iranzo et al., 2006). Demented patients frequently experience so-called sundowning and night-time agitation, which respond to melatonin administration in the evening (Mahlberg et al., 2004; Mishima et al., 2000), as well as to light treatment during the day (Mishima et al., 2000; Someren van et al., 1997).

Some caveats need to be considered: only a small sample size was included, thus questioning generalizability. Nevertheless, the study was confirmatory and patients were included unselected in a consecutive manner. Only one night of polysomnography was included in the evaluation for each phase. However, no reports exist on a high night-to-night variation of REM sleep muscle atonia.

It should be emphasized that our RBD patients differ partly from others reported in the literature in terms of the severity of their clinical symptoms. In most of our patients, RBD was identified by chance at an early stage. Of our eight subjects, only one was suffering from Parkinson’s disease and five had idiopathic RBD. Except for the two narcolepsy patients, most patients had contacted the sleep clinic primarily for unrestorative sleep. Most RBD patients in other studies contacted the sleep clinic because they had been acting out their dreams, which indicates more severe disease. Accordingly, the percentage of REM sleep epochs without muscle atonia in these patients was higher than in our sample. In our experience, melatonin improves RBD symptoms in neurodegenerative disorders, but we observed a complete resolution of symptoms only in idiopathic RBD patients. Thus, it may well be that combining melatonin and clonazepam will produce superior results, especially in neurodegenerative disorders.

Melatonin did not cure RBD in our patients. Four of our patients exhibited complete clinical resolution of RBD behaviour, two showed marked improvement, one showed little improvement, and one remained unchanged. REM sleep without muscle atonia did not resolve completely in any of the subjects. Elsewhere we have published a case report on a patient who showed gradual improvements over the course of 3 months (Kunz and Bes, 1997). Thus, it needs to be determined whether a longer period of melatonin treatment might result in even better results.

In conclusion, our data show that melatonin is effective, both clinically and neurophysiologically, in RBD patients. Because it has been postulated that RBD is a predictor and early marker of neurodegenerative diseases (Boeve et al., 1998; Gagnon et al., 2006a; Iranzo et al., 2006; Schenck et al., 1996; Turek and Dugovic, 2005), melatonin may prove beneficial in these disorders. The exact dosage and duration of therapy still need to be determined.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References
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