Introduction
Sleep problems are recognized in more than 60% of patients with Parkinson’s disease (PD) and have been related to a worse quality of life (QoL) and greater PD non-motor symptoms (NMS) burden [
1,
2]. Degenerative processes in the sleep–wake regulatory brainstem centers and hypothalamic nuclei have been proposed as possible causes of sleep-related symptoms in PD [
3].
Among sleep-related symptoms, insomnia is considered a common NMS in PD [
4], which can markedly affect motor symptoms and impair patients’ QoL [
2,
4]. Moreover, in patients with PD, insomnia has been described more frequently than other sleep disorders and can appear concomitantly with excessive daytime sleepiness (EDS) or rapid eye movement (REM) sleep behavior disorder [
4,
5]. Moreover, insomnia in PD may also cause EDS in a bidirectional relation or even represents a part of a circadian sleep–wake rhythm dysregulation [
4]. The typical manifestations of insomnia in PD patients are sleep-onset insomnia, sleep fragmentation, and early awakening in the morning, which may be triggered by the nocturnal worsening of motor symptoms, their re-emergence in the nighttime, and the wearing off phenomenon in motor fluctuating PD patients [
6].
In PD, the risk factors for insomnia include the co-existence of other NMS such as depression, anxiety, and cognitive impairment, the use of dopamine agonists, the severity of motor impairment, and long disease duration [
7,
8]. However, insomnia can also happen in the earliest stages of the disease in untreated patients [
9] and thus increase in frequency and severity once dopaminergic treatment is started.
Insomnia treatment in PD patients is still challenging since validated drugs have not yet been approved, although long-acting dopamine agonists, such as rotigotine, proved to be useful for treating PD sleep-related symptoms [
10,
11]. Considering the unsuccessful trials with non-benzodiazepine hypnotics and the unrecommended long-lasting use of benzodiazepine in PD [
12,
13], melatonin may represent a newsworthy candidate to treat insomnia in patients with PD [
14]. In this framework, clinical studies showed the effectiveness of melatonin, also in the prolonged-release (PR) formulation, in the treatment of insomnia in patients with PD [
14,
15]. Furthermore, experimental studies suggested the positive effect of melatonin on neurodegenerative processes in PD animal models [
16‐
20], whereas more recent clinical data propose a favorable influence of melatonin on PD NMS [
14,
15,
21]. Although there are reports of PD patients experiencing a beneficial effect of sleep on motor mobility, the efficacy of melatonin on motor symptoms is still under debate [
14,
22].
Despite the high prevalence and detrimental effect of insomnia in PD, this line of research was not extended to identify treatments to improve sleep. Therefore, considering the proposed effects of melatonin on sleep and motor symptoms in PD, the present pilot study aimed at evaluating the effects of a 3-month treatment with 2 mg melatonin PR on sleep and motor disability in PD patients.
Results
Twelve patients with PD ranging from H&Y stage I to III and under stable antiparkinsonian treatment were included in the study. Males represent most of the sample (83.3%;
n = 10), and females were two (16.7%). At T0, one patient was taking benzodiazepine medication (8.3%), and two patients were taking anti-depressive drugs (16.7%), which remained stable during the study period. Patients’ demographic and clinical characteristics are presented in Table
1.
Table 1
Demographic and clinical information of patients with PD
Males, n (%) | 10 (83.3%) |
Mean age, years | 62.83 ± 10.68 |
Disease duration, years | 6.67 ± 5.89 |
H&Y stage | 1.75 ± 0.62 |
LEDD (mg/day) | 500.42 ± 269.35 |
UPDRS-III | 21.50 ± 8.80 |
Regarding the objective sleep evaluation, the PSG parameters analysis between T0 and T1 showed that the mean values of SL significantly decreased after 3-month treatment with melatonin-PR, but no other significant differences were found. Notably, at the 3-month follow-up visit, SE improved without reaching statistical significance. All PSG data are reported in Table
2.
Table 2
PSG data from baseline to the 3-month follow-up visit
Lights off time (hh:mm:ss PM) | 11:10:33 ± 1:10:23 | 11:14:18 ± 0:56:54 | 0.386 |
Time in bed (min) | 408.93 ± 84.83 | 427.99 ± 62.86 | 0.814 |
Sleep latency (min) | 24.43 ± 45.68 | 6.13 ± 7.22 | 0.034 |
Total sleep time (min) | 316.92 ± 74.30 | 369.92 ± 65.03 | 0.136 |
Sleep efficiency (%) | 78.56 ± 13.86 | 86.11 ± 7.03 | 0.084 |
REM sleep latency (min) | 94.29 ± 46.11 | 116.96 ± 79.79 | 0.388 |
N1 (%) | 6.41 ± 3.01 | 6.74 ± 6.59 | 0.505 |
N2 (%) | 53.24 ± 10.30 | 50.10 ± 13.59 | 0.272 |
N3 (%) | 25.79 ± 12.13 | 27.98 ± 12.99 | 0.308 |
REM (%) | 14.53 ± 4.33 | 15.18 ± 7.20 | 1.000 |
WASO (min) | 92.01 ± 67.41 | 58.38 ± 28.31 | 0.117 |
The analyses of subjective sleep questionnaires, as shown in Table
3, demonstrated that melatonin PR significantly reduced the ESS scores and presented a trend of improvement at the PSQI global scores from T0 to T1. Regarding motor symptoms, a trend in reducing the UPDRS-III score was evident although no significant differences were found between baseline and 3-month follow-up (Table
3).
Table 3
Subjective sleep data and motor symptoms from baseline to the 3-month FU visit
PSQI | 8.08 ± 2.81 | 6.58 ± 2.68 | 0.057 |
PDSS-2 | 16.75 ± 5.91 | 14.42 ± 5.89 | 0.239 |
ESS | 8.75 ± 3.65 | 6.75 ± 2.86 | 0.026 |
UPDRS-III | 21.50 ± 8.80 | 20.50 ± 8.24 | 0.072 |
Regarding the PCGI scale, 33.3% of the patients considered that their insomnia symptoms had minimally improved after treatment, 25% answered that it had much improved, 16.7% reported no change, and the remaining 16.7% referred a minimally worsening after the treatment. The evaluation in terms of clinical global improvement change performed by the physician (CGI) was similar to the patients’ perception (Table
4).
Table 4
Patients’ and physicians’ clinical global improvement scores for sleep quality
PCGI | Very much improved | 1 | 8.3 |
Much improved | 3 | 25.0 |
Minimally improved | 4 | 33.3 |
No change | 2 | 16.7 |
Minimally worse | 2 | 16.7 |
Much worse | 0 | 0 |
CGI | Very much improved | 1 | 8.3 |
Much improved | 3 | 25.0 |
Minimally improved | 4 | 33.3 |
No change | 3 | 25.0 |
Minimally worse | 1 | 8.3 |
Much worse | 0 | 0 |
Finally, the D score from T0 to T1 for PDSS-2 positively correlated with the D score for the REM stage (
rho = 0.78,
p < 0.001) and negatively correlated with both the D scores for N2 (
rho = − 0.74,
p < 0.001) and LREM (
rho = − 0.63,
p < 0.05) (Table
5). The D score for PSQI negatively correlated with the D for LREM (
rho = − 0.68,
p < 0.05). The D score for UPDRS-III negatively correlated with the D for SE (
rho = − 0.89,
p < 0.001). PCGI scores were negatively correlated with LEDD (
rho = − 0.65,
p < 0.05), and D scores for LREM (
rho = − 0.70,
p < 0.05) and N2 (
rho = − 0.76,
p < 0.01), and positively correlated with D for PDSS-2 (
rho = 0.95,
p < 0.01) and REM (
rho = 0.71,
p < 0.01). CGI scores were positively correlated the D score for ESS (
rho = 0.59,
p < 0.05), UPDRS-III (
rho = 0.86,
p < 0.01), and WASO (
rho = 0.61,
p < 0.05). Moreover, CGI scores were negatively correlated with the H&Y stage (
rho = − 0.75,
p < 0.01) and with the D scores for SE (
rho = − 0.80,
p < 0.01).
Table 5
Correlations between clinical characteristics and Delta change mean scores for PSG, subjective sleep questionnaires and motor symptoms
Discussion
Sleep-related symptoms, especially insomnia, are frequently reported by patients with PD, impair their well-being, influence their daily living activities, and aggravate motor functioning [
2]. In support of the importance of maintaining sleep quality and continuity in patients with PD, the concept of sleep benefit has been established several years ago. Sleep benefit can ameliorate patients’ QoL [
40,
41], but its main effect is the reduction of motor impairment and the improvement in levodopa response. Although clinicians should target sleep benefit in patients with PD, currently available pharmacological or non-pharmacological strategies failed to ensure this positive effect [
42].
Among the different approaches for sleep disorders, melatonin has been reported to produce beneficial effects on sleep-related symptoms and non-motor symptoms in PD [
14,
15,
21,
43]. Pointedly, animal studies proved that melatonin may improve PD-related neurodegenerative processes, including dopamine cell loss, neuroinflammation, and alpha-synuclein pathology [
16‐
20]. Moreover, both research studies involving humans and clinical trials in patients with PD reported that melatonin or melatonin PR significantly improves subjective sleep quality [
14,
15,
21,
22], prolongs total sleep time measured by actigraphy [
21], and reduces the burden of NMS [
14,
15,
22]. Despite these few studies have shown that melatonin improves the quality of sleep, the effects on motor symptoms are still not clear since the improvement of UPDRS-III scores was not documented [
15,
22]. To further explore these findings and recognize the importance of targeting sleep benefit for improving PD motor and non-motor symptoms, this observational pilot study preliminary investigated the effects of melatonin PR on subjective and objective sleep related-symptoms and motor disability in a representative sample of PD patients.
The main results of the present study are the objective improvement in sleep quality, as documented by the reduction of SL, combined with the subjective improvement of daytime sleepiness, measured through ESS, a validated instrument currently used in PD patients [
44,
45], after 3 months of melatonin 2 mg PR treatment. Although not achieving the statistical significance, probably due to the small sample of patients included, a clear trend in improving SE, estimated through the PSG recording, was evident. The PSQI also presents a clear trend in reducing the total score at follow-up thus reflecting a better objective and subjective sleep quality. Notably, motor impairment evaluated the morning after the PSG recording, before anti-PD treatment administration, also presented a trend in amelioration, since scores at the UPDRS-III reduced after 3 months of melatonin 2 mg PR treatment. Combining the motor and sleep data, the documentation of a significant correlation between the improvement in SE and the reduction of UPDRS-III scores after the 3 months of treatment supports the importance of targeting sleep benefit in patients with PD.
As previously stated, melatonin treatment has been already suggested in patients with PD since its beneficial effects on both neurodegenerative processes and PD symptoms. The dysregulation of the pituitary gland and melatonin secretion has been demonstrated in PD. In particular, Videnovic and colleagues documented that the melatonin circadian rhythmicity is altered in PD patients, contributing to their excessive daytime sleepiness [
46]. The main dysregulation in circadian melatonin secretion was the reduced amplitude of the melatonin rhythm and its circulating levels [
46], possibly due to the dysfunction of the suprachiasmatic nucleus (SCN) and its afferent and efferent pathways. Moreover, an autoptic study documented the impairment of SCN in patients with in vivo diagnosis of PD, which showed the typical PD neuropathological features [
47]. These findings lead to the hypothesis that the SCN and pituitary dysfunction seem to play a role in the multi-faced etiopathology of sleep impairment in PD patients.
Therefore, the present findings, although achieved in a small sample of patients, propose melatonin PR as a beneficial treatment for sleep-related symptoms in PD patients, who can improve their motor and sleep-related PD symptoms through the sleep benefit effect, without changing antiparkinsonian treatment. Moreover, the significant reduction of daytime sleepiness after melatonin PR treatment can be also related to the restoration of the circadian melatonin secretion, which is altered in PD patients and can not be completely related to sleep impairment [
48].
The present study presents some limitations. First, the lack of a control group and the single-blinded observation requires a double-blind placebo-controlled trial to confirm this preliminary observation, although PSG raters were blinded to the subjective sleep data and to patients’ perception of sleep. Second, considering the nature of this pilot investigation, more studies are needed to confirm these findings, also contemplating wider sample sizes. In fact, the number of participants for this study is small and thus prevents the generalization of the results. Third, a quarter of patients were currently taking benzodiazepine or antidepressant drugs, which may have affected the current results, although all the treatments remained unchanged during the study period.
Although we are aware of the limitations of the present study, this study suggests the clinical potential of using melatonin 2 mg PR in PD patients to improve sleep quality, excessive daytime sleepiness, and possibly to reduce motor symptoms through the sleep benefit effect. Moreover, the improvement in sleep quality and motor symptoms was more evident in patients with lower LEDD doses and at lower H&Y stages. This finding opens the possibility to early identify sleep problems to reduce motor impairment, and also the LEDD in patients with PD. However, our results should be considered with caution since their preliminary nature.
In conclusion, although the exact mechanism to increase melatonin function and activity remains unclear, there is a growing interest in melatonin as a potential therapeutic agent in neurodegenerative disorders, including Alzheimer’s disease and PD. Therefore, melatonin presents itself as a safe therapeutic option for sleep disorders [
14,
49,
50], and the potentiality of a supplementation regimen with both melatonin and melatonin PR should be considered in PD patients for obtaining the sleep benefit on motor and non-motor symptoms.
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