Exploratory pilot study of exogenous sustained- release melatonin on nocturia in Parkinson's disease

Introduction: Nocturia is one of the commonest non- motor symptoms in Parkinson's disease (PD). Nocturia has evolved from being understood as a symptom of urological disorders or neurogenic bladder dysfunction to being considered as a form of circadian dysregulation. Exogenous melatonin is known to help circadian function and can be an effective strategy for nocturia in PD. Methods: In this open- label, single- site, exploratory, phase 2 pilot study, adults with PD and nocturia underwent assessments using standardized questionnaires, urodynamics studies and a bladder scan. This was followed by completion of a frequency volume chart (FVC) and 2- week sleep diary. Sustained- release melatonin 2 mg was then administered once- nightly for 6 weeks. A repeat assessment using questionnaires, the FVC and sleep diary was performed whilst on treatment with melatonin. Companion or bed partners filled in sleep questionnaires to assess their sleep during the intervention. Results: Twenty patients (12 males; mean age 68.2 [SD = 7.8] years; mean PD duration 8.0 [±5.5] years) with PD reporting nocturia were included. Administration of melatonin was associated with a significant reduction in the primary outcome bother related to nocturia measured using the International Consultation on Incontinence Questionnaire Nocturia (ICIQ- N) ( p = 0.01), number of episodes of nocturia per night ( p = 0.013) and average urine volume voided at night ( p = 0.013). No serious adverse events were reported. No significant improvement was noted in bed partner sleep scores. Conclusions: In this preliminary open- label study, administration of sustained- release melatonin 2 mg was found to be safe for clinical use and was associated with significant improvements in night- time frequency and nocturnal voided volumes in PD patients.


INTRODUC TI ON
Nocturia is the most commonly reported non-motor symptom in Parkinson's disease (PD) [1][2][3] and negatively impacts quality of life, affecting both patients and their carers. [4,5] Nocturia has been shown to be an important risk factor for falls and for sustaining fractures, [6] and is associated with greater cardiovascular morbidity [7] and mortality. [8] The mechanisms responsible for nocturia are uncertain; however, pathophysiological underpinnings include reduced bladder capacity, most commonly from detrusor overactivity, and increased night-time urine production, known as nocturnal polyuria (NP). [9] Specifically in PD, impairment of circadian regulation or autonomic dysfunction with nocturnal redistribution across the extracellular fluid compartments are likely contributors to nocturia. [10] The treatment options for managing nocturia are limited and include use of a daytime diuretic or desmopressin. [11,12] Circadian rhythm disturbances are common in PD and lead to sleep disturbance, insomnia and excessive daytime sleepiness. [13] The suprachiasmatic nucleus (SCN) is the seat of neurological regulation of the circadian rhythm. Melatonin is a hormone secreted from the pineal gland in response to dark that provides feedback to the SCN and helps to synchronize the circadian rhythm by affecting both the phase and amplitude of rhythmic neuronal firing. [14,15] The concept of nocturia has evolved from being a symptomatic aspect of urological disease to a form of circadian dysfunction [16] Moreover, studies have demonstrated an inverse relationship between melatonin levels and degree of nocturia. [17] Exogenous administration of melatonin has been shown to be effective in reducing night-time frequency and improve quality of life in the elderly. [18] A significant improvement in night-time frequency and nocturia-related bother was demonstrated in a cohort of men with lower urinary tract (LUT) symptoms with benign prostate enlargement. [19] Exogenous melatonin has not been evaluated in neurodegenerative disorders and the aim of this study was to explore the feasibility and efficacy of exogenous melatonin administration for the management of nocturia in PD, and the impact this has on carers.

ME THODS
In this open-label, single-site, exploratory, phase 2b pilot study, patients with a clinical diagnosis of PD (Queen Square Brain Bank criteria [20]) age >18 years and reporting more than two episodes of nocturia as per the Non-Motor Symptoms Questionnaire (NMSQuest) item 9, "Getting up regularly at night to pass urine", [21] were included. The study was approved by the National Research Ethics Service Committee London -Hampstead (REC Reference No. 15/LO/0441). All patients and carers participating in the study were provided with written information and informed consent was obtained, and the trial adhered to the CONSORT statement. Patients with cognitive impairment, a history suggestive of rapid eye movement (REM) sleep behaviour disorder, congestive heart failure, liver failure or kidney failure, uncontrolled diabetes, presence of urinary tract infection, incomplete bladder emptying or presence of significantly enlarged prostate were excluded. The detailed selection criteria (inclusion and exclusion) and plan of study visits and investigations are provided in Appendix 1.
Patients completed the following questionnaires and diaries: Questionnaire-Nocturia) is a validated tool for evaluating nocturia frequency as well as nocturia-related bother. [22] • Urinary Symptom Profile (USP) is a standardized questionnaire assessing LUT symptoms in terms of Overactive Bladder (OAB), Low Stream (LS) and Stress Incontinence (SI) symptoms. [23] • SF Qualiveen is an eight-item validated questionnaire that evaluates LUT symptoms-related quality of life. [24] • EQ-5D is a standardized questionnaire evaluating generic health status and quality of life. [25] • PD Sleep Scale (PDSS) [26] and Pittsburgh Sleep Quality Index [27] are standardized sleep questionnaires that have been validated to capture sleep-related parameters and quality of sleep.
• Three-day frequency volume chart (FVC) that recorded voiding times, fluid intake and respective volumes. The nocturnal polyuria index (NPi) was calculated as nocturnal urine volume (NUV) divided by 24-hour urine volume and is normally <33%.
• A 14-day sleep diary was used to record the number of awakenings at night.

Statistical plan
This was a pilot study, and in the absence of clinical studies evaluating the effects of treatment on nocturia in PD, no sample size could be calculated.
Normality of data was checked at baseline and after intervention.
If data were normally distributed, differences between the outcome measures at baseline and post-intervention were compared using the two independent sample t-test. If at least one variable (baseline or post-intervention) was not normally distributed, differences between the outcome measures at baseline and post-intervention were compared using the non-parametric Wilcoxon signed-ranked test. Differences were considered statistically significant for p values <0.05.

RE SULTS
Twenty patients (

Primary outcomes
Administration of melatonin was associated with a significant reduction in bother related to nocturia measured using the ICIQ-N with a decrease in the score from 7 ± 2.08 at week 0 to 4 ± 2.6 at week 6 (p = 0.01) ( Table 1).
One patient discontinued melatonin because of insomnia.

DISCUSS ION
The results of this open-label pilot study suggest that the use of lowdose sustained-release melatonin was associated with improvement of the primary outcome, namely nocturia-related bother. Melatonin reduced night-time urinary frequency as per the questionnaire.
These improvements were associated with improvements in different sleep parameters. There was no impact on daytime symptoms.
In health, a reduction of urine production nocturnally is mediated by alterations in sodium handling. Moreover, a greater bladder storage capacity at night accommodates urine that is produced. [17] This ensures that sleep is not disturbed by the need to void. Nocturia can result from reduced bladder capacity due to poor compliance or detrusor overactivity. In PD, nocturia can also result from NP and in an earlier study we reported an NPi as high as 0.81 (normal <0.33). [29] NP can be associated with increased solute excretion (osmotic diuresis) or excessive free water clearance [30] NP is uncertain and increased nocturnal urine production has been found to be associated with raised daytime arterial blood pressures and reduced plasma levels of angiotensin II and arginine vasopressin. [31] Natriuresis at night was attributed to suppressed levels of plasma angiotensin II. [31] Though this open-label study was not designed to determine the mechanisms underpinning this improvement, the reduction of nocturnal voided urine volumes suggests the benefit could be due to reduced urinary volume at night possibly through the effects of melatonin on circadian control. The SCN regulates the central circadian clock, [15] and also entrains peripheral clocks in different visceral organs including the kidneys. [30] Renal sodium and water excretion is regulated by circadian biological rhythms and the 20-HETE synthesis pathway is one of the principal renal targets. [32,33] Proteins associated with the 20-HETE synthesis pathway are involved in the regulation of the renal transport genes and thereby can modulate the circadian fluctuations in renal excretion. [

ACK N OWLED G EM ENTS
The study was funded by Parkinson's UK through project grant K- Saurabh Prakash in preparing the database for the study, and the patients involved in designing and participating in the study.  Writing-review & editing (lead).

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available in the supplementary material of this article (Appendix 1). Further data that support the findings of this study are available from the corresponding author upon reasonable request. The trial was registered with EudraCT (Reference: 2014-002697-37) and ClinicalTrials.gov (Identifier: NCT02359448). The study data and results are available in the public domain. [43] O RCI D Amit Batla https://orcid.org/0000-0001-8952-2160