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Abstract
The pineal hormone melatonin plays a major role in numerous physiological functions such as circadian sleep-wake rhythm, mood, immunity, and reproduction. Patients on hemodialysis (HD) frequently suffer from sleep and psychiatric disturbances. The aim of this study is to assess the effect of exogenous oral melatonin in HD patients regarding sleep disturbances, depression, and anxiety alongside the quality of life (QoL). In this randomized double-blind placebo-controlled study, 60 stable HD patients suffering from sleep disorders [according to Pittsburgh sleep quality index (PSQI) equal or more than 5] were randomized to receive melatonin 3 mg at 10 pm every night or placebo tablets for three months. Routine laboratory investigations were done, moreover, patients were asked to fill the following six questionnaires at the beginning of the study and after three months of treatment; PSQI, Epworth Sleepiness Scale (ESS), and the Insomnia Severity Index (ISI) to assess sleep disorders, assessment of depression by Hamilton Depression Rating Scale (HDRS), assessment of anxiety by Hamilton Anxiety Rating Scale (HARS), and assessment of QoL using Quality of Life Index-dialysis version (QLI). This study showed a significant improvement in serum calcium, low-density lipoprotein level (P ≤0.005), and scores of HDRS, HARS, and total QLI in the melatonintreated group (P ≤0.001, 0.001, and 0.002, respectively). Moreover, there was a highly significant improvement in sleep disorders in melatonin-treated patients regarding total score of PSQI, ISI, subjective sleep quality, and daytime dysfunction (P ≤0.001), also regarding sleep duration, latency, and disturbances (P ≤0.05). However, there was no significant difference in sleep efficiency and ESS scores. Exogenous melatonin treatment was well-tolerated, safe, and efficient in improving sleep disturbances, depression, anxiety, and QoL in HD patients.
Introduction 
Sleep disturbances which are common among end-stage renal disease (ESRD) patients are associated with reduced quality of life (QoL) and higher mortality rates.[1] Studies of patients on hemodialysis (HD) have found that 50%–80% report some sleep complaints or excessive daytime somnolence suggestive of poor sleep quality.[2] In a study done at Urology and Nephrology Center, Mansoura University, Egypt, insomnia was the most common sleep abnormality noted in 65.9% of HD patients and proper management of sleep disorders showed a positive effect on QoL in those patients.[3] The etiology of sleep disturbances in HD patients is not fully known, but various conditions including dialysis, medications, fatigue, metabolic abnormalities, malnutrition, muscle cramps, peripheral neuropathy, and emotional problems can affect the normal sleep pattern in ESRD patients.[4] Moreover, sleep disturbances can be considered as a state of chronic stress that may negatively affect the QoL with all domains, and hence the reported high prevalence of depression and anxiety in these patients should not be surprising.[5]
Depression and anxiety are the primary psychiatric problems encountered in patients with ESRD.[6] Based on self-report depression scales, depressive symptoms are present in 8.1%–65.4% of HD patients.[7] When depression accompanies medical conditions, this is generally associated with reduced QoL, more symptom burden, more disability, and low adherence to medical treatment.[8]
Melatonin is a neuroendocrine hormone which is known for its role in the regulation of the circadian sleep-wake rhythm. In physiologic conditions, its plasma concentration trials a circadian rhythm, with low levels during the day and high levels at night, so it has been called the darkness hormone. The vital role of melatonin as a modulator of sleep is well acknowledged. Furthermore, disturbances in the levels of melatonin have been documented with circadian rhythm sleep disorders. An absence of a nocturnal rise in melatonin concentration in daytime HD patients has been described earlier.[9] Melatonin also has a sedative, anxiolytic, antidepressant, analgesic, antihypertensive, anti-inflammatory, and oncostatic effect.[8]
Exogenous melatonin may lead to improvement of sleep-wake rhythm disturbances in HD patients.[10] However, its role in improving depression and anxiety in HD patients is still unknown.
To the best of our knowledge, there is neither a clinical trial about the effect of exogenous melatonin on depression nor anxiety in HD patients. The aim of this work is to study the effect of exogenous melatonin on sleep disturbance, depression, anxiety, and QoL in HD patients.
Patients and Methods This study is a randomized, double-blind, placebo-controlled study on end-stage kidney disease patients on HD who were selected from attendees of the dialysis unit, Internal Medicine Department, Mansoura University and Talkha Central Hospital, Egypt. The study was conducted between May 2015 and May 2016, and included adult patients of both sexes, on a regular HD program for at least one year with a stable medical condition (no hospital admission) within the last three months. Only HD patients with baseline Pittsburgh sleep quality index (PSQI) 5 or more (denoting sleep disturbance) were selected. While patients with advanced liver disease (Child-Pugh C), major illness (malignancy, uncontrolled heart failure, and active infection), chronic obstructive pulmonary disease, pregnancy, morbid obesity (body mass index >40), endocrine dysfunction, psychosis, and patients on hypnotics were excluded from the study. Consents were obtained from the patients after clarifying to them the aim of the study, the importance of data they are going to offer, and that these data are confidential. The research project is approved by the Human Research Ethics Committee of the Mansoura University.
At the start of the study, we interviewed 78 HD patients who agreed to participate in the study, and then they fulfilled questionnaires to screen for sleep disturbances, depression, and anxiety. Seventy patients of them scored ≥5 in the PSQI denoting that they have sleep disturbance. Only 60 patients met the inclusion criteria and were enrolled in the study. Patients were asked to fill questionnaires at the beginning of the study and after three months of treatment. Patients were randomly assigned into two groups; melatonin group and placebo group. The melatonin group (including 30 patients) received immediate release tablets of 3 mg melatonin (Puritans Pride, USA) at 10 pm every night and the control placebo group (30 patients) received placebo for three months.
Randomization was simple and balanced (1:1) and carried by a nurse through sealed, unlabeled, opaque, and identical containers. The patients and investigators were blinded to group assignment. At the end of the study, seven patients were dropped, three patients from the melatonin group and form patients from the placebo group. The cause of dropout was either due to death (3 patients), noncompliance (1 patient), or adverse effects (1 patient with skin rash and 2 patients due to excessive daytime sleepiness). Fifty-three patients completed the study, 27 patients representing the melatonin group and 26 patients representing the placebo group.
All patients were subjected to history taking, clinical examination, and neuropsychiatric examination. Laboratory investigations included complete blood count, serum creatinine, calorimetric determination of serum albumin, alanine aminotransferase, aspartate aminotransferase (AST), total bilirubin, total cholesterol, triglycerides, high-density lipoprotein (HDL)-cholesterol, and low-density lipoprotein (LDL)-cholesterol calculation using the Friedewald formula: LDL-cholesterol = Total cholesterol - HDL-cholesterol - (triglycerides/2.2).[11] Serum total calcium, phosphorus, and intact parathyroid hormone measured by two-site or sandwich immunoassays (normal value: 10–65 pg/mL).[12]
Assessment of sleep disorders using three questionnaires:
The PSQI is a 19-item self-report questionnaire used for the evaluation of subjective sleep quality over the past month. The 19 questions are joined into seven clinically derived component scores; each one is given a value between 0 and 3. All scores are summed to get a global score between 0 and 21, with higher scores signifying poor sleep quality. The psychometric and clinical properties of the PSQI have been properly assessed by numerous research groups. The PSQI has a sensitivity of 89.6% and specificity of 86.5% for detecting patients with sleep disorder, with a cut-off score of 5. Its validity is supported by similar differences between groups using PSQI or polysomnography (PSG). The PSQI has been translated into 48 languages and has been used in a wide range of population and clinical studies.[13] The Arabic PSQI demonstrated preliminary reliability evidence and good convergent validity.[14]
The Epworth Sleepiness Scale (ESS) is an 8-item self-report scale of excessive daytime sleepiness. Subjects indicate on a four-point Liker t-type scale (0 = never, 3 = high chance) the possibility that they will fall asleep in eight different unsuitable conditions. Answers are summed to give a total score from 0 to 24, with higher scores signifying excessive sleepiness throughout daily activities. ESS total scores of >10 indicate excessive daytime sleepiness.[15] The validated Arabic ESS questionnaire was just as good as its English counterpart.[16]
The Insomnia Severity Index (ISI) is a 7-item self-report questionnaire that was constructed to measure the severity of daytime and nighttime components of insomnia. It is available in many languages and is widely used as a metric of treatment response in clinical research. The evaluated period is the “last month” and the dimensions assessed are the severity of sleep onset, sleep maintenance, and problems of sleep dissatisfaction, early morning awakening, interference of sleep problems with daytime functioning, noticeability of sleep problems by others, and distress due to the sleep difficulties. A 5-point Likert scale is used to value each item (e.g., 0 = no problem; 4 = very severe problem), giving a sum ranging from 0 to 28. The total score is interpreted as follows: no insomnia (0–7); subthreshold insomnia (8–14); moderate insomnia (15–21); and severe insomnia (22–28).[17] The Arabic version of the ISI is valid and reliable tool.[18]
Assessment of depression using Hamilton Depression Rating Scale
The Hamilton Depression Rating Scale (HDRS) has been the most commonly used scale to divide patients into groups according to depression severity and inspect the treatment effects of symptom severity.[19] The HDRS contains 17 variables measured either on five-pointer or three-point scales, the latter being used when quantification of the variable is hard or impossible. No difference is made between intensity and frequency of symptom, the examiner having to weight both of them to make his judgment.[20] Scores between 0 and 7 signify no depression, 8–16 signifies mild depression, 17–23 signifies moderate depression and ≥24 signifies severe depression.[19]
Assessment of anxiety using Hamilton Anxiety Rating Scale
The Hamilton Anxiety Rating Scale (HARS) was one of the first rating scales created to rate the severity of anxiety symptoms and is still commonly used these days in both clinical and research settings. The scale is made of 14 items; each defined by a series of symptoms and assesses psychic (mental agitation and psychological distress) and somatic anxiety (physical complaints related to anxiety). Although the HARS remains commonly used as an outcome measure in clinical trials, it has been criticized for its sometimes reduced ability to differentiate between anxiolytic and antidepressant effects and somatic anxiety versus somatic side effects.[21] Scale consists of 14 items with a total score range of 0–56, where 0–5 indicates no anxiety, 6–14 indicates mild anxiety, 15–28 indicates moderate anxiety, and ≥29 indicates severe anxiety.[22] The Arabic version was prepared and standardized by Fateem (1998).[23]
Assessment of quality of life using the quality of life index-dialysis version
The quality of life index (QLI) is designed to assess the patients’ perceived level of social support and QoL. QLI is divided into two parts with 35 items each and uses a 6-point Likert scale: the first part measures satisfaction (1 = very dissatisfied, 6 = very satisfied) with multiple aspects of life, and the second part measures the importance of the aspects to the patient (1 = very unimportant, 6 = very important). Scores from the first part are weighted with scores from the second part. The items are grouped into four subscales: health-functioning, socioeconomic, psychological-spiritual, and family. The higher the score, the higher is the QoL of patient.[24] The range for the final scores is the same for all subscales and the total score. Total scores may be categorized into desirable (score: 20–30), relatively desirable (score: 10–19), and unfavorable (score: 0–9).[25] The Arabic version showed a high degree of precision of the translation when back-translated into English and this validated the Arabic version to a great degree. However, some points were still of concern and needed more refinement and clarification.[26]
Statistical Analysis Data were tabulated, coded, then analyzed using IBM SPSS Statistics version 23.0 (IBM Corp., Armonk, NY, USA). Descriptive statistics were calculated as mean ± standard deviation (SD), median and interquartile range, and frequency (number-percent).
In the statistical comparison between the different groups, the significance of difference was tested using one of the following tests; Student’s t-test (unpaired) used to compare between means of two different groups of numerical (parametric) data, Mann–Whitney used to compare between different groups of non-parametric data and intergroup comparison of categorical data was performed using Pearson’s Chi-square test (χ[2] value) or Fisher’s exact test as indicated. Pearson’s correlation coefficient was used to measure the linear correlation between variables. A P <0.05 was considered statistically significant.
Results This study is a randomized, double-blind, placebo-controlled study completed on 53 patients (47.2% males and 48.8% females, with a mean age of 54.49 ± 14.51 years), the patients were randomly classified into two groups; the melatonin group (27 patients) received immediate release tablets of 3 mg melatonin every night and the placebo group (26 patients) received placebo for three months. Both groups are matched as regards age (55.19 ± 14.93 vs. 53.77 ± 14.33) and sex.
Seventy-eight patients fulfilled the baseline PSQI questionnaires; 70 of them scored ≥5 (denoting sleep disturbances in 89.7% of patients). Insomnia was found in 67 patients (85.8%) and excessive daytime sleepiness in 22 patients (28%). All of the 78 patients have depression (100%) ranging from mild (14 patients = 18%) to moderate (25 patients = 32%) and severe (39 patients = 50%). Seventy-seven patients have anxiety (98.7%), mild anxiety (10 patients = 13%), moderate (37 patients = 48%), and severe (30 patients = 39%). Sixty patients met the inclusion criteria and were enrolled in the study, while only 53 patients completed it.
Melatonin and placebo groups were matched at the baseline laboratory investigations except for platelet count and AST level which were higher in the melatonin group. After three months of treatment, there was a significant increase in serum calcium and a significant decrease in LDL in the melatonin group compared to placebo group, as shown in [Table 1] and [Table 2].
Table 1: Comparison of laboratory data between placebo and melatonin groups before and after treatment.
Table 2: Comparison of laboratory data between placebo and melatonin groups before and after treatment.As regards the scales of depression, anxiety, and QoL, there was no significant difference between both groups at the baseline questionnaires, but after three months of treatment there was a high significant decrease in the scores of HDRS and HARS (P ≤0.001) in the melatonin group compared to the placebo group. Further there was a significant increase in the total score of QoL index including all four subscales in the melatonin group compared to the placebo group (P <0.05) as shown in [Table 3] and [Figure 1][Figure 2][Figure 3].
Figure 1: Comparison between placebo and melatonin groups regarding Hamilton Depression Rating Scale before and after treatment.
Figure 2: Comparison between placebo and melatonin groups regarding Hamilton Anxiety Rating Scale before and after treatment.
Figure 3: Comparison between placebo and melatonin groups regarding quality of life before and after treatment.
Table 3: Comparison of scales of depression, anxiety, and quality of life between both groups before and after treatment.As regards to PSQI, ESS, and ISI scales, there was no significant difference between both groups at the baseline questionnaires before treatment. After three months of treatment, there was a high significant decrease in the total score of PSQI and ISI in the melatonin group compared to placebo (P ≤0.001). Moreover, there was a high significant decrease in the scores of subjective sleep quality and daytime dysfunction (P ≤0.001), sleep duration, latency, and disturbances (P <0.05) in the melatonin group. While there was no significant statistical difference in sleep efficiency and ESS scores between both groups as shown in [Table 4].
Table 4: Comparison between both groups regarding Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, and Insomnia Severity Index before and after treatment.[Table 5] and [Figure 4],[Figure 5] show comparisons between both groups before and after treatment regarding the severity of disorders in ESS, ISI, HAMD, HARS, and QoL scales. In the melatonin-treated group, there was a significant decrease in the number of patients with severe insomnia (P = 0.017) while there was a significant increase in the number of patients with no insomnia (P = 0.003). Further, there was a significant reduction of the number of patients with severe degree of depression and anxiety (P = 0.025, 0.03) and a significant increase in the number of patients with a mild degree of depression and anxiety (P = 0.001, 0.004, respectively). Finally, there was a significant increase in the number of patients with desirable QoL index outcome in the melatonin group compared to the placebo group (P <0.05).
Figure 4: Comparison between both groups before and after treatment regarding the severity of Insomnia Severity Index.
Figure 5: Comparison between both groups before and after treatment regarding the degree of quality of life.
Table 5: Comparison between both groups before and after treatment regarding the severity of disorders in Epworth Sleepiness Scale, Insomnia Severity Index, HAMD, Hamilton Anxiety Rating Scale, and Quality of Life scales. Discussion Due to the limited data about the effect of exogenous melatonin on sleep disturbances, depression, anxiety, and QoL in HD patients, we performed this study. In our study, the prevalence of poor sleep in the studied patients using PSQI (≥5) is 89.7%, this result is close to the results of Masoumi et al and Dashti et al who reported poor sleep by PSQI in 86.6% and 87.8% of HD patients, respectively.[4],[27]
We found the prevalence of insomnia 85.8% using ISI, and excessive day sleepiness in 28% of our patients using ESS, and this is in agreement with Čengić et al who found insomnia in 84.5% and excessive day sleepiness in 34% of dialysis patients using PSQI.[28] While Chavoshi et al reported insomnia and daytime sleepiness in 25.2% and 24.2% of 397 HD patients, respectively using ISI and ESS.[29]
As regards the effect of melatonin on subjective sleep parameters, we found a significant decrease (improvement) in subjective sleep parameters and insomnia with no significant difference in ESS scores in melatonin group compared to placebo group.
The results of our study are similar to the results of Edalat-Nejad et al regarding the significant improvement of global scores of PSQI in melatonin-treated group, as well as the significant improvement in the sub-scores of sleep duration and sleep disturbance. The differences between the two studies are that our study was longer in duration and showed improvement in sleep latency and daytime dysfunction after melatonin administration with no effect on sleep efficiency.[10]
Our study is different from Koch et al in the assessment tools and number of included patients, as we used PSQI and ISI subjective questionnaires on larger group of patients with no crossover, while they used objective actigraphy and the validated Dutch sleep questionnaires on 20 patients. However, the results of our study are comparable to their results in improving sleep duration, sleep latency, and sleep disturbances.[30]
The improved sleep latency and duration by exogenous melatonin shown in our results are supported by a meta-analysis (17 studies and 284 patients) done by Brzezinski et al However, they showed improved sleep efficiency with no comment on daytime dysfunction. Moreover, this meta-analysis included healthy, insomniac, schizophrenics, and Alzheimer’s patients, but did not include renal patients.[31]
Another meta-analysis by Braam et al (nine studies including 183 individuals with intellectual disabilities) concluded that melatonin was effective in increasing the sleep duration and decreasing the sleep latency and the sleep disturbances, again this is in agreement with our results.[32]
In contrast to our results, Russcher et al studied the effect of long-term melatonin on sleep and QoL in HD patients and found no significant outcomes.[33]
The improved score of daytime dysfunction in our study agrees with the study of Garfinkel et al which was performed in diabetic patients and the study of Lemoine et al performed in insomniac patients aged 55 years or more. However, both studies used prolonged release melatonin.[34],[35]
Our study shows improvement in depression and anxiety scores in melatonin-treated group. This can be related to the improvement in insomnia and sleep quality, as we used the HDRS which assessed the insomnia symptom with three separate items with disproportionate contribution to the total score. This comes in parallel with the finding of Hansen et al who showed that oral 6 mg melatonin significantly decreased the risk of depressive symptoms and anxiety in women with breast cancer during a three-month postsurgery.[36]
Moreover, in another study, 20 patients with delayed sleep phase syndrome were divided into two groups depending on whether they had depressive symptoms. Melatonin treatment significantly improved depression scores as measured by the Center for Epidemiologic Studies Depression Scale and HDRS – 17. As well as, it improved sleep continuity in both the groups.[37]
We found a significant improvement in the total scores of the questionnaire on QoL (dialysis version, along with the four subscales (socioeconomic, health, psychic, and family) in the melatonin group compared to the placebo group. This can be attributed to the improvement of sleep, depression, and anxiety as mentioned by Parker et al whose results supported their initial hypotheses that better sleep quality and less daytime sleepiness are associated with improved QoL in stable HD subjects.[38]
Although there is an improvement of QoL, still our numbers are lower than other studies on QoL in HD patients. After treatment with melatonin, compared to a study in the United Arab Emirates (UAE), our total score of QoL is 18 while their score was 23, our health 15.6 and their score was 21.5, our socioeconomic 16.7 and their score was 23, psychic 19.7 and their score 24.2. We only are relatively close in family subscale (23.6–26), this may be due to the fact that people in Arab and Muslims countries receive huge family care when they become sick.[39] The results of Ayoub in UAE also, matched the scores of Parker.[40] The low scores of QoL in our study can be attributed to low socioeconomic status, huge financial burden, other comorbidities, the fact that dialysis can hinder social and professional life, low self-esteem, insufficient medical care, underestimation of psychological troubles, and ignorance.
Studying QoL can benefit patients to gain insight into the stressors and limitations. This will provide them with the chance to discover their coping skills. It also can help healthcare providers to make a treatment plan by setting up specific, measurable, realistic, and achievable goals.[39]
In our study, we also followed up on some of the laboratory tests of patients before and after treatment. Such as the lipid profile that showed significant improvement in the levels of LDL, this can be attributed to the antioxidant effect of melatonin. In agreement to our finding of decreased levels of LDL, Koziróg et al found a significant decrease in the level of LDL after oral intake of 5 mg melatonin daily for two months in patients with metabolic syndrome.[41] But in contrast to our results, Edalat-Nejad et al showed significant increases in HDL levels in the melatonin-treated group.[10] However, Garfinkel et al found no significant changes in lipid profile after three weeks of 2 mg melatonin treatment in 36 type 2 diabetic patients with insomnia.[35]
In our view, the variances in findings between studies could be explained by the differences in the sample size, characteristics of population, dosage of melatonin, time of administration, duration of treatment, and the tools of assessment.
Limitation of the study The only limitation in this study is our dependence on subjective sleep assessment using different questionnaires while no actigraphy or PSG was performed for objective assessment.
Conclusion Melatonin may be a safe, efficient, and good tolerated drug for the treatment of sleep disturbances and insomnia in HD patients. Furthermore, its role in improving depression, anxiety, and QoL should be noted along with the improvement in the levels of LDL.
Conflict of interest: None declared.
References 
Correspondence Address:
Elshahat Ali Yousef
Department of Internal Medicine, Faculty of Medicine, Mansoura University, Mansoura
Egypt
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/1319-2442.367802
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