Effect of Melatonin on the Sleep Quality: A Systematic Review

Introduction
Sleep is an urgent need for human health and is referred to as a reversible state of reduced consciousness and response to external stimuli. Normal healthy sleep reduces the activity of the sympathetic system, decreases the heart rate, lowers the blood pressure, and increases the activity of the parasympathetic system.
Usually, sleepers pass through 5 stages, namely stages 1 (i.e., drifting from consciousness to falling asleep), 2,3,4 (i.e., nonrapid eye movement [NREM]), and 5 (i.e., rapid eye movement [REM]).Sleep starts at stage 1 and then drifts into stages 2, 3, and 4. Stages 3 and 2 are repeated prior to drifting into stage 5. Ending with time in REM sleep, the body usually returns to stage 2. These stages are repeated for 4 or 5 times during night sleep. Generally, REM sleep occurs 90 min after the onset of sleep; however, it lasts for 10-20 min. The REM and NREM stages constitute about 15-20% and 80-50% of sleep duration, respectively (1,2). Sleep changes due to many environmental and pathogenic factors. These changes may include sleep onset, sleep duration, sleep depth, and sleep quality (3). Numerous factors, including a variety of cultural, social, psychological, behavioral, pathophysiological, and environmental ones, affect the quantity and quality of sleep patterns. Sleep quality refers to the wellness of a person’s sleep, while sleep quantity refers to the amount of sleep per night (usually defined as 7-9 h for adults) (4). Sleep disorders not only endanger the quality of life through increasing the health risks, including hypertension, type 2 diabetes, depression, obesity, and cancer, but also reduce the efficacy (5). Negative effects on public health, lack of satisfaction with life, mood disorders, disability in the performance of duties and personal affairs, occupational accidents caused by fatigue, job loss, and impaired sociofamily functioning are also other side effects of sleep disorders and chronic sleep deprivation. The circadian rhythm is a 24-hour span complex system starting from the eyes and leading to the secretion of melatonin from the pineal gland (6). The suprachiasmatic nucleus in the anterior hypothalamus sets the 24-hour day-night cycle of sleep and wakefulness for the body circadian rhythms (7). In addition to the regulation of sleep and wakefulness, the suprachiasmatic nucleus also regulates physiological and behavioral rhythms, including temperature, nutrition, 24-hour neuroendocrine, and autonomic effects (8). Melatonin or N-acetyl-5-methoxytryptamine is a hormone released from the pineal gland in the anterior suprachiasmatic nucleus of the anterior hypothalamus and sleep-dependent nerve hormone (9). Its highest secretion is about 2 in the morning and 10-100 times daily. In addition, melatonin levels are regulated by exposure to light (10, 11). Melatonin has hydrophilic and lipophilic properties and two major receptors in mammals, particularly humans, including methoxytryptamine 1 (MT1) and methoxytryptamine 2 (MT2). The main site of melatonin metabolism is the liver (12). Melatonin easily crosses the blood-brain barrier via the glycoproteins of MT1 and MT2 membrane receptors and retinoid Z receptors/retinoid orphan receptors (13,14). Both receptors are widely present in the central and peripheral nervous system and have been linked to the regulation of cell differentiation and immune response. In addition, melatonin receptors are expressed on CD4T cells, CD8T cells, and B cells. Melatonin and its metabolites also perform many physiological functions, including immunity, antioxidative activity, homeostasis, and glucose regulation (15-17). The main function of melatonin is based on a physiological signal from peripheral darkness. Following dark signaling from the environment, the pineal gland in the suprachiasmatic nucleus stimulates and induces melatonin synthesis (8). Melatonin released from the pineal gland is distributed through the bloodstream by the MT1 and MT2 receptors. Similarly, melatonin levels rise during sleep, especially at night; however, they are suppressed during the day due to light with lower levels. Therefore, melatonin is a chronobiotic (chronobiotics are able to alter the phase of daily timing and synchronization of short- and long-term circadian rhythms) with hypnotic properties that play an important role in initiating sleep and staying asleep (18). In medicine, melatonin and its agonists are only used for the treatment of insomnia; however, melatonin is also commonly utilized in other sleep disorders caused by daily rhythm (11,19,20). There are some pieces of evidence on the effect of Melatonin in the creation of a normal pattern of REM or its increased duration. It seems that Melatonin induces normal sleep (21-24). Melatonin has minimal side effects even in extremely large doses, in comparison to other sedatives and hypnotics. Moreover, it can increase the activity of T cells (25,26). In some countries, it is consumed as an over-the-counter drug. To the best of our knowledge, the results of very few studies have rejected the efficacy of melatonin on sleep quality (27).

Due to the importance of the quality of life and considering the changes in modern society that have led to increased tiredness and excessive daytime sleepiness, the assessment of the influential factors on the quality of life is highly important. The current systematic review aimed to evaluate the evidence on the effectiveness of melatonin treatment on sleep quality. In this regard, the following questions are answered in the present review:
-Does melatonin affect sleep quality?
-Is melatonin secretion effective in circadian rhythm?
-How does melatonin affect sleep quality?
 
Methods
This systematic review was conducted to assess melatonin therapy on sleep quality. The Cochrane Handbook guidelines were utilized to collect data through seven stages, including asking questions, determining eligibility criteria, searching process, eliminating unrelated articles, extracting data, evaluating the quality assessment, and discussing the topic.

Inclusion and Exclusion Criteria
This review included all the articles published in English with a focus on the effect of melatonin
melatonin therapy on sleep quality. All randomized clinical trials were included in the present review to assess the effect of melatonin on sleep in human samples. Nonrandomized clinical trials or those without a control group were excluded from the study. The papers examining the samples aged less than 18 years were also excluded (age of 18 years or older as an inclusion criterion). In addition, the studies in which the patients were treated for sleep quality using other treatments except for melatonin therapy were removed from this study. Moreover, the articles focusing on animal samples, reviews, meta-analyses, letters to the editor, case series, case reports, and experimental, qualified, narrative, and questionnaire studies were removed from the current review
performed using Gram staining and a conventional biochemical test.

Antimicrobial susceptibility testing
Antibiotic susceptibility testing was performed based on Kirby-Bauer disk diffusion method. The antibiotic discs used for this purpose included: Cefotaxime, Ceftazidime, Cefepime, Azithromycin, Erythromycin, Clindamycin, Cefoxitin, Levofloxacin, Gentamicin, Trimethoprim/ Sulfamethoxazole, Ciprofloxacin, Amopenem, Meropenem, Amikacin, and Imipenem. Interpretation of inhibitory zone (susceptible, intermediate, and resistant) was performed using clinical and laboratory standard institute (CLSI) instructions.

Statistical analysis
The time series analyses was applied for evaluation of antimicrobial resistance pattern over the times. All statistical analyses was performed using Microsoft Excell software. the results considered as significant, if p-value was ≤0.05. 

Results and Discussion
Changes in the pattern of antibiotic resistance of the most common nosocomial pathogens were investigated in the period 2018-2021 to monitor the drug resistance of these bacteria. During 4 years, 70,234 isolates were identified (A. baumannii: n = 19,374; K. pneumonia n=17,206; E. coli n =23,777; S. epidermidis: n=9,877). The bacteria were isolated from the clinical specimens such as sputum, urine, wounds, biopsy, blood, and sterile fluids.
The overall antibiotic resistance rate of S. epidermidis to different classes of antibiotics included Azithromycin: 84.63%, Erythromycin: 81.25%, Clindamycin: 68.19%, Cefoxitin: 62.20%, Levofloxacin: 45.18%, and Gentamicin: 26.35%. The total resistance to E.coli strain was as follows: Trimethoprim/Sulfamethoxazole: 45.31%, Cefotaxime: 48.62%, Ceftazidime: 59.16%, Ciprofloxacin: 62.0%, Cefepime: 62.73%, Gentamicin: 50.23%, Ceftazidime/Clavulanic acid: 15.60%, Meropenem: 36.39%, Amikacin: 44.74%, and Imipenem: 49.87%. In addition, the overall antibiotic resistance for K. pneumonia included: Cefotaxime: 81.11%, Ceftazidime: 77.46%, and Cefepime: 74.55%. Also, the resistance in relation to A. baumannii was reported as Ceftriaxone: 95.78%, Ceftazidime: 89.54%, Meropenem: 87.03%, Ciprofloxacin: 84.88%, Imipenem: 81.61%, Gentamicin: 80.08% and Amikacin: 76.80%.
The pattern of antibiotic resistance varied over 4 years. Regarding the antibiotic resistance pattern of S. epidermidis, the trend of antibiotic resistance was uniform over four years, and except for levofloxacin, which had a significant increase (p-value: 0.002), the rates of antibiotic resistance for other antibiotics showed no significant difference (Fig 1). Over the last four years, Azithromycin resistance has changed from 85.8% to 83.8%, the resistance of Erythromycin has altered from cantly higher than that of the neonates who did not recover (2141.7 ± 755.2 g) (p < 0.01). There was also a significant relationship between the TSH level and birth weight (p < 0.01). Moreover, the mean age of mothers in participants was 26.9 ± 3.7 years, with a minimum and maximum of 12 and 35 years, and did not have any significant relation with the level of TSH and with the recovery rate (p > 0.05).

The mean level of TSH in neonates who recovered within three-month was 9.4 ± 3 mIU/L, and in neonates who did not recover was 22 ± 6.5 mIU/L. The relation between the recovery and TSH level  

Discussion
The present study showed that the prevalence of febrile seizures was associated with gender, living place, temperature, family history of seizure, and the serum level of zinc. In this regard, the frequency of zinc deficiency was higher in patients with febrile seizures compared to febrile patients without seizure, before and after adjusting for gender.
Zinc plays a vital role in the neuronal terminals of the hippocampus and amygdala by producing pyridoxal phosphate and affecting glutamatergic, gamma-aminobutyric acidergic (GABAergic), and glycinergic synapses (13).
Glutamic acid decarboxylase (GAD) acts as a major inhibitory neurotransmitter in the synthesis of gamma-aminobutyric acid (GABA) (14). A study by Ganesh R. and Janakiraman L. on 38 children with febrile convulsion and 38 children as a control group, aged between 3 months and 5 years, indicated that a serum zinc deficiency was significantly more prevalent in their case group than in the control group (15). Another study has reported that there is a correlation between disruption in Zn2+ homeostasis and fever seizure (16).
In studies by Papierkowski A., Mollah M.A., and Gündüz Z. et al., the mean serum zinc level in the febrile convulsion group was significantly lower than in the control group, which indicates the role of zinc in febrile seizure. Comparing the groups in terms of age and gender, no significant difference was found, similar to our study (17-19). Abdel Hameed Z.A. et al. (20), in a study on 100 infants in Egypt, observed that temperature had no significant difference between the case and control groups. But Berg A.T. (21), Ahmed B.W. (22), and our study showed the importance of temperature in febrile seizure. The geographic area can be the cause of this difference. Duangpetsang J. in a study from 2014 to 2017 reported that a high fever with electrolyte disturbance hyponatremia has an important role in FS (23). Sharifi R. et al., in a study in 2007-2014, showed the importance of family history in febrile seizure (24), which is similar to our results.

Conclusion
The findings of this study show that zinc deficiency is significantly associated with the occurrence of febrile seizures. Zinc supplementation in children can therefore be helpful for the prevention and treatment of FS.

Conflict of interest
The authors declare no conflicts of interest.