Rhythm Sleep-wake Disorders Research Articles

Difficulties in management of a sighted patient with non-24-hour sleep-wake rhythm disorder

Difficulties in management of a sighted patient with non-24-hour sleep-wake rhythm disorder

Orexin Receptor Antagonists for the Prevention and Treatment of Alzheimer's Disease and Associated Sleep Disorders.

Orexins/hypocretins are neuropeptides produced by the hypothalamic neurons, binding two G-protein coupled receptors (orexin 1 and orexin 2 receptors) and playing a critical role in regulating arousal, wakefulness, and various physiological functions. Given the high prevalence of sleep disturbances in Alzheimer's disease (AD) and their reported involvement in AD pathophysiology, the orexin system is hypothesized to contribute to the disease pathogenesis. Specifically, recent evidence suggests that orexin's influence may extend beyond sleep regulation, potentially affecting amyloid-β and tau pathologies. Dual orexin receptor antagonists (DORAs), namely suvorexant, lemborexant, and daridorexant, demonstrated efficacy in treating chronic insomnia disorder across diverse clinical populations. Considering their stabilizing effects on sleep parameters and emerging evidence of a possible neuroprotective role, these agents represent a promising strategy for AD management. This leading article reviews the potential use of orexin receptor antagonists in AD, particularly focusing on their effect in modulating disease-associated sleep disturbances and clinical outcomes. Overall, clinical studies support the use of DORAs to enhance sleep quality in patients with AD with comorbid sleep and circadian sleep-wake rhythm disorders. Preliminary results also suggest that these compounds might influence AD pathology, potentially affecting disease progression. Conversely, research on selective orexin receptor antagonists in AD is currently limited. Further investigation is needed to explore orexin antagonism not only as a symptomatic treatment for sleep disturbances, but also for its broader implications in modifying AD neurodegeneration, emphasizing mechanisms of action and long-term outcomes.

Chinese formula Guben-Jiannao Ye alleviates the dysfunction of circadian and sleep rhythms in APP/PS1 mice implicated in activation of the PI3K/AKT/mTOR signaling pathway

Ethnopharmacological relevanceThe Chinese formula Guben-Jiannao Ye (GBJNY) formula has a long history of usage in traditional Chinese medicine (TCM) for the treatment of learning and memory disorders as well as senile insomnia. This formulation is derived from Sun Simiao's five tonic pills. Furthermore, modern pharmacological investigations have revealed its ability to improve cognitive impairment and ameliorate sleep-wake circadian rhythm disorders. However, the precise mechanism underlying its efficacy remains elusive. Aim of the studyThe current research explored the modulatory effects and possible mechanisms of GBJNY in circadian rhythm sleep-wake disorders and cognitive dysfunction in Alzheimer's disease using transcriptome sequencing and experimental validation. Materials and methodsThe LC-MS/MS tandem technology was utilized to qualitatively discern the active components present in GBJNY. The APP/PS1 mice received continuous treatment with GBJNY or Melatonin for 3 months. The learning and memory abilities of mice were assessed utilizing the Morris water maze (MWM) test, while sleep changes were studied utilizing the electroencephalogram (EEG) and electromyogram (EMG). Concurrently, mice's hippocampus clock gene rhythmicity was investigated. Subsequently, we employed HE staining, Golgi staining, and immunofluorescence to observe GBJNY's impact on synaptic damage and neuronal loss. We performed high-throughput sequencing to analyze the mRNA expression profiles of mice, aiming to identify differentially expressed genes (DEGs). Subsequently, we conducted GO and KEGG enrichment analyses to explore associated signaling pathways. Furthermore, we evaluated the expression levels of proteins involved in the PI3K/AKT/mTOR pathway and Aβ deposition in the hippocampus of mice. Through this comprehensive approach, we sought to elucidate and validate the potential mechanisms of action of GBJNY in APP/PS1 mice. ResultsResults showed 216 DEGs. Following this, we conducted GO enrichment and KEGG pathway analyses to delve deeper into the distinctions and fundamental functions of the mRNA target genes. The enrichment analysis underscored the prominence of the PI3K/Akt/mTOR signaling pathway as the most pivotal among them. Through in vivo experiments, it was further demonstrated that the administration of GBJNY enhanced memory and learning capacities in APP/PS1 mice. Additionally, GBJNY treatment resulted in alterations in the sleep-wake circadian rhythm, characterized by reduced wakefulness and an increase in non-rapid eye movement (NREM) sleep. Moreover, alterations in the peak expression of Per1, Per2, Clock, Cry1, Cry2, and Bmal1 mRNA were noted in the hippocampus of treated mice. Particularly noteworthy were the observed reductions in amyloid-beta (Aβ) deposition within the hippocampus, improvements in neuronal synaptic integrity, and upregulation of mTOR, Akt, and PI3K protein expression in the hippocampal region. These findings underscore the critical involvement of the PI3K/Akt/mTOR signaling pathway in mitigating disturbances in sleep-wake circadian rhythms. ConclusionsGBJNY enhanced the cognitive performance of APP/PS1 mice and altered clock gene expression patterns, alleviating sleep-wake circadian rhythm disruptions. The fundamental mechanism appears to be linked to the PI3K/Akt/mTOR pathway regulation, offering a foundation for potential clinical applications.

Pain, obesity, adenosine salvage disruption, and smoking behavior mediate the effect of gut microbiota on sleep disorders: results from network Mendelian randomization and 16S rDNA sequencing.

The objective of this study is to investigate the indirect causalities between gut microbiota and sleep disorders. In stage 1, we utilized 196 gut microbiota as the exposure factor and conducted a two-sample univariable Mendelian randomization (MR) analysis on five sleep disorders: insomnia, excessive daytime sleepiness (EDS), sleep-wake rhythm disorders (SWRD), obstructive sleep apnea (OSA), and isolated REM sleep behavior disorder (iRBD). In stage 2, we validated the MR findings by comparing fecal microbiota abundance between patients and healthy controls through 16S rDNA sequencing. In stage 3, we explored the indirect pathways by which the microbiota affects sleep, using 205 gut microbiota metabolic pathways and 9 common risk factors for sleep disorders as candidate mediators in a network MR analysis. In stage 1, the univariable MR analysis identified 14 microbiota potentially influencing five different sleep disorders. In stage 2, the results from our observational study validated four of these associations. In stage 3, the network MR analysis revealed that the Negativicutes class and Selenomonadales order might worsen insomnia by increasing pain [mediation: 12.43% (95% CI: 0.47, 24.39%)]. Oxalobacter could raise EDS by disrupting adenosine reuptake [25.39% (1.84, 48.95%)]. Allisonella may elevate OSA risk via obesity promotion [36.88% (17.23, 56.54%)], while the Eubacterium xylanophilum group may lower OSA risk by decreasing smoking behavior [7.70% (0.66, 14.74%)]. Triangulation of evidence from the MR and observational study revealed indirect causal relationships between the microbiota and sleep disorders, offering fresh perspectives on how gut microbiota modulate sleep.

Sleep Disturbance in Bipolar Disorder. Treatment Implications

IntroductionRelationship between sleep and bipolar disorder involves the following aspects: decreased need for sleep is a fundamental marker of the manic state, sleep deprivation is one cause of mania and may in fact be a fundamental etiological agent in mania, total sleep time is a predictor of future manic episodes, and total sleep time may be a marker of response as well as a target of treatment in mania.ObjectivesThis e-poster aimed to summarize evidence regarding the sleep disturbance in Bipolar Disorder.MethodsBibliopgraphical review was performed using PubMed platform. All relevant articles were found using the keywords: sleep disturbance, bipolar disorder, mania.ResultsSleep disturbances are frequent in BD patients in different phases of illness, including the euthymic state and remission. These sleep aberrations are represented not only by insomnia but also by sleep–wake rhythm disorders, especially delayed sleep–wake phase disorders. During the manic state, most patients experience a reduced need for sleep and longer sleep onset latency. Likewise, in the depressive state, insomnia and hypersomnia are commonly observed. Meta-analyses of trials conducted on remitted BD patients demonstrated prolonged total sleep time, increased awakenings after sleep onset, greater variability of sleep–wake variables, and reduced sleep efficiency.ConclusionsOverall, all kinds of sleep disorders and parasomnias are very common especially in youth patients with BD. Thus, compared to the general population, youth with BD exhibit lower sleep efficiency, longer slow wave sleep, and reduced REM sleep, features that could affect the genesis and prognosis of the disorder. Sleep disturbances may also be used as predictors of the onset of BD in a subset of high-risk young subjects.Disclosure of InterestNone Declared

Improvement in non-24-h sleep-wake rhythm disorder in a sighted individual treated with a melatonin receptor agonist

Non-24-hour sleep-wake rhythm disorder (N24SWD) typically presents in patients with visual impairments that disrupt the ability to entrain to the 24 hour solar cycle. We discuss a 43 year old sighted man who presented with periodic daytime hypersomnia and nighttime insomnia, occasionally leading to <3 hours of sleep per day. Previous polysomnography showed an apnea hypopnea index of 6.2 events per hour. A sleep log of 3 months showed irregular time of sleep onset, and an average of 3 hours of sleep per day. Wrist actigraphy confirmed N24SWD. A trial of tasimelteon 20 mg/day resulting in improved daytime hypersomnia (pre-Epworth Sleepiness Scale (ESS) = 21/24, post-ESS = 5/24; a score of > 10/24 is considered sleepy). Follow-up actigraphy showed marked resolution of phase delay with an average of five hours of sleep. The case demonstrates that tasimelteon is a possible treatment for N24SWD in sighted individuals.

Registry and survey of circadian rhythm sleep-wake disorder patients

ObjectiveCircadian Sleep Disorders Network has created a registry of circadian rhythm sleep-wake disorder (CRSWD) patients, and a survey of their experiences. The purpose of the registry is to provide volunteers willing to participate in research; the purpose of the survey is to fill some of the knowledge gaps on these disorders, including information on subjective patient experience and the efficacy and durability of treatments.Researchers are invited to contact Circadian Sleep Disorders Network for permission to use the registry to find potential research participants, and to further analyze the survey data. PatientsOver 1627 patients have participated; 1298 have completed the entire survey. Here we present results based on the 479 clinically diagnosed CRSWD patients. MethodsThe survey covers a variety of topics relating to CRSWDs, including diagnosis, comorbidities, treatments, and work/educational accommodations. ConclusionsResults of this survey diverged from much of the literature. More than half the participants reported tiredness even when sleeping on their preferred schedule. While depression may cause sleep problems, our data suggests that sleep/circadian problems often precede depression.There were more people suffering from sighted non-24-hour sleep-wake rhythm disorder than some of the literature would lead us to expect.Current treatments did not appear to be helpful to a large percentage of our participants. Most of them did not find light therapy helpful and nearly all participants who tried phase-delay chronotherapy reported at best only short-term improvement. A sizable proportion of people who tried phase-delay chronotherapy subsequently developed non-24-hour sleep-wake rhythm disorder.

Role of sleep in neurodegeneration: the consensus report of the 5th Think Tank World Sleep Forum.

Sleep abnormalities may represent an independent risk factor for neurodegeneration. An international expert group convened in 2021 to discuss the state-of-the-science in this domain. The present article summarizes the presentations and discussions concerning the importance of a strategy for studying sleep- and circadian-related interventions for early detection and prevention of neurodegenerative diseases. An international expert group considered the current state of knowledge based on the most relevant publications in the previous 5years; discussed the current challenges in the field of relationships among sleep, sleep disorders, and neurodegeneration; and identified future priorities. Sleep efficiency and slow wave activity during non-rapid eye movement (NREM) sleep are decreased in cognitively normal middle-aged and older adults with Alzheimer's disease (AD) pathology. Sleep deprivation increases amyloid-β (Aβ) concentrations in the interstitial fluid of experimental animal models and in cerebrospinal fluid in humans, while increased sleep decreases Aβ. Obstructive sleep apnea (OSA) is a risk factor for dementia. Studies indicate that positive airway pressure (PAP) treatment should be started in patients with mild cognitive impairment or AD and comorbid OSA. Identification of other measures of nocturnal hypoxia and sleep fragmentation could better clarify the role of OSA as a risk factor for neurodegeneration. Concerning REM sleep behavior disorder (RBD), it will be crucial to identify the subset of RBD patients who will convert to a specific neurodegenerative disorder. Circadian sleep-wake rhythm disorders (CSWRD) are strong predictors of caregiver stress and institutionalization, but the absence of recommendations or consensus statements must be considered. Future priorities include to develop and validate existing and novel comprehensive assessments of CSWRD in patients with/at risk for dementia. Strategies for studying sleep-circadian-related interventions for early detection/prevention of neurodegenerative diseases are required. CSWRD evaluation may help to identify additional biomarkers for phenotyping and personalizing treatment of neurodegeneration.

Effect of Smartphone Use on Sleep in Undergraduate Medical Students: A Cross-Sectional Study

Smartphone use, particularly at night, has been shown to provoke various circadian sleep–wake rhythm disorders such as insomnia and excessive daytime tiredness. This relationship has been mainly scrutinized among patient groups with higher rates of smartphone usage, particularly adolescents and children. However, it remains obscure how smartphone usage impacts sleep parameters in adults, especially undergraduate college students. This study sought to (1) investigate the association between smartphone use (actual screen time) and four sleep parameters: Pittsburgh sleep quality score (PSQI), self-reported screen time, bedtime, and rise time; (2) compare the seven PSQI components between good and poor sleep quality subjects. In total, 264 undergraduate medical students (aged 17 to 25 years) were recruited from the Government Doon Medical College, Dehradun, India. All participants completed a sleep questionnaire, which was electronically shared via a WhatsApp invitation link. Hierarchical and multinomial regression analyses were performed in relation to (1) and (2). The average PSQI score was 5.03 ± 0.86, with approximately one in two respondents (48.3%) having a poor sleep index. Smartphone use significantly predicted respondents’ PSQI score (β = 0.142, p = 0.040, R2 = 0.027), perceived screen time (β = 0.113, p = 0.043, R2 = 343), bedtime (β = 0.106, p = 0.042, R2 = 045), and rise time (β = 0.174, p = 0.015, R2 = 0.028). When comparing poor-quality sleep (PSQI ≥ 5) to good-quality sleep (PSQI &lt; 5), with good-quality sleep as the reference, except sleep efficiency and sleep medications (p &gt; 0.05), five PSQI components declined significantly: subjective sleep quality (β = −0.096, p &lt; 0.001); sleep latency (β = −0.034, p &lt; 0.001); sleep duration (β = −0.038, p &lt; 0.001); sleep disturbances (β = 1.234, p &lt; 0.001); and sleep dysfunction (β = −0.077, p &lt; 0.001). Consequently, public health policymakers should take this evidence into account when developing guidelines around smartphone use—i.e., the when, where, and how much smartphone use—to promote improved sleep behaviour and reduce the rate of sleep–wake rhythm disorders.

Consequences and management of sleep-wake rhythm disorders resulting from social jetlag and nightshifts

Our day to night cycle is ruled by a social, biological and sun clock. The social clock being a local time is aligned with others’ lives. The biological clock (circadian time) that controls our physiology and the sun clock that defines natural light and darkness. Social jetlag refers to the misalignment between local and circadian time. This term is usually used in reference to travels to places in different time zones. Nevertheless, it is worth noticing that “jetlag” also applies to people working in a medical industry such as doctors, nurses, paramedics, and others involved in an on-call work. Thus, I would like to look closer to the physiology of social jetlag and to analyze its implications.

Images: Irregular sleep-wake rhythm disorder in transgender individuals.

Kokash A, Vendrame M. Images: irregular sleep-wake rhythm disorder in transgender individuals. J Clin Sleep Med. 2023;19(11):1981-1984.

Non-24-h sleep-wake rhythm disorder in a sighted individual with bipolar disorder.

HJB is a consultant for Natrol, LLC and F. Hoffmann-La Roche Ltd. JSE has served as an expert witness in legal cases, including those involving Teva Pharmaceuticals USA, Inc., Apotex, Inc., Apotex Corp., MSN Pharmaceuticals, Inc. and MSN Laboratories Pvt. Ltd. All other authors report no financial or nonfinancial interests to disclose. The data sets generated and/or analyzed during the current study are not publicly available due to privacy restrictions but are available from the Prechter study upon reasonable request.

The Effect of Blindness on Biological Rhythms and the Consequences of Circadian Rhythm Disorder.

Various physiological systems and behaviors such as the sleep-wake cycle, vigilance, body temperature, and the secretion of certain hormones are governed by a 24-hour cycle called the circadian system. While there are many external stimuli involved the regulation of circadian rhythm, the most powerful environmental stimulus is the daily light-dark cycle. Blind individuals with no light perception develop circadian desynchrony. This leads to non-24-hour sleep-wake rhythm disorder, which is associated with sleep-wake disorders, as well as mood disorders and loss of appetite and gastrointestinal disturbances due to disrupted circadian hormone regulation. As the diagnosis is often delayed because of under-recognition in clinical practice, patients must cope with varying degrees of social and academic dysfunction. Most blind individuals report that non-24-hour sleep-wake rhythm disorder affects them more than blindness. In the treatment of totally blind patients suffering from non-24-hour sleep-wake rhythm disorder, the first-line management is behavioral approaches. Drug therapy includes melatonin and the melatonin agonist tasimelteon. Diagnosing blind individuals' sleep disorders is also relevant to treatment because they can be improved with the use of melatonin and its analogues or by phototherapy if they have residual vision. Therefore, assessing sleep problems and planning treatment accordingly for individuals presenting with blindness is an important issue for ophthalmologists to keep in mind.

Novel CLOCK and NR1D2 variants in 64 sighted Japanese individuals with non-24-hour sleep-wake rhythm disorder.

Novel CLOCK and NR1D2 variants in 64 sighted Japanese individuals with non-24-hour sleep-wake rhythm disorder.

Molecular targets and mechanisms involved in the action of Banxia Shumi decoction in insomnia treatment.

Insomnia is a common sleep-wake rhythm disorder, which is closely associated with the occurrence of many serious diseases. Recent researches suggest that circadian rhythms play an important role in regulating sleep duration and sleep quality. Banxia Shumi decoction (BSXM) is a well-known Chinese formula used to treat insomnia in China. However, the overall molecular mechanism behind this therapeutic effect has not yet been fully elucidated. This study aimed to identify the molecular targets and mechanisms involved in the action of BSXM during the treatment of insomnia. Using network pharmacology and molecular docking methods, we investigated the molecular targets and underlying mechanisms of action of BSXM in insomnia therapy. We identified 8 active compounds from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform and the traditional Chinese medicine integrative database that corresponded to 26 target genes involved in insomnia treatment. The compound-differentially expressed genes of the BXSM network indicated that cavidine and gondoic acid could potentially become key components of drugs used for insomnia treatment. Further analysis revealed that GSK3B, MAPK14, IGF1R, CCL5, and BCL2L11 were core targets significantly associated with the circadian clock. Pathway enrichment analysis of Kyoto Encyclopedia of Genes and Genomes revealed that epidermal growth factor receptor tyrosine kinase inhibitor resistance was the most prominently enriched pathway for BSXM in the insomnia treatment. The forkhead box O signaling pathway was also found to be significantly enriched. These targets were validated using the Gene Expression Omnibus dataset. Molecular docking studies were performed to confirm the binding of cavidine and gondoic acid to the identified core targets. To our knowledge, our study confirmed for the first time that the multi-component, multi-target, and multi-pathway characteristics of BXSM may be the potential mechanism for treating insomnia with respect to the circadian clock gene. The results of this study provided theoretical guidance for researchers to further explore its mechanism of action.

Melatonin – the New Multipotential Drug of the Future?

Introduction: Melatonin is a well-known drug and dietary supplement that is steadily growing in popularity on the pharmaceutical market. This indolamine, which has been known for more than 50 years, is produced by the pineal gland depending on the circadian rhythm. Also referred to as the "darkness hormone" and secreted mainly during nighttime hours, it is primarily associated with the treatment of sleep-wake rhythm disorders or disorders associated with sudden shifting time zones (jet lag). However, many scientific studies have shown that melatonin has multidirectional effects. It is used both as a chronobiotic, i.e., a drug that regulates circadian rhythms, as well as having anti-inflammatory, anti-oxidative, and anti-carcinogenic properties, regulating mitochondrial function, and affecting many systems and organs, keeping the organism in a state of homeostasis. Purpose: This review article aims to provide an overview of the mechanism of action of melatonin, its current indications in clinical practice, and potential future directions for therapy use. Materials and methods: A summary of reports available in publications and scientific studies posted in medical information databases: Pubmed, CrossRef, Google Scholar, and book positions. Results: The pleiotropic effect of melatonin can be used as an supportive drug in the treatment of sleep disorders, disorders of the central nervous system, the cardiovascular system, the gastrointestinal system, and many oncological diseases. Conclusions: Despite a number of important reports on the positive effects of melatonin in the treatment of disorders in many areas of medicine, it is necessary to deepen research with its participation and the emergence of recommendations for its use in order to safely introduce the drug into common clinical practice.

Prevalence of Insomnia and Sleep Habits during the First and Second Wave of COVID-19 in Belgium.

Belgium has one of the highest numbers of COVID-19 cases per 1 million inhabitants. The pandemic has led to significant societal changes with repercussions on sleep and on mental health. We aimed to investigate the effect of the first and the second wave of COVID-19 on the sleep of the Belgian populationWe launched two online questionnaires, one during the first lockdown (7240 respondents) and one during the second (3240 respondents), to test differences in self-reported clinical insomnia (as measured by the Insomnia Severity Index) and sleep habits during the two lockdowns in comparison with the pre-COVID period. The number of persons with clinical insomnia rose during the first lockdown (19.22%) and further during the second (28.91%) in comparison with pre-lockdown (7.04-7.66%). Bed and rise times were delayed and there was an increased time in bed and sleep onset latency. There was further a decrease in total sleep time and in sleep efficiency during both confinements. The prevalence of clinical insomnia quadrupled during the second wave in comparison with the pre-lockdown situation. Sleep habits were most altered in the younger population, indicating a greater risk for this group to develop a sleep-wake rhythm disorder.

Continuous positive airway pressure as an accurate marker for non-24-hour sleep-wake rhythm disorder.

Non-24-h sleep-wake rhythm disorder is quite rare in sighted patients and frequently associated with psychiatric disorders. We report the case of a 46-year-old man with autism spectrum disorder (ASD) and agoraphobia who had been referred for a suspicion of obstructive sleep apnea syndrome (OSAS). Polysomnography and arterial blood gas confirmed moderate OSAS associated with hypoventilation. Continuous positive airway pressure (CPAP) was started on fixed mode with excellent results. At follow-up, his CPAP report data revealed an irregular sleep-wake rhythm with a progressive offset of sleep schedule and wake time delayed from 1 h from day to day. Melatonin (or agonist) is efficacious and safe for long-term treatment in ASD and circadian rhythm sleep-wake disorder (CRSWD) with light therapy and wakefulness promoting medication. This case underlines the importance to sensitise psychiatrists to sleep and CRSWD, and also that CPAP data offer a possible objective alternative to sleep diary.

Irregular sleep-wake rhythm disorder Masquerading as hypersomnia in Moebius syndrome

Irregular sleep-wake rhythm disorder Masquerading as hypersomnia in Moebius syndrome

0813 Post-Pinealectomy Insomnia and Melatonin Therapy

Abstract Introduction Melatonin is a hormone produced in the pineal gland that has an important role in sleep; immune, neurologic, psychiatric, metabolic, and endocrinologic function; cardiac-autonomic regulation and even cancer risk. We present a case of insomnia, somnambulism, dream enactment, and periodic limb movements of sleep (PLMS) after a pinealectomy. Report of Cases: A 40-year-old woman with a history of a complete pinealectomy due to a pineal cyst presented to the sleep medicine clinic. Shortly after the pinealectomy, she developed sleep onset and maintenance insomnia. Two years later she developed somnambulism, and four years later she developed dream enactment and PLMS. She reported no prior treatments for her sleep issues, including no history of melatonin use. On average, her total sleep time (TST) was 2-8 hours/night with awakenings every 2 hours. Sleep latency was 10-45 minutes. Polysomnograghy demonstrated an apnea-hypopnea index of 0.6/hr, PLM index of 68.1/hr, normal REM atonia, and no complex behaviors. The patient started 1mg immediate release (IR) melatonin, which did not help her insomnia, but parasomnias resolved. She had improvement in her PLMS with iron supplementation and melatonin. The melatonin dose was increased to 3mg IR which helped increase her TST to 4-8 hours. She was switched to 3mg extended release (ER) melatonin, and then increased to 4mg ER. She obtained the most benefit for her insomnia with 1mg IR plus 4mg ER with sleep latency reduced to 5-10 minutes and TST improved up to 7.5 hours with rare awakenings. Conclusion Pinealectomy in humans is rarely reported. Most data about the consequences of pinealectomy and pathophysiology of melatonin come from animal research. Melatonin level after pinealectomy is often undetectable or severely diminished. Current limited literature on patients with pinealectomy consists of case reports about patients who experienced insomnia, non-24-hour sleep-wake rhythm disorder [SSM1] and mood disorders. Melatonin doses ranging from 0.5mg to 14mg IR and up to 5mg ER have been trialed with most patients having symptomatic improvement with doses above 3mg. We found that a combination of 1mg immediate and 4mg extended release melatonin was the most beneficial for our patient. Support (If Any)