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Suicide is the second leading cause of death among 10- to 25-year-olds, and suicidal behavior is four times more likely among youth who enter juvenile justice settings. The current quality improvement work aimed to improve the use of suicide prevention practices in a behavioral health unit within a juvenile detention center and was informed by the Plan-Do-Study-Act method and the Exploration, Preparation, Implementation, and Sustainment model of evidence-based practice implementation. Aligned with guidelines for suicide prevention in juvenile detention, the quality improvement work resulted in the implementation of universal screening and assessment of behavioral health concerns and the Stanley and Brown Safety Planning Intervention. We review the quality improvement process, provide an overview of the final clinical model, including methods for tailoring and sustainably implementing the Safety Planning Intervention within juvenile detention, and end with a case example and future directions to expand the impact of this work. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Exposure to an adequate light-dark cycle is important for the speedy recovery of hospitalized and institutionalized patients. Light exposure, including natural light, offers several health benefits to both patients and nursing staff. This includes physical (e.g., decreased confusion and disorientation) and mental health benefits (e.g., prevention of depression) and a reduction in the hospital stay. Improved alertness and performance can also be noted among hospital staff. In this commentary, we discuss disrupting factors that include light during the nighttime along with noise and physical procedures on the patient and others. We then address some of the important steps that can be undertaken to restore a more normal environment for patients in the intensive care unit, which can be particularly important for COVID-19 patients.

Aging is accompanied by circadian changes, including disruptive alterations in the sleep/wake cycle, as well as the beginning of low-degree inflammation ("inflammaging"), a scenario that leads to several chronic illnesses, including cancer, and metabolic, cardiovascular, and neurological dysfunctions. As a result, any effective approach to healthy aging must consider both the correction of circadian disturbance and the control of low-grade inflammation. One of the most important prerequisites for healthy aging is the preservation of robust circadian rhythmicity (particularly of the sleep/wake cycle). Sleep disturbance disrupts various activities in the central nervous system, including waste molecule elimination. Melatonin is a chemical with extraordinary phylogenetic conservation found in all known aerobic creatures whose alteration plays an important role in sleep changes with aging. Every day, the late afternoon/nocturnal surge in pineal melatonin helps to synchronize both the central circadian pacemaker found in the hypothalamic suprachiasmatic nuclei (SCN) and a plethora of peripheral cellular circadian clocks. Melatonin is an example of an endogenous chronobiotic substance that can influence the timing and amplitude of circadian rhythms. Moreover, melatonin is also an excellent anti-inflammatory agent, buffering free radicals, down-regulating proinflammatory cytokines, and reducing insulin resistance, among other things. We present both scientific and clinical evidence that melatonin is a safe drug for treating sleep disturbances in the elderly.

Fil: Pandi Perumal, Seithikurippu R. Somnogen Canada Inc; Canadá Fil: Cardinali, Daniel Pedro. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas; Argentina Fil: Reiter, R. UT Health San Antonio. Department of Cell Systems and Anatomy; Estados Unidos Fil: Brown, Gregory M. Univeridad de Toronto. Centro para la Adicción y la Salud Mental. Ciencias Moleculares del Cerebro; Canadá Abstract: That the pineal gland is a source of melatonin is widely known; however, by comparison, few know of the much larger pool of extrapineal melatonin. That pool is widely distributed in all animals, including those that do not have a pineal gland, e.g., insects. Extrapineal melatonin is not released into the blood but is used locally to function as an antioxidant, anti-inflammatory agent, etc. A major site of action of peripherally-produced melatonin is the mitochondria where it neutralizes reactive oxygen species (ROS) that are generated during oxidative phosphorylation. Its role also includes major actions as an immune modulator reducing overreactions to foreign agents while simultaneously boosting immune processes. During a pandemic such as coronavirus disease 2019 (COVID-19), caused by the virus SARS-CoV-2, melatonin is capable of suppressing the damage inflicted by the cytokine storm. The implications of melatonin in susceptibility and treatment of COVID-19 disease are discussed.

Fil: Ghosh, Hindole. Kalinga University. Department of Zoology; India Fil: Rai, Seema. Guru Ghasidas Vishwavidyalaya. Department of Zoology; India Fil: Manzar, Md Dilshad. Majmaah University. College of Applied Medical Sciences. Department of Nursing; Arabia Saudita Fil: Pandi Perumal, Seithikurippu R. Saveetha University. Saveetha Institute of Medical and Technical Sciences. Saveetha Medical College and Hospitals; India Fil: Brown, Gregory M. University of Toronto. Centre for Addiction and Mental Health. Department of Psychiatry; Canada Fil: Reiter, Russel J. University of Texas. Health Science Center at San Antonio. Department of Cell Systems and Anatomy, Estados Unidos Fil: Cardinali, Daniel Pedro. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Abstract: The objective of the present study was to investigate the effect of melatonin and L-thyroxine (T4) on the expression of various receptors, and some metabolic, reproductive, and gonadotropic hormones in letrozole-induced polycystic ovary syndrome (PCOS) in rats. - Material and methods: Assessment of gravimetric, hormonal profile and thyroid histology and relative expression of melatonin receptors (MT1, MT2) and estrogen receptor α (Erα) in thyroid and ovary, and type II iodothyronine deiodinase (Dio2) and thyroid hormone receptor α (TRα) in the ovary were performed using standard protocols. - Key findings: A significant increase in thyroid follicles numbers was noted in the hyperthyroid rat. T4 treatment to PCOS showed the expected increment in the circulating level of triiodothyronine (T3) and T4. Melatonin and T4 treatment of PCOS rats resulted in a significant decrease in the circulating level of T3 and T4. Hyperthyroid rats showed a decrement in plasma melatonin levels. However, T4 treatment to PCOS rats showed increased circulating melatonin levels, and a decrease in the circulating level of gonadotropins (LH and FSH), and testosterone. Melatonin treatment to PCOS-hyperthyroid rats resulted in the normal expression of ovarian and thyroid MT1 and ERα, receptors, which had been altered in PCOS and hyperthyroid rats, without any significant change in the MT2 receptor. - Significance: The present findings suggest a fine interplay and cross-talk via melatonin and its two receptors with ERα, TRα, and Dio2in thyroid and ovarian tissue during PCOS and hyperthyroidism pathogenicity.

The objective of chronotherapy is to optimize medical treatments taking into account the body's circadian rhythms. Chronotherapy is referred to and practiced in two different ways: (1) to alter the sleep-wake rhythms of patients to improve the sequels of several pathologies; (2) to take into account the circadian rhythms of patients to improve therapeutics. Even minor dysfunction of the biological clock can greatly affect sleep/wake physiology causing excessive diurnal somnolence, increase in sleep onset latency, phase delays or advances in sleep onset, frequent night awakenings, reduced sleep efficiency, delayed and shortened rapid eye movement sleep, or increased periodic leg movements. Chronotherapy aims to restore the proper circadian pattern of the sleep-wake cycle, through adequate sleep hygiene, timed light exposure, and the use of chronobiotic medications, such as melatonin, that affect the output phase of circadian rhythms, thus controlling the clock. Concerning the second use of chronotherapy, therapeutic outcomes as diverse as the survival after open-heart surgery or the efficacy and tolerance to chemotherapy vary according to the time of day. However, humans are heterogeneous concerning the timing of their internal clocks. Not only different chronotypes exist but also the endogenous human circadian period (τ) is not a stable trait as it depends on many internal and external factors. If any scheduled therapeutic intervention is going to be optimized, a tool is needed for simple diagnostic and objectively measurement of an individual's internal time at any given time. Methodologic advances like the use of single-sample gene expression and metabolomics are discussed.

Melatonin is an ancient molecule that is evident in high concentrations in various tissues throughout the body. It can be separated into two pools; one of which is synthesized by the pineal and can be found in blood, and the second by various tissues and is present in these tissues. Pineal melatonin levels display a circadian rhythm while tissue melatonin does not. For decades now, melatonin has been implicated in promoting and maintaining sleep. More recently, evidence indicates that it also plays an important role in neuroprotection. The beginning of our review will summarize this literature. As an amphiphilic, pleiotropic indoleamine, melatonin has both direct actions and receptor-mediated effects. For example, melatonin has established effects as an antioxidant and free radical scavenger both in vitro and in animal models. This is also evident in melatonin’s prominent role in mitochondria, which is reviewed in the next section. Melatonin is synthesized in, taken up by, and concentrated in mitochondria, the powerhouse of the cell. Mitochondria are also the major source of reactive oxygen species as a byproduct of mitochondrial oxidative metabolism. The final section of our review summarizes melatonin’s potential role in aging and psychiatric disorders. Pineal and tissue melatonin levels both decline with age. Pineal melatonin declines in individuals suffering from psychiatric disorders. Melatonin’s ability to act as a neuroprotectant opens new avenues of exploration for the molecule as it may be a potential treatment for cases with neurodegenerative disease.

The biology underlying sleep is not yet fully elucidated, but it is known to be complex and largely influenced by circadian rhythms. Compelling evidence supports of a link among circadian rhythms, sleep and metabolism, which suggests a role for mitochondria. These organelles play a significant role in energy metabolism via oxidative phosphorylation (OXPHOS) and several mitochondrial enzymes display circadian oscillations. However, the interplay between mitochondria and sleep is not as well-known. This review summarises human and animal studies that have examined the role of mitochondria in sleep. Literature searches were conducted using PubMed and Google Scholar.Using various models of sleep deprivation, animal studies support the involvement of mitochondria in sleep via differential gene and protein expression patterns, OXPHOS enzyme activity, and morphology changes. Human studies are more limited but also show differences in OXPHOS enzyme activity and protein levels among individuals who have undergone sleep deprivation or suffer from different forms of insomnia.Taken altogether, both types of study provide evidence for mitochondria's involvement in the sleep-wake cycle. We briefly discuss the potential clinical implications of these studies.

Fil: Cardinali, Daniel Pedro. Pontificia Universidad Católica Argentina. Facultad de Medicina; Argentina Fil: Brown, Gregory M. University of Toronto. Department of Psychiatry. Centre for Addiction and Mental Health; Canada Fil: Pandi Perumal, Seithikurippu R. Somnogen Canada Inc; Canada Abstract: Competition among pharmaceutical companies to develop safe and effective vaccines against SARS-CoV-2 is high. However, based on the prior experience with the influenza vaccine, up to 50% in lack of effectiveness would be found among healthy adults receiving effective vaccines against SARS-CoV-2. There is growing evidence that insufficient sleep may potentially be a pervasive and prominent factor accounting for this variability. Individuals experiencing total or partial sleep loss exhibit markedly reduced antigen-specific antibodies as compared to healthy sleepers. Besides, pre-vaccination sleep quality is also an important contributing factor. Several meta-analyses and expert consensus reports support the view that the chronobiotic/hypnotic properties of melatonin are useful in patients with primary sleep disorders to decrease sleep onset latency and to increase total sleep time. Hence, the prescription of melatonin for at least 2 weeks prior to vaccination can be a useful approach to improve sleep quality and to ensure that the vaccination is performed at a moment of optimal sleep conditions. Moreover, melatonin enhances the immune response to vaccines by increasing peripheral blood CD4+ T cells and IgG-expressing B cells. Administration of exogenous melatonin could increase the potency of the immune response and the duration of the immunity induced by the vaccine. Besides, melatonin could also prevent adverse effects of the vaccination due to its antioxidant and immunomodulatory properties. Therefore, the administration of melatonin from 2 weeks to at least 4 weeks after vaccination may constitute an effective means to enhance the efficacy of vaccination against SARS-CoV-2.

Fil: Hajam, Younis Ahmad. Universidad Central Guru Ghasidas Vishwavidyalaya. Departamento de Zoología; India Fil: Hajam, Younis Ahmad. Universidad Career Point. Departamento de Biociencias. División de Zoología; India Fil: Rai, Seema. Universidad Central Guru Ghasidas Vishwavidyalaya. Departamento de Zoología; India Fil: Pandi-Perumal Seithikurippu R. Somnogen Canada Inc.; Canadá Fil: Brown, Gregory M. Univeridad de Toronto. Centro para la Adicción y la Salud Mental. Ciencias Moleculares del Cerebro; Canadá Fil: Pandi Perumal, Seithikurippu R. Universidad Saveetha. Instituto Saveetha de Medicina y Ciencias Médicas. Hospital Universitario Saveetha; India Fil: Reiter, R. Universidad de Texas. Departamento de Sistemas Celulares y Anatomía; Estados Unidos Fil: Cardinali, Daniel Pedro. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Abstract: Introduction: The present study was designed to evaluate the therapeutic efficacy of melatonin and insulin coadministration in diabetes-induced renal injury in rats. Research Design and Methods: Diabetes was achieved by giving streptozotocin (15 mg/kg) for 6 consecutive days. The diabetic condition was confirmed by assessing the blood glucose level; animals having blood glucose levels above 250 mg were considered as diabetic. Following the confirmation, animals were randomly divided into different experimental groups, viz group I served as the control (CON), group II diabetic (D), group III D+melatonin (MEL), group IV D+insulin (INS), group V D+MEL+INS, group VI D+glibenclamide (GB), group VII CON+MEL, group VIII CON+INS, and group IX CON+GB. Following the completion of the experimental period, animals were sacrificed, blood was collected via a retro-orbital puncture, and kidneys were harvested. Diabetic rats exhibited a significant increment in blood glucose and biochemical indexes of renal injury (tubular disruption, swollen glomeruli with loss of glomerular spaces, and distortion of the endothelial lining) including augmented levels of serum creatinine, urea, uric acid, Na+, and K+, and inhibition/suppression of the activity of glutathione (GSH) peroxidase, GSH reductase, glucose-6-phosphate dehydrogenase, and GSH-Stransferase in the renal cortex. Results: By examining thiobarbiturate reactive substances, reduced GSH, superoxide dismutase activity, and catalase activity in the renal cortex of control and diabetic rats, it was documented that treatment with melatonin or insulin alone or in combination showed a significant ad integrum recovery of GSH-dependent antioxidative enzymatic activities. Melatonin and insulin coadministration caused greater reductions in circulating tumor necrosis factor-α, tumor growth factor-β1, interleukin (IL)-1β, and IL-6 levels in diabetic rats, whereas IL-10 levels increased, as compared to each treatment alone. Diabetic rats showed a significant increase in the expression of both MT1 and MT2 melatonin receptor genes. Melatonin or insulin treatment alone or in combination resulted in significant restoration of the relative expression of both melatonin receptors in the renal cortex. Conclusion: The coadministration of exogenous melatonin and insulin abolished many of the deleterious effects of type 1 diabetes on rat renal function.

Fil: Reiter, Russel J. University of Texas Health Science Center at San Antonio. Department of Cell Systems and Anatomy; Estados Unidos Fil: Cardinali, Daniel Pedro. Pontificia Universidad Católica Argentina. Facultad de Ciencias Medicas; Argentina Fil: Neel, Richard L. Family Doctor; Estados Unidos Fil: Dominguez Rodriguez, Alberto. University Hospital of Canary Islands San Cristóbal de La Laguna. Department of Cardiology; España Fil: Brown, Gregory M. University of Toronto. Department of Psychiatry; Canada Fil: Tesarik, Jan. MAR & Gen Clinic Granada; España Abstract: Melatonin was shown to prevent or mitigate a number of different respiratory and nonrespiratory viral diseases. Given its non-specific anti-viral action, it is likely to be effective against the delta variant of SARS-CoV-2 as well as any eventual future variants of the virus.

Objective: The prevalence of sleep disorders during the perinatal period is high and large health administrative database surveys have shown that the use of exogenous melatonin in pregnant populations is quite common, about 4%. Much of the concern about using melatonin during pregnancy and breastfeeding stems from animal research. Thus, the objective of this article is to provide a critical review of human studies related to exogenous melatonin use during pregnancy and breastfeeding. Methods: The electronic databases Ovid, MEDLINE, Embase, and the Cochrane Library were searched using terms and keywords related to melatonin, pregnancy, and breastfeeding. Results: Fifteen studies were included in this review. Eight focused on melatonin use during pregnancy and seven focused on melatonin use during breastfeeding. There was a variety of study designs, including case reports, cohort studies, and clinical trials. There is a lack of randomized, controlled trials examining the efficacy and safety of melatonin as a treatment for sleep disorders during pregnancy or breastfeeding and, notably, insomnia was not the primary outcome measure in any of the studies included in this review. Clinical trials that used exogenous melatonin during pregnancy and breastfeeding for other clinical conditions have not suggested major safety concerns or adverse events. Conclusion: Contrary to what animal studies have suggested, evidence from clinical studies to date suggests that melatonin use during pregnancy and breastfeeding is probably safe in humans. This review further emphasizes the need for clinical studies on sleep disorders, including exogenous melatonin, during pregnancy and lactation.

Fil: Cardinali, Daniel Pedro. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas; Argentina Fil: Pandi Perumal, Seithikurippu R. Somnogen Canada Inc; Canadá Fil: Pandi Perumal, Seithikurippu R. Universidad Saveetha. Instituto Saveetha de Medicina y Ciencias Médicas. Hospital Universitario Saveetha; India Fil: Zaki, Nevin F. W. Universidad de Mansoura. Facultad de Medicina. Departamento de Psiquiatría; Egipto Fil: Karthikeyan, Ramanujam. Investigador independiente; India Fil: Spence, David Warren. Investigador independiente; Canadá Fil: Reiter, R. Universidad de Texas. Departamento de Sistemas Celulares y Anatomía; Estados Unidos Fil: Brown, Gregory M. Univeridad de Toronto. Centro para la Adicción y la Salud Mental. Ciencias Moleculares del Cerebro; Canadá Abstract: Sleep and the circadian clock are intertwined and have persisted throughout history. The suprachiasmatic nucleus (SCN) orchestrates sleep by controlling circadian (Process C) and homeostatic (Process S) activities. As a "hand" on the endogenous circadian clock, melatonin is critical for sleep regulation. Light serves as a cue for sleep/wake control by activating retino-recipient cells in the SCN and subsequently suppressing melatonin. Clock genes are the molecular timekeepers that keep the 24 h cycle in place. Two main sleep and behavioural disorder diagnostic manuals have now officially recognised the importance of these processes for human health and well-being. The body's ability to respond to daily demands with the least amount of effort is maximised by carefully timing and integrating all components of sleep and waking. In the brain, the organization of timing is essential for optimal brain physiology.

Fil: Karthikeyan, Ramanujam. School of Biological Sciences. Department of Animal Behavior & Physiology; India Fil: Cardinali, Daniel Pedro. Pontificia Universidad Católica Argentina. Facultad de Ciencias Medicas; Argentina Fil: Shakunthala, Venkat. University of Mysuru. Department of Zoology; India Fil: Spence, David Warren. Independent Research Consultant; Canada Fil: Brown, Gregory M. University of Toronto. Department of Psychiatry. Centre for Addiction and Mental Health. Molecular Brain Science; Canada Fil: Pandi Perumal, Seithikurippu R. Somnogen Canada Inc.; Canada Abstract: Sleep difficulties are one of the significant complications associated with autism spectrum disorder (ASD). Despite their possible role as contributors to the overall symptoms of ASD, the symptoms of disturbed sleep experienced by many affected patients have only recently started to receive attention from clinicians, caretakers, and family members. Many types of sleep disorders have been reported in ASD individuals, but these have not been categorized under a common terminology. Nevertheless, several studies have established that a positive relationship exists between the occurrence of sleep difficulties and heightenedsymptomatology in ASD children. When ASD children show evidence of sleep problems there is also an increased frequency of behavioral problems such as social impairment, decreased cognitive functioning, aggressiveness, and anxiety. Several hypotheses have been put forward regarding the linkage between disturbed sleep and ASD. These have included suggestions that sleep difficulties and other ASD symptoms are induced by disruption of the circadian clock, the presence of comorbid physical or psychological conditions, elevated anxiety levels, or emotional distress. This article reviews the use of sleep therapies in ASD, among which melatonin has shown promise because of its lack ofsignificant side effects. A better understanding of sleep problems in the etiology of ASD, their impact on the symptoms and behavior of ASD individuals, and their potential use as a secondary aid for treating ASD would represent a significant contribution todevelop strategies to manage the disorder.

Background: Sleep disturbances are a common symptom of major depressive disorder (MDD). Sleep is highly regulated by circadian rhythms, controlled by circadian genes, that act through a series of f...

Mood disorders are wide spread with estimates that one in seven of the population are affected at some time in their life (Kessler et al., 2012). Many of those affected with severe depressive disorders have cognitive deficits which may progress to frank neurodegeneration. There are several peripheral markers shown by patients who have cognitive deficits that could represent causative factors and could potentially serve as guides to the prevention or even treatment of neurodegeneration. Circadian rhythm misalignment, immune dysfunction and oxidative stress are key pathologic processes implicated in neurodegeneration and cognitive dysfunction in depressive disorders. Novel treatments targeting these pathways may therefore potentially improve patient outcomes whereby the primary mechanism of action is outside of the monoaminergic system. Moreover, targeting immune dysfunction, oxidative stress and circadian rhythm misalignment (rather than primarily the monoaminergic system) may hold promise for truly disease modifying treatments that may prevent neurodegeneration rather than simply alleviating symptoms with no curative intent. Further research is required to more comprehensively understand the contributions of these pathways to the pathophysiology of depressive disorders to allow for disease modifying treatments to be discovered.

Fil: Brown, Gregory M. Univeridad de Toronto. Centro para la Adicción y la Salud Mental. Ciencias Moleculares del Cerebro; Canadá Fil: Pandi Perumal, Seithikurippu R. Universidad Saveetha. Instituto Saveetha de Medicina y Ciencias Médicas. Hospital Universitario Saveetha; India Fil: Pandi Perumal, Seithikurippu R. Somnogen Canada Inc.; Canadá Fil: Pupko, Harold. Investigador independiente; Canadá Fil: Kennedy, James L. Univeridad de Toronto. Centro para la Adicción y la Salud Mental. Ciencias Moleculares del Cerebro; Canadá Fil: Cardinali, Daniel Pedro. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas; Argentina Abstract: This brief review was written to provide a perspective on the flurry of reports suggesting that melatonin can be an important add-on therapy for COVID-19. Despite the passage of more than 60 years since its discovery and much evidence representing the contrary, there has been great reluctance to conceive melatonin as anything other than a hormone. Many other body chemicals are known to have multiple roles. Melatonin was first shown to be a hormone derived from the pineal gland, to be actively synthesized there only at night, and to act on targets directly or via the G-proteincoupled receptors (GPCRs) superfamily. It is of note that over 40 years ago, it was also established that melatonin is present, synthesized locally, and acts within the gastrointestinal tract. A wider distribution was then found, including the retina and multiple body tissues. In addition, melatonin is now known to have non-hormonal actions, acting as a free radical scavenger, an antioxidant, and as modulating immunity, dampening down innate tissue responses to invaders while boosting the production of antibodies against them. These actions make it a potentially excellent weapon against infection by the SARS-CoV-2 virus. Early published results support that thesis. Recently, a randomized controlled study reported that low doses of melatonin significantly improved symptoms in hospitalized COVID-19 patients, leading to more rapid discharge with no side effects, while significantly decreasing levels of CRP, proinflammatory cytokines, and modulating dysregulated genes governing cellular and humoral immunity. It is now critical that these trials be repeated, with dose-response studies conducted and safety proven. Numerous randomized controlled trials are ongoing, which should complete those objectives while also allowing for a more thorough evaluation of the mechanisms of action and possible applications to other severe diseases.

Fil: Zaki, Nevin F. W. Mansoura University. Faculty of Medicine. Department of Psychiatry; Egipto Fil: Spence, David Warren. Investigador independiente; Canadá Fil: BaHammam, Ahmed S. King Saud University. College of Medicine. University Sleep Disorders Center; Arabia Saudita Fil: Pandi Perumal, Seithikurippu R. Somnogen Inc; Estados Unidos Fil: Cardinali, Daniel Pedro. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Cardinali, Daniel Pedro. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Cardinali, Daniel Pedro. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Departamento de Docencia e Investigación; Argentina Fil: Brown, Gregory M. University of Toronto. Department of Psychiatry. Centre for Addiction and Mental Health; Canadá Abstract: Major depressive disorder (MDD) remains the most prevalent mental disorder and a leading cause of disability, affecting approximately 100 million adults worldwide. The disorder is characterized by a constellation of symptoms affecting mood, anxiety, neurochemical balance, sleep patterns, and circadian and/or seasonal rhythm entrainment. However, the mechanisms underlying the association between chronobiological parameters and depression remain unknown. A PubMed search was conducted to review articles from 1979 to the present, using the following search terms: "chronobiology," "mood," "sleep," and "circadian rhythms." We aimed to synthesize the literature investigating chronobiological theories of mood disorders. Current treatments primarily include tricyclic antidepressants and selective serotonin reuptake inhibitors, which are known to increase extracellular concentrations of monoamine neurotransmitters. However, these antidepressants do not treat the sleep disturbances or circadian and/or seasonal rhythm dysfunctions associated with depressive disorders. Several theories associating sleep and circadian rhythm disturbances with depression have been proposed. Current evidence supports the existence of associations between these, but the direction of causality remains elusive. Given the existence of chronobiological disturbances in depression and evidence regarding their treatment in improving depression, a chronobiological approach, including timely use of light and melatonin agonists, could complement the treatment of MDD.

Fil: Zaki, Nevin F. W. Mansoura University. Faculty of Medicine. Department of Psychiatry. Sleep Research Unit; Egipto Fil: Spence, David Warren. Investigador Independiente; Canada Fil: BaHammam, Ahmed S. King Saud University. College of Medicine. University Sleep Disorders Center; Arabia Saudita Fil: Pandi Perumal, Seithikurippu R. Somnogen Canada Inc.; Canada Fil: Cardinali, Daniel Pedro. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Cardinali, Daniel Pedro. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Brown, Gregory M. University of Toronto. Centre for Addiction and Mental Health. Department of Psychiatry; Canada Abstract: We read with interest the letter to editor by Bernstein et al. [1], in response to our recently published paper [12]. Unfortunately, Bernstein et al. [1] mistakenly assumed that our literature search did not provide appropriate citations. They also state that we failed to mention the already existing literature on circadian and seasonal changes of the suprachiasmatic nucleus (SCN) in mentally health and in disease. Their comments concern a particular reference to alterations of the chemical composition of this nucleus in depression in humans. In particular, they complain that the significant contributions of Bernstein and colleagues and Swaab and colleagues (referenced elsewhere, Bernstein et al. [1]) were not cited in our paper.

Patients with Autism Spectrum Disorder (ASD) may be particularly prone to develop COVID-19. An unusual extended course of COVID-19 disease illness has been reported in one ASD patient and a group of patients have COVID-19 disease in a neurodevelopmental facility. It has been widely reported that many of those with ASD have substantial sleep disorders with low levels of melatonin and various genetic alterations related to melatonin production have been found. Several lines of evidence point to a substantial role of melatonin in the body's innate defense system including acting as a scavenger, an antioxidant and modulating the immune system. We therefore hypothesize that melatonin deficiency may predispose those ASD patients who have low melatonin output to COVID-19 disease. Potential implications for treatment are discussed.

Emergency departments (ED) are prime locations for identifying individuals at high risk of suicide and for making life-saving interventions. In an ideal scenario, all ED patients at risk of suicide could be identified and connected with effective, feasible interventions, and this would occur in a supportive system not overburdened by screening or assessment requirements. In this review, we focus on challenges to achieving this ideal--along with potential solutions--at the level of patients, providers, the ED environment, and the larger health care system.

Fil: Cardinali, Daniel Pedro. Pontificia Universidad Católica Argentina. Facultad de Ciencias Medicas; Argentina Fil: Brown, Gregory M. University of Toronto. Department of Psychiatry. Centre for Addiction; Canadá Fil: Pandi Perumal, Seithikurippu R. Somnogen Canada Inc; Canadá Abstract: The therapeutic potential of melatonin as a chronobiotic cytoprotective agent to counteract the consequences of COVID-19 infections has been advocated. Because of its wide-ranging effects as an antioxidant, anti-inflammatory, and immunomodulatory compound, melatonin could be unique in impairing the consequences of SARS-CoV-2 infection. Moreover, indirect evidence points out to a possible antiviral action of melatonin by interfering with SARS-CoV-2/angiotensin-converting enzyme 2 association. Melatonin is also an effective chronobiotic agent to reverse the circadian disruption of social isolation and to control delirium in severely affected patients. As a cytoprotector, melatonin serves to combat several comorbidities such as diabetes, metabolic syndrome, and ischemic and non-ischemic cardiovascular diseases, which aggravate COVID-19 disease. In view of evidence on the occurrence of neurological sequels in COVID-19-infected patients, another putative application of melatonin emerges based on its neuroprotective properties. Since melatonin is an effective means to control cognitive decay in minimal cognitive impairment, its therapeutic significance for the neurological sequels of SARS-CoV-2 infection should be considered. Finally, yet importantly, exogenous melatonin can be an adjuvant capable of augmenting the efficacy of anti-SARS-CoV-2 vaccines. We discuss in this review the experimental evidence suggesting that melatonin is a potential “silver bullet” in the COVID 19 pandemic.

It has been established that 4.4 to 20% of the general population suffers from a major depressive disorder (MDD), which is frequently associated with a dysregulation of normal sleep-wake mechanisms. Disturbances of circadian rhythms are a cardinal feature of psychiatric dysfunctions, including MDD, which tends to indicate that biological clocks may play a role in their pathophysiology. Thus, episodes of depression and mania or hypomania can arise as a consequence of the disruption of zeitgebers (time cues). In addition, the habit of sleeping at a time that is out of phase with the body's other biological rhythms is a common finding in depressed patients. In this review, we have covered a vast area, emerging from human and animal studies, which supports the link between sleep and depression. In doing so, this paper covers a broad range of distinct mechanisms that may underlie the link between sleep and depression. This review further highlights the mechanisms that may underlie such link (e.g. circadian rhythm alterations, melatonin, and neuroinflammatory dysregulation), as well as evidence for a link between sleep and depression (e.g. objective findings of sleep during depressive episodes, effects of pharmacotherapy, chronotherapy, comorbidity of obstructive sleep apnea and depression), are presented.

Background Emergency departments (EDs) are important for preventing suicide. Historically, many patients with suicide risk are not detected during routine clinical care, and those who are often do not receive suicide-specific intervention. The original Emergency Department Safety Assessment and Follow-up Evaluation (ED-SAFE 1) study examined the implementation of universal suicide risk screening and a multi-component ED-initiated suicide prevention intervention. Purpose The ED-SAFE 2 aims to study the impact of using a continuous quality improvement approach (CQI) to improve suicide related care, with a focus on improving universal suicide risk screening in adult ED patients and evaluating implementation of a new brief intervention called the Safety Planning Intervention (SPI) into routine clinical practice. CQI is a quality management process that uses data and collaboration to drive incremental, iterative improvements. The SPI is a personalized approach that focuses on early identification of warning signs and execution of systematic steps to manage suicidal thoughts. ED-SAFE 2 will provide data on the effectiveness of CQI procedures in improving suicide-related care processes, as well as the impact of these improvements on reducing suicide-related outcomes. Methods Using a stepped wedge design, eight EDs collected data cross three study phases: Baseline (retrospective), Implementation (12 months), and Maintenance (12 months). Lean methods, a specific approach to pursuing CQI which focuses on increasing value and eliminating waste, were used to evaluate and improve suicide-related care. Conclusions The results will build upon the success of the ED-SAFE 1 and will have a broad public health impact through promoting better suicide-related care processes and improved suicide prevention.

Fil: Hardeland, Rüdiger. University of Goettingen. Johann Friedrich Blumenbach Institute of Zoology and Anthropology; Alemania Fil: Cardinali, Daniel Pedro. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Brown, Gregory M. University of Toronto. Faculty of Medicine. Department of Psychiatry; Canada Fil: Pandi Perumal, Seithikurippu R. Clinical & Translational Research Institute. New York University Medical Center. Department of Population Health. Division of Health and Behavior. Center for Healthful Behavior Change; Estados Unidos Abstract: Melatonin is known to possess several properties of value for healthy aging, as a direct and indirect antioxidant, protectant and modulator of mitochondrial function, antiexcitotoxic agent, enhancer of circadian amplitudes, immune modulator and neuroprotectant. It is levels tend to decrease in the course of senescence and are more strongly reduced in several neurodegenerative disorders, especially Alzheimer’s disease, and in diseases related to insulin resistance such as diabetes type 2. Although the role of melatonin in aging and age-related diseases has been repeatedly discussed, the newly emerged concept of inflammaging, that is, the contribution of low-grade inflammation to senescence progression has not yet been the focus of melatonin research. This review addresses the multiple protective actions of melatonin and its kynuramine metabolites that are relevant to the attenuation of inflammatory responses and progression of inflammaging in the brain, i.e. avoidance of excitotoxicity, reduction of free radical formation by support of mitochondrial electron flux, prevention of NADPH oxidase activation and suppression of inducible nitric oxide synthase, as well as downregulation of proinflammatory cytokines. The experimental evidence is primarily discussed on the basis of aging and senescence-accelerated animals, actions in the immune system, and the relationship between melatonin and sirtuins, having properties of aging suppressors. Sirtuins act either as accessory components or downstream factors of circadian oscillators, which are also under control by melatonin. Inflammaging is assumed to strongly contribute to neurodegeneration of the circadian master clock observed in advanced senescence and, even more, in Alzheimer’s disease, a change that affects countless physiological functions.

Introduction: Our goal was to explore whether emergency department (ED) patients would disclose their sexual orientation in a research evaluation and to examine demographic and clinical characteristics of patients by self-identified sexual orientation. Methods: Participants (n=177) presented for psychiatric treatment at three urban EDs in New York City, Rochester, NY, and Philadelphia, PA. Participants were interviewed in the context of a larger study of a standardized suicide risk assessment. We assessed participants’ willingness to answer questions regarding sexual orientation along three dimensions: a self-description of sexual orientation, a self-description of sexual attraction, and the gender of any prior sexual partners. Results: No participants (0/177) refused to respond to the categorical question about sexual orientation, 168/177 (94.9%) agreed to provide information about prior sexual partners, and 100/109 (91.7%) provided information about current sexual attraction toward either gender. Of all 177 participants, 154 (87.0%) self-identified as heterosexual, 11 (6.2%) as bisexual, 10 (5.6%) as gay or lesbian, and 2 (1.1%) indicated they were not sure. As compared with heterosexual patients, lesbian, gay and bisexual (LGB) patients were significantly younger and more likely to be non-white, but did not differ significantly in terms of education, income, employment, or religious affiliation or participation. Further, LGB participants did not differ from self-identified heterosexual participants for lifetime suicide attempt rate or lifetime history of any mood, substance-related, psychotic spectrum, or other Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) Axis I disorder. Of self-identified heterosexual participants 5.6% (5/89) reported sexual attraction as other than ‘only opposite sex,’ and 10.3% (15/142) of sexually active ‘heterosexual’ participants reported previous same-gender sexual partners. Conclusion: Assessing patients’ sexual orientation in the ED by a three-question approach appeared feasible in the ED and acceptable to ED patients. However, since many patients have sexual experiences not suggested by simple labels, self-report of sexual identity alone may not inform clinicians of health risks inherent in same or opposite gender sexual contact. [West J Emerg Med. 2015;16(1):–0.]

Insomnia is common among elderly people and nearly 30 to 40% of the adult population also suffer from insomnia. Pharmacological treatment of insomnia include the use of benzodiazepine and non-benzodiazepine drugs like zolpidem, zaleplon, Zopiclone. Although these drugs improve sleep, their usage is also associated with number of adverse effects, Melatonin, the hormone secreted by the pineal gland of all animals and human beings has been used for treatment of insomnias, since the timing of its secretion in humans as well as in most of the animals coincides with the increase of nocturnal sleep propensity. Because of its short half life, melatonin slow release preparations were introduced for treatment of insomnia. Recently ramelteon, a selective MT1, MT2 receptor agonist with greater efficacy of action in treating insomnia has been used clinically and has been found effective in improving sleep quality, sleep efficacy and also in reducing the sleep onset time when compared to melatonin or slow melatonin preparations. The mechanism of action of ramelteon in improving sleep is discussed in the paper. Another melatonergic drug agomelatine besides acting on MT1/MT2 receptors also displays 5-HT2c antagonism and this drug has been found effective as a novel antidepressant for treating major depressive disorders. Agomelatine besides causing remission of depressive symptoms also improves sleep quality and efficiency. Other antidepressants depressants that are in clinical use today do not improve sleep. There are other melatonergic drugs like tasimelteon, 6-chloromelatonin. But ramelteon and agomelatine deserve special attention for treatment of insomnia and sleep disturbances associated with depressive disorders and have promising role for treatment of sleep disorders.

The last decade has witnessed the emergence of new chronopharmacological perspectives. In the case of sleep disorders, the accumulating evidence suggests that even a minor dysfunction in the biological clock can impact broadly upon body physiology causing increases in sleep onset latency, phase delays or advances in sleep initiation, frequent nocturnal awakenings, reduced sleep efficiency, delayed and shortened rapid eye movement sleep and increased periodic leg movements, among others. Thus, restoration of the adequate circadian pattern of proper sleep hygiene, targeted exposure to light and the use of chronobiotic drugs, such as melatonin, which affect the output phase of clock-controlled circadian rhythms, can help to recover the sleep–wake cycle. The optimization of drug effects and/or minimization of toxicity by timing medications with regard to biological rhythms is known as chronotherapeutics. While chronotherapeutical approaches have been particularly successful in the treatment of hypertension, allergies and some forms of cancer, a time-dependent pharmacological approach can be also effective when dealing with sleep disruptions like insomnia. A large proportion of patients under benzodiazepine (BZD)/Z drug treatment fail to achieve a complete and sustained recovery and are left with residual symptoms, like tolerance or dependency, that make relapse or recurrence more likely, and poorer quality of life a reality. Thus the chronic and extensive use of BZD/Z drugs has become a public health issue and has led to multiple campaigns to reduce both prescription and consumption of BZD/Z-drugs. This short review discusses available data on the efficacy of melatonin to reduce chronic BZD use in insomnia patients. Fil: Golombek, Diego Andres. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnologia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Pandi Perumal, Seithikurippu R.. Somnogen Canada; Canadá Fil: Brown, Gregory M.. University of Toronto; Canadá Fil: Cardinali, Daniel Pedro. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Facultad de Ciencias Médicas. Departamento de Docencia e Investigación; Argentina

Ramanujam Karthikeyan,1 Ganapathy Marimuthu,1 Chellamuthu Ramasubramanian,2 Gautham Arunachal,2 Ahmed S BaHammam,3 David Warren Spence,4 Daniel P Cardinali,5 Gregory M Brown,6 Seithikurippu R Pandi-Perumal7 1Department of Animal Behaviour and Physiology, School of Biological Sciences, Madurai Kamaraj University, Madurai, India; 2MS Chellamuthu Trust and Research Foundation, KKNagar, Madurai, India; 3University Sleep Disorders Center, College ofMedicine, National Plan for Science and Technology, King Saud University, Riyadh, Saudi Arabia; 4Independent researcher, Toronto, Ontario, Canada; 5Department ofTeaching and Research, Faculty of Medical Sciences, Pontificia Universidad Católica Argentina, Buenos Aires, Argentina; 6Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada; 7Center for Healthful Behavior Change (CHBC), Division of Health and Behavior, Department of Population Health, NYU Langone Medical Center, Clinical and Translational Research Institute, New York, New York, USA Background: Sleep–wake disturbances have frequently been reported in bipolar disorder and schizophrenia, and are considered to be caused by an underlying circadian rhythm disorder. The study presented here was designed to investigate the existence of Per3 polymorphism in bipolar disorder type I (BD-I) and schizophrenic patients in South India.Methods: Blood samples were collected from 311 BD-I patients, 293 schizophrenia patients, and 346 age- and sex-matched normal controls. Per3 genotyping was performed on DNA by polymerase chain reaction using specific primers.Results: An increased prevalence of five repeat homozygotes was seen in BD-I patients as compared with healthy controls (odds ratio =1.72 [95% confidence interval: 1.08–2.76, P=0.02]). In BD-I patients, the frequency of the five repeat allele was higher (allele frequency =0.41), and that of the four repeat allele lower (allele frequency =0.36) (χ2=4.634; P