Adam Moscovitch

Bidirectional communication between sleep and circadian rhythms and its implications for depression: Lessons from agomelatine

Depression is a family of complex and multifactorial illnesses that are characterized by disruptions in the functioning of a number of physiological, neuroendocrine and behavioral processes. Of these, sleep disturbance and circadian rhythm abnormalities constitute the most prevalent signs of depressive illness. Difficulty in falling asleep, decreases in total sleep time and sleep efficiency, early morning awakenings, and rapid eye movement sleep alterations are all commonly seen in depressed patients. Advances or delays in the phase of circadian rhythms have been documented in patients with major depressive disorder (MDD), bipolar disorder and patients with seasonal affective disorder (SAD). The disturbances in the amplitude and rhythm of melatonin secretion that occur in patients with depression resemble those seen in subjects with chronobiological disorders. The finding that insomnia and circadian rhythm abnormalities are prominent features in depression suggests that a close link exists between melatonin secretion disturbance and depressed mood. This inference has been further strengthened by the finding that agomelatine, a recently introduced melatonergic agent with a novel mechanism of action, has beneficial effects in patients with MDD, bipolar disorder or SAD. Among agomelatines characteristics are a rapid onset of action and a pronounced effectiveness for improving sleep efficiency and correcting circadian rhythm abnormalities. Disruptions in melatonin secretion or availability may be the common factor, which underlies depressive disorder and its prominent signs and symptoms such as sleep and circadian rhythm abnormalities.

Potential use of melatonergic drugs in analgesia: mechanisms of action.

Melatonin is a remarkable molecule with diverse physiological functions. Some of its effects are mediated by receptors while other, like cytoprotection, seem to depend on direct and indirect scavenging of free radicals not involving receptors. Among melatonins many effects, its antinociceptive actions have attracted attention. When given orally, intraperitoneally, locally, intrathecally or through intracerebroventricular routes, melatonin exerts antinociceptive and antiallodynic actions in a variety of animal models. These effects have been demonstrated in animal models of acute pain like the tail-flick test, formalin test or endotoxin-induced hyperalgesia as well as in models of neuropathic pain like nerve ligation. Glutamate, gamma-aminobutyric acid, and particularly, opioid neurotransmission have been demonstrated to be involved in melatonins analgesia. Results using melatonin receptor antagonists support the participation of melatonin receptors in melatonins analgesia. However, discrepancies between the affinity of the receptors and the very high doses of melatonin needed to cause effects in vivo raise doubts about the uniqueness of that physiopathological interpretation. Indeed, melatonin could play a role in pain through several alternative mechanisms including free radicals scavenging or nitric oxide synthase inhibition. The use of melatonin analogs like the MT(1)/MT(2) agonist ramelteon, which lacks free radical scavenging activity, could be useful to unravel the mechanism of action of melatonin in analgesia. Melatonin has a promising role as an analgesic drug that could be used for alleviating pain associated with cancer, headache or surgical procedures.

Measurement of melatonin in body fluids: Standards, protocols and procedures

Background and PurposeThe circadian rhythm of melatonin in saliva or plasma, or of the melatonin metabolite 6-sulfatoxymelatonin (a6MTs) in urine, is a defining feature of suprachiasmatic nucleus (SCN) function, the body’s endogenous oscillatory pacemaker. The primary objective of this review is to ascertain the clinical benefits and limitations of current methodologies employed for detection and quantification of melatonin in biological fluids and tissues.Data IdentificationA search of the English-language literature (Medline) and a systematic review of published articles were carried out.Study SelectionArticles that specified both the methodology for quantifying melatonin and indicated the clinical purpose were chosen for inclusion in the review.Data ExtractionThe authors critically evaluated the methodological issues associated with various tools and techniques (e.g. standards, protocols, and procedures).Results of Data SynthesisMelatonin measurements are useful for evaluating problems related to the onset or offset of sleep and for assessing phase delays or advances of rhythms in entrained individuals. They have also become an important tool for psychiatric diagnosis, their use being recommended for phase typing in patients suffering from sleep and mood disorders. Additionally, there has been a continuous interest in the use of melatonin as a marker for neoplasms of the pineal region. Melatonin decreases such as found with aging are or post pinealectomy can cause alterations in the sleep/wake cycle. The development of sensitive and selective methods for the precise detection of melatonin in tissues and fluids has increasingly been shown to have direct relevance for clinical decision making.ConclusionsDue to melatonin’s low concentration, as well as the coexistence of numerous other compounds in the blood, the routine determination of melatonin has been an analytical challenge. The available evidence indicates however that these challenges can be overcome and consequently that evaluation of melatonins presence and activity can be an accessible and useful tool for clinical diagnosis.

Ramelteon: a Review of its Therapeutic Potential in Sleep Disorders

Ramelteon is a tricyclic synthetic analog of melatonin that acts specifically on MT1 and MT2 melatonin receptors. Ramelteon’s half-life is longer than that of melatonin, being metabolized in the body to four main metabolites, M-I, M-II, M-III, and M-IV. M-II has an affinity to MT1 and MT2 of about one-tenth of the parent compound, but its concentration in the circulation exceeds that of ramelteon by more than an order of magnitude. Ramelteon is effective in decreasing latency to persistent sleep and increasing total sleep time in freely moving monkeys. A number of clinical studies have been undertaken to study the efficacy of ramelteon in subjects with chronic insomnia. In almost all of these studies, ramelteon, in various doses of 4, 8, or 16 mg most commonly, significantly reduced sleep latency and increased sleep duration. Its primary action in sleep promotion is not a generalized gamma-aminobutyric (GABA)-ergic central nervous system depression, but rather it acts as a melatonergic agonist in the suprachiasmatic nucleus (and at other central nervous system sites), from where downstream processes, including GABA-ergic effects, are controlled via the hypothalamic sleep switch. Unlike other commonly prescribed hypnotic drugs, ramelteon is not associated with next morning hangover effects or reductions in alertness, nor has it been shown to cause withdrawal symptoms. The adverse symptoms reported with ramelteon are mild. All long-term investigations that have been carried out support the conclusion that ramelteon is a well tolerated and effective drug for the treatment of insomnia.

Malaria: therapeutic implications of melatonin

Abstract:  Malaria, which infects more than 300 million people annually, is a serious disease. Epidemiological surveys indicate that of those who are affected, malaria will claim the lives of more than one million individuals, mostly children. There is evidence that the synchronous maturation of Plasmodium falciparum, the parasite that causes a severe form of malaria in humans and Plasmodium chabaudi, responsible for rodent malaria, could be linked to circadian changes in melatonin concentration. In vitro melatonin stimulates the growth and development of P. falciparum through the activation of specific melatonin receptors coupled to phospholipase‐C activation and the concomitant increase of intracellular Ca2+. The Ca2+ signaling pathway is important to stimulate parasite transition from the trophozoite to the schizont stage, the final stage of intraerythrocytic cycle, thus promoting the rise of parasitemia. Either pinealectomy or the administration of the melatonin receptor blocking agent luzindole desynchronizes the parasitic cell cycle. Therefore, the use of melatonin antagonists could be a novel therapeutic approach for controlling the disease. On the other hand, the complexity of melatonin’s action in malaria is underscored by the demonstration that treatment with high doses of melatonin is actually beneficial for inhibiting apoptosis and liver damage resulting from the oxidative stress in malaria. The possibility that the coordinated administration of melatonin antagonists (to impair the melatonin signal that synchronizes P. falciparum) and of melatonin in doses high enough to decrease oxidative damage could be a novel approach in malaria treatment is discussed.

Development of an adjective checklist to measure five FACES of fatigue and sleepiness Data from a national survey of insomniacs

Development and initial validation of the FACES of fatigue and sleepiness adjective checklist. An initial item pool of 65 adjectives, descriptive of fatigue, sleepiness and related deprivation states, was developed and administered to 372 individuals referred by their family physicians for psychiatric investigation and treatment of severe insomnia. Participants attended one of six Canadian university-affiliated sleep clinics where they completed a psychiatric assessment and a 766-item questionnaire, including a number of standard indices of sleep-related behavior and symptoms, medical history, sleep hygiene, psychosocial well-being and psychopathology. Principal-components and item analyses were undertaken to refine the initial 65-item pool to a smaller 50-item set, consisting of five subscales: Fatigue, Anergy, Consciousness, Energized and Sleepiness. Coefficient alpha was calculated and indicated high internal consistency reliability for all subscales. Convergent and discriminant validity were also evaluated by calculating correlations between FACES subscales and a number of independent indices. The resulting five-scale FACES questionnaire appears to offer a promising self-report instrument for the measurement of fatigue and related subjective experiences.

Comorbid depression in obstructive sleep apnea: an under-recognized association.

BackgroundObstructive sleep apnea (OSA) and depression may coexist in the same patient. This article aims to review the link between OSA and comorbid depression and critically evaluate the results of studies that assessed the correlation between OSA and depression, the impact of OSA treatment on comorbid depression, and the impact of comorbid depression on continuous positive airway pressure (CPAP) adherence.MethodsAn integrative review was conducted on English language studies and reports that assessed the relationship between OSA and depression. Studies were identified by searching PubMed, Web of Science and Google Scholar databases, and reference lists of included studies.ResultsGenerally, cross-sectional studies show a higher prevalence of depression among OSA patients with both community and sleep disorder clinic samples. Nevertheless, the relationship between OSA and depression is complicated by the fact that the disorders have overlapping symptoms. Longitudinal studies demonstrate an increased risk of developing depression among people with OSA, as well as an association between OSA severity and the likelihood of developing depression. On the other hand, studies assessing the impact of CPAP therapy on depression among OSA patients report conflicting results. Therefore, it is essential to consider how the disorders affect one another and to understand the clinical consequences of treating each disorder in isolation.ConclusionDepression is prevalent among patients with OSA both in the community and in sleep disorder clinics. Clinicians in general should be aware of this significant association and should aim to treat both disorders.

Sleep disturbances and memory impairment among pregnant women consuming khat: An under-recognized problem

Khat (Catha edulis) is a evergreen flowering shrub that is cultivated at high altitudes, especially in East Africa and the southwest of the Arabian Peninsula. The plant contains alkaloids, of which cathinone and cathine have structural similarity and pharmacological action similar to amphetamines. The leaves are, therefore, consumed in some regions as a psychoactive stimulant due to cultural beliefs and misperceptions on the health benefits of khat consumption. This resulted in a growing prevalence of khat consumption among pregnant women. The myriad of physiological changes associated with pregnancy impairs sleep and memory. Moreover, khat has also been shown to have adverse effects on memory and sleep. Therefore, its use during pregnancy may further aggravate those impairments. The purpose of this mini-review is to summarize the changes in sleep and memory during pregnancy and the evidence supporting a relationship between khat consumption and neurocognitive deficits and sleep dysfunctions. The misperceptions of beneficial effects of khat, the high prevalence of consumption among pregnant women, and the possibility of under-reporting of khat abuse do necessitate the development of alternative methodologies to identify cases of unreported khat abuse in pregnant women. It is proposed that screening for sleep problems and memory deficits may help identify under-reported cases of khat abuse in pregnant women.

Dimensionality of the Pittsburgh Sleep Quality Index: a systematic review

BackgroundThe Pittsburgh Sleep Quality Index (PSQI) dimensionality is much debated, with the greatest number of reported factor structures. Therefore, this review appraised the methodologies of studies investigating the factor structure of the PSQI.Material and methodsMEDLINE, PsycInfo, AJOL, BASE, Cochrane Library, Directory of Open Access Journals (Lund University), CINAHL, and Embase were searched systematically to include articles published till 23rd March, 2018. The articles with the objective of factor analysis of the PSQI (20 articles) or with a major section on the same subject (25 articles) were included. There was no limitation about participant characteristics. Descriptive analysis of articles for measures of the suitability of the data for factor analysis, details of the exploratory factor analysis (EFA) and details of the confirmatory factor analysis (CFA) was performed.ResultsThe analysis used by the majority did not employ the simplest scheme for interpreting the observed data: the parsimony principle. Other shortcomings included under- or non-reporting of sample adequacy measures (11 out of 45 articles), non-use of EFA (20 out of 45 articles), use of EFA without relevant details, non-use of CFA (11 out of 45 articles), and use of CFA without relevant details. Overall, 31 out of 45 articles did not use either EFA or CFA.ConclusionWe conclude that the various PSQI factor structures for standard sleep assessment in research and clinical settings may need further validation.Trial registrationNot applicable because this was a review of existing literature.

Electrolyte imbalance and sleep problems during anti-retroviral therapy: an under-recognized problem

Human immunodeficiency virus (HIV) infection, and the anti-retroviral therapy (ART) associated complications necessitate that the medical care system keeps evolving for proper management of this group of patients. Electrolyte imbalance and sleep problems are common in patients on ART. Both of these conditions are associated with increased morbidity (such as acute kidney injury, chronic kidney disease, low CD4 count, non-adherence and depression) and mortality. Therefore, screening for both sleep problems and electrolytes imbalance may help to decrease the risk of complications in patients on ART.