Melatonin (MEL) and its use in neurological diseases and insomnia: Recommendations of the French Medical and Research Sleep Society (SFRMS)

The French Medicine and Research Sleep Society had organized a consensus conference about sleep/wake circadian rhythms and their disorders. During this conference a subgroup of 11 sleep doctors/researchers looked specifically at the use of MEL in different pathologies. This article gives a summary of the main results of MEL therapy in some neurological diseases and insomnia approved by this consensus group. Exogenous MEL, which crosses the blood-brain barrier, has been used as a treatment in its two available forms: an immediate release form that principally shows a chronobiotic action and a long release form that mimics the physiological MEL secretion rhythm and is used to replace reduced physiological secretion. MEL secretion decreases frequently with age, mostly in elderly insomniacs and dementia patients. Results of level A studies show that MEL therapy, used as an add-on treatment, has beneficial effects in mild cognitive impairment (MCI) and Alzheimer patients with sleep disorders in improving sleep quality and in regulating the sleep/wake rhythm. MEL has to be prescribed as early as possible and for a long period, at a dose of 2 to 5 or 10 mg. It may have a beneficial effect on cognitive function in MCI but shows no effect in moderate to severe Alzheimer's disease. It should be emphasized that there are no serious side effects with MEL treatment. In these diseases, light therapy used 12 hours before melatonin treatment has a positive synergic effect. In REM sleep behavior disorder, immediate release MEL should be prescribed first as its side effect profile is much better than clonazepam shortly before bedtime. MEL has a good efficacy on clinical symptoms and PSG REM sleep without atonia episodes and is well tolerated. In Parkinson disease with sleep disorders and without REM sleep behavior disorder, MEL seems to improve subjective sleep quality but no conclusions can be drawn. There is insufficient scientific proof for using MEL as a prophylactic treatment in primary headache, migraine and cluster headache. In epileptic patients, MEL can be safely used to regulate the sleep/wake rhythm and to improve insomnia but more randomized controlled studies are necessary. In primary or no-comorbid insomnia, only a 2 mg dose of slow release MEL, 1 to 2 hours before bedtime, over a period of 3 to 12 weeks, is recommended. It decreases sleep onset latency, improves quality of sleep, morning alertness and quality of life without serious side effects and without withdrawal symptoms.     

Circadian rhythm in bipolar disorder: A review of the literature

Sleep disturbances and circadian rhythm dysfunction have been widely demonstrated in patients with bipolar disorder (BD). Irregularity of the sleep–wake rhythm, eveningness chronotype, abnormality of melatonin secretion, vulnerability of clock genes, and the irregularity of social time cues have also been well‐documented in BD. Circadian rhythm dysfunction is prominent in BD compared with that in major depressive disorders, implying that circadian rhythm dysfunction is a trait marker of BD. In the clinical course of BD, the circadian rhythm dysfunctions may act as predictors for the first onset of BD and the relapse of mood episodes. Treatments focusing on sleep disturbances and circadian rhythm dysfunction in combination with pharmacological, psychosocial, and chronobiological treatments are believed to be useful for relapse prevention. Further studies are therefore warranted to clarify the relation between circadian rhythm dysfunction and the pathophysiology of BD to develop treatment strategies for achieving recovery in BD patients.     

A practical approach to circadian rhythm sleep disorders

Circadian rhythm sleep disorders are common in clinical practice. The disorders covered in this review are delayed sleep phase disorder, advanced sleep phase disorder, free-running, irregular sleep-wake rhythm, jet lag disorder and shift work disorder. Bright light treatment and exogenous melatonin administration are considered to be the treatments of choice for these circadian rhythm sleep disorders. Circadian phase needs to be estimated in order to time the treatments appropriately. Inappropriately timed bright light and melatonin will likely worsen the condition. Measurements of core body temperature or endogenous melatonin rhythms will objectively assess circadian phase; however, such measurements are seldom or never used in a busy clinical practice. This review will focus on how to estimate circadian phase based on a careful patient history. Based on such estimations of circadian phase, we will recommend appropriate timing of bright light and/or melatonin in the different circadian rhythm sleep disorders. We hope this practical approach and simple recommendations will stimulate clinicians to treat patients with circadian rhythm sleep disorders.     

How the circadian rhythm affects sleep, wakefulness, and overall health: background for understanding shift work disorder

It is estimated that 15 to 25% of the U.S. labor force works night, evening, or rotating shifts. These non-traditional schedules can affect the circadian rhythm, a self-sustained rhythm of biological processes that plays an important role in modulating sleep/wake function, resulting in circadian rhythm sleep disorder, shift work type, usually referred to as shift work disorder. The disorder consists of a constant or recurrent pattern of sleep interruption that results in insomnia when sleep is needed and excessive sleepiness during waking hours. Clinicians need more information about the role of the circadian rhythm in human functioning as well as the pathophysiology, prevalence, and consequences of shift work disorder, so that they can recognize and diagnose this problem in clinical practice.     

Prevalence and patterns of problematic sleep among older adolescents

OBJECTIVE: Despite many constraints on time schedules among teenagers, epidemiological data on sleep complaints in adolescence remain limited and are nonexistent for sleep disorders. This study provides additional data on sleep habits and DSM-IV sleep disorders in late adolescence. METHOD: A representative sample of 1,125 adolescents aged 15 to 18 years was interviewed by telephone using the Sleep-EVAL system. These adolescents came from 4 European countries: France, Great Britain, Germany, and Italy. Information was collected about sociodemographic characteristics, sleep/wake schedule, sleep habits, and sleep disorders and was compared with information from 2,169 young adults (19-24 years of age). RESULTS: Compared with young adults, adolescents presented with a distinct sleep/wake schedule: they went to sleep earlier, they woke up later, and they slept longer than young adults did. On weekends and days off, they also slept more than young adults did. However, the prevalence rates of sleep symptoms and sleep disorders were comparable in both groups. Approximately 25% reported insomnia symptoms and approximately 4% had a DSM-IV insomnia disorder. Fewer than 0.5% had a circadian rhythm disorder. CONCLUSIONS: Prevalence of insomnia disorders is lower in the adolescent population than in middle-aged or elderly adults. However, a rate of 4% in this young population is important given their young age and the consequences for daytime functioning.     

Objective investigation of the sleep–wake cycle in adults with intellectual disabilities and autistic spectrum disorders

Background Disturbances in circadian rhythm functioning, as manifest in abnormal sleep–wake cycles, have been postulated to be present in people with autistic spectrum disorders (ASDs). To date, research into the sleep–wake cycle in people with ASDs has been primarily dependant on third‐party data collection. Method The utilization of non‐invasive objective recording technologies such as actigraphy permits investigation of both sleep and circadian rhythm functioning in people with ASDs, together with the collection of data on daytime activity. Results Data were collected from 31 participants with intellectual disabilities living in supported community‐based residential provision aged between 20 and 58 years, of whom 14 had an ASD. Analysis indicated that there were no significant differences in sleep patterns and circadian rhythm function between those participants with an ASD and those without. Conclusions The mean scores of the participants as a whole indicated abnormalities in the two key circadian rhythm parameters of interdaily stability and intradaily variability. The implications of these findings for both clinical practice and theory are discussed.     

Sleep and circadian alterations in people at risk for bipolar disorder: A systematic review

BackgroundSleep and circadian abnormalities have been mostly demonstrated in bipolar patients. However, it is not clear whether these alterations are present in population at high risk for bipolar disorder (BD), indicating a possible risk factor for this condition.ObjectiveThis systematic review aims to define current evidence about sleep and rhythm alterations in people at risk for BD and to evaluate sleep and circadian disorders as risk factor for BD.MethodsThe systematic review included all articles about the topic until February 2016. Two researchers performed an electronic search of PubMed and Cochrane Library. Keywords used were ‘sleep’ or ‘rhythm’ or ‘circadian’ AND ‘bipolar disorder’ or ‘mania’ or ‘bipolar depression’ AND ‘high-risk’ or ‘risk’.ResultsThirty articles were analyzed (7451 participants at risk for BD). Sleep disturbances are frequent in studies using both subjective measures and actigraphy. High-risk individuals reported irregularity of sleep/wake times, poor sleep and circadian rhythm disruption. Poor sleep quality, nighttime awakenings, and inadequate sleep are possible predictive factors for BD. A unique study suggested that irregular rhythms increase risk of conversion. People at risk for BD showed high cortisol levels in different times of day. Studies about anatomopathology, melatonin levels, inflammatory cytokines and oxidative stress were not identified. The most important limitations were differences in sleep and rhythm measures, heterogeneity of study designs, and lack of consistency in the definition of population at risk.ConclusionSleep and circadian disturbances are common in people at risk for BD. However, the pathophysiology of these alterations and the impact on BD onset are still unclear.     

Disorder of the saliva melatonin circadian rhythm in patients with Meniere's disease

OBJECTIVES: Stress is involved in the development of symptoms of Meniere's disease (MD). Stress-related disease has been reported to be associated with disorders in the circadian rhythm of melatonin (MEL) which regulates that rhythm. We therefore investigated MEL circadian rhythm of patients with MD. PATIENTS AND METHODS: A comparison of 13 MD patients was made with age-matched controls. Saliva samples were collected every 3 h. A statistical analysis of the circadian rhythm of saliva MEL was performed for a circadian rhythm by the fit of a 24- and 12-h composite cosine model. In addition, we assessed the stress and depression status of the two groups. RESULTS: The rhythmic amplitude of MEL in the MD group was significantly lower than that in the control group (P < 0.05). The acrophase in the MD group was significantly earlier than that in the control group (P < 0.05). MD patients had significantly higher stress score and depression score than control subjects (P < 0.05). The amplitude in MD patients had no significant correlation with their otologic clinical data. CONCLUSIONS: These results suggest that MD patients have a MEL deficiency, which is related to their stress and depression status rather than the otologic pathological status of MD.     

Circadian rhythms and sleep in bipolar disorder

Murray G, Harvey A. Circadian rhythms and sleep in bipolar disorder.
Bipolar Disord 2010: 12: 459–472. © 2010 The Authors. Journal compilation © 2010 John Wiley & Sons A/S. Objective: Biological rhythm pathways are highlighted in a number of etiological models of bipolar disorder, and the management of circadian instability appears in consensus treatment guidelines. There are, however, significant conceptual and empirical limitations on our understanding of a hypothesised link between circadian, sleep, and emotion regulation processes in bipolar disorder. The aim of this article is to articulate the limits of scientific knowledge in relation to this hypothesis. Methods: A critical evaluation of various literatures was undertaken. The basic science of circadian and sleep processes, their involvement in normal emotion regulation, and the types of evidence suggesting circadian/sleep involvement in bipolar disorder are reviewed. Results: Multiple lines of evidence suggest that circadian and sleep‐wake processes are causally involved in bipolar disorder. These processes demonstrably interact with other neurobiological pathways known to be important in bipolar disorder, but are unique in that they are open to behavioural manipulation. Conclusion: Further research into biological rhythm pathways to bipolar disorder is warranted. Person‐environment feedback loops are fundamental to circadian adaptation, and models of circadian pathogenesis (and treatment) should recognize this complexity.     

Clinical features of circadian rhythm sleep disorders in outpatients

The clinical data of 86 cases of primary circadian rhythm sleep disorder (primary CRSD) were retrospectively examined and compared to 40 cases of secondary circadian rhythm sleep disorder (secondary CRSD), who had presented with some kind of psychiatric or medical disorder, and had exhibited sleep-wake rhythm disorders that were judged to be secondary CRSD based on sleep logs. The comparison of cases found that: (i) the mean age at first presentation to the clinic was significantly younger for primary CRSD compared to secondary CRSD; (ii) more secondary CRSD cases were unemployed than were Primary CRSD cases; (iii) more cases in the secondary CRSD group had a clear trigger for sleep-wake rhythm disorder onset than cases in the primary CRSD group; and (iv) the types of sleep-wake rhythm disorders in the primary CRSD group consisted of delayed sleep phase syndrome (DSPS), 72 (83.7%), non-24 pattern, 11 (12.8%), and irregular, 3 (3.5%). In the secondary CRSD group there were 25 (62.5%) cases of DSPS pattern, 1 (2.5%) of non-24 pattern and 14 (35.0%) with irregular pattern. The 56 (65.1%) cases with primary CRSD showed good response to vitamin B12 and bright light therapy; however, 28 (70.0%) cases with secondary CRSD did not respond to such therapies.     

A clinical approach to circadian rhythm sleep disorders

Circadian rhythm sleep disorders are characterized by complaints of insomnia and excessive sleepiness that are primarily due to alterations in the internal circadian timing system or a misalignment between the timing of sleep and the 24-h social and physical environment. In addition to physiological and environmental factors, maladaptive behaviors often play an important role in the development of many of the circadian rhythm sleep disorders. This review will focus on the clinical approach to the diagnosis and management of the various circadian rhythm sleep disorders, including delayed sleep phase disorder, advanced sleep phase disorder, non-entrained type, irregular sleep-wake rhythm, shift work sleep disorder and jet lag disorder. Diagnostic tools such as sleep diaries and wrist activity monitoring are often useful in confirming the diagnosis. Because behavioral and environmental factors often are involved in the development of these conditions, a multimodal approach is usually necessary. Interventions include sleep hygiene education, timed exposure to bright light as well as avoidance of bright light at the wrong time of the day and pharmacologic approaches, such as melatonin. However, it should be noted that the use of melatonin is not an FDA-approved indication for the treatment of circadian rhythm sleep disorders.     

Comment caractériser et traiter les plaintes de sommeil dans les troubles bipolaires ?

Objectives

Sleep complaints are very common in bipolar disorders (BD) both during acute phases (manic and depressive episodes) and remission (about 80 % of patients with remitted BD have poor sleep quality). Sleep complaints during remission are of particular importance since they are associated with more mood relapses and worse outcomes. In this context, this review discusses the characterization and treatment of sleep complaints in BD.

Systematic evaluation of Axis-I DSM diagnoses in delayed sleep phase disorder and evening-type circadian preference

BackgroundAlterations in circadian rhythms can have profound effects on mental health. High co-morbidity for psychiatric disorders has been observed in patients with circadian rhythm disorders, such as delayed sleep phase disorder (DSPD), and in those with an evening-type circadian preference. The aim of this study was to systematically determine the prevalence and type of Diagnostic and Statistical Manual of Mental Disorders fourth edition (DSM IV) Axis-I disorders in those with DSPD compared to evening-type controls.MethodsForty-eight DSPD and 25 evening-type participants took part in this study. Sleep and wake parameters were assessed with actigraphy, diary and questionnaires (Pittsburgh Sleep Quality Index (PSQI) and Functional Outcomes of Sleep Questionnaire (FOSQ). Evening-type preference was defined by the Horne–Ostberg questionnaire. DSPD was determined by an interview according to International Classification of Sleep Disorders criteria. Current and past diagnoses of psychiatric disorders were assessed with a Structured Clinical Interview for DSM-IV disorders.ResultsDSPD was associated with a later wake time, longer sleep time, higher PSQI score and lower Horne–Ostberg and FOSQ scores compared to evening-types. There were no significant differences in the prevalence or type of Axis-I disorders between those with DSPD or evening-type preference. Over 70% of participants met criteria for at least one past Axis-I disorder. Approximately 40% of both the DSPD and evening-types met criteria for a past diagnosis of mood, anxiety (most frequently phobia) or substance-use disorders. Evening types were more likely to have a past diagnosis of more than one Axis-I disorder.ConclusionsThese results highlight the important link between circadian rhythms and mental disorders. Specifically, an evening circadian chronotype regardless of DSPD status is associated with a risk for anxiety, depressive or substance-use disorders.     

Neurobiology of circadian rhythm sleep disorders

To adapt to a 24-hour environment, nearly all organisms, from mammals to single-celled organisms, have developed endogenous mechanisms that generate nearly 24-hour (circadian) rhythms in physiology and behavior, the most notable being that of the daily cycles of sleep and wake. Disruption of these circadian rhythms is often accompanied by disorders of sleep and wakefulness. With the recent advances in the molecular biology that underlies the development and maintenance of these rhythms, the pathophysiology behind circadian rhythm sleep disorders is becoming better understood.     

Neurobiology of circadian rhythm sleep disorders

To adapt to a 24-hour environment, nearly all organisms, from mammals to single-celled organisms, have developed endogenous mechanisms that generate nearly 24-hour (circadian) rhythms in physiology and behavior, the most notable being that of the daily cycles of sleep and wake. Disruption of these circadian rhythms is often accompanied by disorders of sleep and wakefulness. With the recent advances in the molecular biology that underlies the development and maintenance of these rhythms, the pathophysiology behind circadian rhythm sleep disorders is becoming better understood.     

Circadian Rhythm Hypotheses of Mixed Features,Antidepressant Treatment Resistance,and Manic Switching in Bipolar Disorder

Numerous hypotheses have been put forth over the years to explain the development of bipolar disorder. Of these, circadian rhythm hypotheses have gained much importance of late. While the hypothalamus-pituitary-adrenal (HPA) axis hyperactivation hypothesis and the monoamine hypothesis somewhat explain the pathogenic mechanism of depression, they do not provide an explanation for the development of mania/hypomania. Interestingly, all patients with bipolar disorder display significant disruption of circadian rhythms and sleep/wake cycles throughout their mood cycles. Indeed, mice carrying the Clock gene mutation exhibit an overall behavioral profile that is similar to human mania, including hyperactivity, decreased sleep, lowered depression-like behavior, and lower anxiety. It was recently reported that monoamine signaling is in fact regulated by the circadian system. Thus, circadian rhythm instability, imposed on the dysregulation of HPA axis and monoamine system, may in turn increase individual susceptibility for switching from depression to mania/hypomania. In addition to addressing the pathophysiologic mechanism underlying the manic switch, circadian rhythm hypotheses can explain other bipolar disorder-related phenomena such as treatment resistant depression and mixed features.     

Circadian rhythm sleep disorders in adolescents: clinical trials of combined treatments based on chronobiology

Delayed sleep phase syndrome (DSPS) and non-24-h sleep-wake rhythm are circadian rhythm sleep disorders that are common in adolescents. Most patients have difficulty adjusting to school life, poor class attendance or refuse to go to school. Since a treatment has not been established, the present paper is presented to propose a strategy for treating circadian rhythm sleep disorders in adolescents, based on our clinical studies. Twenty subjects (12 males and eight females, mean age 16.2+/-1.7 years) participated in the study. The onset of sleep disorder occurred between the ages of 11 and 17. The most common factors affecting the onset of disorders were changes in social environment. The subjects kept a sleep-log for the periods before and during treatments. The treatments were based on chronobiology: resetting the daily life schedule, chronotherapy, regulation of the lighting environment, methylcobalamin, and/or melatonin. Bright light exposure was successful in 10 patients, of whom four were treated with methylcobalamin. Melatonin treatment was successful in two patients (one with and one without chronotherapy). Thirteen of the 20 patients were successfully, treated with therapies based on chronobiology. After consideration of these results, a step-by-step procedure of combined treatments for the circadian rhythm sleep disorders is proposed.     

Circadian rhythm sleep disorders in the blind and their treatment with melatonin

People who are blind, in addition to having to cope with partial or no sight, have an added handicap; the transmission of ocular light from the retina to their circadian clock is impaired. At its worse, for example in people with both eyes enucleated, this lesion results in desynchronisation of the biological clock (located in the hypothalamic suprachiasmatic nuclei) from the 24h day/night environment. While in a desynchronised state, symptoms akin to jet lag are experienced (e.g., daytime sleepiness, poor night sleep, reduced alertness and performance during waking). This is a lifelong condition. Daily administration of exogenous melatonin is the current treatment of choice for this so-called "non-24h sleep/wake disorder". Melatonin has been shown to correct the underlying circadian rhythm abnormality as well as improve sleep and reduce daytime napping. The effectiveness of melatonin therapy depends upon its time of administration relative to the timing of the person's circadian clock. If practicable, assessment of an individual's circadian phase (by measurement of the endogenous melatonin rhythm in plasma, saliva or urine) is recommended prior to commencing treatment to optimise melatonin's effectiveness.