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.     

Circadian rhythm sleep disorders (CRSD)

Circadian Rhythm Sleep Disorders (CRSD) are a group of sleep disorders characterized by a malsynchronization between a person's biological clock and the environmental 24-h schedule. These disorders can lead to harmful psychological and functional difficulties and are often misdiagnosed and incorrectly treated due to the fact that doctors are unaware of their existence. In the following review we describe the characteristics of CRSD, diagnosis, treatment as well as their relationship to psychopathology, psychotropic drugs and head trauma.     

Circadian rhythm sleep disorders and phototherapy.

Circadian rhythm sleep disorders are characterized by a desynchronization between the timing of the intrinsic circadian clock and the extrinsic light-dark and social/activity cycles resulting in symptoms of excessive sleepiness and insomnia. This article explores the six recognized circadian rhythm sleep disorders: delayed sleep phase syndrome, advanced sleep phase syndrome, non-24-hour sleep-wake syndrome, irregular sleep-wake pattern, shift work sleep syndrome, and time zone change syndrome. Additionally discussed are the therapeutic roles of synchronizing agents, such as light and melatonin.     

Circadian rhythm disorders

Circadian rhythm sleep disorders occur when individuals attempt to sleep at the wrong circadian time. The misalignment between the internal circadian timing system and the external environment is typically due to either an alteration in the functioning of the circadian timing system (e.g., delayed or advanced sleep phase syndrome) or to changes in the external environment (e.g., jet lag). However, the clinical presentation of most of the circadian rhythm sleep disorders is influenced by a combination of physiological, behavioral, and environmental factors. These disorders lead to complaints of insomnia and excessive daytime sleepiness, with impairment in important areas of functioning and quality of life. Current treatments primarily involve the use of circadian synchronizing agents, such as light, to realign the internal and external environment. These treatments are limited by the availability of adequate diagnostic tools and well-controlled clinical trials. A better understanding of the pathophysiology of these disorders is required to develop more effective treatments.     

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: characteristics and entrainment pathology in delayed sleep phase and non-24-h sleep-wake syndrome

This paper presents a clinical review of delayed sleep phase syndrome (DSPS) and non-24-h sleep-wake syndrome (non-24). These syndromes seem to be common and under-recognized in society, not only in the blind, but also typically emerging during adolescence. Both types of syndrome can appear alternatively or intermittently in an individual patient. Psychiatric problems are also common in both syndromes. DSPS and non-24 could share a common circadian rhythm pathology in terms of clinical process and biological evidence. The biological basis is characterized by a longer sleep period, a prolonged interval from the body temperature nadir-to-sleep offset, a relatively advanced temperature rhythm, lower sleep propensity after total sleep deprivation, and higher sensitivity to light than in normal controls. There are multiple lines of evidence suggesting dysfunctions at the behavioral, physiological and genetic levels. Treatment procedures and prevention of the syndromes require further attention using behavioral, environmental, and psychiatric approaches, since an increasing number of patients in modern society suffer from these disorders.     

Circadian rhythm sleep disorder associated with pontine lesion

A 55-year-old man presented with excessive daytime sleepiness and a circadian rhythm sleep disorder. Magnetic resonance imaging of the brain revealed a pontine lesion distinguishable from major cerebrovascular disease, demyelination and neoplasm. Benzodiazepines, antidepressants, methylcobalamine and thyroxine failed to synchronize the circadian rhythm. Antiepileptic drugs aggravated the condition, while melatonin and protireline partially relieved the patient from poorly controlled sleep disorder. A pontine lesion appeared to be related to the circadian rhythm sleep disorder of the patient.     

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.     

Melatonin treatment for circadian rhythm sleep disorders

Abstract We administered 1–3 mg melatonin to 11 patients (eight men, three women, aged 16–46 years) with circadian rhythm sleep disorders; nine with delayed sleep phase syndrome and two with non-24-hour sleep-wake syndrome. Sleep logs were recorded throughout the study periods and actigraph and rectal temperature were monitored during treatment periods. Melatonin was administered 1–2 h before the desirable bedtime for expected phase-shifting, or 0.5-1 h before habitual bedtime for gradual advance expecting an hypnotic effect of the melatonin. Melatonin treatments were successful in 6/11 patients. Timing and dose of melatonin administration, together with its pharmacological properties for circadian rhythm sleep disorders, should be further studied.     

Melatonin treatment for circadian rhythm sleep disorders

This study investigated the effects of melatonin administration on circadian rhythm sleep disorders, and aimed to clarify clinical characteristics of melatonin responders. The subjects were 46 patients with circadian rhythm sleep disorders: 30 Delayed Sleep Phase Syndrome (DSPS) and 16 non-24 h sleep-wake syndrome (non-24). Patients took 0.3-1.0 mg of melatonin 5, 3 and 1 h before habitual bedtime. Seventeen patients responded to melatonin (12 DSPS, five non-24). Comparison of clinical background between responders and non-responders revealed that the responders were characterized by short total sleep time and later onset age of clinical symptoms.     

Clinical characteristics of circadian rhythm sleep disorders

Abstract From our practice at the sleep disorders clinic in Kohnodai Hospital, National Center of Neurology and Psychiatry (NCNP), we report the clinical characteristics of circadian sleep-wake rhythm disorders. Nearly 90% of circadian rhythm sleep disorders were diagnosed as delayed sleep phase syndrome (DSPS) or as non-24 sleep-wake syndrome (non-24). While DSPS was equally common in males and females, non-24 was more frequently seen in men. It was of psychiatric interest that a considerable number of patients had depressive states in the course of their circadian rhythm sleep disorders. Difficulty in adapting to social life was more severe in patients with non-24 than in those with DSPS.     

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.     

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.     

Melatonin, sleep, and circadian rhythm disorders

In the 1970s and early 1980s, neuroendocrinology was viewed by many neuroscientists as a "window to the brain" to an understanding of brain function." In psychiatry, many have viewed sleep physiology as a window in biological psychiatry. This is, in part, because sleep is one of the few easily quantifiable functions of interest to psychiatrists. Melatonin is a hormone with powerful effects on behavior particularly circadian and sleep behavior. In contrast with other hormones, the pathophysiology and pathology of abnormal melatonin secretion is poorly understood. In this article, we document the well-established phase-shifting and sleep-promoting effects of melatonin and discuss some implications for neuropsychiatrists when the neurophysiology of melatonin goes array. It is both striking and in some ways not surprising that the majority of patients with phase delay syndrome described in our research studies have been misdiagnosed as having depression. The reason for this is elucidated in this article and the information concerning this condition may be helpful to many who are relatively unfamiliar with this particular sleep disorder. We can anticipate that patients with specific neurological disorders may have changes in their melatonin secretion and future research, for example in patients with head injury and conditions such as retinitis pigmentosa may be the basis for reviews a few years hence.     

Circadian rhythm of plasma norepinephrine in depressive disorders. Preliminary study

The biological desynchronisation hypothesis of (endogenous) depressive disorders arises from the disturbances in the circadian rhythmicity of several biological functions in depressive illness and clinical improvement during various sleep deprivation processes. Furthermore, supportive evidence exists to postulate a central noradrenergic dysfunction, at least in a sub group of depressive disorders. We studied the 24 h kinetics of plasma norepinephrine in patients suffering from Affective Disorders-Major Depressive Episode according to DSM III criteria. Blood samples were drawn hourly from an indwelling venous catheter in supine subjects. Plasma NE was measured by HPLC with electrochemical detection. 5 patients (age: 35-63) were studied in base line drug free depressive state and compared with 5 control subjects (age: 44-53), then, in 4 patients, on the 8th and 21st days under antidepressant treatment. Control subjects exhibited a circadian rhythm of TP but a weak amplitude and low values during sleep, as previously described. Depressed patients did not display any rhythmicity because of a reduced amplitude and high plasma levels during sleep. Antidepressants did not restore the rhythm. Our results suggest a rhythmic instability involving a circadian lability linked to an ultradian release during sleep. This NA disinhibition could participate in the depressive desynchronisation and the potential relationships with sleep disorders must be discussed.