Daily melatonin intake resets circadian rhythms of a sighted man with non-24-hour sleep-wake syndrome who lacks the nocturnal melatonin rise

Abstract Effects of daily melatonin intake on the circadian rhythms of sleep and wakefulness, rectal temperature and plasma cortisol were examined in a sighted man who had suffered from the non-24-hour sleep-wake syndrome. The subject lacked the nocturnal melatonin rise in plasma, but showed robust circadian rhythms in rectal temperature and plasma cortisol. The sleep-wake rhythm free-ran with a period longer than 24 hours. Daily melatonin intake at 21:00 h concentrated sleep episodes in the nocturnal period (24:00–8:00 h), and increased the length of the episodes. A single oral dose (3 mg) of melatonin increased plasma melatonin levels to about 1300 pg/mL within one hour and remained at pharmacological levels for approximately 6 hours. The trough of rectal temperature and the circadian rise of plasma cortisol were fixed to the early morning. A higher dose of melatonin (6 mg) did not improve the general feature. After the cessation of melatonin intake, the sleep-wake rhythm began to free-run together with the circadian rhythms in rectal temperature and plasma cortisol. It is concluded that daily intake of melatonin at early night time resets the circadian rhythms in a sighted man who lacked the nocturnal melatonin rise and showed free-running circadian rhythms in routine life.     

Serum melatonin kinetics and long-term melatonin treatment for sleep disorders in Rett syndrome

We studied the circadian rhythm of serum melatonin levels in two patients with classical Rett syndrome having severe sleep disorders; serum melatonin levels were measured before and during melatonin treatment using radioimmunoassay. Patient 1 had a free-running rhythm of sleep-wake cycle from 3 years of age. At the age of 4 years, the peak time of melatonin was delayed 6 h compared to normal control and the peak value was at the lower limit. Patient 2 had a fragmented sleep pattern accompanied by night screaming from 1 year and 6 months of age. At the age of 10 years, the peak time of melatonin secretion was normal but the peak value was at the lower limit. These patients were given 5 mg melatonin orally prior to bedtime. Exogenous melatonin dramatically improved the sleep-wake cycle in patient 1. In patient 2, exogenous melatonin showed a hypnotic effect but early morning awakenings occurred occasionally. When melatonin treatment was stopped, the sleep disorders recurred and re-administration of 3 mg melatonin was effective in both patients. The effect was maintained over 2 years without any adverse effects. These findings suggests that sleep disorders in patients with Rett syndrome may relate with an impaired secretion of melatonin.     

Case of a non-24 h sleep-wake syndrome patient improved by phototherapy

Polysomnography (PSG) and body temperature were examined in a patient with non-24 h sleep-wake syndrome who responded to phototherapy. The patient was a 17-year-old male who had been suffering from a free-running sleep-wake rhythm for 2 months. Phototherapy was administered to the patient while he was admitted to our hospital. This treatment immediately changed the free-running sleep-wake and body temperature rhythm of the patient to the environmental 24-h rhythm. On a polysomnography, total sleep time and stages 1 and 2 and REM sleep were decreased, and percentage stage 3+4 was increased by phototherapy. The time of minimum body temperature (mBT) was located at the latter half of the sleep phase through the clinical course of the patient.     

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.     

Free-running of plasma melatonin rhythm prior to full manifestation of a non-24 hour sleep-wake syndrome

Abstract A long-term observation of a sighted man who developed a non-24 h sleep-wake syndrome is reported. A partial entrainment was observed first, whereby the sleep-wake rhythm was entrained by the day-night alternation whereas the circadian rhythm in plasma melatonin was free-running. Two years later, the sleep-wake rhythm of this subject started to free-run together with the melatonin rhythm. Oral administration of melatonin for 2 weeks improved the entrainability of both rhythms but failed to entrain the rhythms completely. It is concluded that the free-running of the circadian pacemaker preceded a full manifestation of a non-24 h sleep-wake syndrome in this particular subject.     

Trials of bright light exposure and melatonin administration in a patient with non-24 hour sleep-wake syndrome

Abstract We report a patient with non-24 h sleep-wake syndrome (non-24) whose free-running sleep-wake cycle was successfully treated with both scheduled bright light exposure and melatonin treatment. In the present study, morning bright light as well as evening melatonin phase-advanced sleep-wake cycles and melatonin rhythm. Both these procedures achieved appropriate entrainment to a 24 h day. However, the patient did not continue morning bright light therapy after the discharge. Rising at appropriate times in the morning for bright light therapy was difficult for him to continue. Melatonin treatment was better tolerated because of its ease of application.     

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.     

Case of a mentally retarded child with non-24 hour sleep-wake syndrome caused by deficiency of melatonin secretion

A case of a 5-year-old boy with non-24 hour sleep-wake syndrome and mental retardation is reported. His free-running sleep-wake rhythm was remarkably improved by the oral administration of melatonin. The circadian variation in melatonin secretion was extremely low, and circadian rhythm of cortisol secretion was noted. It was speculated that his non-24 hour sleep-wake syndrome was due to a congenital deficiency of melatonin secretion, and supplemental melatonin therapy proved effective for treating his condition.     

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.     

A circadian system model with feedback of cross-correlation between sleep-wake rhythm and oscillator.

Recent findings suggest that social entrainment factors work on an oscillator other than the temperature and melatonin rhythms. This indicates that there is a feedback loop affected on oscillators. In the present study, a circadian system model, including mutually coupled two oscillators and sleep-wake rhythm, is constructed, where cross-correlation between a sleep-wake rhythm and an oscillator is set to modify the coupling from one oscillator to the other. Based on the model simulation, a mechanism underlying delayed sleep phase syndrome is elucidated by the reduction in the cross-correlation resulting from dissociation between the delayed sleep phase and the oscillator.     

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.     

Disorganized sleep–wake schedule associated with neuroendocrine abnormalities in dementia. A clinical study

Demented patients were investigated by blood sampling at 10 occasions during a 24-hour period. Serum levels of melatonin and cortisol were determined. One patient with probable vascular dementia had a severely disorganized sleep-wake schedule and showed disturbed patterns of serum melatonin and cortisol. After withdrawal of alprenolol, substitution of a vitamin B₁₂ deficiency and cataract surgery, the patient regained normal sleep habits and a normal circadian pattern of serum cortisol and melatonin. A patient with frontal lobe dementia and a disorganized sleep-wake schedule showed a disturbed melatonin rhythm, unexpected cortisol peaks and a disability to suppress melatonin by light. Two Alzheimer patients with regular sleep habits had normal circadian patterns of serum melatonin and cortisol.     

Effect of melatonin on sleep-wake rhythm: the sleep diary of an autistic male

This study reports on melatonin treatment in autism. A 14-year-old autistic male with severe mental retardation was given melatonin at a dose of 6 mg at 9:00 pm (C1) or 11:00 pm (C2). His parents kept a sleep diary. In C1, he often experienced early morning waking and fragmented night sleep but in C2, night sleep was prolonged and sleep-wake rhythm was improved. Suitable medication time, therefore, improved the sleep-wake rhythm.     

Long-term melatonin treatment in blind children and young adults with circadian sleep-wake disturbances

Oral melatonin therapy was used to treat severe circadian sleep-wake disturbances in eight children and young adults in an open study. All patients were functionally blind, six of them because of defects in the anterior visual pathway. All were mentally retarded. Baseline sleep diaries kept by the caregivers before treatment showed non-24-hour sleep-wake syndrome. Diurnal variations in serum and urinary melatonin were examined. Melatonin secretion peak time was delayed in seven patients. Body temperature variation was out of phase relative to sleep and melatonin in five patients, and thus they had signs of internal desynchronisation. Melatonin given in the evening dramatically improved the sleep-wake pattern in all patients. The effect was maintained during long-term therapy for between 1 and 6 years in six patients. One patient fell back into the earlier sleep pattern after 6 to 8 months, and another had increasing sleep disturbance because of reflux oesophagitis, although the improvement regarding the circadian component remained. No side effects have been noted during the therapy. Oral melatonin is promising as an efficient and seemingly safe alternative for treatment of severe circadian sleep disturbances.     

Therapeutic progress of two sibling cases exhibiting sleep-wake rhythm disorder

In this study, two females, siblings who exhibited a non-24 h sleep-wake rhythm (non-24 h) at home were observed. However, they showed a delayed sleep phase syndrome (DSPS) immediately after admission to Kurume University Hospital. Melatonin (3 mg) was commenced following chronotherapy and this improved their sleep-wake rhythm. Polysomnography (PSG) showed decreased sleep latency and increased sleep stage. In these cases, the involvement of environmental factors was strongly suggested for the sleep-wake rhythm abnormalities as well as familial factors.     

The roles of melatonin and light in the pathophysiology and treatment of circadian rhythm sleep disorders

Normal circadian rhythms are synchronized to a regular 24 h environmental light-dark cycle, and the suprachiasmatic nucleus and the hormone melatonin have important roles in this process. Desynchronization of circadian rhythms, as occurs in chronobiological disorders, can produce severe disturbances in sleep patterns. According to the International Classification of Sleep Disorders, circadian rhythm sleep disorders (CRSDs) include delayed sleep phase syndrome, advanced sleep phase syndrome, non-24 h sleep-wake disorder, jet lag and shift-work sleep disorder. Disturbances in the circadian phase position of plasma melatonin levels have been documented in all of these disorders. There is compelling evidence to implicate endogenous melatonin as an important mediator in CRSD pathophysiology, although further research involving large numbers of patients will be required to clarify whether the disruption of melatonin secretion is a causal factor in CRSDs. In this Review, we focus on the use of exogenous melatonin and light therapy to treat the disturbed sleep-wake rhythms seen in CRSDs.     

Etiology and treatment of intrinsic circadian rhythm sleep disorders

Some individuals experience an acute or chronic sleep disturbance, associated with a misalignment between the timing of their sleep and the sleep-wake cycle that is desired, or considered normal by society. It is estimated that 5-10% of insomniacs seeking treatment have this type of disorder, collectively called circadian rhythm sleep disorders. This paper reviews circadian rhythm sleep disorders of the intrinsic type, which include delayed sleep phase syndrome, advanced sleep phase syndrome, non-24-hour sleep-wake syndrome, and irregular sleep-wake pattern. For each disorder, we present data addressing its pathophysiology and potential treatments, including the use of behavioral measures and chronotherapy, bright light treatment and pharmacological treatments such as melatonin. We conclude by addressing some of the limitations and drawbacks of the various treatments.     

Emerging and entraining patterns of the sleep-wake rhythm in preterm and term infants.

It has been repeatedly reported that the sleep-wake rhythm in infants entrains around 3-4 months of age after a transient free-run rhythm. To clarify the emerging and entraining patterns of the sleep-wake rhythm, the sleep and wakefulness of 84 infants (44 preterm and 40 term infants) were longitudinally recorded at home for more than 16 weeks by the day-by-day plot method. Our results showed that the entrained sleep-wake rhythm emerged after transient manifestation of either ultradian or irregular sleep-wake patterns for 3-4 weeks in 75% of the infants. Only 7% of the infants showed a free-running sleep-wake rhythm before the entrainment. These facts suggest that most infants would be entrained to an ordinary daily schedule of mothers without expression of overt free-running rhythm of the biological clock. The mean age of the entrainment was 44.8 postconceptional weeks. There were no significant differences in either frequency of each pattern or the mean age of the entrainment, between preterm and term infants. In conclusion, the entrained sleep-wake rhythm emerges around 1 corrected month, after ultradian patterns in the majority of infants.     

A Treatment Trial of Delayed Sleep Phase Syndrome with Triazolam

Abstract: Triazolam causes a phase-shift of the circadian rhythm of locomotor activity in golden hamsters. We attempted to treat two patients with delayed sleep phase syndrome (DSPS) with triazolam. In one male patient we administered triazolam when the sleep phase began to delay afkr chronotherapy. Triazolam combined with chronotherapy enabled him to normalize and stabilize his sleep-wake cycle. But in the other female patient despite normalization of her sleep-wake cycle, she became depressive and did not Continue taking the drug. In some cases triazalam is useful for the treatment of DSPS, but in others, triazolam induces a depressive state.     

Periodic fatigue symptoms due to desynchronization in a patient with non-24-h sleep-wake syndrome

A 43-year-old man complaining of recurrent fatigue symptoms and sleep disorders occurring periodically every 4 weeks was studied. Using a wrist worn actigraphy and an ambulatory rectal temperature monitoring apparatus, his sleep-wake cycle and rectal temperature were measured continuously for 4 months, while diagnostic evaluation and therapeutic interventions were conducted. It was found that after he gave up an attempt to keep to a 24-h-day, a free-running sleep wake pattern appeared but his fatigue symptoms disappeared. An analysis of the relationship between his sleep-wake cycle and the rectal temperature rhythm found that his fatigue symptoms did not appear when both rhythms were synchronized with each other. Artificial bright light therapy entrained him to a 24-h day without relapsing of fatigue symptoms. Desynchronization between a 24-h sleep-wake schedule and his circadian pacemaker may have caused his periodically appearing fatigue symptoms.