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.     

A sighted man with non-24-hour sleep-wake syndrome shows damped plasma melatonin rhythm

Abstract Twenty-four-hour profiles of plasma melatonin, cortisol and rectal temperature were measured longitudinally in a sighted man who has been suffering from sleep disorders for more than 10 years. The sleep-wake rhythm of this subject free-ran, despite his routine life, and occasionally showed a sign of internal desyn-chronization, where sleep was lengthened up to 30 h. These states were classified into the non-24-hour sleep-wake syndrome. Plasma melatonin concentrations in the subjective night remained at a low level and showed a damped circadian rhythm. At the same time, robust circadian rhythms were detected in plasma cortisol and rectal temperature, indicating that the circadian pacemaker was intact. The causal relationship between the damping of nocturnal melatonin rise and a failure of entrainment of the sleep-wake cycle is discussed.     

Non-24-hour sleep-wake syndrome following a car accident

The authors report the case of a 39-year-old sighted woman who displayed non-24-hour sleep-wake cycles following a car accident. The phase relationship between endogenous circadian markers such as plasma melatonin and 6-sulfatoxymelatonin rhythms and self-selected sleep times was abnormal. A laboratory investigation indicated that she was sensitive to bright light as a circadian synchronizer. MRI and brain CT scans were normal, but microscopic brain damage in the vicinity of the suprachiasmatic nucleus or its output pathways is plausible.     

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.     

Correction of non-24-hour sleep/wake cycle by melatonin in a blind retarded boy

A 9-year-old, blind boy with severe mental retardation with a chronic sleep/wake disturbance had a circadian rhythm of 24.75 hours and an internal desynchronization of the endogenous rhythms. Treatment with oral melatonin given at 6 PM induced a regular sleep/wake pattern. Melatonin, in this patient, convincingly entrained the endogenous rhythm to the appropriate chronological 24-hour day.     

Re-entrainment of circadian rhythm of plasma melatonin on an 8-h eastward flight

To estimate the process of re-entrainment we measured the melatonin rhythm on an eastward flight. After the baseline study, 24-hour blood sampling of six male subjects was done on the first and fifth days. During the daytime the subjects were exposed to natural zeitgeber outdoors every day except the blood sampling day. They were analyzed with an illuminometer when under the bright light condition. Four of the six subjects showed orthodromic re-entrainment, another subject showed antidromic re-entrainment, and the other subject kept the baseline pattern of plasma melatonin. The rate of re-entrainment in orthodromic re-entrainment was about 55 min per day. Measuring the circadian rhythm of plasma melatonin has clarified the interindividual re-entrainment difference.     

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.     

Correlation between the circadian sleep propensity rhythm and hormonal rhythms under ultra-short sleep–wake cycle

The aim of this study was to clarify effects of hormonal and temperature rhythms on circadian fluctuations of sleep propensity. Ten healthy females underwent 24-h sleep deprivation and entered the circadian sleep propensity assessment setting under the ultra-short sleep-wake schedule. During the experiment, sleep propensity rhythm, rectal temperature, and 24-h serum hormone profiles (melatonin, cortisol and thyroid-stimulating hormone) were investigated. The circadian sleep propensity rhythms had two apparent peaks (afternoon and nocturnal peaks) and a trough (nocturnal sleep gate). The timings of the nocturnal sleep gate and the nocturnal peak were correlated exclusively with temperature and melatonin rhythms (P < 0.05), while that of the afternoon peak was significantly correlated with habitual wake time and melatonin rhythm. These results indicate that the circadian sleep propensity rhythm is influenced not only by the circadian pacemaker, but also by sleep habit.     

Case study: psychiatric misdiagnosis of non-24-hours sleep-wake schedule disorder resolved by melatonin

This case study describes a 14-year-old male suffering from significant academic and personal difficulties, who has been diagnosed with depression, schizotypal personality disorder, and learning disabilities. Because of excessive sleepiness, assessment for a potential sleep disorder was performed. An overnight polysomnographic study revealed no primary sleep disorders. Wrist actigraphy revealed a non-24-hour sleep-wake pattern. Delay in temperature rhythm and dissociation with melatonin rhythms were also noted. Treatment with oral melatonin restored normal sleep-wake schedule. In a follow-up psychiatric evaluation, none of the above diagnoses were present. Greater awareness of sleep disorders may prevent psychiatric misdiagnosis of treatable sleep-wake schedule disorders.     

Amplitude reduction of plasma melatonin rhythm in association with an internal desynchronization in a subject with non-24-hour sleep–wake syndrome

The plasma melatonin rhythm was measured longitudinally in a subject with non-24-h sleep-wake syndrome, and the amplitude and area under the curve (AUC) of the melatonin rhythm were investigated in relation to the sleep-wake cycle. When the melatonin rhythm and sleep-wake rhythm were internally desynchronized, the amplitude and the AUC were reduced significantly. These parameters were not influenced by external melatonin administration. These results suggest that a causal relationship between the reduction of circadian oscillation and internal desynchronization exists in this subject.     

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.     

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.     

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.     

Phase-relationship and mutual effects between circadian rhythms of ocular melatonin and dopamine in the pigeon

In order to study the mechanisms of ocular circadian rhythms in the pigeon, we measured melatonin and dopamine simultaneously from the eye using in vivo microdialysis. In experiment 1, the phase relationship between circadian rhythms of ocular melatonin and dopamine under light-dark cycles (LD) and continuous dim light (LLdim) was examined. Under LD, melatonin was high during the dark and low during the light. On the other hand dopamine was high during the light and low during the dark. These rhythms with the anti-phase relationship were maintained after the birds were transferred from LD to LLdim. In experiment 2, effects of a single light pulse on melatonin and dopamine rhythms were examined. A light pulse at CT18 rapidly suppressed melatonin release to the daytime level, whereas it rapidly increased dopamine release to the daytime level. The light pulse also affected the phases of melatonin and dopamine rhythms, inducing phase advances of both rhythm without changing the anti-phase relationship before the light pulse. In experiment 3, effects of an intraocular injection of dopamine or melatonin on their circadian rhythms were examined. A dopamine injection during the subjective night suppressed melatonin release and induced a light-pulse type phase shift in both melatonin and dopamine rhythms. On the other hand, a melatonin injection during the subjective day suppressed dopamine release and induced a dark-pulse type phase shift. These results are compatible with either one or two oscillator models, but the interaction between melatonin and dopamine is, in either case considered as an important mechanism regulating ocular circadian rhythms of the pigeon.     

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.     

Melatonin alleviates jet lag symptoms caused by an 11-hour eastward flight

The effect of 3 mg of melatonin on the rate of re-entrainment of plasma melatonin rhythm after an 11-h eastward flight was assessed. Eight subjects participated in the study, and underwent 24-h blood samplings once before the flight and twice after the flight. Subjects were exposed to natural zeitgeber outdoors and took 3 mg of malatonin at 20:00 h local time on the days when no blood sampling was done. Antidromic re-entrainment was dominant whereby melatonin administration in the evening promoted re-entrainment. Melatonin accelerated the rate of re-entrainment by 15 min per day and alleviated the jet lag symptoms.     

Effect of 3 mg melatonin on jet lag syndrome in an 8-h eastward flight

In order to assess the effect of melatonin on jet lag a field study was undertaken. The process of re-entrainment of circadian melatonin rhythm was investigated in six subjects. Except during 24-h blood sampling, the subjects were exposed to natural zeitgeber (time giver) outdoors and given 3 mg melatonin at 23:00 h. The subjects were exposed to bright sunlight from 3000 to 12000 lx. All of them showed orthodromic re-entrainment with taking melatonin, while two out of the six did not show orthodromic re-entrainment without taking melatonin. Melatonin accelerated the rate of the re-entrainment of the circadian melatonin rhythm. Melatonin was useful to jet travel from Tokyo to Los Angeles.     

Sleep deprivation: Effects on circadian rhythms of rat brain neurotransmitter receptors

Specific binding of ligands to rat forebrain α- and β-adrenergic, muscarinic cholinergic, opiate, benzodiazepine, and striatal dopamine receptors was measured at 4-hour intervals during the last 13 hours of a 24-hour sleep deprivation period, and during the first 11 hours of the recovery sleep period. In non-sleep-deprived controls a 24-hour rhythm in binding was evident. The minor differences between the sleep deprivation group and the control group consisted mainly in a reduced amplitude of the 24-hour rhythm under the sleep deprivation schedule. The results indicate that neither the 24-hour forced locomotion nor the subsequent prominent sleep rebound is accompanied by marked changes in the number of neurotransmitter receptors and their circadian rhythms.     

Melatonin circadian rhythm in anorexia nervosa and obesity

The mean 24-hour secretion and circadian rhythm of melatonin were studied in 12 female subjects with anorexia nervosa (AN), 13 massively obese (OB) women, and 9 normal weight healthy volunteers to investigate the relationship between type of feeding behavior and hormonal secretory pattern. Blood samples for melatonin were drawn every 4 hours from 0400 h to 2400 h and every 2 hours from 2400 h to 0400 h. Mean 24-hour melatonin secretion was significantly higher in AN than in OB patients and controls. Melatonin circadian rhythms were disrupted in 8 of the 12 AN patients and in 9 of the 13 OB subjects, with phase-advanced nocturnal rises, abnormal diurnal peaks, or no nocturnal rises. The population mean cosinor analysis validated the existence of a significant circadian rhythm of the hormone in AN but not in OB subjects. No significant correlation between mean 24-hour secretion or type of circadian alterations and degree of weight deficit or excess was observed. The circadian alterations of melatonin in AN and OB may be linked to impaired secretory tonus of noradrenalin in the central nervous system, possibly unrelated to feeding patterns.