Daily activity and persistent sleep-wake schedule disorders.

1. Patients with disorders of entrainment to external time cues such as delayed sleep phase syndrome (DSPS) and non-24-hour sleep-wake syndrome (HNS) were treated with non-pharmacological interventions and/or pharmacological agents. 2. Resetting the circadian clock with chronotherapy was easy in all DSPS patients, but it was not as easy to maintain the reset rhythm without additional therapy. Triazolam was effective in treating the phase delay that reappeared after chronotherapy. 3. Vitamin B12 (methylcobalamin) was strikingly effective in some patients with DSPS or HNS. 4. All the adolescent patients who complained of inability to attend school finally returned to their classes after treatment. Maintaining the reset rhythm in adolescent patients was easier than in adults.     

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.     

A treatment trial of delayed sleep phase syndrome with triazolam

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 after 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 triazolam is useful for the treatment of DSPS, but in others, triazolam induces a depressive state.     

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.     

A multicenter study of sleep-wake rhythm disorders: Therapeutic effects of vitamin B12, bright light therapy, chronotherapy and hypnotics

One hundred and six subjects with primary sleep-wake rhythm disorders [13 non-24 hour sleep-wake syndrome (non-24), 76 delayed sleep phase syndrome (DSPS), 11 irregular sleep-wake pattern (irregular) and six long sleepers] were treated with vitamin B₁₂, bright light, chronotherapy and/or hypnotics. These therapies caused moderate or remarkable improvement in 32% of the non-24, 42% of DSPS, 45% of irregular and 67% of long sleepers. A lack of adequate sleep, unpleasant feelings at waking and daytime drowsiness were also improved in DSPS.     

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.     

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.     

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.     

Effects of phototherapy on the phase relationship between sleep and body temperature rhythm in a delayed sleep phase syndrome case

We examined polysomnography (PSG) and body temperature of a patient with delayed sleep phase syndrome (DSPS) who was successfully treated with only phototherapy. This case showed a possible improvement of the phase relationship between sleep and body temperature rhythm given that the time of minimum body temperature (mBT) shifted to the latter portion of the sleep phase after constant phototherapy.     

Effects of phototherapy in patients with delayed sleep phase syndrome

Phototherapy was given to six patients with delayed sleep phase syndrome (DSPS). Polysomnography (PSG) and core body temperature were examined before and after phototherapy. Phototherapy was administered to each patient for 5 days, and this treatment not only advanced the delayed sleep phase but also delayed the time of minimum body temperature in all patients. On the PSG, decreases in total sleep time and amounts of stages 2 and REM were observed after phototherapy. These results suggest that phototherapy is effective even in the short term in advancing delays in sleep phase and time of minimum body temperature in DSPS patients.     

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.     

Posttraumatic delayed sleep phase syndrome

Circadian rhythm sleep disorders may occur after traumatic brain injury. We describe a 48-year-old man who presented with sleep onset insomnia and cognitive dysfunction after a car accident. A diagnosis of delayed sleep phase syndrome (DSPS) was confirmed by sleep logs and actigraphy, which revealed sleep onset in the early morning hours and awakening around noon.     

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.     

Clinical efficacy of dim light melatonin onset testing in diagnosing delayed sleep phase syndrome

BackgroundDelayed Sleep Phase Syndrome (DSPS) arises from biological clock desynchrony and accounts for 10% of chronic insomnia patients. Currently DSPS is diagnosed based on sleep/wake cycle disruptions rather than examining the underlying biological clock alterations. The objective of the study was to determine the sensitivity and specificity of the Dim Light Melatonin Onset (DLMO) Test in diagnosing DSPS in a clinical setting.MethodsFifty-six patients (mean age 28 years) symptomatic of DSPS participated in the study. Following an initial assessment of DSPS using sleep diaries, participants underwent two consecutive nights of polysomnography (PSG), with an imposed sleep period on the second night to demonstrate the delay in the timing of habitual sleep period and to thereby confirm DSPS. Circadian phase delays were also measured using melatonin secretion profiles, and the efficacy of diagnosing DSPS using DLMO was compared to using sleep diaries and PSG. Melatonin secretion was assayed for each individual by ELISA using saliva samples.ResultsMain outcome measures included the time of melatonin secretion onset, clinical sensitivity and specificity of the DLMO test. The time of melatonin secretion onset was significantly delayed in DSPS patients. Clinical sensitivity and specificity of the DLMO test in diagnosing DSPS were 90.3% and 84.0%, respectively.ConclusionsThe DLMO test is an accurate tool for differentiating between sleep disorder patients with or without underlying circadian rhythm disruption. It is effective for phase typing DSPS patients in a clinical setting.     

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.     

Poor recovery sleep after sleep deprivation in delayed sleep phase syndrome

To clarify disturbances in sleep regulation in patients with delayed sleep phase syndrome (DSPS), we studied three patients with DSPS and seven healthy controls. Sleep propensity and melatonin rhythms after 24-h sleep deprivation were investigated under dim light condition by using the ultra-short sleep-wake schedule. The sleep propensity curves displayed clear differences between DSPS patients and the controls. During the subjective day when melatonin was not produced, recovery sleep after the sleep deprivation did not occur in DSPS patients, while recovery sleep occurred during the subjective day in controls. This suggests that DSPS may involve problems related to the homeostatic regulation of sleep after sleep deprivation.     

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.     

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.     

Constant light housing during nursing causes human DSPS (delayed sleep phase syndrome) behaviour in Clock-mutant mice

Delayed sleep phase syndrome (DSPS) is very often seen among patients with sleep-wake rhythm disorders. Humans with the 3111C allele of the human Clock gene tend to demonstrate a higher evening preference on the morningness-eveningness (ME) preference test. DSPS is thought to be an extreme form of this evening preference. Clock-mutant mice have been proposed as an animal model of evening preference. In this study, we looked at whether constant light (LL) housing of Clock-mutant mice during lactation would result in evening preference and/or DSPS. Housed under light-dark (LD) or constant dark (DD) conditions during the lactation period, both wild-type and Clock-mutant mice did not show a phase-delay in the locomotor activity measured under light-dark conditions, whereas constant light housing during lactation significantly caused a delayed onset. The magnitude of the delay during the light-dark cycle was positively associated with free-running period measured during constant darkness. Among wild, heterozygote, and homozygote pups born from heterozygous dams, only homozygote pups showed a delayed onset. Constant light-housed Clock-mutant mice exhibited a lower number and delayed peak of phospho-MAPK-immunoreactive cells in core regions of the suprachiasmatic nucleus (SCN) compared to light-dark housed wild-type or Clock-mutant mice. Activity onset returned to normal with daily melatonin injection at the lights-off time for 5 days. The present results demonstrate that Clock-mutant mice exposed to constant light during lactation can function as an animal model of DSPS and can be used to gain an understanding of the ethological aspects of DSPS as well as to find medication for its treatment.     

Vitamin B12 treatment for delayed sleep phase syndrome: A multi-center double-blind study

Abstract  The active form of vitamin B₁₂ (methylcobalamin) has been reported to be effective on sleep-wake rhythm disorders. Previous studies, however, were performed under open trial, and the effect of vitamin B₁₂ has not been properly evaluated. The aim of this double-blind study was to investigate the efficacy of methylcobalamin on delayed sleep phase syndrome (DSPS). Methylcobalamin (3 mg/day) or placebo was administered for 4 weeks. The subjects were 50 patients with DSPS aged 13–55 years (26.8 ± 1.3), 27 of whom received the active drug while 23 received the placebo. No significant differences were observed between the 2 groups in subjective evaluations of mood or drowsiness during the daytime or in night sleep by sleep-log evaluation. These results indicate that 3 mg methylcobalamin administered over 4 weeks is not an effective treatment for DSPS.