Disorders of the circadian sleep-wake cycle.

Wagner DR

ABSTRACT: This article reviews several disorders of the circadian sleep-wake cycle, including delayed sleep phase syndrome, advanced sleep phase syndrome, non-24-hour sleep-wake syndrome, irregular sleep-wake pattern, time zone change (jet lag) syndrome, and shift work sleep disorder. For each disorder, the cause, diagnostic work-up, and management are outlined.

Neurol Clin 1996 Aug;14(3):651-70

Circadian rhythm sleep disorders: pathophysiology and treatment.

Richardson GS; Malin HV

ABSTRACT: The prediction that abnormalities of circadian clock function in humans would manifest principally as sleep/wake disruption led to the description of the first circadian sleep/wake disorders almost 20 years ago. Since then, formal classification of sleep pathology has expanded this category to include six specific disorders. In this review, the physiology of mammalian circadian clocks is summarized with emphasis on the role of light and hormonal signals in circadian adjustment and entrainment. Each of the circadian sleep disorders-time zone change (jet lag) syndrome, shift work sleep disorder, irregular sleep/wake pattern, delayed sleep phase syndrome, advanced sleep phase syndrome, and non-24-h sleep wake disorder-is reviewed. Presenting characteristics, approaches to diagnosis, models of pathophysiology, and methods of treatment are summarized for each sleep disorder. Developments in the understanding of circadian physiology offer promise for important advances in the diagnosis and treatment of these sleep disorders.

J Clin Neurophysiol 1996 Jan;13(1):17-31

Delayed sleep phase syndrome: a review of its clinical aspects

Regestein QR; Monk TH

ABSTRACT: OBJECTIVE: Delayed sleep phase syndrome is a common but little reported cause of severe insomnia. Since it was first described, few detailed reports of delayed sleep phase syndrome have appeared, and treatment methods have not been reviewed. From the literature, the authors provide diagnostic descriptions and review treatment methods, and from their sleep disorder clinic, they describe the management and outcome of the largest series of patients with delayed sleep phase syndrome thus far reported. METHOD: The authors reviewed all articles with primary data on delayed sleep phase syndrome published through 1993 and add data from a group of 33 patients at their sleep disorder clinic. RESULTS: Delayed sleep phase syndrome involves undesirably late bedtimes and arising times, early night insomnia, and poor morning alertness but lack of insomnia on vacations. The mean bedtime and arising time for the 33 patients were 4:00 a.m. and 10:38 a.m., respectively. Twenty-five patients were, or had been, depressed. Individual responses to treatments varied widely. Seventeen patients showed little treatment response. Delayed sleep phase syndrome had a worse treatment outcome than other sleep disorders. CONCLUSIONS: Delayed sleep phase syndrome presents in a heterogeneous manner. In the sleep disorder clinic population, it was often associated with major depression and was more resistant to treatment than other sleep disorders. Multiple and varied treatments are required.

Am J Psychiatry 1995 Apr;152(4):602-8

Light therapy for seasonal affective disorder. A review of efficacy.

Terman M; Terman JS; Quitkin FM; McGrath PJ Stewart JW; Rafferty B

ABSTRACT: Bright artificial light has been found effective in reducing winter depressive symptoms of Seasonal Affective Disorder, although conclusions about the true magnitude of treatment effect and importance of time of day of light exposure have been limited by methodologic problems. Individual subjects' data from 14 research centers studying 332 patients over 5 years were analyzed with a pooled clustering technique. Overall, 2500-lux intensity light exposure for at least 2 hours daily for 1 week resulted in significantly more remissions-- Hamilton Depression Rating Scale (HAM-D) score reduction of 50% or more to a level under 8--when administered in the early morning (53%) than in the evening (38%) or at midday (32%). All three times were significantly more effective than dim light controls (11%). Dual daily exposures (morning-plus-evening light) provided no benefit over morning light alone. In morning-evening crossovers, remission rates were 62% under morning light alone, compared with 28% under evening light alone, with a differential morning-evening response present in 59% of morning responders compared with 10% of evening responders (p less than 0.001). Remission rates with morning light were highest given low severity at baseline (HAM-D score of 10-16: 67% remission), as compared with moderate-to-severe cases (HAM-D score above 16: approximately 40% remission) where no morning-evening differences were found. Firmer conclusions await treatment studies with larger sample sizes and full assessment of atypical vegetative symptoms seen in winter depression but underrepresented in the Hamilton scale. Longer treatment course and greater light intensity may help clarify clinical response despite the impossibility of achieving a conventional blind placebo control.

Neuropsychopharmacology 1989 Mar;2(1):1-22

Melatonin administration can entrain the free-running circadian system of blind subjects.

Lockley SW; Skene DJ; James K; Thapan K; Wright J Arendt J

ABSTRACT: Although melatonin treatment has been shown to phase shift human circadian rhythms, it still remains ambiguous as to whether exogenous melatonin can entrain a free-running circadian system. We have studied seven blind male subjects with no light perception who exhibited free- running urinary 6-sulphatoxymelatonin (aMT6s) and cortisol rhythms. In a single-blind design, five subjects received placebo or 5 mg melatonin p.o. daily at 2100 h for a full circadian cycle (35-71 days). The remaining two subjects also received melatonin (35-62 days) but not placebo. Urinary aMT6s and cortisol (n=7) and core body temperature (n=1) were used as phase markers to assess the effects of melatonin on the During melatonin treatment, four of the seven free-running subjects exhibited a shortening of their cortisol circadian period (tau). Three of these had taus which were statistically indistinguishable from entrainment. In contrast, the remaining three subjects continued to free-run during the melatonin treatment at a similar tau as prior to and following treatment. The efficacy of melatonin to entrain the free- running cortisol rhythms appeared to be dependent on the circadian phase at which the melatonin treatment commenced. These results show for the first time that daily melatonin administration can entrain free- running circadian rhythms in some blind subjects assessed using reliable physiological markers of the circadian system.

J Endocrinol 2000 Jan;164(1):R1-R6

Jet lag: clinical features, validation of a new syndrome-specific scale, and lack of response to melatonin in a randomized, double-blind trial.

Spitzer RL; Terman M; Williams JB; Terman JS Malt UF; Singer F; Lewy AJ

ABSTRACT: OBJECTIVE: The goals of this study were to validate a new rating scale for measuring severity of jet lag and to compare the efficacy of contrasting melatonin regimens to alleviate jet lag. METHOD: This was a randomized, double-blind trial of placebo and three alternative regimens of melatonin (5.0 mg at bedtime, 0.5 mg at bedtime, and 0.5 mg taken on a shifting schedule) for jet lag. The subjects were 257 Norwegian physicians who had visited New York for 5 days. Jet lag ratings were made on the day of travel from New York back to Oslo (6 hours eastward) and for the next 6 days in Norway. The main outcome measures were scale and item scores from a new, syndrome-specific instrument, the Columbia Jet Lag Scale, that identifies prominent daytime symptoms of jet lag distress. RESULTS: There was a marked increase in total jet lag score in all four treatment groups on the first day at home, followed by progressive improvement over the next 5 days. However, there were no significant group differences or group-by- time interactions. In addition, there was no group effect for sleep onset, time of awakening, hours slept, or hours napping. Ratings on a summary jet lag item were highly correlated with total jet lag scores (from a low of r = 0.54 on the day of travel to a high of r = 0.80 on day 3). The internal consistency of the total jet lag score was high on each day of the study. CONCLUSIONS: The use of melatonin for preventing jet lag needs further study.

Am J Psychiatry 1999 Sep;156(9):1392-6

A controlled study of light therapy in women with late luteal phase dysphoric disorder.

Lam RW; Carter D; Misri S; Kuan AJ; Yatham LN Zis AP

ABSTRACT: Previous studies suggest that light therapy, as used to treat seasonal affective disorder, may be beneficial for pre-menstrual depressive disorders. We conducted a six-menstrual cycle randomized, double-blind, counter-balanced, crossover study of dim vs. bright light therapy in women with late luteal phase dysphoric disorder (LLPDD). Fourteen women who met DSM-III-R criteria for LLPDD completed two menstrual cycles of prospective baseline monitoring of pre-menstrual symptoms, followed by two cycles of each treatment. During the 2-week luteal phase of each treatment cycle, patients were randomized to receive 30 min of evening light therapy using: (1) 10000 lx cool-white fluorescent light (active condition); or (2) 500 lx red fluorescent light (placebo condition), administered by a light box at their homes. After two menstrual cycles of treatment, patients were immediately crossed over to the other condition for another two cycles. Outcome measures were assessed at the mid-follicular and luteal phases of each cycle. Results showed that the active bright white light condition significantly reduced depression and pre-menstrual tension scores during the symptomatic luteal phase, compared to baseline, while the placebo dim red light condition did not. These results suggest that bright light therapy is an effective treatment for LLPDD.

Psychiatry Res 1999 Jun 30;86(3):185-92

Sleep and activity rhythms are related to circadian phase in the blind.

Lockley SW; Skene DJ; Butler LJ; Arendt J

ABSTRACT: STUDY OBJECTIVES: Sleep is controlled by both circadian and homeostatic mechanisms. As the light-dark cycle is the most important time cue in humans, blind individuals may have circadian rhythm disorders including sleep. The aim of the study was to assess sleep with simultaneous measurement of an endogenous marker of the circadian clock, namely 6- sulphatoxymelatonin (aMT6s). SETTING AND PARTICIPANTS: 59 registered blind subjects were studied in their own homes. DESIGN: Subjects completed daily sleep and nap diaries for at least four weeks, wore activity monitors continuously, and collected urine samples over 48 hours each week for 3-5 weeks for assessment of aMT6s rhythms. RESULTS: The most sensitive indicator of a circadian rhythm disorder was day- time napping. Subjects with normally entrained (NE) aMT6s rhythms had fewer naps of a shorter duration than abnormally entrained (AE) or free- running (FR) subjects. The timing of these naps was not random; significantly more naps occurred within a five-hour range before and after the aMT6s acrophase (phi (phi)) than outside this range. Disorders in the timing and duration of night sleep in AE subjects manifested as either a permanent advance (advanced sleep phase syndrome, ASPS) or delay (delayed sleep phase syndrome, DSPS). In FR subjects there were transient advances and delays in sleep timing that paralleled aMT6s timing with increased night sleep duration and reduced number and duration of day-time naps associated with a normal aMT6s phase. CONCLUSIONS: Changes in sleep and activity rhythms reflect changes in circadian phase.

Sleep 1999 Aug 1;22(5):616-23

Nonphotic entrainment of the human circadian pacemaker.

Klerman EB; Rimmer DW; Dijk DJ; Kronauer RE Rizzo JF 3rd; Czeisler CA

ABSTRACT: In organisms as diverse as single-celled algae and humans, light is the primary stimulus mediating entrainment of the circadian biological clock. Reports that some totally blind individuals appear entrained to the 24-h day have suggested that nonphotic stimuli may also be effective circadian synchronizers in humans, although the nonphotic stimuli are probably comparatively weak synchronizers, because the circadian rhythms of many totally blind individuals "free run" even when they maintain a 24-h activity-rest schedule. To investigate entrainment by nonphotic synchronizers, we studied the endogenous circadian melatonin and core body temperature rhythms of 15 totally blind subjects who lacked conscious light perception and exhibited no suppression of plasma melatonin in response to ocular bright-light exposure. Nine of these fifteen blind individuals were able to maintain synchronization to the 24-h day, albeit often at an atypical phase angle of entrainment. Nonphotic stimuli also synchronized the endogenous circadian rhythms of a totally blind individual to a non-24- h schedule while living in constant near darkness. We conclude that nonphotic stimuli can entrain the human circadian pacemaker in some individuals lacking ocular circadian photoreception.

Am J Physiol 1998 Apr;274(4 Pt 2):R991-6

Efficacy of melatonin treatment in jet lag, shift work, and blindness.

Arendt J; Skene DJ; Middleton B; Lockley SW Deacon S

ABSTRACT: Melatonin has chronobiotic properties in humans. It is able to phase shift strongly endogenous rhythms, such as core temperature and its own endogenous rhythm, together with the sleep-wake cycle. Its ability to synchronize free-running rhythms has not been fully investigated in humans. There is evidence for synchronization of the sleep-wake cycle, but the available data suggest that it is less effective with regard to endogenous melatonin and core temperature rhythms. When suitably timed, most studies indicate that fast release preparations are able to hasten adaptation to phase shift in both field and simulation studies of jet lag and shift work. Both subjective and objective measures support this statement. However, not all studies have been successful. Careful evaluation of the effects on work-related performance is required. When used to alleviate the non-24-h sleep-wake disorder in blind subjects, again most studies report a successful outcome using behavioral measures, albeit in a small number of individuals. The present data suggest, however, that although sleep-wake can be stabilized to 24 h, entrainment of other rhythms is exceptionally rare.

J Biol Rhythms 1997 Dec;12(6):604-17

Melatonin as a chronobiotic: treatment of circadian desynchrony in night workers and the blind.

Sack RL; Lewy AJ

ABSTRACT: Although the causes are different, totally blind people (without light perception) and night shift workers have in common recurrent bouts of insomnia and wake-time sleepiness that occur when their preferred (or mandated) sleep and wake times are out of synchrony with their endogenous circadian rhythms. In this article, the patterns of circadian desynchrony in these two populations are briefly reviewed with special emphasis on longitudinal studies in individual subjects that used the timing of melatonin secretion as a circadian marker. In totally blind people, the most commonly observed pattern is a free- running rhythm with a stable non-24-h circadian period (24.2-24.5 h), although some subjectively blind people are normally entrained, perhaps by residually intact retinoypothalamic photic pathways. Experiments at the cellular and behavioral levels have shown that melatonin can produce time dependent circadian phase shifts. With this in mind, melatonin has been administered to blind people in an attempt to entrain abnormal circadian rhythms, and substantial phase shifts have been accomplished; however, it remains to be demonstrated unequivocally that normal long-term entrainment can be produced. In untreated night shift workers, the degree and direction of phase shifting in response to an inverted sleep-wake schedule appears to be quite variable. When given at the optimal circadian time, melatonin treatment appears to facilitate phase shifting in the desired direction. Melatonin given prior to a night worker's daytime sleep also may attenuate interference from the circadian alerting process. Because melatonin has both phase- shifting and sleep-promoting actions, night shift workers, who number in the millions, may be the most likely group to benefit from treatment.

J Biol Rhythms 1997 Dec;12(6):595-603

Chronobiotics--drugs that shift rhythms.

Dawson D; Armstrong SM

ABSTRACT: A chronobiotic is defined and levels of action within the mammalian circadian pacemaker system, such as the retina, retinohypothalamic tract, geniculohypothalamic tract, suprachiasmatic nuclei, output and feedback systems are identified. Classes of drug that include the indoleamines, cholinergic agents, peptides, and benzodiazepines, which might act as chronobiotics within these levels, are evaluated. Particular emphasis is placed on the indole, melatonin (MLT). The clinical circumstances for use of chronobiotics in sleep disturbances of the circadian kind, such as jet lag, shift work, delayed sleep-phase syndrome, advanced sleep-phase syndrome, irregular and non-24-hr sleep- wake cycles, are described under reorganized headings of disorders of entrainment, partial entrainment, and desynchronization. Specific attention is given to the blind and the aged. Both human and animal studies suggest that MLT has powerful chronobiotic properties. MLT shows considerable promise as a prophylactic and therapeutic alternative or supplement to the use of natural and artificial bright light for resetting the circadian pacemaker. Throughout this discussion, the hypnotic and hypothermic versus the chronobiotic actions of MLT are raised. Finally, problems in the design of delivery systems for MLT are discussed.

Pharmacol Ther 1996;69(1):15-36

The prevalence of delayed and advanced sleep phase syndromes.

Schrader H; Bovim G; Sand T

ABSTRACT: To determine the prevalence of the delayed sleep phase syndrome (DSPS) and the contrasting advanced sleep phase syndrome (ASPS), a cross- sectional nationwide epidemiological study was performed in Norway. Screening questionnaires were sent to a random sample of 10,000 adult individuals (18-67 y), of both sexes, taken from the National register of Norway. The response rate was 77%. Diagnoses of DSPS and ASPS were based on International Classification of Sleep Disorders (ICSD) criteria. All individuals suspected of having DSPS or ASPS were requested to fill out a second questionnaire, and a sleep log for four weeks. Subjects for whom the suspicion of DSPS or ASPS could be upheld were contacted by telephone for a final confirmation. Of the 129 possible DSPS cases identified from the screening questionnaires, 17 (9 f; 8 m) remained with the confirmed diagnosis of DSPS. The prevalence was calculated to be 0.17% (95% Confidence Intervals: 0.10-0.28). Thirteen individuals had a mild to moderate DSPS and four had a severe DSPS. The mean age of onset was 15.4 y, and mean duration was 19.2 y. There was no significant correlation between prevalence and age. A sleep phase delay (MSPD) induced by social/environmental or psychological factors was found in 55 subjects (prevalence = 0.72%). Using strict ICSD criteria, no case of ASPS was detected, confirming earlier assumptions of the extreme rarity of this condition.

J Sleep Res 1993 Mar;2(1):51-55

Practice parameters for the use of light therapy in the treatment of sleep disorders. Standards of Practice Committee, American Academy of Sleep Medicine.

Chesson AL Jr; Littner M; Davila D; Anderson WM Grigg-Damberger M; Hartse K; Johnson S; Wise M

ABSTRACT: These clinical guidelines were developed by the Standards of Practice Committee and reviewed and approved by the Board of Directors of the American Academy of Sleep Medicine. The guidelines provide recommendations for the practice of sleep medicine in North America regarding the use of light therapy for treatment of various sleep disorders. This paper is based on a series of articles in the Journal of Biological Rhythms and also includes evidence tables from an updated Medline review covering the period January 1994 to December 1997. Evidence is presented by grade and level. Recommendations are identified as standards, guidelines, or options. Recommendations are provided for delayed sleep phase syndrome (DSPS), advanced sleep phase syndrome (ASPS), non-24-hour sleep-wake syndrome, jet lag, shift work, dementia, and sleep complaints in the healthy elderly. Light therapy appears generally safe if used within recommended intensity and time limits. Light therapy can be useful in treatment of DSPS and ASPS. Benefits of light therapy are less clear and treatment is an option in jet lag, shift work, and non-24-hour sleep-wake syndrome in some blind patients.

Sleep 1999 Aug 1;22(5):641-60

Circadian rhythm sleep disorders: toward a more precise definition and diagnosis.

Dagan Y; Eisenstein M

ABSTRACT: The present article presents a survey of the characteristics of our case series of 322 patients suffering from circadian rhythm sleep disorders (CRSDs), a case-control study comparing a group of 50 CRSD patients and 56 age- and gender-matched normal subjects, and a proposal for new guidelines for improving the diagnosis of CRSD. The major findings were that 83.5% of our CRSD patients who seek medical help are of the delayed sleep phase syndrome (DSPS) type; 89.6% report that the onset of CRSD occurred in early childhood or adolescence; CRSD exhibits no gender differences: a familial trait exists in 44% of patients; and learning disorders (19.3%) and personality disorders (22.4%) in the DSPS-type patients are of high prevalence. The findings of this study point to the importance of clinician awareness of the clinical picture of patients presenting with CRSD so that early diagnosis and effective treatment can be achieved to prevent harmful consequences.

Chronobiol Int 1999 Mar;16(2):213-22

Evaluating the role of melatonin in the long-term treatment of delayed sleep phase syndrome (DSPS).

Dagan Y; Yovel I; Hallis D; Eisenstein M; Raichik I

ABSTRACT: Delayed sleep phase syndrome (DSPS) involves a mismatch between the usual daily schedule required by the individual's environment and his or her circadian sleep-wake pattern. Patients suffering from DSPS are treated with chronotherapy, light therapy, or melatonin administration. While chronotherapy and light therapy are demanding and difficult treatments that usually lead to compliance problems, melatonin administration is a relatively simple and easy treatment option. Previous studies carried out on relatively small samples of DSPS patients have shown that melatonin has a sleep-promoting and entraining action when taken in the evening. The present study, which accompanied routine treatment in our sleep clinic, examined the efficiency of melatonin treatment in a relatively large population of DSPS subjects by means of subjective reports. The 61 subjects, 37 males and 24 females, were diagnosed with DSPS by means of clinical assessment and actigraphy at our sleep clinic. Their mean pretreatment falling asleep and waking times were 03:09 (SD = 86.22 minutes) and 11:31 (SD = 98.58 minutes), respectively. They were treated with a 6-week course of 5 mg of oral melatonin taken daily at 22:00. A survey questionnaire was sent to the home of each subject 12-18 months after the end of the treatment; the survey investigated the efficiency of the melatonin treatment and its possible side effects. Of the patients, 96.7% reported that the melatonin treatment was helpful, with almost no side effects. Of these, 91.5% reported a relapse to their pretreatment sleeping patterns within 1 year of the end of treatment. Only 28.8% reported that the relapse occurred within 1 week. The pretreatment falling asleep and waking times of patients in whom the changes were retained for a relatively long period of time were significantly earlier than those of patients whose relapse was immediate (t = 2.18, p < .05; t = 2.39, p < .05, respectively), with no difference in sleep duration. The implications of these findings, as well as further research possibilities, are discussed.

Chronobiol Int 1998 Mar;15(2):181-90

Non-24-hour sleep-wake syndrome in a sighted man: circadian rhythm studies and efficacy of melatonin treatment.

McArthur AJ; Lewy AJ; Sack RL

ABSTRACT: The case of a 41-year-old sighted man with non-24-hour sleep-wake syndrome is presented. A 7-week baseline assessment confirmed that the patient expressed endogenous melatonin and sleep-wake rhythms with a period of 25.1 hours. We sought to investigate the underlying pathology and to entrain the patient to a normal sleep-wake schedule. No deficiency in melatonin synthesis was found. Furthermore, normal coupling between the melatonin and sleep propensity rhythms was documented using an "ultrashort" sleep-wake protocol. Environmental light exposure was monitored for 41 days, and the circadian timing was calculated. Sensitivity to photic input was determined with light- induced melatonin-suppression tests. Three intensities (500, 1,000, and 2,500 lux) were examined during three separate trials. The 2,500-lux trial resulted in 78% suppression, but the lesser intensity exposures were without substantial effect. Thus, the patient appeared to be subsensitive to bright light. A 4-week trial of daily melatonin administration (0.5 mg at 2100 hours) stabilized the endogenous melatonin and sleep rhythms to a period of 24.1 hours, albeit at a somewhat delayed phase. A 14-month follow-up interview revealed that the patient continued to take melatonin daily, and his sleep-wake schedule was stable to a near 24-hour schedule.

Sleep 1996 Sep;19(7):544-53