Functional genetic variation in the Rev-Erbα pathway and lithium response in the treatment of bipolar disorder.

Bipolar disorder (BD) is characterized by disruptions in circadian rhythms such as sleep and daily activity that often normalize after lithium treatment in responsive patients. As lithium is known to interact with the circadian clock, we hypothesized that variation in circadian 'clock genes' would be associated with lithium response in BD. We determined genotype for 16 variants in seven circadian clock genes and conducted a candidate gene association study of these in 282 Caucasian patients with BD who were previously treated with lithium. We found that a variant in the promoter of NR1D1 encoding Rev-Erbα (rs2071427) and a second variant in CRY1 (rs8192440) were nominally associated with good treatment response. Previous studies have shown that lithium regulates Rev-Erbα protein stability by inhibiting glycogen synthase kinase 3ß (GSK3ß). We found that GSK3ß genotype was also suggestive of a lithium response association, but not statistically significant. However, when GSK3ß and NR1D1 genotypes were considered together, they predicted lithium response robustly and additively in proportion to the number of response-associated alleles. Using lymphoblastoid cell lines from patients with BD, we found that both the NR1D1 and GSK3ß variants are associated with functional differences in gene expression. Our findings support a role for Rev-Erbα in the therapeutic mechanism of lithium and suggest that the interaction between Rev-Erbα and GSK3ß may warrant further study.

Circadian phase in adults of contrasting ages.

There is evidence that aging may impair phase-shifting responses to light synchronizers, which could lead to disturbed or malsynchronized circadian rhythms. To explore this hypothesis, 62 elder participants (age, 58 to 84 years) and 25 young adults (age, 19 to 40 years) were studied, first with baseline 1-wk wrist actigraphy at home and then by 72 h in-laboratory study using an ultra-short sleep-wake cycle. Subjects were awake for 60 minutes in 50 lux followed by 30 minutes of darkness for sleep. Saliva samples were collected for melatonin, and urine samples were collected for aMT6s (a urinary metabolite of melatonin) and free cortisol every 90 minutes. Oral temperatures were also measured every 90 minutes. The timing of the circadian rhythms was not significantly more variable among the elders. The times of lights-out and wake-up at home and urinary free cortisol occurred earlier among elders, but the acrophases (cosinor analysis-derived peak time) of the circadian rhythm of salivary melatonin, urinary aMT6s, and oral temperature were not significantly phase-advanced among elders. The estimated duration of melatonin secretion was 9.9 h among elders and 8.4 h among young adults (p < 0.025), though the estimated half-life of blood melatonin was shorter among elders (p < 0.025), and young adults had higher saliva melatonin and urinary aMT6s levels. In summary, there was no evidence for circadian desynchronization associated with aging, but there was evidence of some rearrangement of the internal phase-angles among the studied circadian rhythms.

Light therapy for non-seasonal depression.

BACKGROUND: Efficacy of light therapy for non-seasonal depression has been studied without any consensus on its efficacy. OBJECTIVES: To evaluate clinical effects of bright light therapy in comparison to the inactive placebo treatment for non-seasonal depression. SEARCH STRATEGY: We searched the Depression Anxiety & Neurosis Controlled Trials register (CCDANCTR January 2003), comprising the results of searches of Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1966 -), EMBASE (1980 -), CINAHL (1982 -), LILACS (1982 -), National Research Register, PsycINFO/PsycLIT (1974 -), PSYNDEX (1977 -), and SIGLE (1982 - ) using the group search strategy and the following terms: #30 = phototherapy or ("light therapy" or light-therapy). We also sought trials from conference proceedings and references of included papers, and contacted the first author of each study as well as leading researchers in the field. SELECTION CRITERIA: Randomized controlled trials comparing bright light with inactive placebo treatments for non-seasonal depression. DATA COLLECTION AND ANALYSIS: Data were extracted and quality assessment was made independently by two reviewers. The authors were contacted to obtain additional information. MAIN RESULTS: Twenty studies (49 reports) were included in the review. Most of the studies applied bright light as adjunctive treatment to drug therapy, sleep deprivation, or both. In general, the quality of reporting was poor, and many reviews did not report adverse effects systematically. The treatment response in the bright light group was better than in the control treatment group, but did not reach statistical significance. The result was mainly based on studies of less than 8 days of treatment. The response to bright light was significantly better than to control treatment in high-quality studies (standardized mean difference (SMD) -0.90, 95% confidence interval (CI) -1.50 to -0.31), in studies applying morning light treatment (SMD -0.38, CI -0.62 to -0.14), and in sleep deprivation responders (SMD -1.02, CI -1.60 to -0.45). Hypomania was more common in the bright light group compared to the control treatment group (risk ratio 4.91, CI 1.66 to 14.46, number needed to harm 8, CI 5 to 20). Twenty studies (49 reports) were included in the review. Most of the studies applied bright light as adjunctive treatment to drug therapy, sleep deprivation, or both. Treatment REVIEWERS' CONCLUSIONS: For patients suffering from non-seasonal depression, bright light therapy offers modest though promising antidepressive efficacy, especially when administered during the first week of treatment, in the morning, and as an adjunctive treatment to sleep deprivation responders. Hypomania as a potential adverse effect needs to be considered. Due to limited data and heterogeneity of studies these results need to be interpreted with caution.

Circadian abnormalities in older adults.

This study examined the circadian phase adjustment of symptomatic elders ages 60-79 years in comparison with that of young, healthy adults ages 20-40 years. Seventy-two elders with complaints of insomnia or depression, and 30 young, healthy adults were assessed for 5-7 days at home. Sleep and illumination were recorded with Actillume wrist monitors and sleep diaries. Urine was collected over two 24-hr periods and assayed for 6-sulphatoxymelatonin (6-smt). The volunteers were then observed continuously for 5 nights and 4 days in the laboratory. In the laboratory, sleep periods were fixed at 8 hr with polysomnographic assessment of sleep, apnea-hypopnea, and nocturnal myoclonus. Circadian dispersion, defined as the mean variation of 6-smt acrophase from the median age-specific acrophase, was significantly greater in the older vs. young adults. Likewise, circadian malsynchronization, defined as the absolute number of hours (advance or delay) between the 6-smt acrophase and the middle of the sleep period, was significantly greater in the older vs. young volunteers. For the older volunteers, multiple regressions were calculated associating sleep with potential correlates of sleep disturbance. Nocturnal myoclonus and circadian malsynchronization were more strongly associated with sleep impairment than other factors (e.g., sleep apnea, depression). These observations suggest that circadian malsynchronization might be a common and significant cause of disturbed sleep among adults over age 60.

Short version of the CES-D (Burnam screen) for depression in reference to the structured psychiatric interview.

A new screen for depression was compared with clinician diagnoses based on the Structured Clinical Interview for DSM-IV (SCID) as the standard. Post-menopausal women (n=436) completed the Burnam screen, a short version of the Center for Epidemiologic Studies Depression Scale (CES-D). The Burnam screen had a sensitivity of 74% and a specificity of 87% for current major depression and dysthymia, but the positive predictive value was low (20%) and the overall error rate was 14%. For lifetime mood disorders, sensitivity was very low for detecting affected subjects, even though specificity and positive predictive value were higher than for current conditions. Substituting a more sensitive cutpoint slightly improved the screen's ability to detect subjects with lifetime mood disorders. Even algorithms that used coefficients optimized for these data gave little improvement in the psychometric properties of the Burnam screen. These results re-emphasize the difficulty of using a one-stage screen to detect accurately a depressive diagnosis.

Sleep estimation from wrist movement quantified by different actigraphic modalities.

Progress in transducer design and empirical characterization of wrist movement has led to diverse wrist activity monitors, each with its unique features and modality of operation. This study compared sleep--wake estimates from nocturnal wrist activity quantified by different motion-quantifying algorithms. Healthy young adults wore an Actillume and a Mini Motionlogger on the same wrist while nocturnal polysomnography data were recorded simultaneously in the laboratory. Activity data were analyzed with ACTION3 using scoring algorithms independently calibrated for each measurement modality. Overall, each modality yielded accurate and reliable sleep estimates relative to polysomnographic estimates (agreement rates: 91.4--96.5%, correlations for sleep duration: 0.79--0.94). Estimates derived from Actillume modalities were comparable to those of Mini Motionloggers, suggesting that the transducers of these two devices performed comparably for monitoring sleep and wakefulness. Wrist movement quantified by the Mini Motionlogger proportional-integrating mode yielded the best accuracy for detection of sleep--wake states.

Sleep detection with an accelerometer actigraph: comparisons with polysomnography.

Two validation studies were conducted to optimize the sleep-detection algorithm of the Actillume. The first study used home recordings of postmenopausal women (age range: 51 to 77 years), which were analyzed to derive the optimal algorithm for detecting sleep and wakefulness from wrist activity data, both for nocturnal in-bed recordings and considering the entire 24 h. The second study explored the optimal algorithm to score in-bed recordings of healthy young adults (age range: 19 to 34 years) monitored in the laboratory. In Study I, the algorithm for in-bed recordings (n=39) showed a minute-by-minute agreement of 85% between Actillume and polysomnography (PSG), a correlation of.98, and a mean measurement error (ME) of 21 min for estimates of sleep duration. Using the same algorithm to score 24-h recordings with Webster's rules, an agreement of 89%, a correlation of.90, and 1 min ME were observed. A different algorithm proved optimal to score in-bed recordings (n=31) of young adults, yielding an agreement of 91%, a correlation of.92, and an ME of 5 min. The strong correlations and agreements between sleep estimates from Actillume and PSG in both studies suggest that the Actillume can reliably monitor sleep and wakefulness both in community-residing elderly and healthy young adults in the laboratory. However, different algorithms are optimal for individuals with different characteristics.

Long-term follow-up of sleep disordered breathing in older adults.

OBJECTIVE: The current study was designed to determine whether, with increasing age, sleep apnea improves, becomes worse, or stays the same. BACKGROUND: There is a high prevalence of sleep disordered breathing (SDB) in older adults, but little is known about longitudinal changes. This study followed older adults to examine the natural history of SDB. METHODS: Subjects were randomly selected community-dwelling elderly (n=427). A subset of subjects was studied approximately every 2 years over an 18-year period. Overnight sleep recordings and sleep questionnaires were completed at each time point. RESULTS: Multiple linear regression showed that three variables were associated with change in respiratory disturbance index (RDI):body mass index (BMI) at initial visit (P=0.001), change in BMI (P=0.02), and a consistent self-report of high blood pressure (P=0.005). RDI increase was associated with BMI increase and presence of self-reported high blood pressure. CONCLUSIONS: The changes in RDI that occurred were associated only with changes in BMI and were independent of age. This underscores the importance of managing weight for older adults, particularly those with hypertension.

Retinal circadian rhythms in humans.

Circadian rhythms in the retina may reflect intrinsic rhythms in the eye. Previous reports on circadian variability in electrophysiological human retinal measures have been scanty, and the results have been somewhat inconsistent. We studied the circadian variation of the electrooculography (EOG), electroretinography (ERG), and visual threshold (VTH) in subjects undergoing a 36h testing period. We used an ultrashort sleep-wake cycle to balance effects of sleep and light-dark across circadian cycles. Twelve healthy volunteers (10 males, 2 females; mean age 26.3 years, standard deviation [SD] 8.0 years, range 19-40 years) participated in the study. The retinal functions and oral temperature were measured every 90 min. The EOG was measured in the light, whereas the ERG and the VTH were measured in the dark. Sleep was inferred from activity detected by an Actillume monitor. The EOG peak-to-peak responses followed a circadian rhythm, with the peak occurring late in the morning (acrophase 12:22). The ERG b-wave implicit time peaked in the early morning (acrophase 06:46). No statistically significant circadian rhythms could be demonstrated in the ERG a-wave implicit time or peak-to-peak amplitude. The VTH rhythm peaked in the early morning (acrophases 07:59 for blue and 07:32 for red stimuli). All retinal rhythms showed less-consistent acrophases than the temperature and sleep rhythms. This study demonstrated several different circadian rhythms in retinal electrophysiological and psychophysical measures of healthy subjects. As the retinal rhythms had much poorer signal-to-noise ratios than the temperature rhythm, these measures cannot be recommended as circadian markers.

Changes in cognitive function associated with sleep disordered breathing in older people.

OBJECTIVES: Sleep disordered breathing (SDB) is very common in older people and is known to be associated with complaints of impaired daily functioning, including excessive daytime sleepiness and cognitive impairments. As part of a larger study on SDB and aging, it became possible to examine the relationship between SDB and cognition in older men and women. DESIGN: A population-based longitudinal study. SETTING: In-home interviews and home sleep recordings in the greater San Diego area. PARTICIPANTS: Community-dwelling people age 65 and older with high risk for SDB were originally studied from 1981 through 1985 and then followed every 2 years. Data from the 46 subjects who completed Visit 3 and Visit 4 are presented. MEASUREMENTS: Subjects were interviewed in the home about their sleep and medical condition before each visit. Cognitive function was assessed using the Mini-Mental State Examination (MMSE). Daytime sleepiness was based on self-report. Objective sleep was recorded in the home and scored for sleep, apneas and hypopneas, and oximetry variables. RESULTS: Increases in respiratory disturbance index (RDI) (P= .036) and increases in daytime sleepiness (P= .002) were associated with decreases in cognitive performance (i.e., increases in cognitive impairment). Increases in RDI were also associated with increases in daytime sleepiness (P= .012). Change in MMSE scores was therefore regressed onto changes in RDI, daytime sleepiness, age, and education, resulting in decreases in MMSE scores being associated with increases in daytime sleepiness (P= .019) but not with changes in RDI (P= .515). There was no significant relationship between changes in oxygen saturation levels and changes in MMSE. CONCLUSIONS: The results of this study suggest that declining cognitive function is associated primarily with increases in daytime sleepiness. Although cognitive decline was also associated with increases in RDI, this association did not hold in the more inclusive model which also included variable of SDB, oximetry, sleep and subjective report. One theoretical model could suggest that any relationship between SDB and cognitive function may be mediated by the effect of SDB on daytime sleepiness. These results suggest that older patients suffering from mild to moderate SDB may benefit from the treatment of SDB, even if they are not markedly hypoxemic.

No melatonin suppression by illumination of popliteal fossae or eyelids.

A recent report that popliteal illumination shifted the circadian rhythms of body temperature and melatonin challenged the longstanding belief that light phase-shifting the circadian system in mammals is mediated only through the retina. The authors tested effects of popliteal illumination and illumination provided through the eyelids on melatonin suppression. In randomized, counterbalanced orders, healthy volunteers received three treatments from midnight until 2:00 AM, one on each of three visits to the laboratory. Treatments included (1) no illumination from light pads applied to the popliteal fossae, with light mask maintained at < 3 lux (control); (2) light mask illuminated at 1700 lux, with popliteal light pads extinguished; and (3) popliteal light pads illuminated (13,000 lux) and light mask at < 3 lux (control). Saliva specimens were sampled at midnight, at 1:00 AM, and at 2:00 AM. Mean salivary melatonin concentrations rose from an average of 30.8 (3.9) pg/ml at midnight (baseline), to 33.2 (4.0) pg/ml at 1:00 AM, and to 37.2 (3.8) pg/ml at 2:00 AM in all three conditions, but no statistical differences were found using repeated-measures ANOVA. No evidence of melatonin suppression by either popliteal or closed eyelid light stimulation was found. These data suggest that bright retinal illumination is necessary for suppression of melatonin mediated through the suprachiasmatic nuclei.

Sleep duration, illumination, and activity patterns in a population sample: effects of gender and ethnicity.

BACKGROUND: Current knowledge of the population's sleep durations emanates primarily from questionnaires and laboratory studies. Using Actillumes, we investigated whether self-reported sleep durations were indicative of a population decline in sleep duration. We also explored illumination and activity patterns. METHODS: San Diego adults (n = 273, age range: 40-64) were recruited through random telephone calls and were monitored at home while engaging in usual daily routines. RESULTS: Volunteers slept an average of 6.22 hours and received an average of 554 lux (environmental illumination). The timing of sleep, illumination, and activity occurred at 2:44, 12:57, and 13:43, respectively. Irrespective of ethnicity, age, and time reference, men received greater illumination than did women, but this gender effect was not independent of work status. Women and men exhibited a similar circadian activity profile; however, women exhibited better sleep-wake patterns. Interactions between gender and ethnicity suggested worse sleep-wake patterns among minority men. An age-related decline in activity was found, but no age trend in sleep duration or illumination patterns was observed. CONCLUSIONS: This study showed an objective population decline in sleep duration. Sociodemographic effects should be considered in analyses of sleep-wake patterns and illumination exposures.

Sleep-wake patterns among postmenopausal women: a 24-hour unattended polysomnographic study.

BACKGROUND: Circadian sleep-wake profiles in postmenopausal women were examined to explore relationships between nocturnal and out-of-bed sleep. METHODS: Twenty-one home recordings were obtained with unattended polysomnography from women ranging from 56 to 77 years of age. RESULTS: While maintaining their daily routines, volunteers slept an average of 439 minutes throughout the 24-hour recordings. Ten percent of the accumulated sleep time was recorded out of bed. CONCLUSIONS: Greater age was associated with more afternoon-evening sleep. Sleep was also frequently observed shortly after volunteers arose from bed in the morning.

Circadian sleep, illumination, and activity patterns in women: influences of aging and time reference.

Patterns of sleep, illumination, and activity of women of different ages were continuously monitored in their natural environments with a wrist activity monitor. Partial correlation analyses were performed to determine relationships between age and sleep and several circadian rhythm measures including the amplitudes, mesors, and timings of sleep, of illumination, and of activity. We found no age-related decline in actigraphic sleep duration. Age was not a significant correlate of circadian rhythm parameters of sleep. Moreover, no age effects were found on daily illumination exposure or on the circadian timing of illumination and activity patterns. However, the level and amplitude of the circadian activity rhythm showed a gradual decline with aging, independent of the time reference (i.e., Daylight Saving Time versus Standard Time) when recordings were obtained. As expected, significant associations were observed between local time reference and the level and timing of peak of illumination patterns. However, changes in local time reference were not significantly and consistently associated with actigraphic sleep or activity measures.

Sleep and quality of well-being.

BACKGROUND: It is commonly believed that sleep duration in the population has been declining gradually. Whereas sleep restriction in the laboratory induces sleepiness and mood disturbances, it is not certain whether a short sleep duration impairs the quality of everyday life. METHODS: Using population-based data, we explored whether greater habitual sleep duration is a predictor of better health-related quality of life, measured by the Quality of Well-Being (QWB) scale. The relationships between QWB and several potential correlates were examined in a stepwise linear regression analysis. RESULTS: Neither subjective nor actigraphic sleep duration were associated with QWB. Greater quality of well-being was associated with greater sleep satisfaction, younger age, less obesity, non-Hispanic White ethnicity, and greater experienced illumination. CONCLUSION: These data suggest that increasing sleep duration may not directly improve quality of life, despite evidence that curtailment of nocturnal sleep is associated with fatigue.

Twenty-four-hour pattern of intraocular pressure in the aging population.

PURPOSE: To characterize the 24-hour pattern of intraocular pressure (IOP) in a sample of the aging human population. METHODS: Twenty-one healthy volunteers 50 to 69 years of age were housed in a sleep laboratory for 24 hours. Experimental conditions were strictly controlled with a 16-hour light period and an 8-hour dark period. Sleep was encouraged in the dark period. Intraocular pressure was measured using a pneumatonometer every 2 hours (total of 12 times). Measurements were taken in both the sitting position and the supine position during the light/wake period but only in the supine position during the dark period. RESULTS: When the sitting IOP data from the light/wake period and the supine IOP data from the dark period were considered, elevation and reduction of IOP occurred around the scheduled lights-off and lights-on transitions, respectively. Mean IOP in the dark period was significantly higher than mean IOP in the light/wake period. The trough appeared at the end of the light/wake period, and the peak appeared at the beginning of the dark period. The magnitude of trough-peak difference was 8.6+/-0.8 mm Hg (mean +/- SEM). Cosine fits of 24-hour IOP data showed a significant 24-hour rhythm. When IOP data from just the supine position were analyzed, the trough-peak IOP difference was 3.4+/-0.7 mm Hg, with similar clock times for the trough and the peak. Cosine fits of supine IOP data showed no statistically significant 24 hour rhythm. CONCLUSIONS: Nocturnal elevation of IOP occurred in this sample of the aging population. The trough of IOP appeared at the end of the light/wake period, and the peak appeared at the beginning of the dark period. The main factor in the nocturnal IOP elevation appeared to be the shift from daytime upright posture to supine posture at night.

Elevation of human intraocular pressure at night under moderate illumination.

PURPOSE: An endogenous elevation of intraocular pressure (IOP) occurs at night in healthy young adults. The authors studied whether or not this IOP elevation can be detected under moderate illumination. METHODS: Twenty-five healthy volunteers, ages 18 to 25 years, were housed overnight in a sleep laboratory under a strictly controlled light-dark environment. Intraocular pressure was measured in the supine position every 2 hours, using a pneumatonometer. An 8-hour sleep period was assigned to each volunteer according to individual's accustomed sleep cycle. In the early part of this assigned period, sleep was encouraged with room lights off. Researchers performed IOP measurements at two time points with the aid of night vision goggles. In the middle to the late part of the assigned period, lights were turned on twice for a 1-hour interval. The light intensity was the same as before the bedtime. At the ending of each light period, IOP was measured under illumination. RESULTS: Average IOP was significantly higher in the assigned sleep period versus outside the period. The trough of mean IOP occurred just before the bedtime, and then IOP gradually increased and peaked at the end of the 8-hour assigned sleep period. The difference between the trough and peak IOP was 3.5 +/- 0.7 mm Hg (mean +/- SEM, n = 25). Within the assigned sleep period, the average IOP determined under illumination was significantly higher than the average IOP preceding the illumination. CONCLUSIONS: Elevation of IOP occurred during the assigned sleep period with two 1-hour light exposures of moderate intensity. Environmental light at night had no significant effect on the nocturnal IOP elevation in healthy young adults.

Is sleep disturbed by vigorous late-night exercise?

PURPOSE: This experiment examined the influence of prolonged, vigorous late-night exercise on sleep. METHODS: Sixteen highly fit male cyclists completed each of two 60-h laboratory treatments involving a baseline night, an experimental treatment night, and a recovery night. In counterbalanced order, subjects 1) cycled for 3 h at 65-75% of heart rate reserve combined with bright light exposure (3000 lux) light, and 2) were exposed to a 3 h pulse of bright light (3000 lux) alone. RESULTS: On the baseline and recovery nights, subjects maintained their usual sleep-wake schedules. On the treatment night, exercise + bright light or bright light alone were centered at 6 h before their usual wake times, followed by bedtimes 30 min after the treatments. Illumination was 3000 lux during the experimental treatments, 0 lux during the sleep periods, and 50 lux at other times. Sleep was assessed with an Actillume (Ambulatory Monitoring, Inc., Ardsley, NY) wrist monitor to define sleep onset latency (SOL), wakefulness after sleep onset (WASO), and total sleep time. Subjective assessments of SOL, WASO, and insomnia were also gathered each morning. No significant differences in objective or subjective sleep variables were found between treatments. CONCLUSIONS: These data are inconsistent with the general opinion that vigorous exercise shortly before bedtime disturbs sleep.

Light mask 500 lux treatment for delayed sleep phase syndrome.

1. Bright light exposure has been demonstrated as an effective treatment for circadian rhythm sleep disorders. Recent studies suggest that more moderate intensities of light might affect endogenous rhythms. A light mask treatment, using light applied through eyelids during sleep, was tested for Delayed Sleep Phase Syndrome. 2. The active light group (n = 5) received 500 lux light for 3 hours prior to awakening for 12 days. The placebo light group (n = 5) received 0.1 lux light with the same timing. Circadian rhythm phase was assessed from core body temperature and urinary 6-sulfatoxymelatonin measurements. The SIGH-SAD-SR mood scale was administered to assess mood. 3. There were slight trends toward a phase advance of the body temperature rhythm and a phase delay of the melatonin rhythm, and both groups reported anti-depressant benefits. However, no statistically significant effects of 500 lux light mask treatment were demonstrated compared with the placebo-light treatment. 4. More extensive studies will be required to clarify the factors of dose-response and phase-response.