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Biomedical subjects

D F Kripke

Publications and source records attributed to D F Kripke.

At least 19 recordsLinked to original sources

Mortality hazard associated with prescription hypnotics.

BACKGROUND: The American Cancer Society's Cancer Prevention Study II was a large survey designed primarily to examine cancer risks such as cigarette smoking. From the same survey and methods, data on usage of "prescription sleeping pills" in 1982 were examined. METHODS: Standardized mortality ratios were computed. Because sleeping pill use could be a proxy for other risk factors, cox proportional hazards models were computed to control for possible confounding factors as extensively as the data permitted. RESULTS: Men and women who reported taking prescription sleeping pills 30+ times in the past month had standardized mortality ratios of 3.18 and 2.82, respectively; controlling for 10-year age groups (p < 0.001). The standardized mortality ratios for usage 1-29 times/month were 1.8 and 1.48, respectively (p < 0.001). In proportional hazards models that controlled for 30 other risk factors and comorbidities simultaneously, the excess mortality risk associated with usage 30+ times per month remained significant, but hazard ratios were reduced to 1.35 for men and 1.22 for women. CONCLUSIONS: Use of hypnotics was associated with excess mortality. This methodology could not determine if hypnotic compounds caused the risks associated with their use, nor could the risks of individual compounds be determined. Since millions of Americans are currently taking hypnotics, long-term controlled trials are urgently needed to further guide both patients and physicians.

Adult

Light treatment for nonseasonal depression: speed, efficacy, and combined treatment.

BACKGROUND: Using bright light for treating major depressive disorders which are not seasonal needs reassessment. METHODS: Clinical trials of light treatment for nonseasonal major depressive disorders were compared with selected trials of light treatment of winter depression and with antidepressant clinical drug trials. RESULTS: Light treatment of nonseasonal depression produces net benefits in the range of 12-35%, often within 1 week. CONCLUSIONS: Light's value for nonseasonal and seasonal depression are comparable. Light appears to produce faster antidepressant benefits than psychopharmacologic treatment. LIMITATIONS: Direct randomizing comparisons between light and medications for nonseasonal depression are not available. CLINICAL RELEVANCE: Bright light can be combined with standard therapies for treating nonseasonal depressions and appears synergistic.

Antidepressive Agents

Periodic leg movements during sleep and sleep disturbances in elders.

BACKGROUND: Periodic limb movements in sleep (PLMS) are an increasingly pervasive disturbance for aging adults. The aims of this experiment were: (a) to describe the index of periodic limb movements in sleep (myoclonus index [MI] in elderly subjects with complaints of poor sleep or depression (N = 22; 68 +/- 5.5 SD years); and (b) to correlate MI with sleep history, depression scores, and objective and subjective indices of sleep. METHOD: Sleep and leg movements were assessed for 5 consecutive nights. Between-subjects, nonparametric correlations were examined between mean MI and sleep history, depression scores, and objective and subjective sleep characteristics. Associations among within-subject night-to-night variabilities of MI, objective, and subjective variables were examined with repeated measures ANCOVA, entering MI as a covariate. RESULTS: A remarkably high level of MI was found (median 25.8 events per hour; 86% of subjects > 5). Nevertheless, no associations were found between MI and sleep disturbance measures. CONCLUSION: These results extend previous reports that PLMS are remarkably persuasive in elderly volunteers and support other reports questioning whether there is a distinct PLMS syndrome.

Aged

Melatonin excretion is not related to sleep in the elderly.

We examined the association between 6-sulphatoxymelatonin (6-SMT) excretion and sleep in 68 volunteers 60-79 years of age who complained of insomnia or depression. An Actillume wrist monitor was worn for 5-7 consecutive days and nights in home-living conditions. Activity was used to estimate total sleep time (TST) and wake after sleep onset (WASO). Throughout two 24 hr periods, urine was collected approximately every 2 hr during the day and after any voidings during the sleep period. During the next week, subjects spent 5 nights and 4 days in the laboratory. Sleep was measured and scored with standard polysomnographic techniques. Urine was collected, as for home recording, on days 1 and 4. Urinary concentrations of 6-SMT were assayed. Cosine-fitting of urine data across both days at home and both laboratory collections established the mesors and amplitudes of 24 hr 6-SMT excretion rhythms, but neither was significantly correlated with sleep. Mean and peak 6-SMT excretion during the sleep period was also determined. Significant correlations were found between mean 6-SMT during the laboratory sleep period and TST and WASO. However, these associations were not independent of circadian timing: sleep was better when sleep occurred near the circadian acrophase of 6-SMT excretion. These data indicate that low melatonin production may not be an important factor in insomnia among the elderly.

Aged

Melatonin: marvel or marker?

Melatonin blanches the skin of frogs, whitens the fur of hamsters, and sometimes makes the gonads atrophy. It is remarkable that such a hormone would be put forward as a defense against ageing. We have been examining excretion of the urinary metabolite of melatonin, 6-sulphatoxymelatonin (6-SMT), in 150 postmenopausal women, in 72 volunteers over the age of 60 years who complained of insomnia or depression, and in 20 healthy younger adult controls, aged 18-40 years. The acrophase or fitted peak of 6-SMT excretion was computed as a marker of the timing of the circadian system. Total daily excretion of 6-SMT was not significantly related to total sleep time, wake-within-sleep or sleep complaints. Nevertheless, whereas the 20 controls displayed a normal range of 6-SMT acrophases from 01.32 to 05.44 h, 42% of the postmenopausal women and 48% of the symptomatic elders had acrophases outside this normal range. Those volunteers with more deviant acrophases displayed more disturbed sleep and more sleep complaints. These data suggest that melatonin is a useful marker of circadian rhythm phase disorders, but suggest a need for more caution in melatonin administration.

Adult

Nocturnal elevation of intraocular pressure in young adults.

PURPOSE: To distinguish 24-hour (circadian) and postural effects on intraocular pressure (IOP) in healthy young adults. METHODS: Thirty-three volunteers were housed in a sleep laboratory for 1 day under a strictly controlled 16-hour light and 8-hour dark environment. Sleep was encouraged in the dark period. Intraocular pressure was measured in each eye every 2 hours using a pneumatonometer. Researchers used night-vision goggles to perform IOP measurements in the dark, while the subject's light exposure was minimized. In the first group of 12 subjects, measurements were taken with subjects in the sitting position during the light-wake period and supine during the dark period. In the second group of 21 subjects, all IOP measurements were taken with the subjects supine. RESULTS: Average IOP was significantly higher in the dark period than in the light-wake period in both groups. The lowest IOP occurred in the last light-wake measurement, and the peak IOP occurred in the last dark measurement. The trough-peak difference in IOP was 8.2+/-1.4 mm Hg (mean +/- SEM) in the first group. Intraocular pressure changed sharply at the transitions between light and dark. In the second group, the trough-peak IOP difference was 3.8+/-0.9 mm Hg. Intraocular pressure changed gradually throughout the 24-hour period. In comparison with the sitting IOP in the first group, the supine IOP in the second group was significantly higher during the light-wake period. CONCLUSIONS: Circadian rhythms of IOP were shown in young adults, with the peaks occurring in the late dark period. A nocturnal IOP elevation can appear independent of body position change, but change of posture from upright to recumbent may contribute to the relative nocturnal IOP elevation.

Adolescent

Nocturnal light effects on menstrual cycle length.

OBJECTIVES: In previous University of California, San Diego (UCSD) studies, nocturnal illumination shortened menstrual cycles that were longer than 33 days. The studies reported here extend the previous findings, confining the illumination to the sleep period. DESIGN: Two light levels (235 to 250 lux and less than 1 lux) and 2 modes of light delivery (lighted sleep mask and bedside lamp) were tested. RESULTS: 235 to 250 lux treatment cycle lengths were significantly shorter than baseline, but not significantly shorter than the less than 1 lux treatment cycle lengths. Subjective reports of sleep disturbance were greater with the 235 to 250 lux treatment, but there was no significant difference in overall quality of sleep between the two light levels. CONCLUSIONS: The current data alone do not exclude spontaneous remission or suggestion, but our previous studies demonstrated significant contrasts between 235 to 250 lux and less than 1 lux light levels. This study suggests that treatment may be effective when confined to the sleep period, and that light masks, which do not disturb bed partners, may be used in place of bedside lamps.

Adolescent

Prevalence of sleep-disordered breathing in ages 40-64 years: a population-based survey.

Previous research has offered widely varying prevalence estimates for sleep apnea in the population, leaving uncertain which breathing patterns are abnormal. To explore the distribution of sleep apnea in the population and its co-morbidities, random telephone dialing was used between 1990 and 1994 to recruit subjects for a prevalence survey of sleep-disordered breathing in San Diego adults. Events from which blood oxygen desaturations > or = 4% resulted were monitored with home recording instruments, usually for three consecutive nights. Among 190 women ages 40-64 years, a median of 4.3 desaturation events per hour of sleep were observed. A higher median of 6.7 events per hour was observed among 165 men. Frequencies were much higher among members of minority groups, leading to a standard estimate that 16.3% of U.S. Hispanics and racial minorities have > or = 20 events/hour as compared to 4.9% of non-Hispanic Whites ages 40-64. Obesity indicated by body-mass index was the most important demographic predictor of sleep-disordered breathing, followed by age, male gender, and ethnicity. Quality of well-being was not significantly impaired in subjects with more respiratory events; however, there was some increase in blood pressure and wake-within-sleep associated with sleep-disordered breathing. This survey indicates that sleep-disordered breathing is more common, especially among minorities, than had been previously believed, but less co-morbidity may be associated.

Adult

Variations in circadian rhythms of activity, sleep, and light exposure related to dementia in nursing-home patients.

We measured 24-hour circadian-rhythm patterns of activity and sleep/wake activity in a group of nursing-home patients (58 women and 19 men with a mean age of 85.7 years). Severely demented patients were contrasted with a composite group of moderate y, mild, or not-demented patients. Sleep/wake activity and light exposure were recorded with the Actillume recorder. Cosinor analyses were computed to determine the mesor, amplitude, acrophase, and circadian quotient of the activity rhythms. The diagnosis of dementia was based on the Mini Mental Examination and on examination of medical records. Sleep was extremely fragmented in both groups of nursing-home patients. Severely demented patients slept more both at night and during the day, but there were no significant differences in the number of awakenings during the night or in the number of naps during the day when compared to the composite group of moderate, mild, or no-dementia patients. The severely demented group had lower activity mesor, more blunted amplitude, and were more phase delayed (i.e. had later acrophases) than the other group. In addition, the severely demented patients spent less time exposed to bright light. These results confirm that circadian rhythms in nursing-home patients are disturbed with more disturbance in the severely demented. Much of the disturbance may be related not just to age but to mental status.

Aged

Light attenuation by the human eyelid.

Although it has been reported that light treatment during sleep can modify biological rhythms, the amount of light that is transmitted through the human eyelid has not been established. We evaluated eyelid transmission with a visual threshold response. Estimated light transmission through the eyelids was 0.3% for blue, 0.3% for green, and 5.6% for red light. The eyelid was an effective attenuator and acted as a red-pass filter. Illumination intensity and color balance after passing through the eyelid should be considered in evaluating the effects of light treatments during sleep.

Adult

Morbidity, mortality and sleep-disordered breathing in community dwelling elderly.

A population-based probability sample of elderly individuals (n = 426), who were originally studied between 1981 and 1986 (mean age at initial study was 72.5 years), were followed for mortality. Those with > or = 30 respiratory disturbances per hour of sleep had significantly shorter survival (p = 0.0034), but the respiratory disturbance index (RDI) was not an independent predictor of death. When Cox proportional hazards analysis was done, only age (the strongest predictor), cardiovascular disease and pulmonary disease were independent predictors of death. It may be that factors that are secondary to or associated with sleep-disordered breathing (SDB), such as cardiovascular or pulmonary disease, predispose these elderly to death.

Age Factors

Circadian rhythms in the human pupil and eyelid.

The human eye was studied to investigate its use as a noninvasive marker of circadian phase state. Subjects were measured every 30 min over 24 h to observe bilateral changes in pupil size and palpebral fissure. Twelve males and twelve females (ages 18-29 yr, mean = 21.6 yr) were studied around the clock while they remained within a light-controlled facility (< 100 lux). The acrophases (maximums) for pupil diameters and palpebral fissure distances were estimated using a cosine curve-fitting technique applied to each 24-h data set. Pupil diameter acrophases occurred randomly throughout the day. The data demonstrated a significant circadian rhythm for both resting and maximum palpebral fissure values. However, palpebral fissure acrophases were widely distributed, with the largest portion of the peaks occurring between 10:00 A.M. and 10:00 P.M.. These data did not support the hypotheses that sympathetic innervation to the pineal is paralleled in the eye, and results do not demonstrate any applicability of human eye measurements as circadian markers.

Adolescent

Antimanic drugs stabilize hamster circadian rhythms.

The circadian wheel-running rhythm of golden hamsters was monitored during chronic oral treatment with four mood-stabilizing drugs in doses relevant for treatment of manic-depressive disorder. Carbamazepine and verapamil shortened the duration of locomotor activity and improved the stability of the pattern of running activity. At comparable doses, valproate had no clear effect on any rhythm variable tested. None of these drugs consistently altered the phase of light-synchronized running rhythms or the period of the rhythm in constant darkness. The results are compared to data showing that lithium, which delays entrained phase and lengthens circadian period in hamsters, also shortens activity duration and increases the stability of wheel-running rhythms. Stabilization of circadian rhythms may be a key action of clinically effective mood-stabilizing drugs.

Animals

The role of actigraphy in the evaluation of sleep disorders.

This paper, which has been reviewed and approved by the Board of Directors of the American Sleep Disorders Association, provides the background for the Standards of Practice Committee's parameters for the practice of sleep medicine in North America. The growing use of activity-based monitoring (actigraphy) in sleep medicine and sleep research has enriched and challenged traditional sleep-monitoring techniques. This review summarizes the empirical data on the validity of actigraphy in assessing sleep-wake patterns and assessing clinical and control groups ranging in age from infancy to elderly. An overview of sleep-related actigraphic studies is also included. Actigraphy provides useful measures of sleep-wake schedule and sleep quality. The data also suggest that actigraphy, despite its limitations, may be a useful, cost-effective method for assessing specific sleep disorders, such as insomnia and schedule disorders, and for monitoring their treatment process. Methodological issues such as the proper use of actigraphy and possible artifacts have not been systematically addressed in clinical research and practice.

Circadian Rhythm

Seasonal variation in human illumination exposure at two different latitudes.

The authors measured ambient illumination exposure in healthy volunteers in San Diego, California (latitude 32 degrees 43' N, n = 30), and Rochester, Minnesota (latitude 44 degrees 1' N, n = 24), during each of the four quarters of the year, which were centered on the solstices and equinoxes. Subjects wore photosensors on their wrists and lapels (or foreheads while in bed) 24 h per day for an average of 5-6 days per quarter. The maximum of the two illumination readings was stored each minute. Annual average time spent per day in outdoor illumination (> or = 1000 lux) was significantly higher in San Diego than it was in Rochester (p < .04). Daily durations of illumination at or exceeding thresholds of 1, 10, 100, 1000, and 10,000 lux were highly seasonal in the sample as a whole (p < .01 at 1 lux, p < .0001 at other thresholds). Seasonal variation in outdoor illumination was far more pronounced in Rochester than it was in San Diego (interaction p < .001) but remained significant in San Diego (p < or = .03). Seasonal variation in indoor illumination was generally similar in the two cities. The median Rochester subject experienced illumination > or = 1000 lux for 2 h 23 min per day during summer and 23 min per day during winter. The corresponding times in San Diego were 2 h 10 min and 1 h 20 min. Neither age nor gender predicted illumination duration at any level. Both season and geographic location strongly influenced human illumination exposure, and behavior (choice of indoor vs. outdoor environment) was the most important mediating factor.

Adult

Low illumination experienced by San Diego adults: association with atypical depressive symptoms.

We explored the illumination exposure of middle-aged adults to determine normal values and to explore several correlates of daily light exposures. Subjects aged 40-64 years in San Diego, CA were recruited by random telephone dialing. Subjects completed a demographic interview and the Center for Epidemiologic Studies Depression self-rating scale (the CES-D) supplemented with eight questions related to seasonal affective disorders (SAD). Data were analyzed for 106 volunteers who wore a device that monitors illumination exposures and activity. The median subject was exposed to illumination > or = 1000 lux for only 4% of the time observed, that is, only about 58 min per day were spent in daylight. Subjects scoring higher on the atypical SAD mood symptoms spent less time in bright illumination rs = -0.266, p = 0.003. The CES-D depression score was similarly correlated with illumination but of borderline significance (rs = -0.150, p = 0.063). These results suggest the hypothesis that many Americans may be receiving insufficient light exposure to maintain optimal mood.

Adult