Daniel F. Kripke

Hypnotics' association with mortality or cancer: a matched cohort study

Objectives An estimated 6%–10% of US adults took a hypnotic drug for poor sleep in 2010. This study extends previous reports associating hypnotics with excess mortality. Setting A large integrated health system in the USA. Design Longitudinal electronic medical records were extracted for a one-to-two matched cohort survival analysis. Subjects Subjects (mean age 54 years) were 10 529 patients who received hypnotic prescriptions and 23 676 matched controls with no hypnotic prescriptions, followed for an average of 2.5 years between January 2002 and January 2007. Main outcome measures Data were adjusted for age, gender, smoking, body mass index, ethnicity, marital status, alcohol use and prior cancer. Hazard ratios (HRs) for death were computed from Cox proportional hazards models controlled for risk factors and using up to 116 strata, which exactly matched cases and controls by 12 classes of comorbidity. Results As predicted, patients prescribed any hypnotic had substantially elevated hazards of dying compared to those prescribed no hypnotics. For groups prescribed 0.4–18, 18–132 and >132 doses/year, HRs (95% CIs) were 3.60 (2.92 to 4.44), 4.43 (3.67 to 5.36) and 5.32 (4.50 to 6.30), respectively, demonstrating a dose–response association. HRs were elevated in separate analyses for several common hypnotics, including zolpidem, temazepam, eszopiclone, zaleplon, other benzodiazepines, barbiturates and sedative antihistamines. Hypnotic use in the upper third was associated with a significant elevation of incident cancer; HR=1.35 (95% CI 1.18 to 1.55). Results were robust within groups suffering each comorbidity, indicating that the death and cancer hazards associated with hypnotic drugs were not attributable to pre-existing disease. Conclusions Receiving hypnotic prescriptions was associated with greater than threefold increased hazards of death even when prescribed <18 pills/year. This association held in separate analyses for several commonly used hypnotics and for newer shorter-acting drugs. Control of selective prescription of hypnotics for patients in poor health did not explain the observed excess mortality.

Exposure to light in healthy elderly subjects and alzheimer's patients

Exposure to light was recorded from 10 healthy elderly adults and 13 age-matched subjects with senile dementia of the Alzheimers type (SDAT). Data were recorded in the home, for an average of 5 days, while subjects continued their normal daily activities. Subjects were exposed to remarkably small intervals of illumination exceeding 2000 lux. Subjects with SDAT were exposed to bright light significantly less than healthy controls (0.5 vs. 1.0 hr). Whether or not they had SDAT, males were exposed to illumination exceeding 2000 lux significantly more than were females. Healthy elderly received about two-thirds the duration of bright light received by healthy younger subjects. These findings suggest an association between decreased exposure to bright light and the declines in sleep quality which typically accompany normal and pathological aging.

Suggestive evidence for association of the circadian genes PERIOD3 and ARNTL with bipolar disorder.

Bipolar affective disorder (BPAD) is suspected to arise in part from malfunctions of the circadian system, a system that enables adaptation to a daily and seasonally cycling environment. Genetic variations altering functions of genes involved with the input to the circadian clock, in the molecular feedback loops constituting the circadian oscillatory mechanism itself, or in the regulatory output systems could influence BPAD as a result. Several human circadian system genes have been identified and localized recently, and a comparison with linkage hotspots for BPAD has revealed some correspondences. We have assessed evidence for linkage and association involving polymorphisms in 10 circadian clock genes (ARNTL, CLOCK, CRY2, CSNK1ε, DBP, GSK3β, NPAS2, PER1, PER2, and PER3) to BPAD. Linkage analysis in 52 affected families showed suggestive evidence for linkage to CSNK1ε. This finding was not substantiated in the association study. Fifty‐two SNPs in 10 clock genes were genotyped in 185 parent proband triads. Single SNP TDT analyses showed no evidence for association to BPAD. However, more powerful haplotype analyses suggest two candidates deserving further studies. Haplotypes in ARNTL and PER3 were found to be significantly associated with BPAD via single‐gene permutation tests (PG = 0.025 and 0.008, respectively). The most suggestive haplotypes in PER3 showed a Bonferroni‐corrected P‐value of PGC = 0.07. These two genes have previously been implicated in circadian rhythm sleep disorders and affective disorders. With correction for the number of genes considered and tests conducted, these data do not provide statistically significant evidence for association. However, the trends for ARNTL and PER3 are suggestive of their involvement in bipolar disorder and warrant further study in a larger sample.

Effect of Light Treatment on Sleep and Circadian Rhythms in Demented Nursing Home Patients

OBJECTIVES To determine whether fragmented sleep in nursing home patients would improve with increased exposure to bright light. DESIGN Randomized controlled trial. SETTING Two San Diego-area nursing homes. PARTICIPANTS Seventy-seven (58 women, 19 men) nursing home residents participated. Mean age +/- standard deviation was 85.7 +/- 7.3 (range 60-100) and mean Mini-Mental State Examination was 12.8 +/- 8.8 (range 0-30). INTERVENTIONS Participants were assigned to one of four treatments: evening bright light, morning bright light, daytime sleep restriction, or evening dim red light. MEASUREMENTS Improvement in nighttime sleep quality, daytime alertness, and circadian activity rhythm parameters. RESULTS There were no improvements in nighttime sleep or daytime alertness in any of the treatment groups. Morning bright light delayed the peak of the activity rhythm (acrophase) and increased the mean activity level (mesor). In addition, subjects in the morning bright light group had improved activity rhythmicity during the 10 days of treatment. CONCLUSION Increasing exposure to morning bright light delayed the acrophase of the activity rhythm and made the circadian rhythm more robust. These changes have the potential to be clinically beneficial because it may be easier to provide nursing care to patients whose circadian activity patterns are more socially acceptable.

Light treatment for nonseasonal depression: speed, efficacy, and combined treatment1

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 Lights 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.

Dementia in Institutionalized Elderly: Relation to Sleep Apnea

Sleep apnea is characterized by transient hypoxemias which are thought to affect mental functioning. Accordingly, speculation and research have focussed on relationships between sleep apnea and dementia. We studied 235 nursing home (ie institutionalized) patients (152 women with a median age of 83.5; 83 men with a median age of 79.7) with portable sleep recording equipment. The Mattis Dementia Rating Scale and the Geriatric Depression Scale were given to each. Seventy percent of the patients had five or more respiratory disturbances per hour of sleep and 96 percent showed some dementia. Sleep apnea was significantly correlated with all sub‐scales on the dementia rating scale. There were trivial differences in dementia ratings between those with mild‐moderate apnea and those with no apnea. There were significant differences, however, between the latter two groups and those with severe apnea. In particular, items reflecting attention, initiation and perseveration, conceptualization, and memory tasks on the DRS distinguished between those with and without severe sleep apnea. Among those patients with no depression, all patients with severe sleep apnea were also severely demented. Our data suggest that there is a strong relationship between dementia and sleep apnea when the sleep apnea and dementia are severe. Although causality cannot be inferred from associations, our hypothesis for study is that sleep apnea causes deficits in brain function, possibly due to global effects rather than any particular cortical or subcortical structure.

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 Websters 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.

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

BACKGROUND Current knowledge of the populations 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.

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.