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Chronotherapeutics for affective disorders: A clinician's manual for light and wake therapy

Sleep duration is genetically regulated, but the genetic variants are largely unknown. We aimed to identify such genes using a genome-wide association study (GWAS) combined with RNA expression at the population level, and with experimental verification. A GWAS was performed in a Finnish sample (n = 1941), and variants with suggestive association (P < 5 × 10(-5) ) were tested in a follow-up sample from the same population with sleep duration (n = 6834) and time in bed (n = 1720). Variants with pointwise association of P < 0.05 in the follow-up sample were analysed further. First, we correlated genotypes with transcript expression levels with sleep duration (n = 207). The expression levels of significant transcripts were further studied in experimental sleep restriction. Of the 31 variants with P < 5 × 10(-5) in the discovery sample, three variants showed nominal allelic association (P < 0.05) in the follow-up sample: rs10914351, near PTPRU (P = 0.049), rs1037079 in PCDH7-CENTD1 (P = 0.011) and rs2031573 near KLF6 (P = 0.044). The risk alleles for shorter sleep (rs2031573 and rs1037079) were also associated with higher KLF6 and PCDH7 expression levels (P < 0.05). Experimental sleep restriction increased the expression of KLF6 (P < 0.01). These data suggest that rs2031573 near KLF6 or related loci and rs1037079 between PCDH7-CENTD1 or related loci may contribute to the regulation of sleep duration via gene expression. These results illustrate the utility of combining different analytical approaches to identify genetic determinants for traits related to sleep physiology. However, additional studies are needed in order to understand the roles of KLF6 and PCDH7 in sleep regulation.

Genome-wide association study of sleep duration in the Finnish population

STUDY OBJECTIVES The amount of recovery sleep needed to fully restore well-established neurobehavioral deficits from sleep loss remains unknown, as does whether the recovery pattern differs across measures after total sleep deprivation (TSD) and chronic sleep restriction (SR). METHODS In total, 83 adults received two baseline nights (10-12-hour time in bed [TIB]) followed by five 4-hour TIB SR nights or 36-hour TSD and four recovery nights (R1-R4; 12-hour TIB). Neurobehavioral tests were completed every 2 hours during wakefulness and a Maintenance of Wakefulness Test measured physiological sleepiness. Polysomnography was collected on B2, R1, and R4 nights. RESULTS TSD and SR produced significant deficits in cognitive performance, increases in self-reported sleepiness and fatigue, decreases in vigor, and increases in physiological sleepiness. Neurobehavioral recovery from SR occurred after R1 and was maintained for all measures except Psychomotor Vigilance Test (PVT) lapses and response speed, which failed to completely recover. Neurobehavioral recovery from TSD occurred after R1 and was maintained for all cognitive and self-reported measures, except for vigor. After TSD and SR, R1 recovery sleep was longer and of higher efficiency and better quality than R4 recovery sleep. CONCLUSIONS PVT impairments from SR failed to reverse completely; by contrast, vigor did not recover after TSD; all other deficits were reversed after sleep loss. These results suggest that TSD and SR induce sustained, differential biological, physiological, and/or neural changes, which remarkably are not reversed with chronic, long-duration recovery sleep. Our findings have critical implications for the population at large and for military and health professionals.

Residual, differential neurobehavioral deficits linger after multiple recovery nights following chronic sleep restriction or acute total sleep deprivation.

Summary


Genetic factors affect many aspects of sleep, such as sleep length. We investigated the contribution of genetic factors to stability and change of sleep length among adults over a 15-year period. In this representative follow-up study we used the Finnish Twin Cohort as the study population. Questionnaire surveys were performed in 1975 (response rate 89%, 11 041 twin pairs; age ≥18 years), 1981 (84%, 9323; ≥24 years) and 1990 (77%, 4507; 33–60 years). Sleep was categorized as short ( 8 h). Pairwise similarity in monozygotic and dizygotic pairs was examined at each survey by age group and sex. Quantitative genetic modelling was used to estimate cross-sectional and longitudinal genetic effects. The proportion of variance in sleep length at one point in time that was accounted for by genetic effects was very stable over the study period, being 0.31 in 1975, 0.32 in 1981 and 0.30 in 1990. Longitudinal genetic modelling indicated that the correlations of genetic effects between the three measurement points were high: 0.85 between 1975 and 1981; 0.93 between 1981 and 1990; and 0.76 between 1975 and 1990. Despite a high contribution of environmental effects, their correlations over time were modest: 0.31 between 1975 and 1981; 0.33 between 1981 and 1990; and 0.18 between 1975 and 1990. In conclusion, genetic factors have a modest but stable effect on the evolution of sleep length over a long time span in adults. Multiple measures are a more robust basis for genetic analyses than a single cross-sectional measure.

Genetic factors in evolution of sleep length - a longitudinal twin study in Finnish adults

Rapid-acting antidepressants and the circadian clock.

Study objectives Sleep loss produces large individual differences in neurobehavioral responses, with marked vulnerability or resilience among individuals. Such differences are stable with repeated exposures to acute total sleep deprivation (TSD) or chronic sleep restriction (SR) within short (weeks) and long (years) intervals. Whether trait-like responses are observed to commonly experienced types of sleep loss and across various demographically defined groups remains unknown. Methods Eighty-three adults completed two baseline nights (10 h-12 h time-in-bed, TIB) followed by five 4 h TIB SR nights or 36 h TSD. Participants then received four 12-h TIB recovery nights followed by five SR nights or 36 h TSD, in counterbalanced order to the first sleep loss sequence. Neurobehavioral tests were completed every 2 h during wakefulness. Results Participants who displayed neurobehavioral vulnerability to TSD displayed vulnerability to SR, evidenced by substantial to near perfect intraclass correlation coefficients (ICCs; 78%-91% across measures). Sex, race, age, body mass index (BMI), season, and sleep loss order did not impact ICCs significantly. Individuals exhibited significant consistency of responses within, but not between, performance and self-reported domains. Conclusions Using the largest, most diverse sample to date, we demonstrate for the first time the remarkable stability of phenotypic neurobehavioral responses to commonly experienced sleep loss types, across demographic variables and different performance and self-reported measures. Since sex, race, age, BMI, and season did not affect ICCs, these variables are not useful for determining stability of responses to sleep loss, underscoring the criticality of biological predictors. Our findings inform mathematical models and are relevant for the general population and military and health professions.

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Robust stability of trait-like vulnerability or resilience to common types of sleep deprivation in a large sample of adults.

Purpose Sleep loss impairs a range of neurobehavioral functions, particularly vigilant attention and arousal. However, the detrimental effects of sleep deprivation on inhibition control and its relationship to vigilant attention impairments remain unclear. This study examined the extent to which vigilant attention deficits contribute to inhibition control performance after one night of total sleep deprivation (TSD) and two nights of partial sleep restriction (PSR). Participants and Methods We analyzed data from N = 49 participants in a one-night of TSD experiment, N=16 participants in a control experiment without sleep loss, and N = 16 participants in a two-nights of PSR experiment (time in bed, TIB = 6 h for each night). Throughout waking periods in each condition, participants completed the psychomotor vigilance test (PVT), which measures vigilant attention, and the Go/No-Go task, which measures inhibition control. Results After TSD and PSR, participants displayed significantly slower reaction times (RT) and more lapses in PVT performance, as well as slower Go RT and more errors of omission during the Go/No-Go task. PVT deficits accounted for 18.0% of the change in Go RT and 12.4% of the change in errors of omission in the TSD study, and 23.7% of the change in Go RT and 20.3% of the change in errors of omission in the PSR study. Conclusion Both TSD and PSR impaired inhibition control during the Go/No-Go task, which can be partly accounted for by vigilant attention deficits during the PVT. These findings support the key role of vigilant attention in maintaining overall neurobehavioral function after sleep loss.

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Impaired Vigilant Attention Partly Accounts for Inhibition Control Deficits After Total Sleep Deprivation and Partial Sleep Restriction.

In this review, we comprehensively discuss recent reports of heritability and genetic associations using candidate gene and genome-wide association (GWA) approaches in circadian and sleep phenotypes in adults, including chronotype (morningness-eveningness), sleep duration and daytime sleepiness, circadian rhythm sleep-wake disorders, and insomnia. Recent findings derive from GWA studies with objective measures and candidate gene studies examining the role of genetic ancestry and health disparities for sleep and circadian measures. The discovery of key, novel genetic markers using various methods has critical implications for future research in terms of identification, treatment, and countermeasures in the field of sleep medicine.

Genetics of Circadian and Sleep Measures in Adults: Implications for Sleep Medicine

BACKGROUND Sleep deprivation (SD) is an antidepressant intervention with multiple administration formats that has been investigated primarily with uncontrolled clinical trials and qualitative reviews of the literature. The validity and applicability of these findings to the treatment of bipolar depression (BPD) is uncertain. METHODS A PRISMA-based systematic review of the literature and meta-analysis were conducted to determine the efficacy of SD in the treatment of BPD and to identify moderator variables that influence response rate. RESULTS From a sample of 15 studies covering 384 patients, the overall, mean response rate to SD was 47.6% (CI 36.0%, 59.5%). This response rate compared post-SD to pre-SD depression scores, and not to a placebo control condition. Of several potential moderating variables examined, the use of adjunctive pharmacotherapy achieved statistical significance with response rates of 59.4% [CI 48.5, 69.5] for patients using adjunctive medication vs 27.4% [CI 17.8, 39.8] for patients not using adjunctive medication. CONCLUSIONS This meta-analysis of SD in the treatment of BPD found an overall, response rate of almost 50%, reinforcing earlier estimates of efficacy. The use of adjunctive pharmacotherapy had a statistically significant moderating effect on SD response suggesting that clinical practice should routinely pair these interventions. These findings provide a higher level of evidence supporting the use of SD, especially when used with medication, and should inform future management guidelines for the treatment of BPD.

Namni Goel

Papers

Residual, differential neurobehavioral deficits linger after multiple recovery nights following chronic sleep restriction or acute total sleep deprivation.

Robust stability of trait-like vulnerability or resilience to common types of sleep deprivation in a large sample of adults.

Impaired Vigilant Attention Partly Accounts for Inhibition Control Deficits After Total Sleep Deprivation and Partial Sleep Restriction.

Genetics of Circadian and Sleep Measures in Adults: Implications for Sleep Medicine

Meta‐analysis of sleep deprivation in the acute treatment of bipolar depression