Michelle Magee

Prevalence of Circadian Misalignment and Its Association With Depressive Symptoms in Delayed Sleep Phase Disorder

Study Objective To examine the prevalence of circadian misalignment in clinically diagnosed delayed sleep phase disorder (DSPD) and to compare mood and daytime functioning in those with and without a circadian basis for the disorder. Methods One hundred and eighty-two DSPD patients aged 16-64 years, engaged in regular employment or school, underwent sleep-wake monitoring in the home, followed by a sleep laboratory visit for assessment of salivary dim light melatonin onset (DLMO). Based on the DLMO assessments, patients were classified into two groups: circadian DSPD, defined as DLMO occurring at or after desired bedtime (DBT), or non-circadian DSPD, defined as DLMO occurring before DBT. Results One hundred and three patients (57%) were classified as circadian DSPD and 79 (43%) as non-circadian DSPD. DLMO occurred 1.66 hours later in circadian DSPD compared to non-circadian DSPD (p < .001). Moderate-severe depressive symptoms (Beck Depression Inventory-II) were more prevalent in circadian DSPD (14.0%) than in non-circadian DSPD (3.8%; p < .05). Relative to non-circadian DSPD patients, circadian DSPD patients had 4.31 times increased odds of at least mild depressive symptoms (95% CI 1.75 to 10.64; p < .01). No group differences were found for daytime sleepiness or function, but DSPD symptoms were rated by clinicians to be more severe in those with circadian DSPD. Conclusions Almost half of patients clinically diagnosed with DSPD did not show misalignment between the circadian pacemaker and the DBT, suggesting that the reported difficulties initiating sleep at the DBT are unlikely to be explained by the (mis)timing of the circadian rhythm of sleep propensity. Circadian misalignment in DSPD is associated with increased depressive symptoms and DSPD symptom severity.

Diagnosis, cause, and treatment approaches for delayed sleep-wake phase disorder

Delayed sleep-wake phase disorder (DSWPD) is commonly defined as an inability to fall asleep and wake at societal times resulting in excessive daytime sleepiness. Although the cause is multifaceted, delays in sleep time are largely driven by misalignment between the circadian pacemaker and the desired sleep-wake timing schedule. Current treatment approaches focus on correcting the circadian delay; however, there is a lack of data investigating combined therapies for treatment of DSWPD.

Associations between number of consecutive night shifts and impairment of neurobehavioral performance during a subsequent simulated night shift

OBJECTIVE This study aimed to investigate sleep and circadian phase in the relationships between neurobehavioral performance and the number of consecutive shifts worked. METHODS Thirty-four shift workers [20 men, mean age 31.8 (SD 10.9) years] worked 2-7 consecutive night shifts immediately prior to a laboratory-based, simulated night shift. For 7 days prior, participants worked their usual shift sequence, and sleep was assessed with logs and actigraphy. Participants completed a 10-minute auditory psychomotor vigilance task (PVT) at the start (~21:00 hours) and end (~07:00 hours) of the simulated night shift. Mean reaction times (RT), number of lapses and RT distribution was compared between those who worked 2-3 consecutive night shifts versus those who worked 4-7 shifts. RESULTS Following 4-7 shifts, night shift workers had significantly longer mean RT at the start and end of shift, compared to those who worked 2-3 shifts. The slowest and fastest 10% RT were significantly slower at the start, but not end, of shift among participants who worked 4-7 nights. Those working 4-7 nights also demonstrated a broader RT distribution at the start and end of shift and had significantly slower RT based on cumulative distribution analysis (5 (th), 25 (th), 50 (th), 75 (th)percentiles at the start of shift; 75th percentile at the end of shift). No group differences in sleep parameters were found for 7 days and 24 hours prior to the simulated night shift. CONCLUSION A greater number of consecutive night shifts has a negative impact on neurobehavioral performance, likely due to cognitive slowing.

Temporal dynamics of circadian phase shifting response to consecutive night shifts in healthcare workers: Role of light-dark exposure

Shift work is highly prevalent and is associated with significant adverse health impacts. There is substantial inter‐individual variability in the way the circadian clock responds to changing shift cycles. The mechanisms underlying this variability are not well understood. We tested the hypothesis that light–dark exposure is a significant contributor to this variability; when combined with diurnal preference, the relative timing of light exposure accounted for 71% of individual variability in circadian phase response to night shift work. These results will drive development of personalised approaches to manage circadian disruption among shift workers and other vulnerable populations to potentially reduce the increased risk of disease in these populations.

Efficacy of melatonin with behavioural sleep-wake scheduling for delayed sleep-wake phase disorder: A double-blind, randomised clinical trial

Background Delayed Sleep-Wake Phase Disorder (DSWPD) is characterised by sleep initiation insomnia when attempting sleep at conventional times and difficulty waking at the required time for daytime commitments. Although there are published therapeutic guidelines for the administration of melatonin for DSWPD, to our knowledge, randomised controlled trials are lacking. This trial tested the efficacy of 0.5 mg melatonin, combined with behavioural sleep-wake scheduling, for improving sleep initiation in clinically diagnosed DSWPD patients with a delayed endogenous melatonin rhythm relative to patient-desired (or -required) bedtime (DBT). Methods This randomised, placebo-controlled, double-blind clinical trial was conducted in an Australian outpatient DSWPD population. Following 1-wk baseline, clinically diagnosed DSWPD patients with delayed melatonin rhythm relative to DBT (salivary dim light melatonin onset [DLMO] after or within 30 min before DBT) were randomised to 4-wk treatment with 0.5 mg fast-release melatonin or placebo 1 h before DBT for at least 5 consecutive nights per week. All patients received behavioural sleep-wake scheduling, consisting of bedtime scheduled at DBT. The primary outcome was actigraphic sleep onset time. Secondary outcomes were sleep efficiency in the first third of time in bed (SE T1) on treatment nights, subjective sleep-related daytime impairment (Patient Reported Outcomes Measurement Information System [PROMIS]), PROMIS sleep disturbance, measures of daytime sleepiness, clinician-rated change in illness severity, and DLMO time. Findings Between September 13, 2012 and September 1, 2014, 307 participants were registered; 116 were randomised to treatment (intention-to-treat n = 116; n = 62 males; mean age, 29.0 y). Relative to baseline and compared to placebo, sleep onset occurred 34 min earlier (95% confidence interval [CI] −60 to −8) in the melatonin group. SE T1 increased; PROMIS sleep-related impairment, PROMIS sleep disturbance, insomnia severity, and functional disability decreased; and a greater proportion of patients showed more than minimal clinician-rated improvement following melatonin treatment (52.8%) compared to placebo (24.0%) (P < 0.05). The groups did not differ in the number of nights treatment was taken per protocol. Post-treatment DLMO assessed in a subset of patients (n = 43) was not significantly different between groups. Adverse events included light-headedness, daytime sleepiness, and decreased libido, although rates were similar between treatment groups. The clinical benefits or safety of melatonin with long-term treatment were not assessed, and it remains unknown whether the same treatment regime would benefit patients experiencing DSWPD sleep symptomology without a delay in the endogenous melatonin rhythm. Conclusions In this study, melatonin treatment 1 h prior to DBT combined with behavioural sleep-wake scheduling was efficacious for improving objective and subjective measures of sleep disturbances and sleep-related impairments in DSWPD patients with delayed circadian phase relative to DBT. Improvements were achieved largely through the sleep-promoting effects of melatonin, combined with behavioural sleep-wake scheduling. Trial registration This trial was registered with the Australian New Zealand Clinical Trials Registry, ACTRN12612000425897.

Randomised controlled trial of the efficacy of a blue-enriched light intervention to improve alertness and performance in night shift workers

Objectives Night workers often experience high levels of sleepiness due to misalignment of the sleep-wake cycle from the circadian pacemaker, in addition to acute and chronic sleep loss. Exposure to light, in particular short wavelength light, can improve alertness and neurobehavioural performance. This randomised controlled trial examined the efficacy of blue-enriched polychromatic light to improve alertness and neurobehavioural performance in night workers. Design Participants were 71 night shift workers (42 males; 32.8±10.5 years) who worked at least 6 hours between 22:00 and 08:00 hours. Sleep-wake logs and wrist actigraphy were collected for 1–3 weeks, followed by 48-hour urine collection to measure the circadian 6-sulphatoxymelatonin (aMT6s) rhythm. On the night following at least two consecutive night shifts, workers attended a simulated night shift in the laboratory which included subjective and objective assessments of sleepiness and performance. Workers were randomly assigned for exposure to one of two treatment conditions from 23:00 hours to 07:00 hours: blue-enriched white light (17 000 K, 89 lux; n=36) or standard white light (4000 K, 84 lux; n=35). Results Subjective and objective sleepiness increased during the night shift in both light conditions (p<0.05, ηp 2=0.06–0.31), but no significant effects of light condition were observed. The 17 000 K light, however, did improve subjective sleepiness relative to the 4000 K condition when light exposure coincided with the time of the aMT6s peak (p<0.05, d=0.41–0.60). Conclusion This study suggests that, while blue-enriched light has potential to improve subjective sleepiness in night shift workers, further research is needed in the selection of light properties to maximise the benefits. Trial registration number The Australian New Zealand Clinical Trials Registry ACTRN12610000097044 (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=320845&isReview=true).

Delayed Sleep Phase Disorder: Mechanisms and Treatment Approaches

This chapter will introduce the basic characteristics of delayed sleep phase disorder and provide an overview of the current methods for diagnosis. Current theories on the etiology and mechanisms of the disorder are described, and a review of treatment options is presented. In summary: DSPD is characterized by a delay in the timing of the sleep-wake cycle, such that sleep onset is difficult to achieve at a desired or required time. Difficulty waking is also experienced, particularly when sleep is attenuated to maintain required schedules. DSPD is associated with a number of negative health consequences, including a high prevalence of comorbid depression. Significant functional impairments are associated with DSPD, including poor school or job performance, dysfunctional relationships, and negative health behaviors such as smoking and excessive alcohol use. Prevalence rates vary between cultures and between adolescents and middle-aged adults. It is likely multiple factors, such as genetic, environmental, and physiological, contribute to the etiology of the disorder, although the underlying basis of the disorder has not been fully elucidated. Assessment of circadian phase is an important diagnostic tool and may improve treatment outcomes. Exogenous melatonin and bright light therapy, both separately and combined, are emerging as effective treatments for DSPD, while further research is required for other promising pharmacological approaches.

Individual vulnerability to insomnia, excessive sleepiness and shift work disorder amongst healthcare shift workers. A systematic review

Shift workers often experience reduced sleep quality, duration and/or excessive sleepiness due to the imposed conflict between work and their circadian system. About 20-30% of shift workers experience prominent insomnia symptoms and excessive daytime sleepiness consistent with the circadian rhythm sleep disorder known as shift work disorder. Individual factors may influence this vulnerability to shift work disorder or sleep-related impairment associated with shift work. This paper was registered with Prospero and was conducted using recommended standards for systematic reviews and meta-analyses. Published literature that measured sleep-related impairment associated with shift work including reduced sleep quality and duration and increased daytime sleepiness amongst healthcare shift workers and explored characteristics associated with individual variability were reviewed. Fifty-eight studies were included. Older age, morning-type, circadian flexibility, being married or having children, increased caffeine intake, higher scores on neuroticism and lower on hardiness were related to a higher risk of sleep-related impairment in response to shift work, whereas physical activity was a protective factor. The review highlights the diverse range of measurement tools used to evaluate the impact of shift work on sleep. Use of standardised and validated tools would enable cross-study comparisons. Longitudinal studies are required to establish causal relationships between individual factors and the development of shift work disorder.

The pupillary light reflex distinguishes between circadian and non-circadian delayed sleep phase disorder (DSPD) phenotypes in young adults

This study investigated the utility of the pupillary light reflex as a method of differentiating DSPD patients with delayed melatonin timing relative to desired/required sleep time (circadian type) and those with non-delayed melatonin timing (non-circadian type). All participants were young adults, with a total of 14 circadian DSPD patients (M = 28.14, SD = 5.26), 12 non-circadian DSPD patients (M = 29.42, SD = 11.51) and 51 healthy controls (M = 21.47 SD = 3.16) completing the protocol. All participants were free of central nervous system acting medications and abstained from caffeine and alcohol on the day of the assessment. Two pupillary light reflex measurements were completed by each participant, one with a 1s dim (~10 lux) light exposure, and one with a 1s bright (~1500 lux) light exposure. Circadian DSPD patients showed a significantly faster pupillary light reflex than both non-circadian DSPD patients and healthy controls. Non-circadian patients and healthy controls did not differ significantly. Receiver operating characteristic curves were generated to determine the utility of mean and maximum constriction velocity in differentiating the two DSPD phenotypes, and these demonstrated high levels of sensitivity (69.23–-100%) and specificity (66.67–91.67%) at their optimal cut offs. The strongest predictor of DSPD phenotype was the mean constriction velocity to bright light (AUC = 0.87). These results support the potential for the pupillary light reflex to clinically differentiate between DSPD patients with normal vs. delayed circadian timing relative to desired bedtime, without the need for costly and time-consuming circadian assessments.