Workshop report. Circadian rhythm sleep-wake disorders: gaps and opportunities

Abstract

This White Paper presents the results from a workshop cosponsored by the Sleep Research Society (SRS) and the Society for Research on Biological Rhythms (SRBR) whose goals were to bring together sleep clinicians and sleep and circadian rhythm researchers to identify existing gaps in diagnosis and treatment and areas of high-priority research in circadian rhythm sleep-wake disorders (CRSWD). CRSWD are a distinct class of sleep disorders caused by alterations of the circadian time-keeping system, its entrainment mechanisms, or a misalignment of the endogenous circadian rhythm and the external environment. In these disorders, the timing of the primary sleep episode is either earlier or later than desired, irregular from day-to-day, and/or sleep occurs at the wrong circadian time. While there are incomplete and insufficient prevalence data, CRSWD likely affect at least 800,000 and perhaps as many as 3 million individuals in the United States, and if Shift Work Disorder and Jet Lag are included, then many millions more are impacted. The SRS Advocacy Taskforce has identified CRSWD as a class of sleep disorders for which additional high-quality research could have a significant impact to improve patient care. Participants were selected for their expertise and were assigned to one of three working groups: Phase Disorders, Entrainment Disorders, and Other. Each working group presented a summary of the current state of the science for their specific CRSWD area, followed by discussion from all participants. The outcome of those presentations and discussions are presented here.

Keywords: actigraphy; advanced sleep–wake phase disorder; bright light therapy; chronotype; circadian amplitude; circadian period; circadian phase; circadian rhythm sleep–wake disorders; delayed sleep–wake phase disorder; dim light melatonin onset; entrainment; irregular sleep–wake rhythm disorder; melatonin; non-24-hour sleep–wake disorder.

Figure 1.

Publications resulting from NIH grant support with “circadian” as key word. Each bar represents the number of publications in that year that had the key word “circadian” and were supported by NIH grants. The number of such NIH-supported publications tripled across the first half of the decade and then remained stable thereafter. In the decade from 2008 to 2018, there were a total of 7,525 publications with the key word “circadian” that were supported by NIH grants. While this explosion of knowledge has revealed much about the workings of the circadian system and some of the consequences of disrupted circadian rhythmicity, relatively few grants and resulting manuscripts have focused on the pathophysiology or prevalence of CRSWDs or on testing new treatments for them.

Figure 2.

Relationship between the timing of the circadian phase of the DLMO and the timing of the nocturnal sleep episode. For all panels, the x-axis represents time; DLMO phase is indicated by the red circle; the grey bar represents time in bed, and the black bar represents sleep. (A) Typical phase relationship (in postpubertal adolescents and adults). (B) Circadian rhythm sleep–wake phase disorders are assumed to be caused by an “early” (in the case of ASWPD) or “late” (in DSWPD) “circadian phase timing” which in turn results in sleep occurring earlier or later than desired. In the cases illustrated here, the relative timing between the circadian phase of DLMO (red circle) and sleep onset is appropriate (i.e. sleep occurs at an appropriate circadian time), but the clock time at which each occurs is inappropriate (see also Figure 3, A). (C) Circadian rhythm sleep–wake phase disorders can also arise when the “relative timing” between the underlying rhythm of sleep–wake propensity is “inappropriately aligned relative to” the timing of sleep. This can occur even if time in bed is at a conventional/desired time. This may result in a prolonged sleep latency (indicated by the gray shading at the beginning of scheduled sleep in the upper sleep bar) or early morning awakening (indicated by the gray shading at the end of the sleep episode in the lower bar; see also Figure 3, B and C).

Figure 3.

Illustration of the complexity of CRSWD. Melatonin data are plotted with respect to clock time; red circle indicates time of DLMO; dashed blue vertical line represents bedtime. (A) “Classic” DSWPD in which the timing of the circadian system and the timing of sleep are both occurring later than normal (circadian phase of DLMO ~02:00 am, bedtime ~04:00 am; see also Figure 2, B). (B) A case where bedtime is at a conventional hour (midnight) but DLMO is occurring later than normal (~02:00 am). Such a patient would likely experience prolonged sleep latency and may be misclassified as having sleep onset insomnia, rather than DSWPD. (C) A case where DLMO is occurring at a conventional hour (~10:00 pm) but bedtime is occurring much later than normal (~04:00 am). According to current standards, such a patient would not have had their DLMO assessed in the process of being diagnosed as having DSWPD. In this case, treatments designed to shift circadian phase earlier (morning light, evening melatonin) may be ineffective, given that circadian phase is already occurring at a conventional time, despite the fact that sleep is not occurring at an appropriate circadian phase (see also Figure 2, C).