Circadian rhythm sleep disorders (CRSD) are due to a misalignment between the timing of the endogenous circadian rhythm and the desired or socially acceptable sleep-wake schedule, or dysfunction of the circadian pacemaker and its afferent/efferent pathways. CRSDs include delayed sleep phase disorder, advanced sleep phase disorder, non-24-hour sleep-wake disorder, irregular sleep-wake rhythm disorder, shift work sleep disorder and jet lag disorder.
The central circadian pacemaker in mammals is located in the suprachiasmatic nucleus (SCN). The endogenous period of circadian rhythms in humans is typically slightly longer than 24 hours [1
]. Therefore, in order to maintain a stable relationship with the recurring daily changes in the 24-hour physical environment, circadian rhythms are entrained by light, social and physical activity cues, and melatonin. Of these, light is the strongest entraining agent for the circadian clock. Light-dark cycle information is relayed from the retina to the SCN primarily via the retinohypothalamic tract, a neural pathway that is distinct from the visual system [2
]. The timing of light exposure is crucial, and determines its ability to effect changes in the timing of circadian rhythms. According to the phase response curve in humans, exposure to bright light in the early morning (after the nadir of the core body temperature rhythm) induces phase advances, whereas light exposure in the evening (before the nadir of the core body temperature rhythm) delays the phase of circadian rhythms [3
Figure 1 Schematic illustration of the human phase response curve (PRC) to melatonin and light. The black circles along the PRC indicate exposure to stimuli (e.g. light or melatonin). The position during which the stimulus occurs indicates whether the effect would (more ...)
Although less potent than bright light, melatonin also has circadian phase shifting properties. The timing of melatonin release from the pineal gland is regulated by the SCN and its secretion is suppressed by exposure to bright light [4
]. In individuals with a typical sleep- wake schedule, endogenous melatonin levels begin to rise approximately 2 hours before sleep onset [5
], and remain elevated during the habitual sleep hours. Melatonin onset measured in dim light (DLMO) has been shown to be a stable marker of circadian phase [6
] and can be used to determine the timing of endogenous circadian rhythms in the research setting as well as in clinical practice. The phase response curve for melatonin is approximately 12 hours out of phase with that for light, but with similar crossover points [8
]. Melatonin administration in the early morning (after the nadir of the core body temperature rhythm) cause phase delay shifts, whereas when given in the evening, elicit phase advance shifts [9
Because the primary synchronizing agents of the circadian system are the light/dark cycle and melatonin, timed exposure to bright light and administration of melatonin have often been used as treatments of circadian rhythm sleep disorders. Although we will focus on pharmacologic therapies, it is important to note that timed exposure to bright light is an indication as either a guideline or option by the American Academy of Sleep Medicine (AASM) Clinical Practice Parameters for the treatment of most CRSDs [10
]. Exogenous melatonin is widely used as a pharmacological treatment and is recommended as either a guideline or option by the AASM Clinical Practice Parameters for the treatment of CRSDs. Melatonin is classified as a nutritional supplement and has been approved by FDA as a treatment for sleep disorders.