Now is the winter of our discontent
Made glorious summer by this
sun of York
—W. Shakespeare, Richard III
Humans were biologically programmed to sleep at times that in the modern era are often in conflict with the demands of bosses, spouses, kids, and pets. In most advanced civilizations, there have been added discontents: there are 52 weekend-to-weekday transitions each year and, more recently, 2 equinoctial time changes—not to mention the advent of various sources of artificial light that now include electronic devices often used in the wee hours of the morning.
Remarkably, until 1980 the scientific wisdom was that humans were uniquely impervious to the non-visual effects of ocularly mediated light. All of this changed overnight when it was discovered that intensity-dependent light can suppress endogenous melatonin production in humans. Key among its many implications was that we are more responsive to sunlight than we are to indoor light. This discovery immediately led to the development of bright light therapy for seasonal affective disorder (SAD), and it continues to be generative.
Most patients with SAD become depressed every winter, some each summer. According to the phase shift hypothesis, winter depression comprises 2 circadian phase types—“owls” and “larks”—with the former predominating. The treatment of choice for both of these phase types is bright light, optimally scheduled in the morning or in the evening, respectively. Bright light in the morning causes a phase advance (a shift to an earlier time), and in the evening it causes a phase delay (a shift to a later time).
At least two-thirds of those who have winter depression have phase-delayed circadian misalignment (the owls); those in the smaller subgroup (the larks) have phase-advanced circadian misalignment (Figure 1). As days get shorter or longer, the body clock shifts in accordance with the change in dawn or dusk, but work and social schedules constrain our sleep time. Thus, there is a mismatch between these two sets of circadian rhythms, resulting in internal misalignment. In vulnerable individuals, misalignment triggers depression.
Phase-delayed misalignment occurs when the body clock is abnormally delayed (late) with respect to the sleep-wake cycle, and phase- advanced misalignment occurs when the body clock is abnormally advanced (early) with respect to the sleep-wake cycle. Sleep times can also occur earlier or later than normal, sometimes in the same direction as the body clock (Figure 2) and sometimes not (thereby further worsening internal misalignment between the set of circadian rhythms closely tied to the body clock and the set related to the sleep-wake cycle and its evoked rhythms).
Assessing body clock time
Objective phase typing of the circadian rhythms closely tied to the body clock can now be accomplished using the salivary dim light melatonin onset obtained at home in the evening; conveniently, it usually occurs before habitual sleep time. The most cumbersome constraint is that saliva samples need to be collected under dim light, because melatonin production is suppressed by light exposure. However, some strategies are in the works to liberalize this requirement, such as the use of blue-blocking amber goggles.
The dim light melatonin onset biomarker is the gold standard for assessing body clock time. Mid-sleep is the best biomarker for the timing of the sleep-wake cycle and its evoked rhythms. The time interval, or phase angle difference between dim light melatonin onset and mid-sleep, is optimally 6 hours in patients with SAD and can be used to phase type circadian misalignment objectively. Phase-delayed types have a phase angle difference shorter than 6 hours (a dim light melatonin onset that is late with respect to mid-sleep), and phase- advanced types have a phase angle difference longer than 6 hours (a dim light melatonin onset that is early with respect to mid-sleep).
In SAD, there appears to be a “sweet spot” for optimal alignment at phase angle difference 6, which turns out to be the vertex of parabolas fitted to depression ratings plotted against phase angle difference before and after treatment (see Figures 2, 3, and 4 in Lewy et al1): the more phase angle difference deviates from the sweet spot in either direction, the worse the depression. Too much phase resetting can result in a shift to the other side of the para-bolic sweet spot, which causes depression ratings to increase.
Effects of melatonin
The phase-shifting effects of melatonin have recently been shown to be equal and additive to those of bright light. Low-dose melatonin (0.3 to 0.6 mg) is preferred to provide a chemical dark signal to the body clock, overriding the effects of ambient light: when taken at wake time it causes a phase delay and in the afternoon/evening it causes a phase advance. If a patient is unusually sensitive to the soporific side effect of melatonin (which rarely occurs at these low doses), he or she should not drive immediately after taking a pill. Low-dose melatonin causes more robust phase shifts than some higher doses, because it provides a more discrete time signal.
Although some patients with SAD enjoy the experience of sitting in front of a light box, taking a pill is much more convenient and should increase adherence. As shown in Figure 2, these phase-resetting agents can be used separately or together (ie, morning melatonin plus evening light—or morning light plus afternoon/evening melatonin). The precise optimal times are tied to the dim light melatonin onset, which can vary widely among individuals. As a patient responds, follow-up dim light melatonin onsets can guide adjustment of these treatment times.
Correcting circadian misalignment
To correct phase-delayed circadian misalignment (Figure 2), the body clock needs to be shifted earlier using bright light in the morning and/or low-dose melatonin in the afternoon/evening. To correct phase-advanced circadian misalignment, the body clock needs to be shifted later using bright light in the evening and/or low-dose melatonin in the morning. The clock times in Figure 2 are averaged for people who habitually awaken at 0600, although the precise optimal times for scheduling light and melatonin are tied to the internal body clock. The gold standard biomarker for the body clock is a person’s salivary dim light melatonin onset. There is not much day-to-day variation in the dim light melatonin onset; among individuals, however, it can occur from several hours before to just before (rarely, just after) sleep onset.
Dr Lewy is Professor Emeritus of Psychiatry and Director of the sleep and mood disorders laboratory at Oregon Health & Science University (OHSU), Portland. Dr Lewy reports that he is co-inventor on several melatonin process patents owned by OHSU and currently are not licensed to any company; he has consulted for pharmaceutical companies (such as Servier and currently, Pfizer).
There are 2 types of circadian misalignment between the circadian rhythms tightly coupled to the body clock (indicated by the beds) and those that are related to the sleep-wake cycle (indicated by the horizontal silhouettes). The best biomarker for the body clock is the dim light melatonin onset (not shown), and the best biomarker for the sleep-wake cycle is the mid-point (not specifically indicated above) of the sleep bout. Phase-delayed circadian misalignment occurs when the body clock is delayed (shifted later) with respect to the sleep-wake cycle; phase-advanced circadian misalignment occurs when the body clock is advanced (shifted earlier) with respect to the sleep-wake cycle. (Adapted with permission from Bahattacharjee Y. Science.2 Copyright © 2007 American Association for the Advancement of Science.).
There are 2 types of treatments for circadian phase disorders: low-dose melatonin (indicated by the capsules) and bright light (indicated by the sun). Although optimal timing of these treatments is best scheduled with respect to the internal body clock (as given by the endogenous dim light melatonin onset biomarker), clock times are indicated for individuals whose average habitual wake time is 0600. To provide a corrective phase advance, light should be scheduled at wake time and melatonin should be taken in the afternoon/evening; to provide a therapeutic phase delay, light should be scheduled in the evening and melatonin should be taken at wake time. These treatments are fundamentally grounded in human biology.3-7 (Adapted with permission from Lewy AJ, Sack RL. Progress in Brain Research: Hypothalamic Integration of Circadian Rhythms. Copyright © Elsevier 1996.)
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