Not long ago, I was consulted on the case of an 11-year-old boy with bipolar disorder who was not able to go to sleep before 1 am. The problem did not seem to stem from ongoing symptoms of bipolar disorder. I did not have the benefit of detailed information about the boy’s endogenous circadian rhythms, but I thought a phase-resetting intervention might be helpful. I recommended a 0.3-mg dose of melatonin to be taken daily at 3 pm. For most people, this would be the time when melatonin is most effective in promoting earlier sleep onset (a so-called phase advance). A few days later, to my chagrin, the boy’s parents reported that his condition had worsened! Fortunately, after moving the melatonin dose to 7 pm, there was a marked change in the boy’s bedtime to a more reasonable hour.

What can this case teach us about circadian rhythms and melatonin? And what further lessons do we need about circadian rhythms, light exposure, and melatonin to help our patients with disturbed sleep/wake cycles? To answer these questions, we need to delve a bit into the melatonin and light phase response curves (PRCs) and how they tell us when to use bright light and low-dose melatonin to shift the body clock.

The circadian system

The neural pathway for melatonin and the circadian system is presented in Figure 1. The retinohypothalamic tract conveys photic information from the retina to the hypothalamus, the location of the suprachiasmatic nucleus. The suprachiasmatic nucleus is the location of the endogenous circadian pacemaker (body clock) that regulates all circadian rhythms. It is linked to the pineal via preganglionic and postganglionic sympathetic neurons that release norepinephrine. This stimulates adrenergic receptors on the pinealocytes and results in the synthesis and immediate release of melatonin into the venous circulation and the cerebrospinal fluid. The suprachiasmatic nucleus thus receives information about the time of day in 2 ways: from ambient light and from melatonin that “feeds back” onto the suprachias-matic nucleus via the cerebrospinal fluid.

The daily ambient light/dark cycle regulates all circadian rhythms, including production and secretion of melatonin by the pineal gland that occurs only during the night (the 12-hour duration of melatonin production defines the “biological night”).1,2 Ambient light acutely suppresses melatonin production by the pineal gland.3 The most useful measure of a person’s internal body-clock time-circadian time (CT) is the time of dim light melatonin onset (DLMO).4 In normal- sighted people, under dim light conditions, the DLMO time occurs about 14 hours after the person’s wake time. However, the DLMO is actually a more accurate marker for CT than for wake time.

While all circadian rhythms are regulated by the suprachiasmatic nucleus, the sleep/wake cycle is less tightly coupled to this master body clock than are most other circadian rhythms, such as temperature regulation or secretion of cortisol and melatonin. This “loose coupling” creates the potential for various “misalignment” conditions. That is, misalignment can occur between the sleep/wake cycle (and its related rhythms) and the circadian rhythms that are more tightly coupled to the suprachiasmatic nucleus.5-8

Melatonin and misalignment

Air travelers who cross several time zones are familiar with jet lag-an example of circadian misalignment. A similar mechanism is also thought to be a primary cause of seasonal affective disorder (SAD). SAD is comparable to having jet lag for 5 months of every 12! In principle, both melatonin and bright light treatment can get circadian rhythms “back in sync” by correcting circadian misalignment.7,8

Treatment of circadian phase disorders with light or melatonin is based on their respective PRCs-graphical representations of how each agent shifts the person’s sleep/wake cycle.9 The PRCs for light and melatonin are about 12 hours out of phase with each other. That is, exposure to morning light causes a phase advance (shift to an earlier time), whereas melatonin administration in the morning causes a phase delay (shift to a later time). Conversely, evening light exposure causes a phase delay, whereas afternoon/evening melatonin administration causes a phase advance. Combining bright light exposure and mela-tonin can be a more powerful realigner of misaligned rhythms than either one alone. Because their respective PRCs are out of phase, however, this is true only if the dosing occurs at the proper times-but those times are different for each agent.

Figure 2 illustrates the optimal times to schedule bright light exposure and low-dose melatonin administration to cause the desired circadian phase shifts. As a general rule: To cause a phase advance, bright light should be scheduled in the morning and low-dose melatonin should be administered in the afternoon. To cause a phase delay, light should be scheduled in the evening and melatonin should be administered in the morning.

The clinician may sometimes make matters worse if treatments are not timed correctly-and this can turn out to be a highly individualized matter. For example, in my 11-year-old patient, I hypothesized that the 3 pm melatonin dose was stimulating the wrong zone of his melatonin PRC, which in his case was delayed. For him, 7 pm was the optimal time for initially inducing the desired phase advance. Because the average psychiatrist or other physician is not likely to obtain laboratory values to determine a patient’s salivary DLMO-or have access to a sleep lab-several empirical trials may be needed before the right melatonin dosing schedule becomes apparent.

Similarly, when it comes to light exposure, subtle shifts in dosing schedule can make a big difference clinically. For example, some years ago, a medical student who heard me lecture decided to treat his own delayed sleep phase syndrome. He typically went to bed between 1 and 4 am and slept as late as noon. As treatment, he woke himself up at 6 am and exposed himself to bright light. But his sleep times did not advance as theory would predict; instead, they were actually delayed a bit further. This was probably because his light PRC was so severely delayed in the first place that bright light at 6 am was stimulating its delay zone.

I advised him to get the bright light exposure at his usual wake time and to shift his wake time (and sunlight exposure) 15 minutes earlier every other day until he awoke consistently at 6 am.

When the psychiatrist runs into cases of this subtlety and complexity, consultation with a sleep disorders specialist is usually a good idea. With patience and perseverance, most people with circadian rhythm disturbances can be helped.

Disclosures:

Dr Lewy is professor of psychiatry, opthalmology, and physiology/pharmacology, senior vice chairman of the department of psychiatry, and director of the sleep and mood disorders laboratory at the Oregon Health & Sciences University, Portland.

Dr Lewy reports that he is co-inventor of several melatonin process patents owned by OHSU; he occasionally provides technical advice to pharmaceutical and other companies.

References:

1. Lewy AJ. Biochemistry and regulation of mammalian melatonin production. In: Relkin RM, ed. The Pineal Gland. New York: Elsevier North-Holland; 1983:77-128.

2. Arendt J. Melatonin and the Mammalian Pineal Gland. London: Chapman & Hall; 1995.

3. Lewy AJ, Wehr TA, Goodwin FK, et al. Light suppresses melatonin secretion in humans. Science. 1980;210:1267-1269.

4. Lewy AJ, Sack RL. The dim light melatonin onset as a marker for circadian phase position. Chronobiol Int. 1989;6:93-102.

5. Kripke DF, Mullaney DJ, Atkinson M, Wolf S. Circadian rhythm disorders in manic-depressives. Biological Psychiatry.1978;13:335-351.

6. Wehr TA, Wirz-Justice A, Goodwin FK, et al. Phase advance of the circadian sleep-wake cycle as an anti-depressant. Science.1979;206:710-713.

7. Lewy AJ, Lefler BJ, Emens JS, Bauer VK. The circadian basis of winter depression. Proc Natl Acad Sci U S A. 2006;103:7414-7419.

8. Emens JS, Lewy AJ, Kinzie MJ, et al. Circadian misalignment in major depressive disorder. Psychiatry Res. 2009;168:259-261.

9. Lewy AJ, Bauer VK, Ahmed S, et al. The human phase response curve (PRC) to melatonin is about 12 hours out of phase with the PRC to light. Chronobiol Int.1998;15:71-83.

10. Lewy AJ. Melatonin and human chronobiology. Cold Spring Harb Symp Quant Biol. 2007;72:623-636.