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(PSYCHIATRIC TIMES) - 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.

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