|Articles|July 10, 2012

Psychiatric Times

  • Psychiatric Times Vol 29 No 7
  • Volume 29
  • Issue 7

The Role of Melatonin in the Circadian Rhythm Sleep-Wake Cycle

Melatonin has a role in psychiatric illness and the treatment of circadian rhythm sleep disorders, insomnia, and comorbid depressive disorders.

Melatonin was first isolated from the bovine pineal gland in 1958.1 In humans, it is the main hormone synthesized and secreted by the pineal gland. It is produced from a pathway that includes both tryptophan and serotonin. Melatonin displays high lipid and water solubility, which allows it to diffuse easily through most cell membranes, including the blood-brain barrier. Its half-life is about 30 minutes, and it is cleared mostly through the liver and subsequently excreted in the urine as urinary 6-sulfatoxymelatonin.

In humans and most diurnal mammals, melatonin is secreted at night with a robust circadian rhythm and maximum plasma levels that occur around 3 to 4 AM. The daily rise of melatonin secretion correlates with a subsequent increase in sleep propensity about 2 hours before the person’s regular bedtime. The time before this secretion is the least likely for sleep to occur, and when it starts, the propensity for sleep increases greatly as the “sleep gate” opens. The rhythmic release of melatonin is regulated by the central circadian rhythm generator-the suprachiasmatic nucleus (SCN) of the anterior hypothalamus.

Most of the chronobiotic and hypnotic effects of melatonin are mediated through 2 receptors: MT1 and MT2. Both subtypes have high density in the SCN, but they are also spread throughout other sites in the brain and other organs, which indicates that melatonin likely affects other biological systems. Given this distribution, it is not surprising that melatonin appears to have a number of effects on human biology that have not been fully elucidated, including regulating the sleep-wake cycle and acting as a neurogenic/neuroprotective agent.

It appears that the function of melatonin is to mediate dark signals and provide night information, a “hormone of darkness,” rather than be the hormone of sleep. It has also been thought to be an “endogenous synchronizer” that stabilizes and reinforces various circadian rhythms in the body.2 Although direct hypnotic effects have been seen, melatonin’s effect on sleep appears more involved in the circadian rhythm of sleep-wake regulation. The phase shifting effects of melatonin appear to be due to the MT2 receptor, while the MT1 receptor is more related to sleep onset.

Melatonin and the circadian rhythm of the sleep-wake cycle

The daily sleep-wake cycle is influenced by 2 factors: process C (circadian), an endogenous “clock” that drives the rhythm of the sleep-wake cycle; and process S (sleep), a homeostatic “sleep propensity” that determines the recent amount of sleep and wakefulness accumulated. The SCN interacts with both processes, and it is where the main component of process C is located. Excitatory signals from the SCN and subsequent melatonin suppression are thought to promote wakefulness during the day in response to light and the suppression of melatonin inhibition of the SCN. This inhibition is released in the dark phase and leads to melatonin synthesis/release with consequent sleep promotion.

The sleep-wake cycle is only one of many circadian rhythms. Left without stimulus, the circadian period of sleep/wake is around 24.2 hours, but this can vary from 23.8 to 27.1 hours. This period is inherited and is closely related to intrinsic circadian preference for nighttime (long period) or daytime (short period), which can be determined by measuring the timing of maximal secretion of melatonin and subsequent related core body temperature (CBT). Maximum sleepiness occurs when CBT is at its lowest and melatonin levels are at their highest.

Many exogenous and endogenous factors (called zeitgebers) can shift a circadian rhythm. The sleep-wake cycle only becomes entrained to the 24-hour solar day by these factors, and by far the most powerful is ocular light exposure. The use of exogenous melatonin is one of the major non-light factors that can entrain the circadian rhythm, but results in clinical samples have been mixed.3 This is not surprising because there can be great individual variability in endogenous melatonin production. Light, medication, and behavior can also change melatonin levels. The pharmacokinetics and pharmacodynamics of exogenous melatonin (high first-pass metabolism, short half-life, and weak MT1/MT2 receptor binding) may also lead to the inconsistent effects in many clinical spheres as well.

Melatonin appears to have 2 probable interacting effects on the sleep-wake cycle. First, it entrains and shifts the circadian rhythm (process C) in a “chronobiotic” function. Second, it promotes sleep onset and continuity in a “hypnotic” function by increasing the homeostatic drive to sleep (process S). These effects appear to be equal. Clinically, exogenous melatonin given in the morning delays the phase of circadian rhythm and subsequent evening sleepiness. Melatonin given in the evening can advance both of these phases.

TABLE 1


Circadian rhythm sleep disorders

Light exposure has the opposite effect and is much more potent in its phase-shifting effects. This can also vary depending on the exact time the melatonin is given and light exposure occurs, in relation to the circadian rhythm of the patient. Patients demonstrate more compliance in taking melatonin at the right time than in pursuing the necessary exposure to light. Thus, timed melatonin administration may be a more viable way to change the circadian rhythm in clinical practice when needed.

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