The Role of Melatonin in the Circadian Rhythm Sleep-Wake Cycle
The Role of Melatonin in the Circadian Rhythm Sleep-Wake Cycle
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.
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.
A circadian rhythm disorder is defined as a persistent or recurrent pattern of sleep disturbance primarily caused by alterations in the circadian timekeeping system or a misalignment between the endogenous circadian rhythm and exogenous factors that affect the timing or duration of sleep. This definition takes into account that both exogenous (lifestyle, job, social and cultural factors) and endogenous (biological circadian rhythm) can contribute to the misalignment. (Details can be found in Table 1.)
Evaluation and treatment of circadian rhythm sleep disorders
Many of the inhibitory pathways of melatonin synthesis and secretion and the SCN use γ-aminobutyric acid (GABA) as the neurotransmitter. Hence, medications that affect the GABA receptors, such as benzodiazepines, or increase GABA tone, such as valproate, can reduce melatonin secretion at night. -Blockers, prostaglandin inhibitors, and dihyropyridine calcium antagonists can profoundly reduce melatonin levels as well.
A few patient questions (Table 2) and the Morningness-Eveningness Questionnaire4 are not supported by formal evidence but are useful to alert the clinician to the patient’s preferred circadian rhythm and the possibility of resultant disorders. A sleep log or diary or the more detailed actigraph measurements are often used as a starting point for objective investigations. Actigraphy, a noninvasive way to approximate the sleep-wake cycle, measures gross motor activity by a sensor usually placed on the wrist. Review of data from a sleep log or actigraphy for 7 days is a criterion for diagnosis of a circadian rhythm sleep disorder. A full sleep study (polysomnography) is not routinely recommended unless there are signs and symptoms of another, more common primary sleep disorder (eg, obstructive sleep apnea), but it is important to inquire about the potential of these disorders.
The use of timed melatonin is indicated with varying degrees of evidence in all circadian rhythm sleep disorders.5 Melatonin is used in conjunction with or instead of other treatments, such as timed light exposure, planned sleep schedules, and stimulants. The time of administration and, to some degree, the dose of melatonin depend on the disorder being treated (Table 1). Dosages have been quite variable (0.3 to 10 mg), but as a rule it is best to use the lowest effective dose. Lower doses (1 to 3 mg) are best for delayed sleep phase syndrome and higher doses (5 to 10 mg) are better for jet lag sleep disorder, shift work sleep disorder, and free-running disorder.
Melatonin for primary insomnia
It is well known that insomnia is an extremely common concern, especially in psychiatric illness. It has multiple deleterious sequelae and large direct and indirect economic costs. A significant proportion of insomnia cases are either due to or comorbid with a secondary cause. Primary insomnia, or a component of it, is only diagnosed when all other factors have been ruled out or fully optimized.
The initial clinical approach to managing insomnia is to rule out, or treat, all secondary causes and comorbidities, primary sleep disorders, and sleep-interfering behavioral concerns. The importance of vigilance for evolving secondary causes (especially mood and anxiety disorders) when treating patients with insomnia cannot be overstated. Insomnia is a strong risk factor for these disorders and may represent an early form of the illness.
Both cognitive-behavioral therapy and hypnotic medications have been the main treatment modalities for primary insomnia. Approved hypnotic medications include benzodiazepines and benzodiazepine receptor agonists such as eszopiclone, zolpidem, and zaleplon. Numerous adverse effects have been seen with benzodiazepines, including amnesia, next day hangover, cognitive effects, and rebound insomnia, which makes their use controversial. Benzodiazepine receptor agonists attenuate these features, but they are still troublesome. The wide off-label clinical use of sedating antidepressants, antipsychotics, and antihistamines for sleep concerns points not only to the inadequacy of current medications for treating primary insomnia but also to possible clinical misdiagnosis of the primary insomnia state or even the lack of identification of key comorbidities.