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.

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.

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.

TABLE 2

Clinical screening questions for circadian rhythm disorders

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.

There are mixed results for the use of exogenous melatonin in primary insomnia. Definite trends toward the efficacy of melatonin were seen in one meta-analysis.⁶ Results from another study reported as negative actually demonstrated a statistically significant positive result of a decrease in sleep latency by an average of 7.2 minutes for melatonin.⁷ For reasons that are unclear, this result was considered clinically insignificant, although such improvement in sleep latency is well within the range of other marketed pharmaceutical hypnotic agents.⁸

Study findings from large groups of middle-aged and elderly patients indicate a clear improvement in primary insomnia with the use of 2 mg of extended-release melatonin. In the largest study of more than 500 patients, positive results were primarily seen in patients aged 55 and older and efficacy was seen over a 6-month period.⁹ The preferential result of exogenous melatonin in an older population may be linked to an age-related decrease in melatonin levels. Some possible causes of this include less effective light input, a decrease of activity of the SCN, or calcification of the pineal gland. Support for this mechanism comes from a study of patients of all ages with relatively low melatonin levels who showed preferential response to the sleep effects of exogenous melatonin.¹⁰

Extended-release melatonin has also been found to be safe and well tolerated.⁹ No significant withdrawal, cognitive adverse effects, or rebound insomnia were seen. These are universally consistent findings in all of the studies of exogenous melatonin in insomnia.^6,8,9,11 As a result of the findings from the studies mentioned above, extended-release melatonin has been indicated by the European Medicines Agency and a number of regulatory agencies in other countries as a monotherapy for the short-term treatment of insomnia in patients aged 55 and older. Given the low risk of adverse effects with short-term use and the excellent safety profile, a recent consensus statement from the British Association for Psychopharmacology went a step further and concluded that “a controlled-release formulation of melatonin is the first-choice treatment when a hypnotic is indicated in patients over 55.”¹²

Ramelteon, a newer MT1/MT2 melatonin receptor agonist approved by the FDA in 2005 for the treatment of insomnia, has addressed some of the intrinsic biological problems linked to the inconsistent findings of melatonin on sleep. It has a much longer half-life than exogenous melatonin and has a 3- to 16-fold greater affinity for the MT1 and MT2 receptors.¹³ It has greater lipophilic properties than melatonin, with increased tissue absorption and an active metabolite that contributes to its action. Most of the action of ramelteon is specifically on the SCN, and it has no affinity for benzodiazepine, opioid, dopamine, or serotonin receptor subtypes.¹⁴ It is also MT1 receptor- selective, which suggests that it targets sleep onset more than melato-nin itself.¹⁵

Ramelteon is clearly effective for treating primary insomnia at a wide dose range (4 to 32 mg) on multiple variables of sleep in patients aged 18 and older, including patients older than 65. Effects occurred as quickly as 1 week and efficacy was seen over 6 months, without significant next morning residual effects, rebound insomnia, cognitive adverse effects, and withdrawal.^16-18 A number of studies also indicate a dose-independent effect of ramelteon, which suggests a more regulatory than sedative mechanism of improving sleep.¹⁹

Ramelteon has also shown phase shifting abilities of the circadian rhythm as well as some mixed positive results in jet lag sleep disorder.^20,21 Given the previously mentioned beneficial effects of melato-nin on natural sleep regulation, this should be considered a first-line treatment for primary insomnia, especially if the patient is elderly or has issues with rebound insomnia, next day effects, withdrawal, or elements of circadian rhythm sleep disorders. Related melatonin receptor agonists are currently in the later stages of development.

Applications of melatonin in major psychiatric disorders

Sleep disturbance and mood disorders are inexorably linked: 80% of patients with depression report poor-quality sleep, and sleep problems are a criterion for both depression and bipolar disorder.²² A number of studies suggest that sleep problems lead to the development or relapse of mood disorders. Indirect data point toward sleep disturbance as an important etiological factor in the development of depressive disorders.²³ Sleep problems also appear to increase the risk of, or can signal subsequent, mood disorder development.²⁴ Clinically, the sleep problem can interact with the mood disorder in many ways-usually as a combination of residual illness symptoms and medication adverse effects-and can lead to misdiagnosis.

Although the theory that disturbances of sleep and mood have a shared pathology is not new, it is beginning to receive more clinical attention. It has been postulated that sleep problems, circadian rhythm disruption, and mood disturbance are either fundamental responses of a shared common mechanism or a mood disorder, and sleep/circadian rhythm dysregulation can occur reciprocally.²⁵ There appears to be a common genetic overlap between circadian rhythm disruption and mood disorders: many of the same features of circadian rhythm sleep disorders can be seen in mood disorders, such as delayed sleep onset and early morning awakening as well as reversal of the normal peaks of energy, mood, and alertness.^24,26

Circadian rhythm sleep disorders can present as depressive type symptoms or can be comorbid with the mood disorder. This is especially true in patients with cyclical depression, such as seasonal affective disorder or bipolar spectrum illness.²⁷ Severe circadian rhythm disruption can often be a clinical clue that points toward bipolar rather than unipolar depression.

Changes in the timing and amount of melatonin secretion and excessive sensitivity to the melatonin response to light have been seen in patients with mood disorders.²⁵ Disruption in melatonin secretion in patients with bipolar disorder and depression has also been noted.²⁸ Whether these changes lead to or are a result of the illness is unknown because it is often difficult to separate true biological disruption from the confounding effects of medication and behavior. Many of the antidepressants used to treat mood disorder can also affect the homeostatic drive to sleep as well as disrupt normal chronobiology and sleep architecture.

Exogenous melatonin has shown some positive treatment effects on the symptoms of depressive disorders, but its monotherapeutic effect in humans does not appear to be robust. However, augmentation strategies in which melatonin is added to antidepressants do show some promise.²⁷ Agomelatine, an agent with effects on both the melatonergic (MT1, MT2) and serotonergic (serotonin-2C and to some degree serotonin-2B) systems, is a novel antidepressant that may address both circadian rhythm disruption and depressive symptom constellations. Theoretically, these effects make this agent a more tolerable and effective antidepressant.²⁹ Unfortunately, it has not received FDA approval and is only available in Europe and Australia.

Numerous trials of agomelatine at doses of 25 to 50 mg have shown antidepressant effects superior to those of placebo and efficacy equal to or greater than that of currently effective antidepressants.^30-34 Relapse prevention over 6 months has also been shown with agomelatine, although these results have been mixed.^35,36 Agomelatine also appears to be safe and tolerable in the short term, with an overall adverse-effect profile that is comparable to that of placebo.³⁰

Compared with placebo and venlafaxine, agomelatine has been found to promote beneficial changes in sleep architecture and overall sleep stability, with fewer problems of next day sedation.^33,34,37-39 The improvement in sleep appears to precede the antidepressant effect, which suggests that the sleep improvement may be related to efficacy of the antidepressant. Agomelatine may also be beneficial in bipolar depression.⁴⁰ In addition, agomelatine has demonstrated a circadian phase advance in healthy volunteers as well as correction of independent circadian rhythm disturbances in depressed patients and seasonally depressed patients, who are prone to circadian rhythm disruption.^31,41,42

Overall, agomelatine is thought to have a balanced dual action. It promotes sleep at night with its melatonergic effects and alertness during the day with its serotonergic effects. Although data have been mixed, the number of positive results for agomelatine in the domains of antidepressant effect, sleep improvement, and regulation of the circadian rhythm speaks to the benefit of melatonin and its receptor agonists in sleep, circadian rhythm, and mood difficulties.

Adverse effects

Melatonin and its receptor agonists have been shown to be safe in the short term.⁶ Trials up to 6 months showed no significant change in major safety parameters for controlled-release melatonin, ramelteon, and agomelatine.^9,18,35 Controlled long-term data do not exist, but case reports indicate that numerous people have taken melatonin for years without any deleterious effects.⁴³ Nonetheless, next day sedation and an increase in vivid dreams or nightmares are often seen clinically with melatonin.

It is possible that other hormone levels may also be disrupted. A rise in prolactin level and a decrease in follicle-stimulating hormone level have been seen, but there have been no changes in luteinizing hormone and thyroid-stimulating hormone levels and in orthostatic blood pressure.⁴⁴ Although not formally recommended, melatonin is widely used clinically in children. Data show that it may have beneficial effects on insomnia in children with developmental delay, autism, and ADHD.^26,42 The safety of melatonin in pregnancy is unknown.

No weight gain has been seen with melatonin treatment. In fact, melatonin appears to have significant cytoprotective properties that prevent metabolic syndrome sequelae in animal models as well as beneficial effects on thrombus growth, cholesterol levels, and blood pressure in humans. Given the well-known high rates of metabolic syndrome and its sequelae in major mental illness, this property of melatonin is one of its many intriguing benefits.

Conclusion

There remains significant debate about the use of melatonin in psychiatry and sleep disorders. Evidence continues to emerge, but studies are limited by the lack of consistent methodology and attention to both the chronobiotic and hypnotic effects of the molecule. Dosing and timing of melatonin can play a large role in its efficacy and can lead to variable effects. A low dose (1 to 3 mg) 3 to 4 hours before the preferred bedtime will help with a delayed sleep-wake phase, while higher doses (3 to 9 mg) given 60 to 90 minutes before the desired bedtime will help with jet lag sleep disorder or primary insomnia. However, significant clinical evaluation is frequently required to understand the roots of insomnia and the proper timing of melatonin administration.

Unfortunately, in the United States, melatonin is considered a dietary supplement; hence, the quality of the source of melatonin is always a concern. Melatonin receptor agonists address some of these concerns about purity and quality, but fewer data are available with these agents.

It is clear that forms of exogenous melatonin (especially controlled-release) and melatonin receptor agonists have a role in the treatment of circadian rhythm sleep disorders in patients with insomnia (especially in the elderly) and in those with comorbid depressive disorders. The safety and tolerability of melatonin, especially compared with other hypnotic agents, suggests a very favorable cost-benefit ratio and is one of the primary considerations in the treatment of insomnia.

Increasing sleep latency through a hypnotic or sedative effect has long been a paradigm that has been overemphasized in the treatment of insomnia and psychiatric illness. Although sleep is necessary, the increase in sleep latency must be balanced with the risk of next day hangover and cognitive effects, which can often be far more detrimental to a patient’s quality of life than the actual insomnia. Melatonin and its receptor analogues appear to be moving away from this traditional “knock out” paradigm of a sleeping pill. It appears that the actual sleep induction effect of melatonin and its receptor analogues is quite modest and their mechanism of action is more sophisticated: amplifying natural circadian differences in alertness and possibly creating a more biologically normal sleep pattern.

References:

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