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I'm interested in whether any studies have determined the intensity of light at eye level that starts melatonin release in humans.
I know that:
- melatonin release is suppressed by blue light with peak suppression occurring at 420-480nanometer range.
- This light is registered by Melanopsin, a photopigment in the eye.
- Melanopsin signals the Suprachiasmatic Nucleus, the master clock of the human body.
- The suprachiasmatic nucleus makes a decision to suppress melatonin release in response to blue light observed.
What I need to know is how much light is "enough" to trigger the suppression by the mechanism described above. I've seen a mention of as little as 200 lumens of white light, but do not have any reference to verify that. Additionally, the figure of 200 lumens was given for a typical smartphone screen, not necessarily translating to 200 lumens at eye level.
I'm aware of this experiment involving rats, where the light intensity at eye level was quantified. I'm looking for a similar measurement in humans.
Here's my original question on the subject, but I've learned quite a lot since then to refine the question
I appreciate your input!
The question piqued my interest, but after hunting through the literature for a bit, I hadn't found any direct answers. Then I went back and read the mouse study you cited a bit more carefully. The mouse study only made a reference to mice being affected at 4 lux, ~100x more sensitive than humans. However, for that number it cited a paper in Science that has a direct answer.
Melatonin concentrations decreased 10 to 20 minutes after the subjects were exposed to 2500-lux incandescent light and reached near-daytime levels within 1 hour (Fig. 1). After the subjects resumed sleeping in the dark, the melatonin concentrations increased immediately and within 40 minutes were at the levels measured before exposure. The fluorescent light (500 lux) did not reduce melatonin, and there was no change after the return to darkness. In the two subjects who were exposed to 1500-lux incandescent light, melatonin concentrations decreased to levels intermediate between those measured during exposure to 500 and 2500 lux (Fig. 2). The return to normal nighttime concentrations after subjects were exposed to 1500 lux was similar to that occurring after their exposure to 2500 lux. The concentration of melatonin in subjects awakened and exposed to 500-lux fluorescent light did not differ significantly from that measured while they were asleep in the dark.
Since that was the granddaddy study of the subject, I just checked the recent citation list on that page for modern articles.
Using pure blue LED lights at 446-477 nm wavelengths, West et al. measured light intensities necessary to induce melatonin suppression. Table 1 of that study converts LED irradiance/lux into retinal irradiance (uW/cm2) based on mean pupil size. Figure 2 shows plasma melatonin falling (p<0.05) at 20 uW/cm2 of corneal irradiance (then curve fit to 14.19 uW/cm2). It's at least twice as powerful as white light, which didn't show significant suppression at 40 uW/cm2, but was "numerically similar" to 10 uW/cm2 exposure. If I've got the conversions right, 20 uW/cm2 is about 136 lux, which is about the brightness of an overcast day or half the brightness of typical office lighting.
As for the discrepancy between the two studies (1500 lux vs. 136 lux), I would blame it mostly on technological advances since 1980. The original study used gas chromatography. You can see the huge error bars and noisy data in the Figure. The modern study uses a radioimmuno assay using antiserum, and is presumably far more sensitive.
I was also going to mention a nice review paper that summarizes more findings, but apparently I can only post 2 links as a new user. So I'll just paste the abstract and citation.
Light is a potent stimulus for regulating the pineal gland's production of melatonin and the broader circadian system in humans. It initially was thought that only very bright photic stimuli (≥ 2500 lux) could suppress nocturnal melatonin secretion and induce other circadian responses. It is now known that markedly lower illuminances (≤ 200 lux) can acutely suppress melatonin or entrain and phase shift melatonin rhythms when exposure conditions are optimized. The elements for physical/biological stimulus processing that regulate photic influences on melatonin secretion include the physics of the light source, gaze behavior relative to the light source, and the transduction of light energy through the pupil and ocular media. Elements for sensory/neural signal processing become involved as photons are absorbed by retinal photopigments and neural signals are generated in the retinohypothalamic tract. Aspects of this physiology include the ability of the circadian system to integrate photic stimuli spatially and temporally as well as the wavelength sensitivity of the operative photoreceptors. Acute, light-induced suppression of melatonin is proving to be a powerful tool for clarifying how these elements of ocular and neural physiology influence the interaction between light and the secretion of melatonin from the human pineal gland.
Photic Regulation of Melatonin in Humans: Ocular and Neural Signal Transduction Brainard, Rollag, and Hanifin J Biol Rhythms December 1997 vol. 12 no. 6 537-546
If you need more information, I'd start by checking the papers cited by the second paper. Alternately, there's probably more historical information available by looking at papers which have cited the first one.
Protecting the melatonin rhythm through circadian healthy light exposure
Currently, in developed countries, nights are excessively illuminated (light at night), whereas daytime is mainly spent indoors, and thus people are exposed to much lower light intensities than under natural conditions. In spite of the positive impact of artificial light, we pay a price for the easy access to light during the night: disorganization of our circadian system or chronodisruption (CD), including perturbations in melatonin rhythm. Epidemiological studies show that CD is associated with an increased incidence of diabetes, obesity, heart disease, cognitive and affective impairment, premature aging and some types of cancer. Knowledge of retinal photoreceptors and the discovery of melanopsin in some ganglion cells demonstrate that light intensity, timing and spectrum must be considered to keep the biological clock properly entrained. Importantly, not all wavelengths of light are equally chronodisrupting. Blue light, which is particularly beneficial during the daytime, seems to be more disruptive at night, and induces the strongest melatonin inhibition. Nocturnal blue light exposure is currently increasing, due to the proliferation of energy-efficient lighting (LEDs) and electronic devices. Thus, the development of lighting systems that preserve the melatonin rhythm could reduce the health risks induced by chronodisruption. This review addresses the state of the art regarding the crosstalk between light and the circadian system.
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General overview of the functional organization of the circadian system in mammals. Inputs:…
Molecular clock of mammals. Circadian…
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Absence and presence of circadian…
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Spectral responses of the pupillary light reflex (PLR). Comparison of the PLR to…
Age-related losses in retinal illumination…
Age-related losses in retinal illumination due to decreasing crystalline lens light transmission and…
Short wavelength light sensitivity for…
Short wavelength light sensitivity for melatonin suppression. Comparison of the effects of 460…
What light intensity starts melatonin release in humans? - Biology
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Melatonin, first identified in the late 1950s was given its name to reflect its melanin granule-aggregating effect. 1 This very ancient molecule exists in organisms as simple and primitive as prokaryotes and as complex as humans. 2 It acts as a free radical scavenger and an antioxidant, possibly its initial function 2–3.5 billion years ago. Since then its actions have diversified in increasingly complex organisms and range from circadian adjustments, 3 to a function in seasonal reproduction. 4 It acts on the suprachiasmatic nucleus to modify the timing of sleep, causing relative hypothermia, 5 and in the retina, rod disc shedding. 6
Although melatonin is present in food such as fruit, vegetables, and wheat, 7 melatonin ingested with a normal diet does not significantly contribute to circulating levels. Instead, it is mostly produced by the pineal gland, and the retina, 8 lens, 9 iris, ciliary body, 10 lacrimal gland, 11 skin, 12 and gut 13 also produce small amounts. It is synthesized through conversion of tryptophan to serotonin, then to N-acetylserotonin, and finally to melatonin (or N-acetyl-5-methoxytryptamine). 14 Two enzymes, arylalkylamine N-acetyltransferase (NAT) and hydoxyindole-O-methyltransferase catalyse the rate-limiting steps.
Serum melatonin concentration varies with age: normal neonates secrete very little but levels rise shortly thereafter and become circadian at about 2–3 months of age, 15 coinciding with a more rhythmical sleep–wake pattern. Daytime concentrations remain low throughout life but night time concentrations peak in humans between 1 and 3 years of age, 16 gradually reducing through puberty owing to dilution in the increased body volume. 17 The diurnal variation persists in adulthood with peak serum levels occurring between 2 AM and 4 AM . Eventually, in old age, this prominent night-time peak becomes markedly attenuated. 18
What can we do to limit blue light exposure?
Light during evening hours is a necessary and indispensable part of our modern lives. As with many issues that pertain to our health, moderation is key.
Limiting use of smartphones and tablets during evening hours, as well as lowering the screen's brightness can all be helpful in reducing overall blue light exposure. Various apps and software can also help shift the light spectrum away from blue-rich wavelengths.
Similarly, reducing the brightness and intensity of light bulbs in your home can help reduce blue light exposure.
Visually intensive activities like reading, however, should not be done in low brightness as this can aggravate eye fatigue.
Nobody loves compromise - and you may be wondering - is there a way to maintain a higher brightness level but simultaneously limit the amount of blue light?
There certainly is, and the best way to measure the extent to which this is possible is using the M/P ratio. The M/P ratio interprets the spectral power distribution of a light source, and compares the relative ratio between its effect on promoting alertness and its effect on producing useful visual illumination.
Therefore, a light source with a low M/P ratio produces less light energy that keeps us alert, but more light energy that is useful for vision.
When looking for light bulbs that provide sufficient illumination with limited amounts of blue light that disrupt sleep, look for one with a lower M/P ratio.
There is no hard and fast rule for what an acceptable M/P ratio would be for a nighttime light bulb, because what matters more is the intensity and duration of overall exposure to blue light.
In other words, just because a light bulb has a low M/P ratio, that does not mean you would be immune to the effects of blue light if you used the light very close to your face for many hours.
Therefore, when comparing M/P ratios, a relative comparison is more meaningful. As a reference point - natural daylight has an M/P ratio of 1.10, and incandescent bulbs have an M/P ratio of 0.55.
Waveform Lighting's Lux24 Circadian LED bulbs, for example, have an M/P ratio of 0.39. Assuming the same positioning and use time as a 40W incandescent bulb, the Lux24 bulbs would have an approximately 30% reduction on total blue light exposure.
Human-centric lighting: light up your life
Human-centric lighting (HCL) has been around for a few years, but has only recently become a buzzword in the technology community. What’s it all about? And could it become commonplace in our homes and places of work?
You’re flying like a bird. Slicing through clouds, flapping your arms, feeling the brisk wind on your face. You’re having the most wonderful dream. Relishing the blissful moment. Suddenly, a crow appears out of nowhere, squawking directly into your ear. And it won’t stop. Then you’re ripped from the ethereal sky and land in your bed, jolted awake by the morning alarm.
Waking up in this unnatural way can often leave you bleary-eyed and sleepily hunting for coffee. When you finally get to work after the exhausting commute, you’re left feeling dishevelled and not fully awake all day, no matter how much caffeine you chug.
That is where the apparent power of human-centric lighting (HCL) comes in. According to the LightingEurope industry association, HCL supports health, wellbeing and performance of humans by combining visual, biological and emotional benefits of light. The use of LEDs means this kind of lighting can be energy-efficient and simple to control with smart, connected systems.
As well as letting us see, light evokes a physiological response in humans depending on its characteristics, such as colour spectrum, intensity and timing. Therefore, if we spend a lot of time indoors, it affects our circadian rhythm – the body’s master clock that helps determine our sleep pattern. HCL is supposed to aid our rhythm to improve health and wellbeing.
Dr Russell Foster, British professor of circadian neuroscience, is credited with > < discovering light-sensitive ganglion cells – which influence the body’s biological clock and are the basis of HCL – in the retina of the eye. The cells respond most sensitively to visible blue light, synchronising our bodies with the external cycle of day and night.
However, Foster says we’re not ready for HCL and it’s too early to implement it. Speaking at the Light & Building 2018 exhibition in Frankfurt, he said: “We can’t develop human-centric lighting until we know what impact light has upon human biology across the day and night cycle.”
According to Foster, there is no standard ‘recipe’ that manufacturers can use, as people are either ‘larks’ or ‘owls’ – lighting affects each group differently.
So what does the industry think? Mark King, product line manager of lighting at power management company Eaton, says: “General understanding around the impact that lighting has on the body – from its influence on the circadian rhythm to affecting moods and general wellbeing – has greatly improved. Yet the idea of human-centric lighting still has a way to go.”
Health and wellbeing is often linked to a good sleep and wake cycle a disrupted rhythm impacts on how we function and our long-term health. Tiredness leads to stress, memory problems, lack of creativity, drug and stimulant use, obesity, lower immunity and even cancer.
Bianca van der Zande, scientist at Signify (formerly Philips Lighting), says the positive influence of light on our sleep-wake cycles has been studied in depth. “Production of melatonin, the hormone that helps to induce sleepiness and regulates our sleep-wake cycle, is impacted by natural and artificial light. In darkness, the body gets a signal to start production of melatonin subsequently, if there is enough light, the body gets a signal to stop production of melatonin to become more alert.”
She adds that our natural body clock runs for between 15 and 30 minutes longer than our artificial 24-hour clocks. “Unless reset, this will make us want to go to bed later, causing us to be more dependent on our morning alarm. Correct quality light and timing can reset the half-hour lag and resynchronise our body clock with our artificial 24-hour clocks.” Morning light is very powerful in adjusting our sleep-wake cycle artificial light that mimics bright daylight is said to be highly effective at regulating and synchronising, contributing to our overall health.
Our mood can be influenced by light colour temperature – warm white is calming and neutral white is more stimulating. The colour rendering index Ra measures what colour display is the closest rendition to daylight. In offices, for instance, Ra greater or equal to 80 is needed.
Light distribution and direction influences visual performance and comfort. Osram Lighting Solutions says optimum HCL in an office requires a wide area with indirect lighting and high, vertical “illuminances” to create an “artificial sky”, with dynamic white colour temperatures and light control, and highly reflective surfaces.
For relaxation, the lighting must be warm with an elevated red component. Higher blue components/colour temperature influences our brain and body clock, increasing alertness, concentration and attention. Osram says the biological effect is strongest when light is emitted from a wide-area source and from above, as with sunlight.
Van der Zande claims there are already examples of the positive and tangible influence of HCL. “In Prague, we installed lighting in the Czech headquarters of energy company Innogy this year. It is tuned to support workers’ circadian sleep-wake cycles and stimulate energy levels at set times in the day.
“Employees enjoy a comfortable bright light, similar to natural daylight, to start their day and after lunch. This helps stimulate energy levels and enhance workplace comfort and vision.” She adds that the stimulus from the HCL fixtures is likened to a strong cup of coffee, which could be music to the ears of many workers who rely on mild stimulants to get through the day.
Yet Dawn Hollingsworth, principal of Darkhorse Lightworks, says the industry needs more funding for research. “There are roadblocks to implementation such as different priorities, costs and control systems that suppress demand,” she adds.
Eaton’s King explains that while many understand the idea on a granular level, i.e. mood versus lighting colour, one could argue that the idea has yet to be understood across the industry – and that lack of awareness is reflected in product development.
He adds that “in order to move forward, key concepts surrounding HCL must be understood by electrical contractors and installers. A deeper understanding of issues surrounding HCL on their part would provide added value for manufacturers, installers, and especially the end user,” such as workers in an office or factory, children in a school, residents in a care home or hospital, or you at home.
Hollingsworth says the lighting industry is great at talking to itself, but more needs to be done to educate the general public and those with the money to build projects.
“When people demand better lighting, the benefits will be evident, but until there is demand, HCL will continue to be a target for cost reductions and widespread adoption will be slow.”
King agrees that while it may be some time before we see HCL implemented on a regular basis, having a basic understanding of it will prepare contractors for when it’s time to move to this next level. “In the meantime, it’s important that installers choose the right luminaire to light every space in the best possible way,” he says. “This will not only maximise staff productivity, but it will deliver the best results overall.”
Alex Gifford, UK brand communications manager at Steelcase, says details like lighting, materiality, informal spaces and natural elements are powerful influences on behaviour and communicate company brand and culture. “It’s important to ensure the technology available is easy-to-use and accessible frustration can build when there is discord between humans and technology.”
Signify’s Van der Zande adds: “Given that we as a species now spend much of our day indoors, as well as the advancements in our understanding of health, I expect the role of lighting in our physical and mental wellbeing to become increasingly commonplace in our daily lives.” *
■ In the early morning hours, correct light can help students to wake up with less sleepiness.
■ Improved light environment can aid alertness and concentration.
■ At the correct time, higher-intensity lighting systems and colour temperature can improve learning quality and sleep.
■ It can prevent mood swings and depression.
■ Stabilises human circadian rhythm.
Wellbeing improves due to better-quality rest and sleep-inducing drugs are reduced.
■ Improves employee wellbeing.
■ Under less pressure as residents experience correct activity and resting phases.
■ More intense and circadian light exposure can help employee alertness during the day and sleep at night.
■ Individual lighting control, which varies from person to person, may increase job satisfaction.
■ Intense lighting installations and tuneable white light may help production, fatigue and errors – effects are more apparent with repetitive tasks.
■ Shift workers may benefit from phase-shift lighting to ease into night work.
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Reduce stress in your life. Physical and mental stress can lead to a rise in stress hormone levels, such as cortisol, that can interfere with your sleep cycle. Try aroma or music therapy during your time before bed to shed some of the stress from the previous day. Reducing your stress at night will help your body release melatonin.
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.
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 Î³-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.
Clinical screening questions for circadian rhythm disorders
A few patient questions (Table 2) and the Morningness-Eveningness Questionnaire 4 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.
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.
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.
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Influence of light intensity and spectral composition of artificial light at night on melatonin rhythm and mRNA expression of gonadotropins in roach Rutilus rutilus
In this study we investigated the influence of artificial light at night (ALAN) of different intensities (0, 1, 10, 100 lx) and different colours (blue, green, red) on the daily melatonin rhythm and mRNA expression of gonadotropins in roach Rutilus rutilus, a ubiquitous cyprinid, which occur in standing and moderately flowing freshwater habitats of central Europe. Melatonin concentrations were significantly lowered under nocturnal white light already at 1 lx. Low intensity blue, green and red ALAN lowered the melatonin levels significantly in comparison to a dark control. We conclude that ALAN can disturb melatonin rhythms in roach at very low intensities and at different wavelengths and thus light pollution in urban waters has the potential to impact biological rhythms in fish. However, mRNA expression of gonadotropins was not affected by ALAN during the period of the experiments. Thus, suspected implications of ALAN on reproduction of roach could not be substantiated.
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Materials and methods
Between May and July 2010 we caught adult male European blackbirds (urban = 20, rural = 20) with mist-nets set up at dawn in the city of Munich, in southeast Germany (48° 07’ N, 11° 34’ E 518 m ASL) and in a rural forest near the village of Raisting (47° 53’ N, 11° 04’ E, 553 m ASL), 40 km southwest of Munich. Birds were placed in cloth cages and transported to our facilities in Radolfzell (47° 44’ N, 8° 58’ E, 404 m asl) where they were initially housed in outdoor aviaries. On November 26 th , 2010, birds were moved indoors into individual cages (width × height × length: 45 × 70 × 80 cm) in two separate rooms. Each room contained 10 city and 10 forest birds, all being initially exposed to light/dark (LD) cycles that simulated the natural variation of photoperiod in Radolfzell, with
0.0001 lux of light at night. One urban bird died on April 1 st , 2011. Birds could hear but not see each other. Food (Granvit, Chemi-Vit, Italy) and drinking water were available ad libitum. All the experimental procedures were carried out in accordance with the guidelines of the Department 35 of the Regional Commission Freiburg, Baden Württemberg, Germany. We used the same animals and the experimental set-up described below to test different hypotheses about the effects of light-at-night on daily and seasonal cycles of blackbirds . Specifically, data on the link between light-at-night and timing of reproduction and molt provide a valuable and unique background for the interpretation of the results of this manuscript .
The experiment started on December 18 th , 2010. Photoperiod followed the local natural variation of daylength in both treatment groups throughout the experiment. All birds stayed under a light/dark (LD) cycle. Control birds were exposed to very low light intensity at night, whereas experimental birds were exposed to dim light-at-night (see below). Daytime light intensity in both groups ranged from 250 to 1250 lux within each cage, and was provided by dimmable fluorescent white bulbs (Biolux 36 W, Osram, Germany) emitting light at wavelengths covering the human visible spectrum. Because lowest light intensity of dimmable fluorescent bulbs was still very high (
20 lux), we used a dimmable incandescent light bulb (SLV Elektronic, Germany, wavelength 450–950 nm) to simulate the low light intensities which free-roaming blackbirds experienced at night . We chose this type of light bulb because it is a common light source in urban areas, e.g. for outdoor light decoration of houses, and is representative of the spectrum that street lights deployed in the city of Munich emit (yellow-red lights). Light intensity at night in the experimental group was set at 0.3 lux, and represents the mean of measurements at all four perches. Control birds were exposed to a light intensity of
0.0001 lux during the night, provided by the same light bulb type as that used for the experimental group. This light intensity of
0.0001 lux was used to allow the birds to orientate in the cage at night. Each group was exposed to a twilight phase of 35 minutes both in the morning and evening. Light programs of both rooms were controlled by Gira Homeserver (Germany). Light intensity in the cages was quantified at all four perches in a cage by using a LI-1400 data logger and LI-210 photometric sensor.
To determine plasma melatonin concentrations, we took blood samples during the periods of July 25–29, 2011, and January 25–29, 2012. Each individual was sampled at four different times of the day during a period of six days. Samples were taken at least 24 h apart from each other to minimize the stress for the animals. The four samples were taken at the following times: at 12:00 (both in summer and winter), 30 minutes after the end of evening twilight (summer: 21:00, winter: 18:00), 24:00 (both summer and winter), and 45 minutes before the start of morning twilight (summer: 3:00, winter 6:00). All reported times are expressed as Greenwich Mean Time (GMT) + 1 h. Each sampling session lasted for a maximum of 15 minutes, for all birds combined. We used headlamps with dim red light to catch and bleed the birds. Birds were bled outside the experimental rooms to minimize disturbance and stress to the other animals. We punctured the brachial vein with a 25-g needle and collected 200 μl of blood in a hematocrit capillary. Blood was immediately stored on ice. Plasma was separated from red blood cells by centrifugation within 30 minutes after the end of the sampling and then stored at −80°C. The concentration of plasma melatonin was measured by Radioimmunoassay (RIA) , which we validated for European blackbirds (Additional file 1: Figure S2). Dilutions of 4 night plasma pools from blackbirds were parallel to dilutions of the melatonin standard, indicating that there were no matrix effects. Further, we spiked 4 daytime samples that were close to or below the detection limit with 20 pg of the melatonin standard. On average we recovered 24.5 ± 3.25 pg (mean ± SD), suggesting that the assay slightly overestimated the melatonin concentration in the samples. For our analyses we ran four assays. All samples from one individual were included in one assay to reduce inter-assay variation. The inter-assay coefficient of variation was 6.9%, while the average intra-assay coefficient of variation was 4.7% + 3.7% (mean ± SD).
Locomotor activity was recorded continuously for the entire duration of the experiment through a passive infrared sensor mounted on each cage (Intellisense, CK Systems, Eindhoven, The Netherlands). Movements were counted and stored as two minute bins on a computer. For the purpose of this study we analysed activity data recorded for seven days prior to each blood sampling session (summer 2011: July 18–24 winter 2012: January 18–24). For each individual we calculated the number of activity counts for each hour of the 24-hr day, averaged for the seven days of recording.
Analyses were conducted with the software R 2.15.0 . All tests were two-tailed and we applied a significance level α = 0.05. All explanatory continuous variables were centred and standardized to facilitate interpretation of the estimates. In all models described we used a Gaussian error structure because they met the assumptions of normality of residuals and homogeneity of variance. If non-significant interactions were present, they were sequentially removed. When linear mixed models (LMMs) were used, individuals were always included as random intercepts to account for non-independency of repeated measures. In these type of models we assessed the significance of model parameters using a Monte Carlo Markov Chain (MCMC) approach through the function pvals.fnc in the R package languageR. P-values (pMCMC) were calculated based on the posterior distribution of model parameters (50000 iterations). When significant interactions were detected, we evaluated them running independent linear models at each time of day (Additional file 1: Table S2).
We analysed the variation in absolute melatonin concentration with LMMs. Log-transformed melatonin concentration was the response variable. We first ran a preliminary model with treatment (dark night/light-at-night), origin (urban/rural), time of day and season as fixed effects. This was done to analyse variation in melatonin concentration between seasons. However, it would have been conceptually misleading to include interaction between time of day and any of the other fixed factors, since the sampling times varied between seasons. Therefore, we ran in-depth models separately for summer and winter, including treatment, origin, time of day, 2 nd order polynomial time of day and all their interactions as fixed effects.
In many studies amplitude of the melatonin cycle is estimated from daily variation in melatonin concentration [82, 83]. However, in our study we collected repeated samples from individuals and were therefore able to derive a more accurate, individual-based estimate of melatonin amplitude. To take account of the fact that birds may differ in melatonin levels, we calculated amplitude as the difference between the maximum and minimum daily melatonin concentrations for each individual. This parameter was then log-transformed and modelled as response variable in the LMM which we used for analysis. Season, origin, treatment, and their interaction were included as fixed effects.
We used LMMs to test for differences in activity levels across treatment groups and origin. Log-transformed mean activity was included as response variable. We first included season as fixed effect, too, but the model did not converge, so we ran two separated models for the winter and the summer. Time of day, treatment, origin, and their interactions were modelled as fixed effects.
Finally, to test the relationship between activity onset and the morning drop in melatonin, we calculated the change in melatonin concentration from night (midnight) to morning (summer: 3 am winter: 6 am). To reduce bias due to different mean daily melatonin concentrations in different birds, these changes were calculated on an individual basis. We used linear models to analyze log-transformed mean activity levels during the hour preceding morning twilight to treatment in relation to origin and change in melatonin level (modelled as fixed effects).