Capturing the circadian rhythms of free-running blind people with 0.5 mg melatonin.

We have recently shown that six of seven totally blind people (who had free-running circadian rhythms with periods longer than 24 h) could be entrained (synchronized) to a nightly dose of 10 mg melatonin. After treatment discontinuation and re-entrainment to the 10 mg dose, we further found in three of these subjects that the dose could be gradually reduced to 0.5 mg without loss of effect. The question then arose: can a de novo (starting) dose of 0.5 mg initially capture free-running rhythms? Following withdrawal of the stepped-down 0.5 mg dose and consequent release into a free-run, the same three individuals were given 0.5 mg of melatonin de novo. All entrained within a few weeks.

Pretreatment circadian period in free-running blind people may predict the phase angle of entrainment to melatonin.

To date, we have entrained (synchronized) eight totally blind people with free-running circadian rhythms to a nightly dose of 10 mg of melatonin. Each person entrained at a different phase angle of entrainment (PAE), which is the interval in hours between the time of the melatonin dose and the time of the endogenous melatonin onset. When the PAE was plotted against the pretreatment free-running (i.e. slightly different than 24.0 h) circadian period (tau), the fitted regression line revealed a significant correlation, which is consistent with previous findings on light entrainment of rest-activity rhythms in free-running rodents [Pittendrigh and Daan, J. Comp. Physiol., 106 (1976) 291-331].

Effects of aging on the intrinsic circadian period of totally blind humans.

Age-related changes in the intrinsic circadian period (tau) have been hypothesized to account for sleep symptoms in the elderly such as early morning awakening. The authors sought to determine whether the aging process produced quantifiable differences in the tau of totally blind men who had free-running circadian rhythms. The melatonin onset was used as the indicator of circadian phase. Melatonin rhythms had been characterized about a decade previously when the participants were 38 +/- 6 (SD) years old. Both previous and current assessments of tau were derived from at least 3 serial measurements of the 24-h melatonin profile from which the melatonin onset was determined. All 6 participants exhibited a longer tau in the 2nd assessment (mean increase +/- SD of 0.13 +/- 0.08 h; p < 0.01). Four participants exhibited differences in tau with nonoverlapping 95% confidence intervals. The results do not support the commonly held view that tau shortens during human aging. On the contrary, tau appears to slightly, but significantly, lengthen during at least 1 decade in midlife.

Entrainment of free-running circadian rhythms by melatonin in blind people.

BACKGROUND: Most totally blind people have circadian rhythms that are "free-running" (i.e., that are not synchronized to environmental time cues and that oscillate on a cycle slightly longer than 24 hours). This condition causes recurrent insomnia and daytime sleepiness when the rhythms drift out of phase with the normal 24-hour cycle. We investigated whether a daily dose of melatonin could entrain their circadian rhythms to a normal 24-hour cycle. METHODS: We performed a crossover study involving seven totally blind subjects who had free-running circadian rhythms. The subjects were given 10 mg of melatonin or placebo daily, one hour before their preferred bedtime, for three to nine weeks. They were then given the other treatment. The timing of the production of endogenous melatonin was measured as a marker of the circadian time (phase), and sleep was monitored by polysomnography. RESULTS: At base line, the subjects had free-running circadian rhythms with distinct and predictable cycles averaging 24.5 hours (range, 24.2 to 24.9). These rhythms were unaffected by the administration of placebo. In six of the seven subjects the rhythm was entrained to a 24.0-hour cycle during melatonin treatment (P<0.001). After entrainment, the subjects spent less time awake after the initial onset of sleep (P=0.05) and the efficiency of sleep was higher (P=0.06). Three subjects subsequently participated in a trial in which a 10-mg dose of melatonin was given daily until entrainment was achieved. The dose was then reduced to 0.5 mg per day over a period of three months; the entrainment persisted, even at the lowest dose. CONCLUSIONS: Administration of melatonin can entrain circadian rhythms in most blind people who have free-running rhythms.

The endogenous melatonin profile as a marker for circadian phase position.

Several circadian rhythms have been used to assess the phase of the endogenous circadian pacemaker (ECP). However, when more than one marker rhythm is measured, results do not always agree. Questions then inevitably arise. Are there multiple oscillators? Are some markers more reliable than others? Masking is a problem for all marker rhythms. Masking of melatonin is minimized by sampling under dim light. The dim-light melatonin onset (DLMO) is particularly convenient since it can usually be obtained before sleep. However, assessing the DLMO in low melatonin producers may be problematic, particularly with the commonly used operationally defined threshold of 10 pg/ml. This study evaluates various circadian phase markers provided by the plasma melatonin profile in 14 individuals, several of whom are low melatonin producers. The amount (amplitude) of melatonin production appears to influence the phase of many points on the melatonin profile. Accordingly, when low producers are in a data set, we now prefer a lower DLMO threshold than the one previously recommended (10 pg/ml). Indeed, there are some low producers who never exceed this threshold at any time. Radioimmunoassays are now available that have the requisite sensitivity and specificity to support the use of a lower threshold. Nevertheless, the dim-light melatonin offset (DLMOff), even when operationally defined at thresholds less than 10 pg/ml, appears to be confounded by amplitude in this study; in such cases, it may be preferable to use the melatonin synthesis offset (SynOff) because it is not confounded by amplitude and because, theoretically, it is temporally closer to the endogenous mechanism signaling the offset of production. The question of whether the termination mechanism of melatonin synthesis is related to an interval timer or to a second oscillator loosely coupled to the onset oscillator is probably best answered using the SynOff rather than the DLMOff. It is hoped that these findings will make a useful contribution to the debate on the best ways to use points on the melatonin profile to assess circadian phase position in humans.

Morning vs evening light treatment of patients with winter depression.

BACKGROUND: According to the phase-shift hypothesis for winter depression, morning light (which causes a circadian phase advance) should be more antidepressant than evening light (which causes a delay). Although no studies have shown evening light to be more antidepressant than morning light, investigations have shown either no difference or morning light to be superior. The present study assesses these light-exposure schedules in both crossover and parallel-group comparisons. METHODS: Fifty-one patients and 49 matched controls were studied for 6 weeks. After a prebaseline assessment and a light/dark and sleep/wake adaptation baseline week, subjects were exposed to bright light at either 6 to 8 AM or 7 to 9 PM for 2 weeks. After a week of withdrawal from light treatment, they were crossed over to the other light schedule. Dim-light melatonin onsets were obtained 7 times during the study to assess circadian phase position. RESULTS: Morning light phase-advanced the dim-light melatonin onset and was more antidepressant than evening light, which phase-delayed it. These findings were statistically significant for both crossover and parallel-group comparisons. Dim-light melatonin onsets were generally delayed in the patients compared with the controls. CONCLUSIONS: These results should help establish the importance of circadian (morning or evening) time of light exposure in the treatment of winter depression. We recommend that bright-light exposure be scheduled immediately on awakening in the treatment of most patients with seasonal affective disorder.

Evaluation of the Actillume wrist actigraphy monitor in the detection of sleeping and waking.

This study evaluated the Actillume instrument and the modified Action 3 sleep-wake scoring algorithm, in which the scoring factor (P) was set at 0.10, 0.14, 0.20, 0.30, 0.40 and 0.50. Fifteen subjects, each of whom underwent polysomnography with simultaneous wrist actigraphy four times, yielded a total of 60 sleep studies. The sleep data from each subject were divided into four groups. In the high sleep efficiency index groups of the calibration and validation samples, the accuracy of the algorithm significantly differed within six P-values and was highest at P=0.14. In the low sleep efficiency index groups of both samples, however, there were no significant differences in the accuracy. Thus, these results indicate that P=0.14 should be most appropriate for this actigraph and algorithm.

Use of melatonin for sleep and circadian rhythm disorders.

Although not licensed as a drug, melatonin is widely sold as a nutritional supplement in the USA for its purported sleep-promoting and antiageing properties. In this article, we provide some guidelines for its use in sleep disorders medicine. In brief, melatonin appears to promote sleep by producing corrective circadian phase shifts, thereby improving the alignment of the endogenous sleep propensity rhythm with the desired sleep schedule. Melatonin may also have a direct soporific effect, especially when administered during the day. We suggest that the direct soporific action results from the release of accumulated sleep drive by melatonin's attenuation of the circadian alerting signal. Melatonin has not been proven safe by the usual clinical trial criteria, but to date no catastrophes have been related to its use. Also, there is little information about the safety and efficacy of chronic administration.

The role of melatonin and circadian phase in age-related sleep-maintenance insomnia: assessment in a clinical trial of melatonin replacement.

The present investigation used a placebo-controlled, double-blind, crossover design to assess the sleep-promoting effect of three melatonin replacement delivery strategies in a group of patients with age-related sleep-maintenance insomnia. Subjects alternated between treatment and "washout" conditions in 2-week trials. The specific treatment strategies for a high physiological dose (0.5 mg) of melatonin were: (1) EARLY: An immediate-release dose taken 30 minutes before bedtime; (2) CONTINUOUS: A controlled-release dose taken 30 minutes before bedtime; (3) LATE: An immediate-release dose taken 4 hours after bedtime. The EARLY and LATE treatments yielded significant and unambiguous reductions in core body temperature. All three melatonin treatments shortened latencies to persistent sleep, demonstrating that high physiological doses of melatonin can promote sleep in this population. Despite this effect on sleep latency, however, melatonin was not effective in sustaining sleep. No treatment improved total sleep time, sleep efficiency, or wake after sleep onset. Likewise, melatonin did not improve subjective self-reports of nighttime sleep and daytime alertness. Correlational analyses comparing sleep in the placebo condition with melatonin production revealed that melatonin levels were not correlated with sleep. Furthermore, low melatonin producers were not preferentially responsive to melatonin replacement. Total sleep time and sleep efficiency were correlated with the timing of the endogenous melatonin rhythm, and particularly with the phase-relationship between habitual bedtime and the phase of the circadian timing system.

The human phase response curve (PRC) to melatonin is about 12 hours out of phase with the PRC to light.

Melatonin's timekeeping function is undoubtedly related to the fact that it is primarily produced during nighttime darkness; that is, melatonin and light occur at opposite times. The human phase response curve (PRC) to melatonin appears to be about 12h out of phase with the PRC to light. These striking complementarities, together with light's acute suppressant effect on melatonin production, suggest that a function for endogenous melatonin is to augment entrainment of the circadian pacemaker by the light-dark cycle. The melatonin PRC also indicates correct administration times for using exogenous melatonin to treat circadian phase disorders.

Percutaneous absorption and model membrane variations of melatonin in aqueous-based propylene glycol and 2-hydroxypropyl-beta-cyclodextrin vehicles.

Percutaneous absorption and model membrane variations of melatonin (MT) in aqueous-based propylene glycol and 2-hydroxypropyl-beta-cyclodextrin vehicles were investigated. The excised hairless mouse skin (HMS) and two synthetic ethylene vinyl acetate (EVA) and microporous polyethylene (MPE) were selected as a model membrane. The solubility of MT was determined by phase equilibrium study. The vertical Franz type cell was used for diffusion study. The concentration of MT was determined using reverse phase HPLC system. The MT solubility was the highest in a mixture of PG and 2-HP beta CD. The percutaneous absorption of MT through excised HMS increased as the solubility increased. However, the permeability coefficient decreased and then slightly increased in a mixture of PG and 2-HP beta CD. On the other hand, both flux and permeability coefficient through EVA membrane decreased as the solubility increased. No MT was detected over 12 h after starting diffusion through MPE membrane. The flux of MT was dependent on the type of membrane selected. Flux of MT was greatest in excised HMS followed by EVA and MPE membrane. Flux of MT through EVA membrane was 5-20 times lower when compared to excised HMS. Interestingly, volumes of donor phase when MPE membrane was used, significantly increased during the study period. The HMS might be applicable to expect plasma concentration of MT in human subjects based on flux and pharmacokinetic parameters as studied previously. The current studies may be applied to deliver MT transdermally using aqueous-based vehicles and to fabricate MT dosage forms.

Melatonin treatment of winter depression: a pilot study.

Five patients with winter depression received low doses of melatonin in the afternoon, and five patients received placebo capsules. Melatonin treatment significantly decreased depression ratings compared to placebo. If these findings are replicated in a larger sample with documentation of expected phase shifts, the phase shift hypothesis will be substantially supported.

Exogenous melatonin's phase-shifting effects on the endogenous melatonin profile in sighted humans: a brief review and critique of the literature.

Melatonin's phase-shifting effects in humans are thought by some investigators to be subtle, particularly in comparison to those achieved with appropriately timed bright light exposure. The initial study in sighted people was only intermittently successful in phase advancing the endogenous melatonin profile. The study of free-running blind people showed statistically significant phase advances the day after melatonin administration. When holding the light-dark cycle constant, consistent phase advances the day after melatonin administration in sighted people were first shown in the course of describing the melatonin phase response curve (PRC), which also provided the first evidence that melatonin could cause phase delays. More recent studies have replicated the PRC and shown that phase shifts can occur in response to physiological doses within 1 day. This article reviews this literature and attempts to reconcile some of the results from differing studies. If the timing of melatonin administration is optimized according to the melatonin PRC, then consistent phase advances and delays can be achieved. If a reliable and sensitive circadian phase marker (e.g., the highly resolved dim light melatonin onset) is used, then phase shifts can be demonstrated consistently--even a small shift the day after a single physiological dose. The present authors predict that in the near future, melatonin administration will become as useful as bright light exposure in the treatment of circadian phase disorders.

Melatonin as a chronobiotic: treatment of circadian desynchrony in night workers and the blind.

Although the causes are different, totally blind people (without light perception) and night shift workers have in common recurrent bouts of insomnia and wake-time sleepiness that occur when their preferred (or mandated) sleep and wake times are out of synchrony with their endogenous circadian rhythms. In this article, the patterns of circadian desynchrony in these two populations are briefly reviewed with special emphasis on longitudinal studies in individual subjects that used the timing of melatonin secretion as a circadian marker. In totally blind people, the most commonly observed pattern is a free-running rhythm with a stable non-24-h circadian period (24.2-24.5 h), although some subjectively blind people are normally entrained, perhaps by residually intact retinoypothalamic photic pathways. Experiments at the cellular and behavioral levels have shown that melatonin can produce time dependent circadian phase shifts. With this in mind, melatonin has been administered to blind people in an attempt to entrain abnormal circadian rhythms, and substantial phase shifts have been accomplished; however, it remains to be demonstrated unequivocally that normal long-term entrainment can be produced. In untreated night shift workers, the degree and direction of phase shifting in response to an inverted sleep-wake schedule appears to be quite variable. When given at the optimal circadian time, melatonin treatment appears to facilitate phase shifting in the desired direction. Melatonin given prior to a night worker's daytime sleep also may attenuate interference from the circadian alerting process. Because melatonin has both phase-shifting and sleep-promoting actions, night shift workers, who number in the millions, may be the most likely group to benefit from treatment.

A comparison of sleep detection by wrist actigraphy, behavioral response, and polysomnography.

Two alternative methods for detecting sleep, wrist actigraphy (ACT) and behavioral response monitoring (BRM), were compared to polysomnography (PSG). In the BRM paradigm, a threshold intensity visual or auditory stimulus generated by a palm-top computer was presented about once per minute, and subjects pressed a microswitch if the stimulus was detected. A response within 5 seconds of the stimulus was scored as "wake" and a failure to respond as "sleep." Four males and four females underwent two nights of simultaneous in-home PSG, BRM, and ACT. Each night, subjects underwent a protocol designed to generate five sleep latency trials. Subjects were awakened by alarm clocks at approximately 1-hour intervals and remained awake for 10 minutes before returning to bed for another sleep onset latency (SOL) trial. Minute-by-minute comparisons were made for PSG versus ACT and BRM. All measures were fairly sensitive in detecting sleep, but BRM was more accurate in determining SOL and subsequent wakefulness. Behavioral response monitoring using a tone resulted in more responses and arousals prior to and during light stages of sleep than BRM using a light. It is concluded that BRM has some important advantages as a simple, minimally invasive method for monitoring sleep.

The amplitude of endogenous melatonin production is not affected by melatonin treatment in humans.

A physiological dose of melatonin (0.5 mg) or placebo was given at bedtime to night shift workers (n = 21) for seven days, and endogenous melatonin profiles were measured on the eighth day. The amplitude of endogenous melatonin secretion was unchanged by treatment. Also, a melatonin treatment trial using a 50 mg daily bedtime dose for 37 days to a blind subject resulted in no change in the endogenous melatonin profile. We conclude that circulating melatonin can shift the phase, but does not alter the amplitude, of pineal melatonin secretion.

Batch variation and pharmacokinetics of oral sustained release melatonin-loaded sugar spheres in human subjects.

The three different batches of an oral sustained release melatonin (MT) delivery system were prepared by aqueous-based fluid-bed coating of the sugar spheres for the evaluation ofin vitro release characteristics and plasma concentration profiles in human subjects. The MT contents in 20% coated sugar spheres of three batches (B1, B2 and B3) were 3.3+/-0.08, 2.4+/-0.1 and 2.5+/-0.13 mg per gram of coated sugar spheres, respectively. The release profiles of three different batches had a very similar fashion. However, the release half-lives (T(50%)) of MT from B1, B2 and B3 was 3.70+/-0.2, 5.2+/-0.2 and 4.9+/-0.07h, respectively. Plasma concentration profiles of sustained release 0.2mg melatonin-loaded sugar spheres containing 10% immediate release melatonin in gelatin capsules (B1 and B2) were then evaluated in human subjects. Thein vivo plasma concentration profiles of the two batches (B1 and B2) were very similar each other and located between the physiological endogenous ranges. The time to reach the peak concentration (T(max)) was more advanced in case of B1 when compared to B2. However, there was no statistically significant difference in the maximum concentration (C(max)) and the area under the curve (AUC) between B1 and B2. The AUC of melatonin-loaded sugar spheres containing 10% and 20% immediate release MT in human subjects had a good linearity between dose and AUC, regardless of the fraction of immediate release MT, indicating the first order elimination process of MT within these doses. The current oral sustained release MT delivery system may be utilized to treat circadian rhythm disorders if it is proven to be more clinically useful when compared to immediate release MT.

Solubility and stability of melatonin in propylene glycol and 2-hydroxypropyl-beta-cyclodextrin vehicles.

The physicochemical properties of melatonin (MT) in propylene glycol (PG) and 2-hydroxypropyl-beta-cyclodextrin (2-HPbetaCD) vehicles were characterized. MT was endothermally decomposed as determined by differential scanning calorimetry (DSC). Melting point and heat of fusion obtained were 116.9+/-0.24 degrees C and 7249+/-217 cal/mol, respectively. MT as received from a manufacture was very pure, at least 99.9%. The solubility of MT in PG solution increased slowly until reaching 40% PG and then steeply increased. Solubility of MT increased linearly as concentration of 2-HPbetaCD without PG increased (R(2)=0.993). MT solubility in the mixtures of PG and 2-HPbetaCD also increased linearly but was less than the sum of its solubility in 2-HPbetaCD and PG individually. The MT solubility was low in water, simulated gastric or intestinal fluid but the highest in the mixture of PG (40 v/v%) and 2-HPbetaCD (30 w/v%) although efficiency of MT solubilization in 2-HPbetaCD decreased as the concentration of PG increased. MT was degraded in a fashion of the first order kinetics (r(2)>0.90). MT was unstable in strong acidic solution (HCl-NaCl buffer, pH 1.4) but relatively stable in other pH values of 4 approximately 10 at 70 degrees C. In HCl-NaCl buffer, MT in 10% PG was more quickly degraded and then slowed down at a higher concentration. However, the degradation rate constant of MT in 2-HPbetaCD was not changed significantly when compared to the water. The current studies can be applied to the dosage formulations for the purpose of enhancing percutaneous absorption or bioavailability of MT.

Sleep-promoting effects of melatonin: at what dose, in whom, under what conditions, and by what mechanisms?

Differing conclusions regarding the sleep-promoting effects of melatonin may be the result of the broad range of doses employed (0.1-2000 mg), the differing categories of subjects tested (normal subjects, insomniac patients, elderly, etc.), and the varying times of administration (for daytime vs. nighttime sleep). We conclude that melatonin may benefit sleep by correcting circadian phase abnormalities and/or by a modest direct soporific effect that is most evident following daytime administration to younger subjects. We speculate that these effects are mediated by interactions with specific receptors concentrated in the suprachiasmatic nucleus (SCN) that result in resetting of the circadian pacemaker and/or attenuation of an SCN-dependent circadian alerting process.

Non-24-hour sleep-wake syndrome in a sighted man: circadian rhythm studies and efficacy of melatonin treatment.

The case of a 41-year-old sighted man with non-24-hour sleep-wake syndrome is presented. A 7-week baseline assessment confirmed that the patient expressed endogenous melatonin and sleep-wake rhythms with a period of 25.1 hours. We sought to investigate the underlying pathology and to entrain the patient to a normal sleep-wake schedule. No deficiency in melatonin synthesis was found. Furthermore, normal coupling between the melatonin and sleep propensity rhythms was documented using an "ultrashort" sleep-wake protocol. Environmental light exposure was monitored for 41 days, and the circadian timing was calculated. Sensitivity to photic input was determined with light-induced melatonin-suppression tests. Three intensities (500, 1,000, and 2,500 lux) were examined during three separate trials. The 2,500-lux trial resulted in 78% suppression, but the lesser intensity exposures were without substantial effect. Thus, the patient appeared to be subsensitive to bright light. A 4-week trial of daily melatonin administration (0.5 mg at 2100 hours) stabilized the endogenous melatonin and sleep rhythms to a period of 24.1 hours, albeit at a somewhat delayed phase. A 14-month follow-up interview revealed that the patient continued to take melatonin daily, and his sleep-wake schedule was stable to a near 24-hour schedule.