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Life Extension Magazine

LE Magazine May 2001

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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 cadian 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.

N Engl J Med 2000 Oct 12;343(15):1070-7

Use of slow-release melatonin in treatment-resistant depression.

OBJECTIVE: To examine antidepressant augmentation with and hypnotic effects of slow-release melatonin (SR-melatonin) in patients with treatment-resistant depression. DESIGN: Open-label trial. SETTING: Tertiary care outpatient depression clinic. PATIENTS: Nine outpatients who had failed to respond to two or more eight week trials of antidepressant medication. INTERVENTIONS: Patients received SR-melatonin 5 mg per day for the first two weeks and 10 mg per day for the final two weeks, in addition to their antidepressant medication. OUTCOME MEASURES: Structured Clinical Interview for DSM-IV, Axis 1 Disorders, Hamilton Rating Scale for Depression (HRSD), Beck Depression Inventory, Response Style Questionnaire, sleep and fatigue measures. RESULTS: One patient was excluded after one week because of the development of a mixed affective state. In the remaining 8 patients there was a 20% mean decrease in HRSD scores after four weeks of treatment, with no individual achieving an improvement of 50% or more. There was a 36% decrease on the three item HRSD related to insomnia, with four of eight patients showing at least a 50% improvement on this measure. The greatest decrease in insomnia occurred during the last two weeks of the study, following the increase in dosage to 10 mg per day of SR-melatonin. Patients also reported significantly lower levels of fatigue post-treatment. CONCLUSIONS: SR-melatonin may be a useful adjunct for sleep, but does not substantially augment existing antidepressant therapies in some patients with treatment-resistant depression.

J Psychiatry Neurosci 2000 Jan;25(1):48-52

The hypnotic effects of melatonin treatment on diurnal sleep in humans.

This study investigated the hypnotic effects of 10 mg melatonin and placebo, which were administered at 10.00 hour, according to a single-blind crossover design, on an 8 hour diurnal sleep from 11.00 to 19.00 hour, following a full night of sleep. The subjects were six healthy male students, each of whom underwent polysomnography and rectal temperature monitoring. Melatonin treatment significantly increased total sleep time in diurnal sleep (403.2+/-SD 72.8 min and 258.5+/-118.3 min, P<0.001). As to changes in rectal temperature during diurnal sleep, however, there were no significant differences between the melatonin and placebo conditions. Thus, these results indicated that melatonin administered at 10.00 hour had direct hypnotic effects on diurnal sleep.

Psychiatry Clin Neurosci 1999 Apr;53(2):243-5

Effects of a low dose of melatonin on sleep in children with Angelman syndrome.

The effects of low dose melatonin therapy on sleep behavior and serum melatonin levels were studied in Angelman syndrome (AS) children suffering from insomnia. 24-hour motor activity was monitored in 13 AS children (age 2-10 yr) in their home environments for seven days prior to melatonin treatment and for five days during which a 0.3 mg dose of melatonin was administered daily 0.5-1 hour before the patient's habitual bedtime. Blood samples were with-drawn at hourly intervals over two 21 hour periods in order to measure individual endogenous serum melatonin levels and the levels induced by melatonin treatment. Actigraphic recording of motor activity, confirmed by parents' reports, showed a significant improvement in the patients' nocturnal sleep pattern as a result of melatonin treatment. Analysis of the group data revealed a significant decrease in motor activity during the total sleep period following melatonin treatment, and an increase in the duration of the total sleep period. Endogenous peak nocturnal melatonin values ranged from 19 to 177 pg/ml. The administration of melatonin elevated peak serum hormone levels to 128 to 2800 pg/ml in children of different ages and body mass. These data suggest that a moderate increase in circulating melatonin levels significantly reduces motor activity during the sleep period in Angelman syndrome children, and promotes sleep.

J Pediatr Endocrinol Metab 1999 Jan-Feb;12(1):57-67

Melatonin treatment of non-epileptic myoclonus in children.

Oral melatonin (MLT) has been used by our Vancouver research group in the treatment of paediatric sleep disorders since 1991; slightly over 200 children, mainly with multiple disabilities, who frequently had seizures, have been treated. Three children with markedly delayed sleep onset due to recurring myoclonus were also referred for MLT treatment: two had non-epileptic, and one had epileptic and non-epileptic myoclonus. Low doses of oral MLT (3 to 5 mg) unexpectedly abolished their myoclonus and allowed them to sleep. There were no adverse effects. It appears that certain types of myoclonus, which might be resistant to conventional anticonvulsant medications, may respond to MLT but the mechanism of action is unclear. Further research on this novel treatment is urgently needed.

Dev Med Child Neurol 1999 Apr;41(4):255-9

Serum melatonin kinetics and long-term melatonin treatment for sleep disorders in Rett syndrome.

We studied the circadian rhythm of serum melatonin levels in two patients with classical Rett syndrome having severe sleep disorders; serum melatonin levels were measured before and during melatonin treatment using radioimmunoassay. Patient 1 had a free-running rhythm of sleep-wake cycle from three years of age. At the age of four years, the peak time of melatonin was delayed six hour compared to normal control and the peak value was at the lower limit. Patient 2 had a fragmented sleep pattern accompanied by night screaming from 1 year and 6 months of age. At the age of 10 years, the peak time of melatonin secretion was normal but the peak value was at the lower limit. These patients were given 5 mg melatonin orally prior to bedtime. Exogenous melatonin dramatically improved the sleep-wake cycle in patient 1. In patient 2, exogenous melatonin showed a hypnotic effect but early morning awakenings occurred occasionally. When melatonin treatment was stopped, the sleep disorders recurred and re-administration of 3 mg melatonin was effective in both patients. The effect was maintained over two years without any adverse effects. These findings suggests that sleep disorders in patients with Rett syndrome may relate with an impaired secretion of melatonin.

Brain Dev 1999 Jan;21(1):59-62

Melatonin in sleep rhythm disorders after cerebral stroke.

Small doses of melatonin were administrated to 30 patients with day/night rhythm disorders, after cerebral stroke. Psychotropic drugs administrated before did not bring any clinical improvement. In evaluation of melatonin the time till falling asleep, sleep duration, anxiety and the following day activity were taken into account. Good results were observed in majority of patients, concerning falling asleep and sleep were obtained continuity. The melatonin is a safe and worth drug in sleep rhythm disorders in patients after cerebral stroke.

Pol Merkuriusz Lek 2000 Jun;8(48):411-2

Effect of melatonin in selected populations of sleep-disturbed patients.

In an open pilot study on the efficacy of melatonin in the treatment of sleep disorders,patients with sleep disturbances alone, patients with sleep disturbances and signs of depression and patients with sleep disorders and dementia received 3 mg melatonin p.o. for 21 days, at bed time. After 2 to 3 days of treatment, melatonin significantly augmented sleep quality and decreased the number of awakening episodes in patients with sleep disturbances associated or not with depression. Estimates of next-day alertness improved significantly only in patients with primary insomnia. Agitated behavior at night (sundowning) decreased significantly in dementia patients. In a second retrospective study, 14 Alzheimer's disease (AD) patients received 9 mg melatonin daily for 22 to 35 months. A significant improvement of sleep quality was found, while there were no significant differences between initial and final neuropsychological evaluation (Functional Assessment Tool for AD, Mini-Mental). The results indicate that melatonin can be useful to treat sleep disturbances in elderly insomniacs and AD patients.

Biol Signals Recept 1999 Jan-Apr;8(1-2):126-31

Melatonin treatment in an institutionalised child with psychomotor retardation and an irregular sleep-wake pattern.

An institutionalized 13 year old girl with psychomotor retardation suffered from an irregular sleep-wake pattern. Multiple measurements of urinary sulphatoxy-melatonin (aMT6) concentrations were abnormally low, without any significant day-night differences. Administration of exogenous melatonin (3 mg) at 18:00 resulted in increased nocturnal urinary aMT6 concentrations and improvements in her sleep-wake pattern. Melatonin may help disabled children suffering from sleep disorders.

Arch Dis Child 1998 Jul;79(1):63-4

Melatonin treatment for rhythm disorder.

We tried melatonin treatment in two patients with non-24 hour sleep-wake syndrome, who did not respond to treatments by vitamin B12, bright light therapy, or hypnotics. In one patient, melatonin 5 to 10 mg improved difficulty in falling asleep and in waking, although it failed to improve the sleep-wake rhythm. In another patient, melatonin 3 mg successfully changed the sleep-wake rhythm from free-running pattern to delayed sleep phase pattern. However, melatonin re-administration after a four month drug-free interval failed to improve his free-running sleep-wake rhythm. These results suggest that melatonin acted as a sleep inducer in one patient and as a phase setter in the other, although the effect on the latter patient was transient.

Psychiatry Clin Neurosci 1998 Apr;52(2):262-3

Melatonin treatment for circadian rhythm sleep disorders.

We administered 1 to3 mg melatonin to 11 patients (eight men, three women, aged 16 to 46 years) with circadian rhythm sleep disorders; nine with delayed sleep phase syndrome and two with non-24-hour sleep-wake syndrome. Sleep logs were recorded throughout the study periods and actigraph and rectal temperature were monitored during treatment periods. Melatonin was administered 1 to 2 hour before the desirable bedtime for expected phase-shifting, or 0.5 to 1 hours before habitual bedtime for gradual advance expecting an hypnotic effect of the melatonin. Melatonin treatments were successful in 6/11 patients. Timing and dose of melatonin administration, together with its pharmacological properties for circadian rhythm sleep disorders, should be further studied.

Psychiatry Clin Neurosci 1998 Apr;52(2):259-60



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