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Inhibition of melatonin secretion onset by low
levels of illumination
Trinder J.; Armstrong S.M.; O'Brien C.; Luke D.; Martin
M.J.
Department of Psychology, University of Melbourne, Parkville,
Vic. 3052 Australia
Journal of Sleep Research (United Kingdom), 1996, 5/2
(77-82)
Melatonin is a hormone released during darkness under the
control of the hypothalamic circadian pacemaker. It has been
shown that melatonin is suppressed by light as a function of
intensity, with low levels of illumination producing small
effects and more intense light greater, but not complete
inhibition. The studies which lead to these conclusions
administered light subsequent to the secretion pattern being
well established. Light as low as 250 lux administered during
the normal onset of secretion can reduce melatonin to below
detectable levels. The onset of melatonin secretion was
delayed for at least an hour during 250 lux exposure and did
not rise until termination of light exposure (two hours after
control melatonin onset) with higher illumination (500, 1000
and 2500 lux). This tentatively indicates that duration of the
inhibition is intensity dependent. It is suggested that the
experimental paradigm used in the present study may be a more
realistic representation of the effect of normal light
exposure (both natural and artificial) on the circadian
system,and that findings may be pertinent to the aetiology of
certain sleep onset insomnias, which would include delayed
sleep phase syndrome (DSPS) and adaptation to shift work.
Melatonin replacement corrects sleep disturbances
in a child with pineal tumor
Etzioni A; Luboshitzky R; Tiosano D; Ben-Harush M; Goldsher
D; Lavie P
Department of Pediatrics, Rambam Medical Center, Haifa,
Israel.
Neurology (USA), 1996, 46/1 (261-263)
A child with a germ cell tumor involving the pineal region
had marked suppressed melatonin secretion associated with
severe insomnia. Exogenous melatonin (3 mg in the evening) for
2 weeks restored sleep continuity, as demonstrated by
objective monitoring of rest-activity cycles. This case report
provides direct evidence of the essential role of melatonin in
normal sleep.
Use of melatonin in circadian rhythm disorders and
following phase shifts
Skene DJ; Deacon S; Arendt J
School of Biological Sciences, University of Surrey,
Guildford, UK.
d.skene@surrey.ac.uk
Acta Neurobiologiae Experimentalis (Poland), 1996, 56/1
(359-362)
Following abrupt phase shifts (real or simulated time zone
changes, night shift work) there is desynchronisation between
the internal circadian rhythms (including melatonin) and the
external environment with consequent disturbances in sleep,
mood and performance. In humans the pineal hormone melatonin
has phase-shifting and resynchronising properties with regard
to a number of circadian rhythms. Suitably timed melatonin
administration hastened adaptation to phase shift and
significantly improved self-rated jet lag in large numbers of
time zone travellers. Preliminary results in night shift
workers showed improved daytime sleep and night-time
alertness. In simulated experiments, appropriately timed
melatonin improved subjective sleep, alertness and performance
and facilitated the readaptation of the melatonin rhythm
following a rapid 9 h advance phase shift. Melatonin has also
been assessed in circadian rhythm disorders with disturbed
sleep (blindness and delayed sleep phase insomnia). Compared
with placebo, melatonin significantly improved sleep and
synchronised the sleep wake cycle in some blind subjects.
Melatonin treatment significantly advanced the sleep onset
time in delayed sleep phase insomnia. Taken together these
findings suggest that melatonin is of benefit in facilitating
adaptation to forced phase shifts and in conditions of
circadian rhythm disturbance.
Current and future strategies for insomnia
management
Lopez-Ibor Jr. J.J.
Psychiatric Unit, San Carlos University Hospital, Complutense
University, C/Martin Lagos, s/n, 28040 Madrid Spain
European Psychiatry (France), 1996, 11/Suppl. 1
(31S-33S)
Different forms of insomnia are present as symptoms of many
psychiatric and other disorders. The first step for a
treatment strategy is therefore a correct diagnosis. As
insomnia is more common in patients with psychiatric disorders
than in the general population, a careful consideration should
be given, depressive and anxiety disorders should especially
be carefully investigated. There are reasons to believe that
even in so-called insomnia not obviously related to
psychiatric disorders, stressful life situations may play a
role. Therefore a co-morbidity with emotional disorders which
may follow these events is worth considering. Insomnia should
always be considered as part of a sleep-wake schedule
disturbance and this has an impact on the importance of the
pharmacological properties of the drugs used to treat
insomnia. The recent trend for more specific agents both on
receptor sub-populations and on relevant sites of the GABA
receptor complex will help very much in selecting the most
appropriate drug for treating patients.
Physiological and therapeutic effects of high
frequency electrical pulses.
Liss S; Liss B
MEDI Consultants, Inc., Paterson, New Jersey 07504,
USA.
Integr Physiol Behav Sci (United States) Apr-Jun 1996, 31 (2)
p88-95
The results of stimulating human subjects with the LISS
Cranial Stimulator (LCS) and the LISS Body Stimulator (LBS)
include an increase or decrease in the activities of certain
neurotransmitters and neurohormones and the reduction of
associated pain, insomnia, depression, and spasticity. The
effects were documented in human subjects with measurements of
the serum concentration of the various agents and assessments
of the symptoms being performed before and after stimulation.
The stimulators had a carrier frequency of 15,000 hz, which
utilizes the bulk capacitance of the body, and a 15 hz
modulating bioactive frequency. The second modulating
frequency presently used, 500 hz, reduces the energy input to
the patient by half. Significant increases in levels of CSF
serotonin and beta endorphin were recorded post stimulation.
There were also elevations in the levels of plasma serotonin,
beta endorphin, GABA and DHEA together with diminished levels
of cortisol and tryptophan. Concomitant with these changes
were significant improvements in the symptoms of pain,
insomnia, spasticity, depression, and headache.
Melatonin replacement therapy of elderly
insomniacs
Haimov I.; Lavie P.; Laudon M.; Herer P.; Vigder C.; Zisapel
N.
Sleep Laboratory, Gutwirth Building, Technion City, Haifa
32000 Israel
Sleep (USA), 1995, 18/7 (598-603)
Changes in sleep-wake patterns are among the hallmarks of
biological aging. Previously, we reported that impaired
melatonin secretion is associated with sleep disorders in old
age. In this study we investigated the effects of melatonin
replacement therapy on melatonin-deficient elderly insomniacs.
The study comprised a running-in, no-treatment period and four
experimental periods. During the second, third and fourth
periods, subjects were administered tablets for 7 consecutive
days, 2 hours before desired bedtime. The tablets were either
2 mg melatonin administered as sustained- release or
fast-release formulations, or an identical-looking placebo.
The fifth period, which concluded the study, was a 2-month
period of daily administration of 1 mg sustained-release
melatonin 2 hours before desired bedtime. During each of these
five experimental periods, sleep-wake patterns were monitored
by wrist-worn actigraphs. Analysis of the first three 1-week
periods revealed that a 1-week treatment with 2 mg
sustained-release melatonin was effective for sleep
maintenance (i.e. sleep efficiency and activity level) of
elderly insomniacs, while sleep initiation was improved by the
fast-release melatonin treatment. Sleep maintenance and
initiation were further improved following the 2-month 1-mg
sustained-release melatonin treatment, indicating that
tolerance had not developed. After cessation of treatment,
sleep quality deteriorated. Our findings suggest that for
melatonin-deficient elderly insomniacs, melatonin replacement
therapy may be beneficial in the initiation and maintenance of
sleep.
Improvement of sleep equality in elderly people by
controlled-release melatonin
Garfinkel D.; Laudon M.; Nof D.; Zisapel N.
Department of Biochemistry, G.S. Wise Faculty of Life
Sciences, Tel-Aviv University, Tel-Aviv 69978 Israel
Lancet (United Kingdom), 1995, 346/8974
(541-544)
Melatonin, produced by the pineal gland at night, has a
role in regulation of the sleep-wake cycle. Among elderly
people, even those who are healthy, the frequency of sleep
disorders is high and there is an association with impairment
of melatonin production. We investigated the effect of a
controlled-release formulation of melatonin on sleep quality
in 12 elderly subjects (aged 76 (SD 8) years) who were
receiving various medications for chronic illnesses and who
complained of insomnia. In all 12 subjects the peak excretion
of the main melatonin metabolite 6-sulphatoxymelatonin during
the night was lower than normal and/or delayed in comparison
with non-insomniac elderly people. In a randomised,
double-blind, crossover study the subjects were treated for 3
weeks with 2 mg per night of controlled-release melatonin and
for 3 weeks with placebo, with a week's washout period. Sleep
quality was objectively monitored by wrist actigraphy. Sleep
efficiency was significantly greater after melatonin than
after placebo (83 (SE 4) vs 75 (3)%, p<0.001) and wake time
after sleep onset was significantly shorter (49 (14) vs 73
(13) min, p<0.001). Sleep latency decreased, but not
significantly (19 (5) vs 33 (7) min, p=0.088). Total sleep
time was not affected. The only adverse effects reported were
two cases of pruritus, one during melatonin and one during
placebo treatment; both resolved spontaneously. Melatonin
deficiency may have an important role in the high frequency of
insomnia among elderly people. Controlled-release melatonin
replacement therapy effectively improves sleep quality in this
population.
Sleep-inducing effects of low doses of melatonin
ingested in the evening
Zhdanova I.V.; Wurtman R.J.; Lynch H.J.; Ives J.R.; Dollins
A.B.; Morabito C.; Matheson J.K.; Schomer D.L.
Dept. of Brain/Cognitive Sciences, Massachusetts Inst. of
Technology, Carleton St., Cambridge, MA 02142 USA
Clinical Pharmacology and Therapeutics (USA), 1995, 57/5
(552-558)
We previously observed that low oral doses of melatonin
given at noon increase blood melatonin concentrations to those
normally occurring nocturnally and facilitate sleep onset, as
assessed using an involuntary muscle relaxation test. In this
study we examined the induction of polysomnographically
recorded sleep by similar doses given later in the evening,
close to the times of endogenous melatonin release and
habitual sleep onset. Volunteers received the hormone (oral
doses of 0.3 or 1.0 mg) or placebo at 6, 8, or 9 PM. Latencies
to sleep onset, to stage 2 sleep, and to rapid eye movement
(REM) sleep were measured polysomnographically. Either dose
given at any of the three time points decreased sleep onset
latency and latency to stage 2 sleep. Melatonin did not
suppress REM sleep or delay its onset. Most volunteers could
clearly distinguish between the effects of melatonin and those
of placebo when the hormone was tested at 6 or 8 PM. Neither
melatonin dose induced 'hangover' effects, as assessed with
mood and performance tests administered on the morning after
treatment. These data provide new evidence that nocturnal
melatonin secretion may be involved in physiologic sleep onset
and that exogenous melatonin may be useful in treating
insomnia.
Light, melatonin and the sleep-wake cycle
Brown G.M.
Clarke Institute of Psychiatry, 250 College Street, Toronto,
Ont. M5T 1R8 Canada
J. Psychiatry Neurosci. (Canada), 1994, 19/5
(345-353)
Blood levels of the pineal hormone melatonin are high at
night and low during the day. Its secretion is regulated by a
rhythm-generating system located in the suprachiasmatic
nucleus of the hypothalamus, which is in turn regulated by
light. Melatonin is regulated not only by the circadian
oscillator but acts as a darkness signal, providing feedback
to the oscillator. Melatonin has both a soporific effect and
an ability to entrain the sleep-wake rhythm. It also has a
major role in regulating the body temperature rhythm.
Melatonin rhythms are altered in a variety of circadian rhythm
disorders. Melatonin treatment has been reported to be
effective in treatment of disorders such as jet lag and
delayed sleep phase syndrome.
Melatonin rhythms in night shift workers
Sack R.L.; Blood M.L.; Lewy A.J.
Department of Psychiatry, School of Medicine, Oregon Health
Sciences University, Portland, OR 97201 USA
Sleep (USA), 1992, 15/5 (434-441)
For some time, it has remained uncertain whether the
circadian rhythms of permanent night shift workers are adapted
to their night-active schedule. Previous studies of this
question have often been limited by 'masking' (evoked) effects
of sleep and activity on body temperature and cortisol, used
as marker rhythms. In this study, the problem of masking was
minimized by measuring the timing of melatonin production
under dim light conditions. Nine permanent night shift workers
were admitted to the Clinical Research Center (CRC) directly
from their last work shift of the week and remained in dim
light while blood samples were obtained hourly for 24 hours.
elatonin concentrations were measured in these samples using a
gas-chromatographic mass-spectrometric method. Sleep diaries
were completed for two weeks prior to the admission to the
CRC. Overall, the onset of the melatonin rhythm was about 7.2
hours earlier (or 16.8 hours later) in the night workers
compared to day-active controls. It was not possible to know
whether the phase of the melatonin rhythm was the result of
advances or delays. In night shift workers, sleep was
initiated (on average) about three hours prior to the onset of
melatonin production. In contrast, day-active subjects
initiated sleep (on average) about three hours after their
melatonin onset. Thus, the sleep times selected by night shift
workers may not be well-synchronized to their melatonin
rhythm, assumed to mark the phase of their underlying
circadian pacemaker.
Effect of melatonin replacement on serum hormone
rhythms in a patient lacking endogenous melatonin
Petterborg L.J.; Thalen B.-E.; Kjellman B.F.; Wetterberg
L.
Department of Anatomy and Neurobiology, School of Medicine,
University of Missouri, Columbia, MO 65212 USA
Brain Res. Bull. (USA), 1991, 27/2 (181-185)
A potentially confounding variable inherent in studies
designed to examine the effect of melatonin administration in
humans is the presence of an endogenous melatonin rhythm in
the experimental subjects. The effects of exogenous melatonin
administration on serum hormone rhythms was recently examined
in a male patient who lacked detectable circulating levels of
endogenous melatonin. The patient's pineal gland had been
destroyed five years previously in the course of treatment for
a pineal astrocytoma. On three separate occasions, over
approximately a one-year period, the patient was given daily
oral melatonin replacement (2 mg/day, 1 mg/day and 0.5
mg/day). These experiments were designed to assess the effects
of exogenous melatonin on serum growth hormone, prolactin,
cortisol and testosterone rhythms. Analysis of blood samples
collected every 2-4 hours for 24-hour periods both before and
during melatonin replacement revealed that the exogenous
melatonin rhythm was associated with improvements in
self-reported sleep and mood ratings. Melatonin administration
produced robust nocturnal peaks in serum growth hormone and
prolactin levels immediately following ingestion of the
hormone, while serum cortisol and testosterone rhythms were
not influenced. These results suggest that melatonin may
modulate the coordination and enhancement of selected
biological rhythms in man.
Melatonin administration in insomnia
James S.P.; Sack D.A.; Rosenthal N.E.; Mendelson W.B.
Hospital of the University of Pennsylvania, 11 Gates
Pavilion, Philadelphia, PA 19104 USA
Neuropsychopharmacology (USA), 1990, 3/1 (19-23)
Ten patients with persistent insomnia were randomized in a
double-blind design and the effects of 1-mg and 5-mg oral
dosages of melatonin on the lectroencephalogram-recorded sleep
were examined. Subjects showed no changes in either the onset
or duration of sleep, nor any effect on mood or alertness the
following day. A significant increase in rapid-eye movement
(REM) latency was noted at the 1-mg dose, though no other
parameter of REM sleep was affected. The patients reported
less sleep on both melatonin conditions. Despite this
perception of decrease, overall subjective quality was
reported to be improved.
Treatment of delayed sleep phase syndrome
Regestein Q.R.; Pavlova M.
Division of Psychiatry, Department of Medicine, Brigham and
Women's Hospital, Boston, MA 02115 USA
General Hospital Psychiatry (USA), 1995, 17/5
(335-345)
Delayed sleep phase syndrome (DSPS) is a common but little
reported cause of severe insomnia. Affected individuals
complain of difficulty falling asleep and difficulty awaking
at socially acceptable hours. It results from a dysregulation
of the circadian sleep-wake cycle. DSPS presents in clinically
heterogenous ways as modulated by motivation, psychopathology,
drug status, and treatment compliance factors. Patients
respond variably to the range of possible treatments. Bright
light treatment potentially corrects the circadian abnormality
of DSPS. Other treatments reported to relieve some DSPS
patients include schedule shifts, drugs, and vitamin and
hormone treatments. The safety and efficacy of light treatment
have trotbeen conventionally defined, but available
information suggests that it is ophthalmologically safe. At
present, DSPS must be managed empirically by various
methods.
Nutritional factors in the etiology of the
premenstrual tension syndromes.
Abraham GE
J Reprod Med (United States) Jul 1983, 28 (7)
p446-64
The premenstrual symptom complex many women experience in a
moderate to severe form can be divided into four subgroups.
Because there is more than one syndrome and nervous tension is
one of the most common symptoms, the term premenstrual tension
syndromes(PMTS) is used. The most common subgroup, PMT-A,
consists of premenstrual anxiety, irritability and nervous
tension, sometimes expressed in behavior patterns detrimental
to self,family and society. Elevated blood estrogen and low
progesterone have been observed in this
subgroup.Administration of vitamin B6 at doses of 200-800
mg/day reduces blood estrogen, increases progesterone and
results in improved symptoms under double-blind conditions.
Women in this subgroup consume an excessive amount of dairy
products and refined sugar, and progesterone may be of value
in them. The second-most-common subgroup, PMT-H, is associated
with symptoms of water and salt retention, abdominal bloating,
mastalgia and weight gain. The severe form of PMT-H is
associated with elevated serum aldosterone. Vitamin B6 at high
dosage suppresses aldosterone and results in diuresis and
clinical improvement. Vitamin E helps the breast symptoms.
Methylxanthines and nicotine should be curtailed and sodium
limited to 3 gm/day. PMT-C is characterized by premenstrual
craving for sweets, increased appetite and indulgence in
eating refined sugar followed by palpitation, fatigue,
fainting spells, headache and sometimes the shakes. PMT-C
patients have increased carbohydrate tolerance and low
red-cell magnesium. Adequate magnesium replacement results in
improved glucose tolerance tests and decreased PMT-C symptoms.
Deficiency of the prostaglandin PGE1 may also be involved in
PMT-C. PMT-D is the least common but most dangerous because
suicide is most frequent in this subgroup. The symptoms are
depression, withdrawal, insomnia, forgetfulness and confusion.
In ten PMT-D patients the mean blood estrogen was lower and
the mean blood progesterone higher than normal during the
midluteal phase. Elevated adrenal androgens are observed in
some hirsute PMT-D patients. Two PMT-D patients with normal
blood progesterone and estrogens had high lead levels in hair
tissue and chronic lead intoxication. This subgroups needs
careful medical attention when the symptoms are severe.
Therapy should be individualized according to the results of
the evaluation.
Effects of intravenously administered vitamin B12
on sleep in the rat.
Chang HY; Sei H; Morita Y
Department of Physiology, School of Medicine, University of
Tokushima, Japan.
Physiol Behav (United States) Jun 1995, 57 (6)
p1019-24
Vitamin B12 (VB12) has been reported to normalize the
entrainment of circadian rhythms in the non-24-h sleep wake
cycle and delayed sleep phase insomnia in humans. The purpose
of this work was to clarify whether the peripheral
administration of VB12 has any sleep-promoting effect on the
sleep-wake rhythm in freely moving rats. After a baseline day
of saline infusion. VB12 (500 micrograms/kg/day) was
administered continuously for 4 days via the jugular vein.
Polysomnographic recordings were carried out concurrently. In
both the light and the 24-h periods, the amount of non-rapid
eye movement (NREM) sleep increased significantly on VB12-days
2 and 3, while the amount of REM sleep increased significantly
on VB12-day 2. In the light period, the increase in NREM sleep
was due to increased duration of the episode, while the
tendency to an increase in REM sleep was due to an increased
number of episodes. Changes in the diurnal sleep-wake rhythm
tended to appear in the earlier light period. The serum B12
concentrations in the VB12 group were 40 times higher than in
controls. These findings suggest that peripherally infused
VB12 has promoting effects on the rat's sleep, especially in
the light period.
Treatment of persistent sleep-wake schedule
disorders in adolescents with methylcobalamin (vitamin
B12).
Ohta T; Ando K; Iwata T; Ozaki N; Kayukawa Y; Terashima M;
Okada T; Kasahara Y
Department of Psychiatry, Nagoya University School of
Medicine, Japan.
Sleep (United States) Oct 1991, 14 (5) p414-8
Two adolescent patients suffering from persistent
sleep-wake schedule disorders appear to have responded to
treatment with vitamin B12 (methylcobalamin). A 15-year-old
girl with delayed sleep phase syndrome (DSPS) and a
17-year-old boy with hypernychthemeral syndrome complained of
not being able to attend school despite many trials of
medication. The improvement of the sleep-wake rhythm disorders
appeared immediately after the administration of high doses
(3,000 micrograms/day) of methylcobalamin. Neither patient
showed any laboratory or clinical evidence of vitamin B12
deficiency or hypothyroidism (which can cause B12 deficiency).
Serum concentrations of vitamin B12 during treatment were in
the high range of normal or above normal. The duration of the
sleep period of the DSPS patient decreased gradually from 10
hours to 7 hours, and the time of sleep onset advanced from 2
a.m. to midnight. The period of the sleep-wake cycle of the
hypernychthemeral patient was 24.6 hours before treatment and
24.0 hours after treatment. The relationship between the
circadian basis of these disorders and vitamin B12 and its
metabolites is discussed.
Vitamin B12 treatment for sleep-wake rhythm
disorders.
Okawa M; Mishima K; Nanami T; Shimizu T; Iijima S; Hishikawa
Y; Takahashi K
Department of Neuropsychiatry, Akita University School of
Medicine, Japan.
Sleep (United States) Feb 1990, 13 (1) p15-23
Vitamin B12 (VB12) was administered to two patients
suffering for many years from different sleep-wake rhythm
disorders. One patient was a 15-year-old blind girl suffering
from a free-running sleep-wake rhythm (hypernychthemeral
syndrome) with a period of about 25 h. In spite of repeated
trials to entrain her sleep-wake cycle to the environmental
24-h rhythm, her free-running rhythm persisted for about 13
years. When she was 14 years old, administration of VB12 per
os was started at the daily dose of 1.5 mg t.i.d. Shortly
thereafter, her sleep-wake rhythm was entrained to the
environmental 24-h rhythm, and her 24-h sleep-wake rhythm was
maintained while she was on the medication. Within 2 months of
the withholding of VB12, her free-running sleep-wake rhythm
reappeared. The VB12 level in the serum was within the normal
range both before and after treatment. The other patient was a
55-year-old man suffering from delayed sleep phase syndrome
since 18 years of age. After administration of VB12 at the
daily doses of 1.5 mg, his sleep-wake rhythm disorder was
improved. The good therapeutic effect lasted for more than 6
months while he was on the medication.
[Folate and the nervous system (author's
transl)]
Audebert M; Gendre JP; Le Quintrec Y
Sem Hop (France) Sep 18-25 1979, 55 (31-32)
p1383-7
The responsibility of the folate deficiency in some
neuropsychiatric disorders is recent knowledge. The role of
the folate on the nervous system is not yet well definite, but
the action on the metabolism of the amino-acids, on the purine
and the pyrimidine synthesis and on the metabolism of the
catecholamins are certainly essential. The neuropsychiatric
diseases secondary to the folate deficiency are numerous:
dementia, schizophrenia like syndromes, insomnia,
irritability, forgetfulness, endogenous depression, organic
psychosis, pueperal psychosis, peripheral neuropathy,
myelopathy (spinal cord syndrome and/or pyramidal tract
damage), restless legs syndrome. Clinically the diagnosis may
be difficult with sub acute combined degenration secondary to
the pernicious anaemia, and the dosage of the folate (in
serum, in red-cells and in cerebrospinal fluid) is necessary.
The congenital defects in the uptake or utilization of the
folate are associated with neuropsychiatric disturbances. The
treatment is easy and safe if the vitamin B12 deficiency is
eliminated and if employed with caution in epileptic patients
because folate can induced seizures.
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