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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.
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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