Melatonin production in patients with duodenal ulcer.

UNLABELLED: OBJECTIVES. This work was designed to study melatonin (M) production levels in duodenal ulcer (DU) patients in the exacerbation and remission stages and in DU patients with a different course of DU in the exacerbation and remission stages. METHODS: DU patients (15 men aged 20 to 45, mean age 34,2 +/- 1,1 years) were studied. The control group included 11 healthy volunteers (men aged 20-45, mean age 32,5 +/- 1,4 years). M was measured by RIA-method using H(3)-labeled M in daily urine collected at 3-hour intervals (8 portions per day). Mathematical processing was carried out using ANOVA, Student's t-test, and cosinor analysis. Differences at p< or = 0,05 were considered to be significant. RESULTS: A strong disturbance of M secretion in DU patients both in the exacerbation and remission stages and a direct correlation between the degree of M production disturbance and severity of clinical course of DU were revealed. CONCLUSION: The obtained results suggest that circadian rhythms of M production are altered in DU patients. M was supposed to be involved in the pathogenesis of DU.

Geomagnetic activity influences the melatonin secretion at latitude 70 degrees N.

Factors other than light may affect variations in melatonin, including disturbances in the geomagnetic field. Such a possibility was tested in Alta, Norway, located at latitude 70 degrees N, where the aurora borealis is a result of large changes in the horizontal component (H) of the geomagnetic field. Geomagnetic disturbances are felt more strongly closer to the pole than at lower latitudes. Also noteworthy in Alta is the fact that the sun does not rise above the horizon for several weeks during the winter. To examine whether changes in geomagnetic activity influence the secretion of melatonin, saliva was collected from 25 healthy subjects in Alta several times during the day-night and at different times of the year. Single cosinor analyses yielded individual estimates of.the circadian amplitude and MESOR of melatonin. A 3-hour mean value for the local geomagnetic activity index, K, was used for approximately the same 24-hour span. A circadian rhythm was found to characterize both melatonin and K, the peak in K (23:24) preceding that of melatonin (06:08). During the span of investigation, a circannual variation also characterized both variables. Correlation analyses suggest that changes in geomagnetic activity had to be of a certain magnitude to affect the circadian amplitude of melatonin. If large enough (> 80 nT/3 h), changes in geomagnetic activity also significantly decreased salivary melatonin concentration.

[Ulcer protective effect of melatonin during artificial simulation of desynchronization in rats]. / Iazvoprotektivnyi éffekt melatonina pri iskusstvenno smodelirovannom desinkhronoze u krys.

The study was made on Wistar rats. A shift in endogenous biological rhythms was simulated by that in the light phase by 12 hours and evaluated by the shift in the rhythm of rectal temperature. Experiments revealed that desynchronization potentiated ulcerative processes in the rat stomach. The study demonstrated the protective effect of intraperitoneally injected melatonin to prevent the formation of ulcerative defects in the rat stomach during artificially simulated desynchronization.

[Mental disease a heritage. New genetic knowledge can reveal "public diseases" such as autism, dyslexia, alcoholism, anorexia, schizophrenia]. / Psykisk sjukdom ett arv. Ny genetisk kunskap kan klarlägga "folksjukdomar" som autism, dyslexi, alkoholism, anorexi, schizofreni.

Family and adoption studies indicate that genetic factors play a role in the development of many psychiatric disorders. A variable number of possible interacting genes predisposing to the diseases is likely. The genetic dissection has been hampered by genetic complexity as well as by difficulties in defining the phenotypes. Genetic mapping efforts using sib pairs, twins and individual large families has revealed preliminary or tentative evidence for susceptibility loci for a number of psychiatric disorders. Illnesses include the prion disease familial fatal insomnia (FFI), alcoholism, anorexia nervosa, autism, bipolar affective disorder, dyslexia, enuresis nocturnal, epilepsia, obsessive-compulsive disorders (OCD), schizophrenia, as well as the dementias, Alzheimer's disease and frontal lobe dementia, and mental retardation. The genes and proteins related to the newly discovered transmitter in the central nervous system, nitric oxide (NO), and its genes and proteins are also reviewed. The number of mapped human genes now exceeds 30,000 of the estimated total number of 60,000 to 100,000 genes. This rapid development will facilitate gene mapping, as well as efforts to isolate and identify the genes responsible for symptom susceptibility in many of the etiologically unclear psychiatric diseases with complex genetic origin.

Melatonin and epileptic seizures in patients with acute intermittent porphyria.

The objective of this study was to assess melatonin production in patients with acute intermittent porphyria (AIP), with and without known epileptic seizures, as a guide to whether melatonin may have anti-convulsive or pro-convulsive effects in AIP. Melatonin concentration in urine, sampled over eight hours on two consecutive nights, was analysed in eight AIP patients with epileptic seizures and in 14 AIP relatives without epilepsy. The AIP patients with epileptic seizures had a significantly lower urinary excretion of melatonin, compared with their AIP relatives without epilepsy, which may indicate that melatonin has a protective effect on seizures.

A multinational study of the relationships between nighttime urinary melatonin production, age, gender, body size, and latitude.

Overnight urines were collected each month for 12-16 months from 321 normal subjects at 19 medical centers in 14 countries distributed on 5 continents at latitudes from 31 01 South to 77 00 North. Mean melatonin concentration was found to negatively correlate with age, weight, and height. When the sexes were considered separately melatonin only correlated with age for female and with age and weight for males. A weak correlation with latitude, but not longitude, was also found.

The role of somatostatin (octreotide) in the regulation of melatonin secretion in healthy volunteers and in patients with primary hypothyroidism.

Somatostatin has been found in the pineal gland of several animal species, which suggests that it may be involved in the regulation of melatonin secretion. Whether somatostatin has regulatory influence on melatonin secretion in man has never been unequivocally shown. We studied the nocturnal melatonin secretion in 8 healthy volunteers, and 6 women with untreated primary hypothyroidism, a disease state that is associated with increased nocturnal secretion of melatonin. The participants were given subcutaneous injections at 18:00 h and 23:00 h of either saline or octreotide (Sandostatin; each injection 50 microg). During the nights when the healthy volunteers were given octreotide, melatonin secretion was similar to that recorded during administration of saline. Also the urinary excretion of melatonin was of similar magnitude at these two occasions. By contrast, the GH secretion was significantly lower the nights the healthy controls were given octreotide (GH AUC 22.6+/-5.4 mU/l x h during octreotide and 126.6+/-21.9 mU/l x h during saline; p<0.01). The patients with hypothyroidism also showed similar nocturnal melatonin secretion during octreotide and saline. Urinary excretion of melatonin also remained unchanged, as did GH secretion. The total nocturnal secretion of TSH was, however, significantly reduced by octreotide (TSH AUC 562+/-136 mU/l x h during octreotide and 851+/-185 mU/l x h during saline; p<0.05), thus suggesting that 100 microg of octreotide should be sufficient to inhibit also the pinealocytes if their function were regulated by somatostatin. Since exogenous somatostatin--in the form of octreotide--fails to influence nocturnal secretion and urinary excretion of melatonin in normal subjects and in patients with primary hypothyroidism, it is reasonable to assume that endogenous somatostatin may not be an important regulator of melatonin secretion in man.

Light treatment of seasonal affective disorder in combination with citalopram or placebo with 1-year follow-up.

This placebo-controlled, double-blind, 1-year pilot study aimed at investigating possible clinical advantages of combining initial light therapy with the selective serotonin reuptake inhibitor (SSRI) citalopram as well as the effects of continuous long-term administration of this drug in patients with seasonal affective disorder (SAD). Eight physically healthy women who met the DSM-III-R criteria for SAD were included in the study. Four women were randomized to the citalopram group receiving 40 mg citalopram daily from the first of 10 light treatment days and throughout the 1-year study. The remaining four women were allocated to the placebo group using the same double-blind repeated measures design. The clinical outcome was measured by using three versions of the Comprehensive Psychopathological Rating Scale (CPRS) and Visual Analog Scales (VAS), respectively. Taking the initial rating scores into account in covariance analyses, no statistically significant group difference was found during the light treatment period. However, during the follow-up period the full version of the CPRS and the self-rating version of CPRS and the VAS-scales for global condition and depressed mood were statistically significantly lower in the citalopram group compared with the placebo group. Thus, in this small but carefully observed sample of SAD-patients combining initial light therapy and long-term citalopram treatment was clinically more effective over time than the placebo combination. Our findings support the notion that light therapy with concomitant and continued SSRI (citalopram) treatment is a useful strategy to achieve beneficial long-term effects in patients with the SAD syndrome.

Seasonal variations in activity of systemic lupus erythematosus in a subarctic region.

Photosensitivity is one of the major clinical features of Systemic Lupus Erythematosus (SLE), and is considered to be implicated in the disease pathogenesis. We studied seasonal variations of SLE disease activity at latitude 70 degrees North where there is no sunlight in the winter time, in contrast to 24 h daily sunlight in the summer (midnight sun). The associations between the level of plasma melatonin in June and December with disease manifestations were also studied. Twenty-one SLE patients were examined each month for 1 y, and disease activity was assessed by laboratory parameters as well as clinical disease activity parameters SLEDAI and doctor's global assessment. Melatonin levels were quantified by a RIA-assay. There was no significant change of clinical measures or laboratory parameters of disease activity from one month to the next during the one year, except photosensitive rashes. January was the only month without SLE-flares or arthritis, in contrast to rest of the year. The levels of plasma melatonin were highest in December for seven patients and highest in June for one patient (P < 0.005). Plasma melatonin levels did not correlate with measures of clinical disease activity. At a latitude of 70 degrees North there were no major seasonal variations in SLE disease activity during the one year. There was an accumulation of photosensitivity in the summer months, but no indications of worsening of the disease in the winter months. In contrast to the rest of the year, there was no flare in January which had only 5.6 h of sunshine. The level of p-melatonin did not correlate with measures of disease activity.

Melatonin and clinical application.

A review of the different publications dealing with melatonin in humans shows that this field has been very active in the last few years. Normative melatonin values have been defined. Various relationships between melatonin and other traits have been studied, such as sleep, circadian rhythm, surgical stress and anaesthesia. Age-related melatonin studies and melatonin during depression and other psychiatric disorders have been reviewed. Finally, some studies have been performed to use melatonin as a medication for sleep disturbance in depression, for jet-lag and as a skin protector for ultraviolet light.

Normative melatonin excretion: a multinational study.

The present study on overnight urinary melatonin was conducted on the most geographically dispersed population to date, over a 1 year period, also covering a broad age range (18-62 years). An inverse relationship between melatonin and age, as well as between melatonin and weight was observed for both genders. Females as a whole, had higher melatonin values than males. Furthermore, the excretion of melatonin exhibited a bimodal distribution, distinguishing two groups of individuals: low and high melatonin excretors. The cut-off point was set at 0.25 nmol/l for ages up to 40 years and at 0.20 nmol/l for subjects above this age. Since melatonin may be involved in several physiological and pathological processes, it could be of importance to detect the type of melatonin excretion that prevails in various conditions, using a simple noninvasive procedure such as the overnight urinary measurement. For that purpose, this large sample could serve as a worldwide reference databank across different ages and locations.

[Complex hereditary diseases with psychiatric symptoms]. / Komplexa ärftliga sjukdomar med psykiatriska symptom.

Family and adoption studies indicate that genetic factors play a role in the development of many psychiatric disorders. A variable number of possible interacting genes giving a predisposition to the diseases is likely. The genetic dissection has been hampered by genetic complexity as well as by difficulties in defining the phenotypes. Genetic mapping efforts using sib pairs, twins and individual large families have revealed preliminary or tentative evidence of susceptibility loci for a number of psychiatric disorders. Illnesses described in this article include the prion disease familial fatal insomnia (FFI), alcoholism, anorexia nervosa, autism, bipolar affective disorder, dyslexia, enuresis nocturna, epilepsia, obsessive-compulsive disorders (OCD), schizophrenia, and the dementias, Alzheimer's disease and frontal lobe dementia. The genes and proteins related to the newly discovered transmitter in the central nervous system, nitric oxide (NO), and its genes and proteins are also reviewed. The number of mapped human genes now exceeds 30,000 of the estimated total number of 60,000 to 100,000 genes. This rapid development will facilitate gene mapping and efforts to isolate and identify the genes responsible for symptom susceptibility in many of the aetiologically unclear psychiatric diseases with complex genetic origin.

Affective disorder subtyped by psychomotor symptoms, monoamine oxidase, melatonin and cortisol: identification of patients with latent bipolar disorder.

A multivariate approach using pattern recognition method was applied on a multivariable data set from patients with affective disorders comprising biological and clinical variables. The depressed patients were rated according to 23 items of the comprehensive psychopathological rating scale (CPRS). Variables of importance were selected and clusters of patients were found by combining monoamine oxidase, melatonin and post-dexamethasone cortisol with symptoms of psychomotor retardation and agitation. Patients were distributed with high scores of agitation in the extreme of one direction and with high scores of retardation in the opposite direction. By using the combined clinical and biological variables, a diagnostic subcategory with latent bipolar disorder was identified. Two clusters of unipolar patients, one with low melatonin and low psychomotor retardation scores, and one with high melatonin and high psychomotor retardation scores, were found. Identification of a patient group with latent bipolar disorder may have potential therapeutic value since bipolar patients should be taken care of by a specialist in psychiatry, avoid tricyclic antidepressant therapy and may be candidates for lithium treatment.

Fibromyalgia--a syndrome associated with decreased nocturnal melatonin secretion.

OBJECTIVE: Most patients with fibromyalgic syndrome (FMS) complain of sleep disturbances, fatigue, and pain. These symptoms might be a consequence of changed melatonin (MT) secretion, since MT is known to have sleep promoting properties. Moreover, serum concentrations of two MT precursors (tryptophan and serotonin)--affecting both sleep and pain perception--appear to be low in patients with FMS. Therefore, the objective of this investigation was to study whether serum MT (s-MT) level is also low in these patients. DESIGN: Eight patients with FMS and 8 healthy sex-, BMI-, and age-matched controls were included in the study. s-MT concentrations were determined every second hour between 1800 and 0800 h. Urine was collected between 2200 and 0700 h for determination of urinary MT excretion. To evaluate total MT secretion between 1800 and 0800 h and MT secretion during the hours of darkness (between 23 and 07 h) individual MT areas under the curve (AUC) were calculated and expressed as group means. RESULTS: The FMS patients had a 31% lower MT secretion than healthy subjects during the hours of darkness (MT AUC 2300-0700 h (mean +/- SEM): 1.70 +/- 0.17 vs 2.48 +/- 0.38 nmol/l; P < 0.05). Also the s-MT peak value was significantly lower in the patient group: 0.28 +/- 0.03 vs 0.44 +/- 0.06 nmol/l; P < 0.05). CONCLUSION: Patients with fibromyalgic syndrome have a lower melatonin secretion during the hours of darkness than healthy subjects. This may contribute to impaired sleep at night, fatigue during the day, and changed pain perception.

The seasonal interrelationship between melatonin, vasopressin, and serum osmolality in elderly subjects.

Plasma concentration of arginine vasopressin (AVP) and melatonin and serum osmolality were measured at noon and at midnight in individuals living in the northern hemisphere on March 22-23, June 13-14, September 26-27, and December 12-13 in 35 healthy volunteers (15 men and 20 women) aged 60-74 years. The nocturnal increase in melatonin was highest in the autumn and lowest in the winter in both sexes. The midnight serum osmolality level was lower in the autumn than in any other time of the year. In both the men and the women the AVP level was higher in winter than in any other season (P < 0.01 and P < 0.0001, respectively). In men, the AVP level was higher at noon than at midnight in 49% of the investigated 24 hr periods, at the same level in 15% and lower in 36% (NS). The corresponding figures for women were 55%, 25%, and 20%, respectively (P < 0.05). This study suggests a possible relationship between melatonin and serum osmolality.

Diagnostic subgrouping of depressed patients by principal component analysis and visualized pattern recognition.

A data-analytical method is described for identifying behavioral and biological variables in psychiatric patients with predictive value in defining clinical subgroups. The procedure, based on principal component analysis (PCA) and graphical analysis, was applied in a group of 28 depressed patients. The 28 depressed patients of unipolar type were observed for up to 15 years for re-evaluation of the diagnoses at the start of the study. Platelet monoamine oxidase activity, post-dexamethasone serum cortisol and serum melatonin predicted two main clinical subgroups as well as a smaller subgroup of bipolar patients. The selection procedure revealed which of several variables were predictive of subgroups that were not possible to identify by univariate methods. The three biological variables may thus be useful in further assessment of clinical subgroups of unipolar depressed patients studied by other research groups.

Cortisol in light treatment of seasonal and non-seasonal depression: relationship between melatonin and cortisol.

The effect of bright light on cortisol and the relationship between melatonin and cortisol were studied in 63 depressed patients (42 patients with a seasonal pattern and 21 patients with a non-seasonal pattern). The patients were matched for age, time of treatment and severity of depression. Before and after light treatment the severity of the depression was rated with the Comprehensive Psychopathological Rating Scale (23 items) and the Hamilton Depression Rating scale (18 items), and serum cortisol and melatonin were drawn at nine time-points between 20.00 and 08.00 hours. Two hours of light treatment (350 cd m-2) was given daily for 10 days either in the morning (06.00-08.00 hours) or in the evening (18.00-20.00 hours). As reported earlier, patients with a seasonal pattern improved significantly more than patients with a non-seasonal pattern of depression, and no significant differences were found between the treatment efficacy of morning compared to evening light. A cosinor analysis showed that the cortisol batyphase was significantly advanced by morning light, but was not delayed by evening light. A delay in batyphase cortisol showed a weak significant correlation with a decrease in the absolute and relative sum of scores. The batyphase of cortisol occurred approximately 3 h earlier than the acrophase of melatonin. Of the changes in the melatonin acrophase 43% were reflected in a change of cortisol batyphase, indicating a hierarchical relationship with melatonin as the co-ordinating hormone transducing part of the information of the external light to the phase position of cortisol. No significant differences between patients with a seasonal or a non-seasonal pattern were seen in mesor, amplitude or batyphase of cortisol before treatment, and no significant changes in mesor or amplitude were seen as a result of light treatment.

Long-term melatonin treatment in blind children and young adults with circadian sleep-wake disturbances.

Oral melatonin therapy was used to treat-severe circadian sleep-wake disturbances in eight children and young adults in an open study. All patients were functionally blind, six of them because of defects in the anterior visual pathway. All were mentally retarded. Baseline sleep diaries kept by the caregivers before treatment showed non-24-hour sleep-wake syndrome. Diurnal variations in serum and urinary melatonin were examined. Melatonin secretion peak time was delayed in seven patients. Body temperature variation was out of phase relative to sleep and melatonin in five patients, and thus they had signs of internal desynchronisation. Melatonin given in the evening dramatically improved the sleep-wake pattern in all patients. The effect was maintained during long-term therapy for between 1 and 6 years in six patients. One patient fell back into the earlier sleep pattern after 6 to 8 months, and another had increasing sleep disturbance because of reflux oesophagitis, although the improvement regarding the circadian component remained. No side effects have been noted during the therapy. Oral melatonin is promising as an efficient and seemingly safe alternative for treatment of severe circadian sleep disturbances.