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.

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.

Staff's experiences with patients' assaults in a Norwegian psychiatric university hospital. A pilot study.

This pilot study addressed the problem of patients' assaults on staff at a Norwegian psychiatric university hospital. The questionnaire-based study had a retrospective design, and involved a random sample of staff (n = 85). It revealed that 100% of the nursing staff and 60.9% of the therapists (doctors, psychologists, and social workers) had been physically assaulted by patients at least once during their careers at the hospital. Most of the assaults did not result in sick leave, and could as such be classified as not serious. There were no significant differences in the number of assaults on male and female staff or between staff in the emergency, intermediary, rehabilitation and psycho-geriatric wards. The staff responded that they believed male patients were more violent and threatening than female patients, although a majority had been assaulted more frequently by female than by male patients. Assault was the reason most frequently given for physically restraining patients, and most of the staff did not believe that physically restraining patients reduced their chances of recovery. The study suggests that patients' assaults on staff in Norwegian psychiatric hospitals is an important problem, which needs further attention.

[Local monitoring center for clozapine (Leponex) treatment]. / Lokalt monitoreringssenter for klozapin (Leponex)-behandling.

A local centre for monitoring clozapine therapy has been in operation in the Pharmacy Department at Asgård Hospital in Tromsø since 1994. The centre utilizes an electronic reporting system and is available to clozapine-prescribers in the three northernmost countries in Norway: Nordland, Troms and Finnmark. The system fosters early detection of poor compliance with frequent blood tests and for signs of white blood cell suppression. This is a new concept in Norway and one way of assuring the quality of clozapine treatment. The purpose of the centre is to improve patient safety by facilitating early detection of potentially dangerous white blood cell suppression, thereby avoiding fatal consequences.

Midwinter insomnia in the subarctic region: evening levels of serum melatonin and cortisol before and after treatment with bright artificial light.

"Midwinter insomnia" (MI), mainly characterized by difficulties in falling asleep at night, is a common complaint during the period of obscuration or "dark period" north of the arctic circle. We hypothesize that MI is a result of a phase delay of the sleep-wake cycle due to insufficient exposure to daylight. In the present study based on this hypothesis, we wanted to find out whether otherwise healthy subjects with MI show abnormalities in the endocrine markers melatonin and cortisol late in the evening, and whether exposure to intensive light for one half hour in the morning for 5 days has any effect on the insomnia and on the endocrine variables. Nine subjects with typical MI were compared to eight controls. Before light exposure, the MI group had a significantly lower level of plasma melatonin in the evening than the controls, and a nonsignificant increase of plasma cortisol. After light exposure, the following results were seen in the MI group: sleep latency was moderately but significantly shortened, plasma melatonin increased to the same level as in the controls, and there was a nonsignificant increase of plasma cortisol. These results are largely in accordance with the predictions made from the phase delay hypothesis. However, other explanations cannot be ruled out.

Insomnia during the "dark period" in northern Norway. An explorative, controlled trial with light treatment.

Midwinter insomnia (MI) is an initial type insomnia that is typically seen north of the Polar Circle during the "dark period", when the sun does not rise above the horizon. The cause of MI is not known, but it seems reasonable to assume that it is the expression of a phase delay of the sleep-wake cycle, due to lack of the entraining effect of normal daylight. Based on his hypothesis, we have studied the effect of intensive light exposure (2000-2500 lux for half an hour between 7.30 and 8.30 a.m. for 5 days) on selected sleep and endocrinological variables (the latter will be reported elsewhere) in nine subjects with typical MI and eight healthy controls. After light exposure, the MI subjects had a significantly shortened sleep latency and a nonsignificant increase in total sleep time. Before light exposure, the MI subjects reported significantly less drowsiness in the evening than in the morning, whereas the opposite was true after light exposure. No significant changes were seen in the control group. The results of this study give some support to the delayed phase hypothesis.

A double-blind comparison of zimelidine and desipramine in endogenous depression.

Zimelidine, a specific 5HT uptake inhibitor (final dose 225 mg), and desipramine, mainly a noradrenaline uptake inhibitor (final dose 150 mg), were given in random order to 24 in- and out-patients fulfilling the Research Diagnostic Criteria for Major Depressive Disorder, definite or probable endogenous type, for a 3-week treatment period. Nonresponders were crossed over to the other drug for another 3 weeks. There was a nonsignificant trend towards more overall improvement on desipramine. Some patients in both groups showed very little change during 3 weeks, indicating a bimodal distribution of response to either drug. Several nonresponders improved markedly upon direct crossing over to the other drug. There were few and mild side effects on both drugs, with no significant difference between them. No significant correlation was found between improvement and plasma concentrations of zimelidine, norzimelidine, or desipramine, whereas a significant positive correlation was found between improvement and platelet serotonin uptake inhibition (measured in fresh platelets incubated in diluted plasma from the patients) in zimelidine-treated patients.

Effect of midazolam, flunitrazepam, and placebo against midwinter insomnia in northern Norway.

Forty-three outpatients with "midwinter insomnia" (an early type insomnia commonly seen north of the Polar Circle when the sun stays below the horizon) were randomly allocated to one of three treatment groups, receiving either 15 mg midazolam, 1 mg flunitrazepam, or placebo, for 5 nights, double blind, after 3 nights without drug. In all three groups, this was followed by 5 nights on placebo (single blind). Several subjective sleep variables were recorded every morning, some variables also at noon. Placebo had practically no effect on any sleep variable, whereas both active drugs markedly improved sleep with regard to the following variables: sleep latency, number of awakenings, total duration of sleep, quality of sleep, total evaluation of sleep, and feelings of drowsiness in the morning and at noon. In the withdrawal period, patients who had received active drug showed a deterioration of sleep on most variables, but not beyond the baseline level. A true "rebound insomnia" could thus not be demonstrated. There was no significant difference in any of the variables between midazolam and flunitrazepam treatment. Side effects were reported by very few patients. Midazolam seems to be as effective as flunitrazepam in this type of insomnia, in spite of its much shorter biological half-life.

Plasma and erythrocyte levels of methotrimeprazine and two of its nonpolar metabolites in psychiatric patients.

Methotrimeprazine (levomepromazine) has two major metabolites in man: N-monodesmethyl methotrimeprazine, which is pharmacologically active and almost as potent as the parent drug; and methotrimeprazine sulfoxide, which is much less active. Blood levels and the distribution between plasma and erythrocytes of methotrimeprazine and the two metabolites were studied in five psychiatric patients on oral methotrimeprazine and after incubation of the compounds in blood from healthy volunteers. The concentrations were measured separately in plasma and erythrocytes by gas chromatography with a nitrogen detector, and the concentrations in whole blood were calculated from the plasma and erythrocyte concentrations. In four of the five patients the blood levels of both metabolites were similar to or higher than the levels of the parent drug. A large interindividual variation was observed in the plasma-erythrocyte concentration ratios. The mean ratios in all individuals were 1.76, 0.57, and 3.02 for methotrimeprazine, N-monodesmethyl methotrimeprazine, and methotrimeprazine sulfoxide, respectively. The relatively high blood concentrations of N-monodesmethyl methotrimeprazine suggest that this metabolite may contribute significantly to the therapeutic action and side effects of oral treatment with methotrimeprazine.

Triazolam (Halcion) versus flunitrazepam (Rohypnol) against midwinter insomnia in Northern Norway.

In a double-blind, cross-over trial, triazolam (0.25 mg) was tested against flunitrazepam (1 mg) in the typical midwinter insomnia which is often seen among otherwise healthy people in Northern Norway. Each drug was given for five nights, in random order, with a five-night placebo period between the active drugs (providing for a single blind comparison with placebo). A total of 2 outpatients started the trial; 19 completed. There were highly significant differences between each active drug and placebo on the subjectively scored variables sleep latency, duration of sleep, and total evaluation of sleep, and also significant differences for feeling in the morning, number of awakenings, and quality of sleep; all differences were in favour of the active drugs. Generally, the sleep variables were rated on the same level in the placebo period as they were for the last five nights prior to the trial. There were no significant differences between triazolam and flunitrazepam on any variable. However, eight patients stated a preference for triazolam and eight for flunitrazepam. These two groups of patients did not differ significantly with regard to sex, age, previous use of hypnotics, or severity of insomnia. Only three patients complained about side effects. Notably, the feeling of being alert and refreshed in the morning was significantly superior in the active drug periods as against the placebo period. It is concluded that both active drugs were highly effective, with a minimum of side effects, in this type of insomnia and with the relatively low dosage used.