Glucocorticoid treatment increases density of serotonin 5-HT2A receptors in humans.

BACKGROUND: Interactions between the serotonergic system and the hypothalamic-pituitary-adrenal axis have been suggested, albeit the details for such interactions have yet to be established. Animal studies have shown that the density of serotonin 5-HT2A receptors is increased after administration of exogenous glucocorticoids. OBJECTIVE: The objective of this study was to explore possible changes in the pattern of density and affinity of 5-HT2A receptors in humans after treatment with glucocorticoids. METHODS: Using a radioactive binding assay, the density and affinity (measured as Bmax and Kd) of 5-HT2A serotonin receptors were measured in blood samples drawn from 27 individuals diagnosed with polymyalgia rheumatica and/or giant cell arteritis before and after start of an oral treatment with prednisolone. For each patient Bmax and Kd at baseline before prednisolone treatment were compared with Bmax and Kd in samples drawn at a first and second follow-up clinic visit at an average of 8.8 (±2.5) days and 33.6 (±6.8) days, respectively. RESULTS: The density of 5-HT2A receptors increased after treatment in 23 individuals. The mean Bmax value at baseline for all patients was 45.2 fmol/mg protein compared with 64.9 fmol/mg protein in the corresponding samples drawn at the second follow-up visit (p=0.001). There also was an association between individuals accumulated prednisolone dose and the magnitude of change in Bmax between baseline and the first follow-up visit. Erythrocyte sedimentation rate, platelet count or gender had no influence on the results. There were no significant differences in Kd during the treatment period. However, a low Kd value at baseline was a predictor for an increase in Bmax following treatment. CONCLUSIONS: The results of this study showed that the density of 5-HT2A serotonin receptors in man is increased after a subchronic treatment with glucocorticoids. The magnitude of the increase appears to be associated with the affinity of 5-HT2A receptors before treatment and the accumulated dose of glucocorticoid early in the treatment period.

Effect of serotonin reuptake inhibitors on pulmonary hemodynamics in humans.

BACKGROUND: Serotonin promotes pulmonary arterial vasoconstriction and pulmonary arterial smooth muscle cell proliferation, thereby having the potential to increase pulmonary arterial blood pressure. Although serotonin reuptake inhibitors (SRIs) might inhibit further deterioration in patients with manifest pulmonary arterial hypertension, they may induce pulmonary hypertension in healthy newborns after fetal exposure. As it is unclear whether treatment with SRIs affects pulmonary hemodynamics in adults without pulmonary hypertension, the aim of the present study was to investigate the effect of SRIs on pulmonary hemodynamics in such subjects. METHODS: Sixteen patients with stable angina pectoris scheduled for first time coronary artery bypass grafting were included in the study. Of these 8 were currently treated with an SRI (the SRI group) and 8 were not (the control group). Pulmonary arterial pressures were measured before induction of anesthesia by means of a pulmonary artery catheter. Serotonin transporter and 5-HT(2A) receptor gene polymorphisms and platelet 5-HT(2A) receptor expression were studied to elucidate their possible role as modifying factors. RESULTS: No patients in any of the groups had pulmonary arterial hypertension. Mean pulmonary artery pressure was 15.0 mmHg in the SRI group and 14.5 mmHg in the control group (P = 0.50; 95% confidence interval for the difference, -2.9 to +3.9 mmHg). Neither were there any significant differences between the groups for any of the other hemodynamic variables studied. The various gene polymorphisms and the extent of platelet 5-HT(2A) receptor expression did not influence the hemodynamic variables. CONCLUSIONS: SRI treatment did not significantly influence pulmonary hemodynamics in patients without pulmonary hypertension. KEYWORDS: Serotonin; Selective serotonin reuptake inhibitors; Pulmonary hemodynamics; Pulmonary hypertension.

Urine monitoring of diazepam abuse- new intake or not?

Testing for drugs-of-abuse in urine is requested for multiple reasons, including legal and workplace policies. Two cases were studied in which there was a suspicion that the patients continued to abuse diazepam, because of repeatedly positive urine samples. In these cases, diazepam metabolites were measured in urine samples by gas or liquid chromatography coupled to mass spectrometry. The concentrations of diazepam metabolites were subsequently creatinine correlated. Very long elimination times were found in the described cases. None of them had in fact ingested diazepam again during the study period. By the use of pharmacogenetic typing, one of the subjects was found to have a slow metabolism for CYP2C9 as well as for CYP2C19. In the second case, there was a possible drug interaction between diazepam and zolpidem.

Serum levels of olanzapine in a non-fatal overdose.

Olanzapine is a widely used second generation antipsychotic drug. Case reports of intoxications have been published, but reports in the literature of non-fatal intoxications of olanzapine containing repeated measurements of serum levels are scarce. Therefore, this case of non-fatal olanzapine intoxication is presented, in which 19 blood samples were drawn during 2 weeks. The highest (initial) measured value was estimated at 800 pg/L. This patient ingested 550 mg of olanzapine resulting in clinical signs of intoxication, including seizures. Because the patient was found the day after the intoxication, the initial concentration had probably been higher. The pharmacokinetics of olanzapine has been described as linear and dose-proportional throughout the therapeutic dosing range. Large overdoses, however, have been described to show non-linear pharmacokinetics. In this study's series of serum concentrations, a two-phase elimination was seen, with an initial elimination half-life of about 24 h during the first 3 days, followed by a second phase with a half-life of about 2.5 days. The patient in this case recovered completely. Because the elimination time after intoxication can be considerably longer than expected, it is recommended that the patient's serum concentrations after intoxication be monitored.

High prevalence of the metabolic syndrome among a Swedish cohort of patients with schizophrenia.

Several cardiovascular risk factors have been linked to antipsychotic treatment and cardiovascular mortality is increased in these patients compared to the general population. The full metabolic syndrome (or its components) is associated with an increased risk of cardiovascular disorders. The prevalence of the metabolic syndrome was investigated using a cross-sectional study design in a cohort of 269 patients, aged 20-69 years, with schizophrenia living in Northern Sweden, and was defined according to the criteria of the National Cholesterol Education program. The prevalence of the metabolic syndrome was 34.6% (95% CI = 28.8-40.3) and highest (43%; 95% CI = 32-53) for participants aged 40-49 years. Clozapine treated subjects reached the highest prevalence of the metabolic syndrome (48%; 95% CI = 34-62). The prevalence was similar for men (32.8%; 95% CI = 25.8-39.8) and women (38.0%; 95% CI = 27.9-48.2). Men had a high prevalence of hypertension (49.2%; 95% CI = 41.7-56.6) and women had high prevalence of low high-density lipoprotein cholesterol (40.2%; 95% CI = 30.0-50.4) and abdominal obesity (75.0%; 95% CI = 66.0-84.0). Subjects with the metabolic syndrome had significantly higher mean body mass index (BMI) (P < 0.001), HbA1c (P = 0.002), and fasting serum insulin (P < 0.001) compared to non-metabolic syndrome subject. Subjects with the metabolic syndrome had also significantly more often a positive history of cardiovascular diseases compared to non-metabolic syndrome subjects (25.8% versus 12.5%; P = 0.01). Of all study subjects 36.8% were obese (BMI > 30). These results clearly show that the metabolic syndrome and its components are highly prevalent in patients with schizophrenia. Physicians treating patients with schizophrenia are recommended to monitor the components included in the metabolic syndrome.

The ethics of research using biobanks: reason to question the importance attributed to informed consent.

BACKGROUND: During the past decade, the use of stored tissue has become an object of increased ethical query. A Swedish biobank and a biotech company have been praised for solving the ethical problems with explicit informed consent procedures, and we decided to investigate donors' perceptions of the system. METHODS: A questionnaire was sent to a randomized sample of 1200 donors who had donated blood and signed informed consent forms. RESULTS: The response rate was 80.9%. Of the respondents, 64.5% were aware that they had consented to donate a blood sample, 55.4% thought that they had consented to donate phenotypic information, and 31.6% believed that they could withdraw their consent. Among respondents, 3.9% considered informing donors about the research objective as the most important ethical issue in relation to biobanks, and 5.6% were unsatisfied with the information they had been given. There was 85.9% acceptance of surrogate decision making by regional research ethics committees. CONCLUSIONS: Considering that the donors in this study were not always aware of their donation but generally were not unsatisfied with the information they had received, and that they did not rate being informed about the research objective as an important issue, informed consent seems to be an inadequate measure of public acceptance of biobank-based research.

Dieting and weight loss do not affect on the platelet serotonin 5-HT2A receptor.

Alterations related to the serotonin 5-HT(2A) receptor have been reported in various psychiatric disorders, and the 5-HT(2A) receptor is also one of the receptors mediating the effects of serotonin on feeding and satiety. The present study was carried out in order to investigate the association between the serotonin 5-HT(2A) receptor and weight loss during dieting in overweight subjects. In nine women studied before, during and after a 6-month period of dieting, body weight loss was not found to affect the platelet 5-HT(2A) receptor status. This finding implies that although body weight decrease is a common feature in many psychiatric disorders, the reported alterations in serotonin 5-HT(2A) receptor status in these disorders do not seem to be caused by the weight loss per se.

Informed consent and biobanks: a population-based study of attitudes towards tissue donation for genetic research.

AIMS: The procurement and usage of tissue samples has begun receiving increasing legal and ethical attention. The authors' aim was to develop an empirically based understanding of public attitudes to the use of tissue for research. METHOD: A questionnaire was distributed to a randomized sample (n=1,000) of the population in the age group 18-85 in Västerbotten County, Sweden. RESULTS: The response rate was approximately 60%. There was a general acceptance of genetic research based on biobank material (71%) but, though it is often a prerequisite for tissue-based research, a majority (62%) would not allow researchers to examine their healthcare records without specific consent. A majority (66.8%) accepted surrogate decisions by research ethical committees; 48% of the respondents estimated that they would feel respected if they were notified each time a sample was used. When compared and ranked with other issues, informed consent was a principal concern to a minority (4%) only. Should research efforts generate information on future health risks, a majority (55%) would want to be told only if treatment was available. CONCLUSION: Though genetic research in bioethical debate is often viewed as a potential threat to the integrity of the donor, the confidentiality of medical records still seems to concern donors more. Research ethical committees have support in the majority of the population for some surrogate decisions. The current emphasis on the question of informed consent in policy making for biobank-based research does not seem to be reflected unambiguously in the concerns of the general public.

Influence of menstrual cycle on platelet serotonin uptake site and serotonin2A receptor binding.

Depression and anxiety are common health problems affecting women, particularly during the reproductive years. Major depression is two to three times as common in women than in men. Neuroendocrine factors are likely to contribute to this overall increased risk for developing mood disorders in women, and the neuroendocrine influence is most obviously seen in women with premenstrual dysphoric disorder (PMDD) as these women experience depressed mood and anxiety premenstrually only during ovulatory cycles. Moreover, dysfunction of serotonergic transmission has been regarded as an important mechanism in several psychiatric disorders and ovarian steroids have been shown to profoundly influence the activity of the serotonergic system. Given these facts, the purpose of this study was to examine whether binding of [3H]paroxetine to the platelet serotonin transporter or binding of [3H]lysergic acid diethylamide ([3H]LSD) to the platelet 5-HT2A receptor are influenced by the cyclical changes in circulating estradiol and progesterone that occur during the menstrual cycle. We examined 28 healthy women, without oral contraceptives and with regular menstrual cycles. In the late follicular phase, Bmax for [3H]paroxetine binding was significantly higher than in the ovulatory (p<0.01), early luteal phase (p<0.05) and mid-luteal phase (p<0.01). Bmax for [3H]LSD binding was significantly higher in the early follicular phase and the early luteal phase compared to the mid-luteal phase (p<0.001 and p<0.05, respectively). In the early follicular phase and the ovulatory phase, significant correlations between estradiol serum concentrations and Kd for [3H]paroxetine were obtained (p<0.001, respectively). In the luteal phase, significant inverse correlations between progesterone as well as estradiol serum concentrations and Kd for [3H]LSD binding were found (p<0.05, respectively).

[Research Ethics Committees--who is to represent the community?]. / Forskningsetikkommittéerna--vem ska representera allmänheten?

The Swedish Government has proposed a law for the ethical regulation of research on human beings. The proposal entails changes in the composition of Research Ethics Committees with regard to community representation. A study indicates that healthcare staff with no ties to research would appear to merit particular public confidence, as would representatives of the legal profession, moral philosophers and priests.

Adverse drug reactions as a cause for admissions to a department of internal medicine.

PURPOSE: To assess the occurrence and pattern of adverse drug reactions as a cause for acute hospital admission. METHODS: In 681 randomly selected patients, acutely admitted to a clinic of internal medicine at a Swedish university hospital, information was collected from their medical records about current symptoms and use of drugs, previous diseases and the results of medical investigations and tests. In addition, a standardized interview according to a questionnaire was carried out. A group of experts in clinical pharmacology assessed the data obtained from the patients' case records and the results of the interviews, and then, according to WHO criteria, judged the probability that an adverse drug reaction could have caused or contributed to the actual admission to hospital. RESULTS: Out of the 681 cases included, 94 (13.8%) had symptoms and signs that were judged as drug-related and that had caused or contributed to the admission. Eighty-two patients (12.0%) had altogether 99 symptoms that were classified as adverse drug reactions. Of these, 91% were type A reactions. The relationship between the medication and the reaction was judged certain in eight, probable in 17, and possible in 74 cases. The most common adverse drug reactions were cardiovascular (36.3%). Twelve patients (1.8%) had symptoms indicating intoxications. CONCLUSIONS: The prevalence of drug-related problems causing or contributing to admission to a clinic of internal medicine is high and is dominated by type A reactions, i.e. reactions in principle predictable and preventable. This implies a possibility to increase drug safety by preventive measures.

1999 WHO/ISH Guidelines applied to a 1999 MONICA sample from northern Sweden.

BACKGROUND: Treating hypertension with drugs is so far the most cost-effective way to reduce this important risk factor for cardiovascular disease (CVD). It is, however, important to determine absolute risk, and thereby estimate indication for drug treatment, in order to maintain a cost-effective drug treatment. WHO/ISH Hypertension Guidelines from 1999 propose a risk stratification for estimating absolute risk for CVD based on blood pressure and additional risk factors, target organ damage (TOD) and CVD. OBJECTIVES: We studied the consequences of applying the recent WHO/ISH risk stratification scheme to a MONICA sample of 6000 subjects from a geographically defined population in northern Sweden, regarding indications for treatment, target blood pressure and risk distribution. METHODS: We have risk-classified each of these patients using a computer program, according to the WHO/ISH scheme. Data on TOD were not available. RESULTS: In all, 917 (15%) had drug-treated hypertension. Three-quarters (n = 737) were inadequately treated, with blood pressure levels at or above 140 or 90 mmHg. 1773 (30% of 5997) untreated subjects had a blood pressure of 140/90 or above; 16% in the low-, 62% in the medium-, 8% in the high-, and 14% in the very-high-risk group. The corresponding risk-group pattern for the inadequately treated hypertensives (n = 737) was 5.5, 48.3, 11.1 and 35.2%, respectively. If we shifted the target blood pressure from below 140/90 to below 130/85 for drug-treated subjects under 60 (n = 278) the number of inadequately treated subjects increased by 34 (12.2% of 278); 14 in the low-risk group, 15 in the medium-risk group, and only five in the high- or very-high-risk groups. CONCLUSIONS: Only one-fifth of the drug-treated hypertensives were well controlled. Moreover, the incidence of newly detected blood pressure elevation was high. The majority of younger subjects with high blood pressure had low risk, but in those aged 45-54 this had already risen to a medium risk. Changing the target blood pressure to below 130/85, for subjects aged below 60, as recommended by WHO/ISH, affects predominantly low- and medium-risk groups.