Connections between cross-tissue and intra-tissue biomarkers of aging biology in older adults.

Background: Saliva measures are generally more accessible than blood, especially in vulnerable populations. However, connections between aging biology biomarkers in different body tissues remain unknown. Methods: The present study included individuals (N = 2406) who consented for saliva and blood draw in the Health and Retirement Telomere length study in 2008 and the Venous blood study in 2016 who had complete data for both tissues. We assessed biological aging based on telomere length in saliva and DNA methylation and physiology measures in blood. DNA methylation clocks combine information from CpGs to produce the aging measures representative of epigenetic aging in humans. We analyzed DNA methylation clocks proposed by Horvath (353 CpG sites), Hannum (71 CpG sites), Levine or PhenoAge, (513 CpG sites), GrimAge, (epigenetic surrogate markers for select plasma proteins), Horvath skin and blood (391 CpG sites), Lin (99 CpG sites), Weidner (3 CpG sites), and VidalBralo (8 CpG sites). Physiology measures (referred to as phenotypic age) included albumin, creatinine, glucose, [log] C-reactive protein, lymphocyte percent, mean cell volume, red blood cell distribution width, alkaline phosphatase, and white blood cell count. The phenotypic age algorithm is based on parametrization of Gompertz proportional hazard models. Average telomere length was assayed using quantitative PCR (qPCR) by comparing the telomere sequence copy number in each patient's sample (T) to a single-copy gene copy number (S). The resulting T/S ratio was proportional to telomere length, mean. Within individual, relationships between aging biology measures in blood and saliva and variations according to sex were assessed. Results: Saliva-based telomere length showed inverse associations with both physiology-based and DNA methylation-based aging biology biomarkers in blood. Longer saliva-based telomere length was associated with 1 to 4 years slower biological aging based on blood-based biomarkers with the highest magnitude being Weidner (ß = - 3.97, P = 0.005), GrimAge (ß = - 3.33, P < 0.001), and Lin (ß = - 3.45, P = 0.008) biomarkers of DNA methylation. Conclusions: There are strong connections between aging biology biomarkers in saliva and blood in older adults. Changes in telomere length vary with changes in DNA methylation and physiology biomarkers of aging biology. We observed variations in the relationship between each body system represented by physiology biomarkers and biological aging, particularly at the DNA methylation level. These observations provide novel opportunities for integration of both blood-based and saliva-based biomarkers in clinical care of vulnerable and clinically difficult to reach populations where either or both tissues would be accessible for clinical monitoring purposes.

Body mass index and Mini Nutritional Assessment-Short Form as predictors of in-geriatric hospital mortality in older adults with COVID-19.

BACKGROUND & AIMS: Overweight and obesity have been consistently reported to carry an increased risk for poorer outcomes in coronavirus disease 2019 (COVID-19) in adults. Existing reports mainly focus on in-hospital and intensive care unit mortality in patient cohorts usually not representative of the population with the highest mortality, i.e. the very old and frail patients. Accordingly, little is known about the risk patterns related to body mass and nutrition in very old patients. Our aim was to assess the relationship between body mass index (BMI), nutritional status and in-geriatric hospital mortality among geriatric patients treated for COVID-19. As a reference, the analyses were performed also in patients treated for other diagnoses than COVID-19. METHODS: We analyzed up to 10,031 geriatric patients with a median age of 83 years of which 1409 (14%) were hospitalized for COVID-19 and 8622 (86%) for other diagnoses in seven geriatric hospitals in the Stockholm region, Sweden during March 2020-January 2021. Data were available in electronic hospital records. The associations between 1) BMI and 2) nutritional status, assessed using the Mini-Nutritional Assessment - Short Form (MNA-SF) scale, and short-term in-geriatric hospital mortality were analyzed using logistic regression. RESULTS: After adjusting for age, sex, comorbidity, polypharmacy, frailty and the wave of the pandemic (first vs. second), underweight defined as BMI<18.5 increased the risk of in-hospital mortality in COVID-19 patients (odds ratio [OR] = 2.30; confidence interval [CI] = 1.17-4.31). Overweight and obesity were not associated with in-hospital mortality. Malnutrition; i.e. MNA-SF 0-7 points, increased the risk of in-hospital mortality in patients treated for COVID-19 (OR = 2.03; CI = 1.16-3.68) and other causes (OR = 6.01; CI = 2.73-15.91). CONCLUSIONS: Our results indicate that obesity is not a risk factor for very old patients with COVID-19, but emphasize the role of underweight and malnutrition for in-hospital mortality in geriatric patients with COVID-19.

Technological readiness and implementation of genomic-driven precision medicine for complex diseases.

The fields of human genetics and genomics have generated considerable knowledge about the mechanistic basis of many diseases. Genomic approaches to diagnosis, prognostication, prevention and treatment - genomic-driven precision medicine (GDPM) - may help optimize medical practice. Here, we provide a comprehensive review of GDPM of complex diseases across major medical specialties. We focus on technological readiness: how rapidly a test can be implemented into health care. Although these areas of medicine are diverse, key similarities exist across almost all areas. Many medical areas have, within their standards of care, at least one GDPM test for a genetic variant of strong effect that aids the identification/diagnosis of a more homogeneous subset within a larger disease group or identifies a subset with different therapeutic requirements. However, for almost all complex diseases, the majority of patients do not carry established single-gene mutations with large effects. Thus, research is underway that seeks to determine the polygenic basis of many complex diseases. Nevertheless, most complex diseases are caused by the interplay of genetic, behavioural and environmental risk factors, which will likely necessitate models for prediction and diagnosis that incorporate genetic and non-genetic data.

Joint impact of common risk factors on incident dementia: A cohort study of the Swedish Twin Registry.

BACKGROUND: As common risk factors of dementia, nine factors (low education, hearing loss, obesity, hypertension, smoking, depression, physical inactivity, diabetes and social isolation) were proposed. However, the joint impact of these factors on incident dementia is still uncertain; hence, we aimed to examine this impact. METHODS: We conducted a cohort study of 9017 cognitively intact individuals aged ≥ 65 years in the Swedish Twin Registry. The main exposure was the total number of reported risk factors (ranging from 0 to 9). Data on dementia diagnoses were based on clinical workup and national health registers. After estimating the adjusted hazard ratios of incident dementia, the population attributable fraction (PAF) was calculated. We then conducted additional analyses, including APOE ε4 status in a genotyped subsample (n = 2810) to check the relative impact of the main exposure and discordant twin pair (n = 1158) analysis to consider confounding by familial effects (shared genetic or familial environmental factors). RESULTS: The number of dementia cases was 1950 (21.6%). A dose-response relationship between the number of risk factors and incident dementia was observed; hazard ratio (95% confidence interval) per one-unit increment in number of risk factors was 1.07 (1.03 to 1.11). The PAF for the combination of the nine risk factors was 10.4%. The PAF of all nine risk factors was smaller than that of APOE ε4 genotype (20.8%) in the subsample. Discordant pair analysis suggested that the observed association was not likely explained by familial effects. CONCLUSION: The nine risk factors may have considerable impact as modifiable factors on incident dementia.

Plasma concentrations of etonogestrel in women using oral desogestrel before and after Roux-en-Y gastric bypass surgery: a pharmacokinetic study.

OBJECTIVE: To investigate whether Roux-en-Y gastric bypass (RYGB) affects oral desogestrel (etonogestrel) pharmacokinetics. DESIGN: Single centre, open label, phase-2 pharmacokinetic study. SETTING: University hospital of Linköping, Sweden. POPULATION: Fourteen women with planned RYGB surgery were included; nine women aged 18-45 years using 75 micrograms desogestrel completed the study. METHODS: Steady-state etonogestrel pharmacokinetic (PK) parameters were measured on three occasions for each individual (at 8 ± 6 weeks before surgery, and at 12 ± 2 and 52 ± 2 weeks after surgery). Each patient served as her own control. On each occasion, serum samples were collected during a 24-hour period and etonogestrel concentrations were determined with ultra-performance liquid chromatography/tandem mass spectrometry. MAIN OUTCOME MEASURES: Area under the plasma concentration time curve of etonogestrel (AUC0-24 hours ). RESULTS: All women had significant postoperative weight loss. There were no significant differences in AUC0-24 hours , terminal half-lives (t½ ), time to peak serum concentrations (Tmax ), or apparent oral clearances of etonogestrel (CLoral ) before and after gastric bypass surgery on any occasion. Peak serum concentrations (Cmax ) increased after 52 ± 2 weeks compared with preoperative values (0.817 ng/ml versus 0.590 ng/ml, P = 0.024). CONCLUSION: To our knowledge, this is the first study to investigate the effects on desogestrel pharmacokinetics after RYGB. This study did not reveal any clinically significant changes in etonogestrel pharmacokinetics, suggesting that oral desogestrel may be used by women after RYGB surgery. The sample size was limited, however, and therefore the results should be interpreted cautiously. TWEETABLE ABSTRACT: The pharmacokinetics of oral desogestrel does not appear to change after gastric bypass surgery.

An epigenome-wide association study meta-analysis of educational attainment.

The epigenome is associated with biological factors, such as disease status, and environmental factors, such as smoking, alcohol consumption and body mass index. Although there is a widespread perception that environmental influences on the epigenome are pervasive and profound, there has been little evidence to date in humans with respect to environmental factors that are biologically distal. Here we provide evidence on the associations between epigenetic modifications-in our case, CpG methylation-and educational attainment (EA), a biologically distal environmental factor that is arguably among the most important life-shaping experiences for individuals. Specifically, we report the results of an epigenome-wide association study meta-analysis of EA based on data from 27 cohort studies with a total of 10 767 individuals. We find nine CpG probes significantly associated with EA. However, robustness analyses show that all nine probes have previously been found to be associated with smoking. Only two associations remain when we perform a sensitivity analysis in the subset of never-smokers, and these two probes are known to be strongly associated with maternal smoking during pregnancy, and thus their association with EA could be due to correlation between EA and maternal smoking. Moreover, the effect sizes of the associations with EA are far smaller than the known associations with the biologically proximal environmental factors alcohol consumption, body mass index, smoking and maternal smoking during pregnancy. Follow-up analyses that combine the effects of many probes also point to small methylation associations with EA that are highly correlated with the combined effects of smoking. If our findings regarding EA can be generalized to other biologically distal environmental factors, then they cast doubt on the hypothesis that such factors have large effects on the epigenome.

Genetic susceptibility to cardiovascular disease and risk of dementia.

Several studies have shown cardiovascular disease (CVD) to be associated with dementia, but it is not clear whether CVD per se increases the risk of dementia or whether the association is due to shared risk factors. We tested how a genetic risk score (GRS) for coronary artery disease (CAD) affects dementia risk after CVD in 13 231 Swedish twins. We also utilized summarized genome-wide association data to study genetic overlap between CAD and Alzheimer´s disease (AD), and additionally between shared risk factors and each disease. There was no direct effect of a CAD GRS on dementia (hazard ratio 0.99, 95% confidence interval (CI): 0.98-1.01). However, the GRS for CAD modified the association between CVD and dementia within 3 years of CVD diagnosis, ranging from a hazard ratio of 1.59 (95% CI: 1.05-2.41) in the first GRS quartile to 1.91 (95% CI: 1.28-2.86) in the fourth GRS quartile. Using summary statistics, we found no genetic overlap between CAD and AD. We did, however, find that both AD and CAD share a significant genetic overlap with lipids, but that the overlap arose from clearly distinct gene clusters. In conclusion, genetic susceptibility to CAD was found to modify the association between CVD and dementia, most likely through associations with shared risk factors.

Short telomere length is associated with impaired cognitive performance in European ancestry cohorts.

The association between telomere length (TL) dynamics on cognitive performance over the life-course is not well understood. This study meta-analyses observational and causal associations between TL and six cognitive traits, with stratifications on APOE genotype, in a Mendelian Randomization (MR) framework. Twelve European cohorts (N=17 052; mean age=59.2±8.8 years) provided results for associations between qPCR-measured TL (T/S-ratio scale) and general cognitive function, mini-mental state exam (MMSE), processing speed by digit symbol substitution test (DSST), visuospatial functioning, memory and executive functioning (STROOP). In addition, a genetic risk score (GRS) for TL including seven known genetic variants for TL was calculated, and used in associations with cognitive traits as outcomes in all cohorts. Observational analyses showed that longer telomeres were associated with better scores on DSST (ß=0.051 per s.d.-increase of TL; 95% confidence interval (CI): 0.024, 0.077; P=0.0002), and MMSE (ß=0.025; 95% CI: 0.002, 0.047; P=0.03), and faster STROOP (ß=-0.053; 95% CI: -0.087, -0.018; P=0.003). Effects for DSST were stronger in APOE ɛ4 non-carriers (ß=0.081; 95% CI: 0.045, 0.117; P=1.0 × 10-5), whereas carriers performed better in STROOP (ß=-0.074; 95% CI: -0.140, -0.009; P=0.03). Causal associations were found for STROOP only (ß=-0.598 per s.d.-increase of TL; 95% CI: -1.125, -0.072; P=0.026), with a larger effect in ɛ4-carriers (ß=-0.699; 95% CI: -1.330, -0.069; P=0.03). Two-sample replication analyses using CHARGE summary statistics showed causal effects between TL and general cognitive function and DSST, but not with STROOP. In conclusion, we suggest causal effects from longer TL on better cognitive performance, where APOE ɛ4-carriers might be at differential risk.

Serum selenium in relation to measures of glucose metabolism and incidence of Type 2 diabetes in an older Swedish population.

AIMS: The relation between selenium status and risk of Type 2 diabetes is controversial. We aimed to evaluate associations of serum selenium, a marker of dietary selenium, with measures of glucose metabolism and risk of diabetes. METHODS: We used data from a population-based, longitudinal cohort of 1925 Swedish men who were 50 years old and did not have diabetes at baseline in the 1970s. At baseline, an intravenous glucose tolerance test was performed and, at a follow-up examination after 20 years, an oral glucose tolerance test and a hyperinsulinaemic euglycaemic clamp for the assessment of insulin sensitivity were conducted. RESULTS: At baseline, the mean (standard deviation) selenium concentration was 75.6 (14.3) µg/l. During 20 years of follow-up, 88 incident cases of diabetes occurred in 1024 participants with follow-up data. Baseline serum selenium levels were not associated with risk of diabetes (odds ratio 1.06; 95% CI 0.83-1.38). Higher selenium levels were associated with lower early insulin response (standardized ß -0.08; 95% CI -0.14 to -0.03) at baseline after adjusting for potential confounders, but not with any other measures of ß-cell function or insulin sensitivity at baseline or follow-up. The association with early insulin response was non-significant after taking multiple testing into account. CONCLUSIONS: Our results do not support a role of dietary selenium in the development of disturbances in glucose metabolism or diabetes in older individuals.

Variation in genes in the endothelin pathway and endothelium-dependent and endothelium-independent vasodilation in an elderly population.

AIM: Indirect evidences by blockade of the endothelin receptors have suggested a role of endothelin in endothelium-dependent vasodilation. This study aimed to investigate whether circulating levels of endotehlin-1 or genetic variations in genes in the endothelin pathway were related to endothelium-dependent vasodilation. METHODS: In 1016 seventy-year-old participants of the population-based Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study (52% women), we measured endothelium-dependent vasodilation using the invasive forearm technique with acetylcholine given in the brachial artery (EDV) and the brachial artery ultrasound technique with measurement of flow-mediated dilatation (FMD). Plasma endothelin-1 levels were measured and 60 SNPs in genes in the endothelin pathway (ECE1, EDN1, EDNRA, EDNRB) were genotyped. RESULTS: No significant associations were found between circulating endothelin levels and EDV or FMD. No single genotype was related to EDV or FMD following adjustment for multiple testing, but a genotype score for 3 SNPs (rs11618266 in EDNRB, rs17675063 in EDNRA, rs3026868 in ECE1) was significantly related to EDV (beta coefficient 0.070, 95% CI 0.025-0.12, P = 0.002) when adjusting for gender, systolic blood pressure, HDL and LDL cholesterol, serum triglycerides, BMI, diabetes, smoking, antihypertensive medication or statins and CRP. This score was also related to nitroprusside-induced vasodilation in the forearm. CONCLUSION: A combination of genotypes in the endothelin pathway was related to both endothelium-dependent and endothelium-independent vasodilation in forearm resistance vessels, but not in the brachial artery in an elderly population, giving evidence for a role of the endothelin system in resistance vessel reactivity independent of major cardiovascular risk factors.

Utilization pattern of metamizole in northern Sweden and risk estimates of agranulocytosis.

OBJECTIVE: This study was carried out in order to investigate the utilization pattern of metamizole to better estimate the quantitative risk of agranulocytosis since a cluster of such cases have been observed in Sweden. METHODS: Cases of agranulocytosis submitted to the Swedish Adverse Drug Reactions Advisory Committee (SADRAC) between 1996 and 1999 were identified. Based on the utilization pattern of metamizole in inpatients at three hospitals and in outpatients in two counties in northern Sweden risk estimates of agranulocytosis during metamizole treatment were estimated. The utilization of metamizole was investigated by scanning 3567 case records at 10 hospital departments as well as stored prescriptions at six pharmacies during a 3-month study period. RESULTS: Ten cases of agranulocytosis during treatment with metamizole have been reported to SADRAC over the period 1996 to 1999. During the 3-month study period metamizole was prescribed to 666 (19%) inpatients. Of these, approximately 96% received the drug for less than 1 week, 7.2% had used the drug previously. At the participating pharmacies 112 metamizole prescriptions for outpatients were found. The drug was prescribed in 34% for less than 1 week, in 28% for 7-15 days, and in 38% for more than 15 days. The mean prescribed daily dose was 2.7 g. Given certain assumptions including the actual amounts prescribed the calculated risks of agranulocytosis would be approximately one out of every 31,000 metamizole-treated inpatients and one of every 1400 metamizole-treated outpatients. CONCLUSION: This study indicates that in most inpatients the use of metamizole in northern Sweden was within the approved indications for the drug. However, a considerable number of outpatients received the drug for a longer time than recommended and this may carry an increased risk for developing agranulocytosis.

Olanzapine disposition in humans is unrelated to CYP1A2 and CYP2D6 phenotypes.

OBJECTIVE: Limited data suggest that CYP1A2 and CYP2D6 are involved in the metabolism of olanzapine. The purpose of this study was to further elucidate the role of these enzymes in the disposition of olanzapine in vivo. METHODS: Seventeen healthy non-smoking male volunteers were included in the study. Five subjects were CYP2D6 poor metabolisers (PMs), and 12 were CYP2D6 extensive metabolisers (EMs). All subjects received a single oral dose of 7.5 mg olanzapine, and serum concentrations were measured for 96 h using gas chromatography. A cross-over study was undertaken in the 12 CYP2D6 EMs who at least 2 weeks before or after the olanzapine dose received a single oral dose of 200 mg caffeine. The concentrations of caffeine and paraxanthine were measured in saliva 10 h after caffeine intake, and the paraxanthine/caffeine ratio was calculated as a measure of CYPIA2 activity. RESULTS: A threefold inter-individual variability in oral clearance (CLoral) and maximum serum concentration (Cmax) of olanzapine was observed and a 2.3-fold inter-individual variability in CYPIA2 activity. There was no significant correlation between CYP1A2 activity and oral clearance of olanzapine (r=-0.19, P=0.56). Moreover, there were no significant differences in any of the olanzapine pharmacokinetic parameters between the CYP2D6 PMs and EMs (CLoral=0.246 l h(-1) kg(-1) and 0.203 l h(-1) kg(-1), respectively, P=0.30). CONCLUSION: Neither CYP1A2 nor CYP2D6 seem to have a dominating role in olanzapine biotransformation after intake of a single dose.

Myocarditis related to clozapine treatment.

Myocarditis has in several case reports been associated with use of clozapine. Eight cases of myocarditis during treatment with clozapine that were submitted to the Swedish Adverse Drug Reaction Advisory Committee and 18 cases that were reported in the literature are summarized. As part of the routine signal detection process on the World Health Organization (WHO) Program on International Drug Monitoring database, which contains more than two million case reports of spontaneously reported suspected adverse drug reactions, a Bayesian confidence propagation neural network (BCPNN) is used. This article also shows the retrospective output of the BCPNN over time for clozapine and myocarditis and discusses its implications. In 19 (79%; duration of treatment not stated for 2 patients) of 24 patients with myocarditis, the symptoms occurred within the first 6 weeks of clozapine treatment. Many patients shared a similar clinical course, with symptoms such as an influenza-like illness, fever, sinus tachycardia, hypotension, chest discomfort, and heart failure. The reaction was fatal in 12 (46%) of these patients. The other patients generally had a prompt recovery. By using the BCPNN technique, a quantitative association between clozapine and myocarditis was demonstrated, and the association might have been high-lighted for clinical review in 1994 had this BCPNN method been in use at the WHO center at the time. Myocarditis seems to be a rare and potentially lethal adverse effect of clozapine. Admittance for observation, interruption of the clozapine treatment, and treatment with corticosteroids should be considered for patients in whom this reaction is suspected.

Influence of gender and oral contraceptives on CYP2D6 and CYP2C19 activity in healthy volunteers.

AIMS: The study was carried out in order to assess the effects of gender and the use of oral contraceptives (OCs) on CYP2D6 and CYP2C19 activities in healthy volunteers. METHODS: Six hundred and eleven Caucasian volunteers (330 males and 281 females; age range 18-49 years) were phenotyped with respect to CYP2D6 and CYP2C19 by means of the probe drugs dextromethorphan and mephenytoin, respectively. Extensive metabolisers were selected for this study. RESULTS: The median dextromethorphan/dextrorphan metabolic ratio in non-OC using females was significantly lower than in males (0.067 vs 0.080; P = 0.033) (mean difference in ln dextromethorphan/dextrorphan metabolic ratio 0.023, 95% CI 0.03-0.43). For the mephenytoin S/R ratio, no such difference was observed. However, OC using females had a significantly higher median mephenytoin S/R ratio than non-OC using females (0.230 vs 0.090; P < 0.001) (mean difference in ln mephenytoin S/R ratio 0.082, 95% CI 0.60-1.04). Moreover, females using combined OCs had a significantly higher median ratio than females using OCs with progestins only (median 0.258 vs 0.135; P = 0.008) (mean difference in ln mephenytoin S/R ratio 0.82, 95% CI 0.21-1.34). CONCLUSIONS: Given certain assumptions, the study indicates that females in the fertile age have a slightly higher CYP2D6 activity compared with males. There was no evidence of a gender difference in CYP2C19 activity. The use of combined OCs reduces the activity of CYP2C19, an effect that seems to be related to the ethinyloestradiol component.

The major fluvoxamine metabolite in urine is formed by CYP2D6.

OBJECTIVE: Previous studies have shown that fluvoxamine is metabolized by CYP1A2 and CYP2D6, but there is no information on the impact the various CYP enzymes have on the different metabolic pathways of fluvoxamine biotransformation. The present study was designed to investigate this issue. METHODS: The major fluvoxamine metabolite, the 5-demethoxylated carboxylic acid metabolite, was analyzed in urine from 50 healthy volunteers after intake of a single oral dose of 50 mg fluvoxamine, and the formation clearance for the metabolite (CLm) was calculated. Of the subjects, 28 were non-smoking CYP2D6 and CYP2C19 extensive metabolizers (EMs), 12 were smokers and were thus considered to have an induced CYP1A2 activity, 5 were CYP2D6 poor metabolizers (PMs), and 5 were CYP2C19 PMs. In 11 of the non-smoking EMs, 200 mg caffeine was given at another occasion in order to calculate oral caffeine clearance as a measure of CYP1A2 activity. In addition, CLm was calculated in ten other subjects given increasing doses of fluvoxamine for 4 weeks. RESULTS: Oral clearance of fluvoxamine was significantly higher in smokers, and significantly lower in CYP2D6 PMs than in non-smoking EMs. CLm was 78% lower in CYP2D6 PMs than in the EMs. Smoking and being a CYP2C19 PM did not influence CLm. There was no significant correlation between oral caffeine clearance and CLm. CLm decreased with increasing fluvoxamine dosage, but the decrease in oral clearance was even higher. CONCLUSION: These results indicate that CYP2D6 catalyzes the major metabolic pathway of fluvoxamine, whereas CYP1A2 seems to catalyze other less important pathways. Both the CYP2D6 and the CYP1A2 pathways seem to be saturated in parallel with increasing fluvoxamine dosage.

Leptin concentrations are increased in subjects treated with clozapine or conventional antipsychotics.

BACKGROUND: Overweight is a considerable clinical problem in patients treated with antipsychotic agents. Recent results suggest that insulin resistance with increased insulin levels is also associated with treatment with the atypical antipsychotic agent clozapine. Leptin is important for the control of body weight and has been proposed to be a link between obesity and the insulin resistance syndrome. This study examined if clozapine-treated subjects and subjects treated with conventional antipsychotics had increased leptin levels compared with the general population and whether there was a gender difference in this respect. METHOD: Clozapine-treated patients (N = 41), patients treated with conventional antipsychotic drugs (N = 62), and healthy subjects from the Northern Sweden Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) project (N = 189) were investigated with a cross-sectional study design. Weight, body mass index (BMI), and plasma leptin concentrations were measured, and all study subjects were investigated for the presence of diabetes mellitus. Drug treatment, health status, and smoking habits were registered. RESULTS: After adjustment for gender, BMI, smoking habits, age, and diabetes, hyperleptinemia was independently (p < .001) associated with clozapine treatment and with treatment with conventional antipsychotics (p < .005) within a multiple regression analysis. In separate multiple regression analyses, leptin levels were significantly associated with clozapine treatment in men (p = .002) and women (p =.023) and with conventional antipsychotic treatment in men (p = .027) but not in women. CONCLUSION: Treatment with clozapine as well as with conventional antipsychotics is associated with increased levels of circulating leptin. Hyperleptinemia can be an important link in the development of overweight and the insulin resistance syndrome in subjects receiving antipsychotic drugs, especially atypical agents like clozapine.

Analgesics and breast-feeding: safety considerations.

The issue of prescription of analgesics during lactation is clinically important but also complex. Most of the information available is based on single dose or short term studies, and for many drugs only a single or a few case reports have been published. As great methodological problems exist in the assessment of possible adverse drug reactions in neonates and infants, there is limited knowledge about the practical impact of the, often very low, concentrations found. Nevertheless, some recommendations can be made. Breast-feeding during maternal treatment with paracetamol (acetaminophen) should be regarded as being safe. Short term use of nonsteroidal anti-inflammatory drugs seems to be compatible with breast-feeding. For long term treatment, short-acting agents without active metabolites, such as ibuprofen, should possibly be preferred. The use of aspirin (acetylsalicylic acid) in single doses should not pose any significant risks to the suckling infant. Use of codeine is probably compatible with breast-feeding, although the effects of long term exposure have not been fully elucidated. For propoxyphene, it seems unlikely that the suckling infant will ingest amounts that will cause any detrimental effects during short term treatment. However, it cannot be excluded that significant amounts of the metabolite norpropoxyphene may arise in the suckling infant during long term exposure. Treatment of the mother with single doses of morphine or pethidine (meperidine) is not expected to cause any risk for the suckling infant. Repeated administration of pethidine, in contrast to morphine, affects the suckling infant negatively. Thus, morphine should be preferred in lactating mothers. However, during long term treatment with morphine, the importance of uninterrupted breast-feeding should be assessed on an individual basis against the potential risk of adverse drug effects in the infant. If it is decided to continue breast-feeding the infant should be observed for possible adverse effects. In general, if treatment of a lactating mother with an analgesic drug is considered necessary, the lowest effective maternal dose should be given. Moreover, infant exposure can be further reduced if breast-feeding is avoided at times of peak drug concentration in milk. As breast milk has considerable nutritional, immunological and other advantages over formula milk, the possible risks to the infant should always, and on an individual basis, be carefully weighed against the benefits of continuing breast-feeding.

Anticonvulsant use during lactation.

The issue of prescribing anticonvulsant drugs during lactation is clinically important, but also complex. Data for some drugs are completely lacking and for other drugs information is only available from single dose or short term studies or case reports. Moreover, limited knowledge exists about the practical impact of the drug concentrations found in breast milk and there are great methodological problems in the assessment of possible adverse drug reactions in infants. Nevertheless, based on current knowledge, some recommendations can be suggested. Treatment with carbamazepine, valproic acid (sodium valproate) and phenytoin is considered compatible with breastfeeding. Treatment with ethosuximide or phenobarbital (phenobarbitone)/primidone should most probably be regarded as potentially unsafe and close clinical monitoring of the infant is recommended if it is decided to continue breastfeeding. Occasional or short term treatment with benzodiazepines could be considered as compatible with breastfeeding, although maternal diazepam treatment has caused sedation in suckling infants after short term use. During long term use of benzodiazepines, infants should be observed for signs of sedation and poor suckling. Only very limited clinical data are available for the new generation anticonvulsant drugs and no clearcut recommendations can be made until further data are present. If it is decided to continue breast feeding during treatment with these drugs, the infant should be monitored for possible adverse effects. In general, the drug should be given in the lowest effective dose, guided by maternal serum or plasma drug concentration monitoring. If breast feeding is avoided at times of peak drug levels in milk, the exposure of the infant can be reduced to some extent. As breast milk has considerable advantages over formula milk, the benefits of continuing breast feeding should always be taken into consideration in the risk-benefit analysis.

Association of venous thromboembolism and clozapine.

Data from the Swedish Adverse Reactions Advisory Committee suggest that use of clozapine is associated with venous thromboembolic complications. We summarise 12 cases of thromboembolism during clozapine treatment. In five cases the outcome was fatal.