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Importance and objective: Self-reported caffeine consumption has been widely used in research while it may be subject to bias. We sought to investigate the associations between self-reported caffeine consumption and plasma levels of caffeine and its two main metabolites (paraxanthine and theophylline) in the community. Methods: Data from two population-based studies (SKIPOGH1 and 2 (N = 1246) and CoLaus|PsyCoLaus (N = 4461)) conducted in Switzerland were used. Self-reported caffeine consumption was assessed using questionnaires. Plasma levels of caffeine and its metabolites were quantified by ultra-high performance liquid chromatography coupled to a tandem quadrupole mass spectrometer. Results: In both studies, mean log plasma levels of caffeine and its two metabolites were over 6.48 (plasma levels = 652 ng/ml) when no caffeine consumption was reported. Subsequently, nonlinear associations between log plasma levels and self-reported caffeine consumption were observed in SKIPOGH, with a change of the slope at 3–5 cups of espresso per day in SKIPOGH1 but not SKIPOGH2. In CoLaus|PsyCoLaus, increased daily consumption of caffeinated beverages was associated with increased log plasma levels with a change of the slope at 3 cups. In both studies, declared caffeine consumption higher than 3–5 cups per day was not associated with higher plasma levels of caffeine and its metabolites. Conclusion: Self-reports of no or low caffeine consumption and consumption of more than 3–5 cups of coffee should be interpreted with caution, with possible under- or over-estimation. Quantifying plasma levels of caffeine and its metabolites may contribute to a better estimation of caffeine intake. [ABSTRACT FROM AUTHOR]

Purpose: The objectives of this study were (1) to estimate caffeine intake and identify the main sources of intake using a dietary questionnaire, (2) to assess 24-h urinary excretion of caffeine and its metabolites, and (3) to assess how self-reported intake estimates correlates with urinary excretion among children in Switzerland. Methods: We conducted a cross-sectional study of children between 6 and 16 years of age in one region of Switzerland. The participants filled in a dietary questionnaire and collected a 24-h urine sample. Caffeine intake was estimated with the questionnaire. Caffeine, paraxanthine, theophylline, and theobromine excretions were measured in the urine sample. Correlations between questionnaire-based intake and urinary excretion estimates were assessed using Spearman correlation coefficients. Results: Ninety-one children were included in the analysis (mean age 10.6 years; 43% female). The mean daily caffeine intake estimate derived from the diet questionnaire was 39 mg (range 0–237), corresponding, when related to body weight, to 1.2 mg/kg (range 0.0–6.3). Seven children (8%) had a caffeine intake above the upper recommended level of 3 mg/kg per day. The main sources of caffeine intake were cocoa milk (29%), chocolate (25%), soft drinks (11%), mocha yogurt (10%), tea (8%), and energy drinks (8%). The 24-h urinary excretion of caffeine was 0.3 mg (range 0.0–1.5), paraxanthine 1.4 mg (range 0.0–7.1), theophylline 0.1 mg (range 0.0–0.6), and theobromine 14.8 mg (range 0.3–59.9). The correlations between estimates of caffeine intake and the 24-h urinary excretion of caffeine was modest (ρ = 0.21, p = 0.046) and with the metabolites of caffeine were weak (ρ = 0.09–0.11, p = 0.288–0.423). Conclusions: Caffeine intake in a sample of children in a region of Switzerland was relatively low. The major sources of intake were cocoa milk, chocolate and soft drinks. Self-reported caffeine intake correlated weakly with urinary excretion of caffeine and some of its main metabolites. Trial registration number: NCT02900261. [ABSTRACT FROM AUTHOR]

Background: Caffeine intake is generally estimated by self-reported consumption, but it remains unclear how well self-report associates with metabolite urinary excretion. We investigated the associations of self-reported consumption of caffeinated drinks with urinary excretion of caffeine and its major metabolites in an adult population. Methods: We used data from the population-based Swiss Kidney Project on Genes in Hypertension (SKIPOGH) study. Consumption of caffeinated coffee, decaffeinated coffee and other caffeinated beverages was assessed by self- administered questionnaire. Quantification of caffeine, paraxanthine, theobromine and theophylline was performed by ultra-high performance liquid chromatography tandem mass spectrometry in 24-h urine. Association of reported consumption of caffeinated drinks with urinary caffeine derived metabolites was determined by quantile regression. We then explored the association between urinary metabolite excretion and dichotomized weekly consumption frequency of caffeinated coffee, with Receiver Operator Characteristic (ROC) analysis. Results: In the present analysis, we included 598 individuals (52% women, mean age =46 ± 17 years). Self-reported caffeinated coffee intake was positively associated with 24-h urinary excretions of paraxanthine, theophylline and caffeine (p < 0.001), whereas reported intakes of decaffeinated coffee and other caffeinated beverages showed no association. In ROC analysis, optimal discrimination between individuals consuming less than one caffeinated coffee/ week, vs. at least one coffee, was obtained for 24-h urinary paraxanthine (Area Under Curve (AUC) = 0.868, 95% Confidence Interval (CI) [0.830;0.906]), with slightly lower performance for theophylline and caffeine, whereas theobromine did not allow any discrimination. Conclusion: Our results suggest that reported consumption of caffeinated coffee is positively associated with 24-h urinary excretion of caffeine, paraxanthine, and theophylline, and may be used as a marker of caffeine intake for epidemiological studies. [ABSTRACT FROM AUTHOR]

Abstract: Background: Co-morbid substance misuse is common in psychiatric disorders, has potentially severe adverse consequences and may be frequently undetected. Aims: To measure the prevalence of substance use among patients admitted to a Swiss psychiatric hospital and to examine the potential utility of routine urine drug screening in this setting. Method: 266 inpatients were included. 238 patients completed the interview and 240 underwent a urine drug screening. Results: Lifetime prevalence of substance use among psychiatric patients was very high for alcohol (98%; 95% CI: 96–100), benzodiazepines (86%; 95% CI: 82–91) and cannabis (53%; 95% CI: 47–60), but also for “hard drugs” like cocaine (25% ; 95% CI: 19–30) or opiates (20%; 95% CI: 15–25). Regular current use of alcohol (32%; 95% CI: 26–38) or cannabis (17%; 95% CI: 12–22) was the most frequent. Substance use was associated with male sex, younger age, unmarried status and nicotine smoking. Urine screening confirms reports from patients on recent use, and remained positive for cannabis during hospitalisation, but not for cocaine nor for opiates. Conclusion: Substance use is frequent among psychiatric patients. Systematic interviewing of patients about their substance use remains essential, and is usually confirmed by urine screening. Urine screening can be useful to provide specific answers about recent use. [Copyright &y& Elsevier]

Patients suffering from mental disorders are at high risk of developing cardiovascular diseases, leading to a reduction in life expectancy. Genetic variants can display greater influence on cardiometabolic features in psychiatric cohorts compared to the general population. The difference is possibly due to an intricate interaction between the mental disorder or the medications used to treat it and metabolic regulations. Previous genome wide association studies (GWAS) on antipsychotic-induced weight gain included a low number of participants and/or were restricted to patients taking one specific antipsychotic. We conducted a GWAS of the evolution of body mass index (BMI) during early (i.e., ≤ 6) months of treatment with psychotropic medications inducing metabolic disturbances (i.e., antipsychotics, mood stabilizers and some antidepressants) in 1135 patients from the PsyMetab cohort. Six highly correlated BMI phenotypes (i.e., BMI change and BMI slope after distinct durations of psychotropic treatment) were considered in the analyses. Our results showed that four novel loci were associated with altered BMI upon treatment at genome-wide significance (p < 5 × 10 -8 ): rs7736552 (near MAN2A1), rs11074029 (in SLCO3A1), rs117496040 (near DEFB1) and rs7647863 (in IQSEC1). Associations between the four loci and alternative BMI-change phenotypes showed consistent effects. Replication analyses in 1622 UK Biobank participants under psychotropic treatment showed a consistent association between rs7736552 and BMI slope (p = 0.017). These findings provide new insights into metabolic side effects induced by psychotropic drugs and underline the need for future studies to replicate these associations in larger cohorts., (© 2023. The Author(s).)

Study Objectives: Insomnia disorders as well as cardiometabolic disorders are highly prevalent in the psychiatric population compared to the general population. We aimed to investigate their association and evolution over time in a Swiss psychiatric cohort., Methods: Data for 2861 patients (8954 observations) were obtained from two prospective cohorts (PsyMetab and PsyClin) with metabolic parameters monitored routinely during psychotropic treatment. Insomnia disorders were based on the presence of ICD-10 "F51.0" diagnosis (non-organic insomnia), the prescription of sedatives before bedtime or the discharge letter. Metabolic syndrome was defined using the International Diabetes Federation definition, while the 10-year risk of cardiovascular event or death was assessed using the Framingham Risk Score and the Systematic Coronary Risk Estimation, respectively., Results: Insomnia disorders were observed in 30% of the cohort, who were older, predominantly female, used more psychotropic drugs carrying risk of high weight gain (olanzapine, clozapine, valproate) and were more prone to suffer from schizoaffective or bipolar disorders. Multivariate analyses showed that patients with high body mass index (OR = 2.02, 95%CI [1.51-2.72] for each ten-kg/m 2 increase), central obesity (OR = 2.20, [1.63-2.96]), hypertension (OR = 1.86, [1.23-2.81]), hyperglycemia (OR = 3.70, [2.16-6.33]), high density lipoprotein hypocholesterolemia in women (OR = 1.51, [1.17-1.95]), metabolic syndrome (OR = 1.84, [1.16-2.92]) and higher 10-year risk of death from cardiovascular diseases (OR = 1.34, [1.17-1.53]) were more likely to have insomnia disorders. Time and insomnia disorders were associated with a deterioration of cardiometabolic parameters., Conclusions: Insomnia disorders are significantly associated with metabolic worsening and risk of death from cardiovascular diseases in psychiatric patients., (© 2022. The Author(s).)

Objective: To investigate the relations between caffeine-derived metabolites (methylxanthines) and plasma lipids by use of population-based data from 2 European countries., Methods: Families were randomly selected from the general population of northern Belgium (FLEMENGHO), from August 12, 1985, until November 22, 1990, and 3 Swiss cities (SKIPOGH), from November 25, 2009, through April 4, 2013. We measured plasma concentrations (FLEMENGHO, SKIPOGH) and 24-hour urinary excretions (SKIPOGH) of 4 methylxanthines-caffeine, paraxanthine, theobromine, and theophylline-using ultra-high-performance liquid chromatography-tandem mass spectrometry. We used enzymatic methods to estimate total cholesterol, high-density lipoprotein cholesterol, and triglyceride levels and the Friedewald equation for low-density lipoprotein cholesterol levels in plasma. We applied sex-specific mixed models to investigate associations between methylxanthines and plasma lipids, adjusting for major confounders., Results: In both FLEMENGHO (N=1987; 1055 [53%] female participants) and SKIPOGH (N=990; 523 [53%] female participants), total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels increased across quartiles of plasma caffeine, paraxanthine, and theophylline (total cholesterol levels by caffeine quartiles in FLEMENGHO, male participants: 5.01±0.06 mmol/L, 5.05±0.06 mmol/L, 5.27±0.06 mmol/L, 5.62±0.06 mmol/L; female participants: 5.24±0.06 mmol/L, 5.15±0.05 mmol/L, 5.25±0.05 mmol/L, 5.42±0.05 mmol/L). Similar results were observed using urinary methylxanthines in SKIPOGH (total cholesterol levels by caffeine quartiles, male participants: 4.54±0.08 mmol/L, 4.94±0.08 mmol/L, 4.87±0.08 mmol/L, 5.27±0.09 mmol/L; female participants: 5.12±0.07 mmol/L, 5.21±0.07 mmol/L, 5.28±0.05 mmol/L, 5.28±0.07 mmol/L). Furthermore, urinary caffeine and theophylline were positively associated with high-density lipoprotein cholesterol in SKIPOGH male participants., Conclusion: Plasma and urinary caffeine, paraxanthine, and theophylline were positively associated with plasma lipids, whereas the associations involving theobromine were less clear. We postulate that the positive association between caffeine intake and plasma lipids may be related to the sympathomimetic function of methylxanthines, mitigating the overall health-beneficial effect of caffeine intake., (Copyright © 2021 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Background: Psychiatric patients are known to be at high risk of developing cardiovascular diseases (CVDs), leading to an increased mortality rate., Objective: To assess the CVD risk (presence of metabolic syndrome [MetS] and calculated 10-year CVD risk) in a Swiss psychiatric cohort taking weight gain-inducing psychotropic drugs, compare the findings to a Swiss population-based cohort, and evaluate the prevalence of participants treated for metabolic disruptions in both cohorts., Methods: Data for 1,216 psychiatric patients (of whom 634 were aged 35-75 years) were obtained between 2007 and 2017 from a study with metabolic parameters monitored during psychotropic treatment and between 2003 and 2006 for 6,733 participants from the population-based CoLaus|PsyCoLaus study., Results: MetS as defined by the International Diabetes Federation (IDF) was identified in 33% of the psychiatric participants and 24.7% of the population-based subjects. Specifically, prevalence per the IDF definition was more than 3 times higher in the psychiatric cohort among women aged 35 to 49 years (25.6% vs 8.0%; P < 10-4). The psychiatric and population-based cohorts, respectively, had comparable predicted CVD risk (10-year risk of CVD event > 20%: 0% vs 0.1% in women and 0.3% vs 1.8% [P = .01] in men; 10-year risk of CVD death > 5%: 8.5% vs 8.4% [P = .58] in women and 13.4% vs 16.6% [P = .42] in men). No difference was observed among the proportion of participants with MetS treated for metabolic disturbances in the two cohorts, with the exception of women aged 35-49 years, for whom those in the psychiatric cohort were half as likely to receive treatment compared to participants in CoLaus|PsyCoLaus (17.8% vs 38.8% per the IDF definition; P = .0004)., Conclusions: These findings emphasize the concern that psychiatric patients present an altered metabolic profile and that they do not receive adequate treatment for metabolic disruptions. Presence of metabolic disturbances should be routinely assessed, and adequate follow-up is needed to intervene early after illness onset., (© Copyright 2020 Physicians Postgraduate Press, Inc.)

The severity of symptoms as well as efficacy of antidepressants in major depressive disorder (MDD) is modified by single nucleotide polymorphisms (SNPs) in different genes, which may contribute in an additive or synergistic fashion. We aimed to investigate depression severity in participants with MDD under treatment with antidepressants in relation to the combinatory effect of selected genetic variants combined using a genetic risk score (GRS). The sample included 150 MDD patients on regular AD therapy from the population-based Swiss PsyCoLaus cohort. We investigated 44 SNPs previously associated with antidepressant response by ranking them with regard to their association to the Center for Epidemiologic Studies Short Depression Scale (CES-D) score using random forest. The three top scoring SNPs (rs12248560, rs878567, rs17710780) were subsequently combined into an unweighted GRS, which was included in linear and logistic regression models using the CES-D score, occurrence of a major depressive episode (MDE) during follow-up and regular antidepressant treatment during the 6 months preceding follow-up assessment as outcomes. The GRS was associated with MDE occurrence (p = .02) and ln CES-D score (p = .001). The HTR1A rs878567 variant was associated with ln CES-D after adjustment for demographic and clinical variables [p = .02, lower scores for minor allele (G) carriers]. Additionally, rs12248560 (CYP2C19) CC homozygotes showed a six-fold higher likelihood of regular AD therapy at follow-up compared to minor allele homozygotes [TT; ultrarapid metabolizers (p = .03)]. Our study suggests that the cumulative consideration of pharmacogenetic risk variants more reliably reflects the impact of the genetic background on depression severity than individual SNPs., (© 2019 The Authors. Drug Development Research published by Wiley Periodicals, Inc.)

Caffeine is a natural psychostimulant with a potentially positive impact on health when consumed in moderation and a negative impact at high dose (> 400 mg/day). So far, no study has examined self-reported caffeine consumption in Switzerland. Our objectives were to determine 1) the caffeine consumption per adult, 2) the main sources of caffeine intake in the Swiss diet, and 3) the timing of caffeine consumption during the day. We used data from the 2014-2015 national nutrition survey menuCH (adults aged 18 to 75 years old, n = 2057, weighted n = 4,627,878), consisting of two 24-hour dietary recalls. Caffeine content in consumed foods was systematically assessed using laboratory analyses in samples of Swiss caffeinated beverages, information from food composition databases, and estimations from standard recipes. Mean (± SD) daily caffeine consumption per person and percentile 95 were 191 mg/day (± 129) and 426 mg/day, respectively. We observed differences in mean caffeine consumption across age groups (18-34 y: 140 mg/day; 50-64 y: 228 mg/day), linguistic regions (German-speaking: 204 mg/day; French-speaking: 170 mg/day, Italian-speaking: 136 mg/day), and smoking status (never smokers: 171 mg/day; current smokers: 228 mg/day). The three main sources of caffeine intake were 1) coffee (83% of total caffeine intake), 2) tea (9%) and 3) soft drinks (4%). Caffeine consumption was highest between 06:00 and 09:00 (29%) and the circadian rhythm slightly differed across linguistic regions and age groups. The mean caffeine consumption in the Swiss adult population was similar to that reported in neighbouring countries., Competing Interests: The authors declare no conflict of interest.

New-onset diabetes mellitus after transplantation (NODAT) is a complication following solid organ transplantation (SOT) and may be related to immune or inflammatory responses. We investigated whether single nucleotide polymorphisms (SNPs) within 158 immune- or inflammation-related genes contribute to NODAT in SOT recipients. The association between 263 SNPs and NODAT was investigated in a discovery sample of SOT recipients from the Swiss Transplant Cohort Study (STCS, n 1  = 696). Positive results were tested in a first STCS replication sample (n 2  = 489) and SNPs remaining significant after multiple test corrections were tested in a second SOT replication sample (n 3  = 156). Associations with diabetic traits were further tested in several large general population-based samples (n > 480 000). Only SP110 rs2114592C>T remained associated with NODAT in the STCS replication sample. Carriers of rs2114592-TT had 9.9 times (95% confidence interval [CI]: 3.22-30.5, P = .00006) higher risk for NODAT in the combined STCS samples (n = 1184). rs2114592C>T was further associated with NODAT in the second SOT sample (odds ratio: 4.8, 95% CI: 1.55-14.6, P = .006). On the other hand, SP110 rs2114592C>T was not associated with diabetic traits in population-based samples, suggesting a specific gene-environment interaction, possibly due to the use of specific medications (ie, immunosuppressants) in transplant patients and/or to the illness that may unmask the gene effect., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Objectives: This retrospective study aims to evaluate off-label prescriptions and administrations of psychotropic medications in adolescents in a university psychiatric hospital in Switzerland., Methods: Data were collected during the entire stays from the electronic database for 76 inpatients in 2008 and 76 inpatients in 2014. Data collected included gender, age, psychiatric diagnosis, duration of hospitalization, and psychotropic drug prescriptions and administrations., Results: A total of 224 psychotropic drugs (mean 2.9 drugs/patient) were prescribed in 2008 and 268 (mean 3.5 drugs/patient) in 2014. Due to the prescriptions of some drugs as required, only 76% of the prescriptions were actually administered in 2008 (mean 2.3 drugs/patient) and 55% in 2014 (mean 1.9 drugs/patient). Antipsychotics were the most frequently prescribed drugs in 2008 (74% of patients) and 2014 (86% of patients). Anxiolytics were also highly prescribed in 2008 (54% of patients) and 2014 (66% of patients), as well as antidepressants in 2008 (30% of patients), but less in 2014 (13% of patients). Overall, 69% of prescriptions were found to be off label in 2008 and 68% in 2014, according to age, diagnosis, dose, or formulation as approved by Swissmedic. The medication classes with the highest rate of off-label prescriptions were antidepressants (100% for both years), antipsychotics (94% in 2008 and 92% in 2014), and hypnotics (67% in 2008 and 100% in 2014). For both study periods, at least one off-label psychotropic drug prescription and administration was recorded in 96% and 79% of the patients, respectively., Conclusion: The high rate of off-label psychotropic drug use strengthens the need for clinical trials to better evaluate the efficacy and safety of these treatments in adolescents.

Purpose: To describe the weight gain-related side-effects of psychotropic drugs and their consequences on metabolic complications (hypercholesterolemia, obesity) in a Swiss cohort of psychiatric patients., Method: This cross-sectional observational study was performed in an out-patient psychiatric division with patients having received for more than 3 months the following drugs: clozapine, olanzapine, quetiapine, risperidone, lithium, and/or valproate. Clinical measures and lifestyle information (smoking behaviour, physical activity) were recorded., Results: 196 inclusions were completed. Weight gain (≥10% of initial weight) following drug treatment was reported in 47% of these patients. Prevalence of obesity (BMI ≥ 30), hypercholesterolemia (≥6.2 mmol/L) and low HDL-cholesterol (<1.0 mmol/L in men, <1.3 mmol/L in women) were present in 38%, 21%, and 27% of patients, respectively. A higher standardised dose, an increase of appetite following medication introduction, the type of medication (clozapine or olanzapine > quetiapine or risperidone > lithium or valproate), and the gender were shown to be significantly associated with evolution of BMI., Conclusion: High prevalence of obesity and hypercholesterolemia was found in an out-patient psychiatric population and confirms drug-induced weight gain complications during long-term treatment. The results support the recently published recommendations of monitoring of metabolic side-effects during treatment with atypical antipsychotics. Moreover, the weight gain predictors found in the present study could help to highlight patients with special health care management requirement., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Purpose: To assess tobacco, alcohol, cannabis and benzodiazepine use in methadone maintenance treatment (MMT) as potential sources of variability in methadone pharmacokinetics., Methods: Trough plasma (R)- and (S)-methadone concentrations were measured on 77 Australian and 74 Swiss MMT patients with no additional medications other than benzodiazepines. Simple and multiple regression analyses were performed for the primary metric, plasma methadone concentration/dose., Results: Cannabis and methadone dose were significantly associated with lower 24-h plasma (R)- and (S)-methadone concentrations/dose. The models containing these variables explained 14-16% and 17-25% of the variation in (R)- and (S)-methadone concentration/dose, respectively. Analysis of 61 patients using only CYP3A4 metabolised benzodiazepines showed this class to be associated with higher (R)-concentration/dose, which is consistent with a potential competitive inhibition of CYP3A4., Conclusion: Cannabis use and higher methadone doses in MMT could in part be a response to-or a cause of-more rapid methadone clearance. The effects of cannabis and benzodiazepines should be controlled for in future studies on methadone pharmacokinetics in MMT.

Background and Objective: Protease inhibitors are highly bound to orosomucoid (ORM) (alpha1-acid glycoprotein), an acute-phase plasma protein encoded by 2 polymorphic genes, which may modulate their disposition. Our objective was to determine the influence of ORM concentration and phenotype on indinavir, lopinavir, and nelfinavir apparent clearance (CL(app)) and cellular accumulation. Efavirenz, mainly bound to albumin, was included as a control drug., Methods: Plasma and cells samples were collected from 434 human immunodeficiency virus-infected patients. Total plasma and cellular drug concentrations and ORM concentrations and phenotypes were determined., Results: Indinavir CL(app) was strongly influenced by ORM concentration (n = 36) (r2 = 0.47 [P = .00004]), particularly in the presence of ritonavir (r2 = 0.54 [P = .004]). Lopinavir CL(app) was weakly influenced by ORM concentration (n = 81) (r2 = 0.18 [P = .0001]). For both drugs, the ORM1 S variant concentration mainly explained this influence (r2 = 0.55 [P = .00004] and r2 = 0.23 [P = .0002], respectively). Indinavir CL(app) was significantly higher in F1F1 individuals than in F1S and SS patients (41.3, 23.4, and 10.3 L/h [P = .0004] without ritonavir and 21.1, 13.2, and 10.1 L/h [P = .05] with ritonavir, respectively). Lopinavir cellular exposure was not influenced by ORM abundance and phenotype. Finally, ORM concentration or phenotype did not influence nelfinavir (n = 153) or efavirenz (n = 198) pharmacokinetics., Conclusion: ORM concentration and phenotype modulate indinavir pharmacokinetics and, to a lesser extent, lopinavir pharmacokinetics but without influencing their cellular exposure. This confounding influence of ORM should be taken into account for appropriate interpretation of therapeutic drug monitoring results. Further studies are needed to investigate whether the measure of unbound drug plasma concentration gives more meaningful information than total drug concentration for indinavir and lopinavir.