Identification of four novel loci associated with psychotropic drug-induced weight gain in a Swiss psychiatric longitudinal study: A GWAS analysis.

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.

A population pharmacokinetic model for sertraline in women during the perinatal period-A contribution from the ConcePTION project.

AIMS: Sertraline is frequently prescribed for mental health conditions in both pregnant and breastfeeding women. According to the limited available data, only small amounts of sertraline are transferred into human milk, yet with a large amount of unexplained interindividual variability. This study aimed to develop a population pharmacokinetic (popPK) model to describe the pharmacokinetics of sertraline during the perinatal period and explain interindividual variability. METHODS: Pregnant women treated with sertraline were enrolled in the multicenter prospective cohort SSRI-Breast Milk study. A popPK model for sertraline maternal plasma and breast milk concentrations was developed and allowed estimating the milk-to-plasma ratio (MPR). An additional fetal compartment allowed cord blood concentrations to be described. Several covariates were tested for significance. Ultimately, model-based simulations allowed infant drug exposure through placenta and breast milk under various conditions to be predicted. RESULTS: Thirty-eight women treated with sertraline were included in the study and provided 89 maternal plasma, 29 cord blood and 107 breast milk samples. Sertraline clearance was reduced by 42% in CYP2C19 poor metabolizers compared to other phenotypes. Doubling milk fat content increased the MPR by 95%. Simulations suggested a median daily infant dosage of 6.9 µg kg-1 after a 50 mg maternal daily dose, representing 0.95% of the weight-adjusted maternal dose. Median cord blood concentrations could range from 3.29 to 33.23 ng mL-1 after maternal daily doses between 25 and 150 mg. CONCLUSIONS: Infant exposure to sertraline, influenced by CYP2C19 phenotype and breast milk fat content, remains low, providing reassurance regarding the use of sertraline during pregnancy and breastfeeding.

Therapeutic Drug Monitoring of Olanzapine: Effects of Clinical Factors on Plasma Concentrations in Psychiatric Patients.

BACKGROUND: Therapeutic drug monitoring (TDM) is strongly recommended for olanzapine due to its high pharmacokinetic variability. This study aimed to investigate the impact of various clinical factors on olanzapine plasma concentrations in patients with psychiatric disorders. METHODS: The study used TDM data from the PsyMetab cohort, including 547 daily dose-normalized, steady-state, olanzapine plasma concentrations (C:D ratios) from 248 patients. Both intrinsic factors (eg, sex, age, body weight) and extrinsic factors (eg, smoking status, comedications, hospitalization) were examined. Univariate and multivariable, linear, mixed-effects models were employed, with a stepwise selection procedure based on Akaike information criterion to identify the relevant covariates. RESULTS: In the multivariable model (based on 440 observations with a complete data set), several significant findings emerged. Olanzapine C:D ratios were significantly lower in smokers (ß = -0.65, P < 0.001), valproate users (ß = -0.53, P = 0.002), and inpatients (ß = -0.20, P = 0.025). Furthermore, the C:D ratios decreased significantly as the time since the last dose increased (ß = -0.040, P < 0.001). The male sex had a significant main effect on olanzapine C:D ratios (ß = -2.80, P < 0.001), with significant interactions with age (ß = 0.025, P < 0.001) and body weight (ß = 0.017, P = 0.011). The selected covariates explained 30.3% of the variation in C:D ratios, with smoking status accounting for 7.7% and sex contributing 6.9%. The overall variation explained by both the fixed and random parts of the model was 67.4%. The model facilitated the prediction of olanzapine C:D ratios based on sex, age, and body weight. CONCLUSIONS: The clinical factors examined in this study, including sex, age, body weight, smoking status, and valproate comedication, remarkably influence olanzapine C:D ratios. Considering these factors, in addition to TDM and the clinical situation, could be important for dose adjustment.

Pharmacokinetics and Pharmacodynamics of Inhaled Nicotine Salt and Free-Base Using an E-cigarette: A Randomized Crossover Study.

INTRODUCTION: Popular "pod-style" e-cigarettes commonly use nicotine salt-based e-liquids that cause less irritation when inhaled and can deliver higher nicotine concentrations than free-base nicotine. This study investigated the pharmacokinetic and pharmacodynamic effects of different nicotine formulations (salt vs. free-base) and concentrations that might influence systemic nicotine absorption and appeal of e-cigarettes. AIMS AND METHODS: In this randomized, double-blind, within-subject crossover study, 20 non-nicotine-naïve participants were switched among three e-liquids (free-base nicotine 20 mg/mL, nicotine salt 20 mg/mL, nicotine salt 40 mg/mL) using a refillable pod system and a standardized vaping protocol (one puff every 30 seconds, 10 puffs total). Serum nicotine concentrations and vital signs were assessed over 180 minutes; direct effects, craving, satisfaction, withdrawal, and respiratory symptoms were measured using questionnaires. CYP2A6 genotypes and the nicotine metabolite ratio were also assessed. RESULTS: Eleven (55%) participants were male and the median age was 23.5 years (range 18-67). All three formulations differed significantly in peak serum nicotine concentration (baseline adjusted Cmax, median (range): 12.0 ng/mL (1.6-27.3), 5.4 ng/mL (1.9-18.7), and 3.0 ng/mL (1.3-8.8) for nicotine salt 40 mg/mL, nicotine salt 20 mg/mL and free-base 20 mg/mL, respectively). All groups reached Cmax 2.0-2.5 minutes (median) after their last puff. Differences in subjective effects were not statistically significant. No serious adverse events were observed. CONCLUSIONS: Free-base 20 mg/mL formulations achieved lower blood nicotine concentrations than nicotine salt 20 mg/mL, while 40 mg/mL nicotine salt yielded concentrations similar to cigarette smoking. The findings can inform regulatory policy regarding e-liquids and their potential use in smoking cessation. IMPLICATIONS: Nicotine salt formulations inhaled by an e-cigarette led to higher nicotine delivery compared to nicotine-free-base formulations with the same nicotine concentration. These findings should be considered in future regulatory discussions. The 40 mg/mL nicotine salt formulation showed similar nicotine delivery as combustible cigarettes, albeit at concentrations over the maximum limit for e-liquids allowed in the European Union. Nicotine delivery resembling combustible cigarettes might be beneficial for smokers willing to quit to adequately alleviate withdrawal symptoms. However, increased nicotine delivery can also pose a public health risk, raising concerns about abuse liability, especially among youth and nonsmokers.

Self-reported caffeine consumption miss-matched consumption measured by plasma levels of caffeine and its metabolites: results from two population-based studies.

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.

Insomnia disorders are associated with increased cardiometabolic disturbances and death risks from cardiovascular diseases in psychiatric patients treated with weight-gain-inducing psychotropic drugs: results from a Swiss cohort.

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/m2 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.

An International Adult Guideline for Making Clozapine Titration Safer by Using Six Ancestry-Based Personalized Dosing Titrations, CRP, and Clozapine Levels.

This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas' original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300-600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75-150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175-300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100-200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250-400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150-300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300-600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

[Psychiatry]. / Psychiatrie.

The media often discuss the impact of climate change on physical health, but much less its influence on mental health, although it appears that it is already present and will be major if nothing concrete is done to fight global warming. The role of patients is paramount in psychiatry, not only in defining individual treatment goals, but also as mental health professionals, in the role of Peer Practitioner in Mental Health, and in defining the care policies and therapeutic offer of our public psychiatric institutions. While many psychotropic drugs induce metabolic disorders and weight gain, it is possible to identify from the first month of treatment those at risk of such complications.

L'impact du changement climatique sur la santé physique est régulièrement discuté mais son influence sur la santé mentale l'est beaucoup moins, bien qu'il apparaisse qu'elle est déjà présente et qu'elle sera majeure si rien de concret n'est entrepris pour lutter contre le réchauffement de la planète. Le rôle des patients est primordial en psychiatrie, non seulement pour définir les objectifs de traitement individuel, mais également comme professionnel de la santé mentale, dans le rôle de pair praticien en santé mentale, et dans la définition des politiques de soins et de l'offre théra peutique de nos institutions de psychiatrie publique. Alors que plusieurs psychotropes induisent des troubles métaboliques et une prise de poids, il est possible d'identifier dès le premier mois de traitement les personnes à risque de telles complications.

Effect of Quetiapine, from Low to High Dose, on Weight and Metabolic Traits: Results from a Prospective Cohort Study.

INTRODUCTION: The atypical antipsychotic quetiapine is known to induce weight gain and other metabolic complications. The underlying mechanisms are multifactorial and poorly understood with almost no information on the effect of dosage. Concerns were thus raised with the rise in low-dose quetiapine off-label prescription (i. e.,<150 mg/day). METHODS: In this study, we evaluated the influence of quetiapine dose for 474 patients included in PsyMetab and PsyClin studies on weight and metabolic parameter evolution. Weight, blood pressure, lipid, and glucose profiles were evaluated during a follow-up period of 3 months after treatment initiation. RESULTS: Significant dose-dependent metabolic alterations were observed. The daily dose was found to influence weight gain and increase the risk of undergoing clinically relevant weight gain (≥7% from baseline). It was also associated with a change in plasma levels of cholesterol (total cholesterol, LDL cholesterol, and HDL cholesterol) as well as with increased odds of developing hypertriglyceridemia, as well as total and LDL hypercholesterolemia. No impact of a dose increase on blood pressure and plasma glucose level was observed. DISCUSSION: The dose-dependent effect highlighted for weight gain and lipid alterations emphasizes the importance of prescribing the minimal effective dose. However, as the effect size of a dose increase on metabolic worsening is low, the potential harm of low-dose quetiapine should not be dismissed. Prescriptions must be carefully evaluated and regularly questioned in light of side effect onset.

A population pharmacokinetic model for escitalopram and its major metabolite in depressive patients during the perinatal period: Prediction of infant drug exposure through breast milk.

BACKGROUND AND OBJECTIVES: Escitalopram (SCIT) is frequently prescribed to breastfeeding women. Available information on SCIT excretion into breast milk is based on heterogeneous and incomplete data. A population pharmacokinetic model that aimed to better characterize maternal and infant exposure to SCIT and its metabolite was developed. METHODS: The study population was composed of women treated by SCIT or racemic citalopram and enrolled in the multicenter prospective cohort study SSRI-Breast Milk study (ClinicalTrial.gov NCT01796132). A joint structural model was first built for SCIT and S-desmethylcitalopram (SDCIT) in plasma using NONMEM and the milk-to-plasma ratio (MPR) was estimated by adding the drug breast milk concentrations. The effect of different influential covariates was tested and the average drug exposure with variability through breastfeeding was predicted under various conditions by simulation. RESULTS: The study enrolled 33 patients treated with SCIT or racemic citalopram who provided 80 blood and 104 milk samples. Mean MPR for both parent drug and metabolite was 1.9. Increased milk fat content was significantly associated with an increased drug transfer into breast milk (+28% for SCIT and +18% for SDCIT when fat amount doubles from 3.1 to 6.2 g/100 mL). Simulations suggested that an exclusively breastfed infant would ingest daily through breast milk 3.3% of the weight-adjusted maternal SCIT dose on average. CONCLUSION: The moderate between-subject variability in milk concentration of SCIT and the limited exposure to escitalopram through breast milk observed provide reassurance for treated mothers of breastfed healthy infants.

Monitoring caffeine intake in children with a questionnaire and urine collection: a cross-sectional study in a convenience sample in Switzerland.

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.

A pharmacogenetic risk score for the evaluation of major depression severity under treatment with antidepressants.

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.

Genetic immune and inflammatory markers associated with diabetes in solid organ transplant recipients.

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, n1  = 696). Positive results were tested in a first STCS replication sample (n2  = 489) and SNPs remaining significant after multiple test corrections were tested in a second SOT replication sample (n3  = 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.

Genetic and clinic predictors of new onset diabetes mellitus after transplantation.

New Onset Diabetes after Transplantation (NODAT) is a frequent complication after solid organ transplantation, with higher incidence during the first year. Several clinical and genetic factors have been described as risk factors of Type 2 Diabetes (T2DM). Additionally, T2DM shares some genetic factors with NODAT. We investigated if three genetic risk scores (w-GRS) and clinical factors were associated with NODAT and how they predicted NODAT development 1 year after transplantation. In both main (n = 725) and replication (n = 156) samples the clinical risk score was significantly associated with NODAT (ORmain: 1.60 [1.36-1.90], p = 3.72*10-8 and ORreplication: 2.14 [1.39-3.41], p = 0.0008, respectively). Two w-GRS were significantly associated with NODAT in the main sample (ORw-GRS 2:1.09 [1.04-1.15], p = 0.001 and ORw-GRS 3:1.14 [1.01-1.29], p = 0.03) and a similar ORw-GRS 2 was found in the replication sample, although it did not reach significance probably due to a power issue. Despite the low OR of w-GRS on NODAT compared to clinical covariates, when integrating w-GRS 2 and w-GRS 3 in the clinical model, the Area under the Receiver Operating Characteristics curve (AUROC), specificity, sensitivity and accuracy were 0.69, 0.71, 0.58 and 0.68, respectively, with significant Likelihood Ratio test discrimination index (p-value 0.0004), performing better in NODAT discrimination than the clinical model alone. Twenty-five patients needed to be genotyped in order to detect one misclassified case that would have developed NODAT 1 year after transplantation if using only clinical covariates. To our knowledge, this is the first study extensively examining genetic risk scores contributing to NODAT development.

Escitalopram population pharmacokinetics in people living with human immunodeficiency virus and in the psychiatric population: Drug-drug interactions and probability of target attainment.

AIMS: The aims of this study were to characterize escitalopram pharmacokinetic profile, to identify factors influencing drug exposure, notably drug-drug interactions with antiretrovirals, and to simulate expected exposure under standard dosage regimen. METHODS: A population pharmacokinetic analysis was performed using NONMEM. A total of 159 plasma concentration measurements were obtained from 39 human immunodeficiency virus (HIV)-infected and 71 uninfected psychiatric patients. The influence of age, weight, sex, HIV and psychiatric cohorts, racemic citalopram treatment, and comedications on oral clearance was examined. Simulations served to calculate the percentage of patients expected to be under- or over-exposed, considering established therapeutic targets (15-80 ng/mL). RESULTS: A 1-compartment model with first-order absorption and elimination described the data adequately. The average escitalopram clearance and volume of distribution were 23.1 L/h (interindividual variability 51%), and 920 L, respectively. Escitalopram disposition did not differ between HIV-infected and uninfected patients, and was not affected by antiretroviral treatments. Coadministration of at least 1 proton-pump inhibitor (CYP2C19 inhibitor) modestly influenced escitalopram elimination (clearance decreased by 19%), with limited clinical relevance. Model-based simulations showed that, under a standard regimen of 10 mg once daily, a significant proportion of patients (56%) might be under-exposed. CONCLUSION: The variability in escitalopram disposition is large and poorly explained by demographic, clinical and environmental covariates, thus suggesting a role for dosage individualization based on therapeutic drug monitoring in case of poor clinical response. Escitalopram disposition is modestly impacted by comedications and therefore no a priori dosage adjustments are needed in patients receiving antiretroviral treatments, including boosted regimens.

Influence of body weight and UGT2B7 polymorphism on varenicline exposure in a cohort of smokers from the general population.

PURPOSE: The abstinence rate to tobacco after varenicline treatment is moderate and might be partially affected by variability in varenicline concentrations. This study aimed at characterizing the sources of variability in varenicline pharmacokinetics and to relate varenicline exposure to abstinence. METHODS: The population pharmacokinetic analysis (NONMEM®) included 121 varenicline concentrations from 82 individuals and tested the influence of genetic and non-genetic characteristics on apparent clearance (CL/F) and volume of distribution (V/F). Model-based average concentrations over 24 h (Cav) were used to test the impact of varenicline exposure on the input rate (Kin) expressed as a function of the number of cigarettes per day in a turnover model of 373 expired carbon monoxide levels. RESULTS: A one-compartment model with first-order absorption and elimination appropriately described varenicline concentrations. CL/F was 8.5 L/h (coefficient of variation, 26%), V/F was 228 L, and the absorption rate (ka) was fixed to 0.98 h-1. CL/F increased by 46% in 100-kg individuals compared to 60-kg individuals and was found to be 21% higher in UGT2B7 rs7439366 TT individuals. These covariates explained 14% and 9% of the interindividual variability in CL/F, respectively. No influence of varenicline Cav was found on Kin in addition to the number of cigarettes. CONCLUSIONS: Body weight mostly and to a smaller extent genetic polymorphisms of UGT2B7 can influence varenicline exposure. Dose adjustment based on body weight and, if available, on UGT2B7 genotype might be useful to improve clinical efficacy and tolerability of varenicline.

Genome-wide association study of caffeine metabolites provides new insights to caffeine metabolism and dietary caffeine-consumption behavior.

Caffeine is the most widely consumed psychoactive substance in the world and presents with wide interindividual variation in metabolism. This variation may modify potential adverse or beneficial effects of caffeine on health. We conducted a genome-wide association study (GWAS) of plasma caffeine, paraxanthine, theophylline, theobromine and paraxanthine/caffeine ratio among up to 9,876 individuals of European ancestry from six population-based studies. A single SNP at 6p23 (near CD83) and several SNPs at 7p21 (near AHR), 15q24 (near CYP1A2) and 19q13.2 (near CYP2A6) met GW-significance (P < 5 × 10-8) and were associated with one or more metabolites. Variants at 7p21 and 15q24 associated with higher plasma caffeine and lower plasma paraxanthine/caffeine (slow caffeine metabolism) were previously associated with lower coffee and caffeine consumption behavior in GWAS. Variants at 19q13.2 associated with higher plasma paraxanthine/caffeine (slow paraxanthine metabolism) were also associated with lower coffee consumption in the UK Biobank (n = 94 343, P < 1.0 × 10-6). Variants at 2p24 (in GCKR), 4q22 (in ABCG2) and 7q11.23 (near POR) that were previously associated with coffee consumption in GWAS were nominally associated with plasma caffeine or its metabolites. Taken together, we have identified genetic factors contributing to variation in caffeine metabolism and confirm an important modulating role of systemic caffeine levels in dietary caffeine consumption behavior. Moreover, candidate genes identified encode proteins with important clinical functions that extend beyond caffeine metabolism.

Influence of polygenic risk scores on lipid levels and dyslipidemia in a psychiatric population receiving weight gain-inducing psychotropic drugs.

OBJECTIVES: Dyslipidemia represents a major health issue in psychiatry. We determined whether weighted polygenic risk scores (wPRSs) combining multiple single-nucleotide polymorphisms (SNPs) associated with lipid levels in the general population are associated with lipid levels [high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol (TC), and triglycerides] and/or dyslipidemia in patients receiving weight gain-inducing psychotropic drugs. We also determined whether genetics improve the predictive power of dyslipidemia. PATIENTS AND METHODS: The influence of wPRS on lipid levels was firstly assessed in a discovery psychiatric sample (n=332) and was then tested for replication in an independent psychiatric sample (n=140). The contribution of genetic markers to predict dyslipidemia was evaluated in the combined psychiatric sample. RESULTS: wPRSs were significantly associated with the four lipid traits in the discovery (P≤0.02) and in the replication sample (P≤0.03). Patients whose wPRS was higher than the median wPRS had significantly higher LDL, TC, and triglyceride levels (0.20, 0.32 and 0.26 mmol/l, respectively; P≤0.004) and significantly lower HDL levels (0.13 mmol/l; P<0.0001) compared with others. Adding wPRS to clinical data significantly improved dyslipidemia prediction of HDL (P=0.03) and a trend for improvement was observed for the prediction of TC dyslipidemia (P=0.08). CONCLUSION: Population-based wPRSs have thus significant effects on lipid levels in the psychiatric population. As genetics improved the predictive power of dyslipidemia development, only 24 patients need to be genotyped to prevent the development of one case of HDL hypocholesterolemia. If confirmed by further prospective investigations, the present results could be used for individualizing psychotropic treatment.